Modulators of TRPML, compositions thereof and methods of use

Abstract

The present disclosure relates to pharmaceutical compounds of formula (I), (Ia), (Ib) or (Ic) or pharma- ceutically acceptable salts or compositions thereof. Methods of using TRPML modulating agents, comprising compounds of formula (I), (Ia), (Ib) or (Ic), to treat disorders are also provided. Such methods of use include the treatment of cilia-associated disorders. [Formula 1] TIFF2024536237000602.tif38147

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to USSN 63 / 250,818, filed September 30, 2021, and USSN 63 / 339,791, filed May 9, 2022, the contents of each of which are incorporated herein by reference in their entirety.

[0002] The present disclosure relates to compounds and compositions that are modulators of TRPML and are useful in the treatment of various disorders. [Background technology]

[0003] Lysosomes are important organelles that function as cellular recycling centers. They degrade various biological materials (proteins, lipids, and membranes) in a highly controlled manner into smaller molecules or chemical building blocks that the cell uses for energy or as starting materials for new proteins or membranes (e.g., de Duve, C., The lysosome turns fifty. Nat Cell Biol, 2005, 7(9): pp. 847-9; Parkinson-Lawrence, EJ, et al., Lysosomal storage disease: revealing lysosomal function and physiology. Physiology (Bethesda), 2010. 25(2): pp. 102-15). Lysosomal dysfunction due to mutations in lysosomal transport hydrolases occurs in over 50 genetically defined lysosomal storage diseases.

[0004] Interestingly, defects in lysosomal processing can have profound effects on organelle function beyond the actual mutated enzyme; in fact, the system may fail altogether, altering lysosomal degradation and membrane trafficking / transport, forming a positive feedback loop. Because lysosomal accumulation is also observed in common neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, understanding the mechanisms underlying this positive feedback loop may provide therapeutic approaches not only for LSDs but also for common sporadic neurodegenerative diseases. The lysosome-localized cation channel TRPML1 has recently been identified as a key regulator of lysosomal function and membrane trafficking processes in lysosomes. Human mutations in TRPML1 cause mucolipidosis IV, a hereditary lysosomal storage disease. This disease is typified by neurodegenerative effects that may be caused by the accumulation of lipids and other biomaterials within the cell. Related channels TRPML2 and TRPML3 also regulate lysosomal function. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] de Duve, C., The lysosome turns fifty. Nat Cell Biol, 2005, 7(9): p.847-9. [Non-patent document 2] Parkinson-Lawrence, EJ, et al., Lysosomal storage disease: revealing lysosomal function and physiology. Physiology (Bethesda), 2010. 25(2): p.102-15. Summary of the Invention [Problem to be solved by the invention]

[0006] Numerous reports suggest that activation of TRPML channels is involved in multiple important lysosomal functions. It can drive the nuclear translocation of transcription factor (TF) EB. TFEB regulates autophagy and lysosomal biogenesis. Overexpression of TFEB has been reported to induce cell clearance in several lysosomal storage diseases, such as Pompe disease, cystinosis, and multiple sulfatase deficiency, as well as common neurodegenerative diseases such as Parkinson's disease and Huntington's disease (Settembre, C., et al., Signals from the lysosome: a control center for cellular clearance and energy metabolism. Nat Rev Mol Cell Biol, 2013.14(5): p. 283-96). Therefore, activation of TRPML channels by TRPML agonists may also lead to cell clearance in all of the aforementioned diseases, providing a potential therapeutic target for these devastating diseases.

[0007] Recently, a potent synthetic agonist for TRPML1 was reported [Shen, D., et al., Lipid storage disorders block lysosomal trafficking by inhibiting a TRP channel and lysosomal calcium release. Nat Commun, 2012.3: p. 731]. This SF-51-related compound (mucolipin synthetic agonist 1 or ML-SA1) significantly reduced [Ca] release in HEK293 cells stably or transiently expressing TRPML1 protein, which was forced to the plasma membrane by deletion of the lysosomal targeting sequence. 2+] may induce an increase in TRPML activity. Effective activation of TRPML requires a high concentration of ML-SA1 (approximately 10 μM). Because achieving this concentration in vivo is typically difficult, ML-SA1 cannot be used to treat the TRPML-related diseases listed above. Liang et al. recently reported a new class of compounds as more potent TRPML activators [WO2018 / 005713A1]. These compounds are thought to be useful for treating disorders associated with TRPML activity, such as lysosomal storage diseases, muscular dystrophies, common age-related neurodegenerative diseases, ROS- or oxidative stress-related diseases, and aging. TRPML activators may also be useful in other disorders. [Means for solving the problem]

[0008] The present disclosure provides compounds of formula (I) and subformulas thereof and pharmaceutically acceptable salts, solvates, hydrates, tautomers and stereoisomers thereof.

[0009] In one embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt of said compound: [ka]

[0010] During the ceremony, W 1 is N or CR 5 and; W 2 is N or CR 6 and; R 1 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, and each R 1 is 1 to 5 independently selected R 7 may be replaced by; R 2 is an aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -O-cycloalkyl, -O-heterocycloalkyl, C 1-6 Alkyl, C 1-6 Alkoxy, -(CH2) 1-2-cycloalkyl, -(CH2) 1-2 -heterocycloalkyl, or NR a R b and each R 2 is 1 to 5 independently selected R 8 may be replaced by; R 3 teeth, [ka] and R 4 , R 5 , and R 6 each independently represents H, hydroxy, halogen, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkylthio and NR a R b selected from the group consisting of: R 7 and R 8 Each of the is in each case deuterium, hydroxy, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-7 Cycloalkyl and NR a R b wherein each C is independently selected from the group consisting of 1-6 Alkyl and C 1-6 Alkoxy is a group containing halogen, hydroxyl, and C 1-6 and each C may be substituted with a substituent independently selected from the group consisting of alkoxy. 3-7 Cycloalkyl is halogen, hydroxyl, C 1-6 Alkoxy and C 1-6 or R 1 or R 2 When R is cycloalkyl or heterocycloalkyl, two R on the same carbon 7 or two R 8can be taken together to form oxo, or any two R 7 or two R 8 may be taken together with the atoms to which they are attached to form an edge-fused or spiro-fused 3- to 7-membered ring or a bridge of 1 to 3 carbons or single bonds, wherein the ring or bridge is not substituted with a halogen, hydroxyl, C 1-6 Haloalkyl, and C 1-6 optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkyl; R 9 is deuterium, halogen, hydroxyl, C 1-3 Alkyl, and C 1-6 C optionally substituted with substituents independently selected from the group consisting of alkoxy 1-6 Alkyl or -(CH2) 0-2 -C 3-7 is cycloalkyl, C 1-3 Alkyl and C 1-6 Alkoxy is a group containing deuterium, hydroxyl, C 1-3 Haloalkyl, C 1-3 Alkoxy and C 1-3 optionally substituted with 1 to 5 substituents independently selected from the group consisting of alkyl; Each R 10 Deuterium, hydroxyl and C 1-6 C optionally substituted with substituents independently selected from the group consisting of alkoxy 1-6 Alkyl and C 1-6 independently selected from the group consisting of haloalkyl; or Two R on the same carbon 10 can be taken together to form oxo; or Any two R's 10 can be taken together with the atoms to which they are attached to form an edge-fused or spiro-fused 3- to 7-membered ring or a 1- to 3-carbon or single bond bridge, wherein the ring or bridge is free of deuterium, halogen, hydroxyl, C 1-6 Haloalkyl, and C 1-6 optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkyl; Each R a and R b are independently H, C 1-6 Alkyl, C(O)-OC 1-6 Alkyl, C(O)-OC 2-6 Alkenyl, C(O)-C 1-6 Alkyl, C(O)-C 2-6 Alkenyl, -(CH2) 0-2 -C 3-7 cycloalkyl, and 3- to 7-membered heterocycloalkyl, wherein each alkyl, cycloalkyl, or heterocycloalkyl is selected from halogen and C 1-6 optionally substituted by 1 to 3 substituents selected from alkoxy; or R a and R b can form a 4- to 7-membered ring together with the nitrogen to which they are attached; m is 1 or 2; n is 1, 2, or 3; m1 is 0, 1 or 2; n1 is 0, 1, 2, or 3; m2 is 0, 1 or 2; n2 is 0, 1, 2, or 3; p is 0, 1, 2, 3, 4, 5, 6, 7, or 8; m+n is 2, 3, or 4; m1+n1 is 0, 1, 2, 3, or 4; m2+n2 is 0, 1, 2, 3, or 4; and R 1 and R 2 cannot both be aryl.

[0011] In another aspect, there is provided a compound of formula (Ib): [ka] wherein the variables are defined as described herein and in the claims.

[0012] In another aspect, there is provided a compound of formula (Ic): [ka] wherein the variables are defined as described herein and in the claims.

[0013] In another aspect, there is provided a compound of formula (I) or any subformula thereof selected from the compounds disclosed herein or in the claims, or a pharmaceutically acceptable salt thereof.

[0014] In another aspect, the disclosure provides a method for treating a disease or disorder treatable by modulation of TRPML, comprising administering to a patient in need of treatment a compound described herein or a composition described herein.

[0015] Still other objects and advantages of the present disclosure will be apparent to those skilled in the art from the disclosure herein, which is intended to be illustrative only and not limiting.

[0016] Accordingly, other embodiments will be apparent to those skilled in the art without departing from the spirit and scope of the present disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0017] As outlined herein, the present disclosure provides compounds (e.g., compounds of Formula (I) and its subformulas (Ia), (Ib) and (Ic), or compounds in Table 1, or pharmaceutically acceptable salts thereof) that are useful for disorders associated with modulation of TRPML (e.g., polycystic kidney disease). Throughout this specification, "TRPML," "TRPML ion channel," and "TRPML channel" are used interchangeably.

[0018] compound In one embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt of said compound: [ka]

[0019] During the ceremony, W 1 is N or CR 5 and; W 2 is N or CR 6 and; R 1 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, and each R 1 is 1 to 5 independently selected R 7 may be replaced by; R 2 is an aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -O-cycloalkyl, -O-heterocycloalkyl, C 1-6 Alkyl, C 1-6 Alkoxy, -(CH2) 1-2 -cycloalkyl, -(CH2) 1-2 -heterocycloalkyl or NR a R b and each R 2 is 1 to 5 independently selected R 8 may be replaced by; R 3 teeth, [ka] and R 4 , R 5 , and R 6 each independently represents H, hydroxy, halogen, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkylthio and NR a R b selected from the group consisting of: R 7 and R 8 Each of the is in each case deuterium, hydroxy, halogen, cyano, C 1-6 Alkyl, C 1-6Alkoxy, C 1-6 Alkylthio, C 3-7 Cycloalkyl and NR a R b wherein each C is independently selected from the group consisting of 1-6 Alkyl and C 1-6 Alkoxy is a group containing halogen, hydroxyl, and C 1-6 and each C may be substituted with a substituent independently selected from the group consisting of alkoxy. 3-7 Cycloalkyl is halogen, hydroxyl, C 1-6 Alkoxy and C 1-6 or R 1 or R 2 When R is cycloalkyl or heterocycloalkyl, two R on the same carbon 7 or two R 8 can be taken together to form oxo, or any two R 7 or two R 8 may be taken together with the atoms to which they are attached to form an edge-fused or spiro-fused 3- to 7-membered ring or a bridge of 1 to 3 carbons or single bonds, wherein the ring or bridge is not substituted with a halogen, hydroxyl, C 1-6 Haloalkyl, and C 1-6 optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkyl; R 9 is deuterium, halogen, hydroxyl, C 1-3 Alkyl, and C 1-6 C optionally substituted with substituents independently selected from the group consisting of alkoxy 1-6 Alkyl or -(CH2) 0-2 -C 3-7 is cycloalkyl, C 1-3 Alkyl and C 1-6 Alkoxy is a group containing deuterium, hydroxyl, C 1-3 Haloalkyl, C 1-3 Alkoxy and C 1-3 optionally substituted with 1 to 5 substituents independently selected from the group consisting of alkyl; Each R10 Deuterium, hydroxyl and C 1-6 C optionally substituted with substituents independently selected from the group consisting of alkoxy 1-6 Alkyl and C 1-6 independently selected from the group consisting of haloalkyl; or Two R on the same carbon 10 can be taken together to form oxo; or Any two R's 10 can be taken together with the atoms to which they are attached to form an edge-fused or spiro-fused 3- to 7-membered ring or a 1- to 3-carbon or single bond bridge, wherein the ring or bridge is free of deuterium, halogen, hydroxyl, C 1-6 Haloalkyl, and C 1-6 optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkyl; Each R a and R b are independently H, C 1-6 Alkyl, C(O)-OC 1-6 Alkyl, C(O)-OC 2-6 Alkenyl, C(O)-C 1-6 Alkyl, C(O)-C 2-6 Alkenyl, -(CH2) 0-2 -C 3-7 cycloalkyl, and 3- to 7-membered heterocycloalkyl, wherein each alkyl, cycloalkyl, or heterocycloalkyl is selected from halogen and C 1-6 optionally substituted by 1 to 3 substituents selected from alkoxy; or R a and R b can form a 4- to 7-membered ring together with the nitrogen to which they are attached; m is 1 or 2; n is 1, 2, or 3; m1 is 0, 1 or 2; n1 is 0, 1, 2, or 3; m2 is 0, 1 or 2; n2 is 0, 1, 2, or 3; p is 0, 1, 2, 3, 4, 5, 6, 7, or 8; m+n is 2, 3, or 4; m1+n1 is 0, 1, 2, 3, or 4; m2+n2 is 0, 1, 2, 3, or 4; and R 1 and R 2 cannot both be aryl.

[0020] In some embodiments, W 1 is N. In some embodiments, W 2 is CR 6 In some embodiments, W 1 is N and W 2 is CR 6 In some embodiments, W 1 is CR 5 and W 2 is N. In some embodiments, W 1 is N and W 2 is N. In some embodiments, W 1 is CR 5 and W 2 is CR 6 is.

[0021] In some embodiments, the compound is a compound of formula (Ia) or a pharmaceutically acceptable salt thereof: [ka]

[0022] R 1 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, and each R 1 are 1 to 5 independently selected R 7 may be replaced by; R 2 is aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -O-cycloalkyl, C 1-6 Alkyl, C 1-6 Alkoxy or NRa R b and each R 2 are 1 to 5 independently selected R 8 may be replaced by; R 3 but, [ka] and R 4 and R 6 each independently selected from H, hydroxy, halogen, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkylthio and NR a R b selected from the group consisting of: R 7 and R 8 Each of these is in each case deuterium, hydroxy, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-7 Cycloalkyl and NR a R b wherein each C is independently selected from the group consisting of 1-6 Alkyl and C 1-6 Alkoxy is halogen, hydroxyl, and C 1-6 and each C may be substituted with a substituent independently selected from the group consisting of alkoxy. 3-7 Cycloalkyl is halogen, hydroxyl, C 1-6 Alkoxy and C 1-6 or R 1 or R 2 When R is cycloalkyl or heterocycloalkyl, two R on the same carbon 7 or two R 8 can be taken together to form oxo, or any two R 7 or two R 8can be taken together with the atoms to which they are attached to form an edge-fused or spiro-fused 3- to 7-membered ring or a 1- to 3-carbon or single bond bridge, wherein the ring or bridge is not substituted with a halogen, hydroxyl, C 1-6 Haloalkyl, and C 1-6 optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkyl; R 9 Deuterium, halogens, hydroxyl, and C 1-6 C optionally substituted with substituents independently selected from the group consisting of alkoxy 1-6 is alkyl; Each R 10 Deuterium, hydroxyl and C 1-6 C optionally substituted with substituents independently selected from the group consisting of alkoxy 1-6 Alkyl and C 1-6 independently selected from the group consisting of haloalkyl; or Two R on the same carbon 10 can be taken together to form oxo; or Any two R's 10 can be taken together with the atoms to which they are attached to form an edge-fused or spiro-fused 3- to 7-membered ring or a 1- to 3-carbon or single bond bridge, wherein the ring or bridge is not substituted with a halogen, hydroxyl, C 1-6 Haloalkyl, and C 1-6 each R a and R b However, independently H, C 1-6 Alkyl, C(O)-OC 1-6 Alkyl, C(O)-OC 2-6 Alkenyl, -(CH2) 0-2 -C 3-7 cycloalkyl, and 3- to 7-membered heterocycloalkyl, wherein each alkyl, cycloalkyl, or heterocycloalkyl is selected from halogen and C 1-6 optionally substituted by 1 to 3 substituents selected from alkoxy; or R a and Rb can form a 4- to 7-membered ring together with the nitrogen to which they are attached; m is 1 or 2; n is 1, 2, or 3; p is 0, 1, 2, 3, 4, 5, 6, 7, or 8; m+n is 2, 3, or 4; and R 1 and R 2 However, there are no compounds in which both are aryl.

[0023] In some embodiments, the compound is a compound of formula (Ia) or a pharmaceutically acceptable salt thereof: [ka]

[0024] R 1 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, and each R 1 are 1 to 5 independently selected R 7 may be replaced by; R 2 is 1 to 5 independently selected R 8 may be replaced by C 1-6 Alkyl or C 3-7 is cycloalkyl; R 3 but [ka] and R 4 and R 6 each independently selected from H, hydroxy, halogen, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkylthio and NR a R b selected from the group consisting of: R7 and R 8 Each of these is in each case deuterium, hydroxy, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-7 Cycloalkyl and NR a R b and each C is independently selected from the group consisting of 1-6 Alkyl and C 1-6 Alkoxy is halogen, hydroxyl and C 1-6 alkoxy, wherein each C 3-7 Cycloalkyl is halogen, hydroxyl, C 1-6 Alkoxy and C 1-6 or R 1 or R 2 When R is cycloalkyl or heterocycloalkyl, two R on the same carbon 7 or two R 8 can be taken together to form oxo, or any two R 7 or two R 8 can be taken together with the atoms to which they are attached to form an edge-fused or spiro-fused 3- to 7-membered ring or a 1- to 3-carbon or single bond bridge, wherein the ring or bridge is not substituted with a halogen, hydroxyl, C 1-6 Haloalkyl, and C 1-6 optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkyl; R 9 Deuterium, halogens, hydroxyl, and C 1-6 C optionally substituted with substituents independently selected from the group consisting of alkoxy 1-6 is alkyl; Each R 10 Deuterium, hydroxyl, and C 1-6 C optionally substituted with substituents independently selected from the group consisting of alkoxy 1-6 Alkyl and C 1-6independently selected from the group consisting of haloalkyl; or Two R on the same carbon 10 can be taken together to form oxo; or Any two R's 10 can be taken together with the atoms to which they are attached to form an edge-fused or spiro-fused 3- to 7-membered ring or a 1- to 3-carbon or single bond bridge, wherein the ring or bridge is not substituted with a halogen, hydroxyl, C 1-6 Haloalkyl, and C 1-6 each R a and R b However, independently H, C 1-6 Alkyl, C(O)-OC 1-6 Alkyl, C(O)-OC 2-6 Alkenyl, -(CH2) 0-2 -C 3-7 cycloalkyl, and 3- to 7-membered heterocycloalkyl, wherein each alkyl, cycloalkyl, or heterocycloalkyl is selected from halogen and C 1-6 optionally substituted by 1 to 3 substituents selected from alkoxy; or R a and R b can form a 4- to 7-membered ring together with the nitrogen to which they are attached; m is 1 or 2; n is 1, 2, or 3; p is 0, 1, 2, 3, 4, 5, 6, 7, or 8; and Compounds in which m+n is 2, 3, or 4.

[0025] In some embodiments, the compound is a compound of formula (Ia): [ka] And, R 1 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, and each R1 are 1 to 5 independently selected R 7 may be replaced by; R 2 is 1 to 5 independently selected R 8 may be replaced by C 1-6 is alkyl; R 3 but [ka] and R 4 and R 6 each independently selected from H, hydroxy, halogen, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkylthio and NR a R b selected from the group consisting of: R 7 and R 8 Each of these is in each case deuterium, hydroxy, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-7 Cycloalkyl and NR a R b wherein each C is independently selected from the group consisting of 1-6 Alkyl and C 1-6 Alkoxy is halogen, hydroxyl, and C 1-6 and each C may be substituted with a substituent independently selected from the group consisting of alkoxy. 3-7 Cycloalkyl is halogen, hydroxyl, C 1-6 Alkoxy and C 1-6 or R 1 or R 2 When R is cycloalkyl or heterocycloalkyl, two R on the same carbon 7 or two R 8can be taken together to form oxo, or any two R 7 or two R 8 can be taken together with the atoms to which they are attached to form an edge-fused or spiro-fused 3- to 7-membered ring or a 1- to 3-carbon or single bond bridge, wherein the ring or bridge is not substituted with a halogen, hydroxyl, C 1-6 Haloalkyl, and C 1-6 optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkyl; R 9 Deuterium, halogens, hydroxyl, and C 1-6 C optionally substituted with substituents independently selected from the group consisting of alkoxy 1-6 is alkyl; Each R 10 Deuterium, hydroxyl, and C 1-6 C optionally substituted with substituents independently selected from the group consisting of alkoxy 1-6 Alkyl and C 1-6 independently selected from the group consisting of haloalkyl; or Two R on the same carbon 10 can be taken together to form oxo; or Any two R's 10 can be taken together with the atoms to which they are attached to form an edge-fused or spiro-fused 3- to 7-membered ring or a 1- to 3-carbon or single bond bridge, wherein the ring or bridge is not substituted with a halogen, hydroxyl, C 1-6 Haloalkyl, and C 1-6 each R a and R b However, independently H, C 1-6 Alkyl, C(O)-OC 1-6 Alkyl, C(O)-OC 2-6 Alkenyl, -(CH2) 0-2 -C 3-7 cycloalkyl, and 3- to 7-membered heterocycloalkyl, wherein each alkyl, cycloalkyl, or heterocycloalkyl is selected from halogen and C1-6 optionally substituted by 1 to 3 substituents selected from alkoxy; or R a and R b can form a 4- to 7-membered ring together with the nitrogen to which they are attached; m is 1 or 2; n is 1, 2, or 3; p is 0, 1, 2, 3, 4, 5, 6, 7, or 8; and Compounds in which m+n is 2, 3, or 4.

[0026] In some embodiments, the compound is a compound of formula (Ia): [ka] And, R 1 is 1 to 5 independently selected R 7 is heteroaryl optionally substituted by R 2 is 1 to 5 independently selected R 8 may be replaced by C 1-6 is alkyl; R 3 but, [ka] and R 4 and R 6 each of which is H; R 7 and R 8 Each of these is in each case deuterium, hydroxy, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-7 Cycloalkyl and NR a R b and each C is independently selected from the group consisting of 1-6 Alkyl and C 1-6Alkoxy is halogen, hydroxyl, and C 1-6 alkoxy, wherein each C 3-7 Cycloalkyl is halogen, hydroxyl, C 1-6 Alkoxy and C 1-6 optionally substituted with substituents independently selected from the group consisting of alkyl; R 9 Deuterium, halogens, hydroxyl, and C 1-6 C optionally substituted with substituents independently selected from the group consisting of alkoxy 1-6 is alkyl; Each R 10 Deuterium, hydroxyl, and C 1-6 C optionally substituted with substituents independently selected from the group consisting of alkoxy 1-6 Alkyl and C 1-6 independently selected from the group consisting of haloalkyl; or Two R on the same carbon 10 can be taken together to form oxo; or Any two R's 10 may be taken together with the atoms to which they are attached to form an edge-fused or spiro-fused 3- to 7-membered ring or a bridge of 1 to 3 carbons or single bonds, wherein the ring or bridge does not contain any of halogen, hydroxyl, C 1-6 Haloalkyl, and C 1-6 each R a and R b However, independently H, C 1-6 Alkyl, C(O)-OC 1-6 Alkyl, C(O)-OC 2-6 Alkenyl, -(CH2) 0-2 -C 3-7 cycloalkyl, and 3- to 7-membered heterocycloalkyl, wherein each alkyl, cycloalkyl, or heterocycloalkyl is selected from halogen and C 1-6 optionally substituted by 1 to 3 substituents selected from alkoxy; or R aand R b can form a 4- to 7-membered ring together with the nitrogen to which they are attached; Compounds in which p is 0, 1, 2, 3, 4, 5, 6, 7, or 8.

[0027] In some embodiments, the compound is a compound of formula (Ia): [ka] And, R 1 is 1 to 5 independently selected R 7 pyridyl optionally substituted by R 2 is 1 to 5 independently selected R 8 may be replaced by C 1-6 is alkyl; R 3 but, [ka] and R 4 and R 6 each of which is H; R 7 and R 8 Each of these is in each case deuterium, hydroxy, halogen, cyano, C 1-6 Alkyl, and C 1-6 independently selected from the group consisting of alkoxy; R 9 Deuterium, halogens, hydroxyl, and C 1-6 C optionally substituted with substituents independently selected from the group consisting of alkoxy 1-6 is alkyl; Each R 10 may be substituted with 1 to 5 deuterium atoms. 1-6 Alkyl, and C 1-6 independently selected from the group consisting of haloalkyl; Compounds in which p is 0, 1, 2, 3, 4, 5, 6, 7, or 8.

[0028] In some embodiments, R 1 aryl is 1 to 5 independently selected R 7 In some embodiments, R 1 is 1 to 3 independently selected R 7 and phenyl optionally substituted by:

[0029] In some embodiments, each R 7 are independently H, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, or C 1-6 haloalkoxy.

[0030] In some embodiments, R 1 is heteroaryl, cycloalkyl, or heterocycloalkyl, and each R 1 is 1 to 5 independently selected R 7 may be replaced by

[0031] In some embodiments, R 1 is heteroaryl or heterocycloalkyl, and each R 1 is 1 to 5 independently selected R 7 In some embodiments, R 1 heteroaryl is 1 to 5 independently selected R 7 In some embodiments, R 1 The monocyclic heteroaryl is 1 to 5 independently selected R 7 In some embodiments, R 1 is a monocyclic heteroaryl of 5 to 6 ring atoms, in which 1, 2, or 3 ring atoms are independently selected from N, O, and S; R 1 is 1 to 4 independently selected R 7 In some embodiments, R 1is a monocyclic nitrogen-containing heteroaryl of 5-6 ring atoms, in which 1, 2, or 3 ring atoms are independently selected from N, O, and S; R 1 is 1 to 4 independently selected R 7 In some embodiments, R 1 is a monocyclic nitrogen-containing heteroaryl of 5-6 ring atoms, in which 1, 2, or 3 ring heteroatoms are selected exclusively from N; R 1 is 1 to 4 independently selected R 7 In some embodiments, R 1 is 1 to 4 independently selected R 7 In some embodiments, R is a pyridine, pyrimidine, pyrazine, pyridazine, thiazole, oxazole, pyrrole, imidazole, or pyrazole, optionally substituted by 1 is 1 to 4 independently selected R 7 In some embodiments, R is a pyridine, thiazole, or pyrazole optionally substituted by 1 is 1 to 4 independently selected R 7 In some embodiments, R is pyridine optionally substituted by 1 is 1 to 4 independently selected R 7 and 2-pyridyl optionally substituted by:

[0032] In some embodiments, R 1 teeth, [ka] is.

[0033] In some embodiments, R 1 teeth, [ka] is.

[0034] In some embodiments, R 1 is 1 to 4 independently selected R 7may be replaced by [ka] In some embodiments, R 1 is heterocycloalkyl of 4 to 8 ring atoms, 1 to 3 ring atoms being selected from N, O and S; R 1 is 1 to 4 independently selected R 7 In some embodiments, R 1 is a monocyclic heterocycloalkyl of 4 to 7 ring atoms, in which 1 to 3 ring atoms are selected from N, O, and S; R 1 is 1 to 4 independently selected R 7 In some embodiments, R 1 is tetrahydropyran, azetidine, pyrrolidine, morpholine, or piperidine; R 1 is 1 to 4 independently selected R 7 may be replaced by

[0035] In some embodiments, R 1 is 1 to 4 independently selected R 7 may be replaced by C 3-7 In some embodiments, R 1 is a cyclohexyl having any one or two carbon bridged rings, and R 1 is 1 to 4 independently selected R 7 may be replaced by

[0036] In some embodiments, R 2 is an aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -O-cycloalkyl, -O-heterocycloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl or NR a R b and each R 2 is 1 to 5 independently selected R 8 may be substituted by R 2 Group Ra and R b cannot both be H. In some embodiments, R 2 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, and each R 2 is 1 to 5 independently selected R 8 In some embodiments, R 2 is 1 to 5 independently selected R 8 In some embodiments, R 2 is 1 to 3 independently selected R 8 In some embodiments, each R 8 are independently H, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, or C 1-6 haloalkoxy.

[0037] In some embodiments, R 2 teeth [ka] is.

[0038] In some embodiments, R 2 is heteroaryl, cycloalkyl, or heterocycloalkyl, and each R 2 is 1 to 5 independently selected R 8 In some embodiments, R 2 is heteroaryl or heterocycloalkyl, and each R 2 is 1 to 5 independently selected R 8 In some embodiments, R 2 is 1 to 5 independently selected R 8 In some embodiments, R 2 is 1 to 5 independently selected R 8In some embodiments, R is a monocyclic heteroaryl optionally substituted by 2 is a monocyclic heteroaryl of 5 to 6 ring atoms, in which 1, 2, or 3 ring atoms are independently selected from N, O, and S; R 2 is 1 to 4 independently selected R 8 In some embodiments, R 2 is 1 to 4 independently selected R 8 In some embodiments, R is a pyridine, pyrimidine, pyrazine, pyridazine, thiazole, oxazole, pyrrole, imidazole, or pyrazole, optionally substituted by 2 is 1 to 4 independently selected R 8 In some embodiments, R is a pyridine, pyrimidine, pyrazine, or pyrazole, optionally substituted by 2 is 1 to 4 independently selected R 8 and optionally substituted pyridine.

[0039] In some embodiments, R 2 is 1 to 4 independently selected R 8 may be replaced by [ka] is.

[0040] In some embodiments, R 2 teeth [ka] and R 2 is not further substituted.

[0041] In some embodiments, R 2 teeth, [ka] is.

[0042] In some embodiments, R2 is 1 to 5 independently selected R 8 In some embodiments, R 2 is 1 to 5 independently selected R 8 may be replaced by C 3-8 In some embodiments, R 2 are each 1 to 3 independently selected R 8 In some embodiments, R is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, optionally substituted by 2 is unsubstituted. In some embodiments, R 2 is cyclopropyl.

[0043] In some embodiments, R 2 is 1 to 5 independently selected R 8 In some embodiments, R 2 is 1 to 5 independently selected R 8 In some embodiments, R is a monocyclic heterocycloalkyl optionally substituted by 2 is a monocyclic heterocycloalkyl of 4 to 6 ring atoms, in which 1, 2, or 3 ring atoms are independently selected from N, O, and S; R 2 are 1 to 4 independently selected R 8 In some embodiments, R 2 is 1 to 4 independently selected R 8 In some embodiments, R is azetidine, oxetane, pyrrolidine, tetrahydrofuran, piperidine, piperazine, tetrahydropyran, or morpholine, optionally substituted by 2 is 1 to 4 independently selected R 8 In some embodiments, R is azetidine, pyrrolidine, piperazine, or morpholine, optionally substituted by 2 contains a ring nitrogen atom and is attached to formula (I) at the ring nitrogen atom.

[0044] In some embodiments, R 2 teeth, [ka] is.

[0045] In some embodiments, R 2 is NR a R b and each R 2 is 1 to 5 independently selected R 8 may be substituted by R 2 Group R a and R b cannot both be H. In some embodiments, R a is C 1-6 alkyl, and R b is C 1-6 Alkyl, C 3-7 cycloalkyl, or 3- to 7-membered heterocycloalkyl. In some embodiments, R a and R b are independently selected C 1-6 It is alkyl.

[0046] In some embodiments, each R 8 are independently deuterium, hydroxy, halogen, cyano, or C 1-6 Alkoxy is selected from:

[0047] In some embodiments, R 2 is 1 to 5 independently selected R 8 may be replaced by C 1-6 In some embodiments, R 2 C optionally substituted with 1 to 5 independently selected halogens 1-6 In some embodiments, R 2 is Me, Et, CHF, or CF. In some embodiments, R 2 is CHF2. In some embodiments, R 2 is CF3.

[0048] In some embodiments, R 2 is not substituted.

[0049] In some embodiments, R 2 is O-cycloalkyl, -O-heterocycloalkyl, or C 1-6 alkoxy, and each R 2 is 1 to 5 independently selected R 8 In some embodiments, R 2 -OC 3-7 Cycloalkyl or C 1-6 alkoxy, and each R 2 is optionally substituted with 1 to 5 groups independently selected from alkyl and halogen. 2 -OC 3-7 Cycloalkyl or C 1-6 alkoxy, and each R 2 is optionally substituted with 1 to 5 independently selected halogens. 2 is —O-cyclobutyl, —O-propyl, —O-methyl, —OCHF2, or —O—CF3.

[0050] In some embodiments, m is 1 and n is 1.

[0051] In some embodiments, p is 0, 1, 2, 3, 4, 5, or 6.

[0052] In some embodiments, each R 10 are independent, C 1-6 Alkyl and C 1-6 haloalkyl, each optionally substituted with 1 to 5 deuterium atoms. 10 is methyl.

[0053] In some embodiments, p is 1, 2, 3, 4, 5, or 6.

[0054] In some embodiments, R 3 is substituted with an edge-fused or spiro-fused cyclopropane; or R 3 contains one or two carbon bridges or single bond bridges; R 3 is an additional 1 to 4 R 10 may be replaced by

[0055] In some embodiments, R 3 teeth [ka] and R 3 is an additional 1 to 4 R 10 may be replaced by

[0056] In some embodiments, R 3 teeth [ka] and R 3 is an additional 1 to 4 R 10 may be replaced by

[0057] In some embodiments, R 3 teeth [ka] is.

[0058] In some embodiments, R 3 is an additional R 10 is not replaced by at all.

[0059] In some embodiments, R 4 is H. In some embodiments, R 5 is H. In some embodiments, R 6 is H. In some embodiments, R 4 and R 6 is H. In some embodiments, R 4 , R 5 , and R6 is H.

[0060] In some embodiments, R 7 and R 8 Each of the groups may be selected from the group consisting of hydroxy, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, and C 3-7 cycloalkyl, and each C 1-6 Alkyl and C 1-6 The alkoxy may be substituted with 1 to 3 halogens. In some embodiments, each R 7 In each case, halogen, cyano, C 1-6 Alkyl, C 1-6 alkoxy, and CF3.

[0061] In some embodiments, R 9 is C optionally substituted with 1 to 5 halogens or 1 to 9 deuteriums 1-6 In some embodiments, R 9 is ethyl, isopropyl, or t-butyl; each optionally substituted with 1 to 5 halogens or 1 to 9 deuteriums. In some embodiments, R 9 is ethyl, isopropyl, or t-butyl. 9 is t-butyl. In some embodiments, R 9 is -C(CD3)3, -CH(CD3)2, or -CD2CD3.

