BAX inhibitors and uses thereof

Abstract

A compound having formula (I) or (II) for use in inhibiting Bax-mediated cell death and / or apoptosis. [Case 1] JPEG2022534902000417.jpg47163 [C2] JPEG2022534902000418.jpg19140

Description

[Technical Field]

[0001] Related Applications This application claims priority to U.S. Provisional Application No. 62 / 855,185, filed May 31, 2019, the subject matter of which is incorporated herein by reference in its entirety.

[0002] government funds This invention was made with government support under Grant No. RO1AG031903 awarded by the National Institutes of Health and the National Institute on Aging, and W81XWH-12-1-0331 awarded by the Department of Defense. The U.S. Government has certain rights in this invention. [Background technology]

[0003] Bax-induced cell death is a major cause of many types of degenerative diseases. Bax is a 21-kDa member of the conserved Bcl-2 family of proteins involved in regulating programmed cell death. Bax plays a key role in the intrinsic pathway of apoptosis. Bcl-2 family proteins are characterized by the presence of four Bcl-2 homology (BH) domains. Anti-apoptotic members (e.g., Bcl-2, Bcl-XL, and Mcl-1) possess all four BH domains (BH1–BH4). Pro-apoptotic members are further divided into multidomain proteins (e.g., Bax, Bak, and Bok) containing three BH domains (BH1–BH3) or BH3-only proteins (e.g., Bim, Bid, and PUMA) containing only the BH-3 domain. Although the molecular mechanisms by which these proteins function and interact are not fully understood, their role in apoptosis is undisputed. Summary of the Invention

[0004] Embodiments described herein relate to compounds for use in inhibiting Bax-mediated cell death and / or apoptosis, and their use in treating conditions, disorders, and / or diseases associated with Bax-mediated cell death and / or apoptosis. The Bax inhibitory compounds described herein suppress Bax-induced cell death (e.g., Bax-induced death of mouse embryonic fibroblasts (MEFs)) at concentrations of 1 nM to 1000 nM and have Bax binding affinities (Kd) in the range of 1 nM to 1000 nM, compared to previously reported Bax inhibitors that require at least 200 nM to inhibit Bax-induced death of MEFs.

[0005] In some embodiments, the Bax inhibitor compound has the following formula (I): [ka] or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R 1 and R 2 are each independently -H, alkyl, -F, -CN, -O-alkyl, cycloalkyl, oxetanyl, or tetrahydrofuranyl, or R 1 is R 2 together with, optionally, one or two R 8 forming a phenyl ring substituted with a group or R 1 is R 2 together with one or two heteroatoms selected from N, O, and S, and optionally one or two R 8 forming a 5- or 6-membered heteroaromatic ring substituted with a group, R 8 is halo, alkyl, cycloalkyl, oxetanyl, tetrahydrofuranyl, —CN, —O-alkyl, —O-cycloalkyl, —SO2-alkyl, or —CH2SO2-alkyl; R 3 is absent, -H, -D, -F, -Cl, -CF3, -alkyl, cyclopropyl-O-alkyl, or -CN; R4 is -H, alkyl, cyclopropyl, or -CF3; R 5 is absent, -H, or alkyl; Alternatively, R 5 and the nitrogen atom to which it is attached may be replaced with an oxygen atom, V, W, X, Y, and Z are each independently —CH or N; X 1 and Z 1 are each independently —CH or N, W 1 and Y 1 are each independently C or N, and Y 1 When N, R 3 does not exist, X 2 is O or N, and X 2 When is O, R 5 does not exist, [ka] represents a single or double bond, R 6 is -H, halo, alkyl, cycloalkyl, -CN, -O-alkyl, -O-cycloalkyl, -O-heterocyclyl, -SO2-alkyl, -CH2SO2-alkyl, -CONH2, -CONH-alkyl, or -CON(alkyl)2; R 7 is -H, halo, alkyl, cycloalkyl, -CN, -O-alkyl, -O-cycloalkyl, -O-heterocyclyl, -SO2-alkyl, -CH2SO2-alkyl, -CONH2, -CONH-alkyl, or -CON(alkyl)2; Alternatively, R 6 or R 7 optionally one or two R 9 aryl substituted with a group; Alternatively, R 6 or R 7contains one or two heteroatoms selected from the group consisting of N, O, and S, and optionally, one or two R , excluding labile heterocycles. 9 a 4- to 6-membered heterocycle substituted with a group, Alternatively, R 6 or R 7 contains 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and optionally, excluding unstable heterocycles, one or two R 9 a 5- to 6-membered heteroaryl group substituted with a group, R 9 is H, halo, alkyl, cycloalkyl, alkyl-CO-, oxetanyl, 3-tetrahydrofuranyl, -CN, -O-alkyl, -O-cycloalkyl, -CONH2, -CONH-alkyl, or -CON(alkyl)2; R 6 is R 7 and together with the phenyl or heteroaryl ring to which they are attached may be a benzimidazole ring, a benzotriazole ring, an azaindole ring, an azaindazole ring, or a benzodioxolane ring, wherein the ring N is an optional substituent R 10 and C of the ring is optionally R 11 is replaced by R 10 is —H, alkyl, or cycloalkyl; R 11 is —H, alkyl, or cycloalkyl.

[0006] In other embodiments, the Bax inhibitor compound having formula (I) has the following formula: [ka] or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R 1 and R 2are each independently -H, C1-C6-alkyl, -F, -CN, -O-C1-C6-alkyl, C3-C7-cycloalkyl, 3-oxetanyl, or 3-tetrahydrofuranyl, or R 1 is R 2 together with, optionally, one or two R 8 forming a phenyl ring substituted with a group or R 1 is R 2 together with one or two heteroatoms selected from N, O, and S, and optionally one or two R 8 forming a 5- or 6-membered heteroaromatic ring substituted with a group, R 8 is halo, C1-C6-alkyl, C3-C7-cycloalkyl, 3-oxetanyl, 3-tetrahydrofuranyl, -CN, -O-C1-C6-alkyl, -O-C3-C7-cycloalkyl, -SO2-C1-C6-alkyl or -CH2SO2-C1-C6-alkyl, R 3 is -H, -D, -F, -Cl, -CF3, -C1-C6-alkyl, cyclopropyl-O-C1-C6-alkyl, or -CN, R 4 is -H, -C1-C6-alkyl, -cyclopropyl, or -CF3, R 5 -H or -C 1- is C6-alkyl, Alternatively, R 5 and the nitrogen atom to which it is attached may be replaced with an oxygen atom, X, Y, and Z are each independently —CH or N; [ka] represents a single or double bond, R 6is -H, halo, C1-C6-alkyl, C3-C7-cycloalkyl, -CN, -O-C1-C6-alkyl, -O-C3-C7-cycloalkyl, -O-heterocyclyl, -SO2-C1-C6-alkyl, -CH2SO2-C1-C6-alkyl, -CONH2, -CONH-C1-C6-alkyl or -CON(C1-C6-alkyl)2, R 7 is -H, halo, C1-C6-alkyl, C3-C7-cycloalkyl, -CN, -O-C1-C6-alkyl, -O-C3-C7-cycloalkyl, -O-heterocyclyl, -SO2-C1-C 6 -alkyl, -CH2SO2-C1-C6-alkyl, -CONH2, -CONH-C1-C6-alkyl, or -CON(C1-C6-alkyl)2; Alternatively, R 6 or R 7 optionally one or two R 9 aryl substituted with a group; Alternatively, R 6 or R 7 contains one or two heteroatoms selected from the group consisting of N, O, and S, and optionally, one or two R , excluding labile heterocycles. 9 a 4- to 6-membered heterocycle substituted with a group, Alternatively, R 6 or R 7 contains 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and optionally, excluding unstable heterocycles, one or two R 9 a 5- to 6-membered heteroaryl group substituted with a group, R 9 is halo, C1-C6-alkyl, C3-C7-cycloalkyl, C1-C5-alkyl-CO—, 3-oxetanyl, 3-tetrahydrofuranyl, —CN, —O—C1-C6-alkyl, —O—C3-C7-cycloalkyl, —CONH2, —CONH-alkyl or —CON(alkyl)2, R 6 is R 7and together with the phenyl or heteroaryl ring to which they are attached may be a benzimidazole ring, a benzotriazole ring, an azaindole ring, an azaindazole ring, or a benzodioxolane ring, wherein the ring N is an optional substituent R 10 and C of the ring is optionally R 11 is replaced by R 10 is —H, C1-C6-alkyl, or C3-C7-cycloalkyl, R 11 is —H, C1-C6-alkyl, or C3-C7-cycloalkyl.

[0007] In some embodiments, R 1 and R 2 are each independently -H, C1-C6-alkyl, -F, -CN, -O-C1-C6-alkyl, C3-C7-cycloalkyl, 3-oxetanyl, or 3-tetrahydrofuranyl, or R 1 is R 2 together with, optionally, one or two R 8 forming a phenyl ring substituted with a group or R 1 is R 2 together with one or two heteroatoms selected from N, O, and S, and optionally one or two R 8 It forms a saturated 5- or 6-membered heteroaromatic ring substituted with a group.

[0008] In other embodiments, R 8 is halo, C1-C6-alkyl, C3-C7-cycloalkyl, 3-oxetanyl, 3-tetrahydrofuranyl, —CN, —O—C1-C6-alkyl, —O—C3-C7-cycloalkyl, —SO2-C1-C6-alkyl, or —CH2SO2-C1-C6-alkyl.

[0009] In other embodiments, R 3 is absent, -H, -D, -F, -Cl, -CF3, -C1-C6-alkyl, cyclopropyl-O-C1-C6-alkyl, or -CN.

[0010] In some embodiments, R 4 -H, -C 1- It is C6-alkyl, -cyclopropyl, or -CF3.

[0011] In other embodiments, R 5 is absent, -H, or -C1-C6-alkyl.

[0012] In other embodiments, R 6 is -H, halo, C1-C6-alkyl, C3-C7-cycloalkyl, -CN, -O-C1-C6-alkyl, -O-C3-C7-cycloalkyl, -SO2-C1-C6-alkyl, -CH2SO2-C1-C6-alkyl, -CONH2, -CONH-C1-C6-alkyl, or -CON(C1-C6-alkyl)2.

[0013] In other embodiments, R 7 is -H, halo, C1-C6-alkyl, C3-C7-cycloalkyl, -CN, -O-C1-C6-alkyl, -O-C3-C7-cycloalkyl, -SO2-C1-C 6 -alkyl, -CH2SO2-C1-C6-alkyl, -CONH2, -CONH-C1-C6-alkyl, or -CON(C1-C6-alkyl).

[0014] In some embodiments, R 9 is H, halo, C1-C6-alkyl, C3-C7-cycloalkyl, C1-C5-alkyl-CO—, 3-oxetanyl, 3-tetrahydrofuranyl, —CN, —O—C1-C6-alkyl, or —O—C3-C7-cycloalkyl.

[0015] In other embodiments, R 10 is —H, C1-C6-alkyl, or C3-C7-cycloalkyl.

[0016] In yet other embodiments, R 11is —H, C1-C6-alkyl, or C3-C7-cycloalkyl.

[0017] In other embodiments, R 1 is R 2 together with, optionally, one or two R 8 A phenyl ring substituted with a group or R 1 is R 2 together with one or two heteroatoms selected from N, O, and S, and optionally one or two R 8 The aromatic rings may be formed as 5- or 6-membered saturated heteroaromatic rings substituted with groups.

[0018] In some embodiments, R 4 -C 1- C-alkyl or -CF3, and R 5 is -H.

[0019] In other embodiments, X and Y are independently H and Z is N.

[0020] In some embodiments, R 6 or R 7 contains one or two heteroatoms selected from the group consisting of N, O, and S, and optionally, one or two R , excluding labile heterocycles. 9 a 4- to 6-membered saturated heterocyclic ring substituted with a group, or R 6 Or R 7 contains 1 to 3 heteroatoms selected from the group consisting of N, O, and S, and optionally, excluding unstable heterocycles, one or two R 9 It is a 5- to 6-membered heteroaryl group substituted with a group.

[0021] In other embodiments, R 6 is selected from the group consisting of: [ka]

[0022] In other embodiments, the Bax inhibitor compound has the following formula (II): [ka] or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R 12 is =O or R 17 and R 12 When =O, R 13 and R 14 is independently absent, —H, alkyl, cycloalkyl, oxetanyl, or tetrahydrofuranyl, or R 12 R 17 When R 13 Or R 14 is absent and the other is —H, alkyl, cycloalkyl, oxetanyl, or tetrahydrofuranyl; A 1 and A 2 are independently CH or N, V 3 , W 3 , X 3 , Y 3 , and Z 3 , and its substituent R 15 , R 16 , R 20 , and R 21 Heterocycles containing V are heteroaromatic rings having two double bonds, such as pyrrole, imidazole, pyrazole, or triazole. 3 , W 3 , X 3 , Y 3 , and Z 3 can independently be CH or N, and one to three of these atoms are N; X 4 is N or O, Y 4 is N or C, [ka] represents a single or double bond, R 15 , R 16 , R 20 , and R 21 are independently absent, H, alkyl, cycloalkyl, bicyclyl, phenyl, or each optionally containing one or more R 18 or heteroaryl substituted with a heterocyclic ring having one or two heteroatoms selected from the group consisting of N, O, and S; R 17 is -H, ═NH, alkyl, cycloalkyl, oxetanyl, or tetrahydrofuranyl; Alternatively, R 15 is R 16 and together with the rings to which they are attached, V 3 and X 3 is N and W 3 is CH and Y 3 and Z 3 is a C atom at the ring fusion, the bicyclic ring can optionally be formed with one or two R 19 is substituted with a substituent, R 18 is halo, alkyl, cycloalkyl, -CN, -O-alkyl, -O-cycloalkyl, -O-alkyl-alkynyl, -SO2-alkyl, -CH2SO2-alkyl, -CONH2, -CONH-alkyl, or -CON(alkyl)2, R 19 is halo, alkyl, cycloalkyl, —CN, —O-alkyl, —O-cycloalkyl, —SO 2 -alkyl, or —CH 2 SO 2 -alkyl.

[0023] In other embodiments, the Bax inhibitor compound having formula (II) has the following formula: [ka] or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R 12 is =O or R 17 and R12 When =O, R 13 and R 14 are independently -H, C1-C6-alkyl, C3-C7-cycloalkyl, 3-oxetanyl, or 3-tetrahydrofuranyl, or R 12 R 17 When R 13 Or R 14 is absent and the other is —H, C1-C6-alkyl, C3-C7-cycloalkyl, 3-oxetanyl, or 3-tetrahydrofuranyl, A 1 and A 2 are independently CH or N, V 1 , W 1 , X 1 , Y 1 , and Z 1 , and its substituent R 15 and R 16 Heterocycles containing V are heteroaromatic rings having two double bonds, such as pyrrole, imidazole, pyrazole, or triazole. 1 , W 1 , X 1 , Y 1 , and Z 1 can independently be CH or N, and one to three of these atoms are N; [ka] represents a single or double bond, R 15 and R 16 are independently C1-C6-alkyl, C3-C7-cycloalkyl, phenyl, or each optionally R 18 or a C5-C6 heteroaryl substituted with a C4-C6 heterocyclic ring having one or two heteroatoms selected from the group consisting of N, O, and S; R 17 is —H, C1-C6-alkyl, C3-C7-cycloalkyl, 3-oxetanyl, or 3-tetrahydrofuranyl, Alternatively, R15 is R 16 and together with the rings to which they are attached, V 1 and X 1 is N and W 1 is CH and Y 1 and Z 1 is a C atom at the ring fusion, a benzimidazole ring can be formed, and the benzimidazole ring can optionally be fused with one or two R 19 is substituted with a substituent, R 18 is halo, C1-C6-alkyl, C3-C7-cycloalkyl, -CN, -O-C1-C6-alkyl, -O-C3-C7-cycloalkyl, -SO2-C1-C6-alkyl, -CH2SO2-C1-C6-alkyl, -CONH2, -CONH-C1-C6-alkyl or -CON(C1-C6-alkyl)2, R 19 is halo, C1-C6-alkyl, C3-C7-cycloalkyl, -CN, -O-C1-C6-alkyl, -O-C3-C7-cycloalkyl, -SO2-C1-C6-alkyl, or -CH2SO2-C1-C6-alkyl.

[0024] In some embodiments, R 12 is =O or R 17 and R 12 When =O, R 13 and R 14 is independently absent, —H, C1-C6-alkyl, C3-C7-cycloalkyl, 3-oxetanyl, or 3-tetrahydrofuranyl, or R 12 R 17 When R 13 Or R 14 is absent, and the other is -H, C1-C6-alkyl, C3-C7-cycloalkyl, 3-oxetanyl, or 3-tetrahydrofuranyl.

[0025] R 15 , R 16 , R 20 , and R 21are independently C1-C6-alkyl, C3-C7-cycloalkyl, phenyl, or optionally R 18 or a C5-C6 heteroaryl substituted with a C4-C6 heterocyclic ring having one or two heteroatoms selected from the group consisting of N, O, and S.

[0026] In yet other embodiments, R 17 is -H, =NH, C1-C6-alkyl, C3-C7-cycloalkyl, 3-oxetanyl, or 3-tetrahydrofuranyl.

[0027] In some embodiments, R 18 is halo, C1-C6-alkyl, C3-C7-cycloalkyl, -CN, -O-C1-C6-alkyl, -O-C3-C7-cycloalkyl, -SO2-C1-C6-alkyl, -CH2SO2-C1-C6-alkyl, -CONH2, -CONH-C1-C6-alkyl, or -CON(C1-C6-alkyl)2.

[0028] In other embodiments, R 19 is halo, C1-C6-alkyl, C3-C7-cycloalkyl, -CN, -O-C1-C6-alkyl, -O-C3-C7-cycloalkyl, -SO2-C1-C6-alkyl, or -CH2SO2-C1-C6-alkyl.

[0029] In some embodiments, A 1 and A 2 are independently CH.

[0030] In other embodiments, R 12 is =O.

[0031] In other embodiments, the Bax inhibitor compound having formula (II) has the following formula: [ka] or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R 12 is =O or R 17 and R 12 When =O, R 13 and R 14 is independently absent, —H, C1-C6-alkyl, C3-C7-cycloalkyl, 3-oxetanyl, or 3-tetrahydrofuranyl, or R 12 R 17 When R 13 Or R 14 is absent and the other is —H, C1-C6-alkyl, C3-C7-cycloalkyl, 3-oxetanyl, or 3-tetrahydrofuranyl, A 1 and A 2 are independently CH or N, V 3 , W 3 , X 3 , Y 3 , and Z 3 , and its substituent R 15 and R 16 Heterocycles containing V are heteroaromatic rings having two double bonds, such as pyrrole, imidazole, pyrazole, or triazole. 3 , W 3 , X 3 , Y 3 , and Z 3 can independently be CH or N, and one to three of these atoms are N; [ka] represents a single or double bond, R 15 and R 16 are independently C1-C6-alkyl, C3-C7-cycloalkyl, phenyl, or optionally R 18 or a C5-C6 heteroaryl substituted with a C4-C6 heterocyclic ring having one or two heteroatoms selected from the group consisting of N, O, and S; R 17is -H, -NH, C1-C6-alkyl, C3-C7-cycloalkyl, 3-oxetanyl, or 3-tetrahydrofuranyl, Alternatively, R 15 is R 16 and together with the rings to which they are attached, V 3 and X 3 is N and W 3 is CH and Y 3 and Z 3 can form a benzimidazole ring where R is the ring fusion C atom, and the benzimidazole ring can optionally be joined by one or two R 19 is substituted with a substituent, R 18 is halo, C1-C6-alkyl, C3-C7-cycloalkyl, -CN, -O-C1-C6-alkyl, -O-C3-C7-cycloalkyl, -SO2-C1-C6-alkyl, -CH2SO2-C1-C6-alkyl, -CONH2, -CONH-C1-C6-alkyl or -CON(C1-C6-alkyl)2, R 19 is halo, C1-C6-alkyl, C3-C7-cycloalkyl, -CN, -O-C1-C6-alkyl, -O-C3-C7-cycloalkyl, -SO2-C1-C6-alkyl, or -CH2SO2-C1-C6-alkyl.

[0032] In some embodiments, A 1 and A 2 are independently CH.

[0033] In other embodiments, R 12 is =O.

[0034] In some embodiments, the Bax inhibitor compound of formula (II) has the following formula: [ka] wherein R 13 and R 14are independently -H, C1-C6-alkyl, C3-C7-cycloalkyl, 3-oxetanyl, 3-tetrahydrofuranyl, R 15 and R 16 are independently C1-C6-alkyl, C3-C7-cycloalkyl, phenyl, or optionally R 18 or a C5-C6 heteroaryl substituted with a C4-C6 heterocyclic ring having one or two heteroatoms selected from the group consisting of N, O, and S; R 17 is —H, C1-C6-alkyl, C3-C7-cycloalkyl, 3-oxetanyl, or 3-tetrahydrofuranyl, Or, R 15 is R 16 and together with the ring to which they are attached can be a benzimidazole ring, and the benzimidazole ring can optionally contain one or two R 19 may be substituted with a substituent; R 18 is halo, C1-C6-alkyl, C3-C7-cycloalkyl, -CN, -O-C1-C6-alkyl, -O-C3-C7-cycloalkyl, -SO2-C1-C6-alkyl, -CH2SO2-C1-C6-alkyl, -CONH2, -CONH-C1-C6-alkyl or -CON(C1-C6-alkyl)2, R 19 is halo, C1-C6-alkyl, C3-C7-cycloalkyl, -CN, -O-C1-C6-alkyl, -O-C3-C7-cycloalkyl, -SO2-C1-C6-alkyl, or -CH2SO2-C1-C6-alkyl.

[0035] In other embodiments, the Bax inhibitor compound having formula (II) has the following formula: [ka] wherein R 14 is —H, C1-C6-alkyl, C3-C7-cycloalkyl, 3-oxetanyl, 3-tetrahydrofuranyl, R 15 and R 16 are independently C1-C6-alkyl, C3-C7-cycloalkyl, phenyl, or optionally R 18 or a C5-C6 heteroaryl substituted with a C4-C6 heterocyclic ring having one or two heteroatoms selected from the group consisting of N, O, and S; R 17 is —H, C1-C6-alkyl, C3-C7-cycloalkyl, 3-oxetanyl, or 3-tetrahydrofuranyl, Or, R 15 is R 16 and together with the ring to which they are attached can be a benzimidazole ring, and the benzimidazole ring can optionally contain one or two R 19 is substituted with a substituent, R 18 is halo, C1-C6-alkyl, C3-C7-cycloalkyl, -CN, -O-C1-C6-alkyl, -O-C3-C7-cycloalkyl, -SO2-C1-C6-alkyl, -CH2SO2-C1-C6-alkyl, -CONH2, -CONH-C1-C6-alkyl or -CON(C1-C6-alkyl)2, R 19 is halo, C1-C6-alkyl, C3-C7-cycloalkyl, -CN, -O-C1-C6-alkyl, -O-C3-C7-cycloalkyl, -SO2-C1-C6-alkyl, or -CH2SO2-C1-C6-alkyl.

[0036] In some embodiments, the Bax inhibitory compound can be provided in a pharmaceutical composition comprising the Bax inhibitory compound and a pharmaceutically acceptable excipient or carrier.

[0037] In other embodiments, the compounds described herein or Bax inhibitory compounds inhibit mouse embryonic fibroblasts (MEFs) from Bax-induced cell death, with an IC of 1 μM or less. 50 , IC below 250 nM 50 , IC below 50 nM 50 , IC below 10 nM50 , IC below 5 nM 50 , IC of about 2.5 nM to about 10 nM 50 , or an IC of approximately 2.5 nM or less 50 And can be inhibited.

[0038] In some embodiments, a Bax inhibitory compound can be administered to a subject to inhibit ocular cell death associated with a degenerative eye disease, which can include, for example, at least one of Stargardt's disease, cone-rod dystrophy, retinitis pigmentosa, macular degeneration, geographic atrophy, glaucoma, optic nerve injury, or Fuchs' endothelial corneal dystrophy.

[0039] In other embodiments, a Bax inhibitory compound can be administered to a subject to inhibit cell death associated with or treat at least one of a disease, disorder, and / or condition of the nervous system, which can include at least one of a neurological disorder, a nerve injury, a neurotoxic disorder, and a neurodegenerative disorder.

[0040] In some embodiments, the neurological disorder may include at least one of traumatic or toxic injury to a peripheral or cranial nerve, spinal cord or brain, cranial nerve, traumatic brain injury, stroke, cerebral aneurysm, and spinal cord injury.

[0041] In other embodiments, the neurological disorder may include at least one of Alzheimer's disease, dementia associated with Alzheimer's disease, Parkinson's disease, Lewy body disease, senile dementia, Huntington's disease, Gilles de la Tourette syndrome, multiple sclerosis, amyotrophic lateral sclerosis, hereditary motor and sensory neuropathies, diabetic neuropathy, progressive supranuclear palsy, epilepsy, or Creutzfeldt-Jakob disease.

[0042] In some embodiments, the nerve damage may be caused by or associated with at least one of epilepsy, cerebrovascular diseases, autoimmune diseases, sleep disorders, autonomic disorders, bladder disorders, abnormal metabolic conditions, disorders of the muscular system, infectious and parasitic diseases, neoplasms, endocrine diseases, nutritional and metabolic diseases, immunological diseases, diseases of the blood and blood-forming organs, psychiatric disorders, diseases of the nervous system, diseases of the sensory organs, diseases of the circulatory system, diseases of the respiratory system, diseases of the digestive system, diseases of the genitourinary system, diseases of the skin and subcutaneous tissue, diseases of the musculoskeletal system and connective tissue, congenital abnormalities, or conditions occurring during the perinatal period.

[0043] In other embodiments, Bax inhibitory compounds can be administered to a subject to inhibit cell death associated with ischemic tissue or tissue damaged by ischemia, or to treat at least one condition associated with such tissue. Ischemia can be caused by acute coronary syndrome, acute lung injury (ALI), acute myocardial infarction (AMI), acute respiratory distress syndrome (ARDS), arterial occlusive disease, arteriosclerosis, articular cartilage defects, sterile systemic inflammation, atherosclerotic cardiovascular disease, autoimmune disease, bone fracture, fracture, cerebral edema, cerebral hypoperfusion, Buerger's disease, burns, cancer, cardiovascular disease, cartilage damage, cerebral infarction, cerebral ischemia, stroke, cerebrovascular disease, chemotherapy-induced neuropathy, chronic inflammatory bowel disease, and the like. Infection, chronic mesenteric ischemia, claudication, congestive heart failure, connective tissue injury, contusion, coronary artery disease (CAD), critical limb ischemia (CLI), Crohn's disease, deep vein thrombosis, deep wounds, delayed ulcer healing, delayed wound healing, diabetes mellitus (types I and II), diabetic neuropathy, diabetes-induced ischemia, disseminated intravascular coagulation (DIC), embolic cerebral ischemia, graft-versus-host disease, hereditary hemorrhagic telangiectasia, ischemic vascular disease, hyperoxic injury, hypoxemia Disease, inflammation, inflammatory bowel disease, inflammatory disease, injured tendon, intermittent claudication, intestinal ischemia, ischemia, ischemic brain disease, ischemic heart disease, ischemic peripheral vascular disease, ischemic placenta, ischemic kidney disease, ischemic vascular disease, ischemic reperfusion injury, laceration, left main coronary artery disease, limb ischemia, lower limb ischemia, myocardial infarction, myocardial ischemia, organ ischemia, osteoarthritis, osteoporosis, osteosarcoma, Parkinson's disease, peripheral arterial disease (PAD), peripheral arterial disease, peripheral ischemia, peripheral neuropathy , peripheral vascular disease, pre-cancer, pulmonary edema, pulmonary embolism, remodeling disorders, renal ischemia, retinal ischemia, retinopathy, sepsis, skin ulcer, solid organ transplant, spinal cord injury, stroke, subchondral bone cyst, thrombosis, thrombotic cerebral ischemia, tissue ischemia, transient ischemic attack (TIA), traumatic brain injury, ulcerative colitis, vascular disease of the kidney, vascular inflammatory conditions, von Hippel-Lindau syndrome, and damage to tissues or organs.

[0044] In other embodiments, a Bax inhibitory compound may be administered ex vivo to one of a cell, tissue, or organ to increase the suitability of the cell, tissue, or organ as a donor graft or transplant, or to enhance the engraftment or transplantation of the cell, tissue, or organ.

[0045] In some embodiments, a Bax inhibitory compound may be administered to a subject or a subject's tissue graft to reduce graft rejection or enhance graft survival.

[0046] In other embodiments, a Bax inhibitory compound may be administered to a subject or a subject's tissue graft to enhance graft survival after treatment of the subject with radiation therapy, chemotherapy, or immunosuppressive therapy.

[0047] In other embodiments, Bax inhibitory compounds may be administered to a subject to confer resistance to the toxic or lethal effects of exposure to radiation.

[0048] In yet other embodiments, Bax inhibitory compounds may be administered to a subject to confer resistance to the toxic effects of chemotherapy or immunosuppressive therapy.

[0049] In other embodiments, Bax inhibitory compounds may be administered to a subject to treat stroke, myocardial infarction, degenerative diseases, and infectious pathogens. [Brief explanation of the drawings]

[0050] [Figure 1] 1 is a graph showing that Bax inhibitory compounds described herein (i.e., Bax41S (a BBI5 / 6 analog) and Bax-11 (a BBI7 analog)) protected mouse embryonic fibroblasts (MEFs) from Bax-induced cell death at concentrations of 1 and 10 nM, respectively. Bax inhibitors reported elsewhere (DAN004, compound 22, the original Bax inhibitor, iMAC2) require at least 200 nM to exhibit protective activity. [Figure 2] 1 shows images demonstrating that Bax inhibitory compounds described herein protected mouse embryonic fibroblast (MEF) cells from Bax-induced cell death. [Figure 3]1 shows images demonstrating that Bax-inhibitory compounds described herein inhibited Bax-induced apoptosis without significantly affecting the expression levels of Bax, Bcl-2, Bcl-XL, and Mcl-1. [Figure 4] Results are shown showing that the Bax inhibitor compounds described herein protected ARPE19 (human retinal cells) cells from atRAL-induced cell death (Figure 4A) and mouse retina from bright light-induced cell death (Stargardt disease mouse model) in vivo (Figure 4B, C). DETAILED DESCRIPTION OF THE INVENTION

[0051] Although the following terms are believed to be well understood by those of ordinary skill in the art, the following definitions are set forth to facilitate description of the presently disclosed subject matter.

[0052] As used herein, the verb "comprise" and its conjugations as used in the description and claims are used in their open-ended sense, meaning that the items that follow the word are included, but not items that are not specifically mentioned are excluded. The present invention may suitably "comprise," "consist," or "consist essentially of" the steps, elements, and / or reagents recited in the claims.

[0053] It is further noted that the claims may be drafted to exclude any optional element, and as such, this statement is intended to serve as a precedent for the use of exclusive terminology, such as "solely," "solely," and the like, in connection with the recitation of claim elements or the use of a "negative" limitation.

[0054] The term "pharmaceutically acceptable" means suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, and the like, and is effective for these intended uses, within the scope of sound medical judgment, at a reasonable benefit / risk ratio.

[0055] The term "pharmaceutically acceptable salts" includes those obtained by reacting an active compound that functions as a base with an inorganic or organic acid to form a salt, such as, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, carbonic acid, etc. Those skilled in the art will further recognize that acid addition salts can be prepared by reacting the compound with the appropriate inorganic or organic acid via any of a number of known methods. The term "pharmaceutically acceptable salts" also includes those obtained by reacting an active compound that functions as an acid with an inorganic or organic base to form a salt, such as salts of ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris-(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids, etc. Non-limiting examples of inorganic or metal salts include lithium salts, sodium salts, calcium salts, potassium salts, magnesium salts, etc.

[0056] Furthermore, the salts of the compounds described herein can exist in either hydrated or non-hydrated (anhydrous) form, or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates, etc. Non-limiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0057] The term "solvate" refers to a solvent addition form containing either stoichiometric or non-stoichiometric amounts of solvent. Some compounds tend to trap a certain molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. When the solvent is water, the solvate formed is a hydrate, and when the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more water molecules with one of the substances in which water retains its molecular state as HO, and such combinations can form one or more hydrates.

[0058] The compounds and salts described herein can exist in several tautomeric forms, including enol and imine forms, and keto and enamine forms, as well as geometric isomers and mixtures thereof. Tautomers exist as a mixture of tautomeric forms in solution. In solid form, one tautomer usually predominates. Although one tautomer may be described, this application includes all tautomers of the compounds. A tautomer is one of two or more structural isomers that exist in equilibrium and are readily converted from one isomer to another. This reaction results in the formal migration of a hydrogen atom, accompanied by the switching of adjacent conjugated double bonds. In solutions where tautomerization is possible, a chemical equilibrium of tautomers is reached. The exact ratio of tautomers depends on several factors, such as temperature, solvent, and pH. The concept of tautomers that are interconvertible by tautomerization is called tautomerism.

[0059] Of the various types of tautomerism possible, two are commonly observed: keto-enol tautomerism, in which a simultaneous shift of electrons and hydrogen atoms occurs.

[0060] Tautomerization can be catalyzed by bases: 1. deprotonation, 2. formation of a delocalized anion (e.g., enolate), 3. protonation at a different position on the anion; acids: 1. protonation, 2. formation of a delocalized cation, 3. deprotonation at another position adjacent to the cation.

[0061] As used herein, the following terms have the following meanings unless otherwise specified: "Amino" refers to the -NH2 radical. "Cyano" refers to the -CN radical. "Halo" or "halogen" refers to a bromo, chloro, fluoro, or iodo radical. "Hydroxy" or "hydroxyl" refers to the --OH radical. "Imino" refers to the =NH substituent. "Nitro" refers to the -NO2 radical. "Oxo" refers to the =O substituent. "Thioxo" refers to the =S substituent.

[0062] "Alkyl" or "alkyl group" refers to a fully saturated, straight or branched hydrocarbon chain radical having from 1 to 12 carbon atoms and attached to the rest of the molecule by a single bond. Alkyl containing any number of carbon atoms from 1 to 12 is included. Alkyl containing up to 12 carbon atoms is C1-C 12 Alkyl, alkyl containing up to 10 carbon atoms is C1-C 10 An alkyl is a C1-C6 alkyl, and an alkyl containing up to 6 carbon atoms is a C1-C6 alkyl, and an alkyl containing up to 5 carbon atoms is a C1-C5 alkyl. C1-C5 alkyl includes C5 alkyl, C4 alkyl, C3 alkyl, C2 alkyl, and C1 alkyl (i.e., methyl). C1-C6 alkyl includes all of the moieties described above for C1-C5 alkyl, but also includes C6 alkyl. C1-C 10 Alkyl includes all of the moieties described above for C1-C5 alkyl and C1-C6 alkyl, but also includes C7, C8, C9, and C 10 Also includes alkyl. Similarly, C1-C 12 Alkyl includes all of the above moieties, but C 11 and C 12 Includes alkyl. C1-C 12Non-limiting examples of alkyl include methyl, ethyl, n-propyl, i-propyl, sec-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, t-amyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl. Unless stated otherwise in the specification, an alkyl group can be optionally substituted.

[0063] "Alkylene" or "alkylene chain" refers to a fully saturated, straight or branched divalent hydrocarbon chain radical having 1 to 12 carbon atoms. C1-C 12 Non-limiting examples of alkylene include methylene, ethylene, propylene, n-butylene, ethenylene, propenylene, n-butenylene, propynylene, N-butynylene, etc. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise in the specification, an alkylene chain can be optionally substituted.

[0064] "Alkenyl" or "alkenyl group" refers to a straight or branched hydrocarbon chain radical having from 2 to 12 carbon atoms and one or more carbon-carbon double bonds. Each alkenyl group is attached to the rest of the molecule by a single bond. Alkenyl groups containing any number of carbon atoms from 2 to 12 are included. Alkenyl groups containing up to 12 carbon atoms are C2-C 12 Alkenyl containing up to 10 carbon atoms is C2-C 10 An alkenyl group containing up to 6 carbon atoms is C2-C6 alkenyl, and an alkenyl containing up to 5 carbon atoms is C2-C5 alkenyl. C2-C5 alkenyl includes C5 alkenyl, C4 alkenyl, C3 alkenyl, and C2 alkenyl. C2-C6 alkenyl includes all of the moieties described above for C2-C5 alkenyl, but also includes C6 alkenyl. C2-C 10Alkenyl includes all of the moieties described above for C2-C5 alkenyl and C2-C6 alkenyl, but also includes C7, C8, C9, and C 10 Also includes alkenyl. Similarly, C2-C 12 Alkenyl includes all of the above moieties, except that C 11 and C 12 Includes alkenyl. C2-C 12 Non-limiting examples of alkenyl include ethenyl (vinyl), 1-propenyl, 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 4-nonenyl, 5-nonenyl, 6-nonenyl, 7-nonenyl, 8-nonenyl, 1-decenyl, 2-decenyl, 3-decenyl, 4-decenyl, 5-decenyl, 6-decenyl, 7-decenyl, 8-decenyl, 9-decenyl, 1-undecenyl, 2-undecenyl, Examples include 3-undecenyl, 4-undecenyl, 5-undecenyl, 6-undecenyl, 7-undecenyl, 8-undecenyl, 9-undecenyl, 10-undecenyl, 1-dodecenyl, 2-dodecenyl, 3-dodecenyl, 4-dodecenyl, 5-dodecenyl, 6-dodecenyl, 7-dodecenyl, 8-dodecenyl, 9-dodecenyl, 10-dodecenyl, and 11-dodecenyl. Unless otherwise stated in this specification, alkyl groups can be optionally substituted.

[0065] "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain radical having 2 to 12 carbon atoms and one or more carbon-carbon double bonds. 12Non-limiting examples of alkenylene include ethene, propene, butene, etc. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise in the specification, an alkenylene chain can be optionally substituted.

[0066] "Alkynyl" or "alkynyl group" refers to a straight or branched hydrocarbon chain radical having from 2 to 12 carbon atoms and having one or more carbon-carbon triple bonds. Each alkynyl group is attached to the rest of the molecule by a single bond. Alkynyl groups containing any number of carbon atoms from 2 to 12 are included. Alkynyl groups containing up to 12 carbon atoms are C2-C 12 Alkynyl containing up to 10 carbon atoms is C2-C 10 Alkynyl is an alkynyl group containing up to 6 carbon atoms, C2-C6 alkynyl, and an alkynyl containing up to 5 carbon atoms is C2-C5 alkynyl. C2-C5 alkynyl includes C5 alkynyl, C4 alkynyl, C3 alkynyl, and C2 alkynyl. C2-C6 alkynyl includes all of the moieties described above for C2-C5 alkynyl, but also includes C6 alkynyl. C2-C 10 Alkynyl includes all of the moieties described above for C2-C5 alkynyl and C2-C6 alkynyl, but also includes C7, C8, C9, and C 10 Also includes alkynyl. Similarly, C2-C 12 Alkynyl includes all of the above moieties, except that C 11 and C 12 Alkynyl is also included. C2-C 12 Non-limiting examples of alkenyl include ethynyl, propynyl, butynyl, pentynyl, etc. Unless stated otherwise in the specification, an alkyl group can be optionally substituted.

[0067] "Alkynylene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain radical having 2 to 12 carbon atoms and one or more carbon-carbon triple bonds. 12 Non-limiting examples of alkynylene include ethynylene, propargylene, and the like. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkynylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise in the specification, an alkynylene chain can be optionally substituted.

[0068] "Alkoxy" means a group of the formula -OR a refers to the radical of R a is an alkyl, alkenyl, or alkenyl radical, as defined above, containing 1 to 12 carbon atoms. Unless stated otherwise in the specification, an alkoxy group can be optionally substituted.

[0069] "Alkylamino" refers to a group of the formula -NHR a or -NR a R a Each R a is independently an alkyl, alkenyl, or alkynyl radical as defined above containing 1 to 12 carbon atoms. Unless stated otherwise in the specification, an alkylamino group can be optionally substituted.

[0070] "Alkylcarbonyl" is -C(=O)R a Refers to the part, R a is an alkyl, alkenyl, or alkynyl radical as defined above. A non-limiting example of an alkylcarbonyl is a methylcarbonyl ("acetal") moiety. An alkylcarbonyl group is defined as "C w -C z Also referred to as "acyl," w and z are R as defined above. a For example, "C1-C 10 "Acyl" refers to an alkylcarbonyl group as defined above; ais C1-C 10 Alkyl, C2-C 10 Alkenyl, or C2-C 10 Unless stated otherwise in the specification, an alkylcarbonyl group may be optionally substituted.

[0071] "Aryl" refers to a hydrocarbon ring system radical containing hydrogen, 6 to 18 carbon atoms, and at least one aromatic ring. For purposes of this invention, an aryl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system and can include fused or bridged ring systems. Aryl radicals include, but are not limited to, aryl radicals derived from phenyl (benzene), aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless otherwise stated in this specification, the term "aryl" is meant to include aryl radicals that are optionally substituted.

[0072] An "aralkyl" or "arylalkyl" is a group of the formula -R b -R c refers to the radical of R b is an alkylene group as defined above, and R c is one or more aryl radicals as defined above. Aralkyl groups include, but are not limited to, benzyl, diphenylmethyl, and the like. Unless stated otherwise in the specification, an aralkyl group may be optionally substituted.

[0073] An "aralkenyl" or "arylalkenyl" is an alkyl group of the formula -R b -R c refers to the radical of R b is an alkenylene group as defined above, and R c is one or more aryl radicals as defined above. Unless stated otherwise in the specification, an aralkenyl group may be optionally substituted.

[0074] An "aralkynyl" or "arylalkynyl" is a group of the formula -R b -R c refers to R b is an alkynylene group as defined above, and R c is one or more aryl radicals as defined above. Unless stated otherwise in the specification, an aralkynyl group may be optionally substituted.

[0075] "Carbocyclyl," "carbocyclic ring," or "carbocycle" refers to a ring structure in which the atoms forming the ring are each carbon. A carbocyclic ring can contain 3 to 20 carbon atoms in the ring. Carbocyclic rings include aryl and cycloalkyl. Cycloalkenyl and cycloalkynyl are defined herein. Unless otherwise stated in the specification, a carbocyclyl group can be optionally substituted.

[0076] "Cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic fully saturated hydrocarbon radical, consisting solely of carbon and hydrogen atoms, which may include fused, bridged, or spiral ring systems, having 3 to 20 carbon atoms, preferably 3 to 10 carbon atoms, and which is attached to the rest of the molecule by a single bond. Monocyclic cycloalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl radicals include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless stated otherwise specifically in the specification, cycloalkyl groups can be optionally substituted.

[0077] "Cycloalkenyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical, consisting solely of carbon and hydrogen atoms, containing one or more carbon-carbon double bonds, which may include fused, bridged, or spiral ring systems, having from 3 to 20 carbon atoms, preferably from 3 to 10 carbon atoms, and attached to the rest of the molecule by a single bond. Monocyclic cycloalkenyl radicals include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclocetenyl, and the like. Polycyclic cycloalkenyl radicals include, for example, bicyclo[2.2.1]hept-2-enyl, and the like. Unless stated otherwise in the specification, a cycloalkenyl group can be optionally substituted.

[0078] "Cycloalkynyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical, consisting solely of carbon and hydrogen atoms, containing one or more carbon-carbon triple bonds, which may include fused, bridged, or spiral ring systems, having from 3 to 20 carbon atoms, preferably from 3 to 10 carbon atoms, and attached to the rest of the molecule by a single bond. Monocyclic cycloalkynyl groups include, for example, cycloheptynyl, cyclooctynyl, and the like. Unless stated otherwise specifically in the specification, a cycloalkynyl group can be optionally substituted.

