NAPHTHYRIDINE COMPOUNDS FOR INHIBITION OF RAF KINASES

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of U.S. Provisional Application No. 63/422,844 filed November 4, 2022, the entire contents of which are incorporated herein by reference.

FIELD OF THE INVENTION

[0002] Provided herein are compounds and compositions for inhibition of RAF serine/threonine protein kinases, methods of preparing said compounds and compositions, and their use in the treatment of various cancers.

BACKGROUND

[0003] The RAF family of serine/threonine protein kinases operate as an essential signaling node within the Ras/Raf/MEK/ERK pathway. Also referred to as the mitogen activated kinase (MAPK) pathway, this signaling cascade is critically involved in the regulation of a diverse array of basic physiological processes. The MAPK pathway is responsive to a variety of stimuli mediated through the input of numerous intracellular second messengers and transmembrane receptors including the receptor tyrosine kinases (RTKs). In the case of the RTKs, upon ligand binding, they act on the MAPK pathway through the recruitment/activation of the RAS GTPases which then bind and activate RAF. RAF then phosphorylates MEK (mitogen activated kinase kinase 1 & 2) at serine residues located within their activation loops that in turn induce certain conformational changes leading to their activation. Activated MEK in turn phosphorylates and activates the ERK kinases (Extracellular Regulated Kinase 1 & 2 also known as MAPK1/2 or mitogen-activated protein kinases 1 & 2) via activation loop phosphorylation. Activated ERK then acts as a broad-based effector of the pathway, modulating the activity of a variety of proteins including other protein kinases, structural proteins, metabolic enzymes and transcription factors that in turn modulate the broad cellular response to these stimuli. Importantly, the primary output of the MAPK pathway is to drive cell growth and proliferation as well as to suppress apoptosis (regulated cell death). Given its central role in the regulation of these processes, it is not surprising that the majority of genetic alterations associated with cellular transformation act entirely or at least in part via the aberrant activation of the MAPK pathway. Therefore, as an essential node in the MAPK pathway, the RAF kinases represent an important therapeutic intervention point for the treatment of a variety of malignancies whose dysregulated growth and survival rely upon this pathway. [0004] Thus, there remains a need for new compounds and compositions for inhibition RAF kinases. SUMMARY OF THE INVENTION [0005] Provided herein are compounds and compositions that inhibit RAF kinases and that are useful for treating disorders mediated by RAF kinases. [0006] In one aspect, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: X ¹ , X ² , X ³ and X ⁴ are each independently N or C-R ¹ ; Y is absent, or is -C(O)-; R ⁰ is H, C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, 3- to 6-membered heterocycloalkyl, or - N(R ⁸ )(R ⁹ ), wherein the aliphatic portions of R ⁰ are optionally substituted with one or more R ¹⁰ groups; or R ⁰ is taken together with R ⁶ and the atoms to which they are attached to form a 4- to 6-membered heterocycloalkenyl or a 5- to 6-membered heteroaryl, wherein the 4- to 6-membered heterocycloalkenyl or 5- to 6-membered heteroaryl is optionally substituted with one or more R ¹⁰ groups; each R ¹ is independently H, halo, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, 5- to 6- membered heteroaryl, -OR ⁷ , -CN, -N(R ⁸ )(R ⁹ ), or -C(O)-N(R ⁸ )(R ⁹ ), wherein R ¹ is optionally substituted with one or more R ¹⁰ groups; R ^2a , R ^2b , and R ^2c are each independently H, -OH, halo, -CN, -S-C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₆ cycloalkyl, -OR ⁷ , or -N(R ⁸ )(R ⁹ ), wherein the aliphatic portions of R ^2a , R ^2b , and R ^2c are each independently optionally substituted with one or more R ¹⁰ groups; or one of R ^2a , R ^2b , and R ^2c is taken together with one of R ⁴ and R ⁵ to form a C ₃ - C ₆ cycloalkyl, and the other two of R ^2a , R ^2b , or R ^2c are each independently H, - OH, halo, -CN, -S-C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₆ cycloalkyl, -OR ⁷ , or -N(R ⁸ )(R ⁹ ), or one or two of R ^2a , R ^2b , and R ^2c is taken together with R ⁴ and R ⁵ to form a 4- to 6- membered heterocycloalkenyl or a 5- to 6-membered heteroaryl; and the remaining one or two of R ^2a , R ^2b , and R ^2c are each independently H, -OH, halo, -CN, -S-C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C ₃ - C ₆ cycloalkyl, -OR ⁷ , or -N(R ⁸ )(R ⁹ ), wherein the C ₃ -C ₆ cycloalkyl, 4- to 6-membered heterocycloalkenyl or 5- to 6-membered heteroaryl formed by any of R ^2a , R ^2b , R ^2c , R ⁴ , and R ⁵ is optionally substituted with one or more R ¹⁰ groups; R ³ is halo or C ₁ -C ₃ alkyl, wherein the aliphatic portions of R ³ are each independently optionally substituted with one or more R ¹⁰ groups; R ⁴ and R ⁵ are each independently H, D, -OH, C ₁ -C ₆ alkyl, or -NHS(O) ₂ C ₁ -C ₆ alkyl, or R ⁴ and R ⁵ are taken together with the atom to which they are attached to form =O or =N- (OH), or one of R ⁴ and R ⁵ is taken together with one of R ^2a , R ^2b , and R ^2c to form a C ₃ - C ₆ cycloalkyl, and the other of R ⁴ and R ⁵ is H, D, OH, C ₁ -C ₆ alkyl, or - NHS(O) ₂ C ₁ -C ₆ alkyl, or R ⁴ and R ⁵ are taken together with one or two of R ^2a , R ^2b , and R ^2c to form a 4- to 6-membered heterocycloalkenyl or a 5- to 6-membered heteroaryl; R ⁶ is H, or R ⁶ is taken together with R ⁰ and the atoms to which they are attached to form a 4- to 6-membered heterocycloalkenyl or a 5- to 6-membered heteroaryl, wherein the 4- to 6-membered heterocycloalkenyl or 5- to 6-membered heteroaryl are optionally substituted with one or more R ¹⁰ groups; each R ⁷ is independently H, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl; R ⁸ and R ⁹ are each independently H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, or C ₁ -C ₆ haloalkyl, or R ⁸ and R ⁹ are taken together with the nitrogen atom to which they are attached to form a 3- to 6-membered heterocycloalkyl, a 4- to 6-membered heterocycloalkenyl, or a 5- to 6-membered heteroaryl; and each R ¹⁰ is independently halo, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, -OR ⁷ , -CN, -N(R ⁸ )(R ⁹ ), - (C ₁ -C ₃ alkyl)-N(R ⁸ )(R ⁹ ). [0007] In some embodiments, the compound of formula (I) is a compound of formula (I- 1), [0008] or a pharmaceutically acceptable salt thereof. In some embodiments, the moiety _{of Formula (I-1) is} , or . In some embodiments, provided herein is a compound of formula (I-1- a), (I-1-b), (I-1-c), (I-1-d), (I-1-e), (I-1-f), or (I-1-g), or a pharmaceutically acceptable salt thereof: , , , , or . In some embodi ^{1 2 3 4} ments, X , X , X and X are each independently N or C-R ¹ ; each R ¹ is independently