[0062] In some embodiments, R 9 is Me, Et, t-butyl, -C(CD3)3, -CH(CD3)2, -C(CD3)3, isopropyl, F3C-CH2-, F3C-CH(CH3)-, F3C-C(CH3)2-, or FCH2-C(CH3)2-, [ka] is.

[0063] In some embodiments, R 9 is Me, Et, t-butyl, -C(CD3)3, -CH(CD3)2, -C(CD3)3, isopropyl, F3C-CH2-, F3C-CH(CH3)-, F3C-C(CH3)2-, or FCH2-C(CH3)2-, [ka] is.

[0064] In another embodiment, a compound of formula (Ib): [ka] is provided, wherein the variables are defined as described herein and in the claims.

[0065] In another embodiment, a compound of formula (Ic): [ka] is provided, wherein the variables are defined as described herein and in the claims.

[0066] In another aspect, there is provided a compound of formula (I) or any subformula thereof selected from the compounds disclosed herein or in the claims, or a pharmaceutically acceptable salt thereof.

[0067] In some embodiments, the compound achieves at least 50% of the maximal current obtained with 30 μM ML-SA1 in a patch clamp assay for TRPML and has an EC 50 In some embodiments, the compound achieves at least 50% of the maximal current obtained with 30 μM ML-SA1 in a patch clamp assay for TRPML1 and has an EC 50In some embodiments, the compound achieves a maximal current obtained with 30 μM ML-SA1 in a patch clamp assay for TRPML1 that is at least 10-fold higher than the maximal current achieved for any other TRPML.

[0068] In another aspect, a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound selected from the compounds disclosed herein or the claims, or a pharmaceutically acceptable salt thereof, in some embodiments, the compound is a compound identified in Table 1 below, or a pharmaceutically acceptable salt thereof.

[0069] Table 1. Exemplary compounds [Table 1] TIFF2024536237000034.tif220158TIFF2024536237000035.tif214158TIFF2024536237000036.tif216158TIFF2024536237000037.tif212158TIFF2024536237000038.tif202158TIFF2024536237000039.tif216158TIFF2024536237000040.tif224158TIFF2024536237000041.tif212158TIFF2024536237000042.tif215162TIFF2024536237000043.tif205159TIFF2024536237000044.tif209158TIFF2024536237000045.tif209158TIFF2024536237000046.tif219159TIFF2024536237000047.tif207158TIFF2024536237000048.tif203158TIFF2024536237000049.tif200158TIFF2024536237000050.tif220158TIFF2024536237000051.tif219158TIFF2024536237000052.tif212158TIFF2024536237000053.tif209158TIFF2024536237000054.tif214159TIFF2024536237000055.tif218158TIFF2024536237000056.tif223158TIFF2024536237000057.tif224158TIFF2024536237000058.tif213159TIFF2024536237000059.tif207158TIFF2024536237000060.tif217159TIFF2024536237000061.tif211159TIFF2024536237000062.tif203161TIFF2024536237000063.tif200158TIFF2024536237000064.tif220158TIFF2024536237000065.tif200159TIFF2024536237000066.tif221159TIFF2024536237000067.tif212159TIFF2024536237000068.tif218160TIFF2024536237000069.tif210157TIFF2024536237000070.tif203159TIFF2024536237000071.tif207159TIFF2024536237000072.tif211159TIFF2024536237000073.tif200158TIFF2024536237000074.tif205159TIFF2024536237000075.tif207159TIFF2024536237000076.tif211159TIFF2024536237000077.tif203159TIFF2024536237000078.tif212159TIFF2024536237000079.tif209158TIFF2024536237000080.tif210159TIFF2024536237000081.tif200159TIFF2024536237000082.tif207159TIFF2024536237000083.tif238160TIFF2024536237000084.tif205158TIFF2024536237000085.tif216158TIFF2024536237000086.tif205159TIFF2024536237000087.tif205158TIFF2024536237000088.tif209158TIFF2024536237000089.tif204158TIFF2024536237000090.tif207158TIFF2024536237000091.tif204158TIFF2024536237000092.tif214160TIFF2024536237000093.tif220158TIFF2024536237000094.tif211159TIFF2024536237000095.tif214159TIFF2024536237000096.tif211159TIFF2024536237000097.tif207159TIFF2024536237000098.tif203158TIFF2024536237000099.tif206159TIFF2024536237000100.tif204159TIFF2024536237000101.tif212161TIFF2024536237000102.tif216159TIFF2024536237000103.tif200158TIFF2024536237000104.tif204158TIFF2024536237000105.tif218159TIFF2024536237000106.tif214137TIFF2024536237000107.tif214130TIFF2024536237000108.tif224130TIFF2024536237000109.tif210126TIFF2024536237000110.tif206124TIFF2024536237000111.tif216138TIFF2024536237000112.tif217139TIFF2024536237000113.tif217129TIFF2024536237000114.tif215124TIFF2024536237000115.tif214124TIFF2024536237000116.tif215126TIFF2024536237000117.tif215126TIFF2024536237000118.tif213128TIFF2024536237000119.tif215121TIFF2024536237000120.tif224120TIFF2024536237000121.tif217120TIFF2024536237000122.tif224121TIFF2024536237000123.tif215122TIFF2024536237000124.tif225120TIFF2024536237000125.tif214116TIFF2024536237000126.tif217119TIFF2024536237000127.tif214124TIFF2024536237000128.tif215118TIFF2024536237000129.tif223117TIFF2024536237000130.tif215121TIFF2024536237000131.tif216122TIFF2024536237000132.tif214122TIFF2024536237000133.tif225131TIFF2024536237000134.tif217135TIFF2024536237000135.tif225136T IFF2024536237000136.tif215137TIFF2024536237000137.tif217138TIFF2024536237000138.tif211137TIFF2024536 237000139.tif215135TIFF2024536237000140.tif214131TIFF2024536237000141.tif216136TIFF2024536237000142. tif215135TIFF2024536237000143.tif216137TIFF2024536237000144.tif210136TIFF2024536237000145.tif206134.

[0070] Deuterated Compounds In some embodiments, the compounds described herein (eg, compounds of Formula I, Ia, Ib, or Ic) are deuterium-enriched.

[0071] Deuterium (D or 2 H) is a stable, non-radioactive isotope of hydrogen with an atomic mass of 2.0144. Hydrogen is naturally 1 H (hydrogen or protium), D ( 2 H or deuterium), and T( 3 Deuterium occurs as a mixture of hydrogen and hydrogen (H or tritium). The natural abundance of deuterium is 0.015%. Those skilled in the art will appreciate that in all compounds with H atoms, the H atoms actually represent a mixture of H and D, with approximately 0.015% being D. Thus, compounds that are enriched and have deuterium levels greater than 0.015% of the natural abundance are considered unnatural and, as a result, novel relative to their non-enriched counterparts.

[0072] Even when deuterium atoms are incorporated at known metabolic sites, the effect of deuterium modification on the metabolic properties of a compound cannot be predicted. Only by actually producing and testing the deuterated compound can one determine whether and how the metabolic rate differs from that of the non-deuterated compound. See, for example, Fukuto et al. (J. Med. Chem. 1991, 34, 2871-76). Many compounds have multiple metabolic sites. The sites required for deuterium substitution and the degree of deuteration required to see an effect on metabolism, if any, will vary from compound to compound.

[0073] Unless otherwise specified, when a position is specifically designated as "H" or "hydrogen," the position is understood to have hydrogen at its natural abundance isotopic composition. Also, unless otherwise specified, when a position is specifically designated as "D" or "deuterium," the position is understood to contain deuterium at an abundance at least 3000 times greater than the natural abundance of deuterium, 0.015% (i.e., the term "D" or "deuterium" indicates at least 45% deuterium incorporation).

[0074] The term "isotopic enrichment factor" as used herein means the ratio between the isotopic abundance of D at a specified position in a compound of the present invention and the natural abundance of that isotope.

[0075] Increasing the amount of deuterium present in a compound herein (e.g., a compound of Formula I, Ia, Ib, or Ic) is referred to as "deuterium enrichment," and such compounds are referred to as "deuterium-enriched" compounds. Unless specifically stated, percent enrichment refers to the percent of deuterium present in the compound.

[0076] In other embodiments, the compounds of the present invention have an isotopic enrichment factor for each deuterium present at a site designated as a deuterium site on the compound of at least 3500 (52.5% deuterium incorporation), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). It is understood that the isotopic enrichment factor for each deuterium present at a site designated as a deuteration site is independent of other deuteration sites. For example, if there are two deuteration sites on a compound, one site may be 52.5% deuterium-rich and the other may be 75% deuterium-rich. The resulting compound would be considered to be one with an isotopic enrichment factor of at least 3500 (52.5%).

[0077] Because the natural abundance of deuterium is approximately 0.015%, it would be expected that a small percentage of the naturally occurring compounds herein (e.g., compounds of Formula I, Ia, Ib, or Ic) will have one naturally occurring compound with one deuterium.

[0078] In some embodiments, the compounds herein (e.g., compounds of Formula I, Ia, Ib, or Ic) comprise a deuterium enrichment that is greater than the deuterium enrichment present in the naturally occurring compounds herein (e.g., compounds of Formula I, Ia, Ib, or Ic).

[0079] All percentages given for the amount of deuterium present are molar percentages. Achieving 100% deuteration at any one site in laboratory-scale quantities of a compound (e.g., milligrams or more) can be difficult in the laboratory. When 100% deuteration is stated, or when deuterium atoms are specifically shown in a structure, it is assumed that a small percentage of hydrogen may still be present. Deuterium enrichment can be achieved by exchanging protons for deuterium or by synthesizing molecules using enriched starting materials.

[0080] Treatment method Provided herein, in certain embodiments, is a method of modulating a TRPML ion channel, comprising administering to a patient in need of treatment a compound described herein (e.g., a compound of Formula I, Ia, Ib, or Ic) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopically labeled derivative thereof, or a composition described herein.

[0081] Provided herein, in certain embodiments, are methods for treating a disease or disorder treatable by modulation of TRPML ion channels, comprising administering to a patient in need of treatment a compound described herein (e.g., a compound of Formula I, Ia, Ib, or Ic) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopically labeled derivative thereof, or a composition described herein.

[0082] Provided herein, in certain embodiments, is a method for treating a disease or disorder treatable by activation of a TRPML ion channel, comprising administering to a patient in need of treatment a compound described herein (e.g., a compound of Formula I, Ia, Ib, or Ic) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopically labeled derivative thereof, or a composition described herein.

[0083] Provided herein, in certain embodiments, is a method for treating a disease or disorder treatable by activation of TRPML1, comprising administering a compound described herein (e.g., Formula I, Ia, Ib, or Ic) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopically labeled derivative thereof, or a composition described herein.

[0084] In addition to compounds of Formula I, Ia, Ib, or Ic, modulators of TRPML channels have been reported in several publications, including WO2018005713 and WO2018208630, which are incorporated herein in their entireties.

[0085] In some embodiments, the TRPML ion channel is TRPML1. In some embodiments, the TRPML ion channel is TRPML2. In some embodiments, the TRPML ion channel is TRPML3.

[0086] In some embodiments, the compound is a modulator of TRPML1. In some embodiments, the compound is a modulator of TRPML2. In some embodiments, the compound is a modulator of TRPML3.

[0087] In some embodiments, modulation of a TRPML ion channel comprises activation of the ion channel.

[0088] In some embodiments, the disease or disorder is a cilia-associated disorder (e.g., polycystic kidney disease). Examples of cilia-associated disorders include, but are not limited to, polycystic kidney disease, pancreatic cysts in polycystic kidney disease, Bardet-Biedl syndrome, nephronophthisis, Joubert syndrome, Mecke-Gruber syndrome, orofacial-digital syndrome, Senior-Loken syndrome, Birt-Hogg-Dubé syndrome, Leber congenital amaurosis, Alström syndrome, Jeune asphyxiating thoracic dystrophy, Ellis-van Creveld syndrome, Sensenbrenner syndrome, and primary ciliary dyskinesia.

[0089] In one aspect, a method for treating a disorder that can be treated by modulation of lysosomes is provided, comprising administering to a patient in need of treatment a therapeutically effective amount of a pharmaceutical composition of the disclosure or a compound of the disclosure.

[0090] In one aspect, provided is a method for treating a disorder selected from the group consisting of a cilia-associated disease, a neurodegenerative disease, a lysosomal storage disorder, a lysosomal trafficking disorder, a glycogen storage disorder, a cholesterol ester storage disease, a muscle disease (e.g., muscular dystrophy), an age-related disease (e.g., photoaging of the skin), macular degeneration (e.g., Stargardt's disease or age-related), and cancer (e.g., cancer of the blood, brain, bone, lung, liver, kidney, bladder, stomach, breast, prostate, ovary, testis, colon, pancreas, or skin), comprising administering to a patient in need of treatment a therapeutically effective amount of a pharmaceutical composition of the present disclosure or a compound of the present disclosure.

[0091] In some embodiments, the disorder is a cilia-associated disorder.

[0092] In some embodiments, the cilia-related disorder is selected from the group consisting of polycystic kidney disease, pancreatic cysts in polycystic kidney disease, Bardet-Biedl syndrome, nephronophthisis, Joubert syndrome, Meckel-Gruber syndrome, orofacial-digital syndrome, Senior-Loken syndrome, Birt-Hogg-Dubé syndrome, Leber congenital amaurosis, Alström syndrome, Jeune asphyxiating thoracic dystrophy, Ellis-van Creveld syndrome, Sensenbrenner syndrome, and primary ciliary dyskinesia.

[0093] In some embodiments, the disorder is polycystic kidney disease. In some embodiments, the disorder is autosomal dominant polycystic kidney disease, autosomal recessive polycystic kidney disease, or autosomal dominant polycystic kidney disease-associated pancreatic cysts. In some embodiments, the disorder is autosomal dominant polycystic kidney disease. In some embodiments, the disorder is a neurodegenerative disorder.

[0094] In some embodiments, the neurodegenerative disorder is selected from the group consisting of Parkinson's disease, GBA-Parkinson's disease, LRRK2 Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), Alzheimer's disease, progressive supranuclear palsy, frontotemporal dementia, FTDP-17, corticobasal degeneration, dementia with Lewy bodies, Pick's disease, and multiple system atrophy.

[0095] In some embodiments, the disorder is a lysosomal storage disorder.

[0096] In some embodiments, the lysosomal storage disorder is selected from the group consisting of Niemann-Pick disease, Gaucher disease, neuropathic Gaucher disease, sphingolipidosis, Farber disease, Krabbe disease, galactosialidosis, gangliosidosis, Gaucher disease, lysosomal acid lipase deficiency, sulfatidosis, mucopolysaccharidoses, mucolipidoses, lipidoses, and oligosaccharidoses.

[0097] In some embodiments, the lysosomal storage disorder is selected from the group consisting of sphingolipidoses, Farber disease, Krabbe disease, galactosialidosis, Fabry disease, Schindler disease, β-galactosidase disorders, GM1 gangliosidosis, GM2 gangliosidosis AB variant, GM2 gangliosidosis activating factor deficiency, Sandhoff disease, Tay-Sachs disease, Gaucher disease, lysosomal acid lipase deficiency, Niemann-Pick disease, metachromatic leukodystrophy, saposin B deficiency, multiple sulfatase deficiency, Hurler syndrome, Scheie syndrome, Hurler-Scheie syndrome, Hunter syndrome, Sanfilippo syndrome, Morquio syndrome, Maroteaux-Lamy syndrome, Sly syndrome, hyaluronidase deficiency, sialic acid lipase ... and / or fucosidosis, I-cell disease, pseudo-Hurler multiple dystrophy, phosphotransferase deficiency, mucolipidin 1 deficiency, Santavuori-Hartier disease, Jansky-Bierschofsky disease, Batten-Spielmeyer-Voigt disease, Kufus disease, Finnish variant neuronal ceroid lipfuscinosis, late infantile variant neuronal ceroid lipfuscinosis, type 7 neuronal ceroid lipfuscinosis, northern epilepsy-type neuronal ceroid lipfuscinosis, Turkish-type late infantile neuronal ceroid lipfuscinosis, German / Serbian-type late infantile neuronal ceroid lipfuscinosis, congenital cathepsin D deficiency, Wolman disease, α-mannosidosis, β-mannosidosis, aspartylglucosaminuria, and fucosidosis.

[0098] In some embodiments, the lysosomal storage disorder is selected from the group consisting of Niemann-Pick disease, Gaucher disease, and neuropathic Gaucher disease.

[0099] In some embodiments, the disorder is a lysosomal trafficking disorder selected from the group consisting of cystinosis, pyknodysostosis, Salla disease, sialic acid storage disease, and infantile free sialic acid storage disease.

[0100] In some embodiments, the disorder is a glycogen storage disease selected from the group consisting of Pompe disease and Danon disease.

[0101] In one aspect, a method of treating a cilia-associated disorder is provided, comprising administering to a patient in need thereof a therapeutically effective amount of a compound capable of modulating TRPML, or a pharmaceutical composition comprising a therapeutically effective amount of such a compound and a pharmaceutically acceptable excipient.

[0102] In some embodiments, the compound is selected from the compounds disclosed herein.

[0103] In some embodiments, the cilia-related disorder is selected from the group consisting of polycystic kidney disease, pancreatic cysts in polycystic kidney disease, Bardet-Biedl syndrome, nephronophthisis, Joubert syndrome, Meckel-Gruber syndrome, orofacial-digital syndrome, Senior-Loken syndrome, Birt-Hogg-Dubé syndrome, Leber congenital amaurosis, Alström syndrome, Jeune asphyxiating thoracic dystrophy, Ellis-van Creveld syndrome, Sensenbrenner syndrome, and primary ciliary dyskinesia.

[0104] In some embodiments, the disorder is polycystic kidney disease.

[0105] In some embodiments, the disorder is autosomal dominant polycystic kidney disease, autosomal recessive polycystic kidney disease, or autosomal dominant polycystic kidney disease-associated pancreatic cysts.

[0106] In some embodiments, the disorder is autosomal dominant polycystic kidney disease. In some embodiments, the method further comprises the use of a second therapeutic agent.

[0107] In some embodiments, the method is for treating a cilia-related disorder.

[0108] In some embodiments, the second therapeutic agent is selected from the group consisting of an mTOR inhibitor, a V2 receptor antagonist, a tyrosine kinase inhibitor, a somatostatin analog, a glucosylceramide synthase inhibitor, a microRNA-17 inhibitor, an siRNA against p53, a KEAP1-Nrf2 activator, a xanthine oxidase inhibitor, a PPARγ agonist, metformin, and beta-hydroxybutyrate.

[0109] In some embodiments, the second therapeutic agent is selected from the group consisting of tolvaptan, lixivaptan, mozavaptan, satavaptan, sirolimus, tacrolimus, everolimus, bosutinib, tesavatinib, imatinib, gefitinib, erlotinib, dasatinib, octreotide, pasireotide, benglustat, eliglustat, miglustat, microRNA-17 inhibitors, bardoxolone methyl, allopurinol, oxypurinol, pioglitazone, rosiglitazone, lobeglitazone, metformin, and beta-hydroxybutyric acid. In some embodiments, the second agent is tolvaptan.

[0110] In some embodiments, the second therapeutic agent is an immunomodulatory agent, a calcineurin inhibitor, a renin-angiotensin-aldosterone system inhibitor, an antiproliferative agent, an alkylating agent, a corticosteroid, an angiotensin-converting enzyme inhibitor, an adrenocorticotropic hormone stimulating agent, an angiotensin receptor blocker, a sodium-glucose transport protein 2 inhibitor, a dual sodium-glucose transport protein 1 / 2 inhibitor, a nuclear factor-1 (erythroid-derived 2)-like 2 agonist, a chemokine receptor 2 inhibitor, a chemokine receptor 5 inhibitor, an endothelin 1 receptor antagonist, or a beta-blocker. , mineralocorticoid receptor antagonists, loop diuretics or thiazide diuretics, calcium channel blockers, statins, short-, intermediate- or long-acting insulin, dipeptidyl peptidase 4 inhibitors, glucagon-like peptide 1 receptor agonists, sulfonylureas, apoptosis signal-regulating kinase 1, chymase inhibitors, selective glycation inhibitors, renin inhibitors, interleukin-33 inhibitors, farnesoid X receptor agonists, soluble guanylate cyclase stimulators, thromboxane receptor antagonists, xanthine oxidase inhibitors, erythropoietin receptor Receptor agonists, cannabinoid receptor type 1 inverse agonists, NADPH oxidase inhibitors, anti-vascular endothelial growth factor B, anti-fibrotic agents, neprilysin inhibitors, dual CD80 / CD86 inhibitors, CD40 antagonists, cellular cholesterol and lipid blockers, PDGFR antagonists, Slit guidance ligand 2, APOL1 inhibitors, Nrl2 activators / NF-κB inhibitors, somatostatin receptor agonists, PPAR gamma agonists, AMP-activated protein kinase stimulators, tyrosine kinase inhibitors, glucosylceramide synthase inhibitors, arginine vasopressin receptor 2 antagonists, xanthine oxidase inhibitors, vasopressin receptor 2 antagonists, anti-amyloid beta antibodies, anti-tau antibodies, anti-synuclein antibodies, dopamine precursors (e.g., L-DOPA), dopamine agonists (e.g., bromocriptine, cabergoline, pergolide, pramipexole, and apomorphine), MAO-B inhibitors (e.g., rasagiline and selegiline), anticholinergics (e.g., orphenadrine, procyclidine, and trihexyphenidyl), enhancers of b-glucocerebrosidase activity (e.g., ambroxol and afegostat), amantadine,and drugs capable of treating Alzheimer's disease (e.g., acetylcholinesterase inhibitors such as tacrine, rivastigmine, galantamine, and donepezil, and NMDA receptor antagonists such as memantine).

[0111] In some embodiments, the second therapeutic agent is selected from the group consisting of arylcarboxylic acids (salicylic acid, acetylsalicylic acid, diflunisal, choline magnesium trisalicylate, salicylates, benorylate, flufenamic acid, mefenamic acid, meclofenamic acid, and triflumic acid), arylalkanoic acids (diclofenac, fenclofenac, alclofenac, fentiazac, ibuprofen, flurbiprofen, ketoprofen, naproxen, fenoprofen, fenbufen, suprofen, indoprofen, tiaprofenic acid, benoxaprofen, COX inhibitors such as pirprofen, tolmetin, zomepirac, clopinac, indomethacin, and sulindac) and enolic acids (phenylbutazone, oxyphenbutazone, azapropazone, feprazone, piroxicam, and isoxicam); drugs for the treatment of pulmonary hypertension such as prostanoids (epoprostenol, iloprost, and treprostinil), endothelin receptor antagonists (bosentan, ambrisentan, and macitentan), phosphodiesterase-5 inhibitors (sildenafil and tadalafil), and sGC stimulators (riociguat); Y-276 ρ-kinase inhibitors such as 32, fasudil, and H-1152P; epoprostenol derivatives such as prostacyclin, treprostinil, beraprost, and iloprost; serotonin blockers such as sarpogrelate; endothelin receptor antagonists such as besentan, sitaxsentan, ambrisentan, and TBC3711; PDE inhibitors such as sildenafil, tadalafil, udenafil, and vardenafil; soluble guanylate cyclase inhibitors such as riociguat and vericiguat; amlodipine, bepridil, clentazem, diltiazem, Calcium channel blockers such as fendiline, gallopamil, mibefradil, prenylamine, semotiadil, terodiline, verapamil, aranidipine, bamidipine, benidipine, cilnidipine, efonidipine, elgodipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, cinnarizine, flunarizine, lidoflazine, lomerizine, bencyclane, etafenone, and perhexiline; tyrosine kinase inhibitors such as imatinib;Nitric oxide donors such as inhaled nitric oxide and inhaled nitrite; IκB inhibitors such as IMD1041; prostacyclin receptor agonists such as selexipag; hematopoietic stimulants such as TXA127 (angiotensin (1-7)), darbepoetin alfa, erythropoietin, and epoetin alfa; anticoagulants and platelet inhibitors; and diuretics; and dietary supplements such as acetyl-L-carnitine, octacosanol, evening primrose oil, vitamin B6, tyrosine, phenylalanine, vitamin C, and L-dopa. and nutritional supplements; immunosuppressants (for transplant and autoimmune-related RKD); antihypertensives (for hypertension-related RKD, e.g., angiotensin-converting enzyme inhibitors and angiotensin receptor blockers); insulin (for diabetic RKD); lipid / cholesterol-lowering agents (e.g., HMG-CoA reductase inhibitors such as atorvastatin or simvastatin); and agents for the treatment of hyperphosphatemia or hyperparathyroidism associated with CKD (sevelamer acetate, cinacalcet);

[0112] The present disclosure further provides a pharmaceutical composition comprising a compound provided herein or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier. The present disclosure further provides a method for modulating TRPML in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof.

[0113] The present disclosure further provides a method of treating a disease or disorder in a subject, comprising: (a) detecting a TRPML-associated disease or disorder; and (b) administering to the subject a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof. The present invention provides a method comprising:

[0114] In certain embodiments, exemplary compounds of Formula (I) or (II) include those set forth in Table 1 and in the Examples, as well as pharmaceutically acceptable salts, solvates, hydrates, tautomers, and stereoisomers thereof.

[0115] Thus, the present disclosure provides compounds useful for treating cilia-related disorders and related diseases.

[0116] Compounds that modulate TRPML channels may be useful in the prevention and treatment of any of the aforementioned injuries, diseases, disorders, or conditions. In addition to in vitro assays of the activity of these compounds, their efficacy can be readily tested in one or more animal models.

[0117] The disclosure is not limited in its application to the details of the methods and compositions described herein, and the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting.

[0118] Pharmaceutical Compositions and Routes of Administration The present disclosure provides pharmaceutical compositions comprising a compound provided herein or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier. Also provided herein is a method for modulating TRPML channels in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof.

[0119] In certain embodiments, a pharmaceutical composition containing a compound described herein, such as a compound of Formula I, Ia, Ib, or Ic described herein, or a pharmaceutically acceptable salt thereof, can be used to treat or ameliorate a disorder described herein, e.g., a ciliopathic disorder.

[0120] The amount and concentration of the compound of Formula I, Ia, Ib, or Ic in the pharmaceutical composition, and the amount of the pharmaceutical composition administered to the subject, can be selected based on clinically relevant factors, such as the subject's medically relevant characteristics (e.g., age, weight, sex, other medical conditions, etc.), the solubility of the compound in the pharmaceutical composition, the potency and activity of the compound, and the method of administration of the pharmaceutical composition. For further information on routes and methods of administration, see Chapter 25.3, Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; editor-in-chief), Pergamon Press, 1990.

[0121] It is preferable to administer the compound as a pharmaceutical formulation in combination with one or more pharmaceutically acceptable diluents, excipients, or carriers. The compounds according to the present disclosure can be formulated for administration in any convenient manner for use in human or veterinary medicine. In certain embodiments, the compound included in the pharmaceutical formulation can be active itself or, for example, a prodrug that can be converted to an active compound in a physiological environment. Regardless of the selected route of administration, the compounds of the present disclosure, which may be used in a suitable hydrated form, and / or the pharmaceutical compositions of the present disclosure are formulated into a pharmaceutically acceptable dosage form as described below or by other conventional methods known to those skilled in the art.

[0122] Accordingly, another aspect of the present disclosure provides pharmaceutically acceptable compositions comprising a therapeutically effective amount of one or more of the above compounds formulated together with one or more pharmaceutically acceptable carriers (excipients) and / or diluents. As described in detail below, the pharmaceutical compositions of the present disclosure can be specially formulated for administration in solid or liquid form, including those adapted for the following administrations: (1) oral administration, e.g., drenches (aqueous or non-aqueous solutions or suspensions), lozenges, dragees, capsules, pills, tablets (e.g., intended for buccal, sublingual, and systemic absorption), boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, e.g., by subcutaneous, intramuscular, intravenous, or epidural injection, e.g., as a sterile solution or suspension, or sustained-release formulation; (3) topical application, e.g., as a cream, ointment, or sustained-release patch or spray applied to the skin; (4) vaginal or rectal, e.g., as a pessary, cream, or foam; (5) sublingual; (6) ocular; (7) transdermal; (8) transmucosal; (9) nasal; or (10) intrathecal administration.

[0123] Additionally, the compounds can be implanted into a patient or injected using a drug delivery system. See, e.g., Urquhart, et al., (1994) Ann Rev Pharmacol Toxicol 24:199-236; Lewis, ed. "Controlled Release of Pesticides and Pharmaceuticals" (Plenum Press, New York, 1981); U.S. Patent No. 3,773,919; and U.S. Patent No. 353,270,960.

[0124] As used herein, the phrase "therapeutically effective amount" means an amount of a compound, material, or composition containing a compound of the present disclosure effective to produce some desired therapeutic effect, e.g., by modulating EHMT1 or EHMT2 in at least a subset of cells in an animal, at a reasonable benefit / risk ratio applicable to any medical treatment, blocking the biological consequences of its function in the treated cells.

[0125] As used herein, the phrases "systemic administration," "administered systemically," "peripheral administration," and "peripherally administered" refer to the administration of a compound, drug, or other material other than directly into the central nervous system, such as by subcutaneous administration, thereby allowing the material to enter the patient's entire body and be subjected to metabolic and other similar processes.

[0126] The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, and at a reasonable benefit / risk ratio.

[0127] As used herein, the phrase "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in carrying or transporting the subject antagonist from one organ or body part to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials that can function as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer; (21) cyclodextrins such as Captisol®; and (22) other non-toxic compatible substances used in pharmaceutical formulations.

[0128] The term "pharmaceutically acceptable salts" is intended to include salts of active compounds prepared using relatively non-toxic acids or bases, depending on the specific substituents found in the compounds described herein. When a compound of the present disclosure contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or similar salts. When a compound of the present disclosure contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid, as well as salts derived from organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, and methanesulfonic acid. Also included are salts of amino acids such as arginic acid, and salts of organic acids such as glucuronic acid or galactunic acid (see, e.g., Berge et al., Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain compounds of the present disclosure contain both basic and acidic functional groups that allow the compounds to be converted into either base or acid addition salts. These salts can be prepared by methods known to those of ordinary skill in the art. Other pharmaceutically acceptable carriers known to those of ordinary skill in the art are also suitable for this disclosure.

[0129] Wetting agents, emulsifiers, and lubricating agents, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring, and perfuming agents, preservatives, and antioxidants can also be present in the composition.

[0130] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, and sodium sulfite; (2) oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, and α-tocopherol; and (3) metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, and phosphoric acid.

[0131] Formulations of the present disclosure include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, and / or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, this amount will range from about 1 percent to about 99 percent of the active ingredient, preferably from about 5 percent to about 70 percent, and most preferably from about 10 percent to about 30 percent, out of one hundred percent.

[0132] Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present disclosure with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present disclosure with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0133] Formulations of the present disclosure suitable for oral administration can be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored base, usually sucrose and acacia or tragacanth), powder, granules, or as a solution or suspension in an aqueous liquid or a non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as a troche (using an inert base such as gelatin and glycerin, or sucrose and acacia)) and / or mouthwash, etc., each containing a predetermined amount of a compound of the present disclosure as an active ingredient. The compounds of the present disclosure can also be administered as a bolus, electuary, or paste.

[0134] In solid dosage forms of the present disclosure for oral administration (e.g., capsules, tablets, pills, dragees, powders, granules, etc.), the active ingredient may be incorporated into one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) humectants, such as glycerol; (4) agar, calcium carbonate, potato starch, or the like. or disintegrating agents such as tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarders such as paraffin; (6) absorption accelerators such as quaternary ammonium compounds; (7) wetting agents such as cetyl alcohol and glycerol monostearate; (8) absorbents such as kaolin or bentonite clay; (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets, and pills, the pharmaceutical compositions may also contain buffering agents. Solid compositions of a similar type may also be employed as fillers in soft- and hard-filled gelatin capsules, using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols.

[0135] Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be made using binders (e.g., gelatin or hydroxypropyl methylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surface active agents, or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0136] Tablets and other solid dosage forms of pharmaceutical compositions of the present disclosure, such as dragees, capsules, pills, and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings known in the pharmaceutical formulation art. They can also be formulated to provide delayed or sustained release of the active ingredient therein, for example, using hydroxypropylmethylcellulose, other polymer matrices, liposomes, and / or microspheres, in varying proportions to provide the desired release profile. They can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water or some other sterile injectable medium immediately before use. These compositions can optionally contain opacifying agents and can be composed to release the active ingredient only, or preferentially, in a certain part of the digestive tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0137] Liquid dosage forms for oral administration of the compounds of the present disclosure include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof.

[0138] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0139] Suspensions may contain, in addition to the active compounds, suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0140] Formulations of pharmaceutical compositions of the present disclosure for rectal, vaginal, or urethral administration can be provided as suppositories, which can be prepared by mixing one or more compounds of the present disclosure with one or more suitable non-irritating excipients or carriers including, for example, cocoa butter, polyethylene glycol, suppository wax, or salicylates, which are solid at room temperature but liquid at body temperature and thus melt in the rectum or vaginal cavity to release the active compound(s).

[0141] Alternatively, or in addition, the compositions can be formulated for delivery via a catheter, stent, wire, or other intraluminal device. Delivery via such devices can be particularly useful for delivery to the heart, lungs, bladder, urethra, ureters, rectum, or intestines. Additionally, the compositions can be formulated for delivery via a dialysis port.

[0142] Ophthalmic formulations, eye ointments, powders, solutions, and the like, are also contemplated as being within the scope of the present disclosure.

[0143] Exemplary modes of administration include, but are not limited to, injection, infusion, infusion, inhalation, or ingestion. "Injection" includes, but is not limited to, intravenous, intramuscular, arterial, intrathecal, intraventricular, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, intracerebrospinal, and intrasternal injection and infusion. In some embodiments, the composition is administered by intravenous infusion or injection.

[0144] As used herein, the phrases "parenteral administration" and "administered parenterally" refer to modes of administration other than enteral and topical administration, usually by injection, and include, but are not limited to, intravenous, intramuscular, arterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, intrathecal, intraspinal, and intrasternal injection and infusion. Pharmaceutical compositions of the present disclosure suitable for parenteral administration include one or more compounds of the present disclosure in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, which may contain antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the subject's blood, or suspending or thickening agents, or sterile powders that can be reconstituted into sterile injectable solutions or dispersions immediately before use.

[0145] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present disclosure include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0146] These compositions may also contain auxiliary agents such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like, in the compositions. Furthermore, prolonged absorption of the injectable pharmaceutical form can be achieved by the inclusion of agents that delay absorption, such as aluminum monostearate and gelatin.

[0147] In some cases, it is desirable to delay the absorption of drugs from subcutaneous or intramuscular injections in order to prolong the effect of the drug. This can be achieved by using a suspension of crystalline or amorphous material with poor water solubility. The absorption rate of the drug is then determined by its dissolution rate, which in turn can depend on the crystal size and crystalline form. Alternatively, delayed absorption of parenterally administered drug forms can be achieved by dissolving or suspending the drug in an oil vehicle.