[0079] "Cycloalkylalkyl" refers to a group of the formula -R b -R d refers to the radical of R b is an alkylene, alkenylene, or alkynylene group as defined above, and R d is a cycloalkyl, cycloalkenyl, cycloalkynyl radical as defined above. Unless stated otherwise in the specification, a cycloalkylalkyl group may be optionally substituted.

[0080] "Haloalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, including, for example, trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. Unless stated otherwise in the specification, a haloalkyl group can be optionally substituted.

[0081] "Haloalkenyl" refers to an alkenyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, such as, for example, 1-fluoropropenyl, 1,1-difluorobutenyl, etc. Unless stated otherwise in the specification, a haloalkenyl group can be optionally substituted.

[0082] "Haloalkynyl" refers to an alkynyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, such as, for example, 1-fluoropropynyl, 1-fluorobutynyl, etc. Unless stated otherwise in the specification, a haloalkynyl group can be optionally substituted.

[0083] "Heterocyclyl," "heterocyclic ring," or "heterocycle" refers to a stable 3- to 20-membered non-aromatic, partially aromatic, or aromatic ring radical consisting of 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Heterocyclyl or heterocyclic ring includes heteroaryl, as defined below. Unless otherwise stated in the specification, a heterocyclyl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system and can include fused, bridged, and spiral ring systems; the nitrogen, carbon, or sulfur atoms in the heterocyclyl radical can be optionally oxidized; the nitrogen atom can be optionally quaternized; and the heterocyclyl radical can be partially or fully saturated. Examples of such heterocyclyl radicals include, but are not limited to, aziridinyl, oxtanyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, pyridin-one, and the like. The point of attachment of a heterocyclyl, heterocyclic ring, or heterocycle to the rest of the molecule via a single bond is through a ring member atom, which can be carbon or nitrogen. Unless stated otherwise in the specification, heterocyclyl groups can be optionally substituted.

[0084] "Heterocyclylalkyl" refers to a group of the formula -R b -R e refers to the radical of R b is an alkylene group as defined above, and R e is a heterocyclyl radical as defined above. Unless stated otherwise in the specification, a heterocyclylalkyl group may be optionally substituted.

[0085] "Heterocyclylalkenyl" has the formula -R b -R e refers to the radical of R b is an alkenylene group as defined above, and R e is a heterocyclyl radical as defined above. Unless stated otherwise in the specification, a heterocyclylalkenyl group may be optionally substituted.

[0086] "Heterocyclylalkynyl" has the formula -R b -R e refers to the radical of R b is an alkynylene group as defined above, and R e is a heterocyclyl radical as defined above. Unless stated otherwise in the specification, a heterocyclylalkynyl group may be optionally substituted.

[0087] "N-heterocyclyl" refers to a heterocyclyl radical as defined above containing at least one nitrogen, and the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. Unless stated otherwise in the specification, an N-heterocyclyl group can be optionally substituted.

[0088] "Heteroaryl" refers to a 5- to 20-membered ring system radical containing, as ring members, 1 to 13 carbon atoms and 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. For purposes of this invention, a heteroaryl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system and can include fused or bridged ring systems, in which at least one ring containing a heteroatom ring member is aromatic. The nitrogen, carbon, or sulfur in a heteroaryl radical can be optionally oxidized, and the nitrogen atom can be optionally quaternized. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindoleyl, phenyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolopyridine, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise in the specification, a heteroaryl group may be optionally substituted.

[0089] "N-heteroaryl" refers to a heteroaryl radical, as defined above, containing at least one nitrogen, and the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. Unless stated otherwise in the specification, an N-heteroaryl group can be optionally substituted.

[0090] "Heteroarylalkyl" has the formula -R b -R f refers to the radical of R b is an alkylene chain as defined above, and R f is a heteroaryl radical as defined above. Unless stated otherwise in the specification, a heteroarylalkyl group may be optionally substituted.

[0091] "Heteroarylalkenyl" has the formula -R b -R f refers to the radical of R b is an alkenylene chain as defined above, and R f is a heteroaryl radical as defined above. Unless stated otherwise in the specification, a heteroarylalkenyl group may be optionally substituted.

[0092] "Heteroarylalkynyl" refers to a group of the formula -R b -R f refers to the radical of R b is an alkynylene chain as defined above, and R f is a heteroaryl radical as defined above. Unless stated otherwise in the specification, a heteroarylalkynyl group may be optionally substituted.

[0093] "Thioalkyl" is -SR a refers to the radical of R a refers to an alkyl, alkenyl, or alkynyl radical, as defined above, containing 1 to 12 carbon atoms. Unless stated otherwise in the specification, a thioalkyl group may be optionally substituted.

[0094] As used herein, the term "substituted" means any of the above groups (e.g., alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, alkoxy, alkylamino, alkylcarbonyl, thioalkyl, aryl, aralkyl, carbocyclyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, etc.) in which at least one hydrogen atom is replaced by a bond to a non-hydrogen atom. Examples of heteroatoms include, but are not limited to, halogen atoms such as F, Cl, Br, and I; oxygen atoms in groups such as hydroxyl, alkoxy, and ester groups; sulfur atoms in groups such as thiol, thioalkyl, sulfone, sulfonyl, and sulfoxide groups; nitrogen atoms in groups such as amine, amide, alkylamine, dialkylamine, arylamine, alkylarylamine, diarylamine, N-oxide, imide, and enamine; silicon atoms in groups such as trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, and triarylsilyl groups; and other heteroatoms in various other groups. "Substituted" also refers to any of the above groups in which one or more hydrogen atoms have been replaced by a higher order bond (e.g., a double or triple bond) to a heteroatom, such as oxygen in oxo, carbonyl, carboxyl, and ester groups, and nitrogen in groups such as imine, oxime, hydrazone, and nitrile. For example, "substituted" refers to any of the above groups in which one or more hydrogen atoms have been replaced by a higher order bond (e.g., a double or triple bond) to a heteroatom, such as oxygen in oxo, carbonyl, carboxyl, and ester groups, and nitrogen in imine, oxime, hydrazone, and nitrile groups. -NR g R h , -NR g C(=O)R h , -NR g C(=O)NR g R h , -NR g C(=O)OR h , -NR g SO2R h , -OC(=O)NR g R h, -OR g , -SR g , -SOR g , -SO2R g , -OSO2R g , -SO2OR g , =NSO2R g , and -SO2NR g R h "Substituted" also includes any of the above groups replaced by -C(=O)R g , -C(=O)OR g , -C(=O)NR g R h , -CH2SO2R g , -CH2SO2NR g R h In the foregoing, R g and R h are the same or different and independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl, and / or heteroarylalkyl. "Substituted" also refers to any of the above groups in which one or more hydrogen atoms are replaced by a bond to an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and / or heteroarylalkyl group. Additionally, each of the foregoing substituents may also be optionally substituted with one or more of the above substituents.

[0095] As used herein, the symbol " [ka] (hereinafter referred to as "attachment bond") indicates a bond that is an attachment point between two chemical entities, one of which is shown as being attached to the attachment bond and the other of which is not shown as being attached to the attachment bond. For example, [ka] " indicates that chemical entity "A" is attached to another chemical entity through a point of attachment. Furthermore, specific points of attachment to chemical entities not shown can be identified by inference. For example, compound [ka] where X is " [ka] " and the point of attachment is presumed to be the bond shown where X is attached to the phenyl ring in the ortho position to the fluorine.

[0096] The phrases "parenteral administration" and "administered parenterally" are art-recognized terms and include modes of administration other than enteral and topical administration, such as injection, including, but not limited to, intravenous, intramuscular, intrapleural, intravascular, intrapericardial, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, intratracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

[0097] The term "treating" is art-recognized and includes inhibiting a disease, disorder, or condition of interest, e.g., preventing its progression, and alleviating a disease, disorder, or condition, e.g., causing regression of the disease, disorder, and / or condition. Treating a disease or condition includes ameliorating at least one symptom of a particular disease or condition, even if the underlying pathophysiology is unaffected.

[0098] The term "preventing" is art-recognized and includes stopping a disease, disorder, or condition from occurring in a subject who may have a predisposition to, but has not yet been diagnosed with, the disease, disorder, and / or condition. Preventing a condition associated with a disease includes stopping the occurrence of the condition after the disease has been diagnosed but before the condition has been diagnosed.

[0099] A "patient," "subject," or "host" to be treated by the subject methods can mean either a human or a non-human animal, such as a mammal, fish, bird, reptile, or amphibian. Thus, the subject of the methods disclosed herein can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig, or rodent. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, are intended to be covered, regardless of male or female. In one aspect, the subject is a mammal. A patient refers to a subject suffering from a disease or disorder.

[0100] The terms "prophylactic" or "therapeutic" treatment are art-recognized and include administration of one or more of the subject compositions to a host. If administered prior to clinical manifestation of an undesirable condition (e.g., a disease or other undesirable condition in a host animal), the treatment is prophylactic, i.e., it protects the host from the onset of the undesirable condition. On the other hand, if administered after the onset of the undesirable condition, the treatment is therapeutic (i.e., aimed at reducing, ameliorating, or stabilizing an existing undesirable condition or its side effects).

[0101] The terms "therapeutic agent," "drug," "pharmaceutical agent," and "bioactive substance" are art-recognized and include molecules and other agents that are biologically, physiologically, or pharmacologically active substances that act locally or systemically on a patient or subject to treat a disease or condition. The terms include, but are not limited to, pharmaceutically acceptable salts and prodrugs thereof. Such agents may be acidic, basic, or salts; they may be neutral molecules, polar molecules, or molecular complexes capable of hydrogen bonding; and they may be prodrugs in the form of ethers, esters, amides, etc., that become biologically activated when administered to a patient or subject.

[0102] The phrases "therapeutically effective amount" or "pharmaceutically effective amount" are art-recognized terms. In certain embodiments, this term refers to an amount of a therapeutic agent that produces some desired effect at a reasonable benefit / risk ratio applicable to any medical treatment. In certain embodiments, this term refers to an amount necessary or sufficient to eliminate, reduce, or maintain the target of a particular therapeutic regimen. An effective amount may vary depending on factors such as the disease or condition being treated, the particular targeting construct being administered, the size of the subject, or the severity of the disease or condition. One of ordinary skill in the art can empirically determine the effective amount of a particular compound without necessitating undue experimentation. In certain embodiments, a therapeutically effective amount of a therapeutic agent for in vivo use will likely depend on many factors, including the rate of release of the agent from the polymer matrix, which depends in part on the chemical and physical properties of the polymer, the identity of the agent, the mode and method of administration, and any other materials incorporated into the polymer matrix in addition to the agent.

[0103] "Optional" or "optionally" means that the situation described below may or may not occur, and the description includes cases where the situation occurs and cases where it does not occur. For example, the phrase "optionally substituted" means that a non-hydrogen substituent may or may not be present on a given atom, and thus the description includes structures where the non-hydrogen substituent is present and structures where the non-hydrogen substituent is not present.

[0104] Throughout this specification, when a composition is described as having, including, or comprising certain components, it is contemplated that the composition also consists essentially of, or consists of, the recited components. Similarly, when a method or process is described as having, including, or comprising certain process steps, the process also consists essentially of, or consists of, the recited processing steps. Furthermore, it should be understood that the order of steps or order for performing certain operations is immaterial so long as the compositions and methods described herein are operable. Moreover, two or more steps or operations can be performed simultaneously.

[0105] All percentages and ratios used herein are by weight unless otherwise indicated.

[0106] Embodiments described herein relate to compounds for use in inhibiting Bax-mediated cell death and / or apoptosis, and their use in treating conditions, disorders, and / or diseases associated with Bax-mediated cell death and / or apoptosis. The Bax inhibitory compounds described herein suppress Bax-induced cell death at 1 nM to 10 nM (in culture medium) and have Bax binding affinities (Kd) in the range of 1 nM to 100 nM, compared to previously reported Bax inhibitors that require at least 1 μM (1000 nM in cell culture medium).

[0107] As shown in Figures 1-4, the Bax inhibitory compounds described herein demonstrated a dose-dependent effect in rescuing cells from Bax, protecting mouse embryonic fibroblast (MEF) cells from Bax-induced cell death, inhibiting Bax-induced apoptosis without significantly affecting the expression levels of Bax, Bcl-2, Bcl-XL, and Mcl-1, and protecting ARP19 (retinal cell) cells from atRAL-induced cell death. Advantageously, the Bax inhibitory compounds described herein can be used to help subjects suffering from cell death-related diseases and / or apoptosis, including, for example, retinal degenerative diseases, cardiovascular diseases, neurodegenerative diseases, and other diseases caused by undesirable Bax-induced programmed cell death. The Bax inhibitory compounds described herein can also be used as Bax inhibitors to prolong cell, tissue, and / or organ survival ex vivo and after transplantation and engraftment. Therefore, Bax inhibitory compounds may be beneficial in improving the efficiency of cell, tissue, and organ storage and transplantation.

[0108] In some embodiments, the Bax inhibitor compound has the following formula (I): [ka] or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R 1 and R 2 are each independently -H, alkyl, -F, -CN, -O-alkyl, cycloalkyl, oxetanyl, or tetrahydrofuranyl, or R 1 is R 2 together with, optionally, one or two R 8 forming a phenyl ring substituted with a group or R 1 is R 2 together with one or two heteroatoms selected from N, O, and S, and optionally one or two R 8 forming a 5- or 6-membered heteroaromatic ring substituted with a group, R 8is halo, alkyl, cycloalkyl, oxetanyl, tetrahydrofuranyl, —CN, —O-alkyl, —O-cycloalkyl, —SO2-alkyl, or —CH2SO2-alkyl; R 3 is absent, -H, -D, -F, -Cl, -CF3, -alkyl, cyclopropyl-O-alkyl, or -CN; R 4 is -H, alkyl, cyclopropyl, or -CF3; R 5 is absent, -H, or alkyl; Alternatively, R 5 and the nitrogen atom to which it is attached may be replaced with an oxygen atom, V, W, X, Y, and Z are each independently —CH or N; X 1 and Z 1 are each independently —CH or N, W 1 and Y 1 are each independently C or N, and Y 1 When N, R 3 does not exist, X 2 is O or N, and X 2 When is O, R 5 does not exist, [ka] represents a single or double bond, R 6 is -H, halo, alkyl, cycloalkyl, -CN, -O-alkyl, -O-cycloalkyl, -O-heterocyclyl, -SO2-alkyl, -CH2SO2-alkyl, -CONH2, -CONH-alkyl, or -CON(alkyl)2; R 7 is -H, halo, alkyl, cycloalkyl, -CN, -O-alkyl, -O-cycloalkyl, -O-heterocyclyl, -SO2-alkyl, -CH2SO2-alkyl, -CONH2, -CONH-alkyl, or -CON(alkyl)2; Alternatively, R 6 or R 7 optionally one or two R 9 aryl substituted with a group; Alternatively, R 6 or R 7 contains one or two heteroatoms selected from the group consisting of N, O, and S, and optionally, one or two R , excluding labile heterocycles. 9 a 4- to 6-membered heterocycle substituted with a group, Alternatively, R 6 or R 7 contains 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and optionally, excluding unstable heterocycles, one or two R 9 a 5- to 6-membered heteroaryl group substituted with a group, R 9 is H, halo, alkyl, cycloalkyl, alkyl-CO-, oxetanyl, 3-tetrahydrofuranyl, -CN, -O-alkyl, -O-cycloalkyl, -CONH2, -CONH-alkyl, or -CON(alkyl)2; R 6 is R 7 and together with the phenyl or heteroaryl ring to which they are attached may be a benzimidazole ring, a benzotriazole ring, an azaindole ring, an azaindazole ring, or a benzodioxolane ring, wherein the ring N is an optional substituent R 10 and C of the ring is optionally R 11 is replaced by R 10 is —H, alkyl, or cycloalkyl; R 11 is —H, alkyl, or cycloalkyl.

[0109] In some embodiments, R 1 and R 2are each independently -H, C1-C6-alkyl, -F, -CN, -O-C1-C6-alkyl, C3-C7-cycloalkyl, 3-oxetanyl, or 3-tetrahydrofuranyl, or R 1 is R 2 together with, optionally, one or two R 8 forming a phenyl ring substituted with a group or R 1 is R 2 together with one or two heteroatoms selected from N, O, and S, and optionally one or two R 8 It forms a saturated 5- or 6-membered heteroaromatic ring substituted with a group.

[0110] In other embodiments, R 8 is halo, C1-C6-alkyl, C3-C7-cycloalkyl, 3-oxetanyl, 3-tetrahydrofuranyl, —CN, —O—C1-C6-alkyl, —O—C3-C7-cycloalkyl, —SO2-C1-C6-alkyl, or —CH2SO2-C1-C6-alkyl.

[0111] In other embodiments, R 3 is absent, -H, -D, -F, -Cl, -CF3, -C1-C6-alkyl, cyclopropyl-O-C1-C6-alkyl, or -CN.

[0112] In some embodiments, R 4 -H, -C 1- It is C6-alkyl, -cyclopropyl, or -CF3.

[0113] In other embodiments, R 5 is absent, -H, or C1-C6-alkyl.

[0114] In other embodiments, R 6is -H, halo, C1-C6-alkyl, C3-C7-cycloalkyl, -CN, -O-C1-C6-alkyl, -O-C3-C7-cycloalkyl, -SO2-C1-C6-alkyl, -CH2SO2-C1-C6-alkyl, -CONH2, -CONH-C1-C6-alkyl, or -CON(C1-C6-alkyl)2.

[0115] In other embodiments, R 7 is -H, halo, C1-C6-alkyl, C3-C7-cycloalkyl, -CN, -O-C1-C6-alkyl, -O-C3-C7-cycloalkyl, -SO2-C1-C 6 -alkyl, -CH2SO2-C1-C6-alkyl, -CONH2, -CONH-C1-C6-alkyl, or -CON(C1-C6-alkyl)2.

[0116] In some embodiments, R 9 is H, halo, C1-C6-alkyl, C3-C7-cycloalkyl, C1-C5-alkyl-CO—, 3-oxetanyl, 3-tetrahydrofuranyl, —CN, —O—C1-C6-alkyl, or —O—C3-C7-cycloalkyl.

[0117] In other embodiments, R 10 is —H, C1-C6-alkyl, or C3-C7-cycloalkyl.

[0118] In yet other embodiments, R 11 is —H, C1-C6-alkyl, or C3-C7-cycloalkyl.

[0119] In other embodiments, R 1 is R 2 together with, optionally, one or two R 8 A phenyl ring substituted with a group or R 1 is R 2 together with one or two heteroatoms selected from N, O, and S, and optionally one or two R 8The aromatic rings may be formed as 5- or 6-membered saturated heteroaromatic rings substituted with groups.

[0120] In some embodiments, R 4 -C 1- C-alkyl or -CF3, and R 5 is -H.

[0121] In other embodiments, X and Y are independently H and Z is N.

[0122] In some embodiments, R 6 or R 7 contains one or two heteroatoms selected from the group consisting of N, O, and S, and optionally, one or two R , excluding labile heterocycles. 9 a 4- to 6-membered saturated heterocyclic ring substituted with a group, or R 6 Or R 7 contains 1 to 3 heteroatoms selected from the group consisting of N, O, and S, and optionally, excluding unstable heterocycles, one or two R 9 It is a 5- to 6-membered heteroaryl group substituted with a group.

[0123] In other embodiments, R 6 is selected from the group consisting of: [ka]

[0124] In other embodiments, the Bax inhibitor compound having formula (I) has the following formula: [ka] or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R 1 and R 2are each independently -H, C1-C6-alkyl, -F, -CN, -O-C1-C6-alkyl, C3-C7-cycloalkyl, 3-oxetanyl, or 3-tetrahydrofuranyl, or R 1 is R 2 together with, optionally, one or two R 8 forming a phenyl ring substituted with a group or R 1 is R 2 together with one or two heteroatoms selected from N, O, and S, and optionally one or two R 8 forming a 5- or 6-membered heteroaromatic ring substituted with a group, R 8 is halo, C1-C6-alkyl, C3-C7-cycloalkyl, 3-oxetanyl, 3-tetrahydrofuranyl, -CN, -O-C1-C6-alkyl, -O-C3-C7-cycloalkyl, -SO2-C1-C6-alkyl or -CH2SO2-C1-C6-alkyl, R 3 is -H, -D, -F, -Cl, -CF3, -C1-C6-alkyl, cyclopropyl-O-C1-C6-alkyl, or -CN, R 4 -H, -C 1- C6-alkyl, -cyclopropyl, or -CF3; R 5 -H or -C 1- is C6-alkyl, Alternatively, R 5 and the nitrogen atom to which it is attached may be replaced with an oxygen atom, X, Y, and Z are each independently —CH or N; [ka] represents a single or double bond, R 6is -H, halo, C1-C6-alkyl, C3-C7-cycloalkyl, -CN, -O-C1-C6-alkyl, -O-C3-C7-cycloalkyl, -O-heterocyclyl, -SO2-C1-C6-alkyl, -CH2SO2-C1-C6-alkyl, -CONH2, -CONH-C1-C6-alkyl or -CON(C1-C6-alkyl)2, R 7 is -H, halo, C1-C6-alkyl, C3-C7-cycloalkyl, -CN, -O-C1-C6-alkyl, -O-C3-C7-cycloalkyl, -O-heterocyclyl, -SO2-C1-C 6 -alkyl, -CH2SO2-C1-C6-alkyl, -CONH2, -CONH-C1-C6-alkyl, or -CON(C1-C6-alkyl)2; Alternatively, R 6 or R 7 optionally one or two R 9 aryl substituted with a group; Alternatively, R 6 or R 7 contains one or two heteroatoms selected from the group consisting of N, O, and S, and optionally, one or two R , excluding labile heterocycles. 9 a 4- to 6-membered heterocycle substituted with a group, Alternatively, R 6 or R 7 contains 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and optionally, excluding unstable heterocycles, one or two R 9 a 5- to 6-membered heteroaryl group substituted with a group, R 9 is halo, C1-C6-alkyl, C3-C7-cycloalkyl, C1-C5-alkyl-CO—, 3-oxetanyl, 3-tetrahydrofuranyl, —CN, —O—C1-C6-alkyl, —O—C3-C7-cycloalkyl, —CONH2, —CONH-alkyl or —CON(alkyl)2, R 6 is R 7and together with the phenyl or heteroaryl ring to which they are attached may be a benzimidazole ring, a benzotriazole ring, an azaindole ring, an azaindazole ring, or a benzodioxolane ring, wherein the ring N is an optional substituent R 10 and C of the ring is optionally R 11 is replaced by R 10 is —H, C1-C6-alkyl, or C3-C7-cycloalkyl, R 11 is —H, C1-C6-alkyl, or C3-C7-cycloalkyl.

[0125] In other embodiments, R 1 is R 2 together with, optionally, one or two R 8 A phenyl ring substituted with a group or R 1 is R 2 together with one or two heteroatoms selected from N, O, and S, and optionally one or two R 8 The aromatic rings may be formed as 5- or 6-membered saturated heteroaromatic rings substituted with groups.

[0126] In some embodiments, R 4 -C 1- C-alkyl or -CF3, and R 5 is -H.

[0127] In other embodiments, X and Y are independently H and Z is N.

[0128] In some embodiments, R 6 or R 7 contains one or two heteroatoms selected from the group consisting of N, O, and S, and optionally, one or two R , excluding labile heterocycles. 9 a 4- to 6-membered saturated heterocyclic ring substituted with a group, or R 6 Or R 7contains 1 to 3 heteroatoms selected from the group consisting of N, O, and S, and optionally, excluding unstable heterocycles, one or two R 9 It is a 5- to 6-membered heteroaryl group substituted with a group.

[0129] In other embodiments, R 6 is selected from the group consisting of: [ka]

[0130] In other embodiments, the Bax inhibitor compound having the formula (I) is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] and pharmaceutically acceptable salts thereof.

[0131] In other embodiments, the Bax inhibitor compound has the following formula (II): [ka] or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R 12 is =O or R 17 and R 12 When =O, R 13 and R 14 is independently absent, —H, alkyl, cycloalkyl, oxetanyl, or tetrahydrofuranyl, or R 12 R 17 When R 13 Or R 14 is absent, and the other is —H, alkyl, cycloalkyl, oxetanyl, or tetrahydrofuran; A 1 and A 2 are independently CH or N, V 3 , W 3 , X 3 , Y 3 , and Z 3 , and its substituent R 15 , R 16 , R 20 , and R 21 Heterocycles containing V are heteroaromatic rings having two double bonds, such as pyrrole, imidazole, pyrazole, or triazole. 3 , W 3 , X 3 , Y 3 , and Z 3 can independently be CH or N, and one to three of these atoms are N; X 4 is N or O, Y 4 is N or C, [ka] represents a single or double bond, R15 , R 16 , R 20 , and R 21 are independently alkyl, cycloalkyl, bicyclyl, phenyl, or optionally one or more R 18 or heteroaryl substituted with a heterocyclic ring having one or two heteroatoms selected from the group consisting of N, O, and S; R 17 is -H, ═NH, alkyl, cycloalkyl, oxetanyl, or tetrahydrofuranyl; Alternatively, R 15 is R 16 and together with the rings to which they are attached, V 3 and X 3 is N and W 3 is CH and Y 3 and Z 3 is a C atom at the ring fusion, the bicyclic ring can optionally be formed with one or two R 19 is substituted with a substituent, R 18 is halo, alkyl, cycloalkyl, -CN, -O-alkyl, -O-cycloalkyl, -O-alkyl-alkynyl, -SO2-alkyl, -CH2SO2-alkyl, -CONH2, -CONH-alkyl, or -CON(alkyl)2, R 19 is halo, alkyl, cycloalkyl, —CN, —O-alkyl, —O-cycloalkyl, —SO 2 -alkyl, or —CH 2 SO 2 -alkyl.

[0132] In some embodiments, R 12 is =O or R 17 and R 12 When =O, R 13 and R 14 is independently absent, —H, C1-C6-alkyl, C3-C7-cycloalkyl, 3-oxetanyl, or 3-tetrahydrofuranyl, or R 12 R 17 When R 13 Or R14 is absent, and the other is -H, C1-C6-alkyl, C3-C7-cycloalkyl, 3-oxetanyl, or 3-tetrahydrofuranyl.

[0133] In other embodiments, R 15 , R 16 , R 20 , and R 21 are independently C1-C6-alkyl, C3-C7-cycloalkyl, phenyl, or optionally R 18 or a C5-C6 heteroaryl substituted with a C4-C6 heterocyclic ring having one or two heteroatoms selected from the group consisting of N, O, and S.

[0134] In yet other embodiments, R 17 is -H, =NH, C1-C6-alkyl, C3-C7-cycloalkyl, 3-oxetanyl, or 3-tetrahydrofuranyl.

[0135] In some embodiments, R 18 is halo, C1-C6-alkyl, C3-C7-cycloalkyl, -CN, -O-C1-C6-alkyl, -O-C3-C7-cycloalkyl, -SO2-C1-C6-alkyl, -CH2SO2-C1-C6-alkyl, -CONH2, -CONH-C1-C6-alkyl, or -CON(C1-C6-alkyl)2.

[0136] In other embodiments, R 19 is halo, C1-C6-alkyl, C3-C7-cycloalkyl, -CN, -O-C1-C6-alkyl, -O-C3-C7-cycloalkyl, -SO2-C1-C6-alkyl, or -CH2SO2-C1-C6-alkyl.

[0137] In some embodiments, A 1 and A 2 are independently CH.

[0138] In other embodiments, R12 is =O.

[0139] In other embodiments, the Bax inhibitor compound having formula (II) has the following formula: [ka] or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R 12 is =O or R 17 and R 12 When =O, R 13 and R 14 is independently absent, —H, C1-C6-alkyl, C3-C7-cycloalkyl, 3-oxetanyl, or 3-tetrahydrofuranyl, or R 12 R 17 When R 13 Or R 14 is absent and the other is —H, C1-C6-alkyl, C3-C7-cycloalkyl, 3-oxetanyl, or 3-tetrahydrofuranyl, A 1 and A 2 are independently CH or N, V 3 , W 3 , X 3 , Y 3 , and Z 3 , and its substituent R 15 and R 16 Heterocycles containing V are heteroaromatic rings having two double bonds, such as pyrrole, imidazole, pyrazole, or triazole. 3 , W 3 , X 3 , Y 3 , and Z 3 can independently be CH or N, and one to three of these atoms are N; [ka] represents a single or double bond, R 15and R 16 are independently C1-C6-alkyl, C3-C7-cycloalkyl, phenyl, or optionally R 18 or a C5-C6 heteroaryl substituted with a C4-C6 heterocyclic ring having one or two heteroatoms selected from the group consisting of N, O, and S; R 17 is -H, -NH, C1-C6-alkyl, C3-C7-cycloalkyl, 3-oxetanyl, or 3-tetrahydrofuranyl, Alternatively, R 15 is R 16 and together with the rings to which they are attached, V 3 and X 3 is N and W 3 is CH and Y 3 and Z 3 is a C atom at the ring fusion, a benzimidazole ring can be formed, and the benzimidazole ring can optionally be fused with one or two R 19 is substituted with a substituent, R 18 is halo, C1-C6-alkyl, C3-C7-cycloalkyl, -CN, -O-C1-C6-alkyl, -O-C3-C7-cycloalkyl, -SO2-C1-C6-alkyl, -CH2SO2-C1-C6-alkyl, -CONH2, -CONH-C1-C6-alkyl or -CON(C1-C6-alkyl)2, R 19 is halo, C1-C6-alkyl, C3-C7-cycloalkyl, -CN, -O-C1-C6-alkyl, -O-C3-C7-cycloalkyl, -SO2-C1-C6-alkyl, or -CH2SO2-C1-C6-alkyl.

[0140] In some embodiments, A 1 and A 2 are independently CH.

[0141] In other embodiments, R 12 is =O.

[0142] In some embodiments, the Bax inhibitor compound of formula (II) has the following formula: [ka] wherein R 13 and R 14 are independently -H, C1-C6-alkyl, C3-C7-cycloalkyl, 3-oxetanyl, 3-tetrahydrofuranyl, R 15 and R 16 are independently C1-C6-alkyl, C3-C7-cycloalkyl, phenyl, or optionally R 18 or a C5-C6 heteroaryl substituted with a C4-C6 heterocyclic ring having one or two heteroatoms selected from the group consisting of N, O, and S; R 17 is —H, C1-C6-alkyl, C3-C7-cycloalkyl, 3-oxetanyl, or 3-tetrahydrofuranyl, Or, R 15 is R 16 and together with the ring to which they are attached can be a benzimidazole ring, and the benzimidazole ring can optionally contain one or two R 19 may be substituted with a substituent; R 18 is halo, C1-C6-alkyl, C3-C7-cycloalkyl, -CN, -O-C1-C6-alkyl, -O-C3-C7-cycloalkyl, -SO2-C1-C6-alkyl, -CH2SO2-C1-C6-alkyl, -CONH2, -CONH-C1-C6-alkyl or -CON(C1-C6-alkyl)2, R 19 is halo, C1-C6-alkyl, C3-C7-cycloalkyl, -CN, -O-C1-C6-alkyl, -O-C3-C7-cycloalkyl, -SO2-C1-C6-alkyl, or -CH2SO2-C1-C6-alkyl.

[0143] In other embodiments, the Bax inhibitor compound having formula (II) has the following formula: [ka] wherein R 14 is —H, C1-C6-alkyl, C3-C7-cycloalkyl, 3-oxetanyl, 3-tetrahydrofuranyl, R 15 and R 16 are independently C1-C6-alkyl, C3-C7-cycloalkyl, phenyl, or optionally R 18 or a C5-C6 heteroaryl substituted with a C4-C6 heterocyclic ring having one or two heteroatoms selected from the group consisting of N, O, and S; R 17 is —H, C1-C6-alkyl, C3-C7-cycloalkyl, 3-oxetanyl, or 3-tetrahydrofuranyl, Or, R 15 is R 16 and together with the ring to which they are attached can be a benzimidazole ring, and the benzimidazole ring can optionally contain one or two R 19 is substituted with a substituent, R 18 is halo, C1-C6-alkyl, C3-C7-cycloalkyl, -CN, -O-C1-C6-alkyl, -O-C3-C7-cycloalkyl, -SO2-C1-C6-alkyl, -CH2SO2-C1-C6-alkyl, -CONH2, -CONH-C1-C6-alkyl or -CON(C1-C6-alkyl)2, R 19 is halo, C1-C6-alkyl, C3-C7-cycloalkyl, -CN, -O-C1-C6-alkyl, -O-C3-C7-cycloalkyl, -SO2-C1-C6-alkyl, or -CH2SO2-C1-C6-alkyl.

[0144] In some embodiments, the Bax inhibitor compound has the formula (II): [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] and pharmaceutically acceptable salts thereof.

[0145] In some embodiments, the Bax inhibitory compound can be provided in a pharmaceutical composition comprising the Bax inhibitory compound and a pharmaceutically acceptable excipient or carrier.

[0146] In other embodiments, the compounds described herein or Bax inhibitory compounds inhibit mouse embryonic fibroblasts (MEFs) from Bax-induced cell death, with an IC of 1 μM or less. 50 , IC below 250 nM 50 , IC below 50 nM 50 , IC below 10 nM 50 , IC below 5 nM 50 , IC of about 2.5 nM to about 10 nM 50 , or an IC of approximately 2.5 nM or less 50 And can be inhibited.

[0147] In some embodiments, the Bas inhibitor compounds (e.g., Formulas I-II) have a human or mouse microsomal stability T of greater than 50 minutes, greater than 60 minutes, greater than 70 minutes, greater than 80 minutes, greater than 90 minutes, or greater than 100 minutes. 1 / 2 In embodiments, the Bax inhibitor compounds described herein have a human or mouse microsomal stability T of greater than 110 minutes, greater than 120 minutes, greater than 130 minutes, or greater than 145 minutes, including all values ​​and ranges therebetween. 1 / 2 In embodiments, the Bax inhibitory compounds described herein have a human or mouse microsomal stability T in the range of 65 to at least 145 (e.g., 65, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, or more, including all values ​​and ranges therebetween). 1 / 2 In embodiments, the Bax inhibitor compounds described herein have a human or mouse microsomal stability T 1 / 2 It has.

[0148] The Bax inhibitory compounds described herein can be used in methods for inhibiting apoptosis in cells by administering a therapeutically effective amount of the Bax inhibitory compound to the cells. An "effective amount" or "therapeutically effective amount" of a Bax inhibitory compound administered to a cell is an amount of the Bax inhibitory compound that is effective in reducing Bax-mediated apoptosis in the cell. In some embodiments, Bax-mediated apoptosis is induced by, for example, cell injury, a degenerative disorder or disease, or cytotoxic stress induced, for example, by chemotherapy and radiation therapy delivered to the cell.

[0149] It is well known that apoptosis, particularly Bax-mediated apoptosis, is centrally involved in the pathogenesis of many human diseases and injury conditions. The following references report on the important role of the Bax protein in various diseases: Injury-induced neuronal death - Deckwerth, et al. Neuron.17:401-411, 1996, Martin, et al., J. Compo Neurol. 433: 299-311, 2001, Kirkland, et al., J. Neurosci. 22:6480-90, 2002, Alzheimer's disease - MacGibbon, et al., Brain Res.750:223-234,1997, Selznick,et al.,J.Neuropathol.Exp.Neurol.59:271-279,2000,Cao,et al.,J.Cereb.Blood Flow Metab.21:321-333,2001,Zhang,et al.,J.Cell Biol. 156:519-529, 2002, Ischemia-induced cell damage - Kaneda, et al., Brain Res. 815:11-20, 1999, Gibson, et al., Mol. Med. 7:644-655, 2001, HIV (AIDS) and Bax: Castedo, et al., J. Exp. Med. 45 194:1097-1110, 2001, Drug-induced neuronal death - Dargusch, et al., J. Neurochem. 76:295-301, 2001, Parkinson's disease - Ploix and Spier, Trends Neurosci. 24:255, 2001, Huntington's disease - Antonawich, et al., Brain Res. Bull. 57:647-649, 2002.

[0150] Therefore, in another embodiment, a pharmaceutical composition comprising the compound described herein can be administered to a subject for the treatment of apoptotic diseases. The method includes administering a therapeutically effective amount of a pharmaceutical composition comprising a Bax inhibitory compound to a subject. For example, a therapeutically effective amount of a pharmaceutical composition comprising a Bax inhibitory compound described herein includes a reduction in Bax-mediated cell or tissue death in a subject.

[0151] Apoptotic diseases and related disorders contemplated herein include, for example, stroke, heart attack, ischemia, degenerative diseases (neuronal and muscular, e.g., Alzheimer's disease, Parkinson's disease, cardiomyocyte degeneration, etc.), macular degeneration, hypoxia-induced apoptosis, ischemia, atrophy, infection with parasites (such as viruses, bacteria, yeast, or protozoa), side effects of other drugs (e.g., anti-cancer drugs), UV / X-ray irradiation, and several other pathological conditions that trigger cell death signals.

[0152] As described above, the compositions described herein can be used to inhibit Bax-mediated cell death, which is induced by chemotherapy and radiotherapy due to Bax overexpression in cells. In one exemplary embodiment, the pharmaceutical composition can protect megakaryocytes from chemotherapy-induced apoptosis without substantially affecting the ability of megakaryocytes to produce and release platelets.

[0153] It is further contemplated that the pharmaceutical compositions described herein may be used in combination or adjunctive therapy with antiproliferative or chemotherapeutic agents for the treatment of proliferative disorders, such as neoplastic disorders or cancer. The phrase "combination therapy" encompasses the administration of a pharmaceutical composition that includes a Bax inhibitor compound described herein and a therapeutic agent as part of a particular treatment regimen, and that is intended to provide a beneficial effect from the co-action of these therapeutic agents.

[0154] The administration of these therapeutic agents in combination is typically carried out over a predetermined period of time (usually minutes, hours, days, or weeks, depending on the combination selected). "Combination therapy" is intended to encompass both sequential administration of these therapeutic agents, i.e., administration of each therapeutic agent at different times, as well as substantially simultaneous administration of these therapeutic agents, or at least two of the therapeutic agents. Substantially simultaneous administration can be achieved, for example, by administering to the subject a single capsule containing a fixed ratio of each therapeutic agent, or multiple single capsules for each therapeutic agent. Sequential or substantially simultaneous administration of each therapeutic agent can be carried out by any suitable route, including, but not limited to, oral, intravenous, intramuscular, and direct absorption through mucosal tissue. The therapeutic agents can be administered by the same or different routes. For example, the first therapeutic agent of the selected combination can be administered by intravenous injection, while the other therapeutic agents of the combination can be administered orally. Alternatively, for example, all therapeutic agents can be administered orally, or all therapeutic agents can be administered by intravenous injection. The order in which the therapeutic agents are administered is not narrowly important. "Combination therapy" can also include the administration of such therapeutic agents in further combination with other biologically active ingredients (such as, but not limited to, a second therapeutic agent and a different therapeutic agent) and non-drug therapies (such as, but not limited to, surgery or radiation therapy). When the combination therapy further includes radiation therapy, the radiation therapy can be performed for any appropriate period of time, as long as a beneficial effect is achieved from the combination of the therapeutic agent and the radiation therapy. For example, in appropriate cases, the beneficial effect can still be achieved even if the radiation therapy is temporarily removed from the administration of the therapeutic agent, perhaps for several days or weeks.

[0155] The phrase "adjuvant therapy" encompasses treatment of a subject with an agent that reduces or avoids side effects associated with the combination therapies of the present invention, including, but not limited to, those agents that reduce the toxic effects of anti-cancer agents, e.g., bone resorption inhibitors, cardioprotective agents, prevent or reduce the incidence of nausea and vomiting associated with chemotherapy, radiation therapy, or surgery, or reduce the incidence of infections associated with the administration of myelosuppressive anti-cancer agents.

[0156] Apoptotic diseases treated by the combination therapy can include proliferative diseases such as neoplastic disorders (e.g., leukemia) and cancer. In addition to being useful for human therapy, the combination therapy is also useful for veterinary treatment of companion animals, exotic animals, and farm animals, including rodents, horses, dogs, and cats.

[0157] In another embodiment of the present invention, the therapeutic agent administered in combination therapy with a Bax inhibitory compound or pharmaceutical composition thereof described herein may include at least one antiproliferative agent selected from the group consisting of chemotherapeutic agents, antimetabolites, antitumorigenic agents, antimitotic agents, antivirals, antineoplastic agents, immunotherapeutic agents, and radiotherapeutic agents.

[0158] Other embodiments described herein relate to methods for preserving tissues and organs for transfusion or transplantation. In some embodiments, cells, tissues, or organs can be preserved in and / or contacted with a composition comprising a Bax inhibitory compound described herein. An effective amount of a Bax inhibitory compound is an amount effective to reduce Bax-mediated apoptosis of a cell, tissue, or organ of interest. In some embodiments, the composition for storing cells or organs can comprise an effective amount of a Bax inhibitory compound and an organ preservation solution.

[0159] Typically, tissues or organs are isolated from their normal source of nutrition, e.g., the blood circulation of living animals or humans. Organ preservation solutions rely on contacting, storing, and / or perfusing with a supportive preservation solution designed to provide pH buffering, osmotic balance, and / or some minimal nutritional support, e.g., in the form of glucose and a limited set of other basic nutrients. This method is usually combined with reducing the organ temperature to just above the freezing point of water. This is intended to reduce the metabolic rate of the organ tissue, slowing nutrient consumption and waste product production. Thus, in some embodiments, pharmaceutical compositions containing the Bax inhibitor compounds described herein can be used in the hypothermic range commonly used in the art, which can range from below 20°C to about 4°C. These art-known preservation solutions include, for example, isotonic saline solutions, which may contain various proportions of salts, sugars, osmotic agents, local anesthetics, buffering agents, and other agents such as those described, by way of example only, in U.S. Pat. No. 5,432,053 to Berdyaev et al., U.S. Pat. Nos. 4,798,824, 4,879,283, and 4,873,230 to Belzer et al., U.S. Pat. No. 5,405,742 to Taylor et al., U.S. Pat. No. 5,565,317 to Dohi et al., and U.S. Pat. Nos. 5,370,989 and 5,552,267 to Stern et al.

[0160] As used herein, the term "organ" encompasses both solid organs, e.g., kidney, heart, liver, lung, pancreas, and functional portions of organs, e.g., portions of skin, portions of arteries, and transplantable lobes of liver, kidney, lung, and other organs. The term "tissue," as used herein, refers to aggregated forms, e.g., small portions of organs, as well as dispersed cells, e.g., cells dispersed, isolated, and / or expanded from myocardium, liver, or kidney, and, unless otherwise specified, includes bone marrow cells and progeny, blood-derived stem cells and progeny, and various other blood elements known in the art.

[0161] Other embodiments described herein relate to the infusion or temporary circulation of Bax inhibitor compounds described herein to support local or systemic circulation or perfusion in organs or tissues that have been suddenly deprived of normal blood circulation caused by trauma, for example, to support a partially amputated limb or similar condition until surgical repair of the damaged vasculature can be achieved.