H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, - OR ⁷ , -CN, -N(R ⁸ )(R ⁹ ), wherein the aliphatic portions of R ¹ are optionally substituted with one or more R ¹⁰ groups; R ^2a , R ^2b , and R ^2c are each independently H, -OH, -SCH ₃ , C ₁ -C ₆ alkyl, or - OR ⁷ ; wherein the aliphatic portions of R ^2a , R ^2b , and R ^2c are each independently optionally substituted with one or more R ¹⁰ groups; or one or two of R ^2a , R ^2b , and R ^2c is taken together with R ⁴ and R ⁵ to form a 4- to 6-membered heterocycloalkenyl or a 5- to 6-membered heteroaryl; and the remaining one or two of R ^2a , R ^2b , and R ^2c are each independently H, -OH, halo, -CN, -S-C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₆ cycloalkyl, - OR ⁷ , or -N(R ⁸ )(R ⁹ ), wherein the 4- to 6-membered heterocycloalkenyl or 5- to 6-membered heteroaryl formed by any of R ^2a , R ^2b , R ^2c , R ⁴ , and R ⁵ is optionally substituted with one or more R ¹⁰ groups; R ³ is halo, or C ₁ -C ₃ alkyl, wherein the aliphatic portions of R ³ are each independently optionally substituted with one or more R ¹⁰ groups; R ⁴ and R ⁵ are each independently H, D, -OH, C ₁ -C ₆ alkyl, or -NHS(O) ₂ C ₁ -C ₆ alkyl, or R ⁴ and R ⁵ are taken together with the atom to which they are attached to form =O or =N-(OH), or R ⁴ and R ⁵ are taken together with one or two of R ^2a , R ^2b , and R ^2c to form a 4- to 6-membered heterocycloalkenyl or a 5- to 6-membered heteroaryl; R ⁶ is H; each R ⁷ is independently H, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl; R ⁸ and R ⁹ are each independently H or C ₁ -C ₆ alkyl, or R ⁸ and R ⁹ are taken together with the nitrogen atom to which they are attached to form a 3- to 6-membered heterocycloalkyl, a 4- to 6- membered heterocycloalkenyl, or a 5- to 6-membered heteroaryl; and each R ¹⁰ is independently halo, -OR ⁷ , or -(C ₁ -C ₃ alkyl)-N(R ⁸ )(R ⁹ ). In some embodiments of the foregoing, one of X ¹ and X ² is C-R ¹ and the other of X ¹ and X ² is N. [0009] In other embodiments, the compound of formula (I) is a compound of formula (I- 2): or a pharmaceutically acceptable salt thereof, wherein R ⁰ is H, C ₁ -C ₃ alkyl, 3- to 6-membered heterocycloalkyl, or -N(R ⁸ )(R ⁹ ), optionally substituted with 1 to 5 independently selected R ¹⁰ groups. In some embodiments, X ¹ , X ² , X ³ and X ⁴ are each independently N or C-R ¹ ; R ⁰ is C ₁ - C ₃ alkyl, wherein the aliphatic portions of R ⁰ are optionally substituted with one or more R ¹⁰ groups; each R ¹ is independently H; R ^2a , R ^2b , and R ^2c are each independently H or C ₁ -C ₆ alkyl, or one of R ^2a , R ^2b , and R ^2c is taken together with one of R ⁴ and R ⁵ to form a C ₃ - C ₆ cycloalkyl, and the other two of R ^2a , R ^2b , or R ^2c are each independently H or C ₁ -C ₆ alkyl; wherein the aliphatic portions of R ^2a , R ^2b , and R ^2c are each independently optionally substituted with one or more R ¹⁰ groups; R ³ is C ₁ -C ₃ alkyl, wherein the aliphatic portions of R ³ are each independently optionally substituted with one or more R ¹⁰ groups; R ⁴ and R ⁵ are each independently H, D, or -OH, or one of R ⁴ and R ⁵ is taken together with one of R ^2a , R ^2b , and R ^2c to form a C ₃ -C ₆ cycloalkyl, and the other of R ⁴ and R ⁵ is H, D, or -OH; R ⁶ is H; each R ⁷ is independently H or C ₁ -C ₆ alkyl; and each R ¹⁰ is independently -OR ⁷ . [0010] In other embodiments, the compound of formula (I) is a compound of formula (I- 3): or a pharmaceutically acceptable salt thereof. In some embodiments, X ¹ , X ² , X ³ and X ⁴ are each independently N or C-R ¹ ; R ⁰ is H or C ₁ -C ₃ alkyl, or R ⁰ is taken together with R ⁶ and the atoms to which they are attached to form a 4- to 6-membered heterocycloalkenyl or a 5- to 6- membered heteroaryl, wherein the 4- to 6-membered heterocycloalkenyl or 5- to 6-membered heteroaryl is optionally substituted with one or more R ¹⁰ groups; each R ¹ is independently H or halo; R ^2a , R ^2b , and R ^2c are each independently H, -OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, or C ₃ -C ₆ cycloalkyl, wherein the aliphatic portions of R ^2a , R ^2b , and R ^2c are each independently optionally substituted with one or more R ¹⁰ groups; R ³ is C ₁ -C ₃ alkyl; R ⁴ and R ⁵ are each independently H or -OH; and R ⁶ is H, or R ⁶ is taken together with R ⁰ and the atoms to which they are attached to form a 4- to 6-membered heterocycloalkenyl or a 5- to 6- membered heteroaryl, wherein the 4- to 6-membered heterocycloalkenyl or 5- to 6-membered heteroaryl is optionally substituted with one or more R ¹⁰ groups. [0011] In some embodiments, of formula (I) is

[0012] In some embodiments, of formula (I) is O HO D HO D [0013] In some embodiments, R ¹ is H, halo, C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, 5- to 6- membered heteroaryl, -OR ⁷ , -CN, -N(R ⁸ )(R ⁹ ), or -C(O)-N(R ⁸ )(R ⁹ ). In some embodiments, R ¹ is H, F, -CH ₃ , cyclopropyl, -OCH ₃ , CN, NH ₂ , -C(O)-NHCH ₃ , -C(O)-N(CH ₃ ) ₂ , , . In some embodiments, X ³ and X ⁴ are each - CH-. [0014] Also provided herein is a compound which is selected from the group consisting of: or a pharmaceutically acceptable salt thereof. [0015] In another aspect, provided herein is a pharmaceutical composition comprising any compound disclosed herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. [0016] In yet another aspect, the present disclosure provides a method of inhibiting ARAF, BRAF and CRAF enzymatic activity in a cell, comprising exposing the cell with an effective amount of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof. [0017] In still yet another aspect, provided herein is a method of treating a cancer or neoplastic disease in a human in need thereof, comprising administering to the human a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof. [0018] In still yet another aspect, provided herein is a method of treating a cancer or neoplastic disease in a human in need thereof, comprising administering to the human a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the cancer or neoplastic disease is associated with one or more genetic alterations that engender elevated RAS/RAF/MEK/ERK pathway activation. In some embodiments, the cancer or neoplastic disease is associated with one or more genetic alterations in KRAS, NRAS, HRAS, ARAF, BRAF or CRAF. In some embodiments, the cancer or neoplastic disease is associated with one or more mutations in KRAS selected from the group consisting of G12D, G12V, G12C, G12S, G12R, G12A, G13D, G13C, G13R, Q61H, Q61K, Q61L, Q61P, Q61R and Q61E. In some embodiments, the cancer or neoplastic disease is associated with one or more mutations in NRAS selected from the group consisting of G12D, G12S, G12C, G12V, G12A, G13D, G13R, G13V, G13C, G13A, G13S, G61R, Q61K Q61H, and G61L. In some embodiments, the cancer or neoplastic disease is associated with one or more mutations in HRAS selected from the group consisting of