[0148] Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. The rate of drug release can be controlled depending on the ratio of drug to polymer and the nature of the particular polymer used. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations can also be prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

[0149] When the compounds of the present disclosure are administered to humans and animals as pharmaceuticals, the compounds can be provided as they are, or can be administered as a pharmaceutical composition containing 0.1 to 99.5% (more preferably 0.5 to 90%) of the active ingredient in combination with, for example, a pharmaceutically acceptable carrier.

[0150] The active compound of the present disclosure is preferably added to animal feed by preparing a suitable feed premix containing an effective amount of the active compound and incorporating the premix into a complete feed. Alternatively, an intermediate concentrate or feed supplement containing the active ingredient can be mixed into the feed. Methods for preparing and administering such feed premixes and complete feeds are described in reference books (e.g., "Applied Animal Nutrition", W.H. Freedman and CO., San Francisco, USA, 1969 or "Livestock Feeds and Feeding", O and B books, Corvallis, Ore., USA, 1977).

[0151] Delivery methods can also be provided by rechargeable or biodegradable devices. In recent years, various sustained-release polymeric devices have been developed and tested in vivo for the controlled delivery of drugs, including proteinaceous biopharmaceuticals. A variety of biocompatible polymers (including hydrogels), including both biodegradable and non-degradable polymers, can be used to form implants for sustained release of compounds at specific target sites.

[0152] Preferably, the subject is a mammal. The mammal can be, but is not limited to, a human, a non-human primate, a mouse, a rat, a dog, a cat, a horse, or a cow. Non-human mammals can be advantageously used as subjects representing animal models of neurodegenerative diseases or disorders, cancer, or disorders associated with viral infection.

[0153] Additionally, the methods described herein can be used to treat livestock and / or pets. The subject can be male or female. The subject can be previously diagnosed with, or confirmed to be suffering from or having, a neurodegenerative disease or disorder, a cancer-related disease or disorder, a viral infection-related disease or disorder, or one or more complications associated with such a disease or disorder, but need not be already undergoing treatment.

[0154] Dosage The actual dosage level of the active ingredient in the pharmaceutical compositions of the present disclosure can be varied so as to obtain an amount of the active ingredient effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, provided that it is not toxic to the patient.

[0155] The selected dose level will depend on a variety of factors, including the activity of the particular compound of the present disclosure being used, or its ester, salt, or amide, the route of administration, the time of administration, the rate of excretion of the particular compound being used, the duration of treatment, other drugs, compounds and / or materials used in combination with the particular compound being used, and factors well known in the medical arts, such as the age, sex, weight, condition, general health and medical history of the patient being treated.

[0156] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian can start dosages of the compounds of the present disclosure used in the pharmaceutical composition at levels lower than those required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[0157] The compound and the pharmaceutically active agent can be administered to a subject in the same pharmaceutical composition or in different pharmaceutical compositions (at the same time or at different times). When administered at different times, the compound and the pharmaceutically active agent can be administered within 5 minutes, 10 minutes, 20 minutes, 60 minutes, 2 hours, 3 hours, 4 hours, 8 hours, 12 hours, or 24 hours of the other administration. When the compound and the pharmaceutically active agent are administered in different pharmaceutical compositions, the route of administration can be different.

[0158] The amount of compound that can be combined with a carrier material to produce a single dosage form will generally be that amount of compound that produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 0.1% to 99% of the compound, preferably from about 5% to about 70%, and most preferably from 10% to about 30%.

[0159] Toxicity and therapeutic efficacy can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., LD 50 (lethal dose for 50% of the population) and ED 50 The dose ratio between toxic and therapeutic effects is the therapeutic index, which is the ratio LD 50 / ED 50 Compositions that exhibit large therapeutic indices are preferred.

[0160] The data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of such compounds is preferably within the ED range with little or no toxicity. 50 The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.

[0161] A therapeutically effective dose can be estimated initially from cell culture assays. A dose can be formulated in animal models and the EC 50 A circulating plasma concentration range that includes the therapeutic agent (i.e., the concentration of the therapeutic agent that achieves half of its maximal effect) can be achieved. Plasma levels can be measured, for example, by high performance liquid chromatography. The effect of a particular dosage can be monitored by a suitable bioassay.

[0162] Dosage will be determined by the physician and can be adjusted as necessary to suit the observed therapeutic effect.

[0163] Regarding the duration and frequency of treatment, a skilled clinician typically monitors the subject to determine when treatment is providing a therapeutic benefit and decides whether to increase or decrease the dosage, increase or decrease the frequency of administration, discontinue treatment, resume treatment, or make other changes to the therapy. Dosing regimens can vary from once a week to daily, depending on numerous clinical factors, such as the subject's sensitivity to the drug. The desired dose can be administered once or divided into sub-doses (e.g., 2 to 4 sub-doses) and administered over a period of time, e.g., at appropriate intervals throughout the day, or according to any other suitable schedule. Such sub-doses can be administered as a unit dosage form. In some embodiments, administration is chronic, e.g., one or more doses per day for several weeks or months. Exemplary dosing schedules include administration once, twice, three, or four or more times per day for 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months or more.

[0164] The present disclosure contemplates formulation of the subject compounds in any of the aforementioned pharmaceutical compositions and formulations. Additionally, the present disclosure contemplates administration via any of the aforementioned routes of administration. One of skill in the art can select an appropriate formulation and route of administration based on the condition being treated and the overall health, age, and size of the patient being treated.

[0165] Selected Chemical Definitions At various places in the present specification, substituents of compounds of the present disclosure are disclosed in groups or in ranges. It is specifically intended that the present disclosure include each and every subcombination of the members of such groups and ranges. For example, "C 1-6 The term "alkyl" is specifically intended to individually disclose methyl, ethyl, propyl, butyl, pentyl, and hexyl.

[0166] For compounds of the present disclosure in which a variable occurs multiple times, each variable can be a different moiety selected from the Markush group defining that variable. For example, when a structure is described having two R groups occurring simultaneously on the same compound, the two R groups can represent different moieties selected from the Markush group defined for R.

[0167] Furthermore, it will be appreciated that certain features of the present disclosure, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the present disclosure, which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.

[0168] When a compound of the present disclosure is shown in chemical name form and as a formula, the formula shall prevail in the event of a conflict.

[0169] An asterisk or wavy line may be used in subformulas to indicate the bond connecting to the defined core molecule.

[0170] As used herein, the term "substituted" means that any one or more hydrogens on a designated atom, usually a carbon, oxygen, or nitrogen atom, are replaced with one selected from a designated group, provided that the replacement does not exceed the normal valence of the designated atom, and that the substitution results in a stable compound. When a substituent is keto or oxo (i.e., =0), two hydrogens on the atom are replaced. As used herein, a ring double bond is a bond formed between two adjacent ring atoms (e.g., C=C, C=N, N=N, etc.).

[0171] As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, C 1-4 Alkyl is intended to include C1, C2, C3, and C4. 1-6Alkyl is intended to include C1, C2, C3, C4, C5, and C6 alkyl groups, and C 1-8 Alkyl is intended to include C1, C2, C3, C4, C5, C6, C7, and C8, including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl, n-hexyl, n-heptyl, and n-octyl.

[0172] As used herein, "alkenyl" is intended to include a hydrocarbon chain of a straight or branched configuration and one or more unsaturated carbon-carbon bonds that may occur at any stable point along the chain, such as ethenyl and propenyl. For example, C 2-6 Alkenyl is intended to include C2, C3, C4, C5, and C6 alkenyl groups, 2-8 Alkenyl is intended to include C2, C3, C4, C5, C6, C7, and C8 alkenyl groups.

[0173] As used herein, "alkylene" is intended to include moieties that are diradicals, i.e., moieties having two points of attachment. A non-limiting example of such an alkylene moiety that is a diradical is -CHCH-, i.e., a C alkyl group covalently bonded to the remainder of the molecule through each terminal carbon atom. Alkylene diradicals are also known as "alkylenyl" radicals. Alkylene groups can be saturated or unsaturated at one or several positions (e.g., containing -CH=CH- or -C≡C- subunits). In some embodiments, alkylene groups contain 1 to 9 carbon atoms (e.g., 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 2 carbon atoms). Some examples of alkylene groups include, but are not limited to, methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, sec-butylene, tert-butylene, n-pentylene, isopentylene, sec-pentylene, and neopentylene.

[0174] As used herein, "cycloalkyl" is intended to include saturated or unsaturated non-aromatic ring groups such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 3-8 The term "cycloalkyl" is intended to include C, C, C, C, C, C, and C cycloalkyl groups. Cycloalkyl may contain multiple spirocyclic or fused or bridged rings. For example, cycloalkyl can include spirobutyl, pentyl, hexyl, heptyl, octyl, nonyl, or decyl groups, bicyclobutyl, pentyl, hexyl, heptyl, octyl, nonyl, or decyl groups, adamantyl groups, and norbornyl groups.

[0175] As used herein, unless otherwise specified, the term "heterocycloalkyl" refers to a saturated or unsaturated non-aromatic 3- to 8-membered monocyclic, 7- to 12-membered bicyclic (fused, bridged, or spirocyclic), or 11- to 14-membered tricyclic ring system (fused, bridged, or spirocyclic) having one or more heteroatoms (e.g., O, N, S, or Se). Heterocycloalkyl groups containing fused aromatic rings can be bonded through any ring-forming atom, including ring-forming atoms of the fused aromatic ring. In some embodiments, a heterocycloalkyl is a monocyclic 4- to 6-membered heterocycloalkyl having one or two heteroatoms independently selected from nitrogen, oxygen, or sulfur and one or more oxidized ring members. In some embodiments, a heterocycloalkyl is a monocyclic or bicyclic 4- to 10-membered heterocycloalkyl having one, two, three, or four heteroatoms independently selected from nitrogen, oxygen, or sulfur and one or more oxidized ring members. Examples of heterocycloalkyl groups include piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahydrofuranyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, tetrahydrofuranyl, tetra ... Examples include, but are not limited to, hydropyranyl, pyranyl, morpholinyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, and 1,4-dioxa-8-azaspiro[4.5]decanyl.

[0176] As used herein, "amine" or "amino" refers to unsubstituted -H2 unless otherwise specified. As used herein, "halo" or "halogen" refers to fluoro, chloro, bromo, and iodo substituents.

[0177] As used herein, "haloalkyl" refers to both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms substituted with one or more halogens (e.g., -C v F w H 2v·w+1 , v=1-3 and w=1-(2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.

[0178] The term "haloalkoxy," as used herein, refers to an alkoxy group, as defined herein, that is substituted with one or more halogens. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, and the like.

[0179] As used herein, "alkoxyl" or "alkoxy" refers to an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. 1-6 Alkoxy is intended to include C1, C2, C3, C4, C5 and C6 alkoxy groups. 1-8 Alkoxy is intended to include C1, C2, C3, C4, C5, C6, C7, and C8 alkoxy groups. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, s-pentoxy, n-heptoxy, and n-octoxy.

[0180] As used herein, "aryl" includes groups having aromatic character, including "conjugation," or polycyclic ring systems having at least one aromatic ring and no heteroatoms in the ring structure. Aryl may be monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings). "C n-mThe term "aryl" refers to an aryl group having n to m ring carbon atoms. In some embodiments, the aryl group has 6 to 10 carbon atoms. In some embodiments, the aryl group is phenyl or naphthyl.

[0181] As used herein, the term "aromatic heterocycle," "aromatic heterocyclic," or "heteroaryl" ring is intended to mean a stable 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered monocyclic or bicyclic aromatic ring consisting of carbon atoms and one or more heteroatoms, e.g., 1, 2, 3, 4, 5, or 6, independently selected from nitrogen, oxygen, and sulfur. In the case of a bicyclic heteroaromatic or heterocyclic or heteroaryl ring, only one of the two rings need be aromatic (e.g., 2,3-dihydroindole), but both can be aromatic (e.g., quinoline). The second ring may be fused or bridged, as defined above for heterocycles. The nitrogen atom may be substituted or unsubstituted (i.e., N or R, where R is H or another defined substituent). The nitrogen and sulfur heteroatoms can optionally be oxidized (i.e., N→O and S(O) P , where p=1 or 2). In certain compounds, the total number of S atoms and O atoms in the aromatic heterocycle is 1 or less.

[0182] Examples of aromatic heterocycles, aromatic heterocyclics, or heteroaryls include acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, benzoxadiazolyl, carbazolyl, 4aH-carbazolyl, carbolinyl, yl, cinnolinyl, furazanyl, imidazolyl, imidazolonyl, 1H-indazolyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylbenzotriazolyl, methylfuranyl, methylimidazolyl, methylthiazolyl, naphthyridinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1 ,3,4-Oxadiazolyl, oxazolyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridinyl, pyridinonyl, pyridyl, pyrimidinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, tetrahydroquinolinyl, tetra Examples include, but are not limited to, thiazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienoxazolyl, thienoimidazolyl, thiophenyl, triazinyl, triazolopyrimidinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, and 1,3,4-triazolyl.

[0183] The term "hydroxyalkyl" means an alkyl group, as defined above, that is substituted with one or more OH groups. Examples of hydroxyalkyl groups include HO-CH2-, HO-CH2-CH2-, and CH3-CH(OH)-.

[0184] As used herein, the term "cyano" refers to a substituent having a carbon atom attached to a nitrogen atom by a triple bond, i.e., C≡N.

[0185] As used herein, "oxo" refers to a "C=O" group.

[0186] As used herein, the phrase "pharmaceutically acceptable" refers to compounds or tautomers thereof, or salts, materials, compositions, and / or dosage forms thereof that are suitable, within the scope of sound medical judgment, for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds or tautomers thereof, wherein the parent compound or tautomer thereof is modified by making acid or base salts of the parent compound or tautomer thereof.

[0187] Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts include the conventional non-toxic salts or quaternary ammonium salts of the parent compound or its tautomers formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, glycollyarsanilic acid, hexylresorcylic acid, hydrabamic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxybenzoic ... Examples of suitable salts include, but are not limited to, salts derived from maleic acid, hydroxynaphthoic acid, isethionic acid, lactic acid, lactobionic acid, laurylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, napsylic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, acetic acid, succinic acid, sulfamic acid, sulfanilic acid, sulfuric acid, tannic acid, tartaric acid, and toluenesulfonic acid.

[0188] The pharmaceutically acceptable salts of the present disclosure can be synthesized from parent compounds or their tautomers containing a basic or acidic moiety by conventional chemical methods. Generally, such pharmaceutically acceptable salts can be prepared by reacting the free acid or base form of these compounds or their tautomers with a stoichiometric amount of an appropriate base or acid in water or an organic solvent, or a mixture of the two; generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, PA, USA, p. 1445 (1990).

[0189] As used herein, "stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0190] As used herein, the term "treating" refers to administering a compound or pharmaceutical composition provided herein for therapeutic purposes. The term "therapeutic treatment" refers to administering therapy to a patient already suffering from a disease, thereby producing a therapeutically beneficial effect, such as ameliorating existing symptoms, ameliorating the underlying metabolic cause of symptoms, postponing or preventing further onset of the disorder, and / or reducing the severity of symptoms that will or are expected to develop.

[0191] As used herein, "unsaturated" refers to a compound having at least one degree of unsaturation (eg, at least one multiple bond), and includes partially and fully unsaturated compounds.

[0192] As used herein, the term "effective amount" refers to an amount of a compound of the present disclosure, or a pharmaceutically acceptable salt of the compound or tautomer (including combinations of the compound and / or a tautomer thereof, and / or a pharmaceutically acceptable salt of said compound or tautomer), that is effective when administered alone or in combination as an antibacterial agent. For example, an effective amount refers to the amount of a compound or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer, present in a composition, formulation, or given to a recipient patient or subject, sufficient to elicit physiological activity.

[0193] As used herein, the singular includes the plural unless the context clearly dictates otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In case of conflict, the present specification will control. As used herein, "mammal" refers to human and non-human patients.

[0194] As used herein, the term "formulas of the present disclosure" or "formulas disclosed herein" includes one or more of Formula I, its sub-formulas Ia, Ib, or Ic, and further sub-formulas thereof.

[0195] As used herein, the term "compounds of the present disclosure" or "compounds disclosed herein" includes one or more compounds of the formula of the present disclosure or compounds explicitly disclosed herein.

[0196] All percentages and ratios used herein are by weight unless otherwise specified. Throughout the description, when a composition is described as having, including, or comprising certain ingredients, or when a process is described as having, including, or comprising certain process steps, it is contemplated that the compositions of the present disclosure also consist essentially of or consist of the recited components, and that the methods of the present disclosure also consist essentially of or consist of the recited process steps. Furthermore, it should be understood that the order of steps or order for performing certain actions is immaterial so long as the present disclosure remains operable.

[0197] Moreover, two or more steps or actions may be conducted simultaneously.

[0198] Contemplated equivalents of the above compounds include compounds that are otherwise equivalent and have the same general properties (e.g., the ability to modulate TRPML), where one or more simple substituent changes are made that do not adversely affect the efficacy of the compound. In general, the compounds of the present disclosure can be prepared using readily available starting materials, reagents, and conventional synthetic procedures, for example, by the methods shown in the general reaction schemes described below, or by modifications thereof. These reactions can also utilize variants that are known per se but not mentioned here.

[0199] As used herein, the articles "a" and "an" refer to one or to more than one (e.g., to at least one) of the grammatical object of the article.

[0200] "About" and "approximately" are generally intended to mean an acceptable degree of error for a measured quantity given the nature or precision of the measurement. Exemplary degrees of error are within 20 percent (%), typically within 10%, and more typically within 5% of a given value or range of values.

[0201] As used herein, the term "treating" or "treatment" refers to the application or administration of a compound, alone or in combination with an additional agent, to a subject, e.g., a subject having a disorder (e.g., a disorder described herein), symptoms of a disorder, or a predisposition to a disorder, for the purpose of curing, curing, alleviating, mitigating, altering, repairing, ameliorating, improving, or affecting the disorder.

[0202] As used herein, the term "subject" is intended to include human and non-human animals. Exemplary human subjects include human subjects having a disorder, such as a disorder described herein. The term "non-human animal" of the present disclosure includes all vertebrates, such as non-mammals (chickens, amphibians, reptiles, etc.) and mammals, such as non-human primates, domestic animals and / or agriculturally useful animals, such as sheep, dogs, cats, cows, pigs, etc.

[0203] The terms "antagonist" and "inhibitor" are used interchangeably to refer to agents that decrease or prevent biological activity.

[0204] The terms "activator" and "agonist" are used interchangeably to refer to an agent that enhances or initiates a biological activity.

[0205] The term "hydrate," as used herein, refers to a compound formed by the combination of water with a parent compound.

[0206] The term "preventing," when used in reference to a condition such as local recurrence (e.g., pain), a disease such as cancer, a complex syndrome such as heart failure, or any other medical condition, is well understood in the art and includes administration of a composition that reduces the frequency of or delays the onset of symptoms of a medical condition in a subject compared to subjects not receiving the composition. Thus, preventing cancer can include, for example, reducing the number of detectable cancerous growths in a population of patients receiving prophylactic treatment compared to an untreated control population by a statistically and / or clinically significant amount, and / or delaying the appearance of detectable cancerous growths in a treated population compared to an untreated control population. Preventing infection can include, for example, reducing the number of diagnoses of infection in a treated population compared to an untreated control population, and / or delaying the onset of symptoms of an infection in a treated population compared to an untreated control population. Preventing pain can include, for example, reducing or delaying the degree of pain experienced by subjects in a treated population compared to an untreated control population.

[0207] The term "solvate," as used herein, refers to a compound formed by solvation (e.g., a compound formed by the combination of a solvent molecule with a molecule or ion of the solute). Another aspect of the disclosure features a pharmaceutical formulation suitable for use in a human patient or for veterinary use, comprising an effective amount of a compound of the disclosed formulas (or a salt thereof, or a solvate, hydrate, oxidative metabolite, or prodrug of the compound or its salt) and one or more pharmaceutically acceptable excipients. The disclosure further contemplates the use of compounds of the disclosed formulas in the manufacture of a medicament or pharmaceutical formulation for treating or alleviating the symptoms of any of the diseases or conditions provided herein. Compounds of the disclosed formulas for use in treating a particular disease or condition can be formulated for administration via a route appropriate for the particular disease or condition.

[0208] The compounds of the disclosed formulas can be administered alone or in combination with another therapeutic agent, for example, the compounds of the disclosed formulas can be administered in combination with one or more agents for treating polycystic kidney disease, etc.

[0209] Compounds of the disclosed formulae can be administered topically, orally, transdermally, rectally, vaginally, parenterally, intranasally, intrapulmonary, intraocular, intravenously, intramuscularly, arterially, intrathecally, intracapsularly, intraorbitally, intracardially, intradermally, intraperitoneally, transtracheally, subcutaneously, subcuticularly, intraarticularly, subcapsularly, intrathecally, intraspinally, intrasternally, sublingually, or by inhalation.

[0210] In some embodiments, the compound of Formula I, Ia, Ib, or Ic can be administered topically.

[0211] In some embodiments, compounds of Formula I, Ia, Ib, or Ic can be administered orally.

[0212] In some embodiments, compounds of Formula I, Ia, Ib, or Ic can be administered parenterally.

[0213] Compounds of Formula I, Ia, Ib, or Ic include molecules with aqueous solubility suitable for oral or parenteral (e.g., intravenous) administration that provide or result in the treatment of a disorder described herein, e.g., pain. In some embodiments, the compounds are formulated into compositions suitable for oral administration.

[0214] In some embodiments, compounds of Formula I, Ia, Ib, or Ic can be administered as part of an oral or parenteral (e.g., intravenous) pharmaceutical composition to treat the disorders described herein in a therapeutically effective manner.

[0215] Certain compounds disclosed herein may exist in particular geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis and trans isomers, R and S enantiomers, diastereomers, (d)-isomers, (l)-isomers, racemic mixtures thereof, and other mixtures thereof, as being within the scope of the present disclosure. For example, if one chiral center is present in the molecule, the present disclosure includes racemic mixtures, enantiomerically enriched mixtures, and substantially enantiomerically or diastereomerically pure compounds. Such compositions may contain, for example, greater than 50%, 60%, 70%, 80%, 90%, 95%, or 99% of a single enantiomer or diastereomer. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, and mixtures thereof, are intended to be encompassed by the present disclosure.

[0216] The "enantiomeric excess" or "% enantiomeric excess" of a composition can be calculated using the equation shown below: In the example shown below, the composition contains 90% of one enantiomer, e.g., the S enantiomer, and 10% of the other enantiomer, i.e., the R enantiomer.

[0217] ee=(90-10) / 100=80%.

[0218] Thus, a composition containing 90% of one enantiomer and 10% of the other is said to have an enantiomeric excess of 80%.

[0219] The "diastereomeric excess" or "% diastereomeric excess" of a composition can be calculated using the equation shown below: In the example shown below, the composition contains 90% of one diastereomer and 10% of the other diastereomer.

[0220] de=(90-10) / 100=80%.

[0221] Thus, a composition containing 90% of one diastereomer and 10% of the other is said to have a diastereomeric excess of 80%.

[0222] Certain compounds disclosed herein can exist in unsolvated and solvated forms, such as hydrated forms. In general, solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present disclosure. Certain compounds disclosed herein can exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure. [Example]

[0223] In order to facilitate a more complete understanding of the present invention, the following examples are provided. The following examples illustrate exemplary modes of making and practicing the invention. However, the scope of the present invention is not limited to the specific embodiments disclosed in these examples, which are for illustrative purposes only, since alternative methods may be utilized to obtain similar results.

[0224] general description All oxygen- and / or moisture-sensitive reactions were carried out under a N atmosphere in glassware that was flame-dried under vacuum (0.5 mmHg) and purged with N prior to use. All reagents and solvents were purchased from commercial suppliers and used as received or synthesized according to the references in the footnotes. NMR spectra were obtained using a Bruker 400 (400 MHz) 1 H, 75MHz 13 C) or Varian (400MHz 1 H, 75MHz 13NMR data were recorded on a NMR spectrometer. Proton and carbon chemical shifts are reported in ppm (δ) relative to the NMR solvent. Data are reported as follows: chemical shift, multiplicity (br = broad, s = singlet, t = triplet, q = quartet, m = multiplet; coupling constant (Hz)). NMR data were collected at 25 °C unless otherwise noted. Flash chromatography was performed using 100-200 mesh silica gel. Liquid chromatography / mass spectrometry (LCMS) was performed on an Agilent 1200 HPLC and 6110 MS. Analytical thin-layer chromatography (TLC) was performed on 0.2 mm silica gel plates. Visualization was performed with UV light and aqueous potassium permanganate (KMnO) staining followed by heating.

[0225] Typical conditions for LCMS: LC-MS Conditions: Apparatus: LCMS2020 (E-LCMS008); Column: Shim-pack GIST C18, 50 x 4.6 mm, 5 μm; Mobile Phase: A: H2O (0.1% FA); B: CH3CN; Temperature: 35°C; Flow Rate: 2.5 mL / min; Run Time: 20% B for 0.1 min, 1.7 min gradient (20% to 95% B), then 95% B for 0.7 min, then 20% B for 0.4 min; Injection Volume: 5 μL; Detector: UV 220 / 254 nm; Mass Range: 100-1000; Scan: Positive / Negative.

[0226] Typical conditions for HPLC: Apparatus: LC-20AD (E-LC006) Column: YMC Triart C18, 50 x 4.6 mm, 5 μm Mobile phase: Solvent A: H2O / CH3CN / TFA = 90 / 10 / 0.1 Solvent B: H2O / CH3CN / TFA = 10 / 90 / 0.1 Flow rate: 2.5 mL / min Run time: 60% B for 0.4 min, 3.4 min gradient (60% to 100% B), then 100% B for 0.8 min Temperature: 35°C Detector: UV

[0227] or Instrument: LC-2010AHT (E-LC001) Column: Gemini, C18, 50 x 4.6 mm, 5 μm Mobile Phase: Solvent A: H2O / CH3CN / TFA = 90 / 10 / 0.1 Solvent B: H2O / CH3CN / TFA = 10 / 90 / 0.1 Flow Rate: 2.5 mL / min Run Time: 20% B for 0.4 min, gradient (20% to 95% B) for 3.4 min, then 95% B for 0.8 min. Temperature: 40°C Detector: UV

[0228] Table 2: Abbreviations [Table 2] TIFF2024536237000147.tif255170TIFF2024536237000148.tif255170TIFF2024536237000149.tif51170

[0229] Example 1. Synthesis of tert-butyl 4-(5-cyclopropyl-7-(3,5-difluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (Compound 146) [ka]

[0230] Step 1. tert-Butyl 4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate To a solution of 4-chloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (4.0 g, 9.2 mmol, prepared according to the procedure described for Compound 134) in EtOH (50 mL) was added tert-butyl piperazine-1-carboxylate (1.7 g, 9.2 mmol) and DIPEA (5.0 mL, 28 mmol). The resulting mixture was heated to 100 °C overnight. After cooling to room temperature, the solvent was removed and the residue was purified by flash column chromatography (silica gel, 0–30%, ethyl acetate / petroleum ether) to give tert-butyl 4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (4.5 g, 83%) as a white solid. LC / MS ESI (m / z): 584 (M+H). + .

[0231] Step 2. tert-Butyl 4-(5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate To a solution of tert-butyl 4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (2.0 g, 3.4 mmol) in toluene (50 mL) was added cyclopropylboronic acid (0.35 g, 4.1 mmol), KCO (9.5 g, 69 mmol), and Pd-118 (0.22 g, 0.34 mmol). The resulting mixture was heated to 80 °C overnight. After cooling to room temperature, the solvent was filtered off. The filtrate was concentrated and purified by flash column chromatography (silica gel, 0 to 30%, ethyl acetate / petroleum ether) to give tert-butyl 4-(5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (1.3 g, 76%) as a white solid. LC / MS ESI(m / z):498(M+H) + .

[0232] Step 3. tert-Butyl 4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate To a solution of tert-butyl 4-(5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (1.3 g, 2.6 mmol) in THF (10 mL) was added TBAF (16 mL, 16 mmol). The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-60%, ethyl acetate / petroleum ether) to afford tert-butyl 4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (810 mg, 90%) as a white solid. LC / MS ESI (m / z): 344 (M+H). + .

[0233] Step 4. tert-Butyl 4-(5-cyclopropyl-7-(3,5-difluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate To a solution of tert-butyl 4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (100 mg, 0.29 mmol) in DMF (5 mL) was added 1,3-difluoro-5-iodobenzene (84 mg, 0.35 mmol), trans-cyclohexane-1,2-diamine (9.9 mg, 0.087 mmol), CuI (17 mg, 0.087 mmol), and KPO (190 mg, 0.87 mmol). The resulting mixture was heated to 120 °C overnight. After cooling to room temperature, the reaction was quenched with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-30%, ethyl acetate / petroleum ether) to give the crude product, which was further purified by preparative HPLC to give tert-butyl 4-(5-cyclopropyl-7-(3,5-difluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (82 mg, 62%) as a white solid. LC / MS ESI(m / z): 456(M+H). + . 1 H NMR (400 MHz, CDCl3) δ 8.46 (s, 1H), 7.38 - 7.33 (m, 2H), 6.91 (d, J = 0.8 Hz, 1H), 6.79 - 6.72 (m, 1H), 3.69 (d, J = 2.7 Hz, 4H), 3.65 - 3.59 (m, 4H), 2.08 - 2.01 (m, 1H), 1.50 (s, 9H), 1.07 - 1.00 (m, 2H), 0.80 - 0.73 (m, 2H).

[0234] The following compounds were prepared from the corresponding aryl halide, boronic ester, or boronic acid and amine using a procedure similar to the synthesis of compound 146. For analogs 474 and 475, trifluoro(oxetan-3-yl)-λ 4-borane (potassium salt) was used in the coupling step. In the case of analogs 465, 466, 467, 468, 469, and 470, the final product was obtained by hydrogenation in the same manner as in Example 69. [Table 3] TIFF2024536237000152.tif249159TIFF2024536237000153.tif255153TIFF20245362370 00154.tif248156TIFF2024536237000155.tif255154TIFF2024536237000156.tif208156

[0235] Example 2. Synthesis of tert-butyl (2R,5S)-4-(5-(2-fluorophenyl)-7-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (Compound 134) [ka]

[0236] Step 1. 4-Chloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine To a suspension of NaH (1.0 g, 27 mmol, 60 wt%) in anhydrous DMF (60 mL) was added 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (5.0 g, 18 mmol) in small portions at 0 °C. The resulting mixture was stirred at the same temperature for 30 minutes, and then TsCl (3.4 g, 18 mmol) was added in small portions. After the addition, the reaction mixture was stirred overnight at room temperature. The reaction mixture was poured into ice water, filtered, and the solid was collected and dried under vacuum to give 4-chloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (6.0 g, 77%) as a white solid. LCMS ESI (m / z): 434 (M+H). + .

[0237] Step 2. tert-Butyl (2R,5S)-4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate To a solution of 4-chloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (4.0 g, 9.2 mmol) in DIPEA (5.0 mL, 28 mmol) was added tert-butyl (2R,5S)-2,5-dimethylpiperazine-1-carboxylate (2.0 g, 9.2 mmol). The resulting mixture was heated to 150 °C under N for 3 h. After cooling to room temperature, the solvent was removed and the residue was purified by flash column chromatography (silica gel, 0–30%, ethyl acetate / petroleum ether) to give tert-butyl (2R,5S)-4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (2.5 g, 43%) as a yellow solid. LC / MS ESI(m / z):612(M+H) + .

[0238] Step 3. tert-Butyl (2R,5S)-4-(5-(2-fluorophenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate To a solution of tert-butyl (2R,5S)-4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (2.5 g, 4.0 mmol) in dioxane (30 mL) and HO (6 mL) was added (2-fluorophenyl)boronic acid (0.68 g, 4.8 mmol), KCO (1.7 g, 12 mmol), and Pd(dppf)Cl (0.29 g, 0.40 mmol). The resulting mixture was stirred at 80 °C under N overnight. After cooling to room temperature, the solvent was removed and the residue was purified by flash column chromatography (silica gel, 0-20%, ethyl acetate / petroleum ether) to give tert-butyl (2R,5S)-4-(5-(2-fluorophenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (1.9 g, 82%) as a yellow solid.

[0239] LC / MS ESI(m / z):580(M+H) + .

[0240] Step 4. tert-Butyl (2R,5S)-4-(5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate To a solution of tert-butyl (2R,5S)-4-(5-(2-fluorophenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (1.9 g, 3.3 mmol) in THF (20 mL) was added TBAF (20 mL, 20 mmol). The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-60%, ethyl acetate / petroleum ether) to give tert-butyl (2R,5S)-4-(5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (1.2 g, 85%) as a white solid. LC / MS ESI (m / z): 426 (M+H). + .

[0241] Step 5. tert-Butyl (2R,5S)-4-(5-(2-fluorophenyl)-7-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate To a solution of tert-butyl (2R,5S)-4-(5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (200 mg, 0.47 mmol) in DMF (10 mL) was added 2-bromopyridine (0.05 mL, 0.56 mmol), trans-cyclohexane-1,2-diamine (16 mg, 0.14 mmol), CuI (27 mg, 0.14 mmol), and KPO (300 mg, 1.4 mmol). The resulting mixture was heated to 100 °C overnight. After cooling to room temperature, the reaction was partitioned between EtOAc and water, the organic layer was separated, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-30%, ethyl acetate / petroleum ether) to give tert-butyl (2R,5S)-4-(5-(2-fluorophenyl)-7-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (110 mg, 47%) as a white solid, of which 30 mg was further purified by preparative HPLC to give 13 mg of a white solid. LC / MS ESI (m / z): 503 (M+H). + . 1 H NMR (400 MHz, CDCl3) δ 8.79 (d, J = 8.3 Hz, 1H), 8.56 (s, 1H), 8.52 - 8.48 (m, 1H), 8.26 (s, 1H), 7.93 - 7.87 (m, 1H), 7.50 (td, J = 7.5, 1.6 Hz, 1H), 7.39 - 7.33 (m, 1H), 7.25 - 7.17 (m, 3H), 4.30 - 4.04 (m, 2H), 3.39 - 3.22 (m, 3H), 2.92 - 2.70 (m, 1H), 1.43 (s, 9H), 1.08 (d, J = 6.8 Hz, 3H), 0.95 (d, J = 6.7 Hz, 3H).

[0242] The following compounds were prepared from the corresponding aryl halides by a procedure similar to the synthesis of compound 134. [Table 4] TIFF2024536237000159.tif193156

[0243] Example 3. Synthesis of ethyl (2R,5S)-4-(5-(2-fluorophenyl)-7-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (Compound 137) [ka]

[0244] Step 1. 4-((2S,5R)-2,5-dimethylpiperazin-1-yl)-5-(2-fluorophenyl)-7-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine To a solution of tert-butyl (2R,5S)-4-(5-(2-fluorophenyl)-7-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (80 mg, 0.16 mmol) in DCM (3 mL) was added HCl (4.0 mL, 4.0 M solution in dioxane). The resulting mixture was stirred at room temperature for 4 hours. After removal of the solvent, the residue was diluted with DCM and washed with NaHCO3 (aq), and the organic layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give 4-((2S,5R)-2,5-dimethylpiperazin-1-yl)-5-(2-fluorophenyl)-7-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine, which was used directly in the next step.