[0162] Symptomatic conditions, traumatic injuries, chronic conditions, medical interventions, or other conditions that cause or are associated with tissue damage and the need for tissue repair, and are therefore suitable for treatment or mitigation using the methods described herein, include acute coronary syndrome, acute lung injury (ALI), acute myocardial infarction (AMI), acute respiratory distress syndrome (ARDS), arterial occlusive disease, arteriosclerosis, articular cartilage defects, sterile systemic inflammation, atherosclerotic cardiovascular disease, autoimmune diseases, bone fractures, fractures, Cerebral edema, cerebral hypoperfusion, Buerger's disease, burns, cancer, cardiovascular disease, cartilage damage, cerebral infarction, cerebral ischemia, stroke, cerebrovascular disease, chemotherapy-induced neuropathy, chronic infection, chronic mesenteric ischemia, claudication, congestive heart failure, connective tissue injury, contusion, coronary artery disease (CAD), critical limb ischemia (CLI), Crohn's disease, deep vein thrombosis, deep wounds, delayed ulcer healing, delayed wound healing, diabetes (type I and type II), diabetes, diabetic neuropathy, diabetes-induced ischemia, disseminated intravascular coagulation (DIC) IC), embolic cerebral ischemia, graft-versus-host disease, frostbite, hereditary hemorrhagic telangiectasia, ischemic vascular disease, hyperoxic injury, hypoxia, inflammation, inflammatory bowel disease, inflammatory disease, injured tendon, intermittent claudication, intestinal ischemia, ischemia, ischemic brain disease, ischemic heart disease, ischemic peripheral vascular disease, ischemic placenta, ischemic kidney disease, ischemic vascular disease, ischemic reperfusion injury, laceration, left main coronary artery disease, limb ischemia, lower limb ischemia, myocardial infarction, myocardial ischemia, organ ischemia, osteoarthritis, osteoporosis, osteosarcoma, Parkinson's disease, peripheral arterial disease ( These conditions include, but are not limited to, peripheral arterial disease (PAD), peripheral ischemia, peripheral neuropathy, peripheral vascular disease, pre-cancer, pulmonary edema, pulmonary embolism, remodeling disorders, renal ischemia, retinal ischemia, retinopathy, sepsis, skin ulcers, solid organ transplant, spinal cord injury, stroke, subchondral bone cyst, thrombosis, thrombotic cerebral ischemia, tissue ischemia, transient ischemic attack (TIA), traumatic brain injury, ulcerative colitis, vascular disease of the kidney, vascular inflammatory conditions, von Hippel-Lindau syndrome, and wounds to tissues or organs.

[0163] Other illustrative examples of genetic disorders, symptomatic conditions, traumatic injuries, chronic conditions, medical interventions, or other conditions that cause or are associated with tissue damage and the need for tissue repair amenable to treatment or mitigation using Bax inhibitor compounds include ischemia resulting from surgery, chemotherapy, radiation therapy, or cell, tissue, or organ transplantation or grafting.

[0164] In various embodiments, the Bax inhibitory compounds described herein can be used to treat ischemia, such as cerebrovascular ischemia, myocardial ischemia, limb ischemia (CLI), myocardial ischemia (particularly chronic myocardial ischemia), ischemic cardiomyopathy, cerebrovascular ischemia, renal ischemia, pulmonary ischemia, and intestinal ischemia.

[0165] In some embodiments, ischemia is a condition caused by acute coronary syndrome, acute lung injury (ALI), acute myocardial infarction (AMI), acute respiratory distress syndrome (ARDS), arterial occlusive disease, arteriosclerosis, articular cartilage defects, sterile systemic inflammation, atherosclerotic cardiovascular disease, autoimmune disease, bone fracture, fracture, cerebral edema, cerebral hypoperfusion, Buerger's disease, burns, cancer, cardiovascular disease, cartilage damage, cerebral infarction, cerebral ischemia, stroke, cerebrovascular disease, chemotherapy-induced nephropathy, or other conditions. Neuropathy, chronic infection, chronic mesenteric ischemia, claudication, congestive heart failure, connective tissue injury, contusion, coronary artery disease (CAD), critical limb ischemia (CLI), Crohn's disease, deep vein thrombosis, deep wounds, delayed ulcer healing, delayed wound healing, diabetes mellitus (types I and II), diabetic neuropathy, diabetes-induced ischemia, disseminated intravascular coagulation (DIC), embolic cerebral ischemia, graft-versus-host disease, hereditary hemorrhagic telangiectasia, ischemic vascular disease, hypertension, Oxygen injury, hypoxia, inflammation, inflammatory bowel disease, inflammatory disease, injured tendon, intermittent claudication, intestinal ischemia, ischemia, ischemic brain disease, ischemic heart disease, ischemic peripheral vascular disease, ischemic placenta, ischemic kidney disease, ischemic vascular disease, ischemic reperfusion injury, laceration, left main coronary artery disease, limb ischemia, lower limb ischemia, myocardial infarction, myocardial ischemia, organ ischemia, osteoarthritis, osteoporosis, osteosarcoma, Parkinson's disease, peripheral arterial disease (PAD), peripheral arterial disease, peripheral ischemia, peripheral neuropathies associated with at least one of the following conditions: pulmonary edema, peripheral vascular disease, pre-cancer, pulmonary edema, pulmonary embolism, remodeling disorders, renal ischemia, retinal ischemia, retinopathy, sepsis, skin ulcer, solid organ transplant, spinal cord injury, stroke, subchondral bone cyst, thrombosis, thrombotic cerebral ischemia, tissue ischemia, transient ischemic attack (TIA), traumatic brain injury, ulcerative colitis, vascular disease of the kidney, vascular inflammatory conditions, von Hippel-Lindau syndrome, and wounds to tissues or organs.

[0166] In some embodiments, a Bax inhibitory compound described herein can be administered to a preparation of hematopoietic stem cells, such as peripheral blood hematopoietic stem cells or umbilical cord blood stem cells, in a subject to increase the suitability of the stem cell preparation as a donor graft or to reduce the number of units of umbilical cord blood required for transplantation.

[0167] In some embodiments, hematopoietic stem cells can be administered or contacted ex vivo with one or more Bax inhibitory compounds described herein to provide a therapeutic composition. In one embodiment, the therapeutic composition comprises a population of hematopoietic stem cells treated ex vivo with one or more of the Bax inhibitory compounds described herein. In certain embodiments, the therapeutic composition comprising enhanced HSPCs is whole bone marrow, umbilical cord blood, or mobilized peripheral blood.

[0168] Preparations of hematopoietic stem cells administered with one or more of the Bax inhibitory compounds described herein and / or hematopoietic stem cells and therapeutic compositions comprising one or more Bax inhibitory compounds described herein can be used to improve hematopoietic stem cell transplantation, to treat ischemia or ischemic damaged tissue, to reduce further damage to ischemic tissue and / or to repair damage to ischemic tissue by cell mobilization, to improve angiogenesis in ischemic tissue, to improve tissue regeneration at the ischemic site, to reduce necrosis or apoptosis of ischemic tissue, and / or to increase cell viability at the ischemic site. In certain embodiments, preparations of hematopoietic stem cells treated with a Bax inhibitory compound and / or therapeutic compositions of a Bax inhibitory compound and hematopoietic stem cells are useful in subjects in need of hematopoietic reconstitution, such as subjects undergoing or scheduled to undergo myeloablative therapy.

[0169] Subjects who can be treated with the Bax inhibitory compound-treated hematopoietic stem cell preparations and / or the Bax inhibitory compound and hematopoietic stem cell therapeutic compositions can include subjects with or diagnosed with various types of leukemia, anemia, lymphoma, myeloma, immunodeficiency disorders, and solid tumors. Subjects also include humans who are candidates for stem cell or bone marrow transplants, such as during a course of treatment for a malignant disease or a component of gene therapy. Subjects can also include individuals or animals donating stem cells or bone marrow for allogeneic transplants. In certain embodiments, subjects may be undergoing myeloablative radiation therapy or chemotherapy or experiencing severe radiation or chemical insults that result in myeloablative therapy. In certain embodiments, subjects may be undergoing radiation therapy or chemotherapy, such as during various cancer treatments. Typical subjects include animals that exhibit abnormal amounts (less than or greater than those of "normal" or "healthy" subjects) of one or more physiological activities that can be modulated by drugs or stem cell or bone marrow transplants.

[0170] Subjects that can be treated with the Bax inhibitory compound-treated hematopoietic stem cell preparations and / or Bax inhibitory compound and hematopoietic stem cell therapeutic compositions can also include subjects undergoing chemotherapy or radiation therapy for cancer, as well as subjects suffering from (e.g., afflicted with) a non-malignant hematologic disorder, particularly an immunodeficiency (e.g., SCID, Fanconi anemia, severe aplastic anemia, or congenital hemoglobinopathies, or metabolic storage diseases such as Hurler disease, Hunter disease, mannosidosis, among others) or cancer, particularly a hematologic malignancy such as acute leukemia, chronic leukemia (myeloid or lymphoid), lymphoma (Hodgkin's or non-Hodgkin's), multiple myeloma, myelodysplastic syndrome, or a non-hematologic cancer such as a solid tumor (including breast, ovarian, brain, prostate, lung, colon, skin, liver, or pancreatic cancer).

[0171] Subjects may also include those suffering from aplastic anemia, immune disorders (severe combined immunodeficiency syndrome or lupus), myelodysplasia, thalassemia, sickle cell disease, or Wiskott-Aldrich syndrome. In some embodiments, the subject suffers from a disorder that is the result of an undesirable side effect or complication of another primary treatment, such as radiation therapy, chemotherapy, or treatment with myelosuppressive drugs such as zidova ginseng, chloramphenicol, or gangliosides. Such disorders include neutropenia, anemia, thrombocytopenia, and immune dysfunction. Other subjects may have a disorder caused by an infection (e.g., a viral, bacterial, or fungal infection) that causes damage to stem or progenitor cells in the bone marrow.

[0172] In other embodiments, the Bax inhibitory compounds described herein can be administered to recipients of bone marrow transplants, hematopoietic stem cell transplants, or umbilical cord blood stem cell transplants to reduce the administration of other therapies or growth factors.

[0173] In some embodiments, the Bax inhibitor compounds described herein can be administered to a subject to enhance neutrophil recovery in individuals with neutropenia from diseases including, but not limited to, after bone marrow transplantation, after umbilical cord blood transplantation, after hematopoietic stem cell transplantation, after conventional chemotherapy, after radiation therapy, and after neutropenia from diseases including, but not limited to, aplastic anemia, myelodysplasia, myelofibrosis, neutropenia due to other bone marrow diseases, drug-induced neutropenia, immune neutropenia, idiopathic neutropenia, and infection with viruses including, but not limited to, HIV, CMV, and parvovirus.

[0174] In other embodiments, the Bax inhibitor compounds described herein can be administered to a subject to enhance platelet recovery in individuals with thrombocytopenia from diseases including, but not limited to, after bone marrow transplantation, after umbilical cord blood transplantation, after hematopoietic stem cell transplantation, after conventional chemotherapy, after radiation therapy, and after thrombocytopenia due to diseases including, but not limited to, aplastic anemia, myelodysplasia, myelofibrosis, thrombocytopenia due to other bone marrow diseases, drug-induced thrombocytopenia, immune thrombocytopenia, idiopathic thrombocytopenia, and infection with viruses including, but not limited to, HIV, CMV, and parvovirus.

[0175] In yet other embodiments, the Bax inhibitor compounds described herein can be administered to a subject to enhance red blood cell recovery in individuals with anemia from disease, including but not limited to, after bone marrow transplantation, after umbilical cord blood transplantation, after hematopoietic stem cell transplantation, after conventional chemotherapy, after radiation therapy, and after infection with viruses, including but not limited to, aplastic anemia, myelodysplasia, myelofibrosis, anemia due to other bone marrow diseases, drug-induced anemia, immune-mediated anemia, anemia of chronic disease, idiopathic anemia, and infection with viruses, including but not limited to, HIV, CMV, and parvovirus.

[0176] In some embodiments, the Bax inhibitor compounds described herein can be administered to a subject to enhance the number of bone marrow stem cells following bone marrow transplantation, following umbilical cord blood transplantation, following hematopoietic stem cell transplantation, following conventional chemotherapy, following radiation therapy, in individuals with other bone marrow diseases, in individuals with cytopenias following viral infections, and in individuals with cytopenias.

[0177] In further embodiments, the Bax inhibitory compounds described herein can be administered to a subject or a tissue transplant in a subject to reduce transplant rejection, enhance transplant survival, enhance transplant survival after treatment of the subject or the subject's bone marrow with radiation therapy, chemotherapy, or immunosuppressive therapy, confer resistance to the toxic or lethal effects of exposure to radiation, confer resistance to the toxic effects of Cytoxan, the toxic effects of fludarabine, the toxic effects of chemotherapy, or the toxic effects of immunosuppressive therapy, reduce infections, and / or reduce pulmonary toxicity from radiation.

[0178] In other embodiments, the Bax inhibitory compounds described herein can be administered to recipients of tissue stem cell transplants, including but not limited to transplants with hematopoietic stem cells, neural stem cells, mesenchymal stem cells, or stem cells from other tissues, to thereby promote tissue regeneration and repair after transplantation.

[0179] The Bax inhibitory compounds described herein can be provided in pharmaceutical or cosmetic compositions depending on the pathological or cosmetic condition or disorder to be treated. Pharmaceutical compositions containing the Bax inhibitory compounds described herein as active ingredients can be prepared by mixing the derivatives with a pharmaceutically acceptable carrier or excipient, or by diluting the Bax inhibitory compounds described herein with a diluent according to conventional methods. The pharmaceutical composition may further include fillers, anti-agglomerating agents, lubricants, lubricants, flavoring agents, emulsifiers, preservatives, etc. The pharmaceutical composition can be formulated into a suitable formulation according to methods known to those skilled in the art so as to provide immediate, controlled, or sustained release of the Bax inhibitory compounds described herein after administration to a mammal.

[0180] In some embodiments, the pharmaceutical composition can be formulated into a parenteral or oral dosage form. Solid dosage forms for oral administration can be prepared by adding excipients to the Bax inhibitor compound, optionally with binders, disintegrants, lubricants, colorants, and / or flavorings, and molding the resulting mixture into tablets, sugar-coated tablets, granules, powder, or capsules. The additives that can be added to the composition can be those commonly used in the art. For example, examples of excipients include lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, silicates, etc. Exemplary binders include water, ethanol, propanol, sweet syrup, sucrose solution, starch solution, gelatin solution, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropyl starch, methylcellulose, ethylcellulose, shellac, calcium phosphonate, and polypyrrolidone. Examples of disintegrants include dry starch, sodium alginate, agar powder, sodium bicarbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, and lactose.In addition, refined talc, stearic acid salts, sodium borate, and polyethylene glycol can be used as lubricants, and sucrose, spruce, citric acid, and tartaric acid can be used as flavoring agents.In some embodiments, the pharmaceutical composition can be made into an aerosol preparation (for example, they can be nebulized) that is administered via inhalation.

[0181] The Bax inhibitor compounds described herein can be incorporated into oral liquid dosage forms such as solutions, syrups, or elixirs according to conventional methods, by combining flavoring agents, buffers, stabilizers, etc. An example of a buffering agent can be sodium citrate. Examples of stabilizers include tragacanth, acacia, and gelatin.

[0182] In some embodiments, the Bax inhibitor compounds described herein can be incorporated into injection dosage forms, for example, for subcutaneous, intramuscular, or intravenous administration, by adding pH adjusters, buffers, stabilizers, relaxants, and local anesthetics. Examples of pH adjusters and buffers include sodium citrate, sodium acetate, and sodium phosphate. Examples of stabilizers include sodium metabisulfite, EDTA, thioglycolic acid, and thiolactic acid. Local anesthetics can be procaine HCl, lidocaine HCl, etc. Relaxants can be sodium chloride, glucose, etc.

[0183] In other embodiments, the Bax inhibitory compounds described herein can be incorporated into suppositories in accordance with conventional methods by adding thereto a pharmaceutically acceptable carrier known in the art, e.g., polyethylene glycol, lanolin, cocoa butter, or fatty acid triglycerides, optionally along with a surfactant such as Tween.

[0184] The pharmaceutical composition may be formulated into various dosage forms as discussed above and administered via various routes, including oral, inhalation, transdermal, subcutaneous, intravenous, or intramuscular routes. The dosage may be a pharmaceutically or therapeutically effective amount. A pharmaceutically effective amount may be the amount of a Bax inhibitor compound described herein that treats or inhibits cell death associated with a disease or disorder. The pharmaceutically effective amount of the compound is determined appropriately depending on the type and severity of the disease being treated, the age, sex, weight, and physical condition of the patient being treated, the route of administration, and the duration of treatment. Generally, the effective amount of the compound may range from about 1 to 1,000 mg for oral administration, about 0.1 to 500 mg for intravenous administration, and about 5 to 1,000 mg for rectal administration. Generally, the daily dosage for an adult ranges from about 0.1 to 5,000 mg, preferably about 1,000 mg, but cannot be uniformly determined because it depends on the age, sex, weight, and physical condition of the patient being treated. The formulation may be administered once a day or several times a day in divided doses.

[0185] Cosmetic compositions containing the Bax inhibitor compounds described herein can include any substance or preparation intended to be in contact with various surfaces of the human body (epidermis, hair system, nails, lips, and external genitalia), or with the teeth or buccal mucosa, exclusively or primarily for the purposes of cleansing them, perfume them, modifying their appearance and / or correcting their body odor, and / or protecting or maintaining them in good condition.

[0186] The cosmetic composition can comprise a cosmetically acceptable medium, which can be water or a mixture of water and at least one solvent selected from a hydrophilic organic solvent, a lipophilic organic solvent, an amphiphilic organic solvent, and mixtures thereof.

[0187] For topical application, the cosmetic composition can be administered in the form of an aqueous, alcoholic, aqueous-alcoholic, or oily solution or suspension, or in the form of a lotion or serum-type dispersion; in the form of an emulsion of liquid or semi-liquid consistency, or a paste obtained by dispersing a fatty phase in an aqueous phase (O / W) or vice versa (W / O) emulsion, or in the form of a loose or compressed powder used as is or incorporated into a physiologically acceptable medium; or in the form of microcapsules or microparticles, or in the form of vesicular dispersions of ionic and / or nonionic type. Thus, it can be in the form of a salve, tincture, emulsion, cream, ointment, powder, patch, impregnated pad, solution, emulsion or vesicular dispersion, lotion, aqueous or anhydrous gel, spray, suspension, shampoo, aerosol, or foam. It can be anhydrous or aqueous. It can also include solid preparations constituting soaps or cleansing cakes.

[0188] The cosmetic composition may include, in particular, hair care compositions, in particular shampoos, setting lotions, treatment lotions, styling creams or gels, restructuring lotions for hair, masks, etc. The cosmetic composition may be a cream, hair lotion, shampoo, or conditioner. These may be used in particular in treatments using application with or without rinsing, or in the form of a shampoo. Compositions in the form of foams, or in the form of sprays or aerosols containing propellants under pressure, are also contemplated. Thus, they may be in the form of lotions, serums, emulsions, creams, gels, salves, ointments, powders, balms, patches, impregnated pads, cakes, or foams.

[0189] In a known manner, the cosmetic composition may also contain adjuvants customary in the cosmetic field, such as hydrophilic or lipophilic gelling agents, hydrophilic or lipophilic additives, preservatives, antioxidants, solvents, fragrances, fillers, UV filters, odor absorbers, and dyes. The amounts of these various adjuvants are those conventionally used in the cosmetic field, for example, 0.1% to 20%, in particular 10% or less, of the total weight of the composition. Depending on their nature, these adjuvants can be incorporated into the fatty phase, the aqueous phase, and / or the lipid globules.

[0190] The following examples are included to demonstrate preferred embodiments of the invention. Those of skill in the art should understand that the techniques disclosed in the examples which follow represent techniques discovered by the inventors to function well in the practice of the invention, and can therefore be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, understand that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention. [Example]

[0191] The following examples describe the synthesis of novel Bax inhibitors. Example 1 [ka]

[0192] To a mixture of 1-(4-bromophenyl)ethanamine (100 mg, 422.77 μmol, 1 equiv., HCl) and TEA (171 mg, 1.69 mmol, 4 equiv.) in i-PrOH (2 mL) was added 4-chloroquinazoline (77 mg, 465.04 μmol, 1.1 equiv.), and the mixture was stirred at 80 °C for 4 h. The reaction was concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 2:1) to give N-[1-(4-bromophenyl)ethyl]quinazolin-4-amine (250 mg, 761.72 μmol, 90.09% yield, two batches in parallel) as a white solid. ESI [M+H] = 328.3 / 330.3. [ka]

[0193] N-[1-(4-Bromophenyl)ethyl]quinazolin-4-amine (100.00 mg, 304.69 μmol, 1 equiv.), 1H-1,2,4-triazole (42 mg, 609.37 μmol, 2 equiv.), CsCO (199 mg, 609.37 μmol, 2 equiv.), and CuI (12 mg, 60.94 μmol, 0.2 equiv.) were placed in a microwave tube in DMF (2 mL). The sealed tube was heated in a microwave at 150° C. for 10 hours. Water (20 mL) was added to the reaction mixture, which was then extracted with EtOAc (10 mL × 3). The organic phase was washed with brine (20 mL), dried over MgSO, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Kromasil 250 × 50 mm × 10 μm, mobile phase: [water (10 mM NH4HCO3)-ACN], B%: 10% to 40%, 10 min) to give N-[1-[4-(1,2,4-triazol-1-yl)phenyl]ethyl]quinazolin-4-amine (43.65 mg, 137.81 μmol, yield 45.23%, purity 99.882%) as a white solid.

[0194] 1 H NMR (400MHz, chloroform-d) δ 8.67(s, 1H), 8.56(s, 1H), 8.12(s, 1H), 7.89(d, J=8.6Hz, 1H), 7.84-7.76 (m, 2H), 7.72-7.66(m, 2H), 7.64-7.57(m, 2H), 7.57-7.50(m, 1H), 5.90(br d, J=6.4Hz, 1H), 5.70 (quintet, J=6.9Hz, 1H), 1.76 (d, J=7.0Hz, 3H). ESI[M+H]=317.1. Example 2 [ka]

[0195] A mixture of (1S)-1-(4-bromophenyl)ethanamine (6 g, 29.99 mmol, 4.32 mL, 1 equiv.), 4-chlorothieno[2,3-d]pyrimidine (5.88 g, 34.49 mmol, 1.15 equiv.), and TEA (6.07 g, 59.98 mmol, 8.35 mL, 2 equiv.) in i-PrOH (200 mL) was stirred at 80 °C for 12 h. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO, petroleum ether:THF = 20:1 to 5:1) to give N-[(1S)-1-(4-bromophenyl)ethyl]thieno[2,3-d]pyrimidin-4-amine (7.8 g, 23.34 mmol, 77.82% yield) as a white solid.

[0196] 1 H NMR (400MHz, chloroform-d) δ 8.50(s, 1H), 7.53-7.46(m, 2H), 7.36-7.30(m, 3H), 7.18(d, J=6.0Hz, 1H), 5.55(quintet, J=7.0Hz, 1H), 5.36(br d, J=7.0Hz, 1H), 1.66(d, J=6.8Hz, 3H). ESI[M+H]=334.2 / 336.2. [ka]

[0197] A mixture of N-[(1S)-1-(4-bromophenyl)ethyl]thieno[2,3-d]pyrimidin-4-amine (1 g, 2.99 mmol, 1 equiv), NaN (233 mg, 3.59 mmol, 1.2 equiv), CuI (57 mg, 299.19 µmol, 0.1 equiv), and N,N-dimethylethane-1,2-diamine (53 mg, 598.38 µmol, 64.40 µL, 0.2 equiv) in EtOH (10 mL) and HO (5 mL) was stirred at 100 °C for 12 h under N. The reaction was added saturated aqueous NaHCO (20 mL) and extracted with EtOAc (10 mL × 3). The organic layer was dried over MgSO and blown dry with N to give N-[(1S)-1-(4-azidophenyl)ethyl]thieno[2,3-d]pyrimidin-4-amine (1 g, crude), which was used in the next step without further purification. ESI [M+H] = 297.3. [ka]

[0198] A mixture of N-[(1S)-1-(4-azidophenyl)ethyl]thieno[2,3-d]pyrimidin-4-amine (100 mg, 337.44 μmol, 1 equiv.), 2-cyclobutylethynyl(trimethyl)silane (62 mg, 404.93 μmol, 1.2 equiv.), CuSO 5HO (17 mg, 67.49 μmol, 0.2 equiv.), and sodium ascorbate (13 mg, 67.49 μmol, 0.2 equiv.) in t-BuOH (2 mL) and HO (2 mL) was stirred at 25 °C for 12 h. Water (10 mL) was added to the mixture, which was then extracted with EtOAc (10 mL × 3). The organic phase was washed with brine (10 mL), dried over MgSO, and concentrated in vacuo. The residue was purified by preparative HPLC (column: HUAPU C8 Extreme BDS 150 × 30 5u, mobile phase: [water (10 mM NH4HCO3)-ACN], B%: 40%-60%, 10 min) to give N-[(1S)-1-[4-(4-cyclobutyltriazol-1-yl)phenyl]ethyl]thieno[2,3-d]pyrimidin-4-amine (45.06 mg, 116.48 µmol, yield 34.52%, purity 97.322%) as a white solid.

[0199] 1 H NMR (400MHz, chloroform-d) δ 8.50(s, 1H), 7.74-7.67(m, 3H), 7.57(d, J=8.4Hz, 2H), 7.33(d, J=6.0Hz, 1H), 7.20(d, J=6.0Hz, 1H), 5.64(quintet, J=6.9Hz, 1H), 5.37(br d. ESI[M+H]=377.1. Example 3 [ka]

[0200] To a solution of oxetane-3-carbaldehyde (0.3 g, 3.48 mmol, 1 equiv.) in MeOH (3 mL) were added 1-diazo-1-dimethoxyphosphoryl-propan-2-one (1 g, 5.23 mmol, 1.5 equiv.) and K2CO3 (963 mg, 6.97 mmol, 2 equiv.) at 0 °C. The mixture was then stirred at 25 °C for 4 h. After filtration, water (3 mL) and MTBE (1 mL × 2) were added to the filtrate. The crude product, 3-ethynyloxetane (289 mg, crude) in 3 mL of HO, was used in the next step without further purification. [ka]

[0201] A mixture of N-[(1S)-1-(4-azidophenyl)ethyl]thieno[2,3-d]pyrimidin-4-amine (100 mg, 337.44 μmol, 1 equiv.), 3-ethynyloxetane (139 mg, 1.69 mmol, 5 equiv.) (solution in 3 mL of HO), CuSO 5HO (17 mg, 67.49 μmol, 0.2 equiv.), and sodium ascorbate (13 mg, 67.49 μmol, 0.2 equiv.) in t-BuOH (3 mL) was stirred at 25 °C for 12 h. Water (10 mL) was added to the mixture, which was then extracted with EtOAc (10 mL × 3). The organic phase was washed with brine (10 mL), dried over MgSO, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Kromasil 250 × 50 mm × 10 μm, mobile phase: [water (10 mM NH4HCO3)-ACN], B%: 20% to 50%, 10 min) to give N-[(1S)-1-[4-[4-(oxetan-3-yl)triazol-1-yl]phenyl]ethyl]thieno[2,3-d]pyrimidin-4-amine (90.64 mg, 234.94 μmol, yield 69.62%, purity 98.093%) as a white solid.

[0202] 1H NMR (400MHz, chloroform-d) δ 8.51(br s, 1H), 7.95(s, 1H), 7.73(d, J=8.6Hz, 2H), 7.61(d, J=8.4Hz, 2H), 7.36(d, J=6.0Hz, 1H), 7.23(d, J=5.9Hz, 1H), 5.66(quintet, J=7.0Hz, 1H), 5.41(br d, J=7.5Hz, 1H), 5.11(dd, J=5.9, 8.4Hz, 2H), 4.92(t, J=6.4Hz, 2H), 4.59-4.46(m, 1H), 1.73(d, J=7.0Hz, 3H). ESI[M+H]=379.1. Example 4 [ka]

[0203] N-[(1S)-1-(4-bromophenyl)ethyl]thieno[2,3-d]pyrimidin-4-amine (0.5 g, 1.50 mmol, 1 equiv.), Zn(CN) (193 mg, 1.65 mmol, 104.45 uL, 1.1 equiv.), and Pd(PPh) (173 mg, 149.60 umol, 74.80 uL, 0.1 equiv.) were placed in a microwave tube in NMP (10 mL) under N. The sealed tube was heated in a microwave at 100 °C for 1 h. Water (20 mL) was added to the reaction and extracted with EtOAc (10 mL × 3). The organic phase was washed with brine (20 mL × 2), dried over MgSO, and concentrated in vacuo. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 20 / 1 to 3:1) to give 4-[(1S)-1-(thieno[2,3-d]pyrimidin-4-ylamino)ethyl]benzonitrile (0.4 g, 1.43 mmol, 95.38% yield) as a yellow oil. ESI [M+H] = 281.1. [ka]

[0204] A mixture of 4-[(1S)-1-(thieno[2,3-d]pyrimidin-4-ylamino)ethyl]benzonitrile (0.4 g, 1.43 mmol, 1 equiv.) in TBAF (2 mL, 1 M) and TMSN3 (0.4 mL) was stirred at 80 °C for 16 h. The reaction was concentrated in vacuo. The residue was purified by reverse-phase HPLC (0.1% TFA) to give N-[(1S)-1-[4-(2H-tetrazol-5-yl)phenyl]ethyl]thieno[2,3-d]pyrimidin-4-amine (0.39 g, 1.21 mmol, 84.53% yield) as a yellow oil. ESI [M+H] = 324.2. [ka]

[0205] To a mixture of N-[(1S)-1-[4-(2H-tetrazol-5-yl)phenyl]ethyl]thieno[2,3-d]pyrimidin-4-amine (200 mg, 618.48 μmol, 1 equiv.), cyclopropylboronic acid (106 mg, 1.24 mmol, 2 equiv.), Cu(OAc) (112 mg, 618.48 μmol, 1 equiv.), and DMAP (227 mg, 1.86 mmol, 3 equiv.) in dioxane (4 mL), pyridine (59 mg, 742.17 μmol, 1.2 equiv.) was added, and the mixture was stirred at 100° C. under O for 12 h. Water (10 mL) was added to the reaction mixture, which was then extracted with EtOAc (5 mL × 3). The organic layer was dried over MgSO and concentrated in vacuo. The residue was purified twice by preparative HPLC and then again by SFC (column: DAICEL CHIRALCEL OJ (250 mm × 30 mm, 10 μm), mobile phase: [0.1% NH₃H₂O MEOH], B%: 40% to 40%, 15 min) to give N-[(1S)-1-[4-(2-cyclopropyltetrazol-5-yl)phenyl]ethyl]thieno[2,3-d]pyrimidin-4-amine (18.3 mg, 49.60 μmol, yield 8.02%, purity 98.504%) as a white solid.

[0206] 1H NMR (400MHz, methanol-d4) δ 8.26(s, 1H), 8.02(d, J=8.4Hz, 2H), 7.66(d, J=6.0Hz, 1H), 7.56(d, J=8.4Hz, 2H), 7.47(d, J=6.0Hz, 1H), 5.5 9(q, J=7.1Hz, 1H), 4.36(tt, J=3.7, 7.5Hz, 1H), 1.66(d, J=7.1Hz, 3H), 1.49-1.42(m, 2H), 1.33-1.24(m, 2H). ESI[M+H]=364.1. Example 5 [ka]

[0207] N-[(1S)-1-(4-bromophenyl)ethyl]thieno[2,3-d]pyrimidin-4-amine (60 mg, 179.52 μmol, 1 equiv.), 4-cyclopropyl-1H-imidazole (29 mg, 269.27 μmol, 1.5 equiv.), CuI (7 mg, 35.90 μmol, 0.2 equiv.), and CsCO (117 mg, 359.03 μmol, 2 equiv.) were placed in a microwave tube in DMF (1 mL). The sealed tube was heated at 150° C. for 10 h in a microwave oven under N. Water (5 mL) was added to the reaction mixture, which was then extracted with EtOAc (5 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Xtimate C18 150 × 25 mm × 5 μm, mobile phase: [water (10 mM NH4HCO3)-ACN], B%: 25% to 50%, 10 min) to give N-[(1S)-1-[4-(4-cyclopropylimidazol-1-yl)phenyl]ethyl]thieno[2,3-d]pyrimidin-4-amine (13.85 mg, 36.76 μmol, yield 20.48%, purity 95.938%) as a white solid.

[0208] 1H NMR (400MHz, methanol-d4) δ 8.28(s, 1H), 7.94(d, J=1.2Hz, 1H), 7.67(d, J=6.0Hz, 1H), 7.57(d, J=8.6Hz, 2H), 7.52-7.46(m, 3H), 7.26(s , 1H), 5.60(q, J=7.0Hz, 1H), 1.94-1.82(m, 1H), 1.68(d, J=7.0Hz, 3H), 0.91-0.83(m, 2H), 0.77-0.69(m, 2H). ESI[M+H]=362.1. Example 6 [ka]

[0209] To a solution of 4-iodo-1H-imidazole (1 g, 5.16 mmol, 1 equiv.) in DCE (60 mL) was added cyclopropylboronic acid (1.33 g, 15.47 mmol, 3 equiv.) and Na2CO3 (1.28 g, 15.47 mmol, 3 equiv.). The mixture was then heated to 70 °C, and 2-(2-pyridyl)pyridine (966 mg, 6.19 mmol, 1.2 equiv.) and Cu(OAC)2 (1.12 g, 6.19 mmol, 1.2 equiv.) were added, and the mixture was stirred at 70 °C for 12 h. Water (100 mL) was added to the reaction mixture, which was then extracted with DCM (30 mL × 3). The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / THF=10 / 1 to 3:1) to give 1 g of a mixture of regioisomers, and then 400 mg of the mixture of regioisomers was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate=1:1) to give 1-cyclopropyl-4-iodo-imidazole (330 mg) and 1-cyclopropyl-5-iodo-imidazole (40 mg) as a yellow oil.

[0210] 2A: 1 H NMR (400 MHz, chloroform-d) δ 7.45 (d, J = 1.0 Hz, 1H), 7.07 (d, J = 1.3 Hz, 1H), 3.40-3.31 (m, 1H), 1.04-0.92 (m, 4H).

[0211] 2B: 1 H NMR (400 MHz, chloroform-d) δ 7.55 (s, 1H), 7.04 (s, 1H), 3.07 (tt, J = 3.7, 7.2 Hz, 1H), 1.10-1.03 (m, 2H), 0.96-0.88 (m, 2H). [ka]

[0212] A mixture of N-[(1S)-1-(4-bromophenyl)ethyl]thieno[2,3-d]pyrimidin-4-amine (500 mg, 1.50 mmol, 1 equiv.), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (418 mg, 1.65 mmol, 1.1 equiv.), KOAc (440 mg, 4.49 mmol, 3 equiv.), and Pd(dppf)Cl (109 mg, 149.60 mmol, 0.1 equiv.) in dioxane (10 mL) was degassed and purged with N three times. The mixture was then stirred under N at 80 °C for 4 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 1 / 0 to 5:1) to give N-[(1S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]thieno[2,3-d]pyrimidin-4-amine (600 mg, crude) as a colorless oil. [ka]

[0213] A mixture of N-[(1S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]thieno[2,3-d]pyrimidin-4-amine (80 mg, 209.81 μmol, 1 equiv.), 1-cyclopropyl-4-iodo-imidazole (98 mg, 419.62 μmol, 2 equiv.), KPO (0.5 M, 839.24 μL, 2 equiv.), [2-(2-aminophenyl)phenyl]chloro-palladium:bis(1-adamantyl)-butyl-phosphane (14 mg, 20.98 μmol, 0.1 equiv.) in EtOH (3 mL) was stirred at 80° C. under N for 12 hours. The reaction was concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge 150 × 25 5u, mobile phase: [water (10 mM NH4HCO3)-ACN], B%: 25% to 55%, 10 min) to give N-[(1S)-1-[4-(1-cyclopropylimidazol-4-yl)phenyl]ethyl]thieno[2,3-d]pyrimidin-4-amine (33.17 mg, 90.88 μmol, yield 43.31%, purity 99.033%) as a white solid.

[0214] 1 H NMR (400MHz, chloroform-d) δ 8.54(s, 1H), 7.76(d, J=8.3Hz, 2H), 7.60(d, J=0.7Hz, 1H), 7.44(d, J=8.3Hz, 2H), 7.31 (s, 1H), 7.28(d, J=1.2Hz, 1H), 7.17(d, J=6.0Hz, 1H), 5.62(quintet, J=7.0Hz, 1H), 5.41(br d, J=7.7Hz, 1H), 3.44-3.36(m, 1H), 1.70(d, J=6.7Hz, 3H), 1.09-1.01(m, 4H). ESI[M+H]=362.1. Example 7 [ka]

[0215] N-[(1S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]thieno[2,3-d]pyrimidin-4-amine (60 mg, 157.36 μmol, 1 equiv), 1-cyclopropyl-5-iodo-imidazole (39 mg, 165.22 μmol, 1.05 equiv), KPO (0.5 M, 629.43 μL, 2 equiv), [2-(2-aminophenyl)phenyl]chloro-palladium:bis(1-adamantyl)-butyl-phosphane (11 mg, 15.74 μmol, 0.1 equiv) in EtOH (3 mL) was stirred at 80° C. under N for 12 hours. The reaction was concentrated in vacuo. The residue was purified by preparative HPLC (column: HUAPU C8 Extreme BDS 150 × 30 5u, mobile phase: [water (10 mM NH4HCO3)-ACN], B%: 40%-60%, 10 min) to give N-[(1S)-1-[4-(3-cyclopropylimidazol-4-yl)phenyl]ethyl]thieno[2,3-d]pyrimidin-4-amine (29.62 mg, 80.10 μmol, yield 50.90%, purity 97.745%) as a white solid.

[0216] 1 H NMR (400MHz, chloroform-d) δ 8.45(s, 1H), 7.52-7.44(m, 3H), 7.43-7.38(m, 2H), 7.24(d, J=6.0Hz, 1H), 7.10(d, J=6.0Hz, 1H), 7.01(s, 1H), 5.58(quintet, J=7.0Hz, 1H), 5.28(br d, J=7.3Hz, 1H), 3.28(tt, J=3.7, 7.1Hz, 1H), 1.64(d, J=6.8Hz, 3H), 0.94-0.88(m, 2H), 0.86-0.79(m, 2H). ESI[M+H]=362.1. Example 8 [ka]

[0217] To a mixture of azidomethylbenzene (0.3 g, 2.25 mmol, 1 equiv.) and ethynylcyclopropane (298 mg, 4.51 mmol, 2 equiv.) in t-BuOH (3 mL) and HO (3 mL), sodium ascorbate (89 mg, 450.62 µmol, 0.2 equiv.) and CuSO 5HO (113 mg, 450.62 µmol, 0.2 equiv.) were added, and the mixture was stirred at 25 °C for 12 h. Water (10 mL) was added to the reaction, and the mixture was extracted with EtOAc (5 mL × 3). The organic phase was washed with brine (10 mL), dried over MgSO, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 5 / 1) to give 1-benzyl-4-cyclopropyl-triazole (430 mg, 2.16 mmol, yield 95.78%) as a white solid.

[0218] 1 H NMR (400 MHz, chloroform-d) δ 7.34-7.26 (m, 3H), 7.19-7.15 (m, 2H), 7.06 (s, 1H), 5.39 (s, 2H), 1.84 (tt, J = 5.0, 8.4 Hz, 1H), 0.89-0.81 (m, 2H), 0.77-0.71 (m, 2H). ESI [M+H] = 200.3. [ka]

[0219] To a solution of 1-benzyl-4-cyclopropyl-triazole (360 mg, 1.81 mmol, 1 equiv.) in MeOH (10 mL) was added Pd / C (20 mg, 10% purity) under N2 atmosphere. The suspension was degassed and purged with H2 three times. The mixture was stirred under H2 (30 Psi) at 25 °C for 12 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give 4-cyclopropyl-1H-triazole (150 mg, 1.37 mmol, 76.08% yield), which was used in the next step without further purification. ESI [M+H] = 110.1. [ka]

[0220] To a mixture of Pd(dba) (27 mg, 29.92 µmol, 0.1 equiv.) and di-tert-butyl-[2,3,4,5-tetramethyl-6-(2,4,6-triisopropylphenyl)phenyl]phosphane (29 mg, 59.84 µmol, 0.2 equiv.) in an oven-dried 8 mL vial under N, toluene (1 mL) was added to the vial via syringe. The resulting mixture was stirred at 120 °C for 3 min. The premixed catalyst solution was then added to a mixture of N-[(1S)-1-(4-bromophenyl)ethyl]thieno[2,3-d]pyrimidin-4-amine (100 mg, 299.19 μmol, 1 equiv.), 4-cyclopropyl-1H-triazole (49 mg, 448.79 μmol, 1.5 equiv.), and KPO (127 mg, 598.38 μmol, 2 equiv.) in toluene (1 mL) under N. The mixture was stirred at 120 °C for 12 h. The reaction was concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge 150 × 25 5u, mobile phase: [water (10 mM NH4HCO3)-ACN], B%: 40%-70%, 10 min) to give N-[(1S)-1-[4-(4-cyclopropyltriazol-2-yl)phenyl]ethyl]thieno[2,3-d]pyrimidin-4-amine (99 mg, 273.42 μmol, 91.39% yield, 100% purity) as a white solid.

[0221] 1 H NMR (400MHz, chloroform-d) δ 8.50(s, 1H), 7.97(d, J=8.6Hz, 2H), 7.49(d, J=7.3Hz, 3H), 7.30(d, J=6.0Hz, 1H), 7.17(d, J=6.2Hz, 1H), 5.61(quintet, J=7.1Hz, 1H), 5.38(br d, J=7.5Hz, 1H), 2.07-1.96(m, 1H), 1.69(d, J=6.8Hz, 3H), 1.08-0.99(m, 2H), 0.91-0.85(m, 2H). ESI[M+H]=363.1. Example 9 [ka]

[0222] Cyclopropanecarbonitrile (500 mg, 7.45 mmol, 548.85 uL, 1 equiv.), hydroxylamine (591 mg, 8.94 mmol, 50% purity, 1.2 equiv.) in EtOH (2 mL) was stirred for 12 h at 80° C. The reaction mixture was concentrated under reduced pressure to give N′-hydroxycyclopropanecarboxamidine (820 mg, crude) as a colorless oil.

