Triazolo WRN inhibitors

Abstract

The present disclosure relates to triazolo-based compounds, including compounds of Formula I: and pharmaceutically acceptable salts thereof, and compositions thereof, and methods of treating cancer, such as cancers involving WRN proteins.

Description

[0001] Cross-references to related applications

[0002] This application claims priority and interest in U.S. Provisional Application No. 63 / 512,493, filed July 7, 2023; U.S. Provisional Application No. 63 / 613,652, filed December 21, 2023; and U.S. Provisional Application No. 63 / 660,947, filed June 17, 2024, the contents of which are incorporated herein by reference. Technical Field

[0003] This invention provides bicyclic compounds and compositions, their use for inhibiting Werner Syndrome RecQ DNA helicase (WRN), methods for inhibiting said WRN using said compounds, and methods for treating diseases using said compounds, specifically, for treating cancer, and more specifically, for treating cancers characterized by microsatellite high instability (MSI-H) or mismatch repair deficiency (dMMR), including colorectal cancer, gastric cancer, and endometrial cancer. This invention also provides the use of said compounds as investigational chemicals, intermediate compounds, combinations, methods, and formulations.

[0004] sequence list

[0005] This application contains a sequence list, which has been submitted via EFS in .xml format and is incorporated herein by reference in its entirety. The ST.26 copy was created on March 30, 2023, named 407274-81WRP2_ST26.xml and is 8,751 bits in size. Background Technology

[0006] The absence of DNA mismatch repair is a common initiation event in cancer development, occurring in 10-30% of colorectal, endometrial, ovarian, and gastric cancers (Aaltonen et al., Clues to the pathogenesis of familial colorectal cancer, Science 260, 812-816 (1993); Bonneville et al., Landscape of Microsatellite Instability Across 39 Cancer Types, JCO Precis Oncol. 1: PO.17.00073 (2017)). Cancers lacking mismatch repair (dMMR) have a high mutational burden in repetitive DNA bundles and experience frequent deletion and insertion events; this phenotype is called microsatellite instability (MSI). Although progress has been made in the treatment of microsatellite high instability (MSI-H) cancers, and pembrolizumab (anti-PD1) has been shown to significantly extend progression-free survival than chemotherapy when it is accepted as first-line therapy for MSI-H-dMMR metastatic colorectal cancer (CRC), leading to its recent approval as a first-line treatment for these cancers, there remains a significant unmet medical need for CRC and other MSI-H indications (André T. et al., Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer., N Engl J Med 383(23):2207-2218 (2020)).Several large-scale functional genomics screenings of numerous cell lines, including Novartis's use of 398 cell lines from the Encyclopedia of Cancer Cell Lines (CCLE) (McDonald ER et al., Project DRIVE: A Compendium of Cancer Dependencies and Synthetic Lethal Relationships Uncovered by Large-Scale, Deep RNAi Screening., Cell 170(3):577-592 (2017)), have identified that the Werner syndrome RecQ helicase (WRN) is selectively essential for the survival of cell lines lacking mismatch repair that become MSI-H (Behan FM et al., Prioritization of cancer therapeutic targets using CRISPR-Cas9 screens., Nature, 568, 511-516). (2019); Chen, EM, et al., WRN helicase is a synthetic lethal target in microsatellite unstable cancers., Nature, 568, 551-556 (2019).Kategaya, L., Perumal, SK, Hager, JH, and Belmont, LD, Werner syndrome helicase is required for the survival of cancer cells with microsatellite instability., iScience 13, 488-497 (2019); Lieb, S. et al., Werner syndrome helicase is a selective vulnerability of microsatellite instability-high tumor cells., eLife 8, e43333 (2019). In the case of MSI cancer, WRN is synthetically lethal. In the MSI-H cancer model, WRN depletion induces an antiproliferative effect, triggers activation of various DNA damage signaling markers, and induces cell cycle arrest and apoptosis. However, this is not the case for cancer cells with intact MMR pathways (also known as microsatellite stability or MSS). The antiproliferative effect of WRN depletion cannot be rescued by helicase-deficient WRN constructs, demonstrating that WRN helicase activity is essential for MSI-H activity. These findings suggest that WRN helicase provides DNA repair and maintenance functions, which are essential for the survival of MSI cancer cells. Recently, the WRN-dependent mechanism has been elucidated. It has been shown that dinucleotide TA repeat sequences are selectively unstable in MSI cells and undergo massive amplification. These amplified TA repeat sequences form secondary DNA structures that require WRN helicase to unfold (van Wietmarschen, N. et al., Repeat expansions confer WRN dependence in microsatellite-unstable cancers., Nature, 586, 292-298, 2020). In the absence of WRN (or after WRN helicase inhibition), the amplified TA repeat sequences undergo nuclease cleavage and chromosome breakage in MSI cells. Therefore, inhibiting WRN helicase is an attractive strategy for treating MSI-H cancers. Summary of the Invention

[0007] Novel treatments and therapies remain needed for the treatment of cancers, particularly those characterized by microsatellite high instability (MSI-H) or mismatch repair deficiency (dMMR), including colorectal cancer, gastric cancer, or endometrial cancer. This invention provides compounds, pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, and combinations thereof, said compounds being inhibitors of Werner syndrome RecQ DNA helicase (WRN). The invention further provides methods for treating, preventing, or alleviating diseases or conditions comprising administering an effective amount of a WRN inhibitor to an individual in need. The invention also provides compounds, pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, and combinations thereof, said compounds suitable for treating cancers, particularly those characterized by microsatellite high instability (MSI-H) or mismatch repair deficiency (dMMR). Compounds that bind to and / or inhibit WRN are also provided, and therefore, said compounds are suitable as investigational chemicals, for example, as chemical probes and tool compounds. Various embodiments of the invention are described herein.

[0008] In one respect, this disclosure provides a compound of formula I or a pharmaceutically acceptable salt thereof:

[0009]

[0010] Where R 1 R 2 R 3 R 4 Y, Z, -L- and ring A are as described and defined in this document.

[0011] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula I of the present invention and one or more pharmaceutically acceptable carriers.

[0012] In another aspect, the present invention provides a combination, particularly a pharmaceutical composition, comprising a compound of formula I of the present invention and one or more therapeutically active agents.

[0013] In another aspect, the present invention provides a compound of formula I of the present invention for use as a pharmaceutical agent, particularly for treating conditions or diseases that can be treated by WRN inhibition.

[0014] In another aspect, the present invention provides a compound of formula I for treating cancer, specifically, wherein the cancer is characterized by microsatellite high instability (MSI-H) or mismatch repair deficiency (dMMR).

[0015] In another aspect, the present invention provides a method for treating an individual for a condition or disease that can be treated by WRN inhibition, comprising administering to the individual a therapeutically effective amount of a compound of formula I of the present invention.

[0016] In another aspect, the present invention provides a method for treating cancer in an individual, more specifically, wherein the cancer is characterized by microsatellite high instability (MSI-H) or mismatch repair deficiency (dMMR), the method comprising administering to the individual a therapeutically effective amount of a compound of formula I of the present invention.

[0017] In another aspect, the present invention provides the use of the compound of formula I of the present invention in the manufacture of a pharmaceutical agent for treating a condition or disease that can be treated by WRN inhibition.

[0018] In another aspect, the present invention provides a compound of formula I of the present invention, which is used as an investigational chemical substance, for example as a chemical probe or as a tool compound.

[0019] In another aspect, the present invention provides the solid form, method or intermediate described herein. Detailed Implementation

[0020] 1. General description of certain embodiments of the present invention:

[0021] In one respect, this disclosure provides a compound of formula I or a pharmaceutically acceptable salt thereof:

[0022]

[0023] Y and Z are independently selected from C and N. ----- Represent a single or double bond, where Z is C when Y is N, or Z is N when Y is C; to form a subformulation selected from equations Ia and Ib:

[0024]

[0025] Where ring A represents:

[0026] a) A 4-7 saturated or partially unsaturated divalent monocyclic system selected from carbocyclic and heterocyclic groups (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or

[0027] b) Fused, bridged or spirocyclic 4-12 saturated or partially unsaturated dicyclic bicyclic systems selected from carbocyclic or heterocyclic groups (with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur);

[0028] Ring A is selected from 0 to 4 independently chosen R. A Substituent substitution;

[0029] -L- is selected from -C(O)-, -S(O)-, -S(O)2- and Linking groups;

[0030] R1 Selected from groups a) to e):

[0031] a) A 5-6 membered monocyclic heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted with 1-3 groups independently selected from halogen, C1-C6 alkyl, halo-C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkoxy groups, wherein the 5-6 membered monocyclic heteroaryl group is further substituted with 0-3 independently selected R groups. A replace;

[0032] b) A 9-10 membered bicyclic heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted with 1 or 2 groups independently selected from C1-C6 aliphatic, C3-C6 cycloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkoxy groups, wherein the 9-10 membered bicyclic heteroaryl group is further substituted with 0-3 independently selected R groups. A replace;

[0033] c) A 4-7 member saturated or partially unsaturated monocyclic heterocyclic group (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted with 1 or 2 groups independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, and -OR groups, wherein the 4-7 member saturated or partially unsaturated monocyclic heterocyclic group is further substituted with 0-3 independently selected R groups. A replace;

[0034] d) Fused, bridged, or spirocyclic 4-12 saturated or partially unsaturated bicyclic systems selected from carbocyclic and heterocyclic groups (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the carbocyclic or heterocyclic group is supported by 0-3 independently selected R atoms. A Replace; and

[0035] e)H, C1-C6 aliphatic group, C3-C7 cycloalkyl, C1-C6 alkylene, -O-C1-C6 alkyl, -C(O)NR 10 R 11 -CH2NR 10 R 11 and -SO2R 12 The C1-C6 aliphatic group, the C3-C7 cycloalkyl group, or the C1-C6 alkylene group (O-C1-C6 alkyl) is selected from 0 to 5 independently chosen R groups. A replace;

[0036] R 10It is H, C1-C6 aliphatic group, halo-C1-C6 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, -C(O)C3-C6 cycloalkyl, -C(O)C1-C6 alkyl or 5-6 heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur), optionally surrounded by 1 or 2 heteroatoms independently selected from R A Substitution of groups;

[0037] R 11 It is H, C1-C6 aliphatic group or C3-C6 cycloalkyl group, or R 10 and R 11 They can be combined to form 5-6 membered rings, which are optionally substituted by 1, 2 or 3 substituents independently selected from halogens, -OH, -CN, C1-C4 alkoxy groups and halo-C1-C4 alkoxy groups;

[0038] R 12 It is a C1-C6 aliphatic group, a C3-C6 cycloalkyl group, or a 5-6-membered heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), which is optionally substituted with 1 or 2 groups independently selected from halogen, C1-C6 aliphatic group, halo-C1-C6 alkyl group, C1-C6 alkoxy group, C3-C6 cycloalkyl group, and C3-C6 cycloalkoxy group;

[0039] R A Each occurrence is independently selected from the group consisting of: optionally substituted phenyl groups, optionally substituted 5-6-membered heteroaryl groups (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted 4-7-membered saturated or partially unsaturated heterocyclic groups (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), halogens, optionally substituted C1-C6 aliphatic groups, hydroxy-C1-C6 alkyl groups, halo-C1-C6 alkyl groups, optionally substituted C3-C6 cycloalkyl groups, halo-C3-C6 cycloalkyl groups, optionally substituted C1-C6 alkoxy groups, halo-C1-C6 alkoxy groups, optionally substituted C3-C6 cycloalkoxy groups. -O-C1-C6 alkylene, -CN, -NO2, oxo, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2 and -N(R)S(O)2R;

[0040] R 2 It is C(R) B)2C(O)N(R)R 2A ;

[0041] R B Each occurrence is independently selected from hydrogen, -CH3 or -CH2CH3, or both R groups. B It combines with the carbon atoms it is attached to to form a cyclopropyl ring;

[0042] R 2A It is a fused or spirocyclic fused or spirocyclic phenyl or pyridyl group, wherein each is optionally substituted by 1, 2 or 3 independently selected substituents from: halogen, C1-C4 aliphatic group, halo-C1-C4 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, -OH, -CN, C1-C4 alkoxy, halo-C1-C4 alkoxy and -SF5; or two substituents on adjacent atoms of the phenyl or pyridyl group together with the adjacent atoms form a 4-7 membered carbon cycloyl group fused with the phenyl or pyridyl group; or two substituents on adjacent atoms of the phenyl or pyridyl group together with the adjacent atoms form a 4-7 membered heterocyclic group (having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur) fused with the phenyl or pyridyl group, wherein the 4-7 membered carbon cycloyl group or the 4-7 membered heterocyclic group is substituted by 0-5 independently selected halogens; or

[0043] R 2A It is 2-benzimidazolyl, 2-naphthyl or 3-quinolinyl, wherein each is optionally substituted by one, two or three substituents independently selected from halogen, C1-C4 aliphatic group, halo-C1-C4 alkyl and -OH;

[0044] R 3 It is hydrogen, C1-C4 aliphatic group, C3-C5 cycloalkyl group, C1-C4 alkoxy group, -NHR 3A -N(R) 3A )2 or C1-C4 alkylthio groups, except for hydrogen, each of which is optionally surrounded by -OH, 1-5 independently chosen halogens, -OR, -C(O)NR 10 R 11 Or N(R)C(O)R can be substituted;

[0045] Each R 3A Each occurrence is independently selected from C1-C4 alkyl groups;

[0046] R 4 It is a phenyl or a first 5-6-membered heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the phenyl or the first 5-6-membered heteroaryl group is surrounded by 0-5 R atoms. ASubstitution, or the two substituents on the adjacent atoms of the phenyl or the first 5-6-membered heteroaryl group together with the adjacent atoms form a 4-7-membered saturated or partially unsaturated fused carbocyclic group, a 4-7-membered saturated or partially unsaturated fused heterocyclic group, or a second 5-6-membered heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the 4-7-membered saturated or partially unsaturated fused carbocyclic group, the 4-7-membered saturated or partially unsaturated fused heterocyclic group, and the second 5-6-membered heteroaryl group are bounded by 0-3 R... A Replace; or

[0047] R 4 It is a C1-C4 alkyl, C1-C4 alkoxy, or C3-C6 cycloalkyl, wherein each is substituted by 0-3 independently selected groups from the following: halogen, -CN, -OH, oxo, NH2, C1-C4 alkyl, C1-C4 alkoxy, optionally substituted 5-6 membered heterocyclic group and optionally substituted 5-6 membered heterocyclic oxy group;

[0048] Each R is independently hydrogen or optionally substituted C. 1-6 Aliphatic group, optionally substituted phenyl group, optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring, optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur) or optionally substituted 5-6 membered heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur); or

[0049] Two R groups on the same atom are bonded together with the same atom to form optionally substituted 4-7 saturated rings, 4-7 partially unsaturated rings, or 5-6 heteroaromatic rings (wherein the 4-7 saturated rings and the 4-7 partially unsaturated rings have 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and wherein the 5-6 heteroaromatic rings have 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0050] In another aspect, the present invention provides a method for treating an individual for a condition or disease that can be treated by WRN inhibition, comprising administering to the individual a therapeutically effective amount of a compound of formula I of the present invention.

[0051] In another respect, this disclosure provides a compound of formula Ia or Ib or a pharmaceutically acceptable salt thereof:

[0052]

[0053] R 4 It is selected from one of a), b), and c):

[0054] a)R 4Choose the ring B that is freely composed of the following groups:

[0055] and ;

[0056] Where * is the connection point with -L- in Equation I;

[0057] And among them:

[0058] Selected from R on ring B 4A R 4B R 4C R 4D R 4E and R F Each substituent is independently selected from hydrogen; -OH; halogen; -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; C1-C4 alkoxy; halo-C1-C4 alkyl; C1-C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo-C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; and NR. 13 R 14 ;or

[0059] R 4A and R 4B Together with its intercalary atom, it forms an optionally substituted 4-7-membered carbocyclic group, an optionally substituted 4-7-membered heterocyclic group, or an optionally substituted 5-6-membered heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) fused with ring B; and present on ring B a group selected from R 4C R 4D R 4E and R 4F Each substituent is independently selected from hydrogen; halogen; -OH; -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; halo-C1-C4 alkyl; C1-C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo-C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; and NR. 13 R 14 ;or

[0060] R 4B and R 4CTogether with its intercalary atom, it forms an optionally substituted 4-7-membered carbocyclic group, an optionally substituted 4-7-membered heterocyclic group, or an optionally substituted 5-6-membered heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) fused with ring B; and present on ring B a group selected from R 4A R 4D R 4E and R 4F Each substituent is independently selected from hydrogen; halogen; -OH; -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; halo-C1-C4 alkyl; C1-C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo-C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; and NR. 13 R 14 ;or

[0061] R 4C and R 4D Together with its intercalary atom, it forms an optionally substituted 4-7-membered carbocyclic group, an optionally substituted 4-7-membered heterocyclic group, or an optionally substituted 5-6-membered heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) fused with ring B; and present on ring B a group selected from R 4A R 4B R 4E and R 4F Each substituent is independently selected from hydrogen; halogen; -OH; -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; halo-C1-C4 alkyl; C1-C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo-C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; and NR. 13 R 14 ;or

[0062] R 4E It is a halogen or -OH, and R 4A R 4B R 4C and R 4D Each is independently selected from hydrogen; halogen; -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; halo-C1-C4 alkyl; C1-C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo-C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; and NR. 13 R 14 ;or

[0063] R 4E and R 4ATogether with its intercalary atom, it forms an optionally substituted 4-7-membered carbocyclic group, an optionally substituted 4-7-membered heterocyclic group, or an optionally substituted 5-6-membered heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) fused with ring B; and R 4B R 4C and R 4D Each is independently selected from hydrogen; halogen; -OH; -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; halo-C1-C4 alkyl; C1-C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo-C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; and NR. 13 R 14 ;or

[0064] R 4F and R 4A Together with its intercalary atom, it forms an optionally substituted 4-7-membered carbocyclic group, an optionally substituted 4-7-membered heterocyclic group, or an optionally substituted 5-6-membered heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) fused with ring B; and R 4B and R 4C Each is independently selected from hydrogen; halogen; -OH; -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; halo-C1-C4 alkyl; C1-C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo-C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; and NR. 13 R 14 ;and

[0065] R 13 Each occurrence is independently selected from hydrogen and C1-C4 alkyl groups optionally substituted with -OH, -OCH3 or -OCH2CH3;

[0066] R 14 It is hydrogen; or NR 13 R 14 Forming a heterocycle selected from nitrogen-containing heterocyclic butyl, pyrrolidinyl, and piperidinyl, wherein the heterocycle is optionally substituted with -CH3; or

[0067] b)R 4 It is a 5-membered heteroaryl group (having one heteroatom independently selected from nitrogen, oxygen, and sulfur, and 0, 1, 2, or 3 additional cyclic nitrogen atoms), wherein the heteroaryl group is substituted by 0-4 groups independently selected from: halogen, -OH, -CN, C1-C4 alkyl, halo-C1-C4 alkyl, C3-C6 cycloalkyl, and C1-C4 alkoxy; or

[0068] c)R 4It is a C1-C4 alkyl, C1-C4 alkoxy, or C3-C6 cycloalkyl, wherein each is substituted by 0-3 independently selected groups from the following: halogen, -CN, -OH, C1-C4 alkyl, C1-C4 alkoxy, optionally substituted 5-6 membered heterocyclic group and optionally substituted 5-6 membered heterocyclic oxy group.

[0069] In another aspect, the present invention provides a method for treating an individual for a condition or disease that can be treated by WRN inhibition, comprising administering to the individual a therapeutically effective amount of a compound of formula I of the present invention or a pharmaceutically acceptable salt thereof.

[0070] In one respect, this disclosure provides a compound of formula I' or a pharmaceutically acceptable salt thereof:

[0071]

[0072] Y and Z are independently selected from C and N. ----- Represent a single or double bond, where Z is C when Y is N, or Z is N when Y is C; to form a subformulation selected from equations Ia and Ib:

[0073]

[0074] Where ring A represents:

[0075] a) A 4-7 saturated or partially unsaturated divalent monocyclic system selected from carbocyclic and heterocyclic groups (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or

[0076] b) Fused, bridged or spirocyclic 4-12 saturated or partially unsaturated dicyclic bicyclic systems selected from carbocyclic or heterocyclic groups (with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur);

[0077] Ring A is selected from 0 to 4 independently chosen R. A Substituent substitution;

[0078] -L- is selected from -C(O)-, -S(O)-, -S(O)2- and Linking groups;

[0079] R 1 Selected from groups a) to e):

[0080] a) A 5-6 membered monocyclic heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted with 1-3 groups independently selected from halogen, C1-C6 alkyl, halo-C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkoxy groups, wherein the 5-6 membered monocyclic heteroaryl group is further substituted with 0-3 independently selected R groups.A replace;

[0081] b) A 9-10 membered bicyclic heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted with 1 or 2 groups independently selected from C1-C6 aliphatic, C3-C6 cycloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkoxy groups, wherein the 9-10 membered bicyclic heteroaryl group is further substituted with 0-3 independently selected R groups. A replace;

[0082] c) A 4-7 member saturated or partially unsaturated monocyclic heterocyclic group (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted with 1 or 2 groups independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, and -OR groups, wherein the 4-7 member saturated or partially unsaturated monocyclic heterocyclic group is further substituted with 0-3 independently selected R groups. A replace;

[0083] d) Fused, bridged, or spirocyclic 4-12 saturated or partially unsaturated bicyclic systems selected from carbocyclic and heterocyclic groups (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the carbocyclic or heterocyclic group is supported by 0-3 independently selected R atoms. A Replace; and

[0084] e)H, C1-C6 aliphatic group, C3-C7 cycloalkyl, C1-C6 alkylene, -O-C1-C6 alkyl, -C(O)NR 10 R 11 -CH2NR 10 R 11 and -SO2R 12 The C1-C6 aliphatic group, the C3-C7 cycloalkyl group, or the C1-C6 alkylene group (O-C1-C6 alkyl) is selected from 0 to 5 independently chosen R groups. A replace;

[0085] R 10 It is H, C1-C6 aliphatic group, halo-C1-C6 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, -C(O)C3-C6 cycloalkyl, -C(O)C1-C6 alkyl or 5-6 heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur), optionally surrounded by 1 or 2 heteroatoms independently selected from R A Substitution of groups;

[0086] R 11 It is H, C1-C6 aliphatic group or C3-C6 cycloalkyl group, or R 10 and R 11They can be combined to form 5-6 membered rings, which are optionally substituted by 1, 2 or 3 substituents independently selected from halogens, -OH, -CN, C1-C4 alkoxy groups and halo-C1-C4 alkoxy groups;

[0087] R 12 It is a C1-C6 aliphatic group, a C3-C6 cycloalkyl group, or a 5-6-membered heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), which is optionally substituted with 1 or 2 groups independently selected from halogen, C1-C6 aliphatic group, halo-C1-C6 alkyl group, C1-C6 alkoxy group, C3-C6 cycloalkyl group, and C3-C6 cycloalkoxy group;

[0088] R A Each occurrence is independently selected from the group consisting of: optionally substituted phenyl groups, optionally substituted 5-6-membered heteroaryl groups (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted 4-7-membered saturated or partially unsaturated heterocyclic groups (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), halogens, optionally substituted C1-C6 aliphatic groups, hydroxy-C1-C6 alkyl groups, halo-C1-C6 alkyl groups, optionally substituted C3-C6 cycloalkyl groups, halo-C3-C6 cycloalkyl groups, optionally substituted C1-C6 alkoxy groups, halo-C1-C6 alkoxy groups, optionally substituted C3-C6 cycloalkoxy groups. -O-C1-C6 alkylene, -CN, -NO2, oxo, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2 and -N(R)S(O)2R;

[0089] R 2 Selected from C(R) B )2C(O)N(R)R 2A C(R) B )2C(R B )2C(O)N(R)R 2A C(R) B )2C(R B )2N(R)C(O)N(R)R 2A and C(R) B )2C(R B )2N(R)C(O)R 2A ;

[0090] RB Each occurrence is independently selected from hydrogen, -CH3 or -CH2CH3, or both R groups. B It combines with the carbon atoms it is attached to to form a cyclopropyl ring;

[0091] R 2A It is a phenyl, pyridyl, cubic alkyl, saturated or partially unsaturated 4-8 membered monocyclic, saturated or partially unsaturated bridged, fused or spirocyclic 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring, wherein the saturated or partially unsaturated monocyclic, or the saturated or partially unsaturated bridged, fused or spirocyclic ring contains 0, 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; and wherein each of the phenyl, pyridyl, cubic alkyl, saturated or partially unsaturated monocyclic or bridged, fused or spirocyclic rings is optionally substituted by 1, 2 or 3 substituents independently selected from: halogen, C1-C4 aliphatic group, halo-C1-C4 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, -OH, -CN, C1-C4 alkoxy, halo-C1 -C4 alkoxy, C3-C6 cycloalkoxy, halogenated C3-C6 cycloalkoxy, and -SF5; or two substituents on adjacent atoms of the phenyl or pyridyl group together with the adjacent atoms to form a 4-7 membered carbon cyclo group fused with the phenyl or pyridyl group; or two substituents on adjacent atoms of the phenyl or pyridyl group together with the adjacent atoms to form a 4-7 membered heterocyclic group fused with the phenyl or pyridyl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the 4-7 membered carbon cyclo group or the 4-7 membered heterocyclic group is substituted by 0-5 independently selected halogens, and wherein two substituents on the same atom of the saturated or partially unsaturated monocyclic ring, or the saturated or partially unsaturated bridged, fused, or spirocyclic ring, form a cyclogroup selected from:

[0092] ●Optionally substituted 3-7 member saturated or partially unsaturated carbon cyclogroups, and

[0093] ●Optionally substituted 4-7 member saturated or partially unsaturated heterocyclic groups, having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or

[0094] R 2A It is 2-benzimidazolyl, 2-naphthyl or 3-quinolinyl, wherein each is optionally substituted by one, two or three substituents independently selected from halogen, C1-C4 aliphatic group, halo-C1-C4 alkyl and -OH;

[0095] R 3 It is hydrogen, C1-C4 aliphatic group, C3-C5 cycloalkyl group, C1-C4 alkoxy group, -NHR 3A -N(R) 3A)2 or C1-C4 alkylthio groups, except for hydrogen, each of which is optionally surrounded by -OH, 1-5 independently chosen halogens, -OR, -C(O)NR 10 R 11 Or N(R)C(O)R can be substituted;

[0096] Each R 3A Each occurrence is independently selected from C1-C4 alkyl groups;

[0097] R 4 It is a phenyl or a first 5-6-membered heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the phenyl or the first 5-6-membered heteroaryl group is surrounded by 0-5 R atoms. A Substitution, or the two substituents on the adjacent atoms of the phenyl or the first 5-6-membered heteroaryl group together with the adjacent atoms form a 4-7-membered saturated or partially unsaturated fused carbocyclic group, a 4-7-membered saturated or partially unsaturated fused heterocyclic group, or a second 5-6-membered heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the 4-7-membered saturated or partially unsaturated fused carbocyclic group, the 4-7-membered saturated or partially unsaturated fused heterocyclic group, and the second 5-6-membered heteroaryl group are bounded by 0-3 R... A Replace; or

[0098] R 4 It is a C1-C4 alkyl, C1-C4 alkoxy, or C3-C6 cycloalkyl, wherein each is substituted by 0-3 independently selected groups from the following: halogen, -CN, -OH, oxo, NH2, C1-C4 alkyl, C1-C4 alkoxy, optionally substituted 5-6 membered heterocyclic group and optionally substituted 5-6 membered heterocyclic oxy group;

[0099] Each R is independently hydrogen or optionally substituted C. 1-6 Aliphatic group, optionally substituted phenyl group, optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring, optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur) or optionally substituted 5-6 membered heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur); or

[0100] Two R groups on the same atom are bonded together with the same atom to form optionally substituted 4-7 saturated rings, 4-7 partially unsaturated rings, or 5-6 heteroaromatic rings (wherein the 4-7 saturated rings and the 4-7 partially unsaturated rings have 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and wherein the 5-6 heteroaromatic rings have 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0101] In another aspect, the present invention provides a method for treating an individual for a condition or disease that can be treated by WRN inhibition, comprising administering to the individual a therapeutically effective amount of the compound of formula I'' of the present invention or a pharmaceutically acceptable salt thereof.

[0102] 2. Compounds and their definitions:

[0103] The compounds of this invention include those generally described herein and further illustrated by the categories, subclasses, and species disclosed herein. Unless otherwise indicated, the following definitions shall apply as used herein. For the purposes of this invention, chemical elements are identified according to the Periodic Table of the Elements, CAS edition, Handbook of Chemistry and Physics, 75th edition. Additionally, the general principles of organic chemistry are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," 5th edition, edited by Smith MB and March J., John Wiley & Sons, New York: 2001.

[0104] As used herein, the term "aliphatic group" or "aliphatic group" means a fully saturated or branched (i.e., unbranched) or substituted or unsubstituted hydrocarbon chain containing one or more unsaturated units, or a fully saturated or bicyclic hydrocarbon (also referred to herein as "carbocyclic", "cycloaliphatic group", or "cycloalkyl") that is not aromatic and has a single connection point to the rest of the molecule. Unless otherwise stated, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-3 aliphatic carbon atoms, and in still other embodiments, an aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, a "cycloaliphatic group" (or "carbocyclic" or "cycloalkyl") refers to a fully saturated or aromatic monocyclic C3-C6 hydrocarbon containing one or more unsaturated units and having a single connection point to the rest of the molecule. Suitable aliphatic groups include (but are not limited to) straight-chain or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl and mixtures thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0105] As used herein, the term "bridged bicyclic" refers to any saturated or partially unsaturated bicyclic system having at least one bridging bond, i.e., a carbocyclic or heterocyclic group. As defined by IUPAC, a "bridging bond" is a non-branched or single-atom valence bond connecting two bridgeheads, wherein a "bridgehead" is any skeletal atom of a ring system bonded to three or more skeletal atoms (other than hydrogen). In some embodiments, unless otherwise stated, the bridged bicyclic group has 5-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the bridged bicyclic group is optionally substituted with one or more substituents as described with respect to aliphatic groups. Additionally or alternatively, any substituted nitrogen atom in the bridged bicyclic group is optionally substituted. The term "alkyl" refers to C 1-12 Straight-chain or branched saturated aliphatic groups. In some cases, alkyl refers to C14. 1-8 Straight-chain or branched saturated aliphatic groups, or C 1-6 Straight-chain or branched saturated aliphatic groups. The term "low-carbon alkyl" refers to C1646 alkyl groups. 1-4 Straight-chain or branched alkyl groups.

[0106] Exemplary low-carbon alkyl groups are methyl (-CH3), ethyl (-CH2CH3), propyl, isopropyl (which may also be referred to interchangeably herein as 2-propyl, iPr, ... i Pr and i-Pr), butyl, isobutyl (which may also be referred to interchangeably as 2-butyl, iBu, in this article), i Bu and i-Bu) and tert-butyl (which may also be referred to interchangeably in this text as 2-methyl-2-butyl, tBu,t Bu and t-Bu).

[0107] The term "alkenyl" refers to a C-type carbon group containing at least one unsaturated carbon-carbon double bond. 2-12 Alkenyl groups are partially unsaturated aliphatic groups, either straight-chain or branched. In some cases, alkenyl groups refer to C groups containing at least one unsaturated carbon-carbon double bond. 2-8 Or C 2-6 A linear or branched partially unsaturated aliphatic group. The term "low-carbon alkenyl" refers to a C-group containing at least one unsaturated carbon-carbon double bond. 2-4 Alkenyl groups are partially unsaturated aliphatic groups, either straight-chain or branched. Alkenyl groups include both cis (Z) and trans (E) regioisomers. Exemplary low-carbon alkenyl groups are vinyl, allyl, 2-propenyl, and butenyl isomers (-CH2CH2CH=CH2, -CH2CH=CHCH3, and -CH=CHCH2CH3).

[0108] The term "alkynyl" refers to a C group containing at least one unsaturated carbon-carbon triple bond. 2-12 A linear or branched partially unsaturated aliphatic group. In some cases, an alkynyl group refers to a C group containing at least one unsaturated carbon-carbon triple bond. 2-8 Or C 2-6 A linear or branched partially unsaturated aliphatic group. The term "low-carbon-number ynylene" refers to a C group containing at least one unsaturated carbon-carbon triple bond. 2-4 A linear or branched partially unsaturated aliphatic group. Exemplary low-carbon alkynyl groups are ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and 3-butynyl.

[0109] The term "haloalkyl" refers to a straight-chain or branched alkyl group substituted with one or more halogen atoms. The term "low-carbon haloalkyl" refers to a C18 alkyl group substituted with one or more halogen atoms. 1-4 Straight-chain or branched alkyl groups.

[0110] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including any oxidized form of nitrogen, sulfur, phosphorus, or silicon; any quaternized form of basic nitrogen; or a substituted nitrogen of a heterocycle, such as N (as in 3,4-dihydro-2H-pyrrole), NH (as in pyrrolealkyl), or NR). + (e.g., in N-substituted pyrroleyl groups).

[0111] As used in this article, the term "unsaturated" means that a part has one or more unsaturated units.

[0112] As used in this article, the term "divalent C" 1-8 (or C) 1-6 "C1-C6) saturated or unsaturated straight or branched hydrocarbon chains" refers to straight or branched divalent alkylene, alkenyl, and ynylene chains as defined in this article.

[0113] As used herein, the term "divalent" to describe cyclic (and acyclic) groups refers to, for example, divalent carbocyclic, phenylene, heterocyclic, and heteroaryl groups, which are the divalent portions of the carbocyclic, phenyl, heterocyclic, and heteroaryl groups described herein. Non-limiting examples include...

[0114] , , , , and .

[0115] As used herein, "carbocyclic" refers to the divalent carbon ring or cycloalkyl moiety described above (i.e., connected to the remainder of the compound at two different points). Non-limiting examples include cyclopropylene, cyclobutyl, cyclopentyl, or cyclohexyl as shown below.

[0116]

[0117] The subcarbonyl group can be saturated as shown in the examples above or partially unsaturated as shown in the examples below.

[0118]

[0119] The subcarbonyl group can be polycyclic, such as bicyclic or tricyclic. Such polycyclic subcarbonyl systems can be saturated or partially unsaturated (although one ring in a bicyclic system can be aromatic, it should be understood that polycyclic ring systems that are not entirely aromatic can also fall under the definition of a subcarbonyl group). The rings can form bridging, fused, or spirosystems. Non-limiting examples are shown below.

[0120]

[0121] As used herein, "hypoheterocyclic group" refers to the divalent heterocyclic or heterocyclic moiety described above (i.e., connected to the remainder of the compound at two different points), and may be saturated or partially unsaturated. Non-limiting examples include those shown below. Hypoheterocyclic groups should be understood to include bicyclic hypoheterocyclic group systems. Non-limiting examples of bicyclic hypoheterocyclic group moieties are also shown below, and said bicyclic systems may be spirocyclic, fused, or bridged, and may be saturated or partially unsaturated.

[0122]

[0123] As used herein, "phenylene" refers to the divalent phenyl moiety described above (i.e., connected to the rest of the compound at two different points). Examples are shown below.

[0124]

[0125] As used herein, "arylene" refers to the divalent monocyclic or polycyclic aryl (i.e., phenyl or polycyclic aryl) moiety described above (i.e., connected to the rest of the compound at two different points), wherein the arylene does not contain heteroatoms. Examples are shown below.

[0126]

[0127] As used herein, "hybrid aryl" refers to a monocyclic or polycyclic aromatic ring system containing at least one heteroatom, wherein the ring system is divalent as described above (i.e., connected to the rest of the compound at two different points). Examples are shown below.

[0128]

[0129] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2). n - where n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. The substituted alkylene chain is polymethylene, wherein one or more methylene hydrogen atoms are replaced by substituents. Suitable substituents include those described below with respect to substituted aliphatic groups.

[0130] A carbocyclic group (or heterocyclic, aryl, phenyl, or heteroaryl group) fused with another phenyl, aryl, heterocyclic, carbocyclic, or heterocyclic group (e.g., "phenyl or pyridyl" as used herein) may be described as "partially unsaturated." This carbocyclic group (or heterocyclic, aryl, phenyl, or heteroaryl group) fused with another ring requires no additional degree of unsaturation other than the carbon-carbon bonds it shares with the ring it is fused with (i.e., "phenyl or pyridyl"). This is illustrated below.

[0131]

[0132] Another example below illustrates a carbocyclic moiety fused with ring B as defined herein. The carbocyclic moiety explicitly does not require the descriptive term "partially unsaturated" to describe it, as it shares two carbons with the aromatic pyridine it is fused with. This language is used herein to describe such systems, such as "R" as shown in the following image. 4A and R 4B Together with its intercalary atoms, it forms a 4-7 membered carbon cycloalcoholic group fused with ring B. Therefore, "ring B" can refer to a monocyclic ring (i.e., pyridine and its substituents shown below, which do not form a fused ring), and its substituents (i.e., R...). 4A and R 4B No other fused rings are formed. Any other fused rings formed by the substituents of ring B are described as "fused with ring B". Similarly, R 4A and R 4BThe same interpretation applies when they bond together with their intermediary atoms to form 4-7 membered carbon cyclic or heterocyclic groups (with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur) fused with ring B.

[0133]

[0134] As shown below, the term "cubic alkyl" refers to a substituent in a cubic alkyl group.

[0135]

[0136] The term "alkenyl" refers to a divalent alkenyl group. The substituted alkenyl chain is a polymethylene containing at least one double bond and one or more hydrogen atoms replaced by a substituent. Suitable substituents include those described below with respect to substituted aliphatic groups.

