MODULATORS OF TRPML, THEIR COMPOSITIONS AND METHODS OF USE CROSS-REFERENCE TO RELATED APPLICATIONS The application claims the benefit of, and priority to, U.S.S.N.63/250,818, filed September 30, 2021; and U.S.S.N.63/339,791, filed May 9, 2022; the contents of each of which are incorporated herein by reference in their entirety. TECHNICAL FIELD The present disclosure relates to compounds and compositions which are modulators of TRPML and are useful for treatment of a variety of disorders. BACKGROUND The lysosome is a key organelle that serves as the cell's recycling center. In a highly regulated manner, it breaks down various biomaterials (proteins, lipids, and membranes) into smaller molecules or chemical building blocks, that the cell then employs for energy or as starting materials for new proteins or membranes [see e.g., de Duve, C., The lysosome turns fifty. Nat Cell Biol, 2005.7(9): p .847-9. Parkinson-Lawrence, E.J., et al., Lysosomal storage disease: revealing lysosomal function and physiology. Physiology (Bethesda), 2010.25(2): p .102-15]. Lysosomal dysfunction due to mutations in the hydrolytic enzyme of lysosomal transport occur in the more than 50 genetically defined Lysosomal Storage Diseases. Interestingly, defects in lysosomal processing can have substantial effects on the function of the organelle beyond the actual enzyme that is mutated – in effect, the system can be gummed up – altering lysosomal degradation and membrane transport/trafficking, creating a positive feedback loop. Because lysosome storage is also seen in common neurodegenerative diseases such as Alzheimer's and Parkinson's, understanding the mechanisms underlying the positive feedback loop may provide therapeutic approaches not only for LSDs, but also for common sporadic neurodegenerative diseases. A lysosome-localized cation channel, TRPML1, has been recently identified as a key regulator of lysosomal function and membrane trafficking processes in the lysosome. Human mutations of TRPML1 cause an inherited lysosomal storage disease, Mucolipidosis IV. This disease is typified by neurodegenerative effects likely driven by the accumulation of lipids and other biomaterials in the cell. The related channels TRPML2 and TRPML3 also regulate lysosomal function. Many reports suggest that TRPML channel activation is involved in multiple, key lysosomal functions. It can drive the translocation of the Transcription factor (TF)EB to the nucleus. TFEB regulates autophagy and lysosome biogenesis. Overexpression of TFEB has been reported to induce cellular clearance in several lysosome storage diseases, including Pompe Disease, Cystinosis, multiple sulfatase deficiency, as well as common neurodegenerative diseases, including 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 cellular clearance in all the aforementioned diseases, providing therapeutic targets for these devastating diseases. Recently, a potent synthetic agonist for TRPMLl has been 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) that could induce significant [Ca2+] increases in HEK293 cells stably or transiently expressing TRPML1 protein that has been forced to the plasma membrane via deletion of its lysosomal targeting sequence. High concentrations of ML-SAl (~10 µΜ) are needed to effectively activate TRPMLs. Since that concentration is usually difficult to achieve in vivo, ML-SAl cannot be used to treat the above TRPML related diseases. Liang et al. recently reported a new class of compounds as more potent TRPML activators [WO 2018/005713A1]. These compounds were thought to be useful in treating disorders related to TRPML activities such as lysosome storage diseases, muscular dystrophy, age-related common neurodegenerative diseases, ROS or oxidative stress related diseases, and aging. TRPML activators may also be useful in other disorders. SUMMARY OF THE DISCLOSURE The present disclosure provides for a compound of Formula (I) and subformulas thereof and pharmaceutically acceptable salts, solvates, hydrates, tautomers, and stereoisomers thereof. In an aspect, provided is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein W ¹ is N or CR ⁵ ; W ² is N or CR ⁶ ; R ¹ is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each R ¹ optionally substituted by 1-5 independently selected R ⁷ ; R ² is aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -O-cycloalkyl, -O-heterocycloalkyl, C _1-6 alkyl, C _1-6 alkoxy, -(CH ₂ ) _1-2 -cycloalkyl, -(CH ₂ ) _1-2 -heterocycloalkyl, or NR ^a R ^b , each R ² optionally substituted by 1-5 independently selected R ⁸ ; R ³ is each of R ⁴ , R ⁵ , and R ⁶ is independently selected from the group consisting of 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 ; each of R ⁷ and R ⁸ are independently selected at each occurrence 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 _1-6 alkyl and C _1-6 alkoxy are optionally substituted with substituents independently selected from the group consisting of halogen, hydroxyl, and C _1-6 alkoxy, and each C _3-7 cycloalkyl is optionally substituted with substituents independently selected from the group consisting of halogen, hydroxyl, C _1-6 alkoxy and C _1-6 alkyl; or when R ¹ or R ² is cycloalkyl or heterocycloalkyl, two R ⁷ or two R ⁸ on the same carbon 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 ring of 3-7 members, or a bridge of 1 to 3 carbons or a single bond, wherein the ring or bridge is optionally substituted with 1- 3 substituents independently selected from the group consisting of halogen, hydroxyl, C _1-6 haloalkyl, and C _1-6 alkyl; R ⁹ is C _1-6 alkyl or –(CH ₂ ) _0-2 -C _3-7 cycloalkyl, optionally substituted with substituents independently selected from the group consisting of deuterium, halogen, hydroxyl, C _1-3 alkyl, and C _1-6 alkoxy, wherein C _1-3 alkyl and C _1-6 alkoxy are optionally substituted with 1-5 substituents independently selected from the group consisting of deuterium, hydroxyl, C _1-3 haloalkyl, C _1-3 alkoxy and C _1-3 alkyl; each R ¹⁰ is selected independently from the group consisting of C _1-6 alkyl and C _1-6 haloalkyl, optionally substituted with substituents independently selected from the group consisting of deuterium, hydroxyl, and C _1-6 alkoxy; or two R ¹⁰ on the same carbon 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 ring of 3-7 members, or a bridge of 1 to 3 carbons or a single bond, wherein the ring or bridge is optionally substituted with 1-3 substituents independently selected from the group consisting of deuterium, halogen, hydroxyl, C _1-6 haloalkyl, and C _1-6 alkyl; each R ^a and R ^b is independently selected from H, C _1-6 alkyl, C(O)-O-C _1-6 alkyl, C(O)-O-C _2-6 alkenyl, C(O)-C _1-6 alkyl, C(O)-C _2-6 alkenyl, –(CH ₂ ) _0-2 -C _3-7 cycloalkyl, and 3-7 membered heterocycloalkyl, wherein each alkyl, cycloalkyl or heterocycloalkyl is optionally substituted by 1-3 substituents selected from halogen and C _1-6 alkoxy; or R ^a and R ^b can be taken together with the nitrogen to which they are attached to form a 4-7 membered ring; 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; wherein 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 are not both aryl. In another aspect, provided is a compound of formula (Ib) wherein the variable definitions are as described in the specification and claims. In another aspect, provided is a compound of formula (Ic) wherein the variable definitions are as described in the specification and claims. In another aspect, provided is a compound of Formula (I), or any subformula thereof, selected from the compounds disclosed in the specification or claims, or a pharmaceutically acceptable salt thereof. In another aspect, the disclosure provides a method of treating a disease or disorder that can be treated by modulation of TRPML, the method comprising administering to a patient in need thereof a compound described herein, or a composition described herein. Still other objects and advantages of the disclosure will become apparent to those of skill in the art from the disclosure herein, which is simply illustrative and not restrictive. Thus, other embodiments will be recognized by the skilled artisan without departing from the spirit and scope of the disclosure. DETAILED DESCRIPTION OF THE DISCLOSURE As generally described herein, the present disclosure provides compounds (e.g., compounds of Formula (I), and its subformulas (Ia), (Ib), and (Ic), or compounds of Table 1, or pharmaceutically acceptable salts thereof) that are useful for disorders (e.g., polycystic kidney disease) associated with modulation of TRPML. “TRPML”, “TRPML ion channel” and “TRPML channel” are used interchangeably throughout. Compounds In an aspect, provided is a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein W ¹ is N or CR ⁵ ; W ² is N or CR ⁶ ; R ¹ is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each R ¹ optionally substituted by 1-5 independently selected R ⁷ ; R ² is aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -O-cycloalkyl, -O-heterocycloalkyl, C _1-6 alkyl, C _1-6 alkoxy, -(CH ₂ ) _1-2 -cycloalkyl, -(CH ₂ ) _1-2 -heterocycloalkyl, or NR ^a R ^b , each R ² optionally substituted by 1-5 independently selected R ⁸ ; each of R ⁴ , R ⁵ , and R ⁶ is independently selected from the group consisting of 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 ; each of R ⁷ and R ⁸ are independently selected at each occurrence 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 _1-6 alkyl and C _1-6 alkoxy are optionally substituted with substituents independently selected from the group consisting of halogen, hydroxyl, and C _1-6 alkoxy, and each C _3-7 cycloalkyl is optionally substituted with substituents independently selected from the group consisting of halogen, hydroxyl, C _1-6 alkoxy and C _1-6 alkyl; or when R ¹ or R ² is cycloalkyl or heterocycloalkyl, two R ⁷ or two R ⁸ on the same carbon 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 ring of 3-7 members, or a bridge of 1 to 3 carbons or a single bond, wherein the ring or bridge is optionally substituted with 1- 3 substituents independently selected from the group consisting of halogen, hydroxyl, C _1-6 haloalkyl, and C1-6 alkyl; R ⁹ is C _1-6 alkyl or –(CH ₂ ) _0-2 -C _3-7 cycloalkyl, optionally substituted with substituents independently selected from the group consisting of deuterium, halogen, hydroxyl, C _1-3 alkyl, and C _1-6 alkoxy, wherein C _1-3 alkyl and C _1-6 alkoxy are optionally substituted with 1-5 substituents independently selected from the group consisting of deuterium, hydroxyl, C _1-3 haloalkyl, C _1-3 alkoxy and C _1-3 alkyl; each R ¹⁰ is selected independently from the group consisting of C _1-6 alkyl and C _1-6 haloalkyl, optionally substituted with substituents independently selected from the group consisting of deuterium, hydroxyl, and C _1-6 alkoxy; or two R ¹⁰ on the same carbon 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 ring of 3-7 members, or a bridge of 1 to 3 carbons or a single bond, wherein the ring or bridge is optionally substituted with 1-3 substituents independently selected from the group consisting of deuterium, halogen, hydroxyl, C _1-6 haloalkyl, and C _1-6 alkyl; each R ^a and R ^b is independently selected from H, C _1-6 alkyl, , C(O)-O-C _1-6 alkyl, C(O)-O-C _2-6 alkenyl, C(O)-C _1-6 alkyl, C(O)-C _2-6 alkenyl,–(CH ₂ ) _0-2 -C _3-7 cycloalkyl, and 3-7 membered heterocycloalkyl, wherein each alkyl, cycloalkyl or heterocycloalkyl is optionally substituted by 1-3 substituents selected from halogen and C _1-6 alkoxy; or R ^a and R ^b can be taken together with the nitrogen to which they are attached to form a 4-7 membered ring; 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; wherein 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 are not both aryl. 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 . In some embodiments, the compound is of formula (Ia) or a pharmaceutically acceptable salt thereof, wherein R ¹ is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each R ¹ optionally substituted by 1-5 independently selected R ⁷ ; R ² is aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -O-cycloalkyl, C _1-6 alkyl, C _1-6 alkoxy, or NR ^a R ^b , each R ² optionally substituted by 1-5 independently selected R ⁸ ; R ³ is each of R ⁴ and R ⁶ is independently selected from the group consisting of 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 ; each of R ⁷ and R ⁸ are independently selected at each occurrence 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 _1-6 alkyl and C _1-6 alkoxy are optionally substituted with substituents independently selected from the group consisting of halogen, hydroxyl, and C1-6 alkoxy, and each C _3-7 cycloalkyl is optionally substituted with substituents independently selected from the group consisting of halogen, hydroxyl, C _1-6 alkoxy and C _1-6 alkyl; or when R ¹ or R ² is cycloalkyl or heterocycloalkyl, two R ⁷ or two R ⁸ on the same carbon 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 ring of 3-7 members, or a bridge of 1 to 3 carbons or a single bond, wherein the ring or bridge is optionally substituted with 1- 3 substituents independently selected from the group consisting of halogen, hydroxyl, C _1-6 haloalkyl, and C _1-6 alkyl; R ⁹ is C _1-6 alkyl, optionally substituted with substituents independently selected from the group consisting of deuterium, halogen, hydroxyl, and C _1-6 alkoxy; each R ¹⁰ is selected independently from the group consisting of C _1-6 alkyl and C _1-6 haloalkyl, optionally substituted with substituents independently selected from the group consisting of deuterium, hydroxyl, and C _1-6 alkoxy; or two R ¹⁰ on the same carbon 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 ring of 3-7 members, or a bridge of 1 to 3 carbons or a single bond, wherein the ring or bridge is optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, hydroxyl, C1-6 haloalkyl, and C1-6 alkyl; each R ^a and R ^b is independently selected from 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 3-7 membered heterocycloalkyl, wherein each alkyl, cycloalkyl or heterocycloalkyl is optionally substituted by 1-3 substituents selected from halogen and C _1-6 alkoxy; or R ^a and R ^b can be taken together with the nitrogen to which they are attached to form a 4-7 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; wherein m + n is 2, 3, or 4; and R ¹ and R ² are not both aryl. In some embodiments, the compound is a compound of formula (Ia) or a pharmaceutically acceptable salt thereof, wherein R ¹ is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each R ¹ optionally substituted by 1-5 independently selected R ⁷ ; R ² is C _1-6 alkyl or C _3-7 cycloalkyl, optionally substituted by 1-5 independently selected R ⁸ ; R ³ is each of R ⁴ and R ⁶ is independently selected from the group consisting of 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 ; each of R ⁷ and R ⁸ are independently selected at each occurrence 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 _1-6 alkyl and C _1-6 alkoxy are optionally substituted with substituents independently selected from the group consisting of halogen, hydroxyl, and C _1-6 alkoxy, and each C _3-7 cycloalkyl is optionally substituted with substituents independently selected from the group consisting of halogen, hydroxyl, C _1-6 alkoxy and C _1-6 alkyl; or when R ¹ or R ² is cycloalkyl or heterocycloalkyl, two R ⁷ or two R ⁸ on the same carbon 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 ring of 3-7 members, or a bridge of 1 to 3 carbons or a single bond, wherein the ring or bridge is optionally substituted with 1- 3 substituents independently selected from the group consisting of halogen, hydroxyl, C _1-6 haloalkyl, and C _1-6 alkyl; R ⁹ is C _1-6 alkyl, optionally substituted with substituents independently selected from the group consisting of deuterium, halogen, hydroxyl, and C _1-6 alkoxy; each R ¹⁰ is selected independently from the group consisting of C _1-6 alkyl and C _1-6 haloalkyl, optionally substituted with substituents independently selected from the group consisting of deuterium, hydroxyl, and C _1-6 alkoxy; or two R ¹⁰ on the same carbon 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 ring of 3-7 members, or a bridge of 1 to 3 carbons or a single bond, wherein the ring or bridge is optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, hydroxyl, C _1-6 haloalkyl, and C _1-6 alkyl; each R ^a and R ^b is independently selected from H, C _1-6 alkyl, C(O)-O-C _1-6 alkyl, C(O)-O-C _2-6 alkenyl,–(CH2)0-2-C3-7 cycloalkyl, and 3-7 membered heterocycloalkyl, wherein each alkyl, cycloalkyl or heterocycloalkyl is optionally substituted by 1-3 substituents selected from halogen and C _1-6 alkoxy; or R ^a and R ^b can be taken together with the nitrogen to which they are attached to form a 4-7 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; and wherein m + n is 2, 3, or 4. In some embodiments, the compound is a compound of formula (Ia) or a pharmaceutically acceptable salt thereof, wherein R ¹ is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each R ¹ optionally substituted by 1-5 independently selected R ⁷ ; R ² is C _1-6 alkyl, optionally substituted by 1-5 independently selected R ⁸ ; R ³ is each of R ⁴ and R ⁶ is independently selected from the group consisting of 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 ; each of R ⁷ and R ⁸ are independently selected at each occurrence 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 _1-6 alkyl and C _1-6 alkoxy are optionally substituted with substituents independently selected from the group consisting of halogen, hydroxyl, and C _1-6 alkoxy, and each C _3-7 cycloalkyl is optionally substituted with substituents independently selected from the group consisting of halogen, hydroxyl, C _1-6 alkoxy and C _1-6 alkyl; or when R ¹ or R ² is cycloalkyl or heterocycloalkyl, two R ⁷ or two R ⁸ on the same carbon 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 ring of 3-7 members, or a bridge of 1 to 3 carbons or a single bond, wherein the ring or bridge is optionally substituted with 1- 3 substituents independently selected from the group consisting of halogen, hydroxyl, C _1-6 haloalkyl, and C _1-6 alkyl; R ⁹ is C _1-6 alkyl, optionally substituted with substituents independently selected from the group consisting of deuterium, halogen, hydroxyl, and C _1-6 alkoxy; each R ¹⁰ is selected independently from the group consisting of C _1-6 alkyl and C _1-6 haloalkyl, optionally substituted with substituents independently selected from the group consisting of deuterium, hydroxyl, and C _1-6 alkoxy; or two R ¹⁰ on the same carbon 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 ring of 3-7 members, or a bridge of 1 to 3 carbons or a single bond, wherein the ring or bridge is optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, hydroxyl, C _1-6 haloalkyl, and C _1-6 alkyl; each R ^a and R ^b is independently selected from 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 3-7 membered heterocycloalkyl, wherein each alkyl, cycloalkyl or heterocycloalkyl is optionally substituted by 1-3 substituents selected from halogen and C _1-6 alkoxy; or R ^a and R ^b can be taken together with the nitrogen to which they are attached to form a 4-7 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; and wherein m + n is 2, 3, or 4. In some embodiments, the compound is a compound of formula (Ia) or a pharmaceutically acceptable salt thereof, wherein R ¹ is heteroaryl optionally substituted by 1-5 independently selected R ⁷ ; R ² is C _1-6 alkyl optionally substituted by 1-5 independently selected R ⁸ ; R ³ is each of R ⁴ and R ⁶ is H; each of R ⁷ and R ⁸ are independently selected at each occurrence 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 _1-6 alkyl and C _1-6 alkoxy are optionally substituted with substituents independently selected from the group consisting of halogen, hydroxyl, and C _1-6 alkoxy, and each C3-7 cycloalkyl is optionally substituted with substituents independently selected from the group consisting of halogen, hydroxyl, C _1-6 alkoxy and C _1-6 alkyl; R ⁹ is C _1-6 alkyl, optionally substituted with substituents independently selected from the group consisting of deuterium, halogen, hydroxyl, and C _1-6 alkoxy; each R ¹⁰ is selected independently from the group consisting of C _1-6 alkyl and C _1-6 haloalkyl, optionally substituted with substituents independently selected from the group consisting of deuterium, hydroxyl, and C _1-6 alkoxy; or two R ¹⁰ on the same carbon 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 ring of 3-7 members, or a bridge of 1 to 3 carbons or a single bond, wherein the ring or bridge is optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, hydroxyl, C _1-6 haloalkyl, and C _1-6 alkyl; each R ^a and R ^b is independently selected from 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 3-7 membered heterocycloalkyl, wherein each alkyl, cycloalkyl or heterocycloalkyl is optionally substituted by 1-3 substituents selected from halogen and C _1-6 alkoxy; or R ^a and R ^b can be taken together with the nitrogen to which they are attached to form a 4-7 membered ring; and p is 0, 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, the compound is a compound of formula (Ia) or a pharmaceutically acceptable salt thereof, wherein R ¹ is pyridyl optionally substituted by 1-5 independently selected R ⁷ ; R ² is C _1-6 alkyl optionally substituted by 1-5 independently selected R ⁸ ; R ³ is each of R ⁴ and R ⁶ is H; each of R ⁷ and R ⁸ are independently selected at each occurrence from the group consisting of deuterium, hydroxy, halogen, cyano, C _1-6 alkyl, and C _1-6 alkoxy; R ⁹ is C _1-6 alkyl, optionally substituted with substituents independently selected from the group consisting of deuterium, halogen, hydroxyl, and C _1-6 alkoxy; each R ¹⁰ is selected independently from the group consisting of C _1-6 alkyl, and C _1-6 haloalkyl, each optionally substituted with 1-5 deuterium; and p is 0, 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, R ¹ is aryl optionally substituted by 1-5 independently selected R ⁷ . In some embodiments, R ¹ is phenyl optionally substituted with 1-3 independently selected R ⁷ . In some embodiments, each R ⁷ is independently selected from H, halogen, cyano, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, or C _1-6 haloalkoxy. In some embodiments, R ¹ is heteroaryl, cycloalkyl, or heterocycloalkyl, each R ¹ optionally substituted by 1-5 independently selected R ⁷ . In some embodiments, R ¹ is heteroaryl or heterocycloalkyl, each R ¹ optionally substituted by 1-5 independently selected R ⁷ . In some embodiments, R ¹ is heteroaryl optionally substituted by 1-5 independently selected R ⁷ . In some embodiments, R ¹ is monocyclic heteroaryl optionally substituted by 1-5 independently selected R ⁷ . In some embodiments, R ¹ is monocyclic heteroaryl of 5-6 ring atoms with 1, 2 or 3 ring atoms selected independently from N, O, and S, wherein R ¹ is optionally substituted by 1-4 independently selected R ⁷ . In some embodiments, R ¹ is monocyclic nitrogen-containing heteroaryl of 5-6 ring atoms with 1, 2 or 3 ring atoms selected independently from N, O, and S, wherein R ¹ is optionally substituted by 1-4 independently selected R ⁷ . In some embodiments, R ¹ is monocyclic nitrogen-containing heteroaryl of 5-6 ring atoms with 1, 2 or 3 ring heteroatoms selected from N only, wherein R ¹ is optionally substituted by 1-4 independently selected R ⁷ . In some embodiments, R ¹ is pyridine, pyrimidine, pyrazine, pyridazine, thiazole, oxazole, pyrrole, imidazole, or pyrazole, optionally substituted by 1-4 independently selected R ⁷ . In some embodiments, R ¹ is pyridine, thiazole, or pyrazole, optionally substituted by 1-4 independently selected R ⁷ . In some embodiments, R ¹ is pyridine, optionally substituted by 1-4 independently selected R ⁷ . In some embodiments, R ¹ is 2-pyridyl, optionally substituted by 1-4 independently selected R ⁷ . In some embodiments, R ¹ is . In some embodiments, R ¹ is , optionally substituted by 1 ⁷ -4 independently selected R . In some embodiments, R ¹ is heterocycloalkyl of 4-8 ring atoms, wherein 1-3 ring atoms are selected from N, O, and S, and R ¹ is optionally substituted by 1-4 independently selected R ⁷ . In some embodiments, R ¹ is monocyclic heterocycloalkyl of 4-7 ring atoms, wherein 1-3 ring atoms are selected from N, O, and S, and R ¹ is optionally substituted by 1-4 independently selected R ⁷ . In some embodiments, R ¹ is tetrahydropyran, azetidine, pyrrolidine, morpholine, or piperidine, and R ¹ is optionally substituted by 1-4 independently selected R ⁷ . In some embodiments, R ¹ is C _3-7 cycloalkyl, optionally substituted by 1-4 independently selected R ⁷ . In some embodiments, R ¹ is a cyclohexyl with an optional one or two carbon bridged ring, and R ¹ is optionally substituted by 1-4 independently selected R ⁷ . In some embodiments, R ² is aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -O- cycloalkyl, -O-heterocycloalkyl, C _1-6 alkoxy, C _1-6 alkyl, or NR ^a R ^b , each R ² optionally substituted by 1-5 independently selected R ⁸ , and wherein R ^a and R ^b of the R ² group are not both H. In some embodiments, R ² is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each R ² optionally substituted by 1-5 independently selected R ⁸ . In some embodiments, R ² is aryl optionally substituted by 1-5 independently selected R ⁸ . In some embodiments, R ² is phenyl optionally substituted with 1-3 independently selected R ⁸ . In some embodiments, each R ⁸ is independently selected from H, halogen, cyano, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, or C _1-6 haloalkoxy. In some embodiments, R ² is In some embodiments, R ² is heteroaryl, cycloalkyl, or heterocycloalkyl, each R ² optionally substituted by 1-5 independently selected R ⁸ . In some embodiments, R ² is heteroaryl or heterocycloalkyl, each R ² optionally substituted by 1-5 independently selected R ⁸ . In some embodiments, R ² is heteroaryl optionally substituted by 1-5 independently selected R ⁸ . In some embodiments, R ² is monocyclic heteroaryl optionally substituted by 1-5 independently selected R ⁸ . In some embodiments, R ² is monocyclic heteroaryl of 5-6 ring atoms with 1, 2 or 3 ring atoms selected independently from N, O, and S, wherein R ² is optionally substituted by 1-4 independently selected R ⁸ . In some embodiments, R ² is pyridine, pyrimidine, pyrazine, pyridazine, thiazole, oxazole, pyrrole, imidazole, or pyrazole, optionally substituted by 1-4 independently selected R ⁸ . In some embodiments, R ² is pyridine, pyrimidine, pyrazine, or pyrazole, optionally substituted by 1-4 independently selected R ⁸ . In some embodiments, R ² is pyridine, optionally substituted by 1-4 independently selected R ⁸ . In some embodiments, R ² is i In some embodiments, R ² is wherein R ² is not further substituted. In some embodiments, R ² is In some embodiments, R ² is cycloalkyl optionally substituted by 1-5 independently selected R ⁸ . In some embodiments, R ² is C _3-8 cycloalkyl optionally substituted with 1-5 independently selected R ⁸ . In some embodiments, R ² is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each optionally substituted with 1-3 independently selected R ⁸ . In some embodiments, R ² is not substituted. In some embodiments, R ² is cyclopropyl. In some embodiments, R ² is heterocycloalkyl optionally substituted by 1-5 independently selected R ⁸ . In some embodiments, R ² is monocyclic heterocycloalkyl optionally substituted by 1-5 independently selected R ⁸ . In some embodiments, R ² is monocyclic heterocycloalkyl of 4-6 ring atoms with 1, 2 or 3 ring atoms selected independently from N, O, and S, wherein R ² is optionally substituted by 1-4 independently selected R ⁸ . In some embodiments, R ² is azetidine, oxetane, pyrrolidine, tetrahydrofuran, piperidine, piperazine, tetrahydropyran, or morpholine, optionally substituted by 1-4 independently selected R ⁸ . In some embodiments R ² is azetidine, pyrrolidine, piperazine, or morpholine, optionally substituted by 1-4 independently selected R ⁸ . In some embodiments, R ² contains a ring nitrogen atom and is bound to formula (I) at the ring nitrogen atom. In some embodiments, In some embodiments, R ² is NR ^a R ^b , each R ² optionally substituted by 1-5 independently selected R ⁸ , and wherein R ^a and R ^b of the R ² group are not both H. In some embodiments, R ^a is C _1-6 alkyl, and R ^b is C _1-6 alkyl, C _3-7 cycloalkyl, or 3-7 membered heterocycloalkyl. In some embodiments, R ^a and R ^b are each independently selected C _1-6 alkyl. In some embodiments, each R ⁸ is independently selected from deuterium, hydroxy, halogen, cyano, or C _1-6 alkoxy. In some embodiments, R ² is C _1-6 alkyl optionally substituted by 1-5 independently selected R ⁸ . In some embodiments, R ² is C _1-6 alkyl optionally substituted by 1-5 independently selected halogens. In some embodiments, R ² is Me, Et, CHF ₂ , or CF ₃ . In some embodiments, R ² is CHF ₂ . In some embodiments, R ² is CF ₃ . In some embodiments, R ² is not substituted. In some embodiments, R ² is O-cycloalkyl, -O-heterocycloalkyl, or C _1-6 alkoxy, each R ² optionally substituted by 1-5 independently selected R ⁸ . In some embodiments, R ² is -O- C _3-7 cycloalkyl or C _1-6 alkoxy, each R ² optionally substituted by 1-5 groups independently selected from alkyl and halogen. In some embodiments, R ² is -O-C _3-7 cycloalkyl or C _1-6 alkoxy, each R ² optionally substituted by 1-5 independently selected halogens. In some embodiments, R ² is -O-cyclobutyl, -O-propyl, -O-methyl, -OCHF ₂ , or -O-CF ₃ . In some embodiments, m is 1 and n is 1. In some embodiments, p is 0, 1, 2, 3, 4, 5, or 6. In some embodiments, each R ¹⁰ is independently selected from the group consisting of C _1-6 alkyl and C _1-6 haloalkyl, each optionally substituted with 1-5 deuteriums. In some embodiments, each R ¹⁰ is methyl. In some embodiments, p is 1, 2, 3, 4, 5, or 6. In some embodiments, R ³ is substituted with an edge fused or spiro fused cyclopropane; or R ³ includes a one or two carbon bridge or a single bond bridge; and R ³ is optionally additionally substituted by 1-4 R ¹⁰ . In some embodiments, R ³ is optionally additionally substituted by 1-4 R ¹⁰ . In some embodiments, R ³ is additionally substituted by 1-4 R ¹⁰ . In some embodiments, R ³ is In some embodiments, R ³ is not substituted by any additional R ¹⁰ . 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 are H. In some embodiments, R ⁴ , R ⁵ , and R ⁶ are H. In some embodiments, each of R ⁷ and R ⁸ are independently selected at each occurrence 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 alkoxy is optionally substituted with 1-3 halogens. In some embodiments, each R ⁷ is independently selected at each occurrence from the group consisting of halogen, cyano, C _1-6 alkyl, C _1-6 alkoxy, and CF ₃ . In some embodiments, R ⁹ is C _1-6 alkyl optionally substituted with 1-5 halogens or 1-9 deuteriums. In some embodiments, R ⁹ is ethyl, isopropyl, or t-butyl; each optionally substituted with 1-5 halogens or 1-9 deuteriums. In some embodiments, R ⁹ is ethyl, isopropyl, or t-butyl. In some embodiments, R ⁹ is t-butyl. In some embodiments, R ⁹ is - C(CD ₃ ) ₃ , -CH(CD ₃ ) ₂ , or -CD ₂ CD ₃ . In some embodiments, R ⁹ is Me, Et, t-butyl, -C(CD ₃ ) ₃ , -CH(CD ₃ ) ₂ , -C(CD ₃ ) ₃ , . In some embodiments, R ⁹ is Me, Et, t-butyl, -C(CD ₃ ) ₃ , -CH(CD ₃ ) ₂ , -C(CD ₃ ) ₃ , isopropyl, In another aspect, provided is a compound of formula (Ib) wherein the variable definitions are as described in the specification and claims. In another aspect, provided is a compound of formula (Ic) wherein the variable definitions are as described in the specification and claims. In another aspect, provided is a compound of Formula (I), or any subformula thereof, selected from the compounds disclosed in the specification or claims, or a pharmaceutically acceptable salt thereof. 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 a TRPML and has an EC ₅₀ less than 1 µM. 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 ₅₀ less than 1 µM. In some embodiments, the compound achieves a maximal current obtained with 30 µM ML-SA1 in a patch clamp assay for TRPML1 which is at least 10 fold the maximal current achieved for any other TRPML. In another aspect pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound selected from the compounds disclosed in the specification or 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. Table 1. Exemplary compounds Cmpd _No. ^Structure N N _N N 149 N N O O N N _N N 150 N N O O F Cl N N N 151 N N N O O Cmpd _No. ^Structure N N N N N 445 N N O O N N N N 446 N N O O N _N N N N N F 447 N N O O

Cmpd N _o. ^Structure CN N N _N N 604 _N ^CF ₃ N O O F ₃ C CN N N _N 605 ^N N F F N H ₃ C O O CN N N _N N 606 _N ^CHF ₂ N O O D _3C CD _{CD3 3} Cmpd N _o. ^Structure CN N _N N 616 N N O O CN N N N _N N 617 N CF ₃ N O O N CN N N _N N 618 N CF ₃ N O O Cmpd N _o. ^{Structure N} _O N _N N 1004 N N O O F F N _N 1005 ^N N N _N N O O F F N _N 1006 N N F ₃ C N B ^oc Deuterated Compounds In some embodiments, compounds described herein herein (e.g., a compound of Formula I, Ia, Ib, or Ic) are deuterium enriched. Deuterium (D or ² H) is a stable, non-radioactive isotope of hydrogen and has an atomic weight of 2.0144. Hydrogen naturally occurs as a mixture of the isotopes ¹ H (hydrogen or protium), D ( ² H or deuterium), and T ( ³ H or tritium). The natural abundance of deuterium is 0.015%. One of ordinary skill in the art recognizes that in all chemical compounds with a H atom, the H atom actually represents a mixture of H and D, with about 0.015% being D. Thus, compounds with a level of deuterium that has been enriched to be greater than its natural abundance of 0.015% should be considered unnatural and, as a result, novel over their non-enriched counterparts. The effects of deuterium modification on a compound’s metabolic properties are not predictable, even when deuterium atoms are incorporated at known sites of metabolism. Only by actually preparing and testing a deuterated compound can one determine if and how the rate of metabolism will differ from that of its non-deuterated counterpart. See, for example, Fukuto et al. (J. Med. Chem.1991, 34, 2871-76). Many compounds have multiple sites where metabolism is possible. The site(s) where deuterium substitution is required and the extent of deuteration necessary to see an effect on metabolism, if any, will be different for each compound. Unless otherwise stated, when a position is designated specifically as “H” or “hydrogen,” the position is understood to have hydrogen at its natural abundance isotopic composition. Also, unless otherwise stated, when a position is designated specifically as “D” or “deuterium,” the position is understood to have deuterium at an abundance that is at least 3000 times greater than the natural abundance of deuterium, which is 0.015% (i.e., the term ”D” or “deuterium” indicates at least 45% incorporation of deuterium). The term “isotopic enrichment factor” as used herein means the ratio between the isotopic abundance of D at the specified position in a compound of this invention and the naturally occurring abundance of that isotope. Increasing the amount of deuterium present in a compound herein (e.g., a compound of Formula I, Ia, Ib, or Ic) is called “deuterium-enrichment,” and such compounds are referred to as “deuterium-enriched” compounds. If not specifically noted, the percentage of enrichment refers to the percentage of deuterium present in the compound. In other embodiments, a compound of this invention has an isotopic enrichment factor for each deuterium present at a site designated at a potential site of deuteration 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), at least 6633.3 (99.5% deuterium incorporation). It is understood that the isotopic enrichment factor of each deuterium present at a site designated as a site of deuteration is independent of other deuterated sites. For example, if there are two sites of deuteration on a compound one site could be deuterated at 52.5% while the other could be deuterated at 75%. The resulting compound would be considered to be a compound wherein the isotopic enrichment factor is at least 3500 (52.5%). Because the natural abundance of deuterium is about 0.015%, a small percentage of naturally occurring compounds of herein (e.g., a compound of Formula I, Ia, Ib, or Ic) would be expected to have one naturally occurring compound with one deuterium present. In some embodiments, the compounds herein (e.g., a compound of Formula I, Ia, Ib, or Ic) comprise an amount of deuterium-enrichment that is more than the amount of deuterium-enrichment present in naturally occurring compounds herein (e.g., a compound of Formula I, Ia, Ib, or Ic) All percentages given for the amount of deuterium present are mole percentages. It can be difficult in the laboratory to achieve 100% deuteration at any one site of a lab scale amount of compound (e.g., milligram or greater). When 100% deuteration is recited or a deuterium atom is specifically shown in a structure, it is assumed that a small percentage of hydrogen may still be present. Deuterium-enriched can be achieved by either exchanging protons with deuterium or by synthesizing the molecule with enriched starting materials. Methods of Treatment Provided herein, in certain embodiments, is a method of modulating TRPML ion channels, the method comprising administering to a patient in need thereof a compound described herein (e.g., a compound of Formula I, Ia, Ib, or Ic) or pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopically labeled derivatives thereof, or a composition described herein. Provided herein, in certain embodiments, is a method of treating a disease or disorder that can be treated by modulation of TRPML ion channels, the method comprising administering to a patient in need thereof a compound described herein (e.g., a compound of Formula I, Ia, Ib, or Ic) or pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopically labeled derivatives thereof, or a composition described herein. Provided herein, in certain embodiments, is a method of treating a disease or disorder that can be treated by activation of TRPML ion channels, the method comprising administering to a patient in need thereof a compound described herein (e.g., a compound of Formula I, Ia, Ib, or Ic) or pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopically labeled derivatives thereof, or a composition described herein. Provided herein, in certain embodiments, is a method of treating a disease or disorder that can be treated by activation of TRPML1, the method comprising administering to a patient in need thereof a compound described herein (e.g., a compound of Formula I, Ia, Ib, or Ic) or pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopically labeled derivatives thereof, or a composition described herein. In addition to compounds of Formula I, Ia, Ib, or Ic, modulators of the TRPML channels have been reported in several publications, including WO2018005713 and WO2018208630, which are incorporated herein in their entirety. 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. 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. In some embodiments, modulation of the TRPML ion channel comprises activation of the ion channel. In some embodiments, the disease or disorder is a ciliopathy (e.g., polycystic kidney disease). Exemplary ciliopathies include, but not limited to, polycystic kidney disease, pancreatic cysts in polycystic kidney disease, Bardet-Biedl syndrome, nephronophthisis, Joubert Syndrome, Mecke-Gruber Syndrome, oral-facial-digital syndrome, Senior Loken Syndrome, Birt-Hogg-Dube syndrome, Leber’s congenital amaurosis, Alstrom syndrome, Jeune asphyxiating thoracic dystrophy, Ellis van Creveld syndrome, Sensenbrenner syndrome, and primary ciliary dyskinesia. In an aspect, provided is a method of treating a disorder which can be treated by modulation of lysosomes, the method comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition of the disclosure or a compound of the disclosure. In an aspect, provided is a method of treating a disorder selected from the group consisting of a ciliopathy, neurodegenerative disease, lysosomal storage disorder, lysosomal transport disorder, glycogen storage disorder, cholesteryl ester storage disease, a muscular disease (e.g., muscular dystrophy), a disease related to aging (e.g., photo aging of the skin), macular degeneration (e.g., Stargardt’s or age-related), and cancer (e.g., cancers of the blood, brain, bone, lung, liver, kidney, bladder, stomach, breast, prostate, ovary, testes, colon, pancreas, or skin), the method comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition of the disclosure or a compound of the disclosure. In some embodiments, the disorder is a ciliopathy. In some embodiments, the ciliopathy is selected from the group consisting of polycystic kidney disease, pancreatic cysts in polycystic kidney disease, Bardet-Biedl syndrome, nephronophthisis, Joubert Syndrome, Mecke-Gruber Syndrome, oral-facial-digital syndrome, Senior Loken Syndrome, Birt-Hogg-Dube syndrome, Leber’s congenital amaurosis, Alstrom syndrome, Jeune asphyxiating thoracic dystrophy, Ellis van Creveld syndrome, Sensenbrenner syndrome, and primary ciliary dyskinesia. 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 pancreatic cysts associated with autosomal dominant polycystic kidney disease. In some embodiments, the disorder is autosomal dominant polycystic kidney disease. In some embodiments, the disorder is a neurodegenerative disorder. 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, Lewy body dementia, Pick’s disease, and multi system atrophy. In some embodiments, the disorder is a lysosomal storage disorder. In some embodiments, the lysosomal storage disorder is selected from the group consisting of Niemann-Pick disease, Gaucher’s disease, neuronopathic Gaucher’s disease, sphingolipidoses, Farber disease, Krabbe disease, Galactosialidosis, gangliosidoses, Gaucher Disease, Lysosomal acid lipase deficiency, sulfatidoses, mucopolysaccharidoses, mucolipidoses, lipidoses, and oligosaccharidoses. In some embodiments, the lysosomal storage disorder is selected from the group consisting of sphingolipidoses, Farber disease, Krabbe disease, Galactosialidosis, Fabry disease, Schindler disease, beta-galactosidase disorder, GM1 gangliosidosis, GM2 gangliosidosis AB variant, GM2 gangliosidosis activator 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 sundrome, Hurler-Scheie syndrome, Hunter syndrome, Sanfilippo syndrome, Morquio syndrome, Maroteaux-Lamy syndrome, Sly syndrome, hyaluronidase deficiency, sialidosis, I-cell disease, pseudo-Hurler polydystrophy, phosphotransferease deficiency, mucolipidin 1 deficiency, Santavuori-Haltia disease, Jansky-Bielchowsky disease, Batten-Spielmeyer-Vogt disease, Kufs disease, Finnish variant neuronal ceroid lipfuscinosis, late infantile variant neuronal ceroid lipfuscinosis, type 7 neuronal ceroid lipfuscinosis, northern epilepsy neuronal ceroid lipfuscinosis, Turkish late infantile neuronal ceroid lipfuscinosis, German/Serbian late infantile neuronal ceroid lipfuscinosis, congential cathepsin D deficiency, Wolman disease, alpha-mannosidosis, beta-mannosidosis, aspartylgluosaminuria, and fucosidosis. In some embodiments, the lysosomal storage disorder is selected from the group consisting of Niemann-Pick disease, Gaucher’s disease, and neuronopathic Gaucher’s disease. In some embodiments, the disorder is a lysosomal transport disease selected from the group consisting of cystinosis, pycnodysostosis, Salla disease, sialic acid storage disease, and infantile free sialic acid storage disease. In some embodiments, the disorder is a glycogen storage disease selected from the group consisting of Pompe disease and Danon disease. In an aspect, provided is a method of treating a ciliopathy disorder, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound capable of modulating TRPML, or a therapeutically effective amount of a pharmaceutical composition comprising the compound and a pharmaceutically acceptable excipient. In some embodiments, the compound is selected from the compounds disclosed in the specification. In some embodiments, the ciliopathy 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, oral-facial- digital syndrome, Senior Loken Syndrome, Birt-Hogg-Dube syndrome, Leber’s congenital amaurosis, Alstrom syndrome, Jeune asphyxiating thoracic dystrophy, Ellis van Creveld syndrome, Sensenbrenner syndrome, and primary ciliary dyskinesia. 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 pancreatic cysts associated with autosomal dominant polycystic kidney disease. 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. In some embodiments, the method is to treat a ciliopathy. In some embodiments, the second therapeutic agent is selected from the group consisting of an mTOR inhibitor, V2 receptor antagonist, tyrosine kinase inhibitor, somatostatin analog, glucosylceramide synthase inhibitor, microRNA-17 inhibitor, siRNA against p53, KEAP1-Nrf2 activator, xanthine oxidase inhibitor, PPARγ agonist, metformin, and beta hydroxybutyrate. 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, venglustat, eliglustat, miglustat, microRNA-17 inhibitor, bardoxolone methyl, allopurinol, oxypurinol, pioglitazone, rosiglitazone, lobeglitazone, metformin, and beta hydroxybutyrate. In some embodiments, the second agent is tolvaptan. In some embodiments, the second therapeutic agent is selected from the group consisting of an immunomodulator, 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 stimulant, 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, a beta blocker, a mineralocorticoid receptor antagonist, a loop or thiazide diuretic, a calcium channel blocker, a statin, a short- intermediate or long-acting insulin, a dipeptidyl peptidase 4 inhibitor, a glucagon-like peptide 1 receptor agonist, a sulfonylurea, an apoptosis signal-regulating kinase- 1, a chymase inhibitor, a selective gly cation inhibitor, a renin inhibitor, an interleukin-33 inhibitor, a farnesoid X receptor agonist, a soluble guanylate cyclase stimulator, a thromboxane receptor antagonist, a xanthine oxidase inhibitor, an erythropoietin receptor agonist, a cannabinoid receptor type 1 inverse agonist, a NADPH oxidase inhibitor, an anti-vascular endothelial growth factor B, an anti-fibrotic agent, a neprilysin inhibitor, a dual CD80/CD86 inhibitor, a CD40 antagonist, a cellular cholesterol and lipid blocker, a PDGFR antagonist, a Slit guidance ligand 2, an APOLl inhibitor, an Nrl2 activator/NF-kB inhibitor, a somatostatin receptor agonist, a PPAR gamma agonist, a AMP activated protein kinase stimulator, a tyrosine kinase inhibitor, a glucosylceramide synthase inhibitor, an arginine vasopressin receptor 2 antagonist, a xanthine oxidase inhibitor, a vasopressin receptor 2 antagonist, 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 agents capable of treating Alzheimer’s (e.g., acetylcholinesterase inhibitors such as tacrine, rivastigmine, galantamine, donepezil, and NMDA receptor antagonists such as memantine). In some embodiments, the second therapeutic agent is selected from the group consisting of COX inhibitors including arylcarboxylic acids (salicylic acid, acetylsalicylic acid, diflunisal, choline magnesium trisalicylate, salicylate, 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, pirprofen, tolmetin, zomepirac, clopinac, indomethacin and sulindac) and enolic acids (phenylbutazone, oxyphenbutazone, azapropazone, feprazone, piroxicam, and isoxicam; treatments for pulmonary hypertension including prostanoids (epoprostenol, iloprost, and treprostinil), endothelin receptor antagonists (bosentan, ambrisentan, and macitentan), phosphodiesterase-5 inhibitors (sildenafil and tadalafil), and sGC stimulators (riociguat); rho-kinase inhibitors, such as Y-27632, 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 gunaylate cyclase inhibtors such as riociguat and vericiguat; calcium channel blockers, such as amlodipine, bepridil, clentiazem, diltiazem, 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; inhaled nitric oxide and nitric oxide- donating agents, such as inhaled nitrite; ΙκΒ inhibitors, such as IMD 1041 ; prostacyclin receptor agonists, such as selexipag; stimulators of hematopoiesis, such as TXA 127 (angiotensin (1-7)), darbepoetin alfa, erythropoetin, and epoetin alfa; anticoagulants and platelet-inhibiting agents; and diuretics; dietary and nutritional supplements such as acetyl- L-carnitine, octacosanol, evening primrose oil, vitamin B6, tyrosine, phenylalanine, vitamin C, L-dopa; immunosuppressants (for transplants and autoimmune-related RKD); anti-hypertensive drugs (for high blood pressure-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 treatments for hyperphosphatemia or hyperparathyroidism associated with CKD (e.g., sevelamer acetate, cinacalcet). The present disclosure further provides pharmaceutical compositions comprising a compound provided herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. The present disclosure further provides methods of 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. The present disclosure further provides a method of treating a disease or disorder in a subject, the method comprising: (a) detecting a disease or disorder associated with TRPML; and (b) administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof. In certain embodiments, exemplary compounds of Formula (I) or (II) include the compounds described in Table 1 and in the Examples, as well as pharmaceutically acceptable salts, solvates, hydrates, tautomers, and stereoisomers thereof. Accordingly, the present disclosure provides compounds useful for treating ciliopathies and related diseases. Compounds that modulate TRPML channels may be useful in the prophylaxis and treatment of any of the foregoing 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. This disclosure is not limited in its application to the details of the methods and compositions described herein. Also, the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. 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 are methods of 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. In certain embodiments, pharmaceutical compositions containing compounds described herein such as a compound of Formula I, Ia, Ib, or Ic, or pharmaceutically acceptable salt thereof can be used to treat or ameliorate a disorder described herein, for example, a ciliopathy. The amount and concentration of compounds of Formula I, Ia, Ib, or Ic in the pharmaceutical compositions, as well as the quantity of the pharmaceutical composition administered to a subject, can be selected based on clinically relevant factors, such as medically relevant characteristics of the subject (e.g., age, weight, gender, other medical conditions, and the like), the solubility of compounds in the pharmaceutical compositions, the potency and activity of the compounds, and the manner of administration of the pharmaceutical compositions. For further information on Routes of Administration and Dosage Regimes the reader is referred to Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990. While it is possible for a compound disclosed herein to be administered alone, it is preferable to administer the compound as a pharmaceutical formulation, where the compound is combined with one or more pharmaceutically acceptable diluents, excipients or carriers. The compounds according to the disclosure may be formulated for administration in any convenient way for use in human or veterinary medicine. In certain embodiments, the compound included in the pharmaceutical preparation may be active itself, or may be a prodrug, e.g., capable of being converted to an active compound in a physiological setting. Regardless of the route of administration selected, 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 pharmaceutically acceptable dosage forms such as described below or by other conventional methods known to those of skill in the art. Thus, another aspect of the present disclosure provides pharmaceutically acceptable compositions comprising a therapeutically effective amount of one or more of the compounds described above, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents. As described in detail below, the pharmaceutical compositions of the present disclosure may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), lozenges, dragees, capsules, pills, tablets (e.g., those targeted for buccal, sublingual, and systemic absorption), boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; (3) topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; (5) sublingually; (6) ocularly; (7) transdermally; (8) transmucosally; (9) nasally; or (10) intrathecally. Additionally, compounds can be implanted into a patient or injected using a drug delivery system. See, for example, 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. The phrase "therapeutically effective amount" as used herein means that amount of a compound, material, or composition comprising a compound of the present disclosure, which is effective for producing some desired therapeutic effect, e.g., by modulating EHMT1 or EHMT2, in at least a sub-population of cells in an animal and thereby blocking the biological consequences of that function in the treated cells, at a reasonable benefit/risk ratio applicable to any medical treatment. The phrases "systemic administration," "administered systemically," "peripheral administration" and "administered peripherally" as used herein mean the administration of a compound, drug, or other material other than directly into the central nervous system, such that it enters the patient's system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration. The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which 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, commensurate with a reasonable benefit/risk ratio. The phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject antagonists from one organ, or portion of the body, to another organ, or portion of the body. 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 which can serve 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 carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (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) buffering agents, 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 solutions; (21) cyclodextrins such as Captisol®; and (22) other non-toxic compatible substances employed in pharmaceutical formulations. The term "pharmaceutically acceptable salt" is meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds 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 salt, or a similar salt. When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, e.g., Berge et al, Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. These salts may be prepared by methods known to those skilled in the art. Other pharmaceutically acceptable carriers known to those of skill in the art are suitable for the present disclosure. Wetting agents, emulsifiers, and lubricants, 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 compositions. Examples of pharmaceutically acceptable antioxidants include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like. 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 being treated, the particular mode of administration. The amount of active ingredient that 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, out of one hundred per cent, this amount will range from about 1 per cent to about ninety-nine percent of active ingredient, preferably from about 5 per cent to about 70 per cent, most preferably from about 10 per cent to about 30 per cent. 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. Formulations of the disclosure suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present disclosure as an active ingredient. A compound of the present disclosure may also be administered as a bolus, electuary or paste. In solid dosage forms of the disclosure for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like. A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets, and other solid dosage forms of the 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 well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be sterilized by, for example, 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 may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal 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 micro-encapsulated form, if appropriate, with one or more of the above-described excipients. Liquid dosage forms for oral administration of the compounds of the 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, for example, 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 (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. 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. Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof. Formulations of the pharmaceutical compositions of the disclosure for rectal, vaginal, or urethral administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the disclosure with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound. Alternatively, or additionally, compositions can be formulated for delivery via a catheter, stent, wire, or other intraluminal device. Delivery via such devices may be especially useful for delivery to the heart, lung, bladder, urethra, ureter, rectum, or intestine. Furthermore, compositions can be formulated for delivery via a dialysis port. Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this disclosure. Exemplary modes of administration include, but are not limited to, injection, infusion, instillation, inhalation, or ingestion. “Injection” includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intraventricular, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, sub capsular, subarachnoid, intraspinal, intracerebro spinal, and intrasternal injection and infusion. In some embodiments, the compositions are administered by intravenous infusion or injection. The phrases "parenteral administration" and "administered parenterally" as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion. Pharmaceutical compositions of this disclosure suitable for parenteral administration comprise one or more compounds of the disclosure in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents. Examples of suitable aqueous and nonaqueous carriers that may be employed in the pharmaceutical compositions of the disclosure include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), 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. These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin. In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue. When the compounds of the present disclosure are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier. The addition of the active compound of the disclosure to animal feed is preferably accomplished by preparing an appropriate feed premix containing the active compound in an effective amount and incorporating the premix into the complete ration. Alternatively, an intermediate concentrate or feed supplement containing the active ingredient can be blended into the feed. The way in which such feed premixes and complete rations can be prepared and administered are described in reference books (such as "Applied Animal Nutrition", W.H. Freedman and CO., San Francisco, U.S.A., 1969 or "Livestock Feeds and Feeding" O and B books, Corvallis, Ore., U.S.A., 1977). Methods of introduction may also be provided by rechargeable or biodegradable devices. Various slow release polymeric devices have been developed and tested in vivo in recent years for the controlled delivery of drugs, including proteinacious biopharmaceuticals. A variety of biocompatible polymers (including hydrogels), including both biodegradable and non-degradable polymers, can be used to form an implant for the sustained release of a compound at a particular target site. Preferably, the subject is a mammal. The mammal can be a human, non-human primate, mouse, rat, dog, cat, horse, or cow, but are not limited to these examples. Mammals other than humans can be advantageously used as subjects that represent animal models of disorders associated with neurodegenerative disease or disorder, cancer, or viral infections. In addition, the methods described herein can be used to treat domesticated animals and/or pets. A subject can be male or female. A subject can be one who has been previously diagnosed with or identified as suffering from or having a neurodegenerative disease or disorder, a disease or disorder associated with cancer, a disease or disorder associated with viral infection, or one or more complications related to such diseases or disorders but need not have already undergone treatment. Dosages Actual dosage levels of the active ingredients in the pharmaceutical compositions of this disclosure may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. The selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present disclosure employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts. 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 could start doses of the compounds of the disclosure employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. The compound and the pharmaceutically active agent can be administrated to the subject in the same pharmaceutical composition or in different pharmaceutical compositions (at the same time or at different times). When administrated 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, 24 hours of administration of the other agent. When the compound and the pharmaceutically active agent are administered in different pharmaceutical compositions, routes of administration can be different. The amount of compound that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound that produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 0.1% to 99% of compound, preferably from about 5% to about 70%, most preferably from 10% to about 30%. Toxicity and therapeutic efficacy can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD ₅₀ (the dose lethal to 50% of the population) and the ED ₅₀ (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD ₅₀ /ED ₅₀ . Compositions that exhibit large therapeutic indices are preferred. The data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED ₅₀ with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. The therapeutically effective dose can be estimated initially from cell culture assays. A dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the EC ₅₀ (i.e., the concentration of the therapeutic which achieves a half- maximal effect) as determined in cell culture. Levels in plasma may be measured, for example, by high performance liquid chromatography. The effects of any particular dosage can be monitored by a suitable bioassay. The dosage may be determined by a physician and adjusted, as necessary, to suit observed effects of the treatment. With respect to duration and frequency of treatment, it is typical for skilled clinicians to monitor subjects in order to determine when the treatment is providing therapeutic benefit, and to determine whether to increase or decrease dosage, increase or decrease administration frequency, discontinue treatment, resume treatment or make other alteration to treatment regimen. The dosing schedule can vary from once a week to daily depending on a number of clinical factors, such as the subject's sensitivity to the drugs. The desired dose can be administered at one time or divided into subdoses, e.g., 2-4 subdoses and administered over a period of time, e.g., at appropriate intervals through the day or other appropriate schedule. Such sub-doses can be administered as unit dosage forms. In some embodiments, administration is chronic, e.g., one or more doses daily over a period of weeks or months. Examples of dosing schedules are administration daily, twice daily, three times daily or four or more times daily over a period of 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months or more. The present disclosure contemplates formulation of the subject compounds in any of the aforementioned pharmaceutical compositions and preparations. Furthermore, the present disclosure contemplates administration via any of the foregoing routes of administration. One of skill in the art can select the appropriate formulation and route of administration based on the condition being treated and the overall health, age, and size of the patient being treated. Selected Chemical Definitions At various places in the present specification, substituents of compounds of the disclosure are disclosed in groups or in ranges. It is specifically intended that the disclosure include each and every individual subcombination of the members of such groups and ranges. For example, the term “C _1-6 alkyl” is specifically intended to individually disclose methyl, ethyl, propyl, butyl, pentyl, and hexyl For compounds of the disclosure in which a variable appears more than once, each variable can be a different moiety selected from the Markush group defining the variable. For example, where a structure is described having two R groups that are simultaneously present on the same compound; the two R groups can represent different moieties selected from the Markush group defined for R. It is further appreciated that certain features of the 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 disclosure which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination. In case a compound of the present disclosure is depicted in form of a chemical name and as a formula in case of any discrepancy the formula shall prevail. An asterisk or wavy line may be used in sub-formulas to indicate the bond which is connected to the core molecule as defined. The term "substituted," as used herein, means that any one or more hydrogens on the designated atom, usually a carbon, oxygen, or nitrogen atom, is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto or oxo (i.e. , then 2 hydrogens on the atom are replaced. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (e.g. , C=C, C=N, N=N, etc.). 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 C ₁ , C ₂ , C ₃ , and C ₄ . C _1-6 alkyl is intended to include C ₁ C ₂ , C ₃ , C ₄ , C ₅ , and C ₆ alkyl groups and C _1-8 alkyl is intended to include C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , and C ₈ . Some examples of alkyl include, but are 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. As used herein, "alkenyl" is intended to include hydrocarbon chains of either straight or branched configuration and one or more unsaturated carbon-carbon bond that can occur in any stable point along the chain, such as ethenyl and propenyl. For example, C ₂ - ₆ alkenyl is intended to include C ₂ , C ₃ , C ₄ , C ₅ , and C ₆ alkenyl groups and C _2-8 alkenyl is intended to include C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , and C ₈ alkenyl groups. As used herein, "alkylene" is intended to include moieties which are diradicals, i.e. , having two points of attachment. A non-limiting example of such an alkylene moiety that is a diradical is -CH ₂ CH ₂ -, i.e., a C ₂ alkyl group that is covalently bonded via each terminal carbon atom to the remainder of the molecule. The alkylene diradicals are also known as "alkylenyl" radicals. Alkylene groups can be saturated or unsaturated (e.g., containing - CH=CH- or -C≡C- subunits), at one or several positions. In some embodiments, alkylene groups include 1 to 9 carbon atoms (for example, 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, iso-propylene, n-butylene, iso-butylene, sec-butylene, tert- butylene, n- pentylene, iso-pentylene, sec-pentylene and neo-pentylene. As used herein, "cycloalkyl" is intended to include saturated or unsaturated nonaromatic ring groups, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. For example, the term "C ₃ - ₈ cycloalkyl" is intended to include C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , and C ₈ cycloalkyl groups. Cycloalkyls may include multiple spiro- or fused or bridged rings. For example, cycloalkyl can include, but is not limited to, spiro butyl, pentyl, hexyl, heptyl, octyl, nonyl, or decyl groups, bicyclo butyl, pentyl, hexyl, heptyl, octyl, nonyl, or decyl groups, adamantyl groups, and norbornyl groups. As used herein, the term "heterocycloalkyl" refers to a saturated or unsaturated nonaromatic 3-8 membered monocyclic, 7-12 membered bicyclic (fused, bridged, or spiro rings), or 11-14 membered tricyclic ring system (fused, bridged, or spiro rings) having one or more heteroatoms (such as O, N, S, or Se), unless specified otherwise. A heterocycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring. In some embodiments, the heterocycloalkyl is a monocyclic 4-6 membered heterocycloalkyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur and having one or more oxidized ring members. In some embodiments, the heterocycloalkyl is a monocyclic or bicyclic 4-10 membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur and having one or more oxidized ring members. Examples of heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3, 6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, 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, l,4- dioxa-8-azaspiro[4.5]decanyl and the like. As used herein, "amine" or "amino" refers to unsubstituted - H ₂ unless otherwise specified. As used herein, "halo" or "halogen" refers to fluoro, chloro, bromo, and iodo substituents. As used herein, "haloalkyl" is intended to include both branched and straight- chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with one or more halogen (for example -C _v F _w H _2v . _w+1 wherein v = 1 to 3 and w = 1 to (2v+l)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. The term "haloalkoxy" as used herein refers to an alkoxy group, as defined herein, which is substituted one or more halogen. Examples of haloalkoxy groups include, but are not limited to, tnfluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, etc. 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. C _1-6 alkoxy, is intended to include C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , and C ₆ alkoxy groups. C _1-8 alkoxy, is intended to include C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , and C ₈ 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. As used herein, "aryl" includes groups with aromaticity, including "conjugated," or multicyclic systems with at least one aromatic ring and do not contain any heteroatom in the ring structure. Aryl may be monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings). The term "C _n-m aryl" refers to an aryl group having from n to m ring carbon atoms. In some embodiments, aryl groups have from 6 to 10 carbon atoms. In some embodiments, the aryl group is phenyl or naphthyl. As used herein, the terms "aromatic heterocycle," "aromatic heterocyclic" or "heteroaryl" ring are intended to mean a stable 5, 6, 7, 8, 9, 10, 11, or 12-membered monocyclic or bicyclic aromatic ring which consists of carbon atoms and one or more heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, independently selected from nitrogen, oxygen, and sulfur. In the case of bicyclic aromatic heterocyclic or heterocycle or heteroaryl rings, only one of the two rings needs to be aromatic (e.g., 2,3-dihydroindole), though both can be (e.g., quinoline). The second ring can also be fused or bridged as defined above for heterocycles. The nitrogen atom can be substituted or unsubstituted (i.e., N or R wherein R is H or another substituent, as defined). The nitrogen and sulfur heteroatoms can optionally be oxidized (i.e., N→O and S(O) _P , wherein p = 1 or 2). In certain compounds, the total number of S and O atoms in the aromatic heterocycle is not more than 1. Examples of aromatic heterocycles, aromatic heterocyclics or heteroaryls include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, benzooxadiazoly, carbazolyl, 4aH- carbazolyl, carbolinyl, cinnolinyl, furazanyl, imidazolyl, imidazolonyl, lH-indazolyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylbenztriazolyl, 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, tetrazolyl, 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, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, triazolopyrimidinyl, 1,2,3-triazolyl, 1,2,4- triazolyl, 1,2,5-triazolyl, and 1,3,4-triazolyl. The term "hydroxyalkyl" means an alkyl group as defined above, where the alkyl group is substituted with one or more OH groups. Examples of hydroxyalkyl groups include HO-CH ₂ -, HO-CH ₂ -CH ₂ - and CH ₃ -CH(OH)-. The term "cyano" as used herein means a substituent having a carbon atom joined to a nitrogen atom by a triple bond, i.e., C≡N. As used herein, "oxo" is means a "C=O" group. As used herein, the phrase "pharmaceutically acceptable" refers to those compounds or tautomers thereof, or salts thereof, materials, compositions, and/or dosage forms which 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, 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 a tautomer thereof, is modified by making of the acid or base salts thereof of the parent compound or a tautomer thereof. 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; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound, or a tautomer thereof, formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxy ethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodide, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicylic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, and toluene sulfonic. The pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound or a tautomer thereof that contains a basic or acidic moiety by conventional chemical methods. Generally, such pharmaceutically acceptable salts can be prepared by reacting the free acid or base forms of these compounds or tautomers thereof with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington 's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, PA, USA, p.1445 (1990). 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. As used herein, the term "treating" refers to administering a compound or pharmaceutical composition as provided herein for therapeutic purposes. The term "therapeutic treatment" refers to administering treatment to a patient already suffering from a disease thus causing a therapeutically beneficial effect, such as ameliorating existing symptoms, ameliorating the underlying metabolic causes of symptoms, postponing, or preventing the further development of a disorder, and/or reducing the severity of symptoms that will or are expected to develop. As used herein, "unsaturated" refers to compounds having at least one degree of unsaturation (e.g., at least one multiple bond) and includes partially and fully unsaturated compounds. As used herein, the term "effective amount" refers to an amount of a compound or a pharmaceutically acceptable salt of the compound or tautomer (including combinations of compounds and/or tautomers thereof, and/or pharmaceutically acceptable salts of said compound or tautomer) of the present disclosure that is effective when administered alone or in combination as an antimicrobial agent. For example, an effective amount refers to an amount of the compound or tautomer thereof, or a pharmaceutically acceptable salt said compound or tautomer that is present in a composition, a formulation given to a recipient patient or subject sufficient to elicit biological activity. In the specification, the singular forms also include the plural, unless the context clearly dictates otherwise. Unless defined otherwise, 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 the case of conflict, the present specification will control. As used herein, "mammal" refers to human and non-human patients. As used herein, the term "formulae of the disclosure" or "formulae disclosed herein" includes one or more of the Formulas I, its subformulas Ia, Ib, or Ic, and further subformulas thereof. As used herein, the term "compound of the disclosure" or "compound disclosed herein" includes one or more compounds of the formulae of the disclosure or a compound explicitly disclosed herein. All percentages and ratios used herein, unless otherwise indicated, are by weight. Throughout the description, where compositions are described as having, including, or comprising specific components, or where processes are described as having, including, or comprising specific process steps, it is contemplated that compositions of the present disclosure also consist essentially of, or consist of, the recited components, and that the processes of the present disclosure also consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps or order for performing certain actions are immaterial so long as the disclosure remains operable. Moreover, two or more steps or actions can be conducted simultaneously. Contemplated equivalents of the compounds described above include compounds which otherwise correspond thereto, and which have the same general properties thereof (e.g., the ability to modulate TRPML), wherein one or more simple variations of substituents are made which do not adversely affect the efficacy of the compound. In general, the compounds of the present disclosure may be prepared by the methods illustrated in the general reaction schemes as, for example, described below, or by modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are in themselves known but are not mentioned here. 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. "About" and "approximately" shall generally mean an acceptable degree of error for the quantity measured given the nature or precision of the measurements. Exemplary degrees of error are within 20 percent (%), typically, within 10%, and more typically, within 5% of a given value or range of values. The term, “treat” or “treatment,” as used herein, refers to the application or administration of a compound, alone or in combination with, an additional agent to a subject, e.g., a subject who has a disorder (e.g., a disorder as described herein), a symptom of a disorder, or a predisposition toward a disorder, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect the disorder. As used herein, the term “subject” is intended to include human and non-human animals. Exemplary human subjects include a human subject having a disorder, e.g., a disorder described herein. The term “non-human animals” of the disclosure includes all vertebrates, e.g., non-mammals (such as chickens, amphibians, reptiles) and mammals, such as non-human primates, domesticated and/or agriculturally useful animals, e.g., sheep, dog, cat, cow, pig, etc. The terms “antagonist” and “inhibitor” are used interchangeably to refer to an agent that decreases or suppresses a biological activity. The terms “activator” and “agonist” are used interchangeably to refer to an agent that increases or initiates a biological activity. The term "hydrate" as used herein, refers to a compound formed by the union of water with the parent compound. The term “preventing,” when used in relation to a condition, such as a local recurrence (e.g., pain), a disease such as cancer, a syndrome complex such as heart failure or any other medical condition, is well understood in the art, and includes administration of a composition which reduces the frequency of, or delays the onset of, symptoms of a medical condition in a subject relative to a subject which does not receive the composition. Thus, prevention of cancer includes, for example, reducing the number of detectable cancerous growths in a population of patients receiving a prophylactic treatment relative to an untreated control population, and/or delaying the appearance of detectable cancerous growths in a treated population versus an untreated control population, e.g., by a statistically and/or clinically significant amount. Prevention of an infection includes, for example, reducing the number of diagnoses of the infection in a treated population versus an untreated control population, and/or delaying the onset of symptoms of the infection in a treated population versus an untreated control population. Prevention of pain includes, for example, reducing the magnitude of, or alternatively delaying, pain sensations experienced by subjects in a treated population versus an untreated control population. The term "solvate" as used herein, refers to a compound formed by solvation (e.g., a compound formed by the combination of solvent molecules with molecules or ions of the solute).Another aspect of the disclosure features a pharmaceutical preparation suitable for use in a human patient, or for veterinary use, comprising an effective amount of a compound of the formulae of the disclosure (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 formulae of the disclosure in the manufacture of a medicament or pharmaceutical preparation to treat or reduce the symptoms of any of the diseases or conditions provided in the specification. The compounds of the formulae of the disclosure for use in treating a particular disease or condition can be formulated for administration via a route appropriate for the particular disease or condition. Compounds of the formulae of the disclosure can be administered alone or in combination with another therapeutic agent. For instance, the compounds of the formulae of the disclosure can be administered conjointly with one or more of an agent for treating polycystic kidney disease, etc. Compounds of the formulae of the disclosure can be administered topically, orally, transdermally, rectally, vaginally, parentally, intranasally, intrapulmonary, intraocularly, intravenously, intramuscularly, intraarterially, intrathecally, intracapsularly, intraorbitally, intracardiacly, intradermally, intraperitoneally, transtracheally, subcutaneously, subcuticularly, intraarticularly, subcapsularly, subarachnoidly, intraspinally, intrasternally, sublingually, or by inhalation. In some embodiments, compounds of Formula I, Ia, Ib, or Ic can be administered topically. In some embodiments, compounds of Formula I, Ia, Ib, or Ic can be administered orally. In some embodiments, compounds of Formula I, Ia, Ib, or Ic can be administered parentally. Compounds of Formula I, Ia, Ib, or Ic include molecules having an aqueous solubility suitable for oral or parenteral (e.g., intravenous) administration leading to or resulting in the treatment of a disorder described herein, for example the treatment of pain. In some embodiments, the compound is formulated into a composition suitable for oral administration. In some embodiments, a compound of Formula I, Ia, Ib, or Ic can be administered as part of an oral or parenteral (e.g., intravenous) pharmaceutical composition to treat a disorder described herein in a therapeutically effective manner. 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, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the disclosure. For example, if one chiral center is present in a molecule, the disclosure includes racemic mixtures, enantiomerically enriched mixtures, and substantially enantiomerically or diastereomerically pure compounds. The composition can contain, e.g., more than 50%, more than 60%, more than 70%, more than 80%, more than 90%, more than 95%, or more than 99% of a single enantiomer or diastereomer. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this disclosure. The “enantiomeric excess” or “% enantiomeric excess” of a composition can be calculated using the equation shown below. In the example shown below a composition contains 90% of one enantiomer, e.g., the S enantiomer, and 10% of the other enantiomer, i.e., the R enantiomer. ee = (90-10)/100 = 80%. Thus, a composition containing 90% of one enantiomer and 10% of the other enantiomer is said to have an enantiomeric excess of 80%. The “diastereomeric excess” or “% diastereomeric excess” of a composition can be calculated using the equation shown below. In the example shown below a composition contains 90% of one diastereomer, and 10% of another enantiomer. de = (90-10)/100 = 80%. Thus, a composition containing 90% of one diastereomer and 10% of the other diastereomer is said to have a diastereomeric excess of 80%. Certain compounds disclosed herein can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present disclosure. Certain compounds disclosed herein may 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. EXAMPLES Examples are provided below to facilitate a more complete understanding of the invention. The following examples illustrate exemplary modes of making and practicing the invention. However, the scope of the invention is not limited to specific embodiments disclosed in these Examples, which are for purposes of illustration only, since alternative methods can be utilized to obtain similar results. General. All oxygen and/or moisture sensitive reactions were carried out under N ₂ atmosphere in glassware that was flame-dried under vacuum (0.5 mmHg) and purged with N ₂ prior to use. All reagents and solvents were purchased from commercial vendors and used as received or synthesized according to the footnoted references. NMR spectra were recorded on a Bruker 400 (400 MHz ¹ H, 75 MHz ¹³ C) or Varian (400 MHz ¹ H, 75 MHz ¹³ C) spectrometer. Proton and carbon chemical shifts are reported in ppm (δ) referenced to the NMR solvent. Data are reported as follows: chemical shifts, multiplicity (br = broad, s = singlet, t = triplet, q = quartet, m = multiplet; coupling constant(s) in Hz). Unless otherwise indicated NMR data were collected at 25 ^o C. Flash chromatography was performed using 100-200 mesh Silica Gel. Liquid Chromatography/Mass Spectrometry (LCMS) was performed on Agilent 1200HPLC and 6110MS. Analytical thin layer chromatography (TLC) was performed on 0.2 mm silica gel plates. Visualization was accomplished with UV light and aqueous potassium permanganate (KMnO ₄ ) stain followed by heating. LCMS typical conditions: LC-MS conditions Instrument : LCMS2020(E-LCMS 008) Column : Shim-pack GIST C18 ,50*4.6mm 5um Mobile Phase : A: H2O(0.1%FA) B: CH3CN Temperature : 35¡æ Flow rate : 2.5mL/min Run time : 0.1min@20%B,1.7min gradient(20-95% B), then0.7min@95% B,then0.4min@20% B Injection volume : 5 uL Detector : UV 220/254nm Mass range : 100- 1000 Scan : Postive/Negative. HPLC Typical Conditions: Instrument : LC-20AD(E-LC 006) Column : YMC Triart C18, 50×4.6 mm,5um Mobile phase : Solvent A: H ₂ O/CH ₃ CN/TFA=90/10/0.1 Solvent B: H ₂ O/CH ₃ CN/TFA=10/90/0.1 Flow rate : 2.5mL/min Run time : 0.4 min@ 60% B, 3.4min gradient (60-100% B), then 0.8min@100%B. Temperature : 35°C Detector : UV. Or Instrument : LC-2010AHT(E-LC 001) Column : Gemini, C18 , 50×4.6 mm,5um Mobile phase : Solvent A: H ₂ O/CH ₃ CN/TFA=90/10/0.1 Solvent B: H ₂ O/CH ₃ CN/TFA=10/90/0.1 Flow rate : 2.5mL/min Run time : 0.4 min@ 20% B, 3.4min gradient (20-95% B), then 0.8min@95%B. Temperature : 40 ℃. Detector : UV. Table 2: Abbreviations

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) C ^{ompound 146} 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 following the procedure outlined in 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 ^o C overnight. After being cooled down to room temperature, solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford 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) ⁺ . 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) were added cyclopropylboronic acid (0.35 g, 4.1 mmol), K ₂ CO ₃ (9.5 g, 69 mmol) and Pd-118 (0.22 g, 0.34 mmol). The resulting mixture was heated to 80 ^o C overnight. After being cooled down to room temperature, the solvent was filtered. The filtrate was concentrated and purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford tert-butyl 4-(5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pip erazine-1- carboxylate (1.3 g, 76%) as a white solid. LC/MS ESI (m/z): 498 (M+H) ⁺ . 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 with EtOAc twice. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0~60%, ethyl acetate in 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) ⁺ . 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) were 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 K ₃ PO ₄ (190 mg, 0.87 mmol). The resulting mixture was heated to 120 ^o C overnight. After being cooled down to room temperature. The reaction was quenched with water, extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford 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, CDCl ₃ ) 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). The following compounds were prepared using a procedure analogous to the synthesis of compound 146 from the corresponding aryl halides, boronic esters or acids and amines. For analogs 474 and 475, trifluoro(oxetan-3-yl)-λ ⁴ -borane (potassium salt) was used in the coupling step. In case of analogs 465, 466, 467, 468, 469, and 470, the final product was obtained by hydrogenation, similar to Example 69, in the last step. 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-carbo xylate (Compound 134) 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 ^o C was added 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (5.0 g, 18 mmol) in portions. The resulting mixture was stirred at the same temperature for 30 minutes before TsCl (3.4 g, 18 mmol) was added in portions. After addition, the reaction was stirred at room temperature overnight. The reaction was poured into ice water, 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) ⁺ . 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 ^o C for 3 h under N ₂ . After being cooled down to room temperature, solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford 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) ⁺ . Step 3. tert-Butyl (2R,5S)-4-(5-(2-fluorophenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrim idin- 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 H ₂ O (6 mL) were added (2-fluorophenyl)boronic acid (0.68 g, 4.8 mmol), K ₂ CO ₃ (1.7 g, 12 mmol) and Pd(dppf)Cl ₂ (0.29 g, 0.40 mmol). The resulting mixture was stirred at 80 ^o C overnight under N ₂ . After being cooled down to room temperature, solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~20%, ethyl acetate in petroleum ether) to afford 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. LC/MS ESI (m/z): 580 (M+H) ⁺ . Step 4. tert-Butyl (2R,5S)-4-(5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-y l)- 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 with EtOAc twice. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0~60%, ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-4-(5-(2-fluorophenyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate (1.2 g, 85%) as a white solid. LC/MS ESI (m/z): 426 (M+H) ⁺ . 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) were 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 K ₃ PO ₄ (300 mg, 1.4 mmol). The resulting mixture was heated to 100 ^o C overnight. After being cooled down to room temperature, the reaction was partitioned between EtOAc and water, the organic layer was separated, and the aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford 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, 30 mg of which was further purified by prep-HPLC to afford 13 mg of white solid. LC/MS ESI (m/z): 503 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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). The following compounds were prepared by the procedure analogous to the synthesis of compound 134 from the corresponding aryl halides. 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-carbo xylate (Compound 137) C ^{ompound 137} 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-carbo xylate (80 mg, 0.16 mmol) in DCM (3 mL) was added HCl (4.0 mL, 4.0 M in dioxane). The resulting mixture was stirred at room temperature for 4h. After removal of solvent, the residue was diluted with DCM, washed with NaHCO ₃ (aq.), and the organic layer was extracted with DCM twice. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated to provide 4-((2S,5R)-2,5-dimethylpiperazin-1-yl)-5-(2-fluorophenyl)-7- (pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine which was carried directly to the next step. LC/MS ESI (m/z): 403 (M+H) ⁺ . 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 0 ^o C 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) was added TEA (0.062 mL, 0.45 mmol), followed by ethyl chloroformate (0.03 mL, 0.29 mmol) dropwise. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water, extracted with DCM twice and the combined organic layers were washed with NaHCO ₃ (aq.), dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to give the product which was further purified by prep-HPLC to afford ethyl (2R,5S)-4- (5-(2-fluorophenyl)-7-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimi din-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, CDCl ₃ ) 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). The following compounds were prepared using a procedure analogous to the synthesis of compound 137 from the corresponding aryl halides. 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-carboxyla te (Compound 159) C ^{ompound 159} Step 1. tert-Butyl 4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate The mixture of 4-chloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (3.0 g, 6.9 mmol, prepared following the procedure outlined in compound 134, step 1) and tert-butyl 3- methylpiperazine-1-carboxylate (5.6 g, 28 mmol) was heated to 150 ^o C for 3 h. After being cooled down to room temperature, the reaction was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford tert-butyl 4-(5-iodo-7-tosyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (2.0 g, 48%) as a white solid. LC/MS ESI (m/z): 598 (M+H) ⁺ . 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-carboxyla te 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) were 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 ₂ (dba) ₃ (0.31 g, 0.33 mmol ). The resulting mixture was stirred at 95 ^o C overnight. After being cooled down to room temperature, the reaction was quenched with water, extracted with DCM twice, the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to afford 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 in the next step directly. LC/MS ESI (m/z): 598 (M+H) ⁺ . 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-car boxylate (700 mg, 1.1 mmol) in dioxane (10 mL) and H ₂ O (2 mL) were added 2-bromopyridine (0.22 mL, 2.3 mmol), K ₂ CO ₃ (810 mg, 5.8 mmol) and Pd(dppf)Cl ₂ (86 mg, 0.11 mmol). The resulting mixture was heated to 90 ^o C overnight. After being cooled down to room temperature, solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~60%, ethyl acetate in petroleum ether) to afford 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) ⁺ . 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 with EtOAc twice. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0~10%, methanol in 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) ⁺ . 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) were added (5-chloro- 2-methylphenyl)boronic acid (130 mg, 0.76 mmol), Cu(OAc) ₂ (180 mg, 1.0 mmol), pyridine (0.12 mL, 1.5 mmol) and 4A molecular sieves (400 mg). The resulting mixture was heated to 40 ^o C for 3 days under an O ₂ atmosphere. After being cooled down to room temperature, the reaction was quenched with NH ₄ OH, diluted with DCM, and then filtered. The filtrate was extracted with DCM twice and the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~80%, ethyl acetate in petroleum ether) to give the product which was further purified by prep-HPLC to afford 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) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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). The following compounds were prepared using a procedure analogous to the synthesis of compound 159 from the corresponding aryl halides. 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-carboxyla te (Compound 280) C ^{ompound 280} 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 ^o C for 1.5 h. After being cooled down to room temperature, solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~20%, ethyl acetate in petroleum ether) to afford tert-butyl (S)- 4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylp iperazine -1-carboxylate (5.8 g, 84%) as a yellow solid. LC/MS ESI (m/z): 598 (M+H) ⁺ . 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-carboxyla te 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) were 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 ₂ (dba) ₃ (0.15 g, 0.16 mmol). The resulting mixture was stirred at 95 ^o C overnight. After being cooled down to room temperature. The reaction was quenched with water, extracted with DCM twice, the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to afford 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) ⁺ . 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-c arboxylate (1.0 g, 1.6 mmol) in dioxane (15 mL) and H ₂ O (3 mL) were added 2-bromopyridine (0.32 mL, 3.3 mmol), K ₂ CO ₃ (1.2 g, 8.3 mmol) and Pd(dppf)Cl ₂ (0.12 g, 0.16 mmol). The resulting mixture was heated to 90 ^o C overnight. After being cooled down to room temperature, the solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to afford 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) ⁺ . 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, 1.0M in THF). The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~10%, methanol in 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. LC/MS ESI (m/z): 395 (M+H) ⁺ . 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) were 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 K ₃ PO ₄ (160 mg, 0.76 mmol). The resulting mixture was heated to 120 ^o C overnight. After being cooled down to room temperature. The reaction was quenched with water, extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford tert-butyl (S)-4-(7-(3- cyanophenyl)-5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-y l)-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). The following compounds were prepared using a procedure analogous to the synthesis of compound 280 from the corresponding aryl halides.

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-carboxyla te (Compound 192) Step 1.4-Chloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine To a 0 ^o C 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 2.0M NaOH (0.53 L) dropwise. After addition, the reaction was allowed to warm up to room temperature and stirred for another 3 hours. The precipitate was collected by filtration, and washed with water twice 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) ⁺ . 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 ^o C under N ₂ atmosphere for 16 hours. After cooling to room temperature, the solvent was removed, and the residue was quenched with H ₂ O and EtOAc and the organic layer was separated. The aqueous phase was extracted with EtOAc twice, the combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was triturated with petroleum ether/EtOAc (10:1) and filtered to afford tert-butyl (R)-4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-met hylpiperazine- 1-carboxylate (48 g, 70%) as a light yellow solid. LC/MS ESI (m/z): 598 (M+H) ⁺ . 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) were added (2-fluorophenyl)boronic acid (77 mg, 0.55 mmol), K ₃ PO ₄ (210 mg, 1.0 mmol), and Pd(dppf)Cl ₂ (37 mg, 0.050 mmol). The resulting mixture was heated to 90℃ overnight. After being cooled down to room temperature, the solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~60% EtOAc in petroleum ether) to afford 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) ⁺ . 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) were added TBAF (3.0 mL, 1.0M 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 in petroleum ether) to afford 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)+. 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) were added trans-1,2-diaminocyclohexane (97 mg, 0.85 mmol), CuI (190 mg, 0.42 mmol) and K ₃ PO ₄ (180 mg, 0.84 mmol). The resulting mixture was stirred at 120 ^o C for 18 hrs. After being cooled down to room temperature, the reaction partitioned between EtOAc, and water and the organic layer was separated. The aqueous layer was extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC (Gilson, C18, MeCN in water) to afford 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) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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). 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-carboxyla te (Compound 226) C ^{ompound 226} 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, prepared following the procedure compound 259, step 1) in dioxane (10 mL) and water (1 mL) were added pyridin-3-ylboronic acid (160 mg, 1.3 mmol), Pd(dppf)Cl ₂ (86 mg, 0.12 mmol), and K ₂ CO ₃ (320 mg, 2.3 mmol). The resulting mixture was heated to 90℃ overnight. After being cooled down to room temperature, the solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~50% EtOAc in petroleum ether) to afford tert-butyl (S)-3- methyl-4-(5-(pyridin-3-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidi n-4-yl)piperazine-1-carboxylate (220 mg, 34%) as a light a yellow solid. LC/MS ESI (m/z): 549 (M+H) ⁺ . 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, 1.0M in THF). The resulting mixture was stirred at room temperature overnight. Solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~70% EtOAc in petroleum ether) to afford tert-butyl (S)-3- methyl-4-(5-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)p iperazine-1-carboxylate (120 mg, 78%) as a light yellow solid. LC/MS ESI (m/z): 395 (M+H) ⁺ . 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 mL, 0.12 mmol) in DMF (6 mL) were added CuI (19 mg, 0.10 mmol), K ₃ PO ₄ (43 mg, 0.20 mmol) and trans-1,2-diaminocyclohexane (23 mg, 0.20 mmol). The resulting mixture was stirred at 120℃ for 18 hrs. After being cooled down to room temperature, the reaction was partitioned between EtOAc and water, organic layer was separated, aqueous layer was extracted with EtOAc twice, 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 in petroleum ether) to give crude product which was further purified by prep-HPLC to afford 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 light yellow solid. LC/MS ESI (m/z): 489 (M+H) ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) 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). The following compound was prepared by the procedure analogous to the synthesis of compound 226 from the corresponding aryl halide. 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-carboxyla te (Compound 259) Step 1. tert-Butyl (S)-4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate To the 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℃ under N ₂ for 2 h. After being cooled down 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 in petroleum ether) to afford tert-butyl (S)-4-(5-iodo-7-tosyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (5.8 g, 54%) as a white solid. LC/MS ESI (m/z): 598 (M+H) ⁺ . Step 2. tert-Butyl (S)-4-(5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl )-3- methylpiperazine-1-carboxylate To the 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) were added Pd- (dtbp)Cl ₂ (220 mg, 0.34 mmol), K ₂ CO ₃ (3.0 g, 22 mmol) and cyclopropylboronic acid (220 mg, 2.5 mmol) respectively. The resulting reaction mixture was stirred at 80℃ for 4 h. After being cooled down to room temperature, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to afford 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) ⁺ . Step 3. tert-Butyl (S)-4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate To the 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 (4.0mL, 1.0M in THF). The resulting reaction mixture was stirred at r.t under N ₂ overnight. The reaction mixture was quenched with ice water, then it was extracted with EtOAc twice, the combined organic layers were washed with water and brine, dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0~80%, ethyl acetate in petroleum ether) to afford tert- butyl (S)-4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-meth ylpiperazine-1- carboxylate (250 mg, 83%) as a white solid. LC/MS ESI (m/z): 358 (M+H) ⁺ . 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 the 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) were added CuI (37 mg, 0.20 mmol), K ₃ PO ₄ (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) respectively. The resulting reaction mixture was stirred at 120℃ under N ₂ overnight. After being cooled down to rt, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0~40%, ethyl acetate in petroleum ether) and prep-HPLC (C-18, MeCN in H ₂ O) to afford tert-butyl (S)-4-(5-cyclopropyl-7-(5-isocyanopyridin-3-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carbox ylate (28 mg, 31%) as white solid. LC/MS ESI (m/z): 460 (M+H) ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) 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). The following compounds were prepared by the procedures analogous to the synthesis of compound 259 from the corresponding aryl halides.

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-methylpiperaz ine-1-carboxylate (Compound 266) 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 the 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) were added CuI (29 mg, 0.15 mmol), K ₃ PO ₄ (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) respectively. The resulting reaction mixture was stirred at 120℃ under N2 overnight. After being cooled down to room temperature, the reaction mixture was partitioned between EtOAc and water, organic layer was separated, aqueous layer was extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to afford 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 white solid. LC/MS ESI (m/z): 459 (M+H) ⁺ . Step 2. (S)-3-(5-Cyclopropyl-4-(2-methylpiperazin-1-yl)-7H-pyrrolo[2 ,3-d]pyrimidin- 7-yl)benzonitrile To the 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 temp under N ₂ overnight. Solvent was removed and the residue was diluted with DCM, washed with sat. NaHCO ₃ , organic layer was dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to obtain the crude product which was used in the next step without further purification. LC/MS ESI (m/z): 359 (M+H) ⁺ . 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-carbox ylate To the 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-carboxyla te (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℃ under N ₂ overnight. After being cooled down to room temperature, the reaction mixture was partitioned between EtOAc and water. the organic layer was separated, and the aqueous layer was extracted EtOAc twice. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by prep-HPLC to afford 1,1,1-trifluoro-2- methylpropan-2-yl (S)-4-(7-(3-cyanophenyl)-5-cyclopropyl-7H-pyrrolo[2,3-d]pyri midin-4- yl)-3-methylpiperazine-1-carboxylate (37 mg, 34%) as a white solid. LC/MS ESI (m/z): 513 (M+H) ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) 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). The following compounds were prepared by the procedures analogous to the synthesis of compound 266 from the corresponding aryl halides.

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-carbox ylate (Compound 274) C ^{ompound 274} Step 1.4-Chloro-7-(3-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimi dine To a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (10 g, 36 mmol) in DCM (400 mL) were added (3-chlorophenyl)boronic acid (8.7 g, 72 mmol), 4Å molecular sieves (5 g), Cu(OAc) ₂ (16 g, 89 mmol) and pyridine (17 mL, 210 mmol). The resulting mixture was stirred at room temperature under O ₂ atmosphere for 48 hours. The reaction was quenched with NH ₄ OH (30 mL) and ice water and filtered. The filtrate was extracted with DCM twice, the combined organic layers were dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30% EtOAc in petroleum ether) to afford 4-chloro-7-(3-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidi ne (7.5 g, 54%) as a white solid. LC/MS ESI (m/z): 390 (M+H) ⁺ . Step 2. tert-Butyl (S)-4-(7-(3-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)- 3-methylpiperazine-1-carboxylate To the solution of 4-chloro-7-(3-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidi ne (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℃ under N ₂ for 2 h. After being cooled down 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 in petroleum ether) to afford tert-butyl (S)-4-(7-(3-chlorophenyl)-5- iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-c arboxylate (3.0 g, 84%) as a white solid. LC/MS ESI (m/z): 554 (M+H) ⁺ . Step 3. tert-Butyl (S)-4-(7-(3-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)- 3-methylpiperazine-1-carboxylate To the 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) were added X-Phos (220 mg, 0.46 mmol), Pd(dba) ₃ (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℃ under N ₂ overnight. After being cooled down to room temperature, the reaction mixture was quenched with ice water, extracted with DCM twice. The combined organic layers were dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to afford the 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]pyrimi din-4-yl)-3-methylpiperazine- 1-carboxylate (3.5 g) as a yellow oil that was used directly in the next step. LC/MS ESI (m/z): 554 (M+H) ⁺ . 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 the 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-methyl piperazine-1-carboxylate (70 mg, 0.13 mmol) in dioxane (2 mL) and H ₂ O (0.4 mL) were added K ₂ CO ₃ (87 mg, 0.63 mmol), Pd(dppf)Cl ₂ (10 mg, 0.01 mmol) and 3-bromopyrazine-2-carbonitrile (47 mg, 0.25 mmol) respectively. The resulting reaction mixture was stirred at 90℃ under N ₂ overnight. After being cooled down to room temperature the solvent was removed. The residue was purified by flash column chromatography (silica gel, 0~20%, ethyl acetate in petroleum ether) and prep-HPLC (Gilson, C-18, MeCN in H ₂ O) to afford tert-butyl (S)-4-(7-(3- chlorophenyl)-5-(3-cyanopyrazin-2-yl)-7H-pyrrolo[2,3-d]pyrim idin-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, CDCl ₃ ) 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). The following compounds were prepared by procedures analogous to the synthesis of compound 274 from the corresponding aryl halides.

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-carboxyla te (Compound 388) C ^{ompound 388} 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, 2M NaOH solution (13 mL) was added. After the addition, the mixture was stirred at rt for 3 h. The mixture was diluted with water and was filtered. The filter cake was washed with water and dried under vacuum to provide 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) ⁺ . 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 rt and filtered. The filter cake was washed with EtOH and dried under vacuum to provide tert- butyl (R)-4-(5-bromo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-me thylpiperazine-1- carboxylate (3.7 g, 86%) as a white solid. LC/MS ESI (m/z): 550 (M+H) ⁺ . 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 in THF) at rt for 2 h. The mixture was diluted with EtOAc, washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50% EtOAc in petroleum ether) to provide tert-butyl (R)-4-(5-bromo-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate (2.1 g, 77%) as a light yellow solid. LC/MS ESI (m/z): 396 (M+H) ⁺ . 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), K ₃ PO ₄ (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 dry DMF (50 mL). trans- dimethylcyclohexane-1,2-diamine (0.74 g, 5.2 mmol) was then added, and the mixture was stirred at 90°C under N ₂ for 2.5 h. Then it was diluted with EtOAc, washed with LiCl (5% aq. solution) and brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash column chromatography (silica gel, 0~15% EtOAc in petroleum ether) to provide tert-butyl (R)-4-(5-bromo-7-(4-chloropyridin-2-yl)-7H-pyrrolo[2,3-d]pyr imidin-4-yl)-2- methylpiperazine-1-carboxylate (2.1 g, 79%). LC/MS ESI (m/z): 507 (M+H) ⁺ . 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-carboxyla te 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) were added K ₃ PO ₄ (250 mg, 1.2 mmol), CuI (110 mg, 0.59 mmol), dry DMF (5 mL) and trans-dimethylcyclohexane-1,2-diamine (170 mg, 1.2 mmol). The mixture was stirred at 90°C under N ₂ overnight. It was then diluted with EtOAc, washed with 5% LiCl (aq) and brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash column chromatography (0~60% EtOAc in petroleum ether, then 0~7% MeOH in DCM) to provide tert-butyl (R)-4-(7-(4-chloropyridin-2-yl)-5-(2-oxoazetidin-1-yl)-7H-py rrolo[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) ⁺ . 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 dry THF (4 mL) was added RhH(CO)(PPh ₃ ) ₃ (32 mg, 0.035 mmol). The mixture was purged with N ₂ . Then PhSiH ₃ (70 mg, 0.65 mmol) was added. The mixture was stirred at 60°C under N ₂ for 2 h and was then concentrated and purified by prep-TLC (petroleum ether / EtOAc = 5:1, v/v) to provide tert-butyl (2R)-4-[5-(azetidin-1-yl)-7-(4-chloropyridin-2-yl)-7H-pyrrol o[2,3- d]pyrimidin-4-yl]-2-methylpiperazine-1-carboxylate (50 mg, 79%) as a light yellow oil. LC/MS ESI (m/z): 484 (M+H) ⁺ . 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) ₂ (75 mg, 0.64 mmol) and Pd(PPh ₃ ) ₄ (75 mg, 0.065 mmol) was added tert- butyl (2R)-4-[5-(azetidin-1-yl)-7-(4-chloropyridin-2-yl)-7H-pyrrol o [2,3-d]pyrimidin-4-yl]-2- methylpiperazine-1-carboxylate (62 mg, 0.13 mmol) in dry DMF (3 mL). The mixture was stirred at 120°C under N ₂ overnight. Then it was diluted with EtOAc, washed with 5% LiCl (aq) and brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by prep-TLC (petroleum ether / EtOAc = 3:1, v/v) to provide tert-butyl (R)-4-(5-(azetidin-1-yl)-7-(4- cyanopyridin-2-yl) -7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carbo xylate (16 mg, 26%) as a yellow solid. LC/MS ESI (m/z): 475 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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).

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-ca rboxylate (Compound 392) C ^{ompound 392} Step1.4-Chloro-5-(2-fluorophenyl)-7-tosyl-7H-pyrrolo[2,3-d]p yrimidine 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) were added (2-fluorophenyl)boronic acid (420 mg, 0.60 mmol), X-Phos (180 mg, 0.37 mmol), K ₃ PO ₄ (1.6 g, 7.5 mmol) and Pd ₂ (dba) ₃ (230 mg, 0.25 mmol), and the resulting mixture was heated to 60 ^o C overnight. After being cooled down 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 with EtOAc twice, the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50% EtOAc in petroleum ether) to afford 4-chloro-5-(2-fluorophenyl)-7-tosyl- 7H-pyrrolo[2,3-d]pyrimidine (600 mg, 60%). LC/MS ESI (m/z): 402 (M+H) ⁺ . Step 2. tert-Butyl 7-(5-(2-fluorophenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-y l)-4,7- diazaspiro[2.5]octane-4-carboxylate To a solution of 4-chloro-5-(2-fluorophenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimid ine (550 mg, 2.2 mmol) in EtOH (6 mL) were added DIEA (0.66 mL, 4.0 mmol) and tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate (440 mg, 2.1 mmol) respectively. The resulting reaction mixture was stirred at 100℃ under N ₂ overnight. After being cooled down 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 in petroleum ether) to afford tert-butyl 7-(5-(2-fluorophenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-y l)- 4,7-diazaspiro[2.5]octane-4-carboxylate (660 mg, 70%) as a white solid. LC/MS ESI (m/z): 578 (M+H) ⁺ . 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 in THF). The resulting reaction mixture was stirred at room temp under N ₂ overnight. The reaction mixture was quenched with ice water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0~60%, ethyl acetate in petroleum ether) to afford 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) ⁺ . 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 the 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) were added CuI (90 mg, 0.47 mmol), K ₃ PO ₄ (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℃ under N ₂ overnight. After being cooled down to room temperature, the reaction mixture was partitioned between EtOAc and water and the organic layer was separated. The aqueous layer was extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford tert-butyl 7-(7-(4-cyanopyridin-2-yl)-5-(2- fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4,7-diazaspir o[2.5]octane-4-carboxylate (450 mg, 91%) as white solid. LC/MS ESI (m/z): 526 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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). 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) C ^{ompound 312} 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) were added CuI (32 mg, 0.17 mmol), L-Proline (38 mg, 0.30 mmol), K ₂ CO ₃ (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℃ under N ₂ overnight. After being cooled down to room temperature, the reaction mixture was partitioned between EtOAc and water. The organic layer was separated and the aqueous was extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0~60%, ethyl acetate in petroleum ether) followed by prep-HPLC (Gilson, C-18, MeCN in water) to afford 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-carboxyla te (100 mg, 23%) as a solid. LC/MS ESI (m/z): 527 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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). 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-ca rboxylate (Compound 396) C ^{ompound 396} 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, prepared following the procedure of compound 192, step 1) in EtOH (5 mL) were 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℃ under N ₂ overnight. After being cooled down 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 in petroleum ether) to afford 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 white solid. LC/MS ESI (m/z): 610 (M+H) ⁺ . 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 the 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) were added Pd- 118 (97 mg, 0.15 mmol), K ₂ CO ₃ (2.6 g, 19 mmol) and cyclopropylboronic acid (190 mg, 2.2 mmol) respectively. The resulting reaction mixture was stirred at 80℃ under N ₂ overnight. After being cooled down 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 in petroleum ether) to afford tert-butyl 7-(5-cyclopropyl-7-tosyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]octane-4-ca rboxylate (240 mg, 33%) as white solid. LC/MS ESI (m/z): 524 (M+H) ⁺ . Step 3. tert-Butyl (S)-4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate To the 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 in THF). The resulting reaction mixture was stirred at rt under N ₂ overnight. The reaction mixture was quenched with ice water, and extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to obtain 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) ⁺ . 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) were added CuI (39 mg, 0.21 mmol), K ₃ PO ₄ (260 mg, 1.2 mmol), trans-cyclohexane-1,2-diamine (0.020 mL, 0.12 mmol) and 2-bromoisonicotinonitrile (150 mg, 0.81 mmol) respectively. The resulting reaction mixture was stirred at 100℃ under N ₂ overnight. After being cooled down to room temperature, the reaction mixture was partitioned between EtOAc and water, organic layer was separated, the aqueous layer was extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) and prep-HPLC to afford 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-ca rboxylate (100 mg, 54%) as white solid. LC/MS ESI (m/z): 472 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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). 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-methylpiper azine-1-carboxylate (Compound 404) 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-carboxyla te To the 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) were added Pd(dppf)Cl ₂ (140 mg, 0.17 mmol), K ₂ CO ₃ (930 mg, 6.7 mmol) and (2- fluorophenyl)boronic acid (280 mg, 2.0 mmol). The resulting reaction mixture was stirred at 90℃ overnight. After being cooled down to room temperature, solvent was removed, the residue was purified by flash column chromatography (silica gel, 0~40%, ethyl acetate in petroleum ether) to obtain 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) ⁺ . Step 2. tert-Butyl (S)-4-(5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3 - methylpiperazine-1-carboxylate To the 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, 1.0M in THF). The resulting reaction mixture was stirred at room temperature under N ₂ overnight. The reaction mixture was quenched with ice water, then it was extracted with EtOAc twice, the combined organic layers were washed with water and brine, dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0~60%, ethyl acetate in petroleum ether) to obtain 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) ⁺ . 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-carboxyla te 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), K ₃ PO ₄ (160 mg, 0.73 mmol) and CuI (69 mg, 0.36 mmol) were mixed in dry DMF. Then (±)-trans-1,2-cyclohexanediamine (100 mg, 0.73 mmol) was added. The mixture was stirred at 90°C under N ₂ for 3.5 h and was cooled to rt. Then it was diluted with EtOAc, washed with 5% LiCl (aq.) and brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash column chromatography (silica gel, 0~11% EtOAc in petroleum ether) to provide 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-carboxyla te (120 mg, 55%) as a yellow foam. LC/MS ESI (m/z): 592 (M+H) ⁺ . Step 4. tert-Butyl (S)-4-(7-(4-cyano-6-methylpyridin-2-yl)-5-(2-fluorophenyl)-7 H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te 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-carbox ylate (120 mg, 0.20 mmol), methylboronic acid (98 mg, 1.6 mmol), Cs ₂ CO ₃ (200 mg, 0.61 mmol) and Pd(dppf)Cl ₂ (20 mg, 0.027 mmol) in dioxane (3 mL) and H ₂ O (0.6 mL) was stirred at 100°C under N ₂ overnight. Then it was diluted with EtOAc and DCM and was filtered. The filtrate was purified by flash column chromatography (silica gel, 0~20% EtOAc in petroleum ether followed by prep-HPLC to provide tert-butyl (S)-4-(7-(4-cyano-6-methylpyridin-2-yl)-5-(2- fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiper azine-1-carboxylate (23 mg, 21%) as a light yellow oil. LC/MS ESI (m/z): 528 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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). The following compound was prepared by a synthetic procedure similar to that described for compound 404, except using tert-butyl (S)-4-(5-cyclopropyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate. 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]hept ane-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) 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 the solution of 4-chloro-5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (170 mg, 0.87 mmol, prepared following the procedure of compound 192, step 1) in EtOH (5 mL) were 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℃ under N ₂ overnight. After removal of solvent, the residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford tert-butyl 5-(5- cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dia zabicyclo[4.1.0]heptane-2- carboxylate (140 mg, 45%) as white solid. LC/MS ESI (m/z): 510 (M+H) ⁺ . 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 the 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) were added TBAF (1.5 mL, 1.0M in THF). The resulting reaction mixture was stirred at room temperature under N ₂ overnight. The reaction mixture was quenched with ice water and extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to afford tert- butyl 5-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-diazab icyclo[4.1.0]heptane-2- carboxylate (90 mg, 64%) as a white solid. LC/MS ESI (m/z): 356 (M+H) ⁺ . 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-carboxyla te To the 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) were added CuI (24 mg, 0.13 mmol), K ₃ PO ₄ (160 mg, 0.75 mmol), trans-cyclohexane-1,2-diamine (9.0 mg, 0.080 mmol) and 2-bromoisonicotinonitrile (93 mg, 0.51 mmol) respectively. The resulting reaction mixture was stirred at 80℃ under N ₂ overnight. After being cooled down to room temperature, the reaction mixture was partitioned between EtOAc and water, organic layer was separated, the aqueous layer was extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~40%, ethyl acetate in petroleum ether), prep-HPLC (Gilson, C18, MeCN in water) to afford 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 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-carboxyla te and tert-butyl (1R,6S)-5-(7- (4-cyanopyridin-2-yl)-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimid in-4-yl)-2,5- _{diazabicyclo[4.1.0]heptane-2-carboxylate} Preparative separation method: Instrument: Waters Thar 80 preparative SFC; Column: ChiralCel OJ, 250×21.2mm I.D., 5µm; Mobile phase: A for CO2 and B for MEOH+0.1%NH3H2O; Gradient: B 40%; Flow rate: 50mL /min; Back pressure: 100 bar; Column temperature: 35℃; Wavelength: 254nm; Cycle-time: 7min; Eluting time: 1.5H tert-Butyl 5-(7-(4-cyanopyridin-2-yl)-5-cyclopropyl-7H-pyrrolo[2,3-d]py rimidin-4-yl)-2,5- diazabicyclo[4.1.0]heptane-2-carboxylate (60 mg) was separated by SFC to give two isomers: Peak 1: shorter retention time, 22 mg as white solid. LC/MS ESI (m/z): 458 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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 white solid. LC/MS ESI (m/z): 458 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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).