G12V, G12S, G12D, G12C, G12R, G12A, G13R, G13V, G13D, G13S, G13C, Q61R, Q61L, Q61K, and Q61H. In some embodiments, the cancer or neoplastic disease is associated with one or more mutations in ARAF selected from the group consisting of S214C and S214F. In some embodiments, the cancer or neoplastic disease is associated with one or more mutations in BRAF selected from the group consisting of Class I, Class IIa, Class IIb, Class IIc, and Class III mutations. In some embodiments, the cancer or neoplastic disease is associated with one or more mutations in CRAF selected from the group consisting of P261A, P261L, E478K, R391W, R391S and T491I, or is associated with a CRAF fusion. In other embodiments, the cancer or neoplastic disease is associated with one or more genetic lesions resulting in the activation of one or more receptor tyrosine kinases (RTKs). In some embodiments, the one or more genetic lesions is a point mutation, a fusion or any combination thereof. In some embodiments, the one or more receptor tyrosine kinase is selected from the group consistion of ALK, EGFR, ERBB2, LTK, MET, NTRK, RET, and ROS1. [0019] In some embodiments of the present aspect, the cancer is a refractory BRAF Class I mutant cancer. In some embodiments, the refractory BRAF Class I mutant cancer is associated with a point mutation selected from the group consisting of V600D, V600E, V600K, and V600R. In certain embodiments of the foregoing, the refractory cancer is associated with a genetic alteration in KRAS, NRAS, HRAS or BRAF that drives BRAF dimerization and confers resistance to approved Type 1.5 inhibitors (including vemurafenib, dabrafenib and encorafenib) both alone and in the context of MEK inhibitor (including cobimetinib, trametinib and binimetinib) combinations. In some embodiments, the refractory cancer is associated with one or more mutations in KRAS selected from the group consisting of G12D, G12V, G12C, G12S, G12R, G12A, G13D, G13C, G13R, Q61H, Q61K, Q61L, Q61P, Q61R and Q61E. In some embodiments, the refractory cancer is associated with one or more mutations in NRAS selected from the group consisting of G12D, G12S, G12C, G12V, G12A, G13D, G13R, G13V, G13C, G13A, G13S, G61R, Q61K Q61H, and G61L. In some embodiments, the refractory cancer is associated with one or more mutations in HRAS selected from the group consisting of G12V, G12S, G12D, G12C, G12R, G12A, G13R, G13V, G13D, G13S, G13C, Q61R, Q61L, Q61K, and Q61H. In some embodiments, the refractory cancer is associated with one or more genetic alterations in BRAF selected from the group consisting of gene amplification, point mutation, BRAF fusion, and gene splicing events. In some embodiments, the refractory cancer is associated with one or more Class II or Class III mutations in BRAF. In some embodiments, the refractory cancer is associated with one or more mutations in BRAF selected from the group consisting of G464V, G469A, G469V, G469R, E586K, K601E, K601N, G466R, G466A, G466E, G466V, N581I, N581S, D594E, D594G, D594N, G596C, G596R, L597R, L597S, and L597Q. In some embodiments, the refractory cancer is associated with one or more alternative splicing events that result in the loss of BRAF gene exons 4-10, 4-8, 2-8 or 2-10. In still further embodiments of the foregoing, the method further comprises administering one or more pharmaceutical agents including anti-microtubular therapies, topoisomerase inhibitors, alkylating agents, nucleotide synthesis inhibitors, DNA synthesis inhibitors, protein synthesis inhibitors, developmental signaling pathway inhibitors, pro-apoptotic agents, RTK inhibitors (including inhibitors against ALK, EGFR, ERBB2, LTK, MET, NTRK, RET, ROS1), RAF inhibitors representing alternative binding modes (such as Type 1.5 or Type II), MEK1/2 inhibitors, ERK1/2 inhibitors, RSK1/2/3/4 inhibitors, AKT inhibitors, TORC1/2 inhibitors, DNA damage response pathway inhibitors (including ATM, ATR), PI3K inhibitors and/or radiation. [0020] In some embodiments of the present aspect, the cancer is a refractory cancer. In certain embodiments of the foregoing, the refractory cancer is associated with one or more genetic alterations in KRAS, NRAS, HRAS, BRAF, or one or more RTKs. In some embodiments, the refractory cancer is associated with one or more mutations in KRAS selected from the group consisting of G12D, G12V, G12C, G12S, G12R, G12A, G13D, G13C, G13R, Q61H, Q61K, Q61L, Q61P, Q61R and Q61E. In some embodiments, the refractory cancer is associated with one or more mutations in NRAS selected from the group consisting of G12D, G12S, G12C, G12V, G12A, G13D, G13R, G13V, G13C, G13A, G13S, G61R, Q61K Q61H, and G61L. In some embodiments, the refractory cancer is associated with one or more mutations in HRAS selected from the group consisting of G12V, G12S, G12D, G12C, G12R, G12A, G13R, G13V, G13D, G13S, G13C, Q61R, Q61L, Q61K, and Q61H. In some embodiments, the refractory cancer is associated with one or more genetic alterations in BRAF selected from the group consisting of gene amplification, point mutation, BRAF fusion, and gene splicing events. In some embodiments, the refractory cancer is associated with one or more Class II or Class III mutations in BRAF. In some embodiments, the refractory cancer is associated with one or more mutations in BRAF selected from the group consisting of G464V, G469A, G469V, G469R, E586K, K601E, K601N, G466R, G466A, G466E, G466V, N581I, N581S, D594E, D594G, D594N, G596C, G596R, L597R, L597S, and L597Q. In some embodiments, the refractory cancer is associated with one or more alternative splicing events that result in the loss of BRAF gene exons 4-10, 4-8, 2-8 or 2-10. In some embodiments wherein the refractory cancer is associated with one or more genetic alterations in one or more RTKs, the one or more RTKs is selected from the group consisting of ALK, EGFR, ERBB2, LTK, MET, NTRK, RET, and ROS1. [0021] In some embodiments, the cancer is a solid tumor or a hematological malignancy. In some embodiments, the cancer is melanoma, lung cancer, pancreatic carcinoma, glioma, colorectal carcincoma, chronic myeloid leukemia (CML), acute myeloid leukemia (AML), or acute lymphoblastic leukemia (ALL). In certain embodiments, the lung cancer is non-small cell lung cancer (NSCLC). [0022] In still further embodiments of the foregoing, the method further comprises administering one or more pharmaceutical agents including anti-microtubular therapies, topoisomerase inhibitors, alkylating agents, nucleotide synthesis inhibitors, DNA synthesis inhibitors, protein synthesis inhibitors, developmental signaling pathway inhibitors, pro- apoptotic agents, RTK inhibitors (including inhibitors against ALK, EGFR, ERBB2, LTK, MET, NTRK, RET, ROS1), RAF inhibitors representing alternative binding modes (such as Type 1.5 or Type II), MEK1/2 inhibitors, ERK1/2 inhibitors, RSK1/2/3/4 inhibitors, AKT inhibitors, TORC1/2 inhibitors, DNA damage response pathway inhibitors (including ATM, ATR), PI3K inhibitors and/or radiation. DETAILED DESCRIPTION [0023] The following description sets forth exemplary methods, parameters, and the like. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure but is instead provided as a description of exemplary embodiments. I. Definitions [0024] As used herein, the following definitions shall apply unless otherwise indicated. Further, if any term or symbol used herein is not defined as set forth below, it shall have its ordinary meaning in the art. [0025] The term “excipient” as used herein means an inert or inactive substance that may be used in the production of a drug or pharmaceutical, such as a tablet containing a compound of the present disclosure as an active ingredient. Various substances may be embraced by the term excipient, including without limitation any substance used as a binder, disintegrant, coating, compression/encapsulation aid, cream or lotion, lubricant, solutions for parenteral administration, materials for chewable tablets, sweetener or flavoring, suspending/gelling agent, or wet granulation agent. Binders include, e.g., carbomers, povidone, xanthan gum, etc.; coatings include, e.g., cellulose acetate phthalate, ethylcellulose, gellan gum, maltodextrin, enteric coatings, etc.; compression/encapsulation aids include, e.g., calcium carbonate, dextrose, fructose dc (dc = “directly compressible”), honey dc, lactose (anhydrate or monohydrate; optionally in combination with aspartame, cellulose, or microcrystalline cellulose), starch dc, sucrose, etc.; disintegrants include, e.g., croscarmellose sodium, gellan gum, sodium starch glycolate, etc.; creams or lotions include, e.g., maltodextrin, carrageenans, etc.; lubricants include, e.g., magnesium stearate, stearic acid, sodium stearyl fumarate, etc.; materials for chewable tablets include, e.g., dextrose, fructose dc, lactose (monohydrate, optionally in combination with aspartame or cellulose), etc.; suspending/gelling agents include, e.g., carrageenan, sodium starch glycolate, xanthan gum, etc.; sweeteners include, e.g., aspartame, dextrose, fructose dc, sorbitol, sucrose dc, etc.; and wet granulation agents include, e.g., calcium carbonate, maltodextrin, microcrystalline cellulose, etc. [0026] The terms “individual”, “subject” and “patient” refer to mammals and includes humans and non-human mammals. Examples of patients include, but are not limited to, mice, rats, hamsters, guinea pigs, pigs, rabbits, cats, dogs, goats, sheep, cows, and humans. In some embodiments, patient refers to a human. [0027] As used herein, the term “mammal” includes, but is not limited to, humans, mice, rats, guinea pigs, monkeys, dogs, cats, horses, cows, pigs, and sheep. [0028] “Pharmaceutically acceptable” refers to safe and non-toxic, and suitable for in vivo or for human administration. [0029] As used herein, the term “alkyl”, by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain hydrocarbon radical, having the number of carbon atoms designated (e.g., C ₁ -C ₆ means one to six carbons). Examples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, iso-butyl, sec-butyl, n-pentyl, n- hexyl, n-heptyl, n-octyl, and the like. In some embodiments, the term “alkyl” may encompass C ₁ -C ₆ alkyl, C ₂ -C ₆ alkyl, C ₃ -C ₆ alkyl, C ₄ -C ₆ alkyl, C ₅ -C ₆ alkyl, C ₁ -C ₅ alkyl, C ₂ -C ₅ alkyl, C ₃ -C ₅ alkyl, C ₄ -C ₅ alkyl, C ₁ -C ₄ alkyl, C ₂ -C ₄ alkyl, C ₃ -C ₄ alkyl, C ₁ -C ₃ alkyl, C ₂ -C ₃ alkyl, or C ₁ -C ₂ alkyl. [0030] As used herein, the term “alkenyl” refers to an unsaturated branched or straight- chain alkyl group having the indicated number of carbon atoms (e.g., 2 to 8, or 2 to 6 carbon atoms) and at least one carbon-carbon double bond. The group may be in either the cis or trans configuration (Z or E configuration) about the double bond(s). Alkenyl groups include, but are not limited to, ethenyl, propenyl (e.g., prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl), and butenyl (e.g., but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1- yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl). In some embodiments, the alkenyl group may be attached to the rest of the molecule by a carbon atom in the carbon-carbon double bond. In other embodiments, the “alkenyl” may be attached to the rest of the molecule by a saturated carbon atom, and the carbon-carbon double bond is located elsewhere along the branched or straight-chain alkyl group. [0031] The term “cycloalkyl,” “carbocyclic,” or “carbocycle” refers to hydrocarbon rings having the indicated number of ring atoms (e.g., C ₃ -C ₆ cycloalkyl means 3-6 carbons) and being fully saturated or having no more than one double bond between ring vertices. As used herein, “cycloalkyl,” “carbocyclic,” or “carbocycle” is also meant to refer to bicyclic, polycyclic and spirocyclic hydrocarbon rings such as, for example, bicyclo[2.2.1]heptane, pinane, bicyclo[2.2.2]octane, adamantane, norborene, spirocyclic C _5-12 alkane, etc. In some embodiments, “cycloalkyl” encompasses C ₃ -C ₇ cycloalkyl, C ₄ -C ₇ cycloalkyl, C ₅ -C ₇ cycloalkyl, C ₅ -C ₇ cycloalkyl, C ₃ -C ₆ cycloalkyl, C ₄ -C ₆ cycloalkyl, C ₅ -C ₆ cycloalkyl, C ₃ -C ₅ cycloalkyl, C ₄ -C ₅ cycloalkyl, or C ₃ -C ₄ cycloalkyl. [0032] The term “heteroalkyl,” by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain hydrocarbon radical, consisting of the stated number of carbon atoms and from one to three heteroatoms selected from the group consisting of O, N, Si and S, and wherein the nitrogen and sulfur atoms can optionally be oxidized and the nitrogen heteroatom can optionally be quaternized. The heteroatom(s) O, N and S can be placed at any interior position of the heteroalkyl group. The heteroatom Si can be placed at any position of the heteroalkyl group, including the position at which the alkyl group is attached to the remainder of the molecule. A “heteroalkyl” can contain up to three units of unsaturation, and also include mono- and poly-halogenated variants, or combinations thereof. Examples include -CH ₂ -CH ₂ -O-CH ₃ , -CH ₂ -CH ₂ -O-CF ₃ , -CH ₂ -CH ₂ -NH-CH ₃ , -CH ₂ -CH ₂ -N(CH ₃ )-CH ₃ , -CH ₂ -S-CH ₂ -CH ₃ , -S(O)-CH ₃ , -CH ₂ -CH ₂ -S(O) ₂ -CH ₃ , -CH=CH-O-CH ₃ -Si(CH ₃ ) ₃ , -CH ₂ -CH=N-OCH ₃ , and -CH=CH=N(CH ₃ )-CH ₃ . Up to two heteroatoms can be consecutive, such as, for example, -CH ₂ -NH-OCH ₃ and -CH ₂ -O-Si(CH ₃ ) ₃ . [0033] The term “heterocycloalkyl”, “heterocyclic,” or “heterocycle,” refers to a cycloalkyl radical group having the indicated number of ring atoms (e.g., 5-6 membered heterocycloalkyl) that contain from one to five heteroatoms selected from the group consisting of N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, nitrogen atom(s) are optionally quaternized, as ring atoms. Unless otherwise stated, a “heterocycloalkyl”, “heterocyclic”, or “heterocycle,” ring can be a monocyclic, a bicyclic, spirocyclic or a polycylic ring system. Non-limiting examples