[0137] The term "halogen" refers to F, Cl, Br, or I.

[0138] The term "aryl," used alone or as part of a larger portion of "aralkyl," "arylalkoxy," or "aryloxyalkyl," refers to a monocyclic or bicyclic system having a total of five to fourteen ring members, wherein at least one ring in the system is an aromatic ring and wherein each ring in the system contains three to seven ring members. The term "aryl" is used interchangeably with the term "aromatic ring." In some embodiments of the invention, "aryl" refers to an aromatic ring system, including (but not limited to) phenyl, biphenyl, naphthyl, anthracene, etc., which may carry one or more substituents. As used herein, the scope of the term "aryl" also includes groups in which the aromatic ring is fused with one or more non-aromatic rings, such as dihydroindenyl, phthalimide, naphthimide, phenanthridine, or tetrahydronaphthyl, etc.

[0139] The terms “heteroaryl” and “heteroaryl-” (e.g., “heteroarylalkyl” or “heteroarylalkoxy”) used alone or as part of a larger part refer to groups having 5 to 10 ring atoms, preferably 5, 6, 9, or 10 ring atoms; having 6, 10, or 14 π electrons shared in a cyclic array; and having one to five heteroatoms in addition to carbon atoms. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur; and any quaternized form of basic nitrogen. Heteroaryl groups include (but are not limited to) pyrazinyl, pyrazolyl, pyridinyl, pyridinyl, pyrimidinyl, triazinyl, thiophenyl, furanyl, pyrroleyl, imidazolyl, pyrazolyl, triazolyl (i.e., 1,2,3-triazolyl), 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, thiazolyl, isothiazolyl, thiazolyl, indoleazinyl, purinel, naphridinyl, and pteridinel. As used herein, the terms “heteroaryl” and “heteroary-” also include groups fused with one or more aryl, heteroaryl, cycloaliphatic, or heterocyclic rings, wherein, unless otherwise specified, the group or the connecting point is on the heteroaryl ring or on one of the rings fused with the heteroaryl ring. Non-limiting examples include indolyl, isoindolyl, benzothiophene, benzofuranyl, dibenzofuranyl, indazole, indolazinyl, isoindololin-1-one, 1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one, 2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, pyrazolo[1, [5-a]pyridinyl, pyrrolo[1,2-b]pyridazinyl, pyrrolo[1,2-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl, benzimidazinyl, benzothiazolyl, quinolinyl, isoquinolinyl, cenolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinazinyl, carbazolyl, acridineyl, phenazinyl, phenothiazinyl, phenotoxazinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl. Heteroaryl groups can be monocyclic or bicyclic. The term "heteroaryl" is used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," any of which includes optionally substituted rings. The term "heteroarylalkyl" refers to an alkyl group substituted with a heteroaryl group, wherein the alkyl and heteroaryl portions are optionally substituted independently.

[0140] As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic portion that is saturated or partially unsaturated and has one or more, preferably one to four, heteroatoms as defined above, in addition to a carbon atom. When referring to the ring atom of a heterocycle, the term “nitrogen” includes substituted nitrogen. For example, in a saturated or partially unsaturated ring having 0 to 3 heteroatoms selected from oxygen, sulfur, or nitrogen, nitrogen may be N (as in 3,4-dihydro-2H-pyrroleyl), NH (as in pyrrolidinyl), or... + NR (as in N-substituted pyrroleyl groups).

[0141] Heterocycles can be attached to their side groups at any heteroatom or carbon atom to produce a stable structure, and any ring atom can optionally be substituted. Examples of these saturated or partially unsaturated heterocyclic groups include (but are not limited to) oxoheterobutyl, azirrobutyl, tetrahydrofuranyl, tetrahydrophenylthio, pyrrolyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazine, dioxyl, dioxacyclopentyl, diazaphenyl, oxazaphenyl, thiaazaphenyl, morpholinyl, 2-oxa-6-azaspiro[3.3]heptane, and quininecycloyl. The terms “heterocyclic,” “heterocyclyl,” “heterocyclic ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical” are used interchangeably herein and also include groups fused with one or more aryl, heteroaryl, or cycloaliphatic rings, such as indololinyl, 3H-indolyl, chromyl, phenanthridineyl, or tetrahydroquinolinyl. Heterocyclic groups can be monocyclic or bicyclic. The term “heterocyclic alkyl” refers to an alkyl group substituted with a heterocyclic group, wherein the alkyl and heterocyclic moieties are optionally substituted independently.

[0142] As used herein, “arylene” or “heteroarylene” (i.e., phenylene) means any divalent aryl or heterocyclic group described herein, which is a dimethyl group substituted at each of the two substituted positions in the ring system described in detail above.

[0143] As used herein, "heterocyclic oxygen group" refers to a -OR group where R is a heterocyclic group. Non-limiting examples are shown below.

[0144]

[0145] As used herein, the term "partially unsaturated" refers to a ring moiety comprising at least one double or triple bond. The term "partially unsaturated" is intended to cover rings having multiple unsaturated sites, but not necessarily aryl or heteroaryl moiety as defined herein.

[0146] As used in this article, "Me" refers to the methyl group, i.e. .

[0147] As described herein, the compounds of the present invention may contain an "optionally substituted" portion. Generally, the term "substituted," whether or not preceded by the term "optionally," means that one or more hydrogens of the specified portion are replaced by suitable substituents. Unless otherwise indicated, the "optionally substituted" group may have suitable substituents at each substituted position of the group, and the substituents at each position may be the same or different when more than one position in any given structure may be substituted by more than one substituent selected from the specified group. The combinations of substituents contemplated in this invention are preferably combinations that form stable or chemically viable compounds. The term "stable" as used herein means that a compound does not substantially change when subjected to conditions that allow it to be generated, detected, and, in some embodiments, recovered, purified, and used for one or more of the purposes disclosed herein.

[0148] The suitable monovalent substituent on the substituted carbon atom of the "optionally substituted" group is independently a halogen; -(CH2) 0-4 B(OR°)2;-(CH2) 0-4 R°;-(CH2) 0-4 OR°;-O(CH2) 0-4 R°;-O-(CH2) 0-4 C(O)OR°;-(CH2) 0-4 CH(OR°)2;-(CH2) 0-4 SR°;-(CH2) 0-4 Ph, which can be replaced by R°; -(CH2) 0-4 O(CH2) 0-1 Ph, which can be substituted by R°; -CH=CHPh, which can be substituted by R°; -(CH2) 0-4 O(CH2) 0-1 -Pyridyl group, which can be substituted with R°; -NO2; -CN; -N3; ​​-(CH2) 0-4 N(R°)2;-(CH2) 0-4 N(R°)C(O)R°;-N(R°)C(S)R°;-(CH2) 0-4 N(R°)C(O)NR°2;-N(R°)C(S)NR°2;-(CH2) 0-4N(R°)C(O)OR°; -N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)NR°2; -N(R°)N(R°)C(O)OR°; -N(R°)C(NR°)N(R°)2; -(CH2) 0-4 C(O)R°;-C(S)R°;-(CH2) 0-4 C(O)OR°;-(CH2) 0-4 C(O)SR°;-(CH2) 0-4 C(O)OSiR°3;-(CH2) 0-4 OC(O)R°;-OC(O)(CH2) 0-4 SR°;-(CH2) 0-4 SC(O)R°;-(CH2) 0-4 C(O)NR°2;-C(S)NR°2;-C(S)SR°;-SC(S)SR°;-(CH2) 0-4 OC(O)NR°2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)R°; -C(NOR°)R°; -(CH2) 0-4 SSR°;-(CH2) 0-4 S(O)2R°;-(CH2) 0-4 S(O)₂OR°;-(CH₂) 0-4 OS(O)2R°;-S(O)2NR°2;-(CH2) 0-4 S(O)R°;-N(R°)S(O)2NR°2;-N(R°)S(O)2R°;-N(OR°)R°;-C(NH)NR°2;-(CH2) 0-4 P(O)₂R°;-(CH₂) 0-4 P(O)R°2;-(CH2) 0-4 OP(O)R°2;-(CH2) 0-4 OP(O)(OR°)2;-SiR°3;-(C 1-4 (linear or branched alkylene)ON(R°)2; or -(C 1-4 (straight-chain or branched alkylene)C(O)ON(R°)2, wherein each R° can be substituted as defined below, and is independently hydrogen, C 1-6 Aliphatic group, -SO2-C 1-4 Aliphatic groups (i.e., -SO2CH3)-CH2Ph, -O(CH2) 0-1Ph, -CH2- (5-6 membered heteroaromatic ring), or a 5-6 membered saturated ring, partially unsaturated ring, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or, although defined above, two independently occurring R° are combined with one or more intermediary atoms to form a 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur and which may be substituted as defined below.

[0149] Suitable monovalent substituents on R° (or a ring formed by combining two independently occurring R° with their intervening atoms) are independently halogens, -(CH2). 0-2 R ● -(halogenated R) ● -(CH2) 0-2 OH, -(CH2) 0-2 OR ● -(CH2) 0-2 CH(OR ● )2;-O(halogenated R ● -CN, -N3, -(CH2) 0-2 C(O)R ● -(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR ● -(CH2) 0-2 SR ● -(CH2) 0-2 SH, -(CH2) 0-2 NH2、-(CH2) 0-2 NHR ● -(CH2) 0-2 NR ● 2, -NO2, -SiR ● 3. -OSiR ● 3. -C(O)SR ● -(C 1-4 (straight-chain or branched alkylene)C(O)OR ● or -SSR ● , where each R ● It is either unsubstituted or, in the case of a preceding "halogen group," substituted by only one or more halogens, and independently selected from C. 1-6 Aliphatic groups, -CH2Ph, -O(CH2) 0-1 Ph or a 5-6 membered saturated ring, partially unsaturated ring, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on the saturated carbon atom of R° include =O and =S.

[0150] Suitable divalent substituents on the saturated carbon atom of the "optionally substituted" group (examples of which include R° (or a ring formed by combining two independently occurring R° with their intervening atom)) include each of the following: =O, =S, =NNR * 2、=NNHC(O)R * =NNHC(O)OR * =NNHS(O)2R * =NR * =NOR * -O(C(R) * 2)) 2-3 O- or -S(C(R) * 2)) 2- 3S-, where each independently occurring R * Selected from hydrogen, and C that can be substituted as defined below. 1-6 Aliphatic group or unsubstituted 5-6 membered saturated ring, partially unsaturated ring, or aromatic ring having 0-4 independent heteroatoms selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents for adjacent substituted carbon bonds to the "optionally substituted" group include: -O(CR * 2) 2-3 O-, where each independently occurring R * Selected from hydrogen, and C that can be substituted as defined below. 1-6 It is an aliphatic group or an unsubstituted 5-6 membered saturated ring, partially unsaturated ring or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0151] R * Suitable substituents on aliphatic groups include halogens, -R ● -(halogenated R) ● -OH, -OR ● -O(halogenated R) ● -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● -NR ● 2 or -NO2, where each R ● It is either unsubstituted or, in the case of a preceding "halogen group," substituted by only one or more halogens, and is independently C. 1-4 Aliphatic groups, -CH2Ph, -O(CH2) 0-1 Ph or a 5-6 membered saturated ring, partially unsaturated ring, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0152] Suitable substituents on the substituted nitrogen of the "optionally substituted" group include -R † -NR † 2. -C(O)R† -C(O)OR † -C(O)C(O)R † -C(O)CH2C(O)R † -S(O)2R † -S(O)2NR † 2. -C(S)NR † 2. -C(NH)NR † 2 or -N(R) † )S(O)2R † ; where each R † Independently, it is hydrogen, and C can be substituted as defined below. 1-6 Aliphatic group, unsubstituted -OPh, or unsubstituted 5-6 membered saturated ring, partially unsaturated ring, or aromatic ring having 0-4 independent heteroatoms selected from nitrogen, oxygen, or sulfur; or, although defined above, two independently occurring R groups. † It combines with one or more intermediary atoms to form an unsubstituted 3-12 saturated, partially unsaturated or aryl monocyclic or bicyclic ring with 0-4 independent heteroatoms selected from nitrogen, oxygen or sulfur.

[0153] R † Suitable substituents on the aliphatic group are independently halogens, -R ● -(halogenated R) ● -OH, -OR ● -O(halogenated R) ● -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● -NR ● 2 or -NO2, where each R ● It is either unsubstituted or, in the case of a preceding "halogen group," substituted by only one or more halogens, and is independently C. 1-4 Aliphatic groups, -CH2Ph, -O(CH2) 0-1 Ph or a 5-6 membered saturated ring, partially unsaturated ring, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0154] As used herein, the term "pharmaceutically acceptable salt" means a salt suitable for use in contact with human and lower animal tissues within a reasonable medical diagnostic range without adverse toxicity, irritation, allergic reactions, etc., and in proportion to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. described pharmaceutically acceptable salts in detail in the Journal of Pharmaceutical Sciences, 1977, 66, 1-19. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and inorganic and organic bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed by amino groups with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or salts formed by other methods used in the art (e.g., ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, disglucuronate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucono-heptahydrate, glyceryl phosphate, gluconate, hemisulfate, heptahydrate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, p-pentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc.

[0155] Salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N salts. + (C 1-4 Alkyl)4 salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium salts. Other pharmaceutically acceptable salts include (where appropriate) non-toxic ammonium, quaternary ammonium, and amine cations formed using relative ions (e.g., halide, hydroxide, carboxyl, sulfate, phosphate, nitrate, low-carbon alkyl sulfonate, and aryl sulfonate).

[0156] Unless otherwise stated, the structures described herein are also intended to include all isomeric (e.g., enantiomers, diastereomers, and geometric (or conformations)) forms of the structures; for example, the R and S configurations of each asymmetry center, the Z and E double bond isomers, and the Z and E conformational isomers, and R... a (or M) and Sa (or P) Transisomers. Therefore, single stereochemical isomers of the compounds of the present invention, as well as mixtures of enantiomers, diastereomers, and geometric isomers (or conformational isomers), are within the scope of the present invention. Unless otherwise stated, all tautomer forms of the compounds of the present invention are within the scope of the present invention. Furthermore, unless otherwise stated, the structures described herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, this includes compounds in which hydrogen is replaced by deuterium or tritium, or carbon by... 13 C or 14 Compounds enriched with carbon substitutions and having the structure of this invention are within the scope of this invention. Such compounds can be used, for example, as analytical tools, probes in bioassays, or therapeutic agents according to the invention. In some embodiments, ring A of the provided compound may be substituted with one or more deuterium atoms.

[0157] The drawn structures represent relative configurations unless marked as absolute configurations. This invention covers individual enantiomers and racemic mixtures.

[0158] 3. Description of exemplary embodiments:

[0159] In one respect, this disclosure provides a compound of formula I or a pharmaceutically acceptable salt thereof:

[0160]

[0161] Y and Z are independently selected from C and N. ----- Represent a single or double bond, where Z is C when Y is N, or Z is N when Y is C; to form a subformulation selected from equations Ia and Ib:

[0162]

[0163] Where ring A represents:

[0164] a) A 4-7 saturated or partially unsaturated divalent monocyclic system selected from carbocyclic and heterocyclic groups (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or

[0165] b) Fused, bridged or spirocyclic 4-12 saturated or partially unsaturated dicyclic bicyclic systems selected from carbocyclic or heterocyclic groups (with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur);

[0166] Ring A is selected from 0 to 4 independently chosen R. A Substituent substitution;

[0167] L is selected from -C(O)-, -S(O)-, -S(O)2- and Linking groups;

[0168] R 1 Selected from groups a) to e):

[0169] a) A 5-6 membered monocyclic heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted with 1-3 groups independently selected from halogen, C1-C6 alkyl, halo-C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkoxy groups, wherein the 5-6 membered monocyclic heteroaryl group is further substituted with 0-3 independently selected R groups. A replace;

[0170] b) A 9-10 membered bicyclic heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted with 1 or 2 groups independently selected from C1-C6 aliphatic, C3-C6 cycloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkoxy groups, wherein the 9-10 membered bicyclic heteroaryl group is further substituted with 0-3 independently selected R groups. A replace;

[0171] c) A 4-7 member saturated or partially unsaturated monocyclic heterocyclic group (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted with 1 or 2 groups independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, and -OR groups, wherein the 4-7 member saturated or partially unsaturated monocyclic heterocyclic group is further substituted with 0-3 independently selected R groups. A replace;

[0172] d) Fused, bridged, or spirocyclic 4-12 saturated or partially unsaturated bicyclic systems selected from carbocyclic and heterocyclic groups (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the carbocyclic or heterocyclic group is supported by 0-3 independently selected R atoms. A Replace; and

[0173] e)H, C1-C6 aliphatic group, C3-C7 cycloalkyl, C1-C6 alkylene, -O-C1-C6 alkyl, -C(O)NR 10 R 11 -CH2NR 10 R 11 -SO2R 12 The C1-C6 aliphatic group, the C3-C7 cycloalkyl group, or the C1-C6 alkylene group (O-C1-C6 alkyl) is selected from 0 to 5 independently chosen R groups. A replace;

[0174] R 10It is H, C1-C6 aliphatic group, halo-C1-C6 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, -C(O)C3-C6 cycloalkyl, -C(O)C1-C6 alkyl or 5-6 heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur), optionally surrounded by 1 or 2 heteroatoms independently selected from R A Substitution of groups;

[0175] R 11 It is H, C1-C6 aliphatic group or C3-C6 cycloalkyl group, or R 10 and R 11 They can be combined to form 5-6 membered rings, which are optionally substituted by 1, 2 or 3 substituents independently selected from halogens, -OH, -CN, C1-C4 alkoxy groups and halo-C1-C4 alkoxy groups;

[0176] R 12 It is a C1-C6 aliphatic group, a C3-C6 cycloalkyl group, or a 5-6-membered heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), which is optionally substituted with 1 or 2 groups independently selected from halogen, C1-C6 aliphatic group, halo-C1-C6 alkyl group, C1-C6 alkoxy group, C3-C6 cycloalkyl group, and C3-C6 cycloalkoxy group;

[0177] R A Each occurrence is independently selected from the group consisting of: optionally substituted phenyl groups, optionally substituted 5-6-membered heteroaryl groups (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted 4-7-membered saturated or partially unsaturated heterocyclic groups (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), halogens, optionally substituted C1-C6 aliphatic groups, hydroxy-C1-C6 alkyl groups, halo-C1-C6 alkyl groups, optionally substituted C3-C6 cycloalkyl groups, halo-C3-C6 cycloalkyl groups, optionally substituted C1-C6 alkoxy groups, halo-C1-C6 alkoxy groups, optionally substituted C3-C6 cycloalkoxy groups. -O-C1-C6 alkylene, -CN, -NO2, oxo, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2 and -N(R)S(O)2R;

[0178] R 2 It is C(R) B)2C(O)N(R)R 2A ;

[0179] R B Each occurrence is independently selected from hydrogen, -CH3 or -CH2CH3, or both R groups. B It combines with the carbon atoms it is attached to to form a cyclopropyl ring;

[0180] R 2A It is a fused or spirocyclic fused or spirocyclic phenyl or pyridyl group, wherein each is optionally substituted by 1, 2 or 3 independently selected substituents from: halogen, C1-C4 aliphatic group, halo-C1-C4 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, -OH, -CN, C1-C4 alkoxy, halo-C1-C4 alkoxy and -SF5; or two substituents on adjacent atoms of the phenyl or pyridyl group together with the adjacent atoms form a 4-7 membered carbon cycloyl group fused with the phenyl or pyridyl group; or two substituents on adjacent atoms of the phenyl or pyridyl group together with the adjacent atoms form a 4-7 membered heterocyclic group (having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur) fused with the phenyl or pyridyl group, wherein the 4-7 membered carbon cycloyl group or the 4-7 membered heterocyclic group is substituted by 0-5 independently selected halogens; or

[0181] R 2A It is 2-benzimidazolyl, 2-naphthyl or 3-quinolinyl, wherein each is optionally substituted by one, two or three substituents independently selected from halogen, C1-C4 aliphatic group, halo-C1-C4 alkyl and -OH;

[0182] R 3 It is hydrogen, C1-C4 aliphatic group, C3-C5 cycloalkyl group, C1-C4 alkoxy group, -NHR 3A -N(R) 3A )2 or C1-C4 alkylthio groups, except for hydrogen, each of which is optionally surrounded by -OH, 1-5 independently chosen halogens, -OR, -C(O)NR 10 R 11 Or N(R)C(O)R can be substituted;

[0183] Each R 3A Each occurrence is independently selected from C1-C4 alkyl groups;

[0184] R 4 It is a phenyl or a first 5-6-membered heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the phenyl or the first 5-6-membered heteroaryl group is surrounded by 0-5 R atoms. ASubstitution, or the two substituents on the adjacent atoms of the phenyl or the first 5-6-membered heteroaryl group together with the adjacent atoms form a 4-7-membered saturated or partially unsaturated fused carbocyclic group, a 4-7-membered saturated or partially unsaturated fused heterocyclic group, or a second 5-6-membered heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the 4-7-membered saturated or partially unsaturated fused carbocyclic group, the 4-7-membered saturated or partially unsaturated fused heterocyclic group, and the second 5-6-membered heteroaryl group are bounded by 0-3 R... A Replace; or

[0185] R 4 It is a C1-C4 alkyl, C1-C4 alkoxy, or C3-C6 cycloalkyl, wherein each is substituted by 0-3 independently selected groups from the following: halogen, -CN, -OH, oxo, NH2, C1-C4 alkyl, C1-C4 alkoxy, optionally substituted 5-6 membered heterocyclic group and optionally substituted 5-6 membered heterocyclic oxy group;

[0186] Each R is independently hydrogen or optionally substituted C. 1-6 Aliphatic group, optionally substituted phenyl group, optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring, optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur) or optionally substituted 5-6 membered heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur); or

[0187] Two R groups on the same atom are bonded together with the same atom to form optionally substituted 4-7 saturated rings, 4-7 partially unsaturated rings, or 5-6 heteroaromatic rings (wherein the 4-7 saturated rings and the 4-7 partially unsaturated rings have 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and wherein the 5-6 heteroaromatic rings have 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0188] In one respect, this disclosure provides a compound of formula I' or a pharmaceutically acceptable salt thereof:

[0189]

[0190] Y and Z are independently selected from C and N. ----- Represent a single or double bond, where Z is C when Y is N, or Z is N when Y is C; to form a subformulation selected from equations Ia and Ib:

[0191]

[0192] Where ring A represents:

[0193] a) A 4-7 saturated or partially unsaturated divalent monocyclic system selected from carbocyclic and heterocyclic groups (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or

[0194] b) Fused, bridged or spirocyclic 4-12 saturated or partially unsaturated dicyclic bicyclic systems selected from carbocyclic or heterocyclic groups (with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur);

[0195] Ring A is selected from 0 to 4 independently chosen R. A Substituent substitution;

[0196] -L- is selected from -C(O)-, -S(O)-, -S(O)2- and Linking groups;

[0197] R 1 Selected from groups a) to e):

[0198] a) A 5-6 membered monocyclic heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted with 1-3 groups independently selected from halogen, C1-C6 alkyl, halo-C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkoxy groups, wherein the 5-6 membered monocyclic heteroaryl group is further substituted with 0-3 independently selected R groups. A replace;

[0199] b) A 9-10 membered bicyclic heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted with 1 or 2 groups independently selected from C1-C6 aliphatic, C3-C6 cycloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkoxy groups, wherein the 9-10 membered bicyclic heteroaryl group is further substituted with 0-3 independently selected R groups. A replace;

[0200] c) A 4-7 member saturated or partially unsaturated monocyclic heterocyclic group (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted with 1 or 2 groups independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, and -OR groups, wherein the 4-7 member saturated or partially unsaturated monocyclic heterocyclic group is further substituted with 0-3 independently selected R groups. A replace;

[0201] d) Fused, bridged, or spirocyclic 4-12 saturated or partially unsaturated bicyclic systems selected from carbocyclic and heterocyclic groups (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the carbocyclic or heterocyclic group is supported by 0-3 independently selected R atoms. A Replace; and

[0202] e)H, C1-C6 aliphatic group, C3-C7 cycloalkyl, C1-C6 alkylene, -O-C1-C6 alkyl, -C(O)NR 10 R 11 -CH2NR 10 R 11 and -SO2R 12 The C1-C6 aliphatic group, the C3-C7 cycloalkyl group, or the C1-C6 alkylene group (O-C1-C6 alkyl) is selected from 0 to 5 independently chosen R groups. A replace;

[0203] R 10 It is H, C1-C6 aliphatic group, halo-C1-C6 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, -C(O)C3-C6 cycloalkyl, -C(O)C1-C6 alkyl or 5-6 heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur), optionally surrounded by 1 or 2 heteroatoms independently selected from R A Substitution of groups;

[0204] R 11 It is H, C1-C6 aliphatic group or C3-C6 cycloalkyl group, or R 10 and R 11 They can be combined to form 5-6 membered rings, which are optionally substituted by 1, 2 or 3 substituents independently selected from halogens, -OH, -CN, C1-C4 alkoxy groups and halo-C1-C4 alkoxy groups;

[0205] R 12 It is a C1-C6 aliphatic group, a C3-C6 cycloalkyl group, or a 5-6-membered heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), which is optionally substituted with 1 or 2 groups independently selected from halogen, C1-C6 aliphatic group, halo-C1-C6 alkyl group, C1-C6 alkoxy group, C3-C6 cycloalkyl group, and C3-C6 cycloalkoxy group;

[0206] R AEach occurrence is independently selected from the group consisting of: optionally substituted phenyl groups, optionally substituted 5-6-membered heteroaryl groups (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted 4-7-membered saturated or partially unsaturated heterocyclic groups (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), halogens, optionally substituted C1-C6 aliphatic groups, hydroxy-C1-C6 alkyl groups, halo-C1-C6 alkyl groups, optionally substituted C3-C6 cycloalkyl groups, halo-C3-C6 cycloalkyl groups, optionally substituted C1-C6 alkoxy groups, halo-C1-C6 alkoxy groups, optionally substituted C3-C6 cycloalkoxy groups. -O-C1-C6 alkylene, -CN, -NO2, oxo, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2 and -N(R)S(O)2R;

[0207] R 2 Selected from C(R) B )2C(O)N(R)R 2A C(R) B )2C(R B )2C(O)N(R)R 2A C(R) B )2C(R B )2N(R)C(O)N(R)R 2A and C(R) B )2C(R B )2N(R)C(O)R 2A ;

[0208] R B Each occurrence is independently selected from hydrogen, -CH3 or -CH2CH3, or both R groups. B It combines with the carbon atoms it is attached to to form a cyclopropyl ring;

[0209] R 2AIt is a phenyl, pyridyl, cubic alkyl, saturated or partially unsaturated 4-8 membered monocyclic, saturated or partially unsaturated bridged, fused or spirocyclic 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring, wherein the saturated or partially unsaturated monocyclic, or the saturated or partially unsaturated bridged, fused or spirocyclic ring contains 0, 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; and wherein each of the phenyl, pyridyl, cubic alkyl, saturated or partially unsaturated monocyclic or bridged ring, fused ring or spirocyclic ring is optionally substituted by 1, 2 or 3 substituents independently selected from: halogen, C1-C4 aliphatic group, halo-C1-C4 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, -OH, -CN, C1-C4 alkoxy, halo-C 1-C4 alkoxy, C3-C6 cycloalkoxy, halogenated C3-C6 cycloalkoxy, and -SF5; or two substituents on adjacent atoms of the phenyl or pyridyl group together with the adjacent atoms to form a 4-7 membered carbon cyclo group fused with the phenyl or pyridyl group; or two substituents on adjacent atoms of the phenyl or pyridyl group together with the adjacent atoms to form a 4-7 membered heterocyclic group fused with the phenyl or pyridyl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the 4-7 membered carbon cyclo group or the 4-7 membered heterocyclic group is substituted by 0-5 independently selected halogens, and wherein two substituents on the same atom of the saturated or partially unsaturated monocyclic ring, or the saturated or partially unsaturated bridged, fused, or spirocyclic ring, form a cyclogroup selected from:

[0210] ●Optionally substituted 3-7 member saturated or partially unsaturated carbon cyclogroups, and

[0211] ●Optionally substituted 4-7 member saturated or partially unsaturated heterocyclic groups, having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or

[0212] R 2A It is 2-benzimidazolyl, 2-naphthyl or 3-quinolinyl, wherein each is optionally substituted by one, two or three substituents independently selected from halogen, C1-C4 aliphatic group, halo-C1-C4 alkyl and -OH;

[0213] R 3 It is hydrogen, C1-C4 aliphatic group, C3-C5 cycloalkyl group, C1-C4 alkoxy group, -NHR 3A -N(R) 3A )2 or C1-C4 alkylthio groups, except for hydrogen, each of which is optionally surrounded by -OH, 1-5 independently chosen halogens, -OR, -C(O)NR 10 R 11 Or N(R)C(O)R can be substituted;

[0214] Each R3A Each occurrence is independently selected from C1-C4 alkyl groups;

[0215] R 4 It is a phenyl or a first 5-6-membered heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the phenyl or the first 5-6-membered heteroaryl group is surrounded by 0-5 R atoms. A Substitution, or the two substituents on the adjacent atoms of the phenyl or the first 5-6-membered heteroaryl group together with the adjacent atoms form a 4-7-membered saturated or partially unsaturated fused carbocyclic group, a 4-7-membered saturated or partially unsaturated fused heterocyclic group, or a second 5-6-membered heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the 4-7-membered saturated or partially unsaturated fused carbocyclic group, the 4-7-membered saturated or partially unsaturated fused heterocyclic group, and the second 5-6-membered heteroaryl group are bounded by 0-3 R... A Replace; or

[0216] R 4 It is a C1-C4 alkyl, C1-C4 alkoxy, or C3-C6 cycloalkyl, wherein each is substituted by 0-3 independently selected groups from the following: halogen, -CN, -OH, oxo, NH2, C1-C4 alkyl, C1-C4 alkoxy, optionally substituted 5-6 membered heterocyclic group and optionally substituted 5-6 membered heterocyclic oxy group;

[0217] Each R is independently hydrogen or optionally substituted C. 1-6 Aliphatic group, optionally substituted phenyl group, optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring, optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur) or optionally substituted 5-6 membered heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur); or

[0218] Two R groups on the same atom are bonded together with the same atom to form optionally substituted 4-7 saturated rings, 4-7 partially unsaturated rings, or 5-6 heteroaromatic rings (wherein the 4-7 saturated rings and the 4-7 partially unsaturated rings have 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and wherein the 5-6 heteroaromatic rings have 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0219] In one respect, this disclosure provides a compound of formula II or a pharmaceutically acceptable salt thereof:

[0220]

[0221] Y and Z are independently selected from C and N. -----This represents a single or double bond, where Z is C when Y is N, or Z is N when Y is C; to form subformulations II-a or II-b:

[0222]

[0223] Where ring A represents:

[0224] a) A 4-7 saturated or partially unsaturated divalent monocyclic system selected from carbocyclic and heterocyclic groups (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or

[0225] b) Fused, bridged or spirocyclic 4-12 saturated or partially unsaturated dicyclic bicyclic systems selected from carbocyclic or heterocyclic groups (with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur);

[0226] Ring A is selected from 0 to 4 independently chosen R. A Substituent substitution;

[0227] R 1 Selected from groups a) to e):

[0228] a) A 5-6 membered monocyclic heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted by 1-3 groups independently selected from: halogen, C1-C6 alkyl, halo-C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkoxy, wherein the 5-6 membered monocyclic heteroaryl group is further substituted by 0-3 independently selected R groups. A replace;

[0229] b) A 9-10 membered bicyclic heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted with 1 or 2 groups independently selected from C1-C6 aliphatic, C3-C6 cycloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkoxy groups, wherein the 9-10 membered bicyclic heteroaryl group is further substituted with 0-3 independently selected R groups. A replace;

[0230] c) A 4-7 member saturated or partially unsaturated monocyclic heterocyclic group (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted with 1 or 2 groups independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, and -OR groups, wherein the 4-7 member saturated or partially unsaturated monocyclic heterocyclic group is further substituted with 0-3 independently selected R groups. A replace;

[0231] d) Fused, bridged, or spirocyclic 4-12 saturated or partially unsaturated bicyclic systems selected from carbocyclic and heterocyclic groups (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the carbocyclic or heterocyclic group is supported by 0-3 independently selected R atoms. A Replace; and

[0232] e)H, C1-C6 aliphatic group, C3-C7 cycloalkyl, C1-C6 alkylene, -O-C1-C6 alkyl, -C(O)NR 10 R 11 -CH2NR 10 R 11 -SO2R 12 The C1-C6 aliphatic group, the C3-C7 cycloalkyl group, or the C1-C6 alkylene group (O-C1-C6 alkyl) is selected from 0 to 5 independently chosen R groups. A replace;

[0233] R 10 It is H, C1-C6 aliphatic group, halo-C1-C6 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, -C(O)C3-C6 cycloalkyl, -C(O)C1-C6 alkyl or 5-6 heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur), optionally surrounded by 1 or 2 heteroatoms independently selected from R A Substitution of groups;

[0234] R 11 It is H, C1-C6 aliphatic group or C3-C6 cycloalkyl group, or R 10 and R 11 They can be combined to form 5-6 membered rings, which are optionally substituted by 1, 2 or 3 substituents independently selected from halogens, -OH, -CN, C1-C4 alkoxy groups and halo-C1-C4 alkoxy groups;

[0235] R 12 It is a C1-C6 aliphatic group, a C3-C6 cycloalkyl group, or a 5-6-membered heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), which is optionally substituted with 1 or 2 groups independently selected from halogen, C1-C6 aliphatic group, halo-C1-C6 alkyl group, C1-C6 alkoxy group, C3-C6 cycloalkyl group, and C3-C6 cycloalkoxy group;

[0236] R AEach occurrence is independently selected from the group consisting of: optionally substituted phenyl groups, optionally substituted 5-6-membered heteroaryl groups (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted 4-7-membered saturated or partially unsaturated heterocyclic groups (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), halogens, optionally substituted C1-C6 aliphatic groups, hydroxy-C1-C6 alkyl groups, halo-C1-C6 alkyl groups, optionally substituted C3-C6 cycloalkyl groups, halo-C3-C6 cycloalkyl groups, optionally substituted C1-C6 alkoxy groups, halo-C1-C6 alkoxy groups, optionally substituted C3-C6 cycloalkoxy groups. -O-C1-C6 alkylene, -CN, -NO2, oxo, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2 and -N(R)S(O)2R;

[0237] R 2 It is C(R) B )2C(O)N(R)R 2A ;

[0238] R B Each occurrence is independently selected from hydrogen, -CH3 or -CH2CH3, or both R groups. B It combines with the carbon atoms it is attached to to form a cyclopropyl ring;

[0239] R 2A The phenyl or pyridyl group is fused or spirocyclic, wherein each is optionally substituted by 1, 2, or 3 substituents independently selected from: halogen, C1-C4 aliphatic group, halo-C1-C4 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, -OH, -CN, C1-C4 alkoxy, halo-C1-C4 alkoxy, and -SF5; or two substituents on adjacent atoms of the phenyl or pyridyl group together with said adjacent atoms form a 4-7 membered carbon cycloyl group fused with the phenyl or pyridyl group; or two substituents on adjacent atoms of the phenyl or pyridyl group together with said adjacent atoms form a 4-7 membered heterocyclic group fused with the phenyl or pyridyl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein said 4-7 membered carbon cycloyl group or said 4-7 membered heterocyclic group is optionally substituted by 0-5 independently selected halogens; or

[0240] R 2AIt is 2-benzimidazolyl, 2-naphthyl or 3-quinolinyl, wherein each is optionally substituted by one, two or three substituents independently selected from halogen, C1-C4 aliphatic group, halo-C1-C4 alkyl and -OH;

[0241] R 3 It is hydrogen, C1-C4 aliphatic group, C3-C5 cycloalkyl group, C1-C4 alkoxy group, -NHR 3A -N(R) 3A )2 or C1-C4 alkylthio groups, except for hydrogen, each of which is optionally surrounded by -OH, 1-5 independently chosen halogens, -OR, -C(O)NR 10 R 11 Or N(R)C(O)R can be substituted;

[0242] Each R 3A Each occurrence is independently selected from C1-C4 alkyl groups;

[0243] R 4 It is a phenyl or a first 5-6-membered heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the phenyl or the first 5-6-membered heteroaryl group is surrounded by 0-5 R atoms. A Substitution, or the two substituents on the adjacent atoms of the phenyl or the first 5-6-membered heteroaryl group together with the adjacent atoms form a 4-7-membered saturated or partially unsaturated fused carbocyclic group, a 4-7-membered saturated or partially unsaturated fused heterocyclic group, or a second 5-6-membered heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the 4-7-membered saturated or partially unsaturated fused carbocyclic group, the 4-7-membered saturated or partially unsaturated fused heterocyclic group, and the second 5-6-membered heteroaryl group are bounded by 0-3 R... A Replace; or

[0244] R 4 It is a C1-C4 alkyl, C1-C4 alkoxy, or C3-C6 cycloalkyl, wherein each is substituted by 0-3 independently selected groups from the following: halogen, -CN, -OH, oxo, NH2, C1-C4 alkyl, C1-C4 alkoxy, optionally substituted 5-6 membered heterocyclic group and optionally substituted 5-6 membered heterocyclic oxy group;

[0245] Each R is independently hydrogen or optionally substituted C. 1-6 Aliphatic group, optionally substituted phenyl group, optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring, optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur) or optionally substituted 5-6 membered heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur); or