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) C ^{ompound 1003} Step 1.4-Chloro-5-(2-fluorophenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrim idine To a solution of 4-chloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (10 g, 23 mmol, prepared following the procedure of compound 192, step 1) in dioxane-H ₂ O (100 mL, v/v=5/1) were added (2-fluorophenyl)boronic acid (3.3 g, 23 mmol), K ₃ PO ₄ (9.8 g, 46 mmol) and Pd(dppf)Cl ₂ (1.7 g, 2.3 mmol). The resulting mixture was heated to 60 ^o C overnight. After being cooled down to room temperature, the reaction was filtered, filtrate was partitioned between EtOAc and water, organic layer was separated, the aqueous phase was extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated, the residue was purified by flash chromatography (silica gel, 0~50% EtOAc in 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) ⁺ . Step 2.4-Chloro-5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidine To a 0 ^o C 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, 1.0M in THF). The resulting mixture was stirred at the same temperature for 5 h. The reaction was quenched with ice water, extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~60% ethyl acetate in petroleum ether) to afford 4-chloro-5-(2- fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidine (530 mg, 85%) LC/MS ESI (m/z): 248 (M+H) ⁺ . Step 3.4-Chloro-5-(2-fluorophenyl)-7-(5-methoxypyridin-3-yl)-7H-p yrrolo[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) were 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 Cs ₂ CO ₃ (2.1 g, 6.4 mmol). The resulting mixture was heated to 110 ^o C under N ₂ overnight. After being cooled down to room temperature, the reaction was partitioned between EtOAc and water, organic layer was separated, aqueous layer was extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated, the residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford 4-chloro-5-(2-fluorophenyl)-7-(5-methoxypyridin-3-yl)-7H-pyr rolo[2,3- d]pyrimidine (400 mg, 53%) as a yellow solid. LC/MS ESI (m/z): 355 (M+H) ⁺ . 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) were added ethyl piperazine-1-carboxylate (63 mg, 0.30 mmol) and DIPEA (110 mg, 0.90 mmol). The resulting mixture was heated to 100 ^o C under N ₂ overnight. After being cooled down to room temperature, solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford ethyl 4-(5-(2- fluorophenyl)-7-(5-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyr imidin-4-yl)piperazine-1- carboxylate (50 mg, 37%) as a white solid, which was further purified by prep-HPLC to afford 22.8 mg of 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). The following compound was prepared by the procedure analogous to the synthesis of compound 1003 from the corresponding amine. 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) C ^{ompound 151} Step 1.4-Chloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine To a 0°C 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 dropwise 2.0M NaOH (0.53 L). After addition, the reaction was allowed to warm up to room temperature and stirred for another 3 hours. The precipitate was collected by filtration and washed with water twice and dried in vacuo to afford 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) ⁺ . 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 being cooled down to r.t, solvent was removed and the residue was purified by flash column chromatography to provide tert-butyl 4-(5-iodo- 7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxy late (5.5 g, 89%) as a white solid. LC/MS ESI (m/z): 584 (M+H) ⁺ . Step 3. tert-Butyl 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-tosyl-7 H- 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) were 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 ₂ (dba) ₃ (47 mg, 0.052 mmol). The resulting mixture was stirred at 95 ^o C overnight. After being cooled down to room temperature. The reaction was quenched with water, extracted with DCM twice, the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to afford 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) ⁺ . 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 H ₂ O (1 mL) were added 2-bromopyridine (0.96 mL, 1.0 mmol), K ₂ CO ₃ (360 mg, 2.5 mmol) and Pd(dppf)Cl ₂ (38 mg, 0.052 mmol). The resulting mixture was heated to 90 ^o C overnight. After being cooled down to room temperature, solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~60%, ethyl acetate in petroleum ether) to afford 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) ⁺ . Step 5. tert-Butyl 4-(5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazi ne-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, 1.0M in THF). The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water, extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~10%, methanol in dichloromethane) to afford tert-butyl 4-(5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazi ne-1-carboxylate (120 mg, 93%) as a white solid. LC/MS ESI (m/z): 381 (M+H) ⁺ . 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 K ₃ PO ₄ (200 mg, 0.94 mmol). The resulting mixture was heated to 120 ^o C overnight. After being cooled down to room temperature. The reaction was quenched with water, extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to afford 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, CDCl ₃ ) 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). The following compound was prepared by analogous procedures to the synthesis of compound 151 from the corresponding amines and aryl halides.

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) C ^{ompound 152} 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, prepared following the procedure of compound 151 in DCM (3 mL) was added HCl (3.0 mL, 4.0M in dioxane). The resulting mixture was stirred at room temperature for 3h. After removal of solvent, the residue was diluted with DCM, washed with NaHCO ₃ (aq.), the organic layer was extracted with DCM twice, the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was used in the next step directly, 7-(3- chloro-4-fluorophenyl)-4-(piperazin-1-yl)-5-(pyridin-2-yl)-7 H-pyrrolo[2,3-d]pyrimidine. LC/MS ESI (m/z): 409 (M+H) ⁺ . 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 0 ^o C 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) were added dropwise ethyl carbonochloridate (0.040 mL, 0.39 mmol) and TEA (0.080 mL, 0.58 mmol). The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water, extracted with DCM twice, the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford 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, CDCl ₃ ) 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). 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-carboxyla te (Compound 164) ^{Compound 164} 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, prepared following the procedure of compound 151, step 1) toluene (50 mL) were added cyclopropylboronic acid (1.1 g, 13 mmol), K ₂ CO ₃ (24 g, 170 mmol) and Pd-118 (880 mg, 1.3 mmol). The resulting mixture was heated to 80 ^o C overnight. After being cooled down to room temperature, solvent was filtered. The filtrate was concentrated and purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in 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) ⁺ . Step 2. tert-Butyl 4-(5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate The 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 ^o C for 3 h. After being cooled down to room temperature, the reaction mixture was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford 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) ⁺ . 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, 1.0M in THF). The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water, extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~60%, ethyl acetate in 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) ⁺ . 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) were 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 K ₃ PO ₄ (210 mg, 1.0 mmol). The resulting mixture was heated to 120 ^o C overnight. After being cooled down to room temperature, the reaction was diluted with water, extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0~40%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford tert-butyl 4-(7-(5-chloropyridin-3-yl)-5- cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperaz ine-1-carboxylate (53 mg, 33%) as a white solid. LC/MS ESI (m/z): 469 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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). The following compounds were prepared by analogous procedures to the synthesis of compound 164 from the corresponding amines and aryl halides. 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-carbox ylate (Compound 267) Step 1. tert-Butyl (S)-4-(5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiper azine- 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 following the procedures of step 1 of compound 259 synthesis) in THF (5 mL) at 0 ^o C was treated with TBAF (6.7 mL, 1.0M in THF). The resulting mixture was stirred at 0 ^o C for 3h. The reaction was quenched with water, extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~70%, ethyl acetate in petroleum ether) to afford tert-butyl (S)- 4-(5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazin e-1-carboxylate (0.55 g, 74%) as a yellow solid. LC/MS ESI (m/z): 444 (M+H) ⁺ . 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) were added (3- chlorophenyl)boronic acid (390 mg, 2.4 mmol), Cu(OAc) ₂ (670 mg, 3.7 mmol), pyridine (0.60 mL, 7.4 mmol) and 4A molecular sieves (400 mg). The resulting mixture was stirred at 40℃ under an O ₂ atmosphere overnight. After cooling in an ice-water bath, the reaction was quenched with aq. NH ₄ OH (2 mL) and filtered. The filtrate was extracted twice with DCM. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford 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) ⁺ . 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-methyl piperazine-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) were 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 ₂ (dba) ₃ (40 mg, 0.043 mmol). The resulting mixture was stirred at 95 ^o C overnight. The reaction was quenched with water and extracted twice with DCM. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to afford 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 in the next step directly. LC/MS ESI (m/z): 554 (M+H) ⁺ . Step 4. tert-Butyl (S)-4-(7-(3-chlorophenyl)-5-(3-fluoropyrazin-2-yl)-7H-pyrrol o[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-methyl piperazine-1-carboxylate (120 mg, 0.21 mmol) in dioxane (5 mL) and H ₂ O (1 mL) were added 2-bromo-3-fluoropyrazine (77 mg, 0.43 mmol), K ₂ CO ₃ (150 mg, 1.0 mmol) and Pd(dppf)Cl ₂ (16 mg, 0.022 mmol). The resulting mixture was heated at 90 ^o C overnight. After cooling to room temperature, solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford tert-butyl (S)-4-(7-(3-chlorophenyl)-5-(3-fluoropyrazin-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (59 mg, 51%) as a white solid. LC/MS ESI (m/z): 524 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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). The following compound was prepared by a procedure analogous to the synthesis of compound 267 using the corresponding aryl halide. 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) C ^{ompound 171} Step 1.4-Chloro-3-iodo-1-tosyl-1H-pyrrolo[3,2-c]pyridine To a 0 ^o C suspension of NaH (400 mg, 10 mmol, 60 wt % in mineral oil) in anhydrous DMF (30 mL) was added 4-chloro-3-iodo-1H-pyrrolo[3,2-c]pyridine (1.4 g, 5.0 mmol, prepared following the procedure for compound 418, step 1) in portions, followed by 4- methylbenzenesulfonyl chloride (1.1 g, 6.0 mmol) in portions. The resulting mixture was stirred at room temperature overnight. The reaction was poured into ice water, extracted with EtOAc twice, the combined organic layers washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford 4-chloro-3-iodo-1-tosyl-1H-pyrrolo[3,2-c]pyridine (1.7 g, 80%) as a light yellow solid. LC/MS ESI (m/z): 433 (M+H) ⁺ . Step 2.4-Chloro-3-(2-fluorophenyl)-1-tosyl-1H-pyrrolo[3,2-c]pyrid ine 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 H ₂ O (2 mL) was added (2-fluorophenyl)boronic acid (300 mg, 2.1 mmol), K ₂ CO ₃ (880 mg, 6.3 mmol) and Pd(dppf)Cl ₂ (160 mg, 0.21 mmol). The resulting mixture was heated at 90 ^o C overnight. After being cooled to room temperature, the solvent was removed in vacuo and the residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford 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) ⁺ . 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]pyridin e (680 mg, 1.7 mmol) in THF (5 mL) was added TBAF (10 mL, 1.0M in THF). The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water, extracted with EtOAc twice, the combined organic layers washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to afford 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) ⁺ . 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) were 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 K ₃ PO ₄ (1.1 mg, 4.9 mmol). The resulting mixture was heated at 120 ^o C overnight. After cooling to room temperature, the reaction was quenched with water, extracted with EtOAc twice, the combined organic layers washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to afford 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) ⁺ . Step 5. tert-Butyl 4-(3-(2-fluorophenyl)-1-(pyrimidin-5-yl)-1H-pyrrolo[3,2-c]py ridin- 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).was heated at 150 ^o C for 3 h. After cooling to room temperature, the reaction mixture was purified by flash column chromatography (silica gel, 0~60%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford 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) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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). 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) C ^{ompound 172} Step 1.1-Fluoro-2-methylpropan-2-ol To a -60°C solution of ethyl 2-fluoroacetate (10 g, 94 mmol) in dry THF (30 mL) under N ₂ was added CH ₃ MgBr (210 mL, 1.0 M in THF, 210 mmol) dropwise. The mixture was kept at the same temperature for 1 h and then at 0°C for 4 h. It was quenched by addition of 50 mL of ice water, and conc. HCl (18 mL) and solid NaCl (10 g) in sequence. The mixture was extracted with DCM. The organic layer was dried over Na ₂ SO ₄ overnight, and concentrated by rotary evaporation, keeping the bath temperature below 25°C. The residue was purified by distillation under normal pressure to afford 1-fluoro-2-methylpropan-2-ol (3.5 g, 40%) as a colorless liquid (bp ~ 92°C). ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.20 (d, J = 47.7 Hz, 2H), 1.25 (t, J = 2.6 Hz, 6H), hydroxyl group proton exchanged. 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 ₂ was added 1-fluoro-2- methylpropan-2-ol (300 mg, 3.3 mmol) dropwise. The mixture was stirred at rt overnight. It was then diluted with DCM, washed with water and brine, dried over Na ₂ SO ₄ and concentrated to provide 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) ⁺ . Step 3. tert-Butyl 4-(5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pipera zine- 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, prepared following the procedure of compound 1003, first two steps) and DIPEA (1.6 mL, 9.7 mmol) in EtOH (10 mL) was stirred at 100 °C overnight. The solvents were removed by rotary evaporation. The residue was purified by flash column chromatography (silica gel, 0~50% EtOAc in petroleum ether, then 100% DCM) to provide tert-butyl 4-(5-(2-fluorophenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperazine-1-carboxylate (560 mg, 60%) as a light yellow solid. LC/MS ESI (m/z): 398 (M+H) ⁺ . Step 4. tert-Butyl 4-(5-(2-fluorophenyl)-7-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyri midin- 4-yl)piperazine-1-carboxylate To tert-butyl 4-(5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pipera zine-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), and K ₃ PO ₄ (320 mg, 1.5 mmol ) and CuI (96 mg, 0.50 mmol) and the mixture was stirred at 100 °C under N ₂ overnight. It was then diluted with EtOAc and filtered. The filtrate was washed with LiCl (5% aq.) and brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50% EtOAc in petroleum ether, then 100% DCM) to provide tert-butyl 4-(5-(2-fluorophenyl)-7-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyri midin-4- yl)piperazine-1-carboxylate (170 mg, ~70% purity, 48%) as a light yellow solid. LC/MS ESI (m/z): 475 (M+H) ⁺ . 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]pyri midin-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 rt overnight. The solvent was evaporated, the residue was diluted with DCM, washed with NaHCO ₃ (aq.), brine, dried over Na ₂ SO ₄ and concentrated to provide 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) ⁺ . 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-py rrolo[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 at 80 °C under N ₂ for 40 h. The mixture was diluted with EtOAc, washed with LiCl (5% aq.), brine and was then concentrated. The residue was purified by flash column chromatography (silica gel, 0~50% EtOAc in petroleum ether) to give 80 mg of the crude product, which was further purified by prep-HPLC to afford 1-fluoro-2-methylpropan-2-yl 4- (5-(2-fluorophenyl)-7-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimi din-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, CDCl ₃ ) 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 = 2.2 Hz, 6H). The following compound was prepared by a synthetic procedure analogous to that described for compound 172, except using 5-iodopyrimidine in step 4.

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) 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, extracted with DCM twice, the combined organic layers washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to afford 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) ⁺ . 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 following a similar procedure of compound 134 in DCM (2 mL) was added HCl/dioxane (0.50 mL, 4.0M). The resulting mixture was stirred at room temperature for 3h. After removal of solvent, the residue was dissolved in DCM, washed with NaHCO ₃ (aq), the organic layer was separated, aqueous layer was extracted with DCM twice, the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was used in the next step directly.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) ⁺ . 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 ^o C for 2d under N ₂ . The reaction was quenched with water, extracted with EtOAc twice, the combined organic layers washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford 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-ca rboxylate (14 mg , 33%) as a white solid. LC/MS ESI (m/z): 560 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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). The following compounds were prepared by the procedures analogous to the synthesis of compound 186 from the corresponding boronic acids and alcohols. 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-carboxyla te (Compound 278) C ^{ompound 278} 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 ^o C for 1.5 h. After being cooled down to room temperature, solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford tert-butyl (S)- 4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methyl piperazine-1-carboxylate (5.8 g, 84%) as a yellow solid. LC/MS ESI (m/z): 598 (M+H) ⁺ . Step 2. tert-Butyl (S)-3-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolane -2-yl)- 7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxy late 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) were 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 ₂ (dba) ₃ (0.15 g, 0.16 mmol). The resulting mixture was stirred at 95 ^o C overnight. After being cooled down to room temperature. The reaction was quenched with water, extracted with DCM twice, the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to afford 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 in the next step directly. LC/MS ESI (m/z): 598 (M+H) ⁺ . 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-c arboxylate (1.0 g, 1.6 mmol) in dioxane (15 mL) and H ₂ O (3 mL) were added 2-bromopyridine (0.32 mL, 3.3 mmol), K ₂ CO ₃ (1.2 g, 8.3 mmol) and Pd(dppf)Cl ₂ (0.12 g, 0.16 mmol). The resulting mixture was heated to 90 ^o C overnight. After being cooled down to room temperature, solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to afford 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) ⁺ . 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, 1.0M in THF). The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water, extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~10%, methanol in 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. LC/MS ESI (m/z): 395 (M+H) ⁺ . 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) were 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 K ₃ PO ₄ (190 mg, 0.91 mmol ). The resulting mixture was heated to 120 ^o C overnight. After being cooled down to room temperature the reaction was quenched with water, extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford 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) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 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). The following compound was prepared by an analogous procedure to the synthesis of compound 278 from the corresponding aryl halide. 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-carboxyla te (Compound 322) 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]pyrimidi ne (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 ^o C for 2 h. After being cooled down to room temperature, solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford 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) ⁺ . 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) were added 1H-pyrazole (49 mg, 0.72 mmol), Cs ₂ CO ₃ (470 mg, 1.4 mmol), Fe(acac) ₃ (38 mg, 0.10 mmol) and Cu(acac) ₂ (9.4 mg, 0.036 mmol). The resulting mixture was heated to 120 ^o C overnight. After being cooled down to room temperature, the reaction was quenched with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0~40%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford 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, CDCl ₃ ) 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). The following compounds were prepared by analogous procedures to the synthesis of compound 322 from the corresponding amines. 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-carboxyla te (Compound 367) 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-carboxyla te 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) were 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 ₂ (dba) ₃ (0.15 g, 0.16 mmol). The resulting mixture was stirred at 95 ^o C overnight. After being cooled down to room temperature, the reaction was quenched with water and extracted with DCM twice. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated to afford 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 in the next step directly. LC/MS ESI (m/z): 598 (M+H) ⁺ . 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-c arboxylate (1.0 g, 1.6 mmol) in dioxane (15 mL) and H ₂ O (3 mL) were added 2-bromopyridine (0.32 mL, 3.3 mmol), K ₂ CO ₃ (1.2 g, 8.3 mmol) and Pd(dppf)Cl ₂ (0.12 g, 0.16 mmol). The resulting mixture was heated to 90 ^o C overnight. After being cooled down to room temperature, solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to afford 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) ⁺ . 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, 1.0M in THF). The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~10%, methanol in dichloromethane) to afford 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) ⁺ . 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) were 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 K ₃ PO ₄ (820 mg, 3.8 mmol). The resulting mixture was heated to 120 ^o C overnight. After being cooled down to room temperature, the reaction was quenched with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to afford 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 further purified by prep-HPLC to obtain 14.8 mg of the tert-butyl (R)-4-(7-(4- cyanopyridin-2-yl)-5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimid in-4-yl)-2-methylpiperazine-1- carboxylate as a white solid. LC/MS ESI (m/z): 497 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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). 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-carbox ylate (Compound 400) C ^{ompound 400} Step 1.4-chloro-5-(pyrrolidin-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimi dine To a 0 ^o C solution of formaldehyde (0.58 g, 7.1 mmol) in H ₂ O (2 mL) and CH ₃ COOH (10 mL, 86 mmol) and dioxane (10 mL). was added pyrrolidine (0.58 mL, 7.1 mmol), followed by a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1.0 g, 6.5 mmol) in dioxane dropwise. After being stirred at 50 ^o C overnight under N ₂ , the reaction was added to anhydrous sodium sulfate to dry and then filtered. The filtrate was concentrated at room temperature and purified by flash column chromatography (silica gel, 0~50%, methanol in dichloromethane) to afford 4-chloro-5-(pyrrolidin-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidi ne (0.63 g, 40%) as a yellow oil. LC/MS ESI (m/z): 237 (M+H) ⁺ . Step 2.3-(4-chloro-5-(pyrrolidin-1-ylmethyl)-7H-pyrrolo[2,3-d]pyr imidin-7-yl) benzonitrile To a solution of 4-chloro-5-(pyrrolidin-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidi ne (0.53 g, 2.2 mmol) in DCM (25 mL) were added (3-cyanophenyl)boronic acid (0.66 g, 4.4 mmol), Cu(OAc) ₂ (1.2 g, 6.7 mmol), pyridine (1.1 mL, 13 mmol) and 4A molecular sieves (800 mg). The resulting mixture was stirred at room temperature under O ₂ atmosphere overnight. The reaction was quenched with NH ₄ OH (2 mL) at 0 ℃ and filtered. The filtrate was extracted with DCM twice and the combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~20%, methanol in dichloromethane) to afford 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) ⁺ . Step 3. tert-butyl (S)-4-(7-(3-cyanophenyl)-5-(pyrrolidin-1-ylmethyl)-7H-pyrrol o [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 ^o C for 3 h. After being cooled down to room temperature, the solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~20%, methanol in dichloromethane). The product was further purified by prep-HPLC to afford 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).

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-carbox ylate (Compound 402) ^p Step 1.5-Bromo-4-methoxy-7H-pyrrolo[2,3-d]pyrimidine At 0℃, to a solution of 4-methoxy-7H-pyrrolo[2,3-d]pyrimidine (1.0 g, 6.7 mmol) in DMF(15 mL) was added NBS (0.95 g, 5.3 mmol) in portions. After being stirred at room temperature for 3 h under N ₂ , the reaction was quenched with water. The reaction mixture was filtered to afford 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) ⁺ . Step 2.5-Bromo-4-methoxy-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine At 0℃, to a solution of 5-bromo-4-methoxy-7H-pyrrolo[2,3-d]pyrimidine (450 mg, 1.9 mmol) in DMF (10 mg) was added NaH (95 mg, 2.3 mmol) in portions. The resulting mixture was stirred at 0℃ for 20 min. Then to above mixture was added 4- methylbenzenesulfonyl chloride (430 mg, 2.2 mmol) and the resulting mixture was stirred at 0℃ for 20 min and then was allowed to warm up to room temperature and stirred overnight under N ₂ . The reaction was quenched with ice water. Then the reaction mixture was filtered to afford 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) ⁺ . Step 3.4-Methoxy-5-(prop-1-en-2-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyri midine 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 H ₂ O (2 mL) were added 4,4,5,5-tetramethyl-2-(prop-1-en- 2-yl)-1,3,2-dioxaborolane (0.51 mL, 2.7 mmol), K ₂ CO ₃ (1000 mg, 7.2 mmol) and Pd(dppf)Cl ₂ (130 mg, 0.18 mmol). The resulting mixture was heated to 90 ^o C overnight. After being cooled down to room temperature, solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford 4-methoxy-5-(prop-1-en-2-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimi dine (460 mg, 74%) as a white solid. LC/MS ESI (m/z): 344 (M+H) ⁺ . Step 4.4-Methoxy-5-(1-methylcyclopropyl)-7-tosyl-7H-pyrrolo[2,3-d ]pyrimidine To a solution of Et ₂ Zn (13 mL) in DCM (10 mL) at 0℃ was added dropwise a solution of TFA (0.50 mL, 6.6 mmol) in DCM (2 mL) and the mixture was stirred at 0℃ for 30 min. Then to the above mixture was added dropwise a solution of CH ₂ I ₂ (0.56 mL, 6.6 mmol) in DCM (2 mL). After being stirred 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 NH ₄ Cl (aq.), extracted with DCM twice, the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~10%, ethyl acetate in petroleum ether) to afford 4-methoxy-5-(1-methylcyclopropyl)-7-tosyl-7H-pyrrolo[2,3-d]p yrimidine (350 mg, 73%) as a yellow oil. LC/MS ESI (m/z): 358 (M+H) ⁺ . Step 5.4-Methoxy-5-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimid ine 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, 1.0M in THF). The resulting mixture was stirred at 30℃ for 4 h. The reaction was quenched with water, extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~60%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford 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) ⁺ . Step 6.3-(4-Methoxy-5-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyri midin-7-yl) benzonitrile To a solution of 4-methoxy-5-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidin e (40 mg, 0.19 mmol) in DMF (5 mL) were 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 K ₃ PO ₄ (130 mg, 0.59 mmol). The resulting mixture was heated to 100 ^o C overnight. After being cooled down to room temperature, the reaction was quenched with water, extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford 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) ⁺ . Step 7.3-(4-Hydroxy-5-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyri midin-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) were added p-toluenesulfonic acid (310 mg, 1.8 mmol) and LiCl (77 mg, 1.8 mmol). The resulting mixture was heated to 110 ^o C for 2 h. After being cooled down to room temperature, the reaction was quenched with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated to afford 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) ⁺ . Step 8.3-(4-Chloro-5-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrim idin-7-yl) benzonitrile The mixture of 3-(4-hydroxy-5-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d] pyrimidin- 7-yl)benzonitrile (50 mg, 0.17 mmol) and POCl ₃ (5 mL) was heated to 120 ^o C overnight. After being cooled down to room temperature, the reaction was concentrated. The residue was dissolved in DCM, washed with NaHCO ₃ (aq.), and the aqueous layer was extracted with DCM twice. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated to afford 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) ⁺ . 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 ^o C for 6 h. After being cooled down to room temperature, the solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~20%, ethyl acetate in petroleum ether) to give the product. Further purification by prep-HPLC provided 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) ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) 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). The following compound was prepared by the procedure analogous to the synthesis of compound 402 from the corresponding aryl halide. 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) C ^{ompound 1004} Step 1. Ethyl 4-(5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pip erazine-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 ^o C overnight. After cooling down to room temperature, the reaction mixture was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford ethyl 4-(5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pip erazine-1-carboxylate (360 mg, 67%) as a white solid. LC/MS ESI (m/z): 470 (M+H) ⁺ . 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, 1.0M 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford 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) ⁺ . 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) were 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 Cs ₂ CO ₃ (310 mg, 0.95 mmol). The resulting mixture was heated to 110 ^o C overnight. After cooling down to room temperature, the reaction was quenched with water, and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~20%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford ethyl 4-(5-cyclopropyl-7-(5- methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperaz ine-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). The following compounds were prepared by procedures analogous to the synthesis of compound 1004 using the corresponding amine. 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) 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 following the procedures described for the synthesis of compound 114 in DCM (10 mL) was added HCl (3.0 mL, 4.0M in dioxane). The resulting mixture was stirred at room temperature for 2 h. After removal of solvent, the residue was diluted with DCM and washed with NaHCO ₃ (aq.). The aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was used in the next step directly. (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) ⁺ . Step 2 Ethyl (S)-4-(7-(4-chlorophenyl)-5-cyclopropyl-7H-pyrrolo[2,3-d]pyr imidin-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) at 0 ^o C was added TEA (76 mg, 0.75 mmol), followed by ethyl carbonochloridate (54 mg, 0.50 mmol) dropwise. 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 ₃ (aq.), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford 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, CDCl ₃ ) 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). Example 32. Synthesis of tert-butyl (S)-4-(7-(4-chlorophenyl)-5-cyclopropyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (Compound 114) C ^{ompound 114} Step 1.4-Chloro-7-(4-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimi dine To a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (1.3 g, 4.7 mmol) in DCM (50 mL) were added (4-chlorophenyl)boronic acid (1.5 g, 9.3 mmol), Cu(OAc) ₂ (2.1 g, 12 mmol) and pyridine (2.2 mL, 28 mmol). The resulting mixture was stirred at room temperature overnight. NH ₃ ^. H ₂ O (30 mL) was added and the reaction was filtered. The filtrate was partitioned between DCM and water. The aqueous phase was extracted twice with DCM. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0~30% EtOAc in petroleum ether) to afford 4-chloro-7-(4-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidi ne (810 mg, 45%) as a solid. LC/MS ESI (m/z): 390 (M+H) ⁺ . 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]pyrimidi ne (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 ^o C for 3 h. After cooling to room temperature, solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford 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)+. 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) were added cyclopropylboronic acid (280 mg, 0.16 mmol), K ₂ CO ₃ (2.9 g, 21 mmol) and Pd- 118 (100 mg, 1.3 mmol). The resulting mixture was heated to 80 ^o 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 in petroleum ether) to give tert-butyl (S)-4-(7-(4-chlorophenyl)-5-cyclopropyl-7H-pyrrolo[2,3-d]pyr imidin-4-yl)-3- methylpiperazine-1-carboxylate (580 mg, 76% yield) as a solid. LC/MS ESI (m/z): 468 (M+H) ⁺ . ¹ H NMR (400MHz, CDCl ₃ ) 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). The following compounds were prepared by procedures analogous to the synthesis of compound 114 using the corresponding boronic acids and amine. 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-carboxyla te (Compound 119) 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]pyrimidi ne (3.0 g, 7.7 mmol, prepared following step 1 of the procedures 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 hours. The reaction mixture was concentrated. The residue was purified by column chromatography on silica gel (0~30% ethyl acetate in 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) ⁺ . 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-methyl piperazine-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 ₂ (dba) ₃ (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 hours. The reaction mixture was filtered. The filtrate was extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was used in the next step directly. LC/MS ESI (m/z): 554 (M+H) ⁺ . 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-methyl piperazine-1-carboxylate (1.0 g, 1.8 mmol), 2-bromopyridine (0.35 mL, 3.6 mmol), Pd(dppf)Cl ₂ (130 mg, 0.18 mmol) and K ₂ CO ₃ (1.3 g, 9.0 mmol) in dioxane (20 mL) and H ₂ O (2 mL) was stirred at 90°C for 12 hours. The reaction mixture was concentrated. The residue was purified by column chromatography on silica gel (0~50% ethyl acetate in petroleum ether) to give the crude product. The crude product was purified by prep-HPLC to give the 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). The following compounds were prepared by procedures analogous to the synthesis of compound 119 using the corresponding aryl halides. 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-methylpi perazine-1-carboxylate (Compound 121) 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 following the procedures 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 with NaHCO ₃ (aq.) to pH 8 and then extracted with DCM (100 mL x 2). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated to afford (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 in the next step directly without further purification. LC/MS ESI (m/z): 405 (M+H) ⁺ . 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-ca rboxylate 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 hours. After cooling to room temperature, the reaction mixture was concentrated. The residue was purified by column chromatography on silica gel (0~50% ethyl acetate in petroleum ether) to give the crude product. The crude product was purified by prep-HPLC to give the 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-methylpipe razine-1-carboxylate (54 mg, 24%) as a white solid. LC/MS ESI (m/z): 559 (M+H) ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) 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). 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-carbox ylate (Compound 123) 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 following step 2 of the procedures described for compound 164 in EtOH (5 mL) were 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 ^o 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 in petroleum ether) to afford 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) ⁺ . 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, 1.0M 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~60%, ethyl acetate in 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) ⁺ . 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) were 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 K ₃ PO ₄ (150 mg, 0.69 mmol). The resulting mixture was heated to 100 ^o C overnight. After cooling to room temperature, the reaction was quenched with water, extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford 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, CD ₃ OD) 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). The following compound was prepared by procedures analogous to the synthesis of compound 123 using the corresponding amines and aryl halides. 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-carboxyla te (Compound 126) C ^{ompound 126} Step 1. (S)-5-(2-Fluorophenyl)-7-(5-methoxypyridin-3-yl)-4-(2-methyl piperazin-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-carboxyla te (80 mg, 0.16 mmol, prepared following an analogous procedure described for compound 1004 in DCM (3 mL) was added HCl (4.0 mL, 4.0 M in dioxane). The resulting mixture was stirred at room temperature for 0.5h. After removal of solvent, the residue was diluted with DCM and washed with NaHCO ₃ (aq.). The organic layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was used in the next step directly. (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) ⁺ . Step 2. Ethyl (S)-4-(5-(2-fluorophenyl)-7-(5-methoxypyridin-3-yl)-7H-pyrro lo[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) at 0 ^o C was added TEA (0.30 mL, 0.30 mmol), followed by ethyl carbonochloridate (0.020 mL, 0.20 mmol) dropwise. 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 ₃ (aq.), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford ethyl (S)-4-(5-(2-fluorophenyl)-7-(5-methoxypyridin-3-yl)-7H-pyrro lo[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). 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-methylpiper azine-1-carboxylate (Compound 140) C ^{ompound 140} 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 Na ₂ SO ₄ , filtered and concentrated to afford 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) ⁺ . 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-carbox ylate 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 following the procedures described for compound 461) in DMF (5 mL) were 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 at 80 ^o C overnight under a N ₂ atmosphere. The reaction was quenched with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford 1,1,1-trifluoro-2- methylpropan-2-yl (S)-4-(7-(3-chlorophenyl)-5-cyclopropyl-7H-pyrrolo[2,3-d]pyr imidin-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, CDCl ₃ ) 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). The following compounds were prepared by a procedure analogous to the synthesis of compound 140 from the corresponding amines. 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-carboxyla te (Compound 153) Step 1. (S)-5-Cyclopropyl-4-(2-methylpiperazin-1-yl)-7-(5-methylpyri din-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-carboxyla te (80 mg, 0.16 mmol, prepared following an analogous procedure described for compound 259) in DCM (3 mL) was added HCl (4.0 mL, 4.0 M in dioxane). The resulting mixture was stirred at room temperature for 0.5h. After removal of solvent, the residue was diluted with DCM and washed with NaHCO ₃ (aq.). The aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was used in the next step directly. (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) ⁺ . 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-methylpyri din-3- yl)-7H-pyrrolo[2,3-d]pyrimidine (40 mg, 0.10 mmol) in DCM (3 mL) at 0 ^o C was added TEA (0.30 mL, 0.30 mmol), followed by ethyl carbonochloridate (0.020 mL, 0.20 mmol) dropwise. 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 ₃ (aq.), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford ethyl (S)-4- (5-cyclopropyl-7-(5-methylpyridin-3-yl)-7H-pyrrolo[2,3-d]pyr imidin-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). 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-carboxyla te (Compound 155) ^p 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-carboxyla te (400 mg, 0.77 mmol, prepared following the procedures described for compound 154 in DCM (5 mL) was added HCl (3.0 mL, 4.0 M in dioxane). The resulting mixture was stirred at room temperature for 2 h. After removal of 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 in the next step directly. (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) ⁺ . Step 2. Ethyl (S)-4-(7-(3-chloro-4-fluorophenyl)-5-(pyridin-2-yl)-7H-pyrro lo[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) at 0 ^o C was added TEA (70 mg, 0.69 mmol), followed by ethyl carbonochloridate (75 mg, 0.69 mmol) dropwise. 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 ₃ (aq), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford 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). The following compounds were prepared by procedures analogous to the synthesis of compound 155 from the corresponding Boc-protected amines. Example 40. Synthesis of tert-butyl (R)-4-(7-(3-chlorophenyl)-5-cyclopentyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (Compound 157) Step 1.4-Chloro-7-(3-chlorophenyl)-5-(cyclopent-1-en-1-yl)-7H-pyr rolo[2,3- d]pyrimidine To a solution of 4-chloro-7-(3-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidi ne (1.0 g, 2.6 mmol, prepared following step 1 of the procedures described for compound 274) in dioxane-H ₂ O (15 mL, 5:1 v/v) were added 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (450 mg, 2.3 mmol), K ₂ CO ₃ (1.1 g, 7.8 mmol) and Pd(dppf)Cl ₂ (190 mg, 0.26 mmol). The resulting mixture was heated to 90 ^o C overnight. After cooling to room temperature, the reaction was filtered and the filtrate was partitioned between EtOAc and waterThe aqueous phase was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0~40% EtOAc in petroleum ether) to give 300 mg of 4- chloro-7-(3-chlorophenyl)-5-(cyclopent-1-en-1-yl)-7H-pyrrolo [2,3-d]pyrimidine (36% yield) as a solid. LC/MS ESI (m/z): 330 (M+H) ⁺ . 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-pyrro lo[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 ^o C for 3 h. After cooling to room temperature, the DIPEA was removed by vacuum. The residue was purified by flash chromatography (silica gel, 0~40% EtOAc in petroleum ether) to afford tert-butyl (R)-4-(7- (3-chlorophenyl)-5-(cyclopent-1-en-1-yl)-7H-pyrrolo[2,3-d]py rimidin-4-yl)-3- methylpiperazine-1-carboxylate (110 mg, 73%) as a white solid. LC/MS ESI (m/z): 494 (M+H) ⁺ . 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-carboxyla te (110 mg, 0.22 mmol ), PtO ₂ (51 mg) in EtOAc (8 mL) was stirred at room temperature for overnight under H ₂ atmosphere (~1 atm) _. The reaction was filtered, and the filtrate was concentrated. The residue was purified by flash chromatography (silica gel, 0~50% EtOAc in petroleum ether) and prep- 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, CDCl ₃ ) 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). The following compound was prepared by procedures analogous to the synthesis of compound 157 from the corresponding amine. 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) C ^{ompound 169} 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 ^o C was added 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (5.0 g, 18 mmol) in portions. The resulting mixture was stirred at 0 ^o C for 30 minutes before TosCl (3.4 g, 18 mmol) was added in portions. After the addition, the reaction was stirred at room temperature overnight. The reaction was poured into ice water, filtered. The solid was collected and further dried in vacuo 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) ⁺ . 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 ^o C for 3 h under a N ₂ atmosphere. After cooling to room temperature, solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford 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) ⁺ . 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 H ₂ O (1 mL) were added phenylboronic acid (60 mg, 0.60 mmol), K ₂ CO ₃ (100 mg, 0.75 mmol) and Pd(dppf)Cl ₂ (18 mg, 0.010 mmol). The resulting mixture was stirred at 90 ^o C overnight under a N ₂ atmosphere. After cooling to room temperature, solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~20%, ethyl acetate in petroleum ether) to afford 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) ⁺ . 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~60%, ethyl acetate in 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) ⁺ . 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) were 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 K ₃ PO ₄ (280 mg, 1.2 mmol). The resulting mixture was heated to 100 ^o 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford 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 prep-HPLC to afford 29 mg of 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). 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-carboxyla te (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) C ^{ompound 174 Compound 175} 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 following the procedures 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 hours. The reaction mixture was concentrated. The residue was purified by column chromatography on silica gel (0~40% EtOAc in petroleum ether) to give the 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) ⁺ . 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 TBAF (4.6 mL, 1.0M in THF) dropwise. The resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was extracted with EtOAc (100 mL x2). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography on silica gel (0~80% EtOAc in petroleum ether) to give the 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) ⁺ . 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-methy lpiperazine-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 K ₃ PO ₄ (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 in petroleum ether) to give the tert-butyl 4-[5- cyclopropyl-7-(5-methylpyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimi din-4-yl]-2-methylpiperazine- 1-carboxylate (120 mg, 0.27 mmol, 44%), which was separated by SFC to afford the two isomers: Peak 1 (shorter retention time): Assigned as tert-butyl (S)-4-(5-cyclopropyl-7-(5- methylpyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methy lpiperazine-1-carboxylate (39 mg) as a light yellow solid. LC/MS ESI (m/z): 449 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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 as tert-butyl (R)-4-(5-cyclopropyl-7-(5- methylpyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methy lpiperazine-1-carboxylate (44 mg) as a light yellow solid. LC/MS ESI (m/z): 449 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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, 250×21.2 mm I.D, 5 µm; Mobile phase: A for CO ₂ and B for MeOH+0.1% NH _3· H ₂ O; 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. 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) 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 (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 18h. The reaction was quenched with water. The aqueous layer was extracted twice with DCM. The combined organic phases were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was used in the next step directly. 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-ph enyl- 7H-pyrrolo[2,3-d]pyrimidin-4-yl]piperazine-1-carboxylate (120 mg, 0.25 mmol, prepared following an analogous procedure described for compound 268) in DCM (5 mL) was added TFA (3 mL). The reaction was stirred at room temperature for 18h. The mixture was concentrated. The residue was neutralized by addition of saturated Na ₂ CO ₃ solution and extracted twice with EtOAc. The combined organic phases were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was used directly without further purification. LC/MS ESI (m/z): 374 (M+H) ⁺ Step 3.1,1,1-Trifluoro-2-methylpropan-2-yl(S)-3-methyl-4-(7-(1-me thyl-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℃ for 2 days, then the mixture was cooled to room temperature and concentrated. The residue was partitioned between water and EtOAc. The aqueous layer was extracted twice by EtOAc. The combined organic phases were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography on silica gel (EtOAc in petroleum ether, 1:100 to 1:5 v/v) and prep-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-carboxyl ate (5.3 mg, 7.5%) as a white solid. LC/MS ESI (m/z): 528 (M+H) ^{+ 1} H NMR (400 MHz, CD ₃ OD) 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). 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) Step 1. tert-Butyl 4-(1-(3-chlorophenyl)-3-(pyridin-2-yl)-1H-pyrrolo[3,2-c]pyri din-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 following the procedures of the first two steps of compound 418 synthesis) in toluene (5 mL) were added 2- (tributylstannyl)pyridine (0.050 mL, 0.14 mmol) and Pd(PPh ₃ ) ₄ (14 mg, 0.012 mmol). The resulting mixture was stirred at 120 ^o 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford tert-butyl 4- (1-(3-chlorophenyl)-3-(pyridin-2-yl)-1H-pyrrolo[3,2-c]pyridi n-4-yl)-3-methylpiperazine-1- carboxylate (8.4 mg, 14%) as a white solid. LC/MS ESI (m/z): 504 (M+H) ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) 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). The following compound was prepared by a procedure analogous to the synthesis of compound 187 using the corresponding tin reagent. 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-carbo xylate (Compound 189) C ^{ompound 189} 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]pyrimidi ne (500 mg, 1.3 mmol, prepared following the procedures described for compound 274), cyclopropylboronic acid (110 mg, 1.3 mmol), Pd(dtbpf)Cl ₂ (170 mg, 0.26 mmol) and K ₂ CO ₃ (3.6 g, 26 mmol) in toluene (20 ml) was heated at 80°C for 12 hours. The reaction mixture was concentrated. The residue was purified by column chromatography on silica gel (0~40% EtOAc in petroleum ether) to give the 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) ⁺ . 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, 1.0M in THF) in DMSO (20 mL) was stirred at 50°C for 3 hours. The resulting mixture was quenched with ice water and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography on silica gel (0~30% EtOAc in 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) ⁺ . 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]p yrimidine (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 hours. 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30% ethyl acetate in petroleum ether) to afford the 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) ⁺ . Step 4.7-(3-Chlorophenyl)-5-cyclopropyl-4-((2S,6S)-2,6-dimethylpi perazin-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-carbo xylate (60 mg, 0.13 mmol) in DCM (10 mL) was added HCl (3.0 mL, 4.0M in dioxane). The resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated to afford 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 in the next step directly without further purification. LC/MS ESI (m/z): 382 (M+H) ⁺ . 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-dimethylpipe razin- 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) at 0 °C was added ethyl carbonochloridate (14 mg, 0.13 mmol) dropwise. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with NaHCO ₃ (aq.), extracted with DCM (50 ml x 2). The organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography on silica gel (0~50% EtOAc in petroleum ether) to give the crude product. The crude product was purified by HPLC to afford the ethyl (3S,5S)-4-(7-(3-chlorophenyl)-5- cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,5-dimethylpip erazine-1-carboxylate (15 mg, 0.033 mmol, 32%) 1006as a white solid. LC/MS ESI (m/z): 454 (M+H) ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) 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). 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-carboxyla te (Compound 193) C ^{ompound 193} Step 1.4-Chloro-7-(3-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimi dine To a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (10 g, 36 mmol) in DCM (600 mL) were added (3-chlorophenyl)boronic acid (11 g, 72 mmol), Cu(OAc) ₂ (16 g, 110 mmol), pyridine (18 mL, 110 mmol) and 4A molecular sieves (10 g). The resulting mixture was stirred at room temperature under an O ₂ atmosphere for 3 days. After cooling with an ice-water bath, the reaction was quenched with NH ₄ OH (aq. solution, 50 mL) and filtered. The filtrate was extracted twice with DCM. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford 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) ⁺ . Step 2.7-(3-Chlorophenyl)-5-iodo-4-methoxy-7H-pyrrolo[2,3-d]pyrim idine To a solution of 4-chloro-7-(3-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidi ne (4.0 g, 10 mmol) in MeOH (40 mL) was added MeONa (8.0 mL, 4.5M in MeOH). The resulting mixture was stirred at 50 ^o C overnight. The reaction was quenched with ice water, extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford 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) ⁺ . Step 3.7-(3-Chlorophenyl)-4-methoxy-5-(pyrrolidin-1-yl)-7H-pyrrol o[2,3- d]pyrimidine To a solution of 7-(3-chlorophenyl)-5-iodo-4-methoxy-7H-pyrrolo[2,3-d]pyrimid ine (2.3 g, 6 mmol) in DMSO (20 mL) were added CuI (230 mg, 1.2 mmol), K ₂ CO ₃ (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 ^o 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0~40%, ethyl acetate in petroleum ether) to afford 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) ⁺ . Step 4.7-(3-Chlorophenyl)-5-(pyrrolidin-1-yl)-7H-pyrrolo[2,3-d]py rimidin-4-ol 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 treated with BBr ₃ (3.0 mL) dropwise at 0 ^o C. The resulting mixture was stirred at 0 ^o 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to afford 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) ⁺ . 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]pyri midin-4-ol (0.40 g, 1.2 mmol) in POCl ₃ (4 mL) was heated at 120 ^o C overnight. After cooling to room temperature, the reaction was concentrated. The residue was re-dissolved in DCM and washed with NaHCO ₃ (aq.). The aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~40%, ethyl acetate in 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) ⁺ . 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) were added DIPEA (230 mg, 1.8 mmol) and tert-butyl (R)-2-methylpiperazine-1-carboxylate (240 mg, 1.2 mmol). The resulting mixture was heated at 100 ^o C overnight. After cooling to room temperature, solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~40%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep- HPLC to afford tert-butyl (R)-4-(7-(3-chlorophenyl)-5-(pyrrolidin-1-yl)-7H-pyrrolo[2,3 - d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate (36 mg, 12%) as a yellow solid. LC/MS ESI (m/z): 497 (M+H) ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ 8.22 (s, 1H), 7.85 (t, J = 2.0 Hz, 1H), 7.67 – 7.63 (m, 1H), 7.49 (t, J = 8.1 Hz, 1H), 7.34 (dd, J = 8.0, 2.0 Hz, 1H), 7.03 (s, 1H), 4.84 – 4.78 (m, 2H), 4.50 – 4.45 (m, 1H), 4.37 – 4.31 (m, 1H), 3.92 – 3.86 (m, 1H), 3.40 – 3.33 (m, 1H), 3.28 – 3.25 (m, 2H), 3.00 (td, J = 12.5, 3.6 Hz, 1H), 2.89 – 2.84 (m, 2H), 2.03 – 1.98 (m, 4H), 1.48 (s, 9H), 1.08 (d, J = 6.8 Hz, 3H). The following compounds were prepared by procedures analogous to the synthesis of compound 193 using the corresponding boronic acids and amines. In cases involving tert- butyl (S)-3-methylpiperazine-1-carboxylate or tert-butyl (R)-3-methylpiperazine-1- carboxylate in the last step, 5 eq. of the amine was used, and the reaction was run at 140 ^o C.

Example 47. Synthesis of tert-butyl (R)-4-(5-cyclopropyl-7-(3,5-difluorophenyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (Compound 211) Step 1. tert-Butyl (R)-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 (12 g, 28 mmol, prepared following step 1 of the procedures described for compound 192 in DIPEA (100 mL) was added tert-butyl (R)-3-methylpiperazine-1-carboxylate (11 g, 55 mmol). The resulting mixture was heated to 150 ^o C for 3 h. After cooling to room temperature, solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford tert-butyl (R)-4-(5-iodo-7-tosyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (11 g, 66%) as a white solid. LC/MS ESI (m/z): 598 (M+H) ⁺ . Step 2. tert-Butyl (R)-4-(5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl )-3- methylpiperazine-1-carboxylate To a solution of tert-butyl (R)-4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate (3.5 g, 5.9 mmol) in toluene (30 mL) were added cyclopropylboronic acid (1.0 g, 12 mmol), K ₂ CO ₃ (11 g, 77 mmol) and Pd-118 (390 mg, 0.59 mmol). The resulting mixture was heated to 80 ^o C overnight. After cooling to room temperature, the reaction mixture was filtered. The filtrate was concentrated and purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford tert-butyl (R)-4-(5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl )-3- methylpiperazine-1-carboxylate (1.9 g, 63%) as a white solid. LC/MS ESI (m/z): 512 (M+H) ⁺ . Step 3. tert-Butyl (R)-4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate To a solution of tert-butyl (R)-4-(5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)-3-methylpiperazine-1-carboxylate (1.9 g, 3.7 mmol) in THF (30 mL) was added TBAF (22 mL, 1.0M 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~60%, ethyl acetate in petroleum ether) to afford tert-butyl (R)-4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate (1.1 g, 83%) as white solid. LC/MS ESI (m/z): 358 (M+H) ⁺ . Step 4. tert-Butyl (R)-4-(5-cyclopropyl-7-(3,5-difluorophenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl (R)-4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate(100 mg, 0.28 mmol) in DMF (10 mL) were added 1,3- difluoro-5-iodobenzene (130 mg, 0.56 mmol), trans-cyclohexane-1,2-diamine (9.7 mg, 0.084 mmol), CuI (27 mg, 0.15 mmol) and K ₃ PO ₄ (180 mg, 0.84 mmol). The resulting mixture was heated to 120 ^o 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep- HPLC to afford tert-butyl (R)-4-(5-cyclopropyl-7-(3,5-difluorophenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (44 mg, 33%) as a white solid. LC/MS ESI (m/z): 470 (M+H) ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ 8.33 (s, 1H), 7.57 – 7.51 (m, 2H), 7.29 (d, J = 0.6 Hz, 1H), 6.97 – 6.89 (m, 1H), 4.75 (s, 1H), 4.06 (d, J = 13.0 Hz, 1H), 3.86 (d, J = 12.7 Hz, 2H), 3.59 – 3.34 (m, 2H), 3.24 – 3.07 (m, 1H), 2.10 – 2.02 (m, 1H), 1.50 (s, 9H), 1.20 (d, J = 6.6 Hz, 3H), 1.07 – 1.01 (m, 2H), 0.91 – 0.86 (m, 1H), 0.80 – 0.72 (m, 1H). The following compounds were prepared by procedures analogous to the synthesis of compound 211 from the corresponding aryl halides. Example 48. Synthesis of tert-butyl (R)-4-(7-(3,5-difluorophenyl)-5-(pyridin-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxyla te (Compound 215) 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-carboxyla te To a solution of tert-butyl (R)-4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2- methylpiperazine-1-carboxylate (500 mg, 0.83 mmol, prepared following the procedures of the first two steps of compound 192 synthesis) in dioxane (10 mL) were added 4,4,5,5- tetramethyl-1,3,2-dioxaborolane (0.48 mL, 3.3 mmol), TEA (0.58 mL, 4.1 mmol), X-Phos (40 mg, 0.084 mmol) and Pd ₂ (dba) ₃ (77 mg, 0.084 mmol). The resulting mixture was stirred at 95 ^o 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 Na ₂ SO ₄ , filtered and concentrated to afford 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 brown oil, which was used in the next step directly. LC/MS ESI (m/z): 598 (M+H) ⁺ . 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-c arboxylate (500 mg, 0.83 mmol) in dioxane (10 mL) and H ₂ O (2 mL) were added 2-bromopyridine (0.16 mL, 1.6 mmol), K ₂ CO ₃ (580 mg, 4.1 mmol) and Pd(dppf)Cl ₂ (61 mg, 0.084 mmol). The resulting mixture was heated at 90 ^o C overnight. After cooling to room temperature, solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to afford tert-butyl (R)-2-methyl-4-(5-(pyridin-2-yl)-7-tosyl- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (410 mg, 89%) as a yellow solid. LC/MS ESI (m/z): 549 (M+H) ⁺ . 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 (410 mg, 0.74 mmol) in THF (5 mL) was added TBAF (4.5 mL, 1.0M 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~10%, methanol in dichloromethane) to afford tert-butyl (R)-2-methyl-4-(5-(pyridin-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (240 mg, 81%) as a yellow solid. LC/MS ESI (m/z): 395 (M+H) ⁺ . Step 4. tert-Butyl (R)-4-(7-(3,5-difluorophenyl)-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 (140 mg, 0.35 mmol) in DMF (5 mL) were added 1,3-difluoro-5-iodobenzene (100 mg, 0.42 mmol), trans-cyclohexane-1,2-diamine (12 mg, 0.11 mmol), CuI (20 mg, 0.11 mmol) and K ₃ PO ₄ (230 mg, 1.1 mmol). The resulting mixture was heated at 120 ^o 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford tert-butyl (R)-4-(7-(3,5-difluorophenyl)- 5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpi perazine-1-carboxylate (110 mg, 61%) as a white solid. LC/MS ESI (m/z): 507 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.72 – 8.67 (m, 1H), 8.52 (s, 1H), 7.79 (td, J = 7.7, 1.8 Hz, 1H), 7.67 (s, 1H), 7.59 (d, J = 7.8 Hz, 1H), 7.49 – 7.43 (m, 2H), 7.31 – 7.26 (m, 1H), 6.82 (tt, J = 8.8, 2.3 Hz, 1H), 4.30 – 4.15 (m, 1H), 3.90 – 3.74 (m, 2H), 3.62 – 3.46 (m, 1H), 3.08 (dd, J = 13.3, 3.9 Hz, 1H), 2.94 – 2.72 (m, 2H), 1.44 (s, 9H), 1.10 (d, J = 6.8 Hz, 3H). The following compounds were prepared by procedures analogous to the synthesis of compound 215 using the corresponding aryl halides in steps 2 and 4.

Example 49. Synthesis of tert-butyl (2R,5S)-4-(5-cyclopropyl-7-(3,5-difluorophenyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate (Compound 232) C ^{ompound 232} To a solution of tert-butyl (2R,5S)-4-[7-(3,5-difluorophenyl)-5-iodo-7H-pyrrolo[2,3- d]pyrimidin-4-yl]-2,5-dimethylpiperazine-1-carboxylate (150 mg, 0.26 mmol, prepared following an analogous procedure described for compound 242) in toluene (5 mL) were added cyclopropylboronic acid (45 mg, 0.52 mmol), 1,1'-bis(di-t-butylphosphino)ferrocene palladium dichloride (17 mg, 0.030 mmol) and K ₂ CO ₃ (730 mg, 5.3 mmol). The resulting mixture was heated to 80℃ overnight. After cooling to room temperature, solvent was removed and the residue was purified by flash column chromatography to afford tert-butyl (2R,5S)-4-(5-cyclopropyl-7-(3,5-difluorophenyl)-7H-pyrrolo[2 ,3-d]pyrimidin-4-yl)-2,5- dimethylpiperazine-1-carboxylate (90 mg, 71%) as a solid. LC/MS ESI (m/z): 484 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.44 (s, 1H), 7.36 (dd, J = 8.3, 2.2 Hz, 2H), 6.93 (d, J = 0.8 Hz, 1H), 6.76 (tt, J = 8.8, 2.3 Hz, 1H), 4.95 – 4.86 (m, 1H), 4.41 (s, 1H), 3.77 (m, 3H), 3.58 (d, J = 11.0 Hz, 1H), 2.05 – 1.97 (m, 1H), 1.50 (s, 9H), 1.17 (t, J = 6.8 Hz, 6H), 1.06 – 1.01 (m, 2H), 0.89 – 0.82 (m, 1H), 0.66 (dd, J = 8.7, 4.3 Hz, 1H). Example 50. Synthesis of tert-butyl-(S)-4-(7-(3,5-difluorophenyl)-5-(pyridin-2-yl)-7H - pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (Compound 235) C ^{ompound 235} Step 1. tert-Butyl-(S)-3-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-diox aborolan-2-yl)-7- tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxyla te A suspension of tert-butyl-(3S)-4-[5-iodo-7-(4-methylbenzenesulfonyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl]-3-methylpiperazine-1-carboxyla te (1.8 g, 3.0 mmol, prepared following the procedure described for compound 268), 4,4,5,5-tetramethyl-1,3,2- dioxaborolane (1.3 mL, 9.0 mmol), Et ₃ N (1.6 mL, 12 mmol), X-Phos (0.43 g, 0.90 mmol) and Pd ₂ (dba) ₃ (0.83 g, 0.90 mmol) in dioxane (30 mL) was stirred at 95℃ under a N ₂ atmosphere for 18h. 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 phases were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was used in the next step directly. LC/MS (ESI) (m/z): 598 (M+H) ⁺ Step 2. tert-Butyl-(S)-3-methyl-4-(5-(pyridin-2-yl)-7-tosyl-7H-pyrro lo[2,3- d]pyrimidin-4-yl)piperazine-1-carboxylate A suspension of tert-butyl-(3S)-3-methyl-4-[7-(4-methylbenzenesulfonyl)-5- (tetramethyl-1,3,2-dioxaborolan-2-yl)-7H-pyrrolo[2,3-d]pyrim idin-4-yl]piperazine-1- carboxylate (500 mg, 0.84 mmol), 2-bromopyridine (130 mg, 0.84 mmol), K ₂ CO ₃ (290 mg, 2.1 mmol) and Pd(dppf)Cl ₂ (61 mg, 0.080 mmol) in dioxane-water (12 mL, 5:1 v/v) was stirred at 90℃ under a N ₂ atmosphere for 18h. After cooling to room temperature, solvent was removed, the residue was purified by column chromatography on silica gel (0~10% MeOH in DCM) to give tert-butyl-(3S)-3-methyl-4-[7-(4-methylbenzenesulfonyl)-5-(p yridin- 2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]piperazine-1-carboxyla te (200 mg, 44%) as a white solid. LC/MS (ESI) (m/z): 549 (M+H) ⁺ Step 3. 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-(3S)-3-methyl-4-[7-(4-methylbenzenesulfonyl)-5-(p yridin- 2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]piperazine-1-carboxyla te (200 mg, 0.36 mmol) in THF (5 mL) was added 1.0M TBAF (1.1 mL, 1.1 mmol). The resulting mixture was stirred at room temperature for 18h. The reaction was partitioned between EtOAc and water. The aqueous layer was extracted twice with EtOAc. The combined organic phases were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography on silica gel (0~20% MeOH in DCM) to give tert-butyl-(S)-3-methyl-4-(5- (pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1- carboxylate (120 mg, 83%) as a white solid. LC/MS (ESI) (m/z): 395 (M+H) ⁺ Step 4. tert-Butyl-(S)-4-(7-(3,5-difluorophenyl)-5-(pyridin-2-yl)-7H -pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate A suspension of tert-butyl-(S)-3-methyl-4-(5-(pyridin-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperazine-1-carboxylate (80 mg, 0.20 mmol), 1,3-difluoro-5-iodobenzene (49 mg, 0.20 mmol), K ₃ PO ₄ (110 mg, 0.51 mmol), CuI (12 mg, 0.060 mmol) and trans- cyclohexane-1,2-diamine (7.0 mg, 0.060 mmol) in DMF (5.0 mL) was stirred at 120℃ under a N ₂ atmosphere for 18h. The mixture was cooled to room temperature and concentrated. The residue was purified by column chromatography on silica gel (0~10% MeOH in DCM) and prep-HPLC to give tert-butyl-(S)-4-(7-(3,5-difluorophenyl)-5-(pyridin-2-yl)-7H - pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (55 mg, 54%) as a white solid. LC/MS(ESI)m/z: 507 (M+H) ^{+ 1} H NMR (400 MHz, CDCl ₃ ) δ 8.69 (dd, J = 4.8, 0.7 Hz, 1H), 8.53 (s, 1H), 7.79 (td, J = 7.7, 1.7 Hz, 1H), 7.68 (s, 1H), 7.59 (d, J = 7.7 Hz, 1H), 7.50 – 7.41 (m, 2H), 7.29 – 7.25 (m, 1H), 6.82 (tt, J = 8.7, 2.3 Hz, 1H), 4.41 – 4.18 (m, 1H), 3.96 – 3.77 (m, 1H), 3.57 (m, 2H), 3.15 (t, J = 11.7 Hz, 1H), 3.06 – 2.61 (m, 2H), 1.43 (s, 9H), 1.04 (s, 3H). The following compounds were prepared by procedures analogous to the synthesis of compound 235 using the corresponding aryl halides. Example 51. Synthesis of tert-butyl (2R,5S)-4-(7-(3-chloro-5-fluorophenyl)-5- cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpip erazine-1-carboxylate (Compound 236) To a solution of tert-butyl (2R,5S)-4-{5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4- yl}-2,5-dimethylpiperazine-1-carboxylate (67 mg, 0.18 mmol, prepared following an analogous procedure described for compound 259) in DMF (5 mL) was added 1-bromo-3- chloro-5-fluorobenzene (76 mg, 0.36 mmol), CuI (34 mg, 0.18 mmol), K ₃ PO ₄ (38 mg, 0.18 mmol) and trans-1,2-diaminocyclohexane (21 mg, 0.18 mmol). The resulting mixture was heated to 120℃ overnight. After cooling to room temperature, solvent was removed and the residue was purified by flash column chromatography to afford tert-butyl (2R,5S)-4-(7-(3- chloro-5-fluorophenyl)-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimi din-4-yl)-2,5- dimethylpiperazine-1-carboxylate (57 mg, 63%) as a solid. LC/MS ESI (m/z): 500 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl3) δ 8.41 (s, 1H), 7.56 – 7.40 (m, 2H), 7.00 (d, J = 8.1 Hz, 1H), 6.91 (s, 1H), 4.89 (s, 1H), 4.40 (s, 1H), 3.76 (m, 3H), 3.56 (d, J = 11.9 Hz, 1H), 1.99 (m, 1H), 1.48 (s, 9H), 1.15 (app. t, J = 6.4 Hz, 6H), 1.01 (d, J = 7.9 Hz, 2H), 0.84 (m, 1H), 0.69 – 0.56 (m, 1H). Example 52. Synthesis of tert-butyl (R)-4-(3-cyclopropyl-1-(3,5-difluorophenyl)-1H- pyrazolo[3,4-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxyl ate (Compound 239) ^{Co pou d 39} Step 1.4-Chloro-1-tosyl-1H-pyrazolo[3,4-d]pyrimidine To a suspension of NaH (780 mg, 19 mmol, 60% wt.) in anhydrous DMF (10 mL) at 0 ^o C was added 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (2.0 g, 13 mmol) in portions, followed by 4-methylbenzenesulfonyl chloride (3.7 g, 19 mmol) in portions. The resulting mixture was stirred at room temperature for 10min. The reaction was poured into ice water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentration. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford 4-chloro-1- tosyl-1H-pyrazolo[3,4-d]pyrimidine (1.4 g, 35%) as a light yellow solid. LC/MS ESI (m/z): 309 (M+H) ⁺ . Step 2. tert-Butyl (R)-2-methyl-4-(1-tosyl-1H-pyrazolo[3,4-d]pyrimidin-4- yl)piperazine-1-carboxylate To a solution of 4-chloro-1-tosyl-1H-pyrazolo[3,4-d]pyrimidine (540 mg, 1.8 mmol) in EtOH (5 mL) were added tert-butyl (R)-2-methylpiperazine-1-carboxylate (420 mg, 2.1 mmol) and TEA (530 mg, 5.3 mmol). The resulting mixture was stirred at 90 ^o C under a N ₂ atmosphere for 4 hours. After cooling to room temperature, solvent was removed and the residue was partitioned between H ₂ O and EtOAc. The aqueous phase was extracted twice with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to afford tert-butyl (R)-2-methyl-4-(1-tosyl-1H-pyrazolo[3,4-d]pyrimidin-4- yl)piperazine-1-carboxylate (350 mg, 42%) as a yellow solid. LC/MS ESI (m/z): 473 (M+H) ⁺ . Step 3. tert-Butyl (R)-2-methyl-4-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazine- 1- carboxylate To a solution of tert-butyl (R)-2-methyl-4-(1-tosyl-1H-pyrazolo[3,4-d]pyrimidin-4- yl)piperazine-1-carboxylate (350 mg, 0.74 mmol) in THF (5 mL) was added TBAF (2.0 mL, 1.0M 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography to afford tert-butyl (R)-2-methyl-4-(1H-pyrazolo[3,4- d]pyrimidin-4-yl)piperazine-1-carboxylate (220 mg, 99%) as a white solid. LC/MS ESI (m/z): 319 (M+H) ⁺ . Step 4. tert-Butyl (R)-4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2- methylpiperazine-1-carboxylate To a solution of tert-butyl (R)-2-methyl-4-(1H-pyrazolo[3,4-d]pyrimidin-4- yl)piperazine-1-carboxylate (220 mg, 0.69 mmol) in DCM (5 mL) at 0 ^o C was added 1- bromopyrrolidine-2,5-dione (140 mg, 0.76 mmol) in portions. The resulting mixture was stirred at room temperature for 3 h. The reaction was quenched with water and extracted twice with DCM. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography to afford tert-butyl (R)-4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-methylpip erazine-1- carboxylate (200 mg, 73%) as a yellow solid. LC/MS ESI (m/z): 397,399 (M+H) ⁺ . Step 5. tert-Butyl (R)-4-(3-bromo-1-(3,5-difluorophenyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate To a solution of tert-butyl (R)-4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2- methylpiperazine-1-carboxylate(200 mg, 0.50 mmol) in DCM (15 mL) were added (3,5- difluorophenyl)boronic acid (160 mg, 1.0 mmol), 4A molecular sieves (200 mg), Cu(OAc) ₂ (370 mg, 2.0 mmol) and pyridine (240 mg, 3.0 mmol). The resulting mixture was stirred at room temperature under an O ₂ atmosphere overnight. The reaction was quenched with NH ₄ OH (10 mL) at 0 ^o C (ice water bath) and filtered. The filtrate was extracted twice with DCM. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0~40% EtOAc in petroleum ether) to afford tert-butyl (R)-4-(3-bromo-1-(3,5-difluorophenyl)-1H-pyrazolo[3,4-d]pyri midin-4- yl)-2-methylpiperazine-1-carboxylate (180 mg, 70%) as a light yellow solid. LC/MS ESI (m/z): 509, 511(M+H) ⁺ . Step 6. tert-Butyl (R)-4-(3-cyclopropyl-1-(3,5-difluorophenyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate To a solution of tert-butyl (R)-4-(3-bromo-1-(3,5-difluorophenyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate (180 mg, 0.34 mmol) in toluene (15 mL) were added cyclopropylboronic acid (91 mg, 1.1 mmol), K ₂ CO ₃ (980 mg, 7.1 mmol) and Pd- 118 (23 mg, 0.040 mmol). The resulting mixture was heated to 100 ^o C overnight. After cooling to room temperature, solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to give crude product (80 mg), which was further purified by prep-HPLC to afford tert-butyl (R)-4-(3- cyclopropyl-1-(3,5-difluorophenyl)-1H-pyrazolo[3,4-d]pyrimid in-4-yl)-2-methylpiperazine- 1-carboxylate (37 mg, 22%) as a white solid. LC/MS ESI (m/z): 471 (M+H)+. ¹ H NMR(400 MHz, CD ₃ OD) δ 8.42 (s, 1H), 8.03 – 7.94 (m, 2H), 6.86 (tt, J = 9.0, 2.3 Hz, 1H), 4.64 (d, J = 9.6 Hz, 1H), 4.48 – 4.37 (m, 2H), 3.97 (m, 1H), 3.60 (dd, J = 13.2, 3.8 Hz, 1H), 3.46 – 3.35 (m, 2H), 2.24 – 2.14 (m, 1H), 1.48 (s, 9H), 1.45 – 1.39 (m, 1H), 1.19 (m, 2H), 1.15 (d, J = 6.7 Hz, 3H), 1.08 (ddd, J = 12.2, 5.1, 2.8 Hz, 1H). The following compound was prepared by procedures analogous to the synthesis of compound 239 using the corresponding amine and boronic acid. Example 53. Synthesis of tert-butyl (R)-4-(7-(3,5-difluorophenyl)-5-(3-methylpyrazin-2- yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-ca rboxylate (Compound

242) and ethyl (R)-4-(7-(3,5-difluorophenyl)-5-(3-methylpyrazin-2-yl)-7H-py rrolo[2,3- d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate (Compound 1005) Step 1. tert-Butyl (R)-4-(7-(3,5-difluorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimi din-4- yl)-2-methylpiperazine-1-carboxylate To a solution of 4-chloro-7-(3,5-difluorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyri midine (1.8 g, 4.6 mmol, prepared following step 1 of the procedures described for compound 193 in EtOH (5 mL) were added tert-butyl (R)-2-methylpiperazine-1-carboxylate (1.1 g, 5.5 mmol) and DIEA (1.7 g, 14 mmol). The resulting mixture was stirred at 90 ^o C under a N ₂ atmosphere overnight. After cooling to room temperature, solvent was removed and the residue partitioned between H ₂ O and EtOAc. The aqueous phase was extracted twice with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30% EtOAc in petroleum ether) to afford tert-butyl (R)-4-(7-(3,5-difluorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimi din-4-yl)-2- methylpiperazine-1-carboxylate (1.6 g, 62%) as a yellow solid. LC/MS ESI (m/z): 556 (M+H) ⁺ . Step 2. tert-Butyl (R)-4-(7-(3,5-difluorophenyl)-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methyl piperazine-1-carboxylate To a solution of tert-butyl (R)-4-(7-(3,5-difluorophenyl)-5-iodo-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate (1.6 g, 2.9 mmol) in 1.4-dioxane (15 mL) were added 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.5 g, 12 mmol), X-Phos (140 mg, 0.29 mmol), Pd ₂ (dba) ₃ (260 mg, 0.29 mmol) and TEA (1.5 g, 14 mmol). The resulting mixture was stirred at 95 ^o C overnight. The reaction was quenched with H ₂ O, extracted twice with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The solvent was removed in vacuo to give tert-butyl (R)-4-(7-(3,5-difluorophenyl)-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-7H-pyrrolo[2,3-d]pyrimi din-4-yl)-2-methylpiperazine- 1-carboxylate which was used in the next step without further purification. LC/MS ESI (m/z): 556 (M+H) ⁺ . Step 3. tert-Butyl (R)-4-(7-(3,5-difluorophenyl)-5-(3-methylpyrazin-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxyla te To a solution of tert-butyl (R)-4-(7-(3,5-difluorophenyl)-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methyl piperazine-1-carboxylate (1.5 g, 2.7 mmol) in dioxane (10 mL) and H ₂ O (2 mL) were added 2-bromo-3-methylpyrazine (1000 mg, 5.8 mmol), K ₂ CO ₃ (2.0 g, 15 mmol) and Pd(dppf)Cl ₂ (210 mg, 0.29 mmol). The resulting mixture was heated to 90 ^o C overnight. After cooling to room temperature, solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to give crude product tert-butyl (R)-4-(7-(3,5- difluorophenyl)-5-(3-methylpyrazin-2-yl)-7H-pyrrolo[2,3-d]py rimidin-4-yl)-2- methylpiperazine-1-carboxylate (1.1 g), 100 mg of which was further purified by prep-HPLC to afford 50 mg white solid. LC/MS ESI (m/z): 522 (M+H) ⁺ . ¹ H NMR(400 MHz, CD ₃ OD) δ 8.59 (dd, J = 7.3, 2.6 Hz, 2H), 8.47 (s, 1H), 7.91 (s, 1H), 7.65 (dd, J = 8.4, 2.2 Hz, 2H), 7.09 – 6.99 (m, 1H), 4.16 (s, 1H), 3.69 (d, J = 13.0 Hz, 1H), 3.57 (d, J = 12.0 Hz, 1H), 3.51 – 3.42 (m, 1H), 2.98 (dd, J = 13.3, 4.2 Hz, 1H), 2.80 – 2.70 (m, 1H), 2.56 (s, 3H), 2.50 (s, 1H), 1.42 (s, 9H), 1.02 (d, J = 6.8 Hz, 3H). Step 4. (R)-7-(3,5-Difluorophenyl)-4-(3-methylpiperazin-1-yl)-5-(3-m ethylpyrazin-2- yl)-7H-pyrrolo[2,3-d]pyrimidine To a solution of tert-butyl (R)-4-(7-(3,5-difluorophenyl)-5-(3-methylpyrazin-2-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carbox ylate (1.0 g, 1.9 mmol) in DCM (5 ml) was added HCl (5.0 mL, 4.0M in dioxane). The resulting mixture was stirred at room temperature for 3 h. After removal of solvent, the residue was dissolved in DCM and washed with NaHCO ₃ (aq.). The aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was used in the next step directly. (R)-7-(3,5-difluorophenyl)-4-(3- methylpiperazin-1-yl)-5-(3-methylpyrazin-2-yl)-7H-pyrrolo[2, 3-d]pyrimidine. LC/MS ESI (m/z): 422 (M+H) ⁺ . Step 5. Ethyl (R)-4-(7-(3,5-difluorophenyl)-5-(3-methylpyrazin-2-yl)-7H-py rrolo[2,3- d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate To a solution of (R)-7-(3,5-difluorophenyl)-4-(3-methylpiperazin-1-yl)-5-(3- methylpyrazin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine (100 mg, 0.24 mmol) in DCM (5 mL) at 0 ^o C were added TEA (72 mg, 0.71 mmol) and ethyl carbonochloridate (39 mg, 0.36 mmol) dropwise. The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with NaHCO ₃ (aq.) and extracted twice with DCM. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give crude product which was further purified by prep-HPLC to afford ethyl (R)-4-(7-(3,5-difluorophenyl)-5-(3- methylpyrazin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methy lpiperazine-1-carboxylate (30 mg, 26%) as a white solid. LC/MS ESI (m/z): 494 (M+H) ⁺ . ¹ H NMR(400 MHz, CD ₃ OD) δ 8.58 (dd, J = 8.3, 2.6 Hz, 2H), 8.47 (s, 1H), 7.91 (s, 1H), 7.65 (dd, J = 8.5, 2.3 Hz, 2H), 7.04 (m, 1H), 4.22 (m, 1H), 4.07 (m, 2H), 3.71 (d, J = 13.3 Hz, 1H), 3.53 (m, 2H), 3.00 (dd, J = 13.2, 4.1 Hz, 1H), 2.76 (td, J = 12.2, 3.3 Hz, 1H), 2.56 (s, 3H), 2.51 (s, 1H), 1.22 (t, J = 7.1 Hz, 3H), 1.04 (d, J = 6.8 Hz, 3H). The following compounds were prepared by procedures analogous to the synthesis of compound 1005 from the corresponding chloroformate and/or aryl halides. Example 54. Synthesis of 1,1,1-trifluoro-2-methylpropan-2-yl (R)-4-(7-(3,5- difluorophenyl)-5-(3-methylpyrazin-2-yl)-7H-pyrrolo[2,3-d]py rimidin-4-yl)-2- methylpiperazine-1-carboxylate (Compound 243) C ^{ompound 243} 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). 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 Na ₂ SO ₄ , filtered and concentrated. The residue was used in the next step directly. LC/MS ESI (m/z): 223 (M+H) ⁺ . Step 2.1,1,1-Trifluoro-2-methylpropan-2-yl (R)-4-(7-(3,5-difluorophenyl)-5-(3- methylpyrazin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methy lpiperazine-1-carboxylate To a solution of (R)-7-(3,5-difluorophenyl)-4-(3-methylpiperazin-1-yl)-5-(3- methylpyrazin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine (50 mg, 0.12 mmol, prepared following the procedure described for compound 1005 in DMF (3 mL) were added 1,1,1-trifluoro-2- methylpropan-2-yl 1H-imidazole-1-carboxylate (40 mg, 0.18 mmol) and DIPEA (0.04 mL, 0.22 mmol). The resulting mixture was stirred at 80 ^o C for 2 days under a N ₂ atmosphere. The reaction was quenched with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford 1,1,1- trifluoro-2-methylpropan-2-yl (R)-4-(7-(3,5-difluorophenyl)-5-(3-methylpyrazin-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxyla te (15 mg, 33%) as a white solid. LC/MS ESI (m/z): 576 (M+H) ⁺ . ¹ H NMR(400 MHz, CD ₃ OD) δ 8.59 (dd, J = 9.6, 2.4 Hz, 2H), 8.47 (s, 1H), 7.91 (s, 1H), 7.65 (dd, J = 8.4, 2.2 Hz, 2H), 7.08 – 7.01 (m, 1H), 4.14 (s, 1H), 3.70 (d, J = 13.3 Hz, 1H), 3.57 (d, J = 11.2 Hz, 1H), 3.51 – 3.42 (m, 1H), 3.03 (dd, J = 13.2, 4.0 Hz, 1H), 2.79 (td, J = 12.3, 3.6 Hz, 1H), 2.56 (s, 3H), 2.56 – 2.53 (m, 1H), 1.63 (s, 6H), 1.05 (d, J = 6.8 Hz, 3H). The following compounds were prepared by procedures analogous to the synthesis of compound 243 using the corresponding alcohols.

Example 55. Synthesis of tert-butyl (S)-4-(7-(3,5-difluorophenyl)-5-(3-methylpyrazin-2- yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-ca rboxylate (Compound 246) C ^{ompound 246} Step 1. tert-Butyl (S)-4-(7-(3,5-difluorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimi din-4- yl)-3-methylpiperazine-1-carboxylate To a solution of 4-chloro-7-(3,5-difluorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyri midine (2.0 g, 5.0 mmol) in DIEA (50 mL) was added tert-butyl (S)-3-methylpiperazine-1- carboxylate (1.5 g, 7.5 mmol). The resulting reaction mixture was stirred at 140℃ under a N ₂ atmosphere for 13 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was extracted twice with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 0~40%, ethyl acetate in petroleum ether) to afford tert-butyl (S)-4-(7-(3,5-difluorophenyl)-5- iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-c arboxylate (1.9 g, 66% yield) as white solid. LC/MS ESI (m/z): 556 (M+H) ⁺ . Step 2. tert-Butyl (S)-4-(7-(3,5-difluorophenyl)-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methyl piperazine-1-carboxylate To a solution of tert-butyl (S)-4-(7-(3,5-difluorophenyl)-5-iodo-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (1.9 g, 3.4 mmol) in dioxane (25 mL) were added XPhos (160 mg, 0.33 mmol), Pd ₂ (dba) ₃ (300 mg, 0.33 mmol), TEA (1.7 g, 2.4 mL, 17 mmol) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.7 g, 2.0 mL, 14 mmol). The resulting reaction mixture was stirred at 95℃ under a N ₂ atmosphere 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 Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to afford the crude product tert-butyl (S)-4-(7-(3,5-difluorophenyl)-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7H-pyrrolo[2,3 -d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate (2.0 g) as yellow oil. It was used directly in the next step. LC/MS ESI (m/z): 556 (M+H) ⁺ . Step 3. tert-Butyl (S)-4-(7-(3,5-difluorophenyl)-5-(3-methylpyrazin-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te To a solution of tert-butyl (S)-4-(7-(3,5-difluorophenyl)-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methyl piperazine-1-carboxylate (280 mg, 0.50 mmol) in dioxane (1 mL) and H ₂ O (90 mL) were added K ₂ CO ₃ (690 mg, 5.0 mmol), Pd(dppf)Cl ₂ (36 mg, 0.050 mmol) and 2-bromo-3-methylpyrazine (170 mg, 1.0 mmol). The resulting reaction mixture was stirred at 90℃ under a N ₂ atmosphere overnight. After cooling to room temperature, solvent was removed under reduced pressure. The residue was extracted twice with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0~10%, MeOH in DCM) to afford crude product (220 mg, 84%). 60 mg of crude product was purified by prep-HPLC (Gilson, C18, MeCN in H ₂ O) to afford tert-butyl (S)-4-(7-(3,5-difluorophenyl)-5-(3-methylpyrazin-2-yl)-7H-py rrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (32 mg) as a white solid. LC/MS ESI (m/z): 522 (M+H) ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ 8.60 (d, J = 2.4 Hz, 1H), 8.58 (d, J = 2.6 Hz, 1H), 8.48 (s, 1H), 7.90 (s, 1H), 7.71 – 7.59 (m, 2H), 7.04 (tt, J = 9.0, 2.3 Hz, 1H), 4.03 (s, 1H), 3.73 (d, J = 12.9 Hz, 1H), 3.50 (t, J = 14.6 Hz, 2H), 3.05 (t, J = 11.2 Hz, 1H), 2.69 (m, 2H), 2.55 (s, 3H), 1.42 (s, 9H), 0.92 (d, J = 7.7 Hz, 3H). Example 56. Synthesis of 1,1,1-trifluoro-2-methylpropan-2-yl (S)-4-(7-(3,5- difluorophenyl)-5-(3-methylpyrazin-2-yl)-7H-pyrrolo[2,3-d]py rimidin-4-yl)-3- methylpiperazine-1-carboxylate (Compound 247) C ^{ompound 247} 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). 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 afford 1,1,1-trifluoro-2-methylpropan-2-yl 1H- imidazole-1-carboxylate (640 mg, 73% yield) as a white solid. LC/MS ESI (m/z): 223 (M+H) ⁺ . Step 2. (S)-7-(3,5-Difluorophenyl)-4-(2-methylpiperazin-1-yl)-5-(3-m ethylpyrazin-2- yl)-7H-pyrrolo[2,3-d]pyrimidine To a solution of tert-butyl (S)-4-(7-(3,5-difluorophenyl)-5-(3-methylpyrazin-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (250 mg, 0.48 mmol, prepared following the procedure of compound 246) in DCM (5 mL) was added HCl/dioxane (5.0 mL, 4.0 M). The resulting mixture was stirred at room temperature for 3 h. After removal of solvent, the residue was dissolved in DCM and washed with aqueous NaHCO ₃ . The aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was used in the next step directly. (S)-7-(3,5-difluorophenyl)-4-(2-methylpiperazin-1-yl)-5-(3-m ethylpyrazin-2- yl)-7H-pyrrolo[2,3-d]pyrimidine (180 mg, 89%). LC/MS ESI (m/z): 422 (M+H) ⁺ . Step 3.1,1,1-Trifluoro-2-methylpropan-2-yl (S)-4-(7-(3,5-difluorophenyl)-5-(3- methylpyrazin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methy lpiperazine-1-carboxylate To a solution of (S)-7-(3,5-difluorophenyl)-4-(2-methylpiperazin-1-yl)-5-(3- methylpyrazin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine (60 mg, 0.14 mmol) in DMF (5 mL) was added 1,1,1-trifluoro-2-methylpropan-2-yl 1H-imidazole-1-carboxylate (64 mg, 0.28 mmol). The resulting mixture was stirred at 80 ^o C overnight under a N ₂ atmosphere. The reaction was quenched with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by prep-HPLC to afford 1,1,1-trifluoro-2-methylpropan-2-yl (S)-4-(7-(3,5-difluorophenyl)-5-(3- methylpyrazin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methy lpiperazine-1-carboxylate (23 mg, 29%) as a white solid. LC/MS ESI (m/z): 576 (M+H) ⁺ . ¹ H NMR (400 MHz, MeOD) δ 8.60 (d, J = 2.4 Hz, 1H), 8.58 (d, J = 2.6 Hz, 1H), 8.48 (s, 1H), 7.91 (s, 1H), 7.71 – 7.60 (m, 2H), 7.04 (tt, J = 9.0, 2.3 Hz, 1H), 4.06 (s, 1H), 3.71 (dd, J = 44.1, 12.8 Hz, 1H), 3.49 (m, 2H), 3.07 (t, J = 12.6 Hz, 1H), 2.91 – 2.59 (m, 2H), 2.55 (s, 3H), 1.64 (s, 6H), 0.92 (d, J = 8.2 Hz, 3H). The following compound was prepared by the procedures analogous to the synthesis of compound 247 from the corresponding alcohol. Example 57. Synthesis of ethyl (S)-4-(7-(3,5-difluorophenyl)-5-(3-methylpyrazin-2-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carbox ylate (Compound 1001) C ^{ompound 1001} Step 1. Ethyl (S)-4-(7-(3,5-difluorophenyl)-5-(3-methylpyrazin-2-yl)-7H-py rrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of (S)-7-(3,5-difluorophenyl)-4-(2-methylpiperazin-1-yl)-5-(3- methylpyrazin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine (27 mg, 0.064 mmol, prepared following step 2 of the procedures described for compound 247) in DCM (5 mL) at 0℃ was added TEA (0.50 mL), followed by ethyl carbonochloridate (0.50 mL) dropwise. The resulting mixture was stirred at 0℃ for 30 min. The solvent was removed under reduced pressure. The residue was purified by prep-HPLC to afford ethyl (S)-4-(7-(3,5-difluorophenyl)-5-(3-methylpyrazin- 2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1- carboxylate (18 mg, 55% yield) as a white solid. LC/MS ESI (m/z): 494 (M+H) ⁺ . ¹ H NMR (400 MHz, MeOD) δ 8.6 (d, J = 2.6 Hz, 1H), 8.6 (d, J = 2.6 Hz, 1H), 8.5 (s, 1H), 7.9 (s, 1H), 7.7 – 7.6 (m, 2H), 7.0 (tt, J = 9.0, 2.3 Hz, 1H), 4.2 – 4.0 (m, 3H), 3.8 (d, J = 13.3 Hz, 1H), 3.5 (dd, J = 23.1, 13.3 Hz, 2H), 3.1 (m, 1H), 2.9 – 2.6 (m, 2H), 2.5 (s, 3H), 1.2 (t, J = 7.0 Hz, 3H), 0.9 (d, J = 6.6 Hz, 3H). The following compound was prepared by procedures analogous to the synthesis of compound 1001 using the corresponding chloroformate. Example 58. Synthesis of tert-butyl (R)-4-(7-(3-chlorophenyl)-5-(2-oxopyrrolidin-1-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carbox ylate (Compound 252) C ^{ompound 252} Step 1. 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 (2.5 g, 5.8 mmol, prepared following step 1 of the procedures for compound 192 in DIPEA (20 mL) was added tert-butyl (2R,5S)-2,5-dimethylpiperazine-1-carboxylate (2.5 g, 12 mmol). The resulting mixture was heated to 140 ^o C for 3 h. After cooling to room temperature, solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-4-(5-iodo-7-tosyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate (3.1 g, 87%) as a white solid. LC/MS ESI (m/z): 612 (M+H) ⁺ . Step 2. tert-Butyl (2R,5S)-4-(5-(2-fluorophenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrim idin- 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 (3.1 g, 5.1 mmol) in dioxane-water (30 mL, 5:1 v/v) were added (2-fluorophenyl)boronic acid (1.4 g, 10 mmol), K ₂ CO ₃ (2.1 g, 15 mmol) and Pd(dppf)Cl ₂ (370 mg, 0.51 mmol). The resulting mixture was heated to 90 ^o C overnight. After cooling to room temperature, the reaction was filtered. The filtrate was partitioned between EtOAc and water. The aqueous phase was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated, the residue was purified by flash chromatography (silica gel, 0~50% EtOAc in petroleum ether) to afford tert-butyl (2R,5S)-4-(5-(2-fluorophenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrim idin-4-yl)- 2,5-dimethylpiperazine-1-carboxylate (2.5 g, 85%) as a white solid. LC/MS ESI (m/z): 580 (M+H) ⁺ . Step 3. tert-Butyl (2R,5S)-4-(5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-y l)- 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 (2.5 g, 4.3 mmol) in THF (10 mL) were added TBAF (20 mL, 1.0M in THF). The resulting mixture was stirred at room temperature overnight. Solvent was removed and the residue was dissolved in DCM, washed with NH ₄ Cl (aq.) and brine and dried over Na ₂ SO ₄ . After filtration, the filtrate was concentrated, the residue was purified by flash column chromatography (silica gel, 0~80% ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-4-(5-(2-fluorophenyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate (1.2 g, 65%). LC/MS ESI (m/z): 426 (M+H) ⁺ . Step 3. tert-Butyl (2R,5S)-4-(5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-y l)- 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 (1.2 g, 2.8 mmol) in DMF (30 mL) were added 4- iodo-1-methyl-1H-pyrazole (1.8 g, 8.5 mmol), trans-cyclohexane-1,2-diamine (97 mg, 0.84 mmol), CuI (270 mg, 1.4 mmol) and K ₃ PO ₄ (1.8 g, 8.4 mmol). The resulting mixture was heated to 120 ^o 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to give 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 (400 mg, 28%) as a white solid. LC/MS ESI (m/z): 506 (M+H) ⁺ . Step 5.4-((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 (400 mg, 0.79 mmol) in DCM (5 mL) was added HCl (3.0 mL, 4.0 M in dioxane). The resulting mixture was stirred at room temperature for 2 h. After removal of solvent, the residue was diluted with DCM, washed with NaHCO ₃ (aq.). The organic layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was used in the next step directly.4-((2S,5R)-2,5- dimethylpiperazin-1-yl)-5-(2-fluorophenyl)-7-(1-methyl-1H-py razol-4-yl)-7H-pyrrolo[2,3- d]pyrimidine (400 mg). LC/MS ESI (m/z): 406 (M+H) ⁺ . Step 6. Isopropyl (2R,5S)-4-(5-(2-fluorophenyl)-7-(1-methyl-1H-pyrazol-4-yl)-7 H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate 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 (90 mg, 0.22 mmol) in DCM (3 mL) at 0 ^o C were added TEA (66 mg, 0.66 mmol), followed by isopropyl carbonochloridate (81 mg, 0.66 mmol) dropwise. 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 ₃ (aq.), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford isopropyl (2R,5S)-4-(5-(2-fluorophenyl)-7-(1-methyl-1H-pyrazol-4-yl)-7 H-pyrrolo[2,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (25 mg, 22%) as a white solid. LC/MS ESI (m/z): 492 (M+H) ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ 8.39 (s, 1H), 8.25 (s, 1H), 7.97 (s, 1H), 7.60 (s, 1H), 7.53 (t, J = 7.6 Hz, 1H), 7.47 – 7.42 (m, 1H), 7.32 (t, J = 7.5 Hz, 1H), 7.26 (t, J = 9.1 Hz, 1H), 4.82 (d, J = 5.7 Hz, 1H), 4.17 (s, 2H), 3.98 (s, 3H), 3.42 (d, J = 13.5 Hz, 1H), 3.32 (d, J = 4.2 Hz, 1H), 3.25 (d, J = 4.0 Hz, 1H), 2.89 – 2.77 (m, 1H), 1.21 (s, 6H), 1.10 (d, J = 6.8 Hz, 3H), 0.90 (d, J = 6.7 Hz, 3H). The following compounds were prepared by procedures analogous to the synthesis of compound 252 using the corresponding chloroformates and coupling partners (aryl halides or boronic acids).

Example 59. Synthesis of 2,2,2-trifluoroethyl (2R,5S)-4-(5-(2-fluorophenyl)-7-(1-methyl- 1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimeth ylpiperazine-1- carboxylate (Compound 254) C ^{ompound 254} Step 1.2,2,2-Trifluoroethyl 1H-imidazole-1-carboxylate To a solution of 2,2,2-trifluoroethan-1-ol (1.0 g, 10 mmol) in DCM (10 mL) was added CDI (1.8 g, 11 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 Na ₂ SO ₄ , filtered and concentrated to afford 1,1,1-trifluoro-2-methylpropan-2-yl 1H-imidazole-1-carboxylate which was used in the next step directly. LC/MS ESI (m/z): 195 (M+H) ⁺ . Step 2.2,2,2-Trifluoroethyl (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 (70 mg, 0.18 mmol, prepared following the first 5 steps of the procedures described for compound 252) in DMF (5 mL) were added 2,2,2-trifluoroethyl 1H-imidazole-1-carboxylate (70 mg, 0.36 mmol) and DIPEA (70 mg, 0.54 mmol). The resulting mixture was stirred at 80 ^o C for overnight under a N ₂ atmosphere. 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford 2,2,2- trifluoroethyl (2R,5S)-4-(5-(2-fluorophenyl)-7-(1-methyl-1H-pyrazol-4-yl)-7 H-pyrrolo[2,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (30 mg, 33%) as a white solid. LC/MS ESI (m/z): 532 (M+H) ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ 8.41 (s, 1H), 8.26 (s, 1H), 7.97 (d, J = 0.6 Hz, 1H), 7.61 (s, 1H), 7.56 – 7.51 (m, 1H), 7.48 – 7.42 (m, 1H), 7.34 – 7.30 (m, 1H), 7.29 – 7.24 (m, 1H), 4.66 – 4.46 (m, 2H), 4.19 (s, 2H), 3.98 (s, 3H), 3.47 – 3.42 (m, 1H), 3.35 (d, J = 2.0 Hz, 1H), 3.30 – 3.26 (m, 1H), 2.97 – 2.83 (m, 1H), 1.13 (d, J = 6.8 Hz, 3H), 0.92 (d, J = 6.7 Hz, 3H). Example 60. Synthesis of tert-butyl (R)-4-(5-cyclopropyl-7-(3,5-difluorophenyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2-ethylpiperazine-1-carboxylat e (Compound 256) C ^{ompound 256} Step 1.4-Chloro-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine To a solution of 4-chloro-5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (2.4 g, 7.0 mmol, prepared following the procedure described for compound 164 in THF (15 mL) at 0 ^o C was added TBAF (42 mL, 1.0M in THF). The resulting mixture was stirred at 0 ^o C for 5 h. The reaction was quenched with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~10%, methanol in dichloromethane) to afford 4-chloro-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine (1.2 g, 90%) as a white solid. LC/MS ESI (m/z): 194 (M+H) ⁺ . Step 2.4-Chloro-5-cyclopropyl-7-(3,5-difluorophenyl)-7H-pyrrolo[2 ,3-d]pyrimidine To a solution of 4-chloro-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine (1.2 g, 6.2 mmol) in DCM (100 mL) were added (3,5-difluorophenyl)boronic acid (2.0 g, 12 mmol), pyridine (2.9 g, 37 mmol) and Cu(OAc) ₂ (2.8 g, 16 mmol). The resulting mixture was stirred at room temperature under an O ₂ atmosphere for 48 h. The reaction was diluted with DCM and filtered. The filtrate was washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford 4-chloro-5-cyclopropyl-7-(3,5-difluorophenyl)-7H- pyrrolo[2,3-d]pyrimidine (1.5 g, 63%) as a solid. LC/MS ESI (m/z): 306 (M+H) ⁺ . Step 3. tert-Butyl (R)-4-(5-cyclopropyl-7-(3,5-difluorophenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2-ethylpiperazine-1-carboxylate To a solution of 4-chloro-5-cyclopropyl-7-(3,5-difluorophenyl)-7H-pyrrolo[2,3 - d]pyrimidine (70 mg, 0.23 mmol) in EtOH (5 mL) were added tert-butyl (R)-2- ethylpiperazine-1-carboxylate (98 mg, 0.46 mmol) and DIPEA (180 mg, 1.4 mmol). The resulting mixture was heated to 100 ^o C overnight. After cooling to room temperature, solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford tert-butyl (R)-4-(5-cyclopropyl-7-(3,5- difluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-ethylpipe razine-1-carboxylate (45 mg, 41%) as a white solid. LC/MS ESI (m/z): 484 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 7.39 – 7.32 (m, 2H), 6.92 (s, 1H), 6.80 – 6.72 (m, 1H), 4.50 (d, J = 13.0 Hz, 1H), 4.27 – 4.12 (m, 2H), 4.03 (d, J = 11.6 Hz, 1H), 3.29 (d, J = 10.0 Hz, 2H), 3.13 – 3.03 (m, 1H), 2.04 – 1.97 (m, 1H), 1.75 – 1.66 (m, 1H), 1.56 – 1.52 (m, 1H), 1.50 (s, 9H), 1.08 – 1.01 (m, 2H), 0.90 – 0.84 (m, 4H), 0.68 – 0.61 (m, 1H). The following compounds were prepared by procedures analogous to the synthesis of compound 256 using the corresponding amines.

Example 61. Synthesis of tert-butyl (S)-4-(7-(4-cyanopyridin-2-yl)-5-cyclopropyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (Compound 260) C ^{ompound 260} Step 1.4-Chloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine To a suspension of NaH (11 g, 270 mmol) in DMF (500 mL) at 0°C was added a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (50 g, 180 mmol) in DMF (150 ml) dropwise. After stirring at 0°C for 10 minutes, a solution of TsCl (50 g, 260 mmol) in DMF (150 ml) was added dropwise. The resulting mixture was stirred at room temperature overnight. The reaction was poured into the ice water (4 L), filtered to give a crude product which was further dried in vacuo to afford 4-chloro-5-iodo-7-tosyl-7H-pyrrolo[2,3- d]pyrimidine (73 g, 94%) as a light yellow solid. LC/MS ESI (m/z): 434.2 (M+H) ⁺ . Step 2. tert-Butyl (S)-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 (50 g, 120 mmol) and tert-butyl (S)-3-methylpiperazine-1-carboxylate (46 g , 230 mmol) in DIPEA (350 ml) was heated to 140 ^o C for 1.5 h. DIPEA was removed and the residue was purified by flash chromatography (silica gel, 0~30% ethyl acetate in petroleum ether) to afford tert-butyl(S)-4- (5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpip erazine-1-carboxylate (52 g, 75%) as a white solid. LC/MS ESI (m/z): 598.4 (M+H) ⁺ . Step 3. 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 (39 g, 65 mmol) in toluene (400 mL) were added cyclopropylboronic acid (8.4 g, 98 mmol), K ₂ CO ₃ (120 g, 850 mmol) and 1,1'-bis (di-tert- butylphosphino)ferrocene palladium dichloride (2.0 g, 3.2 mmol). The resulting mixture was heated to 80 ^o C overnight. After cooling to room temperature, the reaction mixture was filtered. The filtrate was partitioned between DCM and water. The aqueous layer was extracted twice with DCM. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography (0~50% ethyl acetate in petroleum ether) to afford tert-butyl (S)-4-(5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (22 g, 67% yield, >98% purity and 10 g, 80% purity) as a white solid. LC/MS ESI (m/z): 512.5(M+H) ⁺ . Step 4. 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 (79 g, 150 mmol) in THF (500 ml) was added TBAF (400 ml, 1.0M in THF). The resulting mixture was stirred at room temperature overnight. After removal of solvent, the residue was diluted with H ₂ O and extracted twice with DCM. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography (0~50% ethyl acetate in petroleum ether) to afford tert- butyl (S)-4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-meth ylpiperazine-1- carboxylate (49 g, 88%) as light yellow solid. LC/MS ESI (m/z): 358.5 (M+H) ⁺ . Step 5. tert-Butyl (S)-4-(7-(4-cyanopyridin-2-yl)-5-cyclopropyl-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 (18 g, 50 mmol) in DMF (180 mL) were added 2- bromoisonicotinonitrile (18 g, 100 mmol), CuI (4.8 g, 25 mmol), (+/-)-trans-1,2- diaminocyclohexane (1.7 g, 15 mmol) and K ₃ PO ₄ (32 g, 150 mmol). The resulting mixture was heated to 120 ^o C overnight. After cooling to room temperature, the reaction was filtered, and solvent was removed. The residue was purified by flash chromatography (0~30% EtOAc (with 50% DCM) in petroleum ether) to afford tert-butyl (S)-4-(7-(4-cyanopyridin-2-yl)-5- cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperaz ine-1-carboxylate (12 g, 51% yield, >98% purity and 4.6 g, 90% purity) as a light yellow solid. LC/MS ESI (m/z): 460.6 (M+H)+. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.32 (s, 1H), 8.58 (d, J = 5.0 Hz, 1H), 8.50 (s, 1H), 7.77 (s, 1H), 7.33 (dd, J = 5.0, 1.2 Hz, 1H), 4.74 – 4.66 (m, 1H), 4.18 – 3.83 (m, 3H), 3.55 (t, J = 11.6 Hz, 1H), 3.39 – 3.09 (m, 2H), 2.06–1.99 (m, 1H), 1.50 (s, 9H), 1.24 (d, J = 6.5 Hz, 3H), 1.06 – 1.02 (m, 2H), 0.90 – 0.84 (m, 1H), 0.80 – 0.74 (m, 1H). The following compounds were prepared by the procedure analogous to the synthesis of compound 260 from the corresponding amines, boronic acids and aryl halides. In the case of preparation of compounds 481 and 483, commercially available intermediate 4-chloro-5- (trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidine, was elaborated using the appropriate synthetic steps as outlined in the synthesis of compound 260. Example 62. Synthesis of tert-butyl (S)-3-methyl-4-(1-phenyl-3-(tetrahydro-2H-pyran-4- yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylat e (Compound 261) A mixture of tert-butyl (S)-4-(1-(3-chlorophenyl)-3-(3,6-dihydro-2H-pyran-4-yl)-1H- pyrazolo[3,4-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyl ate (170 mg, 0.33 mmol, prepared following the procedures described for compound 284), PtO ₂ (100 mg) in MeOH (8 mL) was stirred at room temperature for overnight under a H ₂ atmosphere. The reaction was filtered, the MeOH was removed by vacuum, the residue was purified by flash column chromatography (silica gel, 0~50% EtOAc in petroleum ether) and prep-HPLC to give tert- butyl (S)-3-methyl-4-(1-phenyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyr azolo[3,4-d]pyrimidin- 4-yl)piperazine-1-carboxylate (50 mg, 32% yield) as a white solid LCMS ESI (m/z): 479. (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.51 (s, 1H), 8.18 – 8.11 (m, 2H), 7.52 (dd, J = 10.8, 5.2 Hz, 2H), 7.35 – 7.28 (m, 1H), 4.56 – 4.41 (m, 1H), 4.19 – 3.80 (m, 5H), 3.63 – 3.50 (m, 3H), 3.33 – 3.03 (m, 3H), 2.25 – 2.13 (m, 1H), 2.09 – 1.98 (m, 3H), 1.50 (s, 9H), 1.31 (d, J = 6.7 Hz, 3H).

