Membrane-associated tyrosine and threonine-specific CDC2 inhibitory kinase (PKMYT1) inhibitors and their uses

Abstract

This document describes PKMYT1 (Myt1) inhibitors and pharmaceutical compositions comprising said inhibitors. The compounds and compositions of this invention can be used to treat diseases or conditions associated with PKMYT1.

Description

[0001] Cross-references

[0002] This patent application claims the benefit of international application PCT / CN2022 / 076941, filed on February 18, 2022, the entire contents of which are incorporated herein by reference. Background Technology

[0003] PKMYT1 (or Myt1) is a member of the Wee family and was first reported as a kinase capable of efficiently phosphorylating Cdc2 on both threonine-14 and tyrosine-15 in the African clawed frog. PKMYT1 inhibits cell cycle progression by suppressing the activity of cell cycle-related proteins such as cyclin A, CDK1, and CDK2. PKMYT1 also drives the progression of various tumors.

[0004] Inhibitory phosphorylation of cdc2 is important for the timing of mitosis initiation. Mitosis initiation is initiated by the M-phase promoting factor (MPF), a complex containing the cdc2 protein kinase and cyclin B. Proper regulation of the MPF ensures that mitosis occurs only after the early stages of the cell cycle have completed. Phosphorylation of cdc2 at Tyr-15 and Thr-14 inhibits this activity during interphase (G1, S, and G2). At the G2-M transition, cdc2 is dephosphorylated at Tyr-15 and Thr-14, thereby allowing the MPF to phosphorylate its mitotic substrates.

[0005] Studies have shown that premature activation of cdc2 leads to mitotic catastrophe and cell death. It is predicted that inhibition of Myt1 will lead to premature activation of cdc2, thereby killing rapidly proliferating cells. Furthermore, it is predicted that Myt1 inhibition will reduce resistance to conventional DNA-damaging chemotherapeutic agents, as the mechanisms by which cells avoid death involve arrest in the G2 phase of the cell cycle, as well as pre-division repair or DNA damage. This arrest should be prevented by blocking Myt1 inhibitory phosphorylation of cdc2, thereby forcing cells to prematurely enter mitosis. Myt1 kinase is an important cell cycle regulator, particularly in the G2 / M phase. This is due to cell cycle regulation and subsequent repair of DNA or mitotic apparatus damage, which are the targets of the most potent chemotherapeutic agents. Myt1 kinase provides an intervention point downstream of these mechanisms that lead to drug resistance in tumor cells. Inhibition of Myt1 itself may have therapeutic benefits in reducing tumor proliferation, and furthermore, it can be used in combination with conventional chemotherapy to overcome resistance.

[0006] Based on the foregoing, there is a need to identify effective PKMYT1 (Myt1) kinase inhibitors for the treatment of cancer. Summary of the Invention

[0007] This article discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0008]

[0009] in:

[0010] Ring A is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group;

[0011] Each R 1 Independently, it is halogen, -CN, -NO2, -OH, -OR a -OC(=O)R a -OC(=O)OR b -OC(=O)NR c R d -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR c R d -NR b C(=O)NR c R d -NR b C(=O)R a -NR b C(=O)OR b -NR b S(=O)2R a -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl group is independently and optionally divided by one or more R 1a replace;

[0012] Or two R atoms on the same atom 1 They combine to form an oxygen group;

[0013] Each R 1a Independently, it is halogen, -CN, -NO2, -OH, -OR a -OC(=O)R a -OC(=O)OR b -OC(=O)NRc R d -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR c R d -NR b C(=O)NR c R d -NR b C(=O)R a -NR b C(=O)OR b -NR b S(=O)2R a -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R;

[0014] Or two R atoms on the same atom 1a They combine to form an oxygen group;

[0015] n is 0-6;

[0016] R 2 It is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl;

[0017] W is N or CR W ;

[0018] R W It is hydrogen, halogen, -CN, -OH, -OR a -SH, -SR a -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R dC1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally separated by one or more R Wa replace;

[0019] Each R Wa Independently, it is halogen, -CN, -NO2, -OH, -OR a -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R;

[0020] Or two R atoms on the same atom Wa They combine to form an oxygen group;

[0021] X is N or CR X ;

[0022] R X It is hydrogen, halogen, -CN, -OH, -OR a -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted by one or more R;

[0023] Y is N or CR Y ;

[0024] R Y It is hydrogen, halogen, -CN, -OH, -OR a -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted by one or more R;

[0025] Z is N or CR Z ;

[0026] R Z It is hydrogen, halogen, -CN, -OH, -OR a -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted by one or more R;

[0027] R 3 It is a halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl;

[0028] R 4 It is a halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl;

[0029] R 5 It is hydrogen, halogen, -CN, -NO2, -OH, -OR a -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NRc R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl;

[0030] R 6 It is hydrogen, halogen, -CN, -NO2, -OH, -OR a -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl;

[0031] Each R a Independently, it is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl) or C1-C6 alkylene (heteroaryl), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R;

[0032] Or two Rs a Together with the atoms to which they are attached, they form heterocyclic alkyl groups that are optionally substituted with one or more R atoms;

[0033] Each R b Independently, it is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted by one or more R;

[0034] Or two Rs b Together with the atoms to which they are attached, they form heterocyclic alkyl groups that are optionally substituted with one or more R atoms;

[0035] R c and Rd Each of the following is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl), wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted by one or more R;

[0036] Or R c and R d Together with the atoms to which they are attached, they form heterocyclic alkyl groups optionally substituted with one or more R atoms; and

[0037] Each R is independently a halogen, -CN, -OH, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, or C3-C6 cycloalkyl;

[0038] Alternatively, two R atoms on the same atom can form an oxo group.

[0039] In some embodiments of the compound of formula (I), the compound has formula (Ia):

[0040]

[0041] In some embodiments of the compound of formula (I), the compound has formula (Ib):

[0042]

[0043] In some embodiments of the compound of formula (I), the compound has formula (Ic):

[0044]

[0045] This document also discloses a pharmaceutical composition comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0046] This article also discloses a method for treating cancer in a subject in need, the method comprising administering to the subject a compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0047] This article also discloses a method for modulating PKMYT1 in a subject, the method comprising administering to the subject a compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0048] This article also discloses a method for inhibiting PKMYT1 in a subject, the method comprising administering to the subject a compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0049] This article also discloses a method for inhibiting PKMYT1 and WEE1 in a subject, the method comprising administering to the subject a compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0050] In some implementations, the subject has cancer. In some implementations, the cancer depends on the activity of PKMYT1. In some implementations, the cancer overexpresses CCNE1. In some implementations, the cancer has an inactivating mutation in the FBXW7 gene. In some implementations, the cancer is a solid tumor. In some implementations, the cancer is breast cancer, colorectal cancer, endometrial cancer, esophageal cancer, glioblastoma, hepatocellular carcinoma, lung cancer, neuroblastoma, ovarian cancer, prostate cancer, gastric cancer, or uterine cancer.

[0051] By incorporating references

[0052] All publications, patents and patent applications mentioned in this specification are incorporated herein by reference to the same extent that each individual publication, patent or patent application is specifically and individually indicated to be incorporated by reference. Detailed Implementation

[0053] definition

[0054] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, those skilled in the art will understand that the invention can be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring the description of the embodiments. Unless the context requires otherwise, throughout the specification and the following claims, the word “comprise” and its variations, such as “comprises” and “comprising”, should be interpreted in an open, inclusive sense, meaning “including, but not limited to”. Furthermore, the headings provided herein are for convenience only and do not constitute an explanation of the scope or meaning of the claimed invention.

[0055] Throughout this specification, references to “some embodiments” or “implementation” mean that a particular feature, structure, or characteristic described in connection with that embodiment is included in at least one embodiment. Therefore, the appearance of the phrase “in one embodiment” or “in an embodiment” throughout this specification does not necessarily refer to the same embodiment. Furthermore, in one or more embodiments, a particular feature, structure, or characteristic may be combined in any suitable manner. Additionally, as used in this specification and the appended claims, unless expressly stated otherwise, the singular forms “a / an” and “the” include multiple referents. It should also be noted that, unless expressly stated otherwise, the term “or” is generally used to include the meaning of “and / or”.

[0056] Unless otherwise specified, the following terms as used herein have the following meanings:

[0057] "O" refers to the =O group.

[0058] "Carboxyl group" refers to -COOH.

[0059] "Cyano" refers to -CN.

[0060] "Alkyl" refers to a straight-chain or branched monovalent group of a saturated hydrocarbon having one to about ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-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, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, and hexyl, as well as longer alkyl groups such as heptyl, octyl, etc. Whenever it appears in this document, numerical ranges such as "C1-C6 alkyl" or "C 1-6 "alkyl" means that an alkyl group can consist of 1, 2, 3, 4, 5, or 6 carbon atoms, but this definition also covers the occurrence of the term "alkyl" without a specified numerical range. In some embodiments, alkyl is C10. 1-10 Alkyl group. In some embodiments, the alkyl group is C10. 1-6 Alkyl group. In some embodiments, the alkyl group is C10. 1-5 Alkyl group. In some embodiments, the alkyl group is C10. 1-4 Alkyl group. In some embodiments, the alkyl group is C10. 1-3Alkyl group. Unless otherwise specified in the specification, the alkyl group may optionally be substituted with, for example, an oxo group, halogen, amino group, nitrile group, nitro group, hydroxyl group, haloalkyl group, alkoxy group, carboxyl group, carboxylate group, aryl group, cycloalkyl group, heterocycloalkyl group, heteroaryl group, etc. In some embodiments, the alkyl group is optionally substituted with an oxo group, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl group is optionally substituted with a halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl group is optionally substituted with a halogen.

[0061] "Alkenyl" refers to a straight-chain or branched hydrocarbon monovalent group having one or more carbon-carbon double bonds and having two to about ten carbon atoms, more preferably two to about six carbon atoms. The group can be in either a cis or trans conformation with respect to the double bond and should be understood to include both isomers. Examples include, but are not limited to, vinyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl, etc. Whenever it appears herein, numerical ranges such as "C2-C6 alkenyl" or "C 2-6 "Alkenyl" means that an alkenyl group can consist of 2, 3, 4, 5, or 6 carbon atoms, but this definition also covers the occurrence of the term "alkenyl" without a specified numerical range. Unless otherwise specified in the specification, the alkenyl group may optionally be substituted with, for example, an oxo group, halogen, amino group, nitrile group, hydroxyl group, haloalkyl group, alkoxy group, carboxyl group, carboxylate group, aryl group, cycloalkyl group, heterocycloalkyl group, heteroaryl group, etc. In some embodiments, the alkenyl group is optionally substituted with an oxo group, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkenyl group is optionally substituted with a halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl group is optionally substituted with a halogen.

[0062] "Alynyl" refers to a straight-chain or branched hydrocarbon monovalent group having one or more carbon-carbon triple bonds and having two to ten carbon atoms, more preferably two to six carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, etc. Whenever it appears in this document, numerical ranges such as "C2-C6 ynyl" or "C 2-6"Alynyl" means that an alkynyl group can consist of 2, 3, 4, 5, or 6 carbon atoms, but this definition also covers the occurrence of the term "alkynyl" without a specified numerical range. Unless otherwise specified in the specification, the alkynyl group may optionally be substituted with, for example, an oxo group, halogen, amino group, nitrile group, hydroxyl group, haloalkyl group, alkoxy group, carboxyl group, carboxylate group, aryl group, cycloalkyl group, heterocycloalkyl group, heteroaryl group, etc. In some embodiments, the alkynyl group is optionally substituted with an oxo group, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkynyl group is optionally substituted with a halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl group is optionally substituted with a halogen.

[0063] "Alkylene" refers to a straight-chain or branched divalent hydrocarbon chain. Unless otherwise specified in the specification, alkylene may optionally be substituted with, for example, an oxo group, halogen, amino group, nitro group, hydroxyl group, haloalkyl group, alkoxy group, carboxyl group, carboxyl group, aryl group, cycloalkyl group, heterocycloalkyl group, heteroaryl group, etc. In some embodiments, alkylene is optionally substituted with an oxo group, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, alkylene is optionally substituted with a halogen, -CN, -OH, or -OMe. In some embodiments, alkylene is optionally substituted with a halogen.

[0064] "Alkoxy" refers to the formula -OR a The group, wherein R a It is an alkyl group as defined. Unless otherwise specified in the specification, the alkoxy group may optionally be substituted with, for example, an oxo group, halogen, amino group, nitrile group, hydroxyl group, haloalkyl group, alkoxy group, carboxyl group, carboxylate group, aryl group, cycloalkyl group, heterocycloalkyl group, heteroaryl group, etc. In some embodiments, the alkoxy group is optionally substituted with a halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy group is optionally substituted with a halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy group is optionally substituted with a halogen.

[0065] "Aryl" refers to a group derived from a hydrocarbon ring system containing 6 to 30 carbon atoms and at least one aromatic ring. Aryl groups can be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, and can include fused (when fused with a cycloalkyl or heterocyclic alkyl ring, the aryl group is bonded through aromatic ring atoms) or bridged ring systems. In some embodiments, the aryl group is a 6- to 10-membered aryl group. In some embodiments, the aryl group is a 6-membered aryl (phenyl). Aryl groups include, but are not limited to, aryl groups derived from hydrocarbon ring systems of anthracene, naphthylene, phenanthrene, anthracene, azulene, benzene, chrysoprase, fluorene, asymmetric inductor, symmetric inductor, indene, naphthalene, phenatene, heptamethrin, pyrene, and triphenylene. Unless otherwise specified in the specification, the aryl group may optionally be substituted with, for example, halogens, amino groups, nitriles, hydroxyl groups, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, alkoxy groups, carboxyl groups, carboxyl groups, aryl groups, cycloalkyl groups, heterocycloalkyl groups, heteroaryl groups, etc. In some embodiments, the aryl group is optionally substituted with halogens, methyl groups, ethyl groups, -CN groups, -COOH groups, COOMe groups, -CF3 groups, -OH groups, -OMe groups, -NH2 groups, or -NO2 groups. In some embodiments, the aryl group is optionally substituted with halogens, methyl groups, ethyl groups, -CN groups, -CF3 groups, -OH groups, or -OMe groups. In some embodiments, the aryl group is optionally substituted with halogens.

[0066] "Cycloalkyl" refers to a partially or fully saturated monocyclic or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or heteroaryl ring, the cycloalkyl is bonded by non-aromatic ring atoms), spirocyclic, or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated. Representative cycloalkyl groups include, but are not limited to, those having three to fifteen carbon atoms (C3-C5). 15 cycloalkyl or C3-C 15 Cycloalkenyl), three to ten carbon atoms (C3-C) 10 cycloalkyl or C3-C 10Cycloalkyl groups are cycloalkyl groups with three to eight carbon atoms (C3-C8 cycloalkyl or C3-C8 cycloalkyl), three to six carbon atoms (C3-C6 cycloalkyl or C3-C6 cycloalkyl), three to five carbon atoms (C3-C5 cycloalkyl or C3-C5 cycloalkyl), or three to four carbon atoms (C3-C4 cycloalkyl or C3-C4 cycloalkyl). In some embodiments, the cycloalkyl group is a 3- to 10-membered cycloalkyl or a 3- to 10-membered cycloalkyl. In some embodiments, the cycloalkyl group is a 3- to 6-membered cycloalkyl or a 3- to 6-membered cycloalkyl. In some embodiments, the cycloalkyl group is a 5- to 6-membered cycloalkyl or a 5- to 6-membered cycloalkyl. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups include, for example, adamantyl, norbornel, decahydronaphthyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decahydronaphthyl, trans-decahydronaphthyl, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, as well as 7,7-dimethyl-bicyclo[2.2.1]heptyl. Partially saturated cycloalkyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless otherwise specified in the specification, cycloalkyl groups may optionally be substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the cycloalkyl group is optionally substituted with an oxo group, a halogen, a methyl group, an ethyl group, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the cycloalkyl group is optionally substituted with an oxo group, a halogen, a methyl group, an ethyl group, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl group is optionally substituted with a halogen.

[0067] "Halogen" or "halogen" refers to bromine, chlorine, fluorine, or iodine. In some embodiments, the halogen is fluorine or chlorine. In some embodiments, the halogen is fluorine.

[0068] "Halogenated alkyl" refers to an alkyl group as defined above that is substituted with one or more halogenated groups as defined above, such as trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc.

[0069] "Hydroxyalkyl" refers to an alkyl group as defined above that is substituted with one or more hydroxyl groups. In some embodiments, the alkyl group is substituted with one hydroxyl group. In some embodiments, the alkyl group is substituted with one, two, or three hydroxyl groups. Hydroxyalkyl groups include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl group is hydroxymethyl.

[0070] "Aminoalkyl" refers to an alkyl group as defined above that is substituted with one or more amines. In some embodiments, the alkyl group is substituted with one amine. In some embodiments, the alkyl group is substituted with one, two, or three amines. Aminoalkyl groups include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl group is aminomethyl.

[0071] "Heteroalkyl" refers to an alkyl group in which one or more skeletal atoms are selected from atoms other than carbon (e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof). The heteroalkyl group is attached to the remainder of the molecule at the carbon atom of the heteroalkyl group. In one aspect, a heteroalkyl group is a C1-C6 heteroalkyl group, wherein the heteroalkyl group consists of 1 to 6 carbon atoms and one or more atoms other than carbon (e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof), wherein the heteroalkyl group is attached to the remainder of the molecule at the carbon atom of the heteroalkyl group. Examples of such heteroalkyl groups are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or -CH2CH2N(CH3)2. Unless otherwise specified in the specification, the heteroalkyl group is optionally substituted with, for example, an oxo group, halogen, amino group, nitrile group, nitro group, hydroxyl group, alkyl group, alkenyl group, alkynyl group, haloalkyl group, alkoxy group, aryl group, cycloalkyl group, heterocycloalkyl group, heteroaryl group, etc. In some embodiments, the heteroalkyl group is optionally substituted with an oxo group, halogen, methyl group, ethyl group, -CN group, -CF3 group, -OH group, -OMe group, -NH2 group, or -NO2 group. In some embodiments, the heteroalkyl group is optionally substituted with an oxo group, halogen, methyl group, ethyl group, -CN group, -CF3 group, -OH group, or -OMe group. In some embodiments, the heteroalkyl group is optionally substituted with a halogen.

[0072] "Heterocyclic alkyl" refers to a 3- to 24-membered partially or fully saturated cyclic group comprising 2 to 23 carbon atoms and 1 to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, silicon, and sulfur. In some embodiments, the heterocyclic alkyl is fully saturated. In some embodiments, the heterocyclic alkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocyclic alkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocyclic alkyl comprises one to three nitrogen atoms. In some embodiments, the heterocyclic alkyl comprises one or two nitrogen atoms. In some embodiments, the heterocyclic alkyl comprises one nitrogen atom. In some embodiments, the heterocyclic alkyl comprises one nitrogen atom and one oxygen atom. Unless otherwise specified in the specification, heterocyclic alkyl groups can be monocyclic, bicyclic, tricyclic, or tetracyclic, and may include fused (when fused with an aryl or heteroaryl ring, the heterocyclic alkyl group is bonded by non-aromatic ring atoms), spirocyclic, or bridged ring systems; and the nitrogen, carbon, or sulfur atom in the heterocyclic alkyl group may optionally be oxidized; the nitrogen atom may optionally be quaternized. Representative heterocyclic alkyl groups include, but are not limited to, those having two to fifteen carbon atoms (C2-C4). 15 Heterocyclic alkyl or C2-C 15 Heterocyclic alkenyl groups, two to ten carbon atoms (C2-C) 10 Heterocyclic alkyl or C2-C 10Heterocyclic alkyl groups consisting of two to eight carbon atoms (C2-C8 heterocyclic alkyl or C2-C8 heterocyclic alkyl), two to seven carbon atoms (C2-C7 heterocyclic alkyl or C2-C7 heterocyclic alkyl), two to six carbon atoms (C2-C6 heterocyclic alkyl or C2-C7 heterocyclic alkyl), two to five carbon atoms (C2-C5 heterocyclic alkyl or C2-C5 heterocyclic alkyl), or two to four carbon atoms (C2-C4 heterocyclic alkyl or C2-C4 heterocyclic alkyl). Examples of such heterocyclic alkyl groups include, but are not limited to, aziridinyl, aziridine, oxadiazinyl, dioxopentyl, thienyl[1,3]dithiaalkyl, decahydroisoquinolinyl, imidazolinyl, imidazoalkyl, isothiazolinyl, isoxazolinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperidinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, oxazolinyl, piperidinyl, piperazinyl, 4-piperidinoneyl, pyrrolyl, Pyrazolyl, quinoline, thiazolyl, tetrahydrofuranyl, trithiayl, tetrahydropyranyl, thiomorpholinyl, thiozamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxacyclopenten-4-yl, and 2-oxo-1,3-dioxacyclopenten-4-yl. The term heterocyclic alkyl also includes all cyclic forms of carbohydrates, including but not limited to monosaccharides, disaccharides, and oligosaccharides. In some embodiments, the heterocyclic alkyl has 2 to 10 carbons in the ring. It should be understood that when referring to the number of carbon atoms in a heterocyclic alkyl group, the number of carbon atoms in the heterocyclic alkyl group is different from the total number of atoms constituting the heterocyclic alkyl group (including heteroatoms) (i.e., the skeletal atoms of the heterocyclic alkyl ring). In some embodiments, the heterocyclic alkyl group is a 3- to 8-membered heterocyclic alkyl group. In some embodiments, the heterocyclic alkyl group is a 3- to 7-membered heterocyclic alkyl group. In some embodiments, the heterocyclic alkyl group is a 3- to 6-membered heterocyclic alkyl group. In some embodiments, the heterocyclic alkyl group is a 4- to 6-membered heterocyclic alkyl group. In some embodiments, the heterocyclic alkyl group is a 5- to 6-membered heterocyclic alkyl group. In some embodiments, the heterocyclic alkyl group is a 3- to 8-membered heterocyclic alkenyl group. In some embodiments, the heterocyclic alkyl group is a 3- to 7-membered heterocyclic alkenyl group. In some embodiments, the heterocyclic alkyl group is a 3- to 6-membered heterocyclic alkenyl group. In some embodiments, the heterocyclic alkyl group is a 4- to 6-membered heterocyclic alkenyl group. In some embodiments, the heterocyclic alkyl group is a 5- to 6-membered heterocyclic alkenyl group. Unless otherwise specified in the specification, heterocyclic alkyl groups may optionally be substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocyclic alkyl, heteroaryl, etc., as described below. In some embodiments, the heterocyclic alkyl group may optionally be substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2.In some embodiments, the heterocyclic alkyl group is optionally substituted with a halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocyclic alkyl group is optionally substituted with a halogen.

[0073] "Heteroaryl" refers to a 5- to 14-membered cyclic group comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl group comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl group comprises one to three nitrogen atoms. In some embodiments, the heteroaryl group comprises one or two nitrogen atoms. In some embodiments, the heteroaryl group comprises one nitrogen atom. The heteroaryl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocyclic alkyl ring, the heteroaryl group is bonded through aromatic ring atoms) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl group may optionally be oxidized; the nitrogen atom may optionally be quaternized. In some embodiments, the heteroaryl group is a 5- to 10-membered heteroaryl group. In some embodiments, the heteroaryl group is a 5- to 6-membered heteroaryl group. In some embodiments, the heteroaryl group is a 6-membered heteroaryl group. In some embodiments, the heteroaryl group is a 5-membered heteroaryl group. Examples include, but are not limited to, azaheptatrienyl, acridine, benzimidazolyl, benzothiazolyl, benzoindolyl, benzodioxacyclopentenyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxacycloheptenyl, 1,4-benzodioxylalkyl, benzonaphthofuranyl, benzooxazolyl, benzodioxacyclohexenyl, benzopyranyl, benzopyranoneyl, benzofuranyl, benzofuranoneyl, benzothiopheneyl (benzophenylthio), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazole, cenyl, dibenzofuranyl, dibenzophenylthio, furanyl, furanoneyl, isothiazolyl, Imidazolyl, indazolyl, indolyl, isoindolyl, indololinyl, isoindololinyl, isoquinolinyl, inazinyl, isoxazolyl, naphridinyl, oxadiazolyl, 2-oxoazacycloheptatrienyl, oxazolyl, ethylene oxide, 1-pyridinyl oxide, 1-pyrimidinyl oxide, 1-pyrazinyl oxide, 1-pyridazinyl oxide, 1-phenyl-1H-pyrroleyl, phenazinyl, phenothiazinyl, phenothiazinyl, phthalazinyl, pteridinyl, purine, pyrroleyl, pyrazolyl, pyridinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quininecycloyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and phenylthio (i.e., thiophene). Unless otherwise specified in the specification, the heteroaryl group may optionally be substituted with, for example, halogens, amino groups, nitriles, hydroxyl groups, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, alkoxy groups, carboxyl groups, carboxylate groups, aryl groups, cycloalkyl groups, heterocycloalkyl groups, heteroaryl groups, etc. In some embodiments, the heteroaryl group may optionally be substituted with halogens, methyl groups, ethyl groups, -CN groups, -COOH groups, COOMe groups, -CF3 groups, -OH groups, -OMe groups, -NH2 groups, or -NO2 groups.In some embodiments, the heteroaryl group is optionally substituted with a halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl group is optionally substituted with a halogen.