[0245] LC / MS ESI(m / z):403(M+H) + .

[0246] Step 2. Ethyl (2R,5S)-4-(5-(2-fluorophenyl)-7-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate To a solution of 4-((2S,5R)-2,5-dimethylpiperazin-1-yl)-5-(2-fluorophenyl)-7-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine (60 mg, 0.15 mmol) in DCM (3 mL) at 0 °C was added TEA (0.062 mL, 0.45 mmol), followed by the dropwise addition of ethyl chloroformate (0.03 mL, 0.29 mmol). The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted twice with DCM, and the combined organic layers were washed with NaHCO (aq), dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-30%, ethyl acetate / petroleum ether) to give the product, which was further purified by preparative HPLC to give ethyl (2R,5S)-4-(5-(2-fluorophenyl)-7-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (39 mg, 54%) as a white solid. LC / MS ESI(m / z): 475(M+H). + . 1 H NMR (400 MHz, CDCl3) δ 8.79 (d, J = 8.3 Hz, 1H), 8.56 (s, 1H), 8.52 - 8.48 (m, 1H), 8.26 (s, 1H), 7.93 - 7.87 (m, 1H), 7.50 (td, J = 7.5, 1.6 Hz, 1H), 7.40 - 7.31 (m, 1H), 7.25 - 7.15 (m, 3H), 4.37 - 4.04 (m, 4H), 3.43 - 3.22 (m, 3H), 2.95 - 2.71 (m, 1H), 1.23 (t, J = 6.5 Hz, 3H), 1.12 (d, J = 6.8 Hz, 3H), 0.95 (d, J = 6.7 Hz, 3H).

[0247] The following compounds were prepared from the corresponding aryl halides using a procedure similar to the synthesis of compound 137. [Table 5] TIFF2024536237000162.tif113156

[0248] Example 4. Synthesis of tert-butyl 4-(7-(5-chloro-2-methylphenyl)-5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Compound 159) [ka]

[0249] Step 1. tert-Butyl 4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate A mixture of 4-chloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (3.0 g, 6.9 mmol, prepared according to the procedure described in Step 1 of Compound 134) and tert-butyl 3-methylpiperazine-1-carboxylate (5.6 g, 28 mmol) was heated to 150 °C for 3 h. After cooling to room temperature, the reaction was purified by flash column chromatography (silica gel, 0-30%, ethyl acetate / petroleum ether) to give tert-butyl 4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (2.0 g, 48%) as a white solid. LC / MS ESI (m / z): 598 (M+H). + .

[0250] Step 2. tert-Butyl 3-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate To a solution of tert-butyl 4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (2.0 g, 3.3 mmol) in dioxane (30 mL) was added 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.9 mL, 13 mmol), TEA (2.3 mL, 17 mmol), X-Phos (0.16 g, 0.33 mmol), and Pd(dba) (0.31 g, 0.33 mmol). The resulting mixture was stirred at 95 °C overnight. After cooling to room temperature, the reaction was quenched with water and extracted twice with DCM, and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give tert-butyl 3-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate as a yellow solid, which was used directly in the next step. LC / MS ESI(m / z): 598(M+H). + .

[0251] Step 3. tert-Butyl 3-methyl-4-(5-(pyridin-2-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate To a solution of tert-butyl 3-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (700 mg, 1.1 mmol) in dioxane (10 mL) and HO (2 mL) was added 2-bromopyridine (0.22 mL, 2.3 mmol), KCO (810 mg, 5.8 mmol), and Pd(dppf)Cl (86 mg, 0.11 mmol). The resulting mixture was heated to 90 °C overnight. After cooling to room temperature, the solvent was removed and the residue was purified by flash column chromatography (silica gel, 0-60%, ethyl acetate / petroleum ether) to give tert-butyl 3-methyl-4-(5-(pyridin-2-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (490 mg, 76%) as a yellow solid. LC / MS ESI(m / z): 549(M+H). + .

[0252] Step 4. tert-Butyl 3-methyl-4-(5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate To a solution of tert-butyl 3-methyl-4-(5-(pyridin-2-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (490 mg, 0.89 mmol) in THF (5 mL) was added TBAF (5.4 mL, 5.3 mmol). The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0–10%, methanol / dichloromethane) to afford tert-butyl 3-methyl-4-(5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (200 mg, 56%) as a white solid. LC / MS ESI(m / z):395(M+H) + .

[0253] Step 5. tert-Butyl 4-(7-(5-chloro-2-methylphenyl)-5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl 3-methyl-4-(5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (100 mg, 0.25 mmol) in DCM (10 mL) was added (5-chloro-2-methylphenyl)boronic acid (130 mg, 0.76 mmol), Cu(OAc) (180 mg, 1.0 mmol), pyridine (0.12 mL, 1.5 mmol), and 4 Å molecular sieves (400 mg). The resulting mixture was heated to 40 °C under an O atmosphere for 3 days. After cooling to room temperature, the reaction was quenched with NH OH, diluted with DCM, and filtered. The filtrate was extracted twice with DCM, and the combined organic layers were washed with brine, dried over Na SO , filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-80%, ethyl acetate / petroleum ether) to give the product, which was further purified by preparative HPLC to give tert-butyl 4-(7-(5-chloro-2-methylphenyl)-5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (30 mg, 22%) as a yellow solid. LC / MS ESI(m / z): 519(M+H). + . 1H NMR (400 MHz, CDCl3) δ 8.70 - 8.65 (m, 1H), 8.47 (s, 1H), 7.78 (td, J = 7.7, 1.7 Hz, 1H), 7.61 (d, J = 7.7 Hz, 1H), 7.46 (s, 1H), 7.39 - 7.31 (m, 3H), 7.26 - 7.23 (m, 1H), 4.48 - 4.19 (m, 1H), 3.96 - 3.78 (m, 1H), 3.68 - 3.48 (m, 2H), 3.23 - 2.72 (m, 3H), 2.11 (s, 3H), 1.44 (s, 9H), 1.07 (s, 3H).

[0254] The following compounds were prepared from the corresponding aryl halides using a procedure similar to the synthesis of compound 159. [Table 6] TIFF2024536237000165.tif179156

[0255] Example 5. Synthesis of tert-butyl (S)-4-(7-(3-cyanophenyl)-5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Compound 280) [ka]

[0256] Step 1. tert-Butyl (S)-4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of 4-chloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (5.0 g, 12 mmol) in DIPEA (15 mL) was added tert-butyl (S)-3-methylpiperazine-1-carboxylate (5.8 g, 29 mmol). The resulting mixture was heated to 140 °C for 1.5 h. After cooling to room temperature, the solvent was removed and the residue was purified by flash column chromatography (silica gel, 0-20%, ethyl acetate / petroleum ether) to give tert-butyl (S)-4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (5.8 g, 84%) as a yellow solid. LC / MS ESI (m / z): 598 (M+H). + .

[0257] Step 2. tert-Butyl (S)-3-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate To a solution of tert-butyl (S)-4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (1.0 g, 1.6 mmol) in dioxane (15 mL) was added 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.97 mL, 6.6 mmol), TEA (1.2 mL, 8.3 mmol), X-Phos (0.08 g, 0.16 mmol), and Pd(dba) (0.15 g, 0.16 mmol). The resulting mixture was stirred at 95 °C overnight. After cooling to room temperature, the reaction was quenched with water, extracted twice with DCM, and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give crude tert-butyl (S)-3-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (1.0 g, 99%) as a yellow oil. LC / MS ESI(m / z): 598(M+H). + .

[0258] Step 3. tert-Butyl (S)-3-methyl-4-(5-(pyridin-2-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate To a solution of tert-butyl (S)-3-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (1.0 g, 1.6 mmol) in dioxane (15 mL) and HO (3 mL) was added 2-bromopyridine (0.32 mL, 3.3 mmol), KCO (1.2 g, 8.3 mmol), and Pd(dppf)Cl (0.12 g, 0.16 mmol). The resulting mixture was heated to 90 °C overnight. After cooling to room temperature, the solvent was removed and the residue was purified by flash column chromatography (silica gel, 0-50%, ethyl acetate / petroleum ether) to give tert-butyl (S)-3-methyl-4-(5-(pyridin-2-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (0.69 g, 75%) as a yellow solid. LC / MS ESI (m / z): 549 (M+H). + .

[0259] Step 4. tert-Butyl (S)-3-methyl-4-(5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate To a solution of tert-butyl (S)-3-methyl-4-(5-(pyridin-2-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (690 mg, 1.3 mmol) in THF (5 mL) was added TBAF (5.0 mL, 5.0 mmol, 1.0 M solution in THF). The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0–10%, methanol / dichloromethane) to afford tert-butyl (S)-3-methyl-4-(5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (450 mg, 90%) as a white solid.

[0260] LC / MS ESI(m / z):395(M+H) + .

[0261] Step 5. tert-Butyl (S)-4-(7-(3-cyanophenyl)-5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl (S)-3-methyl-4-(5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (100 mg, 0.25 mmol) in DMF (5 mL) was added 3-iodobenzonitrile (87 mg, 0.38 mmol), (1S,2S)-cyclohexane-1,2-diamine (8.6 mg, 0.076 mmol), CuI (48 mg, 0.25 mmol), and KPO (160 mg, 0.76 mmol). The resulting mixture was heated to 120 °C overnight. After cooling to room temperature, the reaction was quenched with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-50%, ethyl acetate / petroleum ether) to give the crude product, which was further purified by preparative HPLC to give tert-butyl (S)-4-(7-(3-cyanophenyl)-5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (52 mg, 41%) as a yellow solid. LC / MS ESI(m / z): 496(M+H). + . 1 H NMR (400 MHz, DMSO-d6) δ 8.69 (dd, J = 4.8, 0.8 Hz, 1H), 8.45 (s, 1H), 8.45 - 8.43 (m, 1H), 8.34 - 8.27 (m, 1H), 8.17 (s, 1H), 7.95 (td, J = 7.7, 1.8 Hz, 1H), 7.86 (dt, J = 7.7, 1.2 Hz, 1H), 7.77 (t, J = 8.0 Hz, 1H), 7.69 (d, J = 7.9 Hz, 1H), 7.41 - 7.35 (m, 1H), 4.21 (d, J = 6.4 Hz, 1H), 3.77 - 3.60 (m, 2H), 3.12 - 2.55 (m, 4H), 1.36 (s, 9H), 0.92 (d, J = 6.6 Hz, 3H).

[0262] The following compounds were prepared using a procedure similar to the synthesis of compound 280 from the corresponding aryl halide. [Table 7] TIFF2024536237000168.tif255154TIFF2024536237000169.tif255153TIFF2024536237000170.tif58155

[0263] Example 6. Synthesis of tert-butyl (R)-4-(5-(2-fluorophenyl)-7-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate (Compound 192) [ka]

[0264] Step 1. 4-Chloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine To a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (200 g, 0.71 mol) and 4-methylbenzene-1-sulfonyl chloride (180 g, 0.93 mol) in acetone (2 L) was added 2.0 M NaOH (0.53 L) dropwise at 0 °C. After the addition, the reaction was warmed to room temperature and stirred for an additional 3 hours. The precipitate was collected by filtration, washed twice with water, and dried under vacuum to give 4-chloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (300 g, 95%) as an off-white solid. LC / MS ESI (m / z): 434 (M+H). + .

[0265] Step 2. tert-Butyl (R)-4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate To a solution of 4-chloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (50 g, 120 mmol) in EtOH (500 mL) was added tert-butyl (R)-2-methylpiperazine-1-carboxylate (28 g, 140 mmol). The resulting mixture was stirred at 90 °C under a N atmosphere for 16 h. After cooling to room temperature, the solvent was removed, the residue was quenched with H O and EtOAc, and the organic layer was separated. The aqueous layer was extracted twice with EtOAc, and the combined organic layers were dried over Na SO , filtered, and concentrated. The residue was triturated with petroleum ether / EtOAc (10:1) and filtered to give tert-butyl (R)-4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate (48 g, 70%) as a pale yellow solid. LC / MS ESI (m / z): 598 (M+H). + .

[0266] Step 3. tert-Butyl (R)-4-(5-(2-fluorophenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate To a solution of tert-butyl (R)-4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate (300 mg, 0.50 mmol) in dioxane (10 mL) and water (1 mL) was added (2-fluorophenyl)boronic acid (77 mg, 0.55 mmol), KPO (210 mg, 1.0 mmol), and Pd(dppf)Cl (37 mg, 0.050 mmol). The resulting mixture was heated to 90 °C overnight. After cooling to room temperature, the solvent was removed and the residue was purified by flash column chromatography (silica gel, 0-60% EtOAc / petroleum ether) to give tert-butyl (R)-4-(5-(2-fluorophenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate (280 mg, 97%) as a white solid. LC / MS ESI (m / z): 566 (M+H). + .

[0267] Step 4. tert-Butyl (R)-4-(5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate To a solution of tert-butyl (R)-4-(5-(2-fluorophenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate (280 mg, 0.49 mmol) in THF (6 mL) was added TBAF (3.0 mL, 1.0 M solution in THF). The reaction mixture was stirred at room temperature overnight. The solvent was removed, and the residue was purified by flash column chromatography (silica gel, 0-64% EtOAc / petroleum ether) to give tert-butyl (R)-4-(5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate (170 mg, 87%) as a colorless oil. LC / MS ESI (m / z): 412 (M+H). + .

[0268] Step 5. tert-Butyl (R)-4-(5-(2-fluorophenyl)-7-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate To a solution of tert-butyl (R)-4-(5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate (170 mg, 0.42 mmol) and 2-bromopyridine (79 mg, 0.50 mmol) in DMF (10 mL) was added trans-1,2-diaminocyclohexane (97 mg, 0.85 mmol), CuI (190 mg, 0.42 mmol), and KPO (180 mg, 0.84 mmol). The resulting mixture was stirred at 120 °C for 18 h. After cooling to room temperature, the reaction was partitioned between EtOAc and water, and the organic layer was separated. The aqueous layer was extracted twice with EtOAc, and the combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-30%, ethyl acetate / petroleum ether) to give the crude product, which was further purified by preparative HPLC (Gilson, C18, MeCN / water) to give tert-butyl (R)-4-(5-(2-fluorophenyl)-7-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate (110 mg, 53%) as a solid. LC / MS ESI (m / z): 489 (M+H). + . 1H NMR (400 MHz, CDCl3) δ 8.79 (d, J = 8.3 Hz, 1H), 8.56 (s, 1H), 8.52 - 8.48 (m, 1H), 8.25 (s, 1H), 7.90 (ddd, J = 8.4, 7.4, 1.9 Hz, 1H), 7.50 (td, J = 7.6, 1.7 Hz, 1H), 7.37 (tdd, J = 7.2, 5.1, 1.8 Hz, 1H), 7.26 - 7.17 (m, 3H), 4.24 (s, 1H), 3.83 (d, J = 13.0 Hz, 1H), 3.67 - 3.61 (m, 1H), 3.43 (d, J = 13.2 Hz, 1H), 3.01 (dd, J = 13.0, 3.9 Hz, 1H), 2.70 (td, J = 12.3, 3.2 Hz, 1H), 2.55 (td, J = 13.0, 3.0 Hz, 1H), 1.43 (s, 9H), 1.13 (d, J = 6.8 Hz, 3H).

[0269] Example 7. Synthesis of tert-butyl (S)-4-(7-(3-fluorophenyl)-5-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Compound 226) [ka]

[0270] Step 1. tert-Butyl (S)-3-methyl-4-(5-(pyridin-3-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate To a solution of tert-butyl (S)-4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (700 mg, 1.2 mmol, Compound 259, prepared according to the procedure in Step 1) in dioxane (10 mL) and water (1 mL) was added pyridin-3-ylboronic acid (160 mg, 1.3 mmol), Pd(dppf)Cl (86 mg, 0.12 mmol), and KCO (320 mg, 2.3 mmol). The resulting mixture was heated to 90 °C overnight. After cooling to room temperature, the solvent was removed and the residue was purified by flash column chromatography (silica gel, 0-50% EtOAc / petroleum ether) to give tert-butyl (S)-3-methyl-4-(5-(pyridin-3-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (220 mg, 34%) as a pale yellow solid. LC / MS ESI(m / z): 549(M+H). + .

[0271] Step 2. tert-Butyl (S)-3-methyl-4-(5-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate To a solution of tert-butyl (S)-3-methyl-4-(5-(pyridin-3-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (220 mg, 0.40 mmol) in THF (3 mL) was added TBAF (3.0 mL, 1.0 M solution in THF). The resulting mixture was stirred at room temperature overnight. The solvent was removed, and the residue was purified by flash column chromatography (silica gel, 0-70% EtOAc / petroleum ether) to give tert-butyl (S)-3-methyl-4-(5-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (120 mg, 78%) as a pale yellow solid. LC / MS ESI (m / z): 395 (M+H). + .

[0272] Step 3. tert-Butyl (S)-4-(7-(3-fluorophenyl)-5-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl (S)-3-methyl-4-(5-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (40 mg, 0.10 mmol) and 1-fluoro-3-iodobenzene (27 mg, 0.12 mmol) in DMF (6 mL) was added CuI (19 mg, 0.10 mmol), KPO (43 mg, 0.20 mmol), and trans-1,2-diaminocyclohexane (23 mg, 0.20 mmol). The resulting mixture was stirred at 120 °C for 18 h. After cooling to room temperature, the reaction was partitioned between EtOAc and water, the organic layer was separated, the aqueous layer was extracted twice with EtOAc, and the combined organic layers were washed with brine, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-50%, ethyl acetate / petroleum ether) to give the crude product, which was further purified by preparative HPLC to give tert-butyl (S)-4-(7-(3-fluorophenyl)-5-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (20 mg, 41%) as a pale yellow solid. LC / MS ESI(m / z): 489(M+H). + . 1H NMR (400 MHz, CD3OD) δ 8.81 (s, 1H), 8.57 (s, 1H), 8.46 (s, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.87 (s, 1H), 7.72 (dt, J = 10.2, 2.2 Hz, 1H), 7.66 - 7.63 (m, 1H), 7.61 - 7.55 (m, 2H), 7.18 (tdd, J = 8.4, 2.4, 0.8 Hz, 1H), 4.07 (dt, J = 9.8, 3.1 Hz, 1H), 3.80 (d, J = 12.4 Hz, 1H), 3.50 (t, J = 12.2 Hz, 2H), 3.20 - 3.13 (m, 1H), 2.95 - 2.78 (m, 2H), 1.42 (s, 9H), 0.98 (d, J = 6.5 Hz, 3H).

[0273] The following compounds were prepared from the corresponding aryl halides by a procedure similar to the synthesis of compound 226. [Table 8]

[0274] Example 8. Synthesis of tert-butyl (S)-4-(5-cyclopropyl-7-(5-isocyanopyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Compound 259) [ka]

[0275] Step 1. tert-Butyl (S)-4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of 4-chloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (5.0 g, 12 mmol) in DIPEA (15 mL) was added tert-butyl (S)-3-methylpiperazine-1-carboxylate (5.8 g, 29 mmol). The resulting reaction mixture was stirred at 140 °C under N for 2 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 0–40%, ethyl acetate / petroleum ether) to give tert-butyl (S)-4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (5.8 g, 54%) as a white solid. LC / MS ESI (m / z): 598 (M+H). + .

[0276] Step 2. tert-Butyl (S)-4-(5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl (S)-4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (1.0 g, 1.7 mmol) in toluene (20 mL) was added Pd(dtbp)Cl (220 mg, 0.34 mmol), KCO (3.0 g, 22 mmol), and cyclopropylboronic acid (220 mg, 2.5 mmol). The resulting reaction mixture was stirred at 80 °C for 4 h. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by flash column chromatography (silica gel, 0-50%, ethyl acetate / petroleum ether) under reduced pressure to give tert-butyl (S)-4-(5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (430 mg, 50%) as a white solid. LC / MS ESI (m / z): 512 (M+H). + .

[0277] Step 3. tert-Butyl (S)-4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl (S)-4-(5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (430 mg, 0.84 mmol) in THF (10 mL) was added TBAF (4.0 mL, 1.0 M solution in THF). The resulting reaction mixture was stirred at room temperature under N2 overnight. The reaction mixture was quenched with ice water, then extracted twice with EtOAc. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0–80%, ethyl acetate / petroleum ether) to afford tert-butyl (S)-4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (250 mg, 83%) as a white solid. LC / MS ESI(m / z):358(M+H) + .

[0278] Step 4. tert-Butyl (S)-4-(5-cyclopropyl-7-(5-isocyanopyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl (S)-4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (70 mg, 0.20 mmol) in DMF (2 mL) was added CuI (37 mg, 0.20 mmol), KPO (83 mg, 0.39 mmol), trans-cyclohexane-1,2-diamine (45 mL, 0.39 mmol), and 5-bromopyridine-3-carbonitrile (43 mg, 0.24 mmol). The resulting reaction mixture was stirred at 120 °C under N overnight. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-40%, ethyl acetate / petroleum ether) and preparative HPLC (C-18, MeCN / HO) to give tert-butyl (S)-4-(5-cyclopropyl-7-(5-isocyanopyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (28 mg, 31%) as a white solid. LC / MS ESI (m / z): 460 (M+H). + . 1 H NMR (400 MHz, CD3OD) δ 9.33 (d, J = 2.5 Hz, 1H), 8.83 (d, J = 1.7 Hz, 1H), 8.75 - 8.72 (m, 1H), 8.36 (s, 1H), 7.42 (d, J = 0.8 Hz, 1H), 4.81 - 4.76 (m, 1H), 4.08 (d, J = 14.4 Hz, 1H), 3.97 - 3.86 (m, 2H), 3.59 - 3.52 (m, 1H), 3.49 - 3.34 (m, 1H), 3.22 - 3.10 (m, 1H), 2.11 - 2.06 (m, 1H), 1.50 (s, 9H), 1.21 (d, J = 6.6 Hz, 3H), 1.09 - 1.04 (m, 2H), 0.93 - 0.88 (m, 1H), 0.82 - 0.76 (m, 1H).

[0279] The following compounds were prepared from the corresponding aryl halides by a procedure similar to that for the synthesis of compound 259. [Table 9] TIFF2024536237000176.tif255154TIFF2024536237000177.tif255154TIFF2024536237000178.tif248156TIFF20245362370 00179.tif255153TIFF2024536237000180.tif250156TIFF2024536237000181.tif249157TIFF2024536237000182.tif125156

[0280] Example 9. Synthesis of 1,1,1-trifluoro-2-methylpropan-2-yl (S)-4-(7-(3-cyanophenyl)-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Compound 266) [ka]

[0281] Step 1. tert-Butyl (S)-4-(5-cyclopropyl-7-(5-isocyanopyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl (S)-4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (110 mg, 0.31 mmol) in DMF (3 mL) was added CuI (29 mg, 0.15 mmol), KPO (200 mg, 0.92 mmol), trans-cyclohexane-1,2-diamine (22 mg, 0.18 mmol), and 2-bromopyridine-4-carbonitrile (140 mg, 0.62 mmol). The resulting reaction mixture was stirred at 120 °C under N overnight. After cooling to room temperature, the reaction mixture was partitioned between EtOAc and water, the organic layer was separated, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-50%, ethyl acetate / petroleum ether) to give tert-butyl (S)-4-(7-(3-cyanophenyl)-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (140 mg, 98%) as a white solid. LC / MS ESI (m / z): 459 (M+H). + .

[0282] Step 2. (S)-3-(5-cyclopropyl-4-(2-methylpiperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)benzonitrile To a solution of tert-butyl (S)-4-(7-(3-cyanophenyl)-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (140 mg, 0.30 mmol) in DCM (1 mL) was added TFA (0.50 mL, 6.7 mmol). The resulting reaction mixture was stirred at room temperature under N2 overnight. The solvent was removed, the residue was diluted with DCM and washed with saturated NaHCO3, and the organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product, which was used in the next step without further purification. LC / MS ESI (m / z): 359 (M+H). + .

[0283] Step 3. 1,1,1-trifluoro-2-methylpropan-2-yl (S)-4-(7-(3-cyanophenyl)-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of (S)-3-(5-cyclopropyl-4-(2-methylpiperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)benzonitrile (75 mg, 0.21 mmol) in DMF (3 mL) were added DIPEA (0.20 mL, 1.0 mmol) and 1,1,1-trifluoro-2-methylpropan-2-yl-1H-imidazole-1-carboxylate (120 mg, 0.52 mmol, prepared from 1,1,1-trifluoro-2-methylpropan-2-ol and CDI), respectively. The resulting reaction mixture was stirred at 80 °C under N overnight. After cooling to room temperature, the reaction mixture was partitioned between EtOAc and water, the organic layer was separated, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by preparative HPLC to give 1,1,1-trifluoro-2-methylpropan-2-yl (S)-4-(7-(3-cyanophenyl)-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (37 mg, 34%) as a white solid. LC / MS ESI(m / z): 513(M+H). + . 1H NMR (400 MHz, CD3OD) δ 8.33 (s, 1H), 8.22 - 8.20 (m, 1H), 8.07 - 8.04 (m, 1H), 7.72 - 7.68 (m, 2H), 7.32 (d, J = 0.6 Hz, 1H), 4.80 (s, 1H), 4.14 - 3.92 (m, 2H), 3.89 - 3.82 (m, 1H), 3.61 - 3.54 (m, 1H), 3.50 - 3.36 (m, 1H), 2.12 - 2.06 (m, 1H), 2.03 (s, 1H), 1.72 (d, J = 6.3 Hz, 6H), 1.22 (d, J = 6.5 Hz, 3H), 1.07 - 1.03 (m, 2H), 0.91 - 0.75 (m, 2H).

[0284] The following compounds were prepared from the corresponding aryl halides by a procedure similar to the synthesis of compound 266. [Table 10]

[0285] Example 10. Synthesis of tert-butyl (S)-4-(7-(3-chlorophenyl)-5-(3-cyanopyrazin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Compound 274) [ka]

[0286] Step 1. 4-Chloro-7-(3-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine To a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (10 g, 36 mmol) in DCM (400 mL) was added (3-chlorophenyl)boronic acid (8.7 g, 72 mmol), 4 Å molecular sieves (5 g), Cu(OAc) (16 g, 89 mmol), and pyridine (17 mL, 210 mmol). The resulting mixture was stirred at room temperature under an O atmosphere for 48 h. The reaction was quenched with NHOH (30 mL) and ice water and filtered. The filtrate was extracted twice with DCM, and the combined organic layers were dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-30% EtOAc / petroleum ether) to give 4-chloro-7-(3-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (7.5 g, 54%) as a white solid. LC / MS ESI (m / z): 390 (M+H). + .

[0287] Step 2. tert-Butyl (S)-4-(7-(3-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of 4-chloro-7-(3-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (2.5 g, 6.4 mmol) in DIEA (8 mL) was added tert-butyl (S)-3-methylpiperazine-1-carboxylate (3.2 g, 16 mmol). The resulting reaction mixture was stirred at 140 °C under N for 2 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 0–40%, ethyl acetate / petroleum ether) to give tert-butyl (S)-4-(7-(3-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (3.0 g, 84%) as a white solid. LC / MS ESI (m / z): 554 (M+H). + .

[0288] Step 3. tert-Butyl (S)-4-(7-(3-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl (S)-4-(7-(3-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (2.5 g, 4.6 mmol) in dioxane (15 mL) was added X-Phos (220 mg, 0.46 mmol), Pd(dba) (0.40 g, 0.46 mmol), and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.7 mL, 18 mmol), respectively. The resulting reaction mixture was stirred at 95 °C under N overnight. After cooling to room temperature, the reaction mixture was quenched with ice water and extracted twice with DCM. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give crude product tert-butyl (S)-4-(7-(3-chlorophenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (3.5 g) as a yellow oil, which was used directly in the next step. LC / MS ESI(m / z): 554(M+H). + .

[0289] Step 4. tert-Butyl (S)-4-(7-(3-chlorophenyl)-5-(3-cyanopyrazin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl (S)-4-(7-(3-chlorophenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (70 mg, 0.13 mmol) in dioxane (2 mL) and HO (0.4 mL) were added KCO (87 mg, 0.63 mmol), Pd(dppf)Cl (10 mg, 0.01 mmol), and 3-bromopyrazine-2-carbonitrile (47 mg, 0.25 mmol), respectively. The resulting reaction mixture was stirred at 90 °C under N overnight. After cooling to room temperature, the solvent was removed. The residue was purified by flash column chromatography (silica gel, 0-20%, ethyl acetate / petroleum ether) and preparative HPLC (Gilson, C-18, MeCN / HO) to give tert-butyl (S)-4-(7-(3-chlorophenyl)-5-(3-cyanopyrazin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (32 mg, 48%) as a white solid. LC / MS ESI (m / z): 531 (M+H). + . 1 H NMR (400 MHz, CDCl3) δ 8.85 (d, J = 2.3 Hz, 1H), 8.69 (d, J = 2.3 Hz, 1H), 8.60 (s, 1H), 7.79 (s, 2H), 7.70 - 7.66 (m, 1H), 7.51 (t, J = 8.0 Hz, 1H), 7.45 - 7.41 (m, 1H), 4.38 - 3.95 (m, 1H), 3.85 - 3.78 (m, 1H), 3.65 - 3.58 (m, 1H), 3.53 - 3.25 (m, 1H), 3.20 - 2.87 (m, 2H), 2.66 (s, 1H), 1.44 (s, 9H), 1.18 - 0.96 (m, 3H).

[0290] The following compounds were prepared from the corresponding aryl halides by the same procedure as in the synthesis of compound 274. [Table 11]

[0291] Example 11. Synthesis of tert-butyl (R)-4-(5-(azetidin-1-yl)-7-(4-cyanopyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate (Compound 388) [ka]

[0292] Step 1. 5-Bromo-4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine To 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (5.0 g, 21 mmol) in acetone (70 mL) was added TsCl (4.1 g, 21 mmol). The mixture was cooled to 0° C. Then, 2 M NaOH solution (13 mL) was added. After the addition, the mixture was stirred at room temperature for 3 hours. The mixture was diluted with water and filtered. The filter cake was washed with water and dried under vacuum to give 5-bromo-4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (7.4 g, 88%) as a white solid. LC / MS ESI (m / z): 386 (M+H). + .

[0293] Step 2. tert-Butyl (R)-4-(5-bromo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate A mixture of 5-bromo-4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (3.0 g, 7.8 mmol), tert-butyl (R)-2-methylpiperazine-1-carboxylate (1.9 g, 9.3 mmol), and DIPEA (3.9 mL, 24 mmol) in EtOH (20 mL) was stirred at 100 °C overnight. The mixture was cooled to room temperature and filtered. The filter cake was washed with EtOH and dried under vacuum to give tert-butyl (R)-4-(5-bromo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate (3.7 g, 86%) as a white solid. LC / MS ESI (m / z): 550 (M+H). + .

[0294] Step 3. tert-Butyl (R)-4-(5-bromo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate tert-Butyl (R)-4-(5-bromo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate (3.7 g, 6.7 mmol) was treated with TBAF (16 mL, 1.0 M solution in THF) at room temperature for 2 h. The mixture was diluted with EtOAc, washed with brine, dried over Na2SO4, and concentrated. The residue was purified by flash column chromatography (silica gel, 0–50% EtOAc / petroleum ether) to give tert-butyl (R)-4-(5-bromo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate (2.1 g, 77%) as a pale yellow solid. LC / MS ESI (m / z): 396 (M+H). + .

[0295] Step 4. tert-Butyl (R)-4-(5-bromo-7-(4-chloropyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate tert-Butyl (R)-4-(5-bromo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate (2.1 g, 5.2 mmol), KPO (2.2 g, 10 mmol), CuI (0.99 g, 5.2 mmol), and 2-bromo-4-chloropyridine (1.5 g, 7.8 mmol) were mixed in anhydrous DMF (50 mL). Next, trans-dimethylcyclohexane-1,2-diamine (0.74 g, 5.2 mmol) was added, and the mixture was stirred at 90 °C under N for 2.5 h. It was then diluted with EtOAc, washed with LiCl (5% aq.) and brine, dried over NaSO, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-15% EtOAc / petroleum ether) to give tert-butyl (R)-4-(5-bromo-7-(4-chloropyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate (2.1 g, 79%). LC / MS ESI (m / z): 507 (M+H). + .

[0296] Step 5. tert-Butyl (R)-4-(7-(4-chloropyridin-2-yl)-5-(2-oxoazetidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate To tert-butyl (R)-4-(5-bromo-7-(4-chloropyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate (300 mg, 0.59 mmol) and azetidin-2-one (130 mg, 1.8 mmol) was added KPO (250 mg, 1.2 mmol), CuI (110 mg, 0.59 mmol), anhydrous THF (5 mL), and trans-dimethylcyclohexane-1,2-diamine (170 mg, 1.2 mmol). The mixture was stirred overnight at 90 °C under N. It was then diluted with EtOAc, washed with 5% LiCl (aq) and brine, dried over NaSO, and concentrated. The residue was purified by flash column chromatography (0-60% EtOAc / petroleum ether, then 0-7% MeOH / DCM) to afford tert-butyl (R)-4-(7-(4-chloropyridin-2-yl)-5-(2-oxoazetidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate (170 mg, 58%) as a pale yellow solid. LC / MS ESI (m / z): 498 (M+H). + .

[0297] Step 6. tert-Butyl (R)-4-(5-(azetidin-1-yl)-7-(4-chloropyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate To tert-butyl (R)-4-(7-(4-chloropyridin-2-yl)-5-(2-oxoazetidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate (65 mg, 0.13 mmol) in anhydrous THF (4 mL) was added RhH(CO)(PPh) (32 mg, 0.035 mmol). The mixture was purged with N. Then, PhSiH (70 mg, 0.65 mmol) was added. The mixture was stirred under N2 at 60 °C for 2 h, concentrated, and purified by preparative TLC (petroleum ether / EtOAc = 5:1, volume ratio) to give tert-butyl (2R)-4-[5-(azetidin-1-yl)-7-(4-chloropyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2-methylpiperazine-1-carboxylate (50 mg, 79%) as a pale yellow oil. LC / MS ESI (m / z): 484 (M+H). + .