Example 63. Synthesis of tert-butyl (S)-4-(7-(4-cyanopyridin-2-yl)-5-(2-fluorophenyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carbox ylate (Compound 268) C ^{ompound 268} Step 1.4-Chloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine At 0°C, to a suspension of NaH (11 g, 270 mmol) in DMF (500 mL) was added solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (50 g, 180 mmol) in DMF (150 ml). After being stirred at 0°C for 10 minutes, a solution of TsCl (50 g, 260 mmol) in DMF (150 ml) was added dropwise into the reaction mixture. The resulting mixture was stirred at room temperature overnight. The reaction was poured into ice water (4 L), filtered and concentrated.4-chloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimi dine (67 g, 86%). as a light yellow solid. LC/MS ESI (m/z): 434.2 (M+H) ⁺ . Step 2. tert-Butyl (S)-4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate The mixture of 4-chloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (50 g, 120 mmol) and tert-butyl (S)-3-methylpiperazine-1-carboxylate (46 g , 230 mmol) in DIEA (350 ml) was heated to 140 ^o C for 1.5 h. the reaction mixture was purified by flash chromatography (silica gel, 0~30% ethyl acetate in petroleum ether) to afford tert-butyl (S)-4-(5-iodo-7-tosyl- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carbox ylate (52 g, 75%) as a white solid. LC/MS ESI (m/z): 598.4 (M+H) ⁺ . Step 3. tert-Butyl (S)-4-(5-(2-fluorophenyl)-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 (52 g, 87 mmol) in dioxane-water (500 mL; v:v=5:1) was added (2-fluorophenyl)boronic acid (24 g, 170 mmol), K ₂ CO ₃ (36 g, 260 mmol) and Pd(dppf)Cl ₂ (3.5 g, 4.3 mmol). The resulting mixture was heated to 80 ^o C overnight. After being cooled down to room temperature, the reaction mixture was filtered. The filtrate was partitioned between DCM and water, organic layer was separated, aqueous layer was extracted with DCM twice, the combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography (0~50% ethyl acetate in petroleum ether) to afford tert-butyl (S)-4-(5-(2-fluorophenyl)-7-tosyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (34 g, 70%) as a white solid. LC/MS ESI (m/z): 566.6 (M+H) ⁺ . Step 4. 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 (3S)-4-[5-(2-fluorophenyl)-7-(4-methylbenzenesulfonyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl]-3-methylpiperazine-1-carbox ylate (37 g, 65 mmol) in THF (300 ml) was added TBAF (220 ml, 1.0M in THF). The resulting mixture was stirred at room temperature overnight. After removed 2/3 solvent, the reaction mixture was poured into ice water, the precipitate was filtered and dried in vacuo to give tert-butyl (S)-4-(5-(2- fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiper azine-1-carboxylate (25 g, 93%) as a gray solid. LC/MS ESI (m/z): 412.5 (M+H) ⁺ . Step 5. tert-Butyl (S)-4-(7-(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-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)-3-methylpiperazine-1-carboxylate (10 g, 24 mmol) in DMF (80 mL) were added 2- bromopyridine-4-carbonitrile (8.9 g, 49 mmol), CuI (1.4 g, 7.3 mmol), trans-cyclohexane- 1,2-diamine (0.83 g, 7.3 mmol) and K ₃ PO ₄ (16 g, 73 mmol). The resulting mixture was heated to 120 ^o C overnight under N ₂ . After being cooled down to room temperature, the reaction was filtered, and solvent was removed. The residue was purified by flash chromatography (ethyl acetate: petroleum ether: dichloromethane = 5:1:1) to afford tert-butyl (S)-4-(7-(4-cyanopyridin-2-yl)-5-(2-fluorophenyl)-7H-pyrrolo [2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate (9.3 g, 75%) as an off-white solid. LC/MS ESI (m/z): 514.6 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl3) δ 9.40 (s, 1H), 8.61 (d, J = 4.9 Hz, 1H), 8.56 (s, 1H), 8.27 (s, 1H), 7.46 (t, J = 7.2 Hz, 1H), 7.41 – 7.35 (m, 2H), 7.27 – 7.18 (m, 2H), 4.24 (s, 1H), 3.77 (s, 1H), 3.56 – 3.44 (m, 2H), 3.08 (t, J = 11.5 Hz, 1H), 2.89 – 2.62 (m, 2H), 1.43 (s, 9H), 1.02 (d, 3H). The following compounds were prepared by the procedures similar to the synthesis of compound 268 from the amines and aryl halides.

Example 64. Synthesis of tert-butyl (S)-4-(5-cyclopropyl-7-(3,5-difluorophenyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2-(fluoromethyl)piperazine-1-c arboxylate (Compound 269) and tert-butyl (R)-4-(5-cyclopropyl-7-(3,5-difluorophenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2-(fluoromethyl)piperazine-1-carboxylate (Compound 270) Step 1. tert-Butyl 4-benzyl-3-(hydroxymethyl)piperazine-1-carboxylate At 0°C, to a solution of tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (4.5 g, 21 mmol) and TEA(4.2 mL, 42 mmol) in MeCN (50 mL) was added (chloromethyl)benzene (3.2 g, 25 mmol) dropwise. The reaction mixture was stirred at 80°C overnight, LCMS showed the reaction was completed and the MeCN was removed by vacuum, the residue was purified by flash column chromatography (silica gel, 0~70% EtOAc in petroleum ether) to afford tert-butyl 4-benzyl-3-(hydroxymethyl)piperazine-1-carboxylate (5.0 g, 71% yield) as a white solid. LCMS ESI (m/z): 307. (M+H) ⁺ . Step 2. tert-Butyl 4-benzyl-3-(((methylsulfonyl)oxy)methyl)piperazine-1-carboxy late At 0 ^o C, to a solution of tert-butyl 4-benzyl-3-(hydroxymethyl)piperazine-1-carboxylate (1.5 g, 5.0 mmol) in DCM (15 mL) was added TEA (0.75 mL, 7.5 mmol), followed by MsCl (0.68 g, 5.9 mmol) dropwise. The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with ice water, extracted with DCM twice. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to give tert-butyl 4-benzyl-3- (((methylsulfonyl)oxy)methyl)piperazine-1-carboxylate (1.8 g, 94%) as an oil which was used in the next step without further purification. Step 3. tert-Butyl 4-benzyl-3-(fluoromethyl)piperazine-1-carboxylate At 0 ^o C, to a solution of tert-butyl 4-benzyl-3- (((methylsulfonyl)oxy)methyl)piperazine-1-carboxylate (1.8 g, 4.7 mmol) in THF (20 mL) was added TBAF (9.4 mL, 1.0M in THF) dropwise. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with ice water, extracted with EtOAc twice. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to give tert-butyl 4-benzyl-3-(fluoromethyl)piperazine-1- carboxylate (1.1 g, 76% yield) as an oil. LCMS ESI (m/z): 309 (M+H) ⁺ . Step 4.1-Benzyl-2-(fluoromethyl)piperazine To a solution of tert-butyl 4-benzyl-3-(fluoromethyl)piperazine-1-carboxylate (300 mg, 0.97 mmol) in DCM (5 mL) was added HCl (4.0 mL, 4.0 M in dioxane). The resulting mixture was stirred at room temperature for 4 h. After removal of solvent, the residue was diluted with DCM, washed with NaHCO ₃ (aq.), the organic layer was extracted with DCM twice, the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give 1-benzyl-2-(fluoromethyl)piperazine which was used in the next step without further purification. LCMS ESI (m/z): 209 (M+H) ⁺ . Step 5.4-(4-Benzylpiperazin-1-yl)-5-cyclopropyl-7-(3,5-difluoroph enyl)-7H- pyrrolo[2,3-d]pyrimidine A mixture of 4-chloro-5-cyclopropyl-7-(3,5-difluorophenyl)-7H-pyrrolo[2,3 - d]pyrimidine (200 mg, 0.66 mmol, prepared following the procedure outlined in compound 256), 1-benzyl-2-(fluoromethyl)piperazine (200 mg, 0.98 mmol) and DIPEA (500 mg, 4.0 mmol) in EtOH (5 mL) was stirred at 100 ^o C overnight. After being cooled down to room temperature, solvent was removed. The residue was purified by flash column chromatography (silica gel, 0~50% EtOAc in petroleum ether) to afford 4-(4- benzylpiperazin-1-yl)-5-cyclopropyl-7-(3,5-difluorophenyl)-7 H-pyrrolo[2,3-d]pyrimidine (200 mg, 68% yield) as a white solid. LCMS ESI (m/z): 478 (M+H) ⁺ . Step 6. tert-Butyl 4-(5-cyclopropyl-7-(3,5-difluorophenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2-(fluoromethyl)piperazine-1-carboxylate A mixture of 4-(4-benzylpiperazin-1-yl)-5-cyclopropyl-7-(3,5-difluorophen yl)-7H- pyrrolo[2,3-d]pyrimidine (200 mg, 0.45 mmol ), (Boc) ₂ O (200 mg, 0.90 mmol) and Pd/C (50 mg, wetted with ca.55% water) in MeOH (8 mL) was stirred at 40 ^o C overnight under H ₂ atmosphere (~1 atm) _. After being cooled down to room temperature, the reaction was filtered, filtrate was partitioned between EtOAc and water, organic layer was separated, the aqueous phase was extracted with EtOAc twice, dried over Na ₂ SO ₄ , filtered and concentrated, the residue was purified by flash chromatography (silica gel, 0~50% EtOAc in petroleum ether) to give tert-butyl 4-(5-cyclopropyl-7-(3,5-difluorophenyl)-7H-pyrrolo[2,3-d]pyr imidin-4-yl)- 2-(fluoromethyl)piperazine-1-carboxylate (96 mg, 44% yield) as a white solid. LCMS ESI (m/z): 488. (M+H) ⁺ . Step 7. tert-Butyl (S)-4-(5-cyclopropyl-7-(3,5-difluorophenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2-(fluoromethyl)piperazine-1-carboxylate and tert-butyl (r)-4-(5- cyclopropyl-7-(3,5-difluorophenyl)-7H-pyrrolo[2,3-d]pyrimidi n-4-yl)-2- (fluoromethyl)piperazine-1-carboxylate 96 mg of tert-butyl 4-(5-cyclopropyl-7-(3,5-difluorophenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2-(fluoromethyl)piperazine-1-carboxylate was separated by SFC to give two isomers: Peak 1: shorter retention time, labeled as compound 269 (tert-butyl (S)-4-(5- cyclopropyl-7-(3,5-difluorophenyl)-7H-pyrrolo[2,3-d]pyrimidi n-4-yl)-2- (fluoromethyl)piperazine-1-carboxylate (23 mg)): LC/MS ESI (m/z): 488. (M+H) ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ 8.35 (s, 1H), 7.57 – 7.52 (m, 2H), 7.33 (d, J = 0.7 Hz, 1H), 6.97 – 6.91 (m, 1H), 4.63 – 4.47 (m, 4H), 4.30 (d, J = 13.6 Hz, 1H), 4.02 (d, J = 13.4 Hz, 1H), 3.45 – 3.35 (m, 2H), 3.17 – 3.10 (m, 1H), 2.08 – 2.02 (m, 1H), 1.49 (s, 9H), 1.07 – 1.03 (m, 2H), 0.99 – 0.93 (m, 1H), 0.72 – 0.67 (m, 1H). Peak 2: longer retention time, labeled as compound 270 ((R)-4-(5-cyclopropyl-7-(3,5- difluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-(fluorome thyl)piperazine-1-carboxylate (22 mg)): LC/MS ESI (m/z): 488. (M+H) ⁺ , ¹ H NMR (400 MHz, CD ₃ OD) δ 8.35 (s, 1H), 7.58 – 7.52 (m, 2H), 7.33 (s, 1H), 6.97 – 6.91 (m, 1H), 4.63 – 4.47 (m, 4H), 4.30 (d, J = 13.6 Hz, 1H), 4.02 (d, J = 13.4 Hz, 1H), 3.43 – 3.35 (m, 2H), 3.18 – 3.11 (m, 1H), 2.08 – 2.02 (m, 1H), 1.49 (s, 9H), 1.07 – 1.02 (m, 2H), 0.99 – 0.94 (m, 1H), 0.72 – 0.67 (m, 1H). Preparative separation method: Instrument: Waters Thar 80 preparative SFC; Column: ChiralPak AD, 250×21.2mm I.D., 5µm; Mobile phase: A for CO ₂ and B for MEOH+0.1%NH ₃ H ₂ O; Gradient: B 30%; Flow rate: 50mL /min; Back pressure: 100 bar; Column temperature: 35℃; Wavelength: 254nm ; Cycle-time: 3.0min; Eluted time: 1.8 h. Example 65. Synthesis of tert-butyl (S)-4-(5-cyclopropyl-7-(3,5-difluorophenyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2-(trifluoromethyl)piperazine- 1-carboxylate (Compound 1006) C ^{ompound 1006} Step 1. (S)-2-(Trifluoromethyl)piperazine To a solution of tert-butyl (S)-3-(trifluoromethyl)piperazine-1-carboxylate (60 mg, 0.27 mmol) in DCM (3 mL) was added HCl (2.0 mL, 4.0 M in dioxane). The resulting mixture was stirred at room temperature for 4 h. After removal of solvent, the residue was used in the next step directly. (S)-2-(trifluoromethyl)piperazine. LC/MS ESI (m/z): 155 (M+H) ⁺ . Step 2. (S)-5-Cyclopropyl-7-(3,5-difluorophenyl)-4-(3-(trifluorometh yl)piperazin-1- yl)-7H-pyrrolo[2,3-d]pyrimidine To a solution of 4-chloro-5-cyclopropyl-7-(3,5-difluorophenyl)-7H-pyrrolo[2,3 - d]pyrimidine (50 mg, 0.16 mmol, prepared following the procedure outlined in compound 256) in EtOH (5 mL) were added (S)-2-(trifluoromethyl)piperazine (38 mg, 0.24 mmol) and DIPEA (120 mg, 0.96 mmol). The resulting mixture was heated to 100 ^o C overnight. After being cooled down to room temperature, solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to afford (S)-5-cyclopropyl-7-(3,5-difluorophenyl)-4-(3-(trifluorometh yl)piperazin-1-yl)-7H- pyrrolo[2,3-d]pyrimidine (60 mg, 86%) as a white solid. LC/MS ESI (m/z): 424 (M+H) ⁺ . Step 3. tert-Butyl (S)-4-(5-cyclopropyl-7-(3,5-difluorophenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2-(trifluoromethyl)piperazine-1-carboxylat e A mixture of (S)-5-cyclopropyl-7-(3,5-difluorophenyl)-4-(3- (trifluoromethyl)piperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine (60 mg, 0.14 mmol), (Boc) ₂ O (61 mg, 0.28 mmol) DMAP(5.1 mg, 0.040 mmol) in THF (8 mL) was stirred at 40 ^o C overnight, under N _2. After being cooled down to room temperature, the reaction mixture was partitioned between EtOAc and water, organic layer was separated, the aqueous phase was extracted with EtOAc twice, dried over Na ₂ SO ₄ , filtered and concentrated, the residue was purified by flash chromatography (silica gel, 0~50% EtOAc in petroleum ether) to give tert- butyl (S)-4-(5-cyclopropyl-7-(3,5-difluorophenyl)-7H-pyrrolo[2,3-d ]pyrimidin-4-yl)-2- (trifluoromethyl)piperazine-1-carboxylate (19 mg, 24% yield) as a white solid. LCMS ESI (m/z): 524 (M+H) ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ 8.37 (s, 1H), 7.58 – 7.52 (m, 2H), 7.34 (s, 1H), 6.99 – 6.87 (m, 1H), 4.95 (s, 1H), 4.58 – 4.45 (m, 2H), 4.14 (d, J = 13.3 Hz, 1H), 3.60 – 3.44 (m, 2H), 3.19 – 3.12 (m, 1H), 2.06 – 1.99 (m, 1H), 1.48 (s, 9H), 1.06 – 0.98 (m, 3H), 0.70 – 0.63 (m, 1H) The following compound was prepared by the procedure similar to the synthesis of compound 1006 from the corresponding amine.

Example 66. Synthesis of tert-butyl (R)-4-(7-(3-cyanophenyl)-5-(pyrrolidin-1-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxyla te (Compound 277) C ^{ompound 277} Step 1.3-(4-Chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)benzoni trile To a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (4.7 g, 17 mmol) in DCM (500 mL) were added (3-cyanophenyl)boronic acid (5.0 g, 34 mmol), Cu(OAc) ₂ (9.4 g, 51 mmol), pyridine (9.0 mL, 54 mmol). The resulting mixture was stirred at room temperature under O ₂ atmosphere over weekend. The reaction was quenched with NH ₄ OH (25 mL) at ice water bath, filtered, the filtrate was extract with DCM twice, the combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated, the residue was purified by flash chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to afford 3-(4- chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)benzonitrile (5.0 g, 78%) as a white solid. LC/MS ESI (m/z): 381 (M+H) ⁺ . Step 2. tert-Butyl (R)-4-(7-(3-cyanophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4 -yl)- 2-methylpiperazine-1-carboxylate To a solution of 3-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)benzonitr ile (100 mg, 0.30 mmol) in EtOH (5 mL) were added DIEA (230 mg, 1.8 mmol) and tert-butyl (R)-2-methylpiperazine-1-carboxylate (240 mg, 1.2 mmol). The resulting mixture was heated to 100 ^o C overnight. After being cooled down to room temperature, solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~20%, ethyl acetate in petroleum ether) to afford tert-butyl (R)-4-(7-(3-cyanophenyl)-5-iodo-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate (100 mg, 70%) as a white solid. LC/MS ESI (m/z): 545 (M+H) ⁺ . Step 3. tert-Butyl (R)-4-(7-(3-cyanophenyl)-5-(pyrrolidin-1-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate To a solution of tert-butyl (R)-4-(7-(3-cyanophenyl)-5-iodo-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate (30 mg, 0.10 mmol) in DMSO (5 mL) were added CuI (2.0 mg, 0.010 mmol), K ₂ CO ₃ (23 mg, 0.17 mmol), L-proline (3.0 mg, 0.020 mmol) and pyrrolidine (71 mg, 1.0 mmol). The resulting mixture was heated to 90 ^o C overnight. After being cooled down to room temperature, the reaction was diluted with water, extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated, the residue was purified by flash chromatography (silica gel, 0~20%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford tert-butyl (R)-4-(7-(3-cyanophenyl)-5-(pyrrolidin-1-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxyla te (8.1 mg, 31%) as a white solid. LC/MS ESI (m/z): 488 (M+H) ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ 8.26 (s, 2H), 8.13 – 8.07 (m, 1H), 7.71 – 7.66 (m, 2H), 7.11 (s, 1H), 4.82 – 4.78 (m, 1H), 4.48 (d, J = 13.5 Hz, 1H), 4.37 – 4.31 (m, 1H), 3.89 (d, J = 13.7 Hz, 1H), 3.39 – 3.32 (m, 2H), 3.29 – 3.25 (m, 2H), 3.02 (dt, J = 16.1, 8.0 Hz, 1H), 2.91 – 2.84 (m, 2H), 2.04 – 1.98 (m, 4H), 1.48 (s, 9H), 1.08 (d, J = 6.8 Hz, 3H). The following compound was prepared by the procedure similar to the synthesis of compound 277 from corresponding amines. Example 67. Synthesis of tert-butyl (S)-4-(1-(3-chlorophenyl)-3-(tetrahydro-2H-pyran-4- yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-methylpiperazine-1-c arboxylate (Compound 284) C ^{ompound 284} Step 1. tert-Butyl (S)-4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate To a suspension of tert-butyl (S)-3-methyl-4-(1H-pyrazolo[3,4-d]pyrimidin-4- yl)piperazine-1-carboxylate (1.3 g, 4.1 mmol) in anhydrous DMF (13 mL) was added NBS (0.87 g, 4.9 mmol). The resulting mixture was stirred at 70 ^o C for 2hr. The reaction was diluted with water, extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~40%, ethyl acetate in petroleum ether) to afford tert- butyl (S)-4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-methylpip erazine-1-carboxylate (1.0 g, 61%) as a light yellow oil. LC/MS ESI (m/z): 397,399 (M+H) ⁺ . Step 2. tert-Butyl (S)-4-(3-bromo-1-(3-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin -4- yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl (S)-4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate (500 mg, 1.3 mmol) in DCM (20 mL) were added (3- nitrophenyl)boronic acid (400 mg, 2.4 mmol), Cu(OAc) ₂ (540 mg, 3.1 mmol), pyridine (0.60 mL, 7.2 mmol) and 4A molecular sieves (500 mg). The resulting mixture was heated to 40 ^o C over the weekend under O ₂ atmosphere. After being cooled down to room temperature, the reaction was quenched with NH ₄ OH, diluted with DCM, and then filtered. The filtrate was extracted with DCM twice, the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~80%, ethyl acetate in petroleum ether) to afford tert-butyl (S)-4-(3-bromo-1-(3- nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-methylpiper azine-1-carboxylate (430 mg, 66%) as a light yellow solid. LC/MS ESI (m/z): 518,520 (M+H) ⁺ Step 3. tert-Butyl (S)-4-(3-(3,6-dihydro-2H-pyran-4-yl)-1-(3-nitrophenyl)-1H- pyrazolo[3,4-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyl ate To a solution of tert-butyl (S)-4-(3-bromo-1-(3-nitrophenyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (430 mg, 0.83 mmol) in dioxane (15 mL) and H ₂ O (3 mL) were added 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (210 mg, 0.99 mmol), K ₂ CO ₃ (340 mg, 2.5 mmol) and Pd(dppf)Cl ₂ (58 mg, 0.080 mmol). The resulting mixture was stirred at 90 ^o C overnight under N ₂ . After being cooled down to room temperature, solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~40%, ethyl acetate in petroleum ether) to afford tert- butyl (S)-4-(3-(3,6-dihydro-2H-pyran-4-yl)-1-(3-nitrophenyl)-1H-py razolo[3,4-d]pyrimidin- 4-yl)-3-methylpiperazine-1-carboxylate (410 mg, 96%) as a yellow solid. LC/MS ESI (m/z): 522 (M+H) ⁺ . Step 4. tert-Butyl (S)-4-(1-(3-aminophenyl)-3-(tetrahydro-2H-pyran-4-yl)-1H- pyrazolo[3,4-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyl ate To a solution of tert-butyl (S)-4-(3-(3,6-dihydro-2H-pyran-4-yl)-1-(3-nitrophenyl)- 1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-methylpiperazine-1-carbo xylate (410 mg, 0.78 mmol) in MeOH (5 mL) was added Pd(OH) ₂ (200 mg, 1.4 mmol). The resulting mixture was heated to 50 ^o C overnight under H ₂ atmosphere. After being cooled down to room temperature, the reaction mixture was filtered and concentrated. The residue was used in the next step directly. tert-butyl (S)-4-(1-(3-aminophenyl)-3-(tetrahydro-2H-pyran-4-yl)-1H-pyr azolo[3,4- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (350 mg, 91%) as a light yellow solid.LC/MS ESI (m/z): 494 (M+H) ⁺ . Step 5. tert-Butyl (S)-4-(1-(3-chlorophenyl)-3-(tetrahydro-2H-pyran-4-yl)-1H- pyrazolo[3,4-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyl ate At 0 ^o C, to a solution of tert-butyl (S)-4-(1-(3-aminophenyl)-3-(tetrahydro-2H-pyran- 4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-methylpiperazine-1 -carboxylate (330 mg, 0.66 mmol) in MeCN (5 mL) was added CuCl (76 mg, 0.79 mmol), after stirred at 0 ^o C for 5 min, t-BuONO (0.1 mL, 0.9 mmol) was added dropwise. The resulting mixture was heated to 60 ^o C for 1 hr. After being cooled down to room temperature, the reaction was partitioned between EtOAc and water, organic layer was separated, aqueous layer was extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated, the residue was purified by flash column chromatography (silica gel, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford tert-butyl (S)-4-(1-(3-chlorophenyl)-3-(tetrahydro-2H-pyran-4-yl)-1H-py razolo[3,4- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (37.2 mg, 11% )as a white solid. LC/MS ESI (m/z): 513 (M+H) ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ 8.46 (s, 1H), 8.31 (t, J = 2.0 Hz, 1H), 8.18 (ddd, J = 8.3, 2.0, 0.9 Hz, 1H), 7.49 (t, J = 8.1 Hz, 1H), 7.32 (ddd, J = 8.0, 2.0, 0.9 Hz, 1H), 4.59 (qd, J = 6.3, 2.8 Hz, 1H), 4.14 – 4.04 (m,3H), 3.92 (t, J = 13.7 Hz, 2H), 3.69 – 3.57 (m, 3H), 3.38 – 3.32 (m, 2H), 3.19 – 3.05 (m, 1H), 2.13 – 2.06 (m, 3H), 1.94 – 1.84 (m, 1H), 1.50 (s, 9H), 1.32 (d, J = 6.7 Hz, 3H). Example 68. Synthesis of tert-butyl (R)-2-methyl-4-(5-(pyrrolidin-1-yl)-7-(3- (trifluoromethoxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pi perazine-1-carboxylate (Compound 311) C ^{ompound 311} Step 1.4-Chloro-5-iodo-7-(3-(trifluoromethoxy)phenyl)-7H-pyrrolo[ 2,3-d]pyrimidine To a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (900 mg, 3.2 mmol) in DCM (25 mL) were added (3-(trifluoromethoxy)phenyl)boronic acid ( 1.3 g, 6.4 mmol), 4A molecular sieves (800 mg), Cu(OAc) ₂ (2.6 g, 12.8 mmol) and pyridine (1.5 g, 19.2 mmol). The resulting mixture was stirred at 40℃ under O ₂ atmosphere for 2 days. The reaction was quenched with NH ₄ OH (3 mL) at ice water bath and then was filtered, the filtrate was extract with DCM twice, the combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated, the residue was purified by flash column chromatography (silica gel, 0~30% EtOAc in petroleum ether) to afford 4-chloro-5-iodo-7-(3-(trifluoromethoxy)phenyl)-7H- pyrrolo[2,3-d]pyrimidine (540 mg, 38%) as a yellow solid. LC/MS ESI (m/z): 440 (M+H) ⁺ . Step 2. tert-Butyl (R)-4-(5-iodo-7-(3-(trifluoromethoxy)phenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate To the solution of 4-chloro-5-iodo-7-(3-(trifluoromethoxy)phenyl)-7H-pyrrolo[2, 3- d]pyrimidine (260 mg, 0.59 mmol) in EtOH (5 mL) were added tert-butyl (R)-2- methylpiperazine-1-carboxylate (236 mg, 1.18 mmol), DIPEA (229 mg, 1.77 mmol). The resulting reaction mixture was stirred at 100 ℃ under N ₂ for overnight. After removal of solvent, the crude product was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford tert-butyl (R)-4-(5-iodo-7-(3- (trifluoromethoxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2 -methylpiperazine-1- carboxylate (220 mg, 61%) as a solid. LC/MS ESI (m/z): 604 (M+H) ⁺ . Step 3. tert-Butyl (R)-2-methyl-4-(5-(pyrrolidin-1-yl)-7-(3-(trifluoromethoxy)p henyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate To the solution of tert-butyl (R)-4-(5-iodo-7-(3-(trifluoromethoxy)phenyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxyla te (220 mg, 0.36 mmol) in DMSO (3 mL) were added CuI (14 mg, 0.07 mmol), L-proline (17 mg, 0.14 mmol), K ₂ CO ₃ (115 mg, 1.08 mmol) and pyrrolidine (103 mg, 1.44 mmol). The resulting reaction mixture was stirred at 80 ℃ under N ₂ overnight. After which the reaction was extracted with EtOAc and water. The combined organic layers were dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 0~30%, EtOAc in petroleum ether) to afford tert-butyl (R)-2-methyl-4-(5- (pyrrolidin-1-yl)-7-(3-(trifluoromethoxy)phenyl)-7H-pyrrolo[ 2,3-d]pyrimidin-4- yl)piperazine-1-carboxylate (23 mg, 12%) as a solid. LC/MS ESI (m/z): 547 (M+H) ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ 8.24 (s, 1H), 7.82 (s, 1H), 7.74 (d, J = 8.9 Hz, 1H), 7.59 (t, J = 8.2 Hz, 1H), 7.25 (d, J = 8.2 Hz, 1H), 7.06 (s, 1H), 4.79 (d, 1H), 4.47 (d, J = 13.3 Hz, 1H), 4.37 – 4.32 (m, 1H), 3.89 (d, J = 13.4 Hz, 1H), 3.39 – 3.32 (m, 1H), 3.29 – 3.24 (m, 3H), 3.04 – 2.96 (m, 1H), 2.90 – 2.84 (m, 2H), 2.03 – 1.97 (m, 4H), 1.48 (s, 9H), 1.08 (d, J = 6.8 Hz, 3H). The following compounds were prepared by the procedures analogous to the synthesis of compound 311 from the corresponding amines. Example 69. Synthesis of tert-butyl (R)-2-methyl-4-(5-(2-oxopyrrolidin-1-yl)-7-(3,4,5- trifluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine- 1-carboxylate (Compound 313) C ^{ompound 313} Step 1.4-Chloro-5-iodo-7-(3,4,5-trifluorophenyl)-7H-pyrrolo[2,3-d ]pyrimidine To a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (2.6 g, 9.3 mmol) in DCM (50 mL) were added (3,4,5-trifluorophenyl)boronic acid (4.1 g, 23 mmol), Cu(OAc) ₂ (4.2 g, 23 mmol), pyridine (4.4 mL, 56 mmol). The resulting mixture was stirred at room temperature under O2 atmosphere overnight. NH3 ^. H2O (80 mL) was added and the reaction was filtered, the filtrate was partitioned between DCM and water, organic layer was separated, the aqueous phase was extracted with DCM twice, the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated, the residue was purified by flash chromatography (silica gel, 0~30% EtOAc in petroleum ether) to afford 4- chloro-5-iodo-7-(3,4,5-trifluorophenyl)-7H-pyrrolo[2,3-d]pyr imidine (2.5 g, 66%) as a white solid. LC/MS ESI (m/z): 410 (M+H) ⁺ Step 2. tert-Butyl (R)-4-(5-iodo-7-(3,4,5-trifluorophenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate To a solution of 4-chloro-5-iodo-7-(3,4,5-trifluorophenyl)-7H-pyrrolo[2,3- d]pyrimidine (600 mg, 1.5 mmol) in EtOH (5 mL) were added tert-butyl (R)-2- methylpiperazine-1-carboxylate (590 mg, 3.0 mmol) and DIPEA (1.5 mg, 8.9 mmol). The resulting mixture was heated to 100 ^o C overnight. After being cooled down to room temperature, solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford tert-butyl (R)- 4-(5-iodo-7-(3,4,5-trifluorophenyl)-7H-pyrrolo[2,3-d]pyrimid in-4-yl)-2-methylpiperazine-1- carboxylate (600 mg, 71%) as a white solid. LC/MS ESI (m/z): 574 (M+H) ⁺ . Step 3 tert-Butyl (R)-2-methyl-4-(5-(2-oxopyrrolidin-1-yl)-7-(3,4,5-trifluorop henyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate To a solution of tert-butyl (R)-4-(5-iodo-7-(3,4,5-trifluorophenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate (100 mg, 0.17 mmol) in DMF (5 mL) were added pyrrolidin-2-one (29 mg, 0.34 mmol), trans-cyclohexane-1,2-diamine (5.9 mg, 0.050 mmol), CuI (9.5 mg, 0.050 mmol) and K ₃ PO ₄ (220 mg, 0.51 mmol). The resulting mixture was heated to 100 ^o C overnight. After being cooled down to room temperature. The reaction was quenched with water, extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford tert-butyl (R)-2-methyl-4-(5-(2-oxopyrrolidin-1-yl)-7-(3,4,5-trifluorop henyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperazine-1-carboxylate (19 mg, 20%) as a white solid. LC/MS ESI (m/z): 531 (M+H) ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ 8.32 (s, 1H), 7.75 – 7.69 (m, 2H), 7.67 (s, 1H), 4.34 – 4.28 (m, 1H), 4.23 – 4.17 (m, 1H), 4.02 – 3.96 (m, 2H), 3.91 – 3.85 (m, 1H), 3.81 – 3.74 (m, 1H), 3.49 – 3.44 (m, 1H), 3.35 (d, J = 3.2 Hz, 1H), 3.23 – 3.15 (m, 1H), 2.65 – 2.60 (m, 2H), 2.29 (dt, J = 11.4, 7.0 Hz, 2H), 1.47 (s, 9H), 1.08 (d, J = 6.8 Hz, 3H). The following compounds were prepared by the procedure analogous to the synthesis of compound 313 from the corresponding amide (pyrrolidin-2-one) or amine (piperidine).

Example 70. Synthesis of tert-butyl (S)-4-(5-cyclopropyl-7-(3,5-difluorophenyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2-(difluoromethyl)piperazine-1 -carboxylate (Compound

314) and tert-butyl (R)-4-(5-cyclopropyl-7-(3,5-difluorophenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2-(difluoromethyl)piperazine-1-carboxylate (Compound 315) C ^{ompound 314 Compound 315} Step 1. tert-Butyl 4-benzyl-3-formylpiperazine-1-carboxylate At 0 ^o C, to a solution of tert-butyl 4-benzyl-3-(hydroxymethyl)piperazine-1- carboxylate (1.8 g, 5.9 mmol) in DCM (30 mL) were added DMSO (20 mL) was added TEA (4.1 mL, 29 mmol), followed by pyridine sulfur trioxide (4.7 g, 29 mmol) dropwise. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water, extracted with DCM twice, the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~60%, ethyl acetate in petroleum ether) to give tert-butyl 4- benzyl-3-formylpiperazine-1-carboxylate (900 mg, 50% yield ) as an oil. LC/MS ESI (m/z): 305 (M+H) ⁺ . Step 2. tert-Butyl 4-benzyl-3-(difluoromethyl)piperazine-1-carboxylate At 0 ^o C, to a solution of tert-butyl 4-benzyl-3-formylpiperazine-1-carboxylate (900 mg, 3.0 mmol) in DCM (10 mL) was added DAST (950 mg, 5.9 mmol) dropwise. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with NaHCO ₃ (aq.), extracted with DCM twice, the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to give tert-butyl 4- benzyl-3-(difluoromethyl)piperazine-1-carboxylate (330 mg, 34% yield ) as an oil. LC/MS ESI (m/z): 327 (M+H) ⁺ . Step 3.1-Benzyl-2-(difluoromethyl)piperazine To a solution of tert-butyl 4-benzyl-3-(difluoromethyl)piperazine-1-carboxylate (330 mg, 1.0 mmol) in DCM (5 mL) was added TFA (2 mL). The resulting mixture was stirred at room temperature for 2 h. After removal of solvent, the residue was diluted with DCM, washed with NaHCO ₃ (aq.), the organic layer was extracted with DCM twice, the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was used in the next step directly. LC/MS ESI (m/z): 227 (M+H) ⁺ . Step 4.4-(4-Benzyl-3-(difluoromethyl)piperazin-1-yl)-5-cyclopropy l-7-(3,5- difluorophenyl)-7H-pyrrolo[2,3-d]pyrimidine A mixture of 4-chloro-5-cyclopropyl-7-(3,5-difluorophenyl)-7H-pyrrolo[2,3 - d]pyrimidine (100 mg, 0.33 mmol, prepared following the procedure outlined in compound 256), 1-benzyl-2-(difluoromethyl)piperazine (150 mg, 0.66 mmol) and DIPEA (260 mg, 2.0 mmol) in EtOH (5 mL) was stirred at 100 ^o C overnight. After being cooled down to room temperature, solvent was removed. The residue was purified by flash chromatography (silica gel, 0~50% EtOAc in petroleum ether) to afford 4-(4-benzyl-3-(difluoromethyl)piperazin-1- yl)-5-cyclopropyl-7-(3,5-difluorophenyl)-7H-pyrrolo[2,3-d]py rimidine (100 mg, 61% yield) as a white solid. LC/MS ESI (m/z): 496 (M+H) ⁺ . Step 5. tert-Butyl 4-(5-cyclopropyl-7-(3,5-difluorophenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2-(difluoromethyl)piperazine-1-carboxylate A mixture of 4-(4-benzyl-3-(difluoromethyl)piperazin-1-yl)-5-cyclopropyl- 7-(3,5- difluorophenyl)-7H-pyrrolo[2,3-d]pyrimidine (100 mg, 0.20 mmol ), (Boc) ₂ O (44 mg, 0.40 mmol) and Pd/C (30 mg, wetted with ca.55% water) in MeOH (8 mL) was stirred at 40 ^o C overnight, under H ₂ atmosphere (~1 atm) _. After being cooled down to room temperature, the reaction was filtered, filtrate was partitioned between EtOAc and water, organic layer was separated, the aqueous phase was extracted with EtOAc twice, dried over Na ₂ SO ₄ , filtered and concentrated, the residue was purified by flash column chromatography (silica gel, 0~50% EtOAc in petroleum ether) to give tert-butyl 4-(5-cyclopropyl-7-(3,5-difluorophenyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-(difluoromethyl)piperazin e-1-carboxylate (93 mg, 91% yield), as a white solid. LCMS ESI (m/z): 506 (M+H) ⁺ . Step 6 tert-Butyl (S)-4-(5-cyclopropyl-7-(3,5-difluorophenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2-(difluoromethyl)piperazine-1-carboxylate and tert-butyl (R)-4-(5- cyclopropyl-7-(3,5-difluorophenyl)-7H-pyrrolo[2,3-d]pyrimidi n-4-yl)-2- (difluoromethyl)piperazine-1-carboxylate tert-butyl 4-(5-cyclopropyl-7-(3,5-difluorophenyl)-7H-pyrrolo[2,3-d]pyr imidin-4-yl)- 2-(difluoromethyl)piperazine-1-carboxylate was separated by SFC to give two isomers: Peak 1: shorter retention time, labeled as compound 314 (tert-butyl (S)-4-(5- cyclopropyl-7-(3,5-difluorophenyl)-7H-pyrrolo[2,3-d]pyrimidi n-4-yl)-2- (difluoromethyl)piperazine-1-carboxylate), LCMS ESI (m/z): 506 (M+H) ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ 8.38 (s, 1H), 7.58 – 7.52 (m, 2H), 7.34 (d, J = 0.6 Hz, 1H), 6.98 – 6.90 (m, 1H), 6.16 (m, J = 56.1, 5.8 Hz, 1H), 4.52 (d, J = 11.1 Hz, 2H), 4.38 (d, J = 14.0 Hz, 1H), 4.10 (d, J = 13.3 Hz, 1H), 3.49 – 3.36 (m, 2H), 3.16 – 3.08 (m, 1H), 2.09 – 2.03 (m, 1H), 1.49 (s, 9H), 1.07 – 0.97 (m, 3H), 0.72 – 0.65 (m, 1H). Peak 2: longer retention time, labeled as compound 315 (tert-butyl (R)-4-(5- cyclopropyl-7-(3,5-difluorophenyl)-7H-pyrrolo[2,3-d]pyrimidi n-4-yl)-2- (difluoromethyl)piperazine-1-carboxylate), LCMS ESI (m/z): 506 (M+H) ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ 8.38 (s, 1H), 7.58 – 7.52 (m, 2H), 7.34 (d, J = 0.7 Hz, 1H), 6.97 – 6.91 (m, 1H), 6.31 – 6.00 (m, 1H), 4.52 (d, J = 10.7 Hz, 2H), 4.38 (d, J = 13.4 Hz, 1H), 4.10 (d, J = 13.2 Hz, 1H), 3.48 – 3.36 (m, 2H), 3.16 – 3.09 (m, 1H), 2.09 – 2.03 (m, 1H), 1.49 (s, 9H), 1.08 – 0.97 (m, 3H), 0.71 – 0.65 (m, 1H). Preparative separation method: Instrument: Waters Thar 80 preparative SFC ; Column: ChiralPak AD, 250×21.2mm I.D., 5µm; Mobile phase: A for CO2 and B for MEOH+0.1%NH3H2O; Gradient: B 30%; Flow rate: 50mL /min; Back pressure: 100 bar; Column temperature: 35℃; Wavelength: 240nm ; Cycle-time: 3min; Elution time: 2 h .

Example 71. Synthesis of tert-butyl (S)-4-(7-(3-chlorophenyl)-5-((S)-2-methylpyrrolidin- 1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1- carboxylate (Compound 316) Step 1.4-Chloro-7-(3-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimi dine To a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (10 g, 36 mmol) in DCM (40 mL) were added (3-chlorophenyl)boronic acid (11 g, 72 mmol), 4A molecular sieves (8 g), Cu(OAc) ₂ (26 g, 140 mmol) and pyridine (17 g, 210 mmol). The resulting mixture was stirred at 40℃ under O2 atmosphere for 2 days. The reaction was quenched with NH ₄ OH (50 mL) at ice water, filtered, the filtrate was extract with DCM twice, the combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated, the residue was purified by flash column chromatography (silica gel, 0~30% EtOAc in petroleum ether) to afford 4- chloro-7-(3-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (8.8 g, 67%) as a solid. LC/MS ESI (m/z): 390 (M+H) ⁺ . Step 2.7-(3-Chlorophenyl)-5-iodo-4-methoxy-7H-pyrrolo[2,3-d]pyrim idine To a solution of 4-chloro-7-(3-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidi ne (5.0 g, 13 mmol) in MeOH (20 ml) was added CH ₃ ONa (77 ml, 5.0M in MeOH) and the mixture was stirred at 55℃ for 4 hours under N ₂ . The reaction was quenched with ice water and it was extracted with DCM twice, the combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated, the residue was purified by flash column chromatography (silica gel, 0~30% EtOAc in petroleum ether) to afford 7-(3-chlorophenyl)-5-iodo-4-methoxy-7H- pyrrolo[2,3-d]pyrimidine (3.8 g, 78%) as a solid. LC/MS ESI (m/z): 386 (M+H) ⁺ Step 3. (S)-7-(3-Chlorophenyl)-4-methoxy-5-(2-methylpyrrolidin-1-yl) -7H- pyrrolo[2,3-d]pyrimidine To the solution of 7-(3-chlorophenyl)-5-iodo-4-methoxy-7H-pyrrolo[2,3-d]pyrimid ine (1000 mg, 2.6 mmol) in DMSO (6 mL) were added CuI (98 mg, 0.46 mmol), L-proline (120 mg, 1.0 mmol), K ₂ CO ₃ (1100 mg, 7.8 mmol) and (S)-2-methylpyrrolidine (880 mg, 10 mmol). The resulting reaction mixture was stirred at 80 ℃ under N ₂ overnight. After which the reaction was extracted with EtOAc and water. The combined organic layers were dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 0~30%, EtOAc in petroleum ether) to afford (S)-7-(3-chlorophenyl)-4-methoxy-5-(2-methylpyrrolidin-1-yl) -7H-pyrrolo[2,3- d]pyrimidine (100 mg, 11%) as a solid. LC/MS ESI (m/z): 343 (M+H) ⁺ . Step 4. (S)-7-(3-Chlorophenyl)-5-(2-methylpyrrolidin-1-yl)-7H-pyrrol o[2,3- d]pyrimidin-4-ol To a solution of (S)-7-(3-chlorophenyl)-4-methoxy-5-(2-methylpyrrolidin-1-yl) -7H- pyrrolo[2,3-d]pyrimidine (100 mg, 0.29 mmol) in DMF (4 mL) were added p- Toluenesulfonic acid (550 mg, 2.9 mmol) and LiCl (120 mg, 2.9 mmol). The resulting mixture was heated to 110 ^o C for 2 hours. After being cooled down to room temperature. The reaction was quenched with water, extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to afford (S)-7-(3- chlorophenyl)-5-(2-methylpyrrolidin-1-yl)-7H-pyrrolo[2,3-d]p yrimidin-4-ol (80 mg, 84%) as a solid. LC/MS ESI (m/z): 329 (M+H) ⁺ . Step 5. (S)-4-Chloro-7-(3-chlorophenyl)-5-(2-methylpyrrolidin-1-yl)- 7H-pyrrolo[2,3- d]pyrimidine To a solution of (S)-7-(3-chlorophenyl)-5-(2-methylpyrrolidin-1-yl)-7H-pyrrol o[2,3- d]pyrimidin-4-ol (40 mg, 0.12 mmol) in POCl ₃ (4 mL). The resulting mixture was heated to 120 ^o C overnight, the reaction was concentrated. The reaction was quenched with NaHCO ₃ (aq.), extracted with DCM twice, the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to afford (S)-4-chloro-7-(3-chlorophenyl)-5-(2- methylpyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine (34 mg, 81%) as a yellow solid. LC/MS ESI (m/z): 347 (M+H) ⁺ . Step 6. tert-Butyl (S)-4-(7-(3-chlorophenyl)-5-((S)-2-methylpyrrolidin-1-yl)-7H - pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te To a solution of (S)-4-chloro-7-(3-chlorophenyl)-5-(2-methylpyrrolidin-1-yl)- 7H- pyrrolo[2,3-d]pyrimidine (17 mg, 0.050 mmol) in DIPEA (1 mL) was added tert-butyl (S)-3- methylpiperazine-1-carboxylate (20 mg, 0.10 mmol). The resulting mixture was heated to 140 ^o C for 3 hours. After being cooled down to room temperature, solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford tert-butyl (S)-4-(7-(3-chlorophenyl)-5-((S)-2-methylpyrrolidin-1-yl)-7H -pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (16 mg, 60%) as a white solid. LC/MS ESI (m/z): 511. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.24 (s, 1H), 7.86 (t, J = 2.0 Hz, 1H), 7.67 – 7.64 (m, 1H), 7.49 (t, J = 8.1 Hz, 1H), 7.37 – 7.34 (m, 1H), 7.09 (s, 1H), 5.35 (s, 1H), 4.12 (d, J = 11.7 Hz, 1H), 4.02 – 3.87 (m, 2H), 3.70 (s, 1H), 3.54 – 3.36 (m, 3H), 3.01 (s, 1H), 2.69 (d, J = 7.9 Hz, 1H), 2.26 – 2.18 (m, 1H), 2.03 – 1.95 (m, 1H), 1.92 – 1.83 (m, 1H), 1.70 – 1.62 (m, 1H), 1.50 (s, 9H), 1.15 (d, J = 5.4 Hz, 3H), 1.01 (d, J = 6.1 Hz, 3H). The following compounds were prepared by the procedures analogous to the synthesis of compound 316 from the corresponding amines.

Example 72. Synthesis of tert-butyl (S)-3-methyl-4-(5-(1-methyl-1H-pyrazol-4-yl)-7-(3- (trifluoromethoxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pi perazine-1-carboxylate (Compound 321) C ^{ompound 321} Step 1. tert-Butyl (S)-3-methyl-4-(5-(1-methyl-1H-pyrazol-4-yl)-7-tosyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate A mixture of tert-butyl (S)-4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate (1.5 g, 2.5 mmol), (1-methyl-1H-pyrazol-4-yl)boronic acid (630 mg, 5.0 mmol), Pd(dppf)Cl ₂ (180 mg, 0.30 mmol) and K ₂ CO ₃ (1000 mg, 7.5 mmol) in dioxane (20 mL) and H ₂ O (5 mL) was stirred at 95°C for 12 hrs. The reaction mixture was concentrated. The residue was purified by column chromatography on silica gel (0~50% EtOAc in petroleum ether) to give the tert-butyl (S)-3-methyl-4-(5-(1-methyl-1H-pyrazol-4- yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-car boxylate (1.3 g, 91%) as a yellow solid. LC/MS ESI (m/z): 552 (M+H) ⁺ . Step 2. tert-Butyl (S)-3-methyl-4-(5-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperazine-1-carboxylate To a solution of tert-butyl (S)-3-methyl-4-(5-(1-methyl-1H-pyrazol-4-yl)-7-tosyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (1.3 g, 2.3 mmol) in THF (10 mL) was added TBAF (9.1 mL, 1.0M in THF). The resulting mixture was stirred at room temperature for 2 hrs. The reaction mixture diluted with water and extracted with EtOAc (100 ml x 2). The combined layers were washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography on silica gel (0~80% EtOAc in petroleum ether) to give the tert-butyl (S)-3-methyl-4-(5-(1-methyl-1H-pyrazol-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (850 mg, 2.1 mmol, 94%) as a yellow solid. LC/MS ESI (m/z): 398 (M+H) ⁺ . Step 3. tert-Butyl (S)-3-methyl-4-(5-(1-methyl-1H-pyrazol-4-yl)-7-(3- (trifluoromethoxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pi perazine-1-carboxylate A mixture of tert-butyl (S)-3-methyl-4-(5-(1-methyl-1H-pyrazol-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (150 mg, 0.38 mmol ), 1-bromo-3- (trifluoromethoxy)benzene (180 mg, 0.76 mmol ), CuI (36 mg, 0.19 mmol), trans-1,2- diaminocyclohexane (13 mg, 0.11 mmol) and K ₃ PO ₄ (240 mg, 1.1 mmol) in DMF (10 mL) was heated at 120°C for 12 hours. The reaction mixture was concentrated. The residue was purified by column chromatography on silica gel (0~50% EtOAc in petroleum ether, V/V) to give the crude product. The crude product was purified by prep-HPLC to give the tert-butyl (S)-3-methyl-4-(5-(1-methyl-1H-pyrazol-4-yl)-7-(3-(trifluoro methoxy)phenyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (80 mg, 0.14 mmol, 38%) as a white solid. LC/MS ESI (m/z): 558.6 (M+H) ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ 8.40 (s, 1H), 7.86 (d, J = 8.9 Hz, 2H), 7.79 (d, J = 8.2 Hz, 1H), 7.70 (br, 1H), 7.67 – 7.62 (m, 2H), 7.32 (d, J = 8.3 Hz, 1H), 4.19 (br, 1H), 3.99 (s, 3H), 3.88 (d, J = 12.8 Hz, 1H), 3.58 (t, J = 15.0 Hz, 2H), 3.28 – 3.21 (m, 1H), 2.99 (br, 2H), 1.45 (s, 9H), 0.99 (d, J = 6.6 Hz, 3H). Example 73. Synthesis of tert-butyl (R)-4-(7-(3-chlorophenyl)-5-((R)-2- (hydroxymethyl)pyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4 -yl)-2-methylpiperazine- 1-carboxylate (Compound 1002) To the solution of tert-butyl (R)-4-(7-(3-chlorophenyl)-5-iodo-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate (400 mg, 0.72 mmol, prepared following the procedure outlined in compound 274) in DMSO (5 mL) were added CuI (28 mg, 0.14 mmol), L-proline (33 mg, 0.29 mmol), K ₂ CO ₃ (140 mg, 2.2 mmol) and (R)-pyrrolidin-2- ylmethanol (290 mg, 2.9). The resulting reaction mixture was stirred at 80℃ under N ₂ overnight. After it was extracted with EtOAc and water. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 0~10%, methonal in DCM) to afford tert-butyl (R)-4-(7-(3-chlorophenyl)-5-((R)-2-(hydroxymethyl)pyrrolidin -1-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxyla te (100 mg, 26%) as brown solid. LC/MS ESI (m/z): 527 (M+H) ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ 8.20 (s, 1H), 7.83 (t, J = 2.0 Hz, 1H), 7.69 – 7.65 (m, 1H), 7.52 – 7.48 (m, 1H), 7.39 – 7.35 (m, 1H), 7.21 (s, 1H), 4.65 – 4.60 (m, 1H), 4.52 – 4.46 (m, 1H), 4.38 – 4.33 (m, 1H), 4.26 – 4.15 (m, 2H), 4.05 – 3.98 (m, 1H), 3.95 – 3.90 (m, 1H), 3.47 (dd, J = 9.0, 4.5 Hz, 1H), 3.40 – 3.33 (m, 2H), 3.28 – 3.21 (m, 2H), 2.31 – 2.23 (m, 1H), 2.12 – 2.00 (m, 2H), 1.87 – 1.79 (m, 1H), 1.49 (s, 9H), 1.14 (d, J = 6.7 Hz, 3H). The following compounds were prepared by the procedures analogous to the synthesis of compound 1002 from the corresponding aryl halides. Example 74. Synthesis of 1,1,1-trifluoro-2-methylpropan-2-yl (S)-4-(7-cyclohexyl-5- cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperaz ine-1-carboxylate (Compound 325) C ^{ompound 325} Step 1. (S)-7-Cyclohexyl-5-cyclopropyl-4-(2-methylpiperazin-1-yl)-7H -pyrrolo[2,3- d]pyrimidine To a solution of tert-butyl (S)-4-(7-cyclohexyl-5-cyclopropyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (130 mg, 0.30 mmol, prepared following the procedure of compound 326, step 3) in DCM (1 mL) was added HCl/dioxane (1.0 mL, 4.0 M). The resulting mixture was stirred at room temperature overnight. After removal of solvent under reduced pressure, the residue was used in the next step directly. (S)-7- cyclohexyl-5-cyclopropyl-4-(2-methylpiperazin-1-yl)-7H-pyrro lo[2,3-d]pyrimidine (95 mg, 93%). LC/MS ESI (m/z): 340 (M+H) ⁺ . Step 2.1,1,1-Trifluoro-2-methylpropan-2-yl (S)-4-(7-cyclohexyl-5-cyclopropyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te To a solution of (S)-7-cyclohexyl-5-cyclopropyl-4-(2-methylpiperazin-1-yl)-7H - pyrrolo[2,3-d]pyrimidine (76 mg, 0.22 mmol) in DMF (0.5 mL) were added 1,1,1-trifluoro-2- methylpropan-2-yl 1H-imidazole-1-carboxylate (88 mg, 0.40 mmol, prepared following the procedure of compound 247, step 1). The reaction mixture was stirred at 80 ^o C overnight under N ₂ . The reaction was quenched with water, extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by prep-HPLC to afford 1,1,1-trifluoro-2-methylpropan-2-yl (S)-4-(7- cyclohexyl-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1- carboxylate (20 mg, 20% yield) as a white solid. LC/MS ESI (m/z): 494 (M+H) ⁺ . ¹ H NMR (400 MHz, MeOD) δ 8.31 (s, 1H), 7.29 (s, 1H), 4.95 – 4.86 (m, 1H), 4.72 – 4.58 (m, 1H), 4.28 – 4.01 (m, 2H), 4.01 – 3.84 (m, 1H), 3.75 (t, J = 11.1 Hz, 1H), 3.57 – 3.37 (m, 1H), 3.26 – 3.08 (m, 1H), 2.04 – 1.88 (m, 5H), 1.88 – 1.75 (m, 3H), 1.72 (d, J = 6.0 Hz, 6H), 1.52 (dd, J = 24.8, 12.4 Hz, 2H), 1.41 – 1.32 (m, 1H), 1.30 (d, J = 6.7 Hz, 3H), 1.10 – 0.94 (m, 2H), 0.89 – 0.79 (m, 1H), 0.79 – 0.67 (m, 1H). ¹⁹ F NMR (377 MHz, MeOD) δ -85.03 (d, J = 40.1 Hz). Example 75. Synthesis of tert-butyl (S)-4-(7-cyclohexyl-5-cyclopropyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Compound 326) Step 1.4-Chloro-7-cyclohexyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine To a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (7.0 g, 25 mmol), cyclohexanol (10 g, 100 mmol) and PPh ₃ (20 g, 75 mmol) in THF (40 mL) were added DIAD (15 g, 15 mL, 75 mmol) at 0 ℃. The resulting mixture was stirred at room temperature under N ₂ atmosphere overnight. The solvent was removed under reduced pressure. The residue is dissolved with petroleum ether and filtered to remove solids. The solvent of filtrate was removed under reduced pressure. The residue was extract with EtOAc twice, the combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0~30% EtOAc in petroleum ether) to afford 4-chloro-7- cyclohexyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (2.2 g, 24% yield) as a white solid. LC/MS ESI (m/z): 362 (M+H) ⁺ . Step 2. tert-Butyl (S)-4-(7-cyclohexyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 3- methylpiperazine-1-carboxylate To the solution of 4-chloro-7-cyclohexyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (1.8 g, 5.0 mmol) in DIEA (5 mL) was added tert-butyl (S)-3-methylpiperazine-1-carboxylate (5.0 g, 25 mmol). The resulting reaction mixture was stirred at 120℃ under N ₂ overnight. After being cooled down to room temperature, the reaction mixture was concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford tert-butyl (S)-4-(7-cyclohexyl-5-iodo- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carbox ylate (1.6 g, 59% yield) as white solid. LC/MS ESI (m/z): 526 (M+H) ⁺ . Step 3. tert-Butyl (S)-4-(7-cyclohexyl-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin -4- yl)-3-methylpiperazine-1-carboxylate To the solution of tert-butyl (S)-4-(7-cyclohexyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)-3-methylpiperazine-1-carboxylate (390 mg, 0.75 mmol) and cyclopropylboronic acid (260 mg, 3.0 mmol) in toluene (10 mL) were added Pd(dtbpf)Cl ₂ (49 mg, 0.075 mmol), K ₂ CO ₃ (2.1 g, 15 mmol) and H ₂ O (270 mg, 0.27 mL, 15 mmol) respectively. The resulting reaction mixture was stirred at 80 ℃ under N ₂ overnight. After being cooled down to room temperature, the solvent was removed under reduced pressure. The residue was extracted with EtOAc twice. The combined organic layers were dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0~40%, ethyl acetate in petroleum ether) to afford the crude product tert-butyl (S)-4-(7-cyclohexyl-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin -4-yl)-3- methylpiperazine-1-carboxylate (290 mg, 88% yield) as yellow solid.50 mg of product was further purified by prep-HPLC (Gilson, C18, MeCN in H ₂ O) to afford pure product (16.9 mg). LC/MS ESI (m/z): 440 (M+H) ⁺ . ¹ H NMR (400 MHz, MeOD) δ 8.23 (s, 1H), 7.01 (s, 1H), 4.80 – 4.68 (m, 1H), 4.57 (ddd, J = 12.1, 7.9, 3.6 Hz, 1H), 4.05 (d, J = 13.1 Hz, 1H), 3.84 (d, J = 12.4 Hz, 2H), 3.57 – 3.45 (m, 1H), 3.45 – 3.33 (m, 1H), 3.24 – 3.03 (m, 1H), 2.07 – 1.98 (m, 1H), 1.98 – 1.83 (m, 4H), 1.82 – 1.66 (m, 3H), 1.61 – 1.50 (m, 2H), 1.49 (s, 9H), 1.40 – 1.29 (m, 1H), 1.16 (d, J = 6.6 Hz, 3H), 1.03 – 0.91 (m, 2H), 0.85 – 0.73 (m, 1H), 0.69 – 0.56 (m, 1H). The following compounds were prepared by the procedure similar to the synthesis of compound 326 from the corresponding alcohols.

Example 76. Synthesis of 1,1,1-trifluoro-2-methylpropan-2-yl (S)-4-(7-(3-cyanophenyl)- 5-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl )-3-methylpiperazine-1- carboxylate (Compound 329) Step 1. tert-Butyl (S)-4-(7-(3-cyanophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te A mixture of tert-butyl (S)-3-methyl-4-(5-(1-methyl-1H-pyrazol-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (300 mg, 0.76 mmol, prepared following the procedure outlined in compound 321), 3-iodobenzonitrile (350 mg, 1.5 mmol), CuI (72 mg, 0.38 mmol), trans-1,2-diaminocyclohexane (26 mg, 0.23 mmol) and K ₃ PO ₄ (480 mg, 2.3 mmol) in DMF (15 mL) was heated at 120°C for 12 hours. The reaction mixture was concentrated. The residue was purified by column chromatography on silica gel (0~70% EtOAc in petroleum ether, V/V) to give the tert-butyl (S)-4-(7-(3-cyanophenyl)-5-(1-methyl- 1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpi perazine-1-carboxylate (300 mg, 80%) as a light yellow solid. LC/MS ESI (m/z): 499 (M+H) ⁺ . Step 2. (S)-3-(5-(1-Methyl-1H-pyrazol-4-yl)-4-(2-methylpiperazin-1-y l)-7H- pyrrolo[2,3-d]pyrimidin-7-yl)benzonitrile To a mixture of tert-butyl (S)-4-(7-(3-cyanophenyl)-5-(1-methyl-1H-pyrazol-4-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carbox ylate (260 mg, 0.52 mmol) in DCM (10 mL) was added HCl (5.0 mL, 4.0M in dioxane). The resulting mixture was stirred at room temperature for 3 hrs. The reaction mixture was concentrated to afford the (S)-3-(5- (1-methyl-1H-pyrazol-4-yl)-4-(2-methylpiperazin-1-yl)-7H-pyr rolo[2,3-d]pyrimidin-7- yl)benzonitrile (210 mg, 100%) as a yellow solid which was used in the next step directly without further purification. LC/MS ESI (m/z): 399 (M+H) ⁺ . Step 3.1,1,1-Trifluoro-2-methylpropan-2-yl (S)-4-(7-(3-cyanophenyl)-5-(1-methyl- 1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpi perazine-1-carboxylate A mixture of (S)-3-(5-(1-methyl-1H-pyrazol-4-yl)-4-(2-methylpiperazin-1-y l)-7H- pyrrolo[2,3-d]pyrimidin-7-yl)benzonitrile (240 mg, 0.60 mmol), 1,1,1-trifluoro-2- methylpropan-2-yl 1H-imidazole-1-carboxylate (150 mg, 0.66 mmol) and DIEA (470 mg, 3.6 mmol) in DMF(10 mL) was heated at 80°C for 12 hours. The reaction mixture was diluted with water, extracted with EtOAc (100 ml x2). The combined layers were washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography on silica gel (0~80% EtOAc in petroleum ether, V/V) to give the crude product. The crude product was purified by prep-HPLC to give the 1,1,1-trifluoro-2-methylpropan-2-yl (S)-4-(7- (3-cyanophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate (27 mg, 8.0%) as a light yellow solid. LC/MS ESI (m/z): 553 (M+H) ^{+ 1} H NMR δ 8.42 (d, J = 3.2 Hz, 1H), 8.29 (s, 1H), 8.16 – 8.11 (m, 1H), 7.85 (s, 1H), 7.75 – 7.68 (m, 4H), 4.22 (br, 1H), 3.99 (s, 3H), 3.94 – 3.77 (m, 1H), 3.63 – 3.53 (m, 2H), 3.25 (d, J = 12.6 Hz, 1H), 3.13 – 2.91 (m, 2H), 1.67 (s, 6H), 1.00 (d, J = 6.7 Hz, 3H). The following compound was prepared by the procedure analogous to the synthesis of compound 329 from the corresponding aryl halide. Example 77. Synthesis of tert-butyl (S)-4-(7-cyclohexyl-5-(pyrrolidin-1-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (Compound 334) C ^{ompound 334} Step 1. tert-Butyl (S)-4-(7-cyclohexyl-5-(pyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyr imidin- 4-yl)-3-methylpiperazine-1-carboxylate To the solution of tert-butyl (S)-4-(7-cyclohexyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)-3-methylpiperazine-1-carboxylate (530 mg, 1.0 mmol, prepared following the procedure of compound 326, step 3) in DMSO (2 mL) were added CuI (38mg, 0.20 mmol), L-proline (46 mg, 0.40 mmol), K ₂ CO ₃ (410 mg, 3.0 mmol) and pyrrolidine (710 mg, 10 mmol) respectively. The reaction mixture was stirred at 80 ℃ under N ₂ overnight. After being cooled down to room temperature, the mixture was extracted with EtOAc twice. The combined organic layers were dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0~40%, ethyl acetate in petroleum ether) to afford the crude product (110 mg) as yellow solid.50 mg of product was further purified by prep-HPLC (Gilson, C18, MeCN in H ₂ O) to afford tert-butyl (S)-4-(7-cyclohexyl-5-(pyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyr imidin-4-yl)-3- methylpiperazine-1-carboxylate (6.3 mg, 1.3% yield). LC/MS ESI (m/z): 469 (M+H) ⁺ . ¹ H NMR (400 MHz, MeOD) δ 8.15 (s, 1H), 6.82 (s, 1H), 5.07 (s, 1H), 4.59 (ddd, J = 12.1, 7.9, 3.6 Hz, 1H), 4.25 – 3.98 (m, 2H), 3.90 (d, J = 13.2 Hz, 1H), 3.39 – 3.32 (m, 1H), 3.30 – 3.20 (m, 1H), 3.19 – 3.09 (m, 2H), 3.09 – 2.90 (m, 1H), 2.90 – 2.76 (m, 2H), 2.07 – 1.85 (m, 8H), 1.84 – 1.69 (m, 3H), 1.60 – 1.51 (m, 2H), 1.48 (s, 9H), 1.40 – 1.30 (m, 1H), 1.05 (d, J = 6.5 Hz, 3H). The following compound was prepared by the procedure similar to the synthesis of compound 334 from the corresponding amine. Example 78. Synthesis of tert-butyl-(S)-4-(7-(3-chlorophenyl)-5-(pyrrolidin-1-ylmethy l)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carbox ylate (Compound 337) Step 1. Methyl-(S)-4-(4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl )-7-(3- chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate A suspension of tert-butyl (3S)-4-[7-(3-chlorophenyl)-5-iodo-7H-pyrrolo[2,3- d]pyrimidin-4-yl]-3-methylpiperazine-1-carboxylate (500 mg, 0.90 mmol, prepared following the procedure outlined in compound 274), TEA (0.37 mL, 2.7 mmol) and Pd(dppf)Cl ₂ (99 mg, 0.13 mmol ) in MeOH (7 mL) was stirred at 70℃ under CO atmosphere for 18h, After being cooled down to room temperature, solvent was removed. The residue was purified by column chromatography on silica gel (0~40% ethyl acetate in petroleum) to give tert-butyl (3S)-4-[7-(3-chlorophenyl)-5-(methoxycarbonyl)-7H-pyrrolo[2, 3-d]pyrimidin-4-yl]-3- methylpiperazine-1-carboxylate (400 mg, 91%) as a white solid. LC/MS (ESI) (m/z): 486 (M+H) ⁺ Step 2. (S)-4-(4-(tert-Butoxycarbonyl)-2-methylpiperazin-1-yl)-7-(3- chlorophenyl)- 7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid A solution of tert-butyl-(3S)-4-[7-(3-chlorophenyl)-5-(methoxycarbonyl)-7H - pyrrolo[2,3-d]pyrimidin-4-yl]-3-methylpiperazine-1-carboxyla te (400 mg, 0.82 mmol) in MeOH (5 mL) was added 2.0M NaOH (1.0 mL), the resulting mixture was stirred at 80℃ for 18 h. After being cooled down to room temperature, the reaction was acidified with 1N HCl to PH 3, then was extracted by EtOAc twice. The combined organic phases were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was used in the next step directly. LC/MS(ESI)m/z: 472 (M+H) ⁺ Step 3. tert-Butyl-(S)-4-(7-(3-chlorophenyl)-5-(pyrrolidine-1-carbon yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te A suspension of 4-[(2S)-4-[(tert-butoxy)carbonyl]-2-methylpiperazin-1-yl]-7- (3- chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid (150 mg, 0.32 mmol), HATU (140 mg, 0.37 mmol) and DIEA (100 mg, 0.80 mmol) in DMF(5.0 mL) was stirred at room temperature for 0.5 h, then the mixture was added pyrrolidine (0.030 mL, 0.38 mmol) and stirred for another 2.5 h. The reaction mixture was partitioned between EtOAc and water, organic layer was separated, the aqueous layer was extracted with EtOAc twice. The combined organic phases were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography on silica gel (0~15% MeOH in DCM) to get tert-butyl-(3S)-4-[7-(3-chlorophenyl)-5-(pyrrolidine-1-carbo nyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl]-3-methylpiperazine-1-carboxyla te (160 mg, 96%) as a white solid. LC/MS(ESI)m/z: 525 (M+H) ⁺ Step 4. tert-Butyl-(S)-4-(7-(3-chlorophenyl)-5-(pyrrolidin-1-ylmethy l)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te At 0 ^o C, to a solution of tert-butyl-(3S)-4-[7-(3-chlorophenyl)-5-(pyrrolidine-1- carbonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-3-methylpiperazin e-1-carboxylate (80 mg, 0.15 mmol) in THF(3.0 mL) was added 1.0M LiAlH ₄ (0.38 mL, THF solution). The resulting mixture was stirred for 3 h. The mixture was added 0.15 mL 10% NaOH. The resulting suspension was stirred for 1h, filtered off and then washed with EtOAc twice, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by prep-HPLC to give tert-butyl-(S)-4-(7-(3-chlorophenyl)-5-(pyrrolidin-1-ylmethy l)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)-3-methylpiperazine-1-carboxylate (20 mg, 26%) as a white solid. LC/MS (ESI) (m/z): 511 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.56 (s, 1H), 7.89 (s, 1H), 7.82 (t, J = 1.9 Hz, 1H), 7.67 – 7.61 (m, 1H), 7.45 (t, J = 8.1 Hz, 1H), 7.35 (d, J = 9.0 Hz, 1H), 4.42 (d, J = 13.2 Hz, 1H), 4.18 (dd, J = 11.3, 5.0 Hz, 1H), 4.11 (d, J = 13.4 Hz, 1H), 3.95 – 3.81 (m, 1H), 3.66 (d, J = 13.4 Hz, 1H), 3.54 – 3.43 (m, 3H), 3.37 – 3.25 (m, 1H), 3.16 – 3.05 (m, 2H), 3.01 – 2.91 (m, 2H), 2.05 – 1.92 (m, 4H), 1.49 (s, 9H), 1.18 (d, J = 6.4 Hz, 3H). Example 79. Synthesis of tert-butyl (S)-4-(7-cyclopentyl-5-(pyrrolidin-1-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (Compound 338) trans-1,2-diaminocyclohexane K ₂ CO ₃ , CuI, DMF, 120°C, 8 h C ^{ompound 338} Step 1.4-Chloro-7-cyclopentyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine At 0 ^o C, to a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (2.0 g, 7.2 mmol) in THF (10 mL) were added cyclopentanol (2.6 mL, 29 mmol), PPh ₃ (5.6 g, 22 mmol) and DIAD (4.3 mL, 22 mmol) dropwise. The reaction mixture was stirred at 0°C for 1 h and then was allowed to warm up to room temperature, and stirred for 3 h. TLC (petroleum ether : EtOAc = 3:1) showed most 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (R _f =0.30) was consumed and two spot (R _f = 0.60, 0.70) were formed. The mixture was poured into H ₂ O (20 mL) and extracted with EtOAc (20 mL x 4). The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated under vacuo. The residue was purified by flash column chromatography to afford 4-chloro-7-cyclopentyl-5-iodo-7H-pyrrolo[2,3- d]pyrimidine (1.7 g, 4.9 mmol) was as an white solid. LC/MS ESI (m/z): 348 (M+H) ⁺ . Step 2. tert-Butyl (S)-4-(7-cyclopentyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl) -3- methylpiperazine-1-carboxylate To a solution of 4-chloro-7-cyclopentyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (1.7 g, 4.9 mmol) in DIEA (4.9 mL, 29 mmol) was added tert-butyl (S)-3-methylpiperazine-1- carboxylate (2.0 g, 9.8 mmol) at 25°C. The mixture was degassed N ₂ 3 times. The mixture was heated to 120°C for 12 h. After being cooled down to room temperature, the reaction mixture was diluted with water, extracted with EtOAc (50 mL x 4). The combined organic phase was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under vacuo. The crude product was purified by silica gel column (SiO ₂ , petroleum ether:EtOAc = 50 : 1 to 30 : 1) to afford tert-butyl (S)-4-(7-cyclopentyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl) -3- methylpiperazine-1-carboxylate (1.8 g, 3.5 mmol). LC/MS ESI (m/z): 512 (M+H) ⁺ . Step 3. tert-Butyl (S)-4-(7-cyclopentyl-5-(pyrrolidin-1-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl (S)-4-(7-cyclopentyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4- yl)-3-methylpiperazine-1-carboxylate (200 mg, 0.39 mmol) in DMF (10 mL) were added pyrrolidine (640 mg, 1.5 mmol), CuI (37 mg, 0.20 mmol), trans-1,2-diaminocyclohexane (180 mg, 1.5 mmol), and K ₂ CO ₃ (110 mg, 0.78 mmol) at 25 °C. The mixture was heated to 120°C for 8 h. The mixture was cooled to 25°C and pour into H ₂ O (50 ml), extracted with EtOAc (20 mL x 4). The combined organic phases were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under vacuo. The crude product was purified by Prep- HPLC to afford tert-butyl (S)-4-(7-cyclopentyl-5-(pyrrolidin-1-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (20 mg, 0.044 mmol) was obtained as a white solid. LC/MS ESI (m/z): 455 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.33 (s, 1H), 6.51 (s, 1H), 5.26 – 5.15 (m, 1H), 4.98 (s, 1H), 4.14 (s, 2H), 3.91 (s, 1H), 3.37 (s, 1H),3.25 (s, 1H), 3.09 (s, 3H), 2.84 (s, 2H), 2.23 – 2.14 (m, 2H), 1.97 – 1.72 (m, 10H), 1.49 (s, 9H), 1.11 (s, 3H).

Example 80. Synthesis of tert-butyl (S)-4-(5-cyclopropyl-7-(tetrahydro-2H-pyran-4-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carbox ylate (Compound 340) P _d(dtbpf)Cl2 ^{, K} ₂ ^CO ₃ ^, toluene, 80°C C ^{ompound 340} Step 1.4-Chloro-5-iodo-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2, 3-d]pyrimidine At 0°C, to a mixture of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (3.0 g, 11 mmol) , tetrahydro-2H-pyran-4-ol (1.3 g, 13 mmol) and PPh ₃ (5.6 g, 22 mmol) in THF (100 mL) was added DIAD (4.3 mL, 22 mmol) dropwise. The resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was filtered. The filter cake was washed with EtOAc (50 ml) to give the 4-chloro-5-iodo-7-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidine (1.7 g, 44%) as a yellow solid which was used in the next step directly without further purification. LC/MS ESI (m/z): 364 (M+H) ⁺ . Step 2. tert-Butyl (S)-4-(5-iodo-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate A mixture of 4-chloro-5-iodo-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidine (1.7 g, 4.7 mmol) and tert-butyl (S)-3-methylpiperazine-1-carboxylate (1.9 g, 9.4 mmol) in DIEA (20 mL) was heated at 150°C for 3 hours. The reaction mixture was concentrated. The residue was purified by column chromatography on silica gel (0~70% EtOAc in petroleum ether, V/V) to give the tert-butyl (S)-4-(5-iodo-7-(tetrahydro-2H-pyran- 4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1- carboxylate (1.5 g, 59%) as a yellow solid. LC/MS ESI (m/z): 528 (M+H) ⁺ . Step 3. tert-Butyl (S)-4-(5-cyclopropyl-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo [2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate A mixture of tert-butyl (S)-4-(5-iodo-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (100 mg, 0.19 mmol), cyclopropylboronic acid (49 mg, 0.57 mmol), Pd(dtbpf)Cl ₂ (25 mg, 0.040 mmol) and K ₂ CO ₃ (520 mg, 3.8 mmol) in toluene (5 mL) was heated at 80°C for 12 hours. The reaction mixture was concentrated. The residue was purified by column chromatography on silica gel (0~80% EtOAc in petroleum ether, V/V) to give the crude product. The crude product was purified by prep-HPLC to give the tert-butyl (S)-4-(5-cyclopropyl-7-(tetrahydro-2H-pyran-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (26 mg, 31%) as a white solid. LC/MS ESI (m/z): 442.3 (M+H) ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ 8.24 (s, 1H), 7.05 (s, 1H), 4.84 – 4.73 (m, 2H), 4.11 – 4.02 (m, 3H), 3.91 – 3.81 (m, 2H), 3.66 – 3.57 (m, 2H), 3.55 – 3.46 (m, 1H), 3.32 (br, 1H), 3.13 (br, 1H), 2.14 – 1.99 (m, 3H), 1.92 – 1.84 (m, 2H), 1.49 (s, 9H), 1.16 (d, J = 6.6 Hz, 3H), 1.00 – 0.95 (m, 2H), 0.84 – 0.78 (m, 1H), 0.67 – 0.62 (m, 1H). The following compound ware prepared by the procedure similar to the synthesis of compound 340 from the corresponding alcohol. Example 81. Synthesis of tert-butyl (S)-4-(3-cyclopropyl-1-(4-isocyanopyridin-2-yl)-1H- pyrazolo[3,4-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyl ate (Compound 343) C ^{ompound 343} Step 1. tert-Butyl (S)-4-(3-cyclopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate The mixture of tert-butyl (S)-4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate (400 mg, 1.0 mmol), cyclopropylboronic acid (260 mg, 3.0 mmol), K ₂ CO ₃ (4.1 g, 30 mmol), Pd-118 (97 mg, 0.15 mmol) and toluene (20 mL) was heated to 90 ^o C overnight. After being cooled down to room temperature, solvent was removed, the residue was purified by flash column chromatography (silica gel, 0~15% MeOH in DCM) to afford tert-butyl (S)-4-(3-cyclopropyl-1H-pyrazolo[3,4-d]pyrimidin-4- yl)-3-methylpiperazine-1-carboxylate (110 mg, 30%). LC/MS ESI (m/z): 359 (M+H) ⁺ . Step 2. tert-Butyl (S)-4-(3-cyclopropyl-1-(4-isocyanopyridin-2-yl)-1H-pyrazolo[ 3,4- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To the solution of tert-butyl (3S)-4-{3-cyclopropyl-1H-pyrazolo[3,4-d]pyrimidin-4- yl}-3-methylpiperazine-1-carboxylate (100 mg, 0.28 mmol) in DMF (2 mL) were added CuI (27 mg, 0.14 mmol), K ₃ PO ₄ (120 mg, 0.56 mmol), trans-cyclohexane-1,2-diamine (41 mg, 0.29 mmol) and 2-bromopyridine-4-carbonitrile (100 mg, 0.56 mmol) respectively. The resulting reaction mixture was stirred at 120℃ under N ₂ overnight. After being cooled down to r.t., the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography and prep-HPLC to afford tert-butyl (S)-4-(3- cyclopropyl-1-(4-isocyanopyridin-2-yl)-1H-pyrazolo[3,4-d]pyr imidin-4-yl)-3- methylpiperazine-1-carboxylate (30 mg, 23%) as solid. LC/MS ESI (m/z): 461.6 (M+H) ⁺ . NMR (400 MHz, CDCl ₃ ) δ 8.88 – 8.80 (m, 1H), 8.60 (s, 1H), 8.53 (s, 1H), 7.46 – 7.39 (m, 1H), 5.11 – 4.95 (m, 1H), 4.43 – 4.34 (m, 1H), 4.30 – 3.92 (m, 2H), 3.67 – 3.50 (m, 1H), 3.30 – 2.94 (m, 2H), 2.10 – 2.02 (m, 1H), 1.51 (s, 9H), 1.38 – 1.33 (m, 5H), 1.20 – 1.13 (m, 2H). Example 82. Synthesis of ethyl (S)-4-(7-(4-cyanopyridin-2-yl)-5-(2-fluorophenyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (Compound 346) C ^{ompound 346} Step 1. (S)-2-(5-(2-Fluorophenyl)-4-(2-methylpiperazin-1-yl)-7H-pyrr olo[2,3- d]pyrimidin-7-yl)isonicotinonitrile At 0 ^o C, to a solution of tert-butyl (S)-4-(7-(4-cyanopyridin-2-yl)-5-(2-fluorophenyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carbox ylate (500 mg, 0.16 mmol, prepared following the procedure outlined in compound 268) in DCM (10 mL) was added TFA (3 mL). The resulting mixture was stirred at the same temperature for 2 h. The reaction was quenched with NaHCO ₃ (aq.), extracted with DCM twice, the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was used in the next step directly. LC/MS ESI (m/z): 414 (M+H) ⁺ . Step 2. Ethyl (S)-4-(7-(4-cyanopyridin-2-yl)-5-(2-fluorophenyl)-7H-pyrrolo [2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate At 0 ^o C, to a solution of (S)-2-(5-(2-fluorophenyl)-4-(2-methylpiperazin-1-yl)-7H- pyrrolo[2,3-d]pyrimidin-7-yl)isonicotinonitrile (100 mg, 0.24 mmol) in DCM (10 mL) was added TEA (73 mg, 0.72 mmol), followed by ethyl carbonochloridate (52 mg, 0.48 mmol) dropwise. The resulting mixture was stirred at room temperature for 20 minutes. The reaction was quenched with NaHCO ₃ (aq.), extracted with DCM twice, the combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford ethyl (S)-4-(7-(4-cyanopyridin-2-yl)-5-(2- fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiper azine-1-carboxylate (70 mg, 59%) as a white solid. LC/MS ESI (m/z): 486 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl3) δ 9.39 (s, 1H), 8.63 (d, J = 5.0 Hz, 1H), 8.58 (s, 1H), 8.28 (s, 1H), 7.49 – 7.44 (m, 1H), 7.42 – 7.35 (m, 2H), 7.26 – 7.17 (m, 2H), 4.36 – 4.18 (m, 1H), 4.15 – 4.08 (m, 2H), 3.85 – 3.73 (m, 1H), 3.59 (d, J = 12.9 Hz, 1H), 3.54 – 3.44 (m, 1H), 3.08 (d, J = 11.8 Hz, 1H), 2.93 – 2.64 (m, 2H), 1.23 (t, J = 7.1 Hz, 3H), 1.03 (s, 3H). The following compounds were prepared by the procedure similar to the synthesis of compound 346 from the corresponding acid chlorides.

Example 83. Synthesis of 1,1,1-trifluoropropan-2-yl (3S)-4-(7-(4-cyanopyridin-2-yl)-5- (2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpi perazine-1-carboxylate (Compound 348) Step 1.1,1,1-Trifluoro-2-methylpropan-2-yl 1H-imidazole-1-carboxylate To a solution of 1,1,1-trifluoropropan-2-ol (1.0 g, 8.8 mmol) in DCM (10 mL) was added di(1H-imidazol-1-yl)methanone (1.7 g, 11 mmol). The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water, extracted with DCM twice, the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to afford 1,1,1-trifluoro-2-methylpropan-2-yl 1H-imidazole-1-carboxylate (1.1 g, 60%) as a white solid. LC/MS ESI (m/z): 209 (M+H) ⁺ . Step 2.1,1,1-Trifluoropropan-2-yl (3S)-4-(7-(4-cyanopyridin-2-yl)-5-(2- fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiper azine-1-carboxylate To a solution of (S)-2-(5-(2-fluorophenyl)-4-(2-methylpiperazin-1-yl)-7H-pyrr olo[2,3- d]pyrimidin-7-yl)isonicotinonitrile (70 mg, 0.17 mmol, prepared following the procedure outlined in compound 346) in DMF (5 mL) were added 1,1,1-trifluoropropan-2-yl 1H- imidazole-1-carboxylate (71 mg, 0.34 mmol) and DIPEA (70 mg, 0.51 mmol). The resulting mixture was stirred at 80 ^o C for 2 days under N ₂ . The reaction was quenched with water, extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford 1,1,1-trifluoropropan-2-yl (3S)-4-(7-(4-cyanopyridin-2-yl)- 5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methyl piperazine-1-carboxylate (29 mg , 30%) as a white solid. LC/MS ESI (m/z): 554 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl3) δ 9.40 (s, 1H), 8.62 (d, J = 5.0 Hz, 1H), 8.58 (s, 1H), 8.29 (s, 1H), 7.46 (t, J = 7.5 Hz, 1H), 7.42 – 7.36 (m, 2H), 7.27 – 7.19 (m, 2H), 5.28 – 5.19 (m, 1H), 4.22 (d, J = 28.8 Hz, 1H), 3.87 – 3.72 (m, 1H), 3.60 – 3.48 (m, 2H), 3.15 – 3.08 (m, 1H), 2.95 – 2.72 (m, 2H), 1.37 (d, J = 6.5 Hz, 3H), 1.01 (t, J = 6.1 Hz, 3H) The following compound was prepared by the procedures similar to the synthesis of compound 348 from 2,2,2-trifluoroethan-1-ol. Example 84. Synthesis of tert-butyl (S)-4-(7-(4-cyanopyridin-2-yl)-5-(pyridin-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (Compound 352) Step 1. tert-Butyl (S)-4-(7-(4-cyanopyridin-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methyl piperazine-1-carboxylate To a solution of tert-butyl (S)-4-(5-bromo-7-(4-cyanopyridin-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (800 mg, 1.6 mmol, prepared following a similar procedure outlined in compound 388) in dioxane (15 mL) were added 4,4,5,5- tetramethyl-1,3,2-dioxaborolane (0.93 mL, 6.4 mmol), X-Phos (77 mg, 0.16 mmol), TEA (1.1 mL, 8.0 mmol) and Pd ₂ (dba) ₃ (150 mg, 0.16 mmol). The resulting mixture was stirred at 95 ^o C for 5 h under N ₂ . After being cooled down to room temperature, the reaction was quenched with water, extracted with DCM twice, the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to afford crude tert-butyl (S)-4-(7-(4- cyanopyridin-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan -2-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (800 mg, 91%) as a black oil. LC/MS ESI (m/z): 546 (M+H) ⁺ . Step 2. tert-Butyl (S)-4-(7-(4-cyanopyridin-2-yl)-5-(pyridin-2-yl)-7H-pyrrolo[2 ,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl (S)-4-(7-(4-cyanopyridin-2-yl)-5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1- carboxylate (200 mg, 0.36 mmol) in dioxane (10 mL) and H ₂ O (2 mL) were added 2- bromopyridine (0.070 mL, 0.73 mmol), K ₂ CO ₃ (250 mg, 1.8 mmol) and Pd(dppf)Cl ₂ (27 mg, 0.037 mmol). The resulting mixture was heated to 90 ^o C overnight. After being cooled down to room temperature, solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~90%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford tert-butyl (S)-4-(7-(4-cyanopyridin-2-yl)- 5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpi perazine-1-carboxylate (26 mg, 14%) as a white solid. LC/MS ESI (m/z): 497 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.39 (s, 1H), 8.73 (d, J = 4.7 Hz, 1H), 8.66 – 8.55 (m, 3H), 7.84 (s, 1H), 7.64 (d, J = 6.2 Hz, 1H), 7.42 (dd, J = 5.0, 1.1 Hz, 1H), 7.32 (s, 1H), 4.30 (d, J = 44.9 Hz, 1H), 3.92 – 3.71 (m, 1H), 3.64 – 3.43 (m, 2H), 3.14 (t, J = 11.3 Hz, 1H), 3.03 – 2.60 (m, 2H), 1.43 (s, 9H), 1.05 (s, 3H). The following compounds were prepared by the procedures similar to the synthesis of compound 352 from the corresponding aryl halides. Example 85. Synthesis of tert-butyl (S)-4-(7-(4-cyanopyridin-2-yl)-5-(pyridin-3-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (Compound 353) C ^{ompound 353} Step 1. tert-Butyl (S)-4-(7-(4-cyanopyridin-2-yl)-5-(pyridin-3-yl)-7H-pyrrolo[2 ,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl (S)-4-(5-bromo-7-(4-cyanopyridin-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (150 mg, 0.30 mmol, prepared following the procedure outlined in compound 388) in dioxane (10 mL) and H ₂ O (2 mL) was added pyridin-3-ylboronic acid (74 mg, 0.60 mmol), K ₂ CO ₃ (210 mg, 1.5 mmol) and Pd(dppf)Cl ₂ (22 mg, 0.030 mmol). The resulting mixture was heated to 90 ^o C overnight. After being cooled down to room temperature, solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~90%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford tert-butyl (S)-4-(7-(4- cyanopyridin-2-yl)-5-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimid in-4-yl)-3-methylpiperazine-1- carboxylate (84 mg, 56%) as a white solid. LC/MS ESI (m/z): 497 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.42 (s, 1H), 8.88 (s, 1H), 8.67 – 8.60 (m, 3H), 8.33 (s, 1H), 7.98 (d, J = 7.3 Hz, 1H), 7.52 – 7.45 (m, 1H), 7.44 (dd, J = 5.0, 1.2 Hz, 1H), 4.12 (s, 1H), 3.91 – 3.69 (m, 1H), 3.61 – 3.51 (m, 1H), 3.43 (d, J = 13.0 Hz, 1H), 3.14 (td, J = 13.4, 2.9 Hz, 1H), 2.99 – 2.66 (m, 2H), 1.43 (s, 9H), 1.03 (d, J = 5.4 Hz, 3H). Example 86. Synthesis of tert-butyl (S)-3-methyl-4-(5-(pyrrolidin-1-yl)-7-(3,4,5- trifluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine- 1-carboxylate (Compound 356) Step 1. tert-Butyl (S)-4-(5-iodo-7-(3,4,5-trifluorophenyl)-7H-pyrrolo[2,3-d]pyr imidin- 4-yl)-3-methylpiperazine-1-carboxylate A mixture of 4-chloro-5-iodo-7-(3,4,5-trifluorophenyl)-7H-pyrrolo[2,3-d]p yrimidine (450 mg, 1.1 mmol, prepared following the procedure outline in compound 313) and tert- butyl (S)-3-methylpiperazine-1-carboxylate (440 mg, 2.2 mmol) in DIEA (5 mL) was heated at 150°C for 3 hours. The reaction mixture was concentrated. The residue was purified by column chromatography on silica gel (0~70% EtOAc in petroleum ether, V/V) to give the tert-butyl (S)-4-(5-iodo-7-(3,4,5-trifluorophenyl)-7H-pyrrolo[2,3-d]pyr imidin-4-yl)-3- methylpiperazine-1-carboxylate (530 mg, 84%) as a yellow solid. LC/MS ESI (m/z): 574 (M+H) ⁺ . Step 2. tert-Butyl (S)-3-methyl-4-(5-(2-oxopyrrolidin-1-yl)-7-(3,4,5-trifluorop henyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate A mixture of tert-butyl (S)-4-(5-iodo-7-(3,4,5-trifluorophenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (530 mg, 0.92 mmol), pyrrolidin-2-one (240 mg, 2.8 mmol), CuI (88 mg, 0.46 mmol), trans-1,2-diaminocyclohexane (32 mg, 0.28 mmol) and K ₃ PO ₄ (590 mg, 2.8 mmol) in DMF (10 mL) was heated at 120°C for 12 hours. The reaction mixture was concentrated. The residue was purified by column chromatography on silica gel (0~100% EtOAc in petroleum ether, V/V) to give the tert-butyl (S)-3-methyl-4- (5-(2-oxopyrrolidin-1-yl)-7-(3,4,5-trifluorophenyl)-7H-pyrro lo[2,3-d]pyrimidin-4- yl)piperazine-1-carboxylate (300 mg, 61%) as a grey oil. LC/MS ESI (m/z): 531 (M+H) ⁺ . Step 3. tert-Butyl (S)-3-methyl-4-(5-(pyrrolidin-1-yl)-7-(3,4,5-trifluorophenyl )-7H- pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate At 0°C, to a solution of tert-butyl (S)-3-methyl-4-(5-(2-oxopyrrolidin-1-yl)-7-(3,4,5- trifluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine- 1-carboxylate (100 mg, 0.19 mmol) in THF (10 mL) was added LiAlH ₄ (0.57 mL, 1.0 M in THF) dropwise. The resulting mixture was stirred at 0 °C for 30 mins. The reaction mixture was quenched with ice water, the resulting mixture was extracted with EtOAc (50 ml x 2). The combined layers were washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography on silica gel (0~10% MeOH in DCM, V/V) to give the crude product. The crude product was purified by prep-HPLC to give the tert-butyl (S)-3-methyl-4-(5- (pyrrolidin-1-yl)-7-(3,4,5-trifluorophenyl)-7H-pyrrolo[2,3-d ]pyrimidin-4-yl)piperazine-1- carboxylate (3.0 mg, 3.1%) as a white solid. LC/MS ESI (m/z): 517 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H), 7.51 (dd, J = 8.8, 6.2 Hz, 2H), 6.63 (s, 1H), 4.97 (br, 1H), 4.23 – 3.87 (m, 3H), 3.38 (t, J = 12.0 Hz, 1H), 3.30 – 2.98 (m, 4H), 2.91 (br, 2H), 1.98 (br, 4H), 1.49 (s, 9H), 1.13 (s, 3H). The following compounds were prepared by the procedure similar to the synthesis of compound 356 from the corresponding aryl halides prepared following the procedure outlined in compound 340, step 1. Example 87. Synthesis of tert-butyl (S)-4-(1-(3-cyanophenyl)-3-cyclopropyl-1H- pyrazolo[3,4-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyl ate (Compound 357) C ^{ompound 357} Step 1. tert-Butyl (S)-4-(3-bromo-1-(3-cyanophenyl)-1H-pyrazolo[3,4-d]pyrimidin -4- yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl (S)-4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate (500 mg, 1.3 mmol, prepared following the procedure outlined in compound 284) in DCM (20 mL) were added (3-cyanophenyl)boronic acid (370 mg, 2.5 mmol), Cu(OAc) ₂ (560 mg, 3.1 mmol), pyridine (0.60 mL, 7.5 mmol) and 4A molecular sieves (500 mg). The resulting mixture was stirred at room temperature overnight under O ₂ atmosphere. The reaction was quenched with NH ₄ OH, diluted with DCM, and then filtered. The filtrate was extracted with DCM twice, the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, ethyl acetate in petroleum ether) to afford tert-butyl (S)-4-(3-bromo-1-(3-cyanophenyl)-1H-pyrazolo[3,4-d]pyrimidin -4-yl)-3-methylpiperazine-1- carboxylate (510 mg, 81%) as a light yellow solid. LC/MS ESI (m/z): 498,500 (M+H) ⁺ Step 2. tert-Butyl (S)-4-(1-(3-cyanophenyl)-3-cyclopropyl-1H-pyrazolo[3,4- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl (S)-4-(3-bromo-1-(3-cyanophenyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (200 mg, 0.40 mmol) in toluene (5 mL) were added cyclopropylboronic acid (52 mg, 0.60 mmol), K ₂ CO ₃ (720 mg, 5.2 mmol) and Pd-118 (13 mg, 0.020 mmol). The resulting mixture was heated to 80 ^o C overnight. After being cooled down to room temperature, solvent was filtered. The filtrate was concentrated and purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford tert-butyl (S)-4-(1-(3-cyanophenyl)-3-cyclopropyl-1H-pyrazolo[3,4-d]pyr imidin-4-yl)-3- methylpiperazine-1-carboxylate (110 mg, 58 % )as a white solid. LC/MS ESI (m/z): 460 (M+H) ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ 8.64 (s, 1H), 8.55 – 8.51 (m, 1H), 8.43 (s, 1H), 7.69 – 7.62 (m, 2H), 5.02 (s, 1H), 4.38 (d, J = 13.1 Hz, 1H), 4.15 (d, J = 11.8 Hz, 1H), 4.00 – 3.95 (m, 1H), 3.63 – 3.55 (m, 1H), 3.27 – 3.01 (m, 2H), 2.20 – 2.14 (m, 1H), 1.50 (s, 9H), 1.33 (d, J = 6.6 Hz, 3H), 1.29 – 1.25 (m, 2H), 1.19 – 1.15 (m, 2H). Example 88. Synthesis of 1,1,1-trifluoro-2-methylpropan-2-yl (S)-4-(7-cyclohexyl-5- (pyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylp iperazine-1-carboxylate (Compound 359) C ^{ompound 359} Step 1. (S)-7-Cyclohexyl-4-(2-methylpiperazin-1-yl)-5-(pyrrolidin-1- yl)-7H- pyrrolo[2,3-d]pyrimidine To a solution of tert-butyl (S)-4-(7-cyclohexyl-5-(pyrrolidin-1-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (50 mg, 0.11 mmol, prepared following the procedure of compound 334, step 1) in DCM (1 mL) was added HCl/dioxane (1.0 mL, 4.0 M). The resulting mixture was stirred at room temperature overnight. After removal of solvent under reduced pressure, the residue was used in the next step directly. (S)-7- cyclohexyl-4-(2-methylpiperazin-1-yl)-5-(pyrrolidin-1-yl)-7H -pyrrolo[2,3-d]pyrimidine (30 mg, 74%) . LC/MS ESI (m/z): 369 (M+H) ⁺ . Step 2.1,1,1-Trifluoro-2-methylpropan-2-yl (S)-4-(7-cyclohexyl-5-(pyrrolidin-1-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carbox ylate To a solution of (S)-7-cyclohexyl-4-(2-methylpiperazin-1-yl)-5-(pyrrolidin-1- yl)-7H- pyrrolo[2,3-d]pyrimidine (30 mg, 0.080 mmol) in DMF (0.5 mL) were added 1,1,1-trifluoro- 2-methylpropan-2-yl 1H-imidazole-1-carboxylate (88 mg, 0.40 mmol, prepared following the procedure of compound 247, step 1). The reaction mixture was stirred at 80 ^o C overnight under N ₂ . The reaction was quenched with water, extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by prep-HPLC to afford 1,1,1-trifluoro-2-methylpropan-2-yl (S)-4-(7- cyclohexyl-5-(pyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)-3-methylpiperazine-1- carboxylate (2.6 mg, 6.2% yield) as a white solid. LC/MS ESI (m/z): 523 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.32 (s, 1H), 6.54 (s, 1H), 5.10 – 4.88 (m, 1H), 4.78 – 4.58 (m, 1H), 4.27 – 3.94 (m, 2H), 3.94 – 3.77 (m, 1H), 3.45 – 3.21 (m, 2H), 3.18 – 2.93 (m, 3H), 2.91 – 2.71 (m, 2H), 2.09 – 1.99 (m, 2H), 1.99 – 1.82 (m, 6H), 1.80 – 1.74 (m, 1H), 1.69 – 1.61 (m, 2H), 1.58 (s, 6H), 1.55 – 1.46 (m, 2H), 1.27 – 1.23 (m, 1H), 1.11 (d, J = 6.6 Hz, 3H). ¹⁹ F NMR (377 MHz, CDCl ₃ ) δ -83.86 (d, J = 36.1 Hz). Example 89. Synthesis of tert-butyl (R)-2-methyl-4-(5-(pyrrolidin-1-yl)-7-(3,4,5- trifluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine- 1-carboxylate (Compound 362) C ^{ompound 362} Step 1. tert-Butyl (R)-2-methyl-4-(5-(2-oxopyrrolidin-1-yl)-7-(3,4,5-trifluorop henyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate To the solution of tert-butyl (R)-4-(5-iodo-7-(3,4,5-trifluorophenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate (300 mg, 0.52 mmol, prepared following a similar procedure outlined in compound 356) in DMF (2 mL) were added CuI (49 mg, 0.26 mmol), K ₃ PO ₄ (330 mg, 1.6 mmol), trans-cyclohexane-1,2-diamine (0.020 mL, 0.16 mmol) and pyrrolidin-2-one (0.080 mL, 1.1 mmol) respectively. The resulting reaction mixture was stirred at 120℃ under N ₂ overnight. After being cooled down to room temperature, the reaction mixture was diluted with ice water, then it was extracted with EtOAc twice, the combined organic layers were washed with and brine, dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to afford tert-butyl (R)- 2-methyl-4-(5-(2-oxopyrrolidin-1-yl)-7-(3,4,5-trifluoropheny l)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)piperazine-1-carboxylate (150 mg, 54%) as yellow solid. LC/MS ESI (m/z): 531 (M+H) ⁺ . Step 2. tert-Butyl (R)-2-methyl-4-(5-(pyrrolidin-1-yl)-7-(3,4,5-trifluorophenyl )-7H- pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate To the solution of tert-butyl (R)-2-methyl-4-(5-(2-oxopyrrolidin-1-yl)-7-(3,4,5- trifluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine- 1-carboxylate (140 mg, 0.26 mmol) in THF (2 mL) was added BH ₃ (5.0 mL, 1.0M in THF) at 0℃ under N ₂ . The resulting reaction mixture was stirred at 0℃ for 1 h. The reaction mixture was quenched with ice water, extracted with EtOAc twice. The combined organic layers were dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The crude product was purified by prep- HPLC to obtain tert-butyl (R)-2-methyl-4-(5-(pyrrolidin-1-yl)-7-(3,4,5-trifluorophenyl )-7H- pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (30 mg, 23%) as yellow solid. LC/MS ESI (m/z): 517 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.36 (s, 1H), 7.54 – 7.48 (m, 2H), 6.64 (s, 1H), 4.76 (d, J = 12.8 Hz, 1H), 4.41 – 4.34 (m, 2H), 3.92 (d, J = 13.3 Hz, 1H), 3.35 – 3.20 (m, 4H), 3.00 – 2.93 (m, 1H), 2.88 – 2.82 (m, 2H), 2.01 – 1.97 (m, 4H), 1.49 (s, 9H), 1.09 (d, J = 6.8 Hz, 3H). Example 90. Synthesis of tert-butyl (3S)-4-(7-(4-cyanopyridin-2-yl)-5-(2,2- difluorocyclopropyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-meth ylpiperazine-1- carboxylate (Compound 365) Step 1. tert-Butyl (S)-4-(5-bromo-7-(4-cyanopyridin-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl (S)-4-(5-bromo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate (900 mg, 2.3 mmol, prepared following the analogous procedure of compound 399) in DMF (5 mL) was added 2-bromoisonicotinonitrile (1.7 g, 9.1 mmol), trans-N,N’-dimethylcyclohexane-1,2-diamine (650 mg, 4.6 mmol), CuI (430 mg, 2.3 mmol) and K ₃ PO ₄ (1.5 g, 6.8 mmol). The resulting mixture was heated at 100 ^o C for 1 h. After cooling down to room temperature, the reaction was partitioned between EtOAc and water, organic layer was separated, aqueous layer was extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated, the residue was purified by flash column chromatography (silica gel, 0~25%, ethyl acetate in petroleum ether) to afford tert-butyl (S)-4-(5-bromo-7-(4-cyanopyridin-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (800 mg, 70 %) as a solid. LC/MS ESI (m/z): 498 (M+H) ⁺ . Step 2. tert-Butyl (S)-4-(7-(4-cyanopyridin-2-yl)-5-vinyl-7H-pyrrolo[2,3-d]pyri midin- 4-yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl (S)-4-(5-bromo-7-(4-cyanopyridin-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (500 mg, 1.0 mmol) in dioxane (5 mL) and H ₂ O (1 mL) was added potassium trifluoro(vinyl)borate (270 mg, 2.0 mmol), K ₂ CO ₃ (410 mg, 3.0 mmol) and Pd(dppf)Cl ₂ (73 mg, 0.10 mmol). The resulting mixture was heated at 90 ^o C overnight under N ₂ . After cooling down to room temperature, the solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~20%, ethyl acetate in petroleum ether) to afford tert-butyl (S)-4-(7-(4-cyanopyridin-2-yl)-5-vinyl- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carbox ylate (260 mg, 58 %) as a solid. LC/MS ESI (m/z): 446(M+H) ⁺ . Step 3. tert-Butyl (3S)-4-(7-(4-cyanopyridin-2-yl)-5-(2,2-difluorocyclopropyl)- 7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te To a solution of tert-butyl (S)-4-(7-(4-cyanopyridin-2-yl)-5-vinyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (100 mg, 0.22 mmol) in THF (5 mL) was added trimethyl(trifluoromethyl)silane (380 mg, 2.6 mmol), NaI (130 mg, 0.88 mmol). The resulting mixture was heated at 100 ^o C for 2 hours in a microwave. After cooling down to room temperature, the solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford tert-butyl (3S)- 4-(7-(4-cyanopyridin-2-yl)-5-(2,2-difluorocyclopropyl)-7H-py rrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate (90 mg, 81 %) as a solid, 90 mg of which was further purified by prep-HPLC to afford 65 mg of white solid. LC/MS ESI (m/z): 496(M+H) ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ 9.24 – 9.18 (m, 1H), 8.70 – 8.66 (m, 1H), 8.52 (d, J = 6.0 Hz, 1H), 8.13 (d, J = 11.6 Hz, 1H), 7.60 – 7.55 (m, 1H), 4.52 – 4.44 (m, 1H), 4.08 – 3.97 (m, 1H), 3.85 – 3.02 (m, 6H), 2.05 – 1.75 (m, 2H), 1.50 (s, 9H), 1.26 – 1.14 (m, 3H). The following compound was prepared by a procedure analogous to the synthesis of compound 365 using the appropriate aryl halide.