[0246] Two R groups on the same atom are bonded together with the same atom to form optionally substituted 4-7 saturated rings, 4-7 partially unsaturated rings, or 5-6 heteroaromatic rings (wherein the 4-7 saturated rings and the 4-7 partially unsaturated rings have 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and wherein the 5-6 heteroaromatic rings have 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0247] In one respect, this disclosure provides a compound of formula II' or a pharmaceutically acceptable salt thereof:

[0248]

[0249] Y and Z are independently selected from C and N. ----- This represents a single or double bond, where Z is C when Y is N, or Z is N when Y is C; to form subformulations II-a or II-b:

[0250]

[0251] Where ring A represents:

[0252] a) A 4-7 saturated or partially unsaturated divalent monocyclic system selected from carbocyclic and heterocyclic groups (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or

[0253] b) Fused, bridged or spirocyclic 4-12 saturated or partially unsaturated dicyclic bicyclic systems selected from carbocyclic or heterocyclic groups (with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur);

[0254] Ring A is selected from 0 to 4 independently chosen R. A Substituent substitution;

[0255] R 1 Selected from groups a) to e):

[0256] a) A 5-6 membered monocyclic heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted by 1-3 groups independently selected from: halogen, C1-C6 alkyl, halo-C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkoxy, wherein the 5-6 membered monocyclic heteroaryl group is further substituted by 0-3 independently selected R groups. A replace;

[0257] b) A 9-10 membered bicyclic heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted with 1 or 2 groups independently selected from C1-C6 aliphatic, C3-C6 cycloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkoxy groups, wherein the 9-10 membered bicyclic heteroaryl group is further substituted with 0-3 independently selected R groups. A replace;

[0258] c) A 4-7 member saturated or partially unsaturated monocyclic heterocyclic group (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted with 1 or 2 groups independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, and -OR groups, wherein the 4-7 member saturated or partially unsaturated monocyclic heterocyclic group is further substituted with 0-3 independently selected R groups. A replace;

[0259] d) Fused, bridged, or spirocyclic 4-12 saturated or partially unsaturated bicyclic systems selected from carbocyclic and heterocyclic groups (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the carbocyclic or heterocyclic group is supported by 0-3 independently selected R atoms. A Replace; and

[0260] e)H, C1-C6 aliphatic group, C3-C7 cycloalkyl, C1-C6 alkylene, -O-C1-C6 alkyl, -C(O)NR 10 R 11 -CH2NR 10 R 11 -SO2R 12 The C1-C6 aliphatic group, the C3-C7 cycloalkyl group, or the C1-C6 alkylene group (O-C1-C6 alkyl) is selected from 0 to 5 independently chosen R groups. A replace;

[0261] R 10 It is H, C1-C6 aliphatic group, halo-C1-C6 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, -C(O)C3-C6 cycloalkyl, -C(O)C1-C6 alkyl or 5-6 heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur), optionally surrounded by 1 or 2 heteroatoms independently selected from R A Substitution of groups;

[0262] R 11 It is H, C1-C6 aliphatic group or C3-C6 cycloalkyl group, or R 10 and R 11They can be combined to form 5-6 membered rings, which are optionally substituted by 1, 2 or 3 substituents independently selected from halogens, -OH, -CN, C1-C4 alkoxy groups and halo-C1-C4 alkoxy groups;

[0263] R 12 It is a C1-C6 aliphatic group, a C3-C6 cycloalkyl group, or a 5-6-membered heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), which is optionally substituted with 1 or 2 groups independently selected from halogen, C1-C6 aliphatic group, halo-C1-C6 alkyl group, C1-C6 alkoxy group, C3-C6 cycloalkyl group, and C3-C6 cycloalkoxy group;

[0264] R A Each occurrence is independently selected from the group consisting of: optionally substituted phenyl groups, optionally substituted 5-6-membered heteroaryl groups (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted 4-7-membered saturated or partially unsaturated heterocyclic groups (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), halogens, optionally substituted C1-C6 aliphatic groups, hydroxy-C1-C6 alkyl groups, halo-C1-C6 alkyl groups, optionally substituted C3-C6 cycloalkyl groups, halo-C3-C6 cycloalkyl groups, optionally substituted C1-C6 alkoxy groups, halo-C1-C6 alkoxy groups, optionally substituted C3-C6 cycloalkoxy groups. -O-C1-C6 alkylene, -CN, -NO2, oxo, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2 and -N(R)S(O)2R;

[0265] R 2 Selected from C(R) B )2C(O)N(R)R 2A C(R) B )2C(R B )2C(O)N(R)R 2A C(R) B )2C(R B )2N(R)C(O)N(R)R 2A and C(R) B )2C(R B )2N(R)C(O)R 2A ;

[0266] RB Each occurrence is independently selected from hydrogen, -CH3 or -CH2CH3, or both R groups. B It combines with the carbon atoms it is attached to to form a cyclopropyl ring;

[0267] R 2A It is a phenyl, pyridyl, cubic alkyl, saturated or partially unsaturated 4-8 membered monocyclic, saturated or partially unsaturated bridged, fused, or spirocyclic 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring, wherein the saturated or partially unsaturated monocyclic, or the saturated or partially unsaturated bridged, fused, or spirocyclic ring contains 0, 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and wherein each of the phenyl, pyridyl, cubic alkyl, saturated or partially unsaturated monocyclic or bridged, fused, or spirocyclic rings is optionally substituted by 1, 2, or 3 substituents independently selected from: halogen, C1-C4 aliphatic group, halo-C1-C4 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, -OH, -CN, C1-C4 alkoxy, halo-C1 -C4 alkoxy, C3-C6 cycloalkoxy, halogenated C3-C6 cycloalkoxy, and -SF5; or two substituents on adjacent atoms of the phenyl or pyridyl group together with the adjacent atoms to form a 4-7 membered carbon cyclo group fused with the phenyl or pyridyl group; or two substituents on adjacent atoms of the phenyl or pyridyl group together with the adjacent atoms to form a 4-7 membered heterocyclic group fused with the phenyl or pyridyl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the 4-7 membered carbon cyclo group or the 4-7 membered heterocyclic group is substituted by 0-5 independently selected halogens, and wherein two substituents on the same atom of the saturated or partially unsaturated monocyclic ring, or the saturated or partially unsaturated bridged, fused, or spirocyclic ring, form a cyclogroup selected from:

[0268] ●Optionally substituted 3-7 member saturated or partially unsaturated carbon cyclogroups, and

[0269] ●Optionally substituted 4-7 member saturated or partially unsaturated heterocyclic groups, having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or

[0270] R 2A It is 2-benzimidazolyl, 2-naphthyl or 3-quinolinyl, wherein each is optionally substituted by one, two or three substituents independently selected from halogen, C1-C4 aliphatic group, halo-C1-C4 alkyl and -OH;

[0271] R 3 It is hydrogen, C1-C4 aliphatic group, C3-C5 cycloalkyl group, C1-C4 alkoxy group, -NHR 3A -N(R) 3A)2 or C1-C4 alkylthio groups, except for hydrogen, each of which is optionally surrounded by -OH, 1-5 independently chosen halogens, -OR, -C(O)NR 10 R 11 Or N(R)C(O)R can be substituted;

[0272] Each R 3A Each occurrence is independently selected from C1-C4 alkyl groups;

[0273] R 4 It is a phenyl or a first 5-6-membered heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the phenyl or the first 5-6-membered heteroaryl group is surrounded by 0-5 R atoms. A Substitution, or the two substituents on the adjacent atoms of the phenyl or the first 5-6-membered heteroaryl group together with the adjacent atoms form a 4-7-membered saturated or partially unsaturated fused carbocyclic group, a 4-7-membered saturated or partially unsaturated fused heterocyclic group, or a second 5-6-membered heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the 4-7-membered saturated or partially unsaturated fused carbocyclic group, the 4-7-membered saturated or partially unsaturated fused heterocyclic group, and the second 5-6-membered heteroaryl group are bounded by 0-3 R... A Replace; or

[0274] R 4 It is a C1-C4 alkyl, C1-C4 alkoxy, or C3-C6 cycloalkyl, wherein each is substituted by 0-3 independently selected groups from the following: halogen, -CN, -OH, oxo, NH2, C1-C4 alkyl, C1-C4 alkoxy, optionally substituted 5-6 membered heterocyclic group and optionally substituted 5-6 membered heterocyclic oxy group;

[0275] Each R is independently hydrogen or optionally substituted C. 1-6 Aliphatic group, optionally substituted phenyl group, optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring, optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur) or optionally substituted 5-6 membered heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur); or

[0276] Two R groups on the same atom are bonded together with the same atom to form optionally substituted 4-7 saturated rings, 4-7 partially unsaturated rings, or 5-6 heteroaromatic rings (wherein the 4-7 saturated rings and the 4-7 partially unsaturated rings have 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and wherein the 5-6 heteroaromatic rings have 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0277] In one aspect, the present invention provides a compound of formula I or I', wherein R 4 Choose one of a), b), and c):

[0278] a)R 4 Choose the ring B that is freely composed of the following groups:

[0279] ;

[0280] Where * is the connection point with -L- in formula I or I';

[0281] And among them:

[0282] Selected from R on ring B 4A R 4B R 4C R 4D R 4E and R 4F Each substituent is independently selected from hydrogen; halogen; -OH; -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; C1-C4 alkoxy; halo-C1-C4 alkyl; C1-C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo-C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; and NR. 13 R 14 ;or

[0283] R 4A and R 4B Together with its intercalary atom, it forms an optionally substituted 4-7-membered carbocyclic group, an optionally substituted 4-7-membered heterocyclic group, or an optionally substituted 5-6-membered heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) fused with ring B; and present on ring B a group selected from R 4C R 4D R 4E and R 4F Each substituent is independently selected from hydrogen; halogen; -OH; -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; halo-C1-C4 alkyl; C1-C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo-C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; and NR. 13 R 14 ;or

[0284] R 4B and R 4CTogether with its intercalary atom, it forms an optionally substituted 4-7 membered carbocyclic group, an optionally substituted 4-7 membered heterocyclic group, or a 5-6 membered heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) fused with ring B; and present on ring B a group selected from R 4A R 4D R 4E and R 4F Each substituent is independently selected from hydrogen; halogen; -OH; -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; halo-C1-C4 alkyl; C1-C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo-C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; and NR. 13 R 14 ;or

[0285] R 4C and R 4D Together with its intercalary atom, it forms an optionally substituted 4-7-membered carbocyclic group, an optionally substituted 4-7-membered heterocyclic group, or an optionally substituted 5-6-membered heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) fused with ring B; and present on ring B a group selected from R 4A R 4B R 4E and R 4F Each substituent is independently selected from hydrogen; halogen; -OH; -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; halo-C1-C4 alkyl; C1-C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo-C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; and NR. 13 R 14 ;or

[0286] R 4E It is a halogen or -OH, and R 4A R 4B R 4C and R 4D Each is independently selected from hydrogen; halogen; -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; halo-C1-C4 alkyl; C1-C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo-C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; and NR. 13 R 14 ;or

[0287] R 4E and R 4ATogether with its intercalary atom, it forms an optionally substituted 4-7-membered carbocyclic group, an optionally substituted 4-7-membered heterocyclic group, or an optionally substituted 5-6-membered heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) fused with ring B; and R 4B R 4C and R 4D Each is independently selected from hydrogen; halogen; -OH; -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; halo-C1-C4 alkyl; C1-C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo-C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; and NR. 13 R 14 ;or

[0288] R 4F and R 4A Together with its intercalary atom, it forms an optionally substituted 4-7-membered carbocyclic group, an optionally substituted 4-7-membered heterocyclic group, or an optionally substituted 5-6-membered heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) fused with ring B; and present on ring B a group selected from R 4B R 4C and R 4D Each substituent is independently selected from hydrogen; halogen; -OH; -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; halo-C1-C4 alkyl; C1-C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo-C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; and NR. 13 R 14 ;and

[0289] R 13 Each occurrence is independently selected from hydrogen and C1-C4 alkyl groups optionally substituted with -OH, -OCH3, or -OCH2CH3; and

[0290] R 14 It is hydrogen; or NR 13 R 14 Forming a heterocycle selected from nitrogen-containing heterocyclic butyl, pyrrolidinyl, and piperidinyl, wherein the heterocycle is optionally substituted with -CH3; or

[0291] b)R 4 It is a 5-membered heteroaryl group (having one heteroatom independently selected from nitrogen, oxygen, and sulfur, and 0, 1, 2, or 3 additional cyclic nitrogen atoms), wherein the heteroaryl group is substituted by 0-4 groups independently selected from: halogen, -OH, -CN, C1-C4 alkyl, halo-C1-C4 alkyl, C3-C6 cycloalkyl, and C1-C4 alkoxy; or

[0292] c)R 4 It is a C1-C4 alkyl, C1-C4 alkoxy, or C3-C6 cycloalkyl, wherein each is substituted by 0-3 independently selected groups from the following: halogen, -CN, -OH, C1-C4 alkyl, C1-C4 alkoxy, optionally substituted 5-6 membered heterocyclic group and optionally substituted 5-6 membered heterocyclic oxy group.

[0293] As described above, ring A is

[0294] a) A 4-7 saturated or partially unsaturated divalent monocyclic system selected from carbocyclic or heterocyclic groups (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or

[0295] b) Fused, bridged, or spirocyclic 4-12 member saturated or partially unsaturated dicyclic bicyclic systems selected from carbocyclic or heterocyclic groups (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0296] Ring A is selected from 0 to 4 independently chosen R. A Substituent substitution.

[0297] In some embodiments, ring A is a 4-7 nucleotide saturated or partially unsaturated divalent monocyclic system selected from carbocyclic and heterocyclic groups (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein ring A is separated by 0-4 independently selected R atoms. A Substituent substitution. In some embodiments, ring A is a 4-7 member saturated or partially unsaturated divalent monocyclic carbocyclic group, wherein ring A is substituted by 0-4 independently selected R groups. A Substituent substitution. In some embodiments, ring A is a 4-7 member saturated or partially unsaturated divalent monocyclic heterocyclic group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein ring A is substituted by 0-4 independently selected R groups. A Substituent substitution.

[0298] In some embodiments, ring A is a fused, bridged, or spirocyclic 4-12 member saturated or partially unsaturated divalent bicyclic system selected from carbocyclic and heterocyclic groups (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein ring A is separated by 0-4 independently selected R atoms. A Substituent substitution. In some embodiments, ring A is a fused, bridged, or spirocyclic 4-12 member saturated or partially unsaturated dicyclic bicyclic system and is a subcarbonyl group, wherein ring A is substituted by 0-4 independently selected R groups. A Substituent substitution. In some embodiments, ring A is a fused, bridged, or spirocyclic 4-12 member saturated or partially unsaturated divalent bicyclic system and is a subheterocyclic group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein ring A is substituted by 0-4 independently selected R groups. ASubstituent substitution.

[0299] In some embodiments, ring A is a 4-12 nucleotide saturated or partially unsaturated dicyclic bicyclic system comprising two fused rings. In some embodiments, ring A is a 4-12 nucleotide saturated or partially unsaturated dicyclic bicyclic system comprising a spirocyclic system. In some embodiments, ring A is a 4-12 nucleotide saturated or partially unsaturated dicyclic bicyclic system comprising a bridging ring system.

[0300] In some embodiments, ring A is selected from

[0301] , , , , , , , , , and

[0302] Ring A is selected from 0 to 4 independently chosen R. A Substituent substitution.

[0303] In some embodiments, ring A is

[0304] .

[0305] In some embodiments, ring A is

[0306] .

[0307] In some embodiments, ring A is

[0308] .

[0309] In some embodiments, ring A is a substituent selected from Table 1, Table 1a, or Table 1b.

[0310] As described above, R 1 Selected from groups a) to e):

[0311] a) A 5-6 membered monocyclic heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted by 1-3 groups independently selected from: halogen, C1-C6 alkyl, halo-C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkoxy, wherein the 5-6 membered monocyclic heteroaryl group is further substituted by 0-3 independently selected R groups. A replace;

[0312] b) A 9-10 membered bicyclic heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted with 1 or 2 groups independently selected from C1-C6 aliphatic, C3-C6 cycloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkoxy groups, wherein the 9-10 membered bicyclic heteroaryl group is further substituted with 0-3 independently selected R groups. A replace;

[0313] c) A 4-7 member saturated or partially unsaturated monocyclic heterocyclic group (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted with 1 or 2 groups independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, and -OR groups, wherein the 4-7 member saturated or partially unsaturated monocyclic heterocyclic group is further substituted with 0-3 independently selected R groups. A replace;

[0314] d) Fused, bridged, or spirocyclic 4-12 saturated or partially unsaturated bicyclic systems selected from carbocyclic and heterocyclic groups (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the carbocyclic or heterocyclic group is supported by 0-3 independently selected R atoms. A Replace; and

[0315] e)H, C1-C6 aliphatic group, C3-C7 cycloalkyl, C1-C6 alkylene, -O-C1-C6 alkyl, -C(O)NR 10 R 11 -CH2NR 10 R 11 -SO2R 12 The C1-C6 aliphatic group, the C3-C7 cycloalkyl group, or the C1-C6 alkylene group is selected by 0-5 independently chosen R groups. A replace.

[0316] In some embodiments, R 1 It is a 5-6 membered monocyclic heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted with 1-3 groups independently selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C3-C6 cycloalkoxy groups, wherein the 5-6 membered monocyclic heteroaryl group is further substituted with 0-2 independently selected R groups. A Replacement. In some embodiments, R 1 It is a 4- or 6-membered saturated or partially unsaturated monocyclic heterocyclic group (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), said heterocyclic group being substituted by 0-2 groups independently selected from: halogen, oxo, -NR2, optionally substituted C 1-4Aliphatic group, -OR, a nitrogen-containing heterocyclic butyl group optionally substituted with one or two independently selected halogens, or a pyrrolidinyl group optionally substituted with one or two independently selected halogens. In some embodiments, R 1 It is a 6-8 nucleotide saturated or partially unsaturated bridged bicyclic heterocyclic group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the heterocyclic group is substituted by 0-2 groups independently selected from: halogen, oxo, -NR2, optionally substituted C 1-4 Aliphatic group, -OR, a nitrogen-containing heterocyclic butyl group optionally substituted with one or two independently selected halogens, or a pyrrolidinyl group optionally substituted with one or two independently selected halogens. In some embodiments, R 1 It is an optionally substituted 3-7 membered carbon cyclogroup. In some embodiments, R 1 It is an optionally substituted C2-C4 alkenyl group. In some embodiments, R 1 It is a C2-C4 alkenyl group substituted with a cyclopropyl group. In some embodiments, R 1 It is a C2 alkenyl group substituted with a methyl group.

[0317] In some embodiments, R 1 It is a 6-membered partially unsaturated heterocyclic group (having 1 oxygen atom). In some embodiments, R 1 It is a 6-membered heteroaryl group (having 1 nitrogen atom), wherein the heteroaryl group may optionally be substituted by 1 or 2 groups independently selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C3-C6 cycloalkoxy groups, wherein the heteroaryl group is further substituted by 0-1 R A Replace, where R A C is arbitrarily replaced 1-6 Aliphatic group. In some embodiments, R 1 It is a 6-membered heteroaryl group (having 2 nitrogen atoms), wherein the heteroaryl group may optionally be substituted with 1 or 2 groups independently selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C3-C6 cycloalkoxy groups, wherein the heteroaryl group is further substituted with 0-1 R A Replace, where R A C is arbitrarily replaced 1-6 Aliphatic groups.

[0318] In some embodiments, R 1 It is a bicyclic 9-10-membered heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted with 1 or 2 groups independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkoxy groups, wherein the bicyclic 9-10-membered heteroaryl group is further substituted with 0-3 independently selected R groups. A replace.

[0319] In some embodiments, R 1 It is a 5-membered heteroaryl group (having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted with 1 or 2 groups independently selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C3-C6 cycloalkoxy groups, wherein the 5-membered heteroaryl group is optionally further substituted with 0-2 independently selected R groups. A Replacement. In some embodiments, R 1 It is a 5-membered heteroaryl group (having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted with 1 or 2 groups independently selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C3-C6 cycloalkoxy groups. In some embodiments, R 1 It is a 5-membered heteroaryl group (having 2 nitrogen atoms) that is substituted by 1 or 2 groups independently selected from C1-C6 alkoxy, C3-C6 cycloalkyl, and C3-C6 cycloalkoxy groups, wherein the 5-membered heteroaryl group is optionally further substituted by 0-1 R groups. A Replace, where R A It is a C1-C4 alkyl group that has been substituted with a hydroxyl group.

[0320] In some embodiments, R 1 It is a 5-6-membered heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted with one of a C1-C6 alkoxy or C3-C6 cycloalkyl group, wherein the 5-6-membered heteroaryl group is optionally further substituted with 0-3 independently selected R groups. A replace.

[0321] In some embodiments, R 1 It is substituted by C1-C4 alkoxy groups and further replaced by 0-2 R groups. A Substituent-substituted pyridyl group.

[0322] In some embodiments, R 1 It is a 5-membered heteroaryl group (having one heteroatom independently selected from nitrogen, oxygen, and sulfur, and 0 or 1 additional cyclic nitrogen atom), wherein the 5-membered heteroaryl group is optionally substituted with a C1-C6 alkyl or a C3-C5 cycloalkyl group and further substituted with 0-2 R atoms. A Substituent substitution.

[0323] In some embodiments, R 1 yes

[0324] a) A 5-6 member saturated or partially unsaturated heterocyclic group (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the heterocyclic group is substituted by 0-2 groups independently selected from: halogen, oxo, -NR2, optionally substituted C 1-4Aliphatic group, -OR, a nitrogen-containing heterocyclic butyl group optionally substituted with one or two independently selected halogens, and a pyrrolidinyl group optionally substituted with one or two independently selected halogens; or

[0325] b) A 6-8 saturated or partially unsaturated bridged bicyclic heterocyclic group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the heterocyclic group is substituted by 0-2 groups independently selected from: halogen, oxo, -NR2, optionally substituted C 1-4 Aliphatic group, -OR, a nitrogen-containing heterocyclic butyl group optionally substituted with one or two independently selected halogens, or a pyrrolidinyl group optionally substituted with one or two independently selected halogens.

[0326] In some embodiments, R 1 It is a 5-6 member saturated or partially unsaturated heterocyclic group (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), said heterocyclic group being substituted by 0-2 groups independently selected from: halogen, oxo, -NR2, optionally substituted C 1-4 Aliphatic group, -OR, azahexacyclobutyl group optionally substituted with one or two independently selected halogens, and pyrrolidinyl group optionally substituted with one or two independently selected halogens.

[0327] In some embodiments, R 1 It is a 5-6-membered heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), which is substituted by one group selected from C1-C6 alkoxy and C3-C6 cycloalkyl groups, wherein the 5-6-membered heteroaryl group is further substituted by 0-3 independently selected R groups. A replace.

[0328] In some embodiments, R 1 yes

[0329] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0330] In some embodiments, R 1 yes

[0331] , , , , , , , , , , , , , , , , , , , , , , or .

[0332] In some embodiments, R 1 yes

[0333] , , , , , , , , , , , , or .

[0334] In some embodiments, R 1 yes

[0335] , , , , , , , , or .

[0336] In some embodiments, R 1 yes

[0337] , , , , , , , , , , , , or .

[0338] In some embodiments, R 1 It is a substituent selected from Table 1, Table 1a or Table 1b.

[0339] As described above, R A Each occurrence is independently selected from the group consisting of: optionally substituted phenyl groups, optionally substituted 5-6-membered heteroaryl groups (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted 4-7-membered saturated or partially unsaturated heterocyclic groups (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), halogens, optionally substituted C1-C6 aliphatic groups, hydroxy-C1-C6 alkyl groups, halo-C1-C6 alkyl groups, optionally substituted C3-C6 cycloalkyl groups, halo-C3-C6 cycloalkyl groups, C1-C6 alkoxy groups, halo-C1-C6 alkoxy groups, and C3-C6 cycloalkoxy groups. -O-C1-C6 alkylene, -CN, -NO2, oxo, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NIOR, -OC(O)R, -OC(O)NR2, -NIC(O)OR, -NIC(O)R, -NIC(O)NR2, -NIC(NR)NR2, -NIS(O)2NR2 and -NIS(O)2R.

[0340] In some embodiments, R A Each occurrence is independently selected from the following groups: halogen, -OR, or optionally substituted C. 1-6 Aliphatic group. In some embodiments, R A It is independently selected from halogens in each occurrence. In some embodiments, R AIt is selected independently of -OR in each occurrence. In some embodiments, R A It is an optionally substituted 5-6 membered heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R A It is an optionally substituted C3-C6 cycloalkyl group. In some embodiments, R A Each occurrence is independently selected from the arbitrarily replaced C. 1-6 Aliphatic groups.

[0341] In some embodiments, R A It is a substituent selected from Table 1, Table 1a or Table 1b.

[0342] As described above, R 2 It is C(R) B )2C(O)NIR 2A In some embodiments, R 2 It is C(R) B )2C(R B )2C(O)NIR 2A In some embodiments, R 2 It is C(R) B )2C(R B )2NIC(O)NIR 2A In some embodiments, R 2 It is C(R) B )2C(R B )2NIC(O)R 2A In some embodiments, R 2 It is CH2C(O)N(H)R 2A In some embodiments, R 2 It is CH2CH2C(O)N(H)R 2A In some embodiments, R 2 It is CH2CH2NIC(O)NIR 2A In some embodiments, R 2 It is CH2CH2N(H)C(O)R 2A In some embodiments, R 2 It is C(R) B )2C(O)N(H)R 2A , where R 2A It is phenyl or bicyclic [1.1.1]pentyl, optionally substituted with one, two, or three substituents independently selected from halogens, C1-C4 alkyl groups, or halo-C1-C4 alkyl groups. In some embodiments, R 2 It is C(R) B )2C(O)N(H)R 2A , where R 2AIt is a phenyl group, optionally substituted with one, two, or three substituents independently selected from halogens, C1-C4 alkyl groups, or halo-C1-C4 alkyl groups. In some embodiments, R 2 It is C(R) B )2C(O)N(H)R 2A , where R 2A It is a bicyclic [1.1.1]pentyl group, which is optionally substituted by 1, 2 or 3 substituents independently selected from halogens, C1-C4 alkyl groups or halo-C1-C4 alkyl groups.

[0343] In some embodiments, R 2 yes

[0344] , , , , , , , , , , , , , , , , , , , , , or In some embodiments, R 2 yes

[0345] or .

[0346] In some embodiments, R 2 yes .

[0347] In some embodiments, R 2 yes .

[0348] In some embodiments, R 2 yes .

[0349] In some embodiments, R 2 It is a substituent selected from Table 1, Table 1a or Table 1b.

[0350] As described above, R BEach occurrence is independently selected from hydrogen, -CH3 or -CH2CH3, or both R groups. B It bonds with the carbon atom it is attached to to form a cyclopropyl ring. In some embodiments, R B Each occurrence is independently selected from hydrogen, -CH3, or -CH2CH3. In some embodiments, R B It is hydrogen. In some embodiments, the two R... B It combines with the carbon it is attached to to form a cyclopropyl ring.

[0351] In some embodiments, R B It is a substituent selected from Table 1, Table 1a or Table 1b.

[0352] As described above, R 2A It is a phenyl, pyridyl, cubic alkyl, saturated or partially unsaturated 4-8 membered monocyclic, saturated or partially unsaturated bridged, fused, or spirocyclic ring of 5, 6, 7, 8, 9, 10, 11, or 12 membered ring, wherein the saturated or partially unsaturated monocyclic, or the saturated or partially unsaturated bridged, fused, or spirocyclic ring contains 0, 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and wherein each of the phenyl, pyridyl, cubic, saturated or partially unsaturated monocyclic, or saturated or partially unsaturated bridged, fused, or spirocyclic rings is optionally substituted by 1, 2, or 3 substituents independently selected from: halogen, C1-C4 aliphatic group, halo-C1-C4 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, -OH, -CN, C1-C4 alkoxy group. The following are possible alternatives: halogenated C1-C4 alkoxy, C3-C6 cycloalkoxy, halogenated C3-C6 cycloalkoxy, and -SF5; or two substituents on adjacent atoms of the phenyl or pyridinium group together with the adjacent atoms to form a 4-7 membered carbon cyclo group fused with the phenyl or pyridinium group; or two substituents on adjacent atoms of the phenyl or pyridinium group together with the adjacent atoms to form a 4-7 membered heterocyclic group fused with the phenyl or pyridinium group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the 4-7 membered carbon cyclo group or the 4-7 membered heterocyclic group is substituted with 0-5 independently selected halogens, and wherein two substituents on the same atom of the saturated or partially unsaturated monocyclic ring, or the saturated or partially unsaturated bridged, fused, or spirocyclic ring, form a cyclogroup selected from:

[0353] ●Optionally substituted 3-7 member saturated or partially unsaturated carbon cyclo groups, and

[0354] ●Optionally substituted 4-7 member saturated or partially unsaturated heterocyclic groups, having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or

[0355] R 2AIt is 2-benzimidazolyl, 2-naphthyl, or 3-quinolinyl, wherein each is optionally substituted by one, two, or three substituents independently selected from halogens, C1-C4 aliphatic groups, halogenated C1-C4 alkyl groups, and -OH.

[0356] In some embodiments, there are 1-6 corresponding examples, wherein two substituents on the same atom of the first, second, third, fourth, fifth, or sixth cyclic ring of the saturated or partially unsaturated monocyclic ring, or the saturated or partially unsaturated bridging, fused, or spirocyclic ring, form 1-6 of the cyclic groups. In some embodiments, there is one example, wherein two substituents on the same atom of the saturated or partially unsaturated monocyclic ring, or the saturated or partially unsaturated bridging, fused, or spirocyclic ring, form one of the cyclic groups. In some embodiments, there are 2 corresponding examples, wherein two substituents on the first and second cyclic rings of the saturated or partially unsaturated monocyclic ring, or the saturated or partially unsaturated bridging, fused, or spirocyclic ring, form two of the cyclic groups. In some embodiments, there are 3 corresponding examples, wherein two substituents on the first, second, and third cyclic rings of the saturated or partially unsaturated monocyclic ring, or the saturated or partially unsaturated bridging, fused, or spirocyclic ring, form three of the cyclic groups. In some embodiments, there are four corresponding examples, wherein two substituents on the same atom of the first, second, third, and fourth atoms of the saturated or partially unsaturated monocyclic ring, or the saturated or partially unsaturated bridging, fused, or spirocyclic ring, form four of the cyclic groups. In some embodiments, there are five corresponding examples, wherein two substituents on the same atom of the first, second, third, fourth, and fifth atoms of the saturated or partially unsaturated monocyclic ring, or the saturated or partially unsaturated bridging, fused, or spirocyclic ring, form five of the cyclic groups. In some embodiments, there are six corresponding examples, wherein two substituents on the same atom of the first, second, third, fourth, fifth, and sixth atoms of the saturated or partially unsaturated monocyclic ring, or the saturated or partially unsaturated bridging, fused, or spirocyclic ring, form six of the cyclic groups.

[0357] In some embodiments, R 2AIt is a phenyl group optionally substituted with 1, 2 or 3 independent substituents selected from the following: halogen, C1-C4 alkyl, halo-C1-C4 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, -OH, -CN, C1-C4 alkoxy, halo-C1-C4 alkoxy and -SF5, wherein two substituents on adjacent atoms of the phenyl group together with their intervening atoms form a 4-7 membered carbon cycloyl group fused with the phenyl group, and two substituents on adjacent atoms of the phenyl group together with their intervening atoms form a 4-7 membered heterocyclic group fused with the phenyl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur).

[0358] In some embodiments, R 2A It is a phenyl group optionally substituted with one, two, or three substituents independently selected from the following: halogen, C1-C4 alkyl, halo-C1-C4 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, -OH, -CN, C1-C4 alkoxy, halo-C1-C4 alkoxy, and -SF5. In some embodiments, R 2A It is a phenyl group optionally substituted with one, two, or three substituents independently selected from halogens, C1-C4 alkyl groups, and halogenated C1-C4 alkyl groups. In some embodiments, R 2A It is a phenyl group optionally substituted with halogen, C1-C4 alkyl, or halo-C1-C4 alkyl. In some embodiments, R 2A It is a phenyl group optionally substituted with two substituents independently selected from halogens, C1-C4 alkyl groups, and halo-C1-C4 alkyl groups. In some embodiments, R 2A It is a phenyl group optionally substituted with three substituents independently selected from halogens, C1-C4 alkyl groups and halo-C1-C4 alkyl groups.

[0359] In some embodiments, R 2A It is a pyridinyl group optionally substituted with 1, 2 or 3 independent substituents selected from the following: halogen, C1-C4 alkyl, halo-C1-C4 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, -OH, -CN, C1-C4 alkoxy, halo-C1-C4 alkoxy and -SF5, wherein the two substituents on the adjacent atoms of the pyridinyl group together with their intervening atoms form a 4-7 membered carbon cycloyl group fused with the pyridinyl group, and the two substituents on the adjacent atoms of the pyridinyl group together with their intervening atoms form a 4-7 membered heterocyclic group (having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur) fused with the pyridinyl group.

[0360] In some embodiments, R 2AIt is a pyridinyl group optionally substituted with one, two, or three substituents independently selected from the following: halogen, C1-C4 alkyl, halo-C1-C4 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, -OH, -CN, C1-C4 alkoxy, halo-C1-C4 alkoxy, and -SF5. In some embodiments, R 2A It is a pyridinyl group optionally substituted with one, two, or three independent substituents selected from halogens, C1-C4 alkyl groups, and halo-C1-C4 alkyl groups. In some embodiments, R 2A It is a pyridinyl group optionally substituted with halogen, C1-C4 alkyl, or halo-C1-C4 alkyl. In some embodiments, R 2A It is a pyridinyl group optionally substituted with two independent substituents selected from halogens, C1-C4 alkyl groups, and halo-C1-C4 alkyl groups. In some embodiments, R 2A It is a pyridyl group optionally substituted with three substituents independently selected from halogens, C1-C4 alkyl groups and halo-C1-C4 alkyl groups.

[0361] In some embodiments, R 2A It is a cubic alkyl, saturated or partially unsaturated 4-8 member monocyclic, bridged, fused or spirocyclic saturated or partially unsaturated 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring, wherein the saturated or partially unsaturated monocyclic ring, or the saturated or partially unsaturated bridged, fused or spirocyclic ring contains 0, 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; and wherein each of the partially unsaturated monocyclic ring, or the saturated or partially unsaturated bridged, fused or spirocyclic ring is optionally substituted by 1, 2 or 3 substituents independently selected from: halogen, C1-C4 alkyl, halo-C1-C4 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, -OH, -CN, C1-C4 alkoxy, halo-C1-C4 alkoxy, C3-C6 cycloalkoxy, halo-C3-C6 cycloalkoxy and -SF5. In some embodiments, R 2A It is a bicyclic [1.1.1]pentyl group optionally substituted with 1, 2 or 3 substituents independently selected from halogens, C1-C4 alkyl groups and halo-C1-C4 alkyl groups.

[0362] In some embodiments, R 2AIt is a saturated or partially unsaturated 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered bridged ring containing 0, 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and wherein the bridged ring is optionally substituted by 1, 2, or 3 substituents independently selected from: halogen, C1-C4 alkyl, halo-C1-C4 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, -OH, -CN, C1-C4 alkoxy, halo-C1-C4 alkoxy, C3-C6 cycloalkoxy, halo-C3-C6 cycloalkoxy, and -SF5.

[0363] In some embodiments, R 2A It is a saturated or partially unsaturated 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered fused ring containing 0, 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and wherein said fused ring is optionally substituted by 1, 2, or 3 substituents independently selected from: halogen, C1-C4 alkyl, halo-C1-C4 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, -OH, -CN, C1-C4 alkoxy, halo-C1-C4 alkoxy, C3-C6 cycloalkoxy, halo-C3-C6 cycloalkoxy, and -SF5.

[0364] In some embodiments, R 2A It is a saturated or partially unsaturated 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered spirocyclic ring containing 0, 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and wherein said spirocyclic ring is optionally substituted by 1, 2, or 3 substituents independently selected from the following: halogen, C1-C4 alkyl, halo-C1-C4 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, -OH, -CN, C1-C4 alkoxy, halo-C1-C4 alkoxy, C3-C6 cycloalkoxy, halo-C3-C6 cycloalkoxy, and -SF5.

[0365] In some embodiments, R 2A It is a bicyclic [1.1.1]pentyl group optionally substituted with one, two, or three substituents independently selected from the following: halogen, C1-C4 alkyl, halo-C1-C4 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, -OH, -CN, C1-C4 alkoxy, halo-C1-C4 alkoxy, C3-C6 cycloalkoxy, halo-C3-C6 cycloalkoxy, and -SF5. In some embodiments, R 2A It is a bicyclic [1.1.1]pentyl group optionally substituted with one, two, or three substituents independently selected from halogens, C1-C4 alkyl groups, and halo-C1-C4 alkyl groups. In some embodiments, R 2AIt is a bicyclic [1.1.1]pentyl group optionally substituted with halogen, C1-C4 alkyl, or halo-C1-C4 alkyl. In some embodiments, R 2A It is a bicyclic [1.1.1]pentyl group optionally substituted with two substituents independently selected from halogens, C1-C4 alkyl groups, and halo-C1-C4 alkyl groups. In some embodiments, R 2A It is a bicyclic [1.1.1]pentyl group optionally substituted with three substituents independently selected from halogens, C1-C4 alkyl groups and halo-C1-C4 alkyl groups.