[0223] 1 H NMR (400MHz, DMSO-d6) δ 8.68(s, 1H), 5.37-5.02(m, 2H), 3.31(s, 1H), 0.65-0.59(m, 2H), 0.59-0.52(m, 2H). [ka]

[0224] To a solution of N-[(1S)-1-(4-bromophenyl)ethyl]thieno[2,3-d]pyrimidin-4-amine (0.3 g, 897.57 μmol, 1 equiv.) in MeOH (10 mL), TEA (454 mg, 4.49 mmol, 5 equiv.) and Pd(dppf)Cl (66 mg, 89.76 μmol, 0.1 equiv.) were added under a N atmosphere. The suspension was degassed and purged with CO three times. The mixture was stirred under CO (50 Psi) at 60 °C for 72 h. The reaction was concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether:ethyl acetate=2:1) ​​to give methyl 4-[(1S)-1-(thieno[2,3-d]pyrimidin-4-ylamino)ethyl]benzoate (230 mg, 733.95 μmol, 81.77% yield) as a yellow solid. ESI [M+H]=314.1. [ka]

[0225] To a solution of methyl 4-[(1S)-1-(thieno[2,3-d]pyrimidin-4-ylamino)ethyl]benzoate (230 mg, 733.95 μmol, 1 equiv.) in MeOH (3 mL) and HO (1 mL), LiOH·HO (62 mg, 1.47 mmol, 2 equiv.) was added, and the mixture was stirred at 25 °C for 5 h. The MeOH was removed, and the aqueous was extracted with EtOAc (10 mL × 1). The aqueous was adjusted to pH = 2 with 1 N HCl and extracted with EtOAc (5 mL × 5). The organic layer was dried over MgSO and concentrated in vacuo to give 4-[(1S)-1-(thieno[2,3-d]pyrimidin-4-ylamino)ethyl]benzoic acid (190 mg, 634.71 μmol, 86.48% yield) as a white solid. ESI [M+H] = 300.1 [ka]

[0226] To a solution of 4-[(1S)-1-(thieno[2,3-d]pyrimidin-4-ylamino)ethyl]benzoic acid (180 mg, 601.31 umol, 1 equiv) in DMF (3 mL) was added N'-hydroxycyclopropanecarboxamidine (120 mg, 1.20 mmol, 2 equiv), HOBt (114 mg, 841.83 umol, 1.4 equiv), NMM (184 mg, 1.80 mmol, 198.33 uL, 3 equiv), and EDCI (161 mg, 841.83 umol, 1.4 equiv) and the mixture was stirred at 25 °C for 12 h. The mixture was stirred at 80 °C for 12 h. The reaction was concentrated in vacuo. The residue was purified by preparative HPLC (column: Xtimate C18 150 × 25 mm × 5 μm, mobile phase: [water (10 mM NH4HCO3)-ACN], B%: 25% to 75%, 10 min) to give N-[(1S)-1-[4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl]ethyl]thieno[2,3-d]pyrimidin-4-amine (50.05 mg, 137.71 μmol, yield 22.90%, purity 100%) as a white solid.

[0227] 1H NMR (400MHz, chloroform-d) δ 8.49(s, 1H), 8.08(d, J=8.4Hz, 2H), 7.57(d, J=8.3Hz, 2H), 7.35(d, J=6.0Hz, 1H), 7.22(d, J=6.0Hz, 1H), 5.64(quintet, J=6.9Hz, 1H), 5.42(br d, J=5.9Hz, 1H), 2.16(tt, J=5.1, 8.1Hz, 1H), 1.72(d, J=7.0Hz, 3H), 1.17-1.07(m, 4H). ESI[M+H]=364.1. Example 10 [ka]

[0228] A mixture of 5-bromo-3-chloro-pyridazine (0.2 g, 1.03 mmol, 1 equiv.), cyclopropylboronic acid (133 mg, 1.55 mmol, 1.5 equiv.), NaCO (219 mg, 2.07 mmol, 2 equiv.), and Pd(dppf)Cl (76 mg, 103.40 umol, 0.1 equiv.) in dioxane (5 mL) and HO (1 mL) was stirred at 100 °C under N for 12 h. The reaction was concentrated in vacuo. The residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate = 1:1) to give 3-chloro-5-cyclopropyl-pyridazine (120 mg, 776.21 umol, 75.07% yield) as a yellow oil.

[0229] 1 H NMR (400MHz, chloroform-d) δ 8.87(d, J=1.8Hz, 1H), 7.10(d, J=1.8Hz, 1H), 1.98-1.84(m, 1H), 1.37-1.24(m, 2H), 0.99-0.90(m, 2H). ESI[M+H]=155.2. [ka]

[0230] A mixture of N-[(1S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]thieno[2,3-d]pyrimidin-4-amine (80 mg, 209.81 μmol, 1 equiv), 3-chloro-5-cyclopropyl-pyridazine (36 mg, 230.79 μmol, 1.1 equiv), KCO (58 mg, 419.62 μmol, 2 equiv), and Pd(PPh) (24 mg, 20.98 μmol, 0.1 equiv) in dioxane (2 mL) and HO (0.5 mL) was stirred at 100° C. for 12 h under N. The reaction was concentrated in vacuo. The residue was purified by preparative HPLC (column: HUAPU C8 Extreme BDS 150 × 30 5u, mobile phase: [water (0.04% HCl)-ACN], B%: 10% to 40%, 11 min) to give N-[(1S)-1-[4-(5-cyclopropylpyridazin-3-yl)phenyl]ethyl]thieno[2,3-d]pyrimidin-4-amine (25.48 mg, 61.68 μmol, yield 29.40%, purity 99.236%, HCl) as a white solid.

[0231] 1 H NMR (400MHz, methanol-d4) δ 9.27(d, J=2.1Hz, 1H), 8.70(s, 1H), 8.46(d, J=2.1Hz, 1H), 8.14-8.08(m, 2H), 7.95(d, J=5.9Hz, 1H), 7.84(d, J=5.9Hz, 1H), 7 .79(d, J=8.3Hz, 2H), 5.85(q, J=7.0Hz, 1H), 2.43-2.34(m, 1H), 1.81(d, J=7.1Hz, 3H), 1.61-1.52(m, 2H), 1.39-1.33(m, 2H). ESI[M+H]=374.1. Example 11 [ka]

[0232] A mixture of 3-bromo-5-cyclopropyl-pyridine (100 mg, 504.90 μmol, 1 equiv.), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (769 mg, 3.03 mmol, 6 equiv.), KOAc (99 mg, 1.01 mmol, 2 equiv.), and Pd(dppf)Cl·CHCl (41 mg, 50.49 μmol, 0.1 equiv.) in dioxane (5 mL) was degassed and purged with N three times, then the mixture was stirred under N at 80 °C for 12 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative HPLC (Column: Waters Xbridge Prep OBD C18 150 × 30 5u, Mobile phase: [water (0.1% TFA)-ACN], B%: 1% to 30%, 13 min) to give (5-cyclopropyl-3-pyridyl)boronic acid (60 mg, 216.60 µmol, Yield 42.90%, TFA) as a colorless oil. ESI [M+H] = 164.1. [ka]

[0233] To a solution of (1S)-1-(6-bromo-3-pyridyl)ethanamine (0.3 g, 1.49 mmol, 1 equiv.) in i-PrOH (6 mL), TEA (303 mg, 2.98 mmol, 2 equiv.) and 4-chlorothieno[2,3-d]pyrimidine (306 mg, 1.79 mmol, 1.2 equiv.) were added, and the mixture was stirred at 80 °C for 12 h. The reaction was concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give N-[(1S)-1-(6-bromo-3-pyridyl)ethyl]thieno[2,3-d]pyrimidin-4-amine (0.38 g, 1.13 mmol, 75.97% yield) as a yellow solid.

[0234] 1H NMR (400MHz, chloroform-d) δ 8.50-8.42(m, 2H), 7.59(dd, J=2.4, 8.2Hz, 1H), 7.43(d, J=8.2Hz, 1H), 7.3 3(d, J=6.0Hz, 1H), 7.18(d, J=6.2Hz, 1H), 5.54(quintet, J=7.0Hz, 1H), 5.39(br d, J=6.8Hz, 1H), 1.68(d, J=7.1Hz, 3H). ESI[M+H]=335.2 / 337.2. [ka]

[0235] A mixture of N-[(1S)-1-(6-bromo-3-pyridyl)ethyl]thieno[2,3-d]pyrimidin-4-amine (60 mg, 178.99 μmol, 1 equiv.), (5-cyclopropyl-3-pyridyl)boronic acid (50 mg, 178.99 μmol, 1 equiv., TFA), KCO (74 mg, 536.96 μmol, 3 equiv.), and Pd(PPh) (21 mg, 17.90 μmol, 0.1 equiv.) in dioxane (2 mL) and HO (0.5 mL) was degassed and purged with N three times, then the mixture was stirred under a N atmosphere at 90 °C for 12 h. The reaction was concentrated in vacuo. The residue was purified by preparative HPLC (HCl condition, column: Luna C18 100 × 30 5u, mobile phase: [water (0.04% HCl)-ACN], B%: 5% to 35%, 11 min) to give N-[(1S)-1-[6-(5-cyclopropyl-3-pyridyl)-3-pyridyl]ethyl]thieno[2,3-d]pyrimidin-4-amine (34.67 mg, 84.53 μmol, yield 47.23%, purity 99.946%, HCl) as a white solid.

[0236] 1H NMR (400MHz, methanol-d4) δ 9.30(d, J=1.2Hz, 1H), 8.96(s, 1H), 8.90(t, J=1.7Hz, 1H), 8.77-8.72(m, 1H), 8.57-8.56(m, 1H), 8.24(d, J=1.3Hz, 2H), 7.98(d, J=5.9 Hz, 1H), 7.86(d, J=5.7Hz, 1H), 5.90(q, J=7.0Hz, 1H), 2.38-2.29(m, 1H), 1.86(d, J=7.0Hz, 3H), 1.38-1.30(m, 2H), 1.15-1.07(m, 2H). ESI[M+H]=374.1. Example 12 [ka]

[0237] A mixture of 5-bromo-1H-benzimidazole (2 g, 10.15 mmol, 1 equiv.), cyclopropylboronic acid (2.62 g, 30.45 mmol, 3 equiv.), Na2CO3 (3.23 g, 30.45 mmol, 3 equiv.), Cu(OAc)2 (2.21 g, 12.18 mmol, 1.2 equiv.), and 2-(2-pyridyl)pyridine (1.90 g, 12.18 mmol, 1.2 equiv.) in DCE (40 mL) was degassed and purged with O2 three times, then the mixture was stirred under O2 atmosphere at 80 °C for 12 h. Water (40 mL) was added to the reaction mixture, which was then extracted with DCM (30 mL × 5). The organic phase was dried over Na2SO4 and then concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 3 / 1) to give a total of 980 mg of a mixture of 5-bromo-1-cyclopropyl-benzimidazole and 6-bromo-1-cyclopropyl-benzimidazole as a brown oil. ESI [M+H] = 237.1 / 239.1. [ka]

[0238] A mixture of 5-bromo-1-cyclopropyl-benzimidazole and 6-bromo-1-cyclopropyl-benzimidazole (total 940 mg, 3.96 mmol), tributyl(1-ethoxyvinyl)stannane (1.72 g, 4.76 mmol, 1.61 mL, 1.2 equiv.), and Pd(PPh3)4 (458 mg, 396.46 µmol, 0.1 equiv.) in toluene (30 mL) was stirred at 80 °C for 12 h. The reaction was concentrated in vacuo to give a total of 900 mg of crude 1-cyclopropyl-5-(1-ethoxyvinyl)benzimidazole and 1-cyclopropyl-6-(1-ethoxyvinyl)benzimidazole as a dark brown oil, which was used in the next step without further purification. ESI [M+H] = 229.2. [ka]

[0239] To a solution of 1-cyclopropyl-5-(1-ethoxyvinyl)benzimidazole and 1-cyclopropyl-6-(1-ethoxyvinyl)benzimidazole (total 0.9 g, 3.94 mmol) in dioxane (20 mL), HCl (1 M, 20 mL, 5.07 equiv.) was added, and the mixture was stirred at 25 °C for 1 h. The reaction was adjusted to pH = 8 with saturated aqueous Na2CO3 and extracted with EtOAc (20 mL × 3). The organic phase was washed with brine (50 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give a total of 0.3 g of 1-(1-cyclopropylbenzimidazol-5-yl)ethanone and 1-(3-cyclopropylbenzimidazol-5-yl)ethanone as a yellow oil. ESI[M+H]=201.2. [ka]

[0240] To a solution of 1-(1-cyclopropylbenzimidazol-5-yl)ethanone and 1-(3-cyclopropylbenzimidazol-5-yl)ethanone (total 300 mg, 1.50 mmol) in HO (3 mL) and EtOH (9 mL), NaOH (539 mg, 13.48 mmol, 9 equiv.) and NHOH HCl (312 mg, 4.49 mmol, 3 equiv.) were added. The mixture was stirred at 25-80 °C for 12 h. Water (40 mL) was added to the reaction mixture and extracted with EtOAc (30 mL × 3). The organic phase was dried over NaSO and then concentrated in vacuo to give a total of 330 mg of a mixture of 1-(1-cyclopropylbenzimidazol-5-yl)ethanone oxime (crude) and 1-(3-cyclopropylbenzimidazol-5-yl)ethanone oxime (crude), which was used in the next step without further purification. ESI [M+H] = 216.1. [ka]

[0241] To a solution of 1-(1-cyclopropylbenzimidazol-5-yl)ethanone oxime and 1-(3-cyclopropylbenzimidazol-5-yl)ethanone oxime (total 300 mg, 1.53 mmol) in MeOH (10 mL) was added Ni (100 mg, 1.70 mmol, 1.11 equiv.) and NH₃·H₂O (455 mg, 3.25 mmol, 25% purity, 2.12 equiv.) under a N₂ atmosphere. The suspension was degassed and purged with H₂ three times. The mixture was stirred under a H₂ (15 Psi) atmosphere at 25 °C for 12 h. The reaction was filtered and then concentrated in vacuo. The residue was purified by preparative HPLC (column: Nano-micro Kromasil C18 100 × 30 mm 5 μm, mobile phase: [water (0.1% TFA)-ACN], B%: 5% to 25%, 10 min) to give 1-(3-cyclopropylbenzimidazol-5-yl)ethanamine (0.14 g, 444.04 μmol, 28.96% yield, TFA) as a white solid and 1-(1-cyclopropylbenzimidazol-5-yl)ethanamine (0.14 g, 444.04 μmol, 28.96% yield, TFA) as a white solid.

[0242] 6A: 1 H NMR (400MHz, methanol-d4) δ 9.08(s, 1H), 8.01(d, J=8.6Hz, 1H), 7.92(d, J=1.3Hz, 1H), 7.69(dd, J=1.6, 8.6Hz, 1H), 4.70(q, J=6 .9Hz, 1H), 3.75(tt, J=3.7, 7.1Hz, 1H), 1.73(d, J=7.0Hz, 3H), 1.37-1.28(m, 2H), 1.25-1.16(m, 2H).

[0243] 6B: 1 H NMR (400 MHz, methanol-d₄) δ 9.13 (s, 1H), 8.07 (s, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.67 (dd, J = 1.6, 8.6 Hz, 1H), 4.74 (q, J = 6.7 Hz, 1H), 3.76 (tt, J = 3.7, 7.2 Hz, 1H), 1.76 (d, J = 7.0 Hz, 3H), 1.39-1.31 (m, 2H), 1.28-1.18 (m, 2H). [ka]

[0244] To a solution of 1-(1-cyclopropylbenzimidazol-5-yl)ethanamine (140 mg, 444.04 μmol, 1 equiv., TFA) in i-PrOH (3 mL) was added 4-chlorothieno[2,3-d]pyrimidine (91 mg, 532.84 μmol, 1.2 equiv.) and TEA (225 mg, 2.22 mmol, 5 equiv.). The mixture was stirred at 80° C. for 12 hours. The reaction was concentrated in vacuo. The residue was purified by preparative HPLC (column: HUAPU C8 Extreme BDS 150 × 30 5 μm, mobile phase: [water (10 mM NH4HCO3)-ACN], B%: 45%-65%, 10 min) to give N-[1-(1-cyclopropylbenzimidazol-5-yl)ethyl]thieno[2,3-d]pyrimidin-4-amine (19.45 mg, 57.99 μmol, 13.06% yield, 100% purity) as a yellow solid. ESI [M+H] = 336.1.

[0245] 1 H NMR (400MHz, methanol-d4) δ 8.24(s, 1H), 8.11(s, 1H), 7.70(s, 1H), 7.65(d, J=6.0Hz, 1H), 7.61(d, J=8.4Hz, 1H), 7.46-7.44(m, 1H), 7.43(s, 1H) ), 5.67(q, J=7.2Hz, 1H), 3.46(tt, J=3.6, 7.1Hz, 1H), 1.68(d, J=6.8Hz, 3H), 1.18-1.12(m, 2H), 1.05-1.01(m, 2H). Example 13 [ka]

[0246] A mixture of 1-(4-bromophenyl)ethanamine (1 g, 4.23 mmol, 1 equiv. HCl), 4-chlorothieno[2,3-d]pyrimidine (794 mg, 4.65 mmol, 1.1 equiv.), and TEA (1.71 g, 16.91 mmol, 4 equiv.) in i-PrOH (20 mL) was stirred at 80 °C for 12 h. The reaction was concentrated in vacuo. The residue was purified by column chromatography (SiO, petroleum ether / THF = 30 / 1 to 3 / 1) to give N-[1-(4-bromophenyl)ethyl]thieno[2,3-d]pyrimidin-4-amine (1.4 g, 4.19 mmol, 99.08% yield) as a white solid.

[0247] 1 H NMR (400MHz, chloroform-d) δ 8.41(s, 1H), 7.43-7.36(m, 2H), 7.25-7.19(m, 3H), 7.09(d, J=6.0Hz, 1H), 5.46(quintet, J=7.0Hz, 1H), 5.28(br d, J=7.1Hz, 1H), 1.57(d, J=6.8Hz, 3H). ESI[M+H]=334.2 / 336.2. [ka]

[0248] To a solution of N-[1-(4-bromophenyl)ethyl]thieno[2,3-d]pyrimidin-4-amine (0.2 g, 598.38 μmol, 1 equiv) in dioxane (8 mL) was added NaI (269.1 mg, 1.80 mmol, 3 equiv), CuI (11.4 mg, 59.84 μmol, 0.1 equiv), and N,N'-dimethylethylenediamine (13.2 mg, 149.60 μmol, 16.10 μL, 0.25 equiv) under N2. The mixture was stirred in a 30 mL sealed tube at 140 °C for 48 h. The reaction was concentrated in vacuo. The residue was purified by pre-TLC (SiO, petroleum ether:ethyl acetate=2:1) ​​to give N-[1-(4-iodophenyl)ethyl]thieno[2,3-d]pyrimidin-4-amine (180 mg, 472.15 μmol, 78.90% yield) as a white solid. ESI [M+H]=382.2 [ka]

[0249] N-[1-(4-iodophenyl)ethyl]thieno[2,3-d]pyridin-4-amine (180 mg, 472.15 μmol, 1 equiv.), 3-iodooxetane (261 mg, 1.42 mmol, 3 equiv.), bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl]phenyl]iridium(1+):4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine:hexafluorophosphate (16 m A mixture of dichloronickel:1,2-dimethoxyethane (5 mg, 23.61 umol, 0.05 eq.), TTMSS (117 mg, 472.15 umol, 1 eq.), Na2CO3 (100 mg, 944.30 umol, 2 eq.), dichloronickel:1,2-dimethoxyethane (5 mg, 23.61 umol, 0.05 eq.), and 4,4'-di-tert-butyl-2,2'-bipyridine (8 mg, 28.33 umol, 0.06 eq.) was stirred and irradiated with a 34 W blue LED lamp under N2 at 25 °C for 12 h. The reaction was concentrated in vacuo. The residue was purified by preparative HPLC (column: Xtimate C 18Purification using a 150 x 25 mm x 5 μm column (mobile phase: water (10 mM NH4HCO3)-ACN], B%: 30%-60%, 10 min) gave N-[1-[4-(oxetan-3-yl)phenyl]ethyl]thieno[2,3-d]pyrimidin-4-amine (54 mg, 172.72 μmol, yield 36.58%, purity 99.656%) as a white solid.

[0250] 1 H NMR (400MHz, chloroform-d) δ 8.53(s, 1H), 7.44(q, J=8.3Hz, 4H), 7.32(d, J=6.0Hz, 1H), 7.17(d, J=6.0Hz, 1H), 5.62(quintet, J=7.1Hz, 1H), 5.36(br d, J=7.3Hz, 1H), 5.09(dd, J=6.0, 8.4Hz, 2H), 4.84-4.74(m, 2H), 4.32-4.19(m, 1H), 1.70(d, J=6.8Hz, 3H) ESI[M+H]=312.1. Example 14 [ka]

[0251] A mixture of (1R)-1-(4-bromophenyl)ethanamine (0.5 g, 2.50 mmol, 1 equiv.), 4-chlorothieno[2,3-d]pyrimidine (469 mg, 2.75 mmol, 1.1 equiv.), and TEA (506 mg, 5.0 mmol, 2 equiv.) in i-PrOH (10 mL) was stirred at 80 °C for 12 h. The reaction mixture was concentrated in vacuo, and the residue was purified by column chromatography (SiO, petroleum ether:THF = 20:1 to 5:1) to give N-[(1R)-1-(4-bromophenyl)ethyl]thieno[2,3-d]pyrimidin-4-amine (0.7 g, 2.09 mmol, 83.81% yield) as a white solid. ESI [M+H] = 334.2 / 336.2. [ka]

[0252] N-[(1R)-1-(4-bromophenyl)ethyl]thieno[2,3-d]pyrimidin-4-amine (400 mg, 1.2 mmol, 1 equiv.), 1H-1,2,4-triazole (124 mg, 1.8 mmol, 1.5 equiv.), CsCO (780 mg, 2.39 mmol, 2 equiv.), and CuI (46 mg, 240 μmol, 0.2 equiv.) were placed in a microwave tube in DMF (8 mL). The sealed tube was heated in a microwave at 150 °C for 12 h. Water (30 mL) was added to the reaction mixture, which was then extracted with EtOAc (15 mL × 3). The organic phase was washed with brine (20 mL), dried over MgSO, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150 × 40 10 μm, mobile phase: [water (10 mM NH4HCO3)-ACN], B%: 15% to 45%, 11 min) to give (R)-N-(1-(4-(1H-1,2,4-triazol-1-yl)phenyl)ethyl)thieno[2,3-d]pyrimidin-4-amine (279.27 mg, 864.78 μmol, yield 72.26%, purity 99.829%) as a white solid.

[0253] 1 H NMR (400MHz, chloroform-d) δ 8.50(d, J=15.2Hz, 2H), 8.09(s, 1H), 7.69-7.62(m, 2H), 7.59-7.53(m, 2H), 7 .32(d, J=6.0Hz, 1H), 7.19(d, J=6.0Hz, 1H), 5.62(quintet, J=7.0Hz, 1H), 5.42(br d, J=7.3Hz, 1H), 1.70(d, J=7.1Hz, 3H). ESI[M+H]=323.1. ee%=90.7%. Example 15 [ka]

[0254] A mixture of (1S)-1-(4-bromophenyl)ethanamine (500 mg, 2.50 mmol, 1 equiv.), 4-chlorothieno[2,3-d]pyrimidine (469 mg, 2.75 mmol, 1.1 equiv.), and TEA (506 mg, 5.00 mmol, 2 equiv.) in i-PrOH (10 mL) was stirred at 80 °C for 12 h. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether:THF = 20:1 to 5:1) to give N-[(1S)-1-(4-bromophenyl)ethyl]thieno[2,3-d]pyrimidin-4-amine (0.7 g, 2.09 mmol, 83.81% yield) as a white solid. ESI [M+H] = 334.2 / 336.2. [ka]

[0255] N-[(1S)-1-(4-bromophenyl)ethyl]thieno[2,3-d]pyrimidin-4-amine (400 mg, 1.20 mmol, 1 equiv.), 1H-1,2,4-triazole (124 mg, 1.80 mmol, 1.5 equiv.), CsCO (780 mg, 2.39 mmol, 2 equiv.), and CuI (46 mg, 239.35 mmol, 0.2 equiv.) were placed in a microwave tube in DMF (8 mL). The sealed tube was heated in a microwave at 150 °C for 10 h. Water (30 mL) was added to the reaction mixture, which was then extracted with EtOAc (15 mL × 3). The organic phase was washed with brine (20 mL), dried over MgSO, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150 × 40 10 μm, mobile phase: [water (10 mM NH4HCO3)-ACN], B%: 15% to 45%, 11 min) to give N-[(1S)-1-[4-(1,2,4-triazol-1-yl)phenyl]ethyl]thieno[2,3-d]pyrimidin-4-amine (222.06 mg, 687.12 μmol, yield 57.41%, purity 99.756%) as a white solid.

[0256] 1H NMR (400MHz, chloroform-d) δ 8.50(d, J=14.8Hz, 2H), 8.09(s, 1H), 7.68-7.61(m, 2H), 7.59-7.52(m, 2H), 7 .32(d, J=6.2Hz, 1H), 7.20(d, J=6.0Hz, 1H), 5.62(quintet, J=7.0Hz, 1H), 5.43(br d, J=7.1Hz, 1H), 1.70(d, J=7.1Hz, 3H). ESI[M+H]=323.1. ee%=97.9%. Example 16 [ka]

[0257] To a suspension of 1-(1,3-benzodioxol-5-yl)ethanone (1 g, 6.09 mmol, 1 equiv.) in EtOH (15 mL) and HO (5 mL), NaOH (2.19 g, 54.83 mmol, 9 equiv.) and NHOH·HCl (1.27 g, 18.28 mmol, 3 equiv.) were added at 20 °C, and the mixture was stirred at 80 °C for 12 h. Water (30 mL) was added to the reaction mixture, which was then extracted with DCM / i-PrOH (3 / 1, 20 mL × 3). The organic layer was dried over MgSO and concentrated in vacuo to give 1-(1,3-benzodioxol-5-yl)ethanone oxime (1.1 g, crude) as a white solid.

[0258] 1 H NMR (400MHz, chloroform-d) δ 7.10(d, J=1.7Hz, 1H), 7.03(dd, J=1.7, 8.2Hz, 1H), 6.74(d, J=8.1Hz, 1H), 5.92(s, 2H), 2.18(s, 3H). ESI[M+H]=180.1. [ka]

[0259] To a solution of 1-(1,3-benzodioxol-5-yl)ethanone oxime (0.2 g, 1.12 mmol, 1 equiv) in MeOH (10 mL) was added Ni (100 mg, 1.70 mmol, 1.53 equiv) and NH₃·H₂O (1.00 mL, 30% purity, 6.98 equiv) under N₂. The suspension was degassed under vacuum and purged with H₂ several times. The mixture was stirred under H₂ (15 psi) at 25 °C for 4 h. The mixture was filtered, and the filtrate was concentrated in vacuo to give 1-(1,3-benzodioxol-5-yl)ethanamine (190 mg, crude) as a white solid. [ka]

[0260] A mixture of 1-(1,3-benzodioxol-5-yl)ethanamine (190 mg, 1.15 mmol, 1 equiv.), 4-chlorothieno[2,3-d]pyrimidine (216 mg, 1.27 mmol, 1.1 equiv.), and TEA (232.78 mg, 2.30 mmol, 320.19 uL, 2 equiv.) in i-PrOH (4 mL) was stirred at 80 °C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (SiO, PE: EtOAc = 2:1) to give the desired compound, which was further purified by SFC (apparatus: Waters prep-SFC80Q, column: Chiralpak Separation on AD-H, 250 × 25 mm diameter, 5 μm, mobile phase: A in CO₂, B in MEOH (0.1% NH₃·H₂O), gradient: B%=40%, flow rate: 70 g / min, column temperature: 40 °C, system back pressure: 100 bar, gave N-[(1S)-1-(1,3-benzodioxol-5-yl)ethyl]thieno[2,3-d]pyrimidin-4-amine (110.72 mg, 368.53 μmol, 32.04% yield, 99.638% purity) as a white solid and N-[(1R)-1-(1,3-benzodioxol-5-yl)ethyl]thieno[2,3-d]pyrimidin-4-amine (83.25 mg, 277.59 μmol, 24.13% yield, 99.816% purity) as a white solid. (Due to the lack of standard data in the reference, stereochemistry was randomly assigned as R or S. The shorter peak (Rt=3.290) was assigned as S, and the longer peak (Rt=3.791) was assigned as R.)

[0261] CLE-27A: 1 HNMR (400MHz, chloroform-d) δ 8.52(s, 1H), 7.31(d, J=6.0Hz, 1H), 7.16(d, J=6.0Hz, 1H), 6.97-6.90(m, 2H), 6.81(d, J=8.2Hz, 1H), 5.97(s, 2H), 5.72-5.08(m, 2H), 1.66(d, J=6.7Hz, 3H). ESI[M+H]=300.0.

[0262] CLE-27B: 1HNMR (400MHz, chloroform-d) δ 8.52(s, 1H), 7.30-7.27(m, 1H), 7.29(d, J=3.1Hz, 1H), 7.16(d, J=6.0Hz, 1H), 6.95- 6.88(m, 2H), 6.83-6.77(m, 1H), 6.07-5.91(m, 2H), 5.51(quintet, J=7.0Hz, 1H), 5.35(br d, J=7.3Hz, 1H), 1.65(d, J=6.8Hz, 3H). ESI[M+H]=300.1. Example 17 [ka]

[0263] 2-[(4-Bromo-5-cyclopropyl-imidazol-1-yl)methoxy]ethyl-trimethyl-silane and 2-[(5-Bromo-4-cyclopropyl-imidazol-1-yl)methoxy]ethyl-trimethyl-silane (200 mg total), cyclopenten-1-ylboronic acid (141 mg, 1.26 mmol, 2 equiv.), KPO (0.5 M, 2.5 mL, 2 equiv.), and [2-(2-aminophenyl)phenyl]-chloro-palladium:bis(1-adamantyl)-butyl-phosphane (42 mg, 63.03 μmol, 0.1 equiv.) in EtOH (6 mL) were stirred at 80° C. under N for 12 hours. The reaction was concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether:ethyl acetate=1:5) to give 2-[[4-(cyclopenten-1-yl)-5-cyclopropyl-imidazol-1-yl]methoxy]ethyl-trimethyl-silane and 2-[[5-(cyclopenten-1-yl)-4-cyclopropyl-imidazol-1-yl]methoxy]ethyl-trimethyl-silane (total 180 mg) as a yellow oil. ESI [M+H]=305.2 [ka]

[0264] To a solution of 2-[[4-(cyclopenten-1-yl)-5-cyclopropyl-imidazol-1-yl]methoxy]ethyl-trimethyl-silane and 2-[[5-(cyclopenten-1-yl)-4-cyclopropyl-imidazol-1-yl]methoxy]ethyl-trimethyl-silane (total 180 mg) in MeOH (10 mL) was added Pd / C (50 mg, 10% purity) under N2 atmosphere. The suspension was degassed and purged with H2 three times. The mixture was stirred under H2 (15 Psi) at 25 °C for 1 h. The mixture was filtered, and the filtrate was concentrated in vacuo to give 2-[(4-cyclopentyl-5-cyclopropyl-imidazol-1-yl)methoxy]ethyl-trimethyl-silane and 2-[(5-cyclopentyl-4-cyclopropyl-imidazol-1-yl)methoxy]ethyl-trimethyl-silane (total 150 mg) as a yellow oil. ESI [M+H] = 307.2. [ka]

[0265] A solution of 2-[(4-cyclopentyl-5-cyclopropyl-imidazol-1-yl)methoxy]ethyl-trimethyl-silane and 2-[(5-cyclopentyl-4-cyclopropyl-imidazol-1-yl)methoxy]ethyl-trimethyl-silane (total 150 mg) in DCM (3 mL) and TFA (1 mL) was stirred at 25 °C for 12 h. The reaction was concentrated in vacuo. Water (10 mL) was added to the residue, adjusted to pH = 8 with saturated aqueous NaHCO3, and extracted with EtOAc (5 mL × 3). The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (SiO2, ethyl acetate:methanol = 30:1) to give 4-cyclopentyl-5-cyclopropyl-1H-imidazole (70 mg, 397.15 μmol, 81.15% yield) as a yellow oil. ESI [M+H] = 177.1. [ka]

[0266] To a solution of t-BuOK (1 M, 596 uL, 1.5 equiv) in DMF (2 mL) was added 5-cyclopentyl-4-cyclopropyl-1H-imidazole (70 mg, 397.15 umol, 1 equiv) in DMF (1 mL) dropwise at 0° C. under N. After 15 min, 5-(chloromethyl)-1,3-dimethyl-benzimidazol-2-one (100.4 mg, 476.57 umol, 1.2 equiv) in DMF (1 mL) was added at 0° C. under N. The mixture was stirred at 20° C. for 12 h. Water (10 mL) was added to the reaction and extracted with EtOAc (5 mL × 3). The organic layer was dried over MgSO and concentrated in vacuo. The residue was purified by preparative HPLC (column: Xamide 150 x 30 mm 5 μm, mobile phase: [water (10 mM NH4HCO3)-ACN], B%: 30%-50%, 10 min) to give 5-[(4-cyclopentyl-5-cyclopropyl-imidazol-1-yl)methyl]-1,3-dimethyl-benzimidazol-2-one (14.75 mg, 40.24 μmol, 10.13% yield, 95.610% purity) (yellow gum) and 5-[(5-cyclopentyl-4-cyclopropyl-imidazol-1-yl)methyl]-1,3-dimethyl-benzimidazol-2-one (11.06 mg, 31.13 μmol, 7.84% yield, 98.628% purity) as white solids. CWRU-WuXi-03: 1 H NMR (400MHz, chloroform-d) δ 7.44(s, 1H), 6.96-6.88(m, 2H), 6.72(s, 1H), 5.19(s, 2H), 3.41(d, J=12.8Hz, 6H), 3.15(quintet, J=8.4Hz, 1H) , 1.94-1.81(m, 6H), 1.69-1.60(m, 2H), 1.36(tt, J=5.3, 8.1Hz, 1H), 0.93-0.84(m, 2H), 0.65-0.58(m, 2H). ESI[M+H]=351.1.

[0267] CWRU-WuXi-03A: 1H NMR (400MHz, chloroform-d) δ 7.32(s, 1H), 6.92(d, J=7.9Hz, 1H), 6.82(dd, J=1.5, 7.9Hz, 1H), 6.65(s, 1H), 5.10(s, 2H), 3.42(s, 3H), 3. 38(s, 3H), 3.02-2.91(m, 1H), 1.87-1.74(m, 8H), 1.59-1.52(m, 1H), 0.99-0.92(m, 2H), 0.88-0.80(m, 2H). ESI[M+H]=351.2. Example 18 [ka]

[0268] A mixture of 4-(bromomethyl)-2-fluoro-1-nitro-benzene (286 mg, 1.22 mmol, 1.5 equiv), 5-cyclopropyl-4-phenyl-1H-imidazole (150 mg, 814.17 umol, 1 equiv), and K2CO3 (225 mg, 1.63 mmol, 2 equiv) in MeCN (4 mL) was stirred at 20 °C for 16 h. Water (10 mL) was added to the reaction and extracted with EtOAc (5 mL × 3). The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (SiO, ethyl acetate:methanol=20:1) to give a mixture of regioisomeric 5-cyclopropyl-1-[(3-fluoro-4-nitro-phenyl)methyl]-4-phenyl-imidazole and 4-cyclopropyl-1-[(3-fluoro-4-nitro-phenyl)methyl]-5-phenyl-imidazole (total 100 mg) as a yellow oil. ESI [M+H]=338.1. [ka]

[0269] A solution of 5-cyclopropyl-1-[(3-fluoro-4-nitro-phenyl)methyl]-4-phenyl-imidazole and 4-cyclopropyl-1-[(3-fluoro-4-nitro-phenyl)methyl]-5-phenyl-imidazole (total 100 mg) in MeNH (0.5 mL, 33% in EtOH), EtOH (1 mL) was stirred at 80 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO, EtAOc / MeOH = 30 / 1) to give a mixture of regioisomeric 5-[(5-cyclopropyl-4-phenyl-imidazol-1-yl)methyl]-N-methyl-2-nitro-aniline and 5-[(4-cyclopropyl-5-phenyl-imidazol-1-yl)methyl]-N-methyl-2-nitro-aniline (total 110 mg) as a yellow oil. ESI[M+H]=349.1. [ka]

[0270] To a solution of 5-[(5-cyclopropyl-4-phenyl-imidazol-1-yl)methyl]-N-methyl-2-nitro-aniline] and 5-[(4-cyclopropyl-5-phenyl-imidazol-1-yl)methyl]-N-methyl-2-nitro-aniline (total 110 mg) in THF (1 mL) was added SnCl2·2H2O (214 mg, 947.19 μmol, 3 equiv.). The mixture was stirred at 20 °C for 48 h. The reaction mixture was quenched at 0 °C by the addition of saturated aqueous NaHCO3 (10 mL), filtered, and then extracted with EtOAc (10 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude products 4-[(5-cyclopropyl-4-phenyl-imidazol-1-yl)methyl]-N2-methyl-benzene-1,2-diamine and 4-[(4-cyclopropyl-5-phenyl-imidazol-1-yl)methyl]-N2-methyl-benzene-1,2-diamine (total 100 mg) as a brown oil. ESI [M+H] = 319.1. [ka]

[0271] A mixture of 4-[(5-cyclopropyl-4-phenyl-imidazol-1-yl)methyl]-N2-methyl-benzene-1,2-diamine and 4-[(4-cyclopropyl-5-phenyl-imidazol-1-yl)methyl]-N2-methylbenzene-1,2-diamine (total 100 mg, 314.06 μmol, 1 equiv.) in trimethoxymethane (4 mL) and MeOH (4 mL) was degassed and purged with N2 three times, then the mixture was stirred under N2 atmosphere at 20 °C for 36 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge 150 × 25 5 μm, mobile phase: [water (10 mM NH4HCO3)-ACN], B%: 20% to 40%, 10 min) to give the regioisomers 6-[(5-cyclopropyl-4-phenyl-imidazol-1-yl)methyl]-1-methyl-benzimidazole and 6-[(4-cyclopropyl-5-phenyl-imidazol-1-yl)methyl]-1-methylbenzimidazole (purity: 99.772%, 23.18 mg) as white solids. ESI [M+H] = 329.1. Example 19 [ka]

[0272] A mixture of 2-[(4-bromo-5-cyclopropyl-imidazol-1-yl)methoxy]ethyl-trimethyl-silane and 2-[(5-bromo-4-cyclopropyl-imidazol-1-yl)methoxy]ethyl-trimethyl-silane (total 0.4 g, 1.26 mmol, 1 equiv.), (2,5-dichlorophenyl)boronic acid (481 mg, 2.52 mmol, 2 equiv.), KPO (0.5 M, 5 mL, 2 equiv.), and [2-(2-aminophenyl)phenyl]chloropalladium:dicyclohexyl-[3-(2,4,6-triisopropylphenyl)phenyl]phosphane (50 mg, 63.03 μmol, 0.05 equiv.) in THF (10 mL) was stirred at 80° C. under N for 12 h. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with EtOAc (10 mL × 3). The organic phase was washed with brine (20 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 1 / 1) to give 2-[[5-cyclopropyl-4-(2,5-dichlorophenyl)imidazol-1-yl]methoxy]ethyl-trimethyl-silane and 2-[[4-cyclopropyl-5-(2,5-dichlorophenyl)imidazol-1-yl]methoxy]ethyl-trimethyl-silane (total 500 mg, crude) as a yellow oil. ESI [M+H] = 383.1. [ka]

[0273] A solution of 2-[[5-cyclopropyl-4-(2,5-dichlorophenyl)imidazol-1-yl]methoxy]ethyl-trimethyl-silane and 2-[[4-cyclopropyl-5-(2,5-dichlorophenyl)imidazol-1-yl]methoxy]ethyl-trimethyl-silane (total 500 mg, 1.30 mmol, 1 equiv.) in DCM (10 mL) and TFA (4 mL) was stirred at 30 °C for 1 h. The reaction was concentrated in vacuo. The residue was dissolved in EtOAc (5 mL) and water (10 mL) and adjusted to pH = 8 with saturated aqueous Na2CO3. The mixture was partitioned between EtOAc (5 mL × 3) and water (10 mL). The organic phase was separated, dried over MgSO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate=0:1) to give 5-cyclopropyl-4-(2,5-dichlorophenyl)-1H-imidazole (150 mg, 592.59 umol, 45.44% yield) as a yellow oil. ESI [M+H]=253.1. [ka]

[0274] To a solution of t-BuOK (1 M, 474 uL, 1.5 equiv) in DMF (2 mL) was added 4-cyclopropyl-5-(2,5-dichlorophenyl)-1H-imidazole (80 mg, 316.05 umol, 1 equiv) in DMF (0.5 mL) dropwise at 0 °C under N. After 15 min, 5-(chloromethyl)-1,3-dimethyl-benzimidazol-2-one (80 mg, 379.26 umol, 1.2 equiv) in DMF (0.5 mL) was added at 0 °C under N. The mixture was stirred at 20 °C for 12 h. Water (10 mL) was added to the reaction and extracted with EtOAc (5 mL × 3). The organic layer was dried over MgSO and concentrated in vacuo. The residue was purified by preparative HPLC (Xtimate C18 150 × 25 mm × 5 μm column, mobile phase: [water (10 mM NH4HCO3)-ACN], B%: 40%-60%, 10 min) to give 5-[[5-cyclopropyl-4-(2,5-dichlorophenyl)imidazol-1-yl]methyl]-1,3-dimethyl-benzimidazol-2-one (12.16 mg, 28.01 μmol, 8.86% yield, 98.422% purity) and 5-[[4-cyclopropyl-5-(2,5-dichlorophenyl)imidazol-1-yl]methyl]-1,3-dimethyl-benzimidazol-2-one (30.81 mg, 71.24 μmol, 22.54% yield, 98.805% purity) as white solids.

[0275] CWRU-WuXi-12: 1 H NMR (400MHz, chloroform-d) δ 7.27(s, 1H), 7.22(d, J=2.4Hz, 1H), 7.10(d, J=8.6Hz, 1H), 6.98(dd, J=2.5, 8.5Hz, 1H), 6.70(d, J=0.7Hz, 2H), 6.47(s, 1H), 5.04(s, 2H), 3.18(s, 3H), 3.13(s, 3H), 1.30-1.23(m, 1H), 0.52-0.46(m, 2H), 0.05-0.01(m, 2H). ESI[M+H]=427.1.

[0276] CWRU-WuXi-12A: 1H NMR (400MHz, chloroform-d) δ 7.48(s, 1H), 7.42-7.37(m, 1H), 7.32-7.27(m, 1H), 7.09(d, J=2.4Hz, 1H), 6.81(d, J=7.9Hz, 1H), 6.68(d, J=7.9Hz, 1H), 6.45(s, 1) H), 5.05-4.96(m, 1H), 4.83(d, J=15.0Hz, 1H), 3.39(s, 3H), 3.32(s, 3H), 1.56-1.49(m, 1H), 0.89-0.81(m, 2H), 0.78-0.71(m, 2H). ESI[M+H]=427.2. Example 20 [ka]

[0277] To a solution of 5-cyclopropyl-1H-imidazole (3.9 g, 36.06 mmol, 1 equiv) in DMF (80 mL) was added NaH (1.4 g, 36.06 mmol, 1 equiv) at 0 °C. The mixture was stirred at 20 °C for 30 min, then SEM-Cl (6.6 g, 39.67 mmol, 1 equiv) was added at 0 °C, and the mixture was stirred at 20 °C for 12 h. The reaction mixture was quenched with cold saturated aqueous NH4Cl (100 mL) and extracted with EtOAc (50 mL × 3). The organic phase was washed with brine (100 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate = 10:1 to 1:1) to give a mixture of regioisomers 2-[(5-cyclopropylimidazol-1-yl)methoxy]ethyl-trimethyl-silane and 2-[(4-cyclopropylimidazol-1-yl)methoxy]ethyl-trimethyl-silane as a yellow oil (7.3 g in total), ESI [M+H] = 239.2. [ka]

[0278] To a solution of 2-[(5-cyclopropylimidazol-1-yl)methoxy]ethyl-trimethyl-silane and 2-[(4-cyclopropylimidazol-1-yl)methoxy]ethyl-trimethyl-silane (total 3 g, 12.58 mmol, 1 equiv.) in THF (90 mL) was added NBS (2.24 g, 12.58 mmol, 1 equiv.) at −70° C. The mixture was then stirred at −70° C. for 3 h. Water (60 mL) was added to the reaction and extracted with EtOAc (20 mL×3). The organic phase was washed with brine (50 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give a mixture of regioisomers 2-[(4-bromo-5-cyclopropyl-imidazol-1-yl)methoxy]ethyl-trimethyl-silane and 2-[(5-bromo-4-cyclopropyl-imidazol-1-yl)methoxy]ethyl-trimethyl-silane (2.8 g in total) as a yellow oil. ESI [M+H] = 317.3 / 319.3. [ka]

[0279] 2-[(4-Bromo-5-cyclopropyl-imidazol-1-yl)methoxy]ethyl-trimethyl-silane and 2-[(5-Bromo-4-cyclopropyl-imidazol-1-yl)methoxy]ethyl-trimethyl-silane (total 2.8 g, 8.82 mol, 1 equiv.), phenylboronic acid (1.3 g, 10.59 mmol, 1.2 equiv.), KPO (0.5 M, 35.30 mL, 2 equiv.), and [2-(2-aminophenyl)phenyl]-chloro-palladium:bis(1-adamantyl)-butyl-phosphane (354 mg, 529.47 μmol, 0.06 equiv.) in EtOH (70 mL) were stirred at 80° C. for 12 h under N. The mixture was concentrated under reduced pressure to remove EtOH, and the aqueous layer was extracted with EtOAc (20 mL × 3). The organic phase was washed with brine (50 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to give a mixture of regioisomers 2-[(5-cyclopropyl-4-phenyl-imidazol-1-yl)methoxy]ethyl-trimethyl-silane and 2-[(4-cyclopropyl-5-phenyl-imidazol-1-yl)methoxy]ethyl-trimethyl-silane (total 2.6 g, 93.5% yield) as a dark brown oil. ESI [M+H] = 315.2. [ka]

[0280] A mixture of 2-[(5-cyclopropyl-4-phenyl-imidazol-1-yl)methoxy]ethyl-trimethyl-silane and 2-[(4-cyclopropyl-5-phenyl-imidazol-1-yl)methoxy]ethyl-trimethyl-silane (total 2.6 g, 8.27 mmol) in TFA (10 mL) and DCM (30 mL) was stirred at 30 °C for 3 h. The reaction was concentrated in vacuo. The residue was dissolved in EtOAc (20 mL) and water (10 mL) and adjusted to pH = 8 with saturated aqueous Na2CO3. The mixture was then partitioned between EtOAc (10 mL × 3) and water (20 mL). The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 1 / 2) to give 5-cyclopropyl-4-phenyl-1H-imidazole (1.8 g) as a yellow solid.