Example 91. Synthesis of tert-butyl (S)-4-(7-(3-chlorophenyl)-5-(diethylamino)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (Compound 366) C ^{ompound 366} Step 1. Methyl (S)-4-(4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)-7-(3- chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-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 (100 mg, 0.18 mmol, prepared following an analogous procedure to compound 114 in MeOH (2.0 mL) was added Pd(dppf)Cl ₂ (13 mg, 0.018 mmol ) at 25°C. The mixture was degassed with CO three times. The mixture was heated at 80°C under CO (15 psi) for 8 hrs. The mixture was poured into H ₂ O (20 mL) and extracted with EtOAc twice. The combined organic phases were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The methyl (S)-4-(4-(tert-butoxycarbonyl)- 2-methylpiperazin-1-yl)-7-(3-chlorophenyl)-7H-pyrrolo[2,3-d] pyrimidine-5-carboxylate (70 mg) was obtained as a brown solid. LC/MS ESI (m/z): 486 (M+H) ⁺ . Step 2. (S)-4-(4-(tert-Butoxycarbonyl)-2-methylpiperazin-1-yl)-7-(3- chlorophenyl)- 7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid To a solution of methyl (S)-4-(4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)-7-(3- chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate in MeOH (10 mL) was added NaOH (10 mL, 2.0N) at 25°C. The mixture was stirred at 80°C for 12 hrs. The pH was adjusted to 2 with dilute HCl (1 N). The mixture was extracted with DCM (20 mL x 4) and concentrated in vacuo. The crude product was used in next step directly. Step 3. tert-Butyl (S)-4-(5-(((benzyloxy)carbonyl)amino)-7-(3-chlorophenyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te To a solution of tert-butyl (S)-4-(7-(3-chlorophenyl)-5-(diethylamino)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (100 mg, 0.21 mmol) in toluene (10 mL) were added benzyl alcohol (0.026 mL, 0.25 mmol), triethylamine (0.032 mL, 0.23 mmol) and DPPA (0.050 mL, 0.23 mmol) at 25°C. The mixture was degassed with N ₂ three times. The mixture was stirred at 80°C for 12 hrs. The mixture was then cooled to 25°C, poured into H ₂ O (20 mL) and extracted with EtOAc twice. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel column (SiO ₂ , eluting with Pet ether : EtOAc = 50 : 1 to 30 : 1, Rf = 0.50) to afford tert-butyl (S)-4-(5-(((benzyloxy)carbonyl)amino)-7-(3- chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiper azine-1-carboxylate (100 mg) as a brown solid. LC/MS ESI (m/z): 577 (M+H) ⁺ . Step 4. tert-Butyl (S)-4-(5-(((benzyloxy)carbonyl)(ethyl)amino)-7-(3-chlorophen yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carbox ylate To a solution of tert-butyl (S)-4-(5-(((benzyloxy)carbonyl)amino)-7-(3-chlorophenyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carbox ylate (50 mg, 0.087 mmol ) in THF (2.0 mL) was added NaH (3.6 mg, 0.091 mmol ) at 0°C. The mixture was stirred at 0 ^o C~25 °C for 1 hr. Then, EtI (0.0070 mL, 0.091 mmol) was added to the mixture at 25°C. The mixture was stirred at 25°C for 8 h. The mixture was poured into H ₂ O (20 mL) and extracted with EtOAc twice. The combine organic phases were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo. tert-Butyl (S)-4-(5- (((benzyloxy)carbonyl)(ethyl)amino)-7-(3-chlorophenyl)-7H-py rrolo[2,3-d]pyrimidin-4-yl)- 3-methylpiperazine-1-carboxylate (50 mg) was obtained as a brown solid which was used in next step directly. LC/MS ESI (m/z): 605 (M+H) ⁺ . Step 5. tert-Butyl (S)-4-(7-(3-chlorophenyl)-5-(ethylamino)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl (S)-4-(5-(((benzyloxy)carbonyl)(ethyl)amino)-7-(3- chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiper azine-1-carboxylate (150 mg, 0.25 mmol ) in DCM (5 mL) were added TEA (0.028 mL, 0.20 mmol), Et ₃ SiH (0.16 mL, 0.99 mmol), and PdCl ₂ (44 mg, 0.25 mmol) at 25°C. The mixture was stirred at 25°C for 0.5 hrs. After the LCMS showed that tert-butyl (S)-4-(5-(((benzyloxy)carbonyl)(ethyl)amino)-7- (3-chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpi perazine-1-carboxylate was consumed, the mixture was filtered and the product in DCM was used directly in the next step. LC/MS ESI (m/z): 471 (M+H) ⁺ . Step 6. tert-Butyl (S)-4-(7-(3-chlorophenyl)-5-(N-ethylacetamido)-7H-pyrrolo[2, 3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate Acetyl chloride (0.088 mL, 1.2 mmol) was added to tert-butyl (S)-4-(7-(3- chlorophenyl)-5-(ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl )-3-methylpiperazine-1- carboxylate (120 mg, 0.25 mmol ) at 25°C. The mixture was stirred at 25°C for 12 h. The mixture was poured into H ₂ O (20 mL) and extracted with EtOAc twice. The combined organic phases were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by Prep-HPLC and tert-butyl (S)-4-(7-(3- chlorophenyl)-5-(N-ethylacetamido)-7H-pyrrolo[2,3-d]pyrimidi n-4-yl)-3-methylpiperazine- 1-carboxylate (30 mg) was obtained as a white solid. LC/MS ESI (m/z): 513 (M+H) ⁺ . Step 7. tert-Butyl (S)-4-(7-(3-chlorophenyl)-5-(diethylamino)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl (S)-4-(7-(3-chlorophenyl)-5-(N-ethylacetamido)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (13 mg, 0.025 mmol) in THF (2.0 mL) was added BH ₃ -THF (0.050 mL, 1.0M in THF) at 0°C under N ₂ . The mixture was stirred at 0°C for 2 h. MeOH (5.0 ml) was added to the mixture at 0 °C and stirred for 0.5 hr. The mixture was poured into H ₂ O (100 mL) and extracted with EtOAc twice. The combined organic phases were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo. The crude product was purified by prep-HPLC and tert-butyl (S)-4-(7- (3-chlorophenyl)-5-(diethylamino)-7H-pyrrolo[2,3-d]pyrimidin -4-yl)-3-methylpiperazine-1- carboxylate (2.8 mg, 24%) was obtained as a white solid. LC/MS ESI (m/z): 499 (M+H) ^{+ 1} H NMR (400 MHz, CDCl ₃ ) δ 8.39 (s, 1H), 7.71 (s, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.43 (t, J = 8.1 Hz, 1H), 7.30 (d, J = 7.4 Hz, 1H), 6.80 (s, 1H), 5.14 (s, 1H), 4.33 – 3.80 (m, 3H), 3.58 – 3.24 (m, 2H), 3.20 – 2.97 (m,5H), 1.56 (s, 9H), 1.18 (s, 3H), 1.02 (t, J = 7.0 Hz, 6H). The following compound was prepared by a procedure analogous to the synthesis of compound 366, using the appropriate piperazine or amine. Example 92. Synthesis of 2,2,2-trifluoroethyl (S)-4-(7-(4-cyanopyridin-2-yl)-5- cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperaz ine-1-carboxylate (Compound 368) Step 1.2,2,2-Trifluoroethyl 1H-imidazole-1-carboxylate To a solution of 2,2,2-trifluoroethan-1-ol (500 mg, 5.0 mmol) in DCM (5 mL) was added di(1H-imidazol-1-yl)methanone (980 mg, 6.0 mmol). The resulting mixture was stirred at rt overnight. The reaction was then quenched with water, extracted with DCM twice, the combined organic layers washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to afford 2,2,2-trifluoroethyl 1H-imidazole-1-carboxylate (650 mg, 67%) as a white solid. LC/MS ESI (m/z): 195 (M+H) ⁺ . Step 2. (S)-2-(5-Cyclopropyl-4-(2-methylpiperazin-1-yl)-7H-pyrrolo[2 ,3-d]pyrimidin- 7-yl)isonicotinonitrile To a 0 ^o C solution of tert-butyl (S)-4-(7-(4-cyanopyridin-2-yl)-5-cyclopropyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (100 mg, 0.22 mmol, prepared following a similar procedure outlined in compound 259) in DCM (5 ml) was added HCl (2.0 mL, 4.0M in dioxane). The resulting mixture was stirred at the same temperature for 3 h. The reaction was quenched with NaHCO ₃ (aq.), extracted with DCM twice, the combined organic layers washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was used in the next step directly. (S)-2-(5-cyclopropyl-4-(2-methylpiperazin-1- yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)isonicotinonitrile. LC/MS ESI (m/z): 360 (M+H) ⁺ . Step 3.2,2,2-Trifluoroethyl (S)-4-(7-(4-cyanopyridin-2-yl)-5-cyclopropyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te To a solution of (S)-2-(5-cyclopropyl-4-(2-methylpiperazin-1-yl)-7H-pyrrolo[2 ,3- d]pyrimidin-7-yl)isonicotinonitrile (50 mg, 0.14 mmol) in DMF (3 mL) was added 2,2,2- trifluoroethyl 1H-imidazole-1-carboxylate (32 mg, 0.17 mmol) and DIPEA (0.040 mL, 0.22 mmol). The resulting mixture was stirred at 50 ^o C overnight. After cooling down to room temperature, the reaction was quenched with water, extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep- HPLC to afford 2,2,2-trifluoroethyl (S)-4-(7-(4-cyanopyridin-2-yl)-5-cyclopropyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (15 mg , 23 %) as a white solid. LC/MS ESI (m/z): 486 (M+H) ⁺ . ¹ H NMR(400 MHz, CD ₃ OD) δ 9.21 – 9.17 (s, 1H), 8.65 (d, J = 5.0, 0.8 Hz, 1H), 8.47 (s, 1H), 7.86 (d, J = 0.7 Hz, 1H), 7.53 (dd, J = 5.0, 1.3 Hz, 1H), 4.76 (m, 1H), 4.63 (m, J = 33.3 Hz, 2H), 4.12 (m, 1H), 3.93 (m, J = 12.8 Hz, 2H), 3.64 – 3.56 (m, 1H), 3.55 – 3.44 (m, 1H), 3.36 - 3.24 (m, 1H), 2.09 (m, 1H), 1.22 (d, J = 6.6 Hz, 3H), 1.07 (dt, J = 4.7, 3.8 Hz, 2H), 0.90 – 0.84 (m, 1H), 0.79 – 0.72 (m, 1H). The following compound was prepared analogous to the synthesis of compound 368 using the corresponding alcohol.

Example 93. Synthesis of 2,2,2-trifluoroethyl 4-(7-(4-cyanopyridin-2-yl)-5-(2- fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-c arboxylate (Compound 373) C ^{ompound 373} Step 1. tert-Butyl-4-(5-(2-fluorophenyl)-7-tosyl-7H-pyrrolo[2,3-d]py rimidin-4- yl)piperazine-1-carboxylate A suspension of tert-butyl-4-[5-iodo-7-(4-methylbenzenesulfonyl)-7H-pyrrolo[ 2,3- d]pyrimidin-4-yl]piperazine-1-carboxylate (2.3 g, 4.0 mmol, prepared according to the procedure outlined in compound 146, (2-fluorophenyl)boronic acid (0.61 g, 4.4 mmol), K ₂ CO ₃ (1.1 g, 8.0 mmol) and Pd(dppf)Cl ₂ (0.29 g, 0.40 mmol) in dioxane-water (18 mL; 5:1 mixture) was stirred at 95℃ under N ₂ atmosphere for 18h, after which the mixture was cooled to room temperature and concentrated. The residue was partitioned between water and EtOAc, organic layer was separated, aqueous layer was extracted by EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated. The residue was used directly in the next step without further purification. LC/MS (ESI) (m/z): 552 (M+H) ⁺ Step 2. tert-Butyl-4-(5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)piperazine- 1-carboxylate To a solution of tert-butyl-4-[5-(2-fluorophenyl)-7-(4-methylbenzenesulfonyl) -7H- pyrrolo[2,3-d]pyrimidin-4-yl]piperazine-1-carboxylate (1.8 g, 3.3 mmol) in THF(15 mL) was added 1.0M TBAF(6.5 mL, 6.5 mmol) and the resulting mixture stirred for 18h. The reaction mixture was concentrated and partitioned between water and EtOAc. The organic layers were separated, and the aqueous layer was extracted with EtOAc twice. The combined organic phases were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (silica gel, 0~20% MeOH in DCM) to give tert-butyl-4- [5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]piperazi ne-1-carboxylate (1.2 g, 92 %) as a white solid. LC/MS (ESI) (m/z): 398 (M+H) ⁺ Step 3. tert-Butyl-4-(7-(4-cyanopyridin-2-yl)-5-(2-fluorophenyl)-7H- pyrrolo[2,3- d]pyrimidin-4-yl)piperazine-1-carboxylate A suspension of tert-butyl-4-[5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin- 4- yl]piperazine-1-carboxylate (1.2 g, 3.0 mmol), 2-bromopyridine-4-carbonitrile (0.66 g, 3.6 mmol), K ₃ PO ₄ (1.3 g, 6.0 mmol ), CuI (0.17 g, 0.90 mmol) and trans-1,2- diaminocyclohexane (0.10 g, 0.90 mmol) in DMF (30 mL) was stirred at 120℃ under N ₂ atmosphere for 18h. After cooling down to room temperature, the reaction mixture was partitioned between EtOAc and water, organic layer separated, and aqueous layer was extracted with EtOAc twice. The combined organic phases were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography on silica gel (0~10% MeOH in DCM) to give tert-butyl-4-[7-(4- cyanopyridin-2-yl)-5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrim idin-4-yl]piperazine-1- carboxylate (1.0 g, 66 %) as a white solid. LC/MS (ESI) (m/z): 500 (M+H) ⁺ Step 4.2-(5-(2-Fluorophenyl)-4-(piperazin-1-yl)-7H-pyrrolo[2,3-d] pyrimidin-7- yl)isonicotinonitrile To a solution of tert-butyl-4-[7-(4-cyanopyridin-2-yl)-5-(2-fluorophenyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl]piperazine-1-carboxylate (1.0 g, 2.0 mmol) in DCM (5.0 mL) was added TFA (4.5 mL, 60 mmol), the reaction was stirred at rt for 3h. The mixture was then partitioned between EtOAc and saturated Na ₂ CO ₃ solution. The organic layer was separated and the aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated. The residue was used directly in next step without further purification. LC/MS ESI (m/z): 400 (M+H) ⁺ Step 5.2,2,2-Trifluoroethyl 4-(7-(4-cyanopyridin-2-yl)-5-(2-fluorophenyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate To a solution of 2,2,2-trifluoroethyl-1H-imidazole-1-carboxylate (58 mg, 0.30 mmol ， prepared following the procedure outlined in compound 254) in DCM (5 mL) was added a solution of 2-[5-(2-fluorophenyl)-4-(piperazin-1-yl)-7H-pyrrolo[2,3-d]py rimidin-7- yl]pyridine-4-carbonitrile (80 mg, 0.20 mmol, prepared from alcohol and CDI), and the resulting mixture was stirred at room temperature overnight. The residue was suspended in water and DCM. The organic layer was separated and the aqueous layer was extracted by DCM twice. The combined organic phases were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by prep-HPLC to give 2,2,2- trifluoroethyl 4-(7-(4-cyanopyridin-2-yl)-5-(2-fluorophenyl)-7H-pyrrolo[2,3 -d]pyrimidin-4- yl)piperazine-1-carboxylate (18 mg, 17 %) as a white solid. LC/MS (ESI) (m/z): 526 (M+H) ^{+ 1} H NMR (400 MHz, CDCl ₃ ) δ 9.40 (s, 1H), 8.63 (d, J = 5.0 Hz, 1H), 8.60 (s, 1H), 8.32 (s, 1H), 7.48 (td, J = 7.5, 1.5 Hz, 1H), 7.39 (ddd, J = 9.4, 6.1, 1.4 Hz, 2H), 7.29 – 7.19 (m, 2H), 4.45 (q, J = 8.5 Hz, 2H), 3.29 (d, J = 18.5 Hz, 8H).

Example 94. Synthesis of tert-butyl (S)-4-(7-(3,5-difluoro-4-methylphenyl)-5-(pyrrolidin- 1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1- carboxylate (Compound 374) C ^{ompound 374} Step 1. tert-Butyl (S)-4-(7-(3,5-difluoro-4-methylphenyl)-7H-pyrrolo[2,3-d]pyri midin- 4-yl)-3-methylpiperazine-1-carboxylate A mixture of tert-butyl (S)-4-(5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate (300 mg, 0.68 mmol), 5-bromo-1,3-difluoro-2- methylbenzene (280 mg, 1.4 mmol), CuI (64 mg, 0.34 mmol), trans-1,2-diaminocyclohexane (23 mg, 0.20 mmol ) and K ₃ PO ₄ (430 mg, 2.0 mmol ) in DMF (10 mL) was heated at 120°C for 12 hours. The reaction mixture was concentrated to a residue. The residue was purified by column chromatography (silica gel, 0~30% EtOAc in Pet Ether) to give tert-butyl (S)-4-(7- (3,5-difluoro-4-methylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-y l)-3-methylpiperazine-1- carboxylate (260 mg, 85 %) as a yellow solid. LC/MS ESI (m/z): 444 (M+H) ⁺ . Step 2. tert-Butyl (S)-4-(5-bromo-7-(3,5-difluoro-4-methylphenyl)-7H-pyrrolo[2, 3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a 0°C mixture of tert-butyl (S)-4-(7-(3,5-difluoro-4-methylphenyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (200 mg, 0.45 mmol) in DMF (10 mL) was added NBS (96 mg, 0.54 mmol) in portions. The resulting mixture was stirred at room temperature for 1 hr. The reaction mixture diluted with water, extracted with EtOAc (50 mL X 2). The combined layers were washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (silica gel, 0~20% EtOAc in Pet Ether) to give the tert-butyl (S)-4-(5-bromo-7-(3,5-difluoro-4-methylphenyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (100 mg, 42 %) as a yellow solid. LC/MS ESI (m/z): 522, 524 (M+H) ⁺ . Step 3. tert-Butyl (S)-4-(7-(3,5-difluoro-4-methylphenyl)-5-(2-oxopyrrolidin-1- yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te A mixture of tert-butyl (S)-4-(5-bromo-7-(3,5-difluoro-4-methylphenyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (100 mg, 0.19 mmol), pyrrolidin-2-one (33 mg, 0.38 mmol), CuI (18 mg, 0.10 mmol), trans-1,2- diaminocyclohexane (6.6 mg, 0.060 mmol) and K ₃ PO ₄ (120 mg, 0.57 mmol) in DMF (10 mL) was heated at 120°C for 12 hours. The reaction mixture was concentrated and the residue was purified by column chromatography (silica gel, 0~100% EtOAc in Pet Ether) to give the tert-butyl (S)-4-(7-(3,5-difluoro-4-methylphenyl)-5-(2-oxopyrrolidin-1- yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (50 mg, 50 %) as a yellow solid. LC/MS ESI (m/z): 527 (M+H) ⁺ . Step 4. tert-Butyl (S)-4-(7-(3,5-difluoro-4-methylphenyl)-5-(pyrrolidin-1-yl)-7 H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te To a 0°C solution of tert-butyl (S)-4-(7-(3,5-difluoro-4-methylphenyl)-5-(2- oxopyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methy lpiperazine-1-carboxylate (50 mg, 0.10 mmol) in THF (5 mL), B ₂ H ₆ (2.0 mL, 1.0M in THF) was added dropwise. The resulting mixture was stirred at room temperature for 2 hrs. The reaction mixture was quenched with ice water, the resulting mixture was extracted with EtOAc (50 ml X 2). The combined layers were washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography on silica gel (0~50% EtOAc in Pet Ether) to give the crude product, which was further purified by HPLC to give the tert-butyl (S)-4-(7-(3,5- difluoro-4-methylphenyl)-5-(pyrrolidin-1-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate (11 mg, 21 %) as yellow solid. LC/MS ESI (m/z): 513 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.37 (s, 1H), 7.34 (d, J = 7.9 Hz, 2H), 6.67 (s, 1H), 4.97 (br, 1H), 4.29 – 3.83 (m, 3H), 3.50 – 3.09 (m, 4H), 2.91 (broad s, 3H), 2.22 (s, 3H), 1.99 (m, 4H), 1.49 (s, 9H), 1.14 (s, 3H). Example 95. Synthesis of 2,2,2-trifluoroethyl (R)-4-(7-(4-cyanopyridin-2-yl)-5- cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperaz ine-1-carboxylate (Compound 377) C ^{ompound 377} Step 1. (R)-4-(7-(4-Cyanopyridin-2-yl)-5-cyclopropyl-7H-pyrrolo[2,3- d]pyrimidin-4- yl)-2-methylpiperazine-1-carbonyl chloride To a 0 ^o C solution of (R)-2-(5-cyclopropyl-4-(3-methylpiperazin-1-yl)-7H-pyrrolo[2 ,3- d]pyrimidin-7-yl)isonicotinonitrile (40 mg, 0.11 mmol, prepared following the procedure outlined in compound 368) in DCM (5 mL) was added DIPEA (28 mg, 0.22 mmol), followed by a solution of triphosgene (22 mg, 0.070 mmol) in DCM (1 mL) dropwise. The resulting mixture was stirred at 0 ^o C for 2 hours under N ₂ . Solvent was removed and the residue was used in the next step directly. LC/MS ESI (m/z): 422 (M+H) ⁺ . Step 2.2,2,2-Trifluoroethyl(R)-4-(7-(4-cyanopyridin-2-yl)-5-cyclo propyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxyla te A solution of (R)-4-(7-(4-cyanopyridin-2-yl)-5-cyclopropyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2-methylpiperazine-1-carbonyl chloride (0.11 mmol) in 2,2,2- trifluoroethan-1-ol (3 mL) was heated to 70 ^o C overnight under N ₂ . After cooling down to room temperature, the solvent was removed in vacuo and the residue purified by flash column chromatography (silica gel, 30% ethyl acetate in petroleum ether) and then by prep- HPLC to afford 2,2,2-trifluoroethyl(R)-4-(7-(4-cyanopyridin-2-yl)-5-cyclopr opyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxyla te (10 mg, 19% over 2 steps) as a white solid. LC/MS ESI (m/z): 486 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.32 (s, 1H), 8.59 (dd, J = 5.0, 0.7 Hz, 1H), 8.51 (s, 1H), 7.82 (d, J = 0.7 Hz, 1H), 7.35 (dd, J = 5.0, 1.3 Hz, 1H), 4.61 – 4.46 (m, 4H), 4.19 – 4.12 (m, 1H), 4.04 (d, J = 12.8 Hz, 1H), 3.56 – 3.48 (m, 1H), 3.39 (dd, J = 13.1, 3.9 Hz, 1H), 3.12 (td, J = 12.5, 3.3 Hz, 1H), 2.04 – 1.98 (m, 1H), 1.27 (d, J = 6.8 Hz, 3H), 1.09 – 1.03 (m, 2H), 1.01 – 0.95 (m, 1H), 0.75 – 0.69 (m, 1H). The following compound was prepared by using an analogous protocol to compound 377 using the appropriate alcohol. Example 96. Synthesis of tert-butyl (S)-4-(7-(4-cyanopyridin-2-yl)-5-morpholino-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (Compound 380) C ^{ompound 380} Step 1. tert-Butyl (S)-4-(7-(4-chloropyridin-2-yl)-5-(3-oxomorpholino)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te To a solution of tert-butyl (S)-4-(5-bromo-7-(4-chloropyridin-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (300 mg, 0.59 mmol, prepared according to the procedure outlined for compound 388) in DMF (8.0 mL) was added CuI (0.020 mL, 0.59 mmol), K ₃ PO ₄ (250 mg, 1.2 mmol) and trans-N,N’-dimethyl-1,2- cyclohexyldiamine (170 mg, 1.2 mmol) at 25°C. The mixture was degassed under N ₂ three times. The mixture was stirred at 95°C for 16 h. The mixture was then cooled, poured into H ₂ O (100 mL) and extracted with EtOAc twice. The combined organic phases were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, petroleum ether: EtOAc = 20 : 1 to 10 : 1) to afford tert-butyl (S)-4-(7-(4-chloropyridin-2-yl)-5-(3-oxomorpholino)-7H-pyrro lo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (30 mg) as a yellow solid. LC/MS ESI (m/z): 528 (M+H) ⁺ . Step 2. tert-Butyl (S)-4-(7-(4-chloropyridin-2-yl)-5-morpholino-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl (S)-4-(7-(4-chloropyridin-2-yl)-5-(3-oxomorpholino)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (30 mg, 0.057 mmol ) in THF (2.0 mL) was added BH ₃ -THF (2.0 mL, 1.0M) at 0°C. The mixture was stirred at 0°C for 1 h. The reaction was then quenched by addition of MeOH (5.0 ml) at 0 °C and was then stirred at 25°C for 0.5 hr. The mixture was concentrated in vacuo and the residue purified by flash chromatography (silica gel column, petroleum ether:EtOAc = 50 : 1 to 30 : 1) to afford tert-butyl (S)-4-(7-(4-chloropyridin-2-yl)-5-morpholino-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate (20 mg) as a yellow oil. LC/MS ESI (m/z): 514 (M+H) ⁺ . Step 3. tert-Butyl (S)-4-(7-(4-cyanopyridin-2-yl)-5-morpholino-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl (S)-4-(7-(4-chloropyridin-2-yl)-5-morpholino-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (50 mg, 0.097 mmol) in DMF (10.0 mL) was added Zn(CN) ₂ (230 mg, 2.0 mmol ) and Pd(PPh ₃ ) ₄ (110 mg, 0.097 mmol ) at 25°C. The mixture was degassed under N ₂ three times and stirred at 120°C for 12 h. The mixture was then cooled to rt and poured into H ₂ O (10 mL) and extracted with EtOAc twice. The combined organic phases were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo. The crude product was purified by Prep-HPLC to afford tert-butyl (S)-4-(7-(4-cyanopyridin-2-yl)-5-morpholino-7H-pyrrolo[2,3-d ]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate (3.0 mg, 6.0%) as a yellow solid. LC/MS ESI (m/z): 505 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 9.14 (s, 1H), 8.73 (d, J = 5.0 Hz, 1H), 8.45 (s, 1H), 7.71 (dd, J = 5.1, 1.3 Hz, 1H), 7.64 (s, 1H), 5.01 (s, 1H), 4.20 (d, J = 14.5 Hz, 1H), 4.06 – 3.91 (m, 2H), 3.80 (M, 5H), 3.07 – 2.76 (m, 6H), 1.42 (s, 9H), 1.04 (d, 3H). The following compounds were prepared by an analogous procedure to compound 380 varying the corresponding amides.

Example 97. Synthesis of tert-butyl (3S)-4-(5-cyclopropyl-7-(3,3-difluorocyclohexyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (Compound 382) C ^{ompound 382} To a solution of tert-butyl (3S)-4-[7-(3,3-difluorocyclohexyl)-5-iodo-7H-pyrrolo[2,3- d]pyrimidin-4-yl]-3-methylpiperazine-1-carboxylate (50 mg, 0.090 mmol, prepared following the procedure outlined in compound 401) in toluene (5 mL) was added cyclopropylboronic acid (7.7 mg, 0.090 mmol), 1,1'-Bis (di-t-butylphosphino)ferrocene palladium dichloride (12 mg, 0.020 mmol) and K ₂ CO ₃ (250 mg, 1.8 mmol). The resulting mixture was heated at 80℃ overnight. After cooling down to room temperature, solvent was removed and the residue was purified by flash column chromatography to afford tert-butyl (3S)-4-(5-cyclopropyl-7- (3,3-difluorocyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate (20 mg, 47 %) as a solid. LC/MS ESI (m/z): 476.6 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.38 (s, 1H), 6.65 (s, 1H), 4.91 – 4.80 (m, 1H), 4.77 – 4.66 (m, 1H), 4.16 – 3.76 (m, 3H), 3.60 – 3.44 (m, 1H), 3.41 – 2.99 (m, 2H), 2.54 – 2.42 (m, 1H), 2.35 – 2.14 (m, 2H), 2.12 – 1.89 (m, 3H), 1.87 – 1.69 (m, 3H), 1.49 (s, 9H), 1.25 – 1.16 (m, 3H), 0.99 – 0.92 (m, 2H), 0.78 – 0.58 (m, 2H).

Example 98. Synthesis of tert-butyl (S)-4-(7-(bicyclo[2.2.2]octan-1-yl)-5-(pyrrolidin-1- yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-ca rboxylate (Compound 383) Step 1.7-(Bicyclo[2.2.2]octan-1-yl)-4-chloro-7H-pyrrolo[2,3-d]pyr imidine To a solution of 2-(4,6-dichloropyrimidin-5-yl)acetaldehyde (340 mg, 1.8 mmol) in EtOH (20 mL) was added bicyclo[2.2.2]octan-1-amine hydrochloride (240 mg, 1.5 mmol) and TEA (610 mg, 0.83 mL, 6.0 mmol). The resulting mixture was stirred at 80℃ under N ₂ atmosphere for 2h. The solvent was removed, the residue extracted with EtOAc twice, the combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0~10% EtOAc in petroleum ether) to afford 7- (bicyclo[2.2.2]octan-1-yl)-4-chloro-7H-pyrrolo[2,3-d]pyrimid ine (330 mg, 84 % yield) as a white solid. LC/MS ESI (m/z): 262 (M+H) ⁺ . Step 2.7-(Bicyclo[2.2.2]octan-1-yl)-4-chloro-5-iodo-7H-pyrrolo[2, 3-d]pyrimidine To a solution of 7-(bicyclo[2.2.2]octan-1-yl)-4-chloro-7H-pyrrolo[2,3-d]pyrim idine (300 mg, 1.1 mmol) in DMF (2 mL) was added NIS (380 mg, 1.7 mmol) and the resulting mixture was heated at 60 ℃ for 5 h. After cooling down to room temperature, the reaction was partitioned between EtOAc and water, organic layer was separated, aqueous layer was extracted with EtOAc twice, the combined organic layers dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0~10% EtOAc in petroleum ether) to afford 7-(bicyclo[2.2.2]octan-1-yl)-4-chloro-5-iodo-7H-pyrrolo[2,3- d]pyrimidine (420 mg, 95 % yield) as a pink solid. LC/MS ESI (m/z): 388 (M+H) ⁺ . Step 3. tert-Butyl (S)-4-(7-(bicyclo[2.2.2]octan-1-yl)-5-iodo-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To the solution of 7-(bicyclo[2.2.2]octan-1-yl)-4-chloro-5-iodo-7H-pyrrolo[2,3- d]pyrimidine (360 mg, 1.0 mmol) in DIEA (2 mL) was added tert-butyl (S)-3- methylpiperazine-1-carboxylate (800 mg, 4.0 mmol). The resulting reaction mixture was stirred at 130℃ under N ₂ for 5h. After cooling down to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was extracted with EtOAc twice, the combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated and purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford tert-butyl (S)-4-(7-(bicyclo[2.2.2]octan-1-yl)-5-iodo-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (390 mg, 71 %) as white solid. LC/MS ESI (m/z): 552 (M+H) ⁺ . Step 4. tert-Butyl (S)-4-(7-(bicyclo[2.2.2]octan-1-yl)-5-(2-oxopyrrolidin-1-yl) -7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te To a solution of tert-butyl (S)-4-(7-(bicyclo[2.2.2]octan-1-yl)-5-iodo-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (140 mg, 0.25 mmol) in DMF (5 mL) was added CuI (47mg, 0.25 mmol), trans-N,N’-dimethylcyclohexane-1,2-diamine (28 mg, 0.25 mmol), K ₃ CO ₄ (420 mg, 2.0 mmol) and pyrrolidin-2-one (170 mg, 2.0 mmol) and the reaction was stirred at 80 ℃ under N ₂ overnight. After cooling down to room temperature, the mixture was extracted with EtOAc twice. The combined organic layers were dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 30~100%, ethyl acetate in petroleum ether) to afford tert- butyl (S)-4-(7-(bicyclo[2.2.2]octan-1-yl)-5-(2-oxopyrrolidin-1-yl) -7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (74 mg, 58%) as white solid. LC/MS ESI (m/z): 509 (M+H) ⁺ . Step 5. tert-Butyl (S)-4-(7-(bicyclo[2.2.2]octan-1-yl)-5-(pyrrolidin-1-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te To the solution of tert-butyl (S)-4-(7-(bicyclo[2.2.2]octan-1-yl)-5-(2-oxopyrrolidin-1- yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-ca rboxylate (74 mg, 0.15 mmol) in THF (2 mL) maintained in an ice bath was added BH ₃ /THF (2.9 mL, 2.9 mmol, 1.0 M). The reaction mixture was stirred at 0 ℃ under N ₂ for 2h. The reaction mixture was quenched by MeOH while in the ice bath, and extracted with EtOAc twice. The combined organic layers were dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by Prep-TLC (silica gel, 20%, ethyl acetate in petroleum ether) to afford tert-butyl (S)-4-(7-(bicyclo[2.2.2]octan-1-yl)-5-(pyrrolidin-1-yl)-7H-p yrrolo[2,3-d]pyrimidin- 4-yl)-3-methylpiperazine-1-carboxylate (28 mg, 39%) as withe solid. LC/MS ESI (m/z): 495 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.30 (s, 1H), 6.57 (s, 1H), 4.90 (s, 1H), 4.07 (d, J = 44.4 Hz, 2H), 3.82 (s, 1H), 3.35 (t, J = 11.2 Hz, 1H), 3.30 – 3.17 (m, 1H), 3.17 – 3.04 (m, 2H), 3.04 – 2.87 (m, 1H), 2.87 – 2.71 (m, 2H), 2.38 – 2.23 (m, 6H), 1.97 – 1.86 (m, 4H), 1.86 – 1.75 (m, 6H), 1.72 – 1.67 (m, 1H), 1.48 (s, 9H), 1.16 – 1.02 (m, 3H). Example 99. Synthesis of 1,1,1-trifluoro-2-methylpropan-2-yl 4-(7-(4-cyanopyridin-2- yl)-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine -1-carboxylate (Compound 385) C ^{ompound 385} Step 1.1,1,1-Trifluoro-2-methylpropan-2-yl 1H-imidazole-1-carboxylate To a solution of 1-(1H-imidazole-1-carbonyl)-1H-imidazole (540 mg, 3.4 mmol) in DCM (20 mL) was added 1,1,1-trifluoro-2-methylpropan-2-ol (430 mg, 3.4 mmol) at room temperature, and then the resulting mixture was stirred for 18h. The mixture was used directly in next step without further purification. LC/MS (ESI) (m/z): 223 (M+H) ⁺ Step 2. tert-Butyl-4-(7-(4-cyanopyridin-2-yl)-5-cyclopropyl-7H-pyrro lo[2,3- d]pyrimidin-4-yl)piperazine-1-carboxylate A suspension of tert-butyl-4-{5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4- yl}piperazine-1-carboxylate (240 mg, 0.70 mmol, prepared following the procedure outlined in compound 146, 2-bromopyridine-4-carbonitrile (150 mg, 0.84 mmol), K ₃ PO ₄ (300 mg, 1.4 mmol), CuI (40 mg, 0.21 mmol) and trans-cyclohexane-1,2-diamine (24 mg, 0.21 mmol) in DMF(5 mL) was stirred at 120℃ under N ₂ atmosphere for 18h, and then the mixture was cooled to room temperature and concentrated. The residue was purified by column chromatography on silica gel (0~10% MeOH in DCM) to give tert-butyl-4-[7-(4- cyanopyridin-2-yl)-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin- 4-yl]piperazine-1-carboxylate (280 mg, 90 %) as a white solid. LC/MS(ESI)m/z: 446 (M+H) ⁺ . Step 3.2-(5-Cyclopropyl-4-(piperazin-1-yl)-7H-pyrrolo[2,3-d]pyrim idin-7- yl)isonicotinonitrile To a 0 ^o C solution of tert-butyl-4-[7-(4-cyanopyridin-2-yl)-5-cyclopropyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl]piperazine-1-carboxylate (280 mg, 0.63 mmol) in DCM (2 mL) was added TFA (4.5 mL, 60 mmol). The resulting mixture was stirred at 0 ^o C for 2 h. The mixture was diluted with DCM, washed with NaHCO ₃ (aq.), the organic layer was extracted with DCM twice, the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was used directly in the next step. LC/MS ESI (m/z): 346 (M+H) ⁺ . Step 4.1,1,1-Trifluoro-2-methylpropan-2-yl 4-(7-(4-cyanopyridin-2-yl)-5- cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-car boxylate To a solution of 2-[5-cyclopropyl-4-(piperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimid in-7- yl]pyridine-4-carbonitrile (100 mg, 0.29 mmol) and DIEA (0.19 mL, 1.2 mmol) in DMF (5 mL) was added a solution of 1,1,1-trifluoro-2-methylpropan-2-yl-1H-imidazole-1- carboxylate (96 mg, 0.43 mmol), and the resulting mixture was stirred at rt for 18h. After removal of solvent, the residue was added partitioned between DCM and water, the organic layer separated, and the aqueous layer was extracted with DCM twice. The combined organic phases were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography on silica gel and prep-HPLC to give 1,1,1- trifluoro-2-methylpropan-2-yl-4-[7-(4-cyanopyridin-2-yl)-5-c yclopropyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl]piperazine-1-carboxylate (20 mg, 14 %) as a white solid. LC/MS (ESI) (m/z): 500 (M+H) ^+.1 H NMR (400 MHz, CDCl ₃ ) δ 9.32 (s, 1H), 8.58 (d, J = 5.0 Hz, 1H), 8.52 (s, 1H), 7.80 (s, 1H), 7.35 (dd, J = 5.0, 1.2 Hz, 1H), 3.71 (s, 4H), 3.64 (s, 4H), 2.04 (ddd, J = 12.0, 7.6, 4.8 Hz, 1H), 1.73 (s, 6H), 1.09 – 1.01 (m, 2H), 0.88 – 0.79 (m, 2H). Example 100. Synthesis of isopropyl (S)-4-(7-(4-cyanopyridin-2-yl)-5-cyclopropyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (Compound 386) C ^{ompound 386} Isopropyl (S)-4-(7-(4-Cyanopyridin-2-yl)-5-cyclopropyl-7H-pyrrolo[2,3- d]pyrimidin- 4-yl)-3-methylpiperazine-1-carboxylate To a 0 ^o C solution of (S)-2-(5-cyclopropyl-4-(2-methylpiperazin-1-yl)-7H-pyrrolo[2 ,3- d]pyrimidin-7-yl)isonicotinonitrile (50 mg, 0.14 mmol, prepared following the procedure outlined in compound 368) in DCM (3 mL) was added TEA (0.050 mL, 0.42 mmol) and isopropyl carbonochloridate (26 mg, 0.21 mmol) dropwise. The resulting mixture was stirred at rt for 20 min under N ₂ . The reaction was quenched with NaHCO ₃ (aq.), extracted with DCM twice, the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford isopropyl (S)-4-(7-(4-cyanopyridin-2-yl)-5-cyclopropyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (20 mg, 32 %) as a white solid. LC/MS ESI (m/z): 446 (M+H) ⁺ . ¹ H NMR(400 MHz, CD ₃ OD) δ 9.12 (s, 1H), 8.66 (dd, J = 5.0, 0.7 Hz, 1H), 8.47 (s, 1H), 7.87 (d, J = 0.9 Hz, 1H), 7.55 (dd, J = 5.0, 1.3 Hz, 1H), 4.93 (m, J = 12.5, 6.2 Hz, 1H), 4.80 (m, J = 7.2, 4.6 Hz, 1H), 4.12 (d, J = 13.3 Hz, 1H), 3.93 (m, J = 13.2 Hz, 2H), 3.64 – 3.56 (m, 1H), 3.42 (m, J = 10.5, 5.7 Hz, 1H), 3.27 – 3.15 (m, 1H), 2.11 – 2.04 (m, 1H), 1.28 (d , J = 6.2 Hz, 6H), 1.23 (d, J = 6.6 Hz, 3H), 1.08 (m, J = 8.1, 4.1 Hz, 2H), 0.91 – 0.85 (m, 1H), 0.78 (ddd, J = 10.7, 6.5, 4.1 Hz, 1H). Example 101. Synthesis of tert-butyl (S)-4-(5-cyclopropyl-7-(4-fluoro-3- (trifluoromethoxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3 -methylpiperazine-1- carboxylate (Compound 387) C ^{ompound 387} Step 1.4-Fluoro-3-(trifluoromethoxy)aniline A mixture of 4-fluoro-3-(trifluoromethoxy)aniline (200 mg, 1.0 mmol) in H ₂ SO ₄ (5 mL, 30% in H ₂ O) was cooled to 0℃, and NaNO ₂ (140 mg, 2.0 mmol) added carefully. After being stirred at 0℃ for 0.5 h, a solution of CuBr (290 mg, 2.0 mmol) and CuBr ₂ (450 g, 2.0 mmol) in HBr (2.5 mL, 48% wt in H ₂ O) was added dropwise to the reaction mixture maintaining the temperature. The mixture was warmed to room temperature and stirred overnight. The reaction was then diluted with DCM, washed with water and brine, dried over Na2SO4 and concentrated in vacuo to give crude 4-bromo-1-fluoro-2- (trifluoromethoxy)benzene (390 mg, DCM seen in NMR), which was used directly in the next step without any further purification. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.47 (d, J = 6.8 Hz, 1H), 7.42 (ddd, J = 8.8, 4.1, 2.4 Hz, 1H), 7.10 (t, J = 9.2 Hz, 1H). ¹⁹ F NMR (377 MHz, CDCl ₃ ) δ -58.85 (d, J = 5.3 Hz), -130.06 (q, J = 4.8 Hz). Step 2. tert-Butyl (S)-4-(5-cyclopropyl-7-(4-fluoro-3-(trifluoromethoxy)phenyl) -7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te To a solution of tert-butyl (S)-4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate (71 mg, 0.20 mmol, prepared similarly as in compound 259, step 4) and 4-bromo-1-fluoro-2-(trifluoromethoxy)benzene (200 mg, 0.30 mmol, contaminated with DCM) in DMF (1 mL) was added CuI (12 mg, 0.060 mmol), K3PO4 (130 mg, 0.60 mmol) and trans-1,2-diaminocyclohexane (7.0 mg, 0.060 mmol). The resulting mixture was stirred at 120℃ overnight. After cooling down to room temperature, the reaction was partitioned between EtOAc and water, organic layer was separated, aqueous layer was extracted with EtOAc twice, the combined organic layers were washed with brine, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford tert-butyl (S)-4-(5-cyclopropyl-7-(4-fluoro-3- (trifluoromethoxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3 -methylpiperazine-1- carboxylate (5.1 mg, 4.7 % yield) as a white solid. LC/MS ESI (m/z): 536 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.42 (s, 1H), 7.74 – 7.54 (m, 2H), 7.33 (t, J = 9.1 Hz, 1H), 6.87 (s, 1H), 4.88 – 4.62 (m, 1H), 4.24 – 3.75 (m, 3H), 3.64 – 3.47 (m, 1H), 3.44 – 3.25 (m, 1H), 3.24 – 3.00 (m, 1H), 2.06 – 1.99 (m, 1H), 1.50 (s, 9H), 1.24 (d, J = 6.6 Hz, 3H), 1.07 – 0.98 (m, 2H), 0.84 – 0.75 (m, 1H), 0.75 – 0.66 (m, 1H). Example 102. Synthesis of tert-butyl (R)-4-(7-(4-cyanopyridin-2-yl)-5-(2-fluorophenyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carbox ylate (Compound 389) C ^{ompound 389} Step 1. tert-Butyl (R)-4-(5-(2-fluorophenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin -4-yl)- 3-methylpiperazine-1-carboxylate A mixture of 4-chloro-5-(2-fluorophenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimid ine (600 mg, 1.50 mmol, prepared following the procedure outlined for compound 392) and tert-butyl (R)-3-methylpiperazine-1-carboxylate (600 mg, 3.0 mmol) in DIEA (20 mL) was heated at 150°C for 3 hours. The reaction mixture was concentrated and the residue was purified by column chromatography on silica gel (0~30% EtOAc in petroleum ether, V/V) to give the tert-butyl (R)-4-(5-(2-fluorophenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin -4-yl)-3- methylpiperazine-1-carboxylate (520 mg, 62%) as a yellow solid. LC/MS ESI (m/z): 566 (M+H) ⁺ . Step 2. tert-Butyl (R)-4-(5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3 - methylpiperazine-1-carboxylate To a solution of tert-butyl (R)-4-(5-(2-fluorophenyl)-7-tosyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (500 mg, 0.88 mmol) in THF (10 mL) was added TBAF (5.0 mL, 1.0M solution in THF) and the resulting mixture was stirred at room temperature for 12 hrs. The reaction mixture was then extracted with EtOAc (100 ml x 2). The combined layers were washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography on silica gel (0~80% EtOAc in petroleum ether) to give the tert-butyl (R)-4-(5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3 - methylpiperazine-1-carboxylate (100 mg, 27 %) as a yellow solid. LC/MS ESI (m/z): 412 (M+H) ⁺ . Step 3. tert-Butyl (R)-4-(7-(4-cyanopyridin-2-yl)-5-(2-fluorophenyl)-7H-pyrrolo [2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate A mixture of tert-butyl (R)-4-(5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 3-methylpiperazine-1-carboxylate (100 mg, 0.24 mmol), 2-bromopyridine-4-carbonitrile (89 mg, 0.49 mmol), CuI (23 mg, 0.12 mmol), trans-1,2-diaminocyclohexane (8.3 mg, 0.070 mmol) and K ₃ PO ₄ (150 mg, 0.73 mmol) in DMF (10 mL) was heated at 120°C for 12 hours. The reaction mixture was concentrated and the residue was purified by column chromatography (silica gel, 0~40% EtOAc in petroleum ether) to afford tert-butyl (R)-4-(7- (4-cyanopyridin-2-yl)-5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]py rimidin-4-yl)-3- methylpiperazine-1-carboxylate (80 mg, 64 %) as a white solid. LC/MS ESI (m/z): 514 (M+H) ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ 9.30 (s, 1H), 8.70 (d, J = 5.0 Hz, 1H), 8.55 (s, 1H), 8.29 (s, 1H), 7.61 (dd, J = 5.0, 1.3 Hz, 1H), 7.54 (td, J = 7.5, 1.7 Hz, 1H), 7.50 – 7.43 (m, 1H), 7.34 (dd, J = 7.5, 6.5 Hz, 1H), 7.31 – 7.24 (m, 1H), 4.19 – 4.11 (m, 1H), 3.72 (d, J = 13.6 Hz, 1H), 3.49 (d, J = 11.7 Hz, 2H), 3.13 – 3.06 (m, 1H), 2.73 (m, 2H), 1.42 (s, 9H), 0.97 (d, J = 6.5 Hz, 3H). The following compound was prepared by a procedure analogous to the synthesis of compound 389 using the corresponding amine.

Example 103. Synthesis of 2-(5-(2-fluorophenyl)-4-(4-isobutyryl-3,3-dimethylpiperazin- 1-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)isonicotinonitrile (Compound 391) C ^{ompound 391} Step 1. tert-Butyl 4-(5-(2-fluorophenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-y l)-2,2- dimethylpiperazine-1-carboxylate To a solution of 4-chloro-5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (600 mg, 1.7 mmol) in EtOH (10 mL) was added tert-butyl 2,2-dimethylpiperazine-1-carboxylate (410 mg, 1.9 mmol) and DIPEA (450 mg, 3.5 mmol) and the resulting mixture was heated at 100 ^o C for 8 hours. After cooling down to room temperature, the reaction was quenched with water, extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~100%, ethyl acetate in petroleum ether) to afford tert-butyl 4- (5-(2-fluorophenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl) -2,2-dimethylpiperazine-1- carboxylate (800 mg, 79 %) as a white solid. LC/MS ESI (m/z): 580 (M+H) ⁺ . Step 2. tert-Butyl 4-(5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,2- dimethylpiperazine-1-carboxylate To a solution of tert-butyl 4-(5-(2-fluorophenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)-2,2-dimethylpiperazine-1-carboxylate (800 mg, 1.4 mmol) in THF (5 mL) was added TBAF (10 mL) and the resulting mixture stirred at room temperature for 4 h. The reaction was quenched with water, extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~100%, ethyl acetate in petroleum ether) to afford tert-butyl 4-(5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,2-d imethylpiperazine-1- carboxylate (400 mg, 68 %) as a white solid. LC/MS ESI (m/z): 426 (M+H) ⁺ . 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 4-(5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 2,2-dimethylpiperazine-1-carboxylate (280 mg, 0.70 mmol) in DMF (10 mL) was added 2- bromoisonicotinonitrile (240 mg, 1.3 mmol), trans-cyclohexane-1,2-diamine (47 mg, 0.30 mmol), CuI (25 mg, 0.10 mmol) and K ₃ PO ₄ (200 mg, 2.0 mmol) and the resulting mixture was heated at 110 ^o C overnight. After cooling down to room temperature, the reaction was quenched with water, extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~100%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford tert-butyl 4-(7-(4-cyanopyridin- 2-yl)-5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2, 2-ethylpiperazine-1-carboxylate (7.3 mg, 2.0 %) as a white solid. LC/MS ESI (m/z): 528 (M+H) ⁺ . ¹ H NMR (400 MHz, MeOD) δ 9.42 (s, 1H), 8.62 (d, J = 5.0 Hz, 1H), 8.52 (s, 1H), 8.20 (s, 1H), 7.45 (td, J = 7.5, 1.7 Hz, 1H), 7.41 – 7.36 (m, 2H), 7.25 – 7.21 (m, 1H), 7.18 (t, J = 9.1 Hz, 1H), 3.50 – 3.42 (m, 4H), 3.26 (s, 2H), 1.44 (s, 9H), 1.22 (s, 6H). The following compound was prepared by the procedure analogous to the synthesis of compound 391 from the corresponding aryl halide.

Example 104. Synthesis of tert-butyl (S)-4-(7-(5-cyanothiazol-2-yl)-5-cyclopropyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (Compound 397) C ^{ompound 397} Step 1. tert-Butyl (S)-4-(7-(5-cyanothiazol-2-yl)-5-cyclopropyl-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 (71 mg, 0.20 mmol, prepared following the procedure of compound 260, step 4) and 2-bromothiazole-5-carbonitrile (76 mg, 0.40 mmol) in DMF (1 mL) was added CuI (12 mg, 0.060 mmol), K ₃ PO ₄ (130 mg, 0.60 mmol) and trans-1,2- diaminocyclohexane (7.0 mg, 0.060 mmol) and the resulting mixture stirred at 90℃ overnight. After cooling down to room temperature, the reaction was partitioned between EtOAc and brine, the organic layer separated, aqueous layer extracted with EtOAc twice, the combined organic layers washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford tert-butyl (S)-4-(7-(5-cyanothiazol-2-yl)-5-cyclopropyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate (14 mg, 15 % yield) as a white solid. LC/MS ESI (m/z): 466 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.52 (s, 1H), 8.03 (s, 1H), 7.60 (s, 1H), 5.00 – 4.60 (m, 1H), 4.33 – 3.99 (m, 2H), 3.99 – 3.77 (m, 1H), 3.54 (t, J = 11.7 Hz, 1H), 3.38 – 3.17 (m, 1H), 3.17 – 2.92 (m, 1H), 2.00 – 1.86 (m, 1H), 1.50 (s, 9H), 1.27 (d, J = 6.6 Hz, 3H), 1.11 – 1.00 (m, 2H), 0.89 – 0.77 (m, 2H). Example 105. Synthesis of tert-butyl (S)-4-(7-cyclobutyl-5-cyclopropyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Compound 398) C ^{ompound 398} Step 1. tert-Butyl (S)-4-(7-cyclobutyl-5-cyclopropyl-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 (180 mg, 0.50 mmol, prepared following the procedure of compound 260, step 4) in DMF (1 mL) was added NaH (40 mg, 1.0 mmol, 60% wt. in mineral oil) in an ice bath. The resulting mixture was stirred at 0℃ under N ₂ atmosphere for 20 min. A solution of bromocyclobutane (140 mg, 1.0 mmol) in DMF(1 mL) was then added to the reaction mixture. The reaction mixture was stirred at 60℃ under N ₂ atmosphere overnight. After cooling down to room temperature, the reaction was quenched with NH ₄ Cl aqueous solution, extracted with EtOAc, the organic layer separated, aqueous layer was extracted with EtOAc twice, the combined organic layers washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~40%, ethyl acetate in petroleum ether) to afford tert-butyl (S)-4-(7-cyclobutyl- 5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiper azine-1-carboxylate (66 mg, 32 % yield) as a white solid. LC/MS ESI (m/z): 412 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H), 6.85 (s, 1H), 5.33 – 5.17 (m, 1H), 4.88 – 4.56 (m, 1H), 4.17 – 3.72 (m, 3H), 3.50 (t, J = 10.9 Hz, 1H), 3.40 – 3.22 (m, 1H), 3.21 – 3.00 (m, 1H), 2.55 – 2.44 (m, 2H), 2.44 – 2.30 (m, 2H), 2.04 – 1.94 (m, 1H), 1.94 – 1.80 (m, 2H), 1.49 (s, 9H), 1.19 (d, J = 6.5 Hz, 3H), 1.01 – 0.91 (m, 2H), 0.81 – 0.71 (m, 1H), 0.70 – 0.61 (m, 1H). Example 106. Synthesis of tert-butyl (S)-4-(7-(3-chloro-5-cyanophenyl)-5-(pyrrolidin-1- yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-ca rboxylate (Compound 399) Step 1.5-Bromo-4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine To a 0 ^o C suspension of NaH (1.0 g, 26 mmol, 60% wt. in mineral oil) in anhydrous DMF (25 mL) was added 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (5.0 g, 22 mmol) in portions, the resulting mixture stirred at 0 ^o C for additional 20 minutes after which, 4- methylbenzenesulfonyl chloride (4.9 g, 26 mmol) was added in portions. The reaction was stirred at room temperature overnight. The reaction was poured into ice water, and the precipitate was collected by filtration.5-bromo-4-chloro-7-tosyl-7H-pyrrolo[2,3- d]pyrimidine (5.4 g, 65 %) as a white solid. LC/MS ESI (m/z): 386, 388 (M+H) ⁺ . Step 2. tert-Butyl (S)-4-(5-bromo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate To a solution of 5-bromo-4-chloro-7-(4-methylbenzenesulfonyl)-7H-pyrrolo[2,3- d]pyrimidine (3.0 g, 7.8 mmol) in DIPEA (9.5 mL, 55 mmol) was added tert-butyl (S)-3- methylpiperazine-1-carboxylate (6.2 mg, 31 mmol). The resulting mixture was heated at 150 ^o C for 3 h under N ₂ . After cooling down to room temperature, the solvent was removed and the residue was purified by flash column chromatography to afford tert-butyl (S)-4-(5- bromo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiper azine-1-carboxylate (3.5 g, 83 %) as a solid. LC/MS ESI (m/z): 550, 552 (M+H) ⁺ . Step 2. tert-Butyl (S)-4-(5-bromo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate To a solution of tert-butyl (S)-4-(5-bromo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 3-methylpiperazine-1-carboxylate (3.0 g, 5.4 mmol) in THF (20 mL) was added TBAF (20 mL, 1.0M in THF). The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water, extracted with EtOAc twice, the combined organic layers washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography to afford tert-butyl (S)-4-(5-bromo-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (500 mg , 23%) as a solid. LC/MS ESI (m/z): 396, 398 (M+H) ⁺ . Step 3. tert-Butyl (S)-4-(5-bromo-7-(3-chloro-5-cyanophenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl (S)-4-(5-bromo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate (300 mg, 0.78 mmol) in DMF (10 mL) was added 3-bromo- 5-chlorobenzonitrile (160 mg, 0.78 mmol), trans-N,N'-dimethyl-cyclohexane-1,2-diamine (210 mg, 1.5 mmol), CuI (270 mg, 1.4 mmol) and K ₃ PO ₄ (320 mg, 1.5 mmol) and the resulting mixture was heated at 90 ^o C overnight. After cooling down to rt, the reaction was partitioned between EtOAc and water, organic layer was separated, aqueous layer extracted with EtOAc twice, the combined organic layers washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography to afford tert-butyl (S)-4-(5-bromo-7-(3-chloro-5-cyanophenyl)-7H-pyrrolo[2,3-d]p yrimidin-4-yl)-3- methylpiperazine-1-carboxylate (350 mg, 87 %) as a solid. LC/MS ESI (m/z): 531, 533 (M+H) ⁺ . Step 4. tert-Butyl (S)-4-(7-(3-chloro-5-cyanophenyl)-5-(2-oxopyrrolidin-1-yl)-7 H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te To a solution of tert-butyl (S)-4-(5-bromo-7-(3-chloro-5-cyanophenyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (300 mg, 0.56 mmol) in DMF (10 mL) was added pyrrolidin-2-one (0.17 mL, 2.3 mmol), trans-N,N'-dimethyl- cyclohexane-1,2-diamine (0.18 mL, 1.1 mmol), CuI (130 mg, 0.70 mmol) and K ₃ PO ₄ (240 mg, 1.1 mmol) and the resulting mixture was heated to 90 ^o C overnight. After cooling down to room temperature, the reaction was partitioned between EtOAc and water, organic layer separated, aqueous layer extracted with EtOAc twice, the combined organic layers washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography to afford tert-butyl (S)-4-(7-(3-chloro-5-cyanophenyl)-5-(2- oxopyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methy lpiperazine-1-carboxylate (130 mg, 43 %) as a solid. LC/MS ESI (m/z): 536 (M+H) ⁺ . Step 5. tert-Butyl (S)-4-(7-(3-chloro-5-cyanophenyl)-5-(pyrrolidin-1-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te To a 0 ^o C solution of tert-butyl (S)-4-(7-(3-chloro-5-cyanophenyl)-5-(2-oxopyrrolidin- 1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1- carboxylate (60 mg, 0.11 mmol) in THF (4 mL) was added borane (2.0 mL, 1.0M in THF) dropwise. The resulting mixture was warmed to 25 ^o C over 3 h. The reaction was quenched with MeOH after cooling in an ice water bath, and then diluted with ethyl acetate and water. The organic layers were separated, the aqueous layer extracted with EtOAc twice, the combined organic layers washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography to afford tert-butyl (S)-4-(7-(3-chloro-5- cyanophenyl)-5-(pyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)-3-methylpiperazine-1- carboxylate (10 mg, 17 %) as a yellow solid. LC/MS ESI (m/z): 522 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.38 (s, 1H), 8.14 – 8.09 (m, 2H), 7.53 – 7.48 (m, 1H), 6.68 (s, 1H), 5.05 – 4.88 (m, 1H), 4.25 – 3.87 (m, 3H), 3.44 – 3.13 (m, 4H), 3.02 – 2.81 (m, 3H), 1.99 (s, 4H), 1.49 (s, 9H), 1.18 – 1.08 (m, 3H).

Example 107. Synthesis of tert-butyl (3S)-4-(7-(3,3-difluorocyclohexyl)-5-(pyrrolidin-1- yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-ca rboxylate (Compound 401) C ^{ompound 401} Step 1.3-(4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexan-1-o l To a solution of 3-aminocyclohexan-1-ol (1.0 g, 8.7 mmol) in EtOH (10 mL) were added 2-(4,6-dichloropyrimidin-5-yl)acetaldehyde (1.6 g, 8.7 mmol) and TEA (2.9 mL, 21 mmol). The resulting mixture was heated at 80 ^o C for 3 h under N ₂ . After cooling down to room temperature, the solvent was removed and the residue was purified by flash column chromatography to afford 3-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexan-1-ol (1.5 g, 69 %) as a solid. LC/MS ESI (m/z): 252.4 (M+H) ⁺ . Step 2.3-(4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexan-1-o ne To a solution of 3-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexan-1-ol (2.0 g, 7.9 mmol) in DCM (20 mL) was added PCC (2.6 g, 12 mmol). The resulting mixture was stirred at room temperature overnight. The solvent was removed, and the residue was purified by flash column chromatography to afford 3-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7- yl)cyclohexan-1-one (1.4 g, 70 %) as a solid. LC/MS ESI (m/z): 250.4 (M+H) ⁺ . Step 3.4-Chloro-7-(3,3-difluorocyclohexyl)-7H-pyrrolo[2,3-d]pyrim idine To a solution of 3-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexan-1-one (1.4 g, 5.6 mmol) in DCM (20 mL) was added DAST (1.4 g, 8.4 mmol) at 0 ^o C. The resulting mixture was allowed to warm to room temperature overnight. The solvent was removed, and the residue was purified by flash column chromatography to afford 4-chloro-7-(3,3- difluorocyclohexyl)-7H-pyrrolo[2,3-d]pyrimidine (1.3 g, 85 %) as a solid. LC/MS ESI (m/z): 272.4 (M+H) ⁺ . Step 4.4-Chloro-7-(3,3-difluorocyclohexyl)-5-iodo-7H-pyrrolo[2,3- d]pyrimidine To a solution of 4-chloro-7-(3,3-difluorocyclohexyl)-7H-pyrrolo[2,3-d]pyrimid ine (600 mg, 2.2 mmol) in DMF (6 mL) was added iodo(sulfanylidene)amine (460 mg, 2.6 mmol). The resulting mixture was heated to 55 ^o C overnight. After cooling down to room temperature, the solvent was removed and the residue purified by flash column chromatography to afford 4-chloro-7-(3,3-difluorocyclohexyl)-5-iodo-7H-pyrrolo[2,3- d]pyrimidine (350 mg, 40 %) as a solid. LC/MS ESI (m/z): 398.3 (M+H) ⁺ . Step 5. tert-Butyl (3S)-4-(7-(3,3-difluorocyclohexyl)-5-iodo-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of 4-chloro-7-(3,3-difluorocyclohexyl)-5-iodo-7H-pyrrolo[2,3- d]pyrimidine (300 mg, 0.76 mmol) in DIPEA (10 mL, 55 mmol) was added tert-butyl (3S)-3- methylpiperazine-1-carboxylate (600 mg, 3.0 mmol). The resulting mixture was heated at 150 ^o C for 3 h under N ₂ . After cooling down to room temperature, the solvent was removed and the residue was purified by flash column chromatography to afford tert-butyl (3S)-4-(7- (3,3-difluorocyclohexyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4 -yl)-3-methylpiperazine-1- carboxylate (370 mg, 87 %) as a solid. LC/MS ESI (m/z): 562.5 (M+H) ⁺ . Step 6. tert-Butyl (3S)-4-(7-(3,3-difluorocyclohexyl)-5-(2-oxopyrrolidin-1-yl)- 7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te To a solution of tert-butyl (3S)-4-[7-(3,3-difluorocyclohexyl)-5-iodo-7H-pyrrolo[2,3- d]pyrimidin-4-yl]-3-methylpiperazine-1-carboxylate (250 mg, 0.40 mmol) in DMF (5 mL) were added pyrrolidin-2-one (0.14 mL, 1.8 mmol), trans-N,N'-dimethyl-cyclohexane-1,2- diamine (130 mg, 0.90 mmol), CuI (85 mg, 0.40 mmol) and K ₃ PO ₄ (95 mg, 0.40 mmol). The resulting mixture was heated at 90 ^o C overnight. After cooling down to room temperature, the reaction was partitioned between EtOAc and water, the organic layer separated, the aqueous layer extracted with EtOAc twice, the combined organic layers washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography to afford tert-butyl (3S)-4-(7-(3,3-difluorocyclohexyl)-5-(2-oxopyrrolidin-1-yl)- 7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (90 mg, 39 %) as a solid. LC/MS ESI (m/z): 519.7 (M+H) ⁺ . Step 7. tert-Butyl (3S)-4-(7-(3,3-difluorocyclohexyl)-5-(pyrrolidin-1-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te To a solution of tert-butyl (3S)-4-(7-(3,3-difluorocyclohexyl)-5-(2-oxopyrrolidin-1- yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-ca rboxylate (50 mg, 0.090 mmol) in THF (4 mL) maintained at 0 ^o C was added borane (2.0 mL, 1.0M in THF). The resulting mixture was allowed to warm to rt over 3 h. The reaction was then quenched with MeOH while cooling in an ice water bath, and then diluted with ethyl acetate. The organic phase was washed with brine and dried with anhydrous sodium sulfate, concentrated, and the residue was purified by flash column chromatography to afford tert-butyl (3S)-4-(7-(3,3- difluorocyclohexyl)-5-(pyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyr imidin-4-yl)-3- methylpiperazine-1-carboxylate (15 mg, 31 %) as a solid. LC/MS ESI (m/z): 505.3 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.31 (s, 1H), 6.44 (s, 1H), 5.03 – 4.86 (m, 2H), 4.27 – 3.82 (m, 3H), 3.37 – 2.81 (m, 7H), 2.54 – 2.44 (m, 1H), 2.35 – 2.15 (m, 2H), 2.12 – 2.05 (m, 1H), 1.98 – 1.89 (m, 5H), 1.85 – 1.72 (m, 3H), 1.49 (s, 9H), 1.16 – 1.04 (m, 3H). Example 108. Synthesis of tert-butyl-(S)-4-(7-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-yl)-5 - (pyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylp iperazine-1-carboxylate (Compound 406) C ^{ompound 406} Step 1.7-((1S,2R,4R)-Bicyclo[2.2.1]heptan-2-yl)-4-chloro-5-iodo-7 H-pyrrolo[2,3- d]pyrimidine To a 0 ^o C solution of PPh ₃ (4.1 g, 16 mmol) in dry toluene (20 mL) was added DIAD (3.1 mL, 16 mmol) dropwise, followed by 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (2.5 g, 8.9 mmol) in portions. The resulting mixture was stirred at ice bath temperature for 30 minutes. (1S,2S,4R)-Bicyclo[2.2.1]heptan-2-ol (0.50 g, 4.5 mmol) was then added and further stirred for 18h and allowed to warm to rt. The reaction mixture was quenched by addition of water and EtOAc. The organic layers were separated and the aqueous layer was extracted by EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography on silica gel to get 7-[(1S,2R,4R)-bicyclo[2.2.1]heptan-2-yl]-4-chloro-5-iodo-7H- pyrrolo[2,3- d]pyrimidine (0.20 g, 12 %) as a white solid. LC/MS (ESI) (m/z): 374 (M+H) ⁺ Step 2. tert-Butyl-(S)-4-(7-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-yl)-5 -iodo-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te To a solution of 7-[(1S,2R,4R)-bicyclo[2.2.1]heptan-2-yl]-4-chloro-5-iodo-7H- pyrrolo[2,3-d]pyrimidine (200 mg, 0.53 mmol) in DIEA (0.35 mL, 2.1 mmol) was added tert- butyl-(3S)-3-methylpiperazine-1-carboxylate (210 mg, 1.1 mmol). The resulting mixture was stirred at 140℃ for 3h. After removal of solvent, the residue was purified by column chromatography (silica gel, 0~10% MeOH in DCM) to give tert-butyl-(3S)-4-{7-[(1S,2R,4R)- bicyclo[2.2.1]heptan-2-yl]-5-iodo-7H-pyrrolo[2,3-d]pyrimidin -4-yl}-3-methylpiperazine-1- carboxylate (100 mg, 35 %) as a white solid. LC/MS (ESI) (m/z): 538 (M+H) ⁺ Step 3. tert-Butyl-(S)-4-(7-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-yl)-5 -(2-oxopyrrolidin- 1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1- carboxylate A suspension of tert-butyl-(3S)-4-{7-[(1S,2R,4R)-bicyclo[2.2.1]heptan-2-yl]- 5-iodo- 7H-pyrrolo[2,3-d]pyrimidin-4-yl}-3-methylpiperazine-1-carbox ylate (100 mg, 0.18 mmol), pyrrolidin-2-one (0.11 mL, 1.5 mmol), K ₃ PO ₄ (320 mg, 1.5 mmol), CuI (35 mg, 0.18 mmol) and trans-cyclohexane-1,2-diamine (24 mg, 0.21 mmol) in DMF (5 mL) was stirred at 80℃ under N ₂ atmosphere for 18h. The mixture was cooled to room temperature and concentrated. The residue was purified by column chromatography (silica gel, 0~10% MeOH in DCM) to give tert-butyl-(3S)-4-{7-[(1S,2R,4R)-bicyclo[2.2.1]heptan-2-yl]- 5-(2-oxopyrrolidin-1-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl}-3-methylpiperazine-1-carbox ylate (80 mg, 87 %) as a white solid. LC/MS (ESI) (m/z): 495 (M+H) ⁺ Step 4. Trans-N ¹ -(2-(4-(2-fluorophenyl)piperazin-1-yl)cyclohexyl)-N ⁴ ,N ⁴ - dimethylbenzene-1,4-disulfonamide To a 0 ^o C solution of tert-butyl-(3S)-4-{7-[(1S,2R,4R)-bicyclo[2.2.1]heptan-2-yl]- 5-(2- oxopyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-3-methy lpiperazine-1-carboxylate (80 mg, 0.16 mmol) in dry THF (3.0 mL) was added BH ₃ /THF (0.65 mL, 1.0M in THF) dropwise, and the resulting mixture stirred for 18h. The reaction was quenched by addition of saturated NaHCO ₃ and ethyl acetate. The organic layers were separated and the aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (silica gel) and prep-HPLC to give tert-butyl-(S)-4-(7-((1S,2R,4R)- bicyclo[2.2.1]heptan-2-yl)-5-(pyrrolidin-1-yl)-7H-pyrrolo[2, 3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate (13 mg, 17 %) as a yellow solid. LC/MS (ESI) (m/z): 481 (M+H) ^{+ 1} H NMR (400 MHz, CDCl ₃ ) δ 8.33 (d, J = 4.1 Hz, 1H), 6.58 (dd, J = 10.7, 4.2 Hz, 1H), 5.14 (dt, J = 9.2, 4.4 Hz, 0.8H), 4.99 (dd, J = 25.8, 10.5 Hz, 1H), 4.74 (td, J = 8.3, 5.0 Hz, 0.2H), 4.32 – 3.78 (m, 3H), 3.44 – 2.81 (m, 7H), 2.68 (s, 1H), 2.49 – 2.36 (m, 1H), 2.25 – 2.11 (m, 1H), 2.07 – 1.87 (m, 4H), 1.76 – 1.57 (m, 4H), 1.52 – 1.31 (m, 12H), 1.18 – 1.01 (m, 3H). Example 109. Synthesis of tert-butyl (S)-4-(5-(azetidin-1-yl)-7-(4-cyanopyridin-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (Compound 407) C ^{ompound 407} The title compound was prepared by an analogous procedure as described for compound 388, using tert-butyl (S)-4-(5-(azetidin-1-yl)-7-(4-chloropyridin-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te as the reactant, as described below. To Zn(CN) ₂ (31 mg, 0.26 mmol) and Pd(PPh ₃ ) ₄ (31 mg, 0.027 mmol) was added a solution of tert-butyl (S)-4-(5-(azetidin-1-yl)-7-(4-chloropyridin-2-yl)-7H-pyrrolo [2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (26 mg, 0.054 mmol) in dry DMF (2 mL). The mixture was stirred at 120°C under N ₂ for 3 h. The reaction was diluted with EtOAc, washed with 5% LiCl (aq.) and brine and concentrated. The residue was purified by prep-TLC (petroleum ether / EtOAc = 4:1, v/v) followed by prep-HPLC to provide tert-butyl (S)-4-(5-(azetidin-1-yl)-7-(4-cyanopyridin-2-yl)-7H-pyrrolo[ 2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate (17 mg, 65%) as a yellow solid. LC/MS ESI (m/z): 475 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.34 (s, 1H), 8.57 (d, J = 5.0 Hz, 1H), 8.44 (s, 1H), 7.46 (s, 1H), 7.29 (d, J = 5.0 Hz, 1H), 4.96 (br. s, 1H), 4.01 (d, J = 82.7 Hz, 3H), 3.82 (dd, J = 13.5, 6.6 Hz, 2H), 3.66 (q, J = 6.9 Hz, 2H), 3.51 (t, J = 11.6 Hz, 1H), 3.40 (br. s, 1H), 2.96 (br. s, 1H), 2.29 (m, J = 7.0 Hz, 2H), 1.50 (s, 9H), 1.16 (d, J = 6.7 Hz, 3H). Example 110. 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]hept ane-2-carboxylate (Compound 408 and Compound 409) 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 the solution of 4-chloro-5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (170 mg, 0.87 mmol) in EtOH (5 mL) were 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) in that order. The resulting reaction mixture was stirred at 100℃ under N ₂ overnight. After being cooled to room temperature, the solvent was removed, and the residue was purified by flash column chromatography (silica gel, 0~20%, ethyl acetate in petroleum ether) to afford tert-butyl 5-(5- cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dia zabicyclo[4.1.0]heptane-2- carboxylate (140 mg, 45 %) as white solid. LC/MS ESI (m/z): 510 (M+H) ⁺ . 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 the 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, 1.0M in THF). The resulting reaction mixture was stirred at rt under N ₂ overnight. The reaction mixture was quenched with ice water, extracted with EtOAc twice, the combined organic layers dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to afford 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) ⁺ . 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-carboxyla te To the 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 (2 mL) was added CuI (24 mg, 0.13 mmol), K ₃ PO ₄ (160 mg, 0.75 mmol), trans-cyclohexane-1,2-diamine (9.0 mg, 0.080 mmol) and 2-bromoisonicotinonitrile (93 mg, 0.51 mmol ) consecutively. The resulting reaction mixture was stirred at 100℃ under N ₂ overnight. After being cooled to room temperature, the reaction was diluted with water, and extracted with EtOAc twice. The combined organic layers were dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 0~20%, ethyl acetate in petroleum ether) and prep-HPLC to afford 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 (66 mg, 57 %) as white solid. LC/MS ESI (m/z): 458 (M+H) ⁺ . Separation of isomers: 44 mg of tert-butyl 5-(7-(4-cyanopyridin-2-yl)-5-cyclopropyl- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[4.1.0]hept ane-2-carboxylate was separated by SFC (Preparative separation method, Instrument: Waters Thar 80 preparative SFC , Column: ChiralCel OJ, 250×21.2mm I.D., 5µm, Mobile phase: A for CO ₂ and B for MEOH+0.1%NH ₃ /H ₂ O, Gradient: B 40%, Flow rate: 50 mL /min, Back pressure: 100 bar, Column temperature: 35℃, Wavelength: 254 nm , Cycle-time: 7 min, Elution time: 1.5 h) to give two isomers: Peak 1: shorter retention time, assigned as compound 408 (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, 22 mg). LC/MS ESI (m/z): 458 (M+H)} ⁺ _. ¹ _{H NMR} (400 MHz, CDCl ₃ ) 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, assigned as compound 409 (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, 22 mg): LC/MS ESI (m/z): 458 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 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). Example 111. Synthesis of tert-butyl (3S)-4-(7-(1-cyanopiperidin-3-yl)-5-cyclopropyl- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carbox ylate (Compound 410) C ^{ompound 410} Step 1. tert-Butyl (3S)-4-(7-(1-((benzyloxy)carbonyl)piperidin-3-yl)-5-cyclopro pyl- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carbox ylate To a solution of tert-butyl (S)-4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate (36 mg, 0.10 mmol, prepared following the procedure of compound 260, step 4) and benzyl 3-hydroxypiperidine-1-carboxylate (47 mg, 0.20 mmol) in toluene (1 mL) were added CMBP (48 mg, 0.20 mmol) under N ₂ atmosphere. The reaction mixture was stirred at 100℃ overnight under N ₂ atmosphere. After cooling to room temperature, the solvent was removed under reduced pressure. the residue was partitioned between EtOAc and water, organic layers separated, aqueous layer extracted with EtOAc twice, the combined organic layers washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to afford tert-butyl (3S)-4-(7-(1- ((benzyloxy)carbonyl)piperidin-3-yl)-5-cyclopropyl-7H-pyrrol o[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate (35 mg, 60 % yield) as a withe solid. LC/MS ESI (m/z): 575 (M+H) ⁺ . Step 2. tert-Butyl (3S)-4-(5-cyclopropyl-7-(piperidin-3-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl (3S)-4-(7-(1-((benzyloxy)carbonyl)piperidin-3-yl)-5- cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperaz ine-1-carboxylate (35 mg, 0.060 mmol) in MeOH (1 mL) was added Pd/C (40 mg, wetted with ca.55% water) under a N ₂ atmosphere. The mixture was stirred at room temperature for 2 h under a H ₂ atmosphere. After purging with N ₂ , the solid was removed by filtration. The solvent was removed under reduced pressure to afford crude tert-butyl (3S)-4-(5-cyclopropyl-7-(piperidin-3-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te as a colorless oil. LC/MS ESI (m/z): 441 (M+H) ⁺ . Step 3. tert-Butyl (3S)-4-(7-(1-cyanopiperidin-3-yl)-5-cyclopropyl-7H-pyrrolo[2 ,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl (3S)-4-(5-cyclopropyl-7-(piperidin-3-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate in CH ₃ CN(1 mL) were added K ₂ CO ₃ (140 mg, 1.0 mmol) and BrCN (110 mg, 1.0 mmol). The resulting mixture was stirred at room temperature for 1 h under N ₂ atmosphere. The reaction was partitioned between EtOAc and water, organic layers separated, aqueous layer extracted with EtOAc twice, the combined organic layers washed with brine, filtered and concentrated. The residue was purified by prep-HPLC to afford tert-butyl (3S)-4-(7-(1-cyanopiperidin-3-yl)-5-cyclopropyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (4.2 mg, 15 % yield, over two steps) as a white solid. LC/MS ESI (m/z): 466 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.36 (s, 1H), 6.66 (s, 1H), 4.89 – 4.64 (m, 2H), 4.18 – 3.73 (m, 3H), 3.64 (dt, J = 10.5, 5.2 Hz, 1H), 3.58 – 3.41 (m, 2H), 3.39 – 3.20 (m, 2H), 3.19 – 2.96 (m, 2H), 2.20 – 2.09 (m, 1H), 2.07 – 1.98 (m, 1H), 1.97 – 1.87 (m, 3H), 1.49 (s, 9H), 1.21 (d, J = 6.0 Hz, 3H), 1.01 – 0.91 (m, 2H), 0.77 – 0.67 (m, 1H), 0.67 – 0.56 (m, 1H). Example 112. Synthesis of tert-butyl 5-(7-(4-cyanopyridin-2-yl)-5-(2-fluorophenyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[4.1.0]heptane -2-carboxylate (Compound 412) C ^{ompound 412} Step 1. tert-Butyl 5-(5-(2-fluorophenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-y l)- 2,5-diazabicyclo[4.1.0]heptane-2-carboxylate To the solution of 4-chloro-5-(2-fluorophenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimid ine (280 mg, 0.70 mmol, Suzuki conditions: Pd ₂ (dba) ₃ , xantphos, K ₃ PO ₄ , DMF, 60 ^o C) in EtOH (10 mL) was added DIEA (0.35 mL, 2.1 mmol) and tert-butyl 2,5- diazabicyclo[4.1.0]heptane-2-carboxylate (210 mg, 1.0 mmol) respectively. The resulting reaction mixture was stirred at 100℃ under N ₂ overnight. After being cooled down to room temperature, solvent was concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford tert-butyl 5-(5-(2-fluorophenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-y l)- 2,5-diazabicyclo[4.1.0]heptane-2-carboxylate (270 mg, 95 %) as white solid. LC/MS ESI (m/z): 564 (M+H) ⁺ . Step 2. tert-Butyl 5-(5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5- diazabicyclo[4.1.0]heptane-2-carboxylate To the solution of tert-butyl 5-(5-(2-fluorophenyl)-7-tosyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2,5-diazabicyclo[4.1.0]heptane-2-carboxyla te (270 mg, 0.66 mmol) in THF (4 mL) was added TBAF (2.8 mL). The resulting reaction mixture was stirred at rt under N ₂ overnight. The reaction was quenched with ice water, then it was extracted with ethyl acetate and the organic layers washed with brine. The combined organic layers were dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to obtain tert-butyl 5-(5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5- diazabicyclo[4.1.0]heptane-2-carboxylate (160 mg, 57%) as a white solid. LC/MS ESI (m/z): 410 (M+H) ⁺ . Step 3. tert-Butyl 5-(7-(4-cyanopyridin-2-yl)-5-(2-fluorophenyl)-7H-pyrrolo[2,3 - d]pyrimidin-4-yl)-2,5-diazabicyclo[4.1.0]heptane-2-carboxyla te To a solution of tert-butyl 5-(5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 2,5-diazabicyclo[4.1.0]heptane-2-carboxylate (160 mg, 0.38 mmol) in DMF (3 mL) was added CuI (36 mg, 0.19 mmol), K3PO4 (240 mg, 1.1 mmol), trans-cyclohexane-1,2-diamine (0.014 mL, 0.11 mmol) and 2-bromoisonicotinonitrile (140 mg, 0.76 mmol) and the resulting reaction mixture was stirred at 100 ℃ under N ₂ overnight. After being cooled down to room temperature, the reaction mixture was poured into ice water, was extracted with ethyl acetate twice. The combined organic layers were dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 0~20%, ethyl acetate in petroleum ether) to afford tert-butyl 5-(7-(4-cyanopyridin-2-yl)- 5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-diaz abicyclo[4.1.0]heptane-2- carboxylate (170 mg, 88 %) as white solid. LC/MS ESI (m/z): 512 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.42 (s, 1H), 8.61 (d, J = 5.0 Hz, 1H), 8.48 (s, 1H), 8.18 (s, 1H), 7.48 (t, J = 7.5 Hz, 1H), 7.40 – 7.38 (m, 1H), 7.37 – 7.31 (m, 1H), 7.22 – 7.12 (m, 2H), 4.48 – 4.39 (m, 1H), 3.44 – 3.28 (m, 1H), 3.28 – 3.17 (m, 2H), 2.66 – 2.57 (m, 1H), 2.41 – 2.33 (m, 1H), 1.43 – 1.38 (m, 9H), 0.63 – 0.52 (m, 1H), 0.20 – 0.13 (m, 1H). Example 113. Synthesis of tert-butyl (S)-4-(7-(5-cyano-1-methyl-1H-pyrazol-3-yl)-5- cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperaz ine-1-carboxylate (Compound 413) Step 1. Methyl 3-bromo-1-methyl-1H-pyrazole-5-carboxylate To a solution of methyl 3-bromo-1H-pyrazole-5-carboxylate (620 mg, 3.0 mmol) in DMF (6 mL) was added K ₂ CO ₃ (620 mg, 4.5 mmol) and MeI (2.1 g, 15 mmol). The mixture was stirred at 60 °C for 2 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, 0-40% ethyl acetate in petroleum ether) and concentrated to afford two compounds: Methyl 3-bromo-1-methyl-1H-pyrazole-5-carboxylate (420 mg, 63 %) as a white solid. LC/MS ESI (m/z): 219/221 (Br) (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.81 (s, 1H), 4.15 (s, 3H), 3.88 (s, 3H). Methyl 5-bromo-1-methyl-1H-pyrazole-3-carboxylate (190 mg, 29 %) as a white solid. LC/MS ESI (m/z): 219/221 (Br) (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.83 (s, 1H), 3.96 (s, 3H), 3.92 (s, 3H). Step 2.3-Bromo-1-methyl-1H-pyrazole-5-carboxamide Methyl 3-bromo-1-methyl-1H-pyrazole-5-carboxylate (500 mg, 2.3 mmol) was dissolved in MeOH (2 mL) and NH ₃ /H ₂ O (4 mL). The reaction mixture was heated at 100°C for 2 h. The reaction was cooled to rt, diluted with water and ethyl acetate and layers were separated. The organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to afford 3- bromo-1-methyl-1H-pyrazole-5-carboxamide as a white solid (290 mg, 63% yield). LC/MS ESI (m/z): 204/206 (Br) (M+H) ⁺ . Step 3.3-Bromo-1-methyl-1H-pyrazole-5-carbonitrile 3-Bromo-1-methyl-1H-pyrazole-5-carboxamide (280 mg, 1.4 mmol) was dissolved in PhP(O)Cl ₂ (3 mL) and stirred at 80°C overnight. After cooling in an ice bath, the reaction was quenched with aqueous NaHCO ₃ , diluted with brine and layers were separated. The organic layers were dried over Na ₂ SO ₄ , filtered, concentrated and purified by flash column chromatography (silica gel, 0~20% ethyl acetate in petroleum ether) to afford 3-bromo-1- methyl-1H-pyrazole-5-carbonitrile as a white solid (230 mg, 89% yield). LC/MS ESI (m/z): none. ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.77 (s, 1H), 4.04 (s, 3H). Step 5. tert-Butyl (S)-4-(7-(5-cyano-1-methyl-1H-pyrazol-3-yl)-5-cyclopropyl-7H - pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te To a solution of tert-butyl (S)-4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate (90 mg, 0.25 mmol, prepared following the procedure of compound 260, step 4) and 3-bromo-1-methyl-1H-pyrazole-5-carbonitrile (70 mg, 0.38 mmol) in DMF (1 mL) was added CuI (24 mg, 0.13 mmol), K ₃ PO ₄ (210 mg, 1.0 mmol) and trans-N,N’-dimethylcyclohexane-1,2-diamine (18 mg, 0.13 mmol) and the resulting mixture was stirred at 100℃ overnight under a N ₂ atmosphere. After being cooled down to room temperature, the reaction was partitioned between EtOAc and water, organic layers separated, aqueous layer extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na ₂ SO ₄ filter and concentrated. The residue was purified by flash column chromatography (silica gel, 0~40%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford tert-butyl (S)-4-(7-(5-cyano-1-methyl- 1H-pyrazol-3-yl)-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4- yl)-3-methylpiperazine-1- carboxylate (13 mg, 11 % yield) as a white solid. LC/MS ESI (m/z): 463 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.44 (s, 1H), 7.64 (s, 1H), 7.28 (s, 1H), 4.79 – 4.66 (m, 1H), 4.34 – 3.66 (m, 6H), 3.53 (t, J = 11.3 Hz, 1H), 3.36 – 3.03 (m, 2H), 2.06 – 1.95 (m, 1H), 1.49 (s, 9H), 1.22 (d, J = 6.4 Hz, 3H), 1.07 – 0.93 (m, 2H), 0.87 – 0.79 (m, 1H), 0.77 – 0.68 (m, 1H). Example 114. Synthesis of tert-butyl (S)-4-(7-(3-cyanocyclobutyl)-5-cyclopropyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (Compound 414) C ^{ompound 414} Step 1. tert-Butyl (S)-4-(5-cyclopropyl-7-(3-(methoxycarbonyl)cyclobutyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te To a solution of tert-butyl (S)-4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate (360 mg, 1.0 mmol, prepared following the procedure of compound 260, step 4) and methyl 3-hydroxycyclobutane-1-carboxylate (260 mg, 2.0 mmol) in dry toluene (5 mL) were added CMBP (480 mg, 2.0 mmol) under N ₂ atmosphere. The resulting mixture was stirred at 100℃ under N ₂ atmosphere overnight. After being cooled down to room temperature, the reaction was partitioned between EtOAc and water, organic layer separated, aqueous layer extracted with EtOAc twice, the combined organic layers washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~40%, ethyl acetate in petroleum ether) to afford tert-butyl (S)-4-(5-cyclopropyl-7-(3-(methoxycarbonyl)cyclobutyl)-7H-py rrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (330 mg, 71 %) as a white solid. LC/MS ESI (m/z): 470 (M+H) ⁺ . Step 2. (S)-3-(4-(4-(tert-Butoxycarbonyl)-2-methylpiperazin-1-yl)-5- cyclopropyl-7H- pyrrolo[2,3-d]pyrimidin-7-yl)cyclobutane-1-carboxylic acid To a solution of tert-butyl (S)-4-(5-cyclopropyl-7-(3-(methoxycarbonyl)cyclobutyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carbox ylate (300 mg, 0.64 mmol) in H ₂ O (5 mL) and THF (5 mL) was added LiOH (330 mg, 8.0 mmol) and the reaction was stirred for 3h at rt. The reaction was partitioned between EtOAc and water, aqueous layer separated, organic layer was extracted with NaHCO ₃ twice. The combined aqueous layers were neutralized with HCl (1.0 M) and stirred with EtOAc. The organic layers were separated, aqueous layer extracted with EtOAc twice, the combined organic layers washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to afford (S)-3-(4-(4-(tert- butoxycarbonyl)-2-methylpiperazin-1-yl)-5-cyclopropyl-7H-pyr rolo[2,3-d]pyrimidin-7- yl)cyclobutane-1-carboxylic acid as a white solid (140 mg, 47 % yield). LC/MS ESI (m/z): 456 (M+H) ⁺ . Step 3. tert-Butyl (S)-4-(7-(3-carbamoylcyclobutyl)-5-cyclopropyl-7H-pyrrolo[2, 3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of (S)-3-(4-(4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)-5- cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclobutane-1-ca rboxylic acid (130 mg, 0.30 mmol) in DMF (2 mL) and DIPEA (0.40 mL) was added NH ₄ Cl (60 mg, 1.1 mmol), HOBT (110 mg, 0.84 mmol) and EDCI (160 mg, 0.84 mol) and stirred at room temperature overnight. The reaction was quenched with NaHCO ₃ aqueous, diluted with brine and layers were separated. The organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to afford crude tert-butyl (S)-4-(7-(3-carbamoylcyclobutyl)-5-cyclopropyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te as an oil (150 mg, contained trapped DMF). LC/MS ESI (m/z): 455 (M+H) ⁺ . Step 4. tert-Butyl (S)-4-(7-(3-cyanocyclobutyl)-5-cyclopropyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl (S)-4-(7-(3-carbamoylcyclobutyl)-5-cyclopropyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (90 mg, contained trapped DMF) in DCM (4 mL) maintained in an ice bath and DIPEA (520 mg, 0.66 mL, 4.0 mmol) was added TFAA (420 mg, 0.27 mL, 2.0 mmol) and stirred at 0°C for 2h. The reaction was quenched with NaHCO ₃ aqueous, diluted with brine and layers were separated. The organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford a crude product which was further purified by prep-HPLC to afford tert-butyl (S)-4-(7-(3-cyanocyclobutyl)-5-cyclopropyl-7H-pyrrolo[2,3-d] pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate as a white solid (19 mg, 21 %). LC/MS ESI (m/z): 437 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.34 (s, 1H), 6.65 (s, 1H), 5.51 – 5.33 (m, 1H), 4.81 – 4.61 (m, 1H), 4.20 – 3.71 (m, 3H), 3.49 (t, J = 11.1 Hz, 1H), 3.40 – 3.20 (m, 2H), 3.18 – 2.99 (m, 3H), 2.94 – 2.82 (m, 2H), 2.02 – 1.87 (m, 1H), 1.48 (s, 9H), 1.19 (d, J = 6.3 Hz, 3H), 1.02 – 0.90 (m, 2H), 0.78 – 0.67 (m, 1H), 0.66 – 0.55 (m, 1H). Example 115. Synthesis of tert-butyl (S)-4-(7-(4-cyanopyridin-2-yl)-5-((R)-2- methylmorpholino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylp iperazine-1-carboxylate (Compound 417) Step 1. tert-Butyl (S)-4-(5-bromo-7-(4-chloropyridin-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl (S)-4-(5-bromo-7-(4-chloropyridin-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (100 mg, 0.20 mmol, prepared following the procedure outlined in compound 388) in DMF (5.0 mL) was added CuI (19 mg, 0.10 mmol), 6-methylmorpholin-3-one (45 mg, 0.40 mmol) and K ₂ CO ₃ (54 mg, 0.40 mmol ) at 25°C. The mixture was degassed with N ₂ three times. The mixture was then heated to 120°C and stirred at 120°C for 12 hrs. The mixture was cooled to 25°C and poured into H ₂ O (20 mL). The mixture was extracted with EtOAc twice, organic layers washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by column chromatography (silica gel, 20 – 25% petroleum ether/ethyl acetate) to afford tert-butyl (3S)- 4-(7-(4-chloropyridin-2-yl)-5-(2-methyl-5-oxomorpholino)-7H- pyrrolo[2,3-d]pyrimidin-4- yl)-3-methylpiperazine-1-carboxylate (60 mg, 55%) as a white solid. LC/MS ESI (m/z): 542 (M+H) ⁺ . Step 2. tert-Butyl (3S)-4-(7-(4-chloropyridin-2-yl)-5-(2-methylmorpholino)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te To a solution of tert-butyl (3S)-4-(7-(4-chloropyridin-2-yl)-5-(2-methyl-5- oxomorpholino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpipe razine-1-carboxylate (60 mg, 0.11 mmol ) in THF (5 mL) was added BH ₃ -THF(1.0 mL, 1.0M in THF) at 0°C under N ₂ . The mixture was warmed to 25°C and then stirred for 2 hrs. The reaction was quenched by addition of MeOH (10.0 mL) at 0°C and concentrated in vacuo. The crude product was purified by column chromatography (silica gel, 50:1 – 40:1 petroleum ether/ ethyl acetate) to afford tert-butyl (3S)-4-(7-(4-chloropyridin-2-yl)-5-(2-methylmorpholino)-7H-p yrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (40 mg, 68 %) as a white solid. LC/MS ESI (m/z): 528 (M+H) ⁺ . Step 3. tert-Butyl (3S)-4-(7-(4-cyanopyridin-2-yl)-5-(2-methylmorpholino)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te To a solution of tert-butyl (3S)-4-(7-(4-chloropyridin-2-yl)-5-(2-methylmorpholino)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carbox ylate (40 mg, 0.076 mmol ) in DMF (3 mL) was added Zn(CN) ₂ (53 mg, 0.45 mmol) and Pd(PPh ₃ ) ₄ (44 mg, 0.040 mmol ) at 25°C. The mixture was degassed with N ₂ three times and then heated to 120°C for 3 hrs. The mixture was poured into H ₂ O (10 mL) and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by column chromatography (silica gel, 50:1 – 30:1 petroleum ether/ ethyl acetate) and Prep-HPLC to afford tert-butyl (3S)-4-(7-(4- cyanopyridin-2-yl)-5-(2-methylmorpholino)-7H-pyrrolo[2,3-d]p yrimidin-4-yl)-3- methylpiperazine-1-carboxylate (10 mg, 26%) as a yellow solid. LC/MS ESI (m/z): 519 (M+H) ⁺ . Step 4. tert-Butyl (S)-4-(7-(4-cyanopyridin-2-yl)-5-((R)-2-methylmorpholino)-7H - pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te Racemic tert-butyl (3S)-4-(7-(4-cyanopyridin-2-yl)-5-(2-methylmorpholino)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (10 mg, 0.019 mmol) was separated by chiral Prep-HPLC (IA-H 4.6*250mm IPA+0.05%DEA 40% 8min). The longer retention time peak was labeled tert-butyl (S)-4-(7-(4-cyanopyridin-2-yl)- 5-((R)-2-methylmorpholino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 3-methylpiperazine-1- carboxylate (2.0 mg, 0.004 mmol) and was obtained as a white solid. LC/MS ESI (m/z): 519 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.30 (s, 1H), 8.52 (d, J = 4.8 Hz, 1H), 8.39 (s, 1H), 7.57 (s, 1H), 7.25 (d, J = 5.0 Hz, 1H), 4.98 (s, 1H), 4.29 – 4.04 (m, 2H), 3.93 – 3.69 (m, 4H), 3.43 – 3.30 (m, 2H), 3.28 – 3.11 (m, 2H), 2.80 (m, 1H), 2.55 – 2.33 (m, 2H), 1.43 (s, 9H), 1.10 – 1.05 (m, 3H), 0.83 – 0.76 (m, 3H) Example 116. Synthesis of tert-butyl (R)-4-(3-cyclopropyl-1-(3,5-difluorophenyl)-1H- pyrrolo[3,2-c]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (Compound 418) Step 1.3-Bromo-4-chloro-1H-pyrrolo[3,2-c]pyridine To a solution of 4-chloro-1H-pyrrolo[3,2-c]pyridine(1.0 g, 6.6 mmol ) in DMF (15 mL) at 0 ^o C was added NBS (1.7 g, 9.8 mmol) in portions. After the addition, the mixture was stirred at room temperature for 12 hrs. The reaction was quenched with saturated Na ₂ SO ₃ solution at 0 ^o C, and then was extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated to give the 3-bromo-4-chloro-1H- pyrrolo[3,2-c]pyridine (1.4 g, 94%) as a light yellow solid which was used directly in next step without further purification. LC/MS ESI (m/z): 231, 233 (M+H) ⁺ . Step 2.3-Bromo-4-chloro-1-(3,5-difluorophenyl)-1H-pyrrolo[3,2-c]p yridine A mixture of 3-bromo-4-chloro-1H-pyrrolo[3,2-c]pyridine (1.4 g, 6.0 mmol), (3,5- difluorophenyl)boronic acid (2.9 g, 18 mmol) , Cu(OAc) ₂ (2.8 g, 15 mmol) and pyridine (3.0 mL, 37 mmol) in DCM (50 mL) was stirred at room temperature for 48 hrs under an oxygen atmosphere. The reaction mixture was treated with ammonia, filtered, the filtrate extracted with DCM twice. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (silica gel, 0~30% ethyl acetate in petroleum ether, v/v) to give 3-bromo-4-chloro-1-(3,5-difluorophenyl)-1H- pyrrolo[3,2-c]pyridine (560 mg, 27%) as a solid. LC/MS ESI (m/z): 343, 345 (M+H) ⁺ . Step 3.3-Bromo-1-(3,5-difluorophenyl)-4-fluoro-1H-pyrrolo[3,2-c]p yridine To a solution of 3-bromo-4-chloro-1-(3,5-difluorophenyl)-1H-pyrrolo[3,2-c]pyr idine (100 mg, 0.30 mmol) in DMSO (2 mL) was added TBAF (4.0 mL, 1.0 M in THF). The resulting mixture was heated at 150 ^o C for 2 days. After being cooled down to room temperature, the reaction was quenched with ice water, extracted with EtOAc twice, the combined organic layers washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford 3-bromo-1-(3,5-difluorophenyl)-4-fluoro-1H-pyrrolo[3,2- c]pyridine (50 mg, 53%) as a yellow solid. LC/MS ESI (m/z): 327, 329 (M+H) ⁺ . Step 4. tert-Butyl (R)-4-(3-bromo-1-(3,5-difluorophenyl)-1H-pyrrolo[3,2-c]pyrid in-4- yl)-2-methylpiperazine-1-carboxylate A mixture of 3-bromo-1-(3,5-difluorophenyl)-4-fluoro-1H-pyrrolo[3,2-c]pyr idine (50 mg, 0.15 mmol) and tert-butyl (R)-2-methylpiperazine-1-carboxylate (310 mg, 1.5 mmol). was heated at 150 ^o C for 3 h. After cooling to room temperature, the reaction mixture was purified by flash column chromatography (silica gel, 0~35%, ethyl acetate in petroleum ether) to afford tert-butyl (R)-4-(3-bromo-1-(3,5-difluorophenyl)-1H-pyrrolo[3,2-c]pyrid in-4- yl)-2-methylpiperazine-1-carboxylate (30 mg, 38%) as a solid. LC/MS ESI (m/z): 507, 509 (M+H) ⁺ . Step 5. tert-Butyl (R)-4-(3-cyclopropyl-1-(3,5-difluorophenyl)-1H-pyrrolo[3,2- c]pyridin-4-yl)-2-methylpiperazine-1-carboxylate To a solution of tert-butyl (R)-4-(3-bromo-1-(3,5-difluorophenyl)-1H-pyrrolo[3,2- c]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (30 mg, 0.060 mmol) in toluene (15 mL) were added cyclopropylboronic acid (51 mg, 0.60 mmol), K ₂ CO ₃ (160 mg, 1.2 mmol) and Pd-118 (19 mg, 0.030 mmol). The resulting mixture was heated to 80 ^o C overnight. After cooling to room temperature, the reaction mixture was filtered. The filtrate was concentrated and purified by flash column chromatography (silica gel, 0~20%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford tert-butyl (R)-4-(3-cyclopropyl-1-(3,5-difluorophenyl)-1H-pyrrolo[3,2-c ]pyridin-4-yl)-2- methylpiperazine-1-carboxylate (6.8 mg, 24%) as a white solid. LC/MS ESI (m/z): 469 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.02 (d, J = 6.0 Hz, 1H), 7.11 (d, J = 6.0 Hz, 1H), 6.98 (dd, J = 9.9, 4.4 Hz, 2H), 6.87 – 6.80 (m, 2H), 4.49 – 4.42 (m, 1H), 4.10 – 4.03 (m, 1H), 4.00 – 3.94 (m, 1H), 3.61 – 3.54 (m, 1H), 3.44 – 3.30 (m, 2H), 2.91 – 2.79 (m, 1H), 2.40 – 2.33 (m, 1H), 1.50 (s, 9H), 1.31 (d, J = 6.7 Hz, 3H), 1.09 – 1.03 (m, 2H), 0.91 – 0.86 (m, 1H), 0.65 – 0.58 (m, 1H). The following compound was prepared analogous to the synthesis of compound 418 from the corresponding amine and aryl halide. Example 117. Synthesis of tert-butyl (S)-4-(7-(4-cyanopyridin-2-yl)-5-((R)-3- methylmorpholino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylp iperazine-1-carboxylate (Compound 419) Step 1.7-(4-Chloropyridin-2-yl)-5-iodo-4-methoxy-7H-pyrrolo[2,3-d ]pyrimidine To a solution of 5-iodo-4-methoxy-7H-pyrrolo[2,3-d]pyrimidine (1.0 g, 3.6 mmol ) in DMF(10 mL) was added CS ₂ CO ₃ (2.4 g, 7.3 mmol) and 4-chloro-2-fluoropyridine (0.96 g, 7.3 mmol ) at 25°C. The mixture was heated to 80°C and stirred for 4 hrs. The mixture was cooled to 25°C and poured into H ₂ O (50 mL) extracted with EtOAc (50 mL x 4). The combined organic phase was washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated. The crude product was purified by silica gel column chromatography (SiO ₂ , petroleum ether:EtOAc 30:1) to give 7-(4-chloropyridin-2-yl)-5- iodo-4-methoxy-7H- pyrrolo[2,3-d]pyrimidine (1.2 g , 3.1 mmol) as a white solid. LC/MS ESI (m/z): 387 (M+H) ⁺ . Step 2. (R)-4-(7-(4-Chloropyridin-2-yl)-4-methoxy-7H-pyrrolo [2,3-d ]pyrimidin-5- yl)-5-methylmorpholin-3-one To a solution of 7-(4-chloropyridin-2-yl)-5-iodo-4-methoxy-7H-pyrrolo[2,3- d]pyrimidine (1.0 g, 2.6 mmol) in DMF (10 mL) was added (6R)-6-methylpiperidin-2-one (0.59 g, 5.2 mmol), K ₃ PO ₄ (1.1 g, 5.2 mmol), CuI (0.088 mL, 2.6 mmol) and trans-N,N'- dimethyl-1,2-cyclohexanediamine (0.74 g, 5.2 mmol ) at 25°C. The mixture was degassed with N ₂ 3 times. The mixture was heated to 120°C and stirred for 12 hrs. The mixture was cooled to 25°C and poured into H ₂ O (50 mL). The mixture was extracted with EtOAc (50 mL x 4). The combined organic phase was washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated. The crude product was purified by silica gel column (SiO ₂ , petroleum ether: EtOAc = 10 : 1) to provide (R)-4-(7-(4-chloropyridin-2-yl)-4-methoxy-7H-pyrrolo[2,3- d]pyrimidin-5-yl)-5-methylmorpholin-3-one (50 mg, 5.0%) as a white solid. LC/MS ESI (m/z): 374 (M+H) ⁺ . Step 3. (R)-4-(7-(4-Chloropyridin-2-yl)-4-methoxy-7H-pyrrolo[2,3-d]p yrimidin-5-yl) -3- methylmorpholine To a solution of (R)-4-(7-(4-chloropyridin-2-yl)-4-methoxy-7H-pyrrolo[2,3- d]pyrimidin-5-yl)-5-methylmorpholin-3-one (50 mg, 0.13 mmol) in THF (2 mL) was added BH ₃ -THF(1.0 mL, 1.0M in THF) at 0°C. The mixture was warmed to 25°C and stirred for 2 hrs. The reaction was quenched by addition of MeOH (5 mL) at 0°C. The mixture was concentrated, and the product was purified by silica gel column chromatography (SiO ₂ , petroleum ether: EtOAc = 50 : 1 to 30 : 1) to provide (R)-4-(7-(4-chloropyridin-2-yl)-4- methoxy-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylmorpholine (40 mg , 85%) as a white solid. LC/MS ESI (m/z): 360 (M+H) ⁺ . Step 4. (R)-7-(4-Chloropyridin-2-yl)-5-(3-methylmorpholino)-7H-pyrro lo[2,3-d] pyrimidin-4-ol To a solution of (R)-4-(7-(4-chloropyridin-2-yl)-4-methoxy-7H-pyrrolo[2,3- d]pyrimidin-5-yl)-3-methylmorpholine (40 mg, 0.11 mmol ) in DMF (5 mL) was added LiCl (4.7mg, 0.11 mmol) and p-toluenesulfonic acid (0.18 mg, 1.1 mmol) at 25°C. The mixture was degassed with N ₂ 3 times. The mixture was heated to 120°C then cooled to 25°C and poured into H ₂ O (30 mL). The mixture was extracted with EtOAc (50 mL x 4). The combined organic phase was washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated. The product (R)-7-(4-chloropyridin-2-yl)-5-(3-methylmorpholino)-7H- pyrrolo[2,3-d]pyrimidin-4-ol (60 mg) was carried directly to the next step without further purification. LC/MS ESI (m/z): 346 (M+H) ⁺ . Step 5. (R)-4-(4-Chloro-7-(4-chloropyridin-2-yl)-7H-pyrrolo[2,3-d]py rimidin-5-yl)-3- methylmorpholine To a solution of (R)-7-(4-chloropyridin-2-yl)-5-(3-methylmorpholino)-7H-pyrro lo [2,3-d]pyrimidin-4-ol (0.11 mmol, theoretical) in POCl ₃ (2.0 mL, 22 mmol) was heated to 120°C and stirred for 12 hrs. The mixture was concentrated under vacuo to remove POCl ₃ . The residue was diluted with EtOAc (10 mL) and washed with H ₂ O (10 ml x 3). The combined organic phase was washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated. Purification by silica gel column chromatography (SiO ₂ , petroleum ether:EtOAc = 50 : 1 to 30 : 1) provided (R)-4-(4-chloro-7-(4-chloropyridin-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-5-yl)-3-methyl morpholine (30 mg , 75%, over 2 steps) as a white solid. LC/MS ESI (m/z): 364 (M+H) ⁺ . Step 6. tert-Butyl (S)-4-(7-(4-chloropyridin-2-yl)-5 -((R)-3-methylmorpholino)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te To a solution of (R)-4-(4-chloro-7-(4-chloropyridin-2-yl) -7H-pyrrolo[2,3- d]pyrimidin-5-yl)-3-methylmorpholine (30 mg, 0.082 mmol) in DIEA (1.0 mL) was added tert-butyl (3S)-3-methylpiperazine-1-carboxylate (36 mg, 0.33 mmol) at 25°C. The mixture was heated 120°C and stirred for 2hrs. The mixture was concentrated under vacuo. The crude product was purified by silica gel column chromatography (SiO ₂ , petroleum ether: EtOAc = 50 : 1 to 30 : 1) to provide tert-butyl (S)-4-(7-(4-chloropyridin-2-yl)-5-((R)-3- methylmorpholino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylp iperazine-1-carboxylate (15 mg , 34%) as a white solid. LC/MS ESI (m/z): 528 (M+H) ⁺ . Step 7. tert-Butyl (S)-4-(7-(4-cyanopyridin-2-yl)-5-((R)-3-methylmorpholino) -7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te To a solution of tert-butyl (S)-4-(7-(4-chloropyridin-2-yl)-5-((R)-3- methylmorpholino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylp iperazine-1-carboxylate (15 mg, 0.028 mmol) in DMF (5 mL) was added Zn(CN) ₂ (20 mg, 0.17 mmol) and Pd(PPh ₃ ) ₄ (33 mg, 0.028 mmol ) at 25°C. The mixture was degassed with N ₂ 3 times. The mixture was heated to 120°C and stirred for 3 hrs. The mixture was cooled to 25°C and poured into H ₂ O (10 mL). The mixture was extracted with EtOAc (50 mL x 4). The combined organic phase was washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated. The product was purified by silica gel column (SiO ₂ , petroleum ether: EtOAc = 50 : 1 to 30 : 1) followed by Prep-HPLC (0.1% formic acid) to provide tert-butyl (S)-4-(7-(4-cyanopyridin-2-yl) -5-((R)-3- methylmorpholino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylp iperazine-1-carboxylate(1.0 mg, 6.9%) as a white solid. LC/MS ESI (m/z): 519 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.38 (s, 1H), 8.59 (d, J = 4.9 Hz, 1H), 8.43 (s, 1H), 7.88 (s, 1H), 7.34 (d, J = 5.0 Hz, 1H), 5.29 – 4.54 (m, 2H), 4.35 – 4.04 (m, 1H), 3.99 – 3.85 (m, 3H), 3.84 – 3.74 (m, 1H), 3.50 – 3.39 (m, 1H), 3.36 – 3.27 (m, 1H), 3.23 – 3.03 (m, 4H), 2.93 (s, 1H), 1.50 (s, 9H), 1.26 (d, J = 6.3 Hz, 3H), 0.98 (d, J = 6.2 Hz, 3H). The following compound was prepared an analogous procedure to the synthesis of compound 419 from the corresponding acid anhydride. Example 118. Synthesis of tert-butyl (S)-4-(7-(4-cyanopyridin-2-yl)-5-(diethylamino)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carbox ylate (Compound 424) and 1,1,1-trifluoro-2-methylpropan-2-yl (S)-4-(7-(4-cyanopyridin-2-yl)-5-

(diethylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylp iperazine-1-carboxylate (Compound 422) Step 1. tert-Butyl (S)-4-(7-(4-chloropyridin-2-yl)-5-(N-ethylacetamido)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te At 0°C, to tert-butyl (S)-4-(5-acetamido-7-(4-chloropyridin-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (400 mg, 0.82 mmol) in dry DMF (5 mL) under N ₂ was added NaH (130 mg, 60% in mineral oil, 3.3 mmol). The mixture was stirred at rt for 15 min. Then CH ₃ CH ₂ I (260 mg, 1.7 mmol) was added. The mixture was stirred for an additional 20 min and was quenched with ice and extracted with EtOAc. The organic layer was washed with 5% LiCl (aq) and brine, dried over Na ₂ SO ₄ , and concentrated. The residue was purified by flash column chromatography (silica gel, 0~33% EtOAc in petroleum ether) to provide tert-butyl (S)-4-(7-(4-chloropyridin-2-yl)-5-(N-ethylacetamido)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carbox ylate (280 mg, 66%) as a yellow foam. LC/MS ESI (m/z): 514 (M+H) ⁺ . Step 2. tert-Butyl (S)-4-(7-(4-chloropyridin-2-yl)-5-(diethylamino)-7H-pyrrolo[ 2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate At 0°C, to tert-butyl (S)-4-(7-(4-chloropyridin-2-yl)-5-(N-ethylacetamido)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (280 mg, 0.55 mmol) in dry THF (4 mL) was added BH ₃ -THF (8.0 mL, 1.0 M in THF) dropwise under N ₂ . The mixture was stirred at 0°C for 2 h. Then it was carefully quenched with MeOH and concentrated. The residue was partitioned between EtOAc and brine. The organic layer was dried over Na ₂ SO ₄ and purified by flash column chromatography (silica gel, 0~13% EtOAc in petroleum ether) to provide tert-butyl (S)-4-(7-(4-chloropyridin-2-yl)-5-(diethylamino)-7H-pyrrolo[ 2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (160 mg, 56%) as a light yellow oil. LC/MS ESI (m/z): 500 (M+H) ⁺ . Step 3. tert-Butyl (S)-4-(7-(4-cyanopyridin-2-yl)-5-(diethylamino)-7H-pyrrolo[2 ,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate In a sealed tube were added Zn(CN) ₂ (90 mg, 0.77 mmol) and Pd(PPh ₃ ) ₄ (90 mg, 0.078 mmol). Then tert-butyl (S)-4-(7-(4-chloropyridin-2-yl)-5-(diethylamino)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (160 mg, 0.31 mmol) in dry DMF (3 mL) was added. The tube was purged with N ₂ and sealed. The mixture was stirred at 120°C for 2.5 h and was allowed to cool to rt. The mixture was partitioned between EtOAc and brine. The organic layer was washed with 5% LiCl (aq) and brine, dried over Na ₂ SO ₄ , and purified by flash column chromatography (silica gel, 0~14% EtOAc in petroleum ether). Further purification by prep-HPLC provided tert-butyl (S)-4-(7-(4-cyanopyridin-2-yl)-5- (diethylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpipe razine-1-carboxylate (140 mg, 92%) as a yellow foam.35 mg of this product was further purified by prep-HPLC and prep- TLC to provide 12 mg of the pure compound for submission. LC/MS ESI (m/z): 491 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.38 (s, 1H), 8.57 (d, J = 5.0 Hz, 1H), 8.43 (s, 1H), 7.62 (s, 1H), 7.29 (dd, J = 5.0, 1.1 Hz, 1H), 5.13 (d, J = 27.8 Hz, 1H), 4.45 – 3.80 (m, 3H), 3.38 (t, J = 12.1 Hz, 1H), 3.30 – 3.10 (m, 5H), 3.01 (d, J = 10.5 Hz, 1H), 1.50 (s, 9H), 1.16 (d, J = 5.1 Hz, 3H), 1.02 (t, J = 7.0 Hz, 6H). Step 4. (S)-2-(5-(Diethylamino)-4-(2-methylpiperazin-1-yl)-7H-pyrrol o[2,3- d]pyrimidin-7-yl)isonicotinonitrile To tert-butyl (S)-4-(7-(4-cyanopyridin-2-yl)-5-(diethylamino)-7H-pyrrolo[2 ,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (110 mg, 0.22 mmol) in DCM (8 mL) was added TFA (1.0 mL) dropwise at rt. The mixture was stirred at rt for 3 h and was diluted with DCM and quenched with NaHCO ₃ (aq.). The organic layer was separated, washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated to give (S)-2-(5-(diethylamino)-4-(2- methylpiperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)isonic otinonitrile which was used directly in the next step. LC/MS ESI (m/z): 391 (M+H) ⁺ . Step 5.1,1,1-Trifluoro-2-methylpropan-2-yl (S)-4-(7-(4-cyanopyridin-2-yl)-5- (diethylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpipe razine-1-carboxylate To (S)-2-(5-(diethylamino)-4-(2-methylpiperazin-1-yl)-7H-pyrrol o[2,3-d]pyrimidin-7- yl)isonicotinonitrile (50 mg, 0.13 mmol) and 1,1,1-trifluoro-2-methylpropan-2-yl 1H- imidazole-1-carboxylate (85 mg, 0.38 mmol) in DMF (2 mL) was added DIPEA (66 mg, 0.51 mmol). The mixture was stirred at 80°C under N ₂ for 24 h. The mixture was partitioned between EtOAc and brine. The organic layer was washed with 5% LiCl (aq) and brine, dried over Na ₂ SO ₄ , and concentrated. Purification by flash column chromatography (silica gel, 0~14% EtOAc in petroleum ether) followed by prep-HPLC provided 1,1,1-trifluoro-2- methylpropan-2-yl (S)-4-(7-(4-cyanopyridin-2-yl)-5-(diethylamino)-7H-pyrrolo[2 ,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (34 mg, 48%) as a yellow solid. LC/MS ESI (m/z): 545 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.38 (s, 1H), 8.58 (d, J = 4.5 Hz, 1H), 8.44 (s, 1H), 7.63 (s, 1H), 7.30 (dd, J = 5.0, 1.1 Hz, 1H), 5.15 (d, J = 30.0 Hz, 1H), 4.51 – 4.23 (m, 1H), 4.09 (dd, J = 67.8, 12.8 Hz, 1H), 3.88 (dd, J = 40.2, 13.3 Hz, 1H), 3.45 – 3.26 (m, 2H), 3.24 – 2.99 (m, 5H), 1.72 (s, 6H), 1.16 (d, J = 6.6 Hz, 3H), 1.02 (t, J = 7.0 Hz, 6H). Example 119. Synthesis of tert-butyl (S)-4-(7-(4-cyanopyridin-2-yl)-5-(dimethylamino)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carbox ylate (Compound 426) C ^{ompound 426} Step 1. tert-Butyl (S)-4-(7-(4-chloropyridin-2-yl)-5-formamido-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate The mixed anhydride was prepared by stirring a mixture of Ac ₂ O (2 mL) and HCOOH (0.9 mL) at 60°C under N ₂ for 2 h. To (S)-4-(4-(tert-butoxycarbonyl)-2- methylpiperazin-1-yl)-7-(4-chloropyridin-2-yl)-7H-pyrrolo[2, 3-d]pyrimidine-5-carboxylic acid (400 mg, 0.85 mmol, prepared following the procedure outlined in compound 427 in toluene (9 mL) were added DPPA (300 mg, 1.1 mmol) and Et ₃ N (170 mg, 1.7 mmol). The mixture was stirred at rt under N ₂ for 3 h. Then 1.5 mL of HCOOH and 1.6 mL of the mixed anhydride were added, and the mixture was heated to 60°C and stirred for 1 h. NaHCO ₃ (aq.) was added and the mixture was extracted with EtOAc, dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash column chromatography (silica gel, 0~40% EtOAc in petroleum ether) to give tert-butyl (S)-4-(7-(4-chloropyridin-2-yl)-5-formamido-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (280 mg, 70%) as a light yellow foam. LC/MS ESI (m/z): 472 (M+H) ⁺ . Step 2. tert-Butyl (S)-4-(7-(4-chloropyridin-2-yl)-5-(N-methylformamido)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te tert-Butyl (S)-4-(7-(4-chloropyridin-2-yl)-5-formamido-7H-pyrrolo[2,3-d ]pyrimidin- 4-yl)-3-methylpiperazine-1-carboxylate (280 mg, 0.59 mmol) in DMF (5 mL) was cooled in an ice bath under N ₂ for 10 min. Then NaH (95 mg, 60% in mineral oil, 2.4 mmol) was added. The mixture was stirred at rt for 15 min. Then it was cooled in the ice bath and CH ₃ I (170 mg, 1.2 mmol) was added. After 30 min, the mixture was carefully quenched with ice. The mixture was extracted with EtOAc, washed with 5% LiCl (aq.) and brine, dried over Na ₂ SO ₄ , and concentrated to dryness to provide tert-butyl (S)-4-(7-(4-chloropyridin-2-yl)-5- (N-methylformamido)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methy lpiperazine-1-carboxylate (280 mg, 97%), which was used directly in the next step. LC/MS ESI (m/z): 486 (M+H) ⁺ . Step 3. tert-Butyl (S)-4-(7-(4-chloropyridin-2-yl)-5-(dimethylamino)-7H-pyrrolo [2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate Tert-butyl (S)-4-(7-(4-chloropyridin-2-yl)-5-(N-methylformamido)-7H-pyr rolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (280 mg, 0.58 mmol) in dry THF (6 mL) was cooled in an ice-bath for 15 min. Then BH ₃ -Me ₂ S (3.0 mL, 2.0 M in THF) was added dropwise. The mixture was stirred at this temperature for 1.5 h and was carefully quenched with MeOH. The mixture was partitioned between EtOAc and H ₂ O. The organic layer was dried over Na ₂ SO ₄ and purified by flash column chromatography (silica gel, 0~14% EtOAc in petroleum ether) to provide tert-butyl (S)-4-(7-(4-chloropyridin-2-yl)-5-(dimethylamino)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carbox ylate (160 mg, 57%) as a light yellow foam. LC/MS ESI (m/z): 472 (M+H) ⁺ . Step 4. tert-Butyl (S)-4-(7-(4-cyanopyridin-2-yl)-5-(dimethylamino)-7H-pyrrolo[ 2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate In a sealed tube, to Zn(CN) ₂ (95 mg, 0.81 mmol) and Pd(PPh ₃ ) ₄ (95 mg, 0.082 mmol) was added a solution of tert-butyl (S)-4-(7-(4-chloropyridin-2-yl)-5-(dimethylamino)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (160 mg, 0.33 mmol) in DMF (3 mL). The mixture was purged with N ₂ and stirred at 120°C for 3 h. The mixture was partitioned between EtOAc and brine. The organic layer was washed with LiCl (5% aq.) and brine and concentrated. Purification by flash column chromatography (silica gel, 0~20% EtOAc in petroleum ether) provided tert-butyl (S)-4-(7-(4-cyanopyridin-2-yl)-5- (dimethylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpip erazine-1-carboxylate (150 mg, 95%) as a yellow foam.60 mg of this product was further purified by prep-HPLC to give 40 mg of the pure product for submission. LC/MS ESI (m/z): 463 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.36 (s, 1H), 8.58 (d, J = 5.0 Hz, 1H), 8.44 (s, 1H), 7.57 (s, 1H), 7.30 (dd, J = 5.0, 1.2 Hz, 1H), 5.04 (s, 1H), 4.35 – 3.84 (m, 3H), 3.42 (td, J = 13.0, 3.2 Hz, 1H), 3.29 (s, 1H), 3.12 – 2.93 (m, 1H), 2.77 (s, 6H), 1.49 (s, 9H), 1.17 (d, J = 6.6 Hz, 3H). The following compound was prepared by an analogous synthetic procedure to that described for compound 426, except using (S)-4-(4-(tert-butoxycarbonyl)-2-methylpiperazin- 1-yl)-7-(3-chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbo xylic acid as the starting material. Example 120. tert-Butyl (R)-4-(7-(4-cyanopyridin-2-yl)-5-(dimethylamino)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxyla te (Compound 427) C ^{ompound 427} Step 1. (R)-4-(4-(tert-Butoxycarbonyl)-3-methylpiperazin-1-yl)-7-(4- chloropyridin -2- yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid To a solution of methyl (R)-4-(4-(tert-butoxycarbonyl)-3-methylpiperazin-1-yl)-7-(4- chloropyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylat e (2.0 g, 4.1 mmol, prepared following the procedure outlined in compound 443) in H ₂ O (4.0 mL) and MeOH (16 mL) was added NaOH (0.66 g, 16 mmol ) at 25°C. The mixture was heated to 70°C and stirred for 12 hrs. The mixture was cooled to 25°C and poured into H2O (40 mL) and adjusted to pH = 7 with NaOH (2N). The mixture was extracted with EtOAc (50 mL x 4). The combined organic phase was washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated. The crude product was purified by silica gel column chromatography (SiO ₂ , petroleum ether: EtOAc = 50 : 1 to 30 : 1) to provide (R)-4-(4-(tert-butoxycarbonyl)-3-methylpiperazin-1-yl)-7-(4- chloropyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid (800 mg , 41%). LC/MS ESI (m/z): 471 (M-H)-. Step 2. tert-Butyl(R)-4-(7-(4-cyanopyridin-2-yl)-5-(dimethylamino)-7 H-pyrrolo[2,3-d] pyrimidin -4-yl)-2-methylpiperazine-1-carboxylate To a solution of (R)-4-(4-(tert-butoxycarbonyl)-3-methylpiperazin-1-yl)-7-(4- chloropyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid (200 mg, 0.42 mmol ) in toluene (3 mL) was added Et ₃ N (86 mg, 0.85 mmol) and DPPA (0.18 mL, 0.85 mmol) at 25°C. The mixture was stirred at 25°C for 2 hrs. Then HCOOH (39 mg, 0.85 mmol) was added to the mixture at 25°C. Formyl acetate (75 mg, 0.85 mmol) was added to the mixture at 25°C. The mixture was heated to 60°C and stirred for 2 hrs then cooled to 25°C. The mixture was poured into H ₂ O (100 mL) and extracted with EtOAc (50 mL x 4). The combined organic phase was washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated. The crude product was purified by silica gel column (SiO ₂ , petroleum ether:EtOAc = 100 : 1 to 10 : 1) to give tert-butyl (R)-4-(7-(4-cyanopyridin-2-yl)-5-(dimethylamino)-7H-pyrrolo[ 2,3- d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate (200 mg, 0.42 mmol ). LC/MS ESI (m/z): 472 (M+H) ⁺ . Step 3. tert-Butyl (R)-4-(7-(4-chloropyridin-2-yl)-5-(N-methylformamido)- 7H-pyrrolo [2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate To a solution of tert-butyl (R)-4-(7-(4-chloropyridin-2-yl)-5-formamido-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxyla te (100 mg, 0.21 mmol) in THF (2 mL) was added NaH (17 mg, 0.42 mmol ) at 0°C. The mixture was stirred at 0°C for 1 hr and then MeI (60 mg, 0.42 mmol) was added to the mixture at 0°C. The mixture was warmed to 25°C and stirred at 25°C for 3 hrs. The mixture was quenched by addition sat. NH ₄ Cl (5.0 mL) and poured into H ₂ O (100 mL) and extracted with EtOAc (50.0 mL x 4). The combined organic phase was washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated. The crude product was purified by silica gel column (SiO ₂ , petroleum ether: EtOAc = 50 : 1 to 30 : 1) to give tert-butyl (R)-4-(7-(4-chloropyridin-2-yl)-5-(N- methylformamido)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpi perazine-1-carboxylate (60.0 mg, 59%) as a white solid. LC/MS ESI (m/z): 486(M+H) ⁺ . Step 4. tert-Butyl (R)-4-(7-(4-chloropyridin-2-yl)-5-(dimethylamino)-7H-pyrrolo [2,3- d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate To a solution of tert-butyl (R)-4-(7-(4-chloropyridin-2-yl)-5-(N-methylformamido)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carbox ylate (50 mg, 0.10 mmol) in THF(5 mL) was added BH ₃ -THF (0.51 mL, 1.0M in THF) at 0°C. The mixture was stirred at 25°C for 2 hrs and then quenched by addition of MeOH (5.0 ml). The mixture was concentrated, and the crude product was purified by silica gel column (SiO ₂ , petroleum ether:EtOAc = 50 : 1 to 40 : 1) to give tert-butyl (R)-4-(7-(4-chloropyridin-2-yl)-5- (dimethylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpip erazine-1-carboxylate (30 mg , 64%) as a white solid. LC/MS ESI (m/z): 472 (M+H) ⁺ . Step 5. tert-Butyl (R)-4-(7-(4-cyanopyridin-2-yl)-5-(dimethylamino)-7H-pyrrolo [2,3- d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate To a solution of tert-butyl (R)-4-(7-(4-chloropyridin-2-yl)-5-(dimethylamino)- 7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxyla te (30 mg, 0.064 mmol ) in DMF (5 mL) was added Zn(CN) ₂ (45 mg, 0.38 mmol ) and Pd(PPh ₃ ) ₄ (37 mg, 0.032 mmol ) at 25°C. The mixture was purged with N ₂ 3 times. The mixture was heated to 120°C and stirred for 3 hrs. The mixture was cooled to 25°C, poured into H ₂ O (100 mL), and extracted with EtOAc (50 mL x 4). The combined organic phase was washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated. The product was purified by silica gel column (SiO ₂ , petroleum ether:EtOAc = 50 : 1 to 30 : 1) to give tert-butyl (R)-4-(7-(4-cyanopyridin-2-yl)-5- (dimethylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpip erazine-1-carboxylate (10 mg, 34%) as a yellow solid. LC/MS ESI (m/z): 463 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.36 (s, 1H), 8.58 (d, J = 5.0 Hz, 1H), 8.43 (s, 1H), 7.58 (s, 1H), 7.30 (dd, J = 5.0, 1.2 Hz, 1H), 4.81 (d, J = 12.1 Hz, 1H), 4.45 (d, J = 13.4 Hz, 1H), 4.38 (s, 1H), 3.93 (d, J = 13.2 Hz, 1H), 3.44 – 3.32 (m, 1H), 3.26 (dd, J = 13.2, 3.6 Hz, 1H), 2.99 (td, J = 12.4, 3.2 Hz, 1H), 2.78 (s, 6H), 1.49 (s, 9H), 1.11 (d, J = 6.8 Hz, 3H). The following compounds were prepared by an analogous procedure to the synthesis of compound 427 from the corresponding acid anhydrides and the appropriate coupling partners/amines in different steps of the synthesis. Example 121. Synthesis of tert-butyl 4-(7-(4-cyanopyridin-2-yl)-5-cyclopropyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]octane-7-ca rboxylate (Compound 429) C ^{ompound 429} Step 1.2-(5-Bromo-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-7-yl)isoni cotinonitrile To a solution of 5-bromo-4-methoxy-7H-pyrrolo[2,3-d]pyrimidine (5.0 g, 22 mmol) in DMF (25 mL) were added 2-fluoroisonicotinonitrile (5.4 g, 44 mmol) and Cs ₂ CO ₃ (36 g, 110 mmol). Then the resulting mixture was stirred at 50 ^o C for 5h. The reaction was quenched with water, extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to afford 2-(5- bromo-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-7-yl)isonicotinon itrile (6.0 g, 83%) as a yellow solid. LC/MS ESI (m/z): 330, 332 (M+H) ⁺ . Step 2.2-(5-Bromo-4-hydroxy-7H-pyrrolo[2,3-d]pyrimidin-7-yl)isoni cotinonitrile To a solution of 2-(5-bromo-4-methoxy-7H-pyrrolo [2,3-d]pyrimidin-7- yl)isonicotinonitrile (6.0 g, 18 mmol) in DMF (20 mL) were added 4-methylbenzenesulfonic acid (31 g, 180 mmol) and LiOH (7.7 g, 180 mmol). Then the resulting mixture was stirred at 110 ^o C for 2 h. The reaction was quenched with water, extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to afford 2-(5-bromo-4-hydroxy-7H-pyrrolo[2,3- d]pyrimidin-7-yl)isonicotinonitrile (5.5 g, 96%) as a yellow solid. LC/MS ESI (m/z): 316, 318 (M+H) ⁺ . Step 3.2-(5-Bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)isonic otinonitrile To a solution of POCl ₃ (20 mL) was added 2-(5-bromo-4-hydroxy-7H-pyrrolo[2,3- d]pyrimidin-7-yl)isonicotinonitrile (5.5 g, 17 mmol) . The resulting mixture was stirred at 120 ^o C under N ₂ atmosphere overnight. The solvent was removed, and the residue poured into water and extracted with EtOAc twice. The combined organic layers were dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 0~30% EtOAc in petroleum ether) to afford 2-(5-bromo-4-chloro-7H-pyrrolo[2,3- d]pyrimidin-7-yl) isonicotinonitrile (5.0 g, 86%) as a light yellow solid. LC/MS ESI (m/z): 334,336 (M+H) ⁺ . Step 4.2-(5-Bromo-4-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)isonic otinonitrile To a solution of 2-(5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7- yl)isonicotinonitrile (500 mg, 1.5 mmol) in THF (5 mL) were added TBAF (5.0 ml, 1.0M in THF) at 0 ^o C. The resulting mixture was stirred at room temp overnight, then quenched with water, and extracted with EtOAc twice. The combined organic layers were dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to afford 2-(5-bromo-4- fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)isonicotinonitrile (100 mg, 25%) as a light yellow solid. LC/MS ESI (m/z): 318,320 (M+H) ⁺ . Step 5. tert-Butyl 4-(5-bromo-7-(4-cyanopyridin-2-yl)-7H-pyrrolo[2,3-d] pyrimidin-4- yl)-4,7-diazaspiro[2.5]octane-7-carboxylate To a solution of 2-(5-bromo-4-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl) isonicotinonitrile (100 mg, 031 mmol) was added tert-butyl 4,7-diazaspiro[2.5]octane-7- carboxylate (270 mg, 1.3 mmol). The resulting mixture was stirred at 150 ^o C under N ₂ atmosphere for 3 hours. After cooling to room temperature, the mixture was diluted with EtOAc, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to afford tert-butyl 4-(5-bromo-7-(4- cyanopyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4,7-diaz aspiro[2.5]octane-7- carboxylate (80 mg, 50%) as a yellow solid. LC/MS ESI (m/z): 510, 512 (M+H) ⁺ . Step 6. tert-Butyl 4-(7-(4-cyanopyridin-2-yl)-5-cyclopropyl- 7H-pyrrolo[2,3- d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]octane-7-carboxylate To a solution of tert-butyl 4-(5-bromo-7-(4-cyanopyridin-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]octane-7-carboxylate (80 mg, 0.16 mmol) in toluene (5 mL) were added cyclopropylboronic acid (27 mg, 0.31 mmol), K ₂ CO ₃ (430 mg, 3.1 mmol) and Pd-118 (4.0 mg, 0.020 mmol). The resulting mixture was heated to 90 ^o C overnight. After cooling to room temperature, the solvent was removed. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to give the product (80 mg) which was further purified by prep-HPLC to afford tert-butyl 4-(7-(4- cyanopyridin-2-yl)-5-cyclopropyl-7H-pyrrolo[2,3-d] pyrimidin-4-yl)-4,7- diazaspiro[2.5]octane-7-carboxylate (35 mg, 40%) as a white solid. LC/MS ESI (m/z): 472 (M+H) ⁺ . ¹ H NMR(400 MHz, CDCl ₃ ) δ 9.25 (s, 1H), 8.54 – 8.48 (m, 2H), 7.69 (s, 1H), 7.28 – 7.26 (m, 1H), 3.91 – 3.79 (m, 2H), 3.69 – 3.58 (m, 2H), 3.49 – 3.21 (m, 2H), 1.92 – 1.84 (m, 1H), 1.41 (s, 9H), 0.97 – 0.88 (m, 4H), 0.75 – 0.64 (m, 4H). The following compounds were prepared by an analogous procedures to the synthesis of compound 429 from the corresponding amine (tert-butyl 3,3-dimethylpiperazine-1- carboxylate) Example 122. tert-butyl (S)-4-(7-(6-cyanopyrimidin-4-yl)-5-cyclopropyl-7H-pyrrolo[2, 3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Compound 431) Step 1. tert-Butyl (S)-4-(7-(6-chloropyrimidin-4-yl)-5-cyclopropyl-7H-pyrrolo[2 ,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl (3S)-4-{5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl}- 3-methylpiperazine-1-carboxylate (100 mg, 0.28 mmol, prepared following the procedure outlined in compound 259) in DMF (5 mL) were added 4,6-dichloropyrimidine (0.051 mL, 0.56 mmol) and Cs ₂ CO ₃ (180 mg, 0.56 mmol) at 25°C. The mixture was stirred at 25°C for 12 hr, then poured into H ₂ O (500 mL) and extracted with EtOAc twice. The combined organic phases were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated. The crude product was purified by silica gel column (SiO ₂ , petroleum ether: EtOAc = 40 : 1 to 30 : 1) to give tert-butyl (S)-4-(7-(6-chloropyrimidin-4-yl)-5-cyclopropyl -7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (110 mg, 82%) as a yellow solid. LC/MS ESI (m/z): 470 (M+H) ⁺ . Step 2. tert-Butyl (S)-4-(7-(6-cyanopyrimidin-4-yl)-5-cyclopropyl -7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl (S)-4-(7-(6-chloropyrimidin-4-yl)-5-cyclopropyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (20 mg, 0.040 mmol) in DMF (5 mL) were added Zn(CN) ₂ (28 mg, 0.24 mmol) and Pd(PPh ₃ ) ₄ (23 mg, 0.020 mmol) at 25°C. The mixture was degassed with N ₂ 3 times followed by stirring at 120°C for 3 hrs. The mixture was cooled to 25°C, poured into H ₂ O (100 mL), and extracted with EtOAc twice. The combined organic phases were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by Prep-HPLC (0.1% formic acid). tert-butyl (S)- 4-(7-(6-cyanopyrimidin-4-yl)-5-cyclopropyl-7H-pyrrolo [2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate (11 mg, 55%) to provide as a yellow solid. LC/MS ESI (m/z): 461 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.53 (d, J = 1.0 Hz, 1H), 9.04 (d, J = 0.9 Hz, 1H), 8.51 (s, 1H), 7.77 (s, 1H), 4.71 (s, 1H), 4.26 – 3.73 (m, 3H), 3.54 (t, J = 11.4 Hz, 1H), 3.39 – 2.93 (m, 2H), 2.04 – 1.94 (m, 1H), 1.50 (s, 9H), 1.24 (d, J = 6.4 Hz, 3H), 1.06 (d, J = 8.1 Hz, 2H), 0.91 – 0.75 (m, 2H). The following compound was prepared by an analogous procedure to the synthesis of compound 431 from the corresponding boronic acid. Example 123. tert-Butyl (S)-4-(7-(4-cyanopyrimidin-2-yl)-5-cyclopropyl-7H-pyrrolo[2, 3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Compound 432) C ^{ompound 432} Step 1. tert-Butyl (S)-4-(7-(4-cyanopyrimidin-2-yl)-5-cyclopropyl-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 (100 mg, 0.28 mmol, prepared following the procedure outlined in compound 259) in dioxane (5.0 mL) were added 2-bromopyrimidine-4- carbonitrile (77 mg, 0.42 mmol ), Pd ₂ (dba) ₃ (130 mg, 0.14 mmol), X-Phos (210 mg, 0.28 mmol) and Cs ₂ CO ₃ (180 mg, 0.56 mmol ) at 25°C. The mixture was degassed with N ₂ 3 times. The mixture was stirred at 100°C for 12 hrs. The mixture was cooled to 25°C, poured into H ₂ O (100 mL), and extracted with EtOAc twice. The combined organic phases were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated under vacuo. The crude product was purified by Prep-HPLC (0.1% FA condition) to give tert-butyl (S)-4-(7-(4- cyanopyrimidin-2-yl)-5-cyclopropyl-7H-pyrrolo[2,3-d] pyrimidin-4-yl)-3-methylpiperazine- 1-carboxylate (2.0 mg, 1.4%) as a yellow solid. LC/MS ESI (m/z): 461 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.30 (d, J = 5.9 Hz, 1H), 8.78 (d, J = 5.8 Hz, 1H), 8.49 (s, 1H), 7.76 (s, 1H), 4.70 (s, 1H), 4.21 – 3.77 (m, 3H), 3.54 (t, J = 11.5 Hz, 1H), 3.20 (d, J = 77.9 Hz, 2H), 2.03 – 1.95 (m, 1H),1.50 (s, 9H), 1.24 (d, J = 6.7 Hz, 3H), 1.08 (d, J = 8.1 Hz, 2H), 0.86 (d, J = 27.0 Hz, 2H). The following compound was prepared by the procedure similar to the synthesis of compound 432 from the corresponding aryl compound. Example 124. Synthesis of tert-butyl 4-(7-(4-cyanopyridin-2-yl)-5-(2-fluorophenyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]octane-7-ca rboxylate (Compound 435) C ^{ompound 435} Step 1.2-(5-Bromo-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-7-yl)isoni cotinonitrile To a solution of 5-bromo-4-methoxy-7H-pyrrolo[2,3-d]pyrimidine (5.0 g, 22 mmol, prepared from MeONa and aryl bromide) in DMF (25 mL) were added 2- fluoroisonicotinonitrile (5.4 g, 44 mmol) and Cs ₂ CO ₃ (36 g, 110 mmol). Then the resulting mixture was stirred at 50 ^o C for 5h. The reaction was quenched with water, extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to afford 2-(5-bromo-4-methoxy-7H- pyrrolo[2,3-d]pyrimidin-7-yl)isonicotinonitrile (6.0 g, 83%) as a yellow solid. LC/MS ESI (m/z): 330, 332 (M+H) ⁺ . Step 2.2-(5-Bromo-4-hydroxy-7H-pyrrolo[2,3-d]pyrimidin-7-yl)isoni cotinonitrile To a solution of 2-(5-bromo-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-7- yl)isonicotinonitrile (6.0 g, 18 mmol) in DMF (20 mL) were added 4-methylbenzenesulfonic acid (31 g, 180 mmol) and LiOH (7.7 g, 180 mmol). Then the resulting mixture was stirred at 110 ^o C for 2h. The reaction was quenched with water, extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to afford 2-(5-bromo-4-hydroxy-7H-pyrrolo[2,3- d]pyrimidin-7-yl)isonicotinonitrile (5.5 g, 96%) as a yellow solid. LC/MS ESI (m/z): 316, 318 (M+H) ⁺ . Step 3.2-(5-Bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)isonic otinonitrile To a solution of POCl ₃ (20 mL) was added 2-(5-bromo-4-hydroxy-7H-pyrrolo[2,3- d]pyrimidin-7-yl)isonicotinonitrile (5.5 g, 17 mmol). The resulting mixture was stirred at 120 ^o C under a N ₂ atmosphere overnight. The solvent was removed, and the residue poured into water and extracted with EtOAc twice. The combined organic layers were dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 0~30% EtOAc in petroleum ether) to afford 2-(5-bromo-4-chloro-7H-pyrrolo[2,3-d] pyrimidin-7-yl)isonicotinonitrile (5.0 g, 86%) as a light yellow solid. LC/MS ESI (m/z): 334,336 (M+H) ⁺ . Step 4.2-(5-Bromo-4-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)isonic otinonitrile To a solution of 2-(5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7- yl)isonicotinonitrile (500 mg, 1.5 mmol) in THF (5 mL) were added TBAF (5.0 ml, 1.0M in THF) at 0 ^o C. The resulting mixture was stirred at rt overnight. The reaction was quenched with water, extracted with EtOAc twice, the combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to afford 2-(5-bromo-4- fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)isonicotinonitrile (100 mg, 25%) as a light yellow solid. LC/MS ESI (m/z): 318, 320 (M+H) ⁺ . Step 5. tert-Butyl 4-(5-bromo-7-(4-cyanopyridin-2-yl)-7H-pyrrolo [2,3-d]pyrimidin-4- yl)-4,7-diazaspiro[2.5]octane-7-carboxylate The mixture of 2-(5-bromo-4-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl) isonicotinonitrile (100 mg, 0.31 mmol) and tert-butyl 4,7-diazaspiro[2.5]octane-7-carboxylate (270 mg, 1.3 mmol) was stirred at 150 ^o C under N ₂ atmosphere for 3 hours. After cooling to room temperature, the reaction was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to afford tert-butyl 4-(5-bromo-7-(4-cyanopyridin- 2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]oc tane-7-carboxylate (80 mg, 50%) as a yellow solid. LC/MS ESI (m/z): 510, 512 (M+H) ⁺ . Step 6. tert-Butyl 4-(7-(4-cyanopyridin-2-yl)-5-(2-fluorophenyl)-7H-pyrrolo[2,3 -d] pyrimidin-4-yl)-4,7-diazaspiro[2.5]octane-7-carboxylate To a solution of tert-butyl 4-(5-bromo-7-(4-cyanopyridin-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]octane-7-carboxylate (80 mg, 0.16 mmol) in 1.4- dioxane (5 mL) and H ₂ O (1 ml) were added (2-fluorophenyl)boronic acid (44 mg, 0.31 mmol), K ₂ CO ₃ (65 mg, 0.47 mmol) and Pd(dppf)Cl ₂ (4.0 mg, 0.020 mmol). The resulting mixture was heated to 90 ^o C overnight. After being cooled down to room temperature, solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to give product (100 mg). Further purification by prep-HPLC provided tert-butyl 4-(7-(4-cyanopyridin-2-yl)-5-(2-fluorophenyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]octane-7-ca rboxylate (70 mg, 80%) as a white solid. LC/MS ESI (m/z): 526 (M+H) ⁺ . ¹ H NMR(400 MHz, CDCl3) δ 9.33 (s, 1H), 8.60 – 8.54 (m, 2H), 8.23 (s, 1H), 7.35 – 7.27 (m, 3H), 7.15 – 7.09 (m, 2H), 3.55 – 3.37 (m, 2H), 3.32 – 2.94 (m, 2H), 2.93 – 2.82 (m, 2H), 1.34 (s, 9H), 0.89 – 0.76 (m, 4H). The following compounds were prepared by analogous procedures to the synthesis of compound 435 from the corresponding amine (tert-butyl 3,3-dimethylpiperazine-1- carboxylate)

Example 125. Synthesis of 1,1,1-trifluoro-2-methylpropan-2-yl(S)-4-(7-(4-cyanopyridin- 2-yl)-5-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methyl piperazine-1-carboxylate (Compound 436) C ^{ompound 436} Step 1. tert-Butyl (S)-4-(5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiper azine -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 (55 g, 110 mmol, prepared following the procedure outlined in compound 268) in THF (400 mL) was added TBAF (440 mL, 440 mmol, 1.0M in THF). The resulting mixture was stirred at 0 ^o C for 1.5 h. The reaction was quenched with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0~10%, methanol in dichloromethane) to afford tert-butyl (S)-4- (5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine- 1-carboxylate (37 g, 91%) as a white solid. LC/MS ESI (m/z): 444 (M+H) ⁺ Step 2. tert-Butyl (S)-4-(7-(4-cyanopyridin-2-yl)-5-iodo- 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} piperidine- 1-carboxylate (4.5 g, 10 mmol) and 2-fluoropyridine-4-carbonitrile (1.8 g, 15 mmol) in DMF (60 mL) was added Cs ₂ CO ₃ (16 g, 50 mmol) and the resulting mixture was stirred at 40℃ for 18h. After being cooled down to room temperature, the reaction mixture was filtered. The filtrate was diluted with ice water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by column chromatography on silica gel (0~80% ethyl acetate in petroleum ether) to give tert-butyl (S)-4-(7-(4-cyanopyridin-2-yl)-5-iodo-7H- pyrrolo [2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (3.6, 66%). LC/MS(ESI)m/z: 546 (M+H) ⁺ Step 3. tert-Butyl(S)-4-(7-(4-cyanopyridin-2-yl)-5-cyclobutyl-7H-pyr rolo [2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate A suspension of tert-butyl (3S)-4-[7-(4-cyanopyridin-2-yl)-5-iodo-7H-pyrrolo[2,3- d]pyrimidin-4-yl]-3-methylpiperazine-1-carboxylate (550 mg, 1.0 mmol), cyclobutylboronic acid (0.19 mL, 2.0 mmol), K ₂ CO ₃ (2.7 g, 19 mmol ) and Pd-118 (66 mg, 0.10 mmol) in toluene (50 mL) was stirred at 80℃ under a N ₂ atmosphere for 18h. After being cooled down to room temperature the solvent was removed. The residue was purified by flash column chromatography on silica gel (0~80% ethyl acetate in petroleum ether) and further purified by prep-HPLC to give tert-butyl (S)-4-(7-(4-cyanopyridin-2-yl)-5-cyclobutyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (50 mg, 10%). LC/MS (ESI) (m/z): 474 (M+H)+. ¹ H NMR (400 MHz, CDCl3) δ 9.33 (s, 1H), 8.66 – 8.58 (m, 1H), 8.54 (s, 1H), 8.12 (s, 1H), 7.40 – 7.32 (m, 1H), 4.36 – 4.17 (m, 1H), 4.07 – 3.89 (m, 1H), 3.80 – 3.63 (m, 2H), 3.58 – 3.43 (m, 3H), 3.29 – 3.12 (m, 1H), 2.53 – 2.38 (m, 2H), 2.29 – 2.02 (m, 3H), 2.00 – 1.92 (m, 1H), 1.50 (s, 9H), 1.20 (d, J = 4.8 Hz, 3H). This reaction was repeated to make another batch for the next step. Step 4. (S)-2-(5-Cyclobutyl-4-(2-methylpiperazin-1-yl)-7H-pyrrolo[2, 3-d]pyrimidin - 7-yl)isonicotinonitrile At 0 ^o C, to a solution of tert-butyl (S)-4-(7-(4-cyanopyridin-2-yl)-5-cyclobutyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (100 mg, 0.21 mmol) in DCM (2 mL) was added TFA (0.31 mL, 4.2 mmol) and the reaction was stirred for 3h. After removal of solvent, the residue used directly in next step without further purification. LC/MS(ESI)m/z: 374 (M+H) ⁺ Step 5.1,1,1-Trifluoro-2-methylpropan-2-yl (S)-4-(7-(4-cyanopyridin-2-yl)-5- cyclobutyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazi ne-1-carboxylate To a solution of 2-{5-cyclobutyl-4-[(2S)-2-methylpiperazin-1-yl]-7H-pyrrolo[2 ,3- d]pyrimidin-7-yl}pyridine-4-carbonitrile (35 mg, 0.090 mmol) and DIEA (0.090 mL, 0.56 mmol) in DMF (2 mL) was added a solution of 1,1,1-trifluoro-2-methylpropan-2-yl 1H- imidazole-1-carboxylate (42 mg, 0.19 mmol, prepared following the procedure outlined in compound 243). The resulting mixture was stirred at 75℃ for 18 h. After being cooled down to room temperature, the reaction mixture was partitioned between EtOAc, and water and the organic layer was separated. The aqueous layer was extracted with EtOAc twice and the combined organic layers dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by column chromatography on silica gel and prep-HPLC to give 1,1,1- trifluoro-2-methylpropan-2-yl(S)-4-(7-(4-cyanopyridin-2-yl)- 5-cyclobutyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (7.5 mg, 15%) as a white solid. LC/MS (ESI) (m/z): 528 (M+H) ^{+ 1} H NMR (400 MHz, CDCl ₃ ) δ 9.34 (s, 1H), 8.61 (d, J = 5.0 Hz, 1H), 8.52 (s, 1H), 8.12 (s, 1H), 7.39 – 7.31 (m, 1H), 4.24 (s, 1H), 3.96 (dd, J = 65.1, 13.4 Hz, 1H), 3.71 (dd, J = 20.3, 11.4 Hz, 2H), 3.51 (d, J = 12.6 Hz, 3H), 3.37 – 3.14 (m, 1H), 2.45 (ddd, J = 14.5, 9.9, 4.9 Hz, 2H), 2.29 – 1.91 (m, 4H), 1.72 (d, J = 3.9 Hz, 6H), 1.19 (d, J = 6.2 Hz, 3H). Example 126. Synthesis of tert-butyl (S)-4-(7-(5-cyano-1H-imidazol-2-yl)-5-cyclopropyl- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carbox ylate (Compound 440) Step 1. Methyl 2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-imidazole-4- carboxylate To a solution of methyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4- carboxylate (260 mg, 1.0 mmol) in carbon tetrachloride (10 mL) was added NBS (200 mg, 1.1 mmol) and AIBN (16 mg, 0.10 mmol). The reaction was heated at 60°C for 3 hours then diluted with sat. NaHCO ₃ and the layers were separated. The organics were concentrated and purified by flash column chromatography (silica gel, 0-60% ethyl acetate in petroleum ether) to afford methyl 2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole- 4-carboxylate as a white solid (200 mg, 61% yield). LC/MS ESI (m/z): 335/337 (Br) (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.77 (s, 1H), 5.30 (s, 2H), 3.90 (s, 3H), 3.59 – 3.51 (m, 2H), 0.96 – 0.89 (m, 2H), -0.01 (s, 9H). Methyl 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4- carboxylate was also obtained as colorless oil (64 mg, 19%). LC/MS ESI (m/z) 335/337 (Br) (M+H) ₊ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.69 (s, 1H), 5.74 (s, 2H), 3.86 (s, 3H), 3.63 – 3.56 (m, 2H), 0.94 – 0.88 (m, 2H), -0.03 (s, 9H). Step 2.2-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole- 4-carboxamide Methyl 2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4- carboxylate (1.3 g, 3.9 mmol) was dissolved in MeOH (2 mL) and NH ₃ /H ₂ O (4 mL) and the reaction mixture was heated at 100°C for 2 h. The reaction was diluted with water and the layers were separated. The organics were concentrated to afford 2-bromo-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxamide as a white solid (950 mg, 77% yield). LC/MS ESI (m/z): 320/322 (Br) (M+H) ⁺ . Step 3.2-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole- 4-carbonitrile To a solution of 2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-imidazole-4- carboxamide (900 mg, 2.8 mmol) was in DCM (20 mL) and DIPEA (7 mL) was added TFAA (2 mL) and the mixture was stirred at 0°C for 3 h. The reaction was diluted with brine and the layers were separated. The organics were concentrated to afford 2-bromo-1-((2- (trimethylsilyl)ethoxy)methyl)-1H- imidazole-4-carbonitrile as a yellow oil that was carried forward to the next step without further purification. LC/MS ESI (m/z): 302/304 (Br) (M+H) ⁺ . Step 4.2-Bromo-1H-imidazole-5-carbonitrile To a mixture of 2-bromo-1-((2-(trimethylsilyl)ethoxy) methyl)-1H-imidazole-4- carbonitrile (obtained from the previous step) was in DCM (5 mL) and EtOH (0.5mL) was added TFA (10 mL). The mixture was stirred at 0°C for 3 h, then diluted with brine and layers were separated. The organics were concentrated, and the residue was purified by flash column chromatography to afford 2-bromo-1H-imidazole-5-carbonitrile as a white solid (400 mg, 83%, over two steps). LC/MS ESI (m/z): 172/174 (Br) (M+H) ⁺ . ¹ H NMR (400 MHz, MeOD) δ 7.90 (s, 1H), 2.67 (s, 1H). Step 5. tert-Butyl (S)-4-(7-(5-cyano-1H-imidazol-2-yl)-5-cyclopropyl-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 (71 mg, 0.20 mmol, prepared following the procedure of compound 260, step 4) and 2-bromothiazole-5-carbonitrile (34 mg, 0.20 mmol) in dioxane (1 mL) were added CuI (19 mg, 0.10 mmol), K ₃ PO ₄ (210 mg, 1.0 mmol) and trans-N,N’- dimethylcyclohexane-1,2-diamine (14 mg, 0.10 mmol). The resulting mixture was stirred at 100℃ under N ₂ for 2 h. After being cooled to room temperature, the reaction was partitioned between EtOAc and water and the organic layer was separated. The aqueous layer was extracted with EtOAc twice and the combined organic layers were washed with brine, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0~10%, MeOH in DCM) to give copper complexes with product as a purple solid. The complexes were partitioned between DCM and EDTANa ₂ (aqueous) until organic phase was colorless. The organic layer was concentrated and further purified by prep-HPLC to afford tert-butyl (S)-4-(7-(5-cyano-1H-imidazol-2-yl)-5-cyclopropyl-7H-pyrrolo [2,3-d]pyrimidin-4- yl)-3-methylpiperazine-1-carboxylate (6.2 mg, 14% yield) as a whitee solid. LC/MS ESI (m/z): 449 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 12.26 (br, 1H), 8.39 (s, 1H), 7.54 (s, 1H), 7.48 (s, 1H), 5.00 – 4.70 (m, 1H), 4.34 – 3.72 (m, 3H), 3.53 (t, J = 11.3 Hz, 1H), 3.36 – 2.88 (m, 2H), 1.96 – 1.89 (m, 1H), 1.49 (s, 9H), 1.26 (d, J = 6.7 Hz, 3H), 1.09 – 0.98 (m, 2H), 0.86 – 0.75 (m, 2H).

Example 127. Synthesis of tert-butyl (S)-4-(7-(4-cyanopyridin-2-yl)-5- (cyclopropyl(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 3-methylpiperazine-1- carboxylate (Compound 442) C ^{ompound 442} Step 1. tert-Butyl (S)-4-(7-(4-chloropyridin-2-yl)-5-(N-cyclopropylformamido)-7 H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te To a solution of tert-butyl (S)-4-(7-(4-chloropyridin-2-yl)-5-formamido-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (100 mg, 0.21 mmol, prepared following the procedure outlined in compound 427) in DCE (40 mL) were added cyclopropylboronic acid (36 mg, 0.42 mmol), K ₂ CO ₃ (88 mg, 0.64 mmol), 2,2'-dipyridyl (330 mg, 0.21 mmol) and Cu(OAc) ₂ (38 mg, 0.21 mmol) at 25°C. The mixture was degassed with O ₂ 3 times and stirred at 40°C under O ₂ overnight. The mixture was cooled to 25°C, then poured into H ₂ O (100 mL) and extracted with EtOAc twice. The combined organic phases were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by silica gel column (SiO2, petroleum ether: EtOAc = 50 : 1 to 30 : 1) to provide tert-butyl (S)-4-(7-(4-chloropyridin-2-yl)-5-(N-cyclopropylformamido) -7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (50 mg, 47%) as a white solid. LC/MS ESI (m/z): 512 (M+H) ⁺ . Step 2. tert-Butyl (S)-4-(7-(4-chloropyridin-2-yl)-5-(cyclopropyl(methyl)amino) -7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te To a solution of tert-butyl (S)-4-(7-(4-chloropyridin-2-yl)-5-(N- cyclopropylformamido)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-met hylpiperazine-1-carboxylate (50 mg, 0.098 mmol) in THF (4 mL) was added BH ₃ -THF (0.98 mL, 1.0M in THF) at 0°C. The mixture was warmed to 25°C and stirred for 2 hrs. The mixture was quenched by addition of MeOH (5 mL) at 0°C and concentrated. The residue was purified by silica gel column (SiO ₂ , petroleum ether: EtOAc = 50 : 1 to 40 : 1) to provide tert-butyl (S)-4-(7-(4- chloropyridin-2-yl)-5-(cyclopropyl(methyl)amino)-7H-pyrrolo[ 2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate (20 mg, 41%) as a white solid. LC/MS ESI (m/z): 498 (M+H) ⁺ . Step 3. tert-Butyl (S)-4-(7-(4-cyanopyridin-2-yl)-5-(cyclopropyl(methyl)amino)- 7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te To a solution of tert-butyl (S)-4-(7-(4-chloropyridin-2-yl)-5- (cyclopropyl(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 3-methylpiperazine-1- carboxylate (20 mg, 0.040 mmol) in DMF (5 mL) were added Zn(CN) ₂ (28 mg, 0.24 mmol) and Pd(PPh ₃ ) ₄ (23 mg, 0.020 mmol) at 25°C. The mixture was purged with N ₂ 3 times. The mixture was stirred at 120°C for 3 hrs then cooled to 25°C. The mixture was poured into H ₂ O (20 mL) and extracted with EtOAc twice. The combined organic phase was washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by Prep-HPLC (0.1% formic acid) to provide tert-butyl (S)-4-(7-(4-cyanopyridin-2-yl)-5- (cyclopropyl(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 3-methylpiperazine-1- carboxylate (11 mg, 55%) as a yellow solid. LC/MS ESI (m/z): 489 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.30 – 9.24 (m, 1H), 8.52 (d, J = 5.0 Hz, 1H), 8.36 (s, 1H), 7.73 (s, 1H), 7.24 (dd, J = 5.0, 1.2 Hz, 1H), 4.78 (s, 1H), 4.19 – 3.67 (m, 3H), 3.28 (t, J = 11.7 Hz, 1H), 3.22 – 2.83 (m, 2H), 2.77 (s, 3H), 2.27 – 2.19 (m, 1H), 1.42 (s, 9H), 1.05 (s, 3H), 0.72 (d, J = 6.4 Hz, 2H), 0.51 – 0.37 (m, 2H).

Example 128. Synthesis of tert-butyl (S)-4-(7-(4-cyanopyridin-2-yl)-5- (isopropyl(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1- carboxylate (Compound 443) Step 1. tert-Butyl (S)-4-(7-(4-chloropyridin-2-yl)-5-formamido-7H-pyrrolo [2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of (S)-4-(4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)-7-(4- chloropyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid (200 mg, 0.42 mmol, prepared following the procedure outlined in compound 366) in toluene (5 mL) were added TEA (0.20 mL, 1.3 mmol) and DPPA (230 mg, 0.84 mmol). The resulting mixture was stirred at room temperature for 2 hr. A second mixture of HCOOH (0.75 mL) and acetic formic anhydride (2.0 mL) was stirred at 60 ^o C for 2 hr to afford the mixed anhydride. The mixed anhydride was added into the first reaction and the resulting mixture was heated to 60 ^o C for 2 hr. After being cooled down to room temperature, the reaction was quenched with NaHCO ₃ and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, ethyl acetate in petroleum ether) to afford tert-butyl (S)- 4-(7-(4-chloropyridin-2-yl)-5-formamido-7H-pyrrolo [2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate (170 mg, 83%) as a light yellow solid. LC/MS ESI (m/z): 472 (M+H) ⁺ . Step 2. tert-Butyl (S)-4-(7-(4-chloropyridin-2-yl)-5-(N-isopropylformamido) -7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te At 0 ^o C, to a solution of NaH (27 mg, 0.68 mmol) in THF (5 mL) was added tert-butyl (S)-4-(7-(4-chloropyridin-2-yl)-5-formamido-7H-pyrrolo[2,3-d ]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate (160 mg, 0.34 mmol) and the mixture stirred at 0 ^o C for 10 min. 2-Iodopropane (86 mg, 0.50 mmol) was added, and the resulting mixture was heated to 50 ^o C overnight under N ₂ . After being cooled down to room temperature, the reaction was quenched with ice water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, ethyl acetate in petroleum ether) to afford tert- butyl (S)-4-(7-(4-chloropyridin-2-yl)-5-(N-isopropylformamido)-7H- pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (130 mg, 74%) as a light yellow solid. LC/MS ESI (m/z): 514 (M+H) ⁺ . Step 3. tert-Butyl (S)-4-(7-(4-chloropyridin-2-yl)-5-(isopropyl(methyl)amino)- 7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te At 0 ^o C, to a solution of tert-butyl (S)-4-(7-(4-chloropyridin-2-yl)-5-(N- isopropylformamido)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methy lpiperazine-1-carboxylate (130 mg, 0.25 mmol) in THF (2 mL) was added BH ₃ -THF (1.0 mL, 1.0 M). After stirring at room temperature for 1 hr, the reaction was quenched with ice water amd extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, ethyl acetate in petroleum ether) to afford tert-butyl (S)-4-(7-(4-chloropyridin-2-yl)-5- (isopropyl(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1- carboxylate (72 mg, 57%) as a colorless oil. LC/MS ESI (m/z): 500 (M+H) ⁺ . Step 4. tert-Butyl (S)-4-(7-(4-cyanopyridin-2-yl)-5-(isopropyl(methyl)amino) -7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te To the solution of tert-butyl (S)-4-(7-(4-chloropyridin-2-yl)-5- (isopropyl(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1- carboxylate (72 mg, 0.14 mmol) in DMF (5 mL) were added Zn(CN) ₂ (98 mg, 0.84 mmol) and Pd(PPh ₃ ) ₄ (80 mg, 0.070 mmol) respectively. The resulting reaction mixture was stirred at 120℃ under N ₂ overnight. After being cooled down to r.t., the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) and prep-HPLC (C18, MeCN in H ₂ O) to afford tert-butyl (S)-4-(7-(4-cyanopyridin-2-yl)-5- (isopropyl(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1- carboxylate (19 mg, 27%) as a yellow solid. LC/MS ESI (m/z): 491 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl 3 ) δ 9.38 (s, 1H), 8.58 (d, J = 5.0 Hz, 1H), 8.42 (s, 1H), 7.61 (s, 1H), 7.29 (dd, J = 5.0, 1.0 Hz, 1H), 5.09 (s, 1H), 4.35 – 3.85 (m, 3H), 3.72 – 3.64 (m, 1H), 3.47 – 3.27 (m, 2H), 3.03 – 2.83 (m, 1H), 2.66 (s, 3H), 1.49 (s, 9H), 1.22 (d, J = 6.5 Hz, 3H), 1.16 (d, J = 5.3 Hz, 3H), 0.95 (d, J = 6.4 Hz, 3H). Example 129. Synthesis of tert-butyl (S)-4-(7-(5-cyano-1-methyl-1H-pyrrol-3-yl)-5- cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperaz ine-1-carboxylate (Compound 445) C ^{ompound 445} Step 1.4-Bromo-1-methyl-1H-pyrrole-2-carboxylic acid A solution of Methyl 4-bromo-1-methyl-1H-pyrrole-2-carboxylate (440 mg, 2.0 mmol) in H ₂ O (2 mL) and THF (2 mL) was added to NaOH (320 mg, 8.0 mmol) and the reaction mixture was heated at 70°C for 4 h. The reaction was quenched with HCl (1.0 M), diluted with water, and the layers were separated. The organics were concentrated to afford 4- bromo-1-methyl-1H-pyrrole-2-carboxylic acid as a white solid (390 mg, 96%). LC/MS ESI (m/z): 202/204 (Br) (M-H) ⁺ . Step 2.4-Bromo-1-methyl-1H-pyrrole-2-carboxamide To a solution of 4-bromo-1-methyl-1H-pyrrole-2-carboxylic acid (450 mg, 2.2 mmol) in DMF (10 mL) and DIPEA (3 mL) was added NH ₄ Cl (470 mg, 8.8 mmol), HOBt (890 mg, 6.6 mmol) and EDCI (1.3 g, 6.6 mol). The reaction mixture was stirred at rt overnight. The reaction was quenched with aqueous NaHCO ₃ , diluted with brine, and the layers were separated. The organics were concentrated to afford crude 4-bromo-1-methyl-1H-pyrrole-2- carboxamide as an oil (1.6 g) that was carried on to the next step without further purification. LC/MS ESI (m/z): 203/205 (Br) (M+H) ⁺ . Step 3.4-Bromo-1-methyl-1H-pyrrole-2-carbonitrile To a solution of 4-bromo-1-methyl-1H-pyrrole-2-carboxamide (1.5 g from the previous step) in DCM (5 mL) and TEA (1.3 mL) was added TFAA (0.56 mL) at 0°C and the mixture was stirred at 0°C for 2 h. The reaction was quenched with NaHCO ₃ , diluted with brine, and the layers were separated, and the organics were concentrated. Purification by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) provided 4-bromo-1-methyl-1H-pyrrole-2-carbonitrile as a yellow solid (330 mg, 80% yield over two steps). LC/MS ESI (m/z): 297/299 (Br) (M-H+TFA) Step 4. tert-Butyl (S)-4-(7-(5-cyano-1-methyl-1H-pyrrol-3-yl)-5- cyclopropyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te To a solution of tert-butyl (S)-4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate (89 mg, 0.25 mmol, prepared following the procedure of compound 260, step 4) and 4-bromo-1-methyl-1H-pyrrole-2-carbonitrile (92 mg, 0.50 mmol) in DMF (1 mL) were added CuI (47 mg, 0.25 mmol), trans-N,N’-dimethylcyclohexane-1,2- diamine (35 mg, 0.25 mmol) and K ₃ PO ₄ (530 mg, 2.5 mmol). The resulting mixture was stirred at 120℃ under N ₂ atmosphere overnight. After being cooled to room temperature, the reaction was partitioned between EtOAc, and water and the organic layer was separated. The aqueous layer was extracted with EtOAc twice and the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0~40%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford tert-butyl (S)-4-(7-(5-cyano-1- methyl-1H-pyrrol-3-yl)-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimi din-4-yl)-3-methylpiperazine- 1-carboxylate (13 mg, 11% yield) as a white solid. LC/MS ESI (m/z): 462 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.42 (s, 1H), 7.49 (s, 1H), 6.95 (s, 1H), 6.81 (s, 1H), 4.93 – 4.56 (m, 1H), 4.25 – 3.73 (m, 6H), 3.62 – 3.45 (m, 1H), 3.42 – 3.02 (m, 2H), 2.04 – 1.98 (m, 1H), 1.50 (s, 9H), 1.22 (d, J = 6.3 Hz, 3H), 1.09 – 0.92 (m, 2H), 0.83 – 0.73 (m, 1H), 0.73 – 0.62 (m, 1H). Example 130. Synthesis of tert-butyl (S)-4-(7-(5-cyanopyridazin-3-yl)-5-(2- fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiper azine-1-carboxylate (Compound 447) C ^{ompound 447} Step 1. tert-Butyl (S)-4-(7-(5-chloropyridazin-3-yl)-5-(2-fluorophenyl)-7H-pyrr olo [2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl (S)-4-(5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)-3-methylpiperazine-1-carboxylate (82 mg, 0.20 mmol, prepared following the procedure of compound 268, step 4) in THF (1 mL) was added NaH (32 mg, 0.80 mmol, 60% wt.) at 0 ℃ and the reaction mixture was stirred for 20 min under N ₂ . Then 3,5-dichloropyridazine (60 mg, 0.40 mmol) was added and the mixture was stirred at room temperature under N ₂ overnight. The mixture was quenched with NH ₄ Cl aqueous, diluted with EtOAc, washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~40% EtOAc in petroleum ether) to afford tert-butyl (S)-4-(7- (5-chloropyridazin-3-yl) -5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate (36 mg, 34% yield) as a white solid. LC/MS ESI (m/z): 524/526 (Cl) (M+H) ⁺ . And tert-butyl (S)-4-(7-(6-chloropyridazin-4-yl)-5-(2-fluorophenyl)- 7H-pyrrolo [2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (36 mg, 34%) as a white solid. LC/MS ESI (m/z): 524/526 (Cl) (M+H) ⁺ . The configuration was determined by NMR analysis. Step 2. tert-Butyl (S)-4-(7-(5-cyanopyridazin-3-yl)-5- (2-fluorophenyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te To a solution of tert-butyl (S)-4-(7-(5-chloropyridazin-3-yl)-5-(2-fluorophenyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (24 mg, 0.046 mmol) in DMF (1 mL) was added Zn(CN) ₂ (32 mg, 0.28 mmol) and Pd(PPh ₃ ) ₄ (53 mg, 0.046 mmol). The mixture was stirred at 120°C under N ₂ overnight then diluted with EtOAc. The mixture was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0~40% EtOAc in petroleum ether) to provide the product which was further purified by prep-HPLC to afford tert-butyl (S)-4-(7-(5- cyanopyridazin-3-yl)-5-(2-fluorophenyl)-7H-pyrrolo[2,3-d] pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate (4.4 mg, 19% yield) as a yellow solid. LC/MS ESI (m/z): 515 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.78 (s, 1H), 9.22 (s, 1H), 8.54 (s, 1H), 8.47 (s, 1H), 7.47 (t, J = 7.2 Hz, 1H), 7.40 (dd, J = 13.3, 6.1 Hz, 1H), 7.26 – 7.16 (m, 2H), 4.43 – 4.11 (m, 1H), 3.91 – 3.63 (m, 1H), 3.57 (d, J = 12.8 Hz, 1H), 3.48 (d, J = 12.6 Hz, 1H), 3.08 (t, J = 11.3 Hz, 1H), 2.95 – 2.51 (m, 2H), 1.43 (s, 9H), 1.03 (s, 3H). ¹⁹ F NMR (377 MHz, CDCl ₃ ) δ -114.54 (s). The following compounds were prepared by analogous procedures to the synthesis of compound 447. The starting material of step 1 were prepared from the corresponding 2- fluorophenyl- or cyclopropyl-boronic acid. Example 131. Synthesis of tert-butyl (S)-4-(1-(4-cyanopyridin-2-yl)-3-(2-fluorophenyl)- 1H-pyrrolo[3,2-c]pyridin-4-yl)-3-methylpiperazine-1-carboxyl ate (Compound 449) C ^{ompound 449} Step 1.3-Bromo-1-tosyl-1H-pyrrolo[3,2-c]pyridine At 0 ^o C, to a solution of NaH (1.2 g, 30 mmol) in DMF (50 mL) was added 3-bromo- 1H-pyrrolo[3,2-c]pyridine (5.0 g, 25 mmol) and the mixture stirred at 0 ^o C for 15 min. TsCl (5.3 g, 28 mmol) was added and the resulting mixture was stirred at room temperature overnight under N ₂ . The mixture was diluted with water and filtered. The filter cake was washed with water and dried under vacuum to provide 3-bromo-1-tosyl-1H-pyrrolo[3,2- c]pyridine (7.5 g, 84%) as a white solid. LC/MS ESI (m/z): 351 (M+H) ⁺ . Step 2.3-Bromo-1-tosyl-1H-pyrrolo[3,2-c]pyridine 5-oxide At 0 ^o C, to a solution of 3-bromo-13-bromo-1-tosyl-1H-pyrrolo[3,2-c]pyridine (7.0 g, 20 mmol) in DCM (70 mL) was added 3-chloroperoxybenzoic acid (5.2 g, 30 mmol) in portions. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with NaHCO ₃ (aq.), extracted with DCM twice, the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0~20 %, MeOH in DCM) to provide 3-bromo-1- tosyl-1H-pyrrolo[3,2-c]pyridine 5-oxide (4.0 g, 54%) as a light yellow solid. LC/MS ESI (m/z): 367, 369 (M+H) ^+. Step 3. tert-Butyl (S)-4-(3-bromo-1-tosyl-1H-pyrrolo[3,2-c]pyridin-4-yl)- 3- methylpiperazine-1-carboxylate To a solution of 3-bromo-1-tosyl-1H-pyrrolo[3,2-c]pyridine 5-oxide (300 mg, 0.80 mmol) in CHCl ₃ (5 mL) were added tert-butyl (S)-3-methylpiperazine-1-carboxylate (390 mg, 1.9 mmol) and the mixture stirred at 0 ^o C for 10 min. TsCl (180 mg, 0.96 mmol) was added and the resulting mixture was stirred at room temperature overnight under N ₂ . The reaction was quenched with NaHCO ₃ (aq.), extracted with DCM twice, the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0~40 %, ethyl acetate in petroleum ether) to provide tert-butyl (S)-4-(3-bromo-1-tosyl-1H-pyrrolo[3,2-c]pyridin-4-yl)-3- methylpiperazine-1-carboxylate (47 mg, 10%) as a light yellow solid. LC/MS ESI (m/z): 549, 551 (M+H) ^+. Step 4. tert-Butyl (S)-4-(3-(2-fluorophenyl)-1-tosyl-1H-pyrrolo[3,2-c]pyridin-4 -yl) -3- methylpiperazine-1-carboxylate To a solution of tert-butyl (S)-4-(3-bromo-1-tosyl-1H-pyrrolo [3,2-c]pyridin-4-yl)-3- methylpiperazine-1-carboxylate (62 mg, 0.10 mmol) in dioxane (5 mL) and H ₂ O (1 mL) were added (2-fluorophenyl)boronic acid (16 mg, 0.11 mmol), K ₃ PO ₄ (43 mg, 0.20 mmol) and Pd(dppf)Cl ₂ (8.0 mg, 0.010 mmol). The resulting mixture was heated to 90 ^o C overnight. After being cooled to room temperature, the solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~40%, ethyl acetate in petroleum ether) to afford tert-butyl (S)-4-(3-(2-fluorophenyl)-1-tosyl-1H-pyrrolo[3,2-c]pyridin-4 -yl)-3- methylpiperazine-1-carboxylate (51 mg, 80%) as a white solid. LC/MS ESI (m/z): 565 (M+H)+. Step 5. tert-Butyl (S)-4-(3-(2-fluorophenyl)-1H-pyrrolo[3,2-c]pyridin-4-yl)- 3- methylpiperazine-1-carboxylate To a solution of tert-butyl (S)-4-(3-(2-fluorophenyl)-1-tosyl-1H-pyrrolo[3,2- c]pyridin-4-yl)-3-methylpiperazine-1-carboxylate (50 mg, 0.090 mmol) in THF (1 mL) was added TBAF (1.0 mL, 1.0M in THF). The resulting mixture was stirred at room temperature overnight under N ₂ . The reaction was quenched with water, extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0~60 %, ethyl acetate in petroleum ether) to provide tert-butyl (S)-4-(3-(2-fluorophenyl)-1H- pyrrolo[3,2-c]pyridin-4-yl)-3-methylpiperazine-1-carboxylate (35 mg, 96%) as a yellow solid. LC/MS ESI (m/z): 411 (M+H) ⁺ . Step 6. tert-Butyl (S)-4-(1-(4-cyanopyridin-2-yl)-3-(2-fluorophenyl) -1H-pyrrolo[3,2- c]pyridin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl (S)-4-(3-(2-fluorophenyl)-1H-pyrrolo [3,2-c]pyridin-4-yl)- 3-methylpiperazine-1-carboxylate (35 mg, 0.080 mmol) in DMF (5 mL) were added 2- fluoroisonicotinonitrile (20 mg, 0.16 mmol), and Cs ₂ CO ₃ (1.2 g, 8.3 mmol). The resulting mixture was heated to 50 ^o C overnight. After being cooled to room temperature, the solvent was removed and the residue was purified by flash column chromatography (silica gel, ethyl acetate in petroleum ether) to give the product which was further purified by prep-HPLC to afford tert-butyl (S)-4-(1-(4-cyanopyridin-2-yl)-3-(2-fluorophenyl)-1H-pyrrolo [3,2-c]pyridin- 4-yl)-3-methylpiperazine-1-carboxylate (51 mg, 80%) as a white solid. LC/MS ESI (m/z): 513 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.77 (d, J = 4.9 Hz, 1H), 8.23 (d, J = 5.9 Hz, 1H), 7.88 (d, J = 5.8 Hz, 1H), 7.71 (d, J = 13.5 Hz, 2H), 7.53 – 7.44 (m, 2H), 7.42 – 7.35 (m, 1H), 7.24 – 7.17 (m, 2H), 3.47 (s, 1H), 3.12 – 2.86 (m, 6H), 1.42 (s, 9H), 0.91 (d, J = 4.7 Hz, 3H). The following compound was prepared by an analogous procedure to the synthesis of compound 449 from the corresponding boronic acid (step 4, cyclopropylboronic acid (1.5 eq), K ₂ CO ₃ (20 eq), Pd-118(0.05 eq), toluene, 90 ^o C, overnight). Example 132. Synthesis of tert-butyl (S)-4-(1-(4-cyanopyridin-2-yl)-3-(2-fluorophenyl)- 1H-pyrrolo[3,2-c]pyridin-4-yl)-3-methylpiperazine-1-carboxyl ate (Compound 450) C ^{ompound 450} Step 1. (S)-2-(3-(2-Fluorophenyl)-4-(2-methylpiperazin-1-yl)-1H-pyrr olo[3,2-c] pyridin-1-yl)isonicotinonitrile At 0 ^o C, to a solution of tert-butyl (S)-4-(1-(4-cyanopyridin-2-yl)-3-(2-fluorophenyl)- 1H-pyrrolo[3,2-c]pyridin-4-yl)-3-methylpiperazine-1-carboxyl ate (130 mg, 0.24 mmol, prepared following the procedure of compound 449) in DCM (2 mL) was added TFA (1 mL). The resulting mixture was stirred at the same temperature for 1.5 h. The reaction was quenched with NaHCO ₃ (aq.), the organic layer was separated, and the aqueous layer was extracted with DCM twice. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was used in the next step directly. (S)-2-(3- (2-fluorophenyl)-4-(2-methylpiperazin-1-yl)-1H-pyrrolo[3,2-c ]pyridin-1-yl)isonicotinonitrile, LC/MS ESI (m/z): 413 (M+H) ⁺ . Step 2. (S)-2-(3-(2-Fluorophenyl)-4-(4-isobutyryl-2-methylpiperazin- 1-yl)-1H- pyrrolo[3,2-c]pyridin-1-yl)isonicotinonitrile At 0 ^o C, to a solution of (S)-2-(3-(2-fluorophenyl)-4-(2-methylpiperazin-1-yl)-1H- pyrrolo[3,2-c]pyridin-1-yl)isonicotinonitrile (98 mg, 0.24 mmol) in DCM (3 mL) were added dropwise TEA (0.060 mL, 0.48 mmol) and isobutyryl chloride (0.040 mL, 0.36 mmol). The resulting mixture was stirred at room temperature for 1.5 h. The reaction was quenched with ice water and extracted with DCM twice. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, ethyl acetate in petroleum ether) to give the product which was further purified by prep-HPLC to afford (S)-2-(3-(2-fluorophenyl)-4-(4- isobutyryl-2-methylpiperazin-1-yl)-1H-pyrrolo[3,2-c]pyridin- 1-yl)isonicotinonitrile (43 mg, 36%) as a white solid. LC/MS ESI (m/z): 483 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.77 (d, J = 4.9 Hz, 1H), 8.25 – 8.20 (m, 1H), 7.90 (s, 1H), 7.72 (d, J = 11.9 Hz, 2H), 7.48 (dd, J = 21.6, 5.9 Hz, 2H), 7.42 – 7.36 (m, 1H), 7.20 (dd, J = 17.9, 8.3 Hz, 2H), 3.57 – 2.71 (m, 8H), 1.13 – 1.06 (m, 6H), 1.03 (d, J = 6.1 Hz, 1.5H), 0.83 (d, J = 6.3 Hz, 1.5H). Example 133. Synthesis of tert-butyl (S)-4-(5-(2-fluorophenyl)-7-(pyridazin-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (Compound 451) C ^{ompound 451} Step 1. tert-Butyl (S)-4-(5-(2-fluorophenyl)-7-(pyridazin-4-yl) -7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl (S)-4-(7-(6-chloropyridazin-4-yl)-5-(2-fluorophenyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (10 mg, 0.019 mmol, prepared following the procedure of compound 447, step 2) in MeOH(1 mL) was added Pd/C (10 mg, with ca.55% water) under N ₂ . The mixture was stirred at room temperature under a H2 atmosphere for 3h and the solid was removed by filtration. The filtrate was concentrated to afford the product which was further purified by prep-HPLC to afford tert-butyl (S)-4-(5- (2-fluorophenyl)-7-(pyridazin-4-yl)-7H-pyrrolo[2,3-d]pyrimid in- 4-yl)-3-methylpiperazine-1- carboxylate (1.9 mg, 20% yield) as a white solid. LC/MS ESI (m/z): 490 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.85 (d, J = 2.3 Hz, 1H), 9.29 (d, J = 5.8 Hz, 1H), 8.55 (s, 1H), 8.37 (dd, J = 5.8, 2.7 Hz, 1H), 7.57 (s, 1H), 7.43 (dt, J = 19.3, 6.6 Hz, 2H), 7.30 – 7.28 (m, 1H), 7.24 – 7.21 (m, 1H), 4.38 – 4.13 (m, 1H), 3.89 – 3.66 (m, 1H), 3.60 – 3.39 (m, 2H), 3.08 (t, J = 11.9 Hz, 1H), 2.91 – 2.58 (m, 2H), 1.43 (s, 9H), 1.08 – 0.96 (m, 3H). Example 134. Synthesis of tert-butyl (2R,5S)-4-(7-(4-chloropyridin-2-yl)-5-(2- fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylp iperazine-1-carboxylate (Compound 454) Step 1. tert-Butyl(2R,5S)-4-(5-(2-fluorophenyl)-7-(4-fluoropyridin-2 -yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate 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 (340 mg, 0.80 mmol, prepared following the procedure outlined in compound 452) and 4-chloro-2-fluoropyridine (210 mg, 1.6 mmol) in DMF (5 mL) was added Cs ₂ CO ₃ (1000 mg, 3.2 mmol). The resulting mixture was stirred at 60℃ for 18h. After being cooled to room temperature, the reaction was partitioned between EtOAc and water, the organic layer was separated, and the aqueous layer was extracted with EtOAc twice. The combined organic phases were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by column chromatography on silica gel (0~50% ethyl acetate in petroleum ether) to give tert-butyl(2R,5S)-4-[7-(4- chloropyridin-2-yl)-5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyri midin-4-yl]-2,5- dimethylpiperazine-1-carboxylate (370 mg, 86%) as a white solid. LC/MS (ESI) (m/z): 537 (M+H) ^{+ 1} H NMR (400 MHz, CDCl ₃ ) δ 9.06 (d, J = 1.5 Hz, 1H), 8.57 (s, 1H), 8.37 (d, J = 5.3 Hz, 1H), 8.27 (s, 1H), 7.49 (td, J = 7.5, 1.5 Hz, 1H), 7.37 (dd, J = 13.1, 5.8 Hz, 1H), 7.27 – 7.14 (m, 3H), 4.34 – 4.07 (m, 2H), 3.44 – 3.18 (m, 3H), 2.89 (dd, J = 28.9, 18.9 Hz, 1H), 1.43 (s, 9H), 1.07 (d, J = 6.8 Hz, 3H), 0.96 (d, J = 6.6 Hz, 3H). Example 135. Synthesis of tert-butyl (S)-4-(7-(5-cyano-1-methyl-1H-pyrrol-2-yl)-5- cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperaz ine-1-carboxylate (Compound 456) Step 1. tert-Butyl (S)-4-(5-cyclopropyl-7-(5-(methoxycarbonyl) -1-methyl- 1H-pyrrol- 2-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 (200 mg, 0.50 mmol, prepared following a similar procedure outlined in compound 259) in dry DMF was added methyl 5-bromo-1-methyl-1H-pyrrole-2- carboxylate (220 mg, 1.0 mmol), K ₃ PO ₄ (320 mg, 1.5 mmol) and CuI (48 mg, 0.25 mmol). trans-1,2-Cyclohexanediamine (72 mg, 0.50 mmol) was added, and the mixture was stirred at 120°C under N ₂ overnight. The mixture was cooled to rt, diluted with EtOAc, washed with H ₂ O, brine, dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0~40% EtOAc in petroleum ether) to provide tert-butyl (S)-4-(5-cyclopropyl-7-(5-(methoxycarbonyl)-1-methyl-1H-pyrr ol-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (220 mg, 88%) as a yellow foam. LC/MS ESI (m/z): 495 (M+H) ⁺ . Step 2. (S)-5-(4-(4-(tert-Butoxycarbonyl)-2-methylpiperazin-1-yl)-5- cyclopropyl -7H- pyrrolo[2,3-d]pyrimidin-7-yl)-1-methyl-1H-pyrrole-2-carboxyl ic acid To the solution of tert-butyl (S)-4-(5-cyclopropyl-7-(5-(methoxycarbonyl)-1-methyl- 1H-pyrrol-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpip erazine-1-carboxylate (220 mg, 0.45 mmol) in MeOH (10 mL) and H ₂ O (10 mL) was added NaOH (89 mg, 2.2 mmol). The resulting reaction mixture was stirred at 90 ^o C overnight. The reaction was quenched with 1 N HCl to PH 4 and extracted with EtOAc twice. The combined organic layers were dried over Na2SO4, filtered and concentrated to afford (S)-5-(4-(4-(tert-butoxycarbonyl)-2- methylpiperazin-1-yl)-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimid in-7-yl)-1-methyl-1H-pyrrole- 2-carboxylic acid (180 mg, 84%) as a light yellow solid. LC/MS ESI (m/z): 481 (M+H) ⁺ . Step 3. tert-Butyl (S)-4-(7-(5-carbamoyl-1-methyl-1H-pyrrol-2-yl) -5-cyclopropyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te To a solution of (S)-5-(4-(4-(tert-butoxycarbonyl) -2-methylpiperazin-1-yl)-5- cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-methyl-1H-pyr role-2-carboxylic acid (180 mg, 0.38 mmol) in DMF (10 mL) were added HATU (210 mg, 0.56 mmol), DIPEA (190 mg, 1.5 mmol) and NH ₄ Cl (40 mg, 0.75 mmol) respectively. The resulting reaction mixture was stirred at r.t. under N ₂ overnight. The reaction mixture was partitioned between EtOAc and water and the organic layer was separated. The aqueous layer was extracted with EtOAc twice and the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to afford tert-butyl (S)-4-(7-(5-carbamoyl-1-methyl- 1H-pyrrol-2-yl)-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-y l)-3-methylpiperazine-1- carboxylate (120 mg, 67%) as yellow solid. LC/MS ESI (m/z): 480 (M+H) ⁺ . Step 4. tert-Butyl (S)-4-(7-(5-cyano-1-methyl-1H-pyrrol-2-yl)-5- cyclopropyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te A mixture of tert-butyl (S)-4-(7-(5-carbamoyl-1-methyl-1H-pyrrol-2-yl)-5- cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperaz ine-1-carboxylate (120 mg, 0.25 mmol) and pyridine (400 mg, 5.0 mmol) in DCM (10 mL) was stirred at 0°C. Then TFAA (260 mg, 1.3 mmol) was dropwise at 0°C, the mixture stirred at 0°C for 0.5h, and extracted with H ₂ O and DCM. The organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, 0~30% EtOAc in petroleum ether) followed by prep-HPLC provided tert-butyl (S)-4-(7-(5-cyano-1-methyl-1H-pyrrol-2-yl)-5- cyclopropyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (75 mg, 65%) as a light yellow solid. LC/MS ESI (m/z): 462 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.32 (s, 1H), 6.79 (d, J = 4.1 Hz, 1H), 6.60 (s, 1H), 6.12 (d, J = 4.1 Hz, 1H), 4.83 – 4.68 (m, 1H), 4.11 – 3.77 (m, 3H), 3.54 – 3.43 (m, 4H), 3.29 – 2.97 (m, 2H), 1.96 – 1.89 (m, 1H), 1.43 (s, 9H), 1.20 (d, J = 6.2 Hz, 3H), 0.98 – 0.91 (m, 2H), 0.72 – 0.62 (m, 2H). The following compounds were prepared by procedures analogous to the synthesis of compound 456 from the corresponding aryl bromide. Example 136. Synthesis of tert-butyl(S)-4-(7-(4-chloropyridin-2-yl)-5-cyclopropyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (Compound 457) C ^{ompound 457} Step 1. tert-Butyl(S)-4-(7-(4-chloropyridin-2-yl)-5-cyclopropyl-7H-p yrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl(3S)-4-{5-cyclopropyl-7H-pyrrolo[2,3-d] pyrimidin-4-yl}- 3-methylpiperazine-1-carboxylate (110 mg, 0.30 mmol, prepared following the procedure outlined in compound 259) and 4-chloro-2-fluoropyridine (99 mg, 0.75 mmol) in DMF (3 mL) was added Cs ₂ CO ₃ (490 mg, 1.5 mmol). The resulting mixture was stirred at 60℃ for 18h. After being cooled to room temperature, the reaction was partitioned between EtOAc and water, the organic layer was separated, and the aqueous layer was extracted with EtOAc twice. The combined organic phases were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by column chromatography on silica gel (0~50% ethyl acetate in petroleum ether) to give tert-butyl (S)-4-(7-(4-chloropyridin-2-yl)-5- cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperaz ine-1-carboxylate (60 mg, 42%) as a white solid. LC/MS (ESI) (m/z): 469 (M+H) ^{+ 1} H NMR (400 MHz, CDCl ₃ ) δ 8.96 (d, J = 1.4 Hz, 1H), 8.49 (s, 1H), 8.32 (d, J = 5.3 Hz, 1H), 7.74 (s, 1H), 7.14 (dd, J = 5.3, 1.7 Hz, 1H), 4.68 (s, 1H), 4.18 – 3.75 (m, 3H), 3.53 (t, J = 11.3 Hz, 1H), 3.41 – 3.02 (m, 2H), 2.03 (d, J = 5.9 Hz, 1H), 1.49 (s, 9H), 1.21 (d, J = 6.4 Hz, 3H), 1.01 (dd, J = 8.0, 1.6 Hz, 2H), 0.91 – 0.73 (m, 2H). Example 137. Synthesis of tert-butyl (2R,5S)-4-(7-(4-cyanopyrimidin-2-yl)-5-(2- fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylp iperazine-1-carboxylate (Compound 460) Step 1. 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 (300 mg, 0.49 mmol, prepared following the procedure outlined in compound 252) in dioxane (6 mL) and H ₂ O (1 mL) were added (2- fluorophenyl)boronic acid (140 mg, 0.98 mmol), K ₂ CO ₃ (200 g, 1.5 mmol) and Pd(dppf)Cl ₂ (37 mg, 0.050 mmol). The resulting mixture was heated to 90 ^o C overnight under N ₂ . After being cooled to room temperature, the solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~40%, ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-4-(5-(2-fluorophenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrim idin-4-yl)-2,5- dimethylpiperazine-1-carboxylate (200 mg, 70%) as a solid. LC/MS ESI (m/z): 580 (M+H) ⁺ . Step 2. 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 (100 mg, 0.17 mmol) in THF (5 mL) was added TBAF (3.0 mL, 1.0 M in THF) and the resulting mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated to afford tert-butyl (2R,5S)-4-(5-(2-fluorophenyl)-7-tosyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (70 mg, 95%) as a solid. LC/MS ESI (m/z): 426 (M+H) ⁺ . Step 3. tert-Butyl (2R,5S)-4-(7-(4-cyanopyrimidin-2-yl)-5- (2-fluorophenyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate 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 (50 mg, 0.13 mmol) in dioxane (5 mL) were added 2-bromopyrimidine-4-carbonitrile (35 mg, 0.19 mmol), Pd(dba) ₃ (64 mg, 0.70 mmol) and X-Phos (75 mg, 0.13 mmol) and Cs ₂ CO ₃ (85 mg, 0.26 mmol). The resulting mixture was heated to 100 ^o C overnight under N ₂ . The mixture was cooled, concentrated, and the residue was purified by flash column chromatography (silica gel, 0~10%, MeOH in DCM) to afford tert-butyl (2R,5S)-4-(7-(4-cyanopyrimidin-2-yl)-5-(2-fluorophenyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate (20 mg, 30%).20 mg of which was further purified by prep-HPLC to afford 10 mg of white solid. LC/MS ESI (m/z): 529 (M+H) ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ 9.13 (d, J = 4.9 Hz, 1H), 8.53 (s, 1H), 8.20 (s, 1H), 7.84 (d, J = 4.9 Hz, 1H), 7.60 – 7.55 (m, 1H), 7.53 – 7.47 (m, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.29 (t, J = 9.1 Hz, 1H), 4.24 – 4.10 (m, 2H), 3.42 – 3.35 (m, 2H), 3.24 – 3.19 (m, 1H), 2.82 (s, 1H), 1.43 (s, 9H), 1.06 (d, J = 6.8 Hz, 3H), 0.95 (d, J = 6.7 Hz, 3H). The following compounds were prepared by analogous procedures to the synthesis of compound 460 from the corresponding aryl halide. Example 138. Synthesis of tert-butyl (2R,5S)-4-(7-(3,5-difluorophenyl)-5-(3- methylpyrazin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dim ethylpiperazine-1- carboxylate (Compound 462) Step 1. 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 (12 g, 28 mmol) in DIPEA (15 mL) was added tert-butyl (2R,5S)-2,5-dimethylpiperazine-1- carboxylate (9.0 g, 42 mmol). The resulting mixture was heated to 150 ^o C for 3 h under N ₂ . After being cooled to room temperature, the solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2 ,5- dimethyl piperazine-1-carboxylate (16 g, 94%) as a light yellow solid. LC/MS ESI (m/z): 612 (M+H) ⁺ . Step 2. tert-Butyl (2R,5S)-2,5-dimethyl-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-c arboxylate 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 (2.0 g, 3.2 mmol) in dioxane (20 mL) were added 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.7 g, 13 mmol), TEA (2.2 mL, 16 mmol), X-Phos (0.31 g, 0.65 mmol) and Pd ₂ (dba) ₃ (0.30 g, 0.32 mmol). The resulting mixture was stirred at 95 ^o C overnight then cooled to room temperature. The reaction was quenched with water and extracted with DCM twice. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated to afford tert-butyl (2R,5S)-2,5-dimethyl-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 which was used in directly in the next step without further purification. LC/MS ESI (m/z): 612 (M+H) ⁺ . Step 3. tert-Butyl (2R,5S)-2,5-dimethyl-4-(5-(3-methylpyrazin-2-yl) -7-tosyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate To a solution of tert-butyl (2R,5S)-2,5-dimethyl-4-(5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)p iperazine-1-carboxylate (2.0 g, 3.2 mmol) in dioxane (20 mL) and H ₂ O (4 mL) were added 2-chloro-3-methylpyrazine (0.92 g, 7.2 mmol), K ₂ CO ₃ (2.5 g, 18 mmol) and Pd(dppf)Cl ₂ (0.26 g, 0.36 mmol). The resulting mixture was heated to 90 ^o C overnight. The mixture was cooled to room temperature and the solvent was removed. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-2,5-dimethyl-4-(5-(3- methylpyrazin-2-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl) piperazine-1-carboxylate (1.3 g, 62 %) as a yellow solid. LC/MS ESI (m/z): 578 (M+H) ⁺ . Step 4. tert-Butyl (2R,5S)-2,5-dimethyl-4-(5-(3-methylpyrazin-2-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- (3-methylpyrazin-2-yl)-7-tosyl- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (1.3 g, 2.2 mmol) in THF (10 mL) was added TBAF (10 mL, 1.0M in THF). The resulting mixture was stirred at room temperature for 2 hr. The reaction was quenched with water and extracted with EtOAc twice. The combined organic layers were washed with NH ₄ Cl (aq.), dried over Na ₂ SO ₄ , filtered and, concentrated to afford crude tert-butyl (2R,5S)-2,5-dimethyl-4-(5-(3-methylpyrazin-2-yl)-7H- pyrrolo [2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (950 mg, 99 %) as a brown solid. LC/MS ESI (m/z): 424 (M+H) ⁺ . Step 5. tert-Butyl (R)-4-(7-(3,5-difluorophenyl)-5-(pyridin-2-yl)- 7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate To a solution of tert-butyl (2R,5S)-2,5-dimethyl-4-(5- (3-methylpyrazin-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (480 mg, 1.1 mmol) in DMF (5 mL) were added 1,3-difluoro-5-iodobenzene (310 mg, 1.3 mmol), trans-N,N’- dimethylcyclohexane-1,2-diamine (71 mg, 0.50 mmol), CuI (210 mg, 1.1 mmol) and K ₃ PO ₄ (700 mg, 3.3 mmol). The resulting mixture was heated to 120 ^o C overnight then cooled to room temperature. The reaction was quenched with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to give the product which was further purified by prep- HPLC to afford tert-butyl (2R,5S)-4-(7-(3,5-difluorophenyl)-5-(3-methylpyrazin-2-yl)-7 H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate (780 mg, 84 %) as a white solid. LC/MS ESI (m/z): 536 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.57 – 8.51 (m, 3H), 7.49 – 7.43 (m, 3H), 6.84 (t, J = 8.7 Hz, 1H), 4.09 (d, J = 58.8 Hz, 2H), 3.31 (dd, J = 24.7, 13.9 Hz, 2H), 3.09 (s, 1H), 2.95 – 2.66 (m, 1H), 2.53 (s, 3H), 1.43 (s, 9H), 1.02 – 0.97 (m, 6H). The following compound was prepared by an analogous procedure to the synthesis of compound 462 from the corresponding amine and aryl halide.