[0366] In some embodiments, R 2A The ring F is selected from the following groups: Where x, y, and z are independently selected from 1, 2, or 3, and Y... 1 Independently selected from O and NR 15 CHR 15 or CR 15 R 15 ;R 15 It is independently selected from halogens, C1-C4 aliphatic groups, halogenated C1-C4 alkyl groups, C3-C6 cycloalkyl groups, halogenated C3-C6 cycloalkyl groups, -OH, -CN, C1-C4 alkoxy groups, halogenated C1-C4 alkoxy groups, C3-C6 cycloalkoxy groups, halogenated C3-C6 cycloalkoxy groups, and -SF5.

[0367] In some embodiments, R 2A It is a ring F with the following structure: , where R 15 It is selected from halogens, C1-C4 aliphatic groups, halogenated C1-C4 alkyl groups, C3-C6 cycloalkyl groups, halogenated C3-C6 cycloalkyl groups, -OH, -CN, C1-C4 alkoxy groups, halogenated C1-C4 alkoxy groups, C3-C6 cycloalkoxy groups, halogenated C3-C6 cycloalkoxy groups, and -SF5.

[0368] In some embodiments, R 2A It is 2-benzimidazolyl, 2-naphthyl, or 3-quinolinyl, wherein each is optionally composed of 1, 2, or 3 independently selected from halogen, C 1-4 Alkyl and -OH substituents. In some embodiments, R 2A It is a 2-benzimidazolyl group, which is optionally composed of 1, 2, or 3 independently selected from halogen, C 1-4 Alkyl and -OH substituents. In some embodiments, R 2A It is a 3-quinolinyl group, which is optionally surrounded by 1, 2, or 3 independently selected from halogens, C 1-4 Alkyl groups and -OH substituents.

[0369] In some embodiments, R 2AIt is a phenyl group containing a -CF3 substituent or a pyridyl group containing a -CF3 substituent.

[0370] In some embodiments, R 2A It is a bicyclic [1.1.1]pentyl containing a -CF3 substituent or a bicyclic [1.1.1]pentyl containing a -CHF2 substituent.

[0371] In some embodiments, R 2A It is a substituent selected from Table 1, Table 1a or Table 1b.

[0372] As described above, R 3 It is hydrogen, C1-C4 alkyl, C3-C5 cycloalkyl, C1-C4 alkoxy, -NHR 3A -N(R) 3A )2 or C1-C4 alkylthio groups, except for hydrogen, each of which is optionally substituted with -OH, 1-5 independently selected halogens or C1-C4 alkoxy groups.

[0373] In some embodiments, R 3 It is hydrogen. In some embodiments, R 3 It is a C1-C4 alkyl group, optionally substituted with -OH, 1-5 independently selected halogens, or C1-C4 alkoxy groups. In some embodiments, R 3 It is a C1-C4 alkyl group. In some embodiments, R 3 It is -CH2CH3. In some embodiments, R 3 It is -CH3. In some embodiments, R 3 It is a C3-C5 cycloalkyl, C1-C4 alkoxy, -NHR 3A -N(R) 3A )2 or C1-C4 alkylthio group, which is optionally substituted with -OH, 1-5 independently selected halogens, or C1-C4 alkoxy groups. In some embodiments, R 3 It is a C3-C5 cycloalkyl group, optionally substituted with -OH, 1-5 independently selected halogens, or C1-C4 alkoxy groups. In some embodiments, R 3 It is a C1-C4 alkoxy group, which may optionally be substituted with -OH, 1-5 independently selected halogens, or C1-C4 alkoxy groups. In some embodiments, R 3 Yes - NHR 3A It is optionally substituted with -OH, 1-5 independently selected halogens, or C1-C4 alkoxy groups. In some embodiments, R 3 It is -N(R) 3A )2, which is optionally substituted with -OH, 1-5 independently selected halogens, or C1-C4 alkoxy groups. In some embodiments, R 3It is a C1-C4 alkylthio group, which is optionally substituted with -OH, 1-5 independently selected halogens, or C1-C4 alkoxy groups. In some embodiments, R 3 Choose from the group consisting of C1-C4 alkyl and C3-C5 cycloalkyl groups.

[0374] In some embodiments, R 3 It is a substituent selected from Table 1, Table 1a or Table 1b.

[0375] As described above, each R 3A Each occurrence is independently selected from C1-C4 alkyl groups. In some embodiments, R 3 It is -CH3. In some embodiments, R 3 It is -CH2CH3. In some embodiments, R 3 It is propyl. In some embodiments, R 3 It is butyl.

[0376] In some embodiments, R 3A It is a substituent selected from Table 1, Table 1a or Table 1b.

[0377] As generally described above, -L- is selected from -C(O)-, -S(O)-, -S(O)2-, and The linking group.

[0378] In some embodiments, -L- is -C(O)-.

[0379] In some embodiments, -L- is -S(O)-.

[0380] In some embodiments, -L- is -S(O)2-.

[0381] In some embodiments, -L- is .

[0382] In some embodiments, -L- is a substituent selected from Table 1, Table 1a or Table 1b.

[0383] As described above, R 4 Choose one of a), b), and c):

[0384] a)R 4 Choose the ring B that is freely composed of the following groups:

[0385] and ;

[0386] Where * is the connection point with the ring A in Formula I, which is connected to the -L-.

[0387] And among them:

[0388] Selected from R on ring B 4A R 4B R 4C R 4D R 4E and R 4F Each substituent is independently selected from hydrogen; halogen; -OH; -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; C1-C4 alkoxy; halo-C1-C4 alkyl; C1-C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo-C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; and NR. 13 R 14 ;or

[0389] R 4A and R 4B Together with its intercalary atom, it forms an optionally substituted 4-7-membered carbocyclic group, an optionally substituted 4-7-membered heterocyclic group, or an optionally substituted 5-6-membered heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) fused with ring B; and present on ring B a group selected from R 4C R 4D R 4E and R 4F Each substituent is independently selected from hydrogen; halogen; -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; halo-C1-C4 alkyl; C1-C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo-C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; and NR. 13 R 14 ;or

[0390] R 4B and R 4C Together with its intercalary atom, it forms an optionally substituted 4-7-membered carbocyclic group, an optionally substituted 4-7-membered heterocyclic group, or an optionally substituted 5-6-membered heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) fused with ring B; and present on ring B a group selected from R 4A R 4D R 4E and R 4FEach substituent is independently selected from hydrogen; halogen; OH; -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; halo-C1-C4 alkyl; C1-C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo-C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; and NR. 13 R 14 ;or

[0391] R 4C and R 4D Together with its intercalary atom, it forms an optionally substituted 4-7-membered carbocyclic group, an optionally substituted 4-7-membered heterocyclic group, or an optionally substituted 5-6-membered heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) fused with ring B; and present on ring B a group selected from R 4A R 4B R 4E and R 4F Each substituent is independently selected from hydrogen; halogen; OH, -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; halo-C1-C4 alkyl; C1-C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo-C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; and NR. 13 R 14 ;or

[0392] R 4E It is a halogen or -OH, and R 4A R 4B R 4C and R 4D Each is independently selected from hydrogen; halogen; -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; halo-C1-C4 alkyl; C1-C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo-C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; and NR. 13 R 14 ;or

[0393] R 4E and R 4A Together with its intercalary atom, it forms an optionally substituted 4-7-membered carbocyclic group, an optionally substituted 4-7-membered heterocyclic group, or an optionally substituted 5-6-membered heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) fused with ring B; and R 4B R 4C and R 4DEach is independently selected from hydrogen; halogen; OH, -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; halo-C1-C4 alkyl; C1-C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo-C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; and NR. 13 R 14 ;or

[0394] R 4F and R 4A Together with its intercalary atom, it forms an optionally substituted 4-7-membered carbocyclic group, an optionally substituted 4-7-membered heterocyclic group, or an optionally substituted 5-6-membered heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) fused with ring B; and present on ring B a group selected from R 4B R 4C and R 4D Each substituent is independently selected from hydrogen; halogen; OH; -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; halo-C1-C4 alkyl; C1-C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo-C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; and NR. 13 R 14 ;and

[0395] R 13 Each occurrence is independently selected from hydrogen and C1-C4 alkyl groups optionally substituted with -OH, -OCH3, or -OCH2CH3; and

[0396] R 14 It is hydrogen; or NR 13 R 14 Forming a heterocycle selected from nitrogen-containing heterocyclic butyl, pyrrolidinyl, and piperidinyl, wherein the heterocycle is optionally substituted with -CH3; or

[0397] b)R 4 It is a 5-membered heteroaryl group (having one heteroatom independently selected from nitrogen, oxygen, and sulfur, and 0, 1, 2, or 3 additional cyclic nitrogen atoms), wherein the heteroaryl group is substituted by 0-4 groups independently selected from: halogen, -OH, -CN, C1-C4 alkyl, halo-C1-C4 alkyl, C3-C6 cycloalkyl, and C1-C4 alkoxy; or

[0398] c)R 4It is a C1-C4 alkyl, C1-C4 alkoxy, or C3-C6 cycloalkyl, wherein each is substituted by 0-3 independently selected groups from the following: halogen, -CN, -OH, C1-C4 alkyl, C1-C4 alkoxy, optionally substituted 5-6 membered heterocyclic group and optionally substituted 5-6 membered heterocyclic oxy group.

[0399] In some embodiments, R 4 Ring B has the following structure:

[0400]

[0401] Where * is the connection point with the ring A in Formula I, which is connected to the -L-.

[0402] And among them:

[0403] R 4A R 4C and R 4D Each is independently selected from hydrogen; halogen; -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; halo-C1-C4 alkyl; C1-C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo-C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; and NR. 13 R 14 ;or

[0404] R 4C and R 4D Together with its intercalary atom, it forms an optionally substituted 4-7-membered carbocyclic group, an optionally substituted 4-7-membered heterocyclic group, or an optionally substituted 5-6-membered heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) fused with ring B; and R 4A It is hydrogen; halogen; -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; halo-C1-C4 alkyl; C1-C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo-C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; or NR 13 R 14 ;and

[0405] R 13 Each time it appears, it is independently selected from hydrogen and C1-C4 alkyl groups optionally substituted with -OH, -OCH3 or -OCH2CH3;

[0406] R 14 It is hydrogen, or NR. 13 R 14 A heterocycle selected from nitrogen-containing heterocyclic butyl, pyrrolidinyl, and piperidinyl is formed, wherein the heterocycle is optionally substituted with -CH3.

[0407] In some embodiments, R 4 Ring B has the following structure:

[0408]

[0409] Where * is the connection point with the ring A in Formula I, which is connected to the -L-.

[0410] And among them:

[0411] R 4A It is -OCH3, -OCH2CH3, or -OCHF2;

[0412] R 4C and R 4D Each is independently selected from hydrogen; -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; halo-C1-C4 alkyl; C1-C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo-C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; and NR. 13 R 14 ;and

[0413] R 13 Each occurrence is independently selected from hydrogen and C1-C4 alkyl groups optionally substituted with -OH, -OCH3 or -OCH2CH3;

[0414] R 14 It is hydrogen, or NR. 13 R 14 A heterocycle selected from nitrogen-containing heterocyclic butyl, pyrrolidinyl, and piperidinyl is formed, wherein the heterocycle is optionally substituted with -CH3.

[0415] In some embodiments, R 4 Ring B has the following structure:

[0416]

[0417] Where * is the connection point with the ring A in Formula I, which is connected to the -L-.

[0418] And among them:

[0419] R 4A It is -OCH3, -OCH2CH3, or -OCHF2;

[0420] R 4C and R 4D Each is independently selected from hydrogen; -CN; C1-C4 alkyl; C2- and R 4DEach is independently selected from hydrogen; -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; halo-C1-C4 alkyl; C1-C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo-C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; and NR. 13 R 14 ;and

[0421] R 13 Each occurrence is independently selected from hydrogen and C1-C4 alkyl groups optionally substituted with -OH, -OCH3, or -OCH2CH3; and

[0422] R 14 It is hydrogen, or NR. 13 R 14 A heterocycle selected from nitrogen-containing heterocyclic butyl, pyrrolidinyl, and piperidinyl is formed, wherein the heterocycle is optionally substituted with -CH3.

[0423] In some embodiments, R 4 Ring B has the following structure:

[0424]

[0425] Where * is the connection point with the ring A in Formula I, which is connected to the -L-.

[0426] And among them:

[0427] R 4A R 4C and R 4D Each is independently selected from hydrogen; halogen; and C1-C4 alkyl.

[0428] In some embodiments, R 4 Ring B has the following structure:

[0429]

[0430] Where * is the connection point with the ring A in Formula I, which is connected to the -L-.

[0431] And among them:

[0432] R 4A R 4B and R 4C Each is independently selected from hydrogen; halogen; -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; C1-C4 alkoxy; halo-C1-C4 alkyl; C1-C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo-C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; and NR. 13 R14 ;or

[0433] R 4A and R 4B Together with its intercalary atom, it forms an optionally substituted 4-7-membered carbocyclic group, an optionally substituted 4-7-membered heterocyclic group, or an optionally substituted 5-6-membered heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) fused with ring B; and R 4C It is hydrogen; halogen; -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; halo-C1-C4 alkyl; C1-C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo-C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; and NR 13 R 14 ;or

[0434] R 4B and R 4C Together with its intercalary atom, it forms an optionally substituted 4-7-membered carbocyclic group, an optionally substituted 4-7-membered heterocyclic group, or an optionally substituted 5-6-membered heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) fused with ring B; and R 4A It is hydrogen; halogen; -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; halo-C1-C4 alkyl; C1-C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo-C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; and NR 13 R 14 ;and

[0435] R 13 Each time it appears, it is independently selected from hydrogen and C1-C4 alkyl groups optionally substituted with -OH, -OCH3 or -OCH2CH3;

[0436] R 14 It is hydrogen; or NR 13 R 14 A heterocycle selected from nitrogen-containing heterocyclic butyl, pyrrolidinyl, and piperidinyl is formed, wherein the heterocycle is optionally substituted with -CH3.

[0437] In some embodiments, R 4 Ring B has the following structure:

[0438]

[0439] Where * is the connection point with the ring A in Formula I, which is connected to the -L-.

[0440] And among them:

[0441] R4A and R 4B Together with its intercalary atom, it forms an optionally substituted 4-7-membered carbocyclic group, an optionally substituted 4-7-membered heterocyclic group, or an optionally substituted 5-6-membered heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) fused with ring B; and

[0442] R 4C It is hydrogen.

[0443] In some embodiments, R 4 Ring B has the following structure:

[0444]

[0445] Where * is the connection point with the ring A in Formula I, which is connected to the -L-.

[0446] And among them:

[0447] R 4A With R 4B It bonds with its intermediary atom to form a 5-membered heterocyclic group (with one oxygen atom) fused to ring B; and

[0448] R 4C It is hydrogen.

[0449] In some embodiments, R 4 Ring B has the following structure:

[0450]

[0451] Where * is the connection point with the ring A in Formula I, which is connected to the -L-.

[0452] And among them:

[0453] R 4A R 4B and R 4D Each is independently selected from hydrogen; halogen; -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; C1-C4 alkoxy; halo-C1-C4 alkyl; C1-C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo-C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; and NR. 13 R 14 ;or

[0454] R 4A and R 4BTogether with its intercalary atom, it forms an optionally substituted 4-7-membered carbocyclic group, an optionally substituted 4-7-membered heterocyclic group, or an optionally substituted 5-6-membered heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) fused with ring B; and R 4D It is hydrogen; halogen; -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; halo-C1-C4 alkyl; C1-C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo-C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; or NR 13 R 14 ;and

[0455] R 13 Each time it appears, it is independently selected from hydrogen and C1-C4 alkyl groups optionally substituted with -OH, -OCH3 or -OCH2CH3;

[0456] R 14 It is hydrogen, or NR. 13 R 14 A heterocycle selected from nitrogen-containing heterocyclic butyl, pyrrolidinyl, and piperidinyl is formed, wherein the heterocycle is optionally substituted with -CH3.

[0457] In some embodiments, R 4 Ring B has the following structure:

[0458]

[0459] Where * is the connection point with the ring A in Formula I, which is connected to the -L-.

[0460] And among them:

[0461] R 4A and R 4D Each is hydrogen; and

[0462] R 4B It is a C1-C4 alkyl group.

[0463] In some embodiments, R 4 Ring B has the following structure:

[0464]

[0465] Where * is the connection point with the ring A in Formula I, which is connected to the -L-.

[0466] And among them:

[0467] R 4A and R 4CEach is independently selected from hydrogen; halogen; -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; C1-C4 alkoxy; halo-C1-C4 alkyl; C1-C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo-C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; and NR. 13 R 14 ;and

[0468] R 13 Each occurrence is independently selected from hydrogen and C1-C4 alkyl groups optionally substituted with -OH, -OCH3 or -OCH2CH3;

[0469] R 14 It is hydrogen; or NR 13 R 14 A heterocycle selected from nitrogen-containing heterocyclic butyl, pyrrolidinyl, and piperidinyl is formed, wherein the heterocycle is optionally substituted with -CH3.

[0470] In some embodiments, R 4 Ring B has the following structure:

[0471]

[0472] Where * is the connection point with the ring A in Formula I, which is connected to the -L-.

[0473] And among them:

[0474] R 4A and R 4C Each is independently selected from hydrogen and C1-C4 alkyl groups.

[0475] In some embodiments, R 4 Ring B has the following structure:

[0476]

[0477] Where * is the connection point with the ring A in Formula I, which is connected to the -L-.

[0478] And among them:

[0479] R 4A R 4B R 4C R 4D and R 4E Each is independently selected from hydrogen; halogen; -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; C1-C4 alkoxy; halo-C1-C4 alkyl; C1-C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo-C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; and NR.13 R 14 ;or

[0480] R 4A and R 4B Together with its intercalary atom, it forms an optionally substituted 4-7-membered carbocyclic group, an optionally substituted 4-7-membered heterocyclic group, or an optionally substituted 5-6-membered heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) fused with ring B; and R 4C R 4D and R 4E Each is independently selected from hydrogen; halogen; -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; halo-C1-C4 alkyl; C1-C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo-C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; and NR. 13 R 14 ;or

[0481] R 4C and R 4D Together with its intercalary atom, it forms an optionally substituted 4-7-membered carbocyclic group, an optionally substituted 4-7-membered heterocyclic group, or an optionally substituted 5-6-membered heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) fused with ring B; and R 4A R 4B and R 4E Each is independently selected from hydrogen; halogen; -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; halo-C1-C4 alkyl; C1-C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo-C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; and NR. 13 R 14 ;or

[0482] R 4E It is a halogen or -OH, and R 4A R 4B R 4C and R 4D Each is independently selected from hydrogen; halogen; -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; halo-C1-C4 alkyl; C1-C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo-C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; and NR. 13 R 14 ;or

[0483] R 4E and R 4ATogether with its intercalary atom, it forms an optionally substituted 4-7-membered carbocyclic group, an optionally substituted 4-7-membered heterocyclic group, or an optionally substituted 5-6-membered heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) fused with ring B; and R 4B R 4C and R 4D Each is independently selected from hydrogen; halogen; -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; halo-C1-C4 alkyl; C1-C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo-C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; and NR. 13 R 14 ;and

[0484] R 13 Each time it appears, it is independently selected from hydrogen and C1-C4 alkyl groups optionally substituted with -OH, -OCH3 or -OCH2CH3;

[0485] R 14 It is hydrogen; or NR 13 R 14 A heterocycle selected from nitrogen-containing heterocyclic butyl, pyrrolidinyl, and piperidinyl is formed, wherein the heterocycle is optionally substituted with -CH3.

[0486] In some embodiments, R 4 Ring B has the following structure:

[0487]

[0488] Where * is the connection point with the ring A in Formula I, which is connected to the -L-.

[0489] And among them:

[0490] R 4A R 4B R 4C R 4D and R 4E Each is independently selected from hydrogen; halogen; C1-C4 alkyl; and C1-C4 alkoxy; or

[0491] R 4C With R 4D It bonds with its intercalary atom to form a 4-7 membered heterocyclic group (with 1-3 nitrogen atoms) fused with ring B; and R 4A R 4B and R 4E Each is hydrogen.

[0492] In some embodiments, R 4 Ring B has the following structure:

[0493]

[0494] Where * is the connection point with the ring A in Formula I, which is connected to the -L-.

[0495] And among them:

[0496] R 4F and R 4A Together with its intercalary atom, it forms an optionally substituted 4-7-membered carbocyclic group, an optionally substituted 4-7-membered heterocyclic group, or an optionally substituted 5-6-membered heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) fused with ring B; and R 4B and R 4C Each is independently selected from hydrogen; halogen; -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; halo-C1-C4 alkyl; C1-C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo-C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; and NR. 13 R 14 ;

[0497] R 13 Each time it appears, it is independently selected from hydrogen and C1-C4 alkyl groups optionally substituted with -OH, -OCH3 or -OCH2CH3;

[0498] R 14 It is hydrogen, or NR. 13 R 14 It can combine with the N to form a heterocycle selected from nitrogen-containing heterocyclic, pyrrolidinyl, or piperidinyl, wherein the heterocycle is optionally substituted with -CH3.

[0499] In some embodiments, R 4 Ring B has the following structure:

[0500]

[0501] Where * is the connection point with the ring A in Formula I, which is connected to the -L-.

[0502] And among them:

[0503] R 4F With R 4A It bonds with its intercalary atom to form a 5-6 membered heteroaryl group fused with ring B (having 1-2 nitrogen atoms); and R 4B and R 4C Each is hydrogen.

[0504] In some embodiments, R 4 Ring B has the following structure:

[0505]

[0506] Where * is the connection point to the ring A in Equation I, specifically the -L- connection point; and where:

[0507] R 4A R 4C R 4D and R 4F Each is independently selected from hydrogen; halogen; -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; C1-C4 alkoxy; halo-C1-C4 alkyl; C1-C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo-C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; and NR. 13 R 14 ;or

[0508] R 4C and R 4D Together with its intercalary atom, it forms an optionally substituted 4-7-membered carbocyclic group, an optionally substituted 4-7-membered heterocyclic group, or an optionally substituted 5-6-membered heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) fused with ring B; and R 4A and R 4F Each is independently selected from hydrogen; halogen; -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; halo-C1-C4 alkyl; C1-C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo-C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; and NR. 13 R 14 ;or

[0509] R 4F and R 4A Together with its intercalary atom, it forms an optionally substituted 4-7-membered carbocyclic group, an optionally substituted 4-7-membered heterocyclic group, or an optionally substituted 5-6-membered heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) fused with ring B; and R 4C and R 4D Each is independently selected from hydrogen; halogen; -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; halo-C1-C4 alkyl; C1-C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo-C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; and NR. 13 R 14 ;and

[0510] R 13Each time it appears, it is independently selected from hydrogen and C1-C4 alkyl groups optionally substituted with -OH, -OCH3 or -OCH2CH3;

[0511] R 14 It is hydrogen, or NR. 13 R 14 It can combine with the N to form a heterocycle selected from nitrogen-containing heterocyclic, pyrrolidinyl, or piperidinyl, wherein the heterocycle is optionally substituted with -CH3.

[0512] In some embodiments, R 4 It is a 5-membered heteroaryl group (having one heteroatom independently selected from nitrogen, oxygen and sulfur and 0, 1, 2 or 3 additional cyclic nitrogen atoms), wherein the heteroaryl group is substituted by 0 to 4 groups independently selected from the following groups: halogen, -OH, -CN, C1-C4 alkyl, halo-C1-C4 alkyl, C3-C6 cycloalkyl and C1-C4 alkoxy.

[0513] In some embodiments, R 4 It is a 5-membered heteroaryl group (having one heteroatom independently selected from nitrogen, oxygen and sulfur and 0, 1, 2 or 3 additional cyclic nitrogen atoms), wherein the heteroaryl group is substituted by 0 to 4 groups independently selected from OH, -CH3, -CHF2, cyclopropyl and -OCH3.

[0514] In some embodiments, R 4 It is a C1-C4 alkyl, C1-C4 alkoxy, or C3-C6 cycloalkyl, wherein each is substituted by 0-3 independently selected groups from: halogen, -CN, -OH, C1-C4 alkyl, C1-C4 alkoxy, optionally substituted 5-6 membered heterocyclic groups, and optionally substituted 5-6 membered heterocyclic oxy groups. In some embodiments, R 4 It is a C1-C4 alkyl group, which is substituted by 0-3 independently selected halogens, -CN, -OH, C1-C4 alkyl groups, and C1-C4 alkoxy groups. In some embodiments, R 4 It is a C1-C4 alkoxy group, which is substituted by 0-3 independently selected halogens, -CN, -OH, C1-C4 alkyl groups, and C1-C4 alkoxy groups. In some embodiments, R 4 It is a C3-C6 cycloalkyl group, which is substituted by 0-3 independently selected halogens, -CN, -OH, C1-C4 alkyl and C1-C4 alkoxy groups.

[0515] In some embodiments, R 4 It is an isoxazolyl group substituted with -OH or C1-C4 alkoxy groups.

[0516] In some embodiments, R 4It is a 5-membered heteroaryl group (having one heteroatom independently selected from nitrogen, oxygen, and sulfur, and 0, 1, 2, or 3 additional cyclic nitrogen atoms), selected from the group consisting of: phenylthio, imidazolyl, pyrazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, wherein the heteroaryl group is substituted by 0 to 4 groups independently selected from the group consisting of: halogen, -OH, -CN, C1-C4 alkyl, halo-C1-C4 alkyl, C3-C6 cycloalkyl, and C1-C4 alkoxy.

[0517] In some embodiments, R 4 yes

[0518] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0519] In some embodiments, R 4 yes

[0520] , , , , , , , , , , , , , , , , , , , , , or .

[0521] In some embodiments, R 4 As shown in Table 1, Table 1a or Table 1b for the substituents.

[0522] As described above, each R is independently hydrogen or optionally substituted C. 1-6Aliphatic group, optionally substituted phenyl group, optionally substituted 3-7 saturated or partially unsaturated carbocyclic ring, optionally substituted 3-7 saturated or partially unsaturated heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur) or optionally substituted 5-6 saturated aromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur); or two R groups on the same atom bonded to the same atom to form optionally substituted 4-7 saturated ring, 4-7 partially unsaturated ring or 5-6 saturated aromatic ring (wherein the 4-7 saturated ring and the 4-7 partially unsaturated ring have 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein the 5-6 saturated aromatic ring has 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur).

[0523] In some embodiments, each R is independently hydrogen or optionally substituted C. 1-6 Aliphatic group, optionally substituted phenyl, optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring, optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur) or optionally substituted 5-6 membered heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur).

[0524] In some embodiments, two R groups on the same atom are bonded together with the same atom to form an optionally substituted 4-7 membered saturated ring, partially unsaturated ring, or heteroaromatic ring (wherein the 4-7 membered saturated ring, partially unsaturated ring, or heteroaromatic ring has 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0525] In some embodiments, each R is independently hydrogen or C. 1-6 Alkyl group. In some embodiments, R is hydrogen.

[0526] In some embodiments, each R is one or more substituents selected from Table 1, Table 1a or Table 1b.

[0527] In some embodiments, the compound of formula I is a compound of formula II-a or II-b or a pharmaceutically acceptable salt thereof:

[0528]

[0529] Among them, rings A and R, both individually and in combination, 1 R 2 R 3 and R 4 As defined in this article.

[0530] In some embodiments, the compound of formula I is a compound of formula II-a, formula II-b, or a pharmaceutically acceptable salt thereof:

[0531]

[0532] Among them, rings A and R, both individually and in combination, 1 R 2 R 3 and R 4 As defined in this article, and R 2a Selected from , , , , .

[0533] In some embodiments, the compound of formula I is a compound of formula II-a, formula II-b, or a pharmaceutically acceptable salt thereof:

[0534]

[0535] R, both individually and in combination 1 R 2 R 3 and R 4 As defined in this article; ring A is selected from , , , , , , , , , and And R 2a Selected from , , , , .

[0536] In some embodiments, the compound of formula I is a compound of formula III-a, formula III-b, formula IIIc, or a pharmaceutically acceptable salt thereof:

[0537]

[0538] Among them, the rings A, -L-, and R, both individually and in combination, are... 2 R 3 and R 4 As defined in this article.

[0539] In some embodiments, the compound of formula I is a compound of formula III-d, formula III-e, formula III-f, or a pharmaceutically acceptable salt thereof:

[0540]

[0541] Among them, the rings A, -L-, and R, both individually and in combination, are... 2 R 3 and R 4 As defined in this article.

[0542] In some embodiments, the compound of formula I is a compound of formula IV-a, IV-b, IV-c, or a pharmaceutically acceptable salt thereof:

[0543]

[0544] Among them, rings A and R, both individually and in combination, 2 R 3 and R 4 As defined in this article.

[0545] In some embodiments, the compound of formula I is a compound of formula IV-d, IV-e, IV-f, or a pharmaceutically acceptable salt thereof:

[0546]

[0547] Among them, rings A and R, both individually and in combination, 2 R 3 and R 4 As defined in this article.

[0548] In some embodiments, the compound of formula I is a compound of formula Va, formula Vb, formula Vc, or a pharmaceutically acceptable salt thereof.

[0549]

[0550] Among them, rings A and R, both individually and in combination, 1 R 2 and R 3 As defined in this article, and wherein:

[0551] X is CH, CR 7 Or N;

[0552] R 5 It is -OH or halogen;

[0553] R 6 It is halogen, C 1-4 Alkyl or C 1-4 Alkoxy;

[0554] Each R 7 Independently, it is hydrogen, halogen, C 1-4 Alkyl or C 1-4 Alkoxy;

[0555] R 8 It is C1-4 alkyl;

[0556] R 9 In the 0-2 examples, each of them is independently hydrogen or C. 1-4 alkyl.

[0557] In some embodiments:

[0558] X is CH or N;

[0559] R 5 It is -OH or fluorine;

[0560] R 6 It is fluorine, -CH3, or -OCH3;

[0561] Each R 7 It can be hydrogen, fluorine, -CH3, or -OCH3 independently;

[0562] R 8 It is -CH3;

[0563] R 9 Each example is independently hydrogen or -CH3.

[0564] In some embodiments, the compound of formula I is a compound of formula Vd, formula Ve, formula Vf, or a pharmaceutically acceptable salt thereof:

[0565]

[0566] Among them, rings A and R, both individually and in combination, 1 R 2 and R 3 As defined in this article, and wherein:

[0567] X is CH, CR 7 Or N;

[0568] R 5 It is -OH or halogen;

[0569] R 6 It is halogen, C 1-4 Alkyl or C 1-4 Alkoxy;

[0570] Each R 7 Independently, it is hydrogen, halogen, C 1-4 Alkyl or C 1-4 Alkoxy;

[0571] R 8 It is C 1-4 alkyl;

[0572] R 9In the 0-2 examples, each of them is independently hydrogen or C. 1-4 alkyl.

[0573] In some embodiments:

[0574] X is CH or N;

[0575] R 5 It is -OH or fluorine;

[0576] R 6 It is fluorine, -CH3, or -OCH3;

[0577] Each R 7 It can be hydrogen, fluorine, -CH3, or -OCH3 independently;

[0578] R 8 It is -CH3;

[0579] R 9 Each example is independently hydrogen or -CH3.

[0580] In some embodiments, the compound of formula I is a compound of formula VI-a, formula VI-b, formula VI-c, or a pharmaceutically acceptable salt thereof:

[0581]

[0582] Among them, rings A and R, both individually and in combination, 2 and R 3 As defined in this article, and wherein:

[0583] R 5 It is -OH or halogen; and

[0584] R 6 It is halogen, C 1-4 Alkyl or C 1-4 Alkoxy. In some embodiments, R 5 It is -OH or fluorine, and R 6 It is fluorine, -CH3, or -OCH3.

[0585] In some embodiments, the compound of formula I is a compound of formula VI-d, formula VI-e, formula VI-f, or a pharmaceutically acceptable salt thereof:

[0586]

[0587]

[0588] Among them, rings A and R, both individually and in combination, 2 and R 3 As defined in this article, and wherein:

[0589] R 5 It is -OH or halogen; and

[0590] R 6 It is halogen, C 1-4 Alkyl or C 1-4 Alkoxy group. In some embodiments: R 5 It is -OH or fluorine; and R 6 It is fluorine, -CH3, or -OCH3.

[0591] In some embodiments, the compound of formula I is a compound of formula VII-a, formula VII-b, formula VII-c, or a pharmaceutically acceptable salt thereof:

[0592]

[0593] Among them, rings A and R, both individually and in combination, 2 and R 3 As defined in this article, and wherein:

[0594] X is CH, CR 7 Or N; and each R 7 Independently, it is hydrogen, halogen, C 1-4 Alkyl or C 1-4 Alkyl group. In some embodiments: X is CH or N; and R 7 It is hydrogen, fluorine, -CH3 or -OCH3.

[0595] In some embodiments, the compound of formula I is a compound of formula VII-d, formula VII-e, formula VII-f, or a pharmaceutically acceptable salt thereof:

[0596]

[0597] Among them, rings A and R, both individually and in combination, 2 and R 3 As defined in this article, and wherein:

[0598] X is CH, CR 7 Or N; and each R 7 Independently, it is hydrogen, halogen, C 1-4 Alkyl or C 1-4 Alkyl group. In some embodiments: X is CH or N; and R 7 It is hydrogen, fluorine, -CH3 or -OCH3.

[0599] In some embodiments, the compound of formula I is a compound of formula VIII-a, VIII-b, VIII-c, or a pharmaceutically acceptable salt thereof:

[0600]

[0601] Among them, rings A and R, both individually and in combination, 2 and R 3 As defined in this article, and wherein:

[0602] R 8 It is C 1-4 Alkyl; and R 9 In the 0-2 examples, each of them is independently hydrogen or C. 1-4 Alkyl group. In some embodiments: R 8 It is -CH3; and R 9 Each example is independently hydrogen or -CH3.

[0603] In some embodiments, the compound of formula I is a compound of formula VIII-d, VIII-e, VIII-f, or a pharmaceutically acceptable salt thereof:

[0604]

[0605] Among them, rings A and R, both individually and in combination, 2 and R 3 As defined in this article, and wherein:

[0606] R 8 It is C 1-4 Alkyl; and R 9 In the 0-2 examples, each of them is independently hydrogen or C. 1-4 Alkyl group. In some embodiments: R 8 It is -CH3; and R 9 Each example is independently hydrogen or -CH3.

[0607] In some embodiments, the compound of formula I is a compound of formula IX, formula IX-a, or a pharmaceutically acceptable salt thereof:

[0608]

[0609] R, both individually and in combination 1 R 2 R 3 R A and R 4 As defined in this article.

[0610] In some embodiments, the compound of formula I is a compound of formula Xa, Xb, or Xc, or a pharmaceutically acceptable salt thereof:

[0611]

[0612] R, both individually and in combination 2 R 3 and R4 As defined in this article.

[0613] In some embodiments, the compound of formula I is a compound of formula Xd, Xe, Xf, or a pharmaceutically acceptable salt thereof:

[0614]

[0615] R, both individually and in combination 2 R 3 and R 4 As defined in this article.

[0616] In some embodiments, the compound of formula I is a compound of formula XI-a, XI-b, XI-c, or a pharmaceutically acceptable salt thereof:

[0617]

[0618] R, both individually and in combination 1 R 2 and R 3 As defined in this article, and wherein:

[0619] X is CH, CR 7 Or N;

[0620] R 5 It is -OH or halogen;

[0621] R 6 It is halogen, C 1-4 Alkyl or C 1-4 Alkoxy;

[0622] Each R 7 Independently, it is hydrogen, halogen, C 1-4 Alkyl or C 1-4 Alkoxy;

[0623] R 8 It is C 1-4 Alkyl; and

[0624] R 9 In the 0-2 examples, each of them is independently hydrogen or C. 1-4 Alkyl group. In some embodiments:

[0625] X is CH or N;

[0626] R 5 It is -OH or fluorine;

[0627] R 6 It is fluorine, -CH3, or -OCH3;

[0628] Each R 7It can be hydrogen, fluorine, -CH3, or -OCH3 independently;

[0629] R 8 It is -CH3; and

[0630] R 9 Each example is independently hydrogen or -CH3.

[0631] In some embodiments, the compound of formula I is a compound of formula XI-d, formula XI-e, formula XI-f, or a pharmaceutically acceptable salt thereof:

[0632]

[0633] R, both individually and in combination 1 R 2 and R 3 As defined in this article, and wherein:

[0634] X is CH, CR 7 Or N;

[0635] R 5 It is -OH or halogen;

[0636] R 6 It is halogen, C 1-4 Alkyl or C 1-4 Alkoxy;

[0637] Each R 7 Independently, it is hydrogen, halogen, C 1-4 Alkyl or C 1-4 Alkoxy;

[0638] R 8 It is C 1-4 Alkyl; and

[0639] R 9 In the 0-2 examples, each of them is independently hydrogen or C. 1-4 Alkyl group. In some embodiments:

[0640] X is CH, CR 7 Or N;

[0641] R 5 It is -OH or halogen;

[0642] R 6 It is a halogen, -CH3 or -OCH3;

[0643] Each R 7 It can be hydrogen, halogen, -CH3, or -OCH3 independently;

[0644] R 8 It is -CH3; and

[0645] R 9 Each example is independently hydrogen or -CH3.

[0646] In some embodiments, the compound of formula I is a compound of formula XII-a, XII-b, XII-c, or a pharmaceutically acceptable salt thereof:

[0647]

[0648] R, both individually and in combination 2 and R 3 As defined in this article, and wherein:

[0649] R 5 It is -OH or halogen; and

[0650] R 6 It is halogen, C 1-4 Alkyl or C 1-4 Alkoxy group. In some embodiments: R 5 It is -OH or fluorine; and R 6 It is fluorine, -CH3, or -OCH3.

[0651] In some embodiments, the compound of formula I is a compound of formula XII-d, XII-e, XII-f, or a pharmaceutically acceptable salt thereof:

[0652]

[0653] R, both individually and in combination 2 and R 3 As defined in this article, and wherein:

[0654] R 5 It is -OH or halogen; and

[0655] R 6 It is halogen, C 1-4 Alkyl or C 1-4 Alkoxy group. In some embodiments: R 5 It is -OH or fluorine; and R 6 It is fluorine, -CH3, or -OCH3.

[0656] In some embodiments, the compound of formula I is a compound of formula XIII-a, XIII-b, XIII-c, or a pharmaceutically acceptable salt thereof:

[0657]

[0658]

[0659] R, both individually and in combination 2 and R 3 As defined in this article, and wherein:

[0660] X is CH, CR 7 Or N; and

[0661] Each R 7 Independently, it is hydrogen, halogen, C 1-4 Alkyl or C 1-4 Alkyl group.

[0662] In some embodiments, the compound of formula I is a compound of formula XIII-d, XIII-e, XIII-f, or a pharmaceutically acceptable salt thereof:

[0663]

[0664] R, both individually and in combination 2 and R 3 As defined in this article, and wherein:

[0665] X is CH, CR 7 Or N; and

[0666] Each R 7 Independently, it is hydrogen, halogen, C 1-4 Alkyl or C 1-4 Alkyl group.

[0667] In some embodiments, X is CH or N; and each R 7 It can be hydrogen, fluorine, -CH3 or -OCH3 independently.

[0668] In some embodiments, the compound of formula I is a compound of formula XIV-a, XIV-b, XIV-c, or a pharmaceutically acceptable salt thereof:

[0669]

[0670] R, both individually and in combination 2 and R 3 As defined in this article, and wherein:

[0671] R 8 It is C 1-4 Alkyl; and

[0672] R 9 In the 0-2 examples, each of them is independently hydrogen or C. 1-4 Alkyl group. In some embodiments: R 8 It is -CH3; and R 9 Each example is independently hydrogen or -CH3.

[0673] In some embodiments, the compound of formula I is a compound of formula XIV-d, XIV-e, XIV-f, or a pharmaceutically acceptable salt thereof:

[0674]

[0675]

[0676] R, both individually and in combination 2 and R 3 As defined in this article, and wherein:

[0677] R 8 It is C 1-4 Alkyl; and

[0678] R 9 In the 0-2 examples, each of them is independently hydrogen or C. 1-4 Alkyl group. In some embodiments: R 8 It is -CH3; and R 9 Each example is independently hydrogen or -CH3.

[0679] In some embodiments, the compound of formula I is a compound of formula XIV-d, XIV-e, XIV-f, or a pharmaceutically acceptable salt thereof:

[0680] R, both individually and in combination 2 and R 3 As defined in this article;

[0681] R 2A It is phenyl, pyridyl or bicyclo[1.1.1]pentyl, wherein each is optionally substituted by 1, 2 or 3 substituents independently selected from the following: halogen, C1-C4 alkyl, halo-C1-C4 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, -OH, -CN, C1-C4 alkoxy, halo-C1-C4 alkoxy and -SF5;

[0682] R 8 It is C 1-4 Alkyl; and

[0683] R 9 In the 0-2 examples, each of them is independently hydrogen or C. 1-4 Alkyl group. In some embodiments: R 8 It is -CH3; and R 9 Each example is independently hydrogen or -CH3.

[0684] In some embodiments, the Formula I compound is selected from one of the compounds depicted in Table 1, Table 1a, or Table 1b, or a pharmaceutically acceptable salt thereof. Tables 1, 1a, or 1b identify compounds by their IUPAC names, and Tables 2, 2a, and 2b list the same compounds and show their chemical structures. In the event of any discrepancy between the name of a compound in Table 1, 1a, or 1b and the structure of the same compound in Table 2, 2a, or 2b, the structure of the compound in Table 2, 2a, or 2b is used as the primary reference, and the compound corresponding to each corresponding compound number (I-#) in Table 1, 1a, or 1b is identified.

[0685] Table 1

[0686]

[0687]

[0688]

[0689]

[0690]

[0691]

[0692]

[0693]

[0694]

[0695]

[0696]

[0697]

[0698]

[0699]

[0700]

[0701]

[0702]

[0703] Table 1a

[0704]

[0705]

[0706]

[0707]

[0708]

[0709]

[0710]

[0711] Table 1b

[0712]

[0713] 4. Pharmaceutical compositions, treatment methods, and uses of compounds

[0714] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In another embodiment, the composition comprises at least two pharmaceutically acceptable carriers, such as those described herein. The pharmaceutical composition may be formulated according to a particular route of administration, such as oral administration, parenteral administration (e.g., by injection, infusion, transdermal or topical administration), and rectal administration, especially oral administration. Topical administration may also involve inhalation or intranasal application. The pharmaceutical compositions of the present invention may be prepared in solid form (including, but not limited to, capsules, tablets, pills, granules, powders, or suppositories) or in liquid form (including, but not limited to, solutions, suspensions, or emulsions). Tablets may be coated with a film or an enteric coating according to methods known in the art. Typically, the pharmaceutical composition is a tablet or gelatin capsule comprising an active ingredient and one or more of the following:

[0715] a) Diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine;

[0716] b) Lubricants, such as silica, talc, stearic acid, magnesium or calcium salts of stearic acid, and / or polyethylene glycol; also included in tablets.

[0717] c) Adhesives, such as magnesium aluminum silicate, starch paste, gelatin, astragalus gum, methylcellulose, sodium carboxymethyl cellulose and / or polyvinylpyrrolidone; if necessary.

[0718] d) Disintegrants, such as starch, agar, alginate, or their sodium salts or foaming mixtures; and

[0719] e) Adsorbents, colorants, flavoring agents, and sweeteners.

[0720] Typical methods for dissolving compounds for parenteral administration include pH optimization or the use of co-solvents (e.g., PEG300, PEG400, propylene glycol, or ethanol). If these methods are not feasible for any reason, surfactants (e.g., Tween® 80 or Cremophor EL®) may be considered. Cyclodextrins have been identified as safe solubilizers. Compounds with high solubility in natural oils are soluble in parenteral fat emulsions.

[0721] Also provided is a pharmaceutical composition comprising a compound of formula I described herein or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

[0722] use

[0723] Compounds of Formula I of the present invention, in free form or in pharmaceutically acceptable salt form, exhibit valuable pharmacological properties, such as WRN inhibitory properties, as indicated by in vitro tests provided in the following sections, and are therefore suitable for therapeutic or investigational chemical purposes, such as as chemical probes and tool compounds.

[0724] A compound of Formula I described herein is also provided. This compound can be used as an investigational chemical substance, a compound containing the added biotin moiety herein, such as a tool compound or a chemical probe, particularly for WRN research. In another embodiment, the use of the compound of Formula I described herein as an investigational chemical substance (e.g., a tool compound or a chemical probe), particularly for WRN research, is provided.

[0725] Also provided is a compound of formula I described herein, or a pharmaceutically acceptable salt thereof, for the treatment of cancer. Cancers that can be treated by WRN inhibition include cancers characterized by microsatellite high instability (MSI-H) or mismatch repair deficiency (dMMR). Specifically, the compound of formula I described herein, or a pharmaceutically acceptable salt thereof, is suitable for the treatment of cancers characterized by microsatellite high instability (MSI-H) or mismatch repair deficiency (dMMR).

[0726] Also provided is a compound of formula I described herein, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical agent. Specifically, the use is:

[0727] ● Used to treat diseases that are treated by WRN inhibition.

[0728] ●Used to treat cancer,

[0729] ● Used to treat cancers characterized by microsatellite high instability (MSI-H) or mismatch repair deficiency (dMMR).

[0730] ● Used to treat cancers characterized by microsatellite instability-high (MSI-H) or mismatch repair deficiency (dMMR), such as colorectal cancer, gastric cancer, prostate cancer, endometrial cancer, adrenocortical cancer, uterine cancer, cervical cancer, esophageal cancer, breast cancer, kidney cancer, and ovarian cancer.

[0731] ● For the treatment of cancers characterized by microsatellite high instability (MSI-H) or mismatch repair deficiency (dMMR), wherein the cancers are selected from colorectal cancer, gastric cancer, prostate cancer, and endometrial cancer, or

[0732] ● Used to treat cancers, including cancers characterized by microsatellite high instability (MSI-H) or mismatch repair deficiency (dMMR) selected from endometrial cancer of the uterine body, colonic adenocarcinoma, gastric adenocarcinoma, rectal adenocarcinoma, adrenocortical carcinoma, uterine carcinosarcoma, cervical squamous cell carcinoma, cervical endometrial adenocarcinoma, esophageal cancer, breast cancer, kidney clear cell carcinoma, prostate cancer, and ovarian serous cystadenocarcinoma.

[0733] A method is also provided, the method being:

[0734] ● Modulating an individual's WRN activity, wherein the method comprises administering to the individual a therapeutically effective amount of a compound of formula I described herein or a pharmaceutically acceptable salt thereof.

[0735] ● Inhibit an individual's WRN, wherein the method comprises administering to the individual a therapeutically effective amount of a compound of formula I described herein or a pharmaceutically acceptable salt thereof.

[0736] ● A condition or disease that can be treated by WRN inhibition in an individual, comprising administering to said individual a therapeutically effective amount of a compound of formula I described herein or a pharmaceutically acceptable salt thereof.

[0737] ● Treating an individual's cancer involves administering to said individual a therapeutically effective amount of a compound of formula I described herein or a pharmaceutically acceptable salt thereof.

[0738] ● Treating an individual's cancer, comprising administering a compound of formula I described herein, wherein the cancer is characterized by microsatellite high instability (MSI-H) or mismatch repair deficiency (dMMR). Specifically, the cancers characterized by microsatellite high instability (MSI-H) or mismatch repair deficiency (dMMR) are selected from colorectal cancer, gastric cancer, prostate cancer, endometrial cancer, adrenocortical cancer, uterine cancer, cervical cancer, esophageal cancer, breast cancer, kidney cancer, and ovarian cancer. More specifically, cancers characterized by microsatellite high instability (MSI-H) or mismatch repair deficiency (dMMR) are selected from colorectal cancer, gastric cancer, prostate cancer, and endometrial cancer. Examples include endometrial cancer of the uterine corpus, colonic adenocarcinoma, gastric adenocarcinoma, rectal adenocarcinoma, adrenocortical carcinoma, uterine carcinosarcoma, cervical squamous cell carcinoma, cervical endometrial adenocarcinoma, esophageal cancer, breast cancer, kidney clear cell carcinoma, prostate cancer, and ovarian serous cystadenocarcinoma.

[0739] Uses of the compounds of formula I described herein, or pharmaceutically acceptable salts thereof, are also provided:

[0740] ●Treatment,

[0741] ●Manufacturing pharmaceuticals,

[0742] ●Manufacturing drugs for the treatment of cancer. Specifically, the cancer is characterized by microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR).

[0743] ●Manufacturing drugs for treating diseases that can be treated by WRN inhibition.

[0744] Specifically, the cancers are characterized by microsatellite high instability (MSI-H) or mismatch repair deficiency (dMMR), such as colorectal cancer, gastric cancer, prostate cancer, endometrial cancer, adrenocortical cancer, uterine cancer, cervical cancer, esophageal cancer, breast cancer, kidney cancer, and ovarian cancer. More specifically, colorectal cancer, gastric cancer, prostate cancer, or endometrial cancer, or endometrial cancer of the uterine corpus, colonic adenocarcinoma, gastric adenocarcinoma, rectal adenocarcinoma, adrenocortical cancer, uterine carcinosarcoma, cervical squamous cell carcinoma, cervical endometrial adenocarcinoma, esophageal cancer, breast cancer, kidney clear cell carcinoma, and ovarian serous cystadenocarcinoma.

[0745] In some embodiments, such as a control individual or a normal individual, the individual has been identified or has been identified as having microsatellite instability (MSI-H) cancer. In one embodiment, the individual has an MSI-H advanced solid tumor, colorectal cancer (CRC), endometrial cancer, uterine cancer, gastric cancer, or other MSI-H cancer. In some embodiments, the individual has colorectal cancer (CRC), endometrial cancer, or gastric cancer, such as a control individual or a normal individual, said cancer has been identified or has been identified as having microsatellite instability (MSI-H). This identification technique is known in the art.

[0746] form

[0747] Depending on the choice of starting material and procedure, the compound may exist in one possible stereoisomer form or in mixtures thereof, for example, depending on the number of asymmetric carbon atoms, in a pure optical isomer form or in a mixture of stereoisomers, such as a racemic mixture and a mixture of diastereomers. This invention is intended to include all such possible stereoisomers, including racemic mixtures, diastereomer mixtures, and optically pure forms. Optically active (R)- and (S)- stereoisomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be E or Z configuration. If the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituent may have a cis or trans configuration. All tautomeric forms are also intended to be included.

[0748] Except for deuteration specifically required in Formula I, any formula specified herein is intended to represent both the unlabeled and isotopically labeled forms of the compound. Isotopically labeled compounds have the structures described by the formulas given herein, differing in that one or more atoms are replaced by atoms having selected atomic masses or mass numbers. Isotopes that may be incorporated into the compounds of this invention include, for example, isotopes of hydrogen.

[0749] Furthermore, the incorporation of an isotope, particularly deuterium (i.e., 2H or D), can yield certain therapeutic advantages resulting from greater metabolic stability, such as prolonged in vivo half-life, reduced dose requirements, or improved therapeutic index or tolerability. It should be understood that, in this context, deuterium is considered a substituent in the compounds of this invention. Deuterium concentration can be defined by an isotope enrichment factor. As used herein, the term "isotope enrichment factor" refers to the ratio between the isotopic abundance of a particular isotope and its natural abundance. If the substituent in the compound of the present invention is deuterium, then such compounds have an isotopic enrichment factor of at least 3500 (52.5% deuterium inclusion at each specified deuterium atom), at least 4000 (60% deuterium inclusion), at least 4500 (67.5% deuterium inclusion), at least 5000 (75% deuterium inclusion), at least 5500 (82.5% deuterium inclusion), at least 6000 (90% deuterium inclusion), at least 6333.3 (95% deuterium inclusion), at least 6466.7 (97% deuterium inclusion), at least 6600 (99% deuterium inclusion), or at least 6633.3 (99.5% deuterium inclusion). It should be understood that the term "isotope enrichment factor" can be applied to any isotope in the same way as it is described for deuterium.

[0750] Other examples of isotopes that can be incorporated into the compounds of this invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as 3H, 11C, 13C, 14C, 15N, 18F, 31P, 32P, 35S, 36CI, 123I, 124I, and 125I, respectively. Therefore, it should be understood that this invention includes compounds incorporating one or more of the aforementioned isotopes, including, for example, radioactive isotopes (e.g., 3H and 14C), or compounds in which non-radioactive isotopes (e.g., 2H and 13C) are present. Such isotopically labeled compounds are suitable for metabolic studies (using 14C); reaction kinetic studies (using, for example, 2H or 3H); detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays; or for use in the radiotherapy of patients. Specifically, 18F-labeled or labeled compounds are particularly desirable for PET or SPECT studies. The isotopically labeled compounds of the present invention can generally be prepared using conventional techniques known to those skilled in the art, or by methods similar to those described in the accompanying examples and preparations, using a suitable isotopically labeled reagent instead of the previously used unlabeled reagent.

[0751] "Compounds of this invention" or "Compounds of Formula I" include their zwitterions, their non-zwitterions (uncharged forms), or pharmaceutically acceptable salts of said zwitterions or their non-zwitterions. "Zwitterion" or "zwitterion form" means a compound containing both positively and negatively charged functional groups.

[0752] The term "cancer" refers to a disease characterized by the rapid and uncontrolled growth of abnormal cells. Cancer cells can spread locally or to other parts of the body via the bloodstream and lymphatic system. This article describes examples of various cancers, including (but not limited to) colorectal cancer, stomach cancer, endometrial cancer, prostate cancer, adrenocortical cancer, uterine cancer, cervical cancer, esophageal cancer, breast cancer, kidney cancer, ovarian cancer, and more.

[0753] The terms “tumor” and “cancer” are used interchangeably in this document, for example, both terms cover both solid and fluid forms, such as diffuse or circulating tumors. As used herein, the terms “cancer” or “tumor” include both pre-existing and malignant cancers and tumors.

[0754] As used herein, “WRN inhibitor” or “WRN helicase inhibitor” refers to a compound that inhibits Werner syndrome RecQ DNA helicase (WRN). The term “WRN” as used herein refers to the Werner syndrome RecQ DNA helicase protein. The term “WRN” includes mutants, fragments, variants, isoforms, and homologs of the full-length wild-type WRN. In one embodiment, the protein is encoded by the WRN gene (Entrez gene ID 7486; Ensembl ID ENSG00000165392). Exemplary WRN sequences are available in the Uniprot database with accession number Q14191.

[0755] “WRN-mediated diseases or conditions” include diseases or conditions that can be treated by WRN inhibition, such as cancer. Specifically, this can include cancers characterized by microsatellite high instability (MSI-H) or mismatch repair deficiency (dMMR).

[0756] “Microsatellite unstable cancer,” “microsatellite highly unstable cancer,” “high microsatellite cancer,” “high MSI cancer,” “MSIhi,” and “MSI-H” are used interchangeably in this document and describe cancers in which the length of simple repetitive genomic sequences within microsatellites varies considerably.

[0757] The MSI-H or dMMR tumor status of a patient can be determined using, for example, polymerase chain reaction (PCR) tests for MSI-H status or immunohistochemical (IHC) tests for dMMR. Methods for identifying MSI-H or dMMR tumor status are described, for example, in Ryan et al., Crit Rev Oncol Hematol. 2017; 116:38-57; Dietmaier and Hofstadter, Lab Invest 2001, 81:1453-1456; and Kawakami et al., Curr Treat Options Oncol. 2015; 16(7): 30.

[0758] Microsatellite instability is particularly evident in colorectal cancer, gastric cancer, and endometrial cancer, and is also found in adrenocortical carcinoma, uterine cancer, cervical cancer, esophageal cancer, breast cancer, kidney cancer, prostate cancer, and ovarian cancer. Examples of cancers with high microsatellite instability include endometrial cancer of the uterine corpus, colonic adenocarcinoma, gastric adenocarcinoma, rectal adenocarcinoma, adrenocortical carcinoma, uterine carcinosarcoma, cervical squamous cell carcinoma, cervical endometrial adenocarcinoma, esophageal cancer, breast cancer, kidney clear cell carcinoma, and ovarian serous cystadenocarcinoma.

[0759] Cancers exhibiting "mismatch repair deficiency" (dMMR) or "dMMR signature" include cancer types associated with documented mutations or epigenetic silencing of MLH1, PMS2, MSH2, MSH3, MSH6, MLH3, and PMS1, microsatellite fragile sites, or other gene inactivation mechanisms, including (but not limited to) lung cancer, breast cancer, kidney cancer, colorectal cancer, ovarian cancer, prostate cancer, upper respiratory and digestive tract cancers, gastric cancer, endometrial cancer, liver cancer, pancreatic cancer, hematopoietic and lymphoid tissue cancers, skin cancer, thyroid cancer, pleural cancer, autonomic ganglion cancers, central nervous system cancers, soft tissue cancers, pediatric rhabdomyosarcoma, melanoma, and other cancers. Cells or cancers exhibiting "mismatch repair deficiency" show a significantly reduced amount of mismatch repair (e.g., a reduction of at least approximately 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%). In some cases, cells or cancers exhibiting "mismatch repair deficiency" will not undergo mismatch repair at all.

[0760] As used herein, the term "pharmaceutical composition" refers to the compound of the present invention or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, in a form suitable for oral or parenteral administration.

[0761] As used herein, the term “pharmaceutically acceptable carrier” means a substance suitable for the preparation or use of a pharmaceutical composition, and includes, for example, suitable diluents, solvents, dispersion media, surfactants, antioxidants, preservatives, isotonic agents, buffers, emulsifiers, absorption delay agents, salts, pharmaceutical stabilizers, binders, excipients, disintegrants, lubricants, wetting agents, sweeteners, flavoring agents, dyes, and combinations thereof (see, for example, Remington The Science and Practice of Pharmacy, 22nd ed., Pharmaceutical Press, 2013, pp. 1049-1070).

[0762] The terms “synthetic lethality” and “synthetic lethality” are used to refer to a decrease in cell viability and / or cell proliferation rate resulting from a combination of mutations or methods that cause the loss of function of two or more genes (e.g., RNA interference or protein function inhibition) but not the loss of function of only one of these genes.

[0763] The term "therapeuticly effective amount" for the compounds of this invention refers to the amount of the compound of this invention that will elicit a biological or medical response in an individual, such as a reduction or inhibition of enzyme or protein activity, or improvement of symptoms, relief of condition, slowing or delaying disease progression, or prevention of disease. In some embodiments, the method of this invention comprises administering a therapeutically effective amount of the compound of this invention.

[0764] In one embodiment, the term "therapeutic effective amount" refers to the amount of the compound of the present invention that, when administered to an individual, can effectively (1) at least partially alleviate, prevent and / or improve (i) a condition or symptom or disease mediated by WRN or (ii) associated with WRN activity or (iii) characterized by WRN activity (normal or abnormal); or (2) reduce or inhibit WRN activity.

[0765] In another embodiment, the term "therapeuticly effective amount" refers to the amount of the compound of the present invention that, when applied to cells or tissues or non-cellular biological materials or culture media, effectively at least partially reduces or inhibits WRN activity or lowers WRN protein content.

[0766] As used herein, the term "individual" refers to a primate (e.g., a human male or female), a dog, a rabbit, a guinea pig, a pig, a rat, or a mouse. In some embodiments, the individual is a primate, a rat, or a mouse. In still other embodiments, the individual is a human.

[0767] As used herein, the term “inhibition” or “inhibiting” means reducing or inhibiting a given condition, symptom, ailment, or disease, or significantly reducing the baseline activity of a biological activity or process.

[0768] As used herein, the terms “treat,” “treating,” or “treatment” refer to any disease or condition that is relieved or improved (i.e., slowed or halted the development of the disease or at least one of its clinical symptoms); or relieved or improved at least one physiological parameter or biomarker associated with the disease or condition, including physiological parameters or biomarkers that are not identifiable to the patient.

[0769] As used herein, the terms “prevent,” “preventing,” or “prevention” refer to preventive treatment of any disease or condition, or delay in the onset or progression of such disease or condition.

[0770] As used herein, an individual “needs” the treatment if he or she will benefit from it biologically, medically, or in terms of quality of life.

[0771] Unless otherwise indicated herein or clearly contradicted by the context, the terms “a”, “an”, “the” and similar terms used herein (especially in the context of the claims) shall be construed as encompassing both the singular and the plural.

[0772] "Can be joined" means to join or not join.

[0773] "Can be replaced by deuterium" means either replaced by deuterium or not replaced by deuterium.

[0774] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. While similar or equivalent methods and materials to those described and used herein may be used to practice or test the invention, suitable methods and materials are described below. Furthermore, materials, methods, and examples are illustrative only and are not intended to be limiting. Unless otherwise indicated herein or where the context clearly contradicts it, all methods described herein may be performed in any suitable order. The use of any and all examples or exemplary language provided herein (e.g., “such as”) is intended only to better illustrate the invention and does not constitute a limitation on the scope of the invention as otherwise claimed.

[0775] Heterogeneous forms

[0776] Any asymmetric atom (e.g., carbon) in one or more compounds of the present invention may be present in a racemic or enantiomerically enriched form, such as (R) configuration, (S) configuration, or (R,S) configuration. In some embodiments, each asymmetric atom has at least 50% enantiomer excess, at least 60% enantiomer excess, at least 70% enantiomer excess, at least 80% enantiomer excess, at least 90% enantiomer excess, at least 95% enantiomer excess, or at least 99% enantiomer excess in the (R) or (S) configuration. If possible, substituents at atoms having unsaturated double bonds may be present in cis-(Z)- or trans-(E)- form.

[0777] Therefore, as used herein, the compounds of the present invention may be in the form of possible stereoisomers, rotational isomers, configurational isomers, tautomers or mixtures thereof, for example, in the form of substantially pure geometric (cis or trans) stereoisomers, diastereomers, optical isomers (enantiomers), racemates or mixtures thereof.

[0778] Any mixture of stereoisomers obtained can be separated into pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example by chromatography and / or stepwise crystallization, based on the physicochemical differences of the components.

[0779] Any resulting racemic mixture of the compounds or intermediates of the present invention can be resolved into optical enantiomers by known methods, for example, by separating their diastereomeric salts obtained with optically active acids or bases and releasing optically active acidic or basic compounds. Specifically, the basic moiety can therefore be used to resolve the compounds of the present invention into their optical enantiomers, for example, by stepwise crystallization of salts formed from optically active acids (e.g., tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, di-O,O'-p-toluamide tartaric acid, mandelic acid, malic acid, or camphor-10-sulfonic acid). The racemic compounds or racemic intermediates of the present invention can also be resolved by chiral chromatography (e.g., high-performance liquid chromatography (HPLC)) using chiral adsorbents.

[0780] The compounds of the present invention, namely compounds of formula (I) containing groups capable of acting as hydrogen bond donors and / or acceptors, are capable of forming cocrystals with suitable cocrystal forming agents. These cocrystals can be prepared from compounds of formula (I) using known cocrystal forming procedures. These procedures include milling, heating, co-sublimation, co-melting, or contacting the compound of formula (I) with a cocrystal forming agent in solution under crystallization conditions, and separating the resulting cocrystal. Suitable cocrystal forming agents include those described in WO 2004 / 078163. Therefore, the present invention further provides cocrystals comprising compounds of formula (I).

[0781] Furthermore, the compounds of the present invention (including their salts) may also be obtained in the form of their hydrates, or may include other solvents for their crystallization.

[0782] The compounds of this invention can inherently or by design form solvates with pharmaceutically acceptable solvents, including water; therefore, this invention is intended to cover both solvated and non-solvated forms. The term "solvate" refers to a molecular complex of a compound of this invention (including its pharmaceutically acceptable salts) with one or more solvent molecules. Such solvent molecules are those commonly used in pharmaceutical techniques and are known to be harmless to the recipient, such as water, ethanol, etc. The term "hydrate" refers to a complex in which the solvent molecule is water.

[0783] Dosage form

[0784] The pharmaceutical compositions or combinations of the present invention may, for example, be in the form of a unit dose of about 1-1000 mg of active ingredient for an individual weighing about 50-70 kg.

[0785] combination

[0786] "Combination" refers to a fixed combination in a single dosage form, or combined administration, wherein a compound of Formula I or a pharmaceutically acceptable salt thereof and a combination thereof (e.g., another drug explained below, also referred to as a "therapeutic agent" or "adjuvant") may be administered simultaneously or separately at time intervals, particularly where such time intervals allow the combination to exhibit synergistic effects, such as a synergistic effect. Single components may be packaged in a kit or separately. One or both components (e.g., powder or liquid) may be reconstituted or diluted to the desired dose prior to administration. The terms "co-administration" or "combination administration" as used herein are intended to cover the administration of selected combination combinations to a single individual in need (e.g., a patient) and are intended to include treatment regimens in which the agents are not necessarily administered via the same route of administration or simultaneously. The term "drug combination" as used herein means a product resulting from mixing or combining more than one therapeutic agent and includes both fixed and non-fixed combinations of therapeutic agents. The term "fixed combination" means that the therapeutic agents, such as the compounds and combination combinations of the present invention, are administered simultaneously to a patient in a single entity or dose form.

[0787] The term "non-fixed combination" means therapeutic agents, such as the compounds and combinations of the present invention, which are administered to a patient simultaneously, in parallel, or sequentially as independent entities without a specific time limit, wherein such administration of two compounds in the patient provides a therapeutically effective level. The latter also applies to cocktail therapies, such as the administration of three or more therapeutic agents.

[0788] The combinations described herein may include compounds of Formula I and one or more other therapeutic agents, such as one or more anticancer agents, cytotoxic agents or cell growth inhibitors, hormone therapy, vaccines and / or other immunotherapies. In other embodiments, the combination is further administered or used in combination with other therapeutic modalities, including surgery, radiation, cryosurgery and / or hyperthermia. Such combination therapies can advantageously utilize lower doses of therapeutic agents, thereby avoiding potential treatment-related toxicities or complications.

[0789] Also provided is a combination comprising a compound of formula I described herein or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents. Other therapeutic agents are, for example, compounds, peptides, antibodies, antibody fragments, or nucleic acids that have therapeutic activity or enhance therapeutic activity when administered to a patient in combination with compounds of this disclosure. Specifically, another therapeutic agent is:

[0790] ●Anticancer agents,

[0791] ●Chemotherapy agents,

[0792] ● Liposome injections (DaunoXome®), dexamethasone, docetaxel (Taxotere®), doxorubicin hydrochloride (Adriamycin®, Rubex®), etoposide (Vepesid®), fludarabine phosphate (Fludara®), 5-fluorouracil (Adrucil®, Efudex®), flutamide (Eulexin®), tezacitibine, gemcitabine (difluorodeoxycytidine), hydroxyurea (Hydrea®), idarubicin (Idamycin®), ifosfamide (IFEXO), irinotecan (Camptosar®), L-asparaginase (ELSPAR®), calcium leucovorin, melphalan. Alkeran®, Purinethol®, Methotrexate Folex®, Mitoxantrone (Novantrone®), Mylotarg, Taxol®, Phoenix (Yttrium 90 / MX-DTPA), Pentostatin, Polifeprosan 20 with Carmustine Implant (Gliadel®), Tamoxifen Citrate (Nolvadex®), Teniposide (Vumon®), 6-Thioguanine, Thiotepa, Tirapazamine (Tirazone®), Topotecan Hydrochloride for Injection (Hycamptin®), Vinblastine (Velban®), vincristine (Oncovin®), and vinorelbine (Navelbine®), especially fluorouracil (5-FU) and irinotecan (Camptosar®).

[0793] ●PD-1 inhibitors,

[0794] ●Anti-PD-1 antibody molecules,

[0795] ●Spartalizumab, or

[0796] ● Tislelizumab (BGB-A317, BeiGene).

[0797] In some embodiments, the additional therapeutic active agent is:

[0798] ● Selected from the following chemotherapeutic agents: anastrozole (Arimidex®), bicalutamide (Casodex®), bleomycin sulfate (Blenoxane®), butacaine sulfate (Myleran®), butacaine sulfate injection (Busulfex®), capecitabine (Xeloda®), N4-pentoxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin (Paraplatin®), carmustine (BiCNU®), chlorambucil (Leukeran®), cisplatin (Platinol®), cladribine. Leustatin®, cyclophosphamide (Cytoxan® or Neosar®), cytarabine, cytosine arabinoside (Cytosar-U®), cytarabine liposome injection (DepoCyt®), dacarbazine (DTIC-Dome®), actinomycin D (cosmegan), daunorubicin hydrochloride (Cerubidine®), daunorubicin citrate, or

[0799] ● PD-1 inhibitors selected from the following: spartazumab (Novartis), nivolumab (Bristol-Myers Squibb), pembrolizumab (Merck & Co.), pidilizumab (CureTech), MED10680 (Medimmune), cemiplimab (REGN2810, Regeneron), dostarlimab (TSR-042, Tesaro), PF-06801591 (Pfizer), tislelizumab (BGB-A317, BeiGene), BGB-108 (BeiGene), INCSHR1210 (Incyte), balstilimab (AGEN2035, Agenus), sintilimab (InnoVent), toripalimab (Shanghai Junshi Bioscience), camrelizumab (Jiangsu Hengrui Medicine Co.), AMP-224 (Amplimmune), penpulimab (Akeso Biopharma Inc.), zimberelimab (Acus Biosciences Inc.), and prolgolimab (Biocad Ltd.). In another embodiment, another therapeutic agent is the chemotherapeutic agent irinotecan (Camptosar®).

[0800] In another embodiment, another therapeutic agent is a PD-1 (e.g., human PD-1) inhibitor. In another embodiment, the immunomodulator is a PD-L1 inhibitor, such as human PD-L1. In one embodiment, a PD-1 or PD-L1 inhibitor is an antibody molecule targeting PD-1 or PD-L1. In another embodiment, another therapeutic agent is an anti-PD-1 antibody molecule.

[0801] In another embodiment, the PD-1 inhibitor is the anti-PD-1 antibody molecule described in US 2015 / 0210769, entitled "Antibody Molecules to PD-1 and Uses Thereof," published on July 30, 2015.

[0802] In another embodiment, a combination of a compound of formula I or a pharmaceutically acceptable salt thereof with a chemotherapeutic agent and a PD-1 inhibitor is provided. Specifically, the chemotherapeutic agent and the PD-1 inhibitor are selected from the above-described pharmaceutical agents. In some embodiments, the PD-1 inhibitor (e.g., tislelizumab) is administered at a uniform dose between about 100 mg and about 600 mg. In some embodiments, the PD-1 inhibitor is administered at a dose between about 100 mg and about 500 mg. In some embodiments, the PD-1 inhibitor is administered at a dose between about 100 mg and about 400 mg. In some embodiments, the PD-1 inhibitor is administered at a dose between about 100 mg and about 300 mg. In some embodiments, the PD-1 inhibitor is administered at a dose between about 100 mg and about 200 mg. In some embodiments, the PD-1 inhibitor is administered at a dose between about 200 mg and about 600 mg. In some embodiments, the PD-1 inhibitor is administered at a dose between about 200 mg and about 500 mg. In some embodiments, the PD-1 inhibitor is administered at a dose between about 200 mg and about 400 mg. In some embodiments, the PD-1 inhibitor is administered at a dose between about 200 mg and about 300 mg. In some embodiments, the PD-1 inhibitor is administered at a dose between about 300 mg and about 600 mg. In some embodiments, the PD-1 inhibitor is administered at a dose between about 300 mg and about 500 mg. In some embodiments, the PD-1 inhibitor is administered at a dose between about 300 mg and about 400 mg. In some embodiments, the PD-1 inhibitor is administered at a dose between about 400 mg and about 600 mg. In some embodiments, the PD-1 inhibitor is administered at a dose between about 400 mg and about 500 mg. In some embodiments, the PD-1 inhibitor is administered at a dose between about 500 mg and about 600 mg. In some embodiments, the PD-1 inhibitor is administered at a dose between about 600 mg and about 700 mg. In some embodiments, the PD-1 inhibitor is administered at a dose between about 700 mg and about 800 mg. In some embodiments, the PD-1 inhibitor is administered at a dose between about 800 mg and about 900 mg. In some embodiments, the PD-1 inhibitor is administered at a dose between about 900 mg and about 1000 mg.

[0803] In some embodiments, a PD-1 inhibitor (e.g., tislelizumab) is administered at a uniform dose of about 100 mg. In some embodiments, a PD-1 inhibitor is administered at a dose of about 200 mg. In some embodiments, a PD-1 inhibitor is administered at a dose of about 300 mg. In some embodiments, a PD-1 inhibitor is administered at a dose of about 400 mg. In some embodiments, a PD-1 inhibitor is administered at a dose of about 500 mg. In some embodiments, a PD-1 inhibitor is administered at a dose of about 600 mg. In some embodiments, a PD-1 inhibitor is administered at a dose of about 700 mg. In some embodiments, a PD-1 inhibitor is administered at a dose of about 800 mg. In some embodiments, a PD-1 inhibitor is administered at a dose of about 900 mg. In some embodiments, a PD-1 inhibitor is administered at a dose of about 1000 mg.

[0804] In some embodiments, a PD-1 inhibitor (e.g., tislelizumab) is administered once every ten weeks. In some embodiments, a PD-1 inhibitor is administered once every nine weeks. In some embodiments, a PD-1 inhibitor is administered once every eight weeks. In some embodiments, a PD-1 inhibitor is administered once every seven weeks. In some embodiments, a PD-1 inhibitor is administered once every six weeks. In some embodiments, a PD-1 inhibitor is administered once every five weeks. In some embodiments, a PD-1 inhibitor is administered once every four weeks. In some embodiments, a PD-1 inhibitor is administered once every three weeks. In some embodiments, a PD-1 inhibitor is administered once every two weeks. In some embodiments, a PD-1 inhibitor is administered once every week.

[0805] In some embodiments, PD-1 inhibitors (such as tislelizumab) are administered intravenously.

[0806] In some embodiments, a PD-1 inhibitor (e.g., tislelizumab) is administered over a period of approximately 20 to 40 minutes (e.g., approximately 30 minutes). In some embodiments, a PD-1 inhibitor is administered over a period of approximately 30 minutes. In some embodiments, a PD-1 inhibitor is administered over a period of approximately one hour. In some embodiments, a PD-1 inhibitor is administered over a period of approximately two hours. In some embodiments, a PD-1 inhibitor is administered over a period of approximately three hours. In some embodiments, a PD-1 inhibitor is administered over a period of approximately four hours. In some embodiments, a PD-1 inhibitor is administered over a period of approximately five hours. In some embodiments, a PD-1 inhibitor is administered over a period of approximately six hours.

[0807] In some embodiments, a PD-1 inhibitor (e.g., tislelizumab) is administered intravenously at a dose between about 300 mg and about 500 mg (e.g., about 400 mg) every four weeks. In some embodiments, a PD-1 inhibitor is administered intravenously at a dose between about 200 mg and about 400 mg (e.g., about 300 mg) every three weeks. In some embodiments, tislelizumab is administered at a dose of 400 mg every four weeks. In some embodiments, tislelizumab is administered at a dose of 300 mg every three weeks.