[0298] Step 7. tert-Butyl (R)-4-(5-(azetidin-1-yl)-7-(4-cyanopyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate To Zn(CN) (75 mg, 0.64 mmol) and Pd(PPh) (75 mg, 0.065 mmol) was added tert-butyl (2R)-4-[5-(azetidin-1-yl)-7-(4-chloropyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2-methylpiperazine-1-carboxylate (62 mg, 0.13 mmol) in anhydrous THF (3 mL). The mixture was stirred overnight at 120 °C under N. It was then diluted with EtOAc, washed with 5% LiCl (aq) and brine, dried over NaSO, and concentrated. The residue was purified by preparative TLC (petroleum ether / EtOAc = 3:1, volume ratio) to give tert-butyl (R)-4-(5-(azetidin-1-yl)-7-(4-cyanopyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate (16 mg, 26%) as a yellow solid. LC / MS ESI (m / z): 475 (M+H). + . 1 H NMR (400 MHz, CDCl3) δ 9.35 (s, 1H), 8.57 (d, J = 5.0 Hz, 1H), 8.41 (s, 1H), 7.46 (s, 1H), 7.29 (dd, J = 5.0, 1.1 Hz, 1H), 4.76 (d, J = 12.6 Hz, 1H), 4.46 (d, J = 13.4 Hz, 1H), 4.40 - 4.29 (m, 1H), 3.95 (d, J = 13.6 Hz, 1H), 3.83 (q, J = 6.9 Hz, 2H), 3.64 (q, J = 6.9 Hz, 2H), 3.46 - 3.33 (m, 2H), 3.02 (td, J = 12.4, 3.4 Hz, 1H), 2.29 (p, J = 7.1 Hz, 2H), 1.49 (s, 9H), 1.02 (d, J = 6.8 Hz, 3H).

[0299] Example 12. Synthesis of tert-butyl 7-(7-(4-cyanopyridin-2-yl)-5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (Compound 392) [ka]

[0300] Step 1. 4-Chloro-5-(2-fluorophenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine To a solution of 4-chloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (1.1 g, 2.5 mmol) in DMF (15 mL) and water (0.5 mL) was added (2-fluorophenyl)boronic acid (420 mg, 0.60 mmol), X-Phos (180 mg, 0.37 mmol), KPO (1.6 g, 7.5 mmol), and Pd(dba) (230 mg, 0.25 mmol), and the resulting mixture was heated to 60 °C overnight. After cooling to room temperature, the reaction mixture was filtered. The filtrate was partitioned between EtOAc and water, and the organic layer was separated. The aqueous layer was extracted twice with EtOAc, and the combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-50% EtOAc / petroleum ether) to give 4-chloro-5-(2-fluorophenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (600 mg, 60%). LC / MS ESI (m / z): 402 (M+H). + .

[0301] Step 2. tert-Butyl 7-(5-(2-fluorophenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate To a solution of 4-chloro-5-(2-fluorophenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (550 mg, 2.2 mmol) in EtOH (6 mL) was added DIEA (0.66 mL, 4.0 mmol) and tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate (440 mg, 2.1 mmol). The resulting reaction mixture was stirred at 100 °C under N overnight. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-30%, ethyl acetate / petroleum ether) to give tert-butyl 7-(5-(2-fluorophenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (660 mg, 70%) as a white solid. LC / MS ESI (m / z): 578 (M+H). + .

[0302] Step 3. tert-Butyl 7-(5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate To a solution of tert-butyl 7-(5-(2-fluorophenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (660 mg, 1.6 mmol) in THF (10 mL) was added TBAF (6.5 mL, 1.0 M solution in THF). The resulting reaction mixture was stirred overnight at room temperature under N. The reaction mixture was quenched with ice water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-60%, ethyl acetate / petroleum ether) to give tert-butyl 7-(5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (410 mg, 62%) as a white solid. LC / MS ESI (m / z): 424 (M+H). + .

[0303] Step 4. tert-Butyl 7-(7-(4-cyanopyridin-2-yl)-5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate To a solution of tert-butyl 7-(5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (400 mg, 0.95 mmol) in DMF (10 mL) was added CuI (90 mg, 0.47 mmol), KPO (600 mg, 2.9 mmol), trans-cyclohexane-1,2-diamine (0.030 mL, 0.28 mmol), and 2-bromoisonicotinonitrile (350 mg, 1.9 mmol), respectively. The resulting reaction mixture was stirred at 80 °C under N overnight. After cooling to room temperature, the reaction mixture was partitioned between EtOAc and water, and the organic layer was separated. The aqueous layer was extracted twice with EtOAc, and the combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-30%, ethyl acetate / petroleum ether) to give tert-butyl 7-(7-(4-cyanopyridin-2-yl)-5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (450 mg, 91%) as a white solid. LC / MS ESI (m / z): 526 (M+H). + . 1 H NMR (400 MHz, CDCl3) δ 9.40 (s, 1H), 8.63 - 8.60 (m, 1H), 8.54 (s, 1H), 8.28 (s, 1H), 7.50 - 7.46 (m, 1H), 7.41 - 7.35 (m, 2H), 7.28 -7.18 (m, 2H), 3.28 (s, 2H), 3.21 (s, 2H), 3.12 (s, 2H), 1.42 (s, 9H), 0.93 - 0.88 (m, 2H), 0.74 (s, 2H).

[0304] Example 13. Synthesis of tert-butyl (S)-4-(7-(3-chlorophenyl)-5-((R)-2-(hydroxymethyl)pyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Compound 312) [ka]

[0305] To a solution of tert-butyl (S)-4-(7-(3-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (460 mg, 0.83 mmol) in DMSO (5 mL) was added CuI (32 mg, 0.17 mmol), L-proline (38 mg, 0.30 mmol), KCO (340 mg, 2.5 mmol), and (R)-pyrrolidin-2-ylmethanol (0.33 mL, 3.3 mmol), respectively. The resulting reaction mixture was stirred at 70 °C under N overnight. After cooling to room temperature, the reaction mixture was partitioned between EtOAc and water. The organic layer was separated, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-60%, ethyl acetate / petroleum ether) followed by preparative HPLC (Gilson, C-18, MeCN / water) to give tert-butyl (S)-4-(7-(3-chlorophenyl)-5-((R)-2-(hydroxymethyl)pyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (100 mg, 23%) as a solid. LC / MS ESI (m / z): 527 (M+H). + . 1H NMR (400 MHz, CDCl3) δ 8.41 (s, 1H), 7.74 - 7.68 (m, 1H), 7.67 - 7.62 (m, 1H), 7.43 (t, J = 8.1 Hz, 1H), 7.33 - 7.28 (m, 1H), 6.90 (s, 1H), 5.19 - 5.01 (m, 1H), 4.23 - 3.92 (m, 3H), 3.91 - 3.82 (m, 1H), 3.79 - 3.69 (m, 2H), 3.65 - 3.61 (m, 1H), 3.55 - 3.43 (m, 2H), 3.41 - 3.29 (m, 1H), 3.04 - 2.89 (m, 1H), 2.82 - 2.74 (m, 1H), 2.19 - 2.12 (m, 1H), 2.00 - 1.88 (m, 3H), 1.49 (s, 9H), 1.18 - 1.04 (m, 3H).

[0306] Example 14. Synthesis of tert-butyl 7-(7-(4-cyanopyridin-2-yl)-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (Compound 396) [ka]

[0307] Step 1. tert-Butyl 7-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate To a solution of 4-chloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (750 mg, 2.7 mmol, Compound 192, prepared according to the procedure in Step 1) in EtOH (5 mL) was added DIEA (0.90 mL, 5.5 mmol) and tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate (550 mg, 2.6 mmol), respectively. The resulting reaction mixture was stirred at 100 °C under N overnight. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-30%, ethyl acetate / petroleum ether) to give tert-butyl 7-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (920 mg, 75%) as a white solid. LC / MS ESI (m / z): 610 (M+H). + .

[0308] Step 2. tert-Butyl 7-(5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate To a solution of tert-butyl 7-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (900 mg, 2.0 mmol) in toluene (12 mL) was added Pd-118 (97 mg, 0.15 mmol), KCO (2.6 g, 19 mmol), and cyclopropylboronic acid (190 mg, 2.2 mmol). The resulting reaction mixture was stirred at 80 °C under N overnight. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-40%, ethyl acetate / petroleum ether) to give tert-butyl 7-(5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (240 mg, 33%) as a white solid. LC / MS ESI (m / z): 524 (M+H). + .

[0309] Step 3. tert-Butyl (S)-4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl 7-(5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (240 mg, 0.65 mmol) in THF (4 mL) was added TBAF (2.4 mL, 1.0 M solution in THF). The resulting reaction mixture was stirred overnight at room temperature under N. The reaction mixture was quenched with ice water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-50%, ethyl acetate / petroleum ether) to give tert-butyl 7-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (150 mg, 62%) as a white solid. LC / MS ESI (m / z): 370 (M+H). + .

[0310] Step 4. tert-Butyl 7-(7-(4-cyanopyridin-2-yl)-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate To a solution of tert-butyl 7-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (150 mg, 0.41 mmol) in DMF (5 mL) was added CuI (39 mg, 0.21 mmol), KPO (260 mg, 1.2 mmol), trans-cyclohexane-1,2-diamine (0.020 mL, 0.12 mmol), and 2-bromoisonicotinonitrile (150 mg, 0.81 mmol). The resulting reaction mixture was stirred overnight at 100 °C under N. After cooling to room temperature, the reaction mixture was partitioned between EtOAc and water, the organic layer was separated, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-30%, ethyl acetate / petroleum ether) and preparative HPLC to give tert-butyl 7-(7-(4-cyanopyridin-2-yl)-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (100 mg, 54%) as a white solid. LC / MS ESI (m / z): 472 (M+H). + . 1 H NMR (400 MHz, CDCl3) δ 9.32 (s, 1H), 8.59 - 8.56 (m, 1H), 8.47 (s, 1H), 7.77 (d, J = 0.7 Hz, 1H), 7.35 - 7.32 (m, 1H), 3.87 - 3.81 (m, 2H), 3.77 - 3.73 (m, 2H), 3.61 (s, 2H), 2.02 - 1.95 (m, 1H), 1.50 (s, 9H), 1.06 - 0.98 (m, 4H), 0.83 - 0.78 (m, 4H).

[0311] Example 15. Synthesis of tert-butyl (S)-4-(7-(4-cyano-6-methylpyridin-2-yl)-5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Compound 404) [ka]

[0312] Step 1. tert-Butyl (S)-4-(7-(6-bromo-4-cyanopyridin-2-yl)-5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl (S)-4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (1.0 g, 1.7 mmol) in dioxane (20 mL) and water (0.5 mL) was added Pd(dppf)Cl (140 mg, 0.17 mmol), KCO (930 mg, 6.7 mmol), and (2-fluorophenyl)boronic acid (280 mg, 2.0 mmol). The resulting reaction mixture was stirred at 90 °C overnight. After cooling to room temperature, the solvent was removed and the residue was purified by flash column chromatography (silica gel, 0-40%, ethyl acetate / petroleum ether) to give tert-butyl (S)-4-(5-(2-fluorophenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (810 mg, 85%) as a white solid. LC / MS ESI (m / z): 566 (M+H). + .

[0313] Step 2. tert-Butyl (S)-4-(5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl (S)-4-(5-(2-fluorophenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (570 mg, 1.0 mmol) in THF (4 mL) was added TBAF (4.0 mL, 1.0 M solution in THF). The resulting reaction mixture was stirred overnight at room temperature under N. The reaction mixture was quenched with ice water, which was then extracted twice with EtOAc, and the combined organic layers were washed with water and brine, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-60%, ethyl acetate / petroleum ether) to give tert-butyl (S)-4-(5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (330 mg, 80%) as a white solid. LC / MS ESI (m / z): 412 (M+H). + .

[0314] Step 3. tert-Butyl (S)-4-(7-(6-bromo-4-cyanopyridin-2-yl)-5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate In a sealed tube, tert-butyl (S)-4-(5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (150 mg, 0.37 mmol), 2,6-dibromoisonicotinonitrile (190 mg, 0.73 mmol), KPO (160 mg, 0.73 mmol), and CuI (69 mg, 0.36 mmol) were combined in anhydrous THF. Next, (±)-trans-1,2-cyclohexanediamine (100 mg, 0.73 mmol) was added. The mixture was stirred at 90 °C under N for 3.5 h and then cooled to room temperature. It was then diluted with EtOAc, washed with 5% LiCl (aq) and brine, dried over NaSO, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-11% EtOAc / petroleum ether) to give tert-butyl (S)-4-(7-(6-bromo-4-cyanopyridin-2-yl)-5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (120 mg, 55%) as a yellow foam. LC / MS ESI(m / z): 592(M+H). + .

[0315] Step 4. tert-Butyl (S)-4-(7-(4-cyano-6-methylpyridin-2-yl)-5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate A mixture of tert-butyl (S)-4-(7-(6-bromo-4-cyanopyridin-2-yl)-5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (120 mg, 0.20 mmol), methylboronic acid (98 mg, 1.6 mmol), CsCO (200 mg, 0.61 mmol), and Pd(dppf)Cl (20 mg, 0.027 mmol) in dioxane (3 mL) and HO (0.6 mL) was stirred at 100 °C under N overnight. It was then diluted with EtOAc and DCM and filtered. The filtrate was purified by flash column chromatography (silica gel, 0-20% EtOAc / petroleum ether, followed by preparative HPLC to give tert-butyl (S)-4-(7-(4-cyano-6-methylpyridin-2-yl)-5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (23 mg, 21%) as a pale yellow oil. LC / MS ESI (m / z): 528 (M+H). + . 1 H NMR (400 MHz, CDCl3) δ 9.16 (s, 1H), 8.56 (s, 1H), 8.29 (s, 1H), 7.46 (td, J = 7.6, 1.5 Hz, 1H), 7.37 (tdd, J = 7.2, 5.1, 1.8 Hz, 1H), 7.26 - 7.17 (m, 3H), 4.32 - 4.06 (m, 1H), 3.86 - 3.61 (m, 1H), 3.56 - 3.42 (m, 2H), 3.08 (td, J = 12.3, 2.5 Hz, 1H), 2.87 - 2.59 (m, 5H), 1.43 (s, 9H), 1.01 (d, J = 5.7 Hz, 3H).

[0316] The following compound was prepared by a synthetic procedure similar to that described for compound 404, except that tert-butyl (S)-4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate was used. [Table 12]

[0317] Example 16. Synthesis of tert-butyl (1S,6R)-5-(7-(4-cyanopyridin-2-yl)-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate (Compound 408) and tert-butyl (1R,6S)-5-(7-(4-cyanopyridin-2-yl)-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate (Compound 409) [ka]

[0318] Step 1. tert-Butyl 5-(5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate To a solution of 4-chloro-5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (170 mg, 0.87 mmol, Compound 192, according to the procedure for the preparation of Step 1) in EtOH (5 mL) was added DIEA (0.14 mL, 0.87 mmol) and tert-butyl 2,5-diazabicyclo[4.1.0]heptane-2-carboxylate (140 mg, 0.72 mmol), respectively. The resulting reaction mixture was stirred at 100° C. under N overnight. After removal of the solvent, the residue was purified by flash column chromatography (silica gel, 0-30%, ethyl acetate / petroleum ether) to give tert-butyl 5-(5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate (140 mg, 45%) as a white solid. LC / MS ESI (m / z): 510 (M+H). + .

[0319] Step 2. tert-Butyl 5-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate To a solution of tert-butyl 5-(5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate (140 mg, 0.40 mmol) in THF (2 mL) was added TBAF (1.5 mL, 1.0 M solution in THF). The resulting reaction mixture was stirred overnight at room temperature under N. The reaction mixture was quenched with ice water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-50%, ethyl acetate / petroleum ether) to give tert-butyl 5-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate (90 mg, 64%) as a white solid. LC / MS ESI (m / z): 356 (M+H). + .

[0320] Step 3. tert-Butyl 5-(7-(4-cyanopyridin-2-yl)-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate To a solution of tert-butyl 5-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate (90 mg, 0.25 mmol) in DMF (6 mL) was added CuI (24 mg, 0.13 mmol), KPO (160 mg, 0.75 mmol), trans-cyclohexane-1,2-diamine (9.0 mg, 0.080 mmol), and 2-bromoisonicotinonitrile (93 mg, 0.51 mmol). The resulting reaction mixture was stirred overnight at 80 °C under N. After cooling to room temperature, the reaction mixture was partitioned between EtOAc and water, the organic layer was separated, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-40%, ethyl acetate / petroleum ether) and preparative HPLC (Gilson, C18, MeCN / water) to give tert-butyl 5-(7-(4-cyanopyridin-2-yl)-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate (60 mg, 53%) as a white solid. LC / MS ESI (m / z): 458 (M+H). + 。 Step 4. tert-Butyl (1S,6R)-5-(7-(4-cyanopyridin-2-yl)-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate and tert-butyl (1R,6S)-5-(7-(4-cyanopyridin-2-yl)-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate Preparative separation methodColumn: ChiralCel OJ, 250 × 21.2 mm i.d., 5 μm; Mobile phase: A is CO and B is MEOH + 0.1% NH HO; Gradient: B 40%; Flow rate: 50 mL / min; Back pressure: 100 bar; Column temperature: 35 °C; Wavelength: 254 nm; Cycle time: 7 min; Elution time: 1.5H. tert-Butyl 5-(7-(4-cyanopyridin-2-yl)-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate (60 mg) was separated by SFC to give two isomers.

[0321] Peak 1 : The one with the shorter retention time, 22 mg as a white solid. LC / MS ESI (m / z): 458 (M+H) + .

[0322] 1 H NMR (400 MHz, CDCl3) δ 9.33 (d, J = 3.2 Hz, 1H), 8.60 - 8.57 (m, 1H), 8.46 - 8.39 (m, 1H), 7.85 - 7.81 (m, 1H), 7.36 - 7.32 (m, 1H), 4.55 - 4.46 (m, 1H), 3.84 - 3.74 (m, 1H), 3.67 - 3.39 (m, 3H), 3.10 - 2.98 (m, 1H), 2.07 - 1.99 (m, 1H), 1.48 (s, 9H), 1.22 - 1.12 (m, 1H), 1.00 - 0.74 (m, 4H), 0.50 - 0.44 (m, 1H). Peak 2 : Longer retention time, 24 mg as a white solid. LC / MS ESI (m / z): 458 (M+H) + .

[0323] 1H NMR (400 MHz, CDCl3) δ 9.37 - 9.29 (m, 1H), 8.59 (d, J = 5.0 Hz, 1H), 8.45 - 8.40 (m, 1H), 7.85 - 7.81 (m, 1H), 7.34 (dd, J = 5.0, 1.3 Hz, 1H), 4.55 - 4.46 (m, 1H), 3.84 - 3.75 (m, 1H), 3.67 - 3.60 (m, 0.5H), 3.56 - 3.46 (m, 1H), 3.45 - 3.36 (m, 1.5H), 3.10 - 2.98 (m, 1H), 2.07 - 2.00 (m, 1H), 1.48 (s, 9H), 1.21 - 1.13 (m, 1H), 0.99 - 0.90 (m, 2H), 0.82 - 0.68 (m, 2H), 0.50 - 0.44 (m, 1H).

[0324] Example 17. Synthesis of ethyl 4-(5-(2-fluorophenyl)-7-(5-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (Compound 1003) [ka]

[0325] Step 1. 4-Chloro-5-(2-fluorophenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine To a solution of 4-chloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (10 g, 23 mmol, 192, compound prepared according to the procedure in Step 1) in dioxane-HO (100 mL, volume ratio = 5 / 1) was added (2-fluorophenyl)boronic acid (3.3 g, 23 mmol), KPO (9.8 g, 46 mmol), and Pd(dppf)Cl (1.7 g, 2.3 mmol). The resulting mixture was heated to 60 °C overnight. After cooling to room temperature, the reaction was filtered, the filtrate was partitioned between EtOAc and water, the organic layer was separated, the aqueous layer was extracted twice with EtOAc, the combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and the residue was purified by flash chromatography (silica gel, 0-50% EtOAc / petroleum ether) to give 4-chloro-5-(2-fluorophenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (7.0 g, 75% yield) as a solid. LC / MS ESI (m / z): 402 (M+H). + .

[0326] Step 2. 4-Chloro-5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidine To a solution of 4-chloro-5-(2-fluorophenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (1.0 g, 2.50 mmol) in THF (5 mL) was added TBAF (7.5 mL, 1.0 M solution in THF) at 0 °C. The resulting mixture was stirred at the same temperature for 5 h. The reaction was quenched with ice water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-60% ethyl acetate / petroleum ether) to give 4-chloro-5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidine (530 mg, 85%). LC / MS ESI (m / z): 248 (M+H). + .

[0327] Step 3. 4-Chloro-5-(2-fluorophenyl)-7-(5-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine To a solution of 4-chloro-5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidine (530 mg, 2.1 mmol) in toluene (20 mL) was added 3-iodo-5-methoxypyridine (600 mg, 2.6 mmol), CuI (81 mg, 0.40 mmol), 1,10-phenanthroline (77 mg, 0.40 mmol), and CsCO (2.1 g, 6.4 mmol). The resulting mixture was heated to 110 °C under N overnight. After cooling to room temperature, the reaction was partitioned between EtOAc and water, the organic layer was separated, the aqueous layer was extracted twice with EtOAc, the combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and the residue was purified by flash column chromatography (silica gel, 0-30%, ethyl acetate / petroleum ether) to give 4-chloro-5-(2-fluorophenyl)-7-(5-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (400 mg, 53%) as a yellow solid. LC / MS ESI (m / z): 355 (M+H). + .

[0328] Step 4. Ethyl 4-(5-(2-fluorophenyl)-7-(5-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate To a solution of 4-chloro-5-(2-fluorophenyl)-7-(5-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (100 mg, 0.30 mmol) in EtOH (10 mL) was added ethyl piperazine-1-carboxylate (63 mg, 0.30 mmol) and DIPEA (110 mg, 0.90 mmol), and the resulting mixture was heated to 100° C. under N overnight. After cooling to room temperature, the solvent was removed and the residue was purified by flash column chromatography (silica gel, 0-30%, ethyl acetate / petroleum ether) to give ethyl 4-(5-(2-fluorophenyl)-7-(5-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (50 mg, 37%) as a white solid, which was further purified by preparative HPLC to give 22.8 mg of a white solid. LC / MS ESI(m / z): 477(M+H). + . 1 H NMR (400 MHz, DMSO-d6) δ 8.77 (d, J = 2.0 Hz, 1H), 8.47 (s, 1H), 8.34 (d, J = 2.6 Hz, 1H), 8.08 (s, 1H), 7.94 (t, J = 2.3 Hz, 1H), 7.60 - 7.54 (m, 1H), 7.52 - 7.46 (m, 1H), 7.41 - 7.36 (m, 2H), 4.00 (q, J = 7.1 Hz, 2H), 3.92 (s, 3H), 3.24 - 3.20 (m, 4H), 3.16 - 3.09 (m, 4H), 1.15 (t, J = 7.1 Hz, 3H).

[0329] The following compounds were prepared from the corresponding amines by a procedure similar to the synthesis of compound 1003. [Table 13]

[0330] Example 18. Synthesis of tert-butyl 4-(7-(3-chloro-4-fluorophenyl)-5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (Compound 151) [ka]

[0331] Step 1. 4-Chloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine To a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (200 g, 0.71 mol) and 4-methylbenzene-1-sulfonyl chloride (180 g, 0.93 mol) in acetone (2 L) was added 2.0 M NaOH (0.53 L) dropwise at 0 °C. After the addition, the reaction was warmed to room temperature and stirred for an additional 3 hours. The precipitate was collected by filtration, washed twice with water, and dried under vacuum to give 4-chloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (300 g, 95%) as an off-white solid. LC / MS ESI (m / z): 434 (M+H). + .

[0332] Step 2. tert-Butyl 4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate A mixture of 4-chloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (4.6 g, 11 mmol), tert-butyl piperazine-1-carboxylate (2.2 g, 12 mmol), and DIPEA (2.8 mL, 16 mmol) in EtOH (20 mL) was stirred at 100 °C overnight. After cooling to room temperature, the solvent was removed and the residue was purified by flash column chromatography to give tert-butyl 4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (5.5 g, 89%) as a white solid. LC / MS ESI (m / z): 584 (M+H). + .

[0333] Step 3. tert-Butyl 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate To a solution of tert-butyl 4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (300 mg, 0.51 mmol) in dioxane (5 mL) was added 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.30 mL, 2.0 mmol), TEA (0.35 mL, 2.5 mmol), X-Phos (25 mg, 0.052 mmol), and Pd(dba) (47 mg, 0.052 mmol). The resulting mixture was stirred at 95 °C overnight. After cooling to room temperature, the reaction was quenched with water, extracted twice with DCM, and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give crude tert-butyl 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (300 mg, 99%) as a yellow oil. LC / MS ESI(m / z): 584(M+H). + .

[0334] Step 4. tert-Butyl 4-(5-(pyridin-2-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate To a solution of tert-butyl 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (300 mg, 0.51 mmol) in dioxane (5 mL) and HO (1 mL) was added 2-bromopyridine (0.96 mL, 1.0 mmol), KCO (360 mg, 2.5 mmol), and Pd(dppf)Cl (38 mg, 0.052 mmol). The resulting mixture was heated to 90 °C overnight. After cooling to room temperature, the solvent was removed and the residue was purified by flash column chromatography (silica gel, 0-60%, ethyl acetate / petroleum ether) to give tert-butyl 4-(5-(pyridin-2-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (180 mg, 65%) as a white solid. LC / MS ESI (m / z): 535 (M+H). + .

[0335] Step 5. tert-Butyl 4-(5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate To a solution of tert-butyl 4-(5-(pyridin-2-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (180 mg, 0.33 mmol) in THF (2 mL) was added TBAF (2.0 mL, 1.0 M solution in THF). The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0–10%, methanol / dichloromethane) to afford tert-butyl 4-(5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (120 mg, 93%) as a white solid. LC / MS ESI(m / z):381(M+H) + .

[0336] Step 6. tert-Butyl 4-(7-(3-chloro-4-fluorophenyl)-5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate To a solution of tert-butyl 4-(5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (120 mg, 0.31 mmol) in DMF (10 mL) was added 2-chloro-1-fluoro-4-iodobenzene (0.048 mL, 0.37 mmol), trans-cyclohexane-1,2-diamine (11 mg, 0.095 mmol), CuI (18 mg, 0.095 mmol), and KPO (200 mg, 0.94 mmol). The resulting mixture was heated to 120 °C overnight. After cooling to room temperature, the reaction was quenched with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-50%, ethyl acetate / petroleum ether) to give tert-butyl 4-(7-(3-chloro-4-fluorophenyl)-5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (130 mg, 80%) as a white solid. LC / MS ESI (m / z): 509 (M+H). + . 1 H NMR (400 MHz, CDCl3) δ 8.69 (d, J = 4.3 Hz, 1H), 8.52 (s, 1H), 7.85 (dd, J = 6.4, 2.6 Hz, 1H), 7.79 (td, J = 7.7, 1.8 Hz, 1H), 7.67 (s, 1H), 7.67 - 7.60 (m, 2H), 7.34 - 7.23 (m, 2H), 3.35 (d, J = 17.5 Hz, 8H), 1.44 (s, 9H).

[0337] The following compounds were prepared from the corresponding amines and aryl halides by a procedure similar to the synthesis of compound 151. [Table 14]

[0338] Example 19. Synthesis of ethyl 4-(7-(3-chloro-4-fluorophenyl)-5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (Compound 152) [ka]

[0339] Step 1. 7-(3-chloro-4-fluorophenyl)-4-(piperazin-1-yl)-5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine To a solution of tert-butyl 4-(7-(3-chloro-4-fluorophenyl)-5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (100 mg, 0.19 mmol, according to the procedure for the preparation of Compound 151) in DCM (3 mL) was added HCl (3.0 mL, 4.0 M solution in dioxane). The resulting mixture was stirred at room temperature for 3 hours. After removal of the solvent, the residue was diluted with DCM and washed with NaHCO3 (aq), the organic layer was extracted twice with DCM, and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was used directly in the next step. 7-(3-chloro-4-fluorophenyl)-4-(piperazin-1-yl)-5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine. LC / MS ESI(m / z): 409(M+H) + .

[0340] Step 2. Ethyl 4-(7-(3-chloro-4-fluorophenyl)-5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate To a solution of 7-(3-chloro-4-fluorophenyl)-4-(piperazin-1-yl)-5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine (80 mg, 0.19 mmol) in DCM (3 mL) was added dropwise ethyl carbonochloridate (0.040 mL, 0.39 mmol) and TEA (0.080 mL, 0.58 mmol) at 0 °C. The resulting mixture was stirred overnight at room temperature. The reaction was quenched with water and extracted twice with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-50%, ethyl acetate / petroleum ether) to give the crude product, which was further purified by preparative HPLC to give ethyl 4-(7-(3-chloro-4-fluorophenyl)-5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (28 mg, 30%) as a white solid. LC / MS ESI(m / z): 481(M+H). + . 1 H NMR (400 MHz, CDCl3) δ 8.72 - 8.66 (m, 1H), 8.53 (s, 1H), 7.85 (dd, J = 6.4, 2.6 Hz, 1H), 7.79 (td, J = 7.7, 1.8 Hz, 1H), 7.67 - 7.59 (m, 3H), 7.34 - 7.24 (m, 2H), 4.12 (q, J = 7.1 Hz, 2H), 3.38 (s, 8H), 1.24 (t, J = 7.1 Hz, 3H).

[0341] Example 20. Synthesis of tert-butyl 4-(7-(5-chloropyridin-3-yl)-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Compound 164) [ka]

[0342] Step 1. 4-Chloro-5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine To a solution of 4-chloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (5.8 g, 13 mmol, compound 151, prepared according to the procedure in Step 1) in toluene (50 mL) was added cyclopropylboronic acid (1.1 g, 13 mmol), KCO (24 g, 170 mmol), and Pd-118 (880 mg, 1.3 mmol). The resulting mixture was heated to 80 °C overnight. After cooling to room temperature, the solvent was filtered off. The filtrate was concentrated and purified by flash column chromatography (silica gel, 0–30%, ethyl acetate / petroleum ether) to give 4-chloro-5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (3.6 g, 77% yield) as a solid. LC / MS ESI (m / z): 348 (M+H). + .

[0343] Step 2. tert-Butyl 4-(5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate A mixture of 4-chloro-5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (500 mg, 1.4 mmol) and tert-butyl 3-methylpiperazine-1-carboxylate (1200 mg, 5.7 mmol) was heated to 150 °C for 3 h. After cooling to room temperature, the reaction mixture was purified by flash column chromatography (silica gel, 0–30%, ethyl acetate / petroleum ether) to give tert-butyl 4-(5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (450 mg, 61%) as a white solid. LC / MS ESI (m / z): 512 (M+H). + .

[0344] Step 3. tert-Butyl 4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl 4-(5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (450 mg, 0.88 mmol) in THF (5 mL) was added TBAF (5.3 mL, 1.0 M solution in THF). The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0–60%, ethyl acetate / petroleum ether) to afford tert-butyl 4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (240 mg, 76%) as a yellow solid. LC / MS ESI (m / z): 358 (M+H). + .

[0345] Step 4. tert-Butyl 4-(7-(5-chloropyridin-3-yl)-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl 4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (120 mg, 0.33 mmol) in DMF (5 mL) was added 3-bromo-5-chloropyridine (78 mg, 0.40 mmol), trans-cyclohexane-1,2-diamine (12 mg, 0.10 mmol), CuI (19 mg, 0.10 mmol), and KPO (210 mg, 1.0 mmol). The resulting mixture was heated to 120 °C overnight. After cooling to room temperature, the reaction was diluted with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-40%, ethyl acetate / petroleum ether) to give the crude product, which was further purified by preparative HPLC to give tert-butyl 4-(7-(5-chloropyridin-3-yl)-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (53 mg, 33%) as a white solid. LC / MS ESI(m / z): 469(M+H). + . 1 H NMR (400 MHz, CDCl3) δ 8.81 (d, J = 2.1 Hz, 1H), 8.52 (d, J = 2.0 Hz, 1H), 8.44 (s, 1H), 8.26 (t, J = 2.1 Hz, 1H), 6.94 (s, 1H), 4.76 (s, 1H), 4.19 - 3.79 (m, 3H), 3.56 (t, J = 12.0 Hz, 1H), 3.37 - 3.03 (m, 2H), 2.06 - 1.99 (m, 1H), 1.50 (s, 9H), 1.25 (d, J = 6.5 Hz, 3H), 1.04 (dd, J = 8.1, 1.7 Hz, 2H), 0.85 - 0.77 (m, 1H), 0.76 - 0.67 (m, 1H).

[0346] The following compounds were prepared from the corresponding amines and aryl halides by a procedure similar to the synthesis of compound 164. [Table 15] TIFF2024536237000201.tif255152TIFF2024536237000202.tif249156TIFF2024536237000203.tif98156

[0347] Example 21. Synthesis of tert-butyl (S)-4-(7-(3-chlorophenyl)-5-(3-fluoropyrazin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Compound 267) [ka]

[0348] Step 1. tert-Butyl (S)-4-(5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate A solution of tert-butyl (S)-4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (1.0 g, 1.6 mmol, prepared according to the procedure in Step 1 of the synthesis of Compound 259) in THF (5 mL) was treated with TBAF (6.7 mL, 1.0 M solution in THF) at 0° C. The resulting mixture was stirred at 0° C. for 3 hours. The reaction was quenched with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-70%, ethyl acetate / petroleum ether) to give tert-butyl (S)-4-(5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (0.55 g, 74%) as a yellow solid. LC / MS ESI (m / z): 444 (M+H). + .

[0349] Step 2. tert-Butyl (S)-4-(7-(3-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl (S)-4-(5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (550 mg, 1.2 mmol) in DCM (15 mL) was added (3-chlorophenyl)boronic acid (390 mg, 2.4 mmol), Cu(OAc) (670 mg, 3.7 mmol), pyridine (0.60 mL, 7.4 mmol), and 4 Å molecular sieves (400 mg). The resulting mixture was stirred overnight at 40 °C under an O atmosphere. After cooling in an ice-water bath, the reaction was quenched with aqueous NH OH (2 mL) and filtered. The filtrate was extracted twice with DCM. The combined organic layers were dried over Na SO , filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-30%, ethyl acetate / petroleum ether) to give tert-butyl (S)-4-(7-(3-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (240 mg, 35%) as a yellow solid. LC / MS ESI (m / z): 554 (M+H). + .

[0350] Step 3. tert-Butyl (S)-4-(7-(3-chlorophenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl (S)-4-(7-(3-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (240 mg, 0.43 mmol) in dioxane (10 mL) was added 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.25 mL, 1.7 mmol), TEA (0.30 mL, 2.1 mmol), X-Phos (21 mg, 0.043 mmol), and Pd(dba) (40 mg, 0.043 mmol). The resulting mixture was stirred at 95 °C overnight. The reaction was quenched with water and extracted twice with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give crude tert-butyl (S)-4-(7-(3-chlorophenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate as a yellow oil, which was used directly in the next step. LC / MS ESI(m / z): 554(M+H). + .

[0351] Step 4. tert-Butyl (S)-4-(7-(3-chlorophenyl)-5-(3-fluoropyrazin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl (S)-4-(7-(3-chlorophenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (120 mg, 0.21 mmol) in dioxane (5 mL) and HO (1 mL) was added 2-bromo-3-fluoropyrazine (77 mg, 0.43 mmol), KCO (150 mg, 1.0 mmol), and Pd(dppf)Cl (16 mg, 0.022 mmol). The resulting mixture was heated at 90 °C overnight. After cooling to room temperature, the solvent was removed and the residue was purified by flash column chromatography (silica gel, 0-50%, ethyl acetate / petroleum ether) to give the crude product, which was further purified by preparative HPLC to give tert-butyl (S)-4-(7-(3-chlorophenyl)-5-(3-fluoropyrazin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (59 mg, 51%) as a white solid. LC / MS ESI(m / z): 524(M+H). + . 1 H NMR (400 MHz, CDCl3) δ 8.59 (dd, J = 3.9, 2.6 Hz, 1H), 8.52 (s, 1H), 8.21 - 8.14 (m, 1H), 7.77 (t, J = 1.9 Hz, 1H), 7.74 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.49 (t, J = 8.0 Hz, 1H), 7.43 - 7.38 (m, 1H), 4.62 - 4.24 (m, 1H), 3.88 - 3.72 (m, 1H), 3.67 (d, J = 13.2 Hz, 1H), 3.60 - 3.39 (m, 1H), 3.18 - 2.64 (m, 3H), 1.44 (s, 9H), 1.13 (d, J = 13.8 Hz, 3H).

[0352] The following compounds were prepared using the corresponding aryl halides by the same procedure as in the synthesis of compound 267. [Table 16]

[0353] Example 22. Synthesis of tert-butyl 4-(3-(2-fluorophenyl)-1-(pyrimidin-5-yl)-1H-pyrrolo[3,2-c]pyridin-4-yl)piperazine-1-carboxylate (Compound 171) [ka]

[0354] Step 1. 4-Chloro-3-iodo-1-tosyl-1H-pyrrolo[3,2-c]pyridine To a suspension of NaH (400 mg, 10 mmol, 60 wt% in mineral oil) in anhydrous DMF (30 mL) at 0 °C, 4-chloro-3-iodo-1H-pyrrolo[3,2-c]pyridine (1.4 g, 5.0 mmol, Compound 418, prepared according to the procedure for Step 1) was added in small portions, followed by 4-methylbenzenesulfonyl chloride (1.1 g, 6.0 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into ice water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0–30%, ethyl acetate / petroleum ether) to give 4-chloro-3-iodo-1-tosyl-1H-pyrrolo[3,2-c]pyridine (1.7 g, 80%) as a pale yellow solid. LC / MS ESI(m / z):433(M+H) + .

[0355] Step 2. 4-Chloro-3-(2-fluorophenyl)-1-tosyl-1H-pyrrolo[3,2-c]pyridine To a solution of 4-chloro-3-iodo-1-tosyl-1H-pyrrolo[3,2-c]pyridine (920 mg, 2.1 mmol) in dioxane (10 mL) and HO (2 mL) was added (2-fluorophenyl)boronic acid (300 mg, 2.1 mmol), KCO (880 mg, 6.3 mmol), and Pd(dppf)Cl (160 mg, 0.21 mmol). The resulting mixture was heated at 90 °C overnight. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0–30%, ethyl acetate / petroleum ether) to give 4-chloro-3-(2-fluorophenyl)-1-tosyl-1H-pyrrolo[3,2-c]pyridine (680 mg, 79%) as a white solid. LC / MS ESI (m / z): 401 (M+H). + .

[0356] Step 3. 4-Chloro-3-(2-fluorophenyl)-1H-pyrrolo[3,2-c]pyridine To a solution of 4-chloro-3-(2-fluorophenyl)-1-tosyl-1H-pyrrolo[3,2-c]pyridine (680 mg, 1.7 mmol) in THF (5 mL) was added TBAF (10 mL, 1.0 M solution in THF). The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-50%, ethyl acetate / petroleum ether) to give 4-chloro-3-(2-fluorophenyl)-1H-pyrrolo[3,2-c]pyridine (410 mg, 97%) as a white solid. LC / MS ESI (m / z): 247 (M+H). + .

[0357] Step 4. 4-Chloro-3-(2-fluorophenyl)-1-(pyrimidin-5-yl)-1H-pyrrolo[3,2-c]pyridine To a solution of 4-chloro-3-(2-fluorophenyl)-1H-pyrrolo[3,2-c]pyridine (410 mg, 1.6 mmol) in DMF (15 mL) was added 5-iodopyrimidine (690 mg, 3.3 mmol), trans-cyclohexane-1,2-diamine (57 mg, 0.49 mmol), CuI (320 mg, 1.6 mmol), and KPO (1.1 mg, 4.9 mmol). The resulting mixture was heated at 120 °C overnight. After cooling to room temperature, the reaction was quenched with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-50%, ethyl acetate / petroleum ether) to give 4-chloro-3-(2-fluorophenyl)-1-(pyrimidin-5-yl)-1H-pyrrolo[3,2-c]pyridine (70 mg, 13%) as a yellow oil. LC / MS ESI (m / z): 325 (M+H). + .

[0358] Step 5. tert-Butyl 4-(3-(2-fluorophenyl)-1-(pyrimidin-5-yl)-1H-pyrrolo[3,2-c]pyridin-4-yl)piperazine-1-carboxylate 4-Chloro-3-(2-fluorophenyl)-1-(pyrimidin-5-yl)-1H-pyrrolo[3,2-c]pyridine (70 mg, 0.21 mmol) and tert-butyl piperazine-1-carboxylate (200 mg, 1.0 mmol) were heated at 150 °C for 3 h. After cooling to room temperature, the reaction mixture was purified by flash column chromatography (silica gel, 0-60%, ethyl acetate / petroleum ether) to give the crude product, which was further purified by preparative HPLC to give tert-butyl 4-(3-(2-fluorophenyl)-1-(pyrimidin-5-yl)-1H-pyrrolo[3,2-c]pyridin-4-yl)piperazine-1-carboxylate (2.5 mg, 2.0%) as a white solid. LC / MS ESI (m / z): 475 (M+H). + . 1H NMR (400 MHz, CDCl3) δ 9.29 (s, 1H), 9.00 (s, 2H), 8.12 (d, J = 5.9 Hz, 1H), 7.54 (td, J = 7.7, 1.8 Hz, 1H), 7.41 - 7.36 (m, 1H), 7.35 (d, J = 0.7 Hz, 1H), 7.25 - 7.17 (m, 2H), 7.08 (d, J = 5.9 Hz, 1H), 3.05 (s, 8H), 1.43 (s, 9H).

[0359] Example 23. Synthesis of 1-fluoro-2-methylpropan-2-yl 4-(5-(2-fluorophenyl)-7-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (Compound 172) [ka]

[0360] Step 1. 1-Fluoro-2-methylpropan-2-ol To a solution of ethyl 2-fluoroacetate (10 g, 94 mmol) in dry THF (30 mL) at −60 °C under N was added dropwise CHMgBr (210 mL, 1.0 M solution in THF, 210 mmol). The mixture was maintained at the same temperature for 1 h and then at 0 °C for 4 h. It was quenched by sequentially adding 50 mL of ice water and concentrated HCl (18 mL) and solid NaCl (10 g). The mixture was extracted with DCM. The organic layer was dried over NaSO overnight and concentrated by rotary evaporation, maintaining the bath temperature below 25 °C. The residue was purified by distillation under atmospheric pressure to give 1-fluoro-2-methylpropan-2-ol (3.5 g, 40%) as a colorless liquid (boiling point approximately 92 °C). 1 H NMR (400 MHz, CDCl3) δ 4.20 (d, J = 47.7 Hz, 2H), 1.25 (t, J = 2.6 Hz, 6H), hydroxyl group proton exchange.

[0361] Step 2. 1-Fluoro-2-methylpropan-2-yl 1H-imidazole-1-carboxylate To CDI (530 mg, 3.3 mmol) in dry DCM (8 mL) under N was added 1-fluoro-2-methylpropan-2-ol (300 mg, 3.3 mmol) dropwise. The mixture was stirred at room temperature overnight. It was then diluted with DCM, washed with water and brine, dried over NaSO, and concentrated to give 1-fluoro-2-methylpropan-2-yl 1H-imidazole-1-carboxylate (290 mg, 47%) as a colorless oil. LC / MS ESI (m / z): 187 (M+H). + .

[0362] Step 3. tert-Butyl 4-(5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate A mixture of 4-chloro-5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidine (580 mg, 2.3 mmol), tert-butyl piperazine-1-carboxylate (520 mg, 2.8 mmol, compound 1003, prepared according to the procedure in the first two steps), and DIPEA (1.6 mL, 9.7 mmol) in EtOH (10 mL) was stirred at 100 °C overnight. The solvent was removed by rotary evaporation. The residue was purified by flash column chromatography (silica gel, 0–50% EtOAc / petroleum ether, then 100% DCM) to give tert-butyl 4-(5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (560 mg, 60%) as a pale yellow solid. LC / MS ESI (m / z): 398 (M+H). + .

[0363] Step 4. tert-Butyl 4-(5-(2-fluorophenyl)-7-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate To tert-butyl 4-(5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (200 mg, 0.50 mmol) and 3-iodopyridine (410 mg, 2.0 mmol) in DMF (8 mL) was added (±)-trans-1,2-cyclohexanediamine (57 mg, 0.50 mmol), KPO (320 mg, 1.5 mmol), and CuI (96 mg, 0.50 mmol), and the mixture was stirred at 100 °C under N overnight. It was then diluted with EtOAc and filtered. The filtrate was washed with LiCl (5% aq.) and brine, dried over NaSO, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-50% EtOAc / petroleum ether, then 100% DCM) to give tert-butyl 4-(5-(2-fluorophenyl)-7-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (170 mg, approx. 70% purity, 48%) as a pale yellow solid. LC / MS ESI (m / z): 475 (M+H). + .

[0364] Step 5. 5-(2-Fluorophenyl)-4-(piperazin-1-yl)-7-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine To tert-butyl 4-(5-(2-fluorophenyl)-7-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (170 mg, 0.24 mmol) in DCM (2 mL) was added HCl / dioxane (3.0 mL, 4.0 M). The mixture was stirred at room temperature overnight. The solvent was evaporated, and the residue was diluted with DCM, washed with NaHCO3 (aq), brine, dried over Na2SO4, and concentrated to give 5-(2-fluorophenyl)-4-(piperazin-1-yl)-7-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (130 mg, 99%) as a solid. LC / MS ESI (m / z): 375 (M+H). + .

[0365] Step 6. 1-Fluoro-2-methylpropan-2-yl 4-(5-(2-fluorophenyl)-7-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate A mixture of 5-(2-fluorophenyl)-4-(piperazin-1-yl)-7-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (120 mg, 0.32 mmol), 1-fluoro-2-methylpropan-2-yl 1H-imidazole-1-carboxylate (180 mg, 0.97 mmol), and DIPEA (0.26 mL, 1.6 mmol) in DMF (5 mL) was stirred under N for 40 h at 80° C. The mixture was diluted with EtOAc, washed with LiCl (5% aq.), brine, and then concentrated. The residue was purified by flash column chromatography (silica gel, 0-50% EtOAc / petroleum ether) to give 80 mg of crude product, which was further purified by preparative HPLC to give 1-fluoro-2-methylpropan-2-yl 4-(5-(2-fluorophenyl)-7-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (38 mg, 24%) as a white solid. LC / MS ESI(m / z): 493(M+H). + . 1 H NMR (400 MHz, CDCl3) δ 8.97 (d, J = 1.9 Hz, 1H), 8.64 (d, J = 4.0 Hz, 1H), 8.52 (s, 1H), 8.22 (ddd, J = 8.2, 2.6, 1.5 Hz, 1H), 7.54 - 7.45 (m, 3H), 7.37 (tdd, J = 7.1, 5.1, 1.8 Hz, 1H), 7.28 - 7.19 (m, 2H), 4.45 (d, J = 47.5 Hz, 2H), 3.27 (d, J = 29.6 Hz, 8H), 1.45 (d, J = 2.2Hz, 6H).

[0366] The following compound was prepared by a synthetic procedure similar to that described for compound 172, except that 5-iodopyrimidine was used in step 4. [Table 17]

[0367] Example 24. Synthesis of 1,1,1-trifluoro-2-methylpropan-2-yl(2R,5S)-4-(5-(2-fluorophenyl)-7-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (Compound 186) [ka]

[0368] Step 1. 1,1,1-trifluoro-2-methylpropan-2-yl 1H-imidazole-1-carboxylate To a solution of 1,1,1-trifluoro-2-methylpropan-2-ol (500 mg, 3.9 mmol) in DCM (10 mL) was added di(1H-imidazol-1-yl)methanone (630 mg, 3.9 mmol), and the resulting mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted twice with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give 1,1,1-trifluoro-2-methylpropan-2-yl 1H-imidazole-1-carboxylate (640 mg, 73%) as a white solid. LC / MS ESI (m / z): 223 (M+H). + .

[0369] Step 2. 4-((2S,5R)-2,5-dimethylpiperazin-1-yl)-5-(2-fluorophenyl)-7-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine To a solution of tert-butyl (2R,5S)-4-(5-(2-fluorophenyl)-7-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (110 mg, 0.21 mmol, prepared according to a similar procedure to compound 134) in DCM (2 mL) was added HCl / dioxane (0.50 mL, 4.0 M). The resulting mixture was stirred at room temperature for 3 h. After removal of the solvent, the residue was dissolved in DCM and washed with NaHCO3 (aq), the organic layer was separated, the aqueous layer was extracted twice with DCM, and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was used directly in the next step. 4-((2S,5R)-2,5-dimethylpiperazin-1-yl)-5-(2-fluorophenyl)-7-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine. LC / MS ESI(m / z): 406(M+H) + .

[0370] Step 3. 1,1,1-trifluoro-2-methylpropan-2-yl(2R,5S)-4-(5-(2-fluorophenyl)-7-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate To a solution of 4-((2S,5R)-2,5-dimethylpiperazin-1-yl)-5-(2-fluorophenyl)-7-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine (30 mg, 0.074 mmol) in DMF (3 mL) was added 1,1,1-trifluoro-2-methylpropan-2-yl 1H-imidazole-1-carboxylate (20 mg, 0.089 mmol) and DIPEA (0.040 mL, 0.22 mmol). The resulting mixture was stirred at 80 °C under N for 2 days. The reaction was quenched with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-50%, ethyl acetate / petroleum ether) to give the crude product, which was further purified by preparative HPLC to give 1,1,1-trifluoro-2-methylpropan-2-yl(2R,5S)-4-(5-(2-fluorophenyl)-7-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (14 mg, 33%) as a white solid. LC / MS ESI(m / z): 560(M+H). + . 1 H NMR (400 MHz, CDCl3) δ 8.51 (s, 1H), 8.12 (s, 1H), 7.79 (d, J = 0.5 Hz, 1H), 7.47 (td, J = 7.5, 1.6 Hz, 1H), 7.39 - 7.31 (m, 2H), 7.26 - 7.16 (m, 2H), 4.27 - 4.03 (m, 2H), 4.00 (s, 3H), 3.39 (d, J = 13.1 Hz, 1H), 3.32 - 3.16 (m, 2H), 3.03 - 2.82 (m, 1H), 1.71 - 1.59 (m, 6H), 1.14 - 1.06 (m, 3H), 1.01 - 0.91 (m, 3H).

[0371] The following compounds were prepared from the corresponding boronic acids and alcohols by a procedure similar to the synthesis of compound 186. [Table 18]

[0372] Example 25. Synthesis of tert-butyl (S)-4-(7-(3-methoxyphenyl)-5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Compound 278) [ka]

[0373] Step 1. tert-Butyl (S)-4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of 4-chloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (5.0 g, 12 mmol) in DIPEA (15 mL) was added tert-butyl (S)-3-methylpiperazine-1-carboxylate (5.8 g, 29 mmol). The resulting mixture was heated to 140 °C for 1.5 h. After cooling to room temperature, the solvent was removed and the residue was purified by flash column chromatography (silica gel, 0–30%, ethyl acetate / petroleum ether) to give tert-butyl (S)-4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (5.8 g, 84%) as a yellow solid. LC / MS ESI (m / z): 598 (M+H). + .

[0374] Step 2. tert-Butyl (S)-3-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate To a solution of tert-butyl (S)-4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (1.0 g, 1.6 mmol) in dioxane (15 mL) was added 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.97 mL, 6.6 mmol), TEA (1.2 mL, 8.3 mmol), X-Phos (0.080 g, 0.16 mmol), and Pd(dba) (0.15 g, 0.16 mmol). The resulting mixture was stirred at 95 °C overnight. After cooling to room temperature, the reaction was quenched with water, extracted twice with DCM, and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give crude tert-butyl (S)-3-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate as a yellow oil, which was used directly in the next step. LC / MS ESI(m / z): 598(M+H). + .

[0375] Step 3. tert-Butyl (S)-3-methyl-4-(5-(pyridin-2-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate To a solution of tert-butyl (S)-3-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (1.0 g, 1.6 mmol) in dioxane (15 mL) and HO (3 mL) was added 2-bromopyridine (0.32 mL, 3.3 mmol), KCO (1.2 g, 8.3 mmol), and Pd(dppf)Cl (0.12 g, 0.16 mmol). The resulting mixture was heated to 90 °C overnight. After cooling to room temperature, the solvent was removed and the residue was purified by flash column chromatography (silica gel, 0-50%, ethyl acetate / petroleum ether) to give tert-butyl (S)-3-methyl-4-(5-(pyridin-2-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (0.69 g, 75%) as a yellow solid. LC / MS ESI (m / z): 549 (M+H). + .

[0376] Step 4. tert-Butyl (S)-3-methyl-4-(5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate To a solution of tert-butyl (S)-3-methyl-4-(5-(pyridin-2-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (690 mg, 1.3 mmol) in THF (5 mL) was added TBAF (5.0 mL, 1.0 M solution in THF). The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted twice with EtOAc, and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-10%, methanol / dichloromethane) to give tert-butyl (S)-3-methyl-4-(5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (450 mg, 90%) as a white solid. LC / MS ESI (m / z): 395 (M+H). +.

[0377] Step 5. tert-Butyl (S)-4-(7-(3-methoxyphenyl)-5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl (S)-3-methyl-4-(5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (120 mg, 0.30 mmol) in DMF (10 mL) was added 1-iodo-3-methoxybenzene (0.054 mL, 0.45 mmol), trans-cyclohexane-1,2-diamine (10 mg, 0.091 mmol), CuI (58 mg, 0.30 mmol), and KPO (190 mg, 0.91 mmol). The resulting mixture was heated to 120 °C overnight. After cooling to room temperature, the reaction was quenched with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-50%, ethyl acetate / petroleum ether) to give the crude product, which was further purified by preparative HPLC to give tert-butyl (S)-4-(7-(3-methoxyphenyl)-5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (13 mg, 8.0%) as a white solid. LC / MS ESI (m / z): 501 (M+H). + . 1H NMR (400 MHz, DMSO-d6) δ 8.67 (d, J = 4.2 Hz, 1H), 8.42 (s, 1H), 8.04 (s, 1H), 7.94 (td, J = 7.7, 1.5 Hz, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.51 - 7.42 (m, 3H), 7.35 (dd, J = 7.0, 5.1 Hz, 1H), 7.05 - 6.92 (m, 1H), 4.18 (d, J = 5.9 Hz, 1H), 3.83 (s, 3H), 3.77 - 3.64 (m, 2H), 3.07 - 2.60 (m, 4H), 1.36 (s, 9H), 0.91 (d, J = 6.5 Hz, 3H).

[0378] The following compounds were prepared from the corresponding aryl halides by a procedure similar to the synthesis of compound 278. [Table 19]

[0379] Example 26. Synthesis of tert-butyl (S)-4-(7-(3-chlorophenyl)-5-(1H-pyrazol-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Compound 322) [ka]

[0380] Step 1. tert-Butyl (S)-4-(7-(3-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of 4-chloro-7-(3-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (5.0 g, 13 mmol) in DIPEA (15 mL) was added tert-butyl (S)-3-methylpiperazine-1-carboxylate (6.4 g, 32 mmol). The resulting mixture was heated to 140 °C for 2 h. After cooling to room temperature, the solvent was removed and the residue was purified by flash column chromatography (silica gel, 0–30%, ethyl acetate / petroleum ether) to give tert-butyl (S)-4-(7-(3-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (5.9 g, 83%) as a yellow solid. LC / MS ESI (m / z): 554 (M+H). + .

[0381] Step 2. tert-Butyl (S)-4-(7-(3-chlorophenyl)-5-(1H-pyrazol-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl (S)-4-(7-(3-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (200 mg, 0.36 mmol) in DMF (6 mL) was added 1H-pyrazole (49 mg, 0.72 mmol), CsCO (470 mg, 1.4 mmol), Fe(acac) (38 mg, 0.10 mmol), and Cu(acac) (9.4 mg, 0.036 mmol). The resulting mixture was heated to 120 °C overnight. After cooling to room temperature, the reaction was quenched with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-40%, ethyl acetate / petroleum ether) to give the crude product, which was further purified by preparative HPLC to give tert-butyl (S)-4-(7-(3-chlorophenyl)-5-(1H-pyrazol-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (9.6 mg, 5.0%) as a white solid. LC / MS ESI(m / z): 494(M+H). + . 1 H NMR (400 MHz, CDCl3) δ 8.50 (s, 1H), 7.77 (d, J = 1.7 Hz, 1H), 7.74 (t, J = 1.8 Hz, 1H), 7.72 (d, J = 2.0 Hz, 1H), 7.63 - 7.60 (m, 1H), 7.51 (s, 1H), 7.47 (t, J = 8.0 Hz, 1H), 7.41 - 7.37 (m, 1H), 6.52 (t, J = 2.1 Hz, 1H), 4.24 - 3.79 (m, 2H), 3.67 (d, J = 12.8 Hz, 1H), 3.32 (m, 1H), 3.14 - 2.70 (m, 3H), 1.45 (s, 9H), 1.09 (s, 3H).

[0382] The following compounds were prepared from the corresponding amines by a procedure similar to the synthesis of compound 322. [Table 20] TIFF2024536237000215.tif72157

[0383] Example 27. Synthesis of tert-butyl (R)-4-(7-(4-cyanopyridin-2-yl)-5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate (Compound 367) [ka]

[0384] Step 1. tert-Butyl (R)-2-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate To a solution of tert-butyl (R)-4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate (1.0 g, 1.6 mmol) in dioxane (15 mL) was added 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.97 mL, 6.6 mmol), X-Phos (0.080 g, 0.16 mmol), TEA (1.2 mL, 8.3 mmol), and Pd(dba) (0.15 g, 0.16 mmol). The resulting mixture was stirred at 95 °C overnight. After cooling to room temperature, the reaction was quenched with water and extracted twice with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give crude tert-butyl (R)-2-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate as a yellow oil, which was used directly in the next step. LC / MS ESI(m / z): 598(M+H). + .

[0385] Step 2. tert-Butyl (R)-2-methyl-4-(5-(pyridin-2-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate To a solution of tert-butyl (R)-2-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (1.0 g, 1.6 mmol) in dioxane (15 mL) and HO (3 mL) was added 2-bromopyridine (0.32 mL, 3.3 mmol), KCO (1.2 g, 8.3 mmol), and Pd(dppf)Cl (0.12 g, 0.16 mmol). The resulting mixture was heated to 90 °C overnight. After cooling to room temperature, the solvent was removed and the residue was purified by flash column chromatography (silica gel, 0-50%, ethyl acetate / petroleum ether) to give tert-butyl (R)-2-methyl-4-(5-(pyridin-2-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (0.72 g, 78%) as a yellow solid. LC / MS ESI (m / z): 549 (M+H). + .

[0386] Step 3. tert-Butyl (R)-2-methyl-4-(5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate To a solution of tert-butyl (R)-2-methyl-4-(5-(pyridin-2-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (720 mg, 1.3 mmol) in THF (5 mL) was added TBAF (5.2 mL, 1.0 M solution in THF). The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-10%, methanol / dichloromethane) to give tert-butyl (R)-2-methyl-4-(5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (510 mg, 98%) as a yellow solid. LC / MS ESI (m / z): 395 (M+H). + .

[0387] Step 4. tert-Butyl (R)-4-(7-(4-cyanopyridin-2-yl)-5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate To a solution of tert-butyl (R)-2-methyl-4-(5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (510 mg, 1.2 mmol) in DMF (10 mL) was added 2-bromoisonicotinonitrile (470 mg, 2.5 mmol), CuI (250 mg, 1.2 mmol), trans-cyclohexane-1,2-diamine (150 mg, 1.2 mmol), and KPO (820 mg, 3.8 mmol). The resulting mixture was heated to 120 °C overnight. After cooling to room temperature, the reaction was quenched with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-50%, ethyl acetate / petroleum ether) to give tert-butyl (R)-4-(7-(4-cyanopyridin-2-yl)-5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate (600 mg, 93%) as a yellow solid. 100 mg of the product was purified by preparative HPLC to give 14.8 mg of tert-butyl (R)-4-(7-(4-cyanopyridin-2-yl)-5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate as a white solid. LC / MS ESI(m / z): 497(M+H). + . 1H NMR (400 MHz, CDCl3) δ 9.40 (s, 1H), 8.73 (d, J = 4.3 Hz, 1H), 8.63 (dd, J = 5.0, 0.5 Hz, 1H), 8.59 - 8.53 (m, 2H), 7.85 - 7.79 (m, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.41 (dd, J = 5.0, 1.3 Hz, 1H), 7.34 - 7.29 (m, 1H), 4.24 - 4.19 (m, 1H), 3.84 (d, J = 12.9 Hz, 2H), 3.58 - 3.53 (m, 1H), 3.08 (dd, J = 13.2, 3.9 Hz, 1H), 2.89 - 2.83 (m, 2H), 1.43 (s, 9H), 1.09 (d, J = 6.8 Hz, 3H).

[0388] Example 28. Synthesis of tert-butyl (S)-4-(7-(3-cyanophenyl)-5-(pyrrolidin-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Compound 400) [ka]

[0389] Step 1. 4-Chloro-5-(pyrrolidin-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine To a solution of formaldehyde (0.58 g, 7.1 mmol) in HO (2 mL), CHCOOH (10 mL, 86 mmol), and dioxane (10 mL) at 0 °C, pyrrolidine (0.58 mL, 7.1 mmol) was added, followed by the dropwise addition of a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1.0 g, 6.5 mmol) in dioxane. After stirring overnight at 50 °C under N, the reaction mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated at room temperature and purified by flash column chromatography (silica gel, 0–50%, methanol / dichloromethane) to give 4-chloro-5-(pyrrolidin-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine (0.63 g, 40%) as a yellow oil. LC / MS ESI(m / z):237(M+H) + .

[0390] Step 2. 3-(4-chloro-5-(pyrrolidin-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)benzonitrile To a solution of 4-chloro-5-(pyrrolidin-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine (0.53 g, 2.2 mmol) in DCM (25 mL) was added (3-cyanophenyl)boronic acid (0.66 g, 4.4 mmol), Cu(OAc) (1.2 g, 6.7 mmol), pyridine (1.1 mL, 13 mmol), and 4 Å molecular sieves (800 mg). The resulting mixture was stirred overnight at room temperature under an O atmosphere. At 0 °C, the reaction was quenched with NH OH (2 mL) and filtered. The filtrate was extracted twice with DCM, and the combined organic layers were dried over Na SO , filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-20%, methanol / dichloromethane) to give 3-(4-chloro-5-(pyrrolidin-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)benzonitrile (0.26 g, 34%) as a yellow solid. LC / MS ESI (m / z): 338 (M+H). + .

[0391] Step 3. tert-Butyl (S)-4-(7-(3-cyanophenyl)-5-(pyrrolidin-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of 3-(4-chloro-5-(pyrrolidin-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)benzonitrile (100 mg, 0.29 mmol) in DIPEA (1 mL) was added tert-butyl (S)-3-methylpiperazine-1-carboxylate (240 mg, 1.1 mmol). The resulting mixture was heated to 140° C. for 3 h. After cooling to room temperature, the solvent was removed and the residue was purified by flash column chromatography (silica gel, 0-20%, methanol / dichloromethane). The product was further purified by preparative HPLC to give tert-butyl (S)-4-(7-(3-cyanophenyl)-5-(pyrrolidin-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (75 mg, 50%) as a white solid. LC / MS ESI(m / z): 502(M+H) + . 1 H NMR (400 MHz, MeOD) δ 8.38 (s, 1H), 8.24 (s, 1H), 8.13 - 8.03 (m, 1H), 7.77 - 7.69 (m, 2H), 7.65 (s, 1H), 4.52 (s, 1H), 4.06 - 3.91 (m, 2H), 3.90 - 3.65 (m, 3H), 3.58 - 3.40 (m, 2H), 3.27 - 3.10 (m, 1H), 2.71 - 2.58 (m, 4H), 1.86 - 1.74 (m, 4H), 1.50 (s, 9H), 1.17 (d, J = 6.4 Hz, 3H).

[0392] Example 29. Synthesis of tert-butyl (S)-4-(7-(3-cyanophenyl)-5-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Compound 402) [ka]

[0393] Step 1. 5-Bromo-4-methoxy-7H-pyrrolo[2,3-d]pyrimidine NBS (0.95 g, 5.3 mmol) was added portionwise to a solution of 4-methoxy-7H-pyrrolo[2,3-d]pyrimidine (1.0 g, 6.7 mmol) in DMF (15 mL) at 0 °C. After stirring at room temperature under N for 3 h, the reaction was quenched with water. The reaction mixture was filtered to give 5-bromo-4-methoxy-7H-pyrrolo[2,3-d]pyrimidine (0.45 g, 29%) as a yellow solid. LC / MS ESI (m / z): 228, 230 (M+H). + .

[0394] Step 2. 5-Bromo-4-methoxy-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine To a solution of 5-bromo-4-methoxy-7H-pyrrolo[2,3-d]pyrimidine (450 mg, 1.9 mmol) in DMF (10 mg) at 0 °C, NaH (95 mg, 2.3 mmol) was added portionwise. The resulting mixture was stirred at 0 °C for 20 min. Next, 4-methylbenzenesulfonyl chloride (430 mg, 2.2 mmol) was added to the above mixture, and the resulting mixture was stirred at 0 °C for 20 min, warmed to room temperature, and stirred overnight under N2. The reaction was quenched with ice water. The reaction mixture was then filtered to give 5-bromo-4-methoxy-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (690 mg, 91%) as a gray solid. LC / MS ESI (m / z): 382, ​​384 (M+H). + .

[0395] Step 3. 4-Methoxy-5-(prop-1-en-2-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine To a solution of 5-bromo-4-methoxy-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (690 mg, 1.8 mmol) in dioxane (10 mL) and HO (2 mL) was added 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (0.51 mL, 2.7 mmol), KCO (1000 mg, 7.2 mmol), and Pd(dppf)Cl (130 mg, 0.18 mmol). The resulting mixture was heated to 90 °C overnight. After cooling to room temperature, the solvent was removed and the residue was purified by flash column chromatography (silica gel, 0-30%, ethyl acetate / petroleum ether) to give 4-methoxy-5-(prop-1-en-2-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (460 mg, 74%) as a white solid. LC / MS ESI (m / z): 344 (M+H). + .

[0396] Step 4. 4-Methoxy-5-(1-methylcyclopropyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine To a solution of EtZn (13 mL) in DCM (10 mL) was added dropwise a solution of TFA (0.50 mL, 6.6 mmol) in DCM (2 mL) at 0 °C, and the mixture was stirred at 0 °C for 30 min. Next, the above mixture was added dropwise to a solution of CHCl (0.56 mL, 6.6 mmol) in DCM (2 mL). After stirring for 20 min, a solution of 4-methoxy-5-(prop-1-en-2-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (460 mg, 1.3 mmol) in DCM (5 mL) was added dropwise. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with NHCl (aq) and extracted twice with DCM. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-10%, ethyl acetate / petroleum ether) to give 4-methoxy-5-(1-methylcyclopropyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (350 mg, 73%) as a yellow oil. LC / MS ESI (m / z): 358 (M+H). + .

[0397] Step 5. 4-Methoxy-5-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine To a solution of 4-methoxy-5-(1-methylcyclopropyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (350 mg, 0.98 mmol) in THF (3 mL) was added TBAF (3.9 mL, 1.0 M solution in THF). The resulting mixture was stirred at 30 °C for 4 h. The reaction was quenched with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0–60%, ethyl acetate / petroleum ether) to give the crude product, which was further purified by preparative HPLC to give 4-methoxy-5-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine (40 mg, 20%) as a white solid. LC / MS ESI (m / z): 204 (M+H). + .

[0398] Step 6. 3-(4-Methoxy-5-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)benzonitrile To a solution of 4-methoxy-5-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine (40 mg, 0.19 mmol) in DMF (5 mL) was added 3-iodobenzonitrile (180 mg, 0.78 mmol), CuI (37 mg, 0.19 mmol), trans-cyclohexane-1,2-diamine (45 mg, 0.39 mmol), and KPO (130 mg, 0.59 mmol). The resulting mixture was heated to 100 °C overnight. After cooling to room temperature, the reaction was quenched with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-30%, ethyl acetate / petroleum ether) to give 3-(4-methoxy-5-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)benzonitrile (55 mg, 91%) as a yellow solid. LC / MS ESI (m / z): 305 (M+H). + .

[0399] Step 7. 3-(4-Hydroxy-5-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)benzonitrile To a solution of 3-(4-methoxy-5-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)benzonitrile (55 mg, 0.18 mmol) in DMF (2 mL) was added p-toluenesulfonic acid (310 mg, 1.8 mmol) and LiCl (77 mg, 1.8 mmol). The resulting mixture was heated to 110 °C for 2 h. After cooling to room temperature, the reaction was quenched with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated to give 3-(4-hydroxy-5-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)benzonitrile (50 mg, 95%) as a yellow solid. LC / MS ESI (m / z): 291 (M+H). + .

[0400] Step 8. 3-(4-chloro-5-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)benzonitrile A mixture of 3-(4-hydroxy-5-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)benzonitrile (50 mg, 0.17 mmol) and POCl (5 mL) was heated to 120 °C overnight. After cooling to room temperature, the reaction was concentrated. The residue was dissolved in DCM and washed with NaHCO (aq), and the aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated to give 3-(4-chloro-5-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)benzonitrile (50 mg, 94%) as a yellow solid. LC / MS ESI (m / z): 309 (M+H). + .

[0401] Step 9. tert-Butyl (S)-4-(7-(3-cyanophenyl)-5-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of 3-(4-chloro-5-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)benzonitrile (50 mg, 0.16 mmol) in DIPEA (1 mL) was added tert-butyl (S)-3-methylpiperazine-1-carboxylate (320 mg, 1.6 mmol). The resulting mixture was heated to 140 °C for 6 h. After cooling to room temperature, the solvent was removed and the residue was purified by flash column chromatography (silica gel, 0–20%, ethyl acetate / petroleum ether) to give the product. Further purification by preparative HPLC afforded tert-butyl (S)-4-(7-(3-cyanophenyl)-5-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (4.3 mg, 5.0%) as a white solid. LC / MS ESI(m / z):473(M+H) + . 1H NMR (400 MHz, CD3OD) δ 8.38 - 8.30 (m, 1H), 8.27 - 8.18 (m, 1H), 8.08 - 8.01 (m, 1H), 7.73 - 7.66 (m, 2H), 7.47 - 7.42 (m, 1H), 4.97 - 4.86 (m, 1H), 4.07 (d, J = 12.9 Hz, 1H), 4.02 - 3.89 (m, 1H), 3.86 (d, J = 12.6 Hz, 1H), 3.61 - 3.36 (m, 2H), 3.25 - 3.05 (m, 1H), 1.54 (s, 3H), 1.50 (d, J = 5.9 Hz, 9H), 1.34 - 1.28 (m, 2H), 1.16 (d, J = 6.5 Hz, 3H), 0.95 - 0.88 (m, 1H), 0.83 - 0.71 (m, 1H).

[0402] The following compounds were prepared from the corresponding aryl halides by a procedure similar to the synthesis of compound 402. [Table 21]

[0403] Example 30. Synthesis of ethyl 4-(5-cyclopropyl-7-(5-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (Compound 1004) [ka]

[0404] Step 1. Ethyl 4-(5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate A mixture of 4-chloro-5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (400 mg, 1.2 mmol) and ethyl piperazine-1-carboxylate (220 mg, 1.4 mmol) was heated to 100 °C overnight. After cooling to room temperature, the reaction mixture was purified by flash column chromatography (silica gel, 0-30%, ethyl acetate / petroleum ether) to give ethyl 4-(5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (360 mg, 67%) as a white solid. LC / MS ESI (m / z): 470 (M+H). + .

[0405] Step 2. Ethyl 4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate To a solution of ethyl 4-(5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (360 mg, 0.77 mmol) in THF (5 mL) was added TBAF (5.3 mL, 1.0 M solution in THF). The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-30%, ethyl acetate / petroleum ether) to give ethyl 4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (200 mg, 83%) as a yellow solid. LC / MS ESI (m / z): 316 (M+H). + .

[0406] Step 3. Ethyl 4-(5-cyclopropyl-7-(5-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate To a solution of ethyl 4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (100 mg, 0.32 mmol) in toluene (15 mL) was added 3-iodo-5-methoxypyridine (82 mg, 0.35 mmol), 1,10-phenanthroline (57 mg, 0.32 mmol), CuI (60 mg, 0.32 mmol), and CsCO (310 mg, 0.95 mmol). The resulting mixture was heated to 110 °C overnight. After cooling to room temperature, the reaction was quenched with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-20%, ethyl acetate / petroleum ether) to give the crude product, which was further purified by preparative HPLC to give ethyl 4-(5-cyclopropyl-7-(5-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (31 mg, 23%) as a white solid. LC / MS ESI(m / z): 423(M+H). + . 1 H NMR (400 MHz, DMSO-d6) δ 8.71 (d, J = 2.1 Hz, 1H), 8.38 (s, 1H), 8.28 (d, J = 2.6 Hz, 1H), 7.88 (t, J = 2.4 Hz, 1H), 7.59 (s, 1H), 4.09 (q, J = 7.1 Hz, 2H), 3.91 (s, 3H), 3.66 - 3.62 (m, 4H), 3.62 - 3.57 (m, 4H), 2.09 - 2.01 (m, 1H), 1.22 (t, J = 7.1 Hz, 3H), 1.03 - 0.97 (m, 2H), 0.88 - 0.83 (m, 2H).

[0407] The following compounds were prepared using the corresponding amines in the same manner as in the synthesis of compound 1004. [Table 22]

[0408] Example 31. Synthesis of ethyl (S)-4-(7-(4-chlorophenyl)-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Compound 112) [ka]

[0409] Step 1. (S)-7-(4-chlorophenyl)-5-cyclopropyl-4-(2-methylpiperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine To a solution of tert-butyl (S)-4-(7-(4-chlorophenyl)-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (500 mg, 1.1 mmol, prepared according to the procedure described for the synthesis of compound 114) in DCM (10 mL) was added HCl (3.0 mL, 4.0 M solution in dioxane). The resulting mixture was stirred at room temperature for 2 hours. After removal of the solvent, the residue was diluted with DCM and washed with NaHCO3 (aq). The aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was used directly in the next step. (S)-7-(4-chlorophenyl)-5-cyclopropyl-4-(2-methylpiperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine (350 mg, 89% yield). LC / MS ESI (m / z): 368 (M+H) + .

[0410] Step 2. Ethyl (S)-4-(7-(4-chlorophenyl)-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of (S)-7-(4-chlorophenyl)-5-cyclopropyl-4-(2-methylpiperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine (90 mg, 0.25 mmol) in DCM (5 mL) was added TEA (76 mg, 0.75 mmol) at 0 °C, followed by the dropwise addition of ethyl carbonochloridate (54 mg, 0.50 mmol). The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with water and extracted twice with DCM. The combined organic layers were washed with NaHCO (aq), dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-30%, ethyl acetate / petroleum ether) to give the crude product, which was further purified by preparative HPLC to give ethyl (S)-4-(7-(4-chlorophenyl)-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (34 mg, 31% yield) as a white solid. LC / MS ESI(m / z): 440(M+H). + . 1 H NMR (400MHz, CDCl3) δ8.43 (s, 1H), 7.62 - 7.58 (m, 2H), 7.48 - 7.44 (m, 2H), 6.90 (d, J = 0.7Hz, 1H), 4.81 - 4.70 (m, 1H), 4.24 - 4.17 (m, 2H), 4.16 - 4.01 (m, 1H), 4.00 - 3.81 (m, 2H), 3.65 - 3.51 (m, 1H), 3.44 - 3.30 (m, 1H), 3.28 - 3.13 (m, 1H), 2.04 (td, J = 8.0, 4.1Hz, 1H), 1.30 (t, J = 7.1Hz, 3H), 1.25 (d, J = 6.6Hz, 3H), 1.04 - 0.99 (m, 2H), 0.83 - 0.77 (m, 1H), 0.74 - 0.68 (m, 1H).

[0411] Example 32. Synthesis of tert-butyl (S)-4-(7-(4-chlorophenyl)-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Compound 114) [ka]

[0412] Step 1. 4-Chloro-7-(4-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine To a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (1.3 g, 4.7 mmol) in DCM (50 mL) was added (4-chlorophenyl)boronic acid (1.5 g, 9.3 mmol), Cu(OAc) (2.1 g, 12 mmol), and pyridine (2.2 mL, 28 mmol). The resulting mixture was stirred at room temperature overnight. NH H O (30 mL) was added, and the reaction was filtered. The filtrate was partitioned between DCM and water. The aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over Na SO , filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 0-30% EtOAc / petroleum ether) to give 4-chloro-7-(4-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (810 mg, 45%) as a solid. LC / MS ESI (m / z): 390 (M+H). + .

[0413] Step 2. tert-Butyl (S)-4-(7-(4-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of 4-chloro-7-(4-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (800 mg, 2.1 mmol) in DIPEA (5 mL) was added tert-butyl (S)-3-methylpiperazine-1-carboxylate (820 mg, 4.1 mmol). The resulting mixture was heated to 140 °C for 3 h. After cooling to room temperature, the solvent was removed and the residue was purified by flash column chromatography (silica gel, 0–30%, ethyl acetate / petroleum ether) to give tert-butyl (S)-4-(7-(4-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (900 mg, 79%) as a white solid. LC / MS ESI (m / z): 554 (M+H). + .

[0414] Step 3. tert-Butyl (S)-4-(7-(4-chlorophenyl)-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl (S)-4-(7-(4-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (900 mg, 1.6 mmol) in toluene (15 mL) was added cyclopropylboronic acid (280 mg, 0.16 mmol), KCO (2.9 g, 21 mmol), and Pd-118 (100 mg, 1.3 mmol). The resulting mixture was heated to 80 °C overnight. After cooling to room temperature, the reaction was filtered. The filtrate was concentrated and purified by flash column chromatography (silica gel, 0-30%, ethyl acetate / petroleum ether) to give tert-butyl (S)-4-(7-(4-chlorophenyl)-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (580 mg, 76% yield) as a solid. LC / MS ESI (m / z): 468 (M+H). + . 1H NMR (400MHz, CDCl3) δ8.43 (s, 1H), 7.62 - 7.58 (m, 2H), 7.48 - 7.44 (m, 2H), 6.89 (s, 1H), 4.78 - 4.69 (m, 1H), 4.15 - 3.80 (m, 3H), 3.60 - 3.50 (m, 1H), 3.40 - 3.27 (m, 1H), 3.22 - 3.05 (m, 1H), 2.07 - 2.00 (m, 1H), 1.50 (s, 9H), 1.24 (d, J = 6.6Hz, 3H), 1.04 - 0.99 (m, 2H), 0.82 - 0.76 (m, 1H), 0.73 - 0.67 (m, 1H).

[0415] The following compounds were prepared using the corresponding boronic acids and amines in a similar manner to the synthesis of compound 114. [Table 23]

[0416] Example 33. Synthesis of tert-butyl (S)-4-(7-(3-chlorophenyl)-5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Compound 119) [ka]

[0417] Step 1. tert-Butyl (S)-4-(7-(3-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate A mixture of 4-chloro-7-(3-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (3.0 g, 7.7 mmol, prepared according to step 1 of the procedure described for compound 274), tert-butyl (S)-3-methylpiperazine-1-carboxylate (3.1 g, 15 mmol) in DIEA (20 mL) was heated at 150 °C for 6 h. The reaction mixture was concentrated. The residue was purified by column chromatography on silica gel (0-30% ethyl acetate / petroleum ether) to give tert-butyl (S)-4-(7-(3-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (3.5 g, 6.2 mmol, 81%) as a yellow solid. LC / MS ESI (m / z): 554 (M+H). + .

[0418] Step 2. tert-Butyl (S)-4-(7-(3-chlorophenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate A mixture of tert-butyl (S)-4-(7-(3-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (3.5 g, 6.2 mmol), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.6 mL, 25 mmol), Pd(dba) (0.60 g, 0.62 mmol), X-Phos (0.60 g, 1.3 mmol), and TEA (4.3 mL, 31 mmol) in dioxane (60 mL) was heated at 95 °C for 12 h. The reaction mixture was filtered. The filtrate was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine, dried over NaSO, and concentrated. The residue was used directly in the next step. LC / MS ESI(m / z):554(M+H) + .

[0419] Step 3. tert-Butyl (S)-4-(7-(3-chlorophenyl)-5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate A mixture of tert-butyl (S)-4-(7-(3-chlorophenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (1.0 g, 1.8 mmol), 2-bromopyridine (0.35 mL, 3.6 mmol), Pd(dppf)Cl (130 mg, 0.18 mmol), and KCO (1.3 g, 9.0 mmol) in dioxane (20 mL) and HO (2 mL) was stirred at 90 °C for 12 h. The reaction mixture was concentrated. The residue was purified by column chromatography on silica gel (0–50% ethyl acetate / petroleum ether) to give the crude product. The crude product was purified by preparative HPLC to give tert-butyl (S)-4-(7-(3-chlorophenyl)-5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (300 mg, 33%) as a white solid. LC / MS ESI (m / z): 505 (M+H). + . 1 H NMR (400 MHz, CDCl3) δ 8.70 (d, J = 4.2 Hz, 1H), 8.53 (s, 1H), 7.82 - 7.76 (m, 2H), 7.69 (d, J = 7.7 Hz, 2H), 7.61 (d, J = 7.9 Hz, 1H), 7.47 (t, J = 8.1 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.29 - 7.24 (m, 1H), 4.40 - 4.16 (m, 1H), 4.03 - 3.76 (m, 1H), 3.58 (t, J = 15.4 Hz, 2H), 3.17 (t, J = 11.8 Hz, 1H), 3.06 - 2.71 (m, 2H), 1.44 (s, 9H), 1.04 (br. s, 3H).

[0420] The following compounds were prepared using the corresponding aryl halides in the same manner as in the synthesis of compound 119. [Table 24] TIFF2024536237000227.tif247157TIFF2024536237000228.tif193157

[0421] Example 34. Synthesis of 1,1,1-trifluoro-2-methylpropan-2-yl (S)-4-(7-(3-chlorophenyl)-5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Compound 121) [ka]

[0422] Step 1. (S)-7-(3-chlorophenyl)-4-(2-methylpiperazin-1-yl)-5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine To a solution of tert-butyl (S)-4-(7-(3-chlorophenyl)-5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (200 mg, 0.40 mmol, prepared according to the procedure described for Compound 119) in DCM (10 mL) was added TFA (5.0 mL, 67 mmol). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was basified to pH 8 with NaHCO3 (aq) and then extracted with DCM (2 x 100 mL). The combined organic layers were washed with brine, dried over NaSO, and concentrated to give (S)-7-(3-chlorophenyl)-4-(2-methylpiperazin-1-yl)-5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine (170 mg, 94%) as a yellow solid, which was used directly in the next step without further purification. LC / MS ESI (m / z): 405 (M+H). + .

[0423] Step 2. 1,1,1-trifluoro-2-methylpropan-2-yl (S)-4-(7-(3-chlorophenyl)-5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate A mixture of (S)-7-(3-chlorophenyl)-4-(2-methylpiperazin-1-yl)-5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine (170 mg, 0.41 mmol), 1,1,1-trifluoro-2-methylpropan-2-yl 1H-imidazole-1-carboxylate (110 mg, 0.50 mmol), and DIEA (0.20 mL, 1.2 mmol) in DMF (10 mL) was stirred at 80 °C for 24 h. After cooling to room temperature, the reaction mixture was concentrated. The residue was purified by column chromatography on silica gel (0-50% ethyl acetate / petroleum ether) to give the crude product. The crude product was purified by preparative HPLC to give 1,1,1-trifluoro-2-methylpropan-2-yl (S)-4-(7-(3-chlorophenyl)-5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (54 mg, 24%) as a white solid. LC / MS ESI(m / z): 559(M+H). + . 1 H NMR (400 MHz, CD3OD) δ 8.70 - 8.68 (m, 1H), 8.45 (s, 1H), 8.01 (td, J = 7.8, 1.7 Hz, 1H), 7.96 (t, J = 1.9 Hz, 1H), 7.90 (s, 1H), 7.78 - 7.73 (m, 2H), 7.58 (t, J = 8.1 Hz, 1H), 7.49 - 7.43 (m, 2H), 4.26 (d, J = 6.4 Hz, 1H), 3.82 (dd, J = 44.3, 12.4 Hz, 1H), 3.58 (dd, J = 32.0, 12.9 Hz, 2H), 3.17 (td, J = 13.1, 3.2 Hz, 1H), 3.07 - 2.81 (m, 2H), 1.67 (s, 6H), 1.02 (d, J = 6.6 Hz, 3H).

[0424] Example 35. Synthesis of tert-butyl (R)-4-(7-(3-chloro-5-fluorophenyl)-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate (Compound 123) [ka]

[0425] Step 1. tert-Butyl (R)-4-(5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate To a solution of 4-chloro-5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (300 mg, 0.87 mmol, prepared according to step 2 of the procedure described for compound 164) in EtOH (5 mL) was added tert-butyl (R)-2-methylpiperazine-1-carboxylate (350 mg, 1.7 mmol) and DIPEA (670 mg, 5.2 mmol). The resulting mixture was heated to 100 °C overnight. After cooling to room temperature, the solvent was removed and the residue was purified by flash column chromatography (silica gel, 0–30%, ethyl acetate / petroleum ether) to give tert-butyl (R)-4-(5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate (300 mg, 73%) as a white solid. LC / MS ESI(m / z):512(M+H) + .

[0426] Step 2. tert-Butyl (R)-4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate To a solution of tert-butyl (R)-4-(5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate (300 mg, 0.60 mmol) in THF (5 mL) was added TBAF (3.6 mL, 1.0 M solution in THF). The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0–60%, ethyl acetate / petroleum ether) to afford tert-butyl (R)-4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate (190 mg, 88%) as a white solid. LC / MS ESI(m / z):358(M+H) + .

[0427] Step 3. tert-Butyl (R)-4-(7-(3-chloro-5-fluorophenyl)-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate To a solution of tert-butyl (3S)-1-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperidine-4-carboxylate (80 mg, 0.23 mmol) in DMF (5 mL) was added 1-chloro-3-fluoro-5-iodobenzene (120 mg, 0.46 mmol), trans-cyclohexane-1,2-diamine (7.9 mg, 0.070 mmol), CuI (13 mg, 0.070 mmol), and KPO (150 mg, 0.69 mmol). The resulting mixture was heated to 100 °C overnight. After cooling to room temperature, the reaction was quenched with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-30%, ethyl acetate / petroleum ether) to give the crude product, which was further purified by preparative HPLC to give tert-butyl (R)-4-(7-(3-chloro-5-fluorophenyl)-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate (61 mg, 56%) as a solid. LC / MS ESI(m / z): 486(M+H). + . 1 H NMR (400 MHz, CD3OD) δ 8.34 (s, 1H), 7.77 (s, 1H), 7.69 - 7.62 (m, 1H), 7.33 (s, 1H), 7.23 - 7.18 (m, 1H), 4.51 (d, J = 12.7 Hz, 1H), 4.43 (s, 1H), 4.13 (d, J = 13.1 Hz, 1H), 3.96 (d, J = 13.3 Hz, 1H), 3.49 - 3.36 (m, 2H), 3.15 - 3.06 (m, 1H), 2.13 - 2.02 (m, 1H), 1.51 (s, 9H), 1.23 (d, J = 6.8 Hz, 3H), 1.10 - 1.04 (m, 2H), 1.02 - 0.96 (m, 1H), 0.76 - 0.69 (m, 1H).

[0428] The following compounds were prepared using the corresponding amines and aryl halides by the same procedure as in the synthesis of compound 123. [Table 25] TIFF2024536237000232.tif255153TIFF2024536237000233.tif246156TIFF2024536237000234.tif251158TIFF2024536237 000235.tif255153TIFF2024536237000236.tif255153TIFF2024536237000237.tif249156TIFF2024536237000238.tif31155

[0429] Example 36. Synthesis of ethyl (S)-4-(5-(2-fluorophenyl)-7-(5-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Compound 126) [ka]

[0430] Step 1. (S)-5-(2-fluorophenyl)-7-(5-methoxypyridin-3-yl)-4-(2-methylpiperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine To a solution of tert-butyl (S)-4-(5-(2-fluorophenyl)-7-(5-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (80 mg, 0.16 mmol, prepared according to a similar procedure described for compound 1004) in DCM (3 mL) was added HCl (4.0 mL, 4.0 M solution in dioxane). The resulting mixture was stirred at room temperature for 0.5 h. After removal of the solvent, the residue was diluted with DCM and washed with NaHCO3 (aq). The organic layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was used directly in the next step. (S)-5-(2-fluorophenyl)-7-(5-methoxypyridin-3-yl)-4-(2-methylpiperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine (40 mg, 63%). LC / MS ESI (m / z): 419 (M+H) + .

[0431] Step 2. Ethyl (S)-4-(5-(2-fluorophenyl)-7-(5-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of (S)-5-(2-fluorophenyl)-7-(5-methoxypyridin-3-yl)-4-(2-methylpiperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine (40 mg, 0.10 mmol) in DCM (3 mL) was added TEA (0.30 mL, 0.30 mmol) at 0 °C, followed by the dropwise addition of ethyl carbonochloridate (0.020 mL, 0.20 mmol). The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted twice with DCM. The combined organic layers were washed with NaHCO (aq), dried over Na SO , filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-30% ethyl acetate / petroleum ether) to give the crude product, which was further purified by preparative HPLC to give ethyl (S)-4-(5-(2-fluorophenyl)-7-(5-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (31 mg, 63%) as a white solid. LC / MS ESI(m / z): 491(M+H). + . 1 H NMR (400 MHz, DMSO-d6) δ 8.77 (d, J = 2.0 Hz, 1H), 8.45 (s, 1H), 8.33 (d, J = 2.6 Hz, 1H), 8.05 (s, 1H), 7.94 (t, J = 2.3 Hz, 1H), 7.56 (td, J = 7.5, 1.5 Hz, 1H), 7.50 - 7.45 (m, 1H), 7.40 - 7.35 (m, 2H), 4.19 - 4.14 (m, 1H), 4.04 - 3.98 (m, 2H), 3.92 (s, 3H), 3.66 - 3.60 (m, 1H), 3.50 - 3.41 (m, 3H), 3.03 - 2.96 (m, 1H), 2.74 - 2.68 (m, 1H), 1.14 (t, J = 7.0 Hz, 3H), 0.91 (d, J = 6.6 Hz, 3H).

[0432] Example 37. Synthesis of 1,1,1-trifluoro-2-methylpropan-2-yl (S)-4-(7-(3-chlorophenyl)-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Compound 140) [ka]

[0433] Step 1. 2,2,2-Trifluoroethyl 1H-imidazole-1-carboxylate To a solution of 1,1,1-trifluoro-2-methylpropan-2-ol (1.0 g, 0.78 mmol) in DCM (10 mL) was added CDI (1.4 g, 0.86 mmol). The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted twice with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give 1,1,1-trifluoro-2-methylpropan-2-yl 1H-imidazole-1-carboxylate (1.1 g, 64%) as a white solid. LC / MS ESI (m / z): 223 (M+H). + .

[0434] Step 2. 1,1,1-trifluoro-2-methylpropan-2-yl (S)-4-(7-(3-chlorophenyl)-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of (S)-7-(4-chlorophenyl)-5-cyclopropyl-4-(2-methylpiperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine (70 mg, 0.19 mmol, prepared according to the procedure described for Compound 461) in DMF (5 mL) was added 1,1,1-trifluoro-2-methylpropan-2-yl 1H-imidazole-1-carboxylate (84 mg, 0.38 mmol) and DIPEA (74 mg, 0.57 mmol). The resulting mixture was stirred overnight at 80 °C under a N atmosphere. The reaction was quenched with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-50% ethyl acetate / petroleum ether) to give the crude product, which was further purified by preparative HPLC to give 1,1,1-trifluoro-2-methylpropan-2-yl (S)-4-(7-(3-chlorophenyl)-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (29 mg, 29% yield) as a white solid. LC / MS ESI (m / z): 522 (M+H). + . 1 H NMR (400 MHz, CDCl3) δ8.45 (s, 1H), 7.68 (t, J = 2.0Hz, 1H), 7.62 - 7.57 (m, 1H), 7.42 (t, J = 8.1Hz, 1H), 7.33 - 7.29 (m, 1H), 6.93 (s, 1H), 4.79 - 4.71 (m, 1H), 4.15 - 3.79 (m, 3H), 3.57 (t, J = 12.6Hz, 1H), 3.43 - 3.32 (m, 1H), 3.30 - 3.11 (m, 1H), 2.08 - 2.00 (m, 1H), 1.73 (d, J = 7.2Hz, 6H), 1.24 (d, J = 6.6Hz, 3H), 1.05 - 0.99 (m, 2H), 0.84 - 0.77 (m, 1H), 0.75 - 0.68 (m, 1H).

[0435] The following compounds were prepared from the corresponding amines by a procedure similar to the synthesis of compound 140. [Table 26]

[0436] Example 38. Synthesis of ethyl (S)-4-(5-cyclopropyl-7-(5-methylpyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Compound 153) [ka]

[0437] Step 1. (S)-5-Cyclopropyl-4-(2-methylpiperazin-1-yl)-7-(5-methylpyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine To a solution of tert-butyl (S)-4-(5-cyclopropyl-7-(5-methylpyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (80 mg, 0.16 mmol, prepared according to a similar procedure described for Compound 259) in DCM (3 mL) was added HCl (4.0 mL, 4.0 M solution in dioxane). The resulting mixture was stirred at room temperature for 0.5 h. After removal of the solvent, the residue was diluted with DCM and washed with NaHCO3 (aq). The aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was used directly in the next step. (S)-5-Cyclopropyl-4-(2-methylpiperazin-1-yl)-7-(5-methylpyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (40 mg, 63%). LC / MS ESI(m / z): 349(M+H) + .

[0438] Step 2. Ethyl (S)-4-(5-cyclopropyl-7-(5-methylpyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of (S)-5-cyclopropyl-4-(2-methylpiperazin-1-yl)-7-(5-methylpyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (40 mg, 0.10 mmol) in DCM (3 mL) was added TEA (0.30 mL, 0.30 mmol) at 0 °C, followed by the dropwise addition of ethyl carbonochloridate (0.020 mL, 0.20 mmol). The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted twice with DCM. The combined organic layers were washed with NaHCO (aq), dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-30% ethyl acetate / petroleum ether) to give the crude product, which was further purified by preparative HPLC to give ethyl (S)-4-(5-cyclopropyl-7-(5-methylpyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (31 mg, 63%) as a white solid. LC / MS ESI(m / z): 421(M+H). + . 1 H NMR (400 MHz, DMSO-d6) δ 8.86 (d, J = 2.4 Hz, 1H), 8.39 (d, J = 1.1 Hz, 1H), 8.36 (s, 1H), 8.08 (s, 1H), 7.54 (s, 1H), 4.74 - 4.67 (m, 1H), 4.14 - 4.07 (m, 2H), 4.03 - 3.91 (m, 2H), 3.81 (d, J = 12.9 Hz, 1H), 3.50 - 3.39 (m, 2H), 3.18 - 3.11 (m, 1H), 2.39 (s, 3H), 2.06 - 2.00 (m, 1H), 1.22 (t, J = 7.2 Hz, 3H), 1.14 (d, J = 6.6 Hz, 3H), 1.01 - 0.96 (m, 2H), 0.90 - 0.86 (m, 1H), 0.81 - 0.77 (m, 1H).

[0439] Example 39. Synthesis of ethyl (S)-4-(7-(3-chloro-4-fluorophenyl)-5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Compound 155) [ka]

[0440] Step 1. (S)-7-(3-chloro-4-fluorophenyl)-4-(2-methylpiperazin-1-yl)-5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine To a solution of tert-butyl (S)-4-(7-(3-chloro-4-fluorophenyl)-5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (400 mg, 0.77 mmol, prepared according to the procedure described for Compound 154) in DCM (5 mL) was added HCl (3.0 mL, 4.0 M solution in dioxane). The resulting mixture was stirred at room temperature for 2 hours. After removal of the solvent, the residue was diluted with DCM and washed with NaHCO3 (aq). The organic layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was used directly in the next step. (S)-7-(3-chloro-4-fluorophenyl)-4-(2-methylpiperazin-1-yl)-5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine (280 mg). LC / MS ESI (m / z): 423 (M+H) + .

[0441] Step 2. Ethyl (S)-4-(7-(3-chloro-4-fluorophenyl)-5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of (S)-7-(3-chloro-4-fluorophenyl)-4-(2-methylpiperazin-1-yl)-5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine (97 mg, 0.23 mmol) in DCM (5 mL) was added TEA (70 mg, 0.69 mmol) at 0 °C, followed by the dropwise addition of ethyl carbonochloridate (75 mg, 0.69 mmol). The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted twice with DCM. The combined organic layers were washed with NaHCO (aq), dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-30%, ethyl acetate / petroleum ether) to give the crude product, which was further purified by preparative HPLC to give ethyl (S)-4-(7-(3-chloro-4-fluorophenyl)-5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (41 mg, 36%) as a white solid. LC / MS ESI(m / z): 495(M+H). + . 1 H NMR (400MHz, CDCl3) δ8.69 (d, J = 4.1Hz, 1H), 8.52 (s, 1H), 7.85 (dd, J = 6.4, 2.6Hz, 1H), 7.79 (td, J = 7.7, 1.8Hz, 1H), 7.67 - 7.63 (m, 2H), 7.59 (d, J = 7.8Hz, 1H), 7.31 (t, J = 8.7Hz, 1H), 7.28 - 7.24 (m, 1H), 4.39 - 4.23 (m, 1H), 4.16 - 4.08 (m, 2H), 3.98 - 3.83 (m, 1H), 3.62 (dd, J = 26.8, 12.6Hz, 2H), 3.22 - 3.13 (m, 1H), 3.09 - 2.79 (m, 2H), 1.24 (t, J = 7.1Hz, 3H), 1.05 (d, J = 6.3Hz, 3H).

[0442] The following compounds were prepared from the corresponding Boc-protected amines by a procedure similar to the synthesis of compound 155. [Table 27]

[0443] Example 40. Synthesis of tert-butyl (R)-4-(7-(3-chlorophenyl)-5-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Compound 157) [ka]

[0444] Step 1. 4-Chloro-7-(3-chlorophenyl)-5-(cyclopent-1-en-1-yl)-7H-pyrrolo[2,3-d]pyrimidine To a solution of 4-chloro-7-(3-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (1.0 g, 2.6 mmol, prepared according to step 1 of the procedure described for Compound 274) in dioxane-HO (15 mL, 5:1 volume ratio) was added 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (450 mg, 2.3 mmol), KCO (1.1 g, 7.8 mmol), and Pd(dppf)Cl (190 mg, 0.26 mmol). The resulting mixture was heated to 90 °C overnight. After cooling to room temperature, the reaction was filtered, and the filtrate was partitioned between EtOAc and water. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 0-40% EtOAc / petroleum ether) to give 300 mg (36% yield) of 4-chloro-7-(3-chlorophenyl)-5-(cyclopent-1-en-1-yl)-7H-pyrrolo[2,3-d]pyrimidine as a solid. LC / MS ESI (m / z): 330 (M+H). + .

[0445] Step 2. tert-Butyl (R)-4-(7-(3-chlorophenyl)-5-(cyclopent-1-en-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate A mixture of 4-chloro-7-(3-chlorophenyl)-5-(cyclopent-1-en-1-yl)-7H-pyrrolo[2,3-d]pyrimidine (100 mg, 0.30 mmol) and tert-butyl (R)-3-methylpiperazine-1-carboxylate (120 mg, 0.60 mmol) in DIPEA (0.5 mL) was stirred at 140 °C for 3 h. After cooling to room temperature, DIPEA was removed under reduced pressure. The residue was purified by flash chromatography (silica gel, 0–40% EtOAc / petroleum ether) to give tert-butyl (R)-4-(7-(3-chlorophenyl)-5-(cyclopent-1-en-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (110 mg, 73%) as a white solid. LC / MS ESI(m / z):494(M+H) + .

[0446] Step 3. tert-Butyl (R)-4-(7-(3-chlorophenyl)-5-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate A mixture of tert-butyl (R)-4-(7-(3-chlorophenyl)-5-(cyclopent-1-en-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (110 mg, 0.22 mmol) and PtO (51 mg) in EtOAc (8 mL) was stirred under a H atmosphere (approximately 1 atm) at room temperature overnight. The reaction was filtered, and the filtrate was concentrated. The residue was purified by flash chromatography (silica gel, 0–50% EtOAc / petroleum ether) and preparative HPLC to give tert-butyl (R)-4-(7-(3-chlorophenyl)-5-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (38 mg, 35% yield) as a white solid. LCMS ESI(m / z):496.(M+H) + . 1 H NMR (400 MHz, CDCl3) δ 8.51 (s, 1H), 7.72 (t, J = 1.9 Hz, 1H), 7.68 - 7.63 (m, 1H), 7.44 (t, J = 8.1 Hz, 1H), 7.31 (d, J = 9.0 Hz, 1H), 7.13 (s, 1H), 4.18 (s, 1H), 3.91 (s, 1H), 3.65 (s, 1H), 3.48 (s, 3H), 3.33 - 3.19 (m, 2H), 2.28 (s, 1H), 2.15 (s, 1H), 1.90 - 1.63 (m, 6H), 1.50 (s, 9H), 1.18 (d, J = 6.1 Hz, 3H).

[0447] The following compounds were prepared from the corresponding amines by a procedure similar to the synthesis of compound 157. [Table 28]

[0448] Example 41. Synthesis of tert-butyl (2R,5S)-2,5-dimethyl-4-(5-phenyl-7-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (Compound 169) [ka]

[0449] Step 1. 4-Chloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine To a suspension of NaH (1.0 g, 27 mmol, 60 wt%) in anhydrous DMF (60 mL) at 0 °C, 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (5.0 g, 18 mmol) was added in portions. The resulting mixture was stirred at 0 °C for 30 minutes, and then TosCl (3.4 g, 18 mmol) was added in portions. After the addition, the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into ice water and filtered. The solid was collected and further dried under vacuum to give 4-chloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (6.0 g, 77%) as a white solid. LCMS ESI (m / z): 434 (M+H). + .

[0450] Step 2. tert-Butyl (2R,5S)-4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate To a solution of 4-chloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (4.0 g, 9.2 mmol) in DIPEA (5.0 mL, 28 mmol) was added tert-butyl (2R,5S)-2,5-dimethylpiperazine-1-carboxylate (2.0 g, 9.2 mmol). The resulting mixture was heated to 150 °C under a N atmosphere for 3 h. After cooling to room temperature, the solvent was removed and the residue was purified by flash column chromatography (silica gel, 0–30%, ethyl acetate / petroleum ether) to give tert-butyl (2R,5S)-4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (2.5 g, 43%) as a yellow solid. LC / MS ESI(m / z):612(M+H) + .

[0451] Step 3. tert-Butyl (2R,5S)-2,5-dimethyl-4-(5-phenyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate To a solution of tert-butyl (2R,5S)-4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (150 mg, 0.30 mmol) in dioxane (10 mL) and HO (1 mL) was added phenylboronic acid (60 mg, 0.60 mmol), KCO (100 mg, 0.75 mmol), and Pd(dppf)Cl (18 mg, 0.010 mmol). The resulting mixture was stirred at 90 °C under a N atmosphere overnight. After cooling to room temperature, the solvent was removed and the residue was purified by flash column chromatography (silica gel, 0-20%, ethyl acetate / petroleum ether) to give tert-butyl (2R,5S)-2,5-dimethyl-4-(5-phenyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (100 mg, 72%) as a yellow solid. LC / MS ESI (m / z): 562 (M+H). + .

[0452] Step 4. tert-Butyl (2R,5S)-2,5-dimethyl-4-(5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate To a solution of tert-butyl (2R,5S)-2,5-dimethyl-4-(5-phenyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (100 mg, 0.18 mmol) in THF (2 mL) was added TBAF (5 mL). The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0–60%, ethyl acetate / petroleum ether) to afford tert-butyl (2R,5S)-2,5-dimethyl-4-(5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (50 mg, 69%) as a white solid. LC / MS ESI(m / z):408(M+H) + .

[0453] Step 5. tert-Butyl (2R,5S)-2,5-dimethyl-4-(5-phenyl-7-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate To a solution of tert-butyl (2R,5S)-2,5-dimethyl-4-(5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (50 mg, 0.12 mmol) in DMF (10 mL) was added 3-iodopyridine (50 mg, 0.24 mmol), trans-cyclohexane-1,2-diamine (15 mg, 0.12 mmol), CuI (25 mg, 0.12 mmol), and KPO (280 mg, 1.2 mmol). The resulting mixture was heated to 100 °C overnight. After cooling to room temperature, the reaction was partitioned between EtOAc and water. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-30%, ethyl acetate / petroleum ether) to give tert-butyl (2R,5S)-2,5-dimethyl-4-(5-phenyl-7-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (50 mg, 85%) as a white solid, which was further purified by preparative HPLC to give 29 mg of a white solid. LC / MS ESI (m / z): 485 (M+H). + . 1 H NMR (400 MHz, MeOD) δ 9.09 (s, 1H), 8.58 (d, J = 4.3 Hz, 1H), 8.41 (s, 1H), 8.33 (ddd, J = 8.3, 2.5, 1.4 Hz, 1H), 7.73 (s, 1H), 7.64 (dd, J = 8.3, 4.8 Hz, 1H), 7.61 - 7.58 (m, 2H), 7.51 (t, J = 7.6 Hz, 2H), 7.41 (t, J = 7.4 Hz, 1H), 4.24 - 4.10 (m, 2H), 3.47 - 3.42 (m, 1H), 3.29 - 3.21 (m, 2H), 2.97 - 2.80 (m, 1H), 1.43 (s, 9H), 1.14 (d, J = 6.8 Hz, 3H), 0.91 (d, J = 6.7 Hz, 3H).

[0454] Example 42. Synthesis of tert-butyl (S)-4-(5-cyclopropyl-7-(5-methylpyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate (Compound 174) and tert-butyl (R)-4-(5-cyclopropyl-7-(5-methylpyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate (Compound 175) [ka]

[0455] Step 1. tert-Butyl 4-(5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate A mixture of 4-chloro-5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (350 mg, 1.0 mmol, prepared according to the procedure described for compound 164), tert-butyl 2-methylpiperazine-1-carboxylate (240 mg, 1.2 mmol), and DIEA (0.50 mL, 3.0 mmol) in EtOH (10 mL) was stirred at 100 °C for 12 h. The reaction mixture was concentrated. The residue was purified by column chromatography on silica gel (0-40% EtOAc / petroleum ether) to give tert-butyl 4-(5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate (390 mg, 0.76 mmol, 76%) as a yellow solid. LC / MS ESI (m / z): 512 (M+H). + .

[0456] Step 2. tert-Butyl 4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate To a solution of tert-butyl 4-(5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate (390 mg, 0.76 mmol) in THF (20 mL) was added dropwise TBAF (4.6 mL, 1.0 M solution in THF). The resulting mixture was stirred at room temperature for 12 h. The reaction mixture was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine, dried over NaSO, and concentrated. The residue was purified by column chromatography on silica gel (0-80% EtOAc / petroleum ether) to afford tert-butyl 4-{5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-2-methylpiperazine-1-carboxylate (220 mg, 0.62 mmol, 81%) as a white solid. LC / MS ESI(m / z):358(M+H) + .

[0457] Step 3. tert-Butyl (S)-4-(5-cyclopropyl-7-(5-methylpyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate and tert-butyl (R)-4-(5-cyclopropyl-7-(5-methylpyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate A mixture of tert-butyl 4-{5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-2-methylpiperazine-1-carboxylate (220 mg, 0.62 mmol), 3-bromo-5-methylpyridine (210 mg, 1.2 mmol), copper(I) iodide (35 mg, 0.18 mmol), trans-1,2-diaminocyclohexane (21 mg, 0.18 mmol), and KPO (391 mg, 1.8 mmol) in DMF (20 mL) was stirred at 120° C. for 16 hours. The reaction mixture was concentrated. The residue was purified by column chromatography on silica gel (0-30% EtOAc / petroleum ether) to give tert-butyl 4-[5-cyclopropyl-7-(5-methylpyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2-methylpiperazine-1-carboxylate (120 mg, 0.27 mmol, 44%), which was separated by SFC to give two isomers.

[0458] Peak 1 (shorter retention time): Assigned to tert-butyl (S)-4-(5-cyclopropyl-7-(5-methylpyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate (39 mg) as a pale yellow solid. LC / MS ESI (m / z): 449 (M+H) + . 1H NMR (400 MHz, CDCl3) δ 8.65 (d, J = 2.3 Hz, 1H), 8.44 - 8.40 (m, 2H), 7.93 (s, 1H), 6.95 (d, J = 0.8 Hz, 1H), 4.53 - 4.47 (m, 1H), 4.41 (s, 1H), 4.11 (d, J = 12.9 Hz, 1H), 3.97 (d, J = 13.1 Hz, 1H), 3.44 - 3.32 (m, 2H), 3.09 (td, J = 12.4, 3.4 Hz, 1H), 2.45 (s, 3H), 2.08 - 2.01 (m, 1H), 1.50 (s, 9H), 1.23 (d, J = 6.8 Hz, 3H), 1.03 (dd, J = 8.3, 3.9 Hz, 2H), 0.91 - 0.86 (m, 1H), 0.70 - 0.65 (m, 1H). Peak 2 (longer retention time): Assigned to tert-butyl (R)-4-(5-cyclopropyl-7-(5-methylpyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate (44 mg) as a pale yellow solid. LC / MS ESI (m / z): 449 (M+H) + . 1 H NMR (400 MHz, CDCl3) δ 8.65 (d, J = 2.2 Hz, 1H), 8.42 (d, J = 5.8 Hz, 2H), 7.93 (s, 1H), 6.95 (d, J = 0.8 Hz, 1H), 4.55 - 4.46 (m, 1H), 4.41 (s, 1H), 4.11 (d, J = 13.0 Hz, 1H), 3.97 (d, J = 13.2 Hz, 1H), 3.44 - 3.31 (m, 2H), 3.09 (td, J = 12.4, 3.4 Hz, 1H), 2.45 (s, 3H), 2.09 - 1.97 (m, 1H), 1.50 (s, 9H), 1.23 (d, J = 6.8 Hz, 3H), 1.07 - 1.02 (m, 2H), 0.91 - 0.86 (m, 1H), 0.70 - 0.65 (m, 1H). SFC preparative separation method: Instrument: Waters Thar 80 preparative SFC; Column: ChiralPak IC, 250 x 21.2 mm i.d., 5 μm; Mobile phase: A is CO2 and B is MeOH + 0.1% NH3·H2O; Gradient: B 40%; Flow rate: 50 mL / min; Back pressure: 100 bar; Column temperature: 35 °C; Wavelength: 220 nm; Cycle time: 5.0 min; Elution time: 4 h.

[0459] Example 43. Synthesis of 1,1,1-trifluoro-2-methylpropan-2-yl (S)-3-methyl-4-(7-(1-methyl-1H-pyrazol-4-yl)-5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (Compound 183) [ka]

[0460] Step 1. 1,1,1-trifluoro-2-methylpropan-2-yl 1 H-imidazole-1-carboxylate To a solution of 1,1,1-trifluoro-2-methylpropan-2-ol (200 mg, 1.6 mmol) in DCM (5.0 mL) was added 1-(1H-imidazole-1-carbonyl)-1H-imidazole (250 mg, 1.6 mmol) at room temperature. The resulting mixture was stirred for 18 hours. The reaction was quenched with water. The aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was used directly in the next step. LC / MS ESI (m / z): 223 (M+H). + Step 2. (S)-7-(1-methyl-1H-pyrazol-4-yl)-4-(2-methylpiperazin-1-yl)-5-phenyl-7H-pyrrolo[2,3-d]pyrimidine To a solution of tert-butyl (3S)-3-methyl-4-[7-(1-methyl-1H-pyrazol-4-yl)-5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]piperazine-1-carboxylate (120 mg, 0.25 mmol, prepared according to a similar procedure described for Compound 268) in DCM (5 mL) was added TFA (3 mL). The reaction was stirred at room temperature for 18 hours. The mixture was concentrated. The residue was neutralized by the addition of saturated Na2CO3 solution and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was used directly without further purification. LC / MS ESI (m / z): 374 (M+H). + .

[0461] Step 3. 1,1,1-trifluoro-2-methylpropan-2-yl (S)-3-methyl-4-(7-(1-methyl-1H-pyrazol-4-yl)-5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate A solution of (2S)-2-methyl-1-[7-(1-methyl-1H-pyrazol-4-yl)-5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]piperazine (50 mg, 0.13 mmol), 1,1,1-trifluoro-2-methylpropan-2-yl-1H-imidazole-1-carboxylate (49 mg, 0.22 mmol), and DIEA (0.050 mL, 0.33 mmol) in DMF (3 mL) was stirred at 80 °C for 2 days, and the mixture was cooled to room temperature and concentrated. The residue was partitioned between water and EtOAc. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by column chromatography on silica gel (EtOAc / petroleum ether, 1:100 to 1:5 by volume) and preparative HPLC to give 1,1,1-trifluoro-2-methylpropan-2-yl (S)-3-methyl-4-(7-(1-methyl-1H-pyrazol-4-yl)-5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (5.3 mg, 7.5%) as a white solid. LC / MS ESI (m / z): 528 (M+H). + . 1 H NMR (400 MHz, CD3OD) δ 8.40 (s, 1H), 8.25 (s, 1H), 7.96 (s, 1H), 7.58 - 7.52 (m, 3H), 7.48 (dd, J = 14.1, 6.2 Hz, 2H), 7.38 (t, J = 7.3 Hz, 1H), 4.14 (dd, J = 6.5, 4.0 Hz, 1H), 3.98 (s, 3H), 3.86 - 3.68 (m, 1H), 3.56 (d, J = 13.2 Hz, 1H), 3.41 (dd, J = 23.2, 14.2 Hz, 1H), 3.18 - 3.10 (m, 1H), 2.85 (dd, J = 48.9, 12.1 Hz, 2H), 1.64 (s, 6H), 0.91 (d, J = 6.7 Hz, 3H).

[0462] Example 44. Synthesis of tert-butyl 4-(1-(3-chlorophenyl)-3-(pyridin-2-yl)-1H-pyrrolo[3,2-c]pyridin-4-yl)-3-methylpiperazine-1-carboxylate (Compound 187) [ka]

[0463] Step 1. tert-Butyl 4-(1-(3-chlorophenyl)-3-(pyridin-2-yl)-1H-pyrrolo[3,2-c]pyridin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl 4-(3-bromo-1-(3-chlorophenyl)-1H-pyrrolo[3,2-c]pyridin-4-yl)-3-methylpiperazine-1-carboxylate (60 mg, 0.12 mmol, prepared according to the procedure of the first two steps of the synthesis of Compound 418) in toluene (5 mL) was added 2-(tributylstannyl)pyridine (0.050 mL, 0.14 mmol) and Pd(PPh) (14 mg, 0.012 mmol). The resulting mixture was stirred at 120 °C overnight. After cooling to room temperature, the reaction was quenched with KF (aq) and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-50%, ethyl acetate / petroleum ether) to give the crude product, which was further purified by preparative HPLC to give tert-butyl 4-(1-(3-chlorophenyl)-3-(pyridin-2-yl)-1H-pyrrolo[3,2-c]pyridin-4-yl)-3-methylpiperazine-1-carboxylate (8.4 mg, 14%) as a white solid. LC / MS ESI(m / z): 504(M+H). + . 1H NMR (400 MHz, CD3OD) δ 8.63 (d, J = 4.7 Hz, 1H), 8.05 (d, J = 6.0 Hz, 1H), 7.97 (td, J = 7.7, 1.7 Hz, 1H), 7.85 (d, J = 7.9 Hz, 1H), 7.78 - 7.75 (m, 1H), 7.69 - 7.67 (m, 1H), 7.64 - 7.55 (m, 2H), 7.51 (dt, J = 7.5, 1.8 Hz, 1H), 7.47 - 7.42 (m, 1H), 7.26 (d, J = 6.0 Hz, 1H), 3.56 - 3.42 (m, 2H), 3.24 - 3.07 (m, 4H), 2.88 - 2.73 (m, 1H), 1.43 (s, 9H), 0.84 (d, J = 6.5 Hz, 3H).

[0464] The following compounds were prepared using the corresponding tin reagents in a similar manner to the synthesis of compound 187. [Table 29]

[0465] Example 45. Synthesis of ethyl (3S,5S)-4-(7-(3-chlorophenyl)-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,5-dimethylpiperazine-1-carboxylate (Compound 189) [ka]

[0466] Step 1. 4-Chloro-7-(3-chlorophenyl)-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine A mixture of 4-chloro-7-(3-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (500 mg, 1.3 mmol, prepared according to the procedure described for compound 274), cyclopropylboronic acid (110 mg, 1.3 mmol), Pd(dtbpf)Cl (170 mg, 0.26 mmol), and KCO (3.6 g, 26 mmol) in toluene (20 mL) was heated at 80 °C for 12 h. The reaction mixture was concentrated. The residue was purified by column chromatography on silica gel (0-40% EtOAc / petroleum ether) to give 4-chloro-7-(3-chlorophenyl)-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine (300 mg, 77%) as a yellow solid. LC / MS ESI (m / z): 304 (M+H). + .

[0467] Step 2. 7-(3-chlorophenyl)-5-cyclopropyl-4-fluoro-7H-pyrrolo[2,3-d]pyrimidine A mixture of 4-chloro-7-(3-chlorophenyl)-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine (300 mg, 1.0 mmol) and TBAF (2.0 mL, 1.0 M solution in THF) in DMSO (20 mL) was stirred at 50 °C for 3 h. The resulting mixture was quenched with ice water and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine, dried over NaSO, and concentrated. The residue was purified by column chromatography on silica gel (0-30% EtOAc / petroleum ether) to give 7-(3-chlorophenyl)-5-cyclopropyl-4-fluoro-7H-pyrrolo[2,3-d]pyrimidine (120 mg, 42%) as a white solid. LC / MS ESI (m / z): 288 (M+H). + .

[0468] Step 3. tert-Butyl (3S,5S)-4-(7-(3-chlorophenyl)-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,5-dimethylpiperazine-1-carboxylate A mixture of 7-(3-chlorophenyl)-5-cyclopropyl-4-fluoro-7H-pyrrolo[2,3-d]pyrimidine (100 mg, 0.35 mmol), tert-butyl (3S,5S)-3,5-dimethylpiperazine-1-carboxylate (150 mg, 0.70 mmol), and DIEA (0.17 mL, 1.1 mmol) in DMSO (10 mL) was stirred at 150 °C for 12 h. After cooling to room temperature, the reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-30% ethyl acetate / petroleum ether) to give tert-butyl (3S,5S)-4-(7-(3-chlorophenyl)-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,5-dimethylpiperazine-1-carboxylate (60 mg, 35%). LC / MS ESI (m / z): 482 (M+H). + .

[0469] Step 4. 7-(3-chlorophenyl)-5-cyclopropyl-4-((2S,6S)-2,6-dimethylpiperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine To a solution of tert-butyl (3S,5S)-4-(7-(3-chlorophenyl)-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,5-dimethylpiperazine-1-carboxylate (60 mg, 0.13 mmol) in DCM (10 mL) was added HCl (3.0 mL, 4.0 M in dioxane). The resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated to give 7-(3-chlorophenyl)-5-cyclopropyl-4-((2S,6S)-2,6-dimethylpiperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine (48 mg, 100%) as a yellow solid, which was used directly in the next step without further purification. LC / MS ESI(m / z): 382 (M+H). + .

[0470] Step 5. Ethyl (3S,5S)-4-(7-(3-chlorophenyl)-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,5-dimethylpiperazine-1-carboxylate To a mixture of 7-(3-chlorophenyl)-5-cyclopropyl-4-((2S,6S)-2,6-dimethylpiperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine (40 mg, 0.11 mmol) and DIEA (0.050 mL, 0.31 mmol) in DCM (10 mL) was added dropwise at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with NaHCO (aq) and extracted with DCM (2 x 50 mL). The organic layer was washed with brine, dried over NaSO, and concentrated. The residue was purified by column chromatography on silica gel (0-50% EtOAc / petroleum ether) to give the crude product. The crude product was purified by HPLC to give ethyl (3S,5S)-4-(7-(3-chlorophenyl)-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,5-dimethylpiperazine-1-carboxylate (15 mg, 0.033 mmol, 32%) 1006 as a white solid. LC / MS ESI(m / z): 454(M+H) + . 1 H NMR (400 MHz, CD3OD) δ 8.49 (s, 1H), 7.88 (t, J = 2.0 Hz, 1H), 7.69 - 7.65 (m, 1H), 7.50 (t, J = 8.1 Hz, 1H), 7.39 - 7.35 (m, 1H), 7.30 (s, 1H), 4.23 - 4.11 (m, 4H), 3.82 (s, 2H), 3.45 (s, 2H), 2.37 - 2.29 (m, 1H), 1.30 (t, J = 5.4 Hz, 6H), 1.06 (d, J = 6.3 Hz, 5H), 0.96 - 0.85 (m, 1H), 0.64 - 0.56 (m, 1H).

[0471] Example 46. Synthesis of tert-butyl (R)-4-(7-(3-chlorophenyl)-5-(pyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate (Compound 193) [ka]

[0472] Step 1. 4-Chloro-7-(3-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine To a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (10 g, 36 mmol) in DCM (600 mL) was added (3-chlorophenyl)boronic acid (11 g, 72 mmol), Cu(OAc) (16 g, 110 mmol), pyridine (18 mL, 110 mmol), and 4 Å molecular sieves (10 g). The resulting mixture was stirred at room temperature under an O atmosphere for 3 days. After cooling in an ice-water bath, the reaction was quenched with NHOH (aq, 50 mL) and filtered. The filtrate was extracted twice with DCM. The combined organic layers were dried over NaSO, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 0-30%, ethyl acetate / petroleum ether) to give 4-chloro-7-(3-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (11 g, 79%) as a white solid. LC / MS ESI (m / z): 390 (M+H). + .

[0473] Step 2. 7-(3-chlorophenyl)-5-iodo-4-methoxy-7H-pyrrolo[2,3-d]pyrimidine To a solution of 4-chloro-7-(3-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (4.0 g, 10 mmol) in MeOH (40 mL) was added MeONa (8.0 mL, 4.5 M solution in MeOH). The resulting mixture was stirred at 50 °C overnight. The reaction was quenched with ice water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 0-30%, ethyl acetate / petroleum ether) to give 7-(3-chlorophenyl)-5-iodo-4-methoxy-7H-pyrrolo[2,3-d]pyrimidine (3.0 g, 79%) as a white solid. LC / MS ESI (m / z): 386 (M+H). + .

[0474] Step 3. 7-(3-chlorophenyl)-4-methoxy-5-(pyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine To a solution of 7-(3-chlorophenyl)-5-iodo-4-methoxy-7H-pyrrolo[2,3-d]pyrimidine (2.3 g, 6 mmol) in DMSO (20 mL) was added CuI (230 mg, 1.2 mmol), KCO (2.5 g, 18 mmol), L-proline (280 mg, 2.4 mmol), and pyrrolidine (850 mg, 12 mmol). The resulting mixture was heated at 90 °C overnight. After cooling to room temperature, the reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 0-40%, ethyl acetate / petroleum ether) to give 7-(3-chlorophenyl)-4-methoxy-5-(pyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine (1.2 g, 61%) as a yellow solid. LC / MS ESI (m / z): 329 (M+H). + .

[0475] Step 4. 7-(3-chlorophenyl)-5-(pyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ol To a solution of 7-(3-chlorophenyl)-4-methoxy-5-(pyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine (0.50 g, 1.5 mmol) in DCM (10 mL) was added BBr3 (3.0 mL) dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 2 h. The reaction was quenched with ice water and extracted twice with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-50%, ethyl acetate / petroleum ether) to give 7-(3-chlorophenyl)-5-(pyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ol (0.40 g, 84%) as a yellow solid. LC / MS ESI (m / z): 315 (M+H). + .

[0476] Step 5. 4-Chloro-7-(3-chlorophenyl)-5-(pyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine A solution of 7-(3-chlorophenyl)-5-(pyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ol (0.40 g, 1.2 mmol) in POCl (4 mL) was heated at 120 °C overnight. After cooling to room temperature, the reaction was concentrated. The residue was redissolved in DCM and washed with NaHCO (aq). The aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0–40%, ethyl acetate / petroleum ether) to afford 4-chloro-7-(3-chlorophenyl)-5-(pyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine (0.20 g, 48%) as a yellow solid. LC / MS ESI (m / z): 333 (M+H). + .

[0477] Step 6. tert-Butyl (R)-4-(7-(3-chlorophenyl)-5-(pyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate To a solution of 4-chloro-7-(3-chlorophenyl)-5-(pyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine (200 mg, 0.60 mmol) in EtOH (5 mL) was added DIPEA (230 mg, 1.8 mmol) and tert-butyl (R)-2-methylpiperazine-1-carboxylate (240 mg, 1.2 mmol), and the resulting mixture was heated at 100° C. overnight. After cooling to room temperature, the solvent was removed and the residue was purified by flash column chromatography (silica gel, 0-40%, ethyl acetate / petroleum ether) to give the crude product, which was further purified by preparative HPLC to give tert-butyl (R)-4-(7-(3-chlorophenyl)-5-(pyrrolidin-1...

Claims

1. A compound of the following formula (Ia) or a pharmaceutically acceptable salt of said compound: 【Chemical 1】 [In the formula, R １ is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, and each R １ represents 1 to 5 independently selected R ７ may be replaced by R ２ represents 1 to 5 independently selected R ８ C which may be replaced by １－６ is alkyl; R ３ teeth, 【Chemistry 2】 and R ４ and R ６ each independently represents H, hydroxy, halogen, cyano, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, C １－６ Alkylthio and NR ａ R ｂ selected from the group consisting of: R ７ and R ８ Each of the groups may be selected from the group consisting of deuterium, hydroxy, halogen, cyano, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Alkylthio, C ３－７ Cycloalkyl and NR ａ R ｂ wherein each C is independently selected from the group consisting of １－６ Alkyl and C １－６ Alkoxy is a group containing halogen, hydroxyl and C １－６ and each C may be substituted with a substituent independently selected from the group consisting of alkoxy. ３－７ Cycloalkyl is substituted with halogen, hydroxyl, C １－６ Alkoxy and C １－６ optionally substituted with substituents independently selected from the group consisting of alkyl; or R １ or R ２ When R is cycloalkyl or heterocycloalkyl, two R on the same carbon ７ or two R ８ can be taken together to form oxo, or any two R ７ or two R ８ can be taken together with the atoms to which they are attached to form an edge-fused or spiro-fused 3- to 7-membered ring or a 1- to 3-carbon or single bond bridge, wherein the ring or bridge is not substituted with any of halogen, hydroxyl, C １－６ Haloalkyl and C １－６ optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkyl; R ９ is deuterium, halogen, hydroxyl and C １－６ C optionally substituted with a substituent independently selected from the group consisting of alkoxy １－６ is alkyl; Each R １０ is deuterium, hydroxyl and C １－６ C may be substituted with a substituent independently selected from the group consisting of alkoxy; １－６ Alkyl and C １－６ independently selected from the group consisting of haloalkyl; or Two R on the same carbon １０ can be taken together to form oxo; or Any two R １０ can be taken together with the atoms to which they are attached to form an edge-fused or spiro-fused 3- to 7-membered ring or a 1- to 3-carbon or single bond bridge, wherein the ring or bridge is not substituted with any of halogen, hydroxyl, C １－６ Haloalkyl, and C １－６ optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkyl; Each R ａ and R ｂ are independently H, C １－６ Alkyl, C(O)—O—C １－６ Alkyl, C(O)—O—C ２－６ Alkenyl, -(CH ２ ) ０－２ -C ３－７ cycloalkyl, and 3- to 7-membered heterocycloalkyl, wherein each alkyl, cycloalkyl, or heterocycloalkyl is selected from halogen and C １－６ optionally substituted by 1 to 3 substituents selected from alkoxy; or R ａ and R ｂ can be taken together with the nitrogen to which they are attached to form a 4- to 7-membered ring; m is 1 or 2; n is 1, 2, or 3; p is 0, 1, 2, 3, 4, 5, 6, 7 or 8; where m+n is 2, 3, or 4; and R １ and R ２ cannot both be aryl.

2. The compound according to claim 1 of the following formula (Ia): 【Chemistry 3】 And, R １ represents 1 to 5 independently selected R ７ is heteroaryl optionally substituted by R ２ represents 1 to 5 independently selected R ８ C which may be replaced by １－６ is alkyl; R ３ teeth, 【Chemistry 4】 and R ４ and R ６ each of is H; R ７ and R ８ Each of the groups may be selected from the group consisting of deuterium, hydroxy, halogen, cyano, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Alkylthio, C ３－７ Cycloalkyl and NR ａ R ｂ wherein each C is independently selected from the group consisting of １－６ Alkyl and C １－６ Alkoxy is a group containing halogen, hydroxyl and C １－６ and each C may be substituted with a substituent independently selected from the group consisting of alkoxy. ３－７ Cycloalkyl is substituted with halogen, hydroxyl, C １－６ Alkoxy and C １－６ optionally substituted with substituents independently selected from the group consisting of alkyl; R ９ is deuterium, halogen, hydroxyl and C １－６ C optionally substituted with a substituent independently selected from the group consisting of alkoxy １－６ is alkyl; Each R １０ is deuterium, hydroxyl and C １－６ C may be substituted with a substituent independently selected from the group consisting of alkoxy; １－６ Alkyl and C １－６ independently selected from the group consisting of haloalkyl; or Two R on the same carbon １０ can be taken together to form oxo; or Any two R １０ can be taken together with the atoms to which they are attached to form an edge-fused or spiro-fused 3- to 7-membered ring or a 1- to 3-carbon or single bond bridge, wherein the ring or bridge is not substituted with any of halogen, hydroxyl, C １－６ Haloalkyl and C １－６ optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkyl; Each R ａ and R ｂ are independently H, C １－６ Alkyl, C(O)—O—C １－６ Alkyl, C(O)—O—C ２－６ Alkenyl, -(CH ２ ) ０－２ -C ３－７ cycloalkyl, and 3- to 7-membered heterocycloalkyl, wherein each alkyl, cycloalkyl, or heterocycloalkyl is selected from halogen and C １－６ optionally substituted by 1 to 3 substituents selected from alkoxy; or R ａ and R ｂ can be taken together with the nitrogen to which they are attached to form a 4- to 7-membered ring; and p is 0, 1, 2, 3, 4, 5, 6, 7 or 8; A compound, or a pharmaceutically acceptable salt of said compound.

3. The compound according to claim 1 of the following formula (Ia): 【Chemistry 5】 And, R １ represents 1 to 5 independently selected R ７ pyridyl optionally substituted by R ２ represents 1 to 5 independently selected R ８ C which may be replaced by １－６ is alkyl; R ３ teeth, 【Chemistry 6】 and R ４ and R ６ each of is H; R ７ and R ８ Each of the groups may be selected from the group consisting of deuterium, hydroxy, halogen, cyano, C １－６ Alkyl and C １－６ independently selected from the group consisting of alkoxy; R ９ is deuterium, halogen, hydroxyl and C １－６ C optionally substituted with a substituent independently selected from the group consisting of alkoxy １－６ is alkyl; Each R １０ is C １－６ Alkyl and C １－６ haloalkyl, each of which may be substituted with 1 to 5 deuterium atoms; and p is 0, 1, 2, 3, 4, 5, 6, 7 or 8; A compound, or a pharmaceutically acceptable salt of said compound.

4. R １ is 1 to 5 independently selected R ７ or an aryl optionally substituted by R １ are 1 to 3 independently selected R ７ is phenyl optionally substituted by 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

5. Each R ７ are independently H, halogen, cyano, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkyl or C １－６ 5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, selected from haloalkoxy.

6. R １ is heteroaryl, cycloalkyl, or heterocycloalkyl, and each R １ represents 1 to 5 independently selected R ７ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, optionally substituted by:

7. R １ is 1 to 4 independently selected R ７ 7. The compound of claim 6, which is pyridine, pyrimidine, pyrazine, pyridazine, thiazole, oxazole, pyrrole, imidazole, or pyrazole, optionally substituted by:

8. R １ but, 【Chemistry 7】 or R １ but, 【Chemistry 9】 and 1 to 4 independently selected R ７ may be replaced by 8. The compound of claim 7, or a pharmaceutically acceptable salt thereof.

9. R １ is tetrahydropyran, azetidine, pyrrolidine, morpholine, or piperidine, and R １ are 1 to 4 independently selected R ７ 7. The compound of claim 6, optionally substituted by:

10. Each R ８ are independently deuterium, hydroxy, halogen, cyano, or C １－６ 2. The compound of claim 1, wherein the alkoxy group is selected from the group consisting of:

11. R ２ C optionally substituted with 1 to 5 independently selected halogens １－６ The compound of claim 1 , wherein the aryl group is alkyl.

12. R ２ But, Me, Et, CHF ２ , or CF ３ 12. The compound of claim 11, wherein:

13. R ２ The compound of claim 1 , wherein is unsubstituted.

14. 2. The compound of claim 1, wherein m is 1 and n is 1.

15. 2. The compound of claim 1, wherein p is 0, 1, 2, 3, 4, 5, or 6.

16. Each R １０ independently, C １－６ Alkyl and C １－６ 16. The compound of claim 15, wherein the compound is selected from the group consisting of haloalkyl, each of which is optionally substituted with 1 to 5 deuterium atoms.

17. Each R １０ 17. The compound of claim 16, wherein is methyl.

18. R ３ but 【Chemistry 10】 and R ３ But 1 to 4 R １０ or R ３ but 【Chemistry 11】 and R ３ But 1 to 4 R １０ or R ３ but 【Chemistry 12】 2. The compound of claim 1, wherein:

19. R ４ The compound of claim 1 , wherein is H.

20. R ６ The compound of claim 1 , wherein is H.

21. R ７ and R ８ each of which is selected from the group consisting of hydroxy, halogen, cyano, C １－６ Alkyl, C １－６ Alkoxy, and C ３－７ cycloalkyl, wherein each C １－６ Alkyl and C １－６ The compound of claim 1, wherein the alkoxy is optionally substituted with 1 to 3 halogens.

22. Each R ７ But halogen, cyano, C １－６ Alkyl, C １－６ Alkoxy and CF ３ 2. The compound of claim 1, independently selected from the group consisting of:

23. R ９ C optionally substituted with 1 to 5 halogens or 1 to 9 deuteriums １－６ The compound of claim 1 , wherein the aryl group is alkyl.

24. R ９ The compound of claim 23, wherein is ethyl, isopropyl, or t-butyl; each of which is optionally substituted with 1 to 5 halogens or 1 to 9 deuteriums.

25. R ９ Me, Et, t-butyl, -C(CD ３ ) ３ , -CH(CD ３ ) ２ , -C(CD ３ ) ３ , isopropyl, F ３ C-CH ２ -, F ３ C-CH(CH ３ ) -, F ３ C-C (CH ３ ) ２ -, FCH ２ -C(CH ３ ) ２ -, 【Chemistry 13】 25. The compound of claim 24, wherein:

26. A compound of the following formula (Ib) or a compound of the following formula (Ic): 【Chemistry 14】 【change】 wherein the variable definitions are as defined in claim 1.

27. 10. The compound of claim 1 selected from the compounds disclosed herein, or a pharmaceutically acceptable salt thereof.

28. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt of said compound.

29. 28. A pharmaceutical composition comprising a compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof for the treatment of a disease or disorder that can be treated by modulation of TRPML ion channels or by modulation of lysosomes.

30. A pharmaceutical composition comprising a compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt of said compound for the treatment of: (a) a disorder selected from the group consisting of a cilia-related disorder, a neurodegenerative disorder, a lysosomal storage disorder, a lysosomal trafficking disorder, a glycogen storage disorder, a cholesterol ester storage disease, a muscle disorder (e.g., muscular dystrophy), an age-related disorder (e.g., photoaging of the skin), macular degeneration (e.g., Stargardt's disease or age-related), and cancer (e.g., cancer of the blood, brain, bone, lung, liver, kidney, bladder, stomach, breast, prostate, ovary, testis, colon, pancreas, or skin); (b) cilia-related disorders; (c) a cilia-related disorder selected from the group consisting of polycystic kidney disease, pancreatic cysts in polycystic kidney disease, Bardet-Biedl syndrome, nephronophthisis, Joubert syndrome, Meckel-Gruber syndrome, orofacial-digital syndrome, Senior-Loken syndrome, Birt-Hogg-Dubé syndrome, Leber congenital amaurosis, Alström syndrome, June asphyxiating thoracic dystrophy, Ellis-van Creveld syndrome, Sensenbrenner syndrome, and primary ciliary dyskinesia; (d) Polycystic kidney disease; (e) autosomal dominant polycystic kidney disease, autosomal recessive polycystic kidney disease, or autosomal dominant polycystic kidney disease-associated pancreatic cysts; (f) autosomal dominant polycystic kidney disease; (g) a neurodegenerative disorder; (h) a neurodegenerative disorder selected from the group consisting of Parkinson's disease, GBA-Parkinson's disease, LRRK2 Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), Alzheimer's disease, progressive supranuclear palsy, frontotemporal dementia, FTDP-17, corticobasal degeneration, dementia with Lewy bodies, Pick's disease, and multiple system atrophy; (i) lysosomal storage disorders; (j) a lysosomal storage disorder selected from the group consisting of Niemann-Pick disease, Gaucher disease, neuropathic Gaucher disease, sphingolipidosis, Farber disease, Krabbe disease, galactosialidosis, gangliosidosis, Gaucher disease, lysosomal acid lipase deficiency, sulfatidosis, mucopolysaccharidoses, mucolipidoses, lipidoses, and oligosaccharidoses; (k) sphingolipidoses, Farber disease, Krabbe disease, galactosialidosis, Fabry disease, Schindler disease, beta-galactosidase disorders, GM1 gangliosidosis, GM2 gangliosidosis AB variant, GM2 gangliosidosis activating factor deficiency, Sandhoff disease, Tay-Sachs disease, Gaucher disease, lysosomal acid lipase deficiency, Niemann-Pick disease, metachromatic leukodystrophy, saposin B deficiency, multiple sulfatase deficiency, Hurler syndrome, Scheie syndrome, Hurler-Scheie syndrome, Hunter syndrome, Sanfilippo syndrome, Morquio syndrome, Maroteaux-Lamy syndrome, Sly syndrome, hyaluronidase deficiency, sialidosis, I-cell disease, pseudo-Hurler multiple a lysosomal storage disorder selected from the group consisting of neurological dystrophy, phosphotransferase deficiency, mucolipidin 1 deficiency, Santavuori-Hartier disease, Jansky-Biaschovsky disease, Batten-Spielmeyer-Voigt disease, Kufus disease, Finnish variant neuronal ceroid lipfuscinosis, late infantile variant neuronal ceroid lipfuscinosis, type 7 neuronal ceroid lipfuscinosis, northern epilepsy-type neuronal ceroid lipfuscinosis, Turkish type late infantile neuronal ceroid lipfuscinosis, German / Serbian type late infantile neuronal ceroid lipfuscinosis, congenital cathepsin D deficiency, Wolman disease, α-mannosidosis, β-mannosidosis, aspartylglucosaminuria, and fucosidosis; (l) a lysosomal storage disorder selected from the group consisting of Niemann-Pick disease, Gaucher disease, and neuropathic Gaucher disease; (m) a lysosomal trafficking disorder selected from the group consisting of cystinosis, pyknodysostosis, Salla disease, sialic acid storage disease, and infantile free sialic acid storage disease; or (n) A glycogen storage disease selected from the group consisting of Pompe disease and Danon disease.

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