Example 139. Synthesis of tert-butyl (S)-4-(7-(5-cyano-4-methylthiazol-2-yl)-5-(2- fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiper azine-1-carboxylate (Compound 463) C ^{ompound 463} Step 1. Ethyl (S)-2-(4-(4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)-5- (2- fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-methylthiaz ole-5-carboxylate To a solution of tert-butyl (S)-4-(5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)-3-methylpiperazine-1-carboxylate (500 mg, 1.2 mmol, prepared following the procedure outlined in compound 268) in DMF (5 mL) were added ethyl 2-bromo-4-methylthiazole-5- carboxylate (610 mg, 2.4 mmol), trans-N,N’-dimethylcyclohexane-1,2-diamine (350 mg, 2.4 mmol), CuI (230 mg, 1.2 mmol) and K ₃ PO ₄ (780 mg, 3.7 mmol). The resulting mixture was heated to 100 ^o C overnight. After being cooling to room temperature, the reaction was partitioned between EtOAc and water and the organic layer was separated. The aqueous layer was extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered. and concentrated. The residue was purified by flash column chromatography (silica gel, 0~15%, ethyl acetate in petroleum ether) to afford ethyl (S)-2-(4- (4-(tert-butoxycarbonyl)-2- methylpiperazin-1-yl)-5-(2-fluorophenyl)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)-4-methylthiazole-5-carboxylate (600 mg, 84%) as a solid. LC/MS ESI (m/z): 581 (M+H) ⁺ . Step 2. (S)-2-(4-(4-(tert-Butoxycarbonyl)-2-methylpiperazin-1-yl)-5- (2-fluorophenyl)- 7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-methylthiazole-5-carboxyl ic acid To a solution of ethyl (S)-2-(4-(4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl) -5-(2- fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-methylthiaz ole-5-carboxylate (450 mg, 0.78 mmol) in MeOH (5 mL) and H ₂ O (5 mL) was added NaOH (160 mg, 3.9 mmol). The resulting mixture was heated to 45 ^o C overnight. The reaction was cooled, adjusted to acidic pH, and filtered to afford (S)-2-(4-(4-(tert-butoxycarbonyl) -2-methylpiperazin-1-yl)-5-(2- fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-methylthiaz ole-5-carboxylic acid (250 mg, 58%) as a solid. LC/MS ESI (m/z): 553 (M+H) ⁺ . Step 3. tert-Butyl (S)-4-(7-(5-carbamoyl-4-methylthiazol-2-yl)-5-(2-fluoropheny l) - 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carbox ylate To a solution of (S)-2-(4-(4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)-5- (2- fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-methylthiaz ole-5-carboxylic acid (70 mg, 0.13 mmol) in DMF (5 mL) were added NH ₄ Cl (14 mg, 0.26 mmol), DIPEA (50 mg, 0.39 mmol) and HATU (98 mg, 0.26 mmol). The resulting mixture was stirred at room temperature overnight under N ₂ . The reaction was partitioned between EtOAc and water and the organic layer was separated. The aqueous layer was extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0~10%, MeOH in DCM) to afford tert-butyl (S)-4-(7-(5-carbamoyl-4-methylthiazol-2-yl)-5-(2- fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiper azine-1-carboxylate (50 mg, 71%). as a solid. LC/MS ESI (m/z): 552 (M+H) ⁺ . Step 4. tert-Butyl (S)-4-(7-(5-cyano-4-methylthiazol-2-yl)-5 -(2-fluorophenyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te To a solution of tert-butyl (S)-4-(7-(5-carbamoyl-4-methylthiazol-2-yl)-5-(2- fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiper azine-1-carboxylate (50 mg, 0.090 mmol) in DCM (3 mL) were added TEA (91 mg, 0.90 mmol) and TFAA (71 mg, 0.34 mmol) and the resulting mixture was stirred at 0 ^o C 1 h under N ₂ . Solvent was removed and the residue was purified by prep-HPLC to afford tert-butyl (S)-4-(7-(5-cyano-4- methylthiazol-2-yl)-5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyri midin-4-yl)-3- methylpiperazine-1-carboxylate (30 mg, 63%) of white solid. LC/MS ESI (m/z): 534 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.57 (s, 1H), 8.06 (s, 1H), 7.47 – 7.34 (m, 3H), 7.21 – 7.19 (m, 1H), 4.46 – 4.17 (m, 1H), 3.85 – 3.69 (m, 1H), 3.63 – 3.56 (m, 1H), 3.55 – 3.46 (m, 1H), 3.07 (t, J = 12.4 Hz, 1H), 2.96 – 2.69 (m, 2H), 2.60 (s, 3H), 1.43 (s, 9H), 1.04 (d, 3H). Example 140. Synthesis of tert-butyl (S)-4-(7-(4-cyanopyridin-2-yl)-5-(2-hydroxypropan- 2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1- carboxylate (Compound 484) C ^{ompound 484} Step 1. tert-Butyl (S)-4-(7-(4-chloropyridin-2-yl)-5-(2-hydroxypropan-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te A solution of i-PrMgCl (3.6 mL, 1.0M in THF) was added dropwise to a solution of tert-butyl (S)-4-(7-(4-chloropyridin-2-yl)-5-iodo-7H-pyrrolo[2,3-d]pyri midin-4-yl)-3- methylpiperazine-1-carboxylate (1.0 g, 1.8 mmol, prepared following the procedure outlined in Compound 486 and acetone (5 mL) in THF (20 mL) at -78 ^o C. The reaction was allowed to warm to room temperature and stirred for 1 h. 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford tert-butyl (S)-4-(7-(4-chloropyridin-2-yl)-5-(2-hydroxypropan-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (30 mg, 3.0%) as an off white solid. LC/MS ESI (m/z): 487 (M+H) ⁺ . Step 2. tert-Butyl (S)-4-(7-(4-cyanopyridin-2-yl)-5-(2-hydroxypropan-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te To a solution of tert-butyl (S)-4-(7-(4-chloropyridin-2-yl)-5-(2-hydroxypropan-2-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carbox ylate (30 mg, 0.060 mmol) in DMF (5 mL) were added Zn(CN) ₂ (72 mg, 0.62 mmol) and Pd(PPh ₃ ) ₄ (360 mg, 0.31 mmol). The resulting mixture was stirred at 120 ^o C overnight under a N ₂ atmosphere. The reaction was quenched with ice water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~20%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford tert-butyl (S)-4-(7-(4-cyanopyridin-2-yl)-5-(2-hydroxypropan-2-yl)-7H-p yrrolo[2,3-d]pyrimidin-4-yl)- 3-methylpiperazine-1-carboxylate (3.7 mg, 13%) as a white solid. LC/MS ESI (m/z): 478 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.36 (s, 1H), 8.91 (s, 1H), 8.65 (d, J = 5.0 Hz, 1H), 8.21 (s, 1H), 7.72 (s, 1H), 7.43 (d, J = 5.1 Hz, 1H), 4.25 – 4.09 (m, 2H), 3.69 – 3.62 (m, 1H), 3.22 – 3.07 (m, 3H), 2.91 – 2.81 (m, 1H), 1.75 (s, 3H), 1.64 (s, 3H), 1.50 (s, 9H), 0.90 (d, J = 6.2 Hz, 3H). Example 141. Synthesis of tert-butyl (S)-4-(7-(5-cyanothiazol-2-yl)-5-(pyrrolidin-1-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carbox ylate (Compound 485) Step 1. tert-Butyl (S)-4-(7-(5-cyanothiazol-2-yl)-5-iodo-7H-pyrrolo[2,3-d]pyrim idin- 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 (600 mg, 1.4 mmol, prepared following the procedure outlined in Compound 514 in DMF (15 mL) were added 2-chlorothiazole-5-carbonitrile (390 mg, 2.7 mmol) and Cs ₂ CO ₃ (2.2 g, 6.8 mmol). The reaction was stirred at room temperature for 3 h. The resulting mixture 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0~30% ethyl acetate in petroleum ether) to afford tert-butyl (S)-4-(7-(5-cyanothiazol-2-yl)-5-iodo-7H-pyrrolo[2,3-d]pyrim idin-4-yl)-3-methylpiperazine- 1-carboxylate (700 mg, 94%). LC/MS ESI (m/z): 552 (M+H) ⁺ . Step 2. tert-Butyl (S)-4-(7-(5-cyanothiazol-2-yl)-5-(2-oxopyrrolidin-1-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te A mixture of tert-butyl (S)-4-(7-(5-cyanothiazol-2-yl)-5-iodo-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (600 mg, 1.1 mmol), pyrrolidin-2-one (190 mg, 2.2 mmol), CuI (100 mg, 0.55 mmol), K ₃ PO ₄ (690 mg, 3.3 mmol) and trans-N ¹ ,N ² - dimethylcyclohexane-1,2-diamine (160 mg, 1.1 mmol) and DMF (15 mL) was stirred at 90 ^o 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford tert-butyl (S)-4-(7-(5-cyanothiazol-2-yl)-5-(2-oxopyrrolidin-1-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (130 mg, 23%) as a solid. LC/MS ESI (m/z): 509 (M+H) ⁺ . Step 3. tert-Butyl (S)-4-(7-(5-cyanothiazol-2-yl)-5-(pyrrolidin-1-yl)-7H-pyrrol o[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl (S)-4-(7-(5-cyanothiazol-2-yl)-5-(2-oxopyrrolidin-1-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carbox ylate (40 mg, 0.080 mmol) in THF (5 mL) at 0 ^o C were added RhH(CO)(PPh) ₃ (36 mg, 0.040 mmol) and PhSiH ₃ (0.090 ml, 0.24 mmol). The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford tert-butyl (S)-4-(7-(5- cyanothiazol-2-yl)-5-(pyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyri midin-4-yl)-3-methylpiperazine- 1-carboxylate (15 mg, 53%) as a white solid. LC/MS ESI (m/z): 495 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.42 (s, 1H), 7.96 (s, 1H), 7.28 (s, 1H), 4.95 – 4.87 (m, 1H), 4.20 – 3.82 (m, 3H), 3.35 – 3.27 (m, 1H), 3.18 – 3.04 (m, 3H), 2.92 – 2.80 (m, 3H), 1.94 – 1.89 (m, 4H), 1.42 (s, 9H), 1.08 (d, J = 6.3 Hz, 3H). Example 142. Synthesis of tert-butyl (S)-4-(7-(4-cyanopyridin-2-yl)-5-(ethyl(2- methoxyethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methy lpiperazine-1- carboxylate (Compound 486) C ^{ompound 486} Step 1. tert-Butyl (S)-4-(7-(4-chloropyridin-2-yl)-5-iodo-7H-pyrrolo[2,3-d]pyri midin- 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) and 4-chloro-2-fluoropyridine (180 mg, 1.4 mmol) in DMF (10 mL) was added Cs ₂ CO ₃ (780 mg, 2.4 mmol). The resulting mixture was stirred at 60℃ for 18 h. 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 anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography on silica gel (0~30% EtOAc in petroleum ether) to give tert-butyl (S)-4-(7-(4-chloropyridin-2-yl)-5-iodo-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (530 mg, 79 %) as a white solid. LC/MS ESI (m/z): 555 (M+H) ⁺ . Step 2. Methyl (S)-4-(4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)-7-(4- chloropyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylat e To a solution of tert-butyl (S)-4-(7-(4-chloropyridin-2-yl)-5-iodo-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (530 mg, 0.94 mmol) in MeOH (6 mL) was added Pd(dppf)Cl ₂ (69 mg, 0.094 mmol ) at 25°C. The mixture was degassed by purging three times with CO gas. The reaction was stirred at 80°C under CO for 8 h. The mixture was poured into H ₂ O (20 mL) and extracted twice with EtOAc. The combined organic phases were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0~35% ethyl acetate in petroleum ether) to afford methyl (S)-4-(4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)-7-(4- chloropyridin-2- yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (360 mg, 79%) as a brown solid. LC/MS ESI (m/z): 487 (M+H) ⁺ . Step 3. (S)-4-(4-(tert-Butoxycarbonyl)-2-methylpiperazin-1-yl)-7-(4- chloropyridin-2- yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid To a solution of methyl (S)-4-(4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)-7-(4- chloropyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylat e (360 mg, 0.74 mmol) in MeOH (5 mL) was added NaOH (5.0 mL, 2.0 N) at room temperature. The reaction was stirred at 80°C for 12 h. The mixture was adjusted to pH 2 with HCl (1 N) and extracted twice with DCM. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was used in next step directly. Step 4. tert-Butyl (S)-4-(5-acetamido-7-(4-chloropyridin-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of (S)-4-(4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)-7-(4- chloropyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid (0.74 mmol) in toluene (5 mL) were added Et ₃ N (320 mg, 3.2 mmol) and DPPA (0.45 mL, 2.1 mmol) at room temperature. The mixture was stirred for 2 h and then treated with acetic anhydride (320 mg, 3.2 mmol). The reaction was heated at 60°C for 2 h. After cooling to room temperature, the mixture was poured into ice water and extracted twice with EtOAc. The combined organic phases were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by silica gel column (silica gel, 0~50%, ethyl acetate in petroleum ether) to afford tert-butyl (S)-4-(5-acetamido-7-(4-chloropyridin-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (350 mg, 67 %) as a yellow oil. LC/MS ESI (m/z): 486 (M+H) ⁺ . Step 5. tert-Butyl (S)-4-(7-(4-chloropyridin-2-yl)-5-(N-(2-methoxyethyl)acetami do)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carbox ylate To a suspension of NaH (55 mg, 1.3 mmol, 60 wt%) in THF (10 mL) at 0 ^o C was added a solution of tert-butyl (S)-4-(5-acetamido-7-(4-chloropyridin-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (320 mg, 0.66 mmol) in THF (5 mL) dropwise. After stirring at 0 ^o C for 15 min, 1-bromo-2-methoxyethane (130 mg, 0.75 mmol) was added. The resulting mixture was stirred at room temperature overnight under N2. The reaction was quenched with ice water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30% ethyl acetate in petroleum ether) to afford tert-butyl (S)-4-(7-(4-chloropyridin-2-yl)-5-(N-(2-methoxyethyl)acetami do)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (160 mg, 45%) as a light yellow solid. LC/MS ESI (m/z): 544 (M+H) ⁺ . Step 6. tert-Butyl (S)-4-(7-(4-chloropyridin-2-yl)-5-(ethyl(2-methoxyethyl)amin o)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te To a solution of tert-butyl (S)-4-(7-(4-chloropyridin-2-yl)-5-(N-(2- methoxyethyl)acetamido)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-m ethylpiperazine-1- carboxylate (160 mg, 0.30 mmol) in THF (2 mL) at 0 ^o C was added BH ₃ -THF (2.0 mL, 1.0 M) dropwise. After stirring at room temperature for 2 h, the reaction was quenched with ice water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~40% ethyl acetate in petroleum ether) to afford tert-butyl (S)- 4-(7-(4-chloropyridin-2-yl)-5-(ethyl(2-methoxyethyl)amino)-7 H-pyrrolo[2,3-d]pyrimidin-4- yl)-3-methylpiperazine-1-carboxylate (87 mg, 55%) as a colorless oil. LC/MS ESI (m/z): 530 (M+H) ⁺ . Step 7. tert-Butyl (S)-4-(7-(4-cyanopyridin-2-yl)-5-(ethyl(2-methoxyethyl)amino )-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te To the solution of tert-butyl (S)-4-(7-(4-chloropyridin-2-yl)-5-(ethyl(2- methoxyethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methy lpiperazine-1-carboxylate (87 mg, 0.16 mmol) in DMF (5 mL) were added Zn(CN)2 (110 mg, 0.96 mmol) and Pd(PPh ₃ ) ₄ (92 mg, 0.080 mmol). The reaction was stirred at 120℃ under N ₂ 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 in petroleum ether) to give crude product which was further purified by prep-HPLC to and to afford tert-butyl (S)-4-(7-(4-cyanopyridin-2-yl)-5-(ethyl(2-methoxyethyl)amino )-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (5.3 mg, 6.0 %) as a yellow solid. LC/MS ESI (m/z): 521 (M+H) ⁺ . ¹ H NMR(400 MHz, CD ₃ OD) δ 9.26 (s, 1H), 8.65 (dd, J = 5.0, 0.7 Hz, 1H), 8.39 (s, 1H), 7.77 (s, 1H), 7.50 (dd, J = 5.0, 1.3 Hz, 1H), 5.23 (s, 1H), 4.29 (s, 1H), 4.12 (d, J = 12.5 Hz, 1H), 3.91 (d, J = 13.2 Hz, 1H), 3.57 – 3.51 (m, 2H), 3.43 – 3.37 (m, 2H), 3.34 – 3.31 (m, 6H), 3.27 – 3.22 (m, 1H), 3.12 (s, 1H), 1.49 (s, 9H), 1.10 (d, J = 6.4 Hz, 3H), 0.98 (t, J = 7.0 Hz, 3H). The following compound was prepared by a procedure similar to the synthesis of compound 486 from the corresponding amine (the Curtius rearrangement was run with acetic formic anhydride instead with acetic anhydride). Example 143. Synthesis of tert-butyl (S)-4-(7-(4-cyanopyridin-2-yl)-5-propoxy-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (Compound 487) To the solution of tert-butyl (S)-4-(7-(4-cyanopyridin-2-yl)-5-iodo-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (100 mg, 0.18 mmol, prepared following the procedure outlined in Compound 514 in propan-1-ol (1 mL) were added CuI (35 mg, 0.18 mmol), 1,10-phenanthroline (65 mg, 0.36 mmol) and C _S 2CO3 (180 mg, 0.54 mmol) respectively. The resulting reaction mixtures were stirred at 100℃ under N2 overnight. This reaction was repeated at the same scale and the combined reaction mixtures were worked up together. After cooling to room temperature, solvent was removed and the residue was purified by column chromatography on silica gel (0~20% ethyl acetate in petroleum ether) and prep-HPLC to obtain tert-butyl (S)-4-(7-(4-cyanopyridin-2-yl)-5-iodo-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (5.5 mg, 3.1%) as a white solid. LC/MS(ESI)m/z: 478 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.38 – 9.36 (m, 1H), 8.55 (dd, J = 5.0, 0.7 Hz, 1H), 8.40 (s, 1H), 7.54 (s, 1H), 7.28 (dd, J = 5.0, 1.3 Hz, 1H), 5.00 – 4.84 (m, 1H), 4.51 – 4.12 (m, 2H), 4.01 (t, J = 6.6 Hz, 2H), 3.97 – 3.83 (m, 1H), 3.39 (t, J = 14.0 Hz, 1H), 3.22 – 3.00 (m, 2H), 1.92 – 1.87 (m, 2H), 1.50 (s, 9H), 1.29 (d, J = 6.6 Hz, 3H), 1.08 (t, J = 7.4 Hz, 3H). Example 144. Synthesis of tert-butyl (S)-4-(5-(((allyloxy)carbonyl)(2- methoxyethyl)amino)-7-(4-cyanopyridin-2-yl)-7H-pyrrolo[2,3-d ]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate (Compound 488) C ^{ompound 488} Step 1. tert-Butyl (S)-4-(5-(((allyloxy)carbonyl)amino)-7-(4-chloropyridin-2-yl )-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te To a solution of (S)-4-(4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)-7-(4- chloropyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid (200 mg, 0.40 mmol, prepared following the procedure outlined in Compound 486 in toluene (5 mL) were added Et ₃ N (0.16 mL, 1.2 mmol), prop-2-en-1-ol (0.040 mL, 0.80 mmol ) and DPPA (0.16 mL, 0.80 mmol). The mixture was stirred at 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 phases were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography on silica gel (0~45 % ethyl acetate in petroleum ether) to give the tert-butyl (S)-4-(5- (((allyloxy)carbonyl)amino)-7-(4-chloropyridin-2-yl)-7H-pyrr olo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate (140 mg, 67%) as a yellow oil. LC/MS ESI (m/z): 528 (M+H) ⁺ . Step 2. tert-Butyl (S)-4-(5-(((allyloxy) carbonyl)(2-methoxyethyl)amino)-7-(4- chloropyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methy lpiperazine-1-carboxylate To a suspension of NaH (24 mg, 0.52 mmol, 60 wt%) in THF (5 mL) at 0 ^o C was added tert-butyl (S)-4-(5-(((allyloxy)carbonyl)amino)-7-(4-chloropyridin-2-yl )-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (140 mg, 0.26 mmol). After stirring at 0 ^o C for 15 min, 1-bromo-2-methoxyethane (71 mg, 0.52 mmol) was added. The resulting mixture was stirred at 40°C overnight under N ₂ . The reaction was quenched with ice water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~20% ethyl acetate in petroleum ether) to afford tert-butyl (S)- 4-(5-(((allyloxy) carbonyl)(2-methoxyethyl)amino)-7-(4-chloropyridin-2-yl)-7H- pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (110 mg, 82 %) as a light yellow solid. LC/MS ESI (m/z): 587 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl3) δ 9.00 (s, 1H), 8.52 – 8.48 (m, 1H), 8.35 (d, J = 5.3 Hz, 1H), 8.13 (d, J = 10.5 Hz, 1H), 7.20 (dd, J = 5.3, 1.6 Hz, 1H), 5.79 (s, 1H), 5.32 – 4.96 (m, 2H), 4.77 – 4.11 (m, 5H), 3.87 – 3.47 (m, 5H), 3.43 – 3.27 (m, 5H), 3.08 – 2.91 (m, 1H), 1.49 (s, 9H), 1.23 – 1.15 (m, 3H). The following compound was prepared by a procedure similar to the synthesis of compound 488 from the corresponding amine and alkyl halide. Example 145. Synthesis of tert-butyl (2R,5S)-4-(5-(azetidin-1-yl)-7-(4-cyanopyridin-2- yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine- 1-carboxylate (Compound 489) Step 1. tert-Butyl (2R,5S)-4-(7-(4-chloropyridin-2-yl)-5-(2-oxoazetidin-1-yl)-7 H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate To a solution of tert-butyl (2R,5S)-4-(7-(4-chloropyridin-2-yl)-5-iodo-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (1.0 g, 1.7 mmol, prepared following the procedure outlined in Compound 521 in DMF (25 mL) were added azetidin-2-one (310 mg, 4.2 mmol), CuI (170 mg, 0.80 mmol), trans-N ¹ ,N ² -dimethylcyclohexane-1,2-diamine (250 mg, 1.7 mmol) and K ₃ PO ₄ (1.2 g, 5.1 mmol). The resulting mixture was heated to 90 ^o 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~80%, ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-4-(7-(4-chloropyridin-2-yl)-5-(2-oxoazetidin-1-yl)-7 H-pyrrolo[2,3-d]pyrimidin-4- yl)-2,5-dimethylpiperazine-1-carboxylate (500 mg, 57%) as a yellow solid. LC/MS ESI (m/z): 512 (M+H) ⁺ . Step 2. tert-Butyl (2R,5S)-4-(5-(azetidin-1-yl)-7-(4-chloropyridin-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate To a solution of tert-butyl (2R,5S)-4-(7-(4-chloropyridin-2-yl)-5-(2-oxoazetidin-1-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-ca rboxylate (350 mg, 0.68 mmol) in THF (10 mL) at 0 ^o C was added RhH(CO)(PPh) ₃ (180 mg, 0.20 mmol), followed by PhSiH ₃ (0.30 ml, 2.7 mmol) dropwise. The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~40% ethyl acetate in petroleum ether) to give the tert-butyl (2R,5S)-4-(5-(azetidin-1-yl)-7-(4- chloropyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dim ethylpiperazine-1-carboxylate (200 mg, 59%) as a yellow solid. LC/MS ESI (m/z): 498 (M+H) ⁺ . Step 3. tert-Butyl (2R,5S)-4-(5-(azetidin-1-yl)-7-(4-cyanopyridin-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate To the solution of tert-butyl (2R,5S)-4-(5-(azetidin-1-yl)-7-(4-chloropyridin-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate (200 mg, 0.40 mmol) in DMF (10 mL) were added Zn(CN) ₂ (190 mg, 1.6 mmol) and Pd(PPh ₃ ) ₄ (230 mg, 0.20 mmol) respectively. The resulting mixture was stirred at 120℃ under N ₂ 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 in petroleum ether) to give crude product which was further purified by prep-HPLC to afford tert-butyl (2R,5S)-4-(5-(azetidin-1-yl)-7-(4-cyanopyridin-2-yl)-7H-pyrr olo[2,3-d]pyrimidin-4-yl)-2,5- dimethylpiperazine-1-carboxylate (120 mg, 61%) as a yellow solid. LC/MS ESI (m/z): 489 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.35 (s, 1H), 8.57 (dd, J = 5.0, 0.8 Hz, 1H), 8.42 (s, 1H), 7.45 (s, 1H), 7.29 (dd, J = 5.0, 1.3 Hz, 1H), 5.11 (br. s, 1H), 4.36 (m, 1H), 4.02 (d, J = 13.9 Hz, 1H), 3.86 (q, J = 7.0 Hz, 2H), 3.80 – 3.71 (m, 2H), 3.66 – 3.57 (m, 3H), 2.33 – 2.26 (m, 2H), 1.49 (s, 9H), 1.16 (d, J = 6.8 Hz, 3H), 0.99 (d, J = 6.8 Hz, 3H). Example 146. tert-Butyl (2R,5S)-4-(7-(3-chlorophenyl)-5-(trifluoromethyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate (Compound 490) C ^{ompound 490} To a solution of tert-butyl (2R,5S)-4-(7-(3-chlorophenyl)-5-iodo-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (200 mg, 0.35 mmol, prepared following the procedure outlined in Compound 491 in DMSO (3 mL) were added azetidine (40 mg, 0.70 mmol), L-Proline (40 mg, 0.37 mmol), CuI (67 mg, 0.35 mmol) and K ₂ CO ₃ (150 mg, 1.1 mmol). The resulting mixture was heated to 90 ^o 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep- HPLC to afford tert-butyl (2R,5S)-4-(5-(azetidin-1-yl)-7-(3-chlorophenyl)-7H-pyrrolo[2 ,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (13 mg, 7.4%) as a white solid. LC/MS ESI (m/z): 497 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 7.78 – 7.65 (m, 2H), 7.42 (t, J = 8.1 Hz, 1H), 7.28 (s, 1H), 6.61 (s, 1H), 5.12 (s, 1H), 4.43 (s, 1H), 4.00 (d, J = 13.4 Hz, 1H), 3.84 – 3.70 (m, 4H), 3.67 – 3.56 (m, 3H), 2.33 – 2.24 (m, 2H), 1.49 (s, 9H), 1.14 (d, J = 6.7 Hz, 3H), 1.03 (d, J = 6.8 Hz, 3H).

Example 147. tert-Butyl (2R,5S)-4-(7-(3-chlorophenyl)-5-(trifluoromethyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate (Compound 491) C ^{ompound 491} Step 1. tert-Butyl (2R,5S)-4-(7-(3-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimi din- 4-yl)-2,5-dimethylpiperazine-1-carboxylate To a solution of 4-chloro-7-(3-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidi ne (5.0 g, 13 mmol, prepared following the procedure outlined in Compound 522 in DIPEA (60 mL) was added tert-butyl (2R,5S)-2,5-dimethylpiperazine-1-carboxylate (5.5 g, 26 mmol). The resulting mixture was heated to 150 ^o C for 1 h. After cooling to room temperature, solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-4-(7-(3- chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-di methylpiperazine-1- carboxylate (7.0 g, 96%) as a white solid. LC/MS ESI (m/z): 568 (M+H) ⁺ . Step 2. tert-Butyl (2R,5S)-4-(7-(3-chlorophenyl)-5-(trifluoromethyl)-7H-pyrrolo [2,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate To a solution of tert-butyl (2R,5S)-4-(7-(3-chlorophenyl)-5-iodo-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (1.0 g, 1.8 mmol) in DMF (15 mL) were added CuI (340 mg, 1.8 mmol) and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (690 mg, 3.6 mmol). The resulting mixture was stirred at 80 ^o 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to give tert-butyl (2R,5S)-4-(7-(3-chlorophenyl)-5- (trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimet hylpiperazine-1-carboxylate (600 mg, 67%) as a white solid. LC/MS ESI (m/z): 510 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.51 (s, 1H), 7.72 – 7.68 (m, 2H), 7.58 (d, J = 7.2 Hz, 1H), 7.49 (t, J = 7.5 Hz, 1H), 7.42 (d, J = 7.1 Hz, 1H), 4.63 – 4.54 (m, 1H), 4.48 – 4.26 (m, 1H), 3.80 – 3.71 (m, 2H), 3.64 (d, J = 13.6 Hz, 1H), 3.49 (d, J = 13.3 Hz, 1H), 1.50 (s, 9H), 1.17 – 1.10 (m, 6H). Example 148. Synthesis of tert-butyl (S)-4-(5-(azetidin-1-yl)-7-(3-chlorophenyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (Compound 493) C ^{ompound 493} Step 1. tert-Butyl (S)-4-(5-bromo-7-(3-chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidin -4- yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl (S)-4-(5-bromo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate (500 mg, 1.3 mmol, prepared following the procedure outlined in Compound 498 in DMF (10 mL) were added 1-chloro-3-iodobenzene (600 mg, 2.5 mmol), CuI (120 mg, 0.63 mmol), trans-N ¹ ,N ² -dimethylcyclohexane-1,2-diamine (180 mg, 1.3 mmol) and K ₃ PO ₄ (800 mg, 3.8 mmol). The resulting mixture was heated to 90 ^o 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~15%, ethyl acetate in petroleum ether) to afford tert-butyl (S)- 4-(5-bromo-7-(3-chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-y l)-3-methylpiperazine-1- carboxylate (400 mg, 62%) as a white solid. LC/MS ESI (m/z): 506, 508 (M+H) ⁺ . Step 2. tert-Butyl (S)-4-(5-(azetidin-1-yl)-7-(3-chlorophenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl (S)-4-(5-bromo-7-(3-chlorophenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (400 mg, 0.79 mmol) in DMSO (10 mL) were added azetidine (91 mg, 1.6 mmol), CuI (150 mg, 0.79 mmol), L-Proline (46 mg, 0.40 mmol) and K ₂ CO ₃ (330 mg, 2.4 mmol). The resulting mixture was heated to 90 ^o 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford tert-butyl (S)-4-(5-(azetidin-1-yl)-7-(3-chlorophenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (100 mg, 38%) as a white solid. LC/MS ESI (m/z): 483 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.30 (s, 1H), 7.67 (s, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7.37 – 7.32 (m, 1H), 7.21 (s, 1H), 6.54 (s, 1H), 4.94 – 4.85 (m, 1H), 4.12 – 3.82 (m, 3H), 3.74 – 3.68 (m, 2H), 3.58 – 3.52 (m, 2H), 3.48 – 3.31 (m, 2H), 2.99 – 2.84 (m, 1H), 2.25 – 2.18 (m, 2H), 1.43 (s, 9H), 1.09 (d, J = 6.7 Hz, 3H).

Example 149. Synthesis of tert-butyl (2R,5S)-4-(7-(3-fluorophenyl)-5-(trifluoromethyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-ca rboxylate (Compound 496) C ^{ompound 496} Step 1.4-Chloro-7-(3-fluorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimi dine To a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (5.0 g, 18 mmol) in DCM (80 mL) were added (3-fluorophenyl)boronic acid (5.0 g, 36 mmol), 4A molecular sieves (2.5 g), Cu(OAc) ₂ (8.1 g, 90 mmol) and pyridine (17 g, 45 mmol). The resulting mixture was stirred at 35 ^o C under O ₂ atmosphere overnight. The reaction was quenched with aqueous NH ₄ OH (30 mL) at 0 ^o C in an ice water bath, filtered and extracted twice with DCM. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography (silica gel, EtOAc in petroleum ether) to afford 4- chloro-7-(3-fluorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (3.0 g, 45%) as a light yellow solid. LC/MS ESI (m/z): 374 (M+H) ⁺ . Step 2. tert-Butyl (2R,5S)-4-(7-(3-fluorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimi din- 4-yl)-2,5-dimethylpiperazine-1-carboxylate A mixture of 4-chloro-7-(3-fluorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidi ne (400 mg, 1.1 mmol), tert-butyl (2R,5S)-2,5-dimethylpiperazine-1-carboxylate (340 mg, 1.6 mmol) in DIPEA (8 mL) was heated at 150°C for 2 h. The reaction mixture was concentrated to a residue and purified by column chromatography on silica gel to give the tert-butyl (2R,5S)-4- (7-(3-fluorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 2,5-dimethylpiperazine-1- carboxylate (470 mg, 79%) as a solid. LC/MS ESI (m/z): 552 (M+H) ⁺ . Step 3. tert-Butyl (2R,5S)-4-(7-(3-fluorophenyl)-5-(trifluoromethyl)-7H-pyrrolo [2,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate A mixture of tert-butyl (2R,5S)-4-(7-(3-fluorophenyl)-5-iodo-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (100 mg, 0.18 mmol), CuI (35 mg, 0.18 mmol) and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (140 mg, 0.73 mmol) in DMF (5 mL) was stirred at 80°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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography on silica gel to give the crude product, which was purified by prep-HPLC to give the tert-butyl (2R,5S)-4-(7-(3- fluorophenyl)-5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin -4-yl)-2,5-dimethylpiperazine- 1-carboxylate (50 mg, 56%) as a white solid. LC/MS ESI (m/z): 494 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.52 (s, 1H), 7.73 (s, 1H), 7.55 – 7.44 (m, 3H), 7.19 – 7.12 (m, 1H), 4.64 – 4.53 (m, 1H), 4.51 – 4.25 (m, 1H), 3.80 – 3.62 (m, 3H), 3.52 – 3.47 (m, 1H), 1.50 (s, 9H), 1.17 – 1.11 (m, 6H). The following compound was prepared by a procedure similar to the synthesis of compound 496 from the corresponding aryl halide. Example 150. Synthesis of tert-butyl (2R,5S)-4-(5-(azetidin-1-yl)-7-(3,5-difluorophenyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-ca rboxylate (Compound 497) C ^{ompound 497} Step 1.4-Chloro-7-(3,5-difluorophenyl)-5-iodo-7H-pyrrolo[2,3-d]py rimidine To a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (10 g, 36 mmol) in DCM (150 mL) were added (3,5-difluorophenyl)boronic acid (11 g, 72 mmol), 4A molecular sieves (5 g), Cu(OAc) ₂ (16 g, 90 mmol) and pyridine (17 g, 210 mmol). The resulting mixture was stirred at 35 ^o C under O ₂ atmosphere overnight. The reaction was quenched with aqueous NH ₄ OH (60 mL) at 0 ^o C in an ice water bath, filtered and extracted twice with DCM. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography (silica gel, EtOAc in petroleum ether) to afford 4-chloro-7- (3,5-difluorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (6.7 g, 48%) as a light yellow solid. LC/MS ESI (m/z): 392 (M+H) ⁺ . Step 2. tert-Butyl (2R,5S)-4-(7-(3,5-difluorophenyl)-5-iodo-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate To the solution of 4-chloro-7-(3,5-difluorophenyl)-5-iodo-7H-pyrrolo[2,3- d]pyrimidine (3.0 g, 7.6 mmol) in DIPEA (20 ml) was added tert-butyl (2R,5S)-2,5- dimethylpiperazine-1-carboxylate (3.2 g, 15 mmol), The resulting reaction mixture was stirred at 150 ℃ under N ₂ for 1 h. After removal of solvent, the crude product was purified by flash column chromatography (silica gel, ethyl acetate in petroleum ether) to afford tert- butyl (2R,5S)-4-(7-(3,5-difluorophenyl)-5-iodo-7H-pyrrolo[2,3-d]py rimidin-4-yl)-2,5- dimethylpiperazine-1-carboxylate (3.7 g, 86%) as a solid. LC/MS ESI (m/z): 570 (M+H) ⁺ . Step 3. tert-Butyl (2R,5S)-4-(7-(3,5-difluorophenyl)-5-(2-oxoazetidin-1-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate To a solution of tert-butyl (2R,5S)-4-(7-(3,5-difluorophenyl)-5-iodo-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (1.0 g, 1.7 mmol) in DMF (10 mL) were added azetidin-2-one (310 mg, 4.2 mmol), CuI (170 mg, 0.80 mmol), trans-N ¹ ,N ² - dimethylcyclohexane-1,2-diamine (250 mg, 1.7 mmol) and K ₃ PO ₄ (1.2 g, 5.1 mmol). The resulting mixture was heated to 90 ^o 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~65%, ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-4-(7-(3,5-difluorophenyl)-5-(2-oxoazetidin-1-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate (420 mg, 48%) as a light yellow solid. LC/MS ESI (m/z): 513 (M+H) ⁺ . Step 4. tert-Butyl (2R,5S)-4-(5-(azetidin-1-yl)-7-(3,5-difluorophenyl)-7H-pyrro lo[2,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate To a solution of tert-butyl (2R,5S)-4-(7-(3,5-difluorophenyl)-5-(2-oxoazetidin-1-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-ca rboxylate (370 mg, 0.71 mmol) in THF (6 mL) at 0 ^o C was added RhH(CO)(PPh) ₃ (340 mg, 0.30 mmol), followed PhSiH ₃ (0.40 ml, 3.5 mmol) dropwise. After stirring at room temperature for 1 h, the reaction was quenched with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, ethyl acetate in petroleum ether) to give a crude product, which was further purified by prep-HPLC to afford tert-butyl (2R,5S)-4-(5-(azetidin- 1-yl)-7-(3,5-difluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl )-2,5-dimethylpiperazine-1- carboxylate (75 mg, 21%) as a white solid. LC/MS ESI (m/z): 499 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.37 (s, 1H), 7.47 – 7.40 (m, 2H), 6.77 – 6.67 (m, 1H), 6.58 (s, 1H), 5.11 (s, 1H), 4.37 (m, 1H), 4.00 (d, J = 13.6 Hz, 1H), 3.85 – 3.71 (m, 4H), 3.67 – 3.55 (m, 3H), 2.30 (m, 2H), 1.49 (s, 9H), 1.15 (d, J = 6.7 Hz, 3H), 1.01 (d, J = 6.8 Hz, 3H). Example 151. Synthesis of tert-butyl (S)-4-(5-(azetidin-1-yl)-7-(3,5-difluorophenyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (Compound 498) Step 1.5-Bromo-4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine To a suspension of NaH (5.0 g, 130 mmol, 60 wt%) in anhydrous DMF (125 mL) at 0 ^o C was added 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (25 g, 110 mmol) in portions. The resulting mixture was stirred at 0 ^o C for 30 minutes and then treated with 4- methylbenzenesulfonyl chloride (25 g, 130 mmol) in portions. The reaction was stirred at room temperature overnight and then quenched by pouring into ice water. The precipitate was collected by filtration and dried in vacuo to provide 5-bromo-4-chloro-7-tosyl-7H- pyrrolo[2,3-d]pyrimidine (27 g, 65%) as a white solid. LC/MS ESI (m/z): 386, 388 (M+H) ⁺ . Step 2. tert-Butyl (S)-4-(5-bromo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate To a solution of 5-bromo-4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (17 g, 43 mmol) in DIPEA (30 mL) was added tert-butyl (S)-3-methylpiperazine-1-carboxylate (22 g, 110 mmol). The resulting mixture was stirred at 150 ^o C for 2.5 h. After cooling to room temperature, solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~20%, ethyl acetate in petroleum ether) to afford tert-butyl (S)- 4-(5-bromo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methyl piperazine-1-carboxylate (20 g, 86%) as a white solid. LC/MS ESI (m/z): 550, 552 (M+H) ⁺ . Step 3. tert-Butyl (S)-4-(5-bromo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate To a solution of tert-butyl (S)-4-(5-bromo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 3-methylpiperazine-1-carboxylate (15 g, 27 mmol) in THF (30 mL) was added TBAF (64 mL, 1.0M in THF). The resulting mixture was stirred at room temperature for 4 h. The reaction was quenched with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to afford tert-butyl (S)-4-(5-bromo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate (9.3 g, 86%) as a white solid. LC/MS ESI (m/z): 396, 398 (M+H) ⁺ . Step 4. tert-Butyl (S)-4-(5-bromo-7-(3,5-difluorophenyl)-7H-pyrrolo[2,3-d]pyrim idin- 4-yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl (S)-4-(5-bromo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate (500 mg, 1.3 mmol) in DMF (10 mL) were added 1,3- difluoro-5-iodobenzene (610 mg, 2.5 mmol), CuI (120 mg, 0.63 mmol), trans-N ¹ ,N ² - dimethylcyclohexane-1,2-diamine (180 mg, 1.3 mmol) and K ₃ PO ₄ (800 mg, 3.8 mmol). The resulting mixture was heated to 90 ^o 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~15%, ethyl acetate in petroleum ether) to afford tert-butyl (S)-4-(5-bromo-7-(3,5-difluorophenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (400 mg, 62%) as a white solid. LC/MS ESI (m/z): 508, 510 (M+H) ⁺ . Step 5. tert-Butyl (S)-4-(7-(3,5-difluorophenyl)-5-(2-oxoazetidin-1-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te To a solution of tert-butyl (S)-4-(5-bromo-7-(3,5-difluorophenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (400 mg, 0.79 mmol) in DMF (10 mL) were added azetidin-2-one (110 mg, 1.6 mmol), CuI (75 mg, 0.40 mmol), trans-N ¹ ,N ² - dimethylcyclohexane-1,2-diamine (110 mg, 0.79 mmol) and K ₃ PO ₄ (500 mg, 2.4 mmol). The resulting mixture was heated to 90 ^o 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~15%, ethyl acetate in petroleum ether) to afford tert-butyl (S)-4-(7-(3,5-difluorophenyl)-5-(2-oxoazetidin-1-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (280 mg, 72%) as a white solid. LC/MS ESI (m/z): 499 (M+H) ⁺ . Step 6. tert-Butyl (S)-4-(5-(azetidin-1-yl)-7-(3,5-difluorophenyl)-7H-pyrrolo[2 ,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl (S)-4-(7-(3,5-difluorophenyl)-5-(2-oxoazetidin-1-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (280 mg, 0.56 mmol) in THF (5 mL) were added RhH(CO)(PPh) ₃ (260 mg, 0.28 mmol) and PhSiH ₃ (0.34 ml, 2.8 mmol) at 0 ^o C. The resulting mixture was stirred at room temperature for 1h. The reaction was quenched with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford tert-butyl (S)-4-(5-(azetidin-1- yl)-7-(3,5-difluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 3-methylpiperazine-1- carboxylate (110 mg, 39%) as a white solid. LC/MS ESI (m/z): 485 (M+H) ⁺ . ¹ H NMR(400 MHz, CDCl ₃ ) δ 8.38 (s, 1H), 7.42 (d, J = 7.5 Hz, 2H), 6.75 – 6.69 (m, 1H), 6.59 (s, 1H), 5.00 – 4.90 (m, 1H), 4.20 – 3.89 (m, 3H), 3.81 – 3.75 (m, 2H), 3.66 – 3.60 (m, 2H), 3.55 – 3.38 (m, 2H), 3.05 – 2.90 (m, 1H), 2.32 – 2.25 (m, 2H), 1.49 (s, 9H), 1.16 (d, J = 6.5 Hz, 3H). Example 152. Synthesis of tert-butyl (2S,5R)-4-(7-(4-cyanopyridin-2-yl)-5- (trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimet hylpiperazine-1- carboxylate (Compound 501) C ^{ompound 501} Step 1. tert-Butyl (2S,5R)-4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2 ,5- dimethylpiperazine-1-carboxylate To the solution of 4-chloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (1.0 g, 2.3 mmol, prepared following the procedure outlined in Compound 536 in DIPEA (5 mL) was added tert-butyl (2S,5R)-2,5-dimethylpiperazine-1-carboxylate (1.0 mL, 4.6 mmol). The resulting reaction mixture was stirred at 150℃ under N ₂ for 40 min. After cooling to room temperature, solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford to afford tert- butyl (2S,5R)-4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2 ,5-dimethylpiperazine-1- carboxylate (1.3 g, 92%) as a white solid. LC/MS ESI (m/z): 612 (M+H) ⁺ . Step 2. tert-Butyl (2S,5R)-2,5-dimethyl-4-(7-tosyl-5-(trifluoromethyl)-7H-pyrro lo[2,3- d]pyrimidin-4-yl)piperazine-1-carboxylate To the solution of tert-butyl (2S,5R)-4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4- yl)-2,5-dimethylpiperazine-1-carboxylate (500 mg, 0.82 mmol) in DMF (5 mL) were added CuI (630 mg, 0.82 mmol) and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (0.41 mL, 3.3 mmol) respectively. The resulting reaction mixture was stirred at 80℃ under N2 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 Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0~20%, ethyl acetate in petroleum ether) to obtain tert-butyl (2S,5R)-2,5-dimethyl-4-(7-tosyl-5-(trifluoromethyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (250 mg, 55%) as a white solid. LC/MS ESI (m/z): 554 (M+H) ⁺ . Step 3. tert-Butyl (2S,5R)-2,5-dimethyl-4-(5-(trifluoromethyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperazine-1-carboxylate To a solution of tert-butyl (2S,5R)-2,5-dimethyl-4-(7-tosyl-5-(trifluoromethyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (250 mg, 0.45 mmol) in THF (7 mL) at 0℃ was added TBAF (2.0 mL, 1.0 M in THF). After stirring at room temperature under N ₂ for 1.5 h, the reaction mixture was quenched with ice water and extracted twice with EtOAc. The combined organic layers were washed with aqueous saturated NH ₄ Cl solution, dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to obtain tert- butyl (2S,5R)-2,5-dimethyl-4-(5-(trifluoromethyl)-7H-pyrrolo[2,3-d ]pyrimidin-4- yl)piperazine-1-carboxylate (170 mg, 91%) as a white solid. LC/MS ESI (m/z): 400 (M+H) ⁺ . Step 4. tert-Butyl (2S,5R)-4-(7-(4-cyanopyridin-2-yl)-5-(trifluoromethyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate To a solution of tert-butyl (2S,5R)-2,5-dimethyl-4-(5-(trifluoromethyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (170 mg, 0.41 mmol) in DMF (3 mL) were added Cs ₂ CO ₃ (270 mg, 0.83 mmol) and 2-fluoroisonicotinonitrile (100 mg, 0.83 mmol) respectively. The resulting mixture was stirred at 40℃ under N2 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 Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC to obtain tert-butyl (2S,5R)-4-(7-(4-cyanopyridin-2-yl)-5-(trifluoromethyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate (130 mg, 60%) as a white solid. LC/MS(ESI)m/z: 502 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.28 – 9.27 (m, 1H), 8.61 – 8.59 (m, 1H), 8.57 (s, 1H), 8.50 (s, 1H), 7.41 (dd, J = 5.0, 1.3 Hz, 1H), 4.55 – 4.48 (m, 1H), 4.39 – 4.23 (m, 1H), 3.74 – 3.69 (m, 1H), 3.69 – 3.64 (m, 1H), 3.59 – 3.54 (m, 1H), 3.43 – 3.39 (m, 1H), 1.42 (s, 9H), 1.09 (d, J = 6.6 Hz, 3H), 1.03 (d, J = 6.8 Hz, 3H). The following compounds were prepared by procedures similar to the synthesis of compound 501 from the corresponding amines.

Example 153. Synthesis of tert-butyl (2R,5S)-4-(7-(4-cyanopyridin-2-yl)-5-(2-oxa-6- azaspiro[3.3]heptan-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2 ,5-dimethylpiperazine-1- carboxylate (Compound 504) ^p Step 1. tert-Butyl (2R,5S)-4-(5-iodo-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 (10 g, 16 mmol, prepared following the procedure outlined in Compound 536 in THF (50 mL) was added TBAF (19 mL, 1.0 M in THF). After stirring at room temperature for 2 h, the reaction mixture was quenched with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~40%, ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-4-(5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimet hylpiperazine-1-carboxylate (6.0 g, 80%) as a yellow solid. LC/MS ESI (m/z): 458 (M+H) ⁺ . Step 2. tert-Butyl (2R,5S)-4-(7-(4-cyanopyridin-2-yl)-5-iodo-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate To a solution of tert-butyl (2R,5S)-4-(5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5- dimethylpiperazine-1-carboxylate (6.0 g, 15 mmol) in DMF (100 mL) were added 2- fluoroisonicotinonitrile (3.2 g, 31 mmol) and Cs ₂ CO ₃ (8.6 g, 31 mmol). The resulting mixture was heated to 40 ^o C for 2 h. 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-4-(7-(4-cyanopyridin-2-yl)-5- iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine -1-carboxylate (2.7 g, 35%) as a yellow solid. LC/MS ESI (m/z): 560 (M+H) ⁺ . Step 3. tert-Butyl (2R,5S)-4-(7-(4-carbamoylpyridin-2-yl)-5-iodo-7H-pyrrolo[2,3 - d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate To a solution of tert-butyl (2R,5S)-4-(7-(4-cyanopyridin-2-yl)-5-iodo-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (1.0 g, 1.8 mmol) and K ₂ CO ₃ (0.99 g, 7.2 mmol) in DMSO (10 mL) at 0℃ was added H ₂ O ₂ (1.0 mL). After stirring at room temperature for 1.5 h under N2, the reaction was quenched with Na2S2O3(aq.) and poured into water. The resultant solids were collected by filtration and dried in vacuo to afford tert-butyl (2R,5S)-4-(7-(4-carbamoylpyridin-2-yl)-5-iodo-7H-pyrrolo[2,3 -d]pyrimidin-4-yl)-2,5- dimethylpiperazine-1-carboxylate (0.88 g, 85%) as a white solid. LC/MS ESI (m/z): 578 (M+H) ⁺ . Step 4. tert-Butyl (2R,5S)-4-(7-(4-carbamoylpyridin-2-yl)-5-(2-oxa-6- azaspiro[3.3]heptan-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2 ,5-dimethylpiperazine-1- carboxylate To a solution of tert-butyl (2R,5S)-4-(7-(4-carbamoylpyridin-2-yl)-5-iodo-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate (400 mg, 0.69 mmol) in DMSO (10 mL) were added CuI (66 mg, 0.34 mmol), L-proline (80 mg, 0.69 mmol), K ₂ CO ₃ (570 mg, 4.2 mmol) and 2-oxa-6-azaspiro[3.3]heptane (270 mg, 2.8 mmol). The resulting mixture was stirred at 100 ^o 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~20%, methanol in dichloromethane) to afford crude tert-butyl (2R,5S)-4-(7-(4-carbamoylpyridin-2- yl)-5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-7H-pyrrolo[2,3-d]py rimidin-4-yl)-2,5- dimethylpiperazine-1-carboxylate (200 mg, 52%) as a brown oil. LC/MS ESI (m/z): 549 (M+H) ⁺ . Step 5. tert-Butyl (2R,5S)-4-(7-(4-cyanopyridin-2-yl)-5-(2-oxa-6-azaspiro[3.3]h eptan- 6-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazin e-1-carboxylate To a solution of tert-butyl (2R,5S)-4-(7-(4-carbamoylpyridin-2-yl)-5-(2-oxa-6- azaspiro[3.3]heptan-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2 ,5-dimethylpiperazine-1- carboxylate (60 mg, 0.11 mmol) and TEA (1.0 mL, 81 mmol) in DCM (5 mL) at 0℃ was added TFAA (0.30 mL, 0.27 mmol) dropwise. After stirring at 0℃ for 20 min, the reaction was quenched with water and extracted twice with DCM. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford tert-butyl (2R,5S)-4-(7-(4- cyanopyridin-2-yl)-5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-7H-p yrrolo[2,3-d]pyrimidin-4-yl)- 2,5-dimethylpiperazine-1-carboxylate (16 mg, 28%) as a yellow solid. LC/MS ESI (m/z): 531 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.27 (s, 1H), 8.50 (d, J = 5.0 Hz, 1H), 8.36 (s, 1H), 7.38 (s, 1H), 7.23 (dd, J = 5.0, 1.3 Hz, 1H), 5.01 – 4.93 (m, 1H), 4.77 (s, 4H), 4.39 – 4.14 (m, 1H), 3.93 (d, J = 7.5 Hz, 2H), 3.91 – 3.84 (m, 1H), 3.71 (d, J = 7.4 Hz, 2H), 3.69 – 3.48 (m, 3H), 1.42 (s, 9H), 1.12 (d, J = 6.4 Hz, 3H), 0.91 (d, J = 6.4 Hz, 3H). Example 154. Synthesis of tert-butyl (2R,5S)-4-(7-(4-chloropyridin-2-yl)-5- (trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimet hylpiperazine-1- carboxylate (Compound 506) To a solution of tert-butyl (2R,5S)-2,5-dimethyl-4-(5-(trifluoromethyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (300 mg, 0.75 mmol, prepared following the procedure outlined in Compound 536 in DMF (5 mL) were added 4-chloro-2- fluoropyridine (200 mg, 1.5 mmol) and Cs ₂ CO ₃ (2.5 g, 7.5 mmol). After stirring at 60 ^o C under N ₂ atmosphere overnight, the reaction was cooled to room temperature and partitioned between EtOAc and water. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by flash column chromatography to give crude product, which was further purified by prep-HPLC to afford tert-butyl (2R,5S)-4-(7-(4-chloropyridin-2-yl)-5-(trifluoromethyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-ca rboxylate (280 mg, 73%) as a white solid. LC/MS ESI (m/z): 511 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.92 (d, J = 1.7 Hz, 1H), 8.57 – 8.54 (m, 1H), 8.50 (s, 1H), 8.33 (d, J = 5.3 Hz, 1H), 7.21 (dd, J = 5.3, 1.8 Hz, 1H), 4.53 – 4.45 (m, 1H), 4.40 – 4.19 (m, 1H), 3.73 – 3.64 (m, 2H), 3.59 – 3.54 (m, 1H), 3.42 – 3.37 (m, 1H), 1.42 (s, 9H), 1.08 – 1.03 (m, 6H).

Example 155. Synthesis of tert-butyl (2R,5S)-4-(7-(4-cyanopyridin-2-yl)-5-propoxy-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate (Compound 507) C ^{ompound 507} Step 1. tert-Butyl (2R,5S)-4-(7-(4-chloropyridin-2-yl)-5-propoxy-7H-pyrrolo[2,3 - d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate To a solution of tert-butyl (2R,5S)-4-(7-(4-chloropyridin-2-yl)-5-iodo-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (20 mg, 0.036 mmol, prepared following the procedure outlined in Compound 521 in propan-1-ol (0.5 mL) were added CuI (7.0 mg, 0.021 mmol), 1,10-phenanthroline (0.007 mL, 0.044 mmol) and K ₂ CO ₃ (12 mg, 0.087 mmol) respectively. The resulting reaction mixture was stirred at 100℃ under N ₂ overnight. The reaction was repeated at the same scale four additional times. After cooling to room temperature, the reaction mixtures from the five reactions were combined, solvent was removed and the residue was purified by column chromatography on silica gel (0~20% ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-4-(7-(4-chloropyridin-2-yl)-5- propoxy-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperaz ine-1-carboxylate (7.0 mg, 8.0%) as a white solid. LC/MS(ESI) (m/z): 501 (M+H) ⁺ . Step 2. tert-Butyl (2R,5S)-4-(7-(4-cyanopyridin-2-yl)-5-propoxy-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate To a solution of tert-butyl (2R,5S)-4-(7-(4-chloropyridin-2-yl)-5-propoxy-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate (7.0 mg, 0.014 mmol) in DMF (2 mL) were added Pd(PPh ₃ ) ₄ (28 mg, 0.024 mmol) and Zn(CN) ₂ (4.0 mg, 0.034 mmol) respectively. After stirring at 120℃ under N2 overnight, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC to afford tert-butyl (2R,5S)-4-(7-(4-cyanopyridin-2-yl)-5-propoxy-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (4.0 mg, 57%) as a white solid. _{LC/MS(ESI) (m/z): 492 (M+H)} ⁺ _. ¹ _{H NMR (400 MHz, CDCl3) δ 9.38 (s, 1H), 8.57 – 8.54 (m,} 1H), 8.39 (s, 1H), 7.54 (s, 1H), 7.30 – 7.29 (m, 0.4H, rotamer), 7.28 – 7.28 (m, 0.6H, rotamer), 5.08 – 5.01 (m, 1H), 4.43 – 4.22 (m, 2H), 4.06 – 3.99 (m, 2H), 3.85 – 3.79 (m, 0.5H, rotamer), 3.75 – 3.69 (m, 0.5H, rotamer), 3.60 – 3.54 (m, 1H), 3.48 – 3.38 (m, 1H), 1.91 (dd, J = 14.0, 6.8 Hz, 2H), 1.50 (s, 9H), 1.26 – 1.25 (m, 3H), 1.18 (d, J = 6.7 Hz, 3H), 1.08 (t, J = 7.4 Hz, 3H). The following compound was prepared by a procedure similar to the synthesis of compound 507 from the corresponding alcohol.

Example 156. Synthesis of tert-butyl (2R,5S)-4-(7-(6-cyanopyrimidin-4-yl)-5- (trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimet hylpiperazine-1- carboxylate (Compound 509) C ^{ompound 509} A mixture of tert-butyl (2R,5S)-2,5-dimethyl-4-(5-(trifluoromethyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperazine-1-carboxylate (200 mg, 0.50 mmol, prepared following the procedure outlined in Compound 536, 6-chloropyrimidine-4-carbonitrile (140 mg, 1.0 mmol) and Cs ₂ CO ₃ (330 mg, 1.0 mmol) in DMF (10 mL) was stirred at room temperature for 2 h. The reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted twice with EtOAc. The combined organic phases were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-4-(7-(6-cyanopyrimidin-4-yl)-5-(trifluoromethyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)- 2,5-dimethylpiperazine-1-carboxylate (130 mg, 51%) as a white solid. LC/MS ESI (m/z): 503 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.60 (d, J = 1.2 Hz, 1H), 9.18 (d, J = 1.2 Hz, 1H), 8.68 (d, J = 0.8 Hz, 1H), 8.59 (s, 1H), 4.61 (br. s, 1H), 4.38 (br. s, 1H), 3.83 – 3.71 (m, 2H), 3.65 – 3.59 (m, 1H), 3.48 (d, J = 13.4 Hz, 1H), 1.49 (s, 9H), 1.18 (d, J = 6.6 Hz, 3H), 1.08 (d, J = 6.8 Hz, 3H).

Example 157. Synthesis of tert-butyl (2R,5S)-4-(7-(4-cyanopyrimidin-2-yl)-5- (trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimet hylpiperazine-1- carboxylate (Compound 510) To a solution of tert-butyl (2R,5S)-2,5-dimethyl-4-(5-(trifluoromethyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (300 mg, 0.75 mmol, prepared following the procedure outlined in Compound 536 in dioxane (10 mL) were added 2- bromopyrimidine-4-carbonitrile (280 mg, 1.5 mmol), Pd ₂ (dba) ₃ (230 mg, 0.25 mmol), X- Phos (290 mg, 0.50 mmol) and Cs ₂ CO ₃ (490 mg, 1.5 mmol). The resulting mixture was heated to 100 ^o C overnight under N2. After cooling to room temperature, solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~10%, MeOH in DCM) and prep-HPLC to afford tert-butyl (2R,5S)-4-(7-(4-cyanopyrimidin-2-yl)-5- (trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimet hylpiperazine-1-carboxylate (180 mg, 46%). LC/MS ESI (m/z): 503 (M+H) ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ 9.18 (d, J = 4.9 Hz, 1H), 8.66 – 8.63 (m, 1H), 8.56 (s, 1H), 7.93 (d, J = 4.9 Hz, 1H), 4.66 – 4.58 (m, 1H), 4.39 – 4.31 (m, 1H), 3.84 – 3.73 (m, 2H), 3.68 – 3.61 (m, 1H), 3.52 (d, J = 12.8 Hz, 1H), 1.50 (s, 9H), 1.16 (d, J = 6.6 Hz, 3H), 1.10 (d, J = 6.8 Hz, 3H).

Example 158. Synthesis of pentan-3-yl (2R,5S)-4-(7-(4-cyanopyridin-2-yl)-5- (trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimet hylpiperazine-1- carboxylate (Compound 512) Step 1. tert-Butyl (2R,5S)-4-(7-(4-cyanopyridin-2-yl)-5-(trifluoromethyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate To a solution of tert-butyl (2R,5S)-2,5-dimethyl-4-(5-(trifluoromethyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (6.0 g, 15 mmol, prepared following the procedure outlined in Compound 536 in DMF (70 mL) at 25°C were added Cs ₂ CO ₃ (9.8 g, 30 mmol) and 2-fluoroisonicotinonitrile (9.2 g, 75 mmol). The reaction was heated to 50°C and stirred for 1h. After cooling to room temperature, the resulting mixture was poured into H ₂ O (300 ml) and extracted twice with EtOAc (200 mL). The combined organic phases were washed twice with brine (200 mL), dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo. The crude product was purified by silica gel column (0~20% ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-4-(7-(4-cyanopyridin-2-yl)-5-(trifluoromethyl)-7H-py rrolo[2,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (6.0 g, 80%) as a white solid. LC/MS ESI (m/z): 502 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.27 (d, J = 0.9 Hz, 1H), 8.60 (d, J = 5.0 Hz, 1H), 8.57 (s, 1H), 8.50 (s, 1H), 7.43 – 7.39 (m, 1H), 4.52 (s, 1H), 4.31 (s, 1H), 3.76 – 3.63 (m, 2H), 3.59 – 3.52 (m, 1H), 3.41 (d, J = 13.3 Hz, 1H), 1.42 (s, 9H), 1.09 (d, J = 6.6 Hz, 3H), 1.03 (d, J = 6.8 Hz, 3H). Step 2.2-(4-((2S,5R)-2,5-Dimethylpiperazin-1-yl)-5-(trifluorometh yl)-7H- pyrrolo[2,3-d]pyrimidin-7-yl)isonicotinonitrile To a solution of tert-butyl (2R,5S)-4-(7-(4-cyanopyridin-2-yl)-5-(trifluoromethyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate (3.0 g, 6.0 mmol) in DCM (15 mL) was added HCl (10 mL, 4.0 M in dioxane). The resulting mixture was stirred at room temperature for 3 h. The reaction was treated with sat. NaHCO ₃ (aq.) and extracted twice with DCM. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to afford 2-(4-((2S,5R)-2,5-dimethylpiperazin-1-yl)-5-(trifluoromethyl )-7H- pyrrolo[2,3-d]pyrimidin-7-yl)isonicotinonitrile (2.0 g, 83%) as a white solid, which was used in the next step directly. LC/MS ESI (m/z): 402 (M+H) ⁺ . Step 3. (2R,5S)-4-(7-(4-Cyanopyridin-2-yl)-5-(trifluoromethyl)-7H-py rrolo[2,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbonyl chloride To a solution of 2-(4-((2S,5R)-2,5-dimethylpiperazin-1-yl)-5-(trifluoromethyl )-7H- pyrrolo[2,3-d]pyrimidin-7-yl)isonicotinonitrile (300 mg, 0.75 mmol) in DCM (10 mL) were added DIPEA (190 mg, 1.5 mmol), followed by triphosgene (300 mg, 0.75 mmol) in portions. The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with ice water and extracted twice with DCM. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated to afford (2R,5S)-4-(7-(4- cyanopyridin-2-yl)-5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyri midin-4-yl)-2,5- dimethylpiperazine-1-carbonyl chloride, which was used in the next step directly. LC/MS ESI (m/z): 464.0 (M+H) ⁺ . Step 4. Pentan-3-yl (2R,5S)-4-(7-(4-cyanopyridin-2-yl)-5-(trifluoromethyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate A mixture of (2R,5S)-4-(7-(4-cyanopyridin-2-yl)-5-(trifluoromethyl)-7H-py rrolo[2,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbonyl chloride (340 mg, 0.75 mmol) and pentan-3-ol (5 mL) was stirred at 110 ^o C for 3 h under N ₂ . 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography to give crude product which was further purified by prep-HPLC to afford pentan-3-yl (2R,5S)-4-(7- (4-cyanopyridin-2-yl)-5-(trifluoromethyl)-7H-pyrrolo[2,3-d]p yrimidin-4-yl)-2,5- dimethylpiperazine-1-carboxylate (250 mg, 65%) as a white solid. LC/MS ESI (m/z): 516 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.31 – 9.23 (m, 1H), 8.61 – 8.56 (m, 2H), 8.53 – 8.49 (m, 1H), 7.43 – 7.39 (m, 1H), 4.69 – 4.62 (m, 1H), 4.56 – 4.48 (m, 1H), 4.45 – 4.29 (m, 1H), 3.77 – 3.69 (m, 2H), 3.64 – 3.58 (m, 1H), 3.45 – 3.40 (m, 1H), 1.58 – 1.51 (m, 4H), 1.08 (dd, J = 9.2, 6.9 Hz, 6H), 0.87 – 0.81 (m, 6H). The following compound was prepared by a procedure similar to the synthesis of compound 512 from the corresponding alcohol.

Example 159. Synthesis of tert-butyl (S)-4-(7-(4-cyanopyridin-2-yl)-5-(difluoromethyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carbox ylate (Compound 514) C ^{ompound 514} 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 (90 g, 0.21 mol) in DIPEA (600 mL) was added tert-butyl (S)-3-methylpiperazine-1-carboxylate (81 g, 0.42 mol). The resulting mixture was heated to 140 ^o C for 3 h. After cooling to room temperature, solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford tert-butyl (S)- 4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylp iperazine-1-carboxylate (100 g, 73%) as a white solid. LC/MS ESI (m/z): 598 (M+H) ⁺ . Step 2. tert-Butyl (S)-4-(5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiper azine- 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 (55 g, 110 mmol) in THF (400 mL) at 0 ^o C was added TBAF (440 mL, 1.0M in THF). After stirring at 0 ^o C for 1.5 h, the reaction was quenched with ice water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~10%, methanol in dichloromethane) to afford tert-butyl (S)-4- (5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine- 1-carboxylate (37 g, 91%) as a white solid. LC/MS ESI (m/z): 444 (M+H) ⁺ . Step 3. tert-Butyl (S)-4-(7-(4-cyanopyridin-2-yl)-5-iodo-7H-pyrrolo[2,3-d]pyrim idin- 4-yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl 4-{5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4- yl}piperidine-1-carboxylate (4.5 g, 10 mmol) and 2-fluoropyridine-4-carbonitrile (1.8 g, 15 mmol) in DMF (60 mL) was added Cs ₂ CO ₃ (16 g, 50 mmol). The resulting mixture was stirred at 40℃ for 18 h. After cooling to room temperature, the reaction mixture was filtered. The filtrate was diluted with ice water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography on silica gel (0~40% ethyl acetate in petroleum ether) to give tert-butyl (S)-4-(7-(4-cyanopyridin-2-yl)-5-iodo-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (3.6 g, 6.6 mmol, 66%). LC/MS(ESI)m/z: 546 (M+H) ⁺ . Step 4. tert-Butyl (S)-4-(7-(4-cyanopyridin-2-yl)-5-(difluoromethyl)-7H-pyrrolo [2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl (S)-4-(7-(4-cyanopyridin-2-yl)-5-iodo-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylatetert-butyl 4-(5-cyclopropyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (200 mg, 0.37 mmol) in dioxane/toluene (10 mL, 3:1 v/v) were added CsF (170 mg, 1.1 mmol), (difluoromethyl)trimethylsilane (920 mg, 7.5 mmol) and (1,3-bis(2,6-diisopropylphenyl)-1,3- dihydro-2H-imidazol-2-ylidene)copper(III) chloride (180 mg, 0.37 mmol). The resulting mixture was heated to 120 ^o 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford tert-butyl (S)-4-(7-(4- cyanopyridin-2-yl)-5-(difluoromethyl)-7H-pyrrolo[2,3-d]pyrim idin-4-yl)-3- methylpiperazine-1-carboxylate (15 mg, 8.6%) as a white solid. LC/MS ESI (m/z): 470 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.34 (s, 1H), 8.67 – 8.53 (m, 3H), 7.48 – 7.42 (m, 1H), 7.00 (t, J = 55.5 Hz, 1H), 4.38 – 4.29 (m, 1H), 3.97 (m, 1H), 3.75 (d, J = 10.8 Hz, 1H), 3.63 – 3.47 (m, 2H), 3.44 – 3.38 (m, 1H), 3.22 (s, 1H), 1.50 (s, 9H), 1.23 (d, J = 6.6 Hz, 3H). The following compounds were prepared by procedures similar to the synthesis of compound 514 from the corresponding aryl halides. Example 160. Synthesis of cyclopropyl (2R,5S)-4-(7-(4-cyanopyridin-2-yl)-5- (trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimet hylpiperazine-1- carboxylate (Compound 515) Step 1. Cyclopropyl carbonochloridate To a solution cyclopropanol (40 mg, 0.70 mmol) in DCE (8 mL) were added DIPEA (44 mg, 1.1 mmol) and triphosgene (68 mg, 0.24 mmol). The reaction was stirred at room temperature for 3 h and the resulting mixture was used in the next step directly. Step 2. Cyclopropyl (2R,5S)-4-(7-(4-cyanopyridin-2-yl)-5-(trifluoromethyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate To a solution of cyclopropyl carbonochloridate (0.70 mmol) in DCE (8 mL) were added DIPEA (44 mg, 1.1 mmol) and 2-(4-((2S,5R)-2,5-dimethylpiperazin-1-yl)-5- (trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)isonicotin onitrile (200 mg, 0.50 mmol, prepared following the procedure outlined in Compound 512. The resulting mixture was stirred at 50 ^o C for 3 h under N ₂ . 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography to give crude product which was further purified by prep-HPLC to afford cyclopropyl (2R,5S)-4-(7-(4- cyanopyridin-2-yl)-5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyri midin-4-yl)-2,5- dimethylpiperazine-1-carboxylate (170 mg, 66%) as a white solid. LC/MS ESI (m/z): 486 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.27 (s, 1H), 8.61 – 8.57 (m, 2H), 8.51 (s, 1H), 7.42 (dd, J = 5.0, 1.3 Hz, 1H), 4.65 – 4.27 (m, 2H), 4.09 – 4.04 (m, 1H), 3.73 – 3.57 (m, 3H), 3.44 – 3.38 (m, 1H), 1.10 – 1.03 (m, 6H), 0.67 – 0.61 (m, 4H). The following compound was prepared by a procedure similar to the synthesis of Compound 515 from the corresponding aryl halogens. Example 161. Synthesis of tert-butyl (2R,5S)-4-(7-(4-cyano-6-methylpyridin-2-yl)-5- (trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimet hylpiperazine-1- carboxylate (Compound 517) Step 1. tert-Butyl (2R,5S)-4-(7-(6-bromo-4-cyanopyridin-2-yl)-5-(trifluoromethy l)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-ca rboxylate To a solution of tert-butyl (2R,5S)-2,5-dimethyl-4-(5-(trifluoromethyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (300 mg, 0.75 mmol, prepared following the procedure outlined in Compound 536 in DMF (5 mL) were added 2,6- dibromoisonicotinonitrile (240 mg, 0.90 mmol), trans-N ¹ ,N ² -dimethylcyclohexane-1,2- diamine (28 mg, 0.20 mmol), CuI (140 mg, 0.75 mmol) and K ₃ PO ₄ (320 mg, 1.5 mmol). The resulting mixture was heated to 90℃ for 1 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to give tert-butyl (2R,5S)-4-(7-(6-bromo-4-cyanopyridin-2-yl)-5-(trifluoromethy l)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (370 mg, 85%) as a yellow oil. LC/MS ESI (m/z): 580, 582 (M+H) ⁺ . Step 2. tert-Butyl (2R,5S)-4-(7-(4-cyano-6-methylpyridin-2-yl)-5-(trifluorometh yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-ca rboxylate To a solution of tert-butyl (2R,5S)-4-(7-(6-bromo-4-cyanopyridin-2-yl)-5- (trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimet hylpiperazine-1-carboxylate (160 mg, 0.30 mmol) in dioxane (5 mL) and H ₂ O (1 mL) were added methylboronic acid (140 mg, 2.4 mmol), Cs ₂ CO ₃ (290 mg, 0.90 mmol) and Pd(dppf)Cl ₂ (22 mg, 0.030 mmol). The resulting mixture was heated to 100℃ overnight. After cooling to room temperature, solvent was removed and the residue was purified by flash column chromatography (silica gel, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford tert-butyl (2R,5S)-4-(7-(4-cyano-6-methylpyridin-2-yl)-5- (trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimet hylpiperazine-1-carboxylate (40 mg, 26 %) as a white solid. LC/MS ESI (m/z): 516 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.11 (s, 1H), 8.65 (s, 1H), 8.57 (s, 1H), 7.34 (s, 1H), 4.57 (s, 1H), 4.38 (s, 1H), 3.81 – 3.71 (m, 2H), 3.64 (dd, J = 13.4, 3.5 Hz, 1H), 3.47 (d, J = 13.3 Hz, 1H), 2.67 (s, 3H), 1.49 (s, 9H), 1.15 (d, J = 6.6 Hz, 3H), 1.11 (d, J = 6.8 Hz, 3H). Example 162. Synthesis of tert-butyl (2R,5S)-4-(7-(4-chloropyridin-2-yl)-5- (difluoromethoxy)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimet hylpiperazine-1- carboxylate (Compound 521) Step 1. tert-Butyl (2R,5S)-4-(5-iodo-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 (3.5 g, 5.7 mmol) in THF (20 mL) at 0℃ was added TBAF (23 mL, 1.0M in THF). After stirring at room temperature under N ₂ for 1 h, the reaction mixture was quenched with ice water and extracted twice with EtOAc. The combined organic layers were washed with aqueous saturated NH4Cl, dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to obtain tert-butyl (2R,5S)-4-(5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimet hylpiperazine-1-carboxylate (1.5 g, 57%) as a white solid. LC/MS ESI (m/z): 458 (M+H) ⁺ . Step 2. tert-Butyl (2R,5S)-4-(7-(4-chloropyridin-2-yl)-5-iodo-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate To the solution of tert-butyl (2R,5S)-4-(5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5- dimethylpiperazine-1-carboxylate (500 mg, 1.1 mmol) in DMF (5 mL) were added Cs ₂ CO ₃ (2.0 g, 6.4 mmol) and 4-chloro-2-fluoropyridine (0.32 mL, 3.2 mmol) respectively. The resulting reaction mixture was stirred at 60℃ under N2 overnight. After cooling to room temperature, the reaction mixture 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 Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0~20%, ethyl acetate in petroleum ether) to obtain tert-butyl (2R,5S)-4-(7-(4-chloropyridin-2-yl)-5-iodo- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-ca rboxylate (330 mg, 53%) as a white solid. LC/MS ESI (m/z): 569 (M+H) ⁺ . Step 3. tert-Butyl (2R,5S)-4-(7-(4-chloropyridin-2-yl)-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dime thylpiperazine-1-carboxylate To the solution of tert-butyl (2R,5S)-4-(7-(4-chloropyridin-2-yl)-5-iodo-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate (420 mg, 0.74 mmol) in dioxane (5 mL) were added X-Phos (35 mg, 0.74 mmol), Pd ₂ (dba) ₃ (68 mg, 0.74 mmol), TEA (0.51 mL, 3.7 mmol) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.43 mL, 3.0 mmol) respectively. The resultant reaction mixture was stirred at 95℃ under N2 overnight. After cooling to room temperature, the reaction mixture was quenched with ice water and extracted twice with EtOAc. The combined organic layers were washed with saturated NaCl, dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (0~20% ethyl acetate in petroleum ether) to obtain tert-butyl (2R,5S)-4-(7-(4-chloropyridin-2-yl)-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dime thylpiperazine-1-carboxylate (270 mg, 64%) as a white solid. LC/MS(ESI)m/z: 569 (M+H) ⁺ . Step 4. tert-Butyl (2R,5S)-4-(7-(4-chloropyridin-2-yl)-5-hydroxy-7H-pyrrolo[2,3 - d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate To the solution of tert-butyl (2R,5S)-4-(7-(4-chloropyridin-2-yl)-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-7H-pyrrolo[2,3-d]pyrimi din-4-yl)-2,5- dimethylpiperazine-1-carboxylate (50 mg, 0.088 mmol) in THF (3 mL) were added AcOH (0.50 mL, 8.7 mmol) and H ₂ O ₂ (0.5 mL) respectively. After stirring at room temperature overnight, the reaction mixture was quenched with ice water and extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford tert-butyl (2R,5S)-4-(7-(4-chloropyridin-2-yl)-5-hydroxy-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate (11 mg, 28%) as a yellow solid. LC/MS(ESI)m/z: 459 (M+H) ⁺ . Step 5. tert-Butyl (2R,5S)-4-(7-(4-chloropyridin-2-yl)-5-(difluoromethoxy)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate To a solution of tert-butyl (2R,5S)-4-(7-(4-chloropyridin-2-yl)-5-hydroxy-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate (100 mg, 0.22 mmol) in MeCN (5 mL) were added a solution of KOH (250 mg, 4.5 mmol) in H ₂ O (5 mL) and diethyl (bromodifluoromethyl)phosphonate (70 mg, 0.26 mmol) respectively. The resulting reaction mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (0~20% ethyl acetate in petroleum ether) and prep-HPLC to obtain tert-butyl (2R,5S)-4-(7-(4- chloropyridin-2-yl)-5-(difluoromethoxy)-7H-pyrrolo[2,3-d]pyr imidin-4-yl)-2,5- dimethylpiperazine-1-carboxylate (6.6 mg, 5.9%) as a white solid. LC/MS(ESI) (m/z): 509 _(M+H) ⁺ _. ¹ _{H NMR (400 MHz, CDCl3) δ 9.00 (d, J = 1.6 Hz, 1H), 8.44 (s, 1H), 8.35 (d, J = 5.3} Hz, 1H), 7.95 (s, 1H), 7.19 (dd, J = 5.3, 1.8 Hz, 1H), 6.52 (t, J = 73.8 Hz, 1H), 4.86 – 4.76 (m, 1H), 4.56 – 4.48 (m, 0.5H, rotamer), 4.36 – 4.27 (m, 0.5H, rotamer), 4.11 – 4.05 (m, 1H), 3.84 – 3.73 (m, 1H), 3.66 – 3.59 (m, 1H), 3.50 – 3.41 (m, 1H), 1.50 (s, 9H), 1.27 – 1.25 (m, 3H), 1.19 – 1.15 (m, 3H). Example 163. Synthesis of tert-butyl (S)-4-(7-(3-chlorophenyl)-5- (cyclopropyl(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 3-methylpiperazine-1- carboxylate (Compound 522) Step 1.4-Chloro-7-(3-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimi dine To a mixture of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (10 g, 36 mmol), (3- chlorophenyl)boronic acid (11 g, 72 mmol) and Cu(OAc) ₂ (10 g, 55 mmol) in DCM (300 mL) were added pyridine (18 mL, 220 mmol) and 4Å MS. The mixture was stirred under O ₂ at room temperature for 2 days. It was then treated with aqueous NH ₄ OH (25%) and filtered through Celite. The filtrate was washed with water, dried over Na ₂ SO ₄ and concentrated to dryness. The crude solid product was triturated with EtOAc/petroleum ether (1:5, v/v) to give 4-chloro-7-(3-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidi ne (12 g, 75% purity, 64%) as a brown solid. LC/MS ESI (m/z): 390 (M+H) ⁺ . Step 2. 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]pyrimidi ne (3.0 g, ~75% purity, 5.8 mmol) and tert-butyl (S)-3-methylpiperazine-1-carboxylate (3.0 g, 15 mmol) in DIPEA (6.5 mL, 39 mmol) was stirred at 140°C for 2.5 h. DIPEA was removed by rotary evaporation. The residue was purified by flash column chromatography (silica gel, 0~16% EtOAc in petroleum ether) to provide tert-butyl (S)-4-(7-(3-chlorophenyl)-5-iodo-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (2.6 g, 82%) as a light brown foam. LC/MS ESI (m/z): 554 (M+H) ⁺ . Step 3. Methyl (S)-4-(4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)-7-(3- chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-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 (400 mg, 0.72 mmol) in MeOH (10 mL) were added TEA (0.20 mL, 1.4 mmol) and Pd(dppf)Cl ₂ (53 mg, 0.070 mmol). The resulting mixture was stirred under CO at 70°C overnight. After cooling to room temperature, the reaction mixture was filtered and concentrated in vacuo to give the crude product which was purified by flash column chromatography (silica gel, 0~30% EtOAc in petroleum ether) to afford methyl (S)-4-(4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)-7-(3- chlorophenyl)-7H- pyrrolo[2,3-d]pyrimidine-5-carboxylate (270 mg, 77%) as a light yellow solid. LC/MS (ESI) (m/z): 486(M+H) ⁺ . Step 4. (S)-4-(4-(tert-Butoxycarbonyl)-2-methylpiperazin-1-yl)-7-(3- chlorophenyl)- 7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid To a solution of methyl (S)-4-(4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)-7-(3- chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (270 mg, 0.60 mmol) in MeOH (8 ml) was added a solution of NaOH (90 mg, 2.2 mmol) in H ₂ O (2 mL). The resulting mixture was stirred at 50 ^o C overnight. After cooling to room temperature, the reaction was quenched with 1N HCl to pH 4~5 and extracted twice with DCM/IPA (85:15 v/v). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to afford (S)-4-(4-(tert- butoxycarbonyl)-2-methylpiperazin-1-yl)-7-(3-chlorophenyl)-7 H-pyrrolo[2,3-d]pyrimidine- 5-carboxylic acid (200 mg, 76%) as a white solid which was used in the next step directly. LC/MS (ESI) (m/z): 472 (M+H) ⁺ . Step 5. tert-Butyl (S)-4-(5-(azidocarbonyl)-7-(3-chlorophenyl)-7H-pyrrolo[2,3-d ]pyri midin-4-yl)-3-methylpiperazine-1-carboxylate (S)-4-(4-(tert-butoxycarbonyl)-2-methylpipera zin-1-yl)-7-(3-chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-c arboxylate To a solution of (S)-4-(4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)-7-(3- chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid (200 mg, 0.42 mmol) in toluene (10 mL) were added TEA (0.20 mL, 1.3 mmol) and DPPA (230 mg, 0.84 mmol). The resulting mixture was stirred at room temperature for 2 h and then treated with acetic formic anhydride (3 mL, prepared from acetic anhydride and formic acid). The reaction mixture was stirred at 60°C for 2 h. After cooling to room temperature, the reaction was quenched with NaHCO ₃ (aq.) and extracted with EtOAc. The organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash column chromatography (silica gel, 0~60% EtOAc in petroleum ether) to afford tert-butyl (S)-4-(7-(3-chlorophenyl)-5-(N- formylformamido)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpi perazine-1-carboxylate (70 mg, 37%) as a light yellow solid. LC/MS (ESI) (m/z): 471 (M+H) ⁺ . Step 6. tert-Butyl (S)-4-(7-(3-chlorophenyl)-5-(N-formylformamido)-7H-pyrrolo[2 ,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl (S)-4-(7-(3-chlorophenyl)-5-formamido-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (70 mg, 0.15 mmol) in DCE (10 mL) were added cyclopropylboronic acid (39 mg, 0.45 mmol), Cu(OAc) ₂ (55 mg, 0.30 mmol), 2,2'-bipyridine (47 mg, 0.30 mmol) and K ₂ CO ₃ (83 mg, 0.60 mmol). The resulting mixture was stirred at 70 ^o C overnight. After cooling to room temperature, the mixture was diluted with H2O and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography on silica gel (0~70% EtOAc in petroleum ether) to afford tert-butyl (S)-4-(7-(3-chlorophenyl)-5-(N-cyclopropylformamido)-7H-pyrr olo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate (36 mg, 47%) as yellow solid. LC/MS (ESI) (m/z): 511 (M+H) ⁺ . Step 7. tert-Butyl (S)-4-(7-(3-chlorophenyl)-5-(cyclopropyl(methyl)amino)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te To a solution of tert-butyl (S)-4-(7-(3-chlorophenyl)-5-(N-cyclopropylformamido)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carbox ylate (36 mg, 0.070 mmol) in THF(5 mml) at 0 ^o C was added BH ₃ -THF (1.4 mL, 1.0 M in THF). After stirring at 0 ^o C for 0.5 h under N ₂ , the reaction was quenched with methanol and partitioned between EtOAc and water. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the crude product which was purified by HPLC to obtain the desired product tert-butyl (S)-4- (7-(3-chlorophenyl)-5-(cyclopropyl(methyl)amino)-7H-pyrrolo[ 2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate (15 mg, 44%) as white solid. LC/MS (ESI) (m/z): 497 (M+H) ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ 8.23 (s, 1H), 7.85 (t, J = 2.0 Hz, 1H), 7.68 – 7.64 (m, 1H), 7.50 (t, J = 7.7 Hz, 1H), 7.38 – 7.31 (m, 1H), 7.26 (s, 1H), 4.95 (s, 1H), 4.08 (br. d, J = 12.6 Hz, 2H), 3.87 (d, J = 13.1 Hz, 1H), 3.42 – 3.31 (m, 2H), 3.15 – 3.00 (m, 1H), 2.87 (s, 3H), 2.38 – 2.29 (m, 1H), 1.49 (s, 9H), 1.09 (s, 3H), 0.79 – 0.70 (m, 2H), 0.60 – 0.42 (m, 2H). The following compound was prepared by a procedure similar to the synthesis of Compound 522 from the corresponding boronic acid. Example 164. Synthesis of 2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6 (2R,5S)-4-(7-(4- cyanopyridin-2-yl)-5-(difluoromethyl)-7H-pyrrolo[2,3-d]pyrim idin-4-yl)-2,5- dimethylpiperazine-1-carboxylate (Compound 538) Step 1.4-Chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2 ,3-d]pyrimidine-5- carbaldehyde To a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde (2.0 g, 11 mmol) in THF (50 mL) at 0ºC was added NaH (790 mg, 33 mmol, 60 wt%) in portions. The resulting mixture was stirred at the same temperature for 20 min and then treated with SEMCl (2.2 g, 13 mmol) dropwise. After stirring at 0 ^o C for 0.5 h, the reaction mixture was quenched with aqueous NH ₄ Cl and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by flash column chromatography (SiO ₂ , 0~40% EtOAc in petroleum ether) to afford 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3 -d]pyrimidine-5-carbaldehyde (2.1 g, 61%) as a white solid. LC/MS ESI (m/z): 312 (M+H) ⁺ . Step 2.4-Chloro-5-(difluoromethyl)-7-((2-(trimethylsilyl)ethoxy)m ethyl)-7H- pyrrolo[2,3-d]pyrimidine To a solution of 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3 - d]pyrimidine-5-carbaldehyde (1.0 g, 3.3 mmol) in DCM (10 mL) at 0 ^o C was added bis(2- methoxyethyl)aminosulfur trifluoride (BAST) (1.2 mL, 6.6 mmol) dropwise. After stirring at room temperature overnight, the reaction was quenched with aqueous NaHCO ₃ and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by flash column chromatography (SiO2, 0~20% EtOAc in petroleum ether) to afford 4-chloro-5-(difluoromethyl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (750 mg, 68%) as a white solid. LC/MS ESI (m/z): 334 (M+H) ⁺ . Step 3. tert-Butyl (2R,5S)-4-(5-(difluoromethyl)-7-((2-(trimethylsilyl)ethoxy)m ethyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-ca rboxylate To a solution of 4-chloro-5-(difluoromethyl)-7-((2-(trimethylsilyl)ethoxy)met hyl)-7H- pyrrolo[2,3-d]pyrimidine (750 mg, 2.2 mmol) in DIPEA (5 mL) was added tert-butyl (2R,5S)-2,5-dimethylpiperazine-1-carboxylate (960 mg, 4.5 mmol). The resulting mixture was stirred at 120 ^o C overnight. After cooling to room temperature, the reaction was concentrated and purified by flash column chromatography (silica gel, 0~20%, ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-4-(5-(difluoromethyl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)-2,5-dimethylpiperazine-1- carboxylate (1.1 g, 95%) as a yellow oil. LC/MS ESI (m/z): 512 (M+H) ⁺ . Step 4. tert-Butyl (2R,5S)-4-(5-formyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5- dimethylpiperazine-1-carboxylate To a solution of tert-butyl (2R,5S)-4-(5-(difluoromethyl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)-2,5-dimethylpiperazine-1- carboxylate (1.1 g, 2.2 mmol) in THF (15 mL) was added TBAF (13 mL, 1.0 M in THF). The resulting mixture was stirred at 60 ^o C overnight. LCMS showed that the CF ₂ group had been hydrolyzed to an aldehyde. 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 Na ₂ SO ₄ , filtered and concentrated, the residue was purified by flash column chromatography (silica gel, 0~90%, ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-4-(5-formyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (0.76 g, 98%) as a yellow solid. LC/MS ESI (m/z): 360 (M+H) ⁺ . Step 5. tert-Butyl (2R,5S)-4-(7-(4-cyanopyridin-2-yl)-5-formyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate To a solution of tert-butyl (2R,5S)-4-(5-formyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5- dimethylpiperazine-1-carboxylate (760 mg, 2.1 mmol) in DMF (10 mL) were added 2- fluoroisonicotinonitrile (520 mg, 4.2 mmol) and Cs ₂ CO ₃ (2.1 g, 6.3 mmol). The resulting mixture was stirred at 50 ^o 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 Na ₂ SO ₄ , filtered and concentrated, the residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-4-(7-(4-cyanopyridin-2-yl)-5- formyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazi ne-1-carboxylate (720 mg, 73%) as a yellow solid. LC/MS ESI (m/z): 462 (M+H) ⁺ . Step 6. tert-Butyl (2R,5S)-4-(7-(4-cyanopyridin-2-yl)-5-(difluoromethyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate To a solution of tert-butyl (2R,5S)-4-(7-(4-cyanopyridin-2-yl)-5-formyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate (720 mg, 1.6 mmol) in DCM (5 mL) at 0 ^o C was added BAST (2.8 mL, 16 mmol) dropwise. After stirring at room temperature overnight, the reaction was quenched with NaHCO ₃ (aq.). The layers were separated and the aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , concentrated and purified by flash column chromatography (silica gel, 0~20%, ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-4-(7-(4-cyanopyridin-2-yl)-5-(difluoromethyl)-7H-pyr rolo[2,3-d]pyrimidin-4-yl)- 2,5-dimethylpiperazine-1-carboxylate (440 mg, 58%) as a white solid. LC/MS ESI (m/z): 484 (M+H) ⁺ . Step 7.2-(5-(Difluoromethyl)-4-((2S,5R)-2,5-dimethylpiperazin-1-y l)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)isonicotinonitrile To a solution of tert-butyl (2R,5S)-4-(7-(4-cyanopyridin-2-yl)-5-(difluoromethyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate (280 mg, 0.57 mmol) in DCM (10 mL) was added HCl (5.0 mL, 4.0 M in dioxane). After stirring at room temperature for 2 h, the reaction was quenched with NaHCO ₃ (aq.). The layers were separated, and the aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , concentrated and purified by flash column chromatography (silica gel, 0~10%, methanol in dichloromethane) to afford 2-(5-(difluoromethyl)-4-((2S,5R)- 2,5-dimethylpiperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl) isonicotinonitrile (150 mg, 67%) as a yellow solid. LC/MS ESI (m/z): 384 (M+H) ⁺ . Step 8.2-(Methyl-d3)propan-2-yl-1,1,1,3,3,3-d6 (2R,5S)-4-(7-(4-cyanopyridin-2-yl)- 5-(difluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dime thylpiperazine-1-carboxylate To a solution of 2-(methyl-d ₃ )propan-1,1,1,3,3,3-d ₆ -2-ol (1.0 g, 12 mmol) in DCM (12 mL) were added DMAP (440 mg, 3.6 mmol) and di(pyridin-2-yl) carbonate (2.59 g, 12 mmol). The resulting mixture was stirred at room temperature for 48 h and used in the next step directly. To a solution of 2-(5-(difluoromethyl)-4-((2S,5R)-2,5-dimethylpiperazin-1-yl) -7H- pyrrolo[2,3-d]pyrimidin-7-yl)isonicotinonitrile (45 mg, 0.11 mmol) in DMF (2 mL) were added 2-(methyl-d ₃ )propan-2-yl-1,1,1,3,3,3-d ₆ pyridin-2-yl carbonate (0.11 mL, 1.0 M in DCM) and DIPEA (0.50 mL, 0.11 mmol). The resulting mixture was stirred at 80℃ 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by prep-HPLC to afford 2-(methyl-d ₃ )propan-2-yl-1,1,1,3,3,3-d ₆ (2R,5S)-4-(7-(4- cyanopyridin-2-yl)-5-(difluoromethyl)-7H-pyrrolo[2,3-d]pyrim idin-4-yl)-2,5- dimethylpiperazine-1-carboxylate (28 mg, 48%) as a white solid. LC/MS ESI (m/z): 493 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.27 (s, 1H), 8.58 (d, J = 4.9 Hz, 1H), 8.50 (s, 1H), 8.44 (s, 1H), 7.38 (d, J = 4.9 Hz, 1H), 6.89 (t, J = 55.6 Hz, 1H), 4.54 – 4.46 (m, 1H), 4.40 – 4.22 (m, 1H), 3.76 – 3.65 (m, 2H), 3.54 (dd, J = 13.5, 3.3 Hz, 1H), 3.45 (d, J = 13.1 Hz, 1H), 1.11 (d, J = 6.6 Hz, 3H), 1.06 (d, J = 6.8 Hz, 3H). Example 165. Synthesis of tert-butyl (2R,5S)-4-(7-(4-cyanopyridin-2-yl)-5- (difluoromethoxy)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimet hylpiperazine-1- carboxylate (Compound 523) Step 1. tert-Butyl (2R,5S)-4-(7-(4-cyanopyridin-2-yl)-5-(4,4,5,5-tetramethyl-1, 3,2- dioxaborolan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dime thylpiperazine-1-carboxylate To a solution of tert-butyl (2R,5S)-4-(7-(4-cyanopyridin-2-yl)-5-iodo-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (950 mg, 1.7 mmol) in dioxane (10 mL) were added Pd ₂ (dba) ₃ (160 mg, 0.17 mmol), X-Phos (81 mg, 0.17 mmol), TEA (1.2 mL, 8.6 mmol) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (880 mg, 6.9 mmol) respectively. The resulting reaction mixture was stirred at 95℃ under N2 overnight. After cooling to room temperature, the reaction was quenched with ice water, and extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , filtered, and concentrated. The crude product was purified by column chromatography on silica gel (0~20% ethyl acetate in petroleum ether) to obtain tert-butyl (2R,5S)-4-(7-(4-cyanopyridin-2-yl)-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-7H-pyrrolo[2,3-d]pyrimi din-4-yl)-2,5- dimethylpiperazine-1-carboxylate (700 mg, 70%) as a white solid. LC/MS(ESI)m/z: 560 (M+H) ⁺ . Step 2. tert-Butyl (2R,5S)-4-(7-(4-cyanopyridin-2-yl)-5-hydroxy-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate To a solution of tert-butyl (2R,5S)-4-(7-(4-cyanopyridin-2-yl)-5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2, 5-dimethylpiperazine-1- carboxylate (700 mg, 1.2 mmol) in THF (30 mL) were added AcOH (20 mL, 350 mmol) and H ₂ O ₂ (20 mL) respectively. The resulting reaction mixture was stirred at room temperature for 5 h. The reaction was quenched with ice water and extracted with EtOAc. The organic layer was dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to afford tert- butyl (2R,5S)-4-(7-(4-cyanopyridin-2-yl)-5-hydroxy-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2,5- dimethylpiperazine-1-carboxylate (580 mg) as a white solid. LC/MS(ESI) (m/z): 450 (M+H) ⁺ . Step 3. tert-Butyl (2R,5S)-4-(7-(4-cyanopyridin-2-yl)-5-(difluoromethoxy)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate To a solution of tert-butyl (2R,5S)-4-(7-(4-cyanopyridin-2-yl)-5-hydroxy-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate (100 mg, 0.22 mmol) in MeCN (5 mL) were added a solution of KOH (250 mg, 0.44 mmol) in H ₂ O (5 mL) and diethyl (bromodifluoromethyl)phosphonate (70 mg, 0.24 mmol) respectively. The reaction was stirred at room temperature for 2 h after which the resulting mixture was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (0~20% ethyl acetate in petroleum ether) and prep-HPLC to obtain tert-butyl (2R,5S)-4- (7-(4-cyanopyridin-2-yl)-5-(difluoromethoxy)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2,5- dimethylpiperazine-1-carboxylate (6.6 mg, 6.0%) as a white solid. LC/MS(ESI) (m/z): 500 _(M+H) ⁺ _. ¹ _{H NMR (400 MHz, CDCl3) δ 9.35 (s, 1H), 8.60 (d, J = 5.0 Hz, 1H), 8.44 (s, 1H),} 7.96 (s, 1H), 7.39 – 7.36 (m, 1H), 6.63 (t, J = 73.6 Hz, 1H), 4.86 – 4.77 (m, 1H), 4.57 – 4.48 (m, 0.5H, rotomer), 4.37 – 4.25 (m, 0.5H, rotomer), 4.14 – 4.07 (m, 1H), 3.85 – 3.73 (m, 1H), 3.66 – 3.59 (m, 1H), 3.49 – 3.39 (m, 1H), 1.50 (s, 9H), 1.27 – 1.24 (m, 3H), 1.18 – 1.14 (m, 3H). Example 166. Synthesis of tert-butyl (2R,5S)-4-(7-(4-cyanopyridin-2-yl)-5- (trifluoromethoxy)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dime thylpiperazine-1- carboxylate (Compound 524) C ^{ompound 524} To a solution of tert-butyl (2R,5S)-4-(7-(4-cyanopyridin-2-yl)-5-hydroxy-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate (100 mg, 0.11 mmol) in DMF (5 mL) was added 1-(trifluoromethyl)-1λ ³ -benzo[d][1,2]iodaoxol-3(1H)-one (230 mg, 0.36 mmol). The resulting reaction mixture was stirred at 90℃ under N ₂ for 30 min. This procedure was repeated at the same scale and both reactions were worked up together. After cooling to room temperature, the solvent was removed. The residue was purified by column chromatography on silica gel (0~20% ethyl acetate in petroleum ether) and prep-HPLC to obtain tert-butyl (2R,5S)-4-(7-(4-cyanopyridin-2-yl)-5-(trifluoromethoxy)-7H-p yrrolo[2,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (4.5 mg, 2.0%) as a white solid. _{LC/MS(ESI) (m/z): 518 (M+H)} ⁺ _. ¹ _{H NMR (400 MHz, CDCl3) δ 9.29 (s, 1H), 8.55 (d, J = 5.0} Hz, 1H), 8.39 (s, 1H), 8.07 – 8.04 (m, 1H), 7.34 (dd, J = 5.0, 1.0 Hz, 1H), 4.77 – 4.69 (m, 1H), 4.50 – 4.40 (m, 0.5H, rotomer), 4.30 – 4.19 (m, 0.5H, rotomer), 3.96 – 3.90 (m, 1H), 3.78 – 3.67 (m, 1H), 3.62 – 3.56 (m, 1H), 3.44 – 3.34 (m, 1H), 1.43 (s, 9H), 1.21 – 1.19 (m, 3H), 1.09 – 1.05 (m, 3H).

Example 167. Synthesis of tert-butyl (2R,5S)-4-(5-(tert-butyl)-7-(4-cyanopyridin-2-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-ca rboxylate (Compound 525) Step 1.4-Methoxy-7H-pyrrolo[2,3-d]pyrimidine To a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (55 g, 360 mmol) in MeOH (20 mL) was added sodium methanolate (360 mL, 5.0M in methanol). The resulting mixture was stirred at 70 ^o C overnight. After cooling to room temperature, the reaction mixture was filtered. The filter cake was washed with water and dried under vacuum to afford 4-methoxy- 7H-pyrrolo[2,3-d]pyrimidine (50 g , 85%) as a light yellow solid. LC/MS ESI (m/z): 150 (M+H) ⁺ . Step 2.5-(tert-Butyl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidine To a solution of 4-methoxy-7H-pyrrolo[2,3-d]pyrimidine (25 g, 170 mmol) in toluene (100 ml) were added 2-bromo-2-methylpropane (46 g, 340 mmol), zinc triflate (61 g, 170 mmol), TBAI (62 g, 170 mmol) and DIEA (65 g, 500 mmol). The resulting mixture was stirred at 120 ^o C under N ₂ for 1.5 h. After cooling to room temperature, the reaction was quenched with water and extracted twice with EtOAc. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to afford 5-(tert- butyl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidine (480 mg, 1.5%) as a white solid. LC/MS ESI (m/z): 206 (M+H) ⁺ . Step 3.2-(5-(tert-Butyl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-7- yl)isonicotinonitrile To a solution of 5-(tert-butyl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidine (45 mg, 0.22 mmol) in DMF (5 mL) were added 2-fluoroisonicotinonitrile (54 mg, 0.44 mmol) and Cs ₂ CO ₃ (360 mg, 1.1 mmol). The resulting mixture was stirred at 50 ^o C for 2 h. The reaction was quenched with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to afford 2-(5-(tert-butyl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-7-yl) isonicotinonitrile (50 mg, 75%) as a white solid. LC/MS ESI (m/z): 308 (M+H) ⁺ . Step 4.2-(5-(tert-Butyl)-4-hydroxy-7H-pyrrolo[2,3-d]pyrimidin-7-y l)isonicotinonitrile To a solution of 2-(5-(tert-butyl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-7- yl)isonicotinonitrile (50 mg, 0.17 mmol) in DMF (5 mL) were added 4- methylbenzenesulfonic acid (280 mg, 1.6 mmol) and LiCl (69 mg, 1.6 mmol). The resulting mixture was stirred at 110 ^o 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 Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0~100%, ethyl acetate in petroleum ether) to afford 2-(5-(tert-butyl)-4-hydroxy-7H-pyrrolo[2,3-d]pyrimidin-7-yl) isonicotinonitrile (40 mg, 82%) as a yellow solid. LC/MS ESI (m/z): 294 (M+H) ⁺ . Step 5.2-(5-(tert-Butyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl )isonicotinonitrile A solution of 2-(5-(tert-butyl)-4-hydroxy-7H-pyrrolo[2,3-d]pyrimidin-7- yl)isonicotinonitrile (40 mg, 0.14 mmol) in POCl ₃ (5 mL) was stirred at 120 ^o C under N ₂ overnight. The solvent was removed. The residue was diluted with EtOAc and washed with saturated NaHCO ₃ . The aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30% EtOAc in petroleum ether) to afford 2- (5-(tert-butyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)iso nicotinonitrile (22 mg, 45%) as a light yellow solid. LC/MS ESI (m/z): 312 (M+H) ⁺ . Step 6. tert-Butyl (2R,5S)-4-(5-(tert-butyl)-7-(4-cyanopyridin-2-yl)-7H-pyrrolo [2,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate The mixture of 2-(5-(tert-butyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7- yl)isonicotinonitrile (22 mg, 0.07 mmol) and tert-butyl (2R,5S)-2,5-dimethylpiperazine-1- carboxylate (61 mg, 0.29 mmol) was stirred at 150 ^o C under N ₂ for 3 h. After cooling to room temperature, the reaction mixture was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to give a crude product (30 mg), which was further purified by prep-HPLC to afford tert-butyl (2R,5S)-4-(5-(tert-butyl)-7-(4-cyanopyridin-2-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-ca rboxylate (15 mg, 50%) as a white solid. LC/MS ESI (m/z): 490 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.35 (s, 1H), 8.62 (dd, J = 5.0, 0.7 Hz, 1H), 8.56 (s, 1H), 8.12 (s, 1H), 7.36 (dd, J = 5.0, 1.3 Hz, 1H), 4.37 – 4.28 (m, 2H), 3.83 – 3.77 (m, 1H), 3.74 – 3.66 (m, 2H), 3.22 – 3.16 (m, 1H), 1.54 (s, 9H), 1.49 (s, 9H), 1.12 (d, J = 6.8 Hz, 3H), 1.03 (d, J = 6.6 Hz, 3H). Example 168. Synthesis of tert-butyl (S)-4-(7-(cis-3-cyanocyclohexyl)-5-cyclopropyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (Compound 527) Step 1. cis-3-(4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexane- 1-carboxylic acid To a solution of cis-3-aminocyclohexane-1-carboxylic acid (850 mg, 5.9 mmol) in EtOH (10 mL) were added 2-(4,6-dichloropyrimidin-5-yl)acetaldehyde (1.6 g, 8.7 mmol) and TEA (2.9 mL, 21 mmol). The resulting mixture was heated to 80 ^o C for 3 h under N ₂ . After cooling to room temperature, the solvent was removed and the residue was purified by flash silica gel column chromatography to afford cis-3-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7- yl)cyclohexane-1-carboxylic acid (1.5 g, 95%) as a solid. LC/MS ESI (m/z): 280 (M+H) ⁺ . Step 2. cis-3-(4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexane- 1-carboxamide To a solution of cis-3-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexane- 1- carboxylic acid (1.5 g, 5.3 mmol) in DMF (4 mL) were added DIPEA (1.0 g, 12 mmol), ammonium chloride (510 mg, 9.6 mmol) and HATU (3.6 g, 9.6 mmol) respectively. The resulting reaction mixture was stirred at room temperature under N ₂ overnight. 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 Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography to afford cis-3-(4-chloro-7H-pyrrolo[2,3- d]pyrimidin-7-yl)cyclohexane-1-carboxamide (960 mg, 59%) as a white solid. LC/MS ESI (m/z): 279 (M+H) ⁺ . Step 3. cis-3-(4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexane- 1-carbonitrile To a solution of cis-3-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexane- 1- carboxamide (960 mg, 3.4 mmol) in DCM (10 mL) at 0 ^o C was added TEA (1.9 mL, 14 mmol) followed by TFAA (0.90 mL, 6.8 mmol) dropwise. The resulting mixture was stirred at the same temperature for 2 h. The reaction was quenched with NaHCO ₃ (aq.) and extracted twice with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography to afford cis-3-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexane- 1- carbonitrile (700 mg, 80%) as a solid. LC/MS ESI (m/z): 261 (M+H) ⁺ . Step 4. tert-Butyl (S)-4-(7-(cis-3-cyanocyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)- 3-methylpiperazine-1-carboxylate The mixture of cis-3-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexane- 1- carbonitrile (680 mg, 2.60 mmol) and tert-butyl (S)-3-methylpiperazine-1-carboxylate (2.6 g, 13 mmol) was stirred at 150℃ for 2 h. After cooling to room temperature, the reaction mixture was purified by column chromatography on silica gel (0~100% EtOAc in petroleum ether) to give tert-butyl (S)-4-(7-(cis-3-cyanocyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)- 3-methylpiperazine-1-carboxylate (800 mg, 72%) as a white solid. LC/MS ESI (m/z): 425(M+H) ⁺ . Step 5. tert-Butyl (S)-4-(5-bromo-7-(cis-3-cyanocyclohexyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl (S)-4-(7-(cis-3-cyanocyclohexyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (800 mg, 1.9 mmol) in DCM (50 mL) at 0 ^o C was added NBS (350 mg, 2.0 mmol) slowly. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was partitioned between water and DCM. The organic layer was separated, and the aqueous layer was extracted twice with DCM. The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel (0~100% EtOAc in petroleum ether) to give tert-butyl (S)-4-(5-bromo-7-(cis-3-cyanocyclohexyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (650 mg, 50%) as a white solid. LC/MS ESI (m/z): 503, 505 (M+H) ⁺ . Step 6. tert-Butyl (S)-4-(7-(cis-3-cyanocyclohexyl)-5-cyclopropyl-7H-pyrrolo[2, 3-d]p yrimidin-4-yl)-3-methylpiperazine-1-carboxylate A suspension of tert-butyl (S)-4-(5-bromo-7-(cis-3-cyanocyclohexyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (100 mg, 0.20 mmol), cyclopropylboronic acid (85 mg, 0.99 mmol), K ₂ CO ₃ (2.7 g, 19 mmol) and Pd(dtbpf)Cl ₂ (97 mg, 0.15 mmol) in toluene (2 mL) was stirred at 90℃ under N ₂ for 18 h. After cooling to room temperature, the solvent was removed and the residue was purified by column chromatography on silica gel (0~50% EtOAc in petroleum ether) and prep-HPLC to give tert-butyl (S)-4-(7-(cis-3-cyanocyclohexyl)-5-cyclopropyl-7H-pyrrolo[2, 3-d]pyrimidin-4-yl)- 3-methylpiperazine-1-carboxylate (15 mg, 16%) as a white solid. LC/MS ESI (m/z): 465 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.35 (s, 1H), 6.67 (s, 1H), 4.82 – 4.57 (m, 2H), 4.19 – 3.74 (m, 3H), 3.59 – 3.45 (m, 1H), 3.40 – 3.05 (m, 2H), 2.81 – 2.66 (m, 1H), 2.41 (t, J = 12.3 Hz, 1H), 2.20 (d, J = 11.2 Hz, 1H), 2.11 – 1.84 (m, 4H), 1.80 – 1.53 (m, 3H), 1.49 (s, 9H), 1.21 (d, J = 6.5 Hz, 3H), 0.96 (dd, J = 8.1, 1.8 Hz, 2H), 0.79 – 0.57 (m, 2H). Example 169. Synthesis of tert-butyl 4-(7-(4-cyanopyridin-2-yl)-5-(trifluoromethyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3,3-dimethylpiperazine-1-carbo xylate (Compound 528) C ^{ompound 528} Step 1.5-Iodo-4-methoxy-7H-pyrrolo[2,3-d]pyrimidine To a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (4.0 g, 14 mmol) in THF (20 mL) was added MeONa (8.0 mL, 4.5 M in MeOH). The resulting mixture was stirred at 60 ^o C overnight.1/3 of the solvent was removed and the reaction mixture was poured into ice water. The precipitate was filtered and washed with water and dried under vacuum to afford 5-iodo-4-methoxy-7H-pyrrolo[2,3-d]pyrimidine (3.0 g, 77%) as a white solid. LC/MS ESI (m/z): 276 (M+H) ⁺ . Step 2.2-(5-Iodo-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-7-yl)isonic otinonitrile To a solution of 5-iodo-4-methoxy-7H-pyrrolo[2,3-d]pyrimidine (3.0 g, 11 mmol) in DMF (20 mL) were added 2-fluoroisonicotinonitrile (2.7 g, 22 mmol) and Cs ₂ CO ₃ (14 g, 44 mmol). The resulting mixture was stirred at 50 ^o 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford 2-(5-iodo-4- methoxy-7H-pyrrolo[2,3-d]pyrimidin-7-yl)isonicotinonitrile (3.5 g, 85%) as a white-yellow solid. LC/MS ESI (m/z): 378 (M+H) ⁺ . Step 3.2-(4-Methoxy-5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidi n-7- yl)isonicotinonitrile To a solution of 2-(5-iodo-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-7- yl)isonicotinonitrile (3.5 g, 9.3 mmol) in DMF (30 mL) were added CuI (1.8 g, 9.3 mmol) and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (7.1 g, 37 mmol). The resulting mixture was heated to 80 ^o C overnight under N ₂ . 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 with EtOAc twice. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford 2-(4- methoxy-5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl) isonicotinonitrile (1.5 g, 51%) as a light yellow solid. LC/MS ESI (m/z): 320 (M+H) ⁺ . Step 4.2-(4-Hydroxy-5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidi n-7- yl)isonicotinonitrile To a solution of 2-(4-methoxy-5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin- 7- yl)isonicotinonitrile (1.5 g, 4.7 mmol) in DMF (20 mL) were added TsOH (8.1 g, 47 mmol) and LiCl (2.0 g, 47 mmol). The resulting mixture was stirred at 110 ^o C for 2 h. The reaction was quenched with ice water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0~60%, ethyl acetate in petroleum ether) to afford 2-(4-hydroxy-5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin- 7- yl)isonicotinonitrile (0.90 g, 63%) as a light yellow solid. LC/MS ESI (m/z): 306 (M+H) ⁺ . Step 5.2-(4-Chloro-5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin -7- yl)isonicotinonitrile A solution of 2-(4-hydroxy-5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin- 7- yl)isonicotinonitrile (0.90 g, 3.0 mmol) in POCl ₃ (4 mL) was heated to 120 ^o C overnight. After cooling to room temperature, the reaction was concentrated. The residue was dissolved in DCM, washed with NaHCO ₃ (aq.). The aqueous layer was extracted with DCM twice. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0~40%, ethyl acetate in petroleum ether) to afford 2-(4-chloro-5-(trifluoromethyl)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)isonicotinonitrile (0.70 g, 74%) as a white-yellow solid. LC/MS ESI (m/z): 324 (M+H) ⁺ . Step 6. tert-Butyl 4-(7-(4-cyanopyridin-2-yl)-5-(trifluoromethyl)-7H-pyrrolo[2, 3- d]pyrimidin-4-yl)-3,3-dimethylpiperazine-1-carboxylate To a solution of 2-(4-chloro-5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-7 - yl)isonicotinonitrile (300 mg, 0.93 mmol) in DIPEA (5 mL) was added tert-butyl 3,3- dimethylpiperazine-1-carboxylate (2.0 g, 9.3 mmol). The resulting mixture was heated to 150ºC for two days. After cooling to room temperature, the solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~20%, ethyl acetate in petroleum ether) to give the product. Further purification by prep-HPLC to afford tert-butyl 4-(7-(4-cyanopyridin-2-yl)-5-(trifluoromethyl)-7H-pyrrolo[2, 3-d]pyrimidin-4-yl)-3,3- dimethylpiperazine-1-carboxylate (62 mg, 13%) as a white solid. LC/MS ESI (m/z): 502 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.34 (s, 1H), 8.76 (s, 1H), 8.70 – 8.66 (m, 2H), 7.49 (dd, J = 5.0, 1.3 Hz, 1H), 3.68 – 3.60 (m, 2H), 3.38 (s, 2H), 3.30 – 3.26 (m, 2H), 1.50 (s, 9H), 1.46 (s, 6H). The following compound was prepared in a similar fashion to Compound 528 using the corresponding amine. Example 170. Synthesis of tert-butyl (S)-4-(7-(cis-3-cyanocyclohexyl)-5-(pyrrolidin-1-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carbox ylate (Compound 529) Step 1. tert-Butyl (S)-4-(7-(cis-3-cyanocyclohexyl)-5-(2-oxopyrrolidin-1-yl)-7H - pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te A suspension of tert-butyl (S)-4-(5-bromo-7-(cis-3-cyanocyclohexyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (500 mg, 0.99 mmol), pyrrolidin-2-one (0.23 mL, 3.0 mmol), K ₃ PO ₄ (630 mg, 3.0 mmol), CuI (95 mg, 0.49 mmol) and trans-N ¹ ,N ² - dimethylcyclohexane-1,2-diamine (210 mg, 1.5 mmol) in DMF (10 mL) was stirred at 90℃ under N ₂ for 18 h. 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 anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography on silica gel (0~20% MeOH in DCM) to give tert-butyl (S)-4-(7-(cis-3- cyanocyclohexyl)-5-(2-oxopyrrolidin-1-yl)-7H-pyrrolo[2,3-d]p yrimidin-4-yl)-3- methylpiperazine-1-carboxylate (300 mg, 60%) as a white solid. LC/MS ESI (m/z): 508(M+H) ⁺ Step 2. tert-Butyl (S)-4-(7-(cis-3-cyanocyclohexyl)-5-(pyrrolidin-1-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te To a solution of tert-butyl (S)-4-(7-(cis-3-cyanocyclohexyl)-5-(2-oxopyrrolidin-1-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carbox ylate (100 mg, 0.19 mmol) in dry THF (2 mL) at 0 ^o C was added BH ₃ (0.79 mL, 2.0 M in THF) dropwise. After stirring at room temperature for 3 h, the reaction was quenched with sat. NaHCO ₃ and extracted twice with EtOAc. The combined organic phases were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by column chromatography on silica gel (0~20% MeOH in DCM) to give tert-butyl (S)-4-(7-(cis-3-cyanocyclohexyl)-5- (pyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylp iperazine-1-carboxylate (15 mg, 15%) as a white solid. LC/MS ESI (m/z): 494(M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.29 (s, 1H), 6.45 (s, 1H), 5.07 – 4.87 (m, 1H), 4.75 – 4.62 (m, 1H), 4.31 – 3.80 (m, 3H), 3.44 – 3.17 (m, 2H), 3.14 – 2.90 (m, 3H), 2.88 – 2.67 (m, 3H), 2.43 (d, J = 12.4 Hz, 1H), 2.20 (d, J = 11.7 Hz, 1H), 2.12 – 1.88 (m, 7H), 1.66 – 1.53 (m, 3H), 1.48 (s, 9H), 1.11 (d, J = 5.4 Hz, 3H). Example 171. Synthesis of tert-butyl (2R,5S)-4-(7-(4-cyanopyridin-2-yl)-6-methyl-5- (trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimet hylpiperazine-1- carboxylate (Compound 531) Step 1.4-Chloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-py rrolo[2,3- d]pyrimidine To a suspension of NaH (430 mg, 11 mol, 60 wt%) in THF (20 mL) at 0 ^o C was added 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (2.0 g, 7.2 mmol) in portions. The resulting mixture was stirred at 0 ^o C for 20 min after which 2-(trimethylsilyl)ethoxymethyl chloride (1.4 g, 8.6 mmol) was added dropwise. After stirring at room temperature for 3 h, the reaction was quenched with ice water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 0~30% ethyl acetate in petroleum ether) to afford 4-chloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrr olo[2,3-d]pyrimidine (2.0 g, 68%). LC/MS ESI (m/z): 410 (M+H) ⁺ . Step 2.4-Chloro-5-iodo-6-methyl-7-((2-(trimethylsilyl)ethoxy)meth yl)-7H- pyrrolo[2,3-d]pyrimidine To a solution of 4-chloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrr olo[2,3- d]pyrimidine (600 mg, 1.5 mmol) in THF (6 mL) at -70 ^o C was added LDA (1.5 mL, 2.0M in THF) dropwise. The resulting mixture was stirred at -70 ^o C for 30 min after which iodomethane (310 mg, 2.2 mmol) was added dropwise. After stirring for 30 min, the reaction was quenched with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford 4-chloro-5-iodo-6-methyl-7-((2-(trimethylsilyl)ethoxy)methyl )-7H-pyrrolo[2,3- d]pyrimidine (600 mg, 96%) as a solid. LC/MS ESI (m/z): 424 (M+H) ⁺ . Step 3. tert-Butyl (2R,5S)-4-(5-iodo-6-methyl-7-((2-(trimethylsilyl)ethoxy)meth yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate To a solution of 4-chloro-5-iodo-6-methyl-7-((2-(trimethylsilyl)ethoxy)methyl )-7H- pyrrolo[2,3-d]pyrimidine (600 mg, 1.4 mmol) in DIPEA (5 mL) was added tert-butyl (2R,5S)-2,5-dimethylpiperazine-1-carboxylate (1.5 g, 7.1 mmol). The resulting mixture was stirred at 150 ^o C for 2 h. After cooling to room temperature, the reaction mixture was purified by flash column chromatography (silica gel, ethyl acetate in petroleum ether) to afford tert- butyl (2R,5S)-4-(5-iodo-6-methyl-7-((2-(trimethylsilyl)ethoxy)meth yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (560 mg, 65%) as a white solid. LC/MS ESI (m/z): 602 (M+H) ⁺ . Step 4. tert-Butyl (2R,5S)-2,5-dimethyl-4-(6-methyl-5-(trifluoromethyl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)piperazine-1-carboxylate To a solution of tert-butyl (2R,5S)-4-(5-iodo-6-methyl-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)-2,5-dimethyl piperazine-1- carboxylate (560 mg, 0.93 mmol) in DMF (8 mL) were added CuI (180 mg, 0.93 mmol) and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (720 mg, 3.7 mmol). The resulting mixture was stirred at 80 ^o 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 Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-2,5-dimethyl-4-(6-methyl-5- (trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-py rrolo[2,3-d]pyrimidin-4- yl)piperazine-1-carboxylate (310 mg, 62%) as a light yellow solid. LC/MS ESI (m/z): 544 (M+H) ⁺ . Step 5. tert-Butyl (2R,5S)-2,5-dimethyl-4-(6-methyl-5-(trifluoromethyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate To a solution of tert-butyl (2R,5S)-2,5-dimethyl-4-(6-methyl-5-(trifluoromethyl)-7- ((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidi n-4-yl)piperazine-1-carboxylate (310 mg, 0.57 mmol) in THF (2 mL) was added TBAF (3.4 mL, 1.0M in THF). The resulting mixture was stirred at 50 ^o C overnight. After cooling to room temperature, the solvent was removed and the residue was dissolved in DCM. The organics were washed twice with saturated NH ₄ Cl, dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50% ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-2,5-dimethyl-4-(6-methyl-5-(trifluoromethyl)-7H-pyrr olo[2,3-d]pyrimidin- 4-yl)piperazine-1-carboxylate (110 mg, 47%) as an oil. LC/MS ESI (m/z): 414 (M+H) ⁺ . Step 6. tert-Butyl (2R,5S)-4-(7-(4-cyanopyridin-2-yl)-6-methyl-5-(trifluorometh yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-ca rboxylate To a solution of tert-butyl (2R,5S)-2,5-dimethyl-4-(6-methyl-5-(trifluoromethyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (80 mg, 0.19 mmol) in DMF (8 mL) were added Cs ₂ CO ₃ (310 mg, 0.95 mmol) and 2-fluoroisonicotinonitrile (46 mg, 0.38 mmol). The resulting mixture was stirred at 50 ^o 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 Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, ethyl acetate in petroleum ether) and prep-HPLC to afford tert-butyl (2R,5S)-4-(7-(4- cyanopyridin-2-yl)-6-methyl-5-(trifluoromethyl)-7H-pyrrolo[2 ,3-d]pyrimidin-4-yl)-2,5- dimethylpiperazine-1-carboxylate (2.8 mg, 2.8%) as a white solid. LC/MS ESI (m/z): 516 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.83 (d, J = 5.0 Hz, 1H), 8.38 (s, 1H), 8.02 (s, 1H), 7.64 (d, J = 5.0 Hz, 1H), 4.59 – 4.42 (m, 1H), 4.41 – 4.19 (m, 1H), 3.82 – 3.68 (m, 2H), 3.66 – 3.60 (m, 1H), 3.44 (d, J = 13.4 Hz, 1H), 2.58 (s, 3H), 1.49 (s, 9H), 1.10 (dd, J = 12.9, 6.7 Hz, 6H). Example 172. Synthesis of tert-butyl (2R,5S)-4-(5-(tert-butyl)-7-(4-cyanopyrimidin-2-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-ca rboxylate (Compound 532) Step 1.5-(tert-Butyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ol To a solution of 5-(tert-butyl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidine (150 mg, 0.73 mmol) in DMF (5 mL) were added 4-methylbenzenesulfonic acid (1.3 g, 7.3 mmol) and LiCl (310 mg, 7.3 mmol). The resulting mixture was stirred at 110 ^o C for 2h. 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 Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to afford 5-(tert-butyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ol (130 mg, 82%) as a yellow solid. LC/MS ESI (m/z): 192 (M+H) ⁺ . Step 2.5-(tert-Butyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidine A mixture of POCl3 (15 mL) and 5-(tert-butyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ol (130 mg, 0.68 mmol) was stirred at 120 ^o C under N ₂ atmosphere overnight. After cooling to room temperature, the solvent was removed and the residue was diluted with EtOAc. The mixture was washed with saturated NaHCO ₃ and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30% EtOAc in petroleum ether) to afford 5-(tert-butyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (90 mg, 63%) as a light yellow solid. LC/MS ESI (m/z): 210 (M+H) ⁺ . Step 3.5-(tert-Butyl)-4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin e To a solution of 5-(tert-butyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (90 mg, 0.43 mmol) in DMF (5 mL) were added NaH (21 mg, 0.86 mmol, 60 wt%) and 4- methylbenzenesulfonyl chloride (98 mg, 0.52 mmol) at 0 ^o C. After stirring at room temperature for 2 h, the reaction was quenched with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0~25%, ethyl acetate in petroleum ether) to afford 5-(tert-butyl)-4-chloro-7-tosyl-7H-pyrrolo[2,3- d]pyrimidine (120 mg, 82%) as a yellow solid. LC/MS ESI (m/z): 364 (M+H) ⁺ . Step 4. tert-Butyl (2R,5S)-4-(5-(tert-butyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin -4-yl)- 2,5-dimethylpiperazine-1-carboxylate A mixture of 5-(tert-butyl)-4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (120 mg, 0.33 mmol) and tert-butyl (2R,5S)-2,5-dimethylpiperazine-1-carboxylate (350 mg, 1.7 mmol) was stirred at 150 ^o C under N ₂ atmosphere for 3 hours. After cooling to room temperature, the reaction mixture was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-4-(5-(tert-butyl)-7-tosyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate (150 mg, 82%) as a yellow solid. LC/MS ESI (m/z): 542 (M+H) ⁺ . Step 5. tert-Butyl (2R,5S)-4-(5-(tert-butyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2 ,5- dimethylpiperazine-1-carboxylate To a solution of tert-butyl (2R,5S)-4-(5-(tert-butyl)-7-tosyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (150 mg, 0.28 mmol) in THF (1 mL) was added TBAF (5.0 ml, 1.0M in THF). The resulting mixture was stirred at rt under N ₂ atmosphere for 2 hours. The reaction was quenched with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-4-(5-(tert-butyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate (100 mg, 92%) as a yellow solid. LC/MS ESI (m/z): 388 (M+H) ⁺ . Step 6. tert-Butyl (2R,5S)-4-(5-(tert-butyl)-7-(4-cyanopyrimidin-2-yl)-7H-pyrro lo[2,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate To a solution of tert-butyl (2R,5S)-4-(5-(tert-butyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 2,5-dimethylpiperazine-1-carboxylate (55 mg, 0.15 mmol) in dioxane (5 mL) were added 2- bromopyrimidine-4-carbonitrile (72 mg, 0.45 mmol), Pd ₂ (dba) ₃ (60 mg, 0.07 mmol), X-Phos (75 mg, 0.15 mmol) and Cs2CO3 (130 mg, 0.45 mmol). The resulting mixture was stirred at 100 ^o 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 Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, ethyl acetate in petroleum ether) to give the product which was further purified by prep-HPLC to afford tert-butyl (2R,5S)-4-(5-(tert-butyl)-7-(4-cyanopyrimidin-2-yl)-7H-pyrro lo[2,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (20 mg, 30%) as a white solid. LC/MS ESI (m/z): 491 (M+H) ⁺ . ¹ H NMR(400 MHz, CDCl ₃ ) δ 9.02 (d, J = 4.8 Hz, 1H), 8.59 (s, 1H), 7.89 (s, 1H), 7.38 (d, J = 4.8 Hz, 1H), 4.30 – 4.22 (m, 2H), 3.77 – 3.70 (m, 1H), 3.67 – 3.58 (m, 2H), 3.14 – 3.08 (m, 1H), 1.48 (s, 9H), 1.41 (s, 9H), 1.02 (d, J = 6.8 Hz, 3H), 0.97 (d, J = 6.7 Hz, 3H). Example 173. Synthesis of tert-butyl (2R,5S)-4-(5-(tert-butyl)-7-(6-cyanopyrimidin-4-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-ca rboxylate (Compound 533) C ^{ompound 533} To a solution of tert-butyl (2R,5S)-4-(5-(tert-butyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 2,5-dimethylpiperazine-1-carboxylate (55 mg, 0.15 mmol) in DMF (5 mL) were added Cs ₂ CO ₃ (140 mg, 0.43 mmol) and 6-chloropyrimidine-4-carbonitrile (40 mg, 0.28 mmol). After stirring at room temperature for 3 h, the reaction was filtered. The filtrate was poured into water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, ethyl acetate in petroleum ether) to give the product which was further purified by prep-HPLC to afford tert-butyl (2R,5S)-4-(5-(tert-butyl)-7-(6- cyanopyrimidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-di methylpiperazine-1- carboxylate (30 mg, 42%) as a white solid. LC/MS ESI (m/z): 491 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.48 (s, 1H), 9.01 (s, 1H), 8.49 (s, 1H), 8.06 (s, 1H), 4.32 – 4.23 (m, 2H), 3.75 – 3.70 (m, 1H), 3.64 – 3.59 (m, 2H), 3.15 – 3.10 (m, 1H), 1.46 (s, 9H), 1.42 (s, 9H), 1.00 (t, J = 6.6 Hz, 6H).

Example 174. Synthesis of 2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6 (2S,5R)-4-(7-(4- cyanopyridin-2-yl)-5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyri midin-4-yl)-2,5- dimethylpiperazine-1-carboxylate (Compound 534) Step 1.2-(4-((2R,5S)-2,5-Dimethylpiperazin-1-yl)-5-(trifluorometh yl)-7H- pyrrolo[2,3-d]pyrimidin-7-yl)isonicotinonitrile To a solution of tert-butyl (2S,5R)-4-(7-(4-cyanopyridin-2-yl)-5-(trifluoromethyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate (140 mg, 0.28 mmol) in DCM (4 mL) was added HCl (0.50 mL, 4.0 M in dioxane). The resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was basicified with saturated NaHCO ₃ and extracted twice with DCM. The combined organic layers were dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash chromatography (0~10% MeOH in DCM) to afford 2-(4-((2R,5S)-2,5-dimethylpiperazin-1-yl)-5-(trifluoromethyl )-7H- pyrrolo[2,3-d]pyrimidin-7-yl)isonicotinonitrile (90 mg, 80%) as a white solid. LC/MS ESI (m/z): 402 (M+H) ⁺ . Step 2.2-(Methyl-d ₃ )propan-2-yl-1,1,1,3,3,3-d ₆ (2S,5R)-4-(7-(4-cyanopyridin-2-yl)-5- (trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimet hylpiperazine-1-carboxylate A mixture of 2-(methyl-d ₃ )propan-1,1,1,3,3,3-d ₆ -2-ol (1.0 g, 12 mmol), di(pyridin-2- yl) carbonate (2.6 g, 12 mmol) and DMAP (440 mg, 3.6 mmol) in DCM (30 mL) was stirred at room temperature for 42 h. The reaction mixture was used directly without further manipulation. To a solution of 2-(4-((2R,5S)-2,5-dimethylpiperazin-1-yl)-5- (trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)isonicotin onitrile (60 mg, 0.15 mmol) in DMF (5 mL) were added 2-(methyl-d ₃ )propan-2-yl-1,1,1,3,3,3-d ₆ pyridin-2-yl carbonate (0.50 mL, 0.40 M in DCM) and DIPEA (58 mg, 0.45 mmol). The resulting mixture was heated to 80 ^o C for 1h. 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 Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0~25%, ethyl acetate in petroleum ether) and prep-HPLC to afford 2-(methyl-d ₃ )propan-2-yl- 1,1,1,3,3,3-d ₆ (2S,5R)-4-(7-(4-cyanopyridin-2-yl)-5-(trifluoromethyl)-7H-py rrolo[2,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (50 mg, 64%) as a solid. A sample of 50 mg was further purified by prep-HPLC to afford 30 mg of a white solid. LC/MS ESI (m/z): 511 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.30 – 9.24 (m, 1H), 8.62 – 8.56 (m, 2H), 8.50 (s, 1H), 7.41 (dd, J = 5.0, 1.3 Hz, 1H), 4.57 – 4.47 (m, 1H), 4.43 – 4.17 (m, 1H), 3.75 – 3.63 (m, 2H), 3.60 – 3.53 (m, 1H), 3.41 (d, J = 13.3 Hz, 1H), 1.09 (d, J = 6.6 Hz, 3H), 1.03 (d, J = 6.8 Hz, 3H). The following compound was prepared by a procedure similar to the synthesis of Compound 534 using tert-butyl (2R,5S)-4-(7-(4-cyanopyridin-2-yl)-5-(trifluoromethyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate.

Example 175. Synthesis of 1-methylcyclobutyl (2R,5S)-4-(7-(4-cyanopyridin-2-yl)-5- (trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimet hylpiperazine-1- carboxylate (Compound 535) C ^{ompound 535} Step 1.1-Methylcyclobutyl pyridin-2-yl carbonate A mixture of 1-methylcyclobutan-1-ol (100 mg, 1.2 mmol), di(pyridin-2-yl) carbonate (240 g, 1.1 mmol), and DMAP (40 mg, 0.33 mmol) in DCM (5 mL) was stirred at room temperature overnight. The reaction mixture quenched with saturated NH ₄ Cl and extracted twice with DCM. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0~35% ethyl acetate in petroleum ether) to afford 1-methylcyclobutyl pyridin-2-yl carbonate (100 mg, 43%). Step 2.1-Methylcyclobutyl (2R,5S)-4-(7-(4-cyanopyridin-2-yl)-5-(trifluoromethyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-ca rboxylate A mixture of 1-methylcyclobutyl pyridin-2-yl carbonate (120 mg, 0.56 mmol), 2-(4- ((2S,5R)-2,5-dimethylpiperazin-1-yl)-5-(trifluoromethyl)-7H- pyrrolo[2,3-d]pyrimidin-7- yl)isonicotinonitrile (150 mg, 0.37 mmol), TEA (0.10 mL, 0.74 mmol) and DMF (5 mL) was heated to 80 ^o C overnight. After cooling to room temperature, the reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted twice with EtOAc and the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0~25%, ethyl acetate in petroleum ether) and prep-HPLC to afford 1-methylcyclobutyl (2R,5S)-4-(7- (4-cyanopyridin-2-yl)-5-(trifluoromethyl)-7H-pyrrolo[2,3-d]p yrimidin-4-yl)-2,5- dimethylpiperazine-1-carboxylate (60 mg, 31%). LC/MS ESI (m/z): 514 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.27 (s, 1H), 8.64 – 8.55 (m, 2H), 8.51 (s, 1H), 7.41 (dd, J = 5.0, 1.2 Hz, 1H), 4.52 (br. s, 1H), 4.32 (br. s, 1H), 3.77 – 3.61 (m, 2H), 3.60- 3.54 (m, J = 12.4 Hz, 1H), 3.41 (d, J = 13.4 Hz, 1H), 2.32 – 2.22 (m, 2H), 2.13 – 2.04 (m, 2H), 1.79 – 1.69 (m, 1H), 1.64 – 1.56 (m, 1H), 1.51 (s, 3H), 1.09 (d, J = 6.6 Hz, 3H), 1.05 (d, J = 6.8 Hz, 3H). Example 176. Synthesis of tert-butyl (2R,5S)-2,5-dimethyl-4-(5-(trifluoromethyl)-7-(4- (trifluoromethyl)pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)piperazine-1- carboxylate (Compound 536) 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) at 0 ^o C was added dropwise 2.0M NaOH (0.53 L). The reaction was allowed to warm up to room temperature and stirred for 3 hours. The resulting precipitate was collected by filtration, washed with water twice, and dried under vacuum to provide 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) ⁺ . 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 (20 g, 46 mmol) in DIEA (100 mL) was added tert-butyl (2R,5S)-2,5-dimethylpiperazine-1-carboxylate (20 g, 92 mmol). The resulting mixture was heated to 140 ^o C for 1 h. 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~10%, ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2 ,5-dimethylpiperazine-1- carboxylate (26 g, 92%) as a yellow solid. LC/MS ESI (m/z): 612 (M+H) ⁺ . Step 3. tert-Butyl (2R,5S)-2,5-dimethyl-4-(7-tosyl-5-(trifluoromethyl)-7H-pyrro lo[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 (7.0 g, 11 mmol) in DMF (120 mL) were added methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (4.3 mL, 34 mmol) and CuI (2.2 g, 11 mmol). The resulting mixture was heated to 80 ^o 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-2,5-dimethyl-4-(7- tosyl-5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pi perazine-1-carboxylate (4.8 g, 75%) as a yellow solid. LC/MS ESI (m/z): 554 (M+H) ⁺ . Step 4. tert-Butyl (2R,5S)-2,5-dimethyl-4-(5-(trifluoromethyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperazine-1-carboxylate To a solution of tert-butyl (2R,5S)-2,5-dimethyl-4-(7-tosyl-5-(trifluoromethyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (4.8 g, 8.6 mmol) in THF (50 mL) was added TBAF (52 mL, 1.0 M in THF). After stirring at room temperature for 1 h, the reaction was quenched with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-2,5-dimethyl-4-(5-(trifluoromethyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperazine-1-carboxylate (3.2 g, 91%) as a yellow solid. LC/MS ESI (m/z): 400 (M+H) ⁺ . Step 5. tert-Butyl (2R,5S)-2,5-dimethyl-4-(5-(trifluoromethyl)-7-(4- (trifluoromethyl)pyridin-2-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-(trifluoromethyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (150 mg, 0.37 mmol) in DMF (5 mL) were added 2-bromo-4-(trifluoromethyl)pyridine (0.09 mL, 0.75 mmol), CuI (72 mg, 0.37 mmol), trans-N ¹ ,N ² -dimethylcyclohexane-1,2-diamine (110 mg, 0.75 mmol) and K ₃ PO ₄ (160 mg, 0.75 mmol). The resulting mixture was stirred at 100 ^o 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~20%, ethyl acetate in petroleum ether) to give the product which was further purified by prep-HPLC to afford tert-butyl (2R,5S)-2,5-dimethyl-4-(5- (trifluoromethyl)-7-(4-(trifluoromethyl)pyridin-2-yl)-7H-pyr rolo[2,3-d]pyrimidin-4- yl)piperazine-1-carboxylate (33 mg, 16%) as a white solid. LC/MS ESI (m/z): 545 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.27 (s, 1H), 8.68 (m, 2H), 8.58 (s, 1H), 7.49 (d, J = 5.1 Hz, 1H), 4.61 – 4.53 (m, 1H), 4.47 – 4.26 (m, 1H), 3.82 – 3.71 (m, 2H), 3.64 (dd, J = 13.4, 3.5 Hz, 1H), 3.48 (d, J = 13.3 Hz, 1H), 1.50 (s, 9H), 1.15 (d, J = 6.6 Hz, 3H), 1.11 (d, J = 6.8 Hz, 3H). The following compounds were prepared by a procedure analogous to the synthesis of Compound 536 from the corresponding aryl halides. Example 177. Synthesis of tert-butyl (2R,5S)-2,5-dimethyl-4-(5-methyl-7-(4- (trifluoromethyl)pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)piperazine-1- carboxylate (Compound 537) Step 1. tert-Butyl (2R,5S)-2,5-dimethyl-4-(5-methyl-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 (610 mg, 1.0 mmol) in dioxane (10 mL) and H ₂ O (1 mL) were added methylboronic acid (600 mg, 10 mmol), K ₂ CO ₃ (410 mg, 3.0 mmol) and Pd(dppf)Cl ₂ (73 mg, 0.10 mmol). After stirring at 90 ^o C overnight under N ₂ , the reaction mixture was filtered. The filtrate was concentrated and purified by flash column chromatography (silica gel, 0~20%, EtOAc in petroleum ether) to afford tert-butyl (2R,5S)- 2,5-dimethyl-4-(5-methyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)piperazine-1-carboxylate (300 mg, 60%) as a white-yellow solid. LC/MS ESI (m/z): 500 (M+H) ⁺ . Step 2. tert-Butyl (2R,5S)-2,5-dimethyl-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin- 4- yl)piperazine-1-carboxylate To a solution of tert-butyl (2R,5S)-2,5-dimethyl-4-(5-methyl-7-tosyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperazine-1-carboxylate (300 mg, 0.60 mmol) in THF (3 mL) was added TBAF (5.0 mL, 1.0M in THF). After stirring at room temperature overnight under N ₂ , the reaction was quenched with water and extracted twice with DCM. The combined organic layers were washed with brine and dried over Na ₂ SO ₄ , concentrated, and purified by flash column chromatography (silica gel, 0~80%, EtOAc in petroleum ether) to afford tert-butyl (2R,5S)-2,5-dimethyl-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)piperazine-1-carboxylate (190 mg, 92%) as a white-yellow solid. LC/MS ESI (m/z): 346 (M+H) ⁺ . Step 3. tert-Butyl (2R,5S)-2,5-dimethyl-4-(5-methyl-7-(4-(trifluoromethyl)pyrid in-2- 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-methyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperazine-1-carboxylate (100 mg, 0.29 mmol) in DMF (10 mL) were added 2-bromo-4-(trifluoromethyl)pyridine (130 mg, 0.58 mmol), trans-N ¹ ,N ² - dimethylcyclohexane-1,2-diamine (82 mg, 0.58 mmol), CuI (55 mg, 0.58 mmol) and K ₃ PO ₄ (120 mg, 0.58 mmol). After stirring at 100 ^o C overnight under N ₂ , the reaction was cooled to room temperature and partitioned between EtOAc and water. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine and dried over Na ₂ SO ₄ , concentrated and purified by flash column chromatography (silica gel, 0~20%, EtOAc in petroleum ether) to give the product which was further purified by prep-HPLC to afford tert-butyl (2R,5S)-2,5-dimethyl-4-(5-methyl-7-(4-(trifluoromethyl)pyrid in-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (140 mg, 95%) as a white solid. LC/MS ESI (m/z): 491 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.24 (s, 1H), 8.61 (d, J = 5.1 Hz, 1H), 8.51 (s, 1H), 7.99 (d, J = 1.0 Hz, 1H), 7.36 (d, J = 4.6 Hz, 1H), 4.52 – 4.33 (m, 2H), 3.81 – 3.73 (m, 2H), 3.67 – 3.59 (m, 1H), 3.53 – 3.47 (m, 1H), 2.46 (d, J = 0.9 Hz, 3H), 1.50 (s, 9H), 1.16 (t, J = 7.2 Hz, 6H). Example 178. Synthesis of tert-butyl (S)-4-(7-(3-chlorophenyl)-5-(trifluoromethyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (Compound 494) C ^{ompound 494} 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 tert-butyl (S)-4-(5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl) -3- methylpiperazine-1-carboxylate (300 mg, 0.67 mmol) in DCM (15 mL) were added (3- chlorophenyl)boronic acid (210 mg, 1.4 mmol), 4A molecular sieves (500 mg), Cu(OAc) ₂ (370 mg, 2.0 mmol) and pyridine (0.33 mL, 4.1 mmol). The resulting mixture was stirred at 40 ^o C under O ₂ atmosphere overnight. The reaction was quenched with aqueous NH ₄ OH (1 mL) at 0 ^o C and filtered. The filtrate was extracted twice with DCM. The combined organic layers were dried over Na ₂ SO ₄ , filtered, concentrated, and the residue was purified by flash column chromatography (silica gel, 0~20%, ethyl acetate in petroleum ether) to afford tert- butyl (S)-4-(7-(3-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)-3- methylpiperazine-1-carboxylate (70 mg, 18%) as a white solid. LC/MS ESI (m/z): 554 (M+H) ⁺ . Step 2. tert-Butyl (S)-4-(7-(3-chlorophenyl)-5-(trifluoromethyl)-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 (70 mg, 0.12 mmol) in DMF (5 mL) were added methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (0.06 mL, 0.50 mmol) and CuI (24 mg, 0.12 mmol). The resulting mixture was heated to 80 ^o 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 Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0~10%, ethyl acetate in petroleum ether) to give the product which was further purified by prep-HPLC to afford tert-butyl (S)-4-(7-(3-chlorophenyl)-5- (trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylp iperazine-1-carboxylate (30 mg, 48%) as a white solid. LC/MS ESI (m/z): 496 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.48 (s, 1H), 7.65 (s, 1H), 7.63 (t, J = 1.9 Hz, 1H), 7.52 – 7.49 (m, 1H), 7.44 – 7.39 (m, 1H), 7.37 – 7.33 (m, 1H), 4.33 – 4.27 (m, 1H), 3.99 – 3.78 (m, 1H), 3.66 (d, J = 11.8 Hz, 1H), 3.53 – 3.34 (m, 3H), 3.20 – 3.04 (m, 1H), 1.43 (s, 9H), 1.13 (d, J = 6.6 Hz, 3H). The following compound was prepared by a procedure analogous to the synthesis of Compound 494 from the corresponding boric acid. Example 179. Synthesis of tert-butyl 4-(7-(4-cyanopyridin-2-yl)-5-(pyrrolidin-1-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3,3-dimethylpiperazine-1-carbo xylate (Compound 601)

Step 1.5-Bromo-7-(4-chloropyridin-2-yl)-4-methoxy-7H-pyrrolo[2,3- d]pyrimidine To a solution of 5-bromo-4-methoxy-7H-pyrrolo[2,3-d]pyrimidine (3.0 g, 13 mmol) in DMF (15 mL) were added 4-chloro-2-fluoropyridine (3.5 g, 26 mmol) and Cs ₂ CO ₃ (6.5 g, 20 mmol). The resulting mixture was stirred at 60 ^o C for 12 h. 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford 5-bromo-7-(4-chloropyridin-2-yl)-4-methoxy-7H- pyrrolo[2,3-d]pyrimidine (2.6 g, 50%) as a yellow solid. LC/MS ESI (m/z): 339, 401 (M+H) ⁺ . Step 2.5-Bromo-7-(4-chloropyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidi n-4-ol To a solution of 5-bromo-7-(4-chloropyridin-2-yl)-4-methoxy-7H-pyrrolo[2,3- d]pyrimidine (2.6 g, 6.5 mmol) in DMF (8 mL) were added 4-methylbenzenesulfonic acid (11 g, 65 mmol) and LiCl (2.8 g, 65 mmol). The resulting mixture was stirred at 110 ^o C for 4 h. 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography to afford 5-bromo-7-(4-chloropyridin-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-ol (1.7 g, 80%) as a yellow solid. LC/MS ESI (m/z): 325, 327 (M+H) ⁺ . Step 3.5-Bromo-4-chloro-7-(4-chloropyridin-2-yl)-7H-pyrrolo[2,3-d ]pyrimidine A mixture of 5-bromo-7-(4-chloropyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-ol (1.7 g, 5.2 mmol) and POCl ₃ (10 mL) was stirred at 120 ^o C under N ₂ overnight. After cooling to room temperature, solvents were removed. The residue was dissolved in DCM and washed with NaHCO ₃ (aq.). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30% ethyl acetate in petroleum ether) to afford 5-bromo-4-chloro-7-(4-chloropyridin-2-yl)-7H-pyrrolo[2,3- d]pyrimidine (1.2 g, 67%) as a light yellow solid. LC/MS ESI (m/z): 343, 345 (M+H) ⁺ . Step 4.5-Bromo-7-(4-chloropyridin-2-yl)-4-fluoro-7H-pyrrolo[2,3-d ]pyrimidine To a solution of 5-bromo-4-chloro-7-(4-chloropyridin-2-yl)-7H-pyrrolo[2,3- d]pyrimidine (800 mg, 2.3 mmol) in THF (1 mL) at 0 ^o C was added TBAF (10 ml, 1.0 M in THF). The resulting mixture was stirred room temperature for 1 h. The reaction was quenched with ice water and extracted with EtOAc. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30% ethyl acetate in petroleum ether) to afford 5-bromo-7-(4-chloropyridin-2- yl)-4-fluoro-7H-pyrrolo[2,3-d]pyrimidine (500 mg, 66%) as a light yellow solid. LC/MS ESI (m/z): 327, 329 (M+H) ⁺ . Step 5. tert-Butyl 4-(5-bromo-7-(4-cyanopyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidi n-4- yl)-4,7-diazaspiro[2.5]octane-7-carboxylate To a solution of 5-bromo-7-(4-chloropyridin-2-yl)-4-fluoro-7H-pyrrolo[2,3- d]pyrimidine (230 mg, 0.70 mmol) in DIEA (0.5 mL) was added tert-butyl 3,3- dimethylpiperazine-1-carboxylate (1.5 g, 7.0 mmol). The resulting mixture was stirred at 150 ^o C under N ₂ for 5 h. After cooling to room temperature, the reaction mixture was purified by flash column chromatography (silica gel, 0~40% ethyl acetate in petroleum ether) to afford tert-butyl 4-(5-bromo-7-(4-chloropyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimid in-4-yl)-3,3- dimethylpiperazine-1-carboxylate (120 mg, 33%) as a yellow solid. LC/MS ESI (m/z): 521, 523 (M+H) ⁺ . Step 6. tert-Butyl 4-(7-(4-chloropyridin-2-yl)-5-(2-oxopyrrolidin-1-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3,3-dimethylpiperazine-1-carbo xylate To a solution of tert-butyl 4-(5-bromo-7-(4-chloropyridin-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3,3-dimethylpiperazine-1-carboxylate (120 mg, 0.23 mmol) in DMF (5 mL) were added pyrrolidin-2-one (29 mg, 0.34 mmol), CuI (44 mg, 0.23 mmol), K ₃ PO ₄ (200 mg, 0.92 mmol) and trans-N ¹ ,N ² -dimethylcyclohexane-1,2-diamine (32 mg, 0.23 mmol). The resulting mixture was heated to 90 ^o C for 2 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 dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~70% ethyl acetate in petroleum ether) to give tert-butyl 4-(7-(4-chloropyridin-2-yl)-5-(2-oxopyrrolidin-1-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3,3-dimethylpiperazine-1-carbo xylate (70 mg, 62%). LC/MS ESI (m/z): 526 (M+H) ⁺ . Step 7. tert-Butyl 4-(7-(4-chloropyridin-2-yl)-5-(pyrrolidin-1-yl)-7H-pyrrolo[2 ,3- d]pyrimidin-4-yl)-3,3-dimethylpiperazine-1-carboxylate To a solution of tert-butyl 4-(7-(4-chloropyridin-2-yl)-5-(2-oxopyrrolidin-1-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3,3-dimethylpiperazine-1-carbo xylate (50 mg, 0.095 mmol) in THF (1 mL) at 0 ^o C was added BH ₃ (2.0 mL, 1.0 M in THF) dropwise. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with saturated NaHCO ₃ (aq.) and extracted twice with EtOAc. The combined organic phases were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography on silica gel (0~50% ethyl acetate in petroleum ether) to give tert-butyl 4-(7-(4-chloropyridin-2-yl)-5-(pyrrolidin-1-yl)-7H-pyrrolo[2 ,3-d]pyrimidin-4-yl)- 3,3-dimethylpiperazine-1-carboxylate (20 mg, 41%) as a yellow solid. LC/MS ESI (m/z): 512 (M+H) ⁺ . Step 8. tert-Butyl 4-(7-(4-cyanopyridin-2-yl)-5-(pyrrolidin-1-yl)-7H-pyrrolo[2, 3- d]pyrimidin-4-yl)-3,3-dimethylpiperazine-1-carboxylate To a solution of tert-butyl 4-(7-(4-chloropyridin-2-yl)-5-(pyrrolidin-1-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3,3-dimethylpiperazine-1-carbo xylate (20 mg, 0.039 mmol) in DMF (5 mL) were added Zn(CN)2 (23 mg, 0.20 mmol) and Pd(PPh3)4 (45 mg, 0.039 mmol). The resulting mixture was heated to 120 ^o C overnight. After cooling to room temperature, solvents were removed and the residue was purified by flash column chromatography (silica gel, 0~60% ethyl acetate in petroleum ether) and prep-HPLC to afford tert-butyl 4-(7-(4- cyanopyridin-2-yl)-5-(pyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyri midin-4-yl)-3,3- dimethylpiperazine-1-carboxylate (5.0 mg, 26%) as a yellow solid. LC/MS ESI (m/z): 503 (M+H) ⁺ . ¹ H NMR(400 MHz, CDCl ₃ ) δ 9.28 (s, 1H), 8.49 (d, J = 5.0 Hz, 1H), 8.43 (s, 1H), 7.52 (s, 1H), 7.21 (dd, J = 5.1, 0.9 Hz, 1H), 3.53 (s, 2H), 3.48 (d, J = 5.2 Hz, 2H), 3.29 (s, 2H), 3.09 (s, 4H), 1.91 (s, 4H), 1.53 (s, 6H), 1.43 (s, 9H). Example 180. Synthesis of 2-(methyl-d ₃ )propan-2-yl-1,1,1,3,3,3-d ₆ (2R,5R)-4-(7-(4- cyanopyridin-2-yl)-5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyri midin-4-yl)-2,5- dimethylpiperazine-1-carboxylate (Compound 602) 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) at 0 ^o C was added dropwise 2.0 M NaOH (0.53 L). The reaction was allowed to warm to room temperature and stirred for 3 hours. The precipitate was collected by filtration, washed twice with water and dried in vacuo to afford 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) ⁺ . Step 2. tert-Butyl (2R,5R)-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 (340 mg, 0.77 mmol) in DIPEA (0.41 mL, 2.3 mmol) was added tert-butyl (2R,5R)-2,5-dimethylpiperazine- 1-carboxylate (250 mg, 1.2 mmol). The resulting mixture was stirred at 150 ^o C for 2 h. After cooling to room temperature, the reaction was concentrated and purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford tert-butyl (2R,5R)-4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2 ,5-dimethylpiperazine-1- carboxylate (260 mg, 54%) as a yellow solid. LC/MS ESI (m/z): 612 (M+H) ⁺ . Step 3. tert-Butyl (2R,5R)-2,5-dimethyl-4-(7-tosyl-5-(trifluoromethyl)-7H-pyrro lo[2,3- d]pyrimidin-4-yl)piperazine-1-carboxylate To a solution of tert-butyl (2R,5R)-4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4- yl)-2,5-dimethylpiperazine-1-carboxylate (260 mg, 0.42 mmol) in DMF (5 mL) were added methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (0.16 mL, 1.30 mmol) and CuI (81 mg, 0.42 mmol). The resulting mixture was heated at 80 ^o 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford tert-butyl (2R,5R)-2,5-dimethyl-4-(7-tosyl-5-(trifluoromethyl)-7H-pyrro lo[2,3-d]pyrimidin-4- yl)piperazine-1-carboxylate (130 mg, 55%) as a yellow oil. LC/MS ESI (m/z): 554 (M+H) ⁺ . Step 4. tert-Butyl (2R,5R)-2,5-dimethyl-4-(5-(trifluoromethyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperazine-1-carboxylate To a solution of tert-butyl (2R,5R)-2,5-dimethyl-4-(7-tosyl-5-(trifluoromethyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (130 mg, 0.23 mmol) in THF (2 mL) was added TBAF (1.4 mL, 1.0 M in THF). The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to afford tert-butyl (2R,5R)-2,5-dimethyl-4-(5- (trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine -1-carboxylate (90 mg, 95%) as a yellow oil. LC/MS ESI (m/z): 400 (M+H) ⁺ . Step 5. tert-Butyl (2R,5R)-4-(7-(4-cyanopyridin-2-yl)-5-(trifluoromethyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate To a solution of tert-butyl (2R,5R)-2,5-dimethyl-4-(5-(trifluoromethyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (90 mg, 0.22 mmol) in DMF (5 mL) were added 2-fluoroisonicotinonitrile (55 mg, 0.45 mmol) and Cs ₂ CO ₃ (220.2 mg, 0.67 mmol). The resulting mixture was heated to 50 ^o C for 1 h. 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~20%, ethyl acetate in petroleum ether) to afford tert-butyl (2R,5R)-4-(7-(4- cyanopyridin-2-yl)-5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyri midin-4-yl)-2,5- dimethylpiperazine-1-carboxylate (80 mg, 70%) as a yellow oil. LC/MS ESI (m/z): 502 (M+H) ⁺ . Step 6.2-(4-((2R,5R)-2,5-Dimethylpiperazin-1-yl)-5-(trifluorometh yl)-7H- pyrrolo[2,3-d]pyrimidin-7-yl)isonicotinonitrile To a solution of tert-butyl (2R,5R)-4-(7-(4-cyanopyridin-2-yl)-5-(trifluoromethyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-ca rboxylate (80 mg, 0.16 mmol) in DCM (2 mL) was added HCl/dioxane (1.0 mL, 4.0M). The resulting mixture was stirred at room temperature for 2 h. After removal of 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 Na ₂ SO ₄ , filtered and concentrated. The residue was used directly in the next step. LC/MS ESI (m/z): 402 (M+H) ⁺ . Step 7.2-(Methyl-d3)propan-2-yl-1,1,1,3,3,3-d6 (2R,5R)-4-(7-(4-cyanopyridin-2-yl)-5- (trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimet hylpiperazine-1-carboxylate To a solution of 2-(4-((2R,5R)-2,5-dimethylpiperazin-1-yl)-5-(trifluoromethyl )-7H- pyrrolo[2,3-d]pyrimidin-7-yl)isonicotinonitrile (60 mg, 0.15 mmol) in DMF (2 mL) were added 2-(methyl-d ₃ )propan-2-yl-1,1,1,3,3,3-d ₆ pyridin-2-yl carbonate (3.0 eq., prepared following the procedure outlined for compound 625) and DIPEA (1 mL). The resulting mixture was heated to 80 ^o 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~20%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep- HPLC to afford 2-(methyl-d ₃ )propan-2-yl-1,1,1,3,3,3-d ₆ (2R,5R)-4-(7-(4-cyanopyridin-2-yl)- 5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dim ethylpiperazine-1-carboxylate (37 mg, 48%) as a white solid. LC/MS ESI (m/z): 511 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.27 (s, 1H), 8.61 – 8.58 (m, 2H), 8.56 (s, 1H), 7.41 (dd, J = 5.0, 1.2 Hz, 1H), 4.44 – 4.35 (m, 1H), 4.04 – 3.88 (m, 2H), 3.58 (dd, J = 13.2, 5.4 Hz, 1H), 3.27 (dd, J = 13.2, 8.2 Hz, 1H), 2.99 (dd, J = 13.9, 11.5 Hz, 1H), 1.14 (d, J = 6.3 Hz, 3H), 1.02 (d, J = 6.2 Hz, 3H). The following compound was prepared by a procedure analogous to the synthesis of compound 602 from the corresponding chiral amine.

Example 181. Synthesis of 1-(trifluoromethyl)cyclobutyl (2R,5S)-4-(7-(4-cyanopyridin-2- yl)-5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5 -dimethylpiperazine-1- carboxylate (Compound 604) Step 1.1-(Trifluoromethyl)cyclobutan-1-ol To a solution of cyclobutanone (500 mg, 7.1 mmol) in THF (5 mL) were added trimethyl(trifluoromethyl)silane (1200 mg, 8.6 mmol), and TBAF (0.10 mL, 1.0 M in THF). After stirring at room temperature for 2 h, the mixture was treated with 6 M HCl (1.6 mL) and stirred for 1 h. The reaction was dried over Na ₂ SO ₄ and filtered. The filtrate was used directly in the next step. Step 2.1-(Trifluoromethyl)cyclobutyl 1H-imidazole-1-carboxylate The solution of 1-(trifluoromethyl)cyclobutan-1-ol (filtrate) was treated with of DCE (20 mL) and CDI (1300 mg, 8.0 mmol). The resulting mixture was heated to 70℃ overnight. After cooling to room temperature, solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~30% ethyl acetate in petroleum ether) to afford 1- (trifluoromethyl)cyclobutyl 1H-imidazole-1-carboxylate (200 mg) as a solid. LCMS ESI (m/z): 235 (M+H) ⁺ . Step 3.1-(Trifluoromethyl)cyclobutyl (2R,5S)-4-(7-(4-cyanopyridin-2-yl)-5- (trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimet hylpiperazine-1-carboxylate To a solution of 1-(trifluoromethyl)cyclobutyl 1H-imidazole-1-carboxylate (70 mg, 0.30 mmol) in DMF (5 mL) were added 2-(4-((2S,5R)-2,5-dimethylpiperazin-1-yl)-5- (trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)isonicotin onitrile (40 mg, 0.10 mmol, prepared following a similar procedure outlined for compound 602) and DIPEA (200 mg, 1.6 mmol). The resulting mixture was heated to 120 ^o 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~35% ethyl acetate in petroleum ether) to give crude product, which was further purified by prep-HPLC to afford 1-(trifluoromethyl)cyclobutyl (2R,5S)-4- (7-(4-cyanopyridin-2-yl)-5-(trifluoromethyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2,5- dimethylpiperazine-1-carboxylate (15 mg, 27%) as a white solid. LC/MS ESI (m/z): 568 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.27 (s, 1H), 8.63 – 8.57 (m, 2H), 8.52 (s, 1H), 7.42 (dd, J = 5.0, 1.2 Hz, 1H), 4.61 – 4.20 (m, 2H), 3.76 – 3.58 (m, 3H), 3.47 – 3.37 (m, 1H), 2.87 – 2.71 (m, 2H), 2.57 – 2.44 (m, 2H), 1.97 – 1.91 (m, 1H), 1.86 – 1.77 (m, 1H), 1.09 (s, 6H).

Example 182. Synthesis of 1-methylcyclobutyl (2R,5S)-4-(7-(4-cyanopyridin-2-yl)-5- (difluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimeth ylpiperazine-1- carboxylate (Compound 605) Compound 605 Step 1. tert-Butyl (2R,5S)-4-(7-(4-cyanopyridin-2-yl)-5-formyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate To a solution of tert-butyl (2R,5S)-4-(5-formyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5- dimethylpiperazine-1-carboxylate (760 mg, 2.1 mmol, prepared following the procedure outlined for compound 635) in DMF (10 mL) were added 2-fluoroisonicotinonitrile (520 mg, 4.2 mmol) and Cs ₂ CO ₃ (2100 mg, 6.3 mmol). The resulting mixture was stirred at 50 ^o 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-4-(7-(4-cyanopyridin-2-yl)-5-formyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (720 mg, 73%) as a yellow solid. LC/MS ESI (m/z): 462 (M+H) ⁺ . Step 2. tert-Butyl (2R,5S)-4-(7-(4-cyanopyridin-2-yl)-5-(difluoromethyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate To a solution of tert-butyl (2R,5S)-4-(7-(4-cyanopyridin-2-yl)-5-formyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate (720 mg, 1.6 mmol) in DCM (5 mL) at 0 ^o C was added BAST (2.8 mL, 16 mmol) dropwise. After stirring at room temperature overnight, the reaction was quenched with NaHCO ₃ (aq.). The aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , concentrated and purified by flash column chromatography (silica gel, 0~20%, ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-4-(7-(4-cyanopyridin-2-yl)-5- (difluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimeth ylpiperazine-1-carboxylate (440 mg, 58%) as a white solid. LC/MS ESI (m/z): 484 (M+H) ⁺ . Step 3.2-(5-(Difluoromethyl)-4-((2S,5R)-2,5-dimethylpiperazin-1-y l)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)isonicotinonitrile To a solution of tert-butyl (2R,5S)-4-(7-(4-cyanopyridin-2-yl)-5-(difluoromethyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate (280 mg, 0.57 mmol) in DCM (10 mL) at 0 ^o C was added HCl/dioxane (5.0 mL, 4.0M). After stirring at room temperature for 2 h, the reaction was quenched with NaHCO ₃ (aq.). The aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , concentrated, and purified by flash column chromatography (silica gel, 0~10%, methanol in dichloromethane) to afford 2-(5-(difluoromethyl)-4-((2S,5R)-2,5- dimethylpiperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ison icotinonitrile (150 mg, 67%) as a yellow solid. LC/MS ESI (m/z): 384 (M+H) ⁺ . Step 4.1-Methylcyclobutyl pyridin-2-yl carbonate To a solution of 1-methylcyclobutan-1-ol (100 mg, 1.2 mmol) in DCM (5 mL) were added di(pyridin-2-yl) carbonate (250 mg, 1.2 mmol) and DMAP (43 mg, 0.34 mmol). After stirring at room temperature overnight, the solvents were removed and the residue was used directly in the next step. Step 5.1-Methylcyclobutyl (2R,5S)-4-(7-(4-cyanopyridin-2-yl)-5-(difluoromethyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate To a solution of 2-(5-(difluoromethyl)-4-((2S,5R)-2,5-dimethylpiperazin-1-yl) -7H- pyrrolo[2,3-d]pyrimidin-7-yl)isonicotinonitrile (45 mg, 0.11 mmol) in DMF (2 mL) were added 1-methylcyclobutyl pyridin-2-yl carbonate (1.0 mL, 0.23 mmol) and DIPEA (0.50 mL, 0.11 mmol). The resulting mixture was stirred at 80℃ 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by prep-HPLC to afford 1- methylcyclobutyl (2R,5S)-4-(7-(4-cyanopyridin-2-yl)-5-(difluoromethyl)-7H-pyr rolo[2,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (17 mg, 29%) as a white solid. LC/MS ESI (m/z): 496 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl3) δ 9.27 (s, 1H), 8.58 (d, J = 4.9 Hz, 1H), 8.50 (s, 1H), 8.45 (s, 1H), 7.38 (d, J = 4.9 Hz, 1H), 6.89 (t, J = 55.6 Hz, 1H), 4.56 – 4.47 (m, 1H), 4.41 – 4.25 (m, 1H), 3.76 – 3.66 (m, 2H), 3.56 (m, 1H), 3.46 (d, J = 13.1 Hz, 1H), 2.27 (m, 2H), 2.15 – 2.04 (m, 2H), 1.80 – 1.70 (m, 1H), 1.64 – 1.55 (m, 1H), 1.52 (s, 3H), 1.12 (d, J = 6.6 Hz, 3H), 1.07 (d, J = 6.8 Hz, 3H). The following compounds were prepared by procedures similar to the synthesis of compound 605 from the corresponding chiral amine and alcohol (Aryl groups of compound 607 and compound 608 were introduced via Ullmann coupling conditions).

Example 183. Synthesis of tert-butyl (S)-4-(1-(4-cyanopyridin-2-yl)-3-(1- methylcyclopropyl)-1H-pyrrolo[3,2-c]pyridin-4-yl)-3-methylpi perazine-1-carboxylate (Compound 612) p Step 1.3-Bromo-1-(phenylsulfonyl)-1H-pyrrolo[3,2-c]pyridine To a suspension of NaH (610 mg, 15 mmol, 60 wt%) in anhydrous DMF (10 mL) at 0 ^o C was added 3-bromo-1H-pyrrolo[3,2-c]pyridine (2.0 g, 10 mmol) in portions, followed by benzenesulfonyl chloride (2.0 g, 11 mmol) dropwise. After stirring at room temperature for 2 h, the reaction was poured into ice water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~40% ethyl acetate in petroleum ether) to afford 3-bromo-1-(phenylsulfonyl)-1H-pyrrolo[3,2-c]pyridine (3.0 g , 89%) as a solid. LC/MS ESI (m/z): 337, 339 (M+H) ⁺ . Step 2.1-(Phenylsulfonyl)-3-(prop-1-en-2-yl)-1H-pyrrolo[3,2-c]pyr idine To a solution of 3-bromo-1-(phenylsulfonyl)-1H-pyrrolo[3,2-c]pyridine (3.0 g , 8.9 mmol) in dioxane (30 mL) and water (1 mL) were added 4,4,5,5-tetramethyl-2-(prop-1-en-2- yl)-1,3,2-dioxaborolane (2.2 g, 13 mmol), K ₂ CO ₃ (3.7 g, 27 mmol) and Pd(dppf)Cl ₂ (650 mg, 0.80 mmol), the resulting mixture was heated to 80 ^o C overnight. After cooling to room temperature, solvents were removed and the residue was purified by flash column chromatography (silica gel, 0~40% ethyl acetate in petroleum ether) to afford 1- (phenylsulfonyl)-3-(prop-1-en-2-yl)-1H-pyrrolo[3,2-c]pyridin e (2.0 g, 76%) as a solid. LC/MS ESI (m/z): 299 (M+H) ⁺ . Step 3.1-(Phenylsulfonyl)-3-(prop-1-en-2-yl)-1H-pyrrolo[3,2-c]pyr idine To a solution of Et ₂ Zn (17 mL, 1.0 M in toluene) in DCM (8 mL) at 0℃ was added dropwise a solution of CH ₂ I ₂ (0.72 mL, 8.5 mmol) in DCM (2 mL). After 20 min, a solution of 1-(phenylsulfonyl)-3-(prop-1-en-2-yl)-1H-pyrrolo[3,2-c]pyrid ine (500 mg, 1.7 mmol) in DCM (5 mL) was added dropwise. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with NH ₄ Cl (aq.) 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, 0~30%, ethyl acetate in petroleum ether) to afford 3-(1-methylcyclopropyl)-1-(phenylsulfonyl)-1H- pyrrolo[3,2-c]pyridine (310 mg, 60%) as a solid. LC/MS ESI (m/z): 313 (M+H) ⁺ . Step 4.3-(1-Methylcyclopropyl)-1-(phenylsulfonyl)-1H-pyrrolo[3,2- c]pyridine 5- oxide To a solution of 3-(1-methylcyclopropyl)-1-(phenylsulfonyl)-1H-pyrrolo[3,2- c]pyridine (1.2 g, 3.9 mmol) in DCM (15 ml) at 0 ^o C was added 3-chlorobenzoperoxoic acid (1.3 g, 7.7 mmol) in portions. The resulting mixture was stirred at room temperature under N ₂ overnight. The reaction was diluted with H ₂ O and extracted twice with DCM. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~15% MeOH in DCM) to afford 3-(1-methylcyclopropyl)-1-(phenylsulfonyl)-1H-pyrrolo[3,2-c] pyridine 5-oxide (950 mg, 75%) as a yellow solid. LC/MS ESI (m/z): 329 (M+H) ⁺ . Step 5. tert-Butyl (S)-3-methyl-4-(3-(1-methylcyclopropyl)-1-(phenylsulfonyl)-1 H- pyrrolo[3,2-c]pyridin-4-yl)piperazine-1-carboxylate To a solution of 3-(1-methylcyclopropyl)-1-(phenylsulfonyl)-1H-pyrrolo[3,2- c]pyridine 5-oxide (330 mg, 1.0 mmol, tert-butyl (S)-3-methylpiperazine-1-carboxylate (1.0 g, 5.0 mmol) and DIPEA (480 mg, 3.8 mmol) in DCM (10 mL) was added PyBroP (610 mg, 1.3 mmol) in portions. The resulting mixture was stirred at room temperature under N ₂ overnight. 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50% ethyl acetate in petroleum ether) to afford tert-butyl (S)- 3-methyl-4-(3-(1-methylcyclopropyl)-1-(phenylsulfonyl)-1H-py rrolo[3,2-c]pyridin-4- yl)piperazine-1-carboxylate (120 mg, 24% yield) as a withe solid. LC/MS ESI (m/z): 511 (M+H) ⁺ . Step 6. tert-Butyl (S)-3-methyl-4-(3-(1-methylcyclopropyl)-1-(phenylsulfonyl)-1 H- pyrrolo[3,2-c]pyridin-4-yl)piperazine-1-carboxylate To a solution of tert-butyl (S)-3-methyl-4-(3-(1-methylcyclopropyl)-1- (phenylsulfonyl)-1H-pyrrolo[3,2-c]pyridin-4-yl)piperazine-1- carboxylate (120 mg, 0.24 mmol) in THF (1 mL) was added TBAF (2.4 mL, 1.0 M in THF). After stirring at room temperature under N ₂ for 2 h, the reaction was partitioned between EtOAc and brine. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to afford crude tert-butyl (S)-3- methyl-4-(3-(1-methylcyclopropyl)-1H-pyrrolo[3,2-c]pyridin-4 -yl)piperazine-1-carboxylate (340 mg that contained TBAF-related impurities) as light yellow oil. LC/MS ESI (m/z): 371 (M+H) ⁺ . Step 7. tert-Butyl (S)-4-(1-(4-cyanopyridin-2-yl)-3-(1-methylcyclopropyl)-1H- pyrrolo[3,2-c]pyridin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl (S)-3-methyl-4-(3-(1-methylcyclopropyl)-1H-pyrrolo[3,2- c]pyridin-4-yl)piperazine-1-carboxylate (340 mg that contained TBAF-related impurities, ~0.20 mmol) and 2-fluoroisonicotinonitrile (120 mg, 1.0 mmol) in DMF (1 mL) was added Cs ₂ CO ₃ (330 mg, 1.0 mmol). After stirring at room temperature under N ₂ overnight, the reaction was partitioned between EtOAc and NH ₄ Cl (aq.). The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~40% ethyl acetate in petroleum ether) and prep-HPLC to afford tert-butyl (S)-4-(1-(4- cyanopyridin-2-yl)-3-(1-methylcyclopropyl)-1H-pyrrolo[3,2-c] pyridin-4-yl)-3- methylpiperazine-1-carboxylate (62 mg, 66% yield) as a white solid. LC/MS ESI (m/z): 473. (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.72 (d, J = 5.0 Hz, 1H), 8.22 (d, J = 5.8 Hz, 1H), 7.89 (d, J = 5.8 Hz, 1H), 7.64 (s, 1H), 7.42 (s, 1H), 7.39 (d, J = 5.0 Hz, 1H), 3.88 (s, 2H), 3.77 (s, 1H), 3.54 (t, J = 9.8 Hz, 1H), 3.41 (s, 1H), 3.17 (dd, J = 12.2, 8.1 Hz, 1H), 3.03 (t, J = 9.0 Hz, 1H), 1.65 (s, 3H), 1.50 (s, 9H), 1.17 – 1.09 (m, 1H), 0.99 (d, J = 6.1 Hz, 3H), 0.90 – 0.84 (m, 1H), 0.75 (m, 2H). Example 184. Synthesis of 1-methylcyclopropyl (2R,5S)-4-(7-(4-cyanopyridin-2-yl)-5- (difluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimeth ylpiperazine-1- carboxylate (Compound 613) Compound 613 To a solution of 1-methylcyclopropan-1-ol (100 mg, 1.4 mmol) and DIPEA (0.10 mL) in DCE (2 mL) at 0℃ was added triphosgene (70 mg, 0.23 mmol). After stirring at room temperature for 30 min, 2-(5-(difluoromethyl)-4-((2S,5R)-2,5-dimethylpiperazin-1-yl) -7H- pyrrolo[2,3-d]pyrimidin-7-yl)isonicotinonitrile (30 mg, 0.078 mmol, prepared following the procedure outlined for compound 605) was added. After 3 h, the reaction 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 ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford 1- methylcyclopropyl (2R,5S)-4-(7-(4-cyanopyridin-2-yl)-5-(difluoromethyl)-7H-pyr rolo[2,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (12 mg, 15%) as a white solid. LC/MS ESI (m/z): 482 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.27 (s, 1H), 8.58 (d, J = 5.0 Hz, 1H), 8.50 (s, 1H), 8.45 (s, 1H), 7.38 (d, J = 5.0 Hz, 1H), 6.88 (t, J = 55.6 Hz, 1H), 4.57 – 4.46 (m, 1H), 4.44 – 4.14 (m, 1H), 3.76 – 3.62 (m, 2H), 3.55 (dd, J = 13.4, 3.6 Hz, 1H), 3.45 (d, J = 13.2 Hz, 1H), 1.51 (s, 3H), 1.10 (d, J = 6.6 Hz, 3H), 1.05 (d, J = 6.8 Hz, 3H), 0.85 – 0.80 (m, 2H), 0.62 – 0.56 (m, 2H). Example 185. Synthesis of 1-(trifluoromethyl)cyclobutyl (2R,5S)-4-(7-(4-cyanopyridin-2- yl)-5-(difluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5- dimethylpiperazine-1- carboxylate (Compound 614) C ^{ompound 614} To a solution of 2-(5-(difluoromethyl)-4-((2S,5R)-2,5-dimethylpiperazin-1-yl) -7H- pyrrolo[2,3-d]pyrimidin-7-yl)isonicotinonitrile (20 mg, 0.052 mmol, prepared following the procedure outlined for compound 605) in DMF (2 mL) were added 1- (trifluoromethyl)cyclobutyl 1H-imidazole-1-carboxylate (18 mg, 0.078 mmol, prepared following the procedure outlined for compound 604) and DIPEA (0.10 mL, 0.052 mmol). The resulting mixture was stirred at 120℃ overnight. After cooling to room temperature, the reaction was partitioned between EtOAc and water. The aqueous layer was extracted twice with EtOAc twice. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30% ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford 1-(trifluoromethyl)cyclobutyl (2R,5S)-4-(7-(4-cyanopyridin-2-yl)-5- (difluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimeth ylpiperazine-1-carboxylate (10 mg, 36%) as a white solid. LC/MS ESI (m/z): 550 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.27 (s, 1H), 8.59 (d, J = 5.0 Hz, 1H), 8.51 (s, 1H), 8.45 (s, 1H), 7.39 (d, J = 5.0 Hz, 1H), 6.88 (t, J = 55.6 Hz, 1H), 4.60 – 4.45 (m, 1H), 4.44 – 4.20 (m, 1H), 3.78 – 3.57 (m, 3H), 3.48 (d, J = 13.4 Hz, 1H), 2.88 – 2.69 (m, 2H), 2.56 – 2.40 (m, 2H), 2.01 – 1.87 (m, 1H), 1.87 – 1.76 (m, 1H), 1.13 – 1.08 (m, 6H). Example 186. Synthesis of tert-butyl (3S)-4-(7-(4-cyanopyridin-2-yl)-5-(2- methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methyl piperazine-1-carboxylate (Compound 615) Step 1. (E)-4-Methoxy-7-(phenylsulfonyl)-5-(prop-1-en-1-yl)-7H-pyrro lo[2,3- d]pyrimidine To a solution of 5-iodo-4-methoxy-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimid ine (690 mg, 1.8 mmol) in dioxane (10 mL) and H ₂ O (1 mL) were added (E)-prop-1-en-1- ylboronic acid (200 mg, 2.3 mmol), K ₂ CO ₃ (990 mg, 7.2 mmol) and Pd(dppf)Cl ₂ (130 mg, 0.18 mmol). The resulting mixture was heated to 80 ^o C overnight. After cooling to room temperature, solvents were removed and the residue was purified by flash column chromatography (silica gel, 0~20%, ethyl acetate in petroleum ether) to afford (E)-4- methoxy-7-(phenylsulfonyl)-5-(prop-1-en-1-yl)-7H-pyrrolo[2,3 -d]pyrimidine (300 mg, 49%) as a yellow solid. LC/MS ESI (m/z): 330 (M+H) ⁺ . Step 2.4-Methoxy-5-(2-methylcyclopropyl)-7-(phenylsulfonyl)-7H-py rrolo[2,3- d]pyrimidine To a solution of Et ₂ Zn (9.2 mL, 1.0 M in toluene) in DCM (2 mL) at 0 ^o C was added CH ₂ I ₂ (1.2 g, 4.6 mmol) dropwise. After 30 min, a solution of (E)-4-methoxy-7- (phenylsulfonyl)-5-(prop-1-en-1-yl)-7H-pyrrolo[2,3-d]pyrimid ine (300 mg, 0.91 mmol) in DCM (10 mL) was added dropwise. The resulting mixture was stirred 0 ^o C for 1 h and then warmed to room temperature overnight. The reaction was quenched with NH ₄ Cl (aq.) and extracted twice with DCM. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~20% ethyl acetate in petroleum ether) to afford 4-methoxy-5-(2- methylcyclopropyl)-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrim idine (150 mg, 48%) as a yellow solid. LC/MS ESI (m/z): 344 (M+H) ⁺ . Step 3.4-Methoxy-5-(2-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimid ine To a solution of 4-methoxy-5-(2-methylcyclopropyl)-7-(phenylsulfonyl)-7H- pyrrolo[2,3-d]pyrimidine (150 mg, 0.44 mmol) in THF (3 mL) was added TBAF (3.9 mL, 1.0 M in THF). After stirring at 50 ^o C for 1 h, the reaction was diluted with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~60%, ethyl acetate in petroleum ether) to give 4-methoxy-5-(2-methylcyclopropyl)- 7H-pyrrolo[2,3-d]pyrimidine (80 mg, 90%) as a yellow solid. LC/MS ESI (m/z): 204 (M+H) ⁺ . Step 4.2-(4-Methoxy-5-(2-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyri midin-7- yl)isonicotinonitrile To a solution of 4-methoxy-5-(2-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidin e (40 mg, 0.20 mmol) in DMF (10 mL) were added 2-fluoroisonicotinonitrile (49 mg, 0.40 mmol) and Cs ₂ CO ₃ (650 mg, 2.0 mmol). After stirring at 50 ^o C for 1 h, the reaction was quenched with ice water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to give 2- (4-methoxy-5-(2-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidi n-7-yl)isonicotinonitrile (50 mg, 82%) as a yellow solid. LC/MS ESI (m/z): 306 (M+H) ⁺ . Step 5.2-(4-Hydroxy-5-(2-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyri midin-7- yl)isonicotinonitrile To a solution of 2-(4-methoxy-5-(2-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimi din- 7-yl)isonicotinonitrile (50 mg, 0.16 mmol) in DMF (2 mL) were added p-toluenesulfonic acid (280 mg, 1.6 mmol) and LiCl (67 mg, 1.6 mmol). The resulting mixture was heated to 110 ^o C for 2 h. 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 Na ₂ SO ₄ , filtered, and concentrated to afford 2-(4-hydroxy-5-(2-methylcyclopropyl)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)isonicotinonitrile (40 mg, 85%) as a yellow solid. LC/MS ESI (m/z): 292 (M+H) ⁺ . Step 6.2-(4-Chloro-5-(2-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrim idin-7- yl)isonicotinonitrile A mixture of 2-(4-hydroxy-5-(2-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimi din-7- yl)isonicotinonitrile (40 mg, 0.14 mmol) and POCl ₃ (5 mL) was heated to 120 ^o C for 2 h. After cooling to room temperature, solvent was removed. The residue was dissolved in DCM, washed with NaHCO ₃ (aq.), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was used directly in the next step. LC/MS ESI (m/z): 310 (M+H) ⁺ . Step 7. tert-Butyl (3S)-4-(7-(4-cyanopyridin-2-yl)-5-(2-methylcyclopropyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te To a solution of 2-(4-chloro-5-(2-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimid in-7- yl)isonicotinonitrile (25 mg, 0.080 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 150 ^o C for 6 h. After cooling to room temperature, solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~20%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford tert-butyl (3S)-4-(7-(4-cyanopyridin-2-yl)-5-(2-methylcyclopropyl)-7H-p yrrolo[2,3-d]pyrimidin-4-yl)- 3-methylpiperazine-1-carboxylate (3.6 mg, 9.0%) as a white solid. LC/MS ESI (m/z): 474 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.25 (s, 1H), 8.52 (dd, J = 8.7, 5.0 Hz, 1H), 8.43 (s, 1H), 7.89 – 7.62 (m, 1H), 7.28 (t, J = 6.0 Hz, 1H), 4.85 – 4.56 (m, 1H), 4.14 – 3.87 (m, 2H), 3.82 – 3.72 (m, 1H), 3.54 – 3.29 (m, 2H), 3.14 – 2.97 (m, 1H), 2.00 – 1.90 (m, 1H), 1.69 – 1.56 (m, 2H), 1.43 (s, 9H), 1.42 – 1.39 (m, 1H), 1.15 – 1.09 (m, 3H), 0.82 – 0.69 (m, 3H). The following compound was prepared by procedures analogous to the synthesis of compound 615using the corresponding 3-iodobenzonitrile using standard Ullmann coupling conditions.

Example 187. Synthesis of tert-butyl (2R,5S)-4-(7-(4-cyanopyrimidin-2-yl)-5-(2,2,2- trifluoroethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethy lpiperazine-1-carboxylate (Compound 617) p Step 1.4-Chloro-7-trityl-7H-pyrrolo[2,3-d]pyrimidine-5-carbaldehy de To a suspension of NaH (1.2 g, 30 mmol, 60 wt%) in anhydrous DMF (15 mL) at 0 ^o C was added 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde (1.1 g, 6.1 mmol) in portions, followed by trityl chloride (3.4 g, 12 mmol) in portions. The resulting mixture was stirred at room temperature for 3 h. The reaction was poured into ice water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford 4-chloro-7-trityl-7H-pyrrolo[2,3- d]pyrimidine-5-carbaldehyde (1.9 g , 74%) as a light yellow solid. LC/MS ESI (m/z): 424 (M+H) ⁺ . Step 2.4-Chloro-5-(2,2-difluorovinyl)-7-trityl-7H-pyrrolo[2,3-d]p yrimidine To a solution of 4-chloro-7-trityl-7H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde (1.1 g, 2.6 mmol) in DMF (15 ml) was added 2,2-difluoro-2-(triphenylphosphonio)acetate (1.9 g, 5.2 mmol). The resulting mixture was stirred at 60 ^o C under N ₂ for 4 h. The reaction was quenched with H ₂ O and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to afford 4-chloro-5-(2,2-difluorovinyl)-7-trityl-7H-pyrrolo[2,3-d]pyr imidine (800 mg, 67%) as a yellow solid. LC/MS ESI (m/z): 458 (M+H) ⁺ . Step 3. tert-Butyl (2R,5S)-4-(5-(2,2-difluorovinyl)-7-trityl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate A mixture of 4-chloro-5-(2,2-difluorovinyl)-7-trityl-7H-pyrrolo[2,3-d]pyr imidine (800 mg, 1.8 mmol) and tert-butyl (2R,5S)-2,5-dimethylpiperazine-1-carboxylate (1.9 g, 8.7 mmol) was stirred at 150 ^o C for 3 h. After cooling to room temperature, the reaction was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-4-(5-(2,2-difluorovinyl)-7-trityl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (310 mg, 28%) as a white solid. LC/MS ESI (m/z): 636 (M+H) ⁺ . Step 4. tert-Butyl (2R,5S)-2,5-dimethyl-4-(5-(2,2,2-trifluoroethyl)-7-trityl-7H - pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate To a solution of tert-butyl (2R,5S)-4-(5-(2,2-difluorovinyl)-7-trityl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (310 mg, 0.49 mmol) in THF (2 mL) was added TBAF (5.0 mL, 1.0M in THF). After stirring 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 in petroleum ether) to afford tert-butyl (2R,5S)-2,5-dimethyl-4-(5-(2,2,2-trifluoroethyl)-7-trityl-7H -pyrrolo[2,3- d]pyrimidin-4-yl)piperazine-1-carboxylate (210 mg, 66%) as a yellow solid. LC/MS ESI (m/z): 656 (M+H) ⁺ . Step 5. tert-Butyl (2R,5S)-2,5-dimethyl-4-(5-(2,2,2-trifluoroethyl)-7H-pyrrolo[ 2,3- d]pyrimidin-4-yl)piperazine-1-carboxylate To a solution of tert-butyl (2R,5S)-2,5-dimethyl-4-(5-(2,2,2-trifluoroethyl)-7-trityl- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (210 mg, 0.32 mmol) in DCM (5 mL) was added TFA (1.0 ml). The resulting mixture was stirred at room temperature for 3 h. The reaction was quenched with NaHCO ₃ (aq.) and extracted twice with DCM. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to afford 4- ((2S,5R)-2,5-dimethylpiperazin-1-yl)-5-(2,2,2-trifluoroethyl )-7H-pyrrolo[2,3-d]pyrimidine (85 mg, 85%) as a light yellow solid. LC/MS ESI (m/z): 314 (M+H) ⁺ . To a solution of 4-((2S,5R)-2,5-dimethylpiperazin-1-yl)-5-(2,2,2-trifluoroeth yl)-7H- pyrrolo[2,3-d]pyrimidine (85 mg, 0.27 mmol) in DCM (5 ml) were added di-tert-butyl dicarbonate (120 mg, 0.54 mmol) and TEA (82 mg, 0.81 mmol). After stirring at room temperature for 3 h, 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, 0~70%, ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-2,5-dimethyl-4-(5-(2,2,2- trifluoroethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1 -carboxylate (80 mg, 71%) as a white solid. LC/MS ESI (m/z): 414 (M+H) ⁺ . Step 6. tert-Butyl (2R,5S)-4-(7-(4-cyanopyrimidin-2-yl)-5-(2,2,2-trifluoroethyl )-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate To a solution of tert-butyl (2R,5S)-2,5-dimethyl-4-(5-(2,2,2-trifluoroethyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (40 mg, 0.10 mmol) in dioxane (10 mL) were added 2-bromopyrimidine-4-carbonitrile (36 mg, 0.19 mmol), Pd ₂ (dba) ₃ (44 mg, 0.05 mmol), X-Phos (56 mg, 0.09 mmol) and Cs ₂ CO ₃ (95 mg, 0.29 mmol). The resulting mixture was stirred at 100 ^o 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 dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0~50% ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford tert-butyl (2R,5S)-4- (7-(4-cyanopyrimidin-2-yl)-5-(2,2,2-trifluoroethyl)-7H-pyrro lo[2,3-d]pyrimidin-4-yl)-2,5- dimethylpiperazine-1-carboxylate (5.0 mg, 11%) as a white solid. LC/MS ESI (m/z): 517 (M+H) ⁺ . ¹ H NMR(400 MHz, CDCl ₃ ) δ 9.08 (d, J = 4.8 Hz, 1H), 8.63 (s, 1H), 8.05 (s, 1H), 7.47 (d, J = 4.8 Hz, 1H), 4.35 – 4.23 (m, 2H), 3.81 – 3.69 (m, 2H), 3.64 – 3.54 (m, 3H), 3.28 – 3.22 (m, 1H), 1.42 (s, 9H), 1.08 (d, J = 6.6 Hz, 3H), 1.04 (d, J = 6.8 Hz, 3H). Example 188. Synthesis of tert-butyl (2R,5S)-4-(7-(6-cyanopyrimidin-4-yl)-5-(2,2,2- trifluoroethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethy lpiperazine-1-carboxylate (Compound 618) C ^{ompound 618} To a solution of tert-butyl (2R,5S)-2,5-dimethyl-4-(5-(2,2,2-trifluoroethyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (40 mg, 0.10 mmol, prepared following the procedure outlined for compound 617) in DMF (5 mL) were added 6- chloropyrimidine-4-carbonitrile (27 mg, 0.19 mmol) and Cs ₂ CO ₃ (95 mg, 0.29 mmol). After stirring at room temperature overnight, the reaction was quenched with H ₂ O (50 mL) and extracted twice with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50% ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford tert-butyl (2R,5S)-4-(7-(6-cyanopyrimidin-4-yl)-5-(2,2,2- trifluoroethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethy lpiperazine-1-carboxylate (16 mg, 30%) as a white solid. LC/MS ESI (m/z): 517 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.50 (s, 1H), 9.05 (s, 1H), 8.52 (s, 1H), 8.20 (s, 1H), 4.36 – 4.27 (m, 2H), 3.79 – 3.69 (m, 2H), 3.63 – 3.53 (m, 3H), 3.30 – 3.25 (m, 1H), 1.43 (s, 9H), 1.10 (d, J = 6.6 Hz, 3H), 1.03 (d, J = 6.8 Hz, 3H). The following compound was prepared by a procedure analogous to the synthesis of compound 618 from the corresponding aryl halide.

Example 189. Synthesis of tert-butyl (2R,5S)-4-(1-(4-cyanopyridin-2-yl)-3- (trifluoromethyl)-1H-pyrrolo[3,2-c]pyridin-4-yl)-2,5-dimethy lpiperazine-1-carboxylate (Compound 620) Step 1.3-Iodo-1-tosyl-1H-pyrrolo[3,2-c]pyridine To a suspension of NaH (740 mg, 18 mmol, 60 wt%) in anhydrous DMF (10 mL) at 0 ^o C was added 3-iodo-1H-pyrrolo[3,2-c]pyridine (1.5 g, 6.2 mmol) in portions, followed by 4-methylbenzenesulfonyl chloride (1.8 g, 9.2 mmol) in portions. After 10 min, the reaction was poured into ice water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30% ethyl acetate in petroleum ether) to afford 3-iodo-1-tosyl-1H-pyrrolo[3,2-c]pyridine (2.2 g , 89%) as a light yellow solid. LC/MS ESI (m/z): 399 (M+H) ⁺ . Step 2.3-Iodo-1-tosyl-1H-pyrrolo[3,2-c]pyridine 5-oxide To a solution of 3-iodo-1-tosyl-1H-pyrrolo[3,2-c]pyridine (2.2 g, 5.5 mmol) in DCM (15 ml) at 0 ^o C was added 3-chloroperoxybenzoic acid (1.9 g, 11 mmol) in portions. After stirring at room temperature under N ₂ overnight, the reaction was quenched with H ₂ O and extracted twice with DCM. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~15% MeOH in DCM) to afford 3-iodo-1-tosyl-1H-pyrrolo[3,2-c]pyridine 5- oxide (1.8 g, 78%) as a yellow solid. LC/MS ESI (m/z): 415 (M+H) ⁺ . Step 3. tert-Butyl (2R,5S)-4-(3-iodo-1-tosyl-1H-pyrrolo[3,2-c]pyridin-4-yl)-2,5 - dimethylpiperazine-1-carboxylate To a solution of 3-iodo-1-tosyl-1H-pyrrolo[3,2-c]pyridine 5-oxide (1.1 g, 2.7 mmol) in DCM (10 mL) were added tert-butyl (2R,5S)-2,5-dimethylpiperazine-1-carboxylate (2.9 g, 13 mmol), PyBroP (1.6 g, 3.5 mmol), DIPEA (1.4 g, 11 mmol). After stirring 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50% ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-4-(3-iodo-1-tosyl-1H- pyrrolo[3,2-c]pyridin-4-yl)-2,5-dimethylpiperazine-1-carboxy late (600 mg, 40%) as a white solid. LC/MS ESI (m/z): 611 (M+H) ⁺ . Step 4. tert-Butyl (2R,5S)-2,5-dimethyl-4-(1-tosyl-3-(trifluoromethyl)-1H-pyrro lo[3,2- c]pyridin-4-yl)piperazine-1-carboxylate To a solution of tert-butyl (2R,5S)-4-(3-iodo-1-tosyl-1H-pyrrolo[3,2-c]pyridin-4-yl)- 2,5-dimethylpiperazine-1-carboxylate (400 mg, 0.66 mmol) in DMF (10 mL) were added methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (380 mg, 2.0 mmol) and CuI (130 mg, 0.66 mmol). The resulting mixture was stirred at 80 ^o 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50% ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-2,5-dimethyl-4-(1-tosyl-3- (trifluoromethyl)-1H-pyrrolo[3,2-c]pyridin-4-yl)piperazine-1 -carboxylate (310 mg, 86%) as a yellow solid. LC/MS ESI (m/z): 553 (M+H) ⁺ . Step 5. tert-Butyl (2R,5S)-2,5-dimethyl-4-(3-(trifluoromethyl)-1H-pyrrolo[3,2- c]pyridin-4-yl)piperazine-1-carboxylate To a solution of tert-butyl (2R,5S)-2,5-dimethyl-4-(1-tosyl-3-(trifluoromethyl)-1H- pyrrolo[3,2-c]pyridin-4-yl)piperazine-1-carboxylate (310 mg, 0.56 mmol) in THF (10 mL) was added TBAF (10 mL, 1.0 M in THF). After stirring at room temperature overnight, the reaction was quenched with H ₂ O (10 mL) and extracted twice with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated, the residue was purified by flash chromatography (silica gel, 0~70% ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-2,5-dimethyl-4-(3-(trifluoromethyl)-1H-pyrrolo[3,2-c ]pyridin-4-yl)piperazine-1- carboxylate (200 mg, 89%) as a light yellow solid. LC/MS ESI (m/z): 399 (M+H) ⁺ . Step 6. tert-Butyl (2R,5S)-4-(1-(4-cyanopyridin-2-yl)-3-(trifluoromethyl)-1H- pyrrolo[3,2-c]pyridin-4-yl)-2,5-dimethylpiperazine-1-carboxy late To a solution of tert-butyl (2R,5S)-2,5-dimethyl-4-(3-(trifluoromethyl)-1H- pyrrolo[3,2-c]pyridin-4-yl)piperazine-1-carboxylate (100 mg, 0.25 mmol) in DMF (8 mL) were added 2-fluoroisonicotinonitrile (92 mg, 0.76 mmol) and Cs ₂ CO ₃ (410 mg, 1.3 mmol). The resulting mixture was heated to 50 ^o C overnight. After cooling to room temperature, the reaction was quenched with H2O (50 mL) and extracted twice with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50% ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford tert-butyl (2R,5S)-4-(1-(4- cyanopyridin-2-yl)-3-(trifluoromethyl)-1H-pyrrolo[3,2-c]pyri din-4-yl)-2,5- dimethylpiperazine-1-carboxylate (35 mg, 28%) as a white solid. LC/MS ESI (m/z): 501 (M+H) ⁺ . ¹ H NMR(400 MHz, CDCl ₃ ) δ 8.74 (d, J = 5.0 Hz, 1H), 8.16 (d, J = 5.9 Hz, 1H), 8.03 (s, 1H), 7.69 (s, 1H), 7.60 (d, J = 5.9 Hz, 1H), 7.49 (dd, J = 5.0, 1.1 Hz, 1H), 4.42 – 4.34 (m, 1H), 3.93 – 3.87 (m, 1H), 3.74 – 3.69 (m, 1H), 3.67 – 3.58 (m, 2H), 2.96 – 2.91 (m, 1H), 1.42 (s, 9H), 1.22 (d, J = 6.8 Hz, 3H), 0.87 (d, J = 6.6 Hz, 3H). Example 190. Synthesis of 2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6 (2R,5S)-4-(1-(4- cyanopyridin-2-yl)-3-(trifluoromethyl)-1H-pyrrolo[3,2-c]pyri din-4-yl)-2,5- dimethylpiperazine-1-carboxylate (Compound 623) Step 1.2-(4-((2S,5R)-2,5-Dimethylpiperazin-1-yl)-3-(trifluorometh yl)-1H- pyrrolo[3,2-c]pyridin-1-yl)isonicotinonitrile To a solution of tert-butyl (2R,5S)-4-(1-(4-cyanopyridin-2-yl)-3-(trifluoromethyl)-1H- pyrrolo[3,2-c]pyridin-4-yl)-2,5-dimethylpiperazine-1-carboxy late (100 mg, 0.20 mmol, prepared following the procedure outlined for compound 620) in THF (5 mL) was added HCl in dioxane (5.0 ml, 4.0M). After stirring at room temperature overnight, the reaction was quenched with NaHCO ₃ (aq.) and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~80% ethyl acetate in petroleum ether) to afford 2-(4-((2S,5R)-2,5-dimethylpiperazin-1-yl)-3-(trifluoromethyl )-1H-pyrrolo[3,2- c]pyridin-1-yl)isonicotinonitrile (60 mg, 75%) as a light yellow solid. LC/MS ESI (m/z): 401 (M+H) ⁺ . Step 2.2-(Methyl-d3)propan-2-yl-1,1,1,3,3,3-d6 (2R,5S)-4-(1-(4-cyanopyridin-2-yl)- 3-(trifluoromethyl)-1H-pyrrolo[3,2-c]pyridin-4-yl)-2,5-dimet hylpiperazine-1-carboxylate To a solution of 2-(methyl-d ₃ )propan-1,1,1,3,3,3-d ₆ -2-ol (3.0 g, 36 mmol) in DCM (20 mL) were added DMAP (1.3 g, 11 mmol) and di(pyridin-2-yl) carbonate (7.8 g, 36 mmol), the reaction was stirred at 35 ^o C for 7 days and the resulting reaction solution was used to the next step directly. To a solution of 2-(4-((2S,5R)-2,5-dimethylpiperazin-1-yl)-3- (trifluoromethyl)-1H-pyrrolo[3,2-c]pyridin-1-yl)isonicotinon itrile (60 mg, 0.15 mmol) in DMF (8 mL) was added DIPEA (58 mg, 0.45 mmol), followed by 2-(methyl-d ₃ )propan-2-yl- 1,1,1,3,3,3-d ₆ pyridin-2-yl carbonate (0.5 mL of the solution described above). After stirring at 80℃ overnight, DCM was removed, the residue diluted with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~5% ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford 2-(methyl-d ₃ )propan-2-yl-1,1,1,3,3,3-d ₆ (2R,5S)-4-(1-(4- cyanopyridin-2-yl)-3-(trifluoromethyl)-1H-pyrrolo[3,2-c]pyri din-4-yl)-2,5- dimethylpiperazine-1-carboxylate (55 mg, 72% yield) as a white solid. LC/MS ESI (m/z): 510 (M+H) ⁺ . ¹ H NMR(400 MHz, CDCl ₃ ) δ 8.74 (dd, J = 5.0, 0.7 Hz, 1H), 8.16 (d, J = 5.9 Hz, 1H), 8.03 (s, 1H), 7.69 (s, 1H), 7.60 (d, J = 5.9 Hz, 1H), 7.48 (dd, J = 5.0, 1.2 Hz, 1H), 4.40 – 4.29 (m, 1H), 3.93 – 3.86 (m, 1H), 3.74 – 3.60 (m, 3H), 2.94 (d, J = 12.0 Hz, 1H), 1.22 (d, J = 6.8 Hz, 3H), 0.87 (d, J = 6.6 Hz, 3H). Example 191. Synthesis of tert-butyl (2R,5S)-4-(1-(4-cyanopyridin-2-yl)-3- (difluoromethyl)-1H-pyrrolo[3,2-c]pyridin-4-yl)-2,5-dimethyl piperazine-1-carboxylate (Compound 624) Step 1. tert-Butyl (2R,5S)-2,5-dimethyl-4-(1-tosyl-3-vinyl-1H-pyrrolo[3,2-c]pyr idin-4- yl)piperazine-1-carboxylate To a solution of tert-butyl (2R,5S)-4-(3-iodo-1-tosyl-1H-pyrrolo[3,2-c]pyridin-4-yl)- 2,5-dimethylpiperazine-1-carboxylate (330 mg, 0.54 mmol, prepared following the procedure outlined for compound 620) in dioxane (10 mL) and H ₂ O (2 mL) were added 4,4,5,5- tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.18 mL, 1.1 mmol), K ₂ CO ₃ (220 mg, 1.6 mmol) and Pd(dppf)Cl ₂ (40 mg, 0.054 mmol), the resulting mixture was heated to 90℃ overnight. After cooling to room temperature, the reaction was concentrated, the residue was purified by flash column chromatography (silica gel, 0~20%, ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-2,5-dimethyl-4-(1-tosyl-3-vinyl-1H-pyrrolo[3,2-c]pyr idin-4-yl)piperazine- 1-carboxylate (260 mg, 94%) as a white solid. LC/MS ESI (m/z): 511 (M+H) ⁺ . Step 2. tert-Butyl (2R,5S)-4-(3-formyl-1-tosyl-1H-pyrrolo[3,2-c]pyridin-4-yl)-2 ,5- dimethylpiperazine-1-carboxylate To a solution of tert-butyl (2R,5S)-2,5-dimethyl-4-(1-tosyl-3-vinyl-1H-pyrrolo[3,2- c]pyridin-4-yl)piperazine-1-carboxylate (260 mg, 0.51 mmol) in THF (5 mL) were added K ₂ OsO ₄ (19 mg, 0.051 mmol) and NaIO ₄ (540 mg, 2.5 mmol). After stirring at room temperature overnight, 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 Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-4-(3-formyl-1-tosyl-1H-pyrrolo[3,2-c]pyridin-4-yl)-2 ,5-dimethylpiperazine-1- carboxylate (100 mg, 38%) as a brown oil. LC/MS ESI (m/z): 513 (M+H) ⁺ . Step 3. tert-Butyl (2R,5S)-4-(3-formyl-1H-pyrrolo[3,2-c]pyridin-4-yl)-2,5- dimethylpiperazine-1-carboxylate To a solution of tert-butyl (2R,5S)-4-(3-formyl-1-tosyl-1H-pyrrolo[3,2-c]pyridin-4- yl)-2,5-dimethylpiperazine-1-carboxylate (100 mg, 0.19 mmol) in THF (2 mL) was added TBAF (1.2 mL, 1.0 M in THF). After 1 h, 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 Na ₂ SO ₄ , filtered, and concentrated to afford tert-butyl (2R,5S)- 4-(3-formyl-1H-pyrrolo[3,2-c]pyridin-4-yl)-2,5-dimethylpiper azine-1-carboxylate (65 mg, 93%) as a yellow oil. LC/MS ESI (m/z): 359 (M+H) ⁺ . Step 4. tert-Butyl (2R,5S)-4-(1-(4-cyanopyridin-2-yl)-3-formyl-1H-pyrrolo[3,2- c]pyridin-4-yl)-2,5-dimethylpiperazine-1-carboxylate To a solution of tert-butyl (2R,5S)-4-(3-formyl-1H-pyrrolo[3,2-c]pyridin-4-yl)-2,5- dimethylpiperazine-1-carboxylate (65 mg, 0.18 mmol) in DMF (3 mL) were added 2- fluoroisonicotinonitrile (44 mg, 0.36 mmol) and Cs ₂ CO ₃ (180 mg, 0.54 mmol). The resulting mixture was stirred at 50℃ for 1 h. 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-4-(1-(4-cyanopyridin-2-yl)-3- formyl-1H-pyrrolo[3,2-c]pyridin-4-yl)-2,5-dimethylpiperazine -1-carboxylate (50 mg, 60%) as a brown oil. LC/MS ESI (m/z): 461 (M+H) ⁺ . Step 5. tert-Butyl (2R,5S)-4-(1-(4-cyanopyridin-2-yl)-3-(difluoromethyl)-1H- pyrrolo[3,2-c]pyridin-4-yl)-2,5-dimethylpiperazine-1-carboxy late To a solution of tert-butyl (2R,5S)-4-(1-(4-cyanopyridin-2-yl)-3-formyl-1H- pyrrolo[3,2-c]pyridin-4-yl)-2,5-dimethylpiperazine-1-carboxy late (50 mg, 0.11 mmol) in DCM (2 mL) at 0℃ was added BAST (0.10 mL, 0.54 mmol). After stirring at room temperature over 3 days, the reaction was quenched with NaHCO ₃ (aq.). The layers were separated, and the aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford tert-butyl (2R,5S)-4-(1-(4-cyanopyridin-2-yl)-3-(difluoromethyl)-1H-pyr rolo[3,2-c]pyridin-4-yl)-2,5- dimethylpiperazine-1-carboxylate (21 mg, 40%) as a white solid. LC/MS ESI (m/z): 483 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.73 (d, J = 5.0 Hz, 1H), 8.14 (d, J = 5.9 Hz, 1H), 7.99 – 7.92 (m, 1H), 7.72 (d, J = 5.7 Hz, 1H), 7.68 (s, 1H), 7.46 (d, J = 5.1 Hz, 1H), 7.21 (t, J = 55.4 Hz, 1H), 4.49 – 4.29 (m, 1H), 3.92 – 3.80 (m, 1H), 3.75 (d, J = 13.0 Hz, 2H), 3.56 (dd, J = 13.6, 2.6 Hz, 1H), 2.96 (d, J = 12.1 Hz, 1H), 1.43 (s, 9H), 1.23 (d, J = 6.8 Hz, 3H), 0.92 (d, J = 6.1 Hz, 3H).

Example 192. Synthesis of tert-butyl (2R,5S)-4-(7-cyclohexyl-5-(trifluoromethyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate (Compound 625) Step 1. Cyclohexyl methanesulfonate To a solution of cyclohexanol (300 mg, 3.0 mmol) and TEA (1.2 mL, 9.0 mmol) in DCM (5 mL) at 0℃ was added MsCl (0.46 mL, 6.0 mmol) dropwise. After 1 h, the reaction 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 ₂ SO ₄ , filtered, and concentrated to afford cyclohexyl methanesulfonate (500 mg, 93%) as a yellow oil. Step 2. tert-Butyl (2R,5S)-4-(7-cyclohexyl-5-(trifluoromethyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate To a solution of tert-butyl (2R,5S)-2,5-dimethyl-4-(5-(trifluoromethyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (50 mg, 0.12 mmol, prepared following the procedure outlined for compound 659) in DMF (3 mL) were added cyclohexyl methanesulfonate (45 mg, 0.25 mmol) and Cs ₂ CO ₃ (120 mg, 0.37 mmol), the resulting mixture was stirred at 80℃ 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 Na ₂ SO ₄ , filtered and concentrated, the residue was purified by flash chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford tert-butyl (2R,5S)-4-(7-cyclohexyl-5-(trifluoromethyl)-7H-pyrrolo[2,3-d ]pyrimidin-4- yl)-2,5-dimethylpiperazine-1-carboxylate (9.2 mg, 15%) as a white solid. LC/MS ESI (m/z): 482 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.40 (s, 1H), 7.47 (s, 1H), 4.71 – 4.62 (m, 1H), 4.46 – 4.39 (m, 1H), 4.37 – 4.13 (m, 1H), 3.69 – 3.61 (m, 2H), 3.55 (dd, J = 13.3, 3.1 Hz, 1H), 3.38 (d, J = 13.3 Hz, 1H), 2.05 (m, 2H), 1.91 – 1.82 (m, 2H), 1.73 (d, J = 13.2 Hz, 1H), 1.66 – 1.55 (m, 2H), 1.48 – 1.44 (m, 1H), 1.42 (s, 9H), 1.28 – 1.17 (m, 2H), 1.04 (m, 6H). The following compound was prepared by the procedure analogous to the synthesis of compound 625 from the corresponding alcohol. Example 193. Synthesis of tert-butyl (2R,5S)-4-(7-cyclohexyl-5-(difluoromethyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate (Compound 627) Step 1. tert-Butyl (2R,5S)-4-(7-cyclohexyl-5-formyl-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)- 2,5-dimethylpiperazine-1-carboxylate To a solution of tert-butyl (2R,5S)-4-(5-formyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5- dimethylpiperazine-1-carboxylate (50 mg, 0.14 mmol, prepared following the procedure outlined for compound 630) in DMF (3 mL) were added cyclohexyl methanesulfonate (50 mg, 0.28 mmol, prepared following the procedure outlined for compound 625) and Cs ₂ CO ₃ (140 mg, 0.41 mmol). The resulting mixture was stirred at 100℃ 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-4-(7-cyclohexyl-5-formyl-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)-2,5-dimethylpiperazine- 1-carboxylate (20 mg, 32%) as a yellow oil. LC/MS ESI (m/z): 442 (M+H) ⁺ . Step 2. tert-Butyl (2R,5S)-4-(7-cyclohexyl-5-(difluoromethyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate To a solution of tert-butyl (2R,5S)-4-(7-cyclohexyl-5-formyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (20 mg, 0.045 mmol) in DCM (2 mL) at 0℃ was added BAST (0.08 mL, 0.45 mmol). After stirring at 30℃ overnight, the reaction was quenched with NaHCO ₃ (aq.). The layers were separated, and the aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , concentrated, and purified by prep-HPLC to afford tert-butyl (2R,5S)-4-(7- cyclohexyl-5-(difluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-y l)-2,5-dimethylpiperazine-1- carboxylate (5.7 mg, 27%) as a white solid. LC/MS ESI (m/z): 464 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.40 (s, 1H), 7.40 – 7.33 (m, 1H), 6.86 (t, J = 56.2 Hz, 1H), 4.69 – 4.59 (m, 1H), 4.45 – 4.39 (m, 1H), 4.37 – 4.16 (m, 1H), 3.72 – 3.61 (m, 2H), 3.52 (dd, J = 13.3, 3.4 Hz, 1H), 3.41 (d, J = 13.0 Hz, 1H), 2.07 (d, J = 12.2 Hz, 1H), 2.00 (d, J = 12.1 Hz, 1H), 1.91 – 1.80 (m, 2H), 1.73 (d, J = 13.1 Hz, 1H), 1.66 – 1.59 (m, 1H), 1.50 – 1.44 (m, 2H), 1.42 (s, 9H), 1.27 – 1.14 (m, 2H), 1.06 (m, 6H). The following compound was prepared by the procedure analogous to the synthesis of compound 625 from the corresponding alcohol. Example 194. Synthesis of tert-butyl (2R,5S)-4-(7-(3-cyanocyclohexyl)-5- (trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimet hylpiperazine-1- carboxylate (Compound 629) Compound 629 Step 1. tert-Butyl (2R,5S)-4-(7-(3-(methoxycarbonyl)cyclohexyl)-5-(trifluoromet hyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-ca rboxylate To a solution of tert-butyl (2R,5S)-2,5-dimethyl-4-(5-(trifluoromethyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (100 mg, 0.25 mmol, prepared following the procedure outlined for compound 659) in toluene (3 mL) were added methyl 3- hydroxycyclohexane-1-carboxylate (120 mg, 0.75 mmol) and (cyanomethylene)tributylphosphorane(CMBP.0.14 mL, 0.50 mmol). The resulting mixture was stirred at 80℃ overnight. After cooling to room temperature, the reaction was concentrated and the residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-4-(7-(3- (methoxycarbonyl)cyclohexyl)-5-(trifluoromethyl)-7H-pyrrolo[ 2,3-d]pyrimidin-4-yl)-2,5- dimethylpiperazine-1-carboxylate (120 mg, 88%) as a yellow oil. LC/MS ESI (m/z): 540 (M+H) ⁺ . Step 2.3-(4-((2S,5R)-4-(tert-Butoxycarbonyl)-2,5-dimethylpiperazi n-1-yl)-5- (trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexan e-1-carboxylic acid To a solution of tert-butyl (2R,5S)-4-(7-(3-(methoxycarbonyl)cyclohexyl)-5- (trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimet hylpiperazine-1-carboxylate (120 mg, 0.22 mmol) in MeOH (5 mL) and H ₂ O (1 mL) was added NaOH (18 mg, 0.44 mmol). The resulting mixture was stirred at 40 ^o C overnight. After cooling to room temperature, MeOH was removed. The residue was acidified with 1 M HCl to pH 6 and extracted twice with DCM. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to afford 3-(4-((2S,5R)-4-(tert- butoxycarbonyl)-2,5-dimethylpiperazin-1-yl)-5-(trifluorometh yl)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)cyclohexane-1-carboxylic acid (40 mg, 34%) as a yellow oil. LC/MS ESI (m/z): 526 (M+H) ⁺ . Step 3. tert-Butyl (2R,5S)-4-(7-(3-carbamoylcyclohexyl)-5-(trifluoromethyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate To a solution of 3-(4-((2S,5R)-4-(tert-butoxycarbonyl)-2,5-dimethylpiperazin- 1-yl)-5- (trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexan e-1-carboxylic acid (40 mg, 0.076 mmol) in DMF (2 mL) were added NH ₄ Cl (8.1 mg, 0.15 mmol), HATU (29 mg, 0.076 mmol) and DIPEA (0.04 mL, 0.22 mmol). After stirring at room temperature overnight, 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 Na ₂ SO ₄ , filtered, and concentrated to afford tert-butyl (2R,5S)-4-(7-(3-carbamoylcyclohexyl)-5- (trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimet hylpiperazine-1-carboxylate (35 mg, 87%) as a yellow oil. LC/MS ESI (m/z): 525 (M+H) ⁺ . Step 4. tert-Butyl (2R,5S)-4-(7-(3-cyanocyclohexyl)-5-(trifluoromethyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate To a solution of tert-butyl (2R,5S)-4-(7-(3-carbamoylcyclohexyl)-5-(trifluoromethyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-ca rboxylate (35 mg, 0.067 mmol) and TEA (0.08 mL, 0.60 mmol) in DCM (2 mL) at 0 ^o C was added TFAA (35 mg, 0.16 mmol). After stirring at 0℃ for 20 min, the reaction was quenched with water. The layers were separated, and the aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , concentrated, and purified by prep-HPLC to afford tert-butyl (2R,5S)-4-(7-(3-cyanocyclohexyl)-5-(trifluoromethyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate (21 mg, 60%) as a white solid. LC/MS ESI (m/z): 507 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.43 – 8.33 (m, 1H), 7.41 (d, J = 8.9 Hz, 1H), 4.97 – 4.62 (m, 1H), 4.51 – 4.21 (m, 2H), 3.72 – 3.59 (m, 2H), 3.54 (dd, J = 13.3, 3.1 Hz, 1H), 3.46 – 3.30 (m, 1H), 3.20 – 2.62 (m, 1H), 2.53 – 2.27 (m, 1H), 2.18 – 1.99 (m, 3H), 1.94 – 1.69 (m, 2H), 1.65 – 1.53 (m, 2H), 1.42 (s, 9H), 1.10 – 0.96 (m, 6H). The following compounds were prepared by procedures analogous to the synthesis of compound 629 from the corresponding alcohols (compound 631 and compound 632 were made from tetrahydro-2H-pyran-3-ol and separated via SFC chiral separation at the last step). Example 195. Synthesis of tert-butyl (2R,5S)-4-(7-(3-cyanocyclohexyl)-5- (difluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimeth ylpiperazine-1- carboxylate (Compound 633) Step 1. Methyl 3-((methylsulfonyl)oxy)cyclohexane-1-carboxylate To a solution of methyl 3-hydroxycyclohexane-1-carboxylate (200 mg, 1.3 mmol) and TEA (0.53 mL, 3.8 mmol) in DCM (3 mL) at 0℃ was added MsCl (0.20 mL, 2.5 mmol). After stirring at room temperature for 2 h, the reaction was quenched with ice water. The aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over Na ₂ SO _4, and concentrated to afford methyl 3- ((methylsulfonyl)oxy)cyclohexane-1-carboxylate (290 mg, 97%) as a yellow oil. Step 2. tert-Butyl (2R,5S)-4-(5-formyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5- dimethylpiperazine-1-carboxylate To a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde (1.0 g, 5.5 mmol) in DIPEA (5 mL) was added tert-butyl (2R,5S)-2,5-dimethylpiperazine-1-carboxylate (2.4 g, 11 mmol). The resulting mixture was stirred at 140℃ for 1 h. After cooling to room temperature, the reaction was concentrated and the residue was purified by flash column chromatography (silica gel, 0~90%, ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-4-(5-formyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dim ethylpiperazine-1-carboxylate (1.3 g, 67%) as a yellow solid. LC/MS ESI (m/z): 360 (M+H) ⁺ . Step 3. tert-Butyl (2R,5S)-4-(5-formyl-7-(3-(methoxycarbonyl)cyclohexyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate To a solution of tert-butyl (2R,5S)-4-(5-formyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5- dimethylpiperazine-1-carboxylate (200 mg, 0.55 mmol) in DMF (5 mL) were added methyl 3-((methylsulfonyl)oxy)cyclohexane-1-carboxylate (260 mg, 1.1 mmol) and Cs ₂ CO ₃ (540 mg, 1.7 mmol). The resulting mixture was stirred at 100℃ 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 Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to afford crude tert- butyl (2R,5S)-4-(5-formyl-7-(3-(methoxycarbonyl)cyclohexyl)-7H-pyr rolo[2,3-d]pyrimidin- 4-yl)-2,5-dimethylpiperazine-1-carboxylate (130 mg, 46%) as a yellow oil. LC/MS ESI (m/z): 500 (M+H) ⁺ . Step 4.3-(4-((2S,5R)-4-(tert-Butoxycarbonyl)-2,5-dimethylpiperazi n-1-yl)-5-formyl- 7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexane-1-carboxylic acid To a solution of tert-butyl (2R,5S)-4-(5-formyl-7-(3-(methoxycarbonyl)cyclohexyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-ca rboxylate (130 mg, 0.26 mmol) in MeOH (5 mL) and H ₂ O (1 mL) was added NaOH (21 mg, 0.52 mmol). The resulting mixture was stirred at 40℃ overnight. After cooling to room temperature, methanol was removed. The residue was acidified by 1 N HCl to pH 6 and the mixture was extracted twice with DCM. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated to afford crude 3-(4-((2S,5R)-4-(tert-butoxycarbonyl)-2,5- dimethylpiperazin-1-yl)-5-formyl-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)cyclohexane-1- carboxylic acid (60 mg, 47%) as a yellow oil. LC/MS ESI (m/z): 486 (M+H) ⁺ . Step 5. tert-Butyl (2R,5S)-4-(7-(3-carbamoylcyclohexyl)-5-formyl-7H-pyrrolo[2,3 - d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate To a solution of 3-(4-((2S,5R)-4-(tert-butoxycarbonyl)-2,5-dimethylpiperazin- 1-yl)-5- formyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexane-1-carboxy lic acid (60 mg, 0.12 mmol) in DMF (3 mL) were added NH ₄ Cl (13 mg, 0.24 mmol), HATU (47 mg, 0.12 mmol) and DIPEA (0.07 mL, 0.37 mmol). After stirring at room temperature overnight, the reaction was partitioned between EtOAc and water. The aqueous layer was extracted twice with EtOAc twice and the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated to afford tert-butyl (2R,5S)-4-(7-(3-carbamoylcyclohexyl)-5-formyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate (55 mg, 91%) as a yellow oil. LC/MS ESI (m/z): 485 (M+H) ⁺ . Step 6. tert-Butyl (2R,5S)-4-(7-(3-cyanocyclohexyl)-5-formyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate To a solution of tert-butyl (2R,5S)-4-(7-(3-carbamoylcyclohexyl)-5-formyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate (55 mg, 0.11 mmol) and TEA (0.14 mL, 1.0 mmol) in DCM (3 mL) at 0℃ was added TFAA (60 mg, 0.28 mmol). After stirring at 0℃ for 30 min, the reaction was quenched with water. The layers were separated, and the aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , concentrated, and purified by flash column chromatography (silica gel, ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-4-(7-(3-cyanocyclohexyl)-5-formyl-7H-pyrrolo[2,3-d]p yrimidin-4-yl)-2,5- dimethylpiperazine-1-carboxylate (50 mg, 94%) as a yellow oil. LC/MS ESI (m/z): 467 (M+H) ⁺ . Step 7. tert-Butyl (2R,5S)-4-(7-(3-cyanocyclohexyl)-5-(difluoromethyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate To a solution of tert-butyl (2R,5S)-4-(7-(3-cyanocyclohexyl)-5-formyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate (50 mg, 0.11 mmol) in DCM (3 mL) at 0℃ was added BAST (0.10 mL, 0.53 mmol). After stirring at 30℃ for three days, the reaction was partitioned between DCM and NaHCO ₃ (aq.). The aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by prep-HPLC to afford tert- butyl (2R,5S)-4-(7-(3-cyanocyclohexyl)-5-(difluoromethyl)-7H-pyrro lo[2,3-d]pyrimidin-4- yl)-2,5-dimethylpiperazine-1-carboxylate (5.5 mg, 10%) as a yellow solid. LC/MS ESI (m/z): 489 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.40 – 8.34 (m, 1H), 7.31 (d, J = 7.9 Hz, 1H), 6.85 (t, J = 56.1 Hz, 1H), 4.92 – 4.59 (m, 1H), 4.51 – 4.24 (m, 2H), 3.74 – 3.62 (m, 2H), 3.58 – 3.13 (m, 3H), 2.76 – 2.19 (m, 2H), 2.16 – 2.00 (m, 2H), 1.96 – 1.77 (m, 2H), 1.74 – 1.54 (m, 2H), 1.42 (s, 9H), 1.10 – 1.01 (m, 6H). The following compound was prepared by a procedure analogous to the synthesis of compound 633 from 3-hydroxycyclopentane-1-carbonitrile.