[0808] In some embodiments, a PD-1 inhibitor (e.g., tislelizumab) is administered intravenously at a dose between about 300 mg and about 500 mg (e.g., about 400 mg) over a period of about 20 minutes to about 40 minutes (e.g., about 30 minutes), once every two weeks. In some embodiments, a PD-1 inhibitor is administered intravenously at a dose between about 200 mg and about 400 mg (e.g., about 300 mg) over a period of about 20 minutes to about 40 minutes (e.g., about 30 minutes), once every three weeks.

[0809] In some embodiments, a PD-1 inhibitor (e.g., tislelizumab) is administered at a dose of approximately 100 mg per week. For example, if a patient is given a 10-week dose, 1000 mg of a PD-1 inhibitor (e.g., tislelizumab) may be given. If a 9-week dose is given, 900 mg of a PD-1 inhibitor (e.g., tislelizumab) may be given. If an 8-week dose is given, 800 mg of a PD-1 inhibitor (e.g., tislelizumab) may be given. If a 7-week dose is given, 700 mg of a PD-1 inhibitor (e.g., tislelizumab) may be given. If a 6-week dose is given, 600 mg of a PD-1 inhibitor (e.g., tislelizumab) may be given. If a 5-week dose is given, 500 mg of a PD-1 inhibitor (e.g., tislelizumab) may be given. If a 4-week dose is given, 400 mg of a PD-1 inhibitor (e.g., tislelizumab) may be given. If a 3-week dose is given, a 300 mg PD-1 inhibitor (e.g., tislelizumab) can be administered. If a 2-week dose is given, a 200 mg PD-1 inhibitor (e.g., tislelizumab) can be administered. If a 1-week dose is given, a 100 mg PD-1 inhibitor (e.g., tislelizumab) can be administered.

[0810] For example, if an anti-PD-1 antibody, such as tislelizumab, is used, it can be administered as an intravenous infusion at a dose of 200 mg every three weeks. Alternatively, tislelizumab can be administered as an intravenous infusion at a dose of 300 mg every four weeks. If an anti-PD-1 antibody, such as tislelizumab, is used, it can be administered as an intravenous infusion at a dose of 300 mg every three weeks. Alternatively, tislelizumab can be administered as an intravenous infusion at a dose of 400 mg every four weeks.

[0811] The compounds mentioned above that can be used in combination with the compounds of the present invention can be prepared and applied according to the descriptions in the art, such as those cited above.

[0812] In one embodiment, the present invention provides a product comprising the compound of the present invention and at least one other therapeutic agent, for use concurrently, separately, or sequentially in a therapy in a combination formulation. In one embodiment, the therapy is the treatment of a disease or condition mediated by WRN. Products provided in combination formulations include compositions comprising a Formula I compound and other therapeutic agents present together in the same pharmaceutical composition, or the compound of the present invention and other therapeutic agents in a standalone form (e.g., in a kit form).

[0813] In one embodiment, the present invention provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains a compound of the present invention. In one embodiment, the kit includes components for separately storing the compositions, such as containers, separator bottles, or separator foil packs. An example of such a kit is blister packaging, as is commonly used for tablets, capsules, etc.

[0814] The kits of the present invention can be used to administer different dosage forms (e.g., oral and parenteral dosage forms), to administer independent compositions at different dosing intervals, or to titrate independent compositions relative to each other. To aid compliance, the kits of the present invention typically include administration instructions.

[0815] In the combination therapy of the present invention, the compounds of the present invention and other therapeutic agents may be manufactured and / or formulated by the same or different manufacturers. Furthermore, the compounds of the present invention and other therapeutic agents may be combined into a combination therapy in the following circumstances: (i) before the combination product is delivered to a physician (e.g., in the case where a kit contains the compounds of the present invention and other therapeutic agents); (ii) immediately before administration, by the physician (or under the physician's guidance); (iii) by the patient, for example, during the sequential administration of the compounds of the present invention and other therapeutic agents.

[0816] Therefore, the present invention provides the use of the compounds of the invention for treating diseases or conditions mediated by WRN, wherein said agent is prepared for administration in conjunction with another therapeutic agent. The present invention also provides the use of another therapeutic agent for treating diseases or conditions mediated by WRN, wherein said agent is administered in conjunction with the compounds of the invention.

[0817] This invention also provides the use of the compounds of the invention for treating WRN-mediated diseases or conditions, wherein the compounds of the invention are prepared for administration in conjunction with another therapeutic agent. This invention also provides another therapeutic agent for treating WRN-mediated diseases or conditions, wherein the other therapeutic agent is prepared for administration in conjunction with the compounds of the invention. This invention also provides the compounds of the invention for treating WRN-mediated diseases or conditions, wherein the compounds of the invention are administered in conjunction with another therapeutic agent. This invention also provides another therapeutic agent in a method for treating WRN-mediated diseases or conditions, wherein the other therapeutic agent is administered in conjunction with the compounds of the invention.

[0818] This invention also provides the use of the compounds of the invention for treating diseases or conditions mediated by WRN, wherein the patient has previously (e.g., within 24 hours) been treated with another therapeutic agent. This invention also provides the use of another therapeutic agent for treating diseases or conditions mediated by WRN, wherein the patient has previously (e.g., within 24 hours) been treated with the compounds of the invention.

[0819] 5. A general synthetic method for producing the compounds disclosed herein

[0820] The compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described in the accompanying synthetic schemes.

[0821] Referring to embodiment 1, the compounds disclosed herein (e.g., I-2) can be made by causing R 1 Substitute 1 is synthesized by reacting with reagent A. 1,2,3-triazole 3 can be synthesized by treating 2 with (PMB)2NH. Butyl-2-one a reacts with the ester of 3 in the presence of a strong base to provide 4, which is subsequently brominated at the α-ketone position to give 5. The bromine is replaced by nucleophilic ring A substitute (the protected piperidine in step 5) to produce 6. 6 can undergo intramolecular cyclization to produce the 2,4-dihydro-7H-[1,2,3]triazolo[4,5-b]pyridin-7-one core 7 of the compound of the present invention. 7 is protected and R... 2 The substituent is introduced into 7 via nucleophilic substitution to provide 9. 9 can then be deprotected, and subsequently combined with R. 4 The substitutes undergo amide coupling to produce compounds of this disclosure, such as I-1.

[0822] Scheme 1: A general synthetic method for producing the triazolo[4,5-b]pyridin-7-one compounds disclosed herein

[0823]

[0824]

[0825] According to Scheme 2, the compound of this disclosure (referred to as intermediate-7a in Scheme 2) containing a 2,5-dihydro-4H-[1,2,3]triazolo[4,5-c]pyridin-4-one core can be prepared as follows. 1,2,3-triazole 10 bromide can be reacted with R... 1 Substitute 11 is cross-coupled to produce 12. 13 can be produced by coupling 12 with the butyne stigma. Manipulating the functional group of the methyl ester of 13 yields amide 15. Under basic conditions, 15 can undergo intramolecular cyclization to produce a bicyclic heterocyclic 2,5-dihydro-4H-[1,2,3]triazolo[4,5-c]pyridin-4-one moiety (characterized by the compounds of this disclosure). A modified photoelectrophoretic reaction is carried out between alcohols 17 and 16 using Tsunoda reagent 18, which links the ring A moiety to 16 to form 19, which is then reacted in R... 2 Bromination at the junction yields 20. 20 and 21 are cross-coupled, followed by hydrolysis to produce acid 23. 23 can be used for amide synthesis with substituted aniline 24 to give intermediates of this disclosure, such as intermediate-7a.

[0826] Option 2: A general synthetic method for producing the triazolo[4,5-c]pyridin-4-one compounds disclosed herein

[0827]

[0828]

[0829] Those skilled in the art will be able to adapt such synthetic procedures to obtain different substituted Formula I compounds for the synthesis of the compounds disclosed herein.

[0830] Example

[0831] As depicted in the following examples, in some exemplary embodiments, compounds are prepared according to the procedures provided herein. It should be understood that although the methods described depict the synthesis of certain compounds of this disclosure, these methods and other methods known to those skilled in the art can be applied to all compounds described herein, as well as subclasses and types of each of these compounds.

[0832] List of abbreviations:

[0833] H2O: water

[0834] ACN: Acetonitrile

[0835] THF: Tetrahydrofuran

[0836] FA: Formic acid

[0837] Na2SO4: Sodium sulfate

[0838] EtOAc: Ethyl acetate

[0839] HCl: hydrochloric acid

[0840] DCM: Dichloromethane

[0841] pH: Hydrogen potential

[0842] Boc2O: Ditert-butyl dicarbonate

[0843] POCl3: Phosphorus oxychloride

[0844] EDCI: N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride

[0845] LCMS: Liquid Chromatography-Mass Spectrometry

[0846] HPLC: High Performance Liquid Chromatography

[0847] NH4Cl: Ammonium chloride

[0848] K3PO4: Tripotassium phosphate

[0849] (Boc)2O: Ditert-butyl dicarbonate

[0850] TFA: Trifluoroacetic acid

[0851] NBS: N-bromosuccinimide

[0852] DIEA: N,N-Diisopropylethylamine

[0853] Pd(dppf)2Cl2-CH2Cl2:1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex

[0854] Boc: tert-butoxycarbonyl

[0855] PMB: p-Methoxybenzyl

[0856] Cu(OAc)₂: Copper(II) acetate

[0857] TsOH-H2O: p-Toluenesulfonic acid monohydrate

[0858] DMSO-d6: Deuterated dimethyl sulfoxide

[0859] NMP: N-methyl-2-pyrrolidone

[0860] DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene

[0861] LiHMDS: Bis(trimethylsilane)aminolithium

[0862] Preparative TLC: Preparative Thin-Layer Chromatography

[0863] s: single peak

[0864] m: multiple peaks

[0865] d: double peak

[0866] dq: Double Quadruple Peak

[0867] t: triple peak

[0868] br: broad peak

[0869] N: Normal state

[0870] eq: equivalent

[0871] M: molar concentration

[0872] PE: Petroleum ether

[0873] aq.: aqueous solution

[0874] h: hours

[0875] TEA: Triethylamine

[0876] AcOH: Acetic acid

[0877] K2CO3: Potassium carbonate

[0878] NaOH: Sodium hydroxide

[0879] Pd / C: Palladium / Carbon

[0880] HBr: hydrobromic acid

[0881] AIBN: 2,2'-Azobis(2-methylpropionitrile)

[0882] CCl4: Carbon tetrachloride

[0883] MeMgBr: Magnesium methyl bromide

[0884] CO: Carbon monoxide

[0885] HI: hydroiodic acid

[0886] Ts: (4-Methylphenyl)sulfonyl group

[0887] MeOH: Methanol

[0888] EtOH: Ethanol

[0889] DMSO: Dimethyl sulfoxide

[0890] NH4HCO3: Ammonium bicarbonate

[0891] LiOH: Lithium hydroxide

[0892] 1 H NMR: Proton nuclear magnetic resonance

[0893] δ: Chemical shift

[0894] min: minutes

[0895] MS: Mass Spectrometry

[0896] RT: Detention Time

[0897] HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0898] Pd(dppf)Cl2: [bis(diphenylphosphino)ferrocene]palladium(II) dichloride

[0899] Gphos Pd G6 TES: [3-(tert-butoxy)-6-methoxy-2,6-bis(propyl-2-yl)-[1,1-biphenyl]-2-yl]biscyclohexylphosphine bromide (4-{[2-(trimethylsilyl)ethoxy]carbonyl}phenyl)palladium

[0900] GPhos: [3-(tert-butoxy)-6-methoxy-2,6-bis(propyl-2-yl)-[1,1-biphenyl]-2-yl]bicyclohexylphosphine

[0901] CbzCl: Benzoic acid chloroformate

[0902] Zn(NTf2)2: Bis(trifluoromethanesulfonyl)iminozinc

[0903] Example 1: Synthesis of the compounds disclosed herein

[0904] Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidin-4-carbonyl)piperazin-1-yl)-2-(2-methoxypyridin-4-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide (I-1)

[0905]

[0906] Step 1. Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidin-4-carbonyl)piperazin-1-yl)-2-(2-methoxypyridin-4-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide

[0907] At room temperature and under a nitrogen atmosphere, EDCI (65 mg, 0.34 mmol, 5.0 eq) was added to a stirred solution of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(2-methoxypyridin-4-yl)-7-oxo-6-(piperazin-1-yl)-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide hydrochloride (intermediate-3) (40 mg, 68 μmol, 1.0 eq) and 5-hydroxy-6-methylpyrimidin-4-carboxylic acid (intermediate-6) (10 mg, 68 μmol, 1.0 eq) in pyridine (5 mL). The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. H2O (30 mL) was added to the reaction mixture and the mixture was extracted with EtOAc (10 mL × 3). The combined organic phases were washed with brine (10 mL × 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by reverse-phase HPLC (C18 column, H₂O (10 mmol / L NH₄HCO₃)-ACN) to obtain the title compound. 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.43 (br s,1H), 8.50 (s, 1H), 8.44 - 8.35 (m, 1H), 8.06 (d, 1H), 8.02 - 7.89 (m, 1H),7.78 - 7.63 (m, 2H), 7.44 (s, 1H), 5.39 (s, 2H), 4.73 - 4.42 (m, 2H), 3.94 (s, 3H), 3.79 - 3.62 (m, 2H), 3.55 - 3.15 (m, 2H), 3.12 - 2.90 (m, 2H), 2.78- 2.71 (m, 1H), 2.69 - 2.56 (m, 1H), 2.42 (br s, 2H), 2.18 - 2.05 (m, 1H), 1.24 (m, 3H). LCMS: 727.2 [M+H] + .

[0908] Synthesis of 2-(5-ethyl-6-((1S,6S)-5-(6-hydroxybenzo[d]oxazol-7-carbonyl)-2,5-diazabicyclo[4.2.0]oct-2-yl)-2-(2-methoxypyridin-4-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)acetamide (I-4)

[0909]

[0910] Step 1. Synthesis of 2-(5-ethyl-6-((1S,6S)-5-(6-hydroxybenzo[d]oxazol-7-carbonyl)-2,5-diazabicyclo[4.2.0]oct-2-yl)-2-(2-methoxypyridin-4-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)acetamide

[0911] At room temperature, under a N2 atmosphere, EDCI (40 mg, 210 μmol, 2.0 eq) was added to a stirred mixture of 2-(6-((1S,6S)-2,5-diazabicyclo[4.2.0]oct-2-yl)-5-ethyl-2-(2-methoxypyridin-4-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)acetamide hydrochloride (intermediate-9) (60 mg, 105 μmol, 1.0 eq) and 6-hydroxy-1,3-benzoxazole-7-carboxylic acid (intermediate-10) (23 mg, 126 μmol, 1.2 eq) in pyridine (5 mL). The resulting mixture was degassed three times with N2, followed by stirring at 60 °C for 5 h. The mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by rapid silica gel chromatography (eluent DCM / MeOH) and concentrated under reduced pressure to obtain the residue. The residue was purified by reversed-phase HPLC (C18 column, water (10 mmol / L NH4HCO3)-ACN) to obtain the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.18 (br s,1H), 9.28 (s, 1H), 8.59 (s, 1H), 8.42 (d, 1H), 7.71 (dd, 1H), 7.62 (d, 1H),7.43 (d, 1H), 7.00 - 6.91 (m, 1H), 5.00 - 4.87 (m, 2H), 4.53 - 4.44 (m, 1H), 3.96 (s, 3H), 3.81 - 3.70 (m, 1H), 3.58 - 3.46 (m, 1H), 3.45 - 3.24 (m, 2H),3.22 - 3.12 (m, 1H), 3.04 - 2.87 (m, 2H), 2.25 (s, 6H), 1.53 - 1.44 (m, 1H), 1.33 - 1.11 (m, 5H), 0.90 - 0.79 (m, 1H). LCMS: 734.4 [M+H] + .

[0912] Synthesis of 2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-((1S,6S)-5-(5-hydroxy-6-methylpyrimidin-4-carbonyl)-2,5-diazabicyclo[4.2.0]oct-2-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)-N-(3-isopropylbicyclo[1.1.1]pent-1-yl)acetamide (I-18)

[0913]

[0914]

[0915] Steps 1 through 10 can be performed as described in the synthesis procedure of intermediates - 11, 12, 13, and 14 of the current document.

[0916] Step 11. Synthesis of (1S,6S)-5-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-4-(2-((3-isopropylbicyclo[1.1.1]pent-1-yl)amino)-2-oxoethyl)-7-oxo-4,7-dihydro-2H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-2,5-diazabicyclo[4.2.0]octane-2-carboxylic acid tert-butyl ester

[0917] Add HATU (177 mg, 0.47 mmol, 2.00 eq) and DIEA (121 mg, 0.93 mmol, 4.00 eq) to a stirred solution of 2-(6-((1S,6S)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo[4.2.0]oct-2-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)acetic acid (intermediate-14) (120 mg, 0.23 mmol, 1.00 eq) and 3-isopropylbicyclo[1.1.1]pentan-1-amine hydrochloride (29 mg, 0.18 mmol, 0.78 eq) in THF (1.00 mL) to a stirred solution. The mixture was stirred at room temperature for 1 h. The resulting mixture was diluted with water (5 mL) and extracted with EtOAc (3 × 5 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (eluent EtOAc / PE) to give the title compound. LCMS: 622 [M + H] + .

[0918] Step 12. Synthesis of 2-(6-((1S,6S)-2,5-diazabicyclo[4.2.0]oct-2-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)-N-(3-isopropylbicyclo[1.1.1]pent-1-yl)acetamide hydrochloride

[0919] A solution of (1S,6S)-5-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-4-(2-((3-isopropylbicyclo[1.1.1]pent-1-yl)amino)-2-oxoethyl)-7-oxo-4,7-dihydro-2H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-2,5-diazabicyclo[4.2.0]octane-2-carboxylic acid tert-butyl ester (120 mg, 0.19 mmol, 1.00 eq) in DCM (2.00 mL) was added to a solution of 1,4-dioxane in 4 M HCl (0.40 mL, 1.60 mmol, 8.29 eq), and the reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure to give the title compound, which was used directly in the next step without further purification. LCMS: 522[M+H] + .

[0920] Step 13. Synthesis of 2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-((1S,6S)-5-(5-hydroxy-6-methylpyrimidin-4-carbonyl)-2,5-diazabicyclo[4.2.0]oct-2-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)-N-(3-isopropylbicyclo[1.1.1]pent-1-yl)acetamide

[0921] HATU (44 mg, 116 μmol, 1.61 eq) was added to a stirred solution of 2-(6-((1S,6S)-2,5-diazabicyclo[4.2.0]oct-2-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)-N-(3-isopropylbicyclo[1.1.1]pent-1-yl)acetamide hydrochloride (40 mg, 72 μmol, 1.00 eq) and sodium 5-hydroxy-6-methylpyrimidin-4-carboxylate (intermediate-20) (18 mg, 102 μmol, 1.42 eq) in pyridine (0.50 mL). The mixture was stirred at room temperature for 1 h and concentrated under reduced pressure. The residue was diluted with water (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (C18 column, (10 mmol / L NH₄HCO₃ aqueous solution)-ACN) to give the title compound. LCMS: 658 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.89 (s, 1H), 8.50 (s, 1H), 6.74 (s,1H), 4.83 (s, 2H), 4.50 - 4.40 (m, 1H), 4.34 (d, 2H), 3.92 (t, 2H), 3.88 -3.80 (m, 1H), 3.56 -3.24 (m, 3H), 3.22 - 3.13 (m, 1H), 2.99 - 2.85 (m, 2H), 2.80 (s, 2H), 2.42 (s, 3H), 1.79 - 1.68 (m, 7H), 1.60 - 1.50 (m, 1H), 1.36 -1.26 (m, 2H), 1.20 - 1.10 (m, 4H), 0.80 (d, 6H).

[0922] Synthesis of N-(3-cyclopropylbicyclo[1.1.1]pent-1-yl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-((1S,6S)-5-(5-hydroxy-6-methylpyrimidin-4-carbonyl)-2,5-diazabicyclo[4.2.0]oct-2-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide (I-26)

[0923]

[0924]

[0925]

[0926] Steps 1 through 9 can be performed as described in the synthesis of intermediates 11, 12, and 13 in the current document.

[0927] Step 10. Synthesis of 2-(6-((1S,6S)-2,5-diazabicyclo[4.2.0]oct-2-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl) ethyl acetate hydrochloride

[0928] A solution of (1S,6S)-5-[2-(3,6-dihydro-2H-pyran-4-yl)-4-(2-ethoxy-2-oxoethyl)-5-ethyl-7-oxo-[1,2,3]triazolo[4,5-b]pyridin-6-yl]-2,5-diazabicyclo[4.2.0]octane-2-carboxylic acid tert-butyl ester (intermediate-13) (140 mg, 258 μmol, 1.00 eq) in DCM (1.00 mL) was added to a solution of 1,4-dioxane in 4 M HCl (1.00 mL, 4.00 mmol, 15.5 eq), and the reaction mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure to give the title compound, which was used in the next step without further purification. LCMS: 443 [M+H] + .

[0929] Step 11. Synthesis of ethyl acetate 2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-((1S,6S)-5-(5-hydroxy-6-methylpyrimidin-4-carbonyl)-2,5-diazabicyclo[4.2.0]oct-2-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)

[0930] HATU (127 mg, 334 μmol, 2.00 eq) was added to a stirred mixture of ethyl acetate 2-(6-((1S,6S)-2,5-diazabicyclo[4.2.0]oct-2-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl) hydrochloride (80 mg, 167 μmol, 1.00 eq) and sodium 5-hydroxy-6-methylpyrimidin-4-carboxylate (intermediate-20) (59 mg, 334 μmol, 2.00 eq) in pyridine (1.60 mL) at room temperature. The mixture was stirred at room temperature for 30 min. The mixture was concentrated under reduced pressure. The residue was diluted with water (10 mL) and then extracted with EtOAc (3 × 10 mL). The combined organic compounds were washed with brine and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (eluent EtOAc / PE) to give the title compound. LCMS: 579 [M+H] + .

[0931] Step 12. Synthesis of 2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-((1S,6S)-5-(5-hydroxy-6-methylpyrimidin-4-carbonyl)-2,5-diazabicyclo[4.2.0]oct-2-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)acetic acid

[0932] At room temperature, NaOH (10 mg, 242 μmol, 2.00 eq) was added to a stirred mixture of ethyl 2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-((1S,6S)-5-(5-hydroxy-6-methylpyrimidin-4-carbonyl)-2,5-diazabicyclo[4.2.0]oct-2-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl) (70 mg, 121 μmol, 1.00 eq) in THF (0.70 mL) and H2O (0.70 mL). The mixture was stirred at room temperature for 1 h. The resulting mixture was diluted with water (5 mL) and then acidified to pH 5 with 1 N HCl (aqueous solution). The mixture was extracted with EtOAc (3 × 5.00 mL). The combined organic compounds were washed with brine and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to obtain the title compound, which was used in the next step without further purification. LCMS: 551 [M+H] + .

[0933] Step 13. Synthesis of N-(3-cyclopropylbicyclo[1.1.1]pent-1-yl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-((1S,6S)-5-(5-hydroxy-6-methylpyrimidin-4-carbonyl)-2,5-diazabicyclo[4.2.0]oct-2-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide

[0934] At room temperature, DIEA (47 mg, 364 μmol, 4.00 eq) and HATU (52 mg, 137 μmol, 1.50 eq) were added to a stirred mixture of 2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-((1S,6S)-5-(5-hydroxy-6-methylpyrimidin-4-carbonyl)-2,5-diazabicyclo[4.2.0]oct-2-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)acetic acid (50 mg, 91 μmol, 1.00 eq) and 3-cyclopropylbicyclo[1.1.1]pentan-1-amine hydrochloride (17 mg, 107 μmol, 1.18 eq) in THF (1.00 mL). The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was poured into water (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (C18 column, (10 mmol / L NH₄HCO₃ aqueous solution)-ACN) to give the title compound. LCMS: 656 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ ppm 10.34 (br s, 1H), 8.89 (s, 1H), 8.62 - 8.53 (m, 1H), 6.73 (s, 1H), 4.89 - 4.75 (m, 2H), 4.52 - 4.40 (m, 1H), 4.33 (s, 2H), 3.98 - 3.79 (m, 3H), 3.55 - 3.10 (m, 4H), 3.01 - 2.73 (m, 4H), 2.44 (s, 3H), 1.75 (s, 6H), 1.59 -1.50 (m, 1H), 1.37 - 1.09 (m, 6H), 0.94 - 0.82 (m, 1H), 0.40 - 0.34 (m, 2H), 0.12 - 0.04 (m, 2H).

[0935] Synthesize N-(3-cyclopropylbicyclo[1.1.1]pent-1-yl)-2-(5-ethyl-6-((1S,6S)-5-(5-hydroxy-6-methylpyrimidin-4-carbonyl)-2,5-diazabicyclo[4.2.0]oct-2-yl)-2-(2-methoxypyridin-4-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide (I-10)

[0936]

[0937]

[0938] Steps 1 through 8 can be performed as described in the synthesis of intermediates 1, 7, and 17 of the current document.

[0939] Step 9. Synthesis of ethyl acetate 2-(6-((1S,6S)-2,5-diazabicyclo[4.2.0]oct-2-yl)-5-ethyl-2-(2-methoxypyridin-4-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)

[0940] At room temperature, a solution of 1,4-dioxane in 4 M HCl (2.00 mL, 8.00 mmol, 22.9 eq) was added to a stirred solution of (1S,6S)-5-(4-(2-ethoxy-2-oxoethyl)-5-ethyl-2-(2-methoxypyridin-4-yl)-7-oxo-4,7-dihydro-2H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-2,5-diazabicyclo[4.2.0]octane-2-carboxylic acid tert-butyl ester (intermediate-17) (200 mg, 0.35 mmol, 1.00 eq) in DCM (10.0 mL). After stirring at room temperature for 1 h, the reaction mixture was concentrated under reduced pressure to give the title compound, which was used directly in the next step without purification. LCMS: 468.0 [M+H] + .

[0941] Step 10. Synthesis of ethyl acetate 2-(5-ethyl-6-((1S,6S)-5-(5-hydroxy-6-methylpyrimidin-4-carbonyl)-2,5-diazabicyclo[4.2.0]oct-2-yl)-2-(2-methoxypyridin-4-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)

[0942] A mixture of sodium 5-hydroxy-6-methylpyrimidin-4-carboxylate (intermediate-20) (156 mg, 0.89 mmol, 2.60 eq) and pyridine hydrochloride (117 mg, 1.02 mmol, 3.00 eq) in DCM (3.00 mL) was added to a mixture of 2-(6-((1S,6S)-2,5-diazabicyclo[4.2.0]oct-2-yl)-5-ethyl-2-(2-methoxypyridin-4-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)ethyl acetate hydrochloride (170 mg, 0.34 mmol, 1.00 eq) and DIEA (131 mg, 1.02 mmol, 3.00 eq) in DCM (3.00 mL), followed by the addition of EDCI (390 mmol) at room temperature. (mg, 2.03 mmol, 6.00 eq). After stirring at 40 °C for 1 h, the reaction mixture was cooled to room temperature. The resulting mixture was filtered and the filter cake was washed with DCM. The combined filtrates were concentrated under reduced pressure to give the title compound, which was used directly in the next step without purification. LCMS: 604.0 [M+H] + .

[0943] Step 11. Synthesis of 2-(5-ethyl-6-((1S,6S)-5-(5-hydroxy-6-methylpyrimidin-4-carbonyl)-2,5-diazabicyclo[4.2.0]oct-2-yl)-2-(2-methoxypyridin-4-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)acetic acid

[0944] A solution of NaOH (167 mg, 4.17 mmol, 19.4 eq) in H₂O (1.00 mL) was added to a solution of ethyl 2-(5-ethyl-6-((1S,6S)-5-(5-hydroxy-6-methylpyrimidin-4-carbonyl)-2,5-diazabicyclo[4.2.0]oct-2-yl)-2-(2-methoxypyridin-4-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl) in MeOH (5.00 mL). After stirring at room temperature for 2 h, the reaction mixture was diluted with H₂O (5 mL) and acidified to pH 3 with 1 N HCl (aqueous solution) at 0 °C. The resulting mixture was extracted with EtOAc (5 × 10 mL). The combined organic layers were washed with brine (1 × 25 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (C18 column, water (0.1% FA)-ACN) to give the title compound. LCMS: 576.0 [M+H] + .

[0945] Step 12. Synthesis of N-(3-cyclopropylbicyclo[1.1.1]pent-1-yl)-2-(5-ethyl-6-((1S,6S)-5-(5-hydroxy-6-methylpyrimidin-4-carbonyl)-2,5-diazabicyclo[4.2.0]oct-2-yl)-2-(2-methoxypyridin-4-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide

[0946] At room temperature, a mixture of 3-cyclopropylbicyclo[1.1.1]pentane-1-amine hydrochloride (33 mg, 0.21 mmol, 1.20 eq) and pyridine (5.00 mL) was stirred for 5 min. At room temperature, 2-(5-ethyl-6-((1S,6S)-5-(5-hydroxy-6-methylpyrimidin-4-carbonyl)-2,5-diazabicyclo[4.2.0]oct-2-yl)-2-(2-methoxypyridin-4-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)acetic acid (100 mg, 0.17 mmol, 1.00 eq) and EDCI (67 mg, 0.35 mmol, 2.00 eq) were stirred for another 1 h at room temperature, followed by concentration under reduced pressure. The residue was purified twice by reverse-phase HPLC (C18 column, water (10 mmol / L NH4HCO3)-ACN). After lyophilization, the resulting mixture was purified by preparative TLC (eluent MeOH / DCM) to give the title compound. LCMS: 681.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.36 (br s, 1H), 8.95 (s, 1H), 8.60 -8.56 (m, 1H), 8.42 (d, 1H), 7.71 (dd, 1H), 7.42 (d, 1H), 4.99 - 4.80 (m, 2H),4.48 - 4.45 (m, 1H), 3.96 (s, 3H), 3.88 - 3.82 (m, 1H), 3.56 - 3.29 (m, 3H),3.25 - 3.16 (m, 1H), 3.05 - 2.85 (m, 2H), 2.44 (s, 3H), 1.76 (s, 6H), 1.61 -1.53 ​​(m, 1H), 1.40 - 1.28 (m, 2 H), 1.27 - 1.11 (m, 4H), 0.94 - 0.85 (m, 1H), 0.41 - 0.33 (m, 2H), 0.11 - 0.05 (m, 2H).

[0947] Table 2

[0948]

[0949]

[0950]

[0951]

[0952]

[0953]

[0954]

[0955]

[0956]

[0957]

[0958]

[0959]

[0960]

[0961]

[0962]

[0963]

[0964]

[0965]

[0966]

[0967]

[0968]

[0969]

[0970]

[0971]

[0972]

[0973]

[0974]

[0975]

[0976]

[0977]

[0978]

[0979]

[0980]

[0981]

[0982]

[0983]

[0984]

[0985]

[0986]

[0987]

[0988]

[0989]

[0990]

[0991]

[0992]

[0993]

[0994]

[0995]

[0996]

[0997]

[0998]

[0999]

[1000]

[1001]

[1002]

[1003]

[1004]

[1005]

[1006]

[1007]

[1008]

[1009]

[1010]

[1011]

[1012]

[1013]

[1014] As will be appreciated by those skilled in the art, the compounds in Table 2a can be obtained from intermediate 3 or other intermediates described herein or synthesized by a procedure similar to that described herein.

[1015] Table 2a

[1016]

[1017]

[1018]

[1019]

[1020]

[1021]

[1022]

[1023]

[1024]

[1025]

[1026]

[1027]

[1028]

[1029]

[1030]

[1031]

[1032]

[1033]

[1034]

[1035]

[1036]

[1037]

[1038]

[1039] As will be known to those skilled in the art, the compounds in Table 2b can be obtained via intermediate -7a.

[1040] Table 2b

[1041]

[1042]

[1043] Synthetic intermediates

[1044] Intermediate-1: 1-(5-(bis(4-methoxybenzyl)amino)-2-(2-methoxypyridin-4-yl)-2H-1,2,3-triazol-4-yl)-2-bromopentane-1,3-dione

[1045] Intermediate-22: Ethyl 5-(bis(4-methoxybenzyl)amino)-2-(2-methoxypyridin-4-yl)-2H-1,2,3-triazol-4-carboxylate

[1046]

[1047] Step 1. Synthesis of ethyl 2-cyano-2-(2-(2-methoxypyridin-4-yl)hydrazine)

[1048] At 0 °C and under a nitrogen atmosphere, a solution of NaNO2 (560 mg, 8.06 mmol, 1 eq) in H2O (0.5 mL) was added dropwise to a stirred solution of 2-methoxypyridine-4-amine (1.00 g, 8.06 mmol, 1.0 eq) in HCl (4 mL, concentrated) and H2O (4 mL). The mixture was stirred at 0 °C under a nitrogen atmosphere for 30 min. At 0 °C, EtOH (4 mL) containing ethyl 2-cyanoacetate (910 mg, 8.06 mmol, 1.0 eq) and H2O (10 mL) containing NaOAc (3.96 g, 48.3 mmol, 6.0 eq) were added to the mixture. The mixture was stirred again at room temperature for 5 h. The mixture was diluted with water (200 mL). The mixture was extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (200 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (eluent DCM / MeOH) to give the title compound. LCMS: 249.1 [M+H] + .

[1049] Step 2. Synthesis of ethyl 5-(bis(4-methoxybenzyl)amino)-2-(2-methoxypyridin-4-yl)-2H-1,2,3-triazol-4-carboxylate

[1050] A solution of ethyl 2-cyano-2-(2-(2-methoxypyridin-4-yl)hydrazine)acetate (10.0 g, 40.3 mmol, 1.0 eq) and bis[(4-methoxyphenyl)methyl]amine (15.6 g, 60.4 mmol, 1.5 eq) in ACN (400 mL) was stirred for 10 min at 80 °C. Cu(OAc)₂ (3.66 g, 20.1 mmol, 0.5 eq) was added to the mixture at 80 °C, and the mixture was stirred again at 80 °C for 1 h. The mixture was then stirred again at 80 °C for 5 h. The mixture was cooled to room temperature. The mixture was filtered, and the filtrate was concentrated. The residue was purified directly by reverse-phase HPLC (C18 column, H2O (10 mmol / L NH4HCO3)-ACN) to obtain the title compound. 1 H NMR (400 MHz, DMSO-d6) δ 8.29 - 8.27 (m, 1H), 7.47 - 7.45 (m, 1H), 7.26- 7.19 (m, 4H), 7.14 - 7.12 (m, 1H), 6.91 - 6.83 (m, 4H), 4.51 (s, 4H), 4.35- 4.29 (m, 2H), 3.91 (s, 3H), 3.71 (s, 6H), 1.30 - 1.25 (m, 3H). LCMS: 504.2[M+H] + .

[1051] Step 3. Synthesis of 1-(5-(bis(4-methoxybenzyl)amino)-2-(2-methoxypyridin-4-yl)-2H-1,2,3-triazol-4-yl)-3-hydroxypent-2-en-1-one

[1052] At 0 °C, under a nitrogen atmosphere, 1 M LiHMDS solution (30.3 mL, 30.3 mmol, 2.5 eq) was added dropwise to a stirred solution of butanone (2.18 g, 30.3 mmol, 2.5 eq) in 200 mL of THF. The resulting mixture was stirred for 30 min at room temperature under a nitrogen atmosphere. At 60 °C, 50 mL of THF containing ethyl 5-(bis(4-methoxybenzyl)amino)-2-(2-methoxypyridin-4-yl)-2H-1,2,3-triazol-4-carboxylate (6.10 g, 12.1 mmol, 1.0 eq) was added dropwise to the above mixture. The mixture was stirred again at 60 °C for 1 h. The mixture was cooled to room temperature and quenched with 0 °C saturated NH4Cl (aqueous solution). The mixture was extracted with EtOAc (3 × 500 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the title compound, which was used directly in the next step without purification. LCMS: 530.2 [M+H] + .

[1053] Step 4. Synthesis of 1-(5-(bis(4-methoxybenzyl)amino)-2-(2-methoxypyridin-4-yl)-2H-1,2,3-triazol-4-yl)-2-bromopentane-1,3-dione

[1054] At 0 °C and under a N2 atmosphere, NBS (4.95 g, 27.8 mmol, 2.0 eq) and TsOH were added to a stirred solution of 1-(5-(bis(4-methoxybenzyl)amino)-2-(2-methoxypyridin-4-yl)-2H-1,2,3-triazol-4-yl)-3-hydroxypent-2-en-1-one (7.36 g, 13.9 mmol, 1.0 eq) in DCM (500 mL). . H₂O (30 mg, 0.14 mmol, 0.01 eq). The mixture was stirred for 2 h at room temperature under a nitrogen atmosphere. The mixture was diluted with water (400 mL). The mixture was extracted with DCM (3 × 400 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound, which was used directly in the next step without purification. LCMS: 608.1 [M+H] + .

[1055] Intermediate-2: 4-(5-ethyl-2-(2-methoxypyridin-4-yl)-7-oxo-4,7-dihydro-2H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)piperazine-1-carboxylic acid tert-butyl ester

[1056]

[1057] Step 1. Synthesis of tert-butyl 4-(1-(5-(bis(4-methoxybenzyl)amino)-2-(2-methoxypyridin-4-yl)-2H-1,2,3-triazol-4-yl)-1,3-dioxopentan-2-yl)piperazine-1-carboxylate

[1058] At 0 °C and under a nitrogen atmosphere, DIEA (3.50 g, 27.1 mmol, 3.0 eq) and tert-butyl piperazine-1-carboxylate (5.05 g, 27.1 mmol, 3.0 eq) were added to a stirred solution of 1-(5-(bis(4-methoxybenzyl)amino)-2-(2-methoxypyridin-4-yl)-2H-1,2,3-triazol-4-yl)-2-bromopentane-1,3-dione (intermediate-1) (5.50 g, 9.04 mmol, 1.0 eq) in THF (200 mL). The mixture was stirred for 30 min at room temperature under a nitrogen atmosphere. H2O (300 mL) was added to the reaction mixture and the mixture was extracted with EtOAc (100 mL × 3). The combined organic phases were washed with brine (100 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by reversed-phase HPLC (C18 column, H2O (0.1% FA)-ACN) to obtain the title compound. LCMS: 714.4 [M+H] + .