of “heterocycloalkyl,” “heterocyclic,” or “heterocycle,” rings include azetidinyl, pyrrolidine, piperidine, N- methylpiperidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, pyrimidine-2,4(1H,3H)-dione, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-5-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrhydrothiophene, quinuclidine, tropane and the like. A “heterocycloalkyl”, “heterocyclic”, or “heterocycle,” group can be attached to the remainder of the molecule through one or more ring carbons or heteroatoms. In some embodiments, “heterocycloalkyl” encompasses 4- to 8-membered heterocycloalkyl, 5- to 8-membered heterocycloalkyl, 6- to 8-membered heterocycloalkyl, 7- to 8-membered heterocycloalkyl, 4- to 7-membered heterocycloalkyl, 5- to 7-membered heterocycloalkyl, 6- to 7-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, 4- to 6-membered heterocycloalkyl, 5- to 6-membered heterocycloalkyl, or 4- to 5-membered heterocycloalkyl. [0034] The term “heterocycloalkenyl” refers to a non-aromatic cycloalkenyl radical group which is partially unsaturated, for example, has at least one double bond, which has the indicated number of ring atoms (e.g., 5-6 membered heterocycloalkyl), which contains from one to five heteroatoms selected from the group consisting of N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, nitrogen atom(s) are optionally quaternized, as ring atoms. Unless otherwise stated, a “heterocycloalkenyl” can be a monocyclic, a bicyclic, spirocyclic or a polycylic ring system. A “heterocycloalkenyl” group can be attached to the remainder of the molecule through one or more ring carbons or heteroatoms. In some embodiments, “heterocycloalkenyl” encompasses 4- to 8-membered heterocycloalkenyl, 5- to 8-membered heterocycloalkenyl, 6- to 8-membered heterocycloalkenyl, 7- to 8-membered heterocycloalkenyl, 4- to 7-membered heterocycloalkenyl, 5- to 7-membered heterocycloalkenyl, 6- to 7-membered heterocycloalkenyl, 4- to 6-membered heterocycloalkenyl, 5- to 6-membered heterocycloalkenyl, or 4- to 5-membered heterocycloalkenyl. [0035] The term “alkylene” by itself or as part of another substituent means a divalent radical derived from an alkane, as exemplified by -CH ₂ CH ₂ CH ₂ CH ₂ -. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms. In some embodiments, an alkyl (or alkylene) group will have 10 or fewer carbon atoms. [0036] The term “heteroalkylene” by itself or as part of another substituent means a divalent radical, saturated or unsaturated or polyunsaturated, derived from heteroalkyl, as exemplified by -CH ₂ -CH ₂ -S-CH ₂ CH ₂ -, -CH ₂ -S-CH ₂ -CH ₂ -NH-CH ₂ -, -O-CH ₂ -CH=CH-, - CH ₂ -CH=C(H)CH ₂ -O-CH ₂ - and -S-CH ₂ -C≡C-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). [0037] The term “heterocycloalkylene” by itself or as part of another substituent means a divalent radical, saturated or unsaturated or polyunsaturated, derived from heterocycloalkyl. For heterocycloalkylene groups, heteroatoms can also occupy either or both of the chain termini. [0038] The terms “alkoxy” and “alkylamino” are used in their conventional sense, and refer to those alkyl groups attached to the remainder of the molecule via an oxygen atom or an amino group, respectively. [0039] The term “heterocycloalkoxy” refers to a heterocycloalkyl-O- group in which the heterocycloalkyl group is as previously described herein. [0040] The terms “halo” or “halogen,” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as “haloalkyl” are meant to include monohaloalkyl and polyhaloalkyl. For example, the term “C ₁ -C ₄ haloalkyl” is mean to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, difluoromethyl, and the like. [0041] The term “haloalkyl-OH” refers to a haloalkyl group as described above which is also substituted by one or more hydroxyl groups. The term “haloalkyl-OH” is meant to include haloalkyl substituted by one hydroxyl group, as well as haloalkyl substituted by multiple hydroxyl groups. The term “haloalkyl-OH” also encompasses haloalkyl groups substituted by one or more hydroxyl groups on any carbon of the haloalkyl group. For example, the term “haloalkyl-OH” includes -CH(F)OH, -CH ₂ CFHCH ₂ OH, -CH(OH)CF ₃ , and the like. [0042] The term “alkyl-OH” or “alkylene-OH” refers to an alkyl or alkylene substituted by one or more hydroxyl groups. The term “alkyl-OH” is meant to include alkyl substituted by one hydroxyl group, as well as alkyl substituted by multiple hydroxyl groups. The term “alkylene-OH” is meant to include alkylene substituted by one hydroxyl group, as well as alkylene substituted by multiple hydroxyl groups. The terms “alkyl-OH” and “alkylene-OH” also encompass alkyl groups and alkylene groups, respectively, that are substituted by one or more hydroxyl groups on any carbon of the alkyl or alkylene group, as valency permits. For example, the term “alkyl-OH” includes -CH ₂ OH, -CH(OH)CH ₃ , -CH ₂ CH ₂ OH, -C(CH ₃ ) ₂ OH, and the like. [0043] The term “alkyl-OR ⁶ ” refers to an alkyl substituted by one or more –OR ⁶ groups. The term “alkyl-OR ⁶ ” is meant to include alkyl substituted by one -OR ⁶ group, as well as alkyl substituted by multiple -OR ⁶ groups. The term “alkyl-OR ⁶ ” also encompasses alkyl groups substituted by one or more OR ⁶ groups on any carbon of the alkyl, as valency permits. [0044] The term “alkyl-CN” refers to an alkyl substituted by one or more cyano groups. The term “alkyl-CN” is meant to include alkyl substituted by one cyano group, as well as alkyl substituted by multiple cyano groups. The term “alkyl-CN” also encompasses alkyl groups substituted by one or more cyano groups on any carbon of the alkyl group. For example, the term “alkyl-CN” includes -CH ₂ CN, -CH ₂ CH ₂ CN, -CH(CN)CH ₃ , and the like. [0045] The term “aryl” means, unless otherwise stated, a polyunsaturated, typically aromatic, hydrocarbon group, which can be a single ring or multiple rings (up to three rings) which are fused together. In some embodiments, “aryl” encompasses C ₆ -C ₁₄ aryl, C ₈ -C ₁₄ aryl, C ₁₀ -C ₁₄ aryl, C ₁₂ -C ₁₄ aryl, C ₆ -C ₁₂ aryl, C ₈ -C ₁₂ aryl, C ₁₀ -C ₁₂ aryl, C ₆ -C ₁₀ aryl, C ₈ -C ₁₀ aryl, or C ₆ -C ₈ aryl. The term “heteroaryl” refers to aryl groups (or rings) that contain from one to five heteroatoms selected from the group consisting of N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom. Non-limiting examples of aryl groups include phenyl, naphthyl and biphenyl, while non- limiting examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimindinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalaziniyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridines, benzothiaxolyl, benzofuranyl, benzothienyl, indolyl, quinolyl, isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furyl, thienyl and the like. In some embodiments, the term “heteroaryl” encompasses 5- to 10-membered heteroaryl, 6- to 10-membered heteroaryl, 7- to 10-membered heteroaryl, 