Example 196. Synthesis of tert-butyl (2R,5S)-4-(5-(azetidin-1-yl)-7-(3-fluorophenyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate (Compound 635) 5 Step 1.4-Chloro-7-(3-fluorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimi dine To a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (3.0 g, 11 mmol) in DCM (50 mL) were added (3-fluorophenyl)boronic acid (2.2 g, 16 mmol), Cu(OAc) ₂ (5.3 g, 27 mmol) and pyridine (1.7 mL, 21 mmol). The resulting mixture was stirred at room temperature under O ₂ atmosphere overnight. Aqueous ammonia (80 mL) was added, and the reaction was filtered. The filtrate was partitioned between DCM and water. The aqueous phase was extracted twice with DCM. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30% ethyl acetate in petroleum ether) to afford 4-chloro-7-(3- fluorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (2.6 g, 66%) as a white solid. LC/MS ESI (m/z): 374 (M+H) ⁺ . Step 2. tert-Butyl (2R,5S)-4-(7-(3-fluorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimi din- 4-yl)-2,5-dimethylpiperazine-1-carboxylate A mixture of 4-chloro-7-(3-fluorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidi ne (2.6 g, 6.9 mmol), tert-butyl (2R,5S)-2,5-dimethylpiperazine-1-carboxylate (2.2 g, 10 mmol) and DIPEA (15 mL) was stirred at 150°C for 1 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 in petroleum ether) to afford tert-butyl (2R,5S)-4-(7-(3-fluorophenyl)-5- iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine -1-carboxylate (2.7 g, 72%) as a white solid. LC/MS ESI (m/z): 552 (M+H) ⁺ . Step 3. tert-Butyl (2R,5S)-4-(7-(3-fluorophenyl)-5-(2-oxoazetidin-1-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate To a solution of tert-butyl (2R,5S)-4-(7-(3-fluorophenyl)-5-iodo-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (800 mg, 1.4 mmol) in DMF (15 mL) were added azetidin-2-one (400 mg, 5.6 mmol), trans-N,N'-dimethylcyclohexane-1,2- diamine (200 mg, 1.4 mmol), CuI (130 mg, 0.70 mmol) and K ₃ PO ₄ (590 mg, 2.8 mmol). The resulting mixture was heated to 90 ^o 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~100%, ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-4-(7-(3-fluorophenyl)-5-(2-oxoazetidin-1-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate (500 mg, 72%) as a white solid. LC/MS ESI (m/z): 495 (M+H) ⁺ . Step 4. tert-Butyl (2R,5S)-4-(5-(azetidin-1-yl)-7-(3-fluorophenyl)-7H-pyrrolo[2 ,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate To a solution of tert-butyl (2R,5S)-4-(7-(3-fluorophenyl)-5-(2-oxoazetidin-1-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate (500 mg, 1.0 mmol) in THF (8 mL) at 0℃ were added RhHCO(PPh3)3 (92 mg, 0.10 mmol) and PhSiH3 (0.60 mL, 5.0 mmol). After stirring at room temperature for 1 h under N ₂ , the reaction was partitioned between EtOAc and water. The aqueous layer was extracted twice with EtOAc, and the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~35% ethyl acetate in petroleum ether) to give crude product which was further purified by prep- HPLC to afford tert-butyl (2R,5S)-4-(5-(azetidin-1-yl)-7-(3-fluorophenyl)-7H-pyrrolo[2 ,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (470 mg, 98%) as a white solid. LC/MS ESI (m/z): 481 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.36 (s, 1H), 7.57 – 7.53 (m, 2H), 7.46 – 7.41 (m, 1H), 7.02 – 6.96 (m, 1H), 6.61 (s, 1H), 5.12 (s, 1H), 4.42 (s, 1H), 4.00 (d, J = 13.5 Hz, 1H), 3.83 – 3.57 (m, 7H), 2.32 – 2.26 (m, 2H), 1.49 (s, 9H), 1.14 (d, J = 6.7 Hz, 3H), 1.03 (d, J = 6.8 Hz, 3H). The following compound was prepared by the procedure analogous to the synthesis of compound 635 from the corresponding chiral amine. Example 197. Synthesis of tert-butyl (S)-4-(3-(azetidin-1-yl)-1-(3-fluorophenyl)-1H- pyrrolo[3,2-c]pyridin-4-yl)-3-methylpiperazine-1-carboxylate (Compound 637) Compound 637 Step 1.1-(3-Fluorophenyl)-3-iodo-1H-pyrrolo[3,2-c]pyridine A mixture of 3-iodo-1H-pyrrolo[3,2-c]pyridine (2.9 g, 12 mmol), (3- fluorophenyl)boronic acid (4.9 g, 35 mmol), Cu(OAc) ₂ (5.8 g, 30 mmol) and pyridine (5.7 mL, 71 mmol) in DCM (50 mL) was stirred at room temperature for 48 h under oxygen atmosphere. The reaction mixture was treated with aqueous ammonia and was filtered. The filtrate was extracted twice with DCM. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography on silica gel (0~30% ethyl acetate in petroleum ether) to give 1-(3- fluorophenyl)-3-iodo-1H-pyrrolo[3,2-c]pyridine (1.5 g, 37%) as a solid. LC/MS ESI (m/z): 339 (M+H) ⁺ . Step 2.1-(3-Fluorophenyl)-3-iodo-1H-pyrrolo[3,2-c]pyridine 5-oxide To a solution of 1-(3-fluorophenyl)-3-iodo-1H-pyrrolo[3,2-c]pyridine (1.5 g, 4.4 mmol) in DCM (20 mL) at 0 ^o C was added 3-chloroperoxybenzoic acid (1.1 g, 6.6 mmol) in portions. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with NaHCO ₃ (aq.) 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, 0~20 % MeOH in DCM) to provide 1- (3-fluorophenyl)-3-iodo-1H-pyrrolo[3,2-c]pyridine 5-oxide (920 mg, 61%) as a light yellow solid. LC/MS ESI (m/z): 355 (M+H) ⁺ . Step 3. tert-Butyl (S)-4-(1-(3-fluorophenyl)-3-iodo-1H-pyrrolo[3,2-c]pyridin-4- yl)-3- methylpiperazine-1-carboxylate To a solution of 1-(3-fluorophenyl)-3-iodo-1H-pyrrolo[3,2-c]pyridine 5-oxide (450 mg, 1.3 mmol) in DCM (10 mL) were added tert-butyl (S)-3-methylpiperazine-1-carboxylate (1.3 g, 6.4 mmol), DIPEA (0.90 mL, 5.1 mmol) and PyBroP (1.2 g, 2.5 mmol). After stirring at room temperature for 3 days, the reaction 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 ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~20%, ethyl acetate in petroleum ether) to afford tert- butyl (S)-4-(1-(3-fluorophenyl)-3-iodo-1H-pyrrolo[3,2-c]pyridin-4- yl)-3-methylpiperazine-1- carboxylate (250 mg, 36%) as a yellow solid. LC/MS ESI (m/z): 537 (M+H) ⁺ . Step 4. tert-Butyl (S)-4-(1-(3-fluorophenyl)-3-(2-oxoazetidin-1-yl)-1H-pyrrolo[ 3,2- c]pyridin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl (S)-4-(1-(3-fluorophenyl)-3-iodo-1H-pyrrolo[3,2-c]pyridin- 4-yl)-3-methylpiperazine-1-carboxylate (150 mg, 0.28 mmol) in DMF (5 mL) were added azetidin-2-one (80 mg, 1.1 mmol), CuI (27 mg, 0.14 mmol), trans-N ¹ ,N ² - dimethylcyclohexane-1,2-diamine (0.05 mL, 0.28 mmol) and K ₃ PO ₄ (180 mg, 0.84 mmol). The resulting mixture was stirred at 90℃ 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to afford tert-butyl (S)-4-(1-(3-fluorophenyl)-3- (2-oxoazetidin-1-yl)-1H-pyrrolo[3,2-c]pyridin-4-yl)-3-methyl piperazine-1-carboxylate (120 mg, 89%) as a yellow oil. LC/MS ESI (m/z): 480 (M+H) ⁺ . Step 5. tert-Butyl (S)-4-(3-(azetidin-1-yl)-1-(3-fluorophenyl)-1H-pyrrolo[3,2- c]pyridin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl (S)-4-(1-(3-fluorophenyl)-3-(2-oxoazetidin-1-yl)-1H- pyrrolo[3,2-c]pyridin-4-yl)-3-methylpiperazine-1-carboxylate (120 mg, 0.25 mmol) in THF (5 mL) at 0℃ were added RhHCO(PPh ₃ ) ₃ (23 mg, 0.025 mmol) and PhSiH ₃ (0.15 mL, 1.3 mmol). After stirring at room temperature for 1 h under N ₂ , 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep- HPLC to afford tert-butyl (S)-4-(3-(azetidin-1-yl)-1-(3-fluorophenyl)-1H-pyrrolo[3,2- c]pyridin-4-yl)-3-methylpiperazine-1-carboxylate (80 mg, 68%) as a white solid. LC/MS ESI (m/z): 466 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.93 (d, J = 5.9 Hz, 1H), 7.46 (m, 1H), 7.25 (d, J = 4.2 Hz, 1H), 7.18 (d, J = 9.7 Hz, 1H), 7.08 – 6.99 (m, 2H), 6.60 (s, 1H), 4.35 (s, 1H), 3.97 (m, 3H), 3.78 – 3.50 (m, 5H), 3.34 (m, 2H), 2.26 (p, J = 7.0 Hz, 2H), 1.49 (s, 9H), 1.03 (d, J = 6.1 Hz, 3H). The following compound was prepared by a procedure analogous to the synthesis of compound 637 from the corresponding chiral amine. Example 198. Synthesis of tert-butyl (S)-4-(5-cyclobutyl-7-(3-fluorophenyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxyla te (Compound 641) Step 1. tert-Butyl (S)-4-(5-cyclobutyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl) -3- methylpiperazine-1-carboxylate To a solution of tert-butyl (S)-4-(5-bromo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 3-methylpiperazine-1-carboxylate (200 mg, 0.36 mmol, prepared following a similar procedure outlined for compound 666) in toluene (10 mL) and H ₂ O (0.1 mL) were added cyclobutylboronic acid (72 mg, 0.72 mmol), K ₂ CO ₃ (250 mg, 1.8 mmol) and Pd(dptf)Cl ₂ (32 mg, 0.04 mmol). The resulting mixture was stirred at 90℃ overnight. After cooling to room temperature, the reaction was concentrated and the residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford tert-butyl (S)- 4-(5-cyclobutyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-m ethylpiperazine-1-carboxylate (80 mg, 42%) as a solid. LC/MS ESI (m/z): 526 (M+H) ⁺ . Step 2. tert-Butyl (S)-4-(5-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate To a solution of tert-butyl (S)-4-(5-cyclobutyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4- yl)-3-methylpiperazine-1-carboxylate (80 mg, 0.15 mmol) in THF (2 mL) was added TBAF (1.0 mL, 1.0 M in THF). After stirring at room temperature under N ₂ for 2 h, the reaction was partitioned between EtOAc and brine. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was used directly in the next step. LC/MS ESI (m/z): 372 (M+H) ⁺ . Step 3. tert-Butyl (S)-4-(5-cyclobutyl-7-(3-fluorophenyl)-7H-pyrrolo[2,3-d]pyri midin- 4-yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl (S)-4-(5-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate (50 mg, 0.13 mmol) in DMF (3 mL) were added 1-fluoro-3- iodobenzene (45 mg, 0.20 mmol), trans-N, N'-dimethylcyclohexane-1,2-diamine (14 mg, 0.10 mmol), CuI (19 mg, 0.10 mmol) and K ₃ PO ₄ (43 mg, 0.20 mmol). The resulting mixture was heated to 100 ^o 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50% ethyl acetate in petroleum ether) to afford tert-butyl (S)- 4-(5-cyclobutyl-7-(3-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidi n-4-yl)-3-methylpiperazine-1- carboxylate (25 mg, 41%) as a white solid. LC/MS ESI (m/z): 466 (M+H) ⁺ . ¹ H NMR(400 MHz, CDCl ₃ ) δ 8.41 (s, 1H), 7.49 – 7.37 (m, 3H), 7.17 (s, 1H), 6.98 (t, J = 8.1 Hz, 1H), 4.17 (s, 1H), 3.94 (s, 1H), 3.76 – 3.59 (m, 2H), 3.43 (s, 3H), 3.16 (s, 1H), 2.44 – 2.32 (m, 2H), 2.12 – 1.86 (m, 4H), 1.43 (s, 9H), 1.12 (d, J = 5.5 Hz, 3H). The following compounds were prepared by procedures analogous to the synthesis of compound 641 from the corresponding chiral amines, boronic acids and aryl halides.

Example 199. Synthesis of tert-butyl (2R,5S)-4-(5-(2-fluorophenyl)-7-(4- (trifluoromethyl)pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)-2,5- dimethylpiperazine-1-carboxylate (Compound 649) Compound 649 Step 1. tert-Butyl (2R,5S)-4-(5-(2-fluorophenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrim idin- 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 (6.0 g, 9.8 mmol) in dioxane (60 mL) and H ₂ O (10 mL) were added (2-fluorophenyl)boronic acid (1.7 g, 12 mmol), K ₂ CO ₃ (4.1 g, 29 mmol) and Pd(dppf)Cl ₂ (0.72 g, 0.98 mmol). The resulting mixture was stirred at 90℃ overnight. After cooling to room temperature, the reaction was concentrated and the residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-4-(5-(2-fluorophenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrim idin-4-yl)-2,5- dimethylpiperazine-1-carboxylate (5.5 g, 96%) as a yellow solid. LC/MS ESI (m/z): 580 (M+H) ⁺ . Step 2. tert-Butyl (2R,5S)-4-(5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-y l)- 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 (500 mg, 0.86 mmol) in THF (5 mL) was added TBAF (5.0 mL, 1.0 M in THF). After stirring at room temperature overnight, the reaction was diluted with water and extracted twice with EtOAc. The combined organic layers were washed four times with brine, dried over Na ₂ SO ₄ , filtered, and concentrated to afford tert-butyl (2R,5S)-4-(5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-y l)-2,5- dimethylpiperazine-1-carboxylate (350 mg, 95%) as a solid. LC/MS ESI (m/z): 426 (M+H) ⁺ . Step 3. tert-Butyl (2R,5S)-4-(5-(2-fluorophenyl)-7-(4-(trifluoromethyl)pyridin- 2-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-ca rboxylate 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 (300 mg, 0.71 mmol) in DMF (10 mL) were added trans-N ¹ ,N ² -dimethylcyclohexane-1,2-diamine (100 mg, 0.71 mmol), 2-bromo-4- (trifluoromethyl)pyridine (400 mg, 1.8 mmol), CuI (140 mg, 0.71 mmol) and K ₃ PO ₄ (450 mg, 2.1 mmol). The resulting mixture was heated to 100 ^o 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~35% ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-4-(5-(2-fluorophenyl)-7-(4-(trifluoromethyl)pyridin- 2-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (350 mg, 86%) as a solid.50 mg of which was further purified by prep-HPLC to afford 30 mg of a white solid. LC/MS ESI (m/z): 571 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.27 (s, 1H), 8.57 (d, J = 5.1 Hz, 1H), 8.51 (s, 1H), 8.25 (s, 1H), 7.43 (td, J = 7.6, 1.8 Hz, 1H), 7.37 – 7.27 (m, 2H), 7.19 – 7.11 (m, 2H), 4.30 – 3.95 (m, 2H), 3.33 – 3.13 (m, 3H), 2.93 – 2.64 (m, 1H), 1.36 (s, 9H), 0.99 (d, J = 6.8 Hz, 3H), 0.89 (d, J = 6.7 Hz, 3H). The following compounds were prepared by procedures analogous to the synthesis of compound 649 from the corresponding aryl halides and amines. Example 200. Synthesis of 1-methylcyclopropyl (2R,5S)-4-(5-(2-fluorophenyl)-7-(4- (trifluoromethyl)pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)-2,5- dimethylpiperazine-1-carboxylate (Compound 652) Step 1.4-((2S,5R)-2,5-Dimethylpiperazin-1-yl)-5-(2-fluorophenyl)- 7-(4- (trifluoromethyl)pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine To a solution of tert-butyl (2R,5S)-4-(5-(2-fluorophenyl)-7-(4- (trifluoromethyl)pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)-2,5-dimethylpiperazine-1- carboxylate (100 mg, 0.18 mmol, prepared following the procedure outlined for compound 649) in DCM (4 mL) was added HCl (0.8 mL, 4.0 M in dioxane). After stirring at room temperature for 3 h, the reaction mixture was basified with NaHCO ₃ (aq.) to pH 8 and extracted twice with DCM. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (0~10% MeOH in DCM) to afford 4-((2S,5R)-2,5-dimethylpiperazin-1-yl)-5-(2-fluorophenyl)-7- (4- (trifluoromethyl)pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine (60 mg, 73%) as a white solid. LC/MS ESI (m/z): 471 (M+H) ⁺ . Step 2.1-Methylcyclopropyl (2R,5S)-4-(5-(2-fluorophenyl)-7-(4- (trifluoromethyl)pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)-2,5-dimethylpiperazine-1- carboxylate To a solution of 2-(4-((2R,5S)-2,5-dimethylpiperazin-1-yl)-5-(trifluoromethyl )-7H- pyrrolo[2,3-d]pyrimidin-7-yl)isonicotinonitrile (50 mg, 0.11 mmol) in DMF (5 mL) were added 1-methylcyclopropyl pyridin-2-yl carbonate (3.0 eq., prepared following a similar procedure outlined for compound 623) and DIPEA (43 mg, 0.33 mmol). The resulting mixture was heated to 80 ^o C for 3 h. 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~80%, ethyl acetate in petroleum ether) to give crude product, which was further purified by prep- HPLC to afford 1-methylcyclopropyl (2R,5S)-4-(5-(2-fluorophenyl)-7-(4- (trifluoromethyl)pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)-2,5-dimethylpiperazine-1- carboxylate (10 mg, 17%) as a white solid. LC/MS ESI (m/z): 569 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.26 (s, 1H), 8.57 (d, J = 5.1 Hz, 1H), 8.51 (s, 1H), 8.25 (s, 1H), 7.46 – 7.37 (m, 1H), 7.37 – 7.26 (m, 2H), 7.19 – 7.10 (m, 2H), 4.30 – 3.92 (m, 2H), 3.35 – 3.11 (m, 3H), 2.94 – 2.61 (m, 1H), 1.44 (s, 3H), 1.00 (d, J = 6.8 Hz, 3H), 0.87 (d, J = 6.7 Hz, 3H), 0.79 – 0.71 (m, 2H), 0.59 – 0.48 (m, 2H). The following compound was prepared by a procedure analogous to the synthesis of compound 652 from the corresponding aryl halide. Example 201. Synthesis of 1-methylcyclopropyl (2R,5S)-4-(7-(3-chlorophenyl)-5- cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpip erazine-1-carboxylate (Compound 654) Step 1. tert-Butyl (2R,5S)-4-(5-cyclopropyl-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 (2.0 g, 3.3 mmol, prepared following the procedure outlined for compound 666) in toluene (25 mL) were added cyclopropylboronic acid (570 mg, 6.6 mmol), K ₂ CO ₃ (6.8 g, 50 mmol) and PdCl ₂ (dtbpf) (190 mg, 0.30 mmol). The resulting mixture was heated to 80 ^o C overnight. After cooling to room temperature, solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~40% ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-4-(5-cyclopropyl-7- tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazin e-1-carboxylate (1.1 g, 65%) as a white solid. LC/MS ESI (m/z): 526 (M+H) ⁺ . Step 2. tert-Butyl (2R,5S)-4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2, 5- dimethylpiperazine-1-carboxylate To a solution of tert-butyl (2R,5S)-4-(5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (1.1 g, 2.1 mmol) in THF (20 mL) was added TBAF (11 mL, 1.0 M in THF). After stirring at room temperature for 5 h, the reaction was diluted with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~70% ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2, 5- dimethylpiperazine-1-carboxylate (600 mg, 77%) as a white solid. LC/MS ESI (m/z): 372 (M+H) ⁺ . Step 3. tert-Butyl (2R,5S)-4-(7-(3-chlorophenyl)-5-cyclopropyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate To a solution of tert-butyl (2R,5S)-4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4- yl)-2,5-dimethylpiperazine-1-carboxylate (300 mg, 0.80 mmol) in DMF (5 mL) were added 1-chloro-3-iodobenzene (360 mg, 1.5 mmol), trans-N,N'-dimethylcyclohexane-1,2-diamine (57 mg, 0.40 mmol), CuI (76 mg, 0.40 mmol) and K ₃ PO ₄ (490 mg, 2.3 mmol). The resulting mixture was heated to 120 ^o 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30% ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-4-(7-(3-chlorophenyl)-5-cyclopropyl-7H-pyrrolo[2,3-d ]pyrimidin-4-yl)- 2,5-dimethylpiperazine-1-carboxylate (330 mg, 85%) as a white solid. LC/MS ESI (m/z): 482 (M+H) ⁺ . Step 4.7-(3-Chlorophenyl)-5-cyclopropyl-4-((2S,5R)-2,5-dimethylpi perazin-1-yl)-7H- pyrrolo[2,3-d]pyrimidine To a solution of tert-butyl (2R,5S)-4-(7-(3-chlorophenyl)-5-cyclopropyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate (330 mg, 0.69 mmol) in DCM (5 ml) was added TFA (2.0 ml). The resulting mixture was stirred at room temperature overnight. After removal of solvents, the residue was diluted with DCM, and washed with NaHCO ₃ (aq.). The aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~80% ethyl acetate in petroleum ether) to afford 7-(3-chlorophenyl)-5-cyclopropyl-4-((2S,5R)-2,5-dimethylpipe razin-1-yl)-7H- pyrrolo[2,3-d]pyrimidine (200 mg, 77%) as a white solid. LC/MS ESI (m/z): 382 (M+H) ⁺ . Step 5.1-Methylcyclopropyl (2R,5S)-4-(7-(3-chlorophenyl)-5-cyclopropyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate To a solution of 7-(3-chlorophenyl)-5-cyclopropyl-4-((2S,5R)-2,5-dimethylpipe razin- 1-yl)-7H-pyrrolo[2,3-d]pyrimidine (100 mg, 0.26 mmol) in DMF (10 mL) were added 1- methylcyclopropyl pyridin-4-yl carbonate (3.0 eq., prepared following a similar procedure outlined for compound 623) and DIEA (100 mg, 0.78 mmol). After stirring at 80 ^o C overnight, the reaction was diluted with H ₂ O (50 mL) and extracted twice with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30% ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford 1- methylcyclopropyl (2R,5S)-4-(7-(3-chlorophenyl)-5-cyclopropyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (14 mg, 11%) as a white solid. LC/MS ESI (m/z): 480 (M+H) ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ 8.28 (s, 1H), 7.82 (s, 1H), 7.62 (d, J = 8.1 Hz, 1H), 7.49 (t, J = 7.3 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.26 (s, 1H), 4.99 – 4.90 (m, 1H), 4.43 (s, 1H), 3.79 (s, 3H), 3.65 (m, 1H), 2.05 (s, 1H), 1.55 (s, 3H), 1.20 – 1.11 (m, 6H), 1.04 (d, J = 8.0 Hz, 2H), 0.97 – 0.86 (m, 3H), 0.67 (m, 3H). The following compounds were prepared by a procedure similar to the synthesis of compound 654 from the corresponding aryl halide. Example 202. Synthesis of 1-methylcyclopropyl (2R,5S)-4-(7-(4-fluoropyridin-2-yl)-5- (trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimet hylpiperazine-1- carboxylate (Compound 659) Compound 659 Step 1. tert-Butyl (2R,5S)-2,5-dimethyl-4-(7-tosyl-5-(trifluoromethyl)-7H-pyrro lo[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 (26 g, 43 mmol, prepared following the procedure outlined for compound 666) in DMF (50 mL) were added methyl 2,2-difluoro-2- (fluorosulfonyl)acetate (24 g, 130 mmol) and CuI (8.0 g, 43 mmol). The resulting mixture was heated to 80 ^o C overnight. After cooling to room temperature, the reaction was partitioned between EtOAc and water. The aqueous layer was extracted twice with EtOAc and the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-2,5-dimethyl-4-(7-tosyl-5- (trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine -1-carboxylate (13 g, 55%) as a yellow oil. LC/MS ESI (m/z): 554 (M+H) ⁺ . Step 2. tert-Butyl (2R,5S)-2,5-dimethyl-4-(5-(trifluoromethyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperazine-1-carboxylate To a solution of tert-butyl (2R,5S)-2,5-dimethyl-4-(7-tosyl-5-(trifluoromethyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (12 g, 22 mmol) in THF (10 mL) was added TBAF (42 mL, 1.0 M in THF). After stirring at room temperature for 2 h, the reaction was diluted with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-2,5-dimethyl-4-(5-(trifluoromethyl)-7H-pyrrolo[2,3-d ]pyrimidin-4- yl)piperazine-1-carboxylate (7.5 g, 87%) as a yellow oil. LC/MS ESI (m/z): 400 (M+H) ⁺ . Step 3. tert-Butyl (2R,5S)-4-(7-(4-fluoropyridin-2-yl)-5-(trifluoromethyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate To a solution of tert-butyl (2R,5S)-2,5-dimethyl-4-(5-(trifluoromethyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (300 mg, 0.75 mmol) in DMF (10 mL) were added 2-bromo-4-fluoropyridine (160 mg, 0.90 mmol), CuI (70 mg, 0.37 mmol), trans-N ¹ ,N ² -dimethylcyclohexane-1,2-diamine (110 mg, 0.75 mmol) and K ₃ PO ₄ (480 mg, 2.3 mmol). The resulting mixture was stirred at 120℃ overnight. After cooling to room temperature, the reaction was partitioned between EtOAc and water and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30% ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-4-(7-(4-fluoropyridin-2-yl)-5-(trifluoromethyl)-7H-p yrrolo[2,3-d]pyrimidin-4-yl)- 2,5-dimethylpiperazine-1-carboxylate (85 mg, 23%) as a colorless oil. LC/MS ESI (m/z): 495 (M+H) ⁺ . Step 4.4-((2S,5R)-2,5-Dimethylpiperazin-1-yl)-7-(4-fluoropyridin- 2-yl)-5- (trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidine To a solution of tert-butyl (2R,5S)-4-(7-(4-fluoropyridin-2-yl)-5-(trifluoromethyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate (85 mg, 0.17 mmol) in DCM (2 mL) was added TFA (1.0 mL). The resulting mixture was stirred at room temperature for 2 h. After removal of solvent, the residue was diluted with DCM, washed with NaHCO ₃ (aq.). The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was used in the next step directly. LC/MS ESI (m/z): 395 (M+H) ⁺ . Step 5.1-Methylcyclopropyl (2R,5S)-4-(7-(4-fluoropyridin-2-yl)-5-(trifluoromethyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-ca rboxylate To a solution of 4-((2S,5R)-2,5-dimethylpiperazin-1-yl)-7-(4-fluoropyridin-2- yl)-5- (trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidine (67 mg, 0.17 mmol) in DMF (2 mL) were added 1-methylcyclopropyl pyridin-2-yl carbonate (3.0 eq., prepared following a similar procedure outlined for compound 623) and DIPEA (0.30 mL). The resulting mixture was heated to 80 ^o 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~20% ethyl acetate in petroleum ether) to give crude product which was further purified by prep- HPLC to afford 1-methylcyclopropyl (2R,5S)-4-(7-(4-fluoropyridin-2-yl)-5- (trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimet hylpiperazine-1-carboxylate (15 mg, 18%) as a white solid. LC/MS ESI (m/z): 493 (M+H) ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ 8.78 – 8.66 (m, 2H), 8.62 – 8.48 (m, 2H), 7.27 – 7.17 (m, 1H), 4.57 (s, 1H), 4.34 (s, 1H), 3.82 – 3.63 (m, 3H), 3.49 (d, J = 13.1 Hz, 1H), 1.55 (s, 3H), 1.15 – 1.08 (m, 6H), 0.89 (m, 2H), 0.71 – 0.59 (m, 2H). The following compounds were prepared by procedures analogous to the synthesis of compound 659 from the corresponding aryl halides.

Example 203. Synthesis of tert-butyl (2R,5S)-4-(7-(3-fluorophenyl)-5-methyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate (Compound 666) Compound 666 Step 1. 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 (10 g, 23 mmol, prepared following the procedure outlined for compound 602) in DIPEA (100 mL) was added tert-butyl (2R,5S)-2,5-dimethylpiperazine-1-carboxylate (9.9 g, 46 mmol). The resulting mixture was stirred at 150 ^o C for 2 h. After cooling to room temperature, the reaction was concentrated and purified by flash column chromatography (silica gel, 0~30% ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-4-(5-iodo-7-tosyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (13 g, 92%) as a yellow solid. LC/MS ESI (m/z): 612 (M+H) ⁺ . Step 2. tert-Butyl (2R,5S)-2,5-dimethyl-4-(5-methyl-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 (4.0 g, 6.7 mmol) in dioxane (50 mL) and H ₂ O (10 mL) were added 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (1.7 g, 13 mmol), K ₂ CO ₃ (2.8 g, 20 mmol) and Pd(dppf)Cl ₂ (490 mg, 0.67 mmol). The resulting mixture was heated to 70 ^o 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50% ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-2,5-dimethyl-4-(5-methyl-7-tosyl-7H-pyrrolo[2,3-d]py rimidin-4- yl)piperazine-1-carboxylate (2.0 g, 61%) as a white solid. LC/MS ESI (m/z): 500 (M+H) ⁺ . Step 3. tert-Butyl (2R,5S)-2,5-dimethyl-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin- 4- yl)piperazine-1-carboxylate To a solution of tert-butyl (2R,5S)-2,5-dimethyl-4-(5-methyl-7-tosyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperazine-1-carboxylate (2.0 g, 4.0 mmol) in THF (20 mL) was added TBAF (24 mL, 1.0 M in THF). After 5 h, the reaction was quenched with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~80% ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-2,5-dimethyl-4-(5- methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxyl ate (1.2 g, 87%) as a white solid. LC/MS ESI (m/z): 346 (M+H) ⁺ . Step 4. tert-Butyl (2R,5S)-4-(7-(3-fluorophenyl)-5-methyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate To a solution of tert-butyl (2R,5S)-2,5-dimethyl-4-(5-methyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperazine-1-carboxylate (50 mg, 0.15 mmol) in DMF (5 mL) were added 1-fluoro-3-iodobenzene (67 mg, 0.30 mmol), trans-N,N’-dimethylcyclohexane-1,2-diamine (11 mg, 0.08 mmol), CuI (14 mg, 0.08 mmol) and K ₃ PO ₄ (95 mg, 0.45 mmol). The resulting mixture was heated to 120 ^o 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford tert-butyl (2R,5S)-4-(7-(3- fluorophenyl)-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5- dimethylpiperazine-1- carboxylate (45 mg, 71%) as a white solid. LC/MS ESI (m/z): 440 (M+H) ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ 8.29 (s, 1H), 7.62 (d, J = 10.3 Hz, 1H), 7.52 (m, 2H), 7.39 (s, 1H), 7.11 (m, 1H), 4.54 (s, 1H), 4.38 (s, 1H), 3.77 (m, 2H), 3.65 (d, J = 12.4 Hz, 1H), 3.56 (d, J = 13.2 Hz, 1H), 2.49 (s, 3H), 1.50 (s, 9H), 1.19 – 1.13 (m, 6H). The following compounds were prepared by procedures analogous to the synthesis of compound 666 from the corresponding aryl halides and amines. Example 204. Synthesis of tert-butyl (2R,5S)-4-(5-(difluoromethyl)-7-(3-fluorophenyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-ca rboxylate (Compound 695) Compound 695 Step 1. tert-Butyl (2R,5S)-4-(7-(3-fluorophenyl)-5-formyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate To a solution of tert-butyl (2R,5S)-4-(5-formyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5- dimethylpiperazine-1-carboxylate (400 mg, 1.1 mmol, prepared following the procedure outlined for compound 633) in DMF (5 mL) were added 1-fluoro-3-iodobenzene (490 mg, 2.2 mmol), trans-N,N’-dimethylcyclohexane-1,2-diamine (78 mg, 0.55 mmol), CuI (105 mg, 0.55 mmol) and K ₃ PO ₄ (1.4 g, 6.7 mmol). The resulting mixture was heated to 120 ^o 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50% ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-4-(7-(3-fluorophenyl)-5-formyl-7H-pyrrolo[2,3-d]pyri midin-4-yl)-2,5- dimethylpiperazine-1-carboxylate (280 mg, 56%) as a white solid. LC/MS ESI (m/z): 454 (M+H) ^+. Step 2. tert-Butyl (2R,5S)-4-(5-(difluoromethyl)-7-(3-fluorophenyl)-7H-pyrrolo[ 2,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate To a solution of tert-butyl (2R,5S)-4-(7-(3-fluorophenyl)-5-formyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (280 mg, 0.61 mmol) in DCM (10 mL) at 0℃ was added BAST (680 mg, 3.1 mmol) dropwise. The resulting mixture was stirred at 40℃ overnight. After cooling to room temperature, the reaction was partitioned between DCM and NaHCO ₃ (aq.). The aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. the residue was purified by prep-HPLC to afford tert-butyl (2R,5S)-4-(5- (difluoromethyl)-7-(3-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimid in-4-yl)-2,5- dimethylpiperazine-1-carboxylate (140 mg, 48%) as a white solid. LC/MS ESI (m/z): 476 (M+H) ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ 8.39 (s, 1H), 7.95 (d, J = 1.6 Hz, 1H), 7.65 – 7.61 (m, 1H), 7.59 – 7.53 (m, 2H), 7.31 – 7.01 (m, 2H), 4.69 – 4.62 (m, 1H), 4.37 (s, 1H), 3.84 – 3.73 (m, 2H), 3.62 (m, 2H), 1.50 (s, 9H), 1.18 – 1.12 (m, 6H). Example 205. Synthesis of tert-butyl (2R,5S)-4-(5-ethyl-7-(4-(trifluoromethyl)pyridin-2- yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine- 1-carboxylate (Compound 696) Step 1. tert-Butyl (2R,5S)-2,5-dimethyl-4-(7-tosyl-5-vinyl-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 (1.5 g, 2.5 mmol, prepared following the procedure outlined for compound 666) in dioxane (15 mL) and H ₂ O (3 mL) were added 4,4,5,5- tetramethyl-2-vinyl-1,3,2-dioxaborolane (770 mg, 5.0 mmol), K ₂ CO ₃ (1.0 g, 7.5 mmol) and Pd(dppf)Cl ₂ (220 mg, 0.30 mmol). The resulting mixture was heated to 90 ^o 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50% ethyl acetate in petroleum ether) to afford tert- butyl (2R,5S)-2,5-dimethyl-4-(7-tosyl-5-vinyl-7H-pyrrolo[2,3-d]pyr imidin-4-yl)piperazine-1- carboxylate (900 mg, 72%) as a white solid. LC/MS ESI (m/z): 512 (M+H) ⁺ . Step 2. tert-Butyl (2R,5S)-2,5-dimethyl-4-(5-vinyl-7H-pyrrolo[2,3-d]pyrimidin-4 - yl)piperazine-1-carboxylate To a solution of tert-butyl (2R,5S)-2,5-dimethyl-4-(7-tosyl-5-vinyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperazine-1-carboxylate (900 mg, 1.8 mmol) in THF (20 mL) was added TBAF (11 mL, 1.0 M in THF). After 5 h, the reaction was diluted with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~80% ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-2,5-dimethyl-4-(5- vinyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxyla te (540 mg, 86%) as a white solid. LC/MS ESI (m/z): 358 (M+H) ⁺ . Step 3. tert-Butyl (2R,5S)-2,5-dimethyl-4-(7-(4-(trifluoromethyl)pyridin-2-yl)- 5-vinyl- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate To a solution of tert-butyl (2R,5S)-2,5-dimethyl-4-(5-vinyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperazine-1-carboxylate (270 mg, 0.75 mmol) in DMF (5 mL) were added 2-bromo-4-(trifluoromethyl)pyridine (340 mg, 1.5 mmol), trans-N,N'-dimethylcyclohexane- 1,2-diamine (53 mg, 0.38 mmol), CuI (71 mg, 0.38 mmol) and K ₃ PO ₄ (490 mg, 2.3 mmol). The resulting mixture was heated to 120 ^o 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50% ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-2,5-dimethyl-4-(7-(4-(trifluoromethyl)pyridin-2-yl)- 5-vinyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (160 mg, 42%) as a white solid. LC/MS ESI (m/z): 503 (M+H) ⁺ . Step 4. tert-Butyl (2R,5S)-2,5-dimethyl-4-(7-(4-(trifluoromethyl)pyridin-2-yl)- 5-vinyl- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate To a solution of tert-butyl (2R,5S)-2,5-dimethyl-4-(7-(4-(trifluoromethyl)pyridin-2- yl)-5-vinyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-car boxylate (160 mg, 0.32 mmol) in MeOH (10 mL) was added Pd/C (100 mg, 10% on carbon, wetted with ca.55% water), the resulting mixture was stirred under H ₂ (~0.1 MPa) overnight. The reaction mixture was then filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50% ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-4-(5-ethyl-7-(4- (trifluoromethyl)pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)-2,5-dimethylpiperazine-1- carboxylate (42 mg, 26%) as a white solid. LC/MS ESI (m/z): 505 (M+H) ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ 9.24 (s, 1H), 8.70 (d, J = 5.1 Hz, 1H), 8.47 (s, 1H), 8.10 (s, 1H), 7.54 – 7.51 (m, 1H), 4.54 – 4.47 (m, 1H), 4.37 (s, 1H), 3.85 – 3.76 (m, 2H), 3.70 – 3.63 (m, 1H), 3.51 – 3.47 (m, 1H), 2.91 (q, J = 7.4 Hz, 2H), 1.50 (s, 9H), 1.38 (t, J = 7.4 Hz, 3H), 1.14 (m, 6H). The following compounds were prepared by procedures analogous to the synthesis of compound 696 from the corresponding aryl halides and boronic pinacol esters. Example 206. Synthesis of tert-butyl (2R,5S)-4-(7-(4-cyanopyridin-2-yl)-5-isopropyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate (Compound 700) Step 1. tert-Butyl (2R,5S)-2,5-dimethyl-4-(5-(prop-1-en-2-yl)-7-tosyl-7H-pyrrol o[2,3- d]pyrimidin-4-yl)piperazine-1-carboxylate The mixture of tert-butyl (2R,5S)-4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4- yl)-2,5-dimethylpiperazine-1-carboxylate (1.2 g, 2.0 mmol, prepared following the procedure outlined for compound 666), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (500 mg, 2.9 mmol), K ₂ CO ₃ (810 mg, 5.9 mmol) and Pd(dppf)Cl ₂ (160 mg, 0.20 mmol) in dioxane (20 mL) and water (1 mL) was heated to 90 ^o 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 in petroleum ether) to afford tert-butyl (2R,5S)-2,5-dimethyl- 4-(5-(prop-1-en-2-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-y l)piperazine-1-carboxylate (620 mg, 60%) as a white solid. LC/MS ESI (m/z): 526 (M+H) ⁺ . Step 2. tert-Butyl (2R,5S)-2,5-dimethyl-4-(5-(prop-1-en-2-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-(prop-1-en-2-yl)-7-tosyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (470 mg, 0.89 mmol) in THF (2 mL) at 0 ^o C was added TBAF (5.0 mL, 1.0M in THF). After 4 h, the reaction was partitioned between EtOAc and sat. NH ₄ Cl (aq.). The aqueous layer was extracted with EtOAc. The combined organic layers were washed twice with sat. NH ₄ Cl (aq.), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~60% ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-2,5-dimethyl-4-(5- (prop-1-en-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine- 1-carboxylate (170 mg, 51%). LC/MS ESI (m/z): 372 (M+H) ⁺ . Step 3. tert-Butyl (2R,5S)-4-(7-(4-(ethoxycarbonyl)pyridin-2-yl)-5-(prop-1-en-2 -yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-ca rboxylate To a solution of tert-butyl (2R,5S)-2,5-dimethyl-4-(5-(prop-1-en-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (170 mg, 0.46 mmol) in DMF (5 mL) were added ethyl 2-bromoisonicotinate (160 mg, 0.69 mmol), CuI (44 mg, 0.23 mmol), K ₃ PO ₄ (390 mg, 1.8 mmol) and trans-N ¹ ,N ² -dimethylcyclohexane-1,2-diamine (33 mg, 0.23 mmol). The resulting mixture was heated to 90 ^o C for 4 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 and dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~40% ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-4-(7-(4-(ethoxycarbonyl)pyridin-2-yl)-5-(prop-1-en-2 -yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (180 mg, 75%) as a solid. LC/MS ESI (m/z): 521 (M+H) ⁺ . Step 4. tert-Butyl (2R,5S)-4-(7-(4-(ethoxycarbonyl)pyridin-2-yl)-5-isopropyl-7H - pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate To a solution of tert-butyl (2R,5S)-4-(7-(4-(ethoxycarbonyl)pyridin-2-yl)-5-(prop-1- en-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpipera zine-1-carboxylate (180 mg, 0.35 mmol) in MeOH (15 mL) was added palladium (100 mg, 10% on carbon, wetted with ca.55% water). The resulting mixture was stirred under H ₂ atmosphere (~0.1 MPa) overnight. The reaction mixture was then filtered and concentrated. The residue was used in the next step directly. LC/MS ESI (m/z): 523 (M+H) ⁺ . Step 5.2-(4-((2S,5R)-4-(tert-Butoxycarbonyl)-2,5-dimethylpiperazi n-1-yl)-5- isopropyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)isonicotinic acid To a solution of tert-butyl (2R,5S)-4-(7-(4-(ethoxycarbonyl)pyridin-2-yl)-5-isopropyl- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-ca rboxylate (180 mg, 0.34 mmol) in MeOH (5 mL) and water (4 mL) was added NaOH (27 mg, 0.68 mmol). After 2h, the resulting mixture was acidified by 1 N HCl to pH 6 and extracted twice with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was used in the next step directly. LC/MS ESI (m/z): 495 (M+H) ⁺ . Step 6. tert-Butyl (2R,5S)-4-(7-(4-carbamoylpyridin-2-yl)-5-isopropyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate To a solution of 2-(4-((2S,5R)-4-(tert-butoxycarbonyl)-2,5-dimethylpiperazin- 1-yl)-5- isopropyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)isonicotinic acid (140 mg, 0.28 mmol) in DMF (5 mL) were added NH ₄ Cl (75 mg, 1.4 mmol), EDCI (81 mg, 0.42 mmol) and DIEA (0.39 mL, 2.2 mmol). The resulting mixture was stirred at room temperature overnight. The reaction was partitioned between EtOAc and water. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~100% ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-4-(7-(4-carbamoylpyridin-2-yl)- 5-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpip erazine-1-carboxylate (110 mg, 79%). LC/MS ESI (m/z): 494 (M+H) ⁺ . Step 7. tert-Butyl (2R,5S)-4-(7-(4-cyanopyridin-2-yl)-5-isopropyl-7H-pyrrolo[2, 3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate To a solution of tert-butyl (2R,5S)-4-(7-(4-carbamoylpyridin-2-yl)-5-isopropyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate (110 mg, 0.22 mmol) in DCM (5 mL) at 0 ^o C were added DIEA (0.08 mL, 0.45 mmol), followed by TFAA (70 mg, 0.33 mmol). After 3 h, the reaction was quenched with ice water. The layers were separated, and the aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. Purification by prep-HPLC afforded tert-butyl (2R,5S)-4-(7-(4-cyanopyridin-2-yl)-5-isopropyl-7H-pyrrolo[2, 3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (41 mg, 39%) as a white solid. LC/MS ESI (m/z): 476 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.27 (d, J = 1.0 Hz, 1H), 8.54 (dd, J = 5.0, 0.8 Hz, 1H), 8.45 (m, 1H), 7.91 (m, 1H), 7.28 (dd, J = 5.0, 1.3 Hz, 1H), 4.46 – 4.21 (m, 2H), 3.76 – 3.66 (m, 2H), 3.58 (m, 1H), 3.36 (m, 1H), 3.19 – 3.02 (m, 1H), 1.43 (s, 9H), 1.39 (d, J = 6.6 Hz, 3H), 1.21 (d, J = 6.7 Hz, 3H), 1.10 – 1.04 (m, 6H). Example 207. Synthesis of tert-butyl (2R,5S)-4-(1-(4-fluoropyridin-2-yl)-3-methyl-1H- pyrrolo[3,2-c]pyridin-4-yl)-2,5-dimethylpiperazine-1-carboxy late (Compound 701) Compound 701 Step 1. tert-Butyl (2R,5S)-2,5-dimethyl-4-(3-methyl-1-tosyl-1H-pyrrolo[3,2-c]py ridin- 4-yl)piperazine-1-carboxylate To a mixture of tert-butyl (2R,5S)-4-[3-iodo-1-(4-methylbenzenesulfonyl)-1H- pyrrolo[3,2-c]pyridin-4-yl]-2,5-dimethylpiperazine-1-carboxy late (2.4 g, 3.9 mmol, prepared following the procedure outlined for compound 620) in toluene (50 mL) and water (3 mL) were added methylboronic acid (0.47 g, 7.9 mmol) and K ₂ CO ₃ (2.7 g, 20 mmol) and PdCl ₂ (dtbpf) (0.32 g, 0.39 mmol). The resulting mixture was stirred at 100 ^o C for 3 h. After cooling to room temperature, the reaction mixture was partitioned between NH ₄ Cl (aq.) and EtOAc, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~40% ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-2,5-dimethyl-4-(3-methyl-1-tosyl-1H-pyrrolo[3,2-c]py ridin-4- yl)piperazine-1-carboxylate (1.3 g, 66%) as a white solid. LC/MS ESI (m/z): 499 (M+H) ⁺ . Step 2. tert-Butyl (2R,5S)-2,5-dimethyl-4-(3-methyl-1H-pyrrolo[3,2-c]pyridin-4- yl)piperazine-1-carboxylate To a solution of tert-butyl (2R,5S)-2,5-dimethyl-4-(3-methyl-1-tosyl-1H-pyrrolo[3,2- c]pyridin-4-yl)piperazine-1-carboxylate (1.3 g, 2.6 mmol) in THF (2 mL) was added TBAF (3.9 mL, 1.0 M in THF) at room temperature. The mixture was stirred at room temperature overnight. The reaction was poured into water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~80% ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-2,5-dimethyl-4-(3-methyl-1H- pyrrolo[3,2-c]pyridin-4-yl)piperazine-1-carboxylate (700 mg, 78%) as a white solid. LC/MS ESI (m/z): 345 (M+H) ⁺ . Step 3. tert-Butyl (2R,5S)-4-(1-(4-fluoropyridin-2-yl)-3-methyl-1H-pyrrolo[3,2- c]pyridin-4-yl)-2,5-dimethylpiperazine-1-carboxylate A mixture of tert-butyl (2R,5S)-2,5-dimethyl-4-(3-methyl-1H-pyrrolo[3,2-c]pyridin- 4-yl)piperazine-1-carboxylate (100 mg, 0.32 mmol), 2-bromo-4-fluoropyridine (62 mg, 0.35 mmol), CuI (60 mg, 0.30 mmol) and K ₃ PO ₄ (200 mg, 0.95 mmol) and trans-N ¹ ,N ² - dimethylcyclohexane-1,2-diamine (14 mg, 0.10 mmol) in DMF (2 mL) was stirred at 80 ^o C for 3 h. After cooling to room temperature, the reaction was poured into water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~40% ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-4-(1-(4- fluoropyridin-2-yl)-3-methyl-1H-pyrrolo[3,2-c]pyridin-4-yl)- 2,5-dimethylpiperazine-1- carboxylate (17 mg, 13%) as a yellow solid. LC/MS ESI (m/z): 440 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 8.60 (dd, J = 9.2, 5.7 Hz, 1H), 8.07 – 8.02 (m, 1H), 7.96 (d, J = 5.9 Hz, 1H), 7.87 (s, 1H), 7.72 (d, J = 10.1 Hz, 1H), 7.31 – 7.24 (m, 1H), 4.37 – 4.31 (m, 1H), 3.94 – 3.88 (m, 1H), 3.69 (d, J = 12.9 Hz, 1H), 3.61 – 3.54 (m, 2H), 2.98 (d, J = 12.1 Hz, 1H), 2.52 (s, 3H), 1.43 (s, 9 H), 1.22 (d, J = 6.7 Hz, 3H), 0.83 (d, J = 6.3 Hz, 3H). The following compounds were prepared by procedures analogous to the synthesis of compound 701 from corresponding chiral amines and boronic acids. Example 208. Synthesis of tert-butyl (2R,5S)-4-(1-(4-cyanopyridin-2-yl)-3-methyl-1H- pyrrolo[3,2-c]pyridin-4-yl)-2,5-dimethylpiperazine-1-carboxy late (Compound 705) Compound 705 To a solution of tert-butyl (2R,5S)-2,5-dimethyl-4-(3-methyl-1H-pyrrolo[3,2- c]pyridin-4-yl)piperazine-1-carboxylate (100 mg, 0.29 mmol, prepared following the procedure outlined for compound 701) in DMF (6 mL) were added 2-fluoropyridine-4- carbonitrile (97 mg, 0.79 mmol) and Cs ₂ CO ₃ (520 mg, 1.6 mmol). The resulting mixture was stirred at 60 ^o C overnight. After cooling to room temperature, the reaction was poured into water and EtOAc. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~40% ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-4-(1-(4-cyanopyridin-2-yl)-3-methyl-1H-pyrrolo[3,2-c ]pyridin-4- yl)-2,5-dimethylpiperazine-1-carboxylate (80 mg, 60%) as a light yellow solid. LC/MS ESI (m/z): 447 (M+H) ⁺ . ¹ H NMR(400 MHz, DMSO-d6) δ 8.79 (d, J = 5.0 Hz, 1H), 8.27 (s, 1H), 8.03 (d, J = 5.9 Hz, 1H), 7.98 (d, J = 5.9 Hz, 1H), 7.92 (s, 1H), 7.74 (dd, J = 5.0, 1.1 Hz, 1H), 4.38 – 4.29 (m, 1H), 3.95 – 3.87 (m, 1H), 3.68 (d, J = 11.5 Hz, 1H), 3.62 – 3.52 (m, 2H), 2.98 (d, J = 12.5 Hz, 1H), 2.53 (s, 3H), 1.43 (s, 9H), 1.22 (d, J = 6.7 Hz, 3H), 0.83 (d, J = 6.5 Hz, 3H). Example 209. Synthesis of tert-butyl (S)-4-(3-cyclobutyl-1-(3-fluorophenyl)-1H- pyrrolo[3,2-c]pyridin-4-yl)-3-methylpiperazine-1-carboxylate (Compound 706)

Step 1.3-Bromo-1-tosyl-1H-pyrrolo[3,2-c]pyridine To a suspension of NaH (120 mg, 3.1 mmol, 60 wt% in mineral oil) in anhydrous DMF (10 mL) at 0 ^o C were added 3-bromo-1H-pyrrolo[3,2-c]pyridine (400 mg, 2.0 mmol) in portions, followed by 4-methylbenzenesulfonyl chloride (580 mg, 3.1 mmol) in portions. After 40 min, the reaction was poured into ice water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~40% ethyl acetate in petroleum ether) to afford 3-bromo-1-tosyl-1H-pyrrolo[3,2-c]pyridine (650 mg , 91%) as a light yellow solid. LC/MS ESI (m/z): 351, 353 (M+H) ⁺ . Step 2.3-Bromo-1-tosyl-1H-pyrrolo[3,2-c]pyridine To a solution of 3-bromo-1-tosyl-1H-pyrrolo[3,2-c]pyridine (600 mg, 1.7 mmol) in toluene (10 mL) and H ₂ O (1 mL) were added cyclobutylboronic acid (340 mg, 3.4 mmol), K ₂ CO ₃ (1.1 g, 8.5 mmol) and Pd(dptf)Cl ₂ (110 mg, 0.17 mmol). The resulting mixture was stirred at 90℃ overnight. After cooling to room temperature, the reaction was concentrated and the residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford 3-cyclobutyl-1-tosyl-1H-pyrrolo[3,2-c]pyridine (220 mg, 39%) as a yellow solid. LC/MS ESI (m/z): 327 (M+H) ⁺ . Step 3.3-Cyclobutyl-1-tosyl-1H-pyrrolo[3,2-c]pyridine 5-oxide To a solution of 3-cyclobutyl-1-tosyl-1H-pyrrolo[3,2-c]pyridine (200 mg, 0.61 mmol) in DCM (10 ml) at 0 ^o C was added 3-chlorobenzoperoxoic acid (210 mg, 1.2 mmol) in portions. The resulting mixture was stirred at room temperature under N ₂ overnight. The reaction was quenched with H ₂ O and extracted twice with DCM. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~20% MeOH in DCM) to afford 3- cyclobutyl-1-tosyl-1H-pyrrolo[3,2-c]pyridine 5-oxide (140 mg, 67%) as a yellow solid. LC/MS ESI (m/z): 343 (M+H) ⁺ . Step 4. tert-Butyl (S)-4-(3-cyclobutyl-1-tosyl-1H-pyrrolo[3,2-c]pyridin-4-yl)-3 - methylpiperazine-1-carboxylate To a solution of 3-cyclobutyl-1-tosyl-1H-pyrrolo[3,2-c]pyridine 5-oxide (140 mg, 0.41 mmol), tert-butyl (S)-3-methylpiperazine-1-carboxylate (410 mg, 2.0 mmol) and DIPEA (200 mg, 1.5 mmol) in DCM (10 mL) was added PyBrOP (290 mg, 0.60 mmol). The resulting mixture was stirred at room temperature under N ₂ overnight. 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~40% ethyl acetate in petroleum ether) to afford tert-butyl (S)-4-(3-cyclobutyl-1-tosyl-1H- pyrrolo[3,2-c]pyridin-4-yl)-3-methylpiperazine-1-carboxylate (60 mg, 28% yield) as a withe solid. LC/MS ESI (m/z): 525 (M+H) ⁺ . Step 5. tert-Butyl (S)-4-(3-cyclobutyl-1H-pyrrolo[3,2-c]pyridin-4-yl)-3- methylpiperazine-1-carboxylate To a solution of ert-butyl (S)-4-(3-cyclobutyl-1-tosyl-1H-pyrrolo[3,2-c]pyridin-4-yl)- 3-methylpiperazine-1-carboxylate (60 mg, 0.12 mmol) in THF (5 mL) was added TBAF (1.0 mL, 1.0 M in THF). After 2 h, the reaction was partitioned between EtOAc and brine. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was used in the next step directly. LC/MS ESI (m/z): 371 (M+H) ⁺ . Step 6. tert-Butyl (S)-4-(3-cyclobutyl-1-(3-fluorophenyl)-1H-pyrrolo[3,2-c]pyri din-4- yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl (S)-4-(3-cyclobutyl-1H-pyrrolo[3,2-c]pyridin-4-yl)-3- methylpiperazine-1-carboxylate (25 mg, 0.07 mmol) in DMF (5 mL) were added 1-fluoro-3- iodobenzene (45 mg, 0.20 mmol), trans-N,N'-dimethylcyclohexane-1,2-diamine (5.0 mg, 0.04 mmol), CuI (7.0 mg, 0.04 mmol) and K ₃ PO ₄ (43 mg, 0.20 mmol). The resulting mixture was heated to 120 ^o 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50% ethyl acetate in petroleum ether) to afford tert-butyl (S)- 4-(3-cyclobutyl-1-(3-fluorophenyl)-1H-pyrrolo[3,2-c]pyridin- 4-yl)-3-methylpiperazine-1- carboxylate (9.6 mg, 31%) as a white solid. LC/MS ESI (m/z): 465 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 5.8 Hz, 1H), 7.52 – 7.46 (m, 1H), 7.30 – 7.27 (m, 1H), 7.23 – 7.16 (m, 3H), 7.12 – 7.06 (m, 1H), 4.09 – 4.01 (m, 1H), 3.91 (s, 1H), 3.81 (s, 1H), 3.68 – 3.61 (m, 1H), 3.51 (s, 1H), 3.27 (d, J = 11.2 Hz, 1H), 3.19 – 3.11 (m, 1H), 3.03 – 2.95 (m, 1H), 2.61 – 2.53 (m, 1H), 2.46 – 2.38 (m, 1H), 2.22 – 2.14 (m, 1H), 2.10 – 2.01 (m, 2H), 1.93 (m, 1H), 1.50 (s, 9H), 0.96 (d, J = 6.2 Hz, 3H).

Example 210. Synthesis of tert-butyl (2R,5S)-4-(7-(4-cyanopyridin-2-yl)-5- (trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-methyl- 2-(methyl-d ₃ )piperazine-1- carboxylate (Compound 707) Compound 707 Step 1.2-(4-Chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)isonico tinonitrile To a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (7.0 g, 25 mmol) and 2-fluoroisonicotinonitrile (18g, 150 mmol) in CH ₃ CN (70 mL) was added Cs ₂ CO ₃ (12 g, 38 mmol). The resulting mixture was stirred at 25℃ under N ₂ for 72 h. The crude product was obtained by filtration and washed with water and CH ₃ CN to afford 2-(4-chloro-5-iodo-7H- pyrrolo[2,3-d]pyrimidin-7-yl)isonicotinonitrile (9.0g , 94%) as a light brown solid. LC/MS ESI (m/z): 382 (M+H) ⁺ . Step 2.2-(4-Chloro-5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin -7- yl)isonicotinonitrile To a mixture of 2-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7- yl)isonicotinonitrile (1.4 g, 3.7 mmol) and CuI (720 mg, 3.8 mmol) in DMF (15 mL) was added methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (2.9 g, 15 mmol) under N ₂ . The resulting mixture was stirred at 100℃ under N ₂ overnight. The reaction was partitioned between EtOAc and brine. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified through flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to afford 2-(4-chloro-5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-7 - yl)isonicotinonitrile (670 mg, 80% purity, 1.7 mmol, 44% yield) as a white solid. LC/MS ESI (m/z): 324 (M+H) ⁺ . Step 3. tert-Butyl (2R,5S)-4-(7-(4-cyanopyridin-2-yl)-5-(trifluoromethyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-5-methyl-2-(methyl-d ₃ )piperazine-1-carboxylate To a solution of tert-butyl (2R,5S)-5-methyl-2-(methyl-d ₃ )piperazine-1-carboxylate (30 mg, 0.13 mmol, prepared following the procedure outlined for compound 709) in DIPEA (2 mL) was added 2-(4-chloro-5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-7 - yl)isonicotinonitrile (89 mg, 0.27 mmol). The resulting mixture was stirred at 120℃ for 2 h. After cooling to room temperature, the reaction was concentrated and the residue was purified by flash column chromatography (silica gel, 0~20%, ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-4-(7-(4-cyanopyridin-2-yl)-5-(trifluoromethyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-5-methyl-2-(methyl-d ₃ )piperazine-1-carboxylate (30 mg, 43%) as a yellow oil. It was purified by prep-HPLC to afford 5.8 mg of title compound as a white solid. LC/MS ESI (m/z): 505 (M+H) ⁺ . ¹ H NMR (400 MHz, CD3OD) δ 9.23 – 9.12 (m, 1H), 8.76 (m, 2H), 8.59 (s, 1H), 7.70 (dd, J = 5.0, 1.3 Hz, 1H), 4.62 – 4.54 (m, 1H), 4.34 (s, 1H), 3.80 (dd, J = 13.6, 4.1 Hz, 1H), 3.75 (dd, J = 13.3, 2.8 Hz, 1H), 3.64 (m, 1H), 3.51 (d, J = 13.6 Hz, 1H), 1.50 (s, 9H), 1.14 (d, J = 6.6 Hz, 3H). The following compound was prepared by a procedure analogous to the synthesis of compound 707 from the corresponding amine (EtOH as solvent, DIEA as base, 100 ^o C). Example 211. Synthesis of tert-butyl (2R,5S)-4-(7-(4-cyanopyridin-2-yl)-5-(2- fluorophenyl)-5H-pyrrolo[3,2-d]pyrimidin-4-yl)-5-methyl-2-(m ethyl-d ₃ )piperazine-1- carboxylate (Compound 709)

Step 1. Ethyl (R,E)-2-((tert-butylsulfinyl)imino)acetate To a solution of ethyl 2-oxoacetate (6.4 g, 63 mmol) in CH ₂ Cl ₂ (300 mL) were added (R)-2-methylpropane-2-sulfinamide (7.6 g, 63 mmol) and 4 Å molecular sieves (20 g). After 72 h, the mixture was filtered through a bed of Celite and washed with EtOAc. The filtrate was dried over Na2SO4, filtered and concentrated. The residue was purified with flash column chromatography (silica gel, 0~20% ethyl acetate in petroleum ether) to afford ethyl (R,E)-2- ((tert-butylsulfinyl)imino)acetate (7.2 g, 56%) as a colorless oil. Step 2. Ethyl ((R)-tert-butylsulfinyl)-D-alaninate-3,3,3-d3 To a solution of ethyl (R,E)-2-((tert-butylsulfinyl)imino)acetate (6.2 g, 30 mmol) in DCM (400 mL) and THF (120 mL) at -78 ^o C was added BF ₃ ·Et ₂ O (7.4 mL, 60 mmol) dropwise under N ₂ . The resulting mixture was stirred at -78 ℃ for 5 min and treated with CD ₃ MgI (1.0 M in Et ₂ O, 60 mL, 60 mmol) dropwise. After stirring at -78 ^o C for 10 min, the reaction was quenched with NaHCO ₃ (aq.) and partitioned between EtOAc and brine. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to afford ethyl ((R)-tert-butylsulfinyl)-D-alaninate-3,3,3-d ₃ (1.4 g, 21% yield, dr = 97/3) as a white solid. LC/MS ESI (m/z): 225 (M+H) ⁺ . The configuration was verified by ¹ H NMR (Reference: J. Org. Chem.1999, 64, 3396-3397). Step 3. Ethyl D-alaninate-3,3,3-d ₃ To a solution of ethyl ((R)-tert-butylsulfinyl)-D-alaninate-3,3,3-d ₃ (1.4 g, 6.2 mmol) in MeOH (30 mL) were added HCl (5.0 mL, 4.0 M in dioxane). The resulting mixture was stirred at room temperature under N ₂ for 2 h. The solvent of reaction was removed under vacuum to afford ethyl D-alaninate-3,3,3-d ₃ , as a white solid (1.0 g crude HCl salt). LC/MS ESI (m/z): 121 (M+H) ⁺ . Step 4. Ethyl (tert-butoxycarbonyl)-D-alaninate-3,3,3-d ₃ To a solution of ethyl D-alaninate-3,3,3-d3 (1.0 g crude HCl salt) in MeOH (30 mL) were added TEA (1.7 mL, 12 mmol) and Boc ₂ O (1.5 g, 6.9 mmol). The resulting mixture was stirred at room temperature under N ₂ for 2 h. The reaction was partitioned between EtOAc and NH ₄ Cl (aq.). The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated to afford crude product ethyl (tert-butoxycarbonyl)-D-alaninate-3,3,3-d ₃ (1.4 g crude) as a white solid. LC/MS ESI (m/z): 221 (M+H) ⁺ . Step 5. (tert-Butoxycarbonyl)-D-alanine-3,3,3-d ₃ To a solution of ethyl (tert-butoxycarbonyl)-D-alaninate-3,3,3-d ₃ (1.4 g crude) in EtOH (20 mL) and H ₂ O (10 mL) in an ice bath was added LiOH (310 mg, 13 mmol). The resulting mixture was stirred at room temperature under N ₂ for 1 h. The reaction was partitioned between EtOAc and brine. The aqueous layer was acidified by HCl (1.0 M) to pH 3 and extracted twice with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to afford (tert-butoxycarbonyl)-D-alanine-3,3,3-d ₃ (900 mg, 75% yield over three steps) LC/MS ESI (m/z): 193 (M+H) ⁺ . Step 6. Methyl N-benzyl-N-((tert-butoxycarbonyl)-D-alanyl-3,3,3-d ₃ )-L-alaninate To a solution of (tert-butoxycarbonyl)-D-alanine-3,3,3-d ₃ (900 mg, 4.7 mmol) and methyl benzyl-L-alaninate hydrochloride (1.2 g, 5.2 mmol) in DMF (20 mL) were added DIPEA (2.4 g, 19 mmol) and HATU (2.7 g, 7.0 mmol). The resulting mixture was stirred at room temperature under N ₂ overnight. The reaction was partitioned between EtOAc and aqueous NaHCO ₃ . The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~60%, ethyl acetate in petroleum ether) to afford methyl N-benzyl-N-((tert-butoxycarbonyl)-D-alanyl-3,3,3-d ₃ )-L- alaninate (1.4 g, 81% yield) as a yellow solid. LC/MS ESI (m/z): 368 (M+H) ⁺ . Step 7. Methyl N-(D-alanyl-3,3,3-d ₃ )-N-benzyl-L-alaninate To a solution of methyl N-benzyl-N-((tert-butoxycarbonyl)-D-alanyl-3,3,3-d ₃ )-L- alaninate (1.4 g, 3.8 mmol) in DCM (20 mL) at 0 ^o C was added TFA (10 mL). The resulting mixture was stirred at room temperature under N ₂ for 3 h. The solvent of the reaction was removed under vacuum to afford crude product methyl N-(D-alanyl-3,3,3-d ₃ )-N-benzyl-L- alaninate (1.5 g crude TFA salt) as a yellow solid. LC/MS ESI (m/z): 268 (M+H) ⁺ . Step 8. (3R,6S)-1-Benzyl-6-methyl-3-(methyl-d ₃ )piperazine-2,5-dione A solution of methyl N-(D-alanyl-3,3,3-d ₃ )-N-benzyl-L-alaninate (1.5 g crude TFA salt) in MeOH (10 mL) was heated at 70 ℃ under N ₂ for 4 h. The reaction mixture was then partitioned between EtOAc and brine aqueous. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated to afford (3R,6S)-1-benzyl-6-methyl-3-(methyl-d ₃ )piperazine-2,5-dione (1.0 g crude) as a yellow solid. LC/MS ESI (m/z): 236 (M+H) ⁺ . Step 9. tert-Butyl (2R,5S)-4-benzyl-5-methyl-2-(methyl-d ₃ )piperazine-1-carboxylate A solution of (3R,6S)-1-benzyl-6-methyl-3-(methyl-d ₃ )piperazine-2,5-dione (1.0 g crude) in THF (10 mL) in an ice bath under N ₂ was treated with LiAlH ₄ (1.0 M in THF, 20 mL) dropwise. The reaction mixture was stirred at 70℃ for 3 h. The reaction mixture was carefully quenched with 20% NaOH (20 mL) and the resulting mixture was used in the next step directly. LC/MS ESI (m/z): 208 (M+H) ⁺ . The mixture was taken up in THF-water and was then treated with Boc ₂ O (1.7 g, 7.6 mmol). After stirring at room temperature overnight, the reaction mixture was filtered. The residue was purified by flash column chromatography (silica gel, 0~10%, ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-4-benzyl-5-methyl-2-(methyl-d ₃ )piperazine-1- carboxylate (990 mg, 85% yield dr = 90/10) as a colorless oil. LC/MS ESI (m/z): 308 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.37 – 7.28 (m, 4H), 7.26 – 7.21 (m, 1H), 4.17 (d, J = 3.9 Hz, 1H), 3.69 – 3.57 (m, 2H), 3.46 (d, J = 13.6 Hz, 1H), 3.30 (dd, J = 13.0, 3.7 Hz, 1H), 2.92 (dd, J = 10.9, 5.9 Hz, 1H), 2.69 (dd, J = 11.7, 4.4 Hz, 1H), 2.19 (dd, J = 11.7, 1.9 Hz, 1H), 1.46 (s, 9H), 0.98 (d, J = 6.5 Hz, 3H). Step 10. tert-Butyl (2R,5S)-5-methyl-2-(methyl-d3)piperazine-1-carboxylate To a solution of tert-butyl (2R,5S)-4-benzyl-5-methyl-2-(methyl-d ₃ )piperazine-1- carboxylate (550 mg, 1.7 mmol) in MeOH (15 mL) was added Pd (200 mg, 10% on carbon(wet)). After stirring at room temperature for 2 h under H ₂ atmosphere (~0.1 MPa), the reaction was filtered and the filtrate was concentrated to afford tert-butyl (2R,5S)-5-methyl-2- (methyl-d ₃ )piperazine-1-carboxylate (320 mg, 82%) as a yellow oil. LC/MS ESI (m/z): 218 (M+H) ⁺ . Step 11.7-Bromo-4-chloro-5-(2-fluoro-4-nitrophenyl)-5H-pyrrolo[3, 2-d]pyrimidine A solution of 7-bromo-4-chloro-5H-pyrrolo[3,2-d]pyrimidine (2.3 g, 10 mmol) and 1,2-difluoro-4-nitrobenzene (9.5 g, 60 mmol) in CH ₃ CN (30 mL) was treated with Cs ₂ CO ₃ (4.9 g, 15 mmol). The reaction was stirred at 100℃ under N ₂ overnight. The crude product was obtained by filtration and washed with water, CH ₃ CN and EtOH to afford 7-bromo-4- chloro-5-(2-fluoro-4-nitrophenyl)-5H-pyrrolo[3,2-d]pyrimidin e (2.4 g, 70% yield) as a light brown solid. LC/MS ESI (m/z): 371, 373 (M+H) ⁺ . Step 12.4-(7-Bromo-4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-3-fl uoroaniline To a solution of 7-bromo-4-chloro-5-(2-fluoro-4-nitrophenyl)-5H-pyrrolo[3,2- d]pyrimidine (1.1 g, 3.0 mmol) in EtOH (20 mL) and H ₂ O (2mL) were added Fe (1.7 g, 30 mmol) and NH ₄ Cl (2.4 g, 45 mmol). After stirring at 80℃ under N ₂ overnight, the reaction filtered. The filtrate was partitioned between EtOAc and NaHCO ₃ (aq.). The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to afford 4-(7-bromo-4-chloro-5H-pyrrolo[3,2- d]pyrimidin-5-yl)-3-fluoroaniline (1.0 g crude) as a yellow solid. LC/MS ESI (m/z): 341, 343 (M+H) ⁺ . Step 13. (3R,6S)-1-Benzyl-6-methyl-3-(methyl-d ₃ )piperazine-2,5-dione To a solution of 4-(7-bromo-4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-3- fluoroaniline (1.0 g crude) in THF (20 mL) was added isopentyl nitrite (1.4 g, 12 mmol) dropwise. The reaction mixture was stirred at 70℃ under N2 overnight. The solvent was removed under vacuum and the residue was purified by flash column chromatography (silica gel, 0~10%, ethyl acetate in petroleum ether) to afford 7-bromo-4-chloro-5-(2-fluorophenyl)- 5H-pyrrolo[3,2-d]pyrimidine (660 mg, 67% yield) as a white solid. LC/MS ESI (m/z): 326, 328 (M+H) ⁺ . Step 14.7-Bromo-4-fluoro-5-(2-fluorophenyl)-5H-pyrrolo[3,2-d]pyri midine A mixture of TBAF (5.0 mL, 1.0 M in THF) and 7-bromo-4-chloro-5-(2- fluorophenyl)-5H-pyrrolo[3,2-d]pyrimidine (200 mg, 0.61 mmol) was stirred at 0℃ for 2 h. The reaction was then partitioned between DCM and ice water. The aqueous layer was extracted twice with DCM and the combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford 7-bromo-4-fluoro-5-(2-fluorophenyl)-5H- pyrrolo[3,2-d]pyrimidine (170 mg, 86%) as a white solid. LC/MS ESI (m/z): 310, 312 (M+H) ⁺ . Step 15. tert-Butyl (2R,5S)-4-(7-bromo-5-(2-fluorophenyl)-5H-pyrrolo[3,2- d]pyrimidin-4-yl)-5-methyl-2-(methyl-d ₃ )piperazine-1-carboxylate To a solution of 7-bromo-4-fluoro-5-(2-fluorophenyl)-5H-pyrrolo[3,2-d]pyrimid ine (86 mg, 0.27 mmol) in DIPEA (2 mL) was added tert-butyl (2R,5S)-5-methyl-2-(methyl- d ₃ )piperazine-1-carboxylate (60 mg, 0.27 mmol). The resulting mixture was stirred at 150℃ for 2 h. After cooling to room temperature, the reaction was concentrated and the residue was purified by flash column chromatography (silica gel, 0~40%, ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-4-(7-bromo-5-(2-fluorophenyl)-5H-pyrrolo[3,2- d]pyrimidin-4-yl)-5-methyl-2-(methyl-d ₃ )piperazine-1-carboxylate (80 mg, 57%) as a yellow oil. LC/MS ESI (m/z): 507, 509 (M+H) ⁺ . Step 16. (4-((2S,5R)-4-(tert-Butoxycarbonyl)-2-methyl-5-(methyl-d3)pi perazin-1-yl)-5- (2-fluorophenyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)boronic acid To a solution of tert-butyl (2R,5S)-4-(7-bromo-5-(2-fluorophenyl)-5H-pyrrolo[3,2- d]pyrimidin-4-yl)-5-methyl-2-(methyl-d ₃ )piperazine-1-carboxylate (40 mg, 0.08 mmol) and (i-PrO) ₃ B (89 mg, 0.47 mmol) in THF (2 mL) at -78℃ was added n-BuLi (0.11 mL, 2.5 M in hexane). After stirring at -78℃ for 1 h, the reaction was quenched with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was used directly in next steps. LC/MS ESI (m/z): 473 (M+H) ⁺ . Step 17. tert-Butyl (2R,5S)-4-(7-(4-cyanopyridin-2-yl)-5-(2-fluorophenyl)-5H- pyrrolo[3,2-d]pyrimidin-4-yl)-5-methyl-2-(methyl-d ₃ )piperazine-1-carboxylate To a solution of (4-((2S,5R)-4-(tert-butoxycarbonyl)-2-methyl-5-(methyl- d ₃ )piperazin-1-yl)-5-(2-fluorophenyl)-5H-pyrrolo[3,2-d]p yrimidin-7-yl)boronic acid (from step 16 above) in dioxane (5 mL) and H ₂ O (1 mL) were added 2-bromoisonicotinonitrile (23 mg, 0.12 mmol), K ₂ CO ₃ (35 mg, 0.25 mmol) and Pd(dppf)Cl ₂ (6.2 mg, 0.01 mmol). The resulting mixture was stirred at 90℃ overnight. After cooling to room temperature, the reaction was concentrated and the residue was purified by flash column chromatography (silica gel, 0~40%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford tert-butyl (2R,5S)-4-(7-(4-cyanopyridin-2-yl)-5-(2- fluorophenyl)-5H-pyrrolo[3,2-d]pyrimidin-4-yl)-5-methyl-2-(m ethyl-d ₃ )piperazine-1- carboxylate (6.7 mg, 15%) as a white solid. LC/MS ESI (m/z): 531 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl3) δ 9.08 (s, 1H), 8.68 (s, 1H), 8.65 (d, J = 4.9 Hz, 1H), 8.20 (s, 1H), 7.47 – 7.22 (m, 5H), 4.10 (br. s, 1H), 3.79 (br. s, 1H), 3.34 – 2.96 (m, 3H), 2.55 – 2.11 (m, 1H), 1.36 (s, 9H), 0.83 (d, J = 6.3 Hz, 3H). Example 212. Synthesis of tert-butyl (2R,5S)-4-(7-(4-cyanopyridin-2-yl)-5-cyclobutyl- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-ca rboxylate (Compound 710) To a solution of tert-butyl (2R,5S)-4-(5-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 2,5-dimethylpiperazine-1-carboxylate (500 mg, 1.3 mmol, prepared following a similar procedure outlined for compound 641) in DMF (5.0 mL) were added 2-fluoropyridine-4- carbonitrile (320 mg, 2.6 mmol) and Cs ₂ CO ₃ (430 mg, 1.3 mmol). The mixture was stirred at 50 ^o C under N ₂ 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) and prep-HPLC to afford tert-butyl (2R,5S)-4-(7-(4-cyanopyridin- 2-yl)-5-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dime thylpiperazine-1-carboxylate (40 mg, 6.0%) as a white solid. LC/MS ESI (m/z): 488 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO- d6) δ 9.15 (s, 1H), 8.78 (dd, J = 5.0, 0.7 Hz, 1H), 8.50 (s, 1H), 8.08 (s, 1H), 7.80 (dd, J = 5.0, 1.4 Hz, 1H), 4.45 (br. s, 1H), 4.25 (br. s, 1H), 3.77 – 3.63 (m, 3H), 3.58 (m, 1H), 3.43 (d, J = 12.6 Hz, 1H), 2.47 – 2.34 (m, 2H), 2.28 – 2.13 (m, 1H), 2.11 – 1.96 (m, 2H), 1.93 – 1.77 (m, 1H), 1.44 (s, 9H), 1.06 (d, J = 6.6 Hz, 3H), 1.00 (d, J = 6.8 Hz, 3H). Example 213. Synthesis of tert-butyl (2R,5S)-4-(7-(4-cyanopyridin-2-yl)-5-cyclopropyl- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-methyl-2-(methyl-d ₃ )piperazine-1-carboxylate Compound 711) Compound 711 Step 1.2-(4-Chloro-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl) isonicotinonitrile To a solution of 2-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7- yl)isonicotinonitrile (500 mg, 1.3 mmol, prepared following the procedure outlined for compound 707) in toluene (15 mL) were added cyclopropylboronic acid (230 mg, 2.5 mmol), Pd-118 (86 mg, 0.13 mmol) and K ₂ CO ₃ (3.6 g, 26 mmol). The resulting mixture was stirred at 80℃ overnight. After cooling to room temperature, the reaction was concentrated and the residue was purified by flash column chromatography (silica gel, 0~20%, ethyl acetate in petroleum ether) to afford 2-(4-chloro-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-7- yl)isonicotinonitrile (130 mg, 34%) as a yellow solid. LC/MS ESI (m/z): 296 (M+H) ⁺ . Step 2. tert-Butyl (2R,5S)-4-(7-(4-cyanopyridin-2-yl)-5-cyclopropyl-7H-pyrrolo[ 2,3- d]pyrimidin-4-yl)-5-methyl-2-(methyl-d ₃ )piperazine-1-carboxylate To a solution of 2-(4-chloro-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-7- yl)isonicotinonitrile (61 mg, 0.20 mmol) in DIPEA (3 mL) was added tert-butyl (2R,5S)-5- methyl-2-(methyl-d ₃ )piperazine-1-carboxylate (30 mg, 0.13 mmol, prepared following the procedure outlined for compound 709). The resulting mixture was stirred at 150℃ for 2 h. After cooling to room temperature, the reaction was concentrated and the residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-4-(7-(4-cyanopyridin-2-yl)-5-cyclopropyl-7H-pyrrolo[ 2,3- d]pyrimidin-4-yl)-5-methyl-2-(methyl-d ₃ )piperazine-1-carboxylate (25 mg, 38%) as a yellow solid.10 mg was purified by prep-HPLC to afford 2.4 mg of the title compound as a white solid. LC/MS ESI (m/z): 477 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl3) δ 9.22 (s, 1H), 8.55 (d, J = 4.6 Hz, 1H), 8.46 (s, 1H), 8.36 (s, 1H), 7.35 (dd, J = 5.0, 1.2 Hz, 1H), 4.57 – 4.33 (m, 2H), 3.86 – 3.78 (m, 1H), 3.69 (dd, J = 13.4, 4.0 Hz, 2H), 3.41 (d, J = 13.6 Hz, 1H), 2.01 – 1.86 (m, 1H), 1.43 (s, 9H), 1.20 – 1.16 (m, 2H), 1.02 (d, J = 6.7 Hz, 3H), 0.83 – 0.76 (m, 2H). The following compound was prepared by a procedure analogous to the synthesis of compound 711 from the corresponding boronic acid. Example 214. Synthesis of tert-butyl (2R,5S)-4-(7-((S)-3,3-difluorocyclohexyl)-5- (trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimet hylpiperazine-1- carboxylate (Compound 713) and tert-butyl (2R,5S)-4-(7-((R)-3,3-difluorocyclohexyl)-5- (trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimet hylpiperazine-1- carboxylate (Compound 714) Step 1.4-Chloro-7-(3,3-difluorocyclohexyl)-7H-pyrrolo[2,3-d]pyrim idine To a solution of 2-(4,6-dichloropyrimidin-5-yl)acetaldehyde (1000 mg, 5.2 mmol) in EtOH (15 mL) were added 3,3-difluorocyclohexan-1-amine HCl salt (900 mg, 5.2 mmol) and TEA (2.1 g, 21 mmol). The resulting mixture was heated to 80 ^o C overnight under N ₂ . After cooling to room temperature, the solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~20%, ethyl acetate in petroleum ether) to afford 4- chloro-7-(3,3-difluorocyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin e (650 mg, 46%) as a solid. LC/MS ESI (m/z): 272 (M+H) ⁺ . Step 2. tert-Butyl (2R,5S)-4-(7-(3,3-difluorocyclohexyl)-7H-pyrrolo[2,3-d]pyrim idin- 4-yl)-2,5-dimethylpiperazine-1-carboxylate To a solution of 4-chloro-7-(3,3-difluorocyclohexyl)-7H-pyrrolo[2,3-d]pyrimid ine (450 mg, 1.7 mmol) in DIPEA (2 mL) was added tert-butyl (2R,5S)-2,5-dimethylpiperazine-1- carboxylate (660 mg, 3.3 mmol). The resulting mixture was heated at 140 ^o 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, 0~25%, ethyl acetate in petroleum ether) to afford tert- butyl (2R,5S)-4-(7-(3,3-difluorocyclohexyl)-7H-pyrrolo[2,3-d]pyrim idin-4-yl)-2,5- dimethylpiperazine-1-carboxylate (700 mg, 94%) as a solid. LC/MS ESI (m/z): 450 (M+H) ⁺ . Step 3. tert-Butyl (2R,5S)-4-(7-(3,3-difluorocyclohexyl)-5-iodo-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate To a solution of tert-butyl (2R,5S)-4-(7-(3,3-difluorocyclohexyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (500 mg, 1.1 mmol) in DMF (10 mL) was added NIS (500 mg, 2.2 mmol) in portions. The resulting mixture was heated at 45 ^o C for 2 h. 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 sat. sodium thiosulfate (aq.), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~20%, ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-4-(7-(3,3-difluorocyclohexyl)-5-iodo-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate (580 mg, 90%) as a solid. LC/MS ESI (m/z): 576 (M+H) ⁺ . Step 4. tert-Butyl (2R,5S)-4-(7-(3,3-difluorocyclohexyl)-5-(trifluoromethyl)-7H - pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate To a solution of tert-butyl (2R,5S)-4-(7-(3,3-difluorocyclohexyl)-5-iodo-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate (580 mg, 1.0 mmol) in DMF (20 mL) were added methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (580 mg, 3.0 mmol) and CuI (190 mg, 1.0 mmol). The resulting mixture was heated at 80 ^o C overnight. After cooling to room temperature, the reaction was filtered and partitioned between EtOAc and water. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~20%, ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-4-(7-(3,3-difluorocyclohexyl)-5-(trifluoromethyl)-7H -pyrrolo[2,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (360 mg, 69%) as a solid. LC/MS ESI (m/z): 518 (M+H) ⁺ . Step 5. tert-Butyl (2R,5S)-4-(7-((S)-3,3-difluorocyclohexyl)-5-(trifluoromethyl )-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate and tert-butyl (2R,5S)-4- (7-((R)-3,3-difluorocyclohexyl)-5-(trifluoromethyl)-7H-pyrro lo[2,3-d]pyrimidin-4-yl)-2,5- dimethylpiperazine-1-carboxylate tert-Butyl (2R,5S)-4-(7-(3,3-difluorocyclohexyl)-5-(trifluoromethyl)-7H -pyrrolo[2,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (220 mg) was separated by chiral HPLC (column: CHIRALPAK AD-H (ADH0CE-XG136), 0.46 cm I.D. × 25 cm L., mobile phase: hexane/IPA=90/10(V/V)) to afford two isomers. Peak 1: retention time: 4.7 min, tert-butyl (2R,5S)-4-(7-((S)-3,3-difluorocyclohexyl)-5- (trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimet hylpiperazine-1-carboxylate (assigned as compound 713 without additional confirmation, 95 mg) as a white solid. LC/MS ESI (m/z): 518 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.39 (s, 1H), 7.41 (s, 1H), 4.92 – 4.80 (m, 1H), 4.53 – 4.16 (m, 2H), 3.69 – 3.59 (m, 2H), 3.58 – 3.50 (m, 1H), 3.42 – 3.34 (m, 1H), 2.55 – 2.44 (m, 1H), 2.30 – 2.08 (m, 3H), 1.95 – 1.67 (m, 4H), 1.42 (s, 9H), 1.08 – 1.01 (m, 6H) Peak 2: retention time: 5.502 min, tert-butyl (2R,5S)-4-(7-((R)-3,3-difluorocyclohexyl)-5- (trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimet hylpiperazine-1-carboxylate (assigned as compound 714 without additional confirmation, 86 mg) as a white solid. LC/MS ESI (m/z): 518 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.39 (s, 1H), 7.41 (s, 1H), 4.94 – 4.83 (m, 1H), 4.53 – 4.17 (m, 2H), 3.69 – 3.59 (m, 2H), 3.57 – 3.49 (m, 1H), 3.38 (d, J = 13.4 Hz, 1H), 2.59 – 2.47 (m, 1H), 2.32 – 2.06 (m, 3H), 1.95 – 1.87 (m, 1H), 1.83 – 1.68 (m, 3H), 1.42 (s, 9H), 1.07 – 1.01 (m, 6H). Example 215. Synthesis of tert-butyl (2R,5S)-4-(5-cyclopropyl-7-(4-ethynylpyridin-2-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-ca rboxylate (Compound 715) Step 1. tert-Butyl (2R,5S)-4-(5-cyclopropyl-7-(4-((trimethylsilyl)ethynyl)pyrid in-2-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-ca rboxylate To a solution of tert-butyl (2R,5S)-4-(5-cyclopropyl-7-(4-iodopyridin-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate (100 mg, 0.17 mmol, prepared following the procedure outlined for compound 717) in dioxane (6 ml) were added ethynyltrimethylsilane (83 mg, 0.85 mmol), Pd(PPh ₃ ) ₄ (23 mg, 0.02 mmol), CuI (16 mg, 0.09 mmol) and TEA (170 mg, 1.7 mmol). The reaction was stirred at 80 ^o C under N ₂ overnight. After cooling to room temperature, solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~30% ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-4-(5-cyclopropyl-7-(4-((trimethylsilyl)ethynyl)pyrid in-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate (80 mg, 86%) as a solid. LC/MS ESI (m/z): 545 (M+H) ⁺ . Step 2. tert-Butyl (2R,5S)-4-(5-cyclopropyl-7-(4-ethynylpyridin-2-yl)-7H-pyrrol o[2,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate To a solution of tert-butyl (2R,5S)-4-(5-cyclopropyl-7-(4- ((trimethylsilyl)ethynyl)pyridin-2-yl)-7H-pyrrolo[2,3-d]pyri midin-4-yl)-2,5- dimethylpiperazine-1-carboxylate (80 mg, 0.15 mmol) in THF (1 mL) was added TBAF (1.0 mL, 1.0 M in THF). After 1 h, the reaction was diluted with EtOAc and washed with sat. NH ₄ Cl (aq.). The aqueous layer was extracted with EtOAc. The organic layer was washed with sat. NH ₄ Cl (aq.), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by prep-HPLC to afford tert-butyl (2R,5S)-4-(5-cyclopropyl-7-(4-ethynylpyridin-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate (35 mg, 49%) as a white solid. LC/MS ESI (m/z): 473 (M+H) ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ 8.80 (s, 1H), 8.44 (d, J = 4.0 Hz, 1H), 8.40 (s, 1H), 7.80 (d, J = 0.9 Hz, 1H), 7.29 (dd, J = 5.1, 1.3 Hz, 1H), 4.89 (m, 1H), 4.40 (br. s, 1H), 3.98 (s, 1H), 3.83 – 3.72 (m, 3H), 3.64 (d, J = 12.3 Hz, 1H), 2.09 – 2.02 (m, 1H), 1.50 (s, 9H), 1.16 (m, 6H), 1.09 – 1.03 (m, 2H), 0.91 (m, 1H), 0.70 – 0.64 (m, 1H). The following compound was prepared by a procedure similar to the synthesis of compound 715 from the corresponding aryl iodide (tert-butyl (2R,5S)-4-(7-(4-iodopyridin-2- yl)-5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5 -dimethylpiperazine-1- carboxylate), which was prepared following similar procedures as outlined for compound 717.

Example 216. Synthesis of tert-butyl (2R,5S)-4-(5-cyclopropyl-7-(4-ethylpyridin-2-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-ca rboxylate (Compound 717) C ^{ompound 717} Step 1. tert-Butyl (2R,5S)-4-(5-cyclopropyl-7-(4-iodopyridin-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-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4- yl)-2,5-dimethylpiperazine-1-carboxylate (350 mg, 0.94 mmol, prepared following the procedure outlined for compound 654) in DMF (8 mL) were added 2-fluoro-4-iodopyridine (320 mg, 1.4 mmol) and Cs ₂ CO ₃ (620 mg, 1.9 mmol). The resulting mixture was heated at 80 ^o 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30% ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-4-(5-cyclopropyl-7-(4-iodopyridin-2-yl)-7H-pyrrolo[2 ,3-d]pyrimidin-4-yl)-2,5- dimethylpiperazine-1-carboxylate (400 mg, 74%) as a white solid. LC/MS ESI (m/z): 575 (M+H) ⁺ . Step 2. tert-Butyl (2R,5S)-4-(5-cyclopropyl-7-(4-vinylpyridin-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-cyclopropyl-7-(4-iodopyridin-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate (100 mg, 0.17 mmol) in dioxane (6 ml) and water (2 drops) were added 4,4,5,5-tetramethyl-2-vinyl-1,3,2- dioxaborolane (31 mg, 0.20 mmol), Pd(dppf)Cl ₂ (16 mg, 0.02 mmol) and K ₂ CO ₃ (70 mg, 0.51 mmol). The reaction was stirred at 90 ^o C under N2 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 in petroleum ether) to afford tert-butyl (2R,5S)-4-(5-cyclopropyl-7-(4-vinylpyridin-2-yl)-7H-pyrrolo[ 2,3-d]pyrimidin-4-yl)-2,5- dimethylpiperazine-1-carboxylate (40 mg, 50%) as a white solid. LC/MS ESI (m/z): 475 (M+H) ⁺ . Step 3. tert-Butyl (2R,5S)-4-(5-cyclopropyl-7-(4-ethylpyridin-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-cyclopropyl-7-(4-vinylpyridin-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carbo xylate (40 mg, 0.084 mmol) in MeOH (10 mL) was added palladium (100 mg, 10% on activated carbon (wetted with ca. 55% water)). The resulting mixture was stirred at room temperature under H ₂ atmosphere (~0.1 MPa) overnight. The reaction was filtered, and the filtrate was concentrated. The residue was purified by flash column chromatography (silica gel, 0~30% ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford tert-butyl (2R,5S)-4-(5-cyclopropyl-7-(4-ethylpyridin-2-yl)-7H-pyrrolo[ 2,3-d]pyrimidin-4- yl)-2,5-dimethylpiperazine-1-carboxylate (33 mg, 83%) as a white solid. LC/MS ESI (m/z): 477 (M+H) ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ 8.41 (s, 1H), 8.38 – 8.30 (m, 2H), 7.72 (s, 1H), 7.17 (m, 1H), 4.89 (m, 1H), 4.40 (br. s, 1H), 3.84 – 3.62 (m, 4H), 2.78 (q, J = 7.6 Hz, 2H), 2.10 – 2.02 (m, 1H), 1.50 (s, 9H), 1.31 (t, J = 4.0 Hz, 3H), 1.16 (m, 6H), 1.08 – 1.02 (m, 2H), 0.91 (s, 1H), 0.71 – 0.64 (m, 1H). The following compound was prepared by a procedure analogous to the synthesis of compound 717 from tert-butyl (2R,5S)-2,5-dimethyl-4-(5-(trifluoromethyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperazine-1-carboxylate which was prepared following the procedures outlined for compound 602. Example 217. Fluorescent TRPML assays. TRPML1 Assay Cell Culture HEK-293 Trex cells were stably transfected with a construct consisting of the human coding sequence for TRPML1 cloned into the tet-inducible plasmid pCDNA5 T/O. Mutations were introduced into the TRPML1 sequence to facilitate expression on the cell surface (Silvia Vergarajauregui, Rosa Puertollano, Traffic.2006 Mar; 7(3): 337–353). Briefly, the cells are cultured in 150 mm round tissue culture dishes containing 20 mL of media. The day before the assay the cells are rinsed with DPBS -Ca -Mg and then treated briefly with Trypsin-EDTA. The Trypsin-EDTA is diluted with growth media, and cells are counted. 38 x 10^6 cells are re-plated into 150 mm round tissue culture dishes in media containing 0.5ug/mL doxycycline to induce expression of hTRPML1. Dye Loading The day of the experiment cells are lifted from the plates as above and collected by centrifugation. The cells are then suspended in dye loading buffer consisting of Ringer’s solution supplemented with 0.1% Pluronic Acid and 1 micromolar Fluo4-AM dye. Cells are loaded for ~60 minutes in the dark with occasional mixing. The cells are collected by centrifugation, the loading media aspirated, and the cells resuspended in 25 mL Ringer’s solution and incubated ~60 minutes in the dark. The cells are again collected by centrifugation, rinsed in Ringer’s Solution and resuspended to 0.2 x10^6 cells / mL in modified Ringer’s solution containing 10 mM calcium. Compound Assay Plates Compounds are dissolved to a concentration of 10 millimolar with DMSO. Compound plates are created by dispensing compounds into 384 well black wall clear bottom plates (Greiner 781091). Positive and negative controls are included on each plate. Typically, different amounts of each compound are tested ranging from 100 nanoMoles (20 micromolar final concentration) decreasing in half-log steps to 31 picoMoles (6 nanomolar final concentration). Each concentration is typically tested in triplicate. Assay 50 microliters of dye-loaded cells are dispensed into each well of the compound assay plate created above. The fluorescence in each well is then determined with an excitation wavelength of 480 nM and an emission wavelength of 540 nM using either a Molecular Devices SpectraMax multimode plate reader or a Hamamatsu FDSS/uCell plate imager. Analysis and Statistics The resulting fluorescence for each well is exported as an ascii file and loaded into our LIMS for analysis. The percent activity of each compound at each concentration is determined by comparison to the positive and negative control wells included in each plate. TRPML2 and TRPML3 Assays Assays for TRPML2 and TRPML3 were performed as above for TRPML1, by substituting the appropriate TRPML2 or TRPML3 subtype for the TRPML1. EC ₅₀ values were calculated using a non-linear regression of Prism. The EC ₅₀ determined for each compound using the assay is summarized in Table 3 below. The compound numbers correspond to those shown in Table 1. In the table, “A” indicates an EC ₅₀ of less than 100 nM, “B” indicates an EC ₅₀ range from 100 nM to 500 nM; “C” indicates an EC ₅₀ range from 500 nM to 2 µM; and “D” indicates an EC ₅₀ greater than 2 µM. Table 3. Efficacy of exemplary compounds of the invention

EQUIVALENTS It will be recognized that one or more features of any embodiments disclosed herein may be combined and/or rearranged within the scope of the invention to produce further embodiments that are also within the scope of the invention. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be within the scope of the present invention. Although the invention has been described and illustrated in the foregoing illustrative embodiments, it is understood that the present disclosure has been made only by way of example, and that numerous changes in the details of implementation of the invention can be made without departing from the spirit and scope of the invention, which is limited only by the claims that follow. Features of the disclosed embodiments can be combined and/or rearranged in various ways within the scope and spirit of the invention to produce further embodiments that are also within the scope of the invention. Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described specifically in this disclosure. Such equivalents are intended to be encompassed in the scope of the following claims. All patents, patent applications and publications cited herein are hereby incorporated by reference in their entirety. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed herein.