[0281] 1 H NMR (400MHz, chloroform-d) δ 7.74(br s, 2H), 7.51(s, 1H), 7.42(t, J=7.7Hz, 2H), 7.32-7.27(m, 1H), 2.05(tt, J=5.2, 8.3Hz, 1H), 1.03-0.92(m, 2H), 0.80(br s, 2H). ESI[M+H]=185.2. [ka]

[0282] To a solution of 2-oxo-1,3-dihydrobenzimidazole-5-carboxylic acid (8 g, 44.91 mmol, 1 equiv.) in DMF (200 mL) was added NaH (6.3 g, 157.18 mmol, 60% purity, 3.5 equiv.) at 0° C. After 30 min, MeI (22.3 g, 157.18 mmol, 3.5 equiv.) was added at 0° C. The mixture was then stirred at 20° C. for 16 h. The reaction was quenched with saturated aqueous NH4Cl (500 mL) and extracted with EtOAc (200 mL × 3). The organic layer was washed with brine (500 mL × 2), dried over MgSO4, and concentrated in vacuo. The residue was triturated with PE / MTBE (50 mL / 5 mL) and the solid precipitate was collected by filtration and dried in vacuo to give methyl 1,3-dimethyl-2-oxo-benzimidazole-5-carboxylate (8.9 g, 40.41 mmol, 89.99% yield) as a brown solid.

[0283] 1 H NMR (400MHz, chloroform-d) δ 7.90(dd, J=1.5, 8.3Hz, 1H), 7.69(d, J=1.3Hz, 1H), 7.01(d, J=8.2Hz, 1H), 3.95(s, 3H), 3.48(d, J=4.0Hz, 6H). ESI[M+H]=221.2. [ka]

[0284] To a solution of methyl 1,3-dimethyl-2-oxo-benzimidazole-5-carboxylate (8.9 g, 40.41 mmol, 1 equiv.) in THF (160 mL) was added LiBH (1.76 g, 80.83 mmol, 2 equiv.) at 20 °C. The mixture was then stirred at 70 °C for 16 h. The reaction was quenched with cold saturated aqueous NH Cl (200 mL) and extracted with EtOAc (100 mL × 3). The organic layer was washed with brine (200 mL), dried over MgSO, and concentrated in vacuo to give 5-(hydroxymethyl)-1,3-dimethyl-benzimidazol-2-one (7 g, crude) as a pale red solid.

[0285] 1H NMR (400MHz, chloroform-d) δ 7.08(d, J=7.9Hz, 1H), 7.02(s, 1H), 6.91(d, J=8.2Hz, 1H), 4.73(s, 2H), 3.40(s, 6H). ESI[M+H]=193.1. [ka]

[0286] To a mixture of 5-(hydroxymethyl)-1,3-dimethyl-benzimidazol-2-one (2 g, 10.41 mmol, 1 equiv.) and TEA (3.2 g, 31.22 mmol, 3 equiv.) in DCM (40 mL) was added MsCl (2.4 g, 20.81 mmol, 2 equiv.) at -10 °C. The mixture was stirred at -10 to 0 °C for 2 h. The reaction was concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to give 5-(chloromethyl)-1,3-dimethyl-benzimidazol-2-one (1 g, 4.75 mmol, 45.62% yield) as a white solid.

[0287] 1 H NMR (400MHz, chloroform-d) δ 7.12 (dd, J=1.5, 7.9Hz, 1H), 7.02 (d, J=1.3Hz, 1H), 6.93 (d, J=7.9Hz, 1H), 4.67 (s, 2H), 3.43 (d, J=4.4Hz, 6H). [ka]

[0288] To a solution of t-BuOK (1 M, 2.44 mL, 1.5 equiv) in DMF (10 mL) was added 4-cyclopropyl-5-phenyl-1H-imidazole (0.3 g, 1.63 mmol, 1 equiv) in DMF (2 mL) dropwise at 0 °C under N. After 15 min, 5-(chloromethyl)-1,3-dimethyl-benzimidazol-2-one (377 mg, 1.79 mmol, 1.1 equiv) in DMF (5 mL) was added at 0 °C under N. The mixture was stirred at 20 °C for 2 h. Water (20 mL) was added to the reaction and extracted with EtOAc (10 mL × 3). The organic layer was dried over MgSO and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 1 / 2) to give the desired compound (560 mg) as a yellow oil, which was further purified by SFC (conditions: apparatus: Waters Prep SFC 80Q, column: Chiralpak OJ-H, 250 × 25 mm diameter 10 μm, mobile phase: A in CO2, B in MEOH (0.1% NH3 HO), gradient: B% = 50%, flow rate: 70 g / min, column temperature: 40 °C, system back pressure: 100 bar) to give 5-[(5-cyclopropyl-4-phenyl-imidazol-1-yl)methyl]-1,3-dimethyl-benzimidazol-2-one (188 mg, 520.46 μmol, 31.96% yield, 99.225% purity, Rt = 3.56 min by SFC) as a white solid.

[0289] BBI-7: 1 H NMR (400MHz, chloroform-d) δ 7.80(d, J=7.2Hz, 2H), 7.55(s, 1H), 7.40(t, J=7.7Hz, 2H), 7.28-7.23(m, 1H), 7.01-6.93(m, 2H), 6.79 (s, 1H), 5.30(s, 2H), 3.43(d, J=15.2Hz, 6H), 1.63-1.55(m, 1H), 1.04-0.95(m, 2H), 0.52-0.45(m, 2H). ESI[M+H]=359.1. Example 21 [ka]

[0290] A mixture of 2-[(4-bromo-5-cyclopropyl-imidazol-1-yl)methoxy]ethyl-trimethyl-silane and 2-[(5-bromo-4-cyclopropyl-imidazol-1-yl)methoxy]ethyl-trimethyl-silane (total 150 mg, 472.74 μmol, 1 equiv.), (2-chlorophenyl)boronic acid (110 mg, 709.12 μmol, 1.5 equiv.), KPO (0.5 M, 1.9 mL, 2 equiv.), and [2-(2-aminophenyl)phenyl]-chloro-palladium:bis(1-adamantyl)-butyl-phosphane (32 mg, 47.27 μmol, 0.1 equiv.) in EtOH (3 mL) was stirred at 70° C. under N for 12 hours. The reaction was concentrated in vacuo. The residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate=0:1) to give 2-[[4-(2-chlorophenyl)-5-cyclopropyl-imidazol-1-yl]methoxy]ethyl-trimethyl-silane and 2-[[5-(2-chlorophenyl)-4-cyclopropyl-imidazol-1-yl]methoxy]ethyl-trimethyl-silane (total 90 mg) as a yellow oil. ESI [M+H]=349.1. [ka]

[0291] A solution of 2-[[4-(2-chlorophenyl)-5-cyclopropyl-imidazol-1-yl]methoxy]ethyl-trimethyl-silane and 2-[[5-(2-chlorophenyl)-4-cyclopropyl-imidazol-1-yl]methoxy]ethyl-trimethyl-silane (total 90 mg, 257.92 μmol) in TFA (1 mL) and DCM (3 mL) was stirred at 30° C. for 3 h. The reaction was concentrated in vacuo. The residue was dissolved in EtOAc (10 mL × 2) and washed with saturated aqueous NaHCO3 (10 mL). The organic layer was dried over MgSO4 and concentrated in vacuo.

[0292] The residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate = 0:1) and then re-purified by preparative HPLC (column: Waters Xbridge 150 × 25 5u, mobile phase: [water (10 mM NH4HCO3)-ACN], B%: 30% to 60%, 10 min) to give 4-(2-chlorophenyl)-5-cyclopropyl-1H-imidazole (44 mg, 201.21 µmol, 78.01% yield) as a white solid. ESI [M+H] = 219.1. [ka]

[0293] To a solution of t-BuOK (1 M, 617 μL, 1.5 equiv) in DMF (1 mL) was added 5-(2-chlorophenyl)-4-cyclopropyl-1H-imidazole (90 mg, 411.56 μmol, 1 equiv) in DMF (1 mL) at 0° C. under a N atmosphere. After 15 min, 5-(chloromethyl)-1,3-dimethyl-benzimidazol-2-one (95.4 mg, 452.71 μmol, 1.1 equiv) in DMF (1 mL) was added to the mixture at 0° C., and the mixture was then stirred at 20° C. under a N atmosphere for 1 h 45 min. The reaction mixture was diluted with HO (5 mL) and extracted with EtOAc (5 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Xtimate C18 150 × 25 mm × 5 μm column, mobile phase: [water (10 mM NH4HCO3)-ACN], B%: 35%-55%, 10 min) to give 5-[[5-(2-chlorophenyl)-4-cyclopropyl-imidazol-1-yl]methyl]-1,3-dimethyl-benzimidazol-2-one (44.3 mg, 111.58 μmol, 27.11% yield, 98.953% purity) as a white solid and 5-[[4-(2-chlorophenyl)-5-cyclopropyl-imidazol-1-yl]methyl]-1,3-dimethyl-benzimidazol-2-one (19.45 mg, 45.97 μmol, 11.17% yield, 92.865% purity) as a white solid.

[0294] CWRU-WuXi-11A: 1 H NMR (400MHz, chloroform-d) δ 7.48-7.36(m, 2H), 7.27(dt, J=1.8, 7.7Hz, 1H), 7.19-7.15(m, 1H), 7.14-7.09(m, 1H), 6.72(d, J=7.9Hz, 1H), 6.64-6.58(m, 1H), 6.3 8(s, 1H), 4.99-4.87(m, 1H), 4.83-4.74(m, 1H), 3.31(s, 3H), 3.24(s, 3H), 1.52-1.46(m, 1H), 0.80-0.75(m, 2H), 0.71-0.62(m, 2H). ESI[M+H]=393.2.

[0295] CWRU-WuXi-11: 1 H NMR (400MHz, chloroform-d) δ 7.56(s, 1H), 7.50-7.43(m, 2H), 7.32-7.28(m, 2H), 7.02-6.95(m, 2H), 6.74(s, 1H), 5.32(s, 2) H), 3.45(s, 3H), 3.42-3.39(m, 3H), 1.61-1.48(m, 1H), 0.74-0.64(m, 2H), 0.35-0.21(m, 2H). ESI[M+H]=393.1. Example 22 [ka]

[0296] A mixture of (1S)-1-(4-bromophenyl)ethanamine (6 g, 29.99 mmol, 4.32 mL, 1 equiv.), 4-chlorothieno[2,3-d]pyrimidine (5.88 g, 34.49 mmol, 1.15 equiv.), and TEA (6.07 g, 59.98 mmol, 8.35 mL, 2 equiv.) in i-PrOH (200 mL) was stirred at 80 °C for 12 h. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO, petroleum ether:THF = 20:1 to 5:1) to give N-[(1S)-1-(4-bromophenyl)ethyl]thieno[2,3-d]pyrimidin-4-amine (7.8 g, 23.34 mmol, 77.82% yield) as a white solid.

[0297] 1 H-NMR (400MHz, chloroform-d) δ 8.50(s, 1H), 7.53-7.46(m, 2H), 7.36-7.30(m, 3H), 7.18(d, J=6.0Hz, 1H), 5.55(quintet, J=7.0Hz, 1H), 5.36(br d, J=7.0Hz, 1H), 1.66(d, J=6.8Hz, 3H). ESI[M+H]=336.2. [ka]

[0298] A mixture of N-[(1S)-1-(4-bromophenyl)ethyl]thieno[2,3-d]pyrimidin-4-amine (1 g, 2.99 mmol, 1 equiv.), NaN (233.40 mg, 3.59 mmol, 1.2 equiv.), CuI (56.98 mg, 299.19 µmol, 0.1 equiv.), and N,N-dimethylethane-1,2-diamine (52.75 mg, 598.38 µmol, 64.40 µL, 0.2 equiv.) in EtOH (10 mL) and HO (5 mL) was stirred at 100 °C for 12 h under N. Saturated aqueous NaHCO (20 mL) was added to the reaction mixture, which was then extracted with EtOAc (10 mL × 3). The organic layer was dried over MgSO and blown dry with N to give N-[(1S)-1-(4-azidophenyl)ethyl]thieno[2,3-d]pyrimidin-4-amine (1 g, crude) as a yellow solid, which was used in the next step without further purification. ESI [M+H] = 297.3. [ka]

[0299] To a solution of N-[(1S)-1-(4-azidophenyl)ethyl]thieno[2,3-d]pyrimidin-4-amine (100 mg, 337.44 μmol, 1 equiv) in DCM (3 mL) was added prop-1-ynylcyclopropane (40.56 mg, 506.16 μmol, 1.5 equiv) and chlororuthenium:(1Z,5Z)-cycloocta-1,5-diene:1,2,3,4,5-pentamethylcyclopentane (12.99 mg, 33.74 μmol, 0.1 equiv), and the mixture was stirred at 40° C. for 48 h. The reaction was concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge 150 × 25 5u, mobile phase: [water (10 mM NH4HCO3)-ACN], B%: 30%-40%, 10 min) to give N-[(1S)-1-[4-(4-cyclopropyl-5-methyl-triazol-1-yl)phenyl]ethyl]thieno[2,3-d]pyrimidin-4-amine (11.4 mg, 29.67 µmol, 8.79% yield, 97.992% purity) and N-[(1S)-1-[4-(5-cyclopropyl-4-methyl-triazol-1-yl)phenyl]ethyl]thieno[2,3-d]pyrimidin-4-amine (24.95 mg, 66.27 µmol, 19.64% yield, 100% purity) as white solids.

[0300] BAX-57(S):1H-NMR (400MHz, chloroform-d) δ 8.51(s, 1H), 7.58(d, J=8.3Hz, 2H), 7.43(d, J=8.4Hz, 2H), 7.34(d, J=6.0Hz, 1H), 7.20(d, J=6.0Hz, 1H), 5.72-5.62(m, 1H), 5.36(br d, J=6.6Hz, 1H), 2.33(s, 3H), 1.85-1.76(m, 1H), 1.72(d, J=6.8Hz, 3H), 1.06-0.94(m, 4H). ESI[M+H]=377.1.

[0301] BAX-57A(S): 1H-NMR (400MHz, chloroform-d) δ 8.43(s, 1H), 7.49(s, 4H), 7.26(d, J=6.0Hz, 1H), 7.13(d, J=6.0Hz, 1H), 5.60(quintet, J=7.0Hz, 1H), 5.32(br d, J=7.5Hz, 1H), 2.30(s, 3H), 1.65(d, J=7.0Hz, 4H), 0.87-0.79(m, 2H), 0.55-0.48(m, 2H). ESI[M+H]=377.0. Example 23 [ka]

[0302] A mixture of N-[(1S)-1-(4-iodophenyl)ethyl]thieno[2,3-d]pyrimidine-4-amine (500 mg, 1.31 mmol, 1 equiv.), ethynyl(trimethyl)silane (257.6 mg, 2.62 mmol, 363.37 μL, 2 equiv.), TEA (2.18 g, 21.55 mmol, 3 mL, 16.43 equiv.), Pd(PPh)Cl (92 mg, 131.15 μmol, 0.1 equiv.), and CuI (25 mg, 131.15 μmol, 0.1 equiv.) in THF (9 mL) was stirred at 70 °C under N for 2 h. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (plate 1, SiO, petroleum ether:ethyl acetate = 10:1 to 3:1) to give N-[(1S)-1-[4-(2-trimethylsilylethynyl)phenyl]ethyl]thieno[2,3-d]pyrimidine-4-aminetese (460 mg, 1.31 mmol, 99.77% yield) as a yellow oil. ESI [M+H] = 351.9. [ka]

[0303] To a solution of N-[(1S)-1-[4-(2-trimethylsilylethynyl)phenyl]ethyl]thieno[2,3-d]pyrimidine-4-aminetacene (460 mg, 1.31 mmol, 1 equiv.) in MeOH (5 mL) was added K2CO3 (361.7 mg, 2.62 mmol, 2 equiv.), and the mixture was stirred at 25 °C for 1 h. Water (10 mL) was added to the reaction mixture, which was then extracted with EtOAc (5 mL × 3). The organic layer was dried over MgSO4 and concentrated in vacuo to give N-[(1S)-1-(4-ethynylphenyl)ethyl]thieno[2,3-d]pyrimidine-4-aminetacene (240 mg, 859.11 μmol, 65.65% yield) as a yellow solid, which was used in the next step without further purification. ESI [M+H] = 280.3. [ka]

[0304] A mixture of HCHO (290 mg, 3.58 mmol, 266.51 µL, 37% purity, 10 equiv.) and AcOH (32 mg, 536.94 µmol, 30.71 µL, 1.5 equiv.) in THF (2 mL) was stirred for 15 min. NaN (35 mg, 536.94 µmol, 1.5 equiv.) was added, followed by N-[(1S)-1-(4-ethynylphenyl)ethyl]thieno[2,3-d]pyrimidine-4-amine (100 mg, 357.96 µmol, 1 equiv.). The mixture was stirred for 10 minutes, and sodium ascorbate (14 mg, 71.59 μmol, 0.2 equiv.) was added, followed by CuSO (17 mg, 17.90 μmol, 16.45 μL, 16.7% purity, 0.05 equiv.) at 25° C. The reaction was stirred at 80° C. for 12 hours. Saturated aqueous NaHCO (5 mL) was added to the reaction mixture, and it was extracted with EtOAc (3 mL). The organic layer was dried over MgSO and concentrated in vacuo. The residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate=1:1) to give N-[(1S)-1-[4-(1H-triazol-4-yl)phenyl]ethyl]thieno[2,3-d]pyrimidine-4-aminetese (75 mg, 232.64 μmol, 64.99% yield) as a white solid. ESI[M+H]=323.1. [ka]

[0305] A mixture of 2-(2-pyridyl)pyridine (55 mg, 353.61 μmol, 1.2 equiv.) and Cu(OAc) (64 mg, 353.61 μmol, 1.2 equiv.) in DCE (6 mL) was heated to 70 °C. To this mixture was added a mixture of N-[(1S)-1-[4-(1H-triazol-4-yl)phenyl]ethyl]thieno[2,3-d]pyrimidine-4-amine (95 mg, 294.68 μmol, 1 equiv.), cyclopropylboronic acid (76 mg, 884.03 μmol, 3 equiv.), and NaCO (94 mg, 884.03 μmol, 3 equiv.), followed by stirring at 70 °C for 12 h under O. Water (20 mL) was added to the reaction mixture, which was then extracted with DCM (10 mL × 3). The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative HPLC (column: HUAPU C8 Extreme BDS 150 × 30 5 μl, mobile phase: [water (10 mM NH4HCO3)-ACN], B%: 45% to 65%, 10 min) to give N-[(1S)-1-[4-(1-cyclopropyltriazol-4-yl)phenyl]ethyl]thieno[2,3-d]pyrimidine-4-aminetese (36.09 mg, 98.10 μmol, yield 33.29%, purity 98.524%) as a white solid.

[0306] 1 H-NMR (400MHz, chloroform-d) δ 8.53(s, 1H), 7.85-7.75(m, 3H), 7.50(d, J=8.1Hz, 2H), 7.33(d, J=6.0Hz, 1H), 7.18(d, J=6.0Hz, 1H), 5.63(quintet, J=7.0Hz, 1H), 5.36(br d, J=7.5Hz, 1H), 4.05(tt, J=3.8, 7.5Hz, 1H), 1.72(d, J=6.8Hz, 3H), 1.45-1.38(m, 2H), 1.19-1.11(m, 2H). ESI[M+H]=363.1. Example 24 [ka]

[0307] To a solution of 1-(4-bromophenyl)ethanamine (2 g, 8.46 mmol, 1.43 mL, 1 equiv., HCl) in DCM (60 mL), TEA (2.57 g, 25.37 mmol, 3.53 mL, 3 equiv.) was added and cooled to 0 °C in an ice bath, followed by the addition of BocO (2.21 g, 10.15 mmol, 2.33 mL, 1.2 equiv.). The mixture was stirred at 0–25 °C for 12 h. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 20 / 1–3:1) to afford tert-butyl N-[1-(4-bromophenyl)ethyl]carbamate (2.5 g, 8.33 mmol, 98.49% yield) as a white solid.

[0308] 1 H-NMR (400MHz, methanol-d4) δ 7.50-7.43(m, 2H), 7.29-7.19(m, 2H), 4.70-4.57(m, 1H), 4.72-4.57(m, 1H), 4.72-4.52(m, 1H), 1.50-1.29(m, 12H). ESI[M+H]=285.0. [ka]

[0309] A mixture of tert-butyl N-[1-(4-bromophenyl)ethyl]carbamate (2.5 g, 8.33 mmol, 1 equiv.), NaN (649.68 mg, 9.99 mmol, 1.2 equiv.), CuI (158.61 mg, 832.80 µmol, 0.1 equiv.), and N,N-dimethylethane-1,2-diamine (146.82 mg, 1.67 mmol, 179.27 µL, 0.2 equiv.) in EtOH (20 mL) and HO (10 mL) was stirred at 100 °C for 12 h under N. Saturated aqueous NaHCO (20 mL) was added to the reaction mixture, which was then extracted with EtOAc (10 mL × 3). The organic layer was dried over MgSO and blown dry with N to give tert-butyl N-[1-(4-azidophenyl)ethyl]carbamate (2.2 g, crude) as a yellow solid, which was used in the next step without further purification. ESI [M+H] = 207.1. [ka]

[0310] A mixture of tert-butyl N-[1-(4-azidophenyl)ethyl]carbamate (2.2 g, 8.39 mmol, 1 equiv.), ethynylcyclopropane (1.11 g, 16.77 mmol, 1.39 mL, 2 equiv.), CuSO 5HO (418.84 mg, 1.68 mmol, 0.2 equiv.), and sodium ascorbate (332.31 mg, 1.68 mmol, 0.2 equiv.) in t-BuOH (20 mL) and HO (20 mL) was stirred at 30 °C for 12 h. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 20 / 1 to 0:1) to give tert-butyl N-[1-[4-(4-cyclopropyltriazol-1-yl)phenyl]ethyl]carbamate (2.4 g, 7.31 mmol, 87.13% yield) as a white solid. ESI [M-56+H] = 279.3 and [M / -100+H] = 229.2. [ka]

[0311] A mixture of tert-butyl N-[1-[4-(4-cyclopropyltriazol-1-yl)phenyl]ethyl]carbamate (2.4 g, 7.31 mmol, 1 equiv.) in HCl / EtOAc (15 mL) and EtOAc (15 mL) was stirred at 25 °C for 1 h. The reaction mixture was adjusted to pH = 8 with NH₃·H₂O and concentrated in vacuo. The residue was purified by preparative HPLC (Column: Waters Xbridge Prep OBD C18 150 × 40 10 u, Mobile phase: [water (10 mM NH₄HCO₃)-ACN], B%: 5% to 45%, 11 min) to give 1-[4-(4-cyclopropyltriazol-1-yl)phenyl]ethanamine (500 mg, 2.19 mmol, 29.97% yield) as a brown solid. ESI [M+H] = 229.1. [ka]

[0312] To a solution of 1-[4-(4-cyclopropyltriazol-1-yl)phenyl]ethanamine (50 mg, 219.02 μmol, 1 equiv) in n-BuOH (2 mL) was added TEA (44.32 mg, 438.03 μmol, 60.97 μL, 2 equiv) and 4-chloro-6-methyl-furo[2,3-d]pyrimidine (40.61 mg, 240.92 μmol, 1.1 equiv). The mixture was stirred at 120° C. for 12 hours. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Luna C18 100 × 30 5 μm, mobile phase: [water (0.04% HCl)-ACN], B%: 25% to 55%, 11 min) to give N-[1-[4-(4-cyclopropyltriazol-1-yl)phenyl]ethyl]-6-methyl-furo[2,3-d]pyrimidin-4-amine (52.28 mg, 138.42 μmol, 63.20% yield, 95.425% purity) as an orange solid. ESI [M+H] = 361.1.

[0313] 1H-NMR (400MHz, methanol-d4) δ 8.21-8.16(m, 1H), 8.15-8.07(m, 1H), 7.79-7.70(m, 2H), 7.62-7.51(m, 2H), 6.67-6.61(m, 1H), 5.51-5.3 9(m, 1H), 2.46-2.40(m, 3H), 2.06-1.96(m, 1H), 1.66-1.58(m, 3H), 1.04-0.95(m, 2H), 0.87-0.79(m, 2H). Example 25 [ka]

[0314] To a solution of 1-(5-bromo-2-pyridyl)ethanamine (200 mg, 994.71 μmol, 204.08 μL, 1 equiv.) in i-PrOH (5 mL), TEA (202 mg, 1.99 mmol, 276.90 μL, 2 equiv.) and 4-chlorothieno[2,3-d]pyrimidine (187 mg, 1.09 mmol, 1.1 equiv.) were added. The mixture was stirred at 80 °C for 12 h. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 2:1) to give N-[1-(5-bromo-2-pyridyl)ethyl]thieno[2,3-d]pyrimidin-4-amine (340 mg) as a yellow solid. ESI [M+H] = 335.0. [ka]

[0315] A mixture of N-[1-(5-bromo-2-pyridyl)ethyl]thieno[2,3-d]pyrimidin-4-amine (100 mg, 298.31 μmol, 1 equiv.), NaN (23 mg, 357.97 μmol, 1.2 equiv.), CuI (6 mg, 29.83 μmol, 0.1 equiv.), and N,N-dimethylethane-1,2-diamine (5 mg, 59.66 μmol, 6.42 μL, 0.2 equiv.) in EtOH (2 mL) and HO (1 mL) was stirred at 100° C. for 12 h under N. Saturated aqueous NaHCO (10 mL) was added to the reaction mixture, which was then extracted with EtOAc (5 mL × 3). The organic layer was dried over MgSO and blown dry with N to give N-[1-(5-azido-2-pyridyl)ethyl]thieno[2,3-d]pyrimidin-4-amine (90 mg, crude) as a yellow oil, which was used in the next step without further purification. ESI [M+H] = 298.1. [ka]

[0316] To a solution of N-[1-(5-azido-2-pyridyl)ethyl]thieno[2,3-d]pyrimidin-4-amine (90 mg, 302.69 μmol, 1 equiv.) in t-BuOH (2 mL) and HO (2 mL), ethynylcyclopropane (40 mg, 605.37 μmol, 50.21 μL, 2 equiv.), CuSO 5HO (15 mg, 60.54 μmol, 0.2 equiv.), and sodium ascorbate (12 mg, 60.54 μmol, 0.2 equiv.) were added, and the mixture was stirred at 25 °C for 12 h. Water (10 mL) was added to the reaction mixture, which was then extracted with EtOAc (5 mL × 3). The organic layer was washed with brine (10 mL), dried over MgSO, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge 150 × 25 5u, mobile phase: [water (10 mM NH4HCO3)-ACN], B%: 20% to 50%, 10 min) to give N-[1-[5-(4-cyclopropyltriazol-1-yl)-2-pyridyl]ethyl]thieno[2,3-d]pyrimidin-4-amine (21.6 mg, 58.23 μmol, 19.24% yield, 97.977% purity) as a white solid.

[0317] 1 H-NMR (400MHz, methanol-d4) δ 8.98(d, J=2.3Hz, 1H), 8.30(s, 1H), 8.24(s, 1H), 8.17(dd, J=2.6, 8.5Hz, 1H), 7.68(d, J=6.0Hz, 1H), 7.63(d, J=8.6Hz, 1H), 7 .49(d, J=6.0Hz, 1H), 5.61(q, J=7.1Hz, 1H), 2.10-2.00(m, 1H), 1.70(d, J=7.1Hz, 3H), 1.06-0.98(m, 2H), 0.90-0.83(m, 2H). ESI[M+H]=364.1. Example 26 [ka]

[0318] To a solution of 1-(4-bromo-2-fluoro-phenyl)ethanamine (250 mg, 982.21 μmol, 1 equiv., HCl) in THF (6 mL) was added TEA (397.56 mg, 3.93 mmol, 546.85 μL, 4 equiv.) and benzene-1,2-dicarbonyl chloride (239.29 mg, 1.18 mmol, 169.71 μL, 1.2 equiv.) at 0° C. The mixture was stirred at 25° C. for 12 h, then it was heated to 70° C. and stirred for an additional 24 h. Water (10 mL) was added to the reaction mixture, which was then extracted with EtOAc (10 mL×4). The organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 20 / 1 to 5:1) to give 2-[1-(4-bromo-2-fluorophenyl)ethyl]isoindoline-1,3-dione (150 mg, 430.83 μmol, 43.86% yield) as a yellow oil. ESI [M+H] = 350.0. [ka]

[0319] 2-[1-(4-Bromo-2-fluorophenyl)ethyl]isoindoline-1,3-dione (150 mg, 430.83 μmol, 1 equiv.), 4-methyl-1H-imidazole (70.75 mg, 861.66 μmol, 2 equiv.), CsCO (280.75 mg, 861.66 μmol, 2 equiv.), and CuI (16.41 mg, 86.17 μmol, 0.2 equiv.) were placed in a microwave tube in DMF (4 mL). The sealed tube was heated at 150 °C for 15 h in a microwave oven under N. Water (10 mL) was added to the reaction mixture, which was then extracted with DCM / i-PrOH (3 / 1, 20 mL × 5). The organic phase was dried over NaSO and concentrated in vacuo. The aqueous phase was freeze-dried in vacuo. The residue was purified by preparative HPLC (column: Luna C18 100 × 30 5 μl, mobile phase: [water (0.04% HCl)-ACN], B%: 15% to 45%, 11 min) to give 2-[1-[2-fluoro-4-(4-methylimidazol-1-yl)phenyl]ethyl]isoindoline-1,3-dione (15 mg, 38.88 μmol, 9.02% yield, HCl) as a white solid and 2-[1-[2-fluoro-4-(4-methylimidazol-1-yl)phenyl]ethylcarbamoyl]benzoic acid (140 mg, 346.68 μmol, 80.47% yield, HCl) as a yellow oil. ESI [M+H] = 368.1. [ka]

[0320] To a solution of 2-[1-[2-fluoro-4-(4-methylimidazol-1-yl)phenyl]ethylcarbamoyl]benzoic acid (130 mg, 321.91 μmol, 1 equiv., HCl) in n-BuOH (3 mL) was added NH2NH2·HO (98.66 mg, 1.93 mmol, 95.79 μL, 98% purity, 6 equiv.). The mixture was stirred at 100 °C for 12 h. The reaction mixture was concentrated in vacuo. HO (15 mL) was added to the residue and extracted with EtOAc (20 mL × 4). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give 1-[2-fluoro-4-(4-methylimidazol-1-yl)phenyl]ethanamine (80 mg) as a yellow oil. ESI [M+H] = 220.1. It was combined with another batch of ET22082-126. [ka]

[0321] To a solution of 1-[2-fluoro-4-(4-methylimidazol-1-yl)phenyl]ethanamine (60 mg, 273.65 μmol, 1 equiv) in MeOH (2 mL) and HO (1 mL) was added NaCO (58.01 mg, 547.30 μmol, 2 equiv) and BocO (179.17 mg, 820.95 μmol, 188.60 μL, 3 equiv). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated in vacuo. Water (15 mL) was added to the residue and extracted with EtOAc (20 mL × 4). The organic phase was dried over NaSO and concentrated in vacuo. The residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate=0:1) to give tert-butyl N-[1-[2-fluoro-4-(4-methylimidazol-1-yl)phenyl]ethyl]carbamate (80 mg, 250.49 μmol, 91.54% yield) as a yellow oil. ESI [M+H]=320.2. [ka]

[0322] To a solution of tert-butyl N-[1-[2-fluoro-4-(4-methylimidazol-1-yl)phenyl]ethyl]carbamate (80 mg, 250.49 μmol, 1 equiv.) in EtOAc (3 mL) was added HCl / EtOAc (4 mL) (4 M). The mixture was stirred at 25° C. for 1 h. The reaction mixture was concentrated in vacuo to give 1-[2-fluoro-4-(4-methylimidazol-1-yl)phenyl]ethanamine (60 mg, 234.63 μmol, 93.67% yield, HCl) as a white solid, which was used in the next step without further purification. ESI [M+H] = 220.3. [ka]

[0323] To a solution of 1-[2-fluoro-4-(4-methylimidazol-1-yl)phenyl]ethanamine (60 mg, 234.63 μmol, 1 equiv., HCl) in i-PrOH (2 mL) was added TEA (94.97 mg, 938.53 μmol, 130.63 μL, 4 equiv.) and 4-chlorothieno[2,3-d]pyrimidine (44.04 mg, 258.10 μmol, 1.1 equiv.). The mixture was stirred at 80° C. for 12 hours. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Luna C18 100 × 30 5u, mobile phase: [water (0.04% HCl)-ACN], B%, 5% to 30%, 11 min) to give N-[1-[2-fluoro-4-(4-methylimidazol-1-yl)phenyl]ethyl]thieno[2,3-d]pyrimidin-4-amine (15.36 mg, 39.07 µmol, 16.65% yield, 99.174% purity, HCl) as a white solid.

[0324] 1H-NMR (400 MHz, methanol-d4) δ 9.41 (s, 1H), 8.70 (s, 1H), 7.98 (d, J = 5.7 Hz, 1H), 7.90-7.74 (m, 3H), 7.67 (br d, J = 10.6 Hz, 1H), 7.59 (br d, J = 7.5 Hz, 1H), 5.97 (q, J = 6.9 Hz, 1H), 2.46 (s, 3H), 1.80 (br d, J = 7.0 Hz, 3H). ESI [M+H] = 354.1 and [M / 2+H] = 177.6. Example 27 [ka]

[0325] To a solution of 1-(4-bromophenyl)propan-1-amine (100 mg, 467.07 μmol, 1 equiv.) in i-PrOH (3 mL), TEA (95 mg, 934.14 μmol, 130.02 μL, 2 equiv.) and 4-chlorothieno[2,3-d]pyrimidine (88 mg, 513.77 μmol, 1.1 equiv.) were added. The mixture was stirred at 80° C. for 12 hours. The reaction was concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 1:1) to afford N-[1-(4-bromophenyl)propyl]thieno[2,3-d]pyrimidin-4-amine (160 mg, 459.43 μmol, 98.36% yield) as a yellow oil. ESI [M+H] = 350.0. [ka]

[0326] N-[1-(4-bromophenyl)propyl]thieno[2,3-d]pyrimidin-4-amine (80 mg, 229.71 μmol, 1 equiv.), 4-methyl-1H-imidazole (38 mg, 459.43 μmol, 2 equiv.), CsCO (150 mg, 459.43 μmol, 2 equiv.), and CuI (9 mg, 45.94 μmol, 0.2 equiv.) were placed in a microwave tube in DMF (2 mL). The sealed tube was heated at 150 °C for 10 h in a microwave under N. Water (10 mL) was added to the mixture, which was then extracted with EtOAc (5 mL × 3). The organic layer was dried over MgSO and concentrated in vacuo. The residue was purified by preparative HPLC (column: Xtimate C18 150 × 25 mm × 5 μm, mobile phase: [water (10 mM NH4HCO3)-ACN], B%: 37%-57%, 10 min), and then the residue was purified again by preparative TLC (ethyl acetate:methanol = 10:1) to give N-[1-[4-(4-methylimidazol-1-yl)phenyl]propyl]thieno[2,3-d]pyrimidin-4-amine (27.11 mg, 76.05 μmol, yield 33.11%, purity 98.032%) as a white solid.

[0327] 1 H-NMR (400MHz, chloroform-d) δ 8.47(s, 1H), 7.73(s, 1H), 7.48(d, J=8.4Hz, 2H), 7.36-7.28(m, 3H), 7.20(d, J=6.2Hz, 1H) ), 6.97(s, 1H), 5.46-5.32(m, 2H), 2.29(s, 3H), 2.10-1.93(m, 2H), 1.02(t, J=7.3Hz, 3H). ESI[M+H]=350.1. Example 28 [ka]

[0328] To a solution of 1-(4-bromo-3-methoxyphenyl)ethanone (90 mg, 392.89 μmol, 1 equiv.) and 2-methylpropane-2-sulfinamide (72 mg, 589.34 μmol, 1.5 equiv.) in toluene (1 mL), Ti(OEt) (179 mg, 785.79 μmol, 162.95 μL, 2 equiv.) was added, and the mixture was stirred at 70 °C for 12 h. Water (10 mL) was added to the reaction mixture to form a precipitate, which was filtered and the filtrate extracted with EtOAc (5 mL × 3). The organic layer was washed with brine (10 mL), dried over MgSO, and concentrated in vacuo to give (NZ)-N-[1-(4-bromo-3-methoxyphenyl)ethylidene]-2-methyl-propane-2-sulfinamide (0.13 g, crude) as a yellow oil, which was used in the next step without further purification. ESI[M+H]=334.0. [ka]

[0329] To a solution of (NZ)-N-[1-(4-bromo-3-methoxy-phenyl)ethylidene]-2-methyl-propane-2-sulfinamide (130 mg, 391.26 μmol, 1 equiv.) in MeOH (3 mL) was added NaBH (30 mg, 782.53 μmol, 2 equiv.) at 0 °C for 30 min. The mixture was then stirred at 25 °C for 12 h. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (5 mL × 3). The organic layer was washed with brine (10 mL), dried over MgSO, and concentrated in vacuo to give N-[1-(4-bromo-3-methoxy-phenyl)ethyl]-2-methyl-propane-2-sulfinamide (130 mg, crude) as a yellow oil, which was used in the next step without further purification. ESI [M+H] = 336.1. [ka]

[0330] To a solution of N-[1-(4-bromo-3-methoxy-phenyl)ethyl]-2-methyl-propane-2-sulfinamide (130 mg, 388.91 μmol, 1 equiv) in EtOAc (1 mL) was added HCl / EtOAc (4 M, 5 mL) and the mixture was stirred for 30 minutes at 25° C. The reaction mixture was concentrated in vacuo to give 1-(4-bromo-3-methoxy-phenyl)ethaneamine (100 mg, crude, HCl) as a yellow solid, which was used in the next step without further purification. [ka]

[0331] To a solution of 1-(4-bromo-3-methoxy-phenyl)ethaneamine (100 mg, 375.15 μmol, 1 equiv., HCl) in i-PrOH (2 mL) was added TEA (114 mg, 1.13 mmol, 156.65 μL, 3 equiv.) and 4-chlorothieno[2,3-d]pyrimidine (77 mg, 450.18 μmol, 1.2 equiv.). The mixture was then stirred at 80° C. for 12 hours. The reaction mixture was concentrated in vacuo. The residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate=1:1) to give N-[1-(4-bromo-3-methoxy-phenyl)ethyl]thieno[2,3-d]pyrimidine-4-amine (100 mg, 274.53 μmol, 73.18% yield) as a yellow solid. ESI[M+H]=364.0, ESI[M+3H]=365.9. [ka]

[0332] N-[1-(4-Bromo-3-methoxyphenyl)ethyl]thieno[2,3-d]pyrimidine-4-amine (60 mg, 164.72 μmol, 1 equiv.), 4-methyl-1H-imidazole (27 mg, 329.44 μmol, 2 equiv.), CsCO (107 mg, 329.44 μmol, 2 equiv.), and CuI (6 mg, 32.94 μmol, 0.2 equiv.) were placed in a microwave tube in DMF (2 mL). The sealed tube was heated at 150 °C for 10 h in a microwave under N. Water (10 mL) was added to the reaction mixture, which was then extracted with EtOAc (5 mL × 3). The organic layer was dried over MgSO and concentrated in vacuo. The residue was purified by preparative HPLC (column: Xtimate C18 150 × 25 mm × 5 μm, mobile phase: [water (10 mM NH4HCO3)-ACN], B%: 38%-48%, 10 min) to give N-[1-[3-methoxy-4-(4-methylimidazol-1-yl)phenyl]ethyl]thieno[2,3-d]pyrimidine-4-aminetese (21.3 mg, 56.20 μmol, yield 34.12%, purity 96.427%) as a white solid.

[0333] 1 H-NMR (400MHz, chloroform-d) δ 8.49(s, 1H), 7.65(br s, 1H), 7.40(dd, J=2.1, 8.5Hz, 1H), 7.32-7.27(m, 2H), 7.20(d, J=6.0Hz, 1H), 7.00(d, J=8.4Hz, 1H), 6.90(br s, 1H), 5.68-5.62(m, 1H), 5.62-5.53(m, 1H), 3.83(s, 3H), 2.27(s, 3H), 1.66(d, J=6.8Hz, 3H). ESI[M+H]=366.1. Example 29 [ka]

[0334] To a solution of 5-cyclopropyl-1H-imidazole (2 g, 18.49 mmol, 1 equiv) in DMF (40 mL) was added NaH (740 mg, 18.49 mmol, 60% purity, 1 equiv) at 0 °C. The mixture was stirred at 20 °C for 30 min, then SEM-Cl (3.39 g, 20.34 mmol, 3.60 mL, 1.1 equiv) was added at 0 °C, and the mixture was stirred at 20 °C for 12 h. The reaction mixture was quenched with cold saturated aqueous NH4Cl (30 mL) and extracted with EtOAc (15 mL × 3). The organic layer was washed with brine (30 mL × 1), dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate = 10:1 to 1:1) to give the regioisomers 2-[(5-cyclopropylimidazol-1-yl)methoxy]ethyl-trimethyl-silane and 2-[(4-cyclopropylimidazol-1-yl)methoxy]ethyl-trimethyl-silane as a yellow oil, totaling 3.3 g (74.8% yield), ESI [M+H] = 239.1. [ka]

[0335] To a solution of 2-[(5-cyclopropylimidazol-1-yl)methoxy]ethyl-trimethyl-silane and 2-[(4-cyclopropylimidazol-1-yl)methoxy]ethyl-trimethyl-silane (total 3.3 g, 13.84 mmol, 1 equiv.) in THF (100 mL) was added NBS (2.46 g, 13.84 mmol, 1 equiv.) at −70° C. The mixture was then stirred at −70° C. for 3 h. TLC (petroleum ether:ethyl acetate=0:1) showed the reaction was complete. Water (60 mL) was added to the reaction mixture, which was then extracted with EtOAc (20 mL × 3). The organic phase was washed with brine (50 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 1 / 0 to 10:1) to give a mixture of regioisomers 2-[(4-bromo-5-cyclopropyl-imidazol-1-yl)methoxy]ethyl-trimethyl-silane and 2-[(5-bromo-4-cyclopropyl-imidazol-1-yl)methoxy]ethyl-trimethyl-silane as a yellow oil (2.3 g in total). ESI [M+H] = 317.0. [ka]

[0336] A mixture of 2-[(4-bromo-5-cyclopropyl-imidazol-1-yl)methoxy]ethyl-trimethyl-silane and 2-[(5-bromo-4-cyclopropyl-imidazol-1-yl)methoxy]ethyl-trimethyl-silane (100 mg total), 2-(2,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (74 mg, 378.20 μmol, 1.2 equiv.), and KPO (134 mg, 630.33 μmol, 2 equiv.), and di-tert-butyl(cyclopentyl)phosphane:dichloropalladium:iron (21 mg, 31.52 μmol, 0.1 equiv.) in THF (2 mL) and HO (0.5 mL) was stirred at 80° C. under N for 12 hours. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 10 / 1 to 3:1) to give a total of 0.3 g of 2-[[5-cyclopropyl-4-(2,5-dihydrofuran-3-yl)imidazol-1-yl]methoxy]ethyl-trimethyl-silane and 2-[[4-cyclopropyl-5-(2,5-dihydrofuran-3-yl)imidazol-1-yl]methoxy]ethyl-trimethyl-silane as a yellow oil. ESI [M+H] = 307.2. [ka]

[0337] To a solution of 2-[[5-cyclopropyl-4-(2,5-dihydrofuran-3-yl)imidazol-1-yl]methoxy]ethyl-trimethyl-silane and 2-[[4-cyclopropyl-5-(2,5-dihydrofuran-3-yl)imidazol-1-yl]methoxy]ethyl-trimethyl-silane (total 0.3 g, 0.98 mmol) in MeOH (10 mL) was added Pd / C (0.1 g, 978.87 μmol, 10% purity) under N atmosphere. The suspension was degassed and purged with H three times. The mixture was stirred under H (15 psi) at 15 °C for 6 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a total of 280 mg of 2-[(5-cyclopropyl-4-tetrahydrofuran-3-yl-imidazol-1-yl)methoxy]ethyl-trimethyl-silane and 2-[(4-cyclopropyl-5-tetrahydrofuran-3-yl-imidazol-1-yl)methoxy]ethyl-trimethyl-silane as a yellow oil. ESI [M+H] = 309.3. [ka]

[0338] To a solution of 2-[(5-cyclopropyl-4-tetrahydrofuran-3-yl-imidazol-1-yl)methoxy]ethyl-trimethyl-silane and 2-[(4-cyclopropyl-5-tetrahydrofuran-3-yl-imidazol-1-yl)methoxy]ethyl-trimethyl-silane (total 280 mg) in DCM (6 mL), TFA (2 mL) was added, and the mixture was stirred at 15 °C for 12 hours. The reaction mixture was concentrated in vacuo. To the residue, DCM (5 mL) and water (10 mL) were added, and the pH was adjusted to 8 with saturated aqueous NaHCO3, followed by extraction with DCM (5 mL x 3). The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (SiO, ethyl acetate:methanol=10:1) to give 5-cyclopropyl-4-tetrahydrofuran-3-yl-1H-imidazole (100 mg, 561.07 μmol, 61.82% yield) as a yellow solid. ESI [M+H]=179.3. [ka]

[0339] To a solution of t-BuOK (1 M, 757.45 uL, 1.5 equiv) in DMF (1 mL) was added 4-cyclopropyl-5-tetrahydrofuran-3-yl-1H-imidazole (90 mg, 504.96 umol, 1 equiv) in DMF (0.5 mL) dropwise at 0° C. under N. After 15 min, 5-(iodomethyl)-1,3-dimethyl-benzimidazol-2-one (198 mg, 656.45 umol, 1.3 equiv) in DMF (0.5 mL) was added at 0° C. under N. The mixture was stirred at 20° C. for 12 h. Water (10 mL) was added to the reaction and extracted with EtOAc (5 mL × 3). The organic layer was dried over MgSO and concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge 150 × 25 5u, mobile phase: [water (10 mM NH4HCO3)-ACN], B%: 20%-40%, 7 min) to give 5-[(5-cyclopropyl-4-tetrahydrofuran-3-yl-imidazol-1-yl)methyl]-1,3-dimethyl-benzimidazol-2-one (40.59 mg, 111.53 umol, 22.09% yield, 96.842% purity) and 5-[(4-cyclopropyl-5-tetrahydrofuran-3-yl-imidazol-1-yl)methyl]-1,3-dimethyl-benzimidazol-2-one (24.44 mg, 67.61 umol, 13.39% yield, 97.501% purity) as white solids.

[0340] Bax-81(RS)_HNMR: 1H-NMR (400MHz, chloroform-d) δ 7.33(s, 1H), 6.88-6.79(m, 2H), 6.64(s, 1H), 5.11(s, 2H), 4.03-3.96(m, 2H), 3.87(q, J=7.6Hz, 1H), 3.69(t, J=8.4Hz, 1H), 3.47(quintet, J=8. 4Hz, 1H), 3.33(d, J=12.0Hz, 6H), 2.25-2.06(m, 2H), 1.29(tt, J=5.4, 8.1Hz, 1H), 0.86-0.79(m, 1H), 0.87-0.79(m, 1H), 0.55-0.49(m, 2H). ESI[M+H]=353.1.

[0341] Bax-81A(RS)_HNMR: 1 H-NMR (400MHz, chloroform-d) δ 7.28(s, 1H), 6.84(d, J=8.1Hz, 1H), 6.71(dd, J=1.3, 8.0Hz, 1H), 6.56(s, 1H), 5.04(s, 2H), 3.93(dt, J=4.5, 8.4Hz, 1H), 3.82-3.7 5(m, 1H), 3.73-3.64(m, 2H), 3.32(d, J=15.7Hz, 7H), 2.07-1.89(m, 2H), 1.80-1.71(m, 1H), 0.89-0.83(m, 2H), 0.81-0.73(m, 2H). ESI[M+H]=353.1. Example 30 [ka]

[0342] To a solution of 2-amino-4-methyl-phenol (1 g, 8.12 mmol, 1 equiv.) in MeCN (30 mL) was added CDI (3.95 g, 24.36 mmol, 3 equiv.), and the mixture was stirred at 70 °C for 12 h. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (plate 1, SiO2, petroleum ether / ethyl acetate = 10 / 1 to 2:1) to give 5-methyl-3H-1,3-benzoxazol-2-one (1.2 g, 8.05 mmol, 99.09% yield) as a white solid. ESI [M+H] = 150.1. [ka]

[0343] A mixture of 5-methyl-3H-1,3-benzoxazol-2-one (1.14 g, 7.64 mmol, 1 equiv.), KCO (2.11 g, 15.29 mmol, 2 equiv.), and MeI (1.63 g, 11.47 mmol, 713.75 uL, 1.5 equiv.) in DMF (10 mL) was stirred at 50 °C for 1 h. Water (30 mL) was added to the reaction mixture, and it was extracted with EtOAc (10 mL × 3). The organic layer was washed with brine (20 mL × 3), dried over MgSO, and concentrated in vacuo to give 3,5-dimethyl-1,3-benzoxazol-2-one (1.2 g, 7.35 mmol, 96.21% yield) as a white solid. ESI [M+H] = 164.2. [ka]

[0344] A mixture of 3,5-dimethyl-1,3-benzoxazol-2-one (1.17 g, 7.17 mmol, 1 equiv.), NBS (1.40 g, 7.89 mmol, 1.1 equiv.), and AIBN (117.74 mg, 717.03 μmol, 0.1 equiv.) in CCl4 (20 mL) was stirred at 90 °C under N2 for 2 h. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (plate 1, SiO2, petroleum ether / ethyl acetate = 20 / 1 to 3:1) to give 5-(bromomethyl)-3-methyl-1,3-benzoxazol-2-one (1.9 g, crude). 300 mg of the crude product was purified by preparative TLC (petroleum ether:ethyl acetate = 2:1) to give 5-(bromomethyl)-3-methyl-1,3-benzoxazol-2-one (200 mg, pure).

[0345] 1 H-NMR (400 MHz, chloroform-d) δ 7.08 (d, J = 1.1 Hz, 2H), 6.95 (s, 1H), 4.48 (s, 2H), 3.35 (s, 3H). ESI [M+H] = 243.9. [ka]

[0346] To a solution of t-BuOK (1 M, 681.14 μL, 1.5 equiv.) in DMF (1 mL) (under N2) was added 4-cyclopropyl-5-(2,6-difluorophenyl)-1H-imidazole (100 mg, 454.10 μmol, 1 equiv.) in DMF (1 mL) dropwise under N2 at 0°C. After 15 min, 5-(bromomethyl)-3-methyl-1,3-benzoxazol-2-one (164.88 mg, 681.14 μmol, 1.5 equiv.) in DMF (1 mL) was added at 0°C under N2. The mixture was stirred at 25°C for 12 h. Water (15 mL) was added to the reaction mixture, which was then extracted with 200 mL (40 mL × 5) of EtOAc. The organic phase was dried over Na2SO4 and then concentrated in vacuo. The residue was purified by preparative HPLC (column: Luna C18 100 × 30 5u, mobile phase: [water (0.04% HCl)-ACN], B%: 20% to 33%, 10 min) to give 5-[[5-cyclopropyl-4-(2,6-difluorophenyl)imidazol-1-yl]methyl]-3-methyl-1,3-benzoxazol-2-one (15.31 mg, 34.70 μmol, 7.64% yield, 86.440% purity) and 5-[[4-cyclopropyl-5-(2,6-difluorophenyl)imidazol-1-yl]methyl]-3-methyl-1,3-benzoxazol-2-one (67.01 mg, 170.12 μmol, 37.46% yield, 96.821% purity) as white solids.

[0347] Bax-84_HNMR:1H-NMR(400MHz, methanol-d4) δ 9.21(s, 1H), 7.76-7.54(m, 1H), 7.22-7.02(m, 3H), 6.89-6.65(m, 2H), 5.32(s, 2) H), 3.31-3.30(m, 2H), 1.87-1.70(m, 1H), 1.04-0.88(m, 2H), 0.81-0.67(m, 2H). ESI[M+H]=382.1.

[0348] Bax-84A_HNMR:1H-NMR(400MHz, methanol-d4) δ 9.08(s, 1H), 7.72-7.58(m, 1H), 7.41-7.30(m, 2H), 7.28-7.17(m, 3H), 5.62(s, 2H), 3.42 (s, 3H), 1.82-1.68(m, 1H), 1.31(t, J=7.3Hz, 1H), 1.02-0.90(m, 2H), 0.51-0.36(m, 2H). ESI[M+H]=382.1. Example 31 [ka]

[0349] To a solution of 1-(4-methoxyphenyl)ethanamine (300 mg, 1.98 mmol, 1 equiv.) in i-PrOH (7 mL) was added TEA (401.53 mg, 3.97 mmol, 552.31 μL, 2 equiv.) and 4-chlorothieno[2,3-d]pyrimidine (406.22 mg, 2.38 mmol, 1.2 equiv.). The mixture was stirred at 80 °C for 12 h. The reaction mixture was concentrated in vacuo. The residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate = 1:1) to give N-[1-(4-methoxyphenyl)ethyl]thieno[2,3-d]pyrimidin-4-amine (566 mg, 1.98 mmol, 99.97% yield) as a white solid. ESI [M+H] = 286.1. [ka]

[0350] To a solution of N-[1-(4-methoxyphenyl)ethyl]thieno[2,3-d]pyrimidin-4-amine (300 mg, 1.05 mmol, 1 equiv.) in DCM (3 mL) was added BBr (526.75 mg, 2.10 mmol, 2.10 mL, 100% pure, 2 equiv.) at 0 °C. The mixture was stirred at 15 °C for 2 h. The reaction mixture was poured into ice water (15 mL) and then extracted with DCM (10 mL × 5). The organic phase was dried over NaSO and then concentrated in vacuo. The residue was purified by preparative TLC (SiO, DCM:MeOH = 10:1) to give 4-[1-(thieno[2,3-d]pyrimidin-4-ylamino)ethyl]phenol (170 mg, 626.53 μmol, 59.60% yield) as a yellow solid. ESI[M+H]=272.2. [ka]

[0351] To a solution of 4-[1-(thieno[2,3-d]pyrimidin-4-ylamino)ethyl]phenol (80 mg, 294.84 μmol, 1 equiv.) in DMF (2 mL) was added 3-iodooxetane (86.79 mg, 471.74 μmol, 1.6 equiv.) and Cs2CO3 (192.13 mg, 589.67 μmol, 2 equiv.). The mixture was stirred at 80 °C for 12 h. Water (10 mL) was added to the reaction mixture, which was then extracted with EtOAc (25 mL × 3). The organic phase was dried over Na2SO4 and then concentrated in vacuo. The residue was purified by preparative HPLC (Xtimate C18 150 × 25 mm × 5 μm column, mobile phase: [water (10 mM NH4HCO3)-ACN], B%: 25% to 55%, 10 min) to give N-[1-[4-(oxetan-3-yloxy)phenyl]ethyl]thieno[2,3-d]pyrimidin-4-amine (37.64 mg, 114.29 μmol, 38.76% yield, 99.410% purity) as a white solid. ESI [M+H] = 328.1.

[0352] 1H-NMR (400MHz, chloroform-d) δ 8.49(s, 1H), 7.34(d, J=8.6Hz, 2H), 7.26(s, 1H), 7.30-7.21(m, 1H), 6.68(d, J=8.6Hz, 2H), 5.54(quintet, J=7.0Hz, 1H), 5.32(br d. Example 32 [ka]

[0353] To a solution of 1-(3-bromophenyl)ethanamine (300 mg, 1.27 mmol, 142.86 μL, 1 equiv., HCl) in i-PrOH (7 mL), TEA (385.02 mg, 3.80 mmol, 529.60 μL, 3 equiv.) and 4-chlorothieno[2,3-d]pyrimidine (259.68 mg, 1.52 mmol, 1.2 equiv.) were added. The mixture was stirred at 80° C. for 12 h. The reaction mixture was concentrated in vacuo. The residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate=1:1) to afford N-[1-(3-bromophenyl)ethyl]thieno[2,3-d]pyrimidin-4-amine (360 mg, 1.08 mmol, 84.92% yield) as a white solid. ESI [M+H] = 334.1 and [M+3H] = 336.1. [ka]

[0354] N-[1-(3-bromophenyl)ethyl]thieno[2,3-d]pyridin-4-amine (200 mg, 598.38 umol, 1 equiv.), 3-iodooxetane (330.26 mg, 1.80 mmol, 3 equiv.), TTMSS (148.79 mg, 598.38 umol, 184.61 uL, 1 equiv.), Na2CO3 (126.84 mg, 1.20 mmol, 2 equiv.), dichloronickel:1,2-dimethoxyethane (6.57 mg, 29.92 umol, 0.05 equiv.), 4-te in DME (1 mL). A mixture of rt-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (9.64 mg, 35.90 μmol, 0.06 equiv.) and bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl]phenyl]iridium(1+):4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine:hexafluorophosphate (20.14 mg, 17.95 μmol, 0.03 equiv.) was stirred and irradiated with a 34 W blue LED lamp under N at 25 °C for 12 h. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with 80 mL (20 mL × 4) of EtOAc. The organic phase was dried over NaSO and then concentrated in vacuo. The residue was purified by preparative HPLC (Column: Waters Xbridge 150 × 25 5u, Mobile phase: [water (10 mM NH4HCO3)-ACN], B%: 20% to 50%, 7 min) to give N-[1-[3-(oxetan-3-yl)phenyl]ethyl]thieno[2,3-d]pyrimidin-4-amine (57.51 mg, 184.68 µmol, 30.86% yield, 100% purity) as a white solid. ESI [M+H] = 312.0.

[0355] 1 H-NMR (400MHz, methanol-d4) δ 8.28(s, 1H), 7.67(d, J=6.0Hz, 1H), 7.54-7.41(m, 2H), 7.40-7.25(m, 3H), 5.57(q, J=7.1Hz, 1 H), 5.15-5.02(m, 2H), 4.75(td, J=6.3, 9.2Hz, 2H), 4.35-4.17(m, 1H), 1.66(d, J=7.1Hz, 3H). Example 33 [ka]

[0356] To a solution of methyl 4-[(1S)-1-aminoethyl]benzoate (200 mg, 1.12 mmol, 1 equiv.) in n-BuOH (4 mL), TEA (339 mg, 3.35 mmol, 465.99 μL, 3 equiv.) and 4-chloro-7-fluoro-2-methyl-quinazoline (241 mg, 1.23 mmol, 1.1 equiv.) were added, and the mixture was stirred at 120 °C for 12 h. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 3:1) to give methyl 4-[(1S)-1-[(7-fluoro-2-methyl-quinazolin-4-yl)amino]ethyl]benzoate (0.26 g, 766.14 μmol, 68.65% yield) as a yellow solid. ESI [M+H] = 340.0. [ka]

[0357] To a solution of methyl 4-[(1S)-1-[(7-fluoro-2-methyl-quinazolin-4-yl)amino]ethyl]benzoate (260 mg, 766.14 μmol, 1 equiv.) in MeOH (6 mL) and HO (2 mL), LiOH·HO (64 mg, 1.53 mmol, 2 equiv.) was added, and the mixture was stirred at 15 °C for 12 h. The MeOH was removed, and the aqueous layer was extracted with MTBE (2 mL), then adjusted to pH = 2 with 1 N HCl. A precipitate was formed, filtered, and the filter cake was collected and concentrated in vacuo to give 4-[(1S)-1-[(7-fluoro-2-methyl-quinazolin-4-yl)amino]ethyl]benzoic acid (0.2 g, 614.75 μmol, 80.24% yield) as a yellow solid. ESI [M+H] = 326.1. [ka]

[0358] To a solution of 4-[(1S)-1-[(7-fluoro-2-methyl-quinazolin-4-yl)amino]ethyl]benzoic acid (100 mg, 307.37 μmol, 1 equiv.) in DMF (2 mL) was added DIEA (119 mg, 922.12 μmol, 160.62 μL, 3 equiv.), N'-hydroxycyclopropanecarboxamidine (46 mg, 461.06 μmol, 1.5 equiv.), and HBTU (140 mg, 368.85 μmol, 1.2 equiv.). The mixture was then stirred at 30°C for 12 hours. Water (5 mL) was added to the reaction mixture, which was then extracted with EtOAc (5 mL x 3). The organic layer was washed with brine (10 mL × 2), dried over MgSO4, and concentrated in vacuo to give the crude product [(Z)-[amino(cyclopropyl)methylene]amino]4-[(1S)-1-[(7-fluoro-2-methyl-quinazolin-4-yl)amino]ethyl]benzoate (0.15 g, crude) as a yellow oil, which was used in the next step without further purification. ESI [M+H] = 408.1. [ka]

[0359] To a solution of [(Z)-[amino(cyclopropyl)methylene]amino]4-[(1S)-1-[(7-fluoro-2-methyl-quinazolin-4-yl)amino]ethyl]benzoic acid (150 mg, 368.15 μmol, 1 equiv) in THF (3 mL) was added TBAF (1 M, 1.10 mL, 3 equiv, in THF) and the mixture was stirred at 80° C. for 1 h. The reaction was concentrated in vacuo. The reaction was purified by preparative TLC (petroleum ether:ethyl acetate = 1:1) and then re-purified by preparative HPLC (column: Xtimate C18 150 × 25 mm × 5 μm, mobile phase: [water (10 mM NH4HCO3)-ACN)], B%: 45% to 75%, 8 min) to give N-[(1S)-1-[4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl]ethyl]-7-fluoro-2-methyl-quinazolin-4-amine (41.4 mg, 105.89 μmol, 28.76% yield, 99.602% purity) as a white solid.

[0360] Bax-88 S_HNMR: 1 H-NMR (400MHz, chloroform-d) δ 8.06(d, J=8.1Hz, 2H), 7.72(dd, J=5.6, 8.9Hz, 1H), 7.57(d, J=8.3Hz, 2H), 7.40(dd, J=2.5, 10.1Hz, 1H), 7.17(dt, J=2.4, 8 .6Hz, 1H), 5.80-5.73(m, 1H), 5.73-5.65(m, 1H), 2.56(s, 3H), 2.19-2.10(m, 1H), 1.71(d, J=6.7Hz, 3H), 1.15-1.05(m, 4H). ESI[M+H]=390.2. Example 34 [ka]

[0361] To a solution of acetamidine (655.78 mg, 6.94 mmol, 1 equiv., HCl) in EtOH (20 mL), EtONa (944.04 mg, 13.87 mmol, 2 equiv.) was added, and the mixture was stirred at 80 °C for 10 min. Then, ethyl 2-methyl-3-oxobutanoate (1 g, 6.94 mmol, 980.39 μL, 1 equiv.) was added, and the mixture was stirred at 80 °C for 12 h. The reaction mixture was concentrated in vacuo. Water (10 mL) was added to the residue, and the pH was adjusted to 5–6 with 1 N HCl. The mixture was extracted with DCM / i-PrOH (3 / 1, 10 mL × 5). The organic layer was dried over MgSO and concentrated in vacuo to give 2,5,6-trimethylpyrimidin-4-ol (800 mg, 5.79 mmol, 83.47% yield) as a white solid. ESI[M+H]=139.1. [ka]

[0362] A mixture of 2,5,6-trimethylpyrimidin-4-ol (300 mg, 2.17 mmol, 1 equiv) in POCl (5 mL) was stirred at 100° C. for 1 h. The reaction mixture was concentrated in vacuo to give 4-chloro-2,5,6-trimethyl-pyrimidine (330 mg, crude) as a yellow oil. ESI [M+H]=157.1. [ka]

[0363] To a solution of 4-chloro-2,5,6-trimethyl-pyrimidine (314.60 mg, 2.01 mmol, 1.2 equiv.) in n-BuOH (5 mL), TEA (846.94 mg, 8.37 mmol, 1.16 mL, 5 equiv.) and methyl 4-[(1S)-1-aminoethyl]benzoate (300 mg, 1.67 mmol, 1 equiv.) were added. The mixture was stirred at 120 °C for 24 h. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO2, PE / THF = 30 / 1 to 0:1) to give methyl 4-[(1S)-1-[(2,5,6-trimethylpyrimidin-4-yl)amino]ethyl]benzoate (400 mg, crude) as a yellow oil. ESI [M+H] = 300.1. [ka]

[0364] To a solution of methyl 4-[(1S)-1-[(2,5,6-trimethylpyrimidin-4-yl)amino]ethyl]benzoate (350 mg, 1.17 mmol, 1 equiv.) in MeOH (12 mL) and HO (4 mL) was added LiOH·HO (98.12 mg, 2.34 mmol, 2 equiv.). The mixture was stirred at 30 °C for 4 h. The reaction mixture was concentrated under reduced pressure to remove MeOH and extracted with 60 mL (20 mL × 3) of MTBE. The aqueous phase was adjusted to pH = 2 with 1 N aqueous HCl (cooled water) and extracted with 60 mL (20 × 3) of EtOAc. The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The aqueous phase was then lyophilized. The entire residue was purified by preparative HPLC (column: Phenomenex Luna C18 200 × 40 mm × 10 μm, mobile phase: [water (0.05% HCl)-ACN], B%: 1% to 30%, 10 min) to give 4-[(1S)-1-[(2,5,6-trimethylpyrimidin-4-yl)amino]ethyl]benzoic acid (140 mg, 490.64 μmol, 41.97% yield) as a yellow solid. ESI [M+H] = 286.1. [ka]

[0365] To a solution of 4-[(1S)-1-[(2,5,6-trimethylpyrimidin-4-yl)amino]ethyl]benzoic acid (60 mg, 210.28 μmol, 1 equiv) in DMF (3 mL) was added HBTU (95.69 mg, 252.33 μmol, 1.2 equiv), DIEA (81.53 mg, 630.83 μmol, 109.88 μL, 3 equiv), and N′-hydroxycyclopropanecarboxamidine (31.58 mg, 315.41 μmol, 1.5 equiv), and the mixture was stirred at 25° C. for 12 hours. The mixture was then stirred at 80° C. for 12 hours. The reaction was concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge 150 × 25 5u, mobile phase: [water (10 mM NH4HCO3)-ACN], B%: 15% to 75%, 10 min) to give N-[(1S)-1-[4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl]ethyl]-2,5,6-trimethyl-pyrimidin-4-amine (26.93 mg, 76.32 µmol, 36.30% yield, 99.031% purity) as a white solid. ESI [M+H] = 350.1.

[0366] 1 H-NMR (400MHz, methanol-d4) δ 8.02(d, J=8.3Hz, 2H), 7.59(d, J=8.3Hz, 2H), 5.51(q, J=7.0Hz, 1H), 2.30(d, J=7.6Hz , 6H), 2.12-2.09(m, 1H), 2.19-2.07(m, 3H), 1.60(d, J=7.1Hz, 3H), 1.16-1.03(m, 4H). Example 35 [ka]

[0367] To a solution of (1S)-1-(4-bromophenyl)ethanamine (100 mg, 499.81 μmol, 71.94 μL, 1 equiv) in n-BuOH (3 mL) was added TEA (151.73 mg, 1.50 mmol, 208.70 μL, 3 equiv) and 4-chloro-7-fluoro-2-methyl-quinazoline (108.09 mg, 549.79 μmol, 1.1 equiv), and the mixture was stirred at 120° C. for 12 hours. The reaction was concentrated in vacuo. The residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate=3:1) to give N-[(1S)-1-(4-bromophenyl)ethyl]-7-fluoro-2-methyl-quinazolin-4-amine (100 mg, 277.61 μmol, 55.54% yield) as a yellow solid. ESI [M+H] = 359.9 and [M+3H] = 361.9. [ka]

[0368] N-[(1S)-1-(4-bromophenyl)ethyl]-7-fluoro-2-methyl-quinazolin-4-amine (100 mg, 277.61 umol, 1 equiv.), 3-iodooxetane (153.22 mg, 832.82 umol, 3 equiv.), TTMSS (69.03 mg, 277.61 umol, 85.64 uL, 1 equiv.), NaCO (58.85 mg, 555.21 umol, 2 equiv.), dichloronickel:1,2-dimethoxyethane (3.05 mg, 13.88 umol, 0.05 equiv.) in DME (4 mL). A mixture of bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl]phenyl]iridium(1+):4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine:hexafluorophosphate (9.34 mg, 8.33 umol, 0.03 eq) was stirred and irradiated with a 34 W blue LED lamp under N at 15 °C for 12 h. Water (5 mL) was added to the reaction mixture, and the mixture was extracted with 30 mL (10 mL × 3) of EtOAc. The organic phase was dried over NaSO and then concentrated in vacuo. The residue was purified by preparative HPLC (Xtimate C18 150 x 25 mm x 5 μm column, mobile phase: [water (10 mM NH4HCO3)-ACN], B%: 35%-65%, 8 min) to give 7-fluoro-2-methyl-N-[(1S)-1-[4-(oxetan-3-yl)phenyl]ethyl]quinazolin-4-amine (25.29 mg, 74.96 μmol, 27.00% yield, 100% purity) as a white solid. ESI [M+H] = 338.1

[0369] 1H-NMR (400MHz, methanol-d4) δ 8.30(dd, J=6.0, 9.9Hz, 1H), 7.48-7.42(m, 2H), 7.39-7.34(m, 2H), 7.27-7.20(m, 2H), 5.68(d, J=7.1Hz, 1H), 5 .05(dd, J=6.0, 8.4Hz, 2H), 4.72(dt, J=2.2, 6.3Hz, 2H), 4.29-4.17(m, 1H), 2.45(s, 3H), 1.64(d, J=7.3Hz, 3H). Example 36 [ka]

[0370] A mixture of 2-[(4-bromo-5-cyclopropyl-imidazol-1-yl)methoxy]ethyl-trimethyl-silane and 2-[(5-bromo-4-cyclopropyl-imidazol-1-yl)methoxy]ethyl-trimethyl-silane (total 2 g), (2-chlorophenyl)boronic acid (1.48 g, 9.45 mmol, 1.5 equiv), KPO (0.5 M, 25.21 mL, 2 equiv), and [2-(2-aminophenyl)phenyl]chloropalladium:bis(1-adamantyl)butyl-phosphane (422 mg, 630.33 µmol, 0.1 equiv) in EtOH (60 mL) was stirred under N at 70 °C for 12 h. EtOH was removed, and the mixture was added with water (30 mL) and extracted with EtOAc (30 mL × 3). The organic phase was washed with brine (40 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 4:1) to give a total of 1.5 g of 2-[[4-(2-chlorophenyl)-5-cyclopropyl-imidazol-1-yl]methoxy]ethyl-trimethyl-silane and 2-[[5-(2-chlorophenyl)-4-cyclopropyl-imidazol-1-yl]methoxy]ethyl-trimethyl-silane as a yellow oil. ESI [M+H] = 349.1 [ka]

[0371] To a solution of 1.5 g of 2-[[4-(2-chlorophenyl)-5-cyclopropyl-imidazol-1-yl]methoxy]ethyl-trimethyl-silane and 2-[[5-(2-chlorophenyl)-4-cyclopropyl-imidazol-1-yl]methoxy]ethyl-trimethyl-silane in DCM (24 mL) was added TFA (8 mL), and the mixture was stirred at 15 °C for 12 h. The reaction mixture was concentrated in vacuo. Water (20 mL) was added to the residue, and the pH was adjusted to 8 with saturated aqueous Na2CO3 solution and extracted with EtOAc (10 mL × 3). The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / THF = 10 / 1 to 2:1) to give 4-(2-chlorophenyl)-5-cyclopropyl-1H-imidazole (0.78 g, 3.57 mmol, 82.97% yield) as a yellow solid. ESI[M+H]=219.0. [ka]

[0372] To a solution of 4-(2-chlorophenyl)-5-cyclopropyl-1H-imidazole (500 mg, 2.29 mmol, 1 equiv.) in MeCN (10 mL) was added K2CO3 (632 mg, 4.57 mmol, 2 equiv.) and 4-(bromomethyl)-2-fluoro-1-nitro-benzene (535 mg, 2.29 mmol, 1 equiv.), and the mixture was stirred at 30 °C for 12 h. Next, 4-(bromomethyl)-2-fluoro-1-nitro-benzene (300 mg) was added to the mixture and stirred at 30 °C for 12 h. Water (30 mL) was added to the reaction and extracted with EtOAc (10 mL × 3). The organic phase was washed with brine (30 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 10 / 1 to 1:2) to give 4-(2-chlorophenyl)-5-cyclopropyl-1-[(3-fluoro-4-nitro)-phenyl)methyl]imidazole and 5-(2-chlorophenyl)-4-cyclopropyl-1-[(3-fluoro-4-nitro-phenyl)methyl]imidazole as a yellow oil, a total of 380 mg. ESI [M+H] = 372.0. [ka]

[0373] A solution of 4-(2-chlorophenyl)-5-cyclopropyl-1-[(3-fluoro-4-nitro-phenyl)methyl]imidazole and 5-(2-chlorophenyl)-4-cyclopropyl-1-[(3-fluoro-4-nitro-phenyl)methyl]imidazole (total 230 mg, 618.63 μmol) in EtOH (3 mL) and MeNH (1 mL) (33% purity in EtOH) was stirred at 80° C. for 2 hours. The reaction mixture was concentrated in vacuo to give a total of 210 mg of crude products, 5-[[4-(2-chlorophenyl)-5-cyclopropyl-imidazol-1-yl]methyl]-N-methyl-2-nitro-aniline and 5-[[5-(2-chlorophenyl)-4-cyclopropyl-imidazol-1-yl]methyl]-N-methyl-2-nitro-aniline, as yellow solids, which were used in the next step without further purification. ESI[M+H]=383.0. [ka]

[0374] To a solution of 5-[[4-(2-chlorophenyl)-5-cyclopropyl-imidazol-1-yl]methyl]-N-methyl-2-nitro-aniline and 5-[[5-(2-chlorophenyl)-4-cyclopropyl-imidazol-1-yl]methyl]-N-methyl-2-nitro-aniline (total 210 mg, 548.53 μmol, 1 equiv.) in THF (3 mL), SnCl2·2H2O (372 mg, 1.65 mmol, 3 equiv.) was added and the reaction was stirred for 48 h at 25 °C. The reaction was quenched with cold saturated aqueous NaHCO3 (10 mL), filtered, and the filtrate was extracted with EtOAc (5 mL × 3). The organic layer was dried over MgSO and concentrated in vacuo to give a total of 200 mg of crude products, 4-[[4-(2-chlorophenyl)-5-cyclopropyl-imidazol-1-yl]methyl]-N2-methylbenzene-1,2-diamine and 4-[[5-(2-chlorophenyl)-4-cyclopropyl-imidazol-1-yl]methyl]-N2-methyl-benzene-1,2-diamine, as a yellow oil, which was used in the next step without further purification. ESI [M+H] = 353.0. [ka]

[0375] To a solution of 4-[[4-(2-chlorophenyl)-5-cyclopropyl-imidazol-1-yl]methyl]-N2-methyl-benzene-1,2-diamine and 4-[[5-(2-chlorophenyl)-4-cyclopropyl-imidazol-1-yl]methyl]-N2-methyl-benzene-1,2-diamine (total 100 mg, 283.40 μmol) in MeOH (2.5 mL) was added trimethoxymethane (2.42 g, 22.80 mmol, 2.5 mL, 80.47 equiv) and the mixture was stirred at 25° C. for 12 h. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Kromasil 150 × 25 mm × 10 μm, mobile phase: [water (0.04% NH3H2O ​​+ 10 mM NH4HCO3)-ACN], B%: 30%-50%, 20 min) to give 6-[[5-(2-chlorophenyl)-4-cyclopropyl-imidazol-1-yl]methyl]-1-methyl-benzimidazole (44.76 mg, 122.62 μmol, yield 43.27%, purity 99.405%) as a white solid. The product 2 was then purified again by preparative HPLC (column: Luna C18 100 × 30 5u, mobile phase: [water (0.04% HCl)-ACN], B%: 1% to 30%, 10 min) to give 6-[[4-(2-chlorophenyl)-5-cyclopropyl-imidazol-1-yl]methyl]-1-methyl-benzimidazole (4.75 mg, 11.37 μmol, yield 4.01%, purity 95.557%, HCl) as a white solid.

[0376] Bax-93_HNMR: 1H-NMR (400MHz, メタノール-d4) δ 9.50 (s, 1H), 9.18 (s, 1H), 8.13 (s, 1H), 7.97 (d, J=8.6Hz, 1H), 7.77 (br d, J=8.4Hz, 1H), 7.67-7.61(m, 1H), 7.60-7.47(m, 3H), 5.85(s, 2H), 4.20 (s, 3H), 1.77-1.67 (m, 1H), 0.88 (q, J=6.2Hz, 2H), 0.37 (q, J=5.2Hz, 2H).

[0377] Bax-93A_HNMR: 1 H-NMR (400MHz, クロロホルム-d) δ 7.83 (s, 1H), 7.67-7.61 (m, 1H), 7.52-7.44 (m, 2H), 7.32 (dt, J=1.8, 7.6Hz, 1H), 7.24-7.13 (m, 2H), 6.92-6.8 4(m, 2H), 5.17-4.94(m, 2H), 3.75(s, 3H), 1.59(tt, J=5.0, 8.4Hz, 1H), 0.90-0.82(m, 2H), 0.79-0.68(m, 2H). ESI[M+H]=363.1 Example 37

change

[0378] A mixture of 4-[[4-(2-chlorophenyl)-5-cyclopropyl-imidazol-1-yl]methyl]-N2-methyl-benzene-1,2-diamine and 4-[[5-(2-chlorophenyl)-4-cyclopropyl-imidazol-1-yl]methyl]-N2-methyl-benzene-1,2-diamine (total 90 mg, 255.06 μmol) in EtOH (3 mL) and 5 M HCl (0.5 mL) was heated to 100 °C, and pentane-2,4-dione (51 mg, 510.12 μmol, 52.38 μL, 2 equiv.) was added. The mixture was then stirred at 100 °C for 1 h. The reaction mixture was adjusted to pH = 8 with saturated aqueous NaHCO3, water (10 mL) was added, and extracted with EtOAc (5 mL × 3). The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative HPLC (column: Kromasil 150 × 25 mm × 10 μm, mobile phase: [water (0.04% NH3H2O ​​+ 10 mM NH4HCO3)-ACN], B%: 30%-50%, 20 min) to give 6-[[5-(2-chlorophenyl)-4-cyclopropyl-imidazol-1-yl]methyl]-1,2-dimethyl-benzimidazole (36.85 mg, 95.04 μmol, yield 37.26%, purity 97.201%) as a white solid. The product 2 was then purified again by preparative HPLC (column: Luna C18 100 × 30 5u, mobile phase: [water (0.04% HCl)-ACN], B%: 1% to 30%, 10 min) to give 6-[[4-(2-chlorophenyl)-5-cyclopropyl-imidazol-1-yl]methyl]-1,2-dimethylbenzimidazole (3.33 mg, 7.50 μmol, yield 2.94%, purity 93.037%, HCl) as a white solid.

[0379] Bax-94_HNMR: 1H-NMR (400MHz, メタノール-d4) δ 9.17 (br s, 1H), 8.05 (s, 1H), 7.85 (br d, J=8.4Hz, 1H), 7.69 (br d, J=8.3Hz, 1H), 7.65-7.61 (m, 1H), 7.60-7.47 (m, 3H), 5.82 (s, 2H), 4.04 (s, 3H), 2.90 (s, 3H), 1.71 (br s, 1H), 0.87 (br d, J=7.0Hz, 2H), 0.36 (br d, J=4.6Hz, 2H)

[0380] Bax-94A_HNMR: 1 H-NMR (400MHz, クロロホルム-d) δ 7.53-7.45(m, 3H), 7.32(dt, J=1.8, 7.6Hz, 1H), 7.25-7.14(m, 2H), 6.85-6.77(m, 2H), 5.14-4.91(m, 2H), 3.6 3(s, 3H), 2.58(s, 3H), 1.59(tt, J=5.0, 8.4Hz, 1H), 0.89-0.82(m, 2H), 0.78-0.68(m, 1H), 0.78-0.68(m, 1H). ESI[M+H]=377.1 Example 38

change

[0381] To a solution of 3H-benzimidazol-5-ylmethanol (400 mg, 2.70 mmol, 1 equiv) in DCM (12 mL) was added TEA (546.38 mg, 5.40 mmol, 751.55 μL, 2 equiv), TBDPSCl (890.46 mg, 3.24 mmol, 832.21 μL, 1.2 equiv), and DMAP (32.98 mg, 269.98 μmol, 0.1 equiv). The mixture was stirred at 30 °C for 12 h. Water (15 mL) was added to the reaction mixture, which was then extracted with DCM (20 mL × 3). The organic layer was dried over MgSO and concentrated in vacuo. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 10 / 1 to 0 / 1) to give 3H-benzimidazol-5-ylmethoxy-tert-butyl-diphenyl-silane (910 mg, 2.35 mmol, 87.20% yield) as a colorless oil. ESI [M+H] = 387.1. [ka]

[0382] A mixture of 3H-benzimidazol-5-ylmethoxy-tert-butyl-diphenyl-silane (910 mg, 2.35 mmol, 1 equiv.), cyclopropylboronic acid (404.42 mg, 4.71 mmol, 2 equiv.), Cu(OAc) (427.57 mg, 2.35 mmol, 1 equiv.), 2-(2-pyridyl)pyridine (367.66 mg, 2.35 mmol, 1 equiv.), and NaCO (748.53 mg, 7.06 mmol, 3 equiv.) in DCE (30 mL) was stirred at 70 °C under an O atmosphere (15 psi) for 12 h. Water (30 mL) was added to the reaction mixture, which was then extracted with DCM (40 mL × 4). The organic layer was dried over MgSO and concentrated in vacuo. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 20 / 1 to 0 / 1) to give 697 mg of tert-butyl-[(3-cyclopropylbenzimidazol-5-yl)methoxy]-diphenyl-silane and tert-butyl-[(1-cyclopropylbenzimidazol-5-yl)methoxy]-diphenyl-silane as a yellow oil. ESI [M+H] = 427.2. [ka]

[0383] To a solution of 697 mg of tert-butyl-[(3-cyclopropylbenzimidazol-5-yl)methoxy]-diphenyl-silane and 697 mg of tert-butyl-[(1-cyclopropylbenzimidazol-5-yl)methoxy]-diphenyl-silane in 10 mL of THF was added TBAF (1 M, 3.13 mL, 2 equiv.) in THF. The mixture was stirred at 30 °C for 1 h. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 10 / 1 to 0 / 1) to give 290 mg of (3-cyclopropylbenzimidazol-5-yl)methanol and (1-cyclopropylbenzimidazol-5-yl)methanol as white solids. ESI [M+H] = 189.1. [ka]

[0384] To a solution of a total of 51.64 mg of (3-cyclopropylbenzimidazol-5-yl)methanol and (1-cyclopropylbenzimidazol-5-yl)methanol in Tol (2 mL) was added (1-cyclopropylbenzimidazol-5-yl)methanol (50 mg, 228.64 μmol, 1 equiv.) and 2-(tributyl-phosphanylidene)acetonitrile (110.37 mg, 457.28 μmol, 2 equiv.). The mixture was stirred at 80° C. under N for 3 hours. Water (20 mL) was added to the reaction mixture, which was then extracted with EtOAc (15 mL×3). The organic layer was dried over MgSO and concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100 × 25 mm × 5 μm, mobile phase: [water (10 mM NH4HCO3)-ACN], B%: 35%-55%, 10 min) to give 5-[[5-(2-chlorophenyl)-4-cyclopropyl-imidazol-1-yl]methyl]-1-cyclopropyl-benzimidazole (14.8 mg, 35.12 μmol, yield 15.36%, purity 92.274%) as a white solid.

[0385] Bax-95 C_HNMR: 1H-NMR (400MHz, chloroform-d) δ 7.83(s, 1H), 7.44-7.34(m, 3H), 7.30-7.23(m, 2H), 7.17(d, J=4.2Hz, 2H), 6.88(dd, J=1.3, 8.3Hz, 1H), 5.03-4.96(m, 1H), 4.87-4.79 (m, 1H), 3.28(qd, J=3.5, 7.1Hz, 1H), 1.55-1.46(m, 1H), 1.11-1.04(m, 2H), 0.99-0.90(m, 2H), 0.80-0.73(m, 2H), 0.68-0.62(m, 2H). ESI[M+H]=389.2.

[0386] The product ET22082-326-P2 was re-purified by preparative HPLC (column: Phenomenex Luna C18 150 x 30 mm x 5 um, mobile phase: [water (0.04% HCl)-ACN], B%: 5% to 35%, 10 min) to give 6-[[5-(2-chlorophenyl)-4-cyclopropyl-imidazol-1-yl]methyl]-1-cyclopropyl-benzimidazole (9.03 mg, 15.48 umol, yield 6.77%, purity 72.911%, HCl) as a white solid.

[0387] Bax-95 B_HNMR:1H-NMR (400MHz, chloroform-d) δ 10.24(br s, 1H), 9.84(br s, 1H), 7.92(br s, 1H), 7.71(br d, J=7.8Hz, 1H), 7.53-7.41(m, 2H), 7.34(br s, 1H), 7.16(br d, J=4.4Hz, 1H), 6.92(br d, J=7.8Hz, 1H), 5.64-5.31(m, 2H), 3.63(br s, 1H), 1.64-1.53(m, 1H), 1.31(br s, 4H), 1.03(br d, J=4.5Hz, 2H), 0.89(br d, J=8.1Hz, 2H). ESI[M+H]=389.1. Example 39 [ka]

[0388] To a solution of (1S)-1-(4-bromophenyl)ethanamine (500 mg, 2.50 mmol, 359.71 μL, 1 equiv.) in i-PrOH (15 mL), TEA (506 mg, 5.00 mmol, 695.68 μL, 2 equiv.) and 4-chlorothieno[2,3-d]pyrimidine (512 mg, 3.00 mmol, 1.2 equiv.) were added. The mixture was stirred at 80 °C for 12 h. The reaction was concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 0 / 1 to 3:1) to afford N-[(1S)-1-(4-bromophenyl)ethyl]thieno[2,3-d]pyrimidin-4-amine (700 mg, 2.09 mmol, 83.81% yield) as a yellow solid. ESI [M+H] = 335.9. [ka]

[0389] N-[(1S)-1-(4-bromophenyl)ethyl]thieno[2,3-d]pyrimidin-4-amine (660 mg, 1.97 mmol, 1 equiv.), tert-butyl 3-iodoazetidine-1-carboxylate (1.68 g, 5.92 mmol, 3 equiv.), TTMSS (491 mg, 1.97 mmol, 609.21 uL, 1 equiv.), NaCO (419 mg, 3.95 mmol, 2 equiv.), dichloronickel:1,2-dimethoxyethane (22 mg, 98.73 umol, 0.05 equiv.) in DME (16 mL). A mixture of bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl]phenyl]iridium(1+):4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine:hexafluorophosphate (66 mg, 59.24 umol, 0.03 eq) was stirred and irradiated with a 34 W blue LED lamp under N at 15 °C for 12 h. Water (10 mL) was added to the reaction mixture, which was then extracted with EtOAc (10 mL × 3). The organic phase was dried over NaSO and then concentrated in vacuo. The residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate=1:1) to give tert-butyl 3-[4-[(1S)-1-(thieno[2,3-d]pyrimidin-4-ylamino)ethyl]phenyl]azetidine-1-carboxylate (360 mg, 876.91 μmol, 44.41% yield) as a yellow oil. ESI [M+H]=411.1. [ka]

[0390] To a solution of tert-butyl 3-[4-[(1S)-1-(thieno[2,3-d]pyrimidin-4-ylamino)ethyl]phenyl]azetidine-1-carboxylate (350 mg, 852.55 μmol, 1 equiv.) in MeOH (4 mL) was added HCl / MeOH (4 M, 4 mL). The mixture was stirred at 15° C. for 12 hours. The reaction mixture was concentrated in vacuo to give N-[(1S)-1-[4-(azetidin-3-yl)phenyl]ethyl]thieno[2,3-d]pyrimidin-4-amine (190 mg, 547.74 μmol, 64.25% yield, HCl) as a yellow solid. ESI [M+H]=311.0. [ka]

[0391] To a solution of N-[(1S)-1-[4-(azetidin-3-yl)phenyl]ethyl]thieno[2,3-d]pyrimidin-4-amine (50 mg, 144.14 μmol, 1 equiv., HCl) in DCM (2 mL), TEA (44 mg, 432.43 μmol, 60.19 μL, 3 equiv.) and acetyl chloride (9 mg, 115.31 μmol, 8.23 ​​μL, 0.8 equiv.) were added and the mixture was stirred at 15° C. for 30 minutes. The reaction was quenched with water (5 mL) and extracted with DCM (5 mL × 3). The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge 150 × 25 5u, mobile phase: [water (10 mM NH4HCO3)-ACN], B%: 15% to 45%, 10 min) to give 1-[3-[4-[(1S)-1-(thieno[2,3-d]pyrimidin-4-ylamino)ethyl]phenyl]azetidin-1-yl]ethanone (18.33 mg, 52.01 μmol, yield 36.08%, purity 100%) as a white solid.

[0392] 1H-NMR (400MHz, chloroform-d) δ 8.50(s, 1H), 7.44(d, J=7.5Hz, 2H), 7.34-7.28(m, 3H), 7.17(dd, J=1.1, 6.1Hz, 1H), 5.59(quintet, J=7.0Hz, 1H), 5.37(br d, J=7.3Hz, 1H), 4.52(t, J=8.6Hz, 1H), 4.41(t, J=9.4Hz, 1H), 4.16-4.03(m, 2H), 3.85-3.75(m, 1H), 1.92(d, J=2.6Hz, 3H), 1.68(d, J=6.8Hz, 3H). ESI[M+H]=353.1. Example 40 [ka]

[0393] To a solution of 2-oxo-1,3-dihydrobenzimidazole-5-carboxylic acid (5 g, 28.07 mmol, 1 equiv.) in DMF (120 mL) was added NaH (3.93 g, 98.23 mmol, 60% purity, 3.5 equiv.) at 0 °C. After 30 min, MeI (13.94 g, 98.23 mmol, 6.12 mL, 3.5 equiv.) was added at 0 °C. The mixture was then stirred at 25 °C for 16 h. The reaction was quenched with saturated aqueous NH4Cl (500 mL) and extracted with EtOAc (200 mL × 3). The organic layer was washed with brine (500 mL × 2), dried over MgSO4, and concentrated in vacuo. The residue was triturated with PE / MTBE (50 mL / 5 mL) and the solid precipitate was collected by filtration and dried in vacuo to give methyl 1,3-dimethyl-2-oxo-benzimidazole-5-carboxylate (5.5 g, 24.97 mmol, 88.98% yield) as a brown solid. ESI [M+H] = 221.1. [ka]

[0394] To a solution of methyl 1,3-dimethyl-2-oxo-benzimidazole-5-carboxylate (5.5 g, 24.97 mmol, 1 equiv.) in THF (100 mL) was added LiBH (1.09 g, 49.95 mmol, 2 equiv.) at 20 °C. The mixture was then stirred at 70 °C for 16 h. The reaction was quenched with cold saturated aqueous NH Cl (200 mL) and extracted with EtOAc (100 mL × 3). The organic phase was washed with brine (200 mL), dried over MgSO, and concentrated in vacuo. The residue was triturated with EtOAc / MTBE (1:1, 50 mL) to give 5-(hydroxymethyl)-1,3-dimethyl-benzimidazol-2-one (4.5 g, 23.41 mmol, 93.74% yield) as a pale red solid. ESI [M+H] = 193.1. [ka]

[0395] To a solution of PPh3 (702.74 mg, 2.68 mmol, 1.03 equiv.) in DCM (6 mL) was added I2 (680.03 mg, 2.68 mmol, 539.71 µL, 1.03 equiv.) under N2 at 20 °C. After 5 min, 5-(hydroxymethyl)-1,3-dimethyl-benzimidazol-2-one (0.5 g, 2.60 mmol, 1 equiv.) in DCM (2 mL) was added, and the mixture was stirred at 20 °C for 1 h. The mixture was purified by column chromatography (petroleum ether:ethyl acetate = 10:1 to 2:1) to give 5-(iodomethyl)-1,3-dimethyl-benzimidazol-2-one (670 mg, 2.22 mmol, 85.26% yield) as a yellow solid. ESI [M+H] = 382.1. [ka]

[0396] To a solution of 2-amino-2-(2,6-difluorophenyl)acetic acid (900 mg, 4.81 mmol, 1 equiv.) in THF (16 mL) was added NaOH (577.06 mg, 14.43 mmol, 3 equiv.) in HO (16 mL), followed by the dropwise addition of tert-butoxycarbonyl tert-butyl carbonate (2.10 g, 9.62 mmol, 2.21 mL, 2 equiv.) over 10 min at 0 °C. The mixture was stirred at 15 °C for 2 h. The reaction mixture was concentrated under reduced pressure to remove THF and extracted with 60 mL (20 mL × 3) of MTBE. The aqueous phase was adjusted to pH = 3 with 1 N aqueous HCl (cooled water) and extracted with 60 mL (20 × 3) of EtOAc. The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give 2-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)acetic acid (1.03 g, 3.59 mmol, 74.56% yield) as a white solid, which was used in the next step without further purification. ESI [M-56+H] = 232.1 and [M-100+H] = 188.1. [ka]

[0397] A mixture of 2-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)acetic acid (1.03 g, 3.59 mmol, 1 equiv), HBTU (1.36 g, 3.59 mmol, 1 equiv), HOBt (484.49 mg, 3.59 mmol, 1 equiv), and DIEA (463.41 mg, 3.59 mmol, 624.54 uL, 1 equiv) in DCM (30 mL) was cooled to 0° C. A mixture of N,O-dimethylhydroxylamine hydrochloride (384.73 mg, 3.94 mmol, 1.1 equiv) and DIEA (509.75 mg, 3.94 mmol, 686.99 uL, 1.1 equiv) in DCM (10 mL) was slowly added, degassed, and purged with N three times, then the mixture was stirred under N atmosphere at 30 °C for 12 h. HO (30 mL) was added to the reaction mixture, and it was extracted with 80 mL (20 mL × 4) of DCM. The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 20 / 1 to 2:1) to give tert-butyl N-[1-(2,6-difluorophenyl)-2-[methoxy(methyl)amino]-2-oxo-ethyl]carbamate (1.1 g, 3.33 mmol, 92.87% yield) as a white solid. ESI [M+H] = 331.2. [ka]

[0398] To a solution of tert-butyl N-[1-(2,6-difluorophenyl)-2-[methoxy(methyl)amino]-2-oxo-ethyl]carbamate (1.1 g, 3.33 mmol, 1 equiv.) in THF (30 mL) was added bromo(cyclopropyl)magnesium (1 M, 26.64 mL, 8 equiv.) dropwise at 0 °C, which was degassed and purged with N three times, and then the mixture was stirred under N atmosphere at 30 °C for 24 h. The reaction mixture was quenched by the addition of cold saturated aqueous NH Cl (100 mL) and HO (50 mL) and extracted with 280 mL (70 mL × 4) of EtOAc. The combined organic layers were dried over MgSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate = 20:1 to 3:1) to give the crude product, which was then purified by preparative HPLC (column: Waters Xbridge 150 × 25 5u, mobile phase: [water (10 mM NH4HCO3)-ACN], B%: 45% to 65%, 7 min) to give tert-butyl N-[2-cyclopropyl-1-(2,6-difluorophenyl)-2-oxo-ethyl]-carbamate (400 mg, 1.28 mmol, 38.58% yield) as a white solid. ESI [M+H] = 212.0. [ka]

[0399] To a solution of tert-butyl N-[2-cyclopropyl-1-(2,6-difluorophenyl)-2-oxo-ethyl]carbamate (200 mg, 642.42 μmol, 1 equiv.) in MeOH (2 mL) was added HCl / EtOAc (4 M, 2.41 mL, 15 equiv.). The mixture was stirred at 15° C. for 12 h. The reaction was concentrated in vacuo to give the crude product, 2-amino-1-cyclopropyl-2-(2,6-difluorophenyl)ethanone (135 mg, crude, HCl) as a yellow oil, which was used in the next step without further purification. ESI [M+H] = 212.1. [ka]

[0400] A mixture of acetyl acetate (111.29 mg, 1.09 mmol, 102.10 μL, 2 equiv.) and formic acid (100.35 mg, 2.18 mmol, 82.25 μL, 4 equiv.) was stirred at 15° C. for 30 min, and then added to a solution of 2-amino-1-cyclopropyl-2-(2,6-difluorophenyl)ethanone (135 mg, 545.08 μmol, 1 equiv., HCl) and TEA (551.57 mg, 5.45 mmol, 758.69 μL, 10 equiv.) in DCM (3 mL) at 0° C. The mixture was then stirred at 30° C. for 1 h. Water (10 mL) was added to the reaction mixture, and it was extracted with DCM (20 mL × 4). The organic phase was dried over NaSO and then concentrated in vacuo to give N-[2-cyclopropyl-1-(2,6-difluorophenyl)-2-oxo-ethyl]formamide (120 mg, crude) as a yellow oil, which was used in the next step without further purification. ESI [M+H] = 240.0. [ka]

[0401] To a solution of N-[2-cyclopropyl-1-(2,6-difluorophenyl)-2-oxo-ethyl]formamide (120 mg, 501.64 μmol, 1 equiv.) in AcOH (2 mL) was added acetic acid:ammonia (1.16 g, 15.05 mmol, 30 equiv.). The mixture was stirred at 120° C. for 2 h. HO (5 mL) (cold) was added to the reaction mixture, diluted with saturated aqueous NaCO at 0° C. to adjust the pH to 8, and then extracted with 80 mL (20 mL × 4) of EtOAc. The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO, ethyl acetate:methanol=30:1) to give the crude product 4-cyclopropyl-5-(2,6-difluorophenyl)-1H-imidazole (55 mg, 249.75 μmol, 49.79% yield) as a brown solid, which was used in the next step without further purification. ESI [M+H]=221.2. [ka]

[0402] To a solution of t-BuOK (1 M, 681.14 μL, 1.5 equiv.) in DMF (1 mL) under N was added 4-cyclopropyl-5-(2,6-difluorophenyl)-1H-imidazole (100 mg, 454.10 μmol, 1 equiv.) in DMF (1 mL) dropwise under N at 0° C. After 15 min, 5-(iodomethyl)-1,3-dimethylbenzimidazol-2-one (178.34 mg, 590.33 μmol, 1.3 equiv.) in DMF (1 mL) was added under N at 0° C. The mixture was stirred at 25° C. for 12 h. Water (15 mL) was added to the reaction mixture, which was then extracted with 200 mL (40 mL × 5) of EtOAc. The organic phase was dried over NaSO and then concentrated in vacuo. The residue was purified by preparative HPLC (column: Luna C18 100×30 5 μm, mobile phase: [water (0.05% HCl)-ACN], B%: 1% to 40%, 12 min) to give the desired compound as a white solid, which was further purified by SFC (column: DAICEL CHIRALPAK AD (250 mm×50 mm, 10 μm), mobile phase: [0.1% NH3H2O ETOH], B%: 35% to 35%, 10 min) to give 5-[[5-cyclopropyl-4-(2,6-difluorophenyl)imidazol-1-yl]methyl]-1,3-dimethyl-benzimidazol-2-one (14.01 mg, 35.17 µmol, 7.75% yield, 99.019% purity) and 5-[[4-cyclopropyl-5-(2,6-difluorophenyl)imidazol-1-yl]methyl]-1,3-dimethyl-benzimidazol-2-one (33.61 mg, 85.21 µmol, 18.77% yield) as white solids.

[0403] Bax-100A_HNMR: 1H-NMR (400MHz, クロロホルム-d) δ 7.49 (s, 1H), 7.39-7.29 (m, 1H), 6.98-6.88 (m, 2H), 6.81-6.66 (m, 2H), 6.50 (s, 1H), 4.96 (s, 2H) , 3.38-3.34(m, 3H), 3.32-3.28(m, 3H), 1.59-1.54(m, 1H), 0.90-0.83(m, 2H), 0.79-0.69(m, 2H). ESI[M+H]=395.1.

[0404] Bax-100_HNMR: 1H-NMR (400MHz, クロロホルム-d) δ=7.57(s,1H),7.26-7.11(m,1H),6.93-6.82(m,4H),6.68(s,1H),5.23(s,2H),3.37-3.34(m,3 H), 3.33-3.31(m, 3H), 1.48(ddd, J=2.9, 5.2, 8.2Hz, 1H), 0.69-0.61(m, 2H), 0.29-0.22(m, 2H). ESI[M+H]=395.1. Example 41

change

[0405] To a mixture of bicyclo[3.1.0]hexan-3-one (620 mg, 6.45 mmol, 1 equiv.) in THF (10 mL) stirred at −76° C. under N was added LiHMDS (1 M, 12.90 mL, 2.0 equiv.) in THF dropwise. After 1 h, 1,1,1-trifluoro-N-phenyl-N(trifluoromethylsulfonyl)methanesulfonamide (2.53 g, 7.09 mmol, 1.1 equiv.) in THF (10 mL) was added dropwise to the mixture at −70° C. The resulting mixture was stirred at 20° C. under N for 4 h. The reaction mixture was quenched by the addition of saturated NaHCO solution (50 mL), then diluted with EtOAc (10 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (30 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, PE) to give 3-bicyclo[3.1.0]hex-2-enyl trifluoromethanesulfonate (1.19 g, 5.21 mmol, 80.85% yield) as a colorless oil. (H-NMR spectrum was taken from a pilot batch).

[0406] 1 H-NMR (400 MHz, chloroform-d) δ 5.69 (d, J = 1.8 Hz, 1H), 2.69 (br dd, J = 7.5, 17.2 Hz, 1H), 2.36 (br d, J = 17.1 Hz, 1H), 1.64-1.51 (m, 1H), 1.43-1.33 (m, 1H), 0.78 (dt, J = 4.8, 7.4 Hz, 1H), 0.83-0.74 (m, 1H), 0.04-0.05 (m, 1H). [ka]

[0407] A mixture of 3-bicyclo[3.1.0]hex-2-enyl trifluoromethanesulfonate (1.19 g, 5.21 mmol, 1 equiv.), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.99 g, 7.82 mmol, 1.5 equiv.), AcOK (1.02 g, 10.43 mmol, 2 equiv.), DPPF (173.46 mg, 312.90 µmol, 0.06 equiv.), and Pd(dppf)Cl CHCl (255.52 mg, 312.90 µmol, 0.06 equiv.) in dioxane (20 mL) was stirred at 80 °C under N for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, PE) to give 2-(3-bicyclo[3.1.0]hex-2-enyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (650 mg, 3.15 mmol, 60.48% yield) as a pale yellow oil (H-NMR spectrum taken from a pilot batch).

[0408] 1 H-NMR (400 MHz, chloroform-d) δ 6.85 (br d, J = 2.0 Hz, 1H), 2.88-2.73 (m, 1H), 2.58 (br d, J = 17.4 Hz, 1H), 2.07-1.95 (m, 1H), 1.84-1.75 (m, 1H), 1.38 (s, 12H), 1.01 (dt, J = 3.5, 7.7 Hz, 1H), 0.06-0.04 (m, 1H). [ka]

[0409] 2-(3-bicyclo[3.1.0]hex-2-enyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (150 mg, 727.84 umol, 1.2 equiv.), 2-[(4-bromo-5-cyclopropyl-imidazol-1-yl)methoxy]ethyl-trimethyl-silane (96.23 mg, 303.27 umol, 0.5 equiv.), 2-[(5-bromo-4-cyclopropyl-imidazol-1-yl) A mixture of [2-(2-aminophenyl)phenyl]-chloro-palladium:bis(1-adamantyl)-butyl-phosphane (40.55 mg, 60.65 umol, 0.1 equiv) under N was stirred at 80 °C for 12 h. The reaction mixture was concentrated to give a residue. The residue was purified by preparative TLC (PE: EtOAc = 1: 1, plate 1) to give 2-[[4-(3-bicyclo[3.1.0]hex-2-enyl)-5-cyclopropyl-imidazol-1-yl] methoxy] ethyl-trimethyl-silane and 2-[[5-(3-bicyclo[3.1.0]hex-2-enyl)-4-cyclopropyl-imidazol-1-yl] methoxy] ethyl-trimethyl-silane (regio-mixture, total 130 mg) as a pale yellow oil. ESI [M+H] = 317.2. [ka]

[0410] To a mixture of 2-[[4-(3-bicyclo[3.1.0]hex-2-enyl)-5-cyclopropyl-imidazol-1-yl]methoxy]ethyl-trimethyl-silane (60 mg, 189.57 μmol, 0.5 equiv.) and 2-[[5-(3-bicyclo[3.1.0]hex-2-enyl)-4-cyclopropyl-imidazol-1-yl]methoxy]ethyl-trimethyl-silane (60.00 mg, 189.57 μmol, 0.5 equiv.) (position-mixture, total 120 mg, 1 equiv.) in THF (3 mL) was added TBAF (1 M, 1.52 mL, 4 equiv.) in THF at 15° C., and the resulting mixture was stirred at 70° C. for 12 hours. The reaction mixture was concentrated in vacuo to provide a residue. The residue was purified by preparative TLC (SiO, EtOAc / MeOH = 10 / 1, plate 1) to give 4-(3-bicyclo[3.1.0]hex-2-enyl)-5-cyclopropyl-1H-imidazole (50 mg, 268.45 μmol, 70.81% yield) as a yellow oil. ESI [M+H] = 187.2. [ka]

[0411] To a solution of t-BuOK (1 M, 322.14 μL, 1.5 equiv.) in THF (0.5 mL) in DMF stirred at 0° C. under N was added 4-(3-bicyclo[3.1.0]hex-2-enyl)-5-cyclopropyl-1H-imidazole (40 mg, 214.76 μmol, 1 equiv.) in DMF (0.5 mL) dropwise. After 15 min, 5-(iodomethyl)-1,3-dimethyl-benzimidazol-2-one (77.86 mg, 257.71 μmol, 1.2 equiv.) in DMF (1.5 mL) was added dropwise under N. The resulting mixture was stirred at 15° C. for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150 × 40 mm × 10 μm, mobile phase: [water (0.04% NH3H2O +Purification by elution with 10 mM NH4HCO3)-ACN, B%: 15%-45%, 10 min) gave 5-[[4-(3-bicyclo[3.1.0]hex-2-enyl)-5-cyclopropyl-imidazol-1-yl]methyl]-1,3-dimethyl-benzimidazol-2-one and 5-[[5-(3-bicyclo[3.1.0]hex-2-enyl)-4-cyclopropyl-imidazol-1-yl]methyl]-1,3-dimethyl-benzimidazol-2-one (regio-mixture, total 14.38 mg, purity: 96.935%) as a white solid. ESI [M+H] = 361.1.

[0412] 1 H-NMR (400MHz, methanol-d4) δ 7.56(s, 1H), 7.50(s, 1H), 7.13-7.04(m, 2H), 7.03-6.95(m, 2H), 6.85(s, 1H), 6.78(d, J=8.1Hz, 1H), 6.11(d, J=1.8Hz, 1H), 5.98(d, J=1.8Hz, 1H), 5.30(s, 1H), 5.17(s, 2H), 3.43-3.34(m, 12H), 3.01(br dd, J=6.7, 17.4Hz, 1H), 2.86(br dd, J=7.2, 17.2Hz, 1H), 2.68(br d, J=17.2Hz, 1H), 2.42(br d, J=17.2Hz, 1H), 1.87(br d, J=7.1Hz, 2H), 1.81-1.71(m, 1H), 1.66-1.55(m, 1H), 1.66-1.55(m, 1H), 1.44-1.34(m, 1H), 1.00(dd, J =1.7, 8.0Hz, 2H), 0.91-0.68(m, 7H), 0.57-0.44(m, 2H), -0.06(q, J=3.5Hz, 1H), -0.21(q, J=3.7Hz, 1H). Example 42 [ka]

[0413] To a solution of 2-oxo-1,3-dihydrobenzimidazole-5-carboxylic acid (5 g, 28.07 mmol, 1 equiv.) in DMF (120 mL) was added NaH (3.93 g, 98.23 mmol, 60% purity, 3.5 equiv.) at 0 °C. After 30 min, MeI (13.94 g, 98.23 mmol, 6.12 mL, 3.5 equiv.) was added at 0 °C. The mixture was then stirred at 25 °C for 16 h. The reaction was quenched with saturated aqueous NH4Cl (500 mL) and extracted with EtOAc (200 mL × 3). The organic layer was washed with brine (500 mL × 2), dried over MgSO4, and concentrated in vacuo. The residue was triturated with PE / MTBE (50 mL / 5 mL), and the solid precipitate was collected by filtration and dried in vacuo to give methyl 1,3-dimethyl-2-oxo-benzimidazole-5-carboxylate (5.5 g, 24.97 mmol, 88.98% yield) as a brown solid. ESI [M+H] = 221.1. [ka]

[0414] To a solution of methyl 1,3-dimethyl-2-oxo-benzimidazole-5-carboxylate (5.5 g, 24.97 mmol, 1 equiv.) in THF (100 mL) was added LiBH (1.09 g, 49.95 mmol, 2 equiv.) at 20 °C. The mixture was then stirred at 70 °C for 16 h. The reaction was quenched with cold saturated aqueous NH Cl (200 mL) and extracted with EtOAc (100 mL × 3). The organic phase was washed with brine (200 mL), dried over MgSO, and concentrated in vacuo. The residue was triturated with EtOAc / MTBE (1:1, 50 mL) to give 5-(hydroxymethyl)-1,3-dimethyl-benzimidazol-2-one (4.5 g, 23.41 mmol, 93.74% yield) as a pale red solid. ESI [M+H] = 193.1. [ka]

[0415] To a solution of PPh3 (429.83 mg, 1.64 mmol, 1.05 equiv) in DCM (5 mL) was added I2 (415.94 mg, 1.64 mmol, 330.11 µL, 1.05 equiv) under N2 at 15 °C. After 5 min, 5-(hydroxymethyl)-1,3-dimethyl-benzimidazol-2-one (300 mg, 1.56 mmol, 1 equiv) in DCM (3 mL) was added, and the mixture was stirred at 15 °C for 1 h. The reaction was concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10:1 to 0:1) to afford 5-(iodomethyl)-1,3-dimethyl-benzimidazol-2-one (440 mg, 1.46 mmol, 93.31% yield) as a yellow solid. [ka]

[0416] To a solution of t-BuOK (1 M, 1.09 mL, 1.5 equiv.) in DMF (1 mL) (under N2) was added 4-bromo-1H-benzimidazole (143 mg, 725.77 μmol, 1 equiv.) in DMF (1 mL) dropwise at 0°C under N2. After 15 min, 5-(iodomethyl)-1,3-dimethyl-benzimidazol-2-one (219.26 mg, 725.77 μmol, 1 equiv.) in DMF (1 mL) was added at 0°C under N2. The mixture was stirred at 30°C for 12 h. Water (20 mL) was added to the reaction mixture, which was then extracted with DCM / i-PrOH (3 / 1, 30 mL × 5). The organic phase was dried over Na2SO4 and then concentrated in vacuo. The residue was purified by preparative TLC (SiO, ethyl acetate:methanol=10:1) to give a total of 136 mg of 5-[(4-bromobenzimidazol-1-yl)methyl]-1,3-dimethyl-benzimidazol-2-one and 5-[(7-bromobenzimidazol-1-yl)methyl]-1,3-dimethyl-benzimidazol-2-one as yellow solids. ESI [M+H and M+3H]=371.1 and 373.1. [ka]

[0417] A total of 130 mg of 5-[(4-bromobenzimidazol-1-yl)methyl]-1,3-dimethyl-benzimidazol-2-one and 5-[(7-bromobenzimidazol-1-yl)methyl]-1,3-dimethyl-benzimidazol-2-one, KPO (223.00 mg, 1.05 mmol, 3 equiv), P(Cy) (19.64 mg, 70.04 µmol, 22.71 µL, 0.2 equiv), cyclopropylboronic acid (60.16 mg, 700.37 µmol, 2 equiv), and Pd(OAc) (7.86 mg, 35.02 µmol, 0.1 equiv) in toluene (3 mL) and HO (1 mL) were mixed under N, and the mixture was then stirred at 90 °C for 12 h under N. Water (10 mL) was added to the reaction and extracted with EtOAc (20 mL x 3). The organic phase was dried over Na2SO4 and then concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge 150 × 25 5u, mobile phase: [water (10 mM NH4HCO3)-ACN], B%: 10% to 40%, 10 min) and purified again by preparative HPLC (column: Luna C18 100 × 30 5u, mobile phase: [water (0.04% HCl)-ACN], B%: 10% to 40%, 10 min) to give a total of 16.24 mg of 5-[(4-cyclopropylbenzimidazol-1-yl)methyl]-1,3-dimethyl-benzimidazol-2-one (purity 99.694%) and 5-[(7-cyclopropylbenzimidazol-1-yl)methyl]-1,3-dimethyl-benzimidazol-2-one (purity 99.694%) as a white solid. ESI[M+H]=333.1.

[0418] 1H NMR (400 MHz, methanol-d4) δ 9.58(s, 1H), 9.24(s, 1H), 7.70(dd, J=8.3, 14.3Hz, 2H), 7.61-7.49(m, 2H), 7.41-7.29(m, 3H), 7.26-7.18(m, 4H), 7.09(d, J=8.1Hz, 1H), 6. 19(s, 2H), 5.79(s, 2H), 3.46-3.40(m, 12H), 2.43-2.13(m, 2H), 1.23- 1.16(m, 2H), 1.12-1.05(m, 2H), 0.98-0.93(m, 2H), 0.93-0.88(m, 2H). Example 43 [ka]

[0419] To a solution of 2-oxo-1,3-dihydrobenzimidazole-5-carboxylic acid (5 g, 28.07 mmol, 1 equiv.) in DMF (120 mL) was added NaH (3.93 g, 98.23 mmol, 60% purity, 3.5 equiv.) at 0 °C. After 30 min, MeI (13.94 g, 98.23 mmol, 6.12 mL, 3.5 equiv.) was added at 0 °C. The mixture was then stirred at 25 °C for 16 h. The reaction was quenched with saturated aqueous NH4Cl (500 mL) and extracted with EtOAc (200 mL × 3). The organic layer was washed with brine (500 mL × 2), dried over MgSO4, and concentrated in vacuo. The residue was triturated with PE / MTBE (50 mL / 5 mL), and the solid precipitate was collected by filtration and dried in vacuo to give methyl 1,3-dimethyl-2-oxo-benzimidazole-5-carboxylate (5.5 g, 24.97 mmol, 88.98% yield) as a brown solid. ESI [M+H] = 221.1. [ka]

[0420] To a solution of methyl 1,3-dimethyl-2-oxo-benzimidazole-5-carboxylate (5.5 g, 24.97 mmol, 1 equiv.) in THF (100 mL) was added LiBH (1.09 g, 49.95 mmol, 2 equiv.) at 20 °C. The mixture was then stirred at 70 °C for 16 h. The reaction was quenched with cold saturated aqueous NH Cl (200 mL) and extracted with EtOAc (100 mL × 3). The organic layer was washed with brine (200 mL), dried over MgSO, and concentrated in vacuo. The residue was triturated with EtOAc / MTBE (1:1, 50 mL) to give 5-(hydroxymethyl)-1,3-dimethyl-benzimidazol-2-one (4.5 g, 23.41 mmol, 93.74% yield) as a pale red solid. ESI [M+H] = 193.1. [ka]

[0421] To a solution of PPh3 (573.11 mg, 2.19 mmol, 1.05 equiv) in DCM (3 mL) was added I2 (554.59 mg, 2.19 mmol, 440.15 µL, 1.05 equiv) under N2 at 15 °C. After 5 min, 5-(hydroxymethyl)-1,3-dimethyl-benzimidazol-2-one (400 mg, 2.08 mmol, 1 equiv) in DCM (2 mL) was added, and the mixture was stirred at 15 °C for 1 h. The reaction was concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10:1 to 0:1) to afford 5-(iodomethyl)-1,3-dimethyl-benzimidazol-2-one (550 mg, 1.82 mmol, 87.48% yield) as a yellow solid. [ka]

[0422] To a solution of t-BuOK (1 M, 913.56 μL, 1.5 equiv.) in DMF (1 mL) (under N2) was added 5-bromo-1H-benzimidazole (120 mg, 609.04 μmol, 1 equiv.) in DMF (1 mL) dropwise at 0°C under N2. After 15 min, 5-(iodomethyl)-1,3-dimethylbenzimidazol-2-one (184.00 mg, 609.04 μmol, 1 equiv.) in DMF (1 mL) was added at 0°C under N2. The mixture was stirred at 30°C for 12 h. Water (20 mL) was added to the reaction mixture, which was then extracted with DCM / i-PrOH (3 / 1, 30 mL × 5). The organic phase was dried over Na2SO4 and then concentrated in vacuo. The residue was purified by preparative TLC (SiO, ethyl acetate:methanol=15:1) to give a total of 135 mg of 5-[(5-bromobenzimidazol-1-yl)methyl]-1,3-dimethyl-benzimidazol-2-one and 5-[(6-bromobenzimidazol-1-yl)methyl]-1,3-dimethyl-benzimidazol-2-one as yellow oils. ESI [M+H and M+3H] = 370.9 and 372.9. [ka]

[0423] A mixture of 135 mg of 5-[(5-bromobenzimidazol-1-yl)methyl]-1,3-dimethyl-benzimidazol-2-one and 5-[(6-bromobenzimidazol-1-yl)methyl]-1,3-dimethyl-benzimidazol-2-one, KPO (231.58 mg, 1.09 mmol, 3 equiv), P(Cy) (20.40 mg, 72.73 µmol, 23.58 µL, 0.2 equiv), cyclopropylboronic acid (93.71 mg, 1.09 mmol, 3 equiv), and Pd(OAC) (8.16 mg, 36.37 µmol, 0.1 equiv) in toluene (3 mL) and HO (1 mL) was stirred at 90 °C for 12 h under a N atmosphere. Water (10 mL) was added to the reaction mixture and extracted with EtOAc (15 mL × 4). The organic layer was dried over NaSO and concentrated in vacuo. The residue was purified by preparative HPLC (Column: Xtimate C18 150 × 25 mm × 5 μm, Mobile phase: [water (10 mM NHHCO)-ACN], B%: 30% to 60%, 8 min) to give a total of 20.93 mg (purity 99.664%) of 5-[(5-cyclopropylbenzimidazol-1-yl)methyl]-1,3-dimethyl-benzimidazol-2-one (purity 99.664%) and 5-[(6-cyclopropylbenzimidazol-1-yl)methyl]-1,3-dimethyl-benzimidazol-2-one (purity 99.664%) as white solids. ESI [M+H] = 333.1.

[0424] 1 H NMR (400MHz, methanol-d4) δ 8.23(s, 1H), 8.20(s, 1H), 7.54(d, J=8.4Hz, 1H), 7.40-7.31(m, 2H), 7.21(s, 1H), 7.15-7.09(m, 6H), 7.02(dt, J=1.5, 8.3Hz, 2H), 5.5 1(s, 4H), 3.41-3.40(m, 6H), 3.38(d, J=2.8Hz, 6H), 2.01(ddd, J=3.0, 5.3, 8.3Hz, 2H), 1.01-0.91(m, 4H), 0.68(dt, J=1.8, 5.7Hz, 4H). Example 44 [ka]

[0425] To a total of 2 g of 2-[(4-bromo-5-cyclopropyl-imidazol-1-yl)methoxy]ethyl-trimethyl-silane and 2-[(5-bromo-4-cyclopropyl-imidazol-1-yl)methoxy]ethyl-trimethyl-silane in DCM (18 mL) was added TFA (9.24 g, 81.04 mmol, 6 mL, 12.86 equiv). The mixture was stirred at 25 °C for 24 hours. The reaction mixture was concentrated in vacuo to give a residue. Water (30 mL) was added to the residue, and the pH was adjusted to 8 with saturated aqueous NaHCO3, followed by extraction with DCM (50 mL x 5). The organic phase was dried over Na2SO4 and then concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate / THF = 10:1:0 to 1:2:1) to give 4-bromo-5-cyclopropyl-1H-imidazole (1.07 g, 5.72 mmol, 90.76% yield) as a white solid. ESI [M+H] = 187.1, [M+3H] = 189.1. [ka]

[0426] To a solution of 4-bromo-5-cyclopropyl-1H-imidazole (1.07 g, 5.72 mmol, 1 equiv.) in MeCN (40 mL) was added K2CO3 (1.58 g, 11.44 mmol, 2 equiv.) and 4-(bromomethyl)-2-fluoro-1-nitro-benzene (1.34 g, 5.72 mmol, 1 equiv.), and the mixture was stirred at 30 °C for 12 h. Water (30 mL) was added to the reaction mixture, which was then extracted with EtOAc (30 mL × 5). The organic layer was dried over MgSO4 and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 20 / 1 to 0:1), and then the residue was purified again by preparative HPLC (column: Xtimate C18 10μ 250 mm × 50 mm, mobile phase: [water (10 mM NH4HCO3)-ACN], B%: 30% to 60%, 20 min) to give 4-bromo-5-cyclopropyl-1-[(3-fluoro-4-nitro-phenyl)methyl]imidazole (330 mg, 970.17 μmol, 16.96% yield) as a white solid and 5-bromo-4-cyclopropyl-1-[(3-fluoro-4-nitro-phenyl)methyl]imidazole (870 mg, 2.56 mmol, 44.71% yield) as a yellow solid.

[0427] 3A's 1 H-NMR: 1 H-NMR (400 MHz, methanol-d₄) δ 8.10 (t, J = 8.1 Hz, 1H), 7.87 (s, 1H), 7.19 (d, J = 11.7 Hz, 1H), 7.14-7.08 (m, 1H), 5.35 (s, 2H), 1.87-1.77 (m, 1H), 0.92-0.86 (m, 2H), 0.85-0.80 (m, 2H).

[0428] of 3 1 H-NMR: 1H-NMR (400MHz, methanol-d4) δ 8.11(t, J=8.1Hz, 1H), 7.74(s, 1H), 7.24(br d, J=11.7Hz, 1H), 7.16-7.11(m, 1H), 5.44(s, 2H), 1.34(tt, J=5.2, 8.2Hz, 1H), 0.93-0.85(m, 2H), 0.77-0.71(m, 2H). ESI[M+H]=340.0, [M+3H]=342.0. [ka]

[0429] To a solution of 4-bromo-5-cyclopropyl-1-[(3-fluoro-4-nitro-phenyl)methyl]imidazole (330 mg, 970.17 μmol, 1 equiv.) in EtOH (4 mL) was added MeNH2 (1.38 g, 14.61 mmol, 2 mL, 15.06 equiv., 33% in EtOH). The mixture was stirred at 80 °C for 1.5 h. The reaction was concentrated in vacuo to give 5-[(4-bromo-5-cyclopropyl-imidazol-1-yl)methyl]-N-methyl-2-nitro-aniline (340 mg, crude) as a yellow solid, which was used in the next step without further purification. ESI [M+H] = 351.1, [M+3H] = 353.1 [ka]

[0430] To a solution of 5-[(4-bromo-5-cyclopropyl-imidazol-1-yl)methyl]-N-methyl-2-nitro-aniline (340 mg, 968.12 μmol, 1 equiv.) in THF (10 mL) was added SnCl₂·2H₂O (655 mg, 2.90 mmol, 3 equiv.). The mixture was stirred at 30 °C under a N₂ atmosphere for 60 h. The reaction was quenched with cold saturated aqueous NaHCO₃ (15 mL), filtered, and the filtrate was added with water (10 mL) and extracted with EtOAc (20 mL × 4). The organic layer was dried over MgSO₄ and concentrated in vacuo to give 4-[(4-bromo-5-cyclopropyl-imidazol-1-yl)methyl]-N₂-methylbenzene-1,2-diamine (290 mg, 902.82 μmol, 93.26% yield) as a yellow solid. ESI[M+H]=321.1, [M+H]=323.1. [ka]

[0431] To 4-[(4-bromo-5-cyclopropyl-imidazol-1-yl)methyl]-N2-methyl-benzene-1,2-diamine (280 mg, 871.69 μmol, 1 equiv.) in MeOH (7 mL) was added trimethoxymethane (6.78 g, 63.85 mmol, 7 mL, 73.25 equiv.). The mixture was stirred at 70 °C for 72 h. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / THF = 10 / 1 to 0 / 1) to give 6-[(4-bromo-5-cyclopropyl-imidazol-1-yl)methyl]-1-methyl-benzimidazole (280 mg, 845.39 μmol, 96.98% yield) as a yellow oil. ESI [M+H] = 331.0, [M+H] = 332.9. [ka]

[0432] A mixture of 6-[(4-bromo-5-cyclopropyl-imidazol-1-yl)methyl]-1-methyl-benzimidazole (40 mg, 120.77 μmol, 1 equiv), (2,5-difluorophenyl)boronic acid (38 mg, 241.54 μmol, 2 equiv), [2-(2-aminophenyl)phenyl]-chloro-palladium:bis(1-adamantyl)-butyl-phosphane (8 mg, 12.08 μmol, 0.1 equiv), KPO (0.5 M, 483.80 μL, 2 equiv) in EtOH (2 mL) was stirred at 80° C. under a N atmosphere for 12 hours. The reaction was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: mobile phase: [water (10 mM NH4HCO3)-ACN], B%: 45-65%, 10 min) to give 6-[[5-cyclopropyl-4)-(2,5-difluorophenyl)imidazol-1-yl]methyl]-1-methyl-benzimidazole (20.97 mg, 54.82 μmol, yield 45.39%, purity 95.251%) as a white solid.

[0433] 1 H-NMR (400 MHz, chloroform-d) δ 7.57 (s, 1H), 7.49 (d, J = 8.4 Hz, 1H), 6.99 (ddd, J = 3.1, 5.7, 9.0 Hz, 1H), 6.95-6.94 (m, 1H), 6.89 (dd, J = 1.4, 8.3 Hz, 1H), 6.78 (s, 1H), 6.76-6.69 (m, 1H), 6.67-6.60 (m, 1H), 5.09 (s, 2H), 3.49 (s, 3H), 1.27 (tt, J = 5.3, 8.2 Hz, 1H), 0.54-0.45 (m, 2H), 0.07-0.03 (m, 2H). ESI[M+H]=365.1. [ka]

[0434] A mixture of 6-[(4-bromo-5-cyclopropyl-imidazol-1-yl)methyl]-1-methyl-benzimidazole (40 mg, 120.77 μmol, 1 equiv), (2,3-difluorophenyl)boronic acid (38 mg, 241.54 μmol, 2 equiv), [2-(2-aminophenyl)phenyl]-chloro-palladium:bis(1-adamantyl)-butyl-phosphane (8 mg, 12.08 μmol, 0.1 equiv), KPO (0.5 M, 483.80 μL, 2 equiv) in EtOH (2 mL) was stirred at 80° C. under a N atmosphere for 12 hours. The reaction was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: mobile phase: [water (10 mM NH4HCO3)-ACN], B%: 45-65%, 10 min) to give 6-[[5-cyclopropyl-4)-(2,3-difluorophenyl)imidazol-1-yl]methyl]-1-methyl-benzimidazole (20.06 mg, 51.43 μmol, yield 42.58%, purity 93.420%) as a white solid.

[0435] 1 H-NMR (400MHz, chloroform-d) δ 7.58(s, 1H), 7.50(d, J=8.2Hz, 1H), 7.08-7.02(m, 1H), 6.96(s, 1H), 6.90(dd, J=1.2, 8.3Hz, 1H), 6.8 3-6.75(m, 3H), 5.10(s, 2H), 3.50(s, 3H), 1.33-1.25(m, 2H), 0.54-0.46(m, 2H), 0.05--0.01(m, 2H). ESI[M+H]=365.1. Example 45 [ka]

[0436] A solution of Na (116 mg, 5.05 mmol, 119.57 μL, 1 equiv.) in MeOH (20 mL) was stirred for 20 min, then diethyl 2-prop-2-ynylpropanedioate (1 g, 5.05 mmol, 1 equiv.) and acetamidine hydrochloride (477 mg, 5.05 mmol, 1 equiv.) were added. The mixture was stirred at 70 °C for 12 h. A precipitate formed, which was collected by filtration and dissolved in 20 mL of water. The solution was adjusted to pH = 3 with 1 N HCl. The mixture was then filtered, and the filter cake was collected to give 4-hydroxy-2-methyl-5-prop-2-ynyl-1H-pyrimidin-6-one (150 mg, 913.74 μmol, 18.11% yield) as a white solid. ESI [M+H] = 165.2. [ka]

[0437] A solution of 4-hydroxy-2-methyl-5-prop-2-ynyl-1H-pyrimidin-6-one (150 mg, 913.74 μmol, 1 equiv) in HSO (1.5 mL) was stirred at 30° C. for 6 hours. The reaction mixture was quenched with cold water (20 mL) and extracted with DCM (30 mL × 5). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give 2,6-dimethyl-3H-furo[2,3-d]pyrimidin-4-one (116 mg, crude) as a white solid. [ka]

[0438] A solution of 2,6-dimethyl-3H-furo[2,3-d]pyrimidin-4-one (100 mg, 609.16 μmol, 1 equiv) in POCl (2 mL) was stirred at 110° C. for 1 h. The reaction was concentrated in vacuo to give the crude product, 4-chloro-2,6-dimethyl-furo[2,3-d]pyrimidine (110 mg, brown oil), which was used in the next step without further purification. [ka]

[0439] To a solution of 4-chloro-2,6-dimethyl-furo[2,3-d]pyrimidine (110 mg, 602.39 μmol, 1 equiv) in n-BuOH (3 mL) was added TEA (244 mg, 2.41 mmol, 335.38 μL, 4 equiv) and methyl 4-[(1S)-1-aminoethyl]benzoate (162 mg, 903.58 μmol, 1.5 equiv). The mixture was stirred at 120 °C for 12 hours. The reaction was concentrated in vacuo to give a residue. The residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate = 1:1) to give methyl 4-[(1S)-1-[(2,6-dimethylfuro[2,3-d]pyrimidin-4-yl)amino]ethyl]benzoate (130 mg, 399.56 μmol, 66.33% yield) as a yellow oil. ESI[M+H]=326.2. [ka]

[0440] To a solution of methyl 4-[(1S)-1-[(2,6-dimethylfuro[2,3-d]pyrimidin-4-yl)amino]ethyl]benzoate (130 mg, 399.56 μmol, 1 equiv.) in MeOH (3 mL) and HO (1 mL), LiOH·HO (34 mg, 799.11 μmol, 2 equiv.) was added. The mixture was stirred at 30 °C for 4 h. The reaction mixture was concentrated under reduced pressure to remove MeOH and extracted with MTBE (20 mL × 2). The aqueous phase was adjusted to pH = 2 with 1 N aqueous HCl and extracted with DCM / i-PrOH (3 / 1, 20 mL × 5). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give 4-[(1S)-1-[(2,6-dimethylfuro[2,3-d]pyrimidin-4-yl)amino]ethyl]benzoic acid (120 mg, 385.44 μmol, 96.47% yield) as a yellow solid. ESI [M+H] = 312.2. [ka]

[0441] To a solution of 4-[(1S)-1-[(2,6-dimethylfuro[2,3-d]pyrimidin-4-yl)amino]ethyl]benzoic acid (80 mg, 256.96 μmol, 1 equiv) in DMF (3 mL), DIEA (100 mg, 770.88 μmol, 134.27 μL, 3 equiv), HBTU (117 mg, 308.35 μmol, 1.2 equiv), and N'-hydroxycyclopropanecarboxamidine (39 mg, 385.44 μmol, 1.5 equiv) were added, and the mixture was stirred at 30°C for 12 h. Water (10 mL) was added to the reaction mixture, which was then extracted with EtOAc (10 mL x 4). The organic layer was washed with brine (30 mL), dried over MgSO4, and concentrated in vacuo to give [(Z)-[amino(cyclopropyl)methylene]amino]4-[(1S)-1-[(2,6-dimethylfuro[2,3-d]pyrimidin-4-yl)amino]ethyl]benzoate (100 mg, crude) as a brown oil. ESI [M+H] = 394.1 [ka]

[0442] To a solution of [(Z)-[amino(cyclopropyl)methylene]amino]4-[(1S)-1-[(2,6-dimethylfuro[2,3-d]pyrimidin-4-yl)amino]ethyl]benzoate (100 mg, 254.17 μmol, 1 equiv.) in THF (3 mL) was added TBAF (1 M, 762.51 μL, 3 equiv.) in THF. The mixture was stirred at 80° C. for 1 hour. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate = 0:1), and then the residue was purified again by preparative HPLC (column: Waters Xbridge 150 × 25 5u, mobile phase: [water (10 mM NHHCO)-ACN], B%: 35%-65%, 10 min) to give N-[(1S)-1-[4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl]ethyl]-2,6-dimethyl-furo[2,3-d]pyrimidin-4-amine (43.04 mg, 114.64 μmol, 45.11% yield, 100% purity) as a white solid.

[0443] 1 H-NMR (400MHz, chloroform-d) δ 8.05(d, J=8.4Hz, 2H), 7.52(d, J=8.4Hz, 2H), 6.05(s, 1H), 5.45-5.31(m, 1H), 5.19(br d, J=5.1Hz, 1H), 2.52(s, 3H), 2.35(s, 3H), 2.19-2.04(m, 1H), 1.64(d, J=6.8Hz, 3H), 1.13-1.05(m, 4H). ESI[M+H]=376.1. Example 46 [ka]

[0444] A mixture of diethyl 2-prop-2-ynylpropanedioate (5 g, 25.23 mmol, 1 equiv.) and guanidine carbonate (2.50 g, 13.88 mmol, 0.55 equiv.) in EtOH (50 mL) was stirred at 80 °C for 72 h under N2. The reaction mixture was cooled to 15 °C, filtered, and the filter cake was collected and then dissolved in water (10 mL). The aqueous layer was adjusted to pH = 3 with 0.5 M HCl, and a precipitate formed. It was filtered, and the filter cake was collected and concentrated in vacuo to give 2-amino-4-hydroxy-5-prop-2-ynyl-1H-pyrimidin-6-one (1 g, 6.06 mmol, 24.00% yield) as a pale red solid. ESI [M+H] = 166.2. [ka]

[0445] A solution of 2-amino-4-hydroxy-5-prop-2-ynyl-1H-pyrimidin-6-one (1.2 g, 7.27 mmol, 1 equiv.) in concentrated H2SO4 (10 mL) was stirred at 25 °C for 12 h. The reaction mixture was added dropwise to cold water (20 mL). 5N NaOH solution was then added dropwise to the mixture until a precipitate formed. The precipitate was filtered, and the filter cake was collected and concentrated in vacuo. The crude product, 2-amino-6-methyl-3H-furo[2,3-d]pyrimidin-4-one (0.4 g, crude), a red solid, was used in the next step without further purification. ESI [M+H] = 166.1. [ka]

[0446] To a mixture of 2-amino-6-methyl-3H-furo[2,3-d]pyrimidin-4-one (0.4 g, 2.42 mmol, 1 equiv.), DBU (737.45 mg, 4.84 mmol, 730.15 uL, 2 equiv.), and BOP (1.29 g, 2.91 mmol, 1.2 equiv.) in DMF (10 mL) and DMSO (10 mL), methyl 4-[(1S)-1-aminoethyl]benzoate (1.30 g, 7.27 mmol, 3 equiv.) was added, and the mixture was stirred at 30 °C for 12 h. The reaction mixture was then heated to 60 °C for 12 h. Water (30 mL) was added to the reaction mixture, and it was extracted with EtOAc (20 mL × 3). The organic layer was washed with brine (50 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography (plate 1, SiO2, petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give methyl 4-[(1S)-1-[(2-amino-6-methyl-furo[2,3-d]pyrimidin-4-yl)amino]ethyl]benzoate (0.6 g, 1.84 mmol, 75.91% yield) as a yellow oil. ESI [M+H] = 327.2. [ka]

[0447] To a solution of methyl 4-[(1S)-1-[(2-amino-6-methyl-furo[2,3-d]pyrimidin-4-yl)amino]ethyl]benzoate (0.6 g, 1.84 mmol, 1 equiv.) in MeOH (15 mL) and HO (5 mL), LiOH·HO (154.30 mg, 3.68 mmol, 2 equiv.) was added, and the mixture was stirred at 30 °C for 12 h. MeOH was removed, and the aqueous layer was washed with MTBE (5 mL × 2), then adjusted to pH ∼2 with 1 N HCl and extracted with EtOAc (10 mL × 3). The organic layer was dried over MgSO4 and concentrated in vacuo to give 4-[(1S)-1-[(2-amino-6-methyl-furo[2,3-d]pyrimidin-4-yl)amino]ethyl]benzoic acid (0.4 g, 1.28 mmol, 69.66% yield) as a yellow solid. ESI [M+H] = 313.1. [ka]

[0448] To a mixture of 4-[(1S)-1-[(2-amino-6-methyl-furo[2,3-d]pyrimidin-4-yl)amino]ethyl]benzoic acid (170 mg, 544.31 μmol, 1 equiv.), DIEA (211.04 mg, 1.63 mmol, 284.43 μL, 3 equiv.), and N'-hydroxycyclopropanecarboxamidine (81.74 mg, 816.46 μmol, 1.5 equiv.) in DMF (5 mL) was added HBTU (247.71 mg, 653.17 μmol, 1.2 equiv.). The mixture was then stirred at 30 °C for 12 h. Water (20 mL) was added to the reaction mixture, which was then extracted with EtOAc (20 mL × 5). The organic layer was washed with brine (20 mL × 2), dried over MgSO and concentrated in vacuo to give [(Z)-[amino(cyclopropyl)methylene]amino]4-[(1S)-1-[(2-amino-6-methyl-furo[2,3-d]pyrimidin-4-yl)amino]ethyl]benzoate (0.4 g, crude) as a yellow solid, which was used in the next step without further purification. ESI [M+H] = 395.1. [ka]

[0449] To a solution of [(Z)-[amino(cyclopropyl)methylene]amino]4-[(1S)-1-[(2-amino-6-methyl-furo[2,3-d]pyrimidin-4-yl)amino]ethyl]benzoate (0.4 g, 1.01 mmol, 1 equiv.) in THF (6 mL) was added TBAF (1 M, 2.03 mL, 2 equiv.), and the mixture was stirred at 80 °C for 1 h. The reaction was concentrated in vacuo. The residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate = 0:1) to afford N-[(1S)-1-[4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl]ethyl]-6-methyl-furo[2,3-d]pyrimidine-2,4-diamine (200 mg, 531.33 μmol, 52.39% yield) as a yellow oil. ESI[M+H]=377.1. [ka]

[0450] To a solution of N4-[(1S)-1-[4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl]ethyl]-6-methyl-furo[2,3-d]pyrimidine-2,4-diamine (70 mg, 185.97 μmol, 1 equiv) in pyridine (0.3 mL) was added pyridine hydrofluoride (660.00 mg, 6.66 mmol, 0.6 mL, 35.81 equiv) at −50° C., and the mixture was stirred at −25° C. for 15 min. Next, tert-butyl nitrite (38.35 mg, 371.93 μmol, 44.24 μL, 2 equiv) was added at −25° C. The mixture was stirred at 15° C. for 1 h. Cold water (15 mL) was added, and the reaction mixture was then adjusted to pH = 8 with saturated aqueous NaHCO3 and extracted with DCM (15 mL × 4). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150 × 30 mm × 5 μm, mobile phase: [water (0.04% HCl)-ACN], B%: 45% to 80%, 10 min) to give N-[(1S)-1-[4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl]ethyl]-2-fluoro-6-methyl-furo[2,3-d]pyrimidin-4-amine (16.18 mg, 42.65 μmol, 22.93% yield, 100% purity) as a white solid.

[0451] 1 H-NMR (400MHz, chloroform-d) δ 8.09(br d, J=8.2Hz, 2H), 7.54(br d, J=8.2Hz, 2H), 6.18(br s, 1H), 5.51-5.28(m, 2H), 2.41(s, 3H), 2.21-2.11(m, 1H), 1.69(br d, J=6.6Hz, 3H), 1.16-1.07(m, 4H). ESI[M+H]=380.2. Example 47 [ka]

[0452] To a solution of methyl 4-[(1S)-1-aminoethyl]benzoate (300 mg, 1.67 mmol, 1 equiv.) in n-BuOH (7 mL), TEA (338.78 mg, 3.35 mmol, 465.99 μL, 2 equiv.) and 4-chloro-2,6-dimethyl-pyrimidine (238.68 mg, 1.67 mmol, 1 equiv.) were added. The mixture was stirred at 120 °C for 12 h. The reaction was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / THF = 10 / 1 to 1 / 1) to give methyl 4-[(1S)-1-[(2,6-dimethylpyrimidin-4-yl)amino]ethyl]benzoate (330 mg, 1.16 mmol, 69.09% yield) as a yellow solid. ESI [M+H] = 286.2. [ka]

[0453] To a solution of methyl 4-[(1S)-1-[(2,6-dimethylpyrimidin-4-yl)amino]ethyl]benzoate (330.00 mg, 1.16 mmol, 1 equiv) in MeOH (3 mL) and HO (1 mL) was added LiOH · HO (97.06 mg, 2.31 mmol, 2 equiv.) was added and the mixture was stirred at 30 °C for 12 h. MeOH was removed, and the aqueous layer was washed with MTBE (15 mL × 2), then adjusted to pH = 2 with 1 N HCl and extracted with DCM / i-PrOH (3 / 1, 15 mL × 5). The organic layer was dried over MgSO and concentrated in vacuo to give 4-[(1S)-1-[(2,6-dimethylpyrimidin-4-yl)amino]ethyl]benzoic acid (165 mg, 608.15 μmol, 52.58% yield) as a white solid. ESI [M+H] = 272.1. [ka]

[0454] To a solution of 4-[(1S)-1-[(2,6-dimethylpyrimidin-4-yl)amino]ethyl]benzoic acid (165.00 mg, 608.15 μmol, 1 equiv) in DMF (3 mL) was added DIEA (235.80 mg, 1.82 mmol, 317.79 μL, 3 equiv), N'-hydroxycyclopropanecarboxamidine (91.33 mg, 912.23 μmol, 1.5 equiv), and HBTU (276.76 mg, 729.78 μmol, 1.2 equiv). The mixture was stirred at 30 °C for 12 h. Water (20 mL) was added to the reaction mixture, which was then extracted with DCM / i-PrOH (3 / 1, 20 mL × 5). The organic layer was washed with brine (20 mL × 2), dried over MgSO and concentrated in vacuo to give [(Z)-[amino(cyclopropyl)methylene]amino]4-[(1S)-1-[(2,6-dimethylpyrimidin-4-yl)amino]ethyl]benzoate (0.4 g, crude) as a brown oil, which was used in the next step without further purification. ESI [M+H] = 354.1. [ka]

[0455] To a solution of [(Z)-[amino(cyclopropyl)methylene]amino]4-[(1S)-1-[(2,6-dimethylpyrimidin-4-yl)amino]ethyl]benzoate (200 mg, 565.90 μmol, 1 equiv.) in THF (3 mL), TBAF (1 M, 1.13 mL, 2 equiv.) was added, and the mixture was stirred at 80° C. for 2 hours. The mixture was concentrated to give a residue. The residue was purified by preparative TLC (EtOAc:MeOH=10:1) to give the crude product. The crude product was purified by preparative HPLC (column: Phenomenex Luna C18 150 x 30 mm x 5 μm, mobile phase: [water (0.04% HCl)-ACN], B%: 15% to 45%, 10 min) to give N-[(1S)-1-[4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl]ethyl]-2,6-dimethyl-pyrimidin-4-amine (34.88 mg, 93.71 μmol, yield 16.56%, purity 99.903%, HCl) as a white solid.

[0456] 1 H-NMR (400MHz, chloroform-d) δ 14.13(br s, 1H), 9.93(br s, 1H), 7.90(d, J=7.8Hz, 2H), 7.50(d, J=8.1Hz, 2H), 6.91(br s, 1H), 5.36(br t, J=6.7Hz, 1H), 2.52(s, 3H), 2.35(s, 3H), 2.10-2.00(m, 1H), 1.59(br d, J=6.8Hz, 3H), 1.05-0.98(m, 4H). ESI[M+H]=336.2. Example 48 [ka]

[0457] To a solution of methyl 4-[(1S)-1-aminoethyl]benzoate (300 mg, 1.67 mmol, 1 equiv.) in n-BuOH (7 mL), TEA (338.78 mg, 3.35 mmol, 465.99 μL, 2 equiv.) and 4-chloro-2,5-dimethyl-pyrimidine (286.42 mg, 2.01 mmol, 1.2 equiv.) were added. The mixture was stirred at 120 °C for 12 h. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / THF = 10 / 1 to 1 / 1) to give methyl 4-[(1S)-1-[(2,5-dimethylpyrimidin-4-yl)amino]ethyl]benzoate (250 mg, 876.15 μmol, 52.34% yield) as a yellow solid. ESI [M+H] = 286.2. [ka]

[0458] To a solution of methyl 4-[(1S)-1-[(2,5-dimethylpyrimidin-4-yl)amino]ethyl]benzoate (250 mg, 876.15 umol, 1 equiv) in MeOH (3 mL) and HO (1 mL) was added LiOH ·HO (73.53 mg, 1.75 mmol, 2 equiv.) was added. The mixture was stirred at 30 °C for 12 h. MeOH was removed, and the aqueous layer was washed with MTBE (20 mL × 2), then adjusted to pH = 2 with 1 N HCl and extracted with DCM / i-PrOH (3 / 1, 20 mL × 5). The organic layer was dried over MgSO and concentrated in vacuo to give 4-[(1S)-1-[(2,5-dimethylpyrimidin-4-yl)amino]ethyl]benzoic acid (100 mg, 368.58 μmol, 42.07% yield) as a white solid. ESI [M+H] = 272.0. [ka]

[0459] To a solution of 4-[(1S)-1-[(2,5-dimethylpyrimidin-4-yl)amino]ethyl]benzoic acid (100 mg, 368.58 μmol, 1 equiv) in DMF (3 mL) was added N'-hydroxycyclopropanecarboxamidine (55.35 mg, 552.87 μmol, 1.5 equiv), DIPEA (142.91 mg, 1.11 mmol, 192.60 μL, 3 equiv), and HBTU (167.74 mg, 442.29 μmol, 1.2 equiv). The mixture was stirred at 30 °C for 16 h. HO (10 mL) was added to the reaction mixture, which was then extracted with DCM / i-PrOH (10 mL × 5, 3:1). The combined organic layers were washed with brine (10 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure to give [(Z)-[amino(cyclopropyl)methylene]amino]4-[(1S)-1-[(2,5-dimethylpyrimidin-4-yl)amino]ethyl]benzoate (120 mg, crude) as a brown oil. ESI [M+H] = 354.1. [ka]

[0460] To a solution of [(Z)-[amino(cyclopropyl)methylene]amino]4-[(1S)-1-[(2,5-dimethylpyrimidin-4-yl)amino]ethyl]benzoate (120.00 mg, 339.54 umol, 1 equiv) in THF (2 mL) was added TBAF (1 M, 679.08 uL, 2 equiv) and the mixture was stirred at 80° C. for 2 hours. The mixture was concentrated to give a residue. The residue was purified by preparative TLC (EtOAc:MeOH=10:1) and preparative HPLC (column: Phenomenex Luna C18 150×30 mm×5 μm, mobile phase: [water (0.04% HCl)-ACN], B%: 15%-45%, 10 min) to give N-[(1S)-1-[4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl]ethyl]-2,5-dimethyl-pyrimidin-4-amine (24.13 mg, 63.44 μmol, yield 18.68%, purity 97.759%, HCl) as a white solid.

[0461] 1 H-NMR (400MHz, chloroform-d) δ 15.17(br s, 1H), 7.95(d, J=7.9Hz, 2H), 7.74(br s, 1H), 7.63(br s, 1H), 7.56(br d, J=7.9Hz, 2H), 5.53(br t, J=6.7Hz, 1H), 2.57(s, 3H), 2.24(s, 3H), 2.10-2.01(m, 1H), 1.72(br d, J=6.8Hz, 3H), 1.05-0.99(m, 4H). ESI[M+H]=336.2. Example 49 [ka]

[0462] A mixture of 3H-benzimidazole-5-carbonitrile (0.5 g, 3.49 mmol, 1 equiv.), cyclopropylboronic acid (600.07 mg, 6.99 mmol, 2 equiv.), 2-(2-pyridyl)pyridine (545.53 mg, 3.49 mmol, 1 equiv.), Cu(OAc) (634.43 mg, 3.49 mmol, 1 equiv.), and NaCO (1.11 g, 10.48 mmol, 3 equiv.) in DCE (60 mL) was stirred at 80° C. under O (15 psi) for 12 h. LCMS indicated that some 3H-benzimidazole-5-carbonitrile remained, so the mixture was stirred at 80° C. under O (15 psi) for an additional 36 h. TLC (PE: EtOAc = 0:1) showed that 3H-benzimidazole-5-carbonitrile was consumed and a main spot with low polarity was detected. LCMS showed that 3H-benzimidazole-5-carbonitrile was consumed and a main peak with the desired MS was detected. The reaction mixture was filtered, and the filtrate was concentrated to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) and preparative HPLC (column: Phenomenex Luna C18 150 x 30 mm x 5 um, mobile phase: [water (0.04% HCl)-ACN], B%: 5% to 40%, 10 min) to give 3-cyclopropylbenzimidazole-5-carbonitrile (140 mg, 764.16 umol, 21.88% yield) and 1-cyclopropylbenzimidazole-5-carbonitrile (200 mg, 1.09 mmol, 31.25% yield) as white solids. P1 was the desired product. 1 Confirmed by H-NMR: ESI [M+H] = 188.1.

[0463] 1 H-NMR (400 MHz, methanol-d₄) δ 9.75 (s, 1H), 8.61 (s, 1H), 8.07-7.99 (m, 2H), 3.90 (td, J = 3.4, 7.2 Hz, 1H), 1.44-1.37 (m, 2H), 1.37-1.31 (m, 2H). [ka]

[0464] To a solution of 3-cyclopropylbenzimidazole-5-carbonitrile (140 mg, 764.16 μmol, 1 equiv) in MeOH (10 mL) and THF (5 mL) was added Pd(OH) (107.31 mg, 764.16 μmol, 1.00 equiv) and HCl (12 M, 63.68 μL, 1 equiv) under N. The suspension was degassed under vacuum and purged with H several times. The mixture was stirred under H (15 psi) at 15 °C for 12 h. LCMS indicated that most of the 3-cyclopropylbenzimidazole-5-carbonitrile remained, and the desired MS was detected. Therefore, Pd(OH) (214.63 mg, 1.53 mmol, 2.00 equiv) was added to the mixture, and the mixture was stirred under H (15 psi) at 15 °C for 16 h. LCMS showed that 3-cyclopropylbenzimidazole-5-carbonitrile was consumed, and only one peak with the desired MS was detected. The mixture was filtered, and the filtrate was concentrated to give a residue. The residue was purified by preparative HPLC (Column: Waters Xbridge Prep OBD C18 150 × 40 mm × 10 μm, Mobile phase: [water (0.04% NH3H2O ​​+ 10 mM NH4HCO3)-ACN], B%: 1% to 15%, 10 min) to give (3-cyclopropylbenzimidazol-5-yl)methanamine (100 mg, 534.07 μmol, 69.89% yield) as a colorless oil. ESI [M+H] = 188.1.

[0465] 1 H-NMR (400 MHz, methanol-d₄) δ 8.17 (s, 1H), 7.72 (s, 1H), 7.63 (d, J = 8.3 Hz, 1H), 7.31 (dd, J = 1.0, 8.3 Hz, 1H), 4.06 (s, 2H), 3.53-3.46 (m, 1H), 1.24-1.16 (m, 2H), 1.11-1.05 (m, 2H). [ka]

[0466] To a mixture of tetrahydrofuran-3-ol (30 g, 340.50 mmol, 27.52 mL, 1 equiv.) and EtN (51.68 g, 510.76 mmol, 71.09 mL, 1.5 equiv.) in DCM (300 mL), TosCl (71.41 g, 374.55 mmol, 1.1 equiv.) was added, and the mixture was stirred at 15 °C for 48 h. TLC (PE: EtOAc = 1:1) showed that most of the tetrahydrofuran-3-ol had been consumed, and one new major spot with low polarity was detected. The mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give tetrahydrofuran-3-yl 4-methylbenzenesulfonate (67 g, 276.53 mmol, 81.21% yield) as a light brown oil.

[0467] 1 H-NMR (400 MHz, chloroform-d) δ 7.72 (d, J = 8.1 Hz, 2H), 7.29 (d, J = 8.1 Hz, 2H), 5.04 (br d, J = 2.4 Hz, 1H), 3.86-3.70 (m, 4H), 2.39 (s, 3H), 2.08-1.97 (m, 2H). [ka]

[0468] To a stirred mixture of tetrahydrofuran-3-yl 4-methylbenzenesulfonate (15 g, 61.91 mmol, 1.2 equiv.) and methyl 2-(benzhydrylideneamino)acetate (13.07 g, 51.59 mmol, 1 equiv.) in Toluene (150 mL) at 15 °C, LiHMDS (1 M, 61.91 mL, 1.2 equiv.) in THF was added dropwise, and the resulting mixture was stirred at 80 °C for 12 h. LCMS showed that the desired MS was detected. TLC (PE: EtOAc = 3:1) showed that most of the methyl 2-(benzhydrylideneamino)acetate was consumed, and the desired spot was detected. The reaction mixture was concentrated under reduced pressure to remove Toluene. H2O (100 mL) was added to the residue, and it was extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give methyl 2-(benzhydrylideneamino)-2-tetrahydrofuran-3-yl acetate (12 g, 37.11 mmol, 71.93% yield) as a brown oil. ESI [M+H] = 324.1. [ka]

[0469] To a solution of 2-(benzhydrylideneamino)-2-tetrahydrofuran-3-yl-methyl acetate (12 g, 37.11 mmol, 1 equiv.) in THF (100 mL), HCl (2 M, 37.11 mL, 2 equiv.) was added dropwise at 15 °C, and the mixture was stirred at 15 °C for 12 h. TLC (PE: EtOAc = 2:1) showed that 2-(benzhydrylideneamino)-2-tetrahydrofuran-3-yl-methyl acetate was consumed. The reaction mixture was concentrated under reduced pressure to remove THF. The residue was extracted with MTBE (30 mL × 3). The aqueous layer was adjusted to pH = 8–9 with solid NaCO to give 2-amino-2-tetrahydrofuran-3-yl-methyl acetate (5 g, crude) as a brown oil, which was used directly in the next step. [ka]

[0470] To a mixture of methyl 2-amino-2-tetrahydrofuran-3-yl acetate (5.00 g, 31.41 mmol, 1 equiv.) and NaCO (3.33 g, 31.41 mmol, 1 equiv.) in dioxane (30 mL) and HO (30 mL) (pH ∼8), BocO (8.23 g, 37.69 mmol, 8.66 mL, 1.2 equiv.) was added at 0 °C. The resulting mixture was stirred at 15 °C for 2.5 h. LCMS showed that methyl 2-amino-2-tetrahydrofuran-3-yl acetate was consumed, and the desired MS was detected. TLC (PE: EtOAc = 3:1) showed that two new major spots with lower polarity were detected. HO (20 mL) was added to the reaction mixture, which was then extracted with DCM (20 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 1 / 0 to 5 / 1) to give methyl 2-(tert-butoxycarbonylamino)-2-tetrahydrofuran-3-ylacetate (5.8 g, 22.37 mmol, 71.21% yield) as a colorless oil. ESI [½M+H] = 160.2, [M-56+H] = 204.2, [M+H] = 260.2.

[0471] 1 H-NMR (400 MHz, chloroform-d) δ 5.16 (br d, J = 7.5 Hz, 1H), 4.34-4.15 (m, 1H), 3.76-3.59 (m, 7H), 2.69-2.53 (m, 1H), 2.08-1.73 (m, 2H), 1.43 (d, J = 1.1 Hz, 9H). [ka]

[0472] To a solution of methyl 2-(tert-butoxycarbonylamino)-2-tetrahydrofuran-3-yl acetate (5.8 g, 22.37 mmol, 1 equiv.) in MeOH (60 mL) and HO (20 mL), LiOH·HO (1.88 g, 44.74 mmol, 2.0 equiv.) was added, and the resulting mixture was stirred at 15 °C for 12 h. LCMS showed that methyl 2-(tert-butoxycarbonylamino)-2-tetrahydrofuran-3-yl acetate was consumed, and the desired MS was detected. The mixture was concentrated to give a residue. HO (20 mL) was added to the residue, which was acidified to pH 5-4 with 1 M HCl solution and extracted with ethyl acetate / THF (3:1, 20 mL × 5). The combined organic phase was washed with brine (20 mL × 2), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give 2-(tert-butoxycarbonylamino)-2-tetrahydrofuran-3-yl-acetic acid (5.4 g, 22.02 mmol, 98.43% yield) as a brown oil. ESI [½M+H] = 146.0, [M-56+H] = 190.0, [M+23] = 268.1.

[0473] 1 H-NMR (400MHz, chloroform-d) δ 10.15(br s, 1H), 5.25(br dd, J=8.4, 14.6Hz, 1H), 4.26(br d, J=6.4Hz, 1H), 3.92-3.77(m, 1H), 3.74-3.57(m, 2H), 2.64(br d, J=7.2Hz, 1H), 2.09-1.89(m, 2H), 1.87-1.67(m, 1H), 1.38(s, 9H). [ka]

[0474] To a stirred solution of 2-(tert-butoxycarbonylamino)-2-tetrahydrofuran-3-yl-acetic acid (5.40 g, 22.02 mmol, 1 equiv.) in DCM (60 mL) at 0 °C, HBTU (10.02 g, 26.42 mmol, 1.2 equiv.) and DIPEA (5.69 g, 44.03 mmol, 7.67 mL, 2 equiv.) were added. The mixture was stirred at 0 °C for 10 min, followed by the addition of N-methoxymethanamine hydrochloride (2.58 g, 26.42 mmol, 1.2 equiv.). The mixture was stirred at 15 °C for 5 h. LCMS indicated that 2-(tert-butoxycarbonylamino)-2-tetrahydrofuran-3-yl-acetic acid had been consumed and the desired MS was detected. H2O (40 mL) was added to the reaction mixture, which was then extracted with DCM (20 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give tert-butyl N-[2-[methoxy(methyl)amino]-2-oxo-1-tetrahydrofuran-3-yl-ethyl]carbamate (6.15 g, 20.81 mmol, 94.52% yield) as a white solid. ESI [½M+H] = 189.1, [M-56+H] = 233.1, [M+H] = 289.1.

[0475] 1 H-NMR (400 MHz, chloroform-d) δ 5.27 (br s, 1H), 4.78 (br s, 1H), 3.93-3.52 (m, 7H), 3.22 (s, 3H), 2.65-2.49 (m, 1H), 2.05-1.74 (m, 2H), 1.43 (s, 9H). [ka]

[0476] To a stirred solution of tert-butyl N-[2-[methoxy(methyl)amino]-2-oxo-1-tetrahydrofuran-3-yl-ethyl]carbamate (1 g, 3.47 mmol, 1 equiv.) in THF (20 mL) at −30° C., i-PrMgCl (2 M, 1.65 mL, 0.95 equiv.) in THF was added dropwise. The mixture was then warmed to 10° C., and bromo(cyclopropyl)magnesium (0.5 M, 10.40 mL, 1.5 equiv.) in THF was added dropwise, and the resulting mixture was stirred at 15° C. for 12 h. LCMS and HPLC indicated that approximately 2 / 5 of the tert-butyl N-[2-[methoxy(methyl)amino]-2-oxo-1-tetrahydrofuran-3-yl-ethyl]carbamate remained, and 3 / 5 of the desired product was detected. Therefore, to the mixture was added bromo(cyclopropyl)magnesium (0.5 M, 3.47 mL, 0.5 equiv.) under N at 15 °C, and the mixture was stirred at 15 °C for 12 h. HPLC showed that 1 / 3 of tert-butyl N-[2-[methoxy(methyl)amino]-2-oxo-1-tetrahydrofuran-3-yl-ethyl]carbamate still remained, and 2 / 3 of the desired product was detected. The reaction mixture was quenched by the addition of saturated aqueous NH Cl (50 ml) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (10 mL × 2), dried over Na SO , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Nano-micro Kromasil C18 100 × 30 mm 5 μm, mobile phase: [water (0.1% TFA)-ACN], B%: 25% to 45%, 10 min) to give tert-butyl N-(2-cyclopropyl-2-oxo-1-tetrahydrofuran-3-yl-ethyl)carbamate (450 mg, 1.67 mmol, 48.18% yield) as a white solid. ESI [½M+H] = 170.2, [M-56+H] = 214.2, [M+H] = 270.2. [ka]

[0477] To a solution of tert-butyl N-(2-cyclopropyl-2-oxo-1-tetrahydrofuran-3-yl-ethyl)carbamate (450 mg, 1.67 mmol, 1 equiv.) in EtOAc (10 mL) was added HCl / MeOH (4 M, 4 mL, 9.58 equiv.). The mixture was stirred at 20 °C for 4 h. LCMS showed that tert-butyl N-(2-cyclopropyl-2-oxo-1-tetrahydrofuran-3-yl-ethyl)carbamate was consumed and a main peak with the desired MS was detected. The reaction mixture was concentrated under reduced pressure to give 2-amino-1-cyclopropyl-2-tetrahydrofuran-3-yl-ethanone (340 mg, crude, HCl) as a colorless oil. ESI [M+H] = 170.1 [ka]

[0478] A mixture of formic acid (167.38 mg, 3.64 mmol, 137.20 μL, 2.2 equiv) and acetyl acetate (185.63 mg, 1.82 mmol, 170.30 μL, 1.1 equiv) was stirred at 15° C. for 1 h. This mixture was then added to a mixture of 2-amino-1-cyclopropyl-2-tetrahydrofuran-3-yl-ethanone (340 mg, 1.65 mmol, 1 equiv, HCl) and EtN (1.67 g, 16.53 mmol, 2.30 mL, 10 equiv) in DCM (20 mL) at 0° C. The mixture was stirred at 30° C. for 4 h. LCMS showed that 2-amino-1-cyclopropyl-2-tetrahydrofuran-3-yl-ethanone was consumed and the desired MS was detected. The reaction mixture was added with HO (10 mL) and extracted with DCM (10 mL × 5). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Column: Waters Xbridge BEH C18 100 × 30 mm × 10 μm, Mobile phase: [water (0.04% NH3H2O ​​+ 10 mM NH4HCO3)-ACN], B%: 1% to 20%, 10 min) to give N-(2-cyclopropyl-2-oxo-1-tetrahydrofuran-3-yl-ethyl)formamide (175 mg, 887.29 μmol, 53.68% yield) as a colorless oil. ESI [M+H] = 198.1. [ka]

[0479] N-(2-cyclopropyl-2-oxo-1-tetrahydrofuran-3-yl-ethyl)formamide (70 mg, 354.91 μmol, 1 equiv.), (3-cyclopropylbenzimidazol-5-yl)methanamine (66.45 mg, 354.91 μmol, 1 equiv.), pivalic acid (181.24 mg, 1.77 mmol, 203.87 μL, 5 equiv.), and 4A molecular sieves were placed in a microwave tube in Toluene (1 mL). The sealed tube was heated at 100° C. in a microwave oven for 2 hours. The reaction mixture was concentrated under reduced pressure to remove the Toluene. The residue was dissolved in EtOAc (10 mL), adjusted to pH 8 with saturated aqueous NaCO solution, and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Phenomenex Luna C18 100 × 30 mm × 5 μm column, mobile phase: [water (0.2% FA)-ACN], B%: 3% to 20%, 10 min) to give the crude product, which was repurified by preparative HPLC (Waters Xbridge BEH C18 100 × 30 mm × 10 μm column, mobile phase: [water (10 mM NH4HCO3)-ACN], B%: 25% to 50%, 10 min) to give 1-cyclopropyl-6-[(5-cyclopropyl-4-tetrahydrofuran-3-yl-imidazol-1-yl)methyl]benzimidazole (7.25 mg, 20.81 μmol, yield 5.86%, purity 100.000%) as a white solid. ESI [M+H] = 349.1.

[0480] 1H-NMR (400 MHz, methanol-d4) δ 8.20 (s, 1H), 7.69-7.63 (m, 2H), 7.47 (s, 1H), 7.17 (d, J = 8.4 Hz, 1H), 5.44 (s, 2H), 4.09-4.01 (m, 2H), 3.91 (q, J = 7.9 Hz, 1H), 3.75-3.68 (m, 1H), 3.68-3.5 8(m, 1H), 3.49(tt, J=3.7, 7.1Hz, 1H), 2.25-2.13(m, 2H), 1.45-1.34(m, 1H), 1.22-1.15(m, 2H), 1.09-1.02(m, 2H), 0.98-0.92(m, 2H), 0.64-0.57(m, 2H). Example 50 [ka]

[0481] To a stirred solution of 5-cyclopropyl-1H-imidazole (9 g, 83.22 mmol, 1 equiv) in DMF (100 mL) at 0 °C, NaH (3.33 g, 83.22 mmol, 60% purity, 1 equiv) was added portionwise. The mixture was stirred at 0 °C for 0.5 h, and then 2-(chloromethoxy)ethyl-trimethyl-silane (15.26 g, 91.55 mmol, 16.20 mL, 1.1 equiv) was added dropwise. The resulting mixture was stirred at 20 °C for 12 h. The reaction mixture was quenched with saturated aqueous NH Cl (300 mL) at 0 °C and then diluted with EtOAc (100 mL). The aqueous phase was extracted with ethyl acetate (200 mL × 3). The combined organic phases were washed with brine (200 mL × 2), dried over anhydrous Na SO , filtered, and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1, plate 1) to give 2-[(5-cyclopropylimidazol-1-yl)methoxy]ethyl-trimethyl-silane (total 11 g) as a yellow oil. ESI [M+H] = 239.2. [ka]

[0482] To a stirred solution of 2-[(5-cyclopropylimidazol-1-yl)methoxy]ethyl-trimethyl-silane (total 10 g, 41.95 mmol, 1 equiv.) in THF (200 mL) at −70° C., 1-bromopyrrolidine-2,5-dione (7.84 g, 44.04 mmol, 1.05 equiv.) was added portionwise. The resulting mixture was stirred at −70° C. for 3 h. The reaction mixture was quenched at −70° C. by the addition of HO (200 mL), then diluted with EtOAc (100 mL) and extracted with EtOAc (200 mL × 3). The combined organic layers were washed with brine (100 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give 2-[(4-bromo-5-cyclopropyl-imidazol-1-yl)methoxy]ethyl-trimethyl-silane (total 6.5 g) as a brown oil. ESI [M+H and M+3H] = 317.0 and 319.0. [ka]

[0483] To a solution of 2-[(4-bromo-5-cyclopropyl-imidazol-1-yl)methoxy]ethyl-trimethyl-silane (250 mg, 630.32 μmol, 1 equiv.), (2-chlorophenyl)boronic acid (184.81 mg, 1.18 mmol, 1.5 equiv.), and K3PO4 (0.5 M, 3.15 mL, 2 equiv.) in EtOH (4 mL) was added [2-(2-aminophenyl)phenyl]-chloropalladium:bis(1-adamantyl)-butyl-phosphane (52.68 mg, 78.79 μmol, 0.1 equiv.). The mixture was stirred under N2 at 70 °C for 12 h. Water (20 mL) was added to the reaction mixture and extracted with EtOAc (30 mL × 4). The organic phase was dried over Na2SO4 and then concentrated in vacuo. The residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate=0 / 1) to give 2-[[4-(2-chlorophenyl)-5-cyclopropyl-imidazol-1-yl]methoxy]ethyl-trimethyl-silane as a yellow oil, a total of 180 mg. ESI [M+H]=349.1. [ka]

[0484] To a solution of 2-[[4-(2-chlorophenyl)-5-cyclopropyl-imidazol-1-yl]methoxy]ethyl-trimethyl-silane (total 180 mg) in DCM (1.8 mL) was added TFA (924.00 mg, 8.10 mmol, 0.6 mL, 15.71 equiv). The mixture was stirred at 30 °C for 12 h. The reaction was concentrated in vacuo. The reaction mixture was adjusted to pH = 8 with saturated aqueous Na2CO3 and extracted with DCM (20 mL × 3). The organic phase was dried over Na2SO4 and then concentrated in vacuo. The residue was purified by preparative TLC (SiO2, ethyl acetate:methanol = 10:1) to give 4-(2-chlorophenyl)-5-cyclopropyl-1H-imidazole (90 mg, 411.56 μmol, 79.78% yield) as a yellow solid. [ka]

[0485] To a stirred solution of 6-bromo-1-methyl-benzotriazole (300 mg, 1.41 mmol, 1 equiv) in THF (5 mL) at −78° C., t-BuLi (1.3 M, 1.31 mL, 1.2 equiv) in hexanes was added dropwise, and the mixture was stirred at −78° C. for 1 h. Then, methyl formate (424.80 mg, 7.07 mmol, 429.09 μL, 5 equiv) was added dropwise at −78° C. The mixture was stirred at −78° C. for 0.5 h and then warmed to 15° C. for 5 h. The reaction mixture was quenched by the addition of saturated aqueous NH4Cl (5 mL), adjusted to pH = 3 with 2 N HCl, and extracted with EtOAc (5 mL × 3). The combined organic layers were washed with brine (5 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue that afforded 3-methylbenzotriazole-5-carbaldehyde (200 mg, crude) as a brown oil. ESI [M+H] = 162.1. [ka]

[0486] To a stirred solution of 3-methylbenzotriazole-5-carbaldehyde (200 mg, 1.24 mmol, 1 equiv.) in MeOH (5 mL) at 0 °C, NaBH (46.95 mg, 1.24 mmol, 1 equiv.) was added portionwise, and the mixture was stirred at 15 °C for 1 h. The reaction mixture was quenched with HO (2 mL) and extracted with EtOAc (5 mL × 3). The combined organic layers were washed with brine (5 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO, PE:EtOAc = 0:1) to give (3-methylbenzotriazol-5-yl)methanol (110 mg, 674.12 μmol, 54.32% yield) as a brown oil. ESI [M+H] = 164.0. [ka]

[0487] To a stirred solution of (3-methylbenzotriazol-5-yl)methanol (110 mg, 674.12 μmol, 1 equiv) and EtN (136.43 mg, 1.35 mmol, 187.66 μL, 2 equiv) in DCM (2 mL) at 0° C., MsCl (115.83 mg, 1.01 mmol, 78.26 μL, 1.5 equiv) was added portionwise and the mixture was stirred at 15° C. for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue that afforded 6-(chloromethyl)-1-methyl-benzotriazole (100 mg, crude) as a yellow oil. [ka]

[0488] To a solution of t-BuOK (1 M, 330.36 uL, 1.5 equiv) in DMF (1 mL) under N was added dropwise 2-methyl-3-oxobutanoate (48.16 mg, 220.24 umol, 47.22 uL, 1 equiv) in DMF (1 mL) at 0 °C under N. After 15 min, 6-(chlor...

Claims

1. A compound selected from the following formulas or a pharma- ceutically acceptable salt thereof. 【Chemistry 1】

2. A pharmaceutical composition for use in treating at least one degenerative eye disease comprising a compound according to claim 1.

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