8- to 10-membered heteroaryl, 9- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, 6- to 9-membered heteroaryl, 7- to 9- membered heteroaryl, 8- to 9-membered heteroaryl, 5- to 8-membered heteroaryl, 6- to 8- membered heteroaryl, 7- to 8-membered heteroaryl, 5- to 7-membered heteroaryl, 6- to 7- membered heteroaryl, or 5- to 6-membered heteroaryl. [0046] The above terms (e.g., “alkyl,” “aryl” and “heteroaryl”), in some embodiments, will include both substituted and unsubstituted forms of the indicated radical. The term “substituted” means that the specified group or moiety bears one or more substituents including, but not limited to, substituents such as alkoxy, acyl, acyloxy, alkoxycarbonyl, carbonylalkoxy, acylamino, amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, cycloalkyl, cycloalkenyl, aryl, heteroaryl, aryloxy, cyano, azido, halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, alkyl, alkenyl, alkynyl, heterocycloalkyl, heterocycloalkenyl, aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo and the like. The term “unsubstituted” means that the specified group bears no substituents. Where the term “substituted” is used to describe a structural system, the substitution is meant to occur at any valency-allowed position on the system. When a group or moiety bears more than one substituent, it is understood that the substituents may be the same or different from one another. In some embodiments, a substituted group or moiety bears from one to five substituents. In some embodiments, a substituted group or moiety bears one substituent. In some embodiments, a substituted group or moiety bears two substituents. In some embodiments, a substituted group or moiety bears three substituents. In some embodiments, a substituted group or moiety bears four substituents. In some embodiments, a substituted group or moiety bears five substituents. [0047] By “optional” or “optionally” is meant that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, “optionally substituted alkyl” encompasses both “alkyl” and “substituted alkyl” as defined herein. It will be understood by those skilled in the art, with respect to any group containing one or more substituents, that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical, synthetically non-feasible, and/or inherently unstable. It will also be understood that where a group or moiety is optionally substituted, the disclosure includes both embodiments in which the group or moiety is substituted and embodiments in which the group or moiety is unsubstituted. [0048] The above terms (e.g., “alkyl,” “aryl” and “heteroaryl”), in some embodiments, will include both substituted and unsubstituted forms of the indicated radical. [0049] As used herein, the term “heteroatom” is meant to include oxygen (O), nitrogen (N), sulfur (S), boron (B), and silicon (Si). [0050] As used herein, the term “chiral” refers to molecules which have the property of non-superimposability of the mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner. [0051] As used herein, the term “stereoisomers” refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space. [0052] As used herein, a wavy line “ ” that intersects a bond in a chemical structure indicates the point of attachment of the atom to which the wavy bond is connected in the chemical structure to the remainder of a molecule, or to the remainder of a fragment of a molecule. [0053] As used herein, the representation of a group (e.g., X ^a ) in parenthesis followed by a subscript integer range (e.g., (X ^a ) _0-1 ) means that the group can have the number of occurrences as designated by the integer range. For example, (X ^a )0-1 means the group X ^a can be absent or can occur one time.

[0054] “Diastereomer” refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g. melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers can separate under high resolution analytical procedures such as electrophoresis and chromatography.

[0055] “Enantiomers” refer to two stereoisomers of a compound which are non- superimposable mirror images of one another.

[0056] Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., New York, 1994. The compounds of the present disclosure can contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the present disclosure, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present disclosure. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1 or (+) and (-) are employed to designate the sign of rotation of plane- polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which can occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomeric species, devoid of optical activity. [0057] As used herein, the term “tautomer” or “tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions by reorganization of some of the bonding electrons. [0058] As used herein, the term “solvate” refers to an association or complex of one or more solvent molecules and a compound of the present disclosure. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. The term “hydrate” refers to the complex where the solvent molecule is water. Certain compounds of the present disclosure 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 intended to be encompassed within the scope of the present disclosure. [0059] The term “co-crystal” as used herein refers to a solid that is a crystalline single phase material composed of two or more different molecular or ionic compounds generally in a stoichiometric ratio which are neither solvates nor simple salts. A co-crystal consists of two or more components that form a unique crystalline structure having unique properties. Co- crystals are typically characterized by a crystalline structure, which is generally held together by freely reversible, non-covalent interactions. As used herein, a co-crystal refers to a compound of the present disclosure and at least one other component in a defined stoichiometric ratio that form a crystalline structure. [0060] As used herein, the term “protecting group” refers to a substituent that is commonly employed to block or protect a particular functional group on a compound. For example, an “amino-protecting group” is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9- fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a “hydroxy-protecting group” refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality. Suitable protecting groups include acetyl and silyl. A “carboxy-protecting group” refers to a substituent of the carboxy group that blocks or protects the carboxy functionality. Common carboxy-protecting groups include phenylsulfonylethyl, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl, 2- (diphenylphosphino)-ethyl, nitroethyl and the like. For a general description of protecting groups and their use, see P. G. M. Wuts and T. W. Greene, Greene's Protective Groups in Organic Synthesis 4 ^th edition, Wiley-Interscience, New York, 2006.