[1059] Step 2. Synthesis of 5-ethyl-2-(2-methoxypyridin-4-yl)-6-(piperazin-1-yl)-2,4-dihydro-7H-[1,2,3]triazolo[4,5-b]pyridin-7-one

[1060] A solution of 1.00 g (700 μmol, 1.0 eq) of 4-(1-(5-(bis(4-methoxybenzyl)amino)-2-(2-methoxypyridin-4-yl)-2H-1,2,3-triazol-4-yl)-1,3-dioxopentan-2-yl)piperazine-1-carboxylic acid tert-butyl ester in 10 mL of TFA was stirred for 30 min at 60 °C. The mixture was then cooled to room temperature. The resulting mixture was concentrated under reduced pressure to give the title compound, which was used directly in the next step without purification. LCMS: 356.2 [M+H] + .

[1061] Step 3. Synthesis of tert-butyl piperazine-1-carboxylate

[1062] A solution of 5-ethyl-2-(2-methoxypyridin-4-yl)-6-(piperazin-1-yl)-2,4-dihydro-7H-[1,2,3]triazolo[4,5-b]pyridin-7-one (1.50 g, 4.22 mmol, 1.0 eq), DIEA (550 mg, 4.22 mmol, 1.0 eq), and (Boc)₂O (1.84 g, 8.44 mmol, 2.0 eq) in DCM (30 mL) was stirred for 1 h at room temperature. H₂O (150 mL) was added to the reaction mixture, and the mixture was extracted with DCM (30 mL × 3). The combined organic phases were washed with brine (30 mL × 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by rapid silica gel chromatography (eluent EtOAc / PE) to give the title compound. 1 H NMR (400 MHz, DMSO-d6) δ 12.40 (s,1H), 8.41 - 8.39 (m, 1H), 7.71 - 7.69 (m, 1H), 7.39 - 7.37 (m, 1H), 3.96 (s,3H), 3.94 - 3.87 (m, 2H), 3.60 - 3.50 (m, 2H), 2.90 -2.77 (m, 4H), 2.60 -2.56 (m, 2H), 1.44 (s, 9H), 1.25 - 1.21 (m, 3H). LCMS: 456.2 [M+H] + .

[1063] Intermediate-3: N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(2-methoxypyridin-4-yl)-7-oxo-6-(piperazin-1-yl)-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide hydrochloride

[1064]

[1065] Step 1. Synthesis of tert-butyl 4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-2-(2-methoxypyridin-4-yl)-7-oxo-4,7-dihydro-2H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)piperazine-1-carboxylate

[1066] A solution of 4-(5-ethyl-2-(2-methoxypyridin-4-yl)-7-oxo-4,7-dihydro-2H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)piperazine-1-carboxylic acid tert-butyl ester (intermediate-2) (200 mg, 439 μmol, 1.0 eq) and DIEA (170 mg, 1.32 mmol, 3.0 eq) in ACN (8 mL) was stirred for 3 h at 60 °C under a N2 atmosphere. The mixture was cooled to room temperature and H2O (50 mL) was added. The mixture was extracted with EtOAc (15 mL × 3), and the combined organic phases were washed with brine (15 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified directly by reverse-phase HPLC (C18 column, H2O (10 mmol / L NH4HCO3)-ACN) to obtain the title compound. 1 H NMR (400 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.42 - 8.40 (m, 1H), 8.08 - 8.06 (m, 1H), 7.99 -7.97 (m, 1H), 7.75 - 7.66 (m, 2H), 7.46 - 7.44 (m, 1H), 5.38 (s, 2H), 3.95(s, 5H), 3.62 - 3.56 (m, 2H), 3.06 - 2.98 (m, 4H), 2.64 - 2.60 (m, 2H), 1.44(s, 9H), 1.23 -1.19 (m, 3H). LCMS: 691.2 [M+H] + .

[1067] Step 2. Synthesis of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(2-methoxypyridin-4-yl)-7-oxo-6-(piperazin-1-yl)-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide hydrochloride

[1068] To a solution of 4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-5-ethyl-2-(2-methoxypyridin-4-yl)-7-oxo-4,7-dihydro-2H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)piperazine-1-carboxylic acid tert-butyl ester (95 mg, 0.14 mmol, 1.0 eq) in DCM (3 mL), 4 M HCl / 1,4-dioxane solution (3 mL) was added and the mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure to give the title compound, which was used directly in the next step without purification. LCMS: 591.2 [M+H] + .

[1069] Intermediate-4: 7-hydroxy-2,3-dihydrofurano[3,2-c]pyridine-6-carboxylic acid

[1070]

[1071] Step 1. Synthesis of methyl 3-(bromomethyl)furan-2-carboxylate

[1072] At room temperature, NBS (6.68 g, 37.5 mmol, 1.05 eq) and AIBN (2.35 g, 14.3 mmol, 0.40 eq) were added to a solution of methyl 3-methylfuran-2-carboxylate (5.00 g, 35.7 mmol, 1.00 eq) in CCl4 (50.0 mL). The mixture was degassed three times with N2 and stirred at 50 °C for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (eluent EtOAc / PE) to give the title compound.

[1073] LCMS: 219 / 221 [M+H] + .

[1074] Step 2. Synthesis of methyl 3-(((N-(2-methoxy-2-oxoethyl)-4-methylphenyl)sulfonamido)methyl)furan-2-carboxylate

[1075] 2-(4-methylbenzenesulfonamide)methyl acetate (5.23 g, 21.5 mmol, 1.00 eq) was added to a solution of methyl 3-(bromomethyl)furan-2-carboxylate (4.70 g, 21.5 mmol, 1.00 eq) and K₂CO₃ (5.93 g, 43.0 mmol, 2.00 eq) in ACN (47.0 mL), and the mixture was stirred at room temperature for 16 h. The reaction mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (eluent EtOAc / PE) to give the title compound. LCMS: 382 [M+H]+ .

[1076] Step 3. Synthesis of methyl 7-hydroxyfurano[3,2-c]pyridine-6-carboxylate

[1077] At -78 °C, under a nitrogen atmosphere, a solution of 1 M LiHMDS (14.2 mL, 14.2 mmol, 3.00 eq) in THF was added dropwise to a solution of methyl 3-(((N-(2-methoxy-2-oxoethyl)-4-methylphenyl)sulfonamide)methyl)furan-2-carboxylate (1.80 g, 4.72 mmol, 1.00 eq) in THF (18.0 mL). After the addition, the reaction mixture was heated to 0 °C under a nitrogen atmosphere and stirred for 5 h. A saturated NH4Cl solution (aqueous solution) was added to the reaction mixture, and the aqueous phase was extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (eluent EtOAc / PE) to give the title compound.

[1078] LCMS: 194 [M+H] + .

[1079] Step 4. Synthesis of methyl 7-hydroxy-2,3-dihydrofurano[3,2-c]pyridine-6-carboxylate

[1080] Pd / C (152 mg, 20%) was added to a mixture of methyl 7-hydroxyfurano[3,2-c]pyridine-6-carboxylate (760 mg, 3.93 mmol, 1.00 eq) and MeOH (10.0 mL). The mixture was degassed and purged with H2 gas (40 psi). The mixture was then stirred at 50 °C for 16 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (eluent DCM / MeOH) to give the title compound. LCMS: 196 [M+H] + .

[1081] Step 5. Synthesis of 7-hydroxy-2,3-dihydrofurano[3,2-c]pyridine-6-carboxylic acid

[1082] At room temperature, NaOH (557 mg, 13.9 mmol, 4.00 eq) was added to a mixture of methyl 7-hydroxy-2,3-dihydrofurano[3,2-c]pyridine-6-carboxylate (680 mg, 3.48 mmol, 1.00 eq) in H₂O (3.00 mL) and MeOH (3.00 mL), and the mixture was stirred at 60 °C for 16 h. After completion, the reaction mixture was concentrated under reduced pressure. The residue was diluted with H₂O and acidified with 3 N HCl. The precipitated solid was collected by filtration and dried to give the title compound, which was used directly in the next step without further purification. LCMS: 182 [M+H] + .

[1083] Intermediate-5: 4-hydroxy-2,3-dihydrofurano[2,3-c]pyridine-5-carboxylic acid

[1084]

[1085] Step 1. Synthesis of methyl 2-(bromomethyl)furan-3-carboxylate

[1086] At room temperature, NBS (15.2 g, 85.6 mmol, 1.20 eq) and AIBN (586 mg, 3.57 mmol, 0.05 eq) were added to a stirred solution of methyl 2-methylfuran-3-carboxylate (10.0 g, 71.4 mmol, 1.00 eq) in CCl4 (55.0 mL). The resulting mixture was degassed three times with N2 and stirred overnight at 50 °C under N2. The reaction mixture was concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (eluent EtOAc / PE) to give the title compound. 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.86 (d, 1H), 6.80 (d, 1H), 4.95 (s, 2H), 3.82 (s, 3H).

[1087] Step 2. Synthesis of methyl 2-(((N-(2-methoxy-2-oxoethyl)-4-methylphenyl)sulfonamido)methyl)furan-3-carboxylate

[1088] At room temperature, K₂CO₃ (15.1 g, 110 mmol, 2.00 eq) was added to a stirred solution of methyl 2-(bromomethyl)furan-3-carboxylate (12.0 g, 54.8 mmol, 1.00 eq) in ACN (100 mL). The resulting mixture was degassed three times with N₂ and then stirred overnight at room temperature. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (eluent EtOAc / PE) to give the title compound. LCMS: 382.1 [M+H] + .

[1089] Step 3. Synthesis of methyl 4-hydroxyfurano[2,3-c]pyridine-5-carboxylate

[1090] At -78 °C and under N2, a solution of 1 M LiHMDS (70.0 mL, 70.0 mmol, 3.00 eq) in THF was added to a stirred solution of methyl 2-([N-(2-methoxy-2-oxoethyl)4-methylbenzenesulfonamido]methylfuran-3-carboxylate (9.00 g, 23.6 mmol, 1.00 eq) in THF (50.0 mL). The mixture was stirred for 1 h at room temperature under N2. The reaction mixture was quenched with saturated NH4Cl solution at 0 °C and diluted with H2O (200 mL). The resulting mixture was extracted with EtOAc (2 × 200 mL). The combined organic layers were washed with brine (3 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (eluent EtOAc / PE) to give a crude product, which was purified by PE (250 g / mL) with silica gel (250 mL / mL). Purification was performed by grinding (mL) to obtain the title compound. LCMS: 194.0 [M+H] + .

[1091] Step 4. Synthesis of methyl 4-hydroxy-2,3-dihydrofurano[2,3-c]pyridine-5-carboxylate

[1092] Pd / C (1.65 g, 10%) was added to a solution of methyl 4-hydroxyfurano[2,3-c]pyridine-5-carboxylate (1.00 g, 5.18 mmol, 1.00 eq) in AcOH (1.00 mL) and MeOH (10.0 mL). The mixture was degassed three times with H2, followed by stirring under H2 at room temperature for 1 h. The reaction mixture was filtered, and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure, and the residue was purified by reverse-phase HPLC (C18 column, H2O (10 mmol / L NH4HCO3)-ACN) to give the title compound. LCMS: 195.9 [M+H] + .

[1093] Step 5. Synthesis of 4-hydroxy-2,3-dihydrofurano[2,3-c]pyridine-5-carboxylic acid

[1094] At room temperature, methyl 4-hydroxy-2H,3H-furano[2,3-c]pyridine-5-carboxylate (300 mg, 1.54 mmol, 1.00 eq) in MeOH (3.00 mL) was added to a stirred solution with NaOH (246 mg, 6.15 mmol, 4.00 eq) and H₂O (3.00 mL). The reaction mixture was stirred overnight at 60 °C. The mixture was acidified to pH 3 with 1 N HCl. The resulting mixture was extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to give the title compound, which was used directly in the next step without further purification.

[1095] LCMS: 181.9 [M+H] + .

[1096] Intermediate-6: 5-hydroxy-6-methylpyrimidine-4-carboxylic acid

[1097] Intermediate-21: Methyl 5-methoxy-6-methylpyrimidine-4-carboxylate

[1098]

[1099] Step 1: Synthesis of 4-chloro-5-methoxy-6-methylpyrimidine

[1100] At 0 °C, a solution of 3 M MeMgBr (61.45 mL, 184.4 mmol, 1.1 eq) in diethyl ether was added dropwise to a mixture of 4,6-dichloro-5-methoxypyrimidine (30.00 g, 167.6 mmol, 1.0 eq) in THF (300 mL), and the mixture was stirred at 5 °C for 1 h. The resulting mixture was poured into H₂O (200 mL) and extracted with EtOAc (100 mL × 3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under vacuum. The residue was purified by rapid silica gel chromatography (eluent EtOAc / PE) to give the title compound. LCMS: 159.1 [M+H] + .

[1101] Step 2: Synthesis of methyl 5-methoxy-6-methylpyrimidine-4-carboxylate

[1102] Pd(dppf)Cl₂-CH₂Cl₂ (6.80 g, 8.32 mmol, 0.06 eq) and TEA (28.1 g, 278 mmol, 2.0 eq) were added to a mixture of 4-chloro-5-methoxy-6-methylpyrimidine (22.00 g, 138.7 mmol, 1.0 eq) in MeOH (250 mL). The reactants were purged with CO₂ (50 psi) and stirred overnight at 50 °C. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (eluent EtOAc / PE) to give the title compound. LCMS: 183.1 [M+H] + .

[1103] Step 3: Synthesis of 5-hydroxy-6-methylpyrimidine-4-carboxylic acid

[1104] A mixture of methyl 5-methoxy-6-methylpyrimidine-4-carboxylate (16.00 g, 87.83 mmol, 1.0 eq) and HBr solution (aqueous solution) (68.5 mL, 68%) was stirred overnight at 50 °C. Then, HI solution (aqueous solution) (67.2 mL, 56%) was added and the mixture was stirred at 50 °C for 6 h. The reaction mixture was cooled to room temperature and basicized to pH 9 at 0 °C with 50% NaOH solution (aqueous solution), followed by adjustment to pH 7 at 0 °C with 2 M HCl solution (aqueous solution). The mixture was filtered, and the filter cake was dried under vacuum to give the title compound, which was used in the next step without further purification. LCMS: 155.1 [M+H] +. 1H NMR (400 MHz, DMSO-d6) δ ppm 15.46 (br s, 1H), 8.37 (s, 1H), 2.34 (s, 3H).

[1105] Intermediate-8: {6-[(1S,6S)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo[4.2.0]oct-2-yl]-5-ethyl-2-(2-methoxypyridin-4-yl)-7-oxo-[1,2,3]triazolo[4,5-b]pyridin-4-yl}acetic acid and

[1106] Intermediate-9: 2-(6-((1S,6S)-2,5-diazabicyclo[4.2.0]oct-2-yl)-5-ethyl-2-(2-methoxypyridin-4-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)acetamide hydrochloride

[1107] Intermediate-17: (1S,6S)-5-(4-(2-ethoxy-2-oxoethyl)-5-ethyl-2-(2-methoxypyridin-4-yl)-7-oxo-4,7-dihydro-2H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-2,5-diazabicyclo[4.2.0]octane-2-carboxylic acid tert-butyl ester

[1108]

[1109] Step 1. Synthesis of (1S,6S)-5-[4-(2-ethoxy-2-oxoethyl)-5-ethyl-2-(2-methoxypyridin-4-yl)-7-oxo-[1,2,3]triazolo[4,5-b]pyridin-6-yl]-2,5-diazabicyclo[4.2.0]octane-2-carboxylic acid tert-butyl ester

[1110] At 0 °C, under a nitrogen atmosphere, NaH (14 mg, 582 μmol, 2.0 eq) was added to a stirred mixture of (1S,6S)-5-(5-ethyl-2-(2-methoxypyridin-4-yl)-7-oxo-4,7-dihydro-2H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-2,5-diazabicyclo[4.2.0]octane-2-carboxylic acid tert-butyl ester (intermediate-7) (140 mg, 291 μmol, 1.0 eq) in THF (15 mL). The resulting mixture was degassed three times with N2, and then stirred at 0 °C under a nitrogen atmosphere for 30 min. Ethyl iodoacetate (75 mg, 349 μmol, 1.2 eq) was added to the mixture at 0 °C. The mixture was then stirred again at room temperature for 4 h. The resulting mixture was concentrated under vacuum. The residue was purified by reverse-phase HPLC (C18 column, water (10 mmol / L NH4HCO3)-ACN) to give the title compound.

[1111] LCMS: 568.3 [M+H] + .

[1112] Step 2. Synthesis of {6-[(1S,6S)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo[4.2.0]oct-2-yl]-5-ethyl-2-(2-methoxypyridin-4-yl)-7-oxo-[1,2,3]triazolo[4,5-b]pyridin-4-yl}acetic acid

[1113] At room temperature, under an air atmosphere, H₂O (2 mL) was added to a stirred mixture of (1S,6S)-5-[4-(2-ethoxy-2-oxoethyl)-5-ethyl-2-(2-methoxypyridin-4-yl)-7-oxo-[1,2,3]triazolo[4,5-b]pyridin-6-yl]-2,5-diazabicyclo[4.2.0]octane-2-carboxylic acid tert-butyl ester (intermediate-17) (117 mg, 206 μmol, 1.0 eq) and LiOH (15 mg, 618 μmol, 3.0 eq) in THF (6 mL). The resulting mixture was stirred at room temperature for 1 h. The residue was acidified to pH 5 with 2 N HCl aqueous solution (4 mL). The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to obtain the title compound, which was used directly in the next step without purification.

[1114] LCMS: 540.3 [M+H] + .

[1115] Step 3. Synthesis of (1S,6S)-5-(5-ethyl-2-(2-methoxypyridin-4-yl)-7-oxo-4-(2-oxo-2-((3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)amino)ethyl)-4,7-dihydro-2H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-2,5-diazabicyclo[4.2.0]octane-2-carboxylic acid tert-butyl ester

[1116] At room temperature, under a nitrogen atmosphere, EDCI (71 mg, 370 μmol, 2.0 eq) was added to a stirred mixture of {6-[(1S,6S)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo[4.2.0]oct-2-yl]-5-ethyl-2-(2-methoxypyridin-4-yl)-7-oxo-[1,2,3]triazolo[4,5-b]pyridin-4-yl}acetic acid (intermediate-8) (100 mg, 185 μmol, 1.0 eq) and 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine (34 mg, 222 μmol, 1.2 eq) in pyridine (5 mL). The resulting mixture was degassed three times with nitrogen and then stirred at 60 °C under a nitrogen atmosphere for 2 h. The mixture was then cooled to room temperature and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (eluent DCM / MeOH) to give the title compound.

[1117] LCMS: 673.3 [M+H] + .

[1118] Step 4. Synthesis of 2-(6-((1S,6S)-2,5-diazabicyclo[4.2.0]oct-2-yl)-5-ethyl-2-(2-methoxypyridin-4-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)-N-(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)acetamide hydrochloride

[1119] At room temperature, a mixture of (1S,6S)-5-(5-ethyl-2-(2-methoxypyridin-4-yl)-7-oxo-4-(2-oxo-2-((3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)amino)ethyl)-4,7-dihydro-2H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-2,5-diazabicyclo[4.2.0]octane-2-carboxylic acid tert-butyl ester (60 mg, 89 μmol, 1.0 eq) in 4M HCl / 1,4-dioxane solution (2.5 mL) was stirred for 1 h. The resulting mixture was concentrated under reduced pressure to give the title compound, which was used directly in the next step without purification.

[1120] LCMS: 609.2 [M+H] + .

[1121] Intermediate-10: 6-hydroxybenzo[d]oxazol-7-carboxylic acid

[1122]

[1123] To a stirred solution of ethyl 6-hydroxybenzo[d]oxazol-7-carboxylate (200 mg, 966 μmol, 1 eq) in MeOH (3 mL) and H₂O (0.6 mL), NaOH (193 mg, 4.83 mmol, 5 eq) was added. The resulting mixture was stirred overnight at 60 °C. The mixture was then cooled to room temperature. The mixture was concentrated under vacuum. H₂O (6 mL) was added, and the mixture was acidified to pH 3 with an aqueous solution of HCl (2 N) at 0 °C. The precipitated solid was collected by filtration and washed with H₂O (3 × 3 mL) to give the title compound. LCMS: 178.0 [MH] - .

[1124] Intermediate-11: 1-(2-(3,6-dihydro-2H-pyran-4-yl)-5-((4-methoxybenzyl)amino)-2H-1,2,3-triazol-4-yl)-3-hydroxypent-2-en-1-one

[1125]

[1126] Step 1. Synthesis of methyl 5-bromo-2H-1,2,3-triazol-4-carboxylate

[1127] A mixture of methyl 2H-1,2,3-triazol-4-carboxylate (5.00 g, 39.3 mmol, 1.00 eq), potassium persulfate (7.28 g, 43.3 mmol, 1.10 eq), and KBr (5.15 g, 43.3 mmol, 1.10 eq) in ACN (50.0 mL) and H₂O (50.0 mL) was stirred overnight at room temperature. The resulting mixture was filtered, and the filter cake was washed with ACN. The filtrate was separated, and the organic layer was collected. The aqueous layer was extracted with ACN. The combined organic layers were concentrated under reduced pressure. The residue was diluted with EtOAc, filtered, and the filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure to give the title compound. LCMS: 206 [M+H] + .

[1128] Step 2. Synthesis of methyl 5-bromo-2-(3,6-dihydro-2H-pyran-4-yl)-2H-1,2,3-triazol-4-carboxylate

[1129] A mixture of methyl 5-bromo-2H-1,2,3-triazol-4-carboxylate (1.00 g, 4.85 mmol, 1.00 eq), (3,6-dihydro-2H-pyran-4-yl)boronic acid (intermediate-15) (312 mg, 2.43 mmol, 0.50 eq), pyridine (1.54 g, 19.5 mmol, 4.00 eq), and Cu(OAc)₂ (971 mg, 4.85 mmol, 1.00 eq) in DCM (10 mL) was stirred overnight at 40 °C. The resulting mixture was filtered, and the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (eluent EtOAc / PE) to give the title compound. LCMS: 288 [M+H] + .

[1130] Step 3. Synthesis of methyl 2-(3,6-dihydro-2H-pyran-4-yl)-5-((4-methoxybenzyl)amino)-2H-1,2,3-triazol-4-carboxylate

[1131] Pd₂(dba)₃ (5.15 g, 5.62 mmol, 0.20 eq) was added to a mixture of methyl 5-bromo-2-(3,6-dihydro-2H-pyran-4-yl)-2H-1,2,3-triazol-4-carboxylate (8.10 g, 28.1 mmol, 1.00 eq), (4-methoxyphenyl)methylamine (5.79 g, 42.2 mmol, 1.50 eq), XantPhos (6.51 g, 11.2 mmol, 0.40 eq), and Cs₂CO₃ (18.3 g, 56.2 mmol, 2.00 eq) in 1,4-dioxane (324 mL). The mixture was degassed three times with N₂ and stirred overnight at 100 °C. The resulting mixture was cooled to room temperature and filtered, and the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (eluent EtOAc / PE) to give the title compound. LCMS: 345 [M+H] + .

[1132] Step 4. Synthesis of 1-(2-(3,6-dihydro-2H-pyran-4-yl)-5-((4-methoxybenzyl)amino)-2H-1,2,3-triazol-4-yl)-3-hydroxypent-2-en-1-one

[1133] At 0 °C and under N2, a 1 M LiHMDS solution in THF (13.1 mL, 13.1 mmol, 5.00 eq) was added dropwise to a solution of butanone (942 mg, 13.1 mmol, 5.00 eq) in THF (5.00 mL). The reaction mixture was stirred for 30 min at room temperature. Next, a solution of methyl 2-(3,6-dihydro-2H-pyran-4-yl)-5-((4-methoxybenzyl)amino)-2H-1,2,3-triazol-4-carboxylate (900 mg, 2.61 mmol, 1.00 eq) in THF (13.0 mL) was added dropwise at 0 °C. The reaction mixture was heated to 60 °C and stirred at 60 °C for 60 min. The reaction mixture was cooled to room temperature, quenched with a saturated aqueous NH4Cl solution, and then extracted with EtOAc. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (eluent EtOAc / PE) to give the title compound. LCMS: 385 [M+H] + .

[1134] Intermediate-12: (1S,6S)-5-(1-(2-(3,6-dihydro-2H-pyran-4-yl)-5-((4-methoxybenzyl)amino)-2H-1,2,3-triazol-4-yl)-1,3-dioxopentan-2-yl)-2,5-diazabicyclo[4.2.0]octane-2-carboxylic acid tert-butyl ester

[1135]

[1136] Step 1. Synthesis of 2-bromo-1-(2-(3,6-dihydro-2H-pyran-4-yl)-5-((4-methoxybenzyl)amino)-2H-1,2,3-triazol-4-yl)pentane-1,3-dione

[1137] NBS (1.16 g, 6.50 mmol, 1.00 eq) was added to a stirred solution of 1-(2-(3,6-dihydro-2H-pyran-4-yl)-5-((4-methoxybenzyl)amino)-2H-1,2,3-triazol-4-yl)-3-hydroxypent-2-en-1-one (intermediate-11) (2.50 g, 6.50 mmol, 1.00 eq) in DCM (25.0 mL) at 0 °C under a nitrogen atmosphere. The mixture was stirred for 1 h at 0 °C. The resulting mixture was used directly in the next step without further purification. LCMS: 463 [M+H] + .

[1138] Step 2. Synthesis of (1S,6S)-5-(1-(2-(3,6-dihydro-2H-pyran-4-yl)-5-((4-methoxybenzyl)amino)-2H-1,2,3-triazol-4-yl)-1,3-dioxopentan-2-yl)-2,5-diazabicyclo[4.2.0]octane-2-carboxylic acid tert-butyl ester

[1139] At room temperature, (1S,6S)-2,5-diazabicyclo[4.2.0]octane-2-carboxylic acid tert-butyl ester (CAS: 2920219-11-8) (916 mg, 4.32 mmol, 0.80 eq) and DIEA (2.09 g, 16.19 mmol, 3.00 eq) were added to the solution from step 1. The mixture was stirred for 2 h at room temperature. The mixture was diluted with water (50 mL) and extracted with DCM (2 × 50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound, which was used directly in the next step without further purification. LCMS: 595 [M+H] + .

[1140] Step 3. Synthesis of 6-((1S,6S)-2,5-diazabicyclo[4.2.0]oct-2-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-2,4-dihydro-7H-[1,2,3]triazolo[4,5-b]pyridin-7-one trifluoroacetate.

[1141] A solution of (1S,6S)-5-(1-(2-(3,6-dihydro-2H-pyran-4-yl)-5-((4-methoxybenzyl)amino)-2H-1,2,3-triazol-4-yl)-1,3-dioxopentan-2-yl)-2,5-diazabicyclo[4.2.0]octane-2-carboxylic acid tert-butyl ester (2.70 g, 4.54 mmol, 1.00 eq) in TFA (20.0 mL) was stirred for 30 min at 60 °C. The resulting mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by grinding with Et2O (30 mL). The solid was collected by filtration and washed with Et2O to give the title compound. LCMS: 357 [M+H] + .

[1142] Step 4. Synthesis of (1S,6S)-5-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-4,7-dihydro-2H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-2,5-diazabicyclo[4.2.0]octane-2-carboxylic acid tert-butyl ester

[1143] DIEA (2.50 g, 19.36 mmol, 3.96 eq) and (Boc)₂O (1.55 g, 7.10 mmol, 1.45 eq) were added to a stirred mixture of 6-((1S,6S)-2,5-diazabicyclo[4.2.0]oct-2-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-2,4-dihydro-7H-[1,2,3]triazolo[4,5-b]pyridin-7-one trifluoroacetate (2.30 g, 4.89 mmol, 1.00 eq) in DCM (20.0 mL). The mixture was stirred for 30 min at room temperature and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (eluting with PE / EA) to give the title compound. LCMS: 457 [M+H] + .

[1144] Intermediate-13: (1S,6S)-5-(2-(3,6-dihydro-2H-pyran-4-yl)-4-(2-ethoxy-2-oxoethyl)-5-ethyl-7-oxo-4,7-dihydro-2H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-2,5-diazabicyclo[4.2.0]octane-2-carboxylic acid tert-butyl ester

[1145]

[1146] Step 1. Synthesis of (1S,6S)-5-(2-(3,6-dihydro-2H-pyran-4-yl)-4-(2-ethoxy-2-oxoethyl)-5-ethyl-7-oxo-4,7-dihydro-2H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-2,5-diazabicyclo[4.2.0]octane-2-carboxylic acid tert-butyl ester

[1147] At 0 °C, NaH (193 mg, 4.82 mmol, 4.00 eq, 60% suspension in mineral oil) was added to a solution of (1S,6S)-5-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-4,7-dihydro-2H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-2,5-diazabicyclo[4.2.0]octane-2-carboxylic acid tert-butyl ester (intermediate-12) (550 mg, 1.21 mmol, 1.00 eq) in THF (6.00 mL). The mixture was stirred for 30 min. Ethyl bromoacetate (402 mg, 2.41 mmol, 2.00 eq) was added and the mixture was heated to 60 °C and stirred for 2 h. The mixture was cooled to room temperature and quenched with a saturated aqueous solution of NH4Cl (10 mL), followed by extraction with EtOAc (3 × 20 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (eluent: EtOAc / PE) to give the title compound. LCMS: 543 [M+H] + .

[1148] Intermediate-14: 2-(6-((1S,6S)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo[4.2.0]oct-2-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)acetic acid

[1149]

[1150] Step 1. Synthesis of 2-(6-((1S,6S)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo[4.2.0]oct-2-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)acetic acid

[1151] LiOH hydrate (23 mg, 0.55 mmol, 2.00 eq) was added to a stirred solution of (1S,6S)-5-(2-(3,6-dihydro-2H-pyran-4-yl)-4-(2-ethoxy-2-oxoethyl)-5-ethyl-7-oxo-4,7-dihydro-2H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-2,5-diazabicyclo[4.2.0]octane-2-carboxylic acid tert-butyl ester (intermediate-13) (150 mg, 0.28 mmol, 1.00 eq) in MeOH (1.00 mL) and H2O (1.00 mL). The mixture was stirred for 1 h at room temperature. The mixture was acidified to pH 3–4 with 1 N HCl (aqueous solution). The resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to give the title compound. LCMS: 515 [M+H] + .

[1152] Intermediate-15: (3,6-dihydro-2H-pyran-4-yl)boronic acid

[1153]

[1154] Step 1. Synthesis of (3,6-dihydro-2H-pyran-4-yl)boronic acid

[1155] At room temperature, a solution of NH4OAc (22.0 g, 286 mmol, 3.00 eq) in H2O (600 mL) was added to a stirred solution of NaIO4 (61.1 g, 286 mmol, 3.00 eq) in H2O (600 mL). At 0 °C, a solution of 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane (20.0 g, 95.2 mmol, 1.00 eq) in ACN (1.20 L) was added to the above mixture. The resulting mixture was stirred for another 4 h at room temperature. The resulting mixture was filtered, and the filter cake was washed with ACN. The combined filtrates were concentrated under reduced pressure to remove ACN, and the residue was extracted with EtOAc (3 × 3 L). The combined organic layers were washed with brine (2 × 500 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was diluted with EtOAc (1 L). The resulting mixture was filtered, and the filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure to give the title compound. LCMS: 129 [M+H] + .

[1156] Intermediate-1: Alternative program for 1-(5-(bis(4-methoxybenzyl)amino)-2-(2-methoxypyridin-4-yl)-2H-1,2,3-triazol-4-yl)-2-bromopentane-1,3-dione

[1157]

[1158] Step 1. Synthesis of 1-(5-(bis(4-methoxybenzyl)amino)-2-(2-methoxypyridin-4-yl)-2H-1,2,3-triazol-4-yl)-3-hydroxypent-2-en-1-one

[1159] A solution of methyl (ethyl) ketone (4.30 g, 59.6 mmol, 3.00 eq) in THF (360 mL) was degassed three times with N2, followed by dropwise addition of a 1 M LiHMDS solution in THF (59.6 mL, 59.6 mmol, 3.00 eq) at 0 °C. The resulting mixture was stirred for 30 min at room temperature. At 60 °C, a solution of ethyl 5-(bis(4-methoxybenzyl)amino)-2-(2-methoxypyridin-4-yl)-2H-1,2,3-triazol-4-carboxylate (intermediate-22) (10.0 g, 19.9 mmol, 1.00 eq) in THF (40.0 mL) was added dropwise to the above mixture. The resulting mixture was stirred for another 1 h at 60 °C. The reaction mixture was cooled to 0 °C and then quenched with saturated NH4Cl (aqueous solution). The mixture was extracted with EtOAc (3 × 500 mL). The combined organic layers were washed with brine (1 × 500 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (eluent EtOAc / PE) to give the title compound. LCMS: 530.0 [M+H] + .

[1160] Step 2. Synthesis of 1-(5-(bis(4-methoxybenzyl)amino)-2-(2-methoxypyridin-4-yl)-2H-1,2,3-triazol-4-yl)-2-bromopentane-1,3-dione

[1161] NBS (1.81 g, 10.2 mmol, 0.90 eq) was added to a solution of 1-(5-(bis(4-methoxybenzyl)amino)-2-(2-methoxypyridin-4-yl)-2H-1,2,3-triazol-4-yl)-3-hydroxypent-2-en-1-one (6.00 g, 11.3 mmol, 1.00 eq) in DCM (300 mL). The resulting mixture was degassed three times with N2 and then stirred at room temperature for 1 h. The resulting mixture was used directly in the next step without further purification. LCMS: 608.0 [M+H] + .

[1162] Intermediate 7: (1S,6S)-5-(5-ethyl-2-(2-methoxypyridin-4-yl)-7-oxo-4,7-dihydro-2H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-2,5-diazabicyclo[4.2.0]octane-2-carboxylic acid tert-butyl ester

[1163]

[1164] Step 1. Synthesis of (1S,6S)-5-(1-(5-(bis(4-methoxybenzyl)amino)-2-(2-methoxypyridin-4-yl)-2H-1,2,3-triazol-4-yl)-1,3-dioxopentan-2-yl)-2,5-diazabicyclo[4.2.0]octane-2-carboxylic acid tert-butyl ester

[1165] At room temperature, THF (300 mL), (1S,6S)-2,5-diazabicyclo[4.2.0]octane-2-carboxylic acid tert-butyl ester (CAS: 2920219-11-8) (1.73 g, 8.15 mmol, 0.9 eq), and DIEA (2.34 g, 18.1 mmol, 2.00 eq) were added to a solution of intermediate-1 (obtained from 10.0 g (19.9 mmol) of intermediate-22 according to the substitutional synthesis procedure for intermediate-1). The resulting mixture was degassed three times with N2 and then stirred at room temperature for 16 h. The resulting mixture was diluted with H2O (300 mL) and extracted with DCM (3 × 500 mL). The combined organic layers were washed with brine (1 × 500 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give the title compound, which was used directly in the next step without purification. LCMS: 740.0 [M+H] + .

[1166] Step 2. Synthesis of 6-((1S,6S)-2,5-diazabicyclo[4.2.0]oct-2-yl)-5-ethyl-2-(2-methoxypyridin-4-yl)-2,4-dihydro-7H-[1,2,3]triazolo[4,5-b]pyridin-7-one trifluoroacetate.

[1167] A solution of (1S,6S)-5-(1-(5-(bis(4-methoxybenzyl)amino)-2-(2-methoxypyridin-4-yl)-2H-1,2,3-triazol-4-yl)-1,3-dioxopentan-2-yl)-2,5-diazabicyclo[4.2.0]octane-2-carboxylic acid tert-butyl ester (15.5 g, 11.5 mmol, 1.00 eq) in TFA (100 mL) was stirred for 30 min at 60 °C. The resulting mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by grinding with Et2O (150 mL). The precipitated solid was collected by filtration and washed with Et2O to give the title compound. LCMS: 382.0 [M+H] + .

[1168] Step 3. Synthesis of (1S,6S)-5-(5-ethyl-2-(2-methoxypyridin-4-yl)-7-oxo-4,7-dihydro-2H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-2,5-diazabicyclo[4.2.0]octane-2-carboxylic acid tert-butyl ester

[1169] At 0 °C, DIEA (2.91 g, 22.5 mmol, 2.00 eq) and (Boc)₂O (2.46 g, 11.3 mmol, 1.00 eq) were added to a stirred mixture of 6-((1S,6S)-2,5-diazabicyclo[4.2.0]oct-2-yl)-5-ethyl-2-(2-methoxypyridin-4-yl)-2,4-dihydro-7H-[1,2,3]triazolo[4,5-b]pyridin-7-one trifluoroacetate (5.40 g, 11.3 mmol, 1.00 eq) in DCM (100 mL). After stirring at room temperature for 30 min, the resulting mixture was diluted with H₂O (200 mL) and extracted with DCM (3 × 200 mL). The combined organic layers were dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (eluent EtOAc / PE) to give the title compound. LCMS: 482.0 [M+H] + .