[0074] The terms “optional” or “optionally” mean that the event or condition described below may or may not occur, and the description includes both the occurrence and non-occurrence of the event or condition. For example, “optionally substituted alkyl” means “alkyl” or “substituted alkyl” as defined above. Furthermore, an optionally substituted group can be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F), or substituted at any level between full and monosubstituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.). Those skilled in the art will understand that, with respect to any group containing one or more substituents, such groups are not intended to introduce any substitution or substitution pattern that is spatially impractical and / or synthetically infeasible (e.g., substituted alkyl includes optionally substituted cycloalkyl, which is in turn defined as including optionally substituted alkyl, possibly indefinitely). Therefore, any substituents mentioned should generally be understood to have a maximum molecular weight of about 1,000 Daltons, and more typically, up to about 500 Daltons.

[0075] When referring to optional substituents, the term "one or more" means that the host group is optionally substituted with one, two, three, or four substituents. In some embodiments, the host group is optionally substituted with one, two, or three substituents. In some embodiments, the host group is optionally substituted with one or two substituents. In some embodiments, the host group is optionally substituted with one substituent. In some embodiments, the host group is optionally substituted with two substituents.

[0076] "Effective dose" or "therapeutic effective dose" refers to the amount of a compound administered to a mammalian subject as a single dose or as part of a series of doses that effectively produces the desired therapeutic effect.

[0077] As used herein, the term “treat / treating / treatment” includes reducing, weakening or improving at least one symptom of a disease or condition, preventing additional symptoms, suppressing a disease or condition, such as preventing the development of a disease or condition, alleviating a disease or condition, causing the remission of a disease or condition, relieving symptoms caused by a disease or condition, or stopping the symptoms of a disease or condition.

[0078] As used herein, “disease or condition associated with PKMYT1” or alternatively “PKMYT1-mediated disease or condition” means any disease or other harmful condition in which PKMYT1 or its mutants are known or suspected to play a role.

[0079] As used herein, “myt1-related disease or condition” or alternatively “myt1-mediated disease or condition” means any disease or other harmful condition in which Myt1 or its mutants are known or suspected to play a role.

[0080] compound

[0081] This article describes compounds or pharmaceutically acceptable salts thereof for the treatment of diseases or conditions associated with PKMYT1.

[0082] This article discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0083]

[0084] in:

[0085] Ring A is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group;

[0086] Each R 1 Independently, it is halogen, -CN, -NO2, -OH, -OR a -OC(=O)R a -OC(=O)OR b -OC(=O)NR c R d -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR c R d -NR b C(=O)NR c R d -NR b C(=O)R a -NR b C(=O)OR b -NR b S(=O)2R a -C(=O)R a -C(=O)OR b -C(=O)NR c R dC1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl group is independently and optionally divided by one or more R 1a replace;

[0087] Or two R atoms on the same atom 1 They combine to form an oxygen group;

[0088] Each R 1a Independently, it is halogen, -CN, -NO2, -OH, -OR a -OC(=O)R a -OC(=O)OR b -OC(=O)NR c R d -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR c R d -NR b C(=O)NR c R d -NR b C(=O)R a -NR b C(=O)OR b -NR b S(=O)2R a -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R;

[0089] Or two R atoms on the same atom 1a They combine to form an oxygen group;

[0090] n is 0-6;

[0091] R 2It is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl;

[0092] W is N or CR W ;

[0093] R W It is hydrogen, halogen, -CN, -OH, -OR a -SH, -SR a -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally separated by one or more R Wa replace;

[0094] Each R Wa Independently, it is halogen, -CN, -NO2, -OH, -OR a -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R;

[0095] Or two R atoms on the same atom Wa They combine to form an oxygen group;

[0096] X is N or CR X ;

[0097] R XIt is hydrogen, halogen, -CN, -OH, -OR a -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted by one or more R;

[0098] Y is N or CR Y ;

[0099] R Y It is hydrogen, halogen, -CN, -OH, -OR a -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted by one or more R;

[0100] Z is N or CR Z ;

[0101] R Z It is hydrogen, halogen, -CN, -OH, -OR a -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted by one or more R;

[0102] R 3It is a halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl;

[0103] R 4 It is a halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl;

[0104] R 5 It is hydrogen, halogen, -CN, -NO2, -OH, -OR a -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl;

[0105] R 6 It is hydrogen, halogen, -CN, -NO2, -OH, -OR a -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl;

[0106] Each R a Independently, it is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl) or C1-C6 alkylene (heteroaryl), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R;

[0107] Or two Rs a Together with the atoms to which they are attached, they form heterocyclic alkyl groups that are optionally substituted with one or more R atoms;

[0108] Each R b Independently, it is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted by one or more R;

[0109] Or two Rs b Together with the atoms to which they are attached, they form heterocyclic alkyl groups that are optionally substituted with one or more R atoms;

[0110] R c and R d Each of the following is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl), wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted by one or more R;

[0111] Or R c and R d Together with the atoms to which they are attached, they form heterocyclic alkyl groups optionally substituted with one or more R atoms; and

[0112] Each R is independently a halogen, -CN, -OH, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, or C3-C6 cycloalkyl;

[0113] Alternatively, two R atoms on the same atom can form an oxo group.

[0114] This article discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0115]

[0116] in:

[0117] Ring A is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group;

[0118] Each R 1 Independently, it is halogen, -CN, -NO2, -OH, -OR a -OC(=O)R a -OC(=O)OR b -OC(=O)NR c R d -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR c R d -NR b C(=O)NR c R d -NR b C(=O)R a -NR b C(=O)OR b -NR b S(=O)2R a -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl group is independently and optionally divided by one or more R 1a replace;

[0119] Or two R atoms on the same atom 1 They combine to form an oxygen group;

[0120] Each R 1a Independently, it is halogen, -CN, -NO2, -OH, -OR a -OC(=O)R a -OC(=O)OR b -OC(=O)NR c R d -SH, -SR a -S(=O)R a -S(=O)2R a-S(=O)2NR c R d -NR c R d -NR b C(=O)NR c R d -NR b C(=O)R a -NR b C(=O)OR b -NR b S(=O)2R a -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R;

[0121] Or two R atoms on the same atom 1a They combine to form an oxygen group;

[0122] n is 0-6;

[0123] R 2 It is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl;

[0124] W is N or CR W ;

[0125] R W It is hydrogen, halogen, -CN, -OH, -OR a -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted by one or more R;

[0126] X is N or CRX ;

[0127] R X It is hydrogen, halogen, -CN, -OH, -OR a -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted by one or more R;

[0128] Y is N or CR Y ;

[0129] R Y It is hydrogen, halogen, -CN, -OH, -OR a -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted by one or more R;

[0130] Z is N or CR Z ;

[0131] R Z It is hydrogen, halogen, -CN, -OH, -OR a -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R dC1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted by one or more R;

[0132] R 3 It is a halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl;

[0133] R 4 It is a halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl;

[0134] R 5 It is hydrogen, halogen, -CN, -NO2, -OH, -OR a -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl;

[0135] R 6 It is hydrogen, halogen, -CN, -NO2, -OH, -OR a -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl;

[0136] Each R aIndependently, it is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl) or C1-C6 alkylene (heteroaryl), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R;

[0137] Or two Rs a Together with the atoms to which they are attached, they form heterocyclic alkyl groups that are optionally substituted with one or more R atoms;

[0138] Each R b Independently, it is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted by one or more R;

[0139] Or two Rs b Together with the atoms to which they are attached, they form heterocyclic alkyl groups that are optionally substituted with one or more R atoms;

[0140] R c and R d Each of the following is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl), wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted by one or more R;

[0141] Or R c and R d Together with the atoms to which they are attached, they form heterocyclic alkyl groups optionally substituted with one or more R atoms; and

[0142] Each R is independently a halogen, -CN, -OH, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, or C3-C6 cycloalkyl;

[0143] Alternatively, two R atoms on the same atom can form an oxo group.

[0144] In some embodiments of the compounds of formula (I), X is N. In some embodiments of the compounds of formula (I), X is CR. X .

[0145] In some embodiments of the compounds of formula (I), Y is N. In some embodiments of the compounds of formula (I), Y is CR. Y .

[0146] In some embodiments of the compounds of formula (I), W is N. In some embodiments of the compounds of formula (I), W is CR. W .

[0147] In some embodiments of the compounds of formula (I), Z is N. In some embodiments of the compounds of formula (I), Z is CR. Z .

[0148] In some embodiments of the compound of formula (I), the compound has formula (Ia):

[0149]

[0150] In some embodiments of the compound of formula (I), the compound has formula (Ib):

[0151]

[0152] In some embodiments of the compound of formula (I), the compound has formula (Ic):

[0153]

[0154] In some embodiments of compounds of formula (I) or (Ia)-(Ic), R 3 It is a halogen, a C1-C6 alkyl group, or a C1-C6 haloalkyl group. In some embodiments of compounds of formula (I) or (Ia)-(Ic), R 3It is a halogen or a C1-C6 alkyl group. In some embodiments of compounds of formula (I) or (Ia)-(Ic), R 3 It is a C1-C6 alkyl group. In some embodiments of compounds of formula (I) or (Ia)-(Ic), R 3 It is a C1-C3 alkyl group. In some embodiments of compounds of formula (I) or (Ia)-(Ic), R 3 It is n-propyl or isopropyl. In some embodiments of compounds of formula (I) or (Ia)-(Ic), R 3 It is ethyl. In some embodiments of compounds of formula (I) or (Ia)-(Ic), R 3 It is a methyl group.

[0155] In some embodiments of compounds of formula (I) or (Ia)-(Ic), R 4 It is a halogen, a C1-C6 alkyl group, or a C1-C6 haloalkyl group. In some embodiments of compounds of formula (I) or (Ia)-(Ic), R 4 It is a halogen or a C1-C6 alkyl group. In some embodiments of compounds of formula (I) or (Ia)-(Ic), R 4 It is a C1-C6 alkyl group. In some embodiments of compounds of formula (I) or (Ia)-(Ic), R 4 It is a C1-C3 alkyl group. In some embodiments of compounds of formula (I) or (Ia)-(Ic), R 4 It is n-propyl or isopropyl. In some embodiments of compounds of formula (I) or (Ia)-(Ic), R 4 It is ethyl. In some embodiments of compounds of formula (I) or (Ia)-(Ic), R 4 It is a methyl group.

[0156] In some embodiments of compounds of formula (I) or (Ia)-(Ic), R 5 It is hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of formula (I) or (Ia)-(Ic), R 5 It is hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl. In some embodiments of compounds of formula (I) or (Ia)-(Ic), R 5 It is hydrogen.

[0157] In some embodiments of compounds of formula (I) or (Ia)-(Ic), R 6 It is hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of formula (I) or (Ia)-(Ic), R 6It is hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl. In some embodiments of compounds of formula (I) or (Ia)-(Ic), R 6 It is hydrogen.

[0158] In some embodiments of compounds of formula (I) or (Ia)-(Ic), R 2 It is hydrogen or a C1-C6 alkyl group. In some embodiments of compounds of formula (I) or (Ia)-(Ic), R 2 It is hydrogen.

[0159] In some embodiments of compounds of formula (I) or (Ia)-(Ib), R X It is hydrogen, halogen, -CN, -OH, -OR a -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl or C1-C6 haloalkyl.

[0160] In some embodiments of compounds of formula (I) or (Ia)-(Ib), R X It is hydrogen, halogen, -CN, -C(=O)NR c R d C1-C6 alkyl or C1-C6 haloalkyl.

[0161] In some embodiments of compounds of formula (I) or (Ia)-(Ib), R X It is hydrogen, halogen, -CN, C1-C6 alkyl or C1-C6 haloalkyl.

[0162] In some embodiments of compounds of formula (I) or (Ia)-(Ib), R X It is hydrogen, halogen, or -CN.

[0163] In some embodiments of compounds of formula (I) or (Ia)-(Ib), R X It is hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl.

[0164] In some embodiments of compounds of formula (I) or (Ia)-(Ib), R X It is hydrogen, halogen, or C1-C6 alkyl. In some embodiments of compounds of formula (I) or (Ia)-(Ib), R X It is hydrogen or halogen. In some embodiments of compounds of formula (I) or (Ia)-(Ib), R XIt is hydrogen. In some embodiments of compounds of formula (I) or (Ia)-(Ib), R X It is a halogen. In some embodiments of compounds of formula (I) or (Ia)-(Ib), R X It is a C1-C6 alkyl group. In some embodiments of compounds of formula (I) or (Ia)-(Ib), R X It is a C1-C3 alkyl group. In some embodiments of compounds of formula (I) or (Ia)-(Ib), R X Yes - CN.

[0165] In some embodiments of compounds of formula (I) or (Ia)-(Ic), R Y It is hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of formula (I) or (Ia)-(Ic), R Y It is hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl. In some embodiments of compounds of formula (I) or (Ia)-(Ic), R Y It is hydrogen.

[0166] In some embodiments of the compound of formula (I), R Z It is hydrogen, halogen, or C1-C6 alkyl. In some embodiments of the compounds of formula (I), R Z It is hydrogen or halogen. In some embodiments of the compound of formula (I), R Z It is hydrogen.

[0167] In some embodiments of compounds of formula (I) or (Ib)-(Ic), R W It is hydrogen, halogen, -CN, -OH, -OR a -SH, -SR a -NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 ynyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, ynyl, cycloalkyl, and heterocycloalkyl are optionally separated by one or more R Wa replace.

[0168] In some embodiments of compounds of formula (I) or (Ib)-(Ic), R W It is hydrogen, halogen, -CN, -OH, -OR a -SR a C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 ynyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, ynyl, cycloalkyl, and heterocycloalkyl are optionally separated by one or more R Wa replace.

[0169] In some embodiments of compounds of formula (I) or (Ib)-(Ic), R W It is hydrogen, halogen, -OR a -SR a C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 ynyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, ynyl, cycloalkyl, and heterocycloalkyl are optionally separated by one or more R Wa replace.

[0170] In some embodiments of compounds of formula (I) or (Ib)-(Ic), R W It is optionally controlled by one or more R Wa Substituted C2-C6 ynyl group.

[0171] In some embodiments of compounds of formula (I) or (Ib)-(Ic), R W It is hydrogen, halogen, -OH, -OR a -NR c R d C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted by one or more R.

[0172] In some embodiments of compounds of formula (I) or (Ib)-(Ic), R W It is hydrogen, halogen, -OR a C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclic alkyl; wherein the alkyl, cycloalkyl, and heterocyclic alkyl are optionally substituted by one or more R. In some embodiments of compounds of formula (I) or (Ib)-(Ic), R W It is hydrogen, -OR a C1-C6 alkyl or heterocyclic alkyl; wherein the alkyl and heterocyclic alkyl groups are optionally substituted with one or more R. In some embodiments of compounds of formula (I) or (Ib)-(Ic), R W It is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group, each of which is optionally substituted with one or more R groups. In some embodiments of compounds of formula (I) or (Ib)-(Ic), R... W It is a cycloalkyl or heterocycloalkyl group, each of which is optionally substituted with one or more R groups. In some embodiments, R groups are... W It is a 5-membered ring. In some implementations, R W It is a 6-membered ring. In some implementations, R W yes In some implementation schemes, R W yes In some implementation schemes, R W yes In some embodiments of compounds of formula (I) or (Ib)-(Ic), R W It is hydrogen. In some embodiments of compounds of formula (I) or (Ib)-(Ic), R W It is a halogen. In some embodiments of compounds of formula (I) or (Ib)-(Ic), R W It is chlorine. In some embodiments of compounds of formula (I) or (Ib)-(Ic), R W It is a heterocyclic alkyl group optionally substituted with one or more R. In some embodiments of compounds of formula (I) or (Ib)-(Ic), R W Yes - OR a In some embodiments of compounds of formula (I) or (Ib)-(Ic), R W Yes - OR a And R a It is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group, each of which is optionally substituted with one or more R groups. In some embodiments, R groups are... a It is a 5-membered ring. In some implementations, R a It is a 5- or 6-membered cycloalkyl or heterocycloalkyl. In some embodiments, R a It is a 6-membered ring. In some implementations, R a It is a 5- or 6-membered aryl or heteroaryl. In some embodiments of compounds of formula (I) or (Ib)-(Ic), R W yes In some embodiments of compounds of formula (I) or (Ib)-(Ic), R W yes In some embodiments of compounds of formula (I) or (Ib)-(Ic), R W It is a C1-C6 alkyl group. In some embodiments of compounds of formula (I) or (Ib)-(Ic), R W It is a C1-C3 alkyl group. In some embodiments of compounds of formula (I) or (Ib)-(Ic), R W It is a C1-C6 haloalkyl group. In some embodiments of compounds of formula (I) or (Ib)-(Ic), R W It is a C1-C3 haloalkyl group.

[0173] In some embodiments of compounds of formula (I) or (Ib)-(Ic), each R Wa Independently, it is halogen, -CN, -OH, -OR a -NR c R dC1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl; wherein each alkyl, cycloalkyl and heterocycloalkyl is optionally substituted independently by one or more R.

[0174] In some embodiments of compounds of formula (I) or (Ib)-(Ic), each R Wa Independently, it is halogen, -CN, -OH, -OR a -NR c R d C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl or heterocycloalkyl; wherein each alkyl, cycloalkyl and heterocycloalkyl is optionally substituted independently by one or more R.

[0175] In some embodiments of compounds of formula (I) or (Ib)-(Ic), each R Wa Independently, it is a halogen, a C1-C6 alkyl, a C1-C6 haloalkyl, a cycloalkyl, or a heterocyclic alkyl; wherein each alkyl, cycloalkyl, and heterocyclic alkyl is optionally substituted by one or more R independently.

[0176] In some embodiments of compounds of formula (I) or (Ia)-(Ic), ring A is a cycloalkyl or heterocycloalkyl. In some embodiments of compounds of formula (I) or (Ia)-(Ic), ring A is a heterocycloalkyl. In some embodiments of compounds of formula (I) or (Ia)-(Ic), ring A is a 5-membered or 6-membered heterocycloalkyl. In some embodiments of compounds of formula (I) or (Ia)-(Ic), ring A is a 5-membered heterocycloalkyl. In some embodiments of compounds of formula (I) or (Ia)-(Ic), ring A is a 6-membered heterocycloalkyl. In some embodiments of compounds of formula (I) or (Ia)-(Ic), ring A is tetrahydropyridyl.

[0177] In some embodiments of compounds of formula (I) or (Ia)-(Ic), ring A is aryl or heteroaryl.

[0178] In some embodiments of compounds of formula (I) or (Ia)-(Ic), ring A is a 5- or 6-membered heteroaryl. In some embodiments of compounds of formula (I) or (Ia)-(Ic), ring A is a 5-membered heteroaryl. In some embodiments of compounds of formula (I) or (Ia)-(Ic), ring A is a 6-membered heteroaryl. In some embodiments of compounds of formula (I) or (Ia)-(Ic), ring A is a monocyclic heteroaryl. In some embodiments of compounds of formula (I) or (Ia)-(Ic), ring A is a bicyclic heteroaryl. In some embodiments of compounds of formula (I) or (Ia)-(Ic), ring A is a 5-6, 6-5, 5-5, or 6-6 fused bicyclic heteroaryl. In some embodiments of compounds of formula (I) or (Ia)-(Ic), ring A is a fused bicyclic heteroaryl. In some embodiments of compounds of formula (I) or (Ia)-(Ic), ring A is pyridyl. In some embodiments of compounds of formula (I) or (Ia)-(Ic), ring A is pyrimidinyl. In some embodiments of compounds of formula (I) or (Ia)-(Ic), ring A is pyrazinyl. In some embodiments of compounds of formula (I) or (Ia)-(Ic), ring A is

[0179] In some embodiments of compounds of formula (I) or (Ia)-(Ic), ring A is

[0180] In some embodiments of compounds of formula (I) or (Ia)-(Ic), ring A is

[0181] In some embodiments of compounds of formula (I) or (Ia)-(Ic), each R 1 Independently, it is halogen, -CN, -OH, -OR a -S(=O)2R a -S(=O)2NR c R d -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl group is independently and optionally divided by one or more R 1aSubstitution; or two R atoms on the same atom 1 They combine to form an oxy group.

[0182] In some embodiments of compounds of formula (I) or (Ia)-(Ic), each R 1 Independently, it is halogen, -CN, -OH, -OR a -S(=O)2R a -NR c R d -C(=O)R a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally radicalized by one or more R 1a Substitution; or two R atoms on the same atom 1 They combine to form an oxy group.

[0183] In some embodiments of compounds of formula (I) or (Ia)-(Ic), each R 1 Independently, it is halogen, -CN, -OH, -OR a -S(=O)2R a -NR c R d -C(=O)R a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, or heteroaryl; wherein each alkyl, alkynyl, cycloalkyl, heterocycloalkyl, and heteroaryl group is independently and optionally radicalized by one or more R 1a Substitution; or two R atoms on the same atom 1 They combine to form an oxy group.

[0184] In some embodiments of compounds of formula (I) or (Ia)-(Ic), each R 1 Independently, it is halogen, -CN, -OH, -OR a -S(=O)2R a -NR c R d -C(=O)R a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl or C2-C6 ynyl; wherein each alkyl and ynyl group is independently and optionally divided by one or more R 1a Substitution; or two R atoms on the same atom 1 They combine to form an oxy group.

[0185] In some embodiments of compounds of formula (I) or (Ia)-(Ic), each R 1 Independently, it is a cycloalkyl, heterocycloalkyl, or heteroaryl group; wherein each cycloalkyl, heterocycloalkyl, and heteroaryl group is independently and optionally influenced by one or more R groups. 1a Substitution; or two R atoms on the same atom 1 They combine to form an oxy group.

[0186] In some embodiments of compounds of formula (I) or (Ia)-(Ic), each R 1 Independently, it is halogen, -CN, -OH, -OR a -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally independently defined by one or more R 1a Replacement. In some implementations, one or more R 1 Yes - OR a In some implementations, one or more R 1 Yes -NR c R d In some implementations, one or more R 1 It is -C(=O)R a In some implementations, one or more R 1 It is an optionally substituted C1-C6 alkyl group. In some embodiments, one or more R 1 It is an optionally substituted C1-C6 haloalkyl group. In some embodiments, one or more R 1 It is an optionally substituted C1-C6 hydroxyalkyl group. In some embodiments, one or more R 1 It is an optionally substituted cycloalkyl group. In some embodiments, one or more R 1 It is an optionally substituted heterocyclic alkyl group. In some embodiments, one or more R 1 It is a 6-membered heterocyclic alkyl group with optional substitution of 1-2 nitrogen atoms.

[0187] In some embodiments of compounds of formula (I) or (Ia)-(Ic), each R 1 Independently, it is halogen, -OR a -NR c Rd -C(=O)R a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally independently formed by one or more R 1a replace.

[0188] In some embodiments of compounds of formula (I) or (Ia)-(Ic), each R 1 Independently, it is halogen, -OR a -NR c R d -C(=O)R a C1-C6 alkyl, C1-C6 hydroxyalkyl, or heterocyclic alkyl; wherein each alkyl and heterocyclic alkyl group is independently and optionally independently formed by one or more R 1a replace.

[0189] In some embodiments of compounds of formula (I) or (Ia)-(Ic), each R 1a Independently, it is halogen, -CN, -OH, -OR a -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl; wherein each alkyl, cycloalkyl or heterocycloalkyl is optionally substituted independently by one or more R.

[0190] In some embodiments of compounds of formula (I) or (Ia)-(Ic), each R 1a Independently, it is a halogen, -OH, -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl or heterocycloalkyl; wherein each alkyl, cycloalkyl or heterocycloalkyl is optionally substituted independently by one or more R.

[0191] In some embodiments of compounds of formula (I) or (Ia)-(Ic), each R 1a Independently, it is halogen, -CN, -OH, -OR a -NR c R d -C(=O)R a -C(=O)ORb -C(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, or heterocycloalkyl group is optionally substituted independently by one or more R. In some embodiments of compounds of formula (I) or (Ia)-(Ic), each R 1a Independently, it is a halogen, a C1-C6 alkyl group, or a C1-C6 haloalkyl group; wherein each alkyl group is independently and optionally substituted by one or more R groups. In some embodiments of compounds of formula (I) or (Ia)-(Ic), each R group is substituted with a halogen, a C1-C6 alkyl group, or a C1-C6 haloalkyl group. 1a It is independently a halogen, a C1-C6 alkyl, or a C1-C6 haloalkyl.

[0192] In some embodiments of compounds of formula (I) or (Ia)-(Ic), n is 0-2. In some embodiments of compounds of formula (I) or (Ia)-(Ic), n is 1 or 2. In some embodiments of compounds of formula (I) or (Ia)-(Ic), n is 0. In some embodiments of compounds of formula (I) or (Ia)-(Ic), n is 1. In some embodiments of compounds of formula (I) or (Ia)-(Ic), n is 2.

[0193] In some embodiments of compounds of formula (I) or (Ia)-(Ic), n is 0.

[0194] In some embodiments of compounds of formula (I) or (Ia)-(Ic), yes

[0195]

[0196] In some embodiments of compounds of formula (I) or (Ia)-(Ic), yes

[0197]

[0198]

[0199] In some embodiments of compounds of formula (I) or (Ia)-(Ic), yes

[0200]

[0201] In some embodiments of compounds of formula (I) or (Ia)-(Ic), yes

[0202]

[0203]

[0204] In some embodiments of compounds of formula (I) or (Ia)-(Ic), yes

[0205]

[0206] In some embodiments of compounds of formula (I) or (Ia)-(Ic), yes

[0207]

[0208]

[0209] In some embodiments of compounds of formula (I) or (Ia)-(Ic), yes

[0210] In some embodiments of compounds of formula (I) or (Ia)-(Ic), yes

[0211] In some embodiments of compounds of formula (I) or (Ia)-(Ic), yes In some embodiments of compounds of formula (I) or (Ia)-(Ic), yes In some embodiments of compounds of formula (I) or (Ia)-(Ic), yes In some embodiments of compounds of formula (I) or (Ia)-(Ic), yes In some embodiments of compounds of formula (I) or (Ia)-(Ic), yes In some embodiments of compounds of formula (I) or (Ia)-(Ic), yes In some embodiments of compounds of formula (I) or (Ia)-(Ic), yes In some embodiments of compounds of formula (I) or (Ia)-(Ic), yes In some embodiments of compounds of formula (I) or (Ia)-(Ic), yes In some embodiments of compounds of formula (I) or (Ia)-(Ic), yes

[0212] In some embodiments of compounds of formula (I) or (Ia)-(Ic), yes In some embodiments of compounds of formula (I) or (Ia)-(Ic), yes In some embodiments of compounds of formula (I) or (Ia)-(Ic), In some embodiments of compounds of formula (I) or (Ia)-(Ic), In some embodiments of compounds of formula (I) or (Ia)-(Ic), In some embodiments of compounds of formula (I) or (Ia)-(Ic),

[0213] In some embodiments of compounds of formula (I) or (Ia)-(Ic), yes

[0214]

[0215] In some embodiments of the compounds disclosed herein, each R a Independently, each of the following is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted by one or more R. In some embodiments of the compounds disclosed herein, each R a Independently, each alkyl, cycloalkyl, or heterocyclic alkyl group is a C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl group; wherein each alkyl, cycloalkyl, or heterocyclic alkyl group is optionally substituted by one or more R groups. In some embodiments of the compounds disclosed herein, each R group is substituted with an R group. a Independently, it is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl). In some embodiments of the compounds disclosed herein, each R aIndependently, it is a C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl, heterocyclic alkyl. In some embodiments of the compounds disclosed herein, each R a Independently, it is a C1-C6 alkyl or a C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, each R a It is independently a C1-C6 alkyl group.

[0216] In some embodiments of the compounds disclosed herein, each R b Independently, it is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted by one or more R. In some embodiments of the compounds disclosed herein, each R b Independently, it is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl or cycloalkyl, heterocyclic alkyl; wherein each alkyl, cycloalkyl and heterocyclic alkyl is independently and optionally substituted by one or more R. In some embodiments of the compounds disclosed herein, each R b Independently, it is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl). In some embodiments of the compounds disclosed herein, each R b Independently, it is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl or cycloalkyl, heterocyclic alkyl. In some embodiments of the compounds disclosed herein, each R b Independently, it is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, each R... b Independently, it is hydrogen or C1-C6 alkyl. In some embodiments of the compounds disclosed herein, each R b It is hydrogen. In some embodiments of the compounds disclosed herein, each R b It is independently a C1-C6 alkyl group.

[0217] In some embodiments of the compounds disclosed herein, each R c and R dIndependently, it is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted by one or more R. In some embodiments of the compounds disclosed herein, each R c and R d Independently, it is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl or cycloalkyl, heterocyclic alkyl; wherein each alkyl, cycloalkyl and heterocyclic alkyl is independently and optionally substituted by one or more R. In some embodiments of the compounds disclosed herein, each R c and R d Independently, it is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl). In some embodiments of the compounds disclosed herein, each R c and R d Independently, it is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl or cycloalkyl, heterocyclic alkyl. In some embodiments of the compounds disclosed herein, each R c and R d Independently, it is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, each R... c and R d Independently, it is hydrogen or C1-C6 alkyl. In some embodiments of the compounds disclosed herein, each R c and R d It is hydrogen. In some embodiments of the compounds disclosed herein, each R c and R d It is independently a C1-C6 alkyl group.

[0218] In some embodiments of the compounds disclosed herein, R c and R d Together with the atoms to which they are attached, they form heterocyclic alkyl groups that are optionally substituted with one or more R atoms.

[0219] In some embodiments of the compounds disclosed herein, each R is independently a halogen, -CN, -OH, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, or C3-C6 cycloalkyl; or two Rs on the same atom form an oxo group. In some embodiments of the compounds disclosed herein, each R is independently a halogen, -CN, -OH, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 haloalkyl; or two Rs on the same atom form an oxo group. In some embodiments of the compounds disclosed herein, each R is independently a halogen, -CN, -OH, or C1-C6 alkyl; or two Rs on the same atom form an oxo group. In some embodiments of the compounds disclosed herein, each R is independently a halogen, -OH, or C1-C6 alkyl. In some embodiments of the compounds disclosed herein, each R is independently a halogen or C1-C6 alkyl. In some embodiments of the compounds disclosed herein, each R is independently a halogen.

[0220] In some embodiments of the compounds disclosed herein, R 1 R 1a R 2 R 3 R 4 R 5 R 6 R X R Y R Z R W R a R b R c and R d One or more of the groups contain a higher percentage of deuterium than the natural abundance of deuterium.

[0221] In some embodiments of the compounds disclosed herein, the following groups R, R 1 R 1a R 2 R 3 R 4 R 5 R 6R X R Y R Z R W R a R b R c and R d One or more of them, one or more 1 H is replaced by one or more deuterium atoms.

[0222] In some embodiments of the compounds disclosed herein, R, R 1 R 1a R 2 R 3 R 4 R 5 R 6 R X R Y R Z R W R a R b R c and R d The deuterium abundance of each of them is independently at least 1 mol%, at least 10 mol%, at least 20 mol%, at least 30 mol%, at least 40 mol%, at least 50 mol%, at least 60 mol%, at least 70 mol%, at least 80 mol%, at least 90 mol%, or 100 mol%.

[0223] In some embodiments of the compounds disclosed herein, one or more hydrogen atoms of ring A are substituted with one or more deuterium atoms.

[0224] This document considers any combination of the aforementioned groups for various variables. Throughout the specification, those skilled in the art select their groups and substituents to provide stable moieties and compounds.

[0225] In some embodiments, the compounds disclosed herein or pharmaceutically acceptable salts thereof are one of the compounds in Table 1.

[0226] Table 1

[0227]

[0228]

[0229]

[0230]

[0231]

[0232]

[0233]

[0234]

[0235]

[0236]

[0237]

[0238]

[0239]

[0240]

[0241]

[0242]

[0243]

[0244] In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are one of the compounds in Table 2.

[0245] Table 2

[0246]

[0247]

[0248] Other forms of the compounds disclosed herein

[0249] Isomers / stereoisomers

[0250] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds described herein include all cis, trans, isolateral, antilateral, trans (E) and cis (Z) isomers and their corresponding mixtures. In some cases, the compounds described herein have one or more chiral centers, and each center exists in an R or S configuration. The compounds described herein include all diastereomers, enantiomers, and epimers and their corresponding mixtures. In other embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereomers produced by a single preparation step, combination, or tautomerization can be used for the applications described herein. In some embodiments, the compounds described herein are prepared as separate stereoisomers by reacting a racemic mixture of compounds with an optically resolving agent to form a pair of diastereomers, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, diastereomers possess different physical properties (e.g., melting point, boiling point, solubility, reactivity, etc.) and are separated by utilizing these differences. In some embodiments, diastereomers are separated by chiral chromatography, or preferably by separation / resolution techniques based on solubility differences. In some embodiments, the optically pure enantiomers and resolving agents are then recovered by any practical method that does not cause racemization.

[0251] In some embodiments, the compounds described herein contain bonds with hindered rotation, allowing for the separation of two separate rotational isomers or transisomers. In some embodiments, the transisomer is... In some embodiments, these transisomers are isolated and found to have different biological activities, which may be advantageous. In some embodiments, the transisomers are... In some implementations, the transisomer is... In some embodiments, the compounds disclosed herein are racemic mixtures:

[0252]

[0253] Labeled compounds

[0254] In some embodiments, the compounds described herein are present in their isotopically labeled form. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically labeled compounds as a pharmaceutical composition. Thus, in some embodiments, the compounds disclosed herein include isotopically labeled compounds that are the same as those described herein, but in fact, one or more atoms are replaced by atoms with atomic masses or mass numbers different from those normally found in nature. Examples of isotopes that can be incorporated into the compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as... 2 H(D), 3 H, 13 C 14 C l5 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F and 36 Cl. The compounds described herein and their pharmaceutically acceptable salts containing the aforementioned isotopes and / or other isotopes are within the scope of this invention. Certain isotope-labeled compounds, such as those doped with radioactive isotopes such as 3 H and 14 Compounds of C can be used for drug and / or substrate tissue distribution assays. Tritiumization (i.e., 3 H) and carbon-14 (i.e., ... 14 C) Isotopes are particularly preferred because they are easy to prepare and detect.

[0255] In some embodiments, the abundance of deuterium in each substituent disclosed herein is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% of the total amount of hydrogen and deuterium. In some embodiments, one or more substituents disclosed herein contain a percentage of deuterium higher than the native abundance of deuterium. In some embodiments, in one or more substituents disclosed herein, one or more hydrogen atoms are replaced by one or more deuterium atoms.

[0256] In some embodiments, the compounds described herein are labeled in other ways, including but not limited to using chromophores or fluorescent moieties, bioluminescent labeling, or chemiluminescent labeling.

[0257] Pharmaceutically acceptable salts

[0258] In some embodiments, the compounds described herein are present in the form of their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts as a pharmaceutical composition.

[0259] In some embodiments, the compounds described herein have acidic or basic groups, and thus react with a variety of inorganic or organic bases, as well as any of inorganic and organic acids, to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or by reacting the purified free form of the compound alone with a suitable acid or base and isolating the resulting salt.

[0260] Examples of pharmaceutically acceptable salts include those prepared by reacting the compounds described herein with inorganic substances, organic acids, or inorganic bases. Such salts include acetates, acrylates, adipates, alginates, aspartates, benzoates, benzenesulfonates, hydrogen sulfates, bisulfites, bromides, butyrates, butyn-1,4-dicitates, camphorates, camphorsulfonates, hexanoates, octanoates, chlorobenzoates, chlorides, citrates, cyclopentanepropionates, decanoates, disglucurons, dihydrogen phosphates, dinitrobenzoates, dodecyl sulfates, ethanesulfonates, formates, fumarates, glucohepate, glycerophosphates, glycolic acid salts, hemisulfates, heptarates, hexyn-1,6-dicitates, hydroxybenzoates, and gamma-hydroxybutyrates. Hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogen phosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmitate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, neopentanoate, propionate, pyrosulfonate, pyrophosphate, propynate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, octanoate, sebacic acid salt, sulfonate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and xylenesulfonate.

[0261] Furthermore, the compounds described herein can be prepared as pharmaceutically acceptable salts by reacting the free base form of the compounds with a pharmaceutically acceptable inorganic or organic acid, including but not limited to inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, metaphosphoric acid, etc.; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, and benzoic acid. The compounds include 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-en-1-carboxylic acid, glucoheponic acid, 4,4'-methylenebis-(3-hydroxy-2-en-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, dodecyl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and mucoconic acid. In some embodiments, other acids that are not pharmaceutically acceptable on their own, such as oxalic acid, are used to prepare salts that can be used as intermediates to obtain the compounds disclosed herein and their pharmaceutically acceptable acid addition salts.

[0262] In some embodiments, the compounds described herein containing free acid groups react with suitable bases (such as hydroxides, carbonates, bicarbonates, and sulfates of pharmaceutically acceptable metal cations), with ammonia, or with pharmaceutically acceptable primary, secondary, tertiary, or quaternary organic amines. Representative salts include alkali metal or alkaline earth metal salts, such as lithium, sodium, potassium, calcium, and magnesium, as well as aluminum salts. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, and N2SO4. + (C 1-4 Alkyl)4, etc.

[0263] Representative organic amines used to form base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, etc. It should be understood that the compounds described herein also include quaternization of any basic nitrogen-containing groups they contain. In some embodiments, such quaternization yields water-soluble, oil-soluble, or dispersible products.

[0264] tautomer

[0265] In some cases, compounds exist as tautomers. The compounds described herein include all possible tautomers of the chemical formulas described herein. Tautomers are compounds that interconvert through the migration of hydrogen atoms, accompanied by the conversion of single bonds and adjacent double bonds. A chemical equilibrium of tautomers will exist in the bonding arrangements where tautomerization is possible. All tautomeric forms of the compounds disclosed herein are considered. The precise ratio of tautomers depends on several factors, including temperature, solvent, and pH.

[0266] Treatment

[0267] This article discloses a method for treating at least part of a PKMYT1-regulated disease in a subject in need, the method comprising administering to the subject a therapeutically effective amount of the disclosed compound or a pharmaceutically acceptable salt thereof.

[0268] This article discloses a method for treating cancer in a subject in need, the method comprising administering to the subject a therapeutically effective amount of the disclosed compound or a pharmaceutically acceptable salt thereof.

[0269] In some implementations, cancer depends on the activity of PKMYT1.

[0270] In some implementations, cancers overexpress CCNE1. Cancers with a high incidence of CCNE1 overexpression include, for example, breast cancer, endometrial cancer, esophageal cancer, lung cancer, ovarian cancer, gastric cancer, and uterine cancer.

[0271] In some implementations, the cancer has an inactivating mutation in the FBXW7 gene. In some implementations, cancers lacking FBXW7 include, for example, breast cancer, colorectal cancer, esophageal cancer, lung cancer, and uterine cancer.

[0272] In some implementations, cancer is a solid tumor.

[0273] In some implementation schemes, the cancer is breast cancer, colorectal cancer, endometrial cancer, esophageal cancer, glioblastoma, hepatocellular carcinoma, lung cancer, neuroblastoma, ovarian cancer, prostate cancer, stomach cancer, or uterine cancer.

[0274] This document discloses a method for modulating PKMYT1 in a subject, comprising administering to the subject a compound disclosed herein or a pharmaceutically acceptable salt thereof. This document also discloses a method for inhibiting PKMYT1 in a subject, comprising administering to the subject a compound disclosed herein or a pharmaceutically acceptable salt thereof. Furthermore, this document discloses a method for selectively inhibiting PKMYT1 in a subject (e.g., selectively beyond WEE1), comprising administering to the subject a compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0275] WEE1 is widely distributed in human tissues and plays an important role in all stages of the cell cycle. In the treatment methods described herein, it may be beneficial to use compounds that selectively inhibit PKMYT1 instead of WEE1. In some embodiments, the compounds disclosed herein do not inhibit WEE1. In some embodiments, the compounds disclosed herein have a WEE1 IC50 value of at least about 100 nM, at least about 500 nM, at least about 1000 nM, or at least about 10,000 nM as determined in a WEE1 ADP-Glo ​​assay. For example, the WEE1 IC50 value can be determined according to Example B.

[0276] Dosage

[0277] In some embodiments, a composition containing the compounds described herein is administered for therapeutic treatment. In some therapeutic applications, the composition is administered to a patient already suffering from the disease or symptom in an amount sufficient to cure or at least partially suppress at least one symptom of the disease or symptom. The effective amount for this use depends on the severity and course of the disease or symptom, prior treatment, the patient's health status, weight, response to the drug, and the judgment of the attending physician. The therapeutically effective amount may optionally be determined by methods including, but not limited to, dose escalation and / or dose range clinical trials.

[0278] In some implementations in which the patient’s condition does not improve, the compound is administered long-term (i.e., over an extended period of time) at the physician’s discretion, including throughout the patient’s life, in order to improve or otherwise control or limit the symptoms of the patient’s disease or condition.

[0279] Once the patient's symptoms improve, a maintenance dose may be administered if necessary. Subsequently, in specific implementation plans, the dose or frequency of administration may be reduced, or both, depending on the symptoms.

[0280] The amount of a given drug corresponding to such quantities varies depending on factors such as the specific compound, the disease condition and its severity, and the identity of the subject or host requiring treatment (e.g., weight, sex), but is still determined based on the specific circumstances surrounding the case, including, for example, the specific drug administered, the route of administration, the condition being treated, and the subject or host being treated.

[0281] In some embodiments, the dosage for adult treatment is typically in the range of 0.01 mg to 5000 mg per day. In some embodiments, the daily dose of the compound described herein or a pharmaceutically acceptable salt thereof is about 0.01 to about 50 mg / kg / body weight. In various embodiments, the daily dose and unit dose vary according to a number of variables, including but not limited to the activity of the compound used, the disease or condition to be treated, the mode of administration, the individual subject's needs, the severity of the disease or condition to be treated, and the physician's judgment.

[0282] Application route

[0283] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transmucosal, transdermal, vaginal, ocular, nasal, and topical administration. Furthermore, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intrathecal, direct intracardiac, intraperitoneal, intralymphatic, and intranasal injection.

[0284] In some embodiments, the compounds described herein are administered locally rather than systemically, for example, by direct injection into an organ, typically in the form of long-acting or sustained-release formulations. In specific embodiments, long-acting formulations are administered via implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. Furthermore, in other embodiments, the drug is delivered in a targeted drug delivery system, for example, in liposomes coated with organ-specific antibodies. In such embodiments, the liposomes target the organ and are selectively absorbed by the organ. In further embodiments, the compounds described herein are provided in the form of rapid-release formulations, extended-release formulations, or immediate-release formulations.

[0285] Pharmaceutical Compositions / Formulations

[0286] In accordance with standard pharmaceutical practice, the compounds described herein are administered, alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, as a pharmaceutical composition to subjects in need. In some embodiments, the compounds described herein are administered to animals.

[0287] On the other hand, this document provides pharmaceutical compositions comprising the compounds described herein or pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable excipient. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate the processing of the active compound into a pharmaceutically usable formulation. Appropriate formulations depend on the chosen route of administration. An overview of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, 19th edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L. (eds.), Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th edition (Lippincott Williams & Wilkins 1999), all of which are incorporated herein by reference.

[0288] In some implementations, pharmaceutically acceptable excipients are selected from carriers, binders, fillers, suspending agents, flavoring agents, sweeteners, disintegrants, dispersants, surfactants, lubricants, colorants, diluents, solubilizers, wetting agents, plasticizers, stabilizers, penetration enhancers, humectants, defoamers, antioxidants, preservatives, and any combination thereof.

[0289] The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, liquids, gels, syrups, elixirs, pastes, suspensions, self-emulsifying dispersions, solid solutions, liposome dispersions, aerosols, solid oral dosage forms, powders, immediate-release formulations, controlled-release formulations, rapidly melting formulations, tablets, capsules, pills, powders, sugar-coated pills, effervescent formulations, lyophilized formulations, delayed-release formulations, extended-release formulations, pulsatile-release formulations, multi-particle formulations, and mixed immediate-release and controlled-release formulations.

[0290] combination

[0291] This article discloses methods for treating diseases or conditions associated with PKMYT1 using the compounds disclosed herein or pharmaceutically acceptable salts thereof in combination with other therapeutic agents.

[0292] In some embodiments, an additional therapeutic agent is administered concurrently with the compounds disclosed herein. In some embodiments, the additional therapeutic agent and the compounds disclosed herein are administered sequentially. In some embodiments, the additional therapeutic agent is administered less frequently than the compounds disclosed herein. In some embodiments, the additional therapeutic agent is administered more frequently than the compounds disclosed herein. In some embodiments, the additional therapeutic agent is administered before the compounds disclosed herein. In some embodiments, the additional therapeutic agent is administered after the compounds disclosed herein.

[0293] In some implementations, the additional therapeutic agent is an anticancer agent.

[0294] Example

[0295] Example 1: Preparation of 2,4-dimethyl-3-(2-(2-methyl-6-(4-methylpiperazin-1-yl)pyridin-3-yl)-3H-imidazo[4,5-b]pyridin-6-yl)phenol

[0296] The title compound was prepared according to the following synthetic procedure.

[0297]

[0298] Step 1: Preparation of compounds 1-2

[0299] To a solution of compound 1-1 (250 mg, 0.48 mmol) in dioxane (2 mL), add Pin₂B₂ (245 mg, 0.97 mmol), KOAc (142 mg, 1.45 mmol), and Pd(dppf)Cl₂ (73 mg, 0.1 mmol). Stir the mixture at 90 °C for 6 hours under N₂. Cool the reaction mixture to room temperature, dilute with water (10 mL), extract with EA (20 mL × 3), wash with brine (80 mL), dry to Na₂SO₄, filter, and concentrate to dryness. Crude compound 1-2 is used in the next step. LCMS: 483.4 [M + H] + .

[0300] Step 2: Preparation of compounds 1-4

[0301] Compounds 1-2 (60 mg, 0.12 mmol) were added to a solution of dioxane (2 mL) and H₂O (0.2 mL) along with compounds 1-3 (33 mg, 0.18 mmol), K₂CO₃ (49 mg, 0.36 mmol), and Pd(PPh₃)₄ (55 mg, 0.048 mmol). The mixture was stirred at 90 °C under N₂ for 3 hours. The reaction mixture was filtered. The filtrate was concentrated to dryness. The residue was purified by preparative TLC to give compounds 1-4. LCMS: 559.3 [M+H]+ .

[0302] Step 3: Preparation of Example 1

[0303] TFA (1.0 mL) was added to a solution of compounds 1-4 (73 mg, 0.12 mmol) in dioxane (2 mL). The mixture was stirred at 20 °C for 1 hour under N2. The reaction mixture was concentrated and purified by preparative HPLC to give Example 1. LCMS: 429.3 [M+H] + ; 1 H NMR: (400MHz, CD3OD) δ8.10(s,1H),7.97(d,J=8.6Hz,1H),7.73(s,1H),6.93(dd,J=29.8,8.5Hz,2H),6.76 (d,J=8.3Hz,1H),3.94(s,4H),3.24(s,4H),2.83(d,J=14.8Hz,3H),2.73(s,3H),1.94(s,3H),1.90(s,3H).

[0304] Example 2: Preparation of 2,4-dimethyl-3-(7-methyl-2-(2-methyl-6-(4-methylpiperazin-1-yl)pyridin-3-yl)-3H-imidazo[4,5-b]pyridin-6-yl)phenol

[0305] The title compound was prepared according to the following synthetic procedure.

[0306]

[0307] Step 1: Preparation of compound 2-2

[0308] Compound 1-3 (20 mg, 0.104 mmol), pd(dtbpf)Cl2 (67 mg, 0.104 mmol), Na2CO3 (10 mg, 0.104 mmol), and H2O (0.2 mL) were added to a solution of compound 2-1 (60 mg, 0.104 mmol) in dioxane (2 mL). The reaction mixture was stirred at 90 °C under N2 for 2 hours. The reaction mixture was quenched with water (20 mL) and extracted with EA (3 × 20 mL). The organic layers were combined, washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography to give compound 2-2. LCMS: 573.3 [M+H] + .

[0309] Step 2: Preparation of Example 2

[0310] TFA (0.5 mL) was added to a stirred solution of compound 2-2 (50 mg, 0.087 mmol) in DCM (2 mL). The reaction mixture was stirred at 25 °C under N2 for 1 hour. The reaction mixture was carefully added to ice water (20 mL) and the pH was adjusted to approximately 8 with NaHCO3. The mixture was extracted with DCM (30 mL × 3). The organic layers were combined and concentrated to dryness. The residue was purified by preparative HPLC to give Example 2. LCMS: 443.0 [M + H] + ; 1 H NMR: (400MHz, DMSO-d6) δ12.86(d,J=188.9Hz,1H),9.18(s,1H),8.18–8.03(m,1H),7.88(d,J=28.6Hz,1H),6.96 (d,J=8.1Hz,2H),6.78(d,J=8.2Hz,1H),3.31–3.00(m,8H),2.80(s,6H),2.20(s,3H),1.79(s,3H),1.73(s,3H).

[0311] Example 3: Preparation of 2,4-dimethyl-3-(3-methyl-2-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenol

[0312] The title compound was prepared according to the following synthetic procedure.

[0313]

[0314] Step 1: Preparation of compound 3-2

[0315] At 0 °C, NaH (0.38 g 9.476 mmol) was added to a solution of compound 3-1 (1.0 g, 4.738 mmol) in THF (20 mL). The mixture was stirred at 0 °C under N2 for 0.5 h. Then, TsCl (1.08 g, 1.780 mmol) was added. The mixture was stirred at 20 °C under N2 for 1 h. The reaction mixture was quenched with NH4Cl (50 mL, saturated aqueous solution), extracted with EA (100 mL × 3), washed with (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 3-2 as a white solid. LCMS: 366.8 [M + H] + .

[0316] Step 2: Preparation of compound 3-3

[0317] Under N2 and at -78°C, LDA (1.03 mL) was added to a solution of compound 3-2 (500 mg, 1.369 mmol) in THF (10 mL). The mixture was stirred under N2 at -78°C for 0.5 h. Then I2 (451 mg, 1.780 mmol) was added. The mixture was stirred under N2 at -78°C for 1 h. The reactants were quenched with NH4Cl (50 mL, saturated aqueous solution), extracted with EA (100 mL × 3), washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 3-3 as a white solid. LCMS: 492.6 [M + H] + .

[0318] Step 3: Preparation of compounds 3-5

[0319] Compound 3-3 (200 mg, 0.407 mmol) was mixed with a solution of dioxane (6 mL) and H₂O (1 mL) containing compound 3-4 (135 mg, 0.448 mmol), Pd(dppf)Cl₂ (30 mg, 0.041 mmol), and CsF (186 mg, 1.221 mmol). The mixture was stirred at 90 °C under N₂ for 1.5 h. The mixture was diluted with EA (100 mL), washed with brine (100 mL × 3), dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography to give compound 3-5. LCMS: 542.2 [M + H] + .

[0320] Step 4: Preparation of compounds 3-6

[0321] Compounds 3-5 (77 mg, 0.143 mmol) were added to a solution of dioxane (2 mL) with Pin₂B₂ (72 mg, 0.285 mmol), KOAc (42 mg, 0.428 mmol), and Pd(dppf)Cl₂ (11 mg, 0.014 mmol). The mixture was reacted at 90 °C under N₂ for 1.5 h, cooled to room temperature, diluted with water (10 mL), extracted with EA (20 mL × 3), washed with brine (60 mL), dried over Na₂SO₄, filtered, and concentrated to dryness. Crude product 3-6 was used directly in the next step. LCMS: 588.3 [M + H] + .

[0322] Step 5: Preparation of compounds 3-7

[0323] Compounds 1-3 (43 mg, 0.214 mmol), K₂CO₃ (59 mg, 0.429 mmol), and Pd(dtbpf)Cl₂ (9.5 mg, 0.014 mmol) were added to a solution of compounds 3-6 (54 mg, 0.009 mmol) in dioxane (2 mL) and H₂O (0.3 mL). The mixture was stirred at 90 °C for 1.5 h under N₂, cooled to room temperature, and filtered. The filtrate was concentrated and purified by silica gel column chromatography to give compounds 3-7. LCMS: 582.3 [M+H] + .

[0324] Step 6: Preparation of Example 3

[0325] To a solution of compounds 3-7 (55 mg, 0.095 mmol) in EtOH (2 mL), NaOH (0.5 mL, 1 M aqueous solution) was added. The mixture was stirred at 60 °C under N2 for 5 hours. The reaction mixture was concentrated to dryness. The residue was purified by preparative HPLC to give Example 3. LCMS: 428.0 [M+H] + . 1 H NMR: (400MHz, DMSO-d6) δ11.69(s,1H),9.12(s,1H),8.49(s,1H),7.88(d,J=9.3Hz,2H),7.62(s,1H),7.00(d,J=12.0Hz,1H),6.93(d ,J=8.0Hz,1H),6.74(d,J=8.1Hz,1H),3.61(s,4H),2.48–2.45(m,3H),2.36(s,3H),2.30(d,J=8.6Hz,4H),1.88(s,3H),1.81(s,3H).

[0326] Example 4: Preparation of 2,4-dimethyl-3-(2-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenol

[0327] The title compound was prepared according to the following synthetic procedure.

[0328]

[0329] Step 1: Preparation of compound 4-2

[0330] At 0 °C, NaH (0.73 g, 30.45 mmol) was added to a solution of compound 4-1 (3 g, 15.23 mmol) in THF (60 mL). The mixture was stirred at 0 °C under N2 for 0.5 h. Then, TsCl (3.48 g, 18.27 mmol) was added. The mixture was stirred at 20 °C under N2 for 1 h. The reactants were quenched with NH4Cl (50 mL, saturated), extracted with EA (100 mL × 3), washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 4-2 as a white solid. LCMS: 352.7 [M + H] + .

[0331] Step 2: Preparation of compound 4-3

[0332] At -78°C, LDA (0.46 g, 4.271 mmol) was added to a solution of compound 4-2 (1 g, 2.390 mmol) in THF (10 mL). The mixture was stirred at -78°C under N2 for 0.5 h. Then I2 (1.64 g, 3.701 mmol) was added. The mixture was stirred at -78°C under N2 for 1 h. The reaction mixture was quenched with NH4Cl (50 mL, saturated), extracted with EA (100 mL × 3), washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 4-3 as a white solid. LCMS: 476.9 [M + H] + .

[0333] Step 3: Preparation of compound 4-4

[0334] Compound 3-4 (629 mg, 2.075 mmol), CsF (860 mg, 5.659 mmol), and Pd(dppf)Cl2 (69 mg, 0.094 mmol) were added to a solution of compound 4-3 (900 mg, 1.886 mmol) in dioxane (6 mL) and H2O (1 mL). The mixture was stirred at 90 °C under N2 for 1.5 h. The mixture was filtered. The filtrate was concentrated and purified by silica gel column chromatography to give compound 4-4. LCMS: 528.1 [M+H] + .

[0335] Step 4: Preparation of compounds 4-5

[0336] To a solution of compound 4-4 (50 mg, 0.095 mmol) in dioxane (2 mL), add Pin₂B₂ (49 mg, 0.190 mmol), KOAc (27.97 mg, 0.285 mmol), and Pd(dppf)Cl₂ (6.20 mg, 0.009 mmol). Stir the mixture at 90 °C under N₂ for 1.5 h. Cool the reaction mixture to room temperature, dilute with water (10 mL), extract with EA (20 mL × 3), wash with brine (80 mL), dry to Na₂SO₄, filter, and concentrate to dryness. Crude product 4-5 is used directly in the next step. LCMS: 574.0 [M + H] + .

[0337] Step 5: Preparation of compounds 4-6

[0338] Compounds 1-3 (28 mg, 0.141 mmol), K₂CO₃ (39 mg, 0.282 mmol), and Pd(dtbpf)Cl₂ (6.14 mg, 0.009 mmol) were added to a solution of compounds 4-5 (54 mg, 0.009 mmol) in dioxane (2 mL) and H₂O (0.3 mL). The mixture was stirred at 90 °C under N₂ for 1.5 hours. The mixture was filtered. The filtrate was concentrated to give crude compounds 4-6, which were ready for use without further purification. LCMS: 568.0 [M+H] + .

[0339] Step 5: Preparation of Example 4

[0340] To a solution of compounds 4-6 (80 mg, 0.141 mmol) in EtOH (2 mL), NaOH (1.4 mL, 1 M aqueous solution) was added. The mixture was stirred at 60 °C under N2 for 5 hours. The reaction mixture was concentrated to dryness. The residue was purified by preparative HPLC to give Example 4. LCMS: 414.2 [M+H] + . 1 H NMR: (400MHz, DMSO-d6) δ12.04(s,1H),9.12(s,1H),8.71(d,J=2.4Hz,1H),8.16(s,1H),8.06(dd,J=8.9,2.5Hz,1H),7.85(d,J=2.0Hz,1H),7.58(d,J =1.9Hz,1H),6.94(dd,J=11.2,8.7Hz,2H),6.76(dd,J=11.2,5.1Hz,2H),3. 60–3.53(m,4H),2.40–2.45(m,4H),2.23(s,3H),1.88(s,3H),1.81(s,3H).

[0341] Example 5: Preparation of 2,4-dimethyl-3-(2-(6-methylpyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenol

[0342] The title compound was prepared according to the following synthetic procedure.

[0343]

[0344] Step 1: Preparation of compound 5-2

[0345] Compound 5-1 (150 mg, 0.339 mmol) was added to a solution of dioxane (6 mL) with 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1,3,2-dioxacyclopentaborane (172 mg, 0.678 mmol), Pd(dppf)Cl2 (25 mg, 0.034 mmol), and potassium acetate (100 mg, 1.017 mmol). The reaction mixture was stirred at 100 °C for 2 hours. The mixture was cooled to room temperature, diluted with water (20 mL), extracted with EA (30 mL × 3), washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated to dryness. Crude compound 5-2 was used directly in the next step. LCMS: 408.2 [M + H] + .

[0346] Step 2: Preparation of compound 5-3

[0347] Compound 1-3 (62 mg, 0.306 mmol), K₂CO₃ (127 mg, 0.919 mmol), and Pd(dtbpf)Cl₂ (20 mg, 0.031 mmol) were added to a solution of compound 5-2 (150 mg, 0.306 mmol) in dioxane (6 mL) and H₂O (1 mL). The reaction mixture was stirred at 90 °C for 2 hours. The reaction mixture was diluted with DCM and water. The organic layer was separated and concentrated under vacuum. The crude substance was purified by silica gel column chromatography to give compound 5-3. LCMS: 484.2 [M+H] + .

[0348] Step 3: Preparation of Example 5

[0349] To a solution of compound 5-3 (120 mg, 0.248 mmol) in EtOH (4 mL) and H₂O (2 mL), NaOH (99 mg, 2.481 mmol) was added. The reaction mixture was stirred at 80 °C for 1 hour. The reaction mixture was diluted with DCM and water. The organic layer was separated and concentrated under vacuum. The organic layer was collected and concentrated under vacuum. The crude product was purified by preparative HPLC to obtain Example 5. LCMS: 330.1 [M+H] + . 1 H NMR: (400MHz, DMSO-d6) δ12.27(s,1H),9.16(s,1H),9.05–9.04(m,1H),8.22–8.19(m,1H),7.94(d,J=2.0Hz,1H),7.68(d,J=1.9Hz,1 H),7.37(d,J=8.1Hz,1H),7.00(d,J=4.0Hz,1H),6.93(d,J=8.0Hz,1H),6.76(d,J=8.2Hz,1H),2.51(s,3H),1.89(s,3H),1.82(s,3H).

[0350] Example 6: Preparation of 1-(4-(5-(3-hydroxy-2,6-dimethylphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3,6-dihydropyridin-1(2H)-yl)ethyl-1-one

[0351] The title compound was prepared according to the following synthetic procedure.

[0352]

[0353] Step 1: Preparation of compound 6-1

[0354] Compounds 4-3 and 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-1,2,3,6-tetrahydropyridin-1-yl]ethyl-1-one (579 mg, 2.306 mmol) were added to a solution of dioxane (10 mL) and H₂O (2 mL) with Pd(dppf)Cl₂ (153 mg, 0.209 mmol) and cesium fluoride (957 mg, 6.300 mmol). The mixture was stirred at 100 °C for 1 hour under N₂. The reaction mixture was cooled to room temperature and extracted with EA (20 mL × 2). The organic layers were combined, dried over Na₂SO₄, and filtered. The filtrate was concentrated and purified by silica gel column chromatography to give compound 6-1. LCMS: 448.9 [M + H] + .

[0355] Step 3: Preparation of compound 6-2

[0356] To a solution of compound 6-1 (350 mg, 0.738 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1,3,2-dioxacyclopentaborane (224 mg, 0.885 mmol) in dioxane (3 mL), KOAc (217 mg, 2.213 mmol) and Pd(dppf)Cl2 (54 mg, 0.074 mmol) were added. The mixture was stirred at 100 °C for 1 hour. The mixture was cooled to room temperature, diluted with water (10 mL), extracted with EA (20 mL × 3), washed with brine (80 mL), dried over Na2SO4, filtered, and concentrated to dryness. Crude compound 6-2 was used directly in the next step. LCMS: 522.3 [M + H] + .

[0357] Step 4: Preparation of compound 6-3

[0358] Compound 6-2 (350 mg, 0.671 mmol) and compound 1-3 (135 mg, 0.671 mmol) were added to a solution of dioxane (5 mL) and H₂O (1 mL) with Pd(dtbpf)Cl₂ (44 mg, 0.067 mmol) and K₂CO₃ (278 mg, 2.014 mmol). The mixture was stirred at 90 °C for 2 hours. The mixture was extracted with EA (10 mL). The organic layer was dried over Na₂SO₄, filtered, concentrated, and purified by silica gel column chromatography to give compound 6-3. LCMS: 516.3 [M+H] + .

[0359] Step 5: Preparation of Example 6

[0360] Sodium hydroxide (8.0 mg, 0.194 mmol) was added to a solution of compound 6-3 (100 mg, 0.194 mmol) in EtOH (2 mL) and H₂O (1 mL). The mixture was stirred at 80 °C for 1 hour. The reaction mixture was cooled to room temperature, diluted with EA (30 mL), and washed with brine (30 mL). The organic layer was dried over Na₂SO₄, filtered, and concentrated to dryness. The residue was purified by preparative HPLC to give Example 6. LCMS: 362.4 [M+H] + . 1H NMR: (400MHz, DMSO-d6) δ11.81(d,J=12.8Hz,1H),9.12(s,1H),7.88(s,1H),7.60(s,1H),6.91(d,J=8.2Hz,1H),6.74(d,J=8.2Hz,1H),6 .52(s,1H),6.47(d,J=5.1Hz,1H),4.21(s,1H),4.15(s,1H),3.65(s,2H),2.60(s,2H),2.07(d,J=12.6Hz,3H),1.86(s,3H),1.79(s,3H).

[0361] Example 7: Preparation of 2,4-dimethyl-3-(2-(2-methylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenol

[0362] The title compound was prepared according to the following synthetic procedure.

[0363]

[0364] Step 1: Preparation of compound 7-2

[0365] A solution of compound 4-3 (170 mg, 0.36 mmol), compound 7-1 (49 mg, 0.36 mmol), K₂CO₃ (123 mg, 0.89 mmol), and Pd(dppf)Cl₂ (26 mg, 0.036 mmol) in dioxane (1.0 mL) and water (0.2 mL) was stirred at 100 °C for 2.5 h. The mixture was concentrated. The residue was purified by silica gel column chromatography to give compound 7-2 as a yellow solid. LCMS: 445.0 [M+H] + .

[0366] Step 2: Preparation of compound 7-3

[0367] A solution of compound 7-2 (100 mg, 0.23 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1,3,2-dioxacyclopentaborane (115 mg, 0.45 mmol), KOAc (67 mg, 0.68 mmol), and Pd(dppf)Cl2 (17 mg, 0.023 mmol) in dioxane (2 mL) was stirred at 100 °C for 16 hours. The mixture was cooled to room temperature, diluted with water (10 mL), extracted with EA (20 mL × 3), washed with brine (80 mL), dried over Na2SO4, filtered, and concentrated to dryness. Crude compound 7-3 was used for the next step without further purification. LCMS: 409.1 [M + H]+ .

[0368] Step 3: Preparation of compound 7-4

[0369] A solution of compound 7-3, compound 1-3 (50 mg, 0.25 mmol), K₂CO₃ (78 mg, 0.57 mmol), and Pd(dtbpf)Cl₂ (15 mg, 0.023 mmol) in dioxane / water (2 mL / 0.2 mL) was stirred at 100 °C for 4 hours. The mixture was concentrated. The residue was purified by silica gel column chromatography to give compound 7-4. LCMS: 485.2 [M+H] + .

[0370] Step 4: Preparation of Example 7

[0371] Compound 7-4 (122 mg, 0.25 mmol) was added to a solution of EtOH (5 mL) with NaOH (2 M, 1.26 mL, 2.52 mmol). The mixture was stirred at 70 °C for 16 hours. The mixture was concentrated, diluted with water (2 mL), neutralized with HCl (2 M) solution to approximately pH 5, and concentrated again. The crude product was purified by preparative HPLC to obtain Example 7. LCMS: 331.2 [M+H] + . 1 HNMR: (400MHz, DMSO-d6) δ12.39(s,1H),9.25(s,2H),9.15(s,1H),7.98(d,J=1.9Hz,1H),7.72(d,J=1.9H z,1H),7.12(s,1H),6.93(d,J=8.2Hz,1H),6.76(d,J=8.1Hz,1H),2.67(s,3H),1.88(s,3H),1.81(s,3H).

[0372] Example 8: Preparation of 3-(2-(5-methoxypyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,4-dimethylphenol

[0373] The title compound was prepared according to the following synthetic procedure.

[0374]

[0375] Step 1: Preparation of compound 8-2

[0376] Pd(dppf)Cl2 (24.54 mg, 0.034 mmol), compound 8-1 (61.55 mg, 0.402 mmol), potassium carbonate (139.04 mg, 1.006 mmol), and H2O (0.8 mL) were added to a stirred solution of compound 4-3 (160 mg, 0.335 mmol) in dioxane (4 mL). The reaction mixture was stirred at 100 °C for 2 hours under argon atmosphere by microwave, and quenched with water (25 mL). The resulting mixture was extracted with EA (3 × 20 mL). The EA layers were combined, washed with brine (2 × 30 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography to give compound 8-2. LCMS: 457.9 [M + H] + .

[0377] Step 2: Preparation of compound 8-3

[0378] Compound 8-2 (80 mg, 0.175 mmol) was added to a stirred solution of dioxane (2 mL) with 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1,3,2-dioxacyclopentaborane (66.49 mg, 0.262 mmol), Pd(dppf)Cl2 (127.72 mg, 0.175 mmol), and KOAC (51.32 mg, 0.524 mmol). The reaction mixture was stirred at 90 °C for 3 hours and quenched with H2O (10 mL). The resulting mixture was extracted with EA (3 × 15 mL). The EA layers were combined, washed with brine (2 × 20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography to give compound 8-3. LCMS: 506.2 [M+H] + .

[0379] Step 4: Preparation of compound 8-4

[0380] Compound 1-3 (27.85 mg, 0.139 mmol), Cs₂CO₃ (173.19 mg, 0.532 mmol), Pd(dtbpf)Cl₂ (9.14 mg, 0.014 mmol), and H₂O (0.4 mL) were added to a stirred solution of dioxane (2 mL). The reaction mixture was stirred at 90 °C for 2 hours under argon atmosphere. The reaction mixture was quenched with water (15 mL). The resulting mixture was extracted with EA (3 × 15 mL). The EA layers were combined, washed with brine (2 × 20 mL), dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography to give compound 8-4. LCMS: 500.2 [M + H] +.

[0381] Step 5: Preparation of Example 8

[0382] Sodium hydroxide (4.80 mg, 0.120 mmol) was added to a stirred solution of compound 8-4 (60 mg, 0.120 mmol) in EtOH (4 mL). The reaction mixture was stirred in a microwave at 70 °C for 2 hours. The reaction mixture was quenched with aqueous HCl (1 M) to a pH of approximately 7. The mixture was concentrated to dryness. The residue was purified by preparative HPLC to give Example 8. LCMS: 346.3 [M+H] + ; 1 H NMR: (400MHz, DMSO-d6) δ12.33(s,1H),9.16(s,1H),8.79(d,J=1.6Hz,1H),8.27(d,J=2.7Hz,1H),8.16(s,1H),7.97(d,J=2.0Hz,1H),7.96–7 .91(m,1H),7.71(d,J=1.9Hz,1H),7.12(d,J=1.9Hz,1H),6.94(d,J=8.2Hz,1H),6.76(d,J=8.2Hz,1H),3.93(s,3H),1.89(s,3H),1.82(s,3H).

[0383] Example 9: Preparation of 4-(5-(3-hydroxy-2,6-dimethylphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-methylpyridin-2(1H)-one

[0384] The title compound was prepared according to the following synthetic procedure.

[0385]

[0386] Step 1: Preparation of compound 9-2

[0387] Compound 9-1 (187.24 mg, 0.796 mmol), cesium fluoride (362.95 mg, 2.389 mmol), and Pd(dppf)Cl2 (58.28 mg, 0.080 mmol) were added to a solution of compound 4-3 (380 mg, 0.796 mmol) in dioxane (6 mL) and H2O (1 mL). The resulting mixture was stirred at 90 °C under N2 for 2 hours. The reaction mixture was quenched with water (20 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to give compound 9-2. LCMS: 460.0 [M + H] + .

[0388] Step 2: Preparation of compound 9-3

[0389] Compound 9-2 (200 mg, 0.436 mmol) was added to a solution of dioxane (6 mL) with 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1,3,2-dioxacyclopentaborane (132.97 mg, 0.524 mmol), KOAc (128.48 mg, 1.309 mmol), and Pd(dppf)Cl2 (31.93 mg, 0.044 mmol). The reaction mixture was stirred at 100 °C for 3 hours under N2. The reaction mixture was diluted with water (20 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to give compound 9-3. LCMS: 506.1 [M + H] + .

[0390] Step 3: Preparation of compound 9-4

[0391] Compound 1-3 (79.25 mg, 0.394 mmol), Pd(dtbpf)Cl2 (25.77 mg, 0.039 mmol), and K2CO3 (163.42 mg, 1.182 mmol) were added to a solution of dioxane (6 mL) and H2O (1 mL). The reaction mixture was stirred at 90 °C under N2 for 2 hours. The reaction mixture was diluted with water (20 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to give compound 9-4. LCMS: 500.2 [M + H] + .

[0392] Step 4: Preparation of Example 9

[0393] To a solution of compound 9-4 (100 mg, 0.200 mmol) in EtOH (3 mL) and H₂O (3 mL), NaOH (80.07 mg, 2.002 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with DCM and ice water, and the pH was adjusted to approximately 7 with HCl (0.5 M aqueous solution). The reaction mixture was diluted with water (20 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na₂SO₄, filtered, and concentrated to dryness. The crude product was purified by preparative HPLC to give Example 9. LCMS: 346.1 [M + H] + . 1 H NMR: (400MHz, DMSO-d6) δ12.27(s,1H),9.17(s,1H),8.01(d,J=1.8Hz,1H),7.84–7.64(m,2H),7.17–7.08(m, 1H),7.02(d,J=1.4Hz,1H),6.94(d,J=8.2Hz,1H),6.82–6.73(m,2H),3.45(s,3H),1.88(s,3H),1.81(s,3H).

[0394] Example 10: Preparation of 3-(4-chloro-2-(6-methylpyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,4-dimethylphenol

[0395] The title compound was prepared according to the following synthetic procedure.

[0396]

[0397] Step 1: Preparation of compound 10-2

[0398] At 0 °C, NaH (328.3 mg, 60% dispersion in mineral oil, 8.208 mmol) was added to a solution of compound 10⁻¹ (950 mg, 4.104 mmol) in THF (20 mL). The mixture was stirred at 0 °C for 0.5 h. Then TsCl (935.72 mg, 4.925 mmol) was added. The mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with saturated NH₄Cl (aqueous solution, 20 mL) and extracted with EA (150 mL). The organic layers were combined and dried over Na₂SO₄. After filtration, the filtrate was concentrated and purified by silica gel column chromatography to give compound 10⁻². LCMS: 387.0 [M + H] + .

[0399] Step 2: Preparation of compound 10-3

[0400] At -78°C, LDA (1.09 mL, 2.182 mmol) was added to a solution of compound 10⁻² (700 mg, 1.818 mmol) in THF (10 mL). The mixture was stirred at this temperature for 1 hour. Then, I₂ (692.18 mg, 2.727 mmol) was added, and the resulting mixture was stirred at -78°C for 1 hour. The mixture was quenched with saturated NH₄Cl (20 mL aqueous solution) and extracted with EA (100 mL). The organic layer was washed with saturated Na₂SO₃ (30 mL aqueous solution). The organic layer was dried over Na₂SO₄ and concentrated to dryness. The residue was purified by silica gel column chromatography to give compound 10⁻³. LCMS: 512.9 [M + H] + .

[0401] Step 3: Preparation of compound 10-5

[0402] Compound 10⁻³ (250 mg, 0.489 mmol) was added to a solution of dioxane (5 mL) and H₂O (1 mL) along with compound 10⁻⁴ (100.38 mg, 0.733 mmol), CsF (222.85 mg, 1.466 mmol), and Pd(dppf)Cl₂ (35.72 mg, 0.049 mmol). The mixture was stirred at 90 °C under N₂ for 6 hours. The reaction mixture was filtered. The filtrate was concentrated to dryness. The residue was purified by silica gel column chromatography to give compound 10⁻⁵. LCMS: 477.8 [M + H] + .

[0403] Step 4: Preparation of compound 10-7

[0404] Compound 10⁻⁵ (93 mg, 0.195 mmol) was added to a solution of dioxane (5 mL) and H₂O (1 mL) along with compound 10⁻⁶ (61.35 mg, 0.234 mmol), Pd(dtbpf)Cl₂ (14.25 mg, 0.020 mmol), and K₂CO₃ (80.85 mg, 0.585 mmol). The mixture was stirred at 90 °C for 2 hours. The reaction mixture was filtered. The filtrate was concentrated to dryness. The residue was purified by preparative TLC to give compound 10⁻⁷. LCMS: 532.2 [M + H] + .

[0405] Step 5: Preparation of compound 10-8

[0406] At 0 °C, 0.1 mL of BBr3 was added to a solution of compound 10⁻⁷ (60 mg, 0.113 mmol) in 3 mL of DCM. The mixture was stirred for 0.5 h. The reaction mixture was quenched with 1 mL of MeOH. The mixture was concentrated to dryness. The residue was purified by silica gel column chromatography to give compound 10⁻⁸. LCMS: 518.2 [M + H] + .

[0407] Step 6: Preparation of Example 10

[0408] To a solution of compound 10-8 (40 mg, 0.077 mmol) in EtOH (5 mL), NaOH (1.5 mL, 1 M aqueous solution) was added. The mixture was stirred at 65 °C for 3 hours. The mixture was concentrated to dryness. The residue was purified by preparative HPLC to obtain Example 10. LCMS: 364.2 [M+H] + . 1 H NMR: (400MHz, DMSO-d6) δ12.75(s,1H),9.21(s,1H),8.48(d,J=7.9Hz,1H),8.04(s,1H),7.59(d,J=7.9Hz,1H),7.54(d,J= 7.7Hz,1H),7.25(s,1H),7.03(d,J=7.9Hz,1H),6.86(d,J=8.1Hz,1H),2.64(s,3H),2.35(s,1H),1.90(s,3H),1.83(s,3H).

[0409] Example 11: Preparation of 2,4-dimethyl-3-(6-(6-methylpyridin-3-yl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)phenol

[0410] The title compound was prepared according to the following synthetic procedure.

[0411]

[0412] Step 1: Preparation of compound 11-2

[0413] At 0 °C, NaH (260.48 mg, 60% dispersion in mineral oil, 6.512 mmol) was added to a solution of compound 11-1 (500 mg, 3.256 mmol) in THF (10 mL). The mixture was stirred at this temperature for 0.5 h. Then TsCl (744.87 mg, 3.907 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. The mixture was quenched with saturated NH4Cl (aqueous solution, 20 mL) and extracted with EA (100 mL). The organic layer was dried over Na2SO4 and concentrated to dryness. The residue was purified by silica gel column chromatography to give compound 11-2. LCMS: 307.9 [M+H] + .

[0414] Step 2: Preparation of compound 11-3

[0415] At -78 °C, LDA (2.32 mL, 4.647 mmol) was added to a solution of compound 11-2 (1.1 g, 3.574 mmol) in THF (20 mL). The mixture was stirred at this temperature for 1 hour. Then, I2 (1.36 g, 5.361 mmol) was added and the mixture was stirred at -78 °C for 1 hour. The mixture was quenched with saturated NH4Cl (20 mL aqueous solution) and extracted with EA (100 mL). The organic layer was washed with Na2SO3 (30 mL saturated aqueous solution), dried over Na2SO4, and concentrated to dryness. The residue was purified by silica gel column chromatography to give compound 11-3. LCMS: 434.0 [M+H] + .

[0416] Step 3: Preparation of compound 11-4

[0417] Compound 11-3 (500 mg, 1.153 mmol) was added to a solution of dioxane (10 mL) and H₂O (2 mL) along with compound 10-4 (236.84 mg, 1.730 mmol), CsF (525.77 mg, 1.730 mmol), and Pd(dppf)Cl₂ (84.28 mg, 0.115 mmol). The mixture was stirred overnight at 90 °C under N₂. The reaction mixture was filtered. The filtrate was concentrated to dryness. The residue was purified by silica gel column chromatography to give compound 11-4. LCMS: 399.0 [M+H] + .

[0418] Step 4: Preparation of compound 11-5

[0419] Compound 10-6 (157.74 mg, 0.60 mmol), Pd(dtbpf)Cl2 (32.7 mg, 0.05 mmol), and K2CO3 (207.89 mg, 1.504 mmol) were added to a mixture of dioxane (5 mL) and H2O (1 mL) to form compound 11-4 (200 mg, 0.50 mmol). The mixture was stirred at 90 °C for 2 hours. The reaction mixture was filtered. The filtrate was concentrated to dryness. The residue was purified by silica gel column chromatography to give compound 11-5. LCMS: 499.2 [M+H] + .

[0420] Step 5: Preparation of Compound 11-6

[0421] At 0 °C, 0.2 mL of BBr3 was added to a solution of compound 11-5 (200 mg, 0.011 mmol) in 10 mL of DCM. The mixture was stirred for 0.5 h. The reaction mixture was quenched with 1 mL of MeOH. The mixture was concentrated to dryness. The residue was purified by silica gel column chromatography to give compound 11-6. LCMS: 485.2 [M+H] + .

[0422] Step 6: Preparation of Example 11

[0423] To a solution of compound 7 (120 mg, 0.248 mmol) in 10 mL of EtOH, 2.5 mL of NaOH (1 M aqueous solution) was added. The mixture was stirred at 65 °C for 3 hours. The mixture was concentrated to dryness. The residue was purified by preparative HPLC to Example 11. LCMS: 331.2 [M+H] + . 1 H NMR: (400MHz, CD3OD) δ9.00(d,J=1.9Hz,1H),8.27(dd,J=8.1,2.2Hz,1H),8.15(s,1H),7.47(d,J=8.2Hz ,1H),7.09(s,1H),6.98(d,J=8.2Hz,1H),6.80(d,J=8.2Hz,1H),2.62(s,3H),1.94(s,3H),1.89(s,3H).

[0424] Example 12: Preparation of 3-(7-fluoro-6-(2-methylpyrimidin-5-yl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-2,4-dimethylphenol

[0425] The title compound was prepared according to the following synthetic procedure.

[0426]

[0427] Step 1: Preparation of compound 12-2

[0428] A selective fluorine reagent (1341.8 mg, 3.787 mmol) was added to a solution of compound 12-1 (500 mg, 2.525 mmol) in HOAc (2 mL) and CH3CN (10 mL). The solution was heated to 90 °C under N2 for 16 hours. The solution was quenched with a saturated aqueous solution of NaHCO3 (50 mL) and extracted with EA (50 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography to give compound 12-2 (100 mg, 0.463 mmol, 18.33%). LCMS: 215.9 [M + H] + .

[0429] Step 2: Preparation of compound 12-3

[0430] At 0 °C, NaH (27.8 mg, 0.694 mmol) was added fractionally to a solution of compound 12-2 (100 mg, 0.463 mmol) in DMF (2 mL). The mixture was stirred at 0 °C for 30 min. Then TsCl (132.4 mg, 0.694 mmol) was added. The reaction mixture was stirred at 0 °C for 1 h and quenched with H2O (10 mL). The suspension was filtered and the solid was dried to give compound 12-3 (150 mg, 0.405 mmol, 87.52%). LCMS: 370.1 [M+H] + .

[0431] Step 3: Preparation of compound 12-4

[0432] Under N2, a mixture of compound 12-3 (150 mg, 0.405 mmol), compound 10-6 (138.1 mg, 0.527 mmol), K2CO3 (168.0 mg, 1.216 mmol), and Pd(dtbpf)Cl2 (26.2 mg, 0.041 mmol) in dioxane-water (5:1) (5 mL) was heated to 90 °C for 2 hours. The mixture was diluted with H2O (10 mL) and extracted with EA (10 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography to give compound 12-4 (100 mg, 0.235 mmol, 58.00%). LCMS: 426.0 [M+H] + .

[0433] Step 4: Preparation of Compound 12-6

[0434] At -78°C, LDA (0.22 mL, 0.447 mmol) was added dropwise to a solution of compound 12-4 (95 mg, 0.223 mmol) in THF (4 mL). The solution was stirred at -78°C for 30 min. Then, a solution of compound 12-5 (145.4 mg, 0.447 mmol) in THF (0.4 mL) was added. The reaction mixture was stirred at -78°C for 1 h under N2. The mixture was quenched with a saturated aqueous solution of NH4Cl (20 mL), diluted with H2O (20 mL), and extracted with EA (30 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography to give compound 12-6 (90 mg, 0.178 mmol, 79.92%). LCMS: 505.6 [M + H] + .

[0435] Step 5: Preparation of Compound 12-7

[0436] A solution of compound 12-6 (200 mg, 0.397 mmol) and NaOH (4.0 mL, 3.965 mmol) in EtOH (4 mL) was heated to 50 °C for 1 hour. The mixture was cooled to 0 °C, the pH was adjusted to 6 with 1 N HCl, diluted with H₂O (10 mL), and extracted with EA (10 mL × 3). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography to give compound 12-7. LCMS: 351.7 [M + H] + .

[0437] Step 6: Preparation of compounds 12-9

[0438] Under a nitrogen atmosphere, a mixture of compound 12-7 (100 mg, 0.286 mmol), compound 12-8 (81.7 mg, 0.371 mmol), K₂CO₃ (118.4 mg, 0.857 mmol), and Pd(dtbpf)Cl₂ (18.7 mg, 0.029 mmol) in dioxane-water (5:1) (2 mL) was heated to 90 °C and maintained for 3 hours. The mixture was concentrated, and the residue was diluted with H₂O (10 mL) and extracted with EA (10 mL × 3). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography to give compound 12-9.

[0439] LCMS:364.1 [M+H] + .

[0440] Step 7: Preparation of Example 12

[0441] At 0 °C, BBr3 (344.7 mg, 1.376 mmol) was added dropwise to a solution of compound 12-9 (50 mg, 0.138 mmol) in DCM (4 mL). The mixture was stirred at room temperature for 1 hour. The mixture was quenched with MeOH (2 mL) and concentrated. The residue was purified by preparative HPLC to give Example 12. LCMS: 350.0 [M+H] + . 1 H NMR: (400MHz, DMSO-d6) δ12.76(s,1H),9.26(s,1H),9.23(s,2H),8.27(s,1H),6. 96(d,J=8.2Hz,1H),6.82(d,J=8.2Hz,1H),2.72(s,3H),1.88(s,3H),1.80(s,3H).

[0442] Example 13: Preparation of 2,4-dimethyl-3-(7-methyl-6-(2-methylpyrimidin-5-yl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)phenol

[0443] Example 13 was synthesized from compound 13-1, which was prepared from similar starting materials according to the method described in Example 12.

[0444]

[0445] Step 1: Preparation of compound 13-2

[0446] NBS (103.1 mg, 0.579 mmol) was added to a solution of compound 13-1 (200.0 mg, 0.579 mmol) in CH3CN (10.0 mL) at 0 °C. The mixture was stirred at room temperature for 2 hours. The reaction mixture was purified by reversed-phase column chromatography to give compound 13-2. LCMS: 426.0 [M+H] + .

[0447] Step 2: Preparation of compound 13-4

[0448] A mixture of compound 13-2 (243.0 mg, 0.573 mmol), compound 13-3 (151.0 mg, 1.203 mmol), K₂CO₃ (336.4 mg, 2.434 mmol), and Pd(dtbpf)Cl₂ (37.4 mg, 0.057 mmol) in dioxane-water (6 mL, 5:1) was stirred at 100 °C for 16 hours under N₂. The reaction mixture was cooled to room temperature and diluted with water (20 mL), then extracted with EA (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography to give compound 13-4. LCMS: 360.2 [M + H] + .

[0449] Step 3: Preparation of Example 13

[0450] At 0 °C, BBr3 (1.69 mg, 6.733 mmol) was added to a solution of compound 13-4 (242.0 mg, 0.673 mmol) in DCM (10.0 mL). The mixture was stirred at 0 °C for 1 hour. The reaction mixture was carefully added to MeOH (5 mL) while stirring, diluted with water (20 mL), adjusted to pH 8 with NaHCO3, and extracted with EA (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by preparative HPLC to give Example 13. LCMS: 346.1 [M + H] + ; 1 H NMR: (400MHz, DMSO-d6) δ12.41(s,1H),9.23(s,1H),9.11(d,J=2.8Hz,2H),8.15(d,J=2.8Hz,1H),6. 95(d,J=8.0Hz,1H),6.84-6.74(m,1H),2.72(s,3H),2.47(d,J=2.8Hz,3H),1.88(s,3H),1.80(s,3H).

[0451] Example 14: Preparation of 3-(6-(2-aminopyrimidin-5-yl)-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-2,4-dimethylphenol

[0452] Example 14 was synthesized from compound 14-1, which was prepared from similar starting materials according to the method described in Example 12.

[0453]

[0454] Step 1: Preparation of compound 14-2

[0455] Compound 14-1 (320 mg, 0.963 mmol) was added to a solution of DMF (2 mL) with Boc₂O (0.2 mL, 1.059 mmol), TEA (0.2 mL, 1.444 mmol), and DMAP (6 mg, 0.048 mmol). The mixture was stirred at 60 °C for 2 hours. The reaction mixture was diluted with EA (10 mL) and washed with brine (10 mL × 3). The organic layer was dried over Na₂SO₄, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to give compound 14-2 (255 mg, 0.590 mmol, 61.2%). LCMS: 433.4 [M + H] + .

[0456] Step 2: Preparation of compound 14-3

[0457] NIS (103 mg, 0.458 mmol) was added to a solution of compound 14-2 (260 mg, 0.509 mmol) in CAN (10 mL). The mixture was stirred at 25 °C for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with EA (10 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to give compound 14-3. LCMS: 559.3 [M + H] + .

[0458] Step 3: Preparation of Compounds 14-5

[0459] Compound 14-3 (250 mg, 0.518 mmol) was added to a solution of TEA (0.9 mL) and DMF (0.3 mL) along with compound 14-4 (51 mg, 0.518 mmol), CuI (40 mg, 0.207 mmol), and PdCl2(PPh3)2 (81 mg, 0.104 mmol). The mixture was stirred at 40 °C under N2 for 2 hours. The solution was purified by preparative HPLC to give compound 14-5. LCMS: 515.4 [M+H] + .

[0460] Step 4: Preparation of Example 14

[0461] K₂CO₃ (28 mg, 0.204 mmol) was added to a solution of compound 14-5 (35 mg, 0.068 mmol) in MeOH (2 mL). The mixture was stirred at 70 °C under N₂ for 2 hours. The reaction mixture was diluted with water (5 mL) and extracted with EA (5 mL × 3). The combined organic layers were washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated to dryness. The residue was purified by preparative TLC to give Example 14. LCMS: 415.1 [M + H] + ; 1 H NMR: (400MHz, DMSO-d6) δ12.68(s,1H),9.24(s,1H),9.07(s,2H),8.11(s,1H),7.27(s,1H),6. 95(d,J=8.4Hz,1H),6.81(d,J=8.4Hz,1H),5.48(s,1H),1.86(s,3H),1.78(s,3H),1.48(s,6H).

[0462] The following Examples 15-27 were prepared using similar starting materials according to the methods described in Examples 12-14.

[0463]

[0464]

[0465]

[0466]

[0467] Example 29: Preparation of 2,4-dimethyl-3-(2-(5-methylpyrazin-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenol

[0468] Example 29 was synthesized from compound 29-1, which was prepared from similar starting materials according to the method described in Example 12.

[0469]

[0470] Step 1: Preparation of compound 29-2

[0471] At -78°C, LDA (1.1 mL, 2.159 mmol) was added to a solution of compound 29-1 (585 mg, 1.439 mmol) in THF (10 mL). The mixture was stirred at this temperature for 0.5 h. Then, I2 (766.05 mg, 5.361 mmol) was added and the mixture was stirred at -78°C for 1 h. The mixture was quenched with NH4Cl (saturated aqueous solution, 20 mL) and extracted with EA (100 mL). The organic layer was washed with Na2SO3 (saturated aqueous solution, 30 mL). The organic layer was dried over Na2SO4 and concentrated to dryness. The residue was purified by silica gel column chromatography to give compound 29-2 (550 mg, 1.03 mmol, 71.78%). LCMS: 533.4 [M+H] + .

[0472] Step 2: Preparation of compound 29-4

[0473] Compound 29-2 (136 mg, 0.255 mmol) was added to a solution of compound 29-3 (97.88 mg, 0.281 mmol), Pd(PPh3)4 (29.47 mg, 0.026 mmol), CuI (9.71 mg, 0.051 mmol), and LiCl (32.43 mg, 0.765 mmol) in 2 mL of DMF. The mixture was stirred at 120 °C for 2 hours. The reaction mixture was filtered. The filtrate was concentrated to dryness. The residue was purified by preparative TLC to give compound 29-4. LCMS: 499.7 [M+H] + .

[0474] Step 3: Preparation of compound 29-5

[0475] BBr3 (0.241 mL, 2.0 M DCM solution) was added to a solution of compound 29-4 (48 mg, 0.096 mmol) in DCM (5 mL). The mixture was stirred at room temperature under N2 for 1 hour. The reaction mixture was quenched with MeOH (5 mL). The mixture was concentrated to dryness. The residue was purified by preparative TLC to give compound 29-5. LCMS: 485.2 [M + H] + .

[0476] Step 4: Preparation of Example 29

[0477] To a solution of compound 29-5 (28 mg, 0.058 mmol) in EtOH (3 mL), 0.6 mL of NaOH (1.0 M) was added. The mixture was stirred at 60 °C for 2 hours. The mixture was concentrated to dryness. The residue was purified by preparative HPLC to give Example 29. LCMS: 331.0 [M+H]+ ; 1 H NMR: (400MHz, CD3OD) δ9.10(s,1H),8.61(s,1H),8.03(s,1H),7.89(s,1H),7 .29(s,1H),6.95(s,1H),6.75(s,1H),2.61(s,3H),1.94(s,3H),1.90(s,3H).

[0478] Example 30: Preparation of 3-(4-amino-2-(2-methylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,4-dimethylphenol

[0479] Example 30 was synthesized from compound 30-1, which was prepared from similar starting materials according to the method described in Example 12.

[0480]

[0481] Step 1: Preparation of compound 30-2

[0482] Compound 30-1 (300.0 mg, 0.563 mmol) was added to a solution of DMSO (6.0 mL) with CuI (750.6 mg, 3.940 mmol), L-proline (453.6 mg, 3.940 mmol), and NaN3 (512.2 mg, 7.880 mmol). The reaction mixture was stirred at 140 °C under N2 for 18 hours. The reaction mixture was diluted with water (20 mL) and extracted with EA (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC to give compound 30-2. LCMS: 360.2 [M + H] + .

[0483] Step 2: Preparation of Example 30

[0484] BBr3 (0.1 mL, 0.111 mmol) was added to a solution of compound 30-2 (40 mg, 0.111 mmol) in DCM (1.5 mL). The mixture was stirred at room temperature for 2 hours. The reaction mixture was carefully added to MeOH (5 mL) while stirring, and the pH was adjusted to 7-8 with NH3 / MeOH. After filtration, the filtrate was concentrated to dryness. The residue was purified by silica gel column chromatography to give Example 30. LCMS: 346.2 [M+H] + ; 1H NMR: (400MHz, CD3OD) δ9.12(s,2H),7.46-7.21(m,3H),7.01(d,J=8.0Hz,1H),6.77(d,J=8.0Hz,1H),2.74(s,3H),1.96(s,3H),1.92(s,3H).

[0485] Example 31: Preparation of (R)-2,4-dimethyl-3-(2-(2-methylpyrimidin-5-yl)-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenol

[0486] Example 31 was prepared according to the following synthesis procedure.

[0487]

[0488] Step 1: Preparation of compound 31-1

[0489] To a solution of compound 10⁻² (4 g, 10.372 mmol) in CH₃CN (60 mL), NaI (7.77 g, 51.859 mmol) and acetyl chloride (2.212 mL, 31.115 mmol) were added. The mixture was stirred overnight at 80 °C under N₂. The reaction mixture was diluted with water (50 mL) and extracted with EA (100 mL × 3). The combined organic layers were washed with brine (300 mL), dried over Na₂SO₄, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to give compound 31⁻¹ (3.2 g, 6.707 mmol, 64.67%). LCMS: 476.8 [M + H] + .

[0490] Step 2: Preparation of compound 31-2

[0491] At 80 °C, CuI (239.50 mg, 1.258 mmol) and methyl 2,2-difluoro-2-fluoro-sulfonyl acetate (965.82 mg, 5.030 mmol) were added to a solution of compound 31-1 (600 mg, 1.258 mmol) in DMF (20 mL). The mixture was stirred at this temperature for 12 hours. The mixture was quenched with H₂O (20 mL) and extracted with EA (100 mL). The organic layer was dried over Na₂SO₄ and concentrated to dryness. The residue was purified by silica gel column chromatography to give compound 31-2 (450 mg, 1.073 mmol, 85.36%). LCMS: 418.9 [M+H] + .

[0492] Step 3: Preparation of Example 31

[0493] Example 31 was prepared from compound 31-2 according to the method described in Example 12. Spectral data of Example 31: LCMS: 399.1 [M+H] + ; 1 H NMR: (400MHz, DMSO-d6) δ12.97(s,1H),9.35(s,2H),9.22(s,1H),8.03(s,1H),7.34(s,1 H),6.94(d,J=8.0Hz,1H),6.78(d,J=8.0Hz,1H),2.69(s,3H),1.78(s,3H),1.71(s,3H).

[0494] Example 32: Preparation of (S)-5-(3-hydroxy-2,6-dimethylphenyl)-2-(2-methylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-4-carboxynitrile

[0495] Example 32 was prepared according to the following synthesis procedure.

[0496]

[0497] Step 1: Preparation of compound 32-1

[0498] Compound 31-1 (23.5 g, 49.255 mmol) was added to a solution of DMF (235 mL) containing Zn(CN)₂ (2.891 g, 24.627 mmol) and Pd(PPh₃)₄ (5.692 g, 4.925 mmol). The mixture was stirred at 110 °C for 16 h. The mixture was quenched with water (100 mL) and extracted with EtOAc (500 mL × 3). The organic layer was washed with brine, concentrated, and purified by silica gel column chromatography to give compound 32-1 (25 g, 35.983 mmol, 73.1%). LCMS: 378.1 [M + H] + .

[0499] Step 2: Preparation of compound 32-2

[0500] Compound 32-1 (10 g, 26.582 mmol) and compound 10-6 (10.5 g, 39.872 mmol) were added to a solution of dioxane (100 mL) and H₂O (20 mL) with Pd(dtbpf)Cl₂ (1.7 g, 2.658 mmol) and K₂CO₃ (11.0 g, 79.745 mmol). The mixture was stirred at 90 °C under N₂ for 16 hours. The mixture was concentrated. The residue was purified by silica gel column chromatography to give compound 32-2 (8.32 g, 19.299 mmol, 72.6%). LCMS: 432.3 [M+H]+ .

[0501] Step 3: Preparation of compound 32-3

[0502] At -78°C, LDA (62.57 mL, 125.142 mmol) was added dropwise to a solution of compound 32-2 (27 g, 62.571 mmol) in THF (500 mL). The mixture was stirred at -78°C for 30 min. Then, a solution of compound 12-5 (40.7 g, 125.142 mmol) in THF (5 mL) was added. The mixture was stirred at -78°C for 1 h, then warmed to room temperature for 16 h. The mixture was quenched with a saturated aqueous solution of NH4Cl (100 mL) and extracted with EA (50 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography to give compound 32-3 (18 g, 35.266 mmol, 56.4%). LCMS: 511.8 [M+H] + .

[0503] Step 4: Preparation of compound 32-4

[0504] A mixture of compound 32-3 (7 g, 13.715 mmol) and NaOH (1 M, 137.15 mL, 137.147 mmol) in EtOH (150 mL) and MeOH (150 mL) was heated to 60 °C for 2 hours. The mixture was cooled to 0 °C, adjusted to pH 6 with 1 N HCl, and extracted with EA (200 mL x 3). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography and further purified by SFC to give compound 32-4. LCMS: 357.9 [M + H] + . 1 H NMR: (400MHz, DMSO-d6) δ13.32 (s, 1H), 8.30-8.02 (m, 1H), 7.18 (d, J = 7.6Hz, 1H),7.06-6.92(m,1H),6.85(s,1H),3.83(s,3H),1.88(s,3H),1.80(s,3H).

[0505] Step 5: Preparation of Example 32

[0506] Example 32 was prepared from compound 32-4 according to the method described in Example 12. Spectral data of Example 32: LCMS: 356.2 [M+H] + ; 1H NMR: (400MHz, DMSO-d6) δ13.09(s,1H),9.37(s,3H),8.21(s,1H),7.43(s,1H),7. 01(d,J=8.2Hz,1H),6.85(d,J=8.2Hz,1H),2.70(s,3H),1.87(s,3H),1.79(s,3H).

[0507] Example 33: Preparation of (S)-3-chloro-5-(3-hydroxy-2,6-dimethylphenyl)-2-(2-methylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-4-carboxynitrile

[0508] The title compound was synthesized from compound 33-1, which was prepared from similar starting materials according to the method described in Example 32.

[0509]

[0510] Step 1: Preparation of compound 33-2

[0511] NCS (14.4 mg, 0.108 mmol) was added to a solution of compound 33-1 (40 mg, 0.108 mmol) in CH3CN (2 mL). The mixture was stirred at 40 °C for 16 hours. The mixture was diluted with H2O (15 mL) and extracted with DCM (10 mL × 3). The combined organic layers were washed with brine (10 mL × 3), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography to give compound 33-2. LCMS: 404.1 [M + H] + .

[0512] Step 2: Preparation of Example 33

[0513] BBr3 (186.2 mg, 0.743 mmol) was added to a solution of compound 33-2 (30 mg, 0.0743 mmol) in DCM (3 mL). The mixture was stirred at room temperature under N2 for 1 hour. The reaction mixture was quenched with MeOH (5 mL). The mixture was concentrated to dryness. The residue was purified by preparative HPLC to give Example 33. LCMS: 390.1 [M+H] + ; 1 H NMR: (400MHz, DMSO-d6) δ13.42(s,1H),9.40(s,1H),9.23(s,2H),8.33(s,1H),7. 02(d,J=8.4Hz,1H),6.86(d,J=8.4Hz,1H),2.74(s,3H),1.87(s,3H),1.79(s,3H).

[0514] Example 34: Preparation of 5-(3-hydroxy-2,6-dimethylphenyl)-2-(2-methylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-4-carboxamide

[0515] The title compound was synthesized from compound 33-1, which was prepared from similar starting materials according to the method described in Example 32.

[0516]

[0517] Step 1: Preparation of compound 34-1

[0518] Compound 33-1 (50 mg, 0.135 mmol) was added to a solution of MeOH (1 mL) and H₂O (0.5 mL) with H₂O₂ (85.72 mg, 0.677 mmol) and NaOH (16.24 mg, 0.406 mmol). The mixture was stirred at 40 °C for 16 hours. The mixture was filtered and concentrated to dryness. The residue was purified by silica gel column chromatography to give compound 34-1. LCMS: 388.4 [M+H] + .

[0519] Step 2: Preparation of Example 34

[0520] BBr3 (0.142 mL, 0.284 mmol) was added to a solution of compound 34-1 (22 mg, 0.057 mmol) in DCM (5 mL). The mixture was stirred at room temperature under N2 for 0.5 h. The reaction mixture was quenched with MeOH (5 mL). The mixture was concentrated to dryness. The residue was purified by preparative HPLC to give Example 34. LCMS: 374.3 [M+H] + ; 1 H NMR: (400MHz, DMSO-d6) δ12.51(s,1H),9.29(s,2H),9.05(s,1H),7.90(s,1H),7.48(s,1H),7.42(s,1 H),7.16(s,1H),6.86(d,J=8.0Hz,1H),6.71(d,J=8.0Hz,1H),2.68(s,3H),1.87(s,3H),1.79(s,3H).

[0521] The following Examples 35-81 were prepared using similar starting materials according to the methods described in Examples 32-34.

[0522]

[0523]

[0524]

[0525]

[0526]

[0527]

[0528]

[0529]

[0530]

[0531]

[0532]

[0533]

[0534]

[0535]

[0536]

[0537] Example 82: Preparation of (R)-3-chloro-5-(3-hydroxy-2,6-dimethylphenyl)-2-(2-(2-oxooxazolidine-3-yl)pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-4-carboxylonitrile

[0538] The title compound was prepared according to the following synthetic procedure.

[0539]

[0540] Step 1: Preparation of compound 82-3

[0541] Compound 82-2 (449.14 mg, 5.158 mmol) was added to a solution of compound 82-1 (1.1 g, 5.687 mmol) in NMP (20 mL), and the reaction mixture was stirred at 80 °C under N2 for 18 hours. The reaction mixture was diluted with water (100 mL) and extracted with EA (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography to give compound 82-3 (500 mg, 2.049 mmol, 37.74%). LCMS: 244.0 [M + H] + .

[0542] Step 2: Preparation of compound 82-4

[0543] Compound 82-3 (500 mg, 2.049 mmol) was added to a solution of dioxane (3 mL) with 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1,3,2-dioxacyclopentaborane (1.30 g, 5.122 mmol), KOAc (603.20 mg, 6.146 mmol), and Pd(dppf)Cl2 (224.86 mg, 0.307 mmol), and the reaction mixture was stirred at 90 °C under N2 for 3 hours. The reaction mixture was filtered and concentrated to dryness. The residue was purified by reversed-phase chromatography to give compound 82-4 (300 mg, 1.436 mmol, 70.07%). LCMS: 209.9 [M+H] + .

[0544] Step 3: Preparation of Example 82

[0545] Example 82 was prepared from compound 82-4 according to the method described in Examples 32-33. Spectral data of Example 82: LCMS: 461.0 [M+H] + ; 1 H NMR: (400MHz, DMSO-d6) δ13.40(s,1H),10.48(s,1H),9.42(d,J=12.0Hz,1H),9.29(d,J=8.8Hz,1H),9.26-9.20(m,1H),8.33(d,J =4.8Hz,1H),7.03(d,J=8.2Hz,1H),6.87(d,J=8.2Hz,1H),4.78(t,J=9.6Hz,2H),4.02(t,J=9.6Hz,2H),1.87(s,3H),1.79(s,3H).

[0546] Example 83: Preparation of (5R)-2-(2-(2,3-dihydroxypropoxy)pyrimidin-5-yl)-5-(3-hydroxy-2,6-dimethylphenyl)-1H-pyrrolo[2,3-b]pyridine-4-carboxynitrile

[0547] The title compound was prepared according to the following synthetic procedure.

[0548]

[0549] Step 1: Preparation of compound 83-2

[0550] At 0 °C, NaH (124.08 mg, 3.102 mmol) was added to a solution of compound 83-1 (512.43 mg, 3.877 mmol) in THF (10 mL) over 0.5 hours, followed by the addition of compound 82-1 (500 mg, 2.585 mmol). The mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with water (20 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to give compound 83-2 (550 mg, 1.902 mmol, 73.6%). LCMS: 291.1 [M+H] + .

[0551] Step 2: Preparation of compound 83-3

[0552] To a solution of compound 83-2 (300 mg, 1.038 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1,3,2-dioxacyclopentaborane (790.4 mg, 3.113 mmol) in dioxane (5 mL), KOAc (305.4 mg, 3.113 mmol) and Pd(dppf)Cl2 (75.9 mg, 0.104 mmol) were added. The reaction mixture was purged with gas three times. The reaction mixture was stirred overnight at 90 °C under N2. The reaction mixture was diluted with water (30 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine (50 mL × 2), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography to give compound 83-3 (130 mg, 1.200 mmol, 26.0%). LCMS: 255.2 [M+H] + .

[0553] Step 3: Preparation of Example 83

[0554] Example 83 was prepared from compound 83-3 according to the methods described in Examples 32-33. Spectral data of Example 83: LCMS: 432.2 [M+H] + ; 1H NMR: (400MHz, DMSO-d6) δ12.88(s,1H),9.37(s,1H),9.26(d,J=9.2Hz,2H),8 .17(s,1H),7.32(d,J=5.2Hz,1H),7.01(d,J=8.4Hz,1H),6.85(d,J=8.4Hz,1 H),4.98-4.94(m,1H),4.72(s,1H),4.43(dd,J=11.0,4.0Hz,1H),4.30(dd,J =11.0,6.4Hz,1H),3.81-3.76(m,1H),3.48(s,2H),1.87(s,3H),1.80(s,3H).

[0555] Example 84: Preparation of (R)-3-chloro-2-(2-(1,1-dioxothiomorpholinyl)pyrimidin-5-yl)-5-(3-hydroxy-2,6-dimethylphenyl)-1H-pyrrolo[2,3-b]pyridine-4-carboxylonitrile

[0556] The title compound was prepared according to the following synthetic procedure.

[0557]

[0558] Step 1: Preparation of compound 84-3

[0559] Compound 84-1 (500 mg, 2.079 mmol) was dissolved in ethanol (10 mL) and then reacted with compound 84-2 (843.1 mg, 6.237 mmol) and TEA (0.87 mL, 6.237 mmol). The reaction mixture was stirred at 80 °C under N2 for 4 hours. The reaction mixture was diluted with water (20 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography to give compound 84-3 (500 mg, 1.945 mmol, 93.55%). LCMS: 258.0 [M + H] + .

[0560] Step 2: Preparation of Example 84

[0561] The title compound was prepared from compound 84-3 according to the method described in Examples 32-33. Spectral data of Example 84: LCMS: 509.1 [M+H] + ; 1H NMR: (400MHz, DMSO-d6) δ9.38(s,1H),9.00(s,2H),8.23(s,1H),7.02(d,J=8.4Hz ,1H),6.85(d,J=8.4Hz,1H),4.33(s,4H),3.26(s,4H),1.87(s,3H),1.78(s,3H).

[0562] Example 85: Preparation of 2-(2-(difluoromethoxy)pyrimidin-5-yl)-5-(3-hydroxy-2,6-dimethylphenyl)-1H-pyrrolo[2,3-b]pyridine-4-carboxynitrile

[0563] The title compound was prepared according to the following synthetic procedure.

[0564]

[0565] Step 1: Preparation of compound 85-2

[0566] A solution of compound 85-1 (5 g, 18.860 mmol) in TFA (20 mL, 18.860 mmol) was stirred at 40 °C for 16 hours. The mixture was diluted with EA (100 mL) and water (100 mL) and stirred for 10 minutes. The mixture was filtered. The filtrate was dried under reduced pressure to give compound 85-2 (2 g, 11.429 mmol, 60.60%).

[0567] Step 2: Preparation of compound 85-4

[0568] Compound 85-3 (7.84 g, 51.432 mmol) was added to a solution of compound 85-2 (3 g, 17.144 mmol) and K2CO3 (7.11 g, 51.432 mmol) in DMF (40 mL) at 80 °C. The mixture was stirred at 100 °C for 2 hours. The mixture was filtered. The filtrate was diluted with EA (50 mL) and washed with brine (50 mL × 3). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography to give compound 85-4 (300 mg, 1.333 mmol, 7.78%).

[0569] Step 3: Preparation of compound 85-5

[0570] To a solution of compound 85-4 (65 mg, 0.289 mmol) in dioxane (2 mL), KOAc (85.06 mg, 0.867 mmol) and Pd(dppf)Cl2 (21.14 mg, 0.029 mmol) were added. The mixture was stirred at 100 °C for 1 hour. The reaction mixture was used directly in the next step. LCMS: 190.9 [M+H] + .

[0571] Step 4: Preparation of Example 85

[0572] Example 85 was prepared from compound 85-5 according to the method described in Examples 32-33. Spectral data of Example 85: LCMS: 408.0 [M+H] + ; 1 H NMR: (400MHz, CD3OD) δ9.26 (s, 2H), 8.19 (s, 1H), 7.69 (t, J = 72.0Hz, 1H), 7.28 ( s,1H),7.04(d,J=8.2Hz,1H),6.84(d,J=8.2Hz,1H),1.95(s,3H),1.90(s,3H).

[0573] Example 86: Preparation of 5-(3-hydroxy-2,6-dimethylphenyl)-2-(2-(2-hydroxypropyl-2-yl)pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-4-carboxynitrile

[0574] The title compound was prepared according to the following synthetic procedure.

[0575]

[0576] Step 1: Preparation of compound 86-2

[0577] Magnesium methane monobromide (18.431 mL, 18.431 mmol) was added to a solution of compound 86-1 (1 g, 4.608 mmol) in THF (10 mL). The mixture was stirred at 0 °C for 2 hours. The reaction mixture was diluted with water (20 mL) and extracted with EA (10 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography to give compound 86-2 (400 mg, 1.843 mmol, 39.99%). LCMS: 219.0 [M + H] + .

[0578] Step 2: Preparation of compound 86-3

[0579] To a solution of compound 86-2 (100 mg, 0.461 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1,3,2-dioxacyclopentaborane (175.48 mg, 0.691 mmol) in dioxane (4 mL), KOAc (45.21 mg, 0.461 mmol) and Pd(dppf)Cl2 (337.08 mg, 0.461 mmol) were added. The mixture was stirred at 100 °C for 2 hours. The mixture was used directly in the next step.

[0580] Step 3: Preparation of Example 86

[0581] The title compound was prepared from compound 86-3 according to the method described in Examples 32-33. Spectral data of Example 86: LCMS: 400.1 [M+H] + ; 1 H NMR: (400MHz, DMSO-d6) δ13.15(s,1H),9.46(s,2H),9.37(s,1H),8.23(s,1H),7.47(s,1H),7. 02(d,J=8.4Hz,1H),6.85(d,J=8.4Hz,1H),5.19(s,1H),1.88(s,3H),1.80(s,3H),1.55(s,6H).

[0582] Example 87: Preparation of (R)-2-(6-amino-5-ethynylpyridin-3-yl)-5-(3-hydroxy-2,6-dimethylphenyl)-1H-pyrrolo[2,3-b]pyridine-4-carboxynitrile

[0583] The title compound was prepared according to the following synthetic procedure.

[0584]

[0585] Step 1: Preparation of compound 87-3

[0586] Compound 87-1 (1.0 g, 3.346 mmol) and triethylamine (10 mL) in THF (10 mL) were reacted with CuI (12.7 mg, 0.067 mmol), bis(triphenylphosphine)palladium(II) chloride (26.0 mg, 0.033 mmol), and compound 87-2 (361.4 mg, 3.680 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was filtered and concentrated, and the residue was purified by silica gel column chromatography to give compound 87-3 (870 mg, 3.232 mmol). LCMS: 310.1 [M + CH3CN + H] + .

[0587] Step 2: Preparation of compound 87-4

[0588] Compound 87-3 (870 mg, 3.232 mmol) was added to a solution of DCM (25 mL) with di-tert-butyl dicarbonate (2.23 mL, 9.695 mmol) and DMAP (39.5 mg, 0.323 mmol). The mixture was stirred at room temperature for 3 hours. The mixture was concentrated and purified by silica gel column chromatography to give compound 87-4 (1220 mg, 2.599 mmol). 1 H NMR (400MHz, CDCl3) δ8.47(d,J=1.2Hz,1H),7.93(d,J=1.2Hz,1H),1.40(s,18H),0.22(d,J=0.6Hz,9H).

[0589] Step 3: Preparation of compound 87-5

[0590] A solution of compound 87-4 (1.35 g, 2.875 mmol), bis(pinacol)diboron (1.46 g, 5.751 mmol), potassium acetate (846.2 mg, 8.626 mmol), and Pd(dppf)Cl2 (210.4 mg, 0.288 mmol) in dioxane (15 mL) was stirred overnight at 90 °C. The mixture was filtered and concentrated, and the residue was purified by silica gel column chromatography to give compound 87-5 (920 mg, 2.118 mmol). LCMS: 435.3 [M+H] + .

[0591] Step 4: Preparation of Example 87

[0592] Example 87 was prepared from compound 87-5 according to the method described in Examples 32-33. Spectral data of Example 87: LCMS: 380.2 [M+H] + ; 1 H NMR: (400MHz, DMSO-d6) δ12.62(s,1H),9.61(s,1H),8.59(s,1H),8.34(s,1H),8.20(s,1H),7.97(s,1 H),7.00(d,J=7.4Hz,2H),6.81(d,J=8.2Hz,1H),6.50(s,2H),4.29(s,1H),1.81(s,3H),1.74(s,3H).

[0593] Example 88: Preparation of 3-(2-(2-(2-hydroxypropyl-2-yl)pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,4-dimethylphenol

[0594] The title compound was prepared according to the following synthetic procedure.

[0595]

[0596] Step 1: Preparation of compound 88-3

[0597] CsF (1.91 g, 12.576 mmol) and Pd(dppf)Cl2 (0.31 g, 0.419 mmol) were added to a solution of dioxane (20 mL) and water (4 mL) for compounds 88-1 (2 g, 4.192 mmol) and 88-2 (0.9 g, 4.192 mmol). The reaction mixture was stirred at 90 °C under N2 for 16 hours. The reaction mixture was diluted with EA (60 mL) and water (50 mL). The organic layer was separated, washed with brine, and concentrated under vacuum. The residue was purified by silica gel column chromatography to give compound 88-3 (360 mg, 0.739 mmol, 17.62%). LCMS: 489.0 [M+H] + .

[0598] Step 2: Preparation of compound 88-4

[0599] MeMgBr (3.7 mL, 0.739 mmol, 1 M) was added to a solution of compound 88-3 (360 mg, 0.739 mmol) in THF (5 mL) at 0 °C, and the reaction mixture was stirred at 0 °C for 3 hours. The reaction mixture was carefully added to water (30 mL) under ice bath conditions and extracted with EA (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na₂SO₄, filtered, and concentrated to dryness. The organic layers were separated and concentrated under vacuum. The residue was purified by silica gel column chromatography to give compound 88-4 (200 mg, 0.410 mmol, 55.55%). LCMS: 488.8 [M + H] + .

[0600] Step 3: Preparation of Example 88

[0601] Example 88 was prepared from compound 88-4 according to the method described in Examples 32-33. Spectral data of Example 88: LCMS: 375.1 [M+H] + ; 1H NMR: (400MHz, DMSO-d6) δ12.45(s,1H),9.35(s,2H),9.15(s,1H),8.00(s,1H),7.75(s,1H),7.16(s,1 H),6.94(d,J=8.0Hz,1H),6.76(d,J=8.0Hz,1H),5.12(s,1H),1.89(s,3H),1.82(s,3H),1.54(s,6H).

[0602] Example 89: Preparation of 5-(3-hydroxy-2,6-dimethylphenyl)-2-(5-(4-hydroxypiperidin-1-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-4-carboxynitrile

[0603] The title compound was prepared according to the following synthetic procedure.

[0604]

[0605] Step 1: Preparation of compound 89-3

[0606] Compound 89-2 (485 mg, 4.219 mmol) and K₂CO₃ (874 mg, 6.33 mmol) were added to a solution of compound 89-1 (500 mg, 2.11 mmol) in DMF (10 mL) at room temperature. The mixture was stirred at 120 °C for 16 hours. The mixture was quenched with H₂O (50 mL) and extracted with EA (60 mL × 3). The organic layer was dried over Na₂SO₄ and concentrated to dryness. The residue was purified by silica gel column chromatography to give compound 89-3 (120 mg, 0.443 mmol, 21%). LCMS: 273.1 [M + H] + .

[0607] Step 2: Preparation of compound 89-4

[0608] To a solution of compound 89-3 (50 mg, 0.185 mmol) in dioxane (1 mL), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1,3,2-dioxacyclopentaborane (140 mg, 0.554 mmol), KOAc (54 mg, 0.554 mmol), and Pd(dppf)Cl2 (18 mg, 0.024 mmol) were added. The mixture was stirred at 90 °C under N2 for 1.5 h. The mixture was used for the next step. LCMS: 237.1 [M+H] + .

[0609] Step 3: Preparation of Example 89

[0610] Example 89 was prepared from compound 89-4 according to the method described in Examples 32-33. Spectral data of Example 89: LCMS: 440.3 [M+H] + ; 1 H NMR: (400MHz, CD3OD) δ8.45(s,1H),8.20(s,1H),8.03(s,1H),7.81(s,1H),7.10(s,1H),6.92(d,J=8.4Hz,1H),6.72(d,J=8 .4Hz,1H),3.78-3.66(m,3H),3.02(t,J=10.0Hz,2H),1.94(d,J=13.1Hz,2H),1.84(s,3H),1.79(s,3H),1.62-1.57(m,2H).

[0611] Example 90: Preparation of 5-(2-ethyl-3-hydroxy-6-methylphenyl)-2-(2-methylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-4-carboxynitrile

[0612] The title compound was prepared according to the following synthetic procedure.

[0613]

[0614] Step 1: Preparation of compound 90-2

[0615] Compound 90-1 (8.0 g, 39.594 mmol) and ethylboric acid (5.9 g, 79.188 mmol) were reacted with Pd(dppf)Cl2 (2.9 g, 3.959 mmol) and K2CO3 (16.4 g, 118.782 mmol) in a solution of dioxane (100 mL) and H2O (20 mL). The mixture was stirred at 100 °C for 12 hours. The reaction mixture was diluted with water (100 mL) and extracted with EA (100 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to give compound 90-2 (2.4 g, 15.872 mmol, 40.09%). LCMS: 152.2 [M+H] + .

[0616] Step 2: Preparation of compound 90-3

[0617] NIS (8.0 g, 46.293 mmol) was added to a solution of compound 90-2 (7.0 g, 46.293 mmol) in DMF (20 mL). The mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with EA (30 mL) and washed with brine (20 mL × 3). The organic layer was dried over Na₂SO₄, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to give compound 90-3 (8 g, 28.869 mmol, 62.36%). LCMS: 278.2 [M + H] + .

[0618] Step 3: Preparation of compound 90-4

[0619] Compound 90-3 (850 mg, 3.067 mmol) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxaborane (770 mg, 6.135 mmol) were added to a solution of dioxane (20 mL) and H₂O (4 mL) along with K₂CO₃ (1271 mg, 9.202 mmol) and Pd(dtbpf)Cl₂ (201 mg, 0.307 mmol). The mixture was stirred at 100 °C for 12 hours. The reaction mixture was diluted with water (20 mL) and extracted with EA (20 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na₂SO₄, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to give compound 90-4 (400 mg, 2.421 mmol, 78.92%). LCMS: 166.3 [M + H] + .

[0620] Step 4: Preparation of compound 90-5

[0621] At 0 °C, a solution of NaNO2 (292 mg, 4.236 mmol) in H2O (1 mL) was added dropwise to a solution of AcOH (8 mL) and HBr (1 mL). The mixture was stirred at 0 °C for 2 hours. Then, a solution of CuBr (608 mg, 4.236 mmol) in HBr (1 mL) was added. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water (10 mL) and extracted with EA (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to give compound 90-5 (300 mg, 1.309 mmol, 30.91%). 1H NMR: (400MHz, DMSO-d6) δ7.17 (t, J = 9.8 Hz, 1H), 6.95-6.86 (m, 1H), 3.82-3.75 (m, 3H), 2.82-2.70 (m, 2H), 2.34-2.25 (m, 3H), 1.11-0.98 (m, 3H).

[0622] Step 5: Preparation of compound 90-6

[0623] To a solution of compound 90-5 (440 mg, 1.920 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1,3,2-dioxacyclopentaborane (732 mg, 2.881 mmol) in DMF (5 mL), potassium acetate (565 mg, 5.761 mmol) and Pd(dppf)Cl2 (140 mg, 0.192 mmol) were added. The mixture was stirred at 130 °C for 12 hours. The reaction mixture was diluted with EA (20 mL) and washed with brine (10 mL × 3). The organic layer was dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by preparative TLC to give compound 90-6 (260 mg, 0.941 mmol, 49.02%). 1 H NMR: (400MHz, DMSO-d6) δ6.92(d,J=8.4Hz,1H),6.82(d,J=8.4Hz,1H),3.72(s ,3H),2.56(q,J=7.4Hz,2H),2.22(s,3H),1.32(s,12H),1.04(t,J=7.4Hz,3H).

[0624] Step 6: Preparation of Example 90

[0625] The title compound is prepared from compound 90-6 according to the method described in Examples 32-33.

[0626] Spectral data of Example 90: LCMS: 370.4 [M+H] + .

[0627] Example 91: Preparation of (R)-5-(2-ethyl-3-hydroxy-6-methylphenyl)-2-(2-methylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-4-carboxynitrile

[0628] Step 1: Preparation of Example 91

[0629] The title compound was isolated from Example 90 by preparative SFC. LCMS: 411.2 [M+H+CH3CN]+ ; 1 HNMR: (400MHz, DMSO-d6) δ13.08(s,1H),9.37(s,2H),9.33(s,1H),8.22(s,1H),7.43(s,1H),7.01(d,J =8.2Hz,1H),6.85(d,J=8.2Hz,1H),2.70(s,3H),2.51-2.19(m,2H),1.84(s,3H),0.87(t,J=7.4Hz,3H).

[0630] Example 92: Preparation of 2-(4-amino-2-methylpyrimidin-5-yl)-5-(3-hydroxy-2,6-dimethylphenyl)-1H-pyrrolo[2,3-b]pyridine-4-carboxynitrile

[0631] The title compound was prepared according to the following synthetic procedure.

[0632]

[0633] Step 1: Preparation of compound 92-2

[0634] Add B2Pin2 (405 mg, 1.60 mmol), KOAc (156 mg, 1.60 mmol), and Pd(dppf)Cl2 (51 mg, 0.07 mmol) to a solution of compound 92-1 (100 mg, 0.53 mmol) in dioxane (2 mL). Stir the mixture at 100 °C for 3 hours. Use the mixture directly in the next step. LCMS: 154.2 [M+H] + .

[0635] Step 2: Preparation of compound 92-4

[0636] Compound 92-3 (148 mg, 0.266 mmol), CsF (121 mg, 0.80 mmol), BrettphPdG3 (30 mg, 0.03 mmol), and water (0.4 mL) were added to the reaction mixture from step 1, and the mixture was stirred at 75 °C for 2 hours. The mixture was extracted with DCM (30 mL × 3). The combined organic phases were washed with brine (40 mL), dried over Na2SO4, filtered, concentrated, and purified by preparative TLC to give compound 92-4 (20 mg, 0.037 mmol). LCMS: 539.3 [M + H] + .

[0637] Step 3: Preparation of Example 92

[0638] Example 92 was prepared from compound 92-4 according to the method described in Examples 32-33. Spectral data of Example 92: LCMS: 371.2 [M+H] + ; 1 H NMR: (400MHz, DMSO-d6) δ9.33(s,1H),8.45-8.39(m,3H),8.09(s,1H),7.17-7.03(m,1H),7.0 0(d,J=8.0Hz,1H),6.88(s,1H),6.83(d,J=8.2Hz,1H),2.40(s,3H),1.87(s,3H),1.79(s,3H).

[0639] Example 93: Preparation of (R)-5-(3-hydroxy-2,6-dimethylphenyl)-2-(2-(pyrrolidone-1-ylmethyl)pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-4-carboxynitrile

[0640] The title compound was prepared according to the following synthetic procedure.

[0641]

[0642] Step 1: Preparation of compound 93-2

[0643] To a solution of compound 93-1 (650 mg, 2.580 mmol) in CH3CN (10 mL), tetrahydropyrrole (0.4 mL, 5.161 mmol) and K2CO3 (1069.8 mg, 7.741 mmol) were added. The mixture was stirred at room temperature for 4 hours. The mixture was concentrated. The residue was purified by silica gel column chromatography to give compound 93-2 (520 mg, 2.148 mmol, 83.23%). LCMS: 244.0 [M+H] + .

[0644] Step 2: Preparation of compound 93-3

[0645] Compound 93-2 (470 mg, 1.941 mmol) was added to a solution of dioxane (8 mL) with 1,1,1,2,2,2-hexabutyldistinane (2252.2 mg, 3.882 mmol), LiCl (164.6 mg, 3.882 mmol), and Pd(PPh3)4 (224.3 mg, 0.194 mmol). The mixture was stirred at 100 °C for 4 hours under a nitrogen atmosphere. The mixture was concentrated. The residue was purified by silica gel column chromatography to give compound 93-3 (530 mg, 1.172 mmol, 60.37%). LCMS: 454.4 [M+H] + .

[0646] Step 3: Preparation of compound 93-4

[0647] Compound 93-3 (253.9 mg, 0.561 mmol), LiCl (11.9 mg, 0.281 mmol), and Pd(PPh3)4 (32.4 mg, 0.028 mmol) were added to a solution of compound 32-4 (100 mg, 0.281 mmol) in dioxane (5 mL). The mixture was added at 100 °C for 16 hours under a nitrogen atmosphere. The reaction mixture was diluted with DCM (30 mL) and washed with brine (10 mL × 3). The organic layer was dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to give compound 93-4. LCMS: 439.5 [M + H] + .

[0648] Step 4: Preparation of Example 93

[0649] BBr3 (134.3 mg, 0.536 mmol) was added to a solution of compound 93-4 (47 mg, 0.107 mmol) in DCM (4 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with MeOH (5 mL). The mixture was concentrated to dryness and purified by preparative HPLC to obtain Example 93. LCMS: 425.4 [M+H] + ; 1 H NMR: (400MHz, DMSO-d6) δ13.14(s,1H),9.44(s,2H),9.37(s,1H),8.22(s,1H),8.18(s,1H),7.47(s,1H),7.02(d,J= 8.4Hz,1H),6.85(d,J=8.4Hz,1H),3.93(s,2H),2.65(t,J=5.6Hz,4H),1.87(s,3H),1.80(s,3H),1.76-1.70(m,4H).

[0650] The following Examples 94-95 were prepared using similar starting materials according to the method described in Example 93.

[0651]

[0652] Example 96: Preparation of (R)-5-(3-hydroxy-2,6-dimethylphenyl)-2-(2-(methyl(oxecyclobutane-3-yl)amino)pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-4-carboxynitrile

[0653] The title compound was synthesized by 96-1, which was prepared using similar starting materials according to the method described in Examples 32-33.

[0654]

[0655] Step 1: Preparation of Example 96

[0656] Compound 96-2 (19 mg, 0.21 mmol) and TEA (32 mg, 0.32 mmol) were added to a solution of compound 96-1 (40 mg, 0.11 mmol) in DMF (1 mL), and the reaction mixture was stirred overnight at 50 °C. The mixture was purified by preparative HPLC and dried to give Example 96. LCMS: 427.1 [M+H] + ; 1 H NMR: (400MHz, DMSO-d6) δ12.19(s,1H),9.30(s,1H),8.40(s,1H),7.87(s,1H),7.43(s,1H),6.97(d,J=8.0Hz,1H),6.81(d,J=8.4Hz,1H),6.17( s,1H),4.18(d,J=11.6Hz,1H),4.04(d,J=12.0Hz,1H),3.62(s,1H),3.5 1(s,1H),3.20(d,J=8.8Hz,1H),2.84(s,3H),1.85(s,3H),1.78(s,3H).

[0657] The following Examples 97-103 were prepared using similar starting materials according to the method described in Example 96.

[0658]

[0659]

[0660]

[0661]

[0662] Example 104: Preparation of (R)-5-(3-hydroxy-2,6-dimethylphenyl)-2-(2-(prop-1-yn-1-yl)pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-4-carboxylonitrile

[0663] The title compound was synthesized from compound 96-1, which was prepared from similar starting materials according to the method described in Example 32.

[0664]

[0665] Step 1: Preparation of Example 104

[0666] A mixture of compound 96-1 (30 mg, 0.080 mmol), compound 104-1 (0.16 mL, 1 M DMF solution, 0.160 mmol), CuI (2.5 mg, 0.008 mmol), bis(triphenylphosphine)palladium(II) chloride (6.2 mg, 0.008 mmol), and TEA (24.2 mg, 0.239 mmol) in THF (3 mL) was stirred at 50 °C for 16 hours. The mixture was concentrated and purified by preparative HPLC to obtain Example 104. LCMS: 380.2 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ13.12(s,1H),9.43(s,2H),9.38(s,1H),8.23(s,1H),7.52(s,1 H),7.02(d,J=8.3Hz,1H),6.85(d,J=8.2Hz,1H),2.16(s,3H),1.87(s,3H),1.80(s,3H).

[0667] Example 105: Preparation of (R)-5-(4-cyano-5-(3-hydroxy-2,6-dimethylphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)pyrimidine-2-carboxamide

[0668] The title compound was synthesized from compound 105-1, which was prepared from similar starting materials according to the method described in Example 32.

[0669]

[0670] Step 1: Preparation of compound 105-2

[0671] Compound 105-1 (120.0 mg, 0.308 mmol) was added to a solution of DMSO (1.5 mL) with 4-azabicyclo[2.2.2]octane-7-ol (7.8 mg, 0.062 mmol) and KCN (40.1 mg, 0.616 mmol). The mixture was stirred at 50 °C for 1 hour. The reaction mixture was diluted with water (20 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to give compound 105-2. LCMS: 381.2 [M + H] + .

[0672] Step 2: Preparation of compound 105-3

[0673] To a solution of compound 105-2 (45.0 mg, 0.118 mmol) in MeOH (3.0 mL), NaOH (14.2 mg, 0.355 mmol) and H₂O₂ (12.1 mg, 0.355 mmol) were added. The mixture was stirred overnight at room temperature. The mixture was concentrated, and the residue was washed with water. The residue was purified by preparative TLC to give compound 105-3. LCMS: 399.2 [M+H] + .

[0674] Step 3: Preparation of Example 105

[0675] At 0 °C, BBr3 (0.03 mL, 0.276 mmol) was added to a solution of compound 105-3 (22.0 mg, 0.055 mmol) in DCM (3.0 mL). The mixture was stirred at 0 °C for 1 hour. While stirring, MeOH (2 mL) was carefully added to the reaction mixture, and the mixture was diluted with water (10 mL). The pH of the mixture was then adjusted to 8 with NaHCO3. The mixture was extracted with DCM (20 mL) and EA (20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by preparative TLC to give Example 105. LCMS: 385.2 [M+H] + ; 1 H NMR: (400MHz, DMSO-d6) δ13.46(s,1H),9.67(s,2H),9.54(s,1H),8.36(s,1H),8.27(s,1H),7. 93(s,1H),7.63(s,1H),7.02(d,J=8.4Hz,1H),6.93(d,J=8.4Hz,1H),1.89(s,3H),1.81(s,3H).

[0676] Example 106: Preparation of (R)-2-(2-aminopyrimidin-5-yl)-5-(3-hydroxy-2,6-dimethylphenyl)-3-methyl-1H-pyrrolo[2,3-b]pyridine-4-carboxynitrile

[0677] The title compound was prepared according to the following synthetic procedure.

[0678]

[0679] Step 1: Preparation of compound 106-1

[0680] NBS (44.9 mg, 0.252 mmol) was added to a solution of compound 39 (100.0 mg, 0.281 mmol) in CH3CN (5 mL) at 0 °C. The mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (30 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to give compound 106-1 (120.0 mg, 0.276 mmol, 98.2%). LCMS: 435.2 [M + H] + .

[0681] Step 2: Preparation of compound 106-2

[0682] Compound 106-1 (120.0 mg, 0.276 mmol) was added to a solution of DMF (6 mL) with (Boc)₂O (60.2 mg, 0.276 mmol), DMAP (1.7 mg, 0.014 mmol), and TEA (41.8 mg, 0.1414 mmol). The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (30 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine (50 mL × 3), dried over Na₂SO₄, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to give compound 106-2. LCMS: 535.2 [M + H] + .

[0683] Step 3: Preparation of compound 106-3

[0684] Compound 13-3 (32.9 mg, 0.262 mmol), K3PO4 (83.4 mg, 0.393 mmol), and Pd(dtbpf)Cl2 (8.6 mg, 0.0132 mmol) were added to a solution of compound 106-2 (70.0 mg, 0.131 mmol) in H2O (0.5 mL) and dioxane (2.5 mL). The mixture was stirred at 80 °C for 6 hours. The reaction mixture was diluted with water (30 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to give compound 106-3. LCMS: 471.4 [M + H] + .

[0685] Step 4: Preparation of Example 106

[0686] The mixture of compound 106-3 (43.0 mg, 0.0914 mmol) in HCl-dioxane (2.5 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated to dryness and purified by preparative HPLC to give Example 106. LCMS: 371.2 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ12.42(s,1H),9.33(s,1H),8.59(s,2H),8.06(s,1H),7.09(s,2 H),7.00(d,J=8.4Hz,1H),6.83(d,J=8.4Hz,1H),2.53(s,3H),1.86(s,3H),1.79(s,3H).

[0687] The following Examples 107-108 were prepared using similar starting materials according to the method described in Example 106.

[0688]

[0689]

[0690] Example 109: Preparation of (S)-3-ethynyl-5-(3-hydroxy-2,6-dimethylphenyl)-2-(2-methylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-4-carboxynitrile

[0691] The title compound was prepared according to the following synthetic procedure.

[0692]

[0693] Step 1: Preparation of compound 109-1

[0694] At 0 °C, NIS (94.5 mg, 0.420 mmol) was added to a solution of compound 33-1 (141 mg, 0.382 mmol) in CAN / DMF (1:1, 5 mL). The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with EA (60 mL) and washed with brine (30 mL × 3). The organic layer was dried over Na₂SO₄, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to give compound 109-1. LCMS: 496.4 [M + H] + .

[0695] Step 2: Preparation of compound 109-2

[0696] BBr3 (215.5 mg, 0.860 mmol) was added to a solution of compound 109-1 (85 mg, 0.172 mmol) in DCM (5 mL). The mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The mixture was quenched with MeOH (5 mL) and concentrated. The residue was purified by silica gel column chromatography to give compound 109-2. LCMS: 482.1 [M+H] + .

[0697] Step 3: Preparation of compound 109-3

[0698] Compound 109-2 (100.0 mg, 0.208 mmol) was added to a solution of compound 109-2 in DMF (3 mL) along with compound 87-2 (61.2 mg, 0.623 mmol), CuI (7.9 mg, 0.042 mmol), PdCl2(PPh3)2 (16.2 mg, 0.021 mmol), and TEA (210.3 mg, 2.078 mmol). The mixture was stirred at 80 °C for 2 hours. The mixture was purified by preparative HPLC to give compound 109-3. LCMS: 452.5 [M+H] + .

[0699] Step 4: Preparation of Example 109

[0700] K₂CO₃ (18.4 mg, 0.133 mmol) was added to a solution of compound 10⁹-3 (20.0 mg, 0.0443 mmol) in MeOH (3 mL). The mixture was stirred at room temperature for 16 hours. The mixture was purified by preparative HPLC to give Example 10⁹. LCMS: 380.1 [M + H₂] + ; 1 H NMR (400MHz, CD3OD) δ9.44(s,2H),8.24(s,1H),7.02(d,J=8.4Hz,1H),6.83(d,J=8.4Hz,1H),4.00(s,1H),2.80(s,3H),1.94(s,3H),1.89(s,3H).

[0701] The following Examples 110-111 were prepared using similar starting materials according to the method described in Example 109.

[0702]

[0703] Example 112: Preparation of 5-(3-hydroxy-2,6-dimethylphenyl)-2-(2-methylpyrimidin-5-yl)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-4-carboxynitrile

[0704] The title compound was prepared according to the following synthetic procedure.

[0705]

[0706] Step 1: Preparation of compound 112-1

[0707] At room temperature, Cu (12.84 mg, 0.202 mmol) and diphenyl(trifluoromethyl)sulfonium (204.20 mg, 0.505 mmol) were added to a solution of compound 109-1 (50 mg, 0.101 mmol) in DMF (2 mL). The mixture was stirred at 60 °C for 24 hours. The mixture was quenched with H₂O (5 mL) and extracted with EA (20 mL). The organic layer was dried over Na₂SO₄ and concentrated to dryness. The residue was purified by silica gel column chromatography to give compound 112-1. LCMS: 438.4 [M+H] + .

[0708] Step 2: Preparation of Example 112

[0709] BBr3 (0.12 mL, 0.251 mmol) was added to a solution of compound 112-1 (22 mg, 0.050 mmol) in DCM (5 mL). The mixture was stirred at room temperature under N2 for 0.5 h. The reaction mixture was quenched with MeOH (5 mL). The mixture was concentrated to dryness. The residue was purified by preparative HPLC to give Example 112. LCMS: 424.1 [M+H] + ; 1 H NMR: (400MHz, DMSO-d6) δ9.40(s,1H),9.00(s,2H),8.39(s,1H),7.02(d,J=8.4Hz,1H),6.85(d,J=8.4Hz,1H),2.74(s,3H),1.85(s,3H),1.78(s,3H).

[0710] Example 113: Preparation of 5-(3-hydroxy-2,6-dimethylphenyl)-2-(2-methylpyrimidin-5-yl)-3-(phenylthio)-1H-pyrrolo[2,3-b]pyridine-4-carboxynitrile

[0711] The title compound was prepared according to the following synthetic procedure.

[0712]

[0713] Step 1: Preparation of compound 113-2

[0714] Compound 113-1 (200 mg, 0.353 mmol) was added to a solution of DMF (10 mL) with sodium thiophene (69.8 mg, 0.529 mmol), CuI (67.1 mg, 0.353 mmol), ethylene glycol (43.8 mg, 0.706 mmol), and K₂CO₃ (146.3 mg, 1.059 mmol). The mixture was stirred at 80 °C for 3 hours. The reaction mixture was filtered. The filtrate was concentrated to dryness. The residue was purified by silica gel column chromatography to give compound 113-2 (170 mg, 0.310 mmol, 87.75%) as a yellow solid. LCMS: 549.1 [M+H] + .

[0715] Step 2: Preparation of Example 113

[0716] Example 113 was prepared from compound 113-2 according to the method described in Examples 32-33. Spectral data of Example 113: LCMS: 464.2 [M+H] + ; 1 H NMR: (400MHz, CD3OD) δ9.15(s,2H),8.26(s,1H),7.21(t,J=7.6Hz,2H),7.11(d,J=7.3Hz,1H),7.03( d,J=7.5Hz,2H),6.97(d,J=8.2Hz,1H),6.78(d,J=8.2Hz,1H),2.75(s,3H),1.86(s,3H),1.81(s,3H).

[0717] Example 114: Preparation of 2,4-dimethyl-3-(2-(2-methylpyrimidin-5-yl)-3H-imidazo[4,5-b]pyridin-6-yl)phenol

[0718] The title compound was prepared according to the following synthetic procedure.

[0719]

[0720] Step 1: Preparation of compound 114-2

[0721] Compound 114-1 (500 mg, 2.659 mmol) was added to a solution of dioxane (5 mL) and water (1 mL) along with compound 10-6 (836.5 mg, 3.191 mmol), Pd(dppf)Cl2 (194.6 mg, 0.266 mmol), and K2CO3 (1.102 g, 7.977 mmol). The mixture was stirred at 90 °C under N2 for 2 hours. The reaction mixture was diluted with water (20 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to give compound 114-2. LCMS: 244.2 [M + H] + .

[0722] Step 2: Preparation of compound 114-4

[0723] Compound 114-3 (75.29 mg, 0.616 mmol) was added to a solution of compound 114-2 (150 mg, 0.616 mmol) in AcOH (5 mL). The mixture was stirred at 90 °C for 1 hour under N2. The reaction mixture was diluted with water (20 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to give compound 114-4. LCMS: 346.0 [M + H] + .

[0724] Step 3: Preparation of Example 114

[0725] BBr3 (1.16 g, 4.63 mmol) was added to a solution of compound 114-4 (160 mg, 0.463 mmol) in DCM (3 mL). The mixture was stirred at room temperature under N2 for 2 hours. The reaction mixture was diluted with water (15 mL) and extracted with EA (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by preparative TLC to give Example 114. LCMS: 332.1 [M + H] + ; 1 H NMR: (400MHz, DMSO-d6) δ9.45(s,2H),8.19(s,1H),7.94(d,J=1.4Hz,1H),6.95(s,1H),6.79(d,J=8.2Hz,1H),2.74(s,3H),1.89(s,3H),1.82(s,3H).

[0726] Example 115: Preparation of 3-(2-(2-(cyclopropylamino)thiazo-5-yl)-3H-imidazo[4,5-b]pyridin-6-yl)-2,4-dimethylphenol

[0727] The title compound was prepared according to the following synthetic procedure.

[0728]

[0729] Step 1: Preparation of compound 115-2

[0730] Compound 115-1 (73 mg, 0.49 mmol) was added to a solution of compound 114-2 (100 mg, 0.41 mmol) in AcOH (1.5 mL). The mixture was stirred at 90 °C under N2 for 20 hours. The reaction mixture was diluted with EA (10 mL) and brine (10 mL). The aqueous layer was extracted with EA (10 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TCL to give compound 115-2. LCMS: 371.0 [M + H] + .

[0731] Step 2: Preparation of compound 115-4

[0732] Compound 115-3 (1 mL) was added to a solution of compound 115-2 (40 mg, 0.11 mmol) in CH3CN (1.5 mL). The mixture was stirred at 100 °C for 3 hours. The reactants were dried to give the crude compound 115-4 (titled). LCMS: 392.1 [M+H] + .

[0733] Step 3: Preparation of Example 115

[0734] Compound 115-4 (55 mg, 0.14 mmol) was added to a solution of DCM (2 mL) with BBr3 (0.1 mL), and the reaction mixture was stirred at room temperature under N2 for 0.5 h. The reaction mixture was quenched with MeOH (3 mL) and NH3 / MeOH (3 mL). The residue was purified by preparative HPLC to give Example 115. LCMS: 378.1 [M+H] + ; 1H NMR: (400MHz, DMSO-d6) δ13.33(s,1H),9.18(s,1H),8.57(s,1H),7.98(s,1H),7.92(s,1H),7.61(s,1H),6.93(d,J=8 .2Hz,1H),6.76(d,J=8.2Hz,1H),2.63-2.59(m,1H),1.88(s,3H),1.81(s,3H),0.93-0.76(m,2H),0.62-0.57(m,2H).

[0735] Example 116: Preparation of (S)-2-(2-aminopyrimidin-5-yl)-6-(3-hydroxy-2,6-dimethylphenyl)-3H-imidazo[4,5-b]pyridine-7-carboxynitrile

[0736] The title compound was prepared according to the following synthetic procedure.

[0737]

[0738] Step 1: Preparation of compound 116-2

[0739] Fe (11.0 g, 198.02 mmol) and AcOH (22.67 mL, 396.040 mmol) were added to a solution of compound 116-1 (5 g, 19.802 mmol) in EtOH (150 mL). The mixture was stirred at 90 °C for 2 h. The reaction mixture was carefully added to ice water (150 mL) while stirring, and the pH was adjusted to 8 with NaOH (4 M aqueous solution). The mixture was extracted with DCM (200 mL × 3). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to give compound 116-2 (3.5 g, 15.730 mmol, 79.4%). LCMS: 221.9 [M + H] + .

[0740] Step 2: Preparation of compound 116-3

[0741] Compound 116-2 (900 mg, 4.045 mmol) was added to a solution of dioxane (22.5 mL) and H₂O (4.5 mL) along with compound 10-6 (3.182 g, 12.135 mmol), Pd(dtbpf)Cl₂ (264.1 mg, 0.404 mmol), and K₂CO₃ (1.677 g, 12.135 mmol). The mixture was stirred at 100 °C for 16 hours. The reaction mixture was diluted with water (50 mL) and extracted with EA (40 mL × 3). The combined organic layers were washed with brine (100 mL), dried over Na₂SO₄, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to give compound 116-3 (240 mg, 0.864 mmol, 21.4%). LCMS: 278.2 [M + H] + .

[0742] Step 3: Preparation of compound 116-5

[0743] Compound 116-4 (102.6 mg, 0.720 mmol) and AcOH (2 mL) were added to a solution of compound 116-3 (200 mg, 0.720 mmol) in dioxane (4 mL). The mixture was stirred at 75 °C for 8 hours. The reaction mixture was carefully added to ice water (20 mL) while stirring, and the pH was adjusted to 8 with NaHCO3 (saturated aqueous solution). The mixture was extracted with EA (20 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to give compound 116-5 (67 mg, 0.167 mmol, 23.2%). LCMS: 400.1 [M + H] + .

[0744] Step 4: Preparation of compound 116-6

[0745] A solution of compound 116-5 (60 mg, 0.150 mmol) in NH3 / EtOH (1.5 mL) was stirred at 70 °C for 48 hours. The reaction mixture was diluted with water (10 mL) and extracted with EA (10 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to give compound 116-6. LCMS: 381.2 [M + H] + .

[0746] Step 5: Preparation of compound 116-7

[0747] BBr3 (0.4 mL) was added to a solution of compound 116-6 (45 mg, 0.118 mmol) in DCM (1 mL). The mixture was stirred at room temperature under N2 for 2 hours. The reaction mixture was carefully added to MeOH (10 mL). The pH of the mixture was then adjusted to 7-8 with TEA. After filtration, the filtrate was concentrated to dryness. The residue was purified by silica gel column chromatography to give compound 116-7. LCMS: 367.1 [M+H] + .

[0748] Step 6: Preparation of Example 116

[0749] Compound 116-7 (21 mg, 0.057 mmol) was added to a solution of DMA (1 mL) with Zn (3.7 mg, 0.057 mmol), Zn(CN)₂ (6.7 mg, 0.057 mmol), Pd(dppf)Cl₂·CH₂Cl₂ (46.8 mg, 0.057 mmol), and Pd₂(dba)₃ (52.4 mg, 0.057 mmol). The mixture was stirred at 140 °C under N₂ for 18 hours. The residue was purified by preparative HPLC and further purified by SFC to obtain Example 116. LCMS: 358.3 [M+H] + ; 1 H NMR: (400MHz, CD3OD) δ9.09(s,2H),8.19(s,1H),7.02(d,J=8.2Hz,1H),6.83(d,J=8.2Hz,1H),1.94(s,3H),1.89(s,3H).

[0750] Example 117: Preparation of (S)-5-(3-hydroxy-2,6-dimethylphenyl)-2-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-4-carboxynitrile

[0751] The title compound was prepared according to the following synthetic procedure.

[0752]

[0753] Step 1: Preparation of compound 117-3

[0754] Cs₂CO₃ (4.2 g, 12.887 mmol) was added to a solution of compound 117-1 (1 g, 5.155 mmol) and compound 117-2 (1.2 g, 10.825 mmol) in DMF (10 mL). The mixture was stirred in a microwave at 140 °C for 2.5 h. The reaction mixture was diluted with EA (20 mL) and washed with brine (20 mL × 3). The organic layer was dried over Na₂SO₄, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to give compound 117-3. LCMS: 266.6 [M + H] + .

[0755] Step 2: Preparation of Example 117

[0756] Compound 117-3 (40 mg, 0.117 mmol) and compound 117-4 (62 mg, 0.234 mmol) were added to a solution of H₂O (0.2 mL) and dioxane (1 mL) with K₂CO₃ (49 mg, 0.351 mmol) and Pd(dtbpf)Cl₂ (8.0 mg, 0.012 mmol). The reaction mixture was diluted with water (10 mL) and extracted with EA (10 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated to dryness. The residue was purified by preparative TLC to give Example 117. LCMS: 402.2 [M + H] + ; 1 H NMR: (400MHz, DMSO-d6) δ12.65(s,1H),9.32(s,1H),8.38(s,1H),8.15(s,1H),8.00(s,1H),7.00(d,J=8. 2Hz,1H),6.85(dd,J=16.3,4.9Hz,2H),4.81(s,1H),4.09(s,2H),1.87(s,3H),1.79(s,3H),1.11(s,6H).

[0757] The following Examples 118-122 were prepared using similar starting materials according to the method described in Example 117.

[0758]

[0759] Example 121: Preparation of (S)-5-(3-hydroxy-2,6-dimethylphenyl)-2-(1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-b]pyridine-4-carboxynitrile

[0760] The title compound was prepared according to the following synthetic procedure.

[0761]

[0762] Step 1: Preparation of Example 121

[0763] A mixture of compound 117-4 (50 mg, 0.146 mmol) and compound 121-1 (101.0 mg, 1.461 mmol) was stirred at 140 °C for 18 hours. The reaction mixture was diluted with water (10 mL) and extracted with EA (10 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to give Example 121. LCMS: 331.1 [M + H] + ; 1 H NMR: (400MHz, DMSO-d6) δ13.62(s,1H),9.44(s,1H),9.37(s,1H),8.43(s,1H),8.21(s,1 H),7.07(s,1H),7.02(d,J=8.2Hz,1H),6.85(d,J=8.2Hz,1H),1.87(s,3H),1.80(s,3H).

[0764] Example 122: Preparation of (S)-5-(3-hydroxy-2,6-dimethylphenyl)-2-(1H-imidazol-1-yl)-1H-pyrrolo[2,3-b]pyridine-4-carboxynitrile

[0765] The title compound was prepared according to the following synthetic procedure.

[0766]

[0767] Step 1: Preparation of Example 122

[0768] A mixture of compound 117-4 (40 mg, 0.117 mmol) and compound 122-1 (119.4 mg, 1.753 mmol) was heated to 140 °C for 16 hours. The mixture was purified by preparative TLC to give Example 122. LCMS: 330.2 [M+H] + ; 1 H NMR: (400MHz, DMSO-d6) δ13.37(s,1H),9.36(s,1H),8.56(s,1H),8.14(s,1H),8.01(s,1 H),7.23(s,1H),7.01(d,J=6.4Hz,2H),6.85(d,J=8.2Hz,1H),1.87(s,3H),1.79(s,3H).

[0769] Example 123: Preparation of (S)-5-(3-hydroxy-2,6-dimethylphenyl)-2-(1H-pyrazolo[3,4-b]pyridin-5-yl)-1H-pyrrolo[2,3-b]pyridin-4-carboxylonitrile

[0770] The title compound was prepared according to the following synthetic procedure.

[0771]

[0772] Step 1: Preparation of compound 123-2

[0773] A mixture of compound 123-1 (1000 mg, 5.051 mmol), 3,4-dihydro-2H-pyran (1274 mg, 15.152 mmol), and PPTS (127 mg, 0.505 mmol) in CH3CN (8 mL) and DCM (8 mL) was stirred at 50 °C for 16 hours. The mixture was concentrated. The residue was purified by silica gel column chromatography to give compound 123-2 (1200 mg, 4.254 mmol, 84.2%) as a yellow solid. LCMS: 282.1 [M+H] + .

[0774] Step 2: Preparation of compound 123-3

[0775] Compound 123-2 (150 mg, 0.532 mmol) was added to a solution of dioxane (2 mL) with 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1,3,2-dioxacyclopentaborane (270 mg, 1.063 mmol), KOAc (130 mg, 1.329 mmol), and Pd(dppf)Cl2 (39 mg, 0.053 mmol). The mixture was stirred at 90 °C for 16 hours. The reactants proceeded directly to the next step. LCMS: 330.2 [M+H] + .

[0776] Step 3: Preparation of compound 123-4

[0777] K₂CO₃ (60 mg, 0.438 mmol) and Pd(dtbpf)Cl₂ (10 mg, 0.015 mmol) were added to a solution of compound 123-3 (87 mg, 0.263 mmol) and compound 117-4 (50 mg, 0.146 mmol) in dioxane (2 mL) and water (0.4 mL). The mixture was stirred at 100 °C for 3 hours. The mixture was concentrated. The residue was purified by preparative TLC to give compound 123-4. LCMS: 465.4 [M+H] + .

[0778] Step 4: Preparation of Example 123

[0779] A mixture of compound 123-4 (20 mg, 0.043 mmol) and hydrogen chloride (4 mL, 16.000 mmol) in MeOH (4 mL) was stirred at room temperature for 4 hours. The mixture was concentrated. The crude product was diluted with water (10 mL) and adjusted to pH approximately 8 with Na₂CO₃ (aqueous solution). The mixture was extracted with EA (40 mL). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated to dryness. The residue was purified by preparative TLC to give Example 123. LCMS: 381.1 [M+H] + ; 1 HNMR: (400MHz, DMSO-d6) δ13.87(s,1H),12.98(s,1H),9.33(s,1H),9.25(d,J=2.0Hz,1H),8.89(d,J=1.8Hz,1H),8.2 9(s,1H),8.14(s,1H),7.31(d,J=1.9Hz,1H),7.01(d,J=8.1Hz,1H),6.85(d,J=8.1Hz,1H),1.89(s,3H),1.81(s,3H).

[0780] The following examples were prepared using similar starting materials according to the method described in Example 123.

[0781]

[0782]

[0783]

[0784] Example 126: Preparation of (S)-2-(2-aminothiazolyl-5-yl)-5-(3-hydroxy-2,6-dimethylphenyl)-1H-pyrrolo[2,3-b]pyridine-4-carboxynitrile

[0785] The title compound was prepared according to the following synthetic procedure.

[0786]

[0787] Step 1: Preparation of compound 126-2

[0788] At -78 °C, n-BuLi (1.26 mL, 3.151 mmol) was added to a solution of compound 126-1 (300.0 mg, 1.498 mmol) in THF (6 mL). The mixture was stirred at -78 °C for 0.5 h. Then (n-Bu)3SnCl (536.4 mg, 1.648 mmol) was added and the mixture was stirred at -78 °C for 0.5 h. The reaction mixture was then warmed to room temperature and stirred for 3 h. The mixture was diluted with water (40 mL) and extracted with EA (40 mL × 3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to give compound 126-2. 1 H NMR: (400MHz, CDCl3) δ12.27 (s, 1H), 7.23 (d, J = 7.3Hz, 1H), 1.52 (s, 9H), 1.49-1. 43(m,6H),1.26(dd,J=14.7,7.3Hz,6H),1.07-0.98(m,6H),0.82(t,J=7.3Hz,9H).

[0789] Step 2: Preparation of compound 126-3

[0790] Compound 126-2 (190.0 mg, 0.388 mmol) was added to a solution of dioxane (5 mL) along with compound 32-4 (69.1 mg, 0.194 mmol), LiCl (16.4 mg, 0.387 mmol), and Pd(PPh3)4 (44.8 mg, 0.0388 mmol). The mixture was stirred at 100 °C for 5 hours. The mixture was diluted with water (30 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by preparative TLC to give compound 126-3. LCMS: 476.3 [M + H] + .

[0791] Step 3: Preparation of Example 126

[0792] At 0 °C, BBr3 (315.7 mg, 1.26 mmol) was added to a solution of compound 126-3 (60.0 mg, 0.126 mmol) in DCM (4 mL). The mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with MeOH (10 mL). The mixture was concentrated to dryness and purified by preparative HPLC to give Example 126. LCMS: 362.1 [M+H] + ; 1H NMR: (400MHz, DMSO-d6) δ12.69(s,1H),9.33(s,1H),8.00(s,1H),7.74(s,1H),7.54(s,2 H),6.99(d,J=8.2Hz,1H),6.83(d,J=8.2Hz,1H),6.52(s,1H),1.86(s,3H),1.78(s,3H).

[0793] The following Example 132 was prepared using similar starting materials according to the method described in Example 126.

[0794]

[0795] Example 127: Preparation of (S)-2-(3-amino-1,2,4-triazine-6-yl)-5-(3-hydroxy-2,6-dimethylphenyl)-1H-pyrrolo[2,3-b]pyridine-4-carboxylonitrile

[0796] The title compound was prepared according to the following synthetic procedure.

[0797]

[0798] Step 1: Preparation of compound 127-1

[0799] Under N2 atmosphere at -78°C, LDA (7.0 mL, 13.905 mmol) was added dropwise to a solution of compound 29-1 (3.0 g, 6.952 mmol) in THF (75.0 mL). The mixture was stirred at -78°C for 30 min. Then (n-Bu)3SnCl (4.53 g, 13.905 mmol) was added. The mixture was stirred at -78°C for 1 h, then warmed to room temperature for 0.5 h. The mixture was quenched with a saturated aqueous solution of NH4Cl (30 mL) and extracted with EA (40 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography to give compound 127-1 (1.28 g, 1.776 mmol, 25.5%). 1H NMR: (400MHz, CDCl3) δ8.18(s,1H),8.07(d,J=8.3Hz,2H),7.30(d,J=8.3Hz,2H),7.10(d,J=8.4Hz,1H),6.90-6.83(m,2H),3.85(s,3 H),2.41(s,3H),1.90(s,3H),1.83(s,3H),1.70-1.56(m,6H),1.41(dd,J=14.6,7.3Hz,6H),1.35-1.25(m,6H),0.94(t,J=7.3Hz,9H).

[0800] Step 2: Preparation of compound 127-3

[0801] Compound 127-2 (97.1 mg, 0.555 mmol), Pd(PPh3)4 (64.1 mg, 0.056 mmol), and CuI (21.1 mg, 0.111 mmol) were added to a solution of compound 127-1 (400.0 mg, 0.555 mmol) in toluene (6.0 mL). The mixture was stirred at 120 °C for 1 hour under N2. The reaction mixture was diluted with water (20 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to give compound 127-3. LCMS: 526.3 [M + H] + .

[0802] Step 3: Preparation of compound 127-4

[0803] A mixture of compound 127-3 (172.0 mg, 0.327 mmol) and NaOH (130.9 mg, 3.272 mmol) in EtOH (6.0 mL) was stirred at 60 °C for 1 hour under N2. The pH of the reaction mixture was adjusted to 7 with HCl (1 M aqueous solution) at 0 °C. The mixture was extracted with EA (20 mL × 3). The combined organic layers were washed with brine (90 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography and further purified by SFC to give compound 127-4. LCMS: 413.1 [M + H + CH3CN] + .

[0804] Step 4: Preparation of Example 127

[0805] At 0 °C, BBr3 (0.04 mL, 0.404 mmol) was added to a solution of compound 127-4 (30.0 mg, 0.081 mmol) in DCM (3.0 mL). The mixture was stirred at room temperature for 1 hour. The reaction mixture was carefully added to MeOH (2 mL) while stirring, and diluted with water (10 mL), adjusting the pH to 8 with NaHCO3. The mixture was extracted with DCM (30 mL) and EA (20 mL × 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by preparative HPLC to give Example 127. LCMS: 358.0 [M + H] + ; 1 H NMR: (400MHz, DMSO-d6) δ9.35(s,1H),9.08(s,1H),8.16(s,1H),7.66(s,2H),7.3 4(s,1H),7.01(d,J=8.2Hz,1H),6.85(d,J=8.2Hz,1H),1.88(s,3H),1.80(s,3H).

[0806] Example 128: Preparation of 3-(6-(2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)pyrimidin-5-yl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-2,4-dimethylphenol

[0807]

[0808] Step 1: Preparation of Example 128

[0809] A mixture of compound 128-1 (165.0 mg, 0.746 mmol), compound 128-2 (274.3 mg, 1.119 mmol), K3PO4 (190.1 mg, 0.896 mmol), and Pd(dtbpf)Cl2 (19.5 mg, 0.030 mmol) in dioxane-water (3 mL) was stirred at 90 °C for 3 hours under N2. The reaction mixture was diluted with water (20 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by preparative HPLC to give Example 128. LCMS: 415.2 [M + H] + ; 1H NMR: (400MHz, DMSO-d6) δ12.49(s,1H),9.21(s,1H),9.00(s,2H),8.02(s,1H), 7.06(s,1H),6.94(d,J=8.2Hz,1H),6.79(d,J=8.1Hz,1H),5.04(s,1H),4.72(s, 1H),3.84(d,J=7.2Hz,1H),3.72(d,J=7.3Hz,1H),3.56(d,J=10.6Hz,1H),3.47( d,J=10.9Hz,1H),1.98(d,J=8.5Hz,1H),1.92(s,1H),1.88(s,3H),1.80(s,3H).

[0810] Example 133: Preparation of (S)-2-(4-amino-1H-pyrazol-1-yl)-5-(3-hydroxy-2,6-dimethylphenyl)-1H-pyrrolo[2,3-b]pyridine-4-carboxynitrile

[0811] The title compound was prepared according to the following synthetic procedure.

[0812]

[0813] A mixture of 2-bromo-5-(3-hydroxy-2,6-dimethylphenyl)-1H-pyrrolo[2,3-b]pyridine-4-carboxylonitrile (70 mg, 0.205 mmol), 1H-pyrazole-4-amine (34.0 mg, 0.409 mmol), methyl[(1S,2S)-2-(methylamino)cyclohexyl]amine (5.8 mg, 0.041 mmol), t-BuONa (59.0 mg, 0.614 mmol), and CuI (7.8 mg, 0.041 mmol) in DMF (0.5 mL) was heated to 100 °C for 16 hours under a nitrogen atmosphere. The mixture was purified by preparative HPLC to give compound 133. LCMS: 345.1 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ13.71–12.17(br s,1H),9.29(s,1H),7.96(s,1H),7.84(s,1H),7.44(s,1H),6.99(d,J=8.1Hz,1 H),6.83(d,J=8.0Hz,1H),6.61(s,1H),4.41(s,1H),1.87(s,3H),1.79(s,3H).

[0814] Example 135: Preparation of 5-(3-hydroxy-2,6-dimethylphenyl)-2-(4H-1,2,4-triazol-3-yl)-1H-pyrrolo[2,3-b]pyridine-4-carboxynitrile

[0815]

[0816] Step 1: Preparation of compound 135-2

[0817] At -78°C, LDA (4.63 mL, 9.270 mmol) was added to a solution of compound 29-1 (2000 mg, 4.635 mmol) in THF (50 mL). The mixture was stirred for 0.5 h, and then a solution of methyl chloroformate (876.0 mg, 9.27 mmol) in THF (15 mL) was added. The mixture was stirred at -78°C for 2 h, quenched with an aqueous solution of NH4Cl (50 mL), diluted with water (200 mL), and extracted with EA (100 mL × 3). The combined organic phases were washed with brine (150 mL × 2), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography to give compound 135-2 (1.0 g, 44.1% yield) as a white solid. LCMS: 489.8 [M + H] + .

[0818] Step 2: Preparation of compound 135-3

[0819] A mixture of compound 135-2 (200 mg, 0.409 mmol) in ammonia (7.0 M MeOH solution, 10 mL, 70.0 mmol) was stirred at 65 °C for 10 hours. The mixture was concentrated to give compound 135-3. LCMS: 321.2 [M+H] +

[0820] Step 3: Preparation of compound 135-4

[0821] A solution of compound 135-3 (100 mg, 0.312 mmol) in N,N-dimethylformamide dimethyl acetal (5 mL) was stirred at 90 °C for 1 hour. The mixture was concentrated and dissolved in EtOH (10 mL) to give P1. P1 was added to a solution of hydrazine hydroxide (1 mL, 20.559 mmol) in AcOH (3 mL) at 0 °C. The mixture was stirred at room temperature for 1 hour and concentrated. The residue was purified by silica gel column chromatography to give compound 135-4. LCMS: 345.1 [M+H] + .

[0822] Step 3: Preparation of Example 135

[0823] Boron tribromide (0.25 mL) was added to a mixture of compound 135-4 (15 mg, 0.044 mmol) and DCM (5 mL) at 0 °C. The mixture was stirred for 1 hour, quenched with NH3 / MeOH (7 M) at 0 °C, and concentrated. The residue was purified by preparative TLC (MeOH:DCM = 1:10) to give Example 135. LCMS: 331.1 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ14.52(s,1H),13.14(s,1H),9.35(s,1H),8.72(s,1H),8 .19(s,1H),7.20–6.94(m,2H),6.85(d,J=8.2Hz,1H),1.87(s,3H),1.80(s,3H).

[0824] Example A: PKMYT1 HTRF Measurement

[0825] The compound was serially diluted using Echo, with final concentrations ranging from 10 μM to 0.5 nM. The plate was filled by adding 5 μL / well of enzyme solution to each well containing the compound. The plate was centrifuged at 1000 rpm for 1 minute and incubated at 25 °C for 15 minutes. Then, 5 μL / well of tracer solution (Tracer 178) was added to initiate the reaction, and the plate was incubated at 25 °C for 60 minutes. Next, 5 μL of GST-Tb was added to the plate, and the plate was centrifuged at 1000 rpm for 1 minute and incubated at 25 °C for 15 minutes. The plate was read on an Envision display.

[0826] The data for Example A are shown in Table 3.

[0827] Table 3

[0828]

[0829]

[0830]

[0831]

[0832]

[0833] MYT1 HTRF IC 50 (nM): 0 <A≤10;10<B≤50;50<C≤500;500<D≤5000;5000<E

[0834] Example B: WEE1 ADP-Glo ​​Measurement

[0835] The compound was serially diluted using Echo, with final concentrations ranging from 10 μM to 0.5 nM. The plate was filled by adding 5 μL / well of enzyme solution to each well containing the compound. The plate was centrifuged at 1000 rpm for 1 minute and incubated at 25 °C for 15 minutes. Then, 5 μL / well of substrate solution was added to initiate the reaction, and the plate was incubated at 25 °C for 60 minutes. Next, 10 μL of kinase assay reagent was added to the plate, and the plate was centrifuged at 1000 rpm for 1 minute and incubated at 25 °C for 60 minutes. The US LUM of the plate was read as the RLU on an Envision display.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: Formula (I), in: Ring A is a 5- to 6-membered heterocyclic alkyl group or a 5- to 10-membered heteroaryl group; Each R 1 Independently, it is halogen, -CN, -OH, -OR a -OC(=O)R a -OC(=O)OR b -OC(=O)NR c R d -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR c R d -NR b C(=O)R a -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkynyl, C3-C6 cycloalkyl or 4- to 8-membered heterocyclic alkyl; wherein each alkyl, alkynyl, cycloalkyl and heterocyclic alkyl is independently and optionally divided by one or more R 1a replace; Or two R atoms on the same atom 1 They combine to form an oxygen group; Each R 1a Independently, it is halogen, -CN, -OH, -OR a -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or 4- to 6-membered heterocyclic alkyl; wherein each alkyl and heterocyclic alkyl is optionally substituted independently by one or more R; Or two R atoms on the same atom 1a They combine to form an oxygen group; n is 0, 1, 2, or 3; R 2 It is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; W is N or CR W ; R W It is hydrogen, halogen, -CN, -OH, -OR a -SH, -SR a -NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 ynyl, or C3-C6 cycloalkyl; wherein the alkyl, ynyl, and cycloalkyl groups are optionally and independently converted by one or more R groups. Wa replace; Each R Wa Independently, it is halogen, -CN, -OH, -OR a C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl or 4- to 6-membered heterocyclic alkyl; wherein each alkyl, cycloalkyl and heterocyclic alkyl is independently and optionally substituted by one or more R; Or two R atoms on the same atom Wa They combine to form an oxygen group; X is N or CR X ; R X It is hydrogen, halogen, -CN, -OH, -OR a -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl or C1-C6 haloalkyl; Y is CR Y ; R Y It is hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl; Z is N; R 3 It is a halogen, a C1-C6 alkyl, or a C1-C6 haloalkyl; R 4 It is a halogen, a C1-C6 alkyl, or a C1-C6 haloalkyl; R 5 It is hydrogen or halogen; R 6 It is hydrogen or halogen; Each R a It is independently a C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclic alkyl or phenyl, wherein each alkyl, cycloalkyl, heterocyclic alkyl and phenyl is independently optionally substituted by one or more R; Each R b It is independently hydrogen, C1-C6 alkyl or C1-C6 haloalkyl, wherein each alkyl group is independently and optionally substituted by one or more R; R c and R d Each is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl or 4 to 6-membered heterocyclic alkyl, wherein each alkyl, cycloalkyl and heterocyclic alkyl is independently and optionally substituted by one or more R; Or R c and R d Together with the atoms to which they are attached, they form 4- to 6-membered heterocyclic alkyl groups optionally substituted with one or more R groups; and Each R is independently a halogen, -CN, -OH, -NH2, -NHCH3, -N(CH3)2, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 haloalkyl; Alternatively, two R atoms on the same atom can form an oxo group.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X is N.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X is a CR X .

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein W is N.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein W is a CR W .

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (Ia): Formula (Ia).

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has the formula (Ib): Formula (Ib).

8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has the formula (Ic): Formula (Ic).

9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 It is a halogen or a C1-C6 alkyl group.

10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 It is a C1-C6 alkyl group.

11. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 It is a halogen or a C1-C6 alkyl group.

12. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 It is a C1-C6 alkyl group.

13. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 5 It is hydrogen.

14. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 6 It is hydrogen.

15. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 It is hydrogen or C1-C6 alkyl.

16. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 It is hydrogen.

17. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R X It is hydrogen, halogen, -CN, -C(=O)NR c R d C1-C6 alkyl or C1-C6 haloalkyl.

18. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R X It is hydrogen, halogen, or C1-C6 alkyl.

19. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R X It is hydrogen or -CN.

20. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R X It is hydrogen.

21. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R X Yes - CN.

22. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R Y It is hydrogen or halogen.

23. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R Y It is hydrogen.

24. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R W It is hydrogen, halogen, -OR a -SR a C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 ynyl, or C3-C6 cycloalkyl; wherein the alkyl, ynyl, and cycloalkyl groups are optionally and independently converted by one or more R groups. Wa replace.

25. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R W It is hydrogen, halogen, -OR a C1-C6 alkyl or C1-C6 haloalkyl; wherein the alkyl group is optionally and independently converted to one or more R Wa replace.

26. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R W It is hydrogen, -OR a Or C1-C6 alkyl; wherein the alkyl group is independently and optionally composed of one or more R Wa replace.

27. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R W It is hydrogen.

28. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R W It is optionally controlled by one or more R Wa Substituted C2-C6 ynyl group.

29. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein ring A is a 5- or 6-membered heterocyclic alkyl group.

30. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein ring A is a 5-membered heterocyclic alkyl group.

31. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein ring A is a 6-membered heterocyclic alkyl group.

32. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein ring A is tetrahydropyridyl.

33. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein ring A is a 5- to 10-membered heteroaryl group.

34. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein ring A is a 5- to 6-membered heteroaryl group.

35. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein ring A is a 6-membered heteroaryl group.

36. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein ring A is a monocyclic 5- to 10-membered heteroaryl group.

37. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein ring A is a bicyclic 5- to 10-membered heteroaryl group.

38. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein ring A is pyridyl.

39. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein each R 1 Independently, it is halogen, -CN, -OH, -OR a -S(=O)2R a -NR c R d -C(=O)R a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C2-C6 ynyl, C3-C6 cycloalkyl, or 4- to 8-membered heterocyclic alkyl; wherein each alkyl, ynyl, cycloalkyl, and heterocyclic alkyl is independently and optionally separated by one or more R 1a Substitution; or two R atoms on the same atom 1 They combine to form an oxo group.

40. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein each R 1 Independently, it is halogen, -OR a -NR c R d -C(=O)R a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, or 4- to 8-membered heterocyclic alkyl; wherein each alkyl, cycloalkyl, and heterocyclic alkyl is independently and optionally divided by one or more R 1a replace.

41. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein each R 1 Independently, it is halogen, -OR a -NR c R d -C(=O)R a C1-C6 alkyl, C1-C6 hydroxyalkyl, or 4- to 8-membered heterocyclic alkyl; wherein each alkyl and heterocyclic alkyl group is independently and optionally composed of one or more R 1a replace.

42. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein each R 1a Independently, it is a halogen, -OH, -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl or 4 to 6-membered heterocyclic alkyl; wherein each alkyl and heterocyclic alkyl is optionally substituted independently by one or more R.

43. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein each R 1a It is independently a halogen, a C1-C6 alkyl, or a C1-C6 haloalkyl; wherein each alkyl group is independently and optionally substituted by one or more R.

44. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein each R 1a It is independently a halogen, a C1-C6 alkyl, or a C1-C6 haloalkyl.

45. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein n is 0-2.

46. ​​The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2.

47. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein n is 1.

48. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: 。 49. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 48 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

50. Use of the compound of any one of claims 1 to 48 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer in a subject in need.

51. Use of the compound of any one of claims 1 to 48 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for regulating PKMYT1 in a subject.

52. Use of the compound of any one of claims 1 to 48 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inhibiting PKMYT1 in a subject.

53. The use as described in claim 51 or 52, wherein the subject has cancer.

54. The use as described in claim 50, wherein the cancer depends on the activity of PKMYT1.

55. The use as claimed in claim 50, wherein the cancer overexpresses CCNE1.

56. The use as described in claim 50, wherein the cancer has an inactivating mutation in the FBXW7 gene.

57. The use as described in claim 50, wherein the cancer is a solid tumor.

58. The use as described in claim 50, wherein the cancer is breast cancer, colorectal cancer, endometrial cancer, esophageal cancer, glioblastoma, hepatocellular carcinoma, lung cancer, neuroblastoma, ovarian cancer, prostate cancer, gastric cancer, or uterine cancer.

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