[0061] As used herein, the term “pharmaceutically acceptable salts” is meant to include salts of the active compounds which 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 salts derived from pharmaceutically-acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like. Salts derived from pharmaceutically-acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally-occurring amines and the like, such as arginine, betaine, caffeine, choline, N,N'- dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like. 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 relatively nontoxic organic acids like acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, 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, for example, Berge, S. M., et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19). 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. [0062] The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present disclosure. [0063] Certain compounds of the present disclosure possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers, regioisomers and individual isomers (e.g., separate enantiomers) are all intended to be encompassed within the scope of the present disclosure. [0064] The compounds of the present disclosure can also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the present disclosure also embraces isotopically-labeled variants of the present disclosure which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having the atomic mass or mass number different from the predominant atomic mass or mass number usually found in nature for the atom. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the present disclosure and include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine and iodine, such as ² H (“D”), ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹³ N, ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ³² P, ³³ P, ³⁵ S, ¹⁸ F, ³⁶ Cl, ¹²³ I and ¹²⁵ I. Certain isotopically labeled compounds of the present disclosure (e.g., those labeled with ³ H or ¹⁴ C) are useful in compound and/or substrate tissue distribution assays. Tritiated ( ³ H) and carbon-14 ( ¹⁴ C) isotopes are useful for their ease of preparation and detectability. Further substitution with heavier isotopes such as deuterium (i.e., ² H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Positron emitting isotopes such as ¹⁵ O, ¹³ N, ¹¹ C, and ¹⁸ F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of the present disclosure can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. [0065] “Treating” or “treatment” of a disease in a patient refers to inhibiting the disease or arresting its development; or ameliorating or causing regression of the disease. As used herein, “treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results. For purposes of this disclosure, beneficial or desired results include, but are not limited to, one or more of the following: decreasing one more symptoms resulting from the disease or disorder, diminishing the extent of the disease or disorder, stabilizing the disease or disorder (e.g., preventing or delaying the worsening of the disease or disorder), delaying the occurrence or recurrence of the disease or disorder, delay or slowing the progression of the disease or disorder, ameliorating the disease or disorder state, providing a remission (whether partial or total) of the disease or disorder, decreasing the dose of one or more other medications required to treat the disease or disorder, enhancing the effect of another medication used to treat the disease or disorder, delaying the progression of the disease or disorder, increasing the quality of life, and/or prolonging survival of a patient. Also encompassed by “treatment” is a reduction of pathological consequence of the disease or disorder. The methods of the present disclosure contemplate any one or more of these aspects of treatment. [0066] “Preventing”, “prevention”, or “prophylaxis” of a disease in a patient refers to preventing the disease from occurring in a patient that is predisposed or does not yet display symptoms of the disease. [0067] The phrase “therapeutically effective amount” means an amount of a compound of the present disclosure that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein. [0068] The terms “cancer” and “cancerous” refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. [0069] It is appreciated that certain features of the present disclosure, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination. All combinations of the embodiments pertaining to the chemical groups represented by the variables are specifically embraced by the present invention and are disclosed herein just as if each and every combination was individually and explicitly disclosed, to the extent that such combinations embrace compounds that are stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity). In addition, all subcombinations of the chemical groups listed in the embodiments describing such variables are also specifically embraced by the present invention and are disclosed herein just as if each and every such sub-combination of chemical groups was individually and explicitly disclosed herein. II. Compounds [0070] In one aspect, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein: X ¹ , X ² , X ³ and X ⁴ are each independently N or C-R ¹ ; Y is absent, or is -C(O)-; R ⁰ is H, C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, 3- to 6-membered heterocycloalkyl, or - N(R ⁸ )(R ⁹ ), wherein the aliphatic portions of R ⁰ are optionally substituted with one or more R ¹⁰ groups; or R ⁰ is taken together with R ⁶ and the atoms to which they are attached to form a 4- to 6-membered heterocycloalkenyl or a 5- to 6-membered heteroaryl, wherein the 4- to 6-membered heterocycloalkenyl or 5- to 6-membered heteroaryl are optionally substituted with one or more R ¹⁰ groups; each R ¹ is independently H, halo, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, 5- to 6- membered heteroaryl, -OR ⁷ , -CN, -N(R ⁸ )(R ⁹ ), or -C(O)-N(R ⁸ )(R ⁹ ), wherein R ¹ is optionally substituted with one or more R ¹⁰ groups; R ^2a , R ^2b , and R ^2c are each independently H, -OH, halo, -CN, -S-C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₆ cycloalkyl, -OR ⁷ , or -N(R ⁸ )(R ⁹ ), wherein the aliphatic portions of R ^2a , R ^2b , and R ^2c are each independently optionally substituted with one or more R ¹⁰ groups; or one of R ^2a , R ^2b , and R ^2c is taken together with one of R ⁴ and R ⁵ to form a C ₃ - C ₆ cycloalkyl, and the other two of R ^2a , R ^2b , or R ^2c are each independently H, - OH, halo, -CN, -S-C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₆ cycloalkyl, -OR ⁷ , or -N(R ⁸ )(R ⁹ ), or one or two of R ^2a , R ^2b , and R ^2c is taken together with R ⁴ and R ⁵ to form a 4- to 6- membered heterocycloalkenyl or a 5- to 6-membered heteroaryl; and the remaining one or two