[1170] Intermediate-17: Alternative procedure for (1S,6S)-5-(4-(2-ethoxy-2-oxoethyl)-5-ethyl-2-(2-methoxypyridin-4-yl)-7-oxo-4,7-dihydro-2H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-2,5-diazabicyclo[4.2.0]octane-2-carboxylic acid tert-butyl ester

[1171]

[1172] Step 1. Synthesis of (1S,6S)-5-(4-(2-ethoxy-2-oxoethyl)-5-ethyl-2-(2-methoxypyridin-4-yl)-7-oxo-4,7-dihydro-2H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-2,5-diazabicyclo[4.2.0]octane-2-carboxylic acid tert-butyl ester

[1173] At 0 °C, NaH (112 mg, 2.81 mmol, 5.00 eq, 60% suspension in mineral oil) was added fractionally to a stirred solution of (1S,6S)-5-(5-ethyl-2-(2-methoxypyridin-4-yl)-7-oxo-4,7-dihydro-2H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-2,5-diazabicyclo[4.2.0]octane-2-carboxylic acid tert-butyl ester (intermediate-7) (270 mg, 0.56 mmol, 1.00 eq) in THF (8.00 mL). The resulting mixture was degassed three times with N2 and then stirred at 0 °C for 30 min. At 0 °C, THF (2.00 mL) containing ethyl 2-bromoacetate (562 mg, 3.37 mmol, 6.00 eq) was added to the above mixture. After stirring at 60 °C for 30 min, the resulting mixture was cooled to 0 °C and then quenched with saturated NH₄Cl (aqueous solution). The mixture was extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (1 × 25 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (eluent EtOAc / PE) to give the title compound. LCMS: 568.0 [M + H] + .

[1174] Intermediate-18: Synthesis of 2-bromo-1-(5-((4-methoxybenzyl)amino)-2-(pyridin-2-yl)-2H-1,2,3-triazol-4-yl)pentane-1,3-dione

[1175]

[1176] Step 1. Synthesis of 2-(4,5-dibromo-2H-1,2,3-triazol-2-yl)pyridine

[1177] DIEA (39.95 g, 309 mmol, 9.0 eq) was added to a stirred mixture of 2-fluoropyridine (5 g, 51.5 mmol, 1.5 eq) and 4,5-dibromo-2H-1,2,3-triazole (7.8 g, 34.34 mmol, 1.0 eq) in DMF (30 mL) at room temperature. The resulting mixture was stirred at 140 °C for 2 days. The mixture was cooled to room temperature and purified by reverse-phase HPLC (C18 column, H2O (0.1% FA)-ACN) to give the title compound. LCMS: 304.9 [M+H] + .

[1178] Step 2. Synthesis of methyl 5-bromo-2-(pyridin-2-yl)-2H-1,2,3-triazol-4-carboxylate

[1179] TEA (8.99 g, 88.8 mmol, 3.00 eq) and Pd(dppf)Cl2 (2.17 g, 2.96 mmol, 0.10 eq) were added to a solution of 2-(4,5-dibromo-1,2,3-triazol-2-yl)pyridine (9.00 g, 29.6 mmol, 1.00 eq) in MeOH (270 mL). The resulting mixture was stirred for 16 h at 100 °C under a CO (30 bar) atmosphere. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (eluting PE / EtOAc) to give the title compound. LCMS: 283.0 [M+H] + .

[1180] Step 3. Synthesis of 5-((4-methoxybenzyl)amino)-2-(pyridin-2-yl)-2H-1,2,3-triazol-4-carboxylic acid

[1181] At room temperature, Cs₂CO₃ (17.2 g, 52.98 mmol, 6.0 eq), GPhos Pd G₆ TES (833.9 mg, 883 μmol, 0.1 eq), and GPhos (947.9 mg, 1.766 mmol, 0.2 eq) were added to a stirred mixture of methyl 5-bromo-2-(pyridin-2-yl)-2H-1,2,3-triazol-4-carboxylate (2.5 g, 8.83 mmol, 1.0 eq) and NH₂PMB (3.02 g, 22.08 mmol, 2.5 eq) in 1,4-dioxane (40 mL). The mixture was heated to 120 °C and stirred at 120 °C under a N₂ atmosphere for 16 h. The mixture was then cooled to room temperature. The reaction mixture was diluted with 100 mL of H₂O and acidified to pH 3 with 1 NHCl, followed by extraction with EtOAc (3 × 200 mL). The combined organic layers were dried over Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure to give the title compound, which was used in the next step without further purification. LCMS: 326.1 [M + H] + .

[1182] Step 4. Synthesis of N-methoxy-5-((4-methoxybenzyl)amino)-N-methyl-2-(pyridin-2-yl)-2H-1,2,3-triazol-4-carboxamide

[1183] At room temperature, HATU (4.16 g, 10.94 mmol, 2.0 eq) and DIEA (3.54 g, 27.36 mmol, 5.0 eq) were added to a stirred mixture of 5-((4-methoxybenzyl)amino)-2-(pyridin-2-yl)-2H-1,2,3-triazol-4-carboxylic acid (1.78 g, 5.47 mmol, 1.0 eq) and N,O-dimethylhydroxylamine (1.0 g, 16.4 mmol, 3.0 eq) in DMF (30 mL). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (3 × 200 mL). The organic layer was washed with brine (3 × 200 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (EtOAc / PE) to give the title compound.

[1184] LCMS: 369.2 [M+H] + .

[1185] Step 5. Synthesis of 3-hydroxy-1-(5-((4-methoxybenzyl)amino)-2-(pyridin-2-yl)-2H-1,2,3-triazol-4-yl)pent-2-en-1-one

[1186] At 0 °C, LiHMDS (1 M in THF, 7.8 mL, 7.8 mmol, 2.5 eq) was added dropwise to a stirred mixture of butanone (561.6 mg, 7.8 mmol, 2.5 eq) in 20 mL of THF. The resulting mixture was stirred for 30 min at room temperature under a N2 atmosphere. At room temperature, 8 mL of THF containing N-methoxy-5-((4-methoxybenzyl)amino)-N-methyl-2-(pyridin-2-yl)-2H-1,2,3-triazol-4-carboxamide (1.15 g, 3.12 mmol, 1.0 eq) was added dropwise to the above mixture. The resulting mixture was then heated to 60 °C and held for 1 h. The mixture was cooled to room temperature and quenched with H2O (100 mL), and extracted with EtOAc (3 × 200 mL). The organic layer was washed with brine (100 mL × 1), dried over Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (EtOAc / PE) to give the title compound.

[1187] LCMS: 380.2 [M+H] + .

[1188] Step 6. Synthesis of 2-bromo-1-(5-((4-methoxybenzyl)amino)-2-(pyridin-2-yl)-2H-1,2,3-triazol-4-yl)pentane-1,3-dione

[1189] At 0 °C, TsOH-H₂O (25.1 mg, 132 μmol, 0.1 eq) and NBS (234.5 mg, 1.318 mmol, 1.0 eq) were added to a stirred mixture of 3-hydroxy-1-(5-((4-methoxybenzyl)amino)-2-(pyridin-2-yl)-2H-1,2,3-triazol-4-yl)pent-2-en-1-one (500 mg, 1.318 mmol, 1.0 eq) in DCM (7 mL). The resulting mixture was stirred at 0 °C for 20 min. The mixture was diluted with H₂O (20 mL) and extracted with DCM (3 × 20 mL). The organic layer was dried over Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (EtOAc / PE) to give the title compound. LCMS: 458.1 [M+H] + .

[1190] Intermediate-19: 3-(trifluoromethoxy)bicyclo[1.1.1]pentane-1-amine trifluoroacetate

[1191]

[1192] Step 1. Synthesis of methyl benzoate (3-hydroxybicyclo[1.1.1]pent-1-yl)carbamate

[1193] At 20 °C, NaHCO3 (985 mg, 11.73 mmol, 3 eq) was added to a suspension of 3-aminobicyclo[1.1.1]pentane-1-ol hydrochloride (530 mg, 3.91 mmol, 1 eq) in THF (5.4 mL) and H2O (2.7 mL). The mixture was cooled to 0 °C, and then Cb2Cl (733 mg, 4.30 mmol, 613 μL, 1.1 eq) was added dropwise at 0 °C under a N2 atmosphere. The resulting mixture was stirred at 0 °C for 15 min, then heated to 20 °C and stirred at 20 °C under a N2 atmosphere for 16 h. The mixture was diluted with brine (10 mL) and then extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by rapid silica gel chromatography (eluent EtOAc / PE) to give the title compound. LCMS: 234.0 [M+H] +

[1194] Step 2. Synthesis of methyl benzoate (3-(trifluoromethoxy)bicyclo[1.1.1]pent-1-yl)carbamate

[1195] 1-(trifluoromethyl)-1,2-benzoiodooxacyclopentanone (992 mg, 3.14 mmol, 1.2 eq) was added to a solution of N-(3-hydroxy-1-bicyclo[1.1.1]pentyl)carbamate (610 mg, 2.62 mmol, 1 eq) and Zn(NTf2)2 (1.96 g, 3.14 mmol, 1.2 eq) in CHCl3 (5 mL). The mixture was stirred for 16 h at 25 °C. The mixture was filtered and the filter cake was washed with DCM (2 × 5 mL). The combined filtrates were concentrated under reduced pressur...

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof: Y and Z are independently selected from C and N. ----- Represent a single or double bond, where Z is C when Y is N, or Z is N when Y is C; to form a subformulation selected from equations Ia and Ib: Where ring A represents: i. 4-7 saturated or partially unsaturated divalent monocyclic systems, selected from carbocyclic and heterocyclic groups (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or ii. Fused, bridged or spirocyclic 4-12 saturated or partially unsaturated dicyclic bicyclic systems selected from subcarbonyl or subheterocyclic groups (having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur); Ring A is selected from 0 to 4 independently chosen R. A Substituent substitution; L is selected from -C(O)-, -S(O)-, -S(O)2- and Linking groups; R 1 Selected from groups a) to e): a) A 5-6 membered monocyclic heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted with 1-3 groups independently selected from halogen, C1-C6 alkyl, halo-C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkoxy groups, wherein the 5-6 membered monocyclic heteroaryl group is further substituted with 0-3 independently selected R groups. A replace; b) A 9-10 membered bicyclic heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted with 1 or 2 groups independently selected from C1-C6 aliphatic, C3-C6 cycloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkoxy groups, wherein the 9-10 membered bicyclic heteroaryl group is further substituted with 0-3 independently selected R groups. A replace; c) A 4-7 member saturated or partially unsaturated monocyclic heterocyclic group (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted with 1 or 2 groups independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, and -OR groups, wherein the 4-7 member saturated or partially unsaturated monocyclic heterocyclic group is further substituted with 0-3 independently selected R groups. A replace; d) Fused, bridged, or spirocyclic 4-12 saturated or partially unsaturated bicyclic systems selected from carbocyclic and heterocyclic groups (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the carbocyclic or heterocyclic group is supported by 0-3 independently selected R atoms. A Replace; and e)H, C1-C6 aliphatic group, C3-C7 cycloalkyl, C1-C6 alkylene, -O-C1-C6 alkyl, -C(O)NR 10 R 11 -CH2NR 10 R 11 -SO2R 12 The C1-C6 aliphatic group, the C3-C7 cycloalkyl group, or the C1-C6 alkylene group (O-C1-C6 alkyl) is selected from 0 to 5 independently chosen R groups. A replace; R 10 It is H, C1-C6 aliphatic group, halo-C1-C6 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, -C(O)C3-C6 cycloalkyl, -C(O)C1-C6 alkyl or 5-6 heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur), optionally surrounded by 1 or 2 heteroatoms independently selected from R A Substitution of groups; R 11 It is H, C1-C6 aliphatic group or C3-C6 cycloalkyl group, or R 10 and R 11 They can be combined to form 5-6 membered rings, which are optionally substituted by 1, 2 or 3 substituents independently selected from halogens, -OH, -CN, C1-C4 alkoxy groups and halo-C1-C4 alkoxy groups; R 12 It is a C1-C6 aliphatic group, a C3-C6 cycloalkyl group, or a 5-6-membered heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), which is optionally substituted with 1 or 2 groups independently selected from halogen, C1-C6 aliphatic group, halo-C1-C6 alkyl group, C1-C6 alkoxy group, C3-C6 cycloalkyl group, and C3-C6 cycloalkoxy group; R A Each occurrence is independently selected from the group consisting of: optionally substituted phenyl groups, optionally substituted 5-6-membered heteroaryl groups (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted 4-7-membered saturated or partially unsaturated heterocyclic groups (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), halogens, optionally substituted C1-C6 aliphatic groups, hydroxy-C1-C6 alkyl groups, halo-C1-C6 alkyl groups, optionally substituted C3-C6 cycloalkyl groups, halo-C3-C6 cycloalkyl groups, optionally substituted C1-C6 alkoxy groups, halo-C1-C6 alkoxy groups, optionally substituted C3-C6 cycloalkoxy groups. -O-C1-C6 alkylene, -CN, -NO2, oxo, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2 and -N(R)S(O)2R; R 2 Selected from C(R) B )2C(O)N(R)R 2A C(R) B )2C(R B )2C(O)N(R)R 2A C(R) B )2C(R B )2N(R)C(O)N(R)R 2A and C(R) B )2C(R B )2N(R)C(O)R 2A ; R B Each occurrence is independently selected from hydrogen, -CH3 or -CH2CH3, or both R groups. B It combines with the carbon atoms it is attached to to form a cyclopropyl ring; R 2A It is a phenyl, pyridyl, cubic alkyl, saturated or partially unsaturated 4-8 membered monocyclic, saturated or partially unsaturated bridged, fused, or spirocyclic ring of 5, 6, 7, 8, 9, 10, 11, or 12 membered ring, wherein the saturated or partially unsaturated monocyclic, or the saturated or partially unsaturated bridged, fused, or spirocyclic ring contains 0, 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and wherein each of the phenyl, pyridyl, cubic, saturated or partially unsaturated monocyclic, or saturated or partially unsaturated bridged, fused, or spirocyclic rings is optionally substituted by 1, 2, or 3 substituents independently selected from: halogen, C1-C4 aliphatic group, halo-C1-C4 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, -OH, -CN, C1-C4 alkoxy group. The following are possible alternatives: halogenated C1-C4 alkoxy, C3-C6 cycloalkoxy, halogenated C3-C6 cycloalkoxy, and -SF5; or two substituents on adjacent atoms of the phenyl or pyridinium group together with the adjacent atoms to form a 4-7 membered carbon cyclo group fused with the phenyl or pyridinium group; or two substituents on adjacent atoms of the phenyl or pyridinium group together with the adjacent atoms to form a 4-7 membered heterocyclic group fused with the phenyl or pyridinium group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the 4-7 membered carbon cyclo group or the 4-7 membered heterocyclic group is substituted with 0-5 independently selected halogens, and wherein two substituents on the same atom of the saturated or partially unsaturated monocyclic ring, or the saturated or partially unsaturated bridged, fused, or spirocyclic ring, form a cyclogroup selected from: ●Optionally substituted 3-7 member saturated or partially unsaturated carbon cyclogroups, and ●Optionally substituted 4-7 member saturated or partially unsaturated heterocyclic groups, having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or R 2A It is 2-benzimidazolyl, 2-naphthyl, or 3-quinolinyl, each of which is optionally substituted by one, two, or three substituents independently selected from halogens, C1-C4 aliphatic groups, halo-C1-C4 alkyl groups, and -OH; R 3 It is hydrogen, C1-C4 aliphatic group, C3-C5 cycloalkyl group, C1-C4 alkoxy group, -NHR 3A -N(R) 3A )2 or C1-C4 alkylthio groups, except for hydrogen, each of which is optionally divided by -OH, 1-5 independently chosen halogens, -OR, -C(O)NR 10 R 11 Or N(R)C(O)R can be substituted; Each R 3A Each occurrence is independently selected from C1-C4 alkyl groups; R 4 It is a phenyl or a first 5-6-membered heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the phenyl or the first 5-6-membered heteroaryl group is surrounded by 0-5 R atoms. A Substitution, or the two substituents on the adjacent atoms of the phenyl or the first 5-6-membered heteroaryl group together with the adjacent atoms form a 4-7-membered saturated or partially unsaturated fused carbocyclic group, a 4-7-membered saturated or partially unsaturated fused heterocyclic group, or a second 5-6-membered heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the 4-7-membered saturated or partially unsaturated fused carbocyclic group, the 4-7-membered saturated or partially unsaturated fused heterocyclic group, and the second 5-6-membered heteroaryl group are bounded by 0-3 R... A Replace; or R 4 It is a C1-C4 alkyl, C1-C4 alkoxy, or C3-C6 cycloalkyl, each of which is substituted by 0-3 independently selected groups from the following: halogen, -CN, -OH, oxo, NH2, C1-C4 alkyl, C1-C4 alkoxy, optionally substituted 5-6 membered heterocyclic group and optionally substituted 5-6 membered heterocyclic oxy group; Each R is independently hydrogen or optionally substituted C. 1-6 Aliphatic group, optionally substituted phenyl group, optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring, optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur) or optionally substituted 5-6 membered heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur); or Two R groups on the same atom are bonded together with the same atom to form optionally substituted 4-7 saturated rings, 4-7 partially unsaturated rings, or 5-6 heteroaromatic rings (wherein the 4-7 saturated rings and the 4-7 partially unsaturated rings have 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and wherein the 5-6 heteroaromatic rings have 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

2. A compound of formula I or a pharmaceutically acceptable salt thereof: Y and Z are independently selected from C and N. ----- Represent a single or double bond, where Z is C when Y is N, or Z is N when Y is C; to form a subformulation selected from equations Ia and Ib: Where ring A represents: a) A 4-7 saturated or partially unsaturated divalent monocyclic system selected from carbocyclic and heterocyclic groups (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or b) Fused, bridged or spirocyclic 4-12 saturated or partially unsaturated dicyclic bicyclic systems selected from carbocyclic or heterocyclic groups (with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur); Ring A is selected from 0 to 4 independently chosen R. A Substituent substitution; -L- is selected from -C(O)-, -S(O)-, -S(O)2- and Linking groups; R 1 Selected from groups a) to e): a) A 5-6 membered monocyclic heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted with 1-3 groups independently selected from halogen, C1-C6 alkyl, halo-C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkoxy groups, wherein the 5-6 membered monocyclic heteroaryl group is further substituted with 0-3 independently selected R groups. A replace; b) A 9-10 membered bicyclic heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted with 1 or 2 groups independently selected from C1-C6 aliphatic, C3-C6 cycloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkoxy groups, wherein the 9-10 membered bicyclic heteroaryl group is further substituted with 0-3 independently selected R groups. A replace; c) A 4-7 member saturated or partially unsaturated monocyclic heterocyclic group (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted with 1 or 2 groups independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, and -OR groups, wherein the 4-7 member saturated or partially unsaturated monocyclic heterocyclic group is further substituted with 0-3 independently selected R groups. A replace; d) Fused, bridged, or spirocyclic 4-12 saturated or partially unsaturated bicyclic systems selected from carbocyclic and heterocyclic groups (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the carbocyclic or heterocyclic group is supported by 0-3 independently selected R atoms. A Replace; and e)H, C1-C6 aliphatic group, C3-C7 cycloalkyl, C1-C6 alkylene, -O-C1-C6 alkyl, -C(O)NR 10 R 11 -CH2NR 10 R 11 -SO2R 12 The C1-C6 aliphatic group, the C3-C7 cycloalkyl group, or the C1-C6 alkylene group (O-C1-C6 alkyl) is selected from 0 to 5 independently chosen R groups. A replace; R 10 It is H, C1-C6 aliphatic group, halo-C1-C6 alkyl, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, -C(O)C3-C6 cycloalkyl, -C(O)C1-C6 alkyl or 5-6 heteroaryl (having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur), optionally surrounded by 1 or 2 heteroatoms independently selected from R A Substitution of groups; R 11 It is H, C1-C6 aliphatic group or C3-C6 cycloalkyl group, or R 10 and R 11 They can be combined to form 5-6 membered rings, which are optionally substituted by 1, 2 or 3 substituents independently selected from halogens, -OH, -CN, C1-C4 alkoxy groups and halo-C1-C4 alkoxy groups; R 12 It is a C1-C6 aliphatic group, a C3-C6 cycloalkyl group, or a 5-6-membered heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), which is optionally substituted with 1 or 2 groups independently selected from halogen, C1-C6 aliphatic group, halo-C1-C6 alkyl group, C1-C6 alkoxy group, C3-C6 cycloalkyl group, and C3-C6 cycloalkoxy group; R A Each occurrence is independently selected from the group consisting of: optionally substituted phenyl groups, optionally substituted 5-6-membered heteroaryl groups (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted 4-7-membered saturated or partially unsaturated heterocyclic groups (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), halogens, optionally substituted C1-C6 aliphatic groups, hydroxy-C1-C6 alkyl groups, halo-C1-C6 alkyl groups, optionally substituted C3-C6 cycloalkyl groups, halo-C3-C6 cycloalkyl groups, optionally substituted C1-C6 alkoxy groups, halo-C1-C6 alkoxy groups, optionally substituted C3-C6 cycloalkoxy groups. -O-C1-C6 alkylene, -CN, -NO2, oxo, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2 and -N(R)S(O)2R; R 2 This is C(R) B )2C(O)N(R)R 2A ; R B Each occurrence is independently selected from hydrogen, -CH3 or -CH2CH3, or both R groups. B It combines with the carbon atoms it is attached to to form a cyclopropyl ring; R 2A It is a phenyl or pyridyl group, each of which is optionally substituted by one, two, or three substituents independently selected from the following: halogen, C1-C4 aliphatic group, halo-C1-C4 alkyl group, C3-C6 cycloalkyl group, halo-C3-C6 cycloalkyl group, -OH, -CN, C1-C4 alkoxy group, halo-C1-C4 alkoxy group, and -SF5; or two substituents on adjacent atoms of the phenyl or pyridyl group together with the adjacent atoms form a 4-7 membered carbon cycloyl group fused with the phenyl or pyridyl group; or two substituents on adjacent atoms of the phenyl or pyridyl group together with the adjacent atoms form a 4-7 membered heterocyclic group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) fused with the phenyl or pyridyl group, wherein the 4-7 membered carbon cycloyl group or the 4-7 membered heterocyclic group is substituted by 0-5 independently selected halogens; or R 2A It is 2-benzimidazolyl, 2-naphthyl, or 3-quinolinyl, each of which is optionally substituted by one, two, or three substituents independently selected from halogens, C1-C4 aliphatic groups, halo-C1-C4 alkyl groups, and -OH; R 3 It is hydrogen, C1-C4 aliphatic group, C3-C5 cycloalkyl group, C1-C4 alkoxy group, -NHR 3A -N(R) 3A )2 or C1-C4 alkylthio groups, except for hydrogen, each of which is optionally divided by -OH, 1-5 independently chosen halogens, -OR, -C(O)NR 10 R 11 Or N(R)C(O)R can be substituted; Each R 3A Each occurrence is independently selected from C1-C4 alkyl groups; R 4 It is a phenyl or a first 5-6-membered heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the phenyl or the first 5-6-membered heteroaryl group is surrounded by 0-5 R atoms. A Substitution, or the two substituents on the adjacent atoms of the phenyl or the first 5-6-membered heteroaryl group together with the adjacent atoms form a 4-7-membered saturated or partially unsaturated fused carbocyclic group, a 4-7-membered saturated or partially unsaturated fused heterocyclic group, or a second 5-6-membered heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the 4-7-membered saturated or partially unsaturated fused carbocyclic group, the 4-7-membered saturated or partially unsaturated fused heterocyclic group, and the second 5-6-membered heteroaryl group are bounded by 0-3 R... A Replace; or R 4 It is a C1-C4 alkyl, C1-C4 alkoxy, or C3-C6 cycloalkyl, each of which is substituted by 0-3 independently selected groups from the following: halogen, -CN, -OH, oxo, NH2, C1-C4 alkyl, C1-C4 alkoxy, optionally substituted 5-6 membered heterocyclic group and optionally substituted 5-6 membered heterocyclic oxy group; Each R is independently hydrogen or optionally substituted C. 1-6 Aliphatic group, optionally substituted phenyl group, optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring, optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur) or optionally substituted 5-6 membered heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur); or Two R groups on the same atom are bonded together with the same atom to form optionally substituted 4-7 saturated rings, 4-7 partially unsaturated rings, or 5-6 heteroaromatic rings (wherein the 4-7 saturated rings and the 4-7 partially unsaturated rings have 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and wherein the 5-6 heteroaromatic rings have 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, having formula II-a or formula II-b: in: R 4 It is selected from one of a), b), and c): a)R 4 Choose the ring B that is freely composed of the following groups: and ; Where * is the connection point of -L- to the ring A in Formula I, and -L- in Formulas II-a and II-b is -C(O)-; And among them: Selected from R on ring B 4A R 4B R 4C R 4D R 4E and R 4F Each substituent is independently selected from hydrogen; halogen; -OH; -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; C1-C4 alkoxy; halo-C1-C4 alkyl; C1-C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo-C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; and NR. 13 R 14 ;or R 4A and R 4B Together with its intercalary atom, it forms an optionally substituted 4-7-membered carbocyclic group, an optionally substituted 4-7-membered heterocyclic group, or an optionally substituted 5-6-membered heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) fused with ring B; and present on ring B a group selected from R 4C R 4D R 4E and R 4F Each substituent is independently selected from hydrogen, halogen; -OH; -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; halo-C1-C4 alkyl; C1-C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo-C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; and NR. 13 R 14 ;or R 4B and R 4C Together with its intercalary atom, it forms an optionally substituted 4-7-membered carbocyclic group, an optionally substituted 4-7-membered heterocyclic group, or an optionally substituted 5-6-membered heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) fused with ring B; and present on ring B a group selected from R 4A R 4D R 4E and R 4F Each substituent is independently selected from hydrogen; halogen; -OH; -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; halo-C1-C4 alkyl; C1-C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo-C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; and NR. 13 R 14 ;or R 4C and R 4D Together with its intercalary atom, it forms an optionally substituted 4-7-membered carbocyclic group, an optionally substituted 4-7-membered heterocyclic group, or an optionally substituted 5-6-membered heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) fused with ring B; and present on ring B a group selected from R 4A R 4B R 4E and R 4F Each substituent is independently selected from hydrogen; halogen; -OH; -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; halo-C1-C4 alkyl; C1-C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo-C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; and NR. 13 R 14 ;or R 4E It is a halogen or -OH, and R 4A R 4B R 4C and R 4D Each is independently selected from hydrogen; halogen; -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; halo-C1-C4 alkyl; C1-C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo-C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; and NR. 13 R 14 ;or R 4E and R 4A Together with its intercalary atom, it forms an optionally substituted 4-7-membered carbocyclic group, an optionally substituted 4-7-membered heterocyclic group, or an optionally substituted 5-6-membered heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) fused with ring B; and R 4B R 4C and R 4D Each is independently selected from hydrogen; halogen; -OH; -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; halo-C1-C4 alkyl; C1-C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo-C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; and NR. 13 R 14 ;or R 4F and R 4A Together with its intercalary atom, it forms an optionally substituted 4-7-membered carbocyclic group, an optionally substituted 4-7-membered heterocyclic group, or an optionally substituted 5-6-membered heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) fused with ring B; and present on ring B a group selected from R 4B R 4C and R 4D Each substituent is independently selected from hydrogen; halogen; -OH; -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; halo-C1-C4 alkyl; C1-C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo-C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; and NR. 13 R 14 ;and R 13 Each occurrence is independently selected from hydrogen and C1-C4 alkyl groups optionally substituted with -OH, -OCH3, or -OCH2CH3; and R 14 It is hydrogen, or NR. 13 R 14 Forming a heterocycle selected from nitrogen-containing heterocyclic butyl, pyrrolidinyl, and piperidinyl, wherein the heterocycle is optionally substituted with -CH3; or b)R 4 It is a 5-membered heteroaryl group (having one heteroatom independently selected from nitrogen, oxygen, and sulfur, and 0, 1, 2, or 3 additional cyclic nitrogen atoms), wherein the heteroaryl group is substituted by 0-4 groups independently selected from: halogen, -OH, -CN, C1-C4 alkyl, halo-C1-C4 alkyl, C3-C6 cycloalkyl, and C1-C4 alkoxy; or c)R 4 It is a C1-C4 alkyl, C1-C4 alkoxy, or C3-C6 cycloalkyl, each of which is substituted by 0-3 independently selected groups from the following: halogen, -CN, -OH, C1-C4 alkyl, C1-C4 alkoxy, optionally substituted 5-6 membered heterocyclic group and optionally substituted 5-6 membered heterocyclic oxy group.

4. The compound according to any one of claims 1 to 3, wherein the compound has formula IX or formula IX-a: Or its pharmaceutically acceptable salt.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from... , , , , , , , , , and ; Ring A is selected from 0 to 4 independently chosen R. A Substituent substitution.

6. The compound according to any one of claims 1 to 5, wherein R 1 It is a C1-C6 alkyl, C2-C4 olefin, C2-C4 alkyne, -C(O)NR 10 R 11 -CH2NR 10 R 11 -SO2R 12 Or a 3-7 membered carbon cyclo group, wherein the C1-C6 alkyl, C2-C4 olefin, C2-C4 alkyne and the 3-7 membered carbon cyclo group are substituted by 0-3 substituents independently selected from the following: halogen, C3-C6 cycloalkyl, halo-C3-C6 cycloalkyl, -OH, -CN, C1-C4 alkoxy and halo-C1-C4 alkoxy.

7. The compound according to any one of claims 1 to 5, wherein R 1 It is a 5-6-membered heteroaryl group (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted by 1-3 groups independently selected from: halogen, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, and C3-C6 cycloalkyl, wherein the 5-6-membered heteroaryl group is further substituted by 0-3 independently selected R groups. A replace.

8. The compound according to any one of claims 1 to 5, wherein R 1 It is substituted by C1-C4 alkoxy groups, and further substituted by 0-2 R groups. A Substituted pyridinyl group.

9. The compound according to any one of claims 1 to 5, wherein R 1 It is a 5-membered heteroaryl group (having one heteroatom independently selected from nitrogen, oxygen, and sulfur and 0 or 1 additional cyclic nitrogen atom), wherein the 5-membered heteroaryl group is substituted with a halogen, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, or C3-C6 cycloalkyl, and further substituted with 0-2 independently selected R atoms. A replace.

10. The compound according to any one of claims 1 to 5, wherein R 1 yes c) A 5-6 member saturated or partially unsaturated monocyclic heterocyclic group (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the monocyclic heterocyclic group is substituted by 0-2 groups independently selected from: halogen, oxo, -NR2, optionally substituted C1-C4 aliphatic group, -OR, optionally substituted aziridine with 1 or 2 independently selected halogens, and optionally substituted pyrrolidinyl with 1 or 2 independently selected halogens; or d) A 6-8 saturated or partially unsaturated bridged bicyclic heterocyclic group (having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur), wherein the heterocyclic group is substituted by 0-2 groups independently selected from the following groups: halogen, oxo, -NR2, optionally substituted C1-C4 aliphatic group, -OR, nitrogen-heterobutyl group optionally substituted by 1 or 2 independently selected halogens, and pyrrolidinyl group optionally substituted by 1 or 2 independently selected halogens.

11. The compound according to any one of claims 1 to 5, wherein R 1 It is a 5-6 member saturated or partially unsaturated heterocyclic group (having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur), said heterocyclic group being substituted by 0-2 groups independently selected from the following groups: halogen, oxo, -NR2, optionally substituted C1-C4 aliphatic group, -OR, nitrogen-heterobutyl group optionally substituted by 1 or 2 independently selected halogens and pyrrolidinyl group optionally substituted by 1 or 2 independently selected halogens.

12. The compound according to any one of claims 1 to 5, wherein R 1 Choose from the following groups: , , , , , , , , , , , , , , , , , , , , and .

13. The compound according to any one of claims 1 to 12, wherein R 4 Ring B has the following structure: , , or Where * is the connection point with -L- in Equation I; R 4A It is hydrogen, halogen, -CH3, -CH2CH3, -F, -CF2H, -CF3, -OCH3, -OCF3, -OCH2CH3 or -OCHF2; R 4B R 4C and R 4D Each is independently selected from hydrogen; halogen; -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; halo-C1-C4 alkyl; C1-C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo-C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; and NR. 13 R 14 ;and R 13 Each occurrence is independently selected from hydrogen and C1-C4 alkyl groups optionally substituted with -OH, -OCH3, or -OCH2CH3; and R 14 It is hydrogen; or R 13 and R 14 It combines with the nitrogen atom to which it is attached to form a heterocycle selected from nitrogen-containing heterocyclic butyl, pyrrolidinyl, and piperidinyl; wherein the heterocycle is optionally substituted with -CH3; or R 4 It is a 5-membered heteroaryl group (having one heteroatom independently selected from nitrogen, oxygen and sulfur and 0, 1, 2 or 3 additional cyclic nitrogen atoms), wherein the heteroaryl group is substituted by 0 to 4 groups independently selected from the following groups: halogen, -OH, -CN, C1-C4 alkyl, halo-C1-C4 alkyl, C3-C6 cycloalkyl and C1-C4 alkoxy.

14. The compound according to any one of claims 1 to 12, wherein R 4 yes: or Where * is the connection point with -L- in Equation I; where: R 4A It is hydrogen, halogen, -CH3, -CH2CH3, -F, -CF2H, -CF3, -OCH3, -OCF3, -OCH2CH3 or -OCHF2; R 4B and R 4C Each is independently selected from hydrogen; -CN; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; halo-C1-C4 alkyl; C1-C3 alkyl substituted with -OH, -OCH3 or -OCH2CH3; halo-C1-C4 alkoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; and NR. 13 R 14 ;and R 13 Each occurrence is independently selected from hydrogen and C1-C4 alkyl groups optionally substituted with -OH, -OCH3, or -OCH2CH3; and R 14 It is hydrogen; or R 13 and R 14 It combines with the nitrogen atom to which it is attached to form a heterocycle selected from nitrogen heterocyclic butyl, pyrrolidinyl and piperidinyl; wherein the heterocycle is optionally substituted with -CH3.

15. The compound according to any one of claims 1 to 12, wherein R 4 It is a 5-membered heteroaryl group (having one heteroatom independently selected from nitrogen, oxygen and sulfur and 0, 1, 2 or 3 additional cyclic nitrogen atoms), wherein the heteroaryl group is substituted by 0 to 4 groups independently selected from the following groups: halogen, -OH, -CN, C1-C4 alkyl, halo-C1-C4 alkyl, C3-C6 cycloalkyl and C1-C4 alkoxy.

16. The compound according to any one of claims 1 to 12, wherein R 4 It is a 5-membered heteroaryl group (having one heteroatom independently selected from nitrogen, oxygen, and sulfur, and 0, 1, 2, or 3 additional cyclic nitrogen atoms), selected from the group consisting of: imidazolyl, pyrazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, and 1,2,4-triazolyl, wherein the heteroaryl group is substituted by 0 to 4 groups independently selected from the group consisting of: halogen, -OH, -CN, C1-C4 alkyl, halo-C1-C4 alkyl, C3-C6 cycloalkyl, and C1-C4 alkoxy.

17. The compound according to claim 16, wherein R 4 It is an isoxazolyl group substituted with -OH or C1-C4 alkoxy groups.

18. The compound according to any one of claims 1 to 12, wherein R 4 yes , , , , , , , , , , , , , , -CH3, -CF3, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

19. The compound according to any one of claims 1 to 18, wherein R 2A It is a phenyl group containing a -CF3 substituent or a pyridyl group containing a -CF3 substituent.

20. The compound according to any one of claims 1 to 18, wherein R 2 yes 。 21. The compound according to claim 1 or any one of claims 3 to 18, wherein R 2 yes 。 22. The compound according to any one of claims 1 to 21, wherein R 3 It is a C1-C4 alkyl or a C3-C5 cycloalkyl.

23. The compound according to any one of claims 1 to 22, wherein ring A and the 0-4 independently selected Rs substituted with ring A A Substituents are selected from , , , , , and .

24. The compound according to any one of claims 1 to 22, wherein ring A and the 0-4 independently selected Rs substituted with ring A A The substituents are: 。 25. The compound according to any one of claims 1 to 22, wherein ring A is: 。 26. The compound according to any one of claims 1 to 22, wherein ring A is: 。 27. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidin-4-carbonyl)piperazin-1-yl)-2-(2-methoxypyridin-4-yl)-7-oxo-2,7-dihydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide.

28. A compound selected from the compounds shown in Tables 1, 1a, 1b, 2, 2a, 2b, 3 and 4; or a pharmaceutically acceptable salt thereof.

29. A pharmaceutical composition comprising a compound according to any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

30. A method of treating cancer in an individual, wherein the cancer is characterized by microsatellite high instability (MSI-H) or mismatch repair deficiency (dMMR), the method comprising administering to the individual a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 28.

31. A method for regulating the WRN activity of an individual, wherein the method comprises administering to the individual a therapeutically effective amount of the compound according to any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof.

32. A method of treating an individual for a condition or disease that can be treated by WRN inhibition, wherein the method comprises administering to the individual a therapeutically effective amount of the compound of any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof.

33. A method for inhibiting WRN in an individual, wherein the method comprises administering to the individual a therapeutically effective amount of the compound according to any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof.

34. The method of claim 32, wherein the condition or disease is a cancer characterized by microsatellite high instability (MSI-H) or mismatch repair deficiency (dMMR).

35. The method of claim 34, wherein the cancer characterized by microsatellite high instability (MSI-H) or mismatch repair deficiency (dMMR) is selected from colorectal cancer, gastric cancer, prostate cancer, endometrial cancer, adrenocortical cancer, uterine cancer, cervical cancer, esophageal cancer, breast cancer, kidney cancer, and ovarian cancer.

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