of R ^2a , R ^2b , and R ^2c are each independently H, -OH, halo, -CN, -S-C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C ₃ - C ₆ cycloalkyl, -OR ⁷ , or -N(R ⁸ )(R ⁹ ), wherein the C ₃ -C ₆ cycloalkyl, 4- to 6-membered heterocycloalkenyl or 5- to 6- membered heteroaryl formed by any of R ^2a , R ^2b , R ^2c , R ⁴ , and R ⁵ is optionally substituted with one or more R ¹⁰ groups; R ³ is halo or C ₁ -C ₃ alkyl, wherein the aliphatic portions of R ³ are each independently optionally substituted with one or more R ¹⁰ groups; R ⁴ and R ⁵ are each independently H, D, -OH, C ₁ -C ₆ alkyl, or -NHS(O) ₂ C ₁ -C ₆ alkyl, or R ⁴ and R ⁵ are taken together with the atom to which they are attached to form =O or =N- (OH), or one of R ⁴ and R ⁵ is taken together with one of R ^2a , R ^2b , and R ^2c to form a C ₃ - C ₆ cycloalkyl, and the other of R ⁴ and R ⁵ is H, D, OH, C ₁ -C ₆ alkyl, or - NHS(O) ₂ C ₁ -C ₆ alkyl, or R ⁴ and R ⁵ are taken together with one or two of R ^2a , R ^2b , and R ^2c to form a 4- to 6-membered heterocycloalkenyl or a 5- to 6-membered heteroaryl; R ⁶ is H, or R ⁶ is taken together with R ⁰ and the atoms to which they are attached to form a 4- to 6-membered heterocycloalkenyl or a 5- to 6-membered heteroaryl, wherein the 4- to 6-membered heterocycloalkenyl or 5- to 6-membered heteroaryl are optionally substituted with one or more R ¹⁰ groups; each R ⁷ is independently H, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl; R ⁸ and R ⁹ are each independently H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, or C ₁ -C ₆ haloalkyl, or R ⁸ and R ⁹ are taken together with the nitrogen atom to which they are attached to form a 3- to 6-membered heterocycloalkyl, a 4- to 6-membered heterocycloalkenyl, or a 5- to 6-membered heteroaryl; and each R ¹⁰ is independently halo, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, -OR ⁷ , -CN, -N(R ⁸ )(R ⁹ ), - (C ₁ -C ₃ alkyl)-N(R ⁸ )(R ⁹ ). [0071] In some embodiments, X ¹ , X ² , X ³ , and X ⁴ are each independently N or C-R ¹ . In some embodiments, X ¹ , X ² , X ³ , and X ⁴ are C-R ¹ . In some embodiments, at least one of X ¹ , X ² , X ³ , and X ⁴ is N and the remaining groups of X ¹ , X ² , X ³ , and X ⁴ are independently N or C- R ¹ . In some embodiments, at least two of X ¹ , X ² , X ³ , and X ⁴ is N and the remaining X ¹ , X ² , X ³ , and X ⁴ are independently N or C-R ¹ . In some embodiments, at least three of X ¹ , X ² , X ³ , and X ⁴ is N and the remaining X ¹ , X ² , X ³ , and X ⁴ are independently N or C-R ¹ . In some embodiments, X ¹ , X ² , X ³ , and X ⁴ are N. In certain embodiments, one of X ¹ and X ² is C-R ¹ and the other of X ¹ and X ² is N. In some embodiments, X ³ and X ⁴ are C-R ¹ . In certain embodiments, X ³ and X ⁴ are CH. [0072] In some embodiments, R ¹ is is independently H, halo, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, 5- to 6-membered heteroaryl, -OR ⁷ , -CN, -N(R ⁸ )(R ⁹ ), or -C(O)-N(R ⁸ )(R ⁹ ), wherein R ¹ is optionally substituted with one or more R ¹⁰ groups. In some embodiments, R ¹ is H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, 5- to 6-membered heteroaryl, -OR ⁷ , -CN, -N(R ⁸ )(R ⁹ ), or - C(O)-N(R ⁸ )(R ⁹ ), wherein R ¹ is optionally substituted with one or more R ¹⁰ groups. In some embodiments, R ¹ is H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, -OR ⁷ , -CN, or -N(R ⁸ )(R ⁹ ), wherein R ¹ is optionally substituted with one or more R ¹⁰ groups. In some embodiments, R ¹ is H, F, -CH ₃ , cyclopropyl, -OCH ₃ , CN, NH ₂ , -C(O)-NHCH ₃ , -C(O)-N(CH ₃ ) ₂ , In some embo ¹ diments, R is H, F, -CH3, cyclopropyl, - OCH ₃ , CN, or NH ₂ . In some embodiments, each R ¹ is independently H or halo. In some embodiments, each R ¹ is H. In some embodiments wherein R ¹ is present, one R ¹ is halo, C ₁ - C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, 5- to 6-membered heteroaryl, -OR ⁷ , -CN, - N(R ⁸ )(R ⁹ ), or -C(O)-N(R ⁸ )(R ⁹ ), wherein R ¹ is optionally substituted with one or more R ¹⁰ groups, and the remaining R ¹ groups are H. [0073] In some embodiments, Y is absent or -C(O)-. In some embodiments, Y is absent. In other embodiments, Y is -C(O)-. [0074] In some embodiments, R ⁰ is H, C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, 3- to 6-membered heterocycloalkyl, or -N(R ⁸ )(R ⁹ ), wherein the aliphatic portions of R ⁰ are optionally substituted with one or more R ¹⁰ groups. In some embodiments, R ⁰ is H, C ₁ -C ₃ alkyl, C ₃ - C ₆ cycloalkyl, or -N(R ⁸ )(R ⁹ ), wherein the aliphatic portions of R ⁰ are optionally substituted with one or more R ¹⁰ groups. In some embodiments, R ⁰ is H, C ₁ -C ₃ alkyl, or C ₃ -C ₆ cycloalkyl, wherein the aliphatic portions of R ⁰ are optionally substituted with one or more R ¹⁰ groups. In some embodiments, R ⁰ is H or C ₃ -C ₆ cycloalkyl, wherein the aliphatic portions of R ⁰ are optionally substituted with one or more R ¹⁰ groups. In some embodiments, R ⁰ is H or C ₁ -C ₃ alkyl, wherein the aliphatic portions of R ⁰ are optionally substituted with one or more R ¹⁰ groups. In some embodiments, R ⁰ is C ₁ -C ₃ alkyl or C ₃ -C ₆ cycloalkyl, wherein the aliphatic portions of R ⁰ are optionally substituted with one or more R ¹⁰ groups. In some embodiments, R ⁰ is H. In some embodiments, R ⁰ is C ₁ -C ₃ alkyl optionally substituted with 1 to 5 independently selected R ¹⁰ groups. In some embodiments, R ⁰ is C ₃ -C ₆ cycloalkyl optionally substituted with one or more R ¹⁰ groups. In some embodiments, R ⁰ is cyclopropyl, cyclobutyl, cyclopentyl, or bicyclo[1.1.1]pentyl, each of which is optionally substituted with one or more R ¹⁰ groups. In certain embodiments, R ⁰ is cyclopropyl optionally substituted with one or more R ¹⁰ groups. In certain embodiments, R ⁰ is cyclopropyl optionally substituted with one or more F. In other embodiments, R ⁰ is H or C ₁ -C ₃ alkyl, wherein the aliphatic portions of R ⁰ are optionally substituted with one or more R ¹⁰ groups. In some embodiments, R ⁰ is H, methyl or ethyl, wherein the aliphatic portions of R ⁰ are optionally substituted with one or more R ¹⁰ groups. In other embodiments, R ⁰ is 3- to 6-membered heterocycloalkyl. In certain embodiments, R ⁰ is oxetanyl. [0075] In other embodiments, R ⁰ is taken together with R ⁶ and the atoms to which they are attached to form a 4- to 6-membered heterocycloalkenyl or a 5- to 6-membered heteroaryl, wherein the 4- to 6-membered heterocycloalkenyl or 5- to 6-membered heteroaryl is optionally substituted with one or more R ¹⁰ groups. In some embodiments, the 4- to 6- membered heterocycloalkenyl or 5- to 6-membered heteroaryl formed by R ⁰ , R ⁶ , and the atoms to which they are attached is , wherein the two indicate the points of attachment to rest of the molecule and the 4- to 6-membered heterocycloalkenyl or 5- to 6-membered heteroaryl is optionally substituted with one or more R ¹⁰ groups. [0076] In some embodiments, R ^2a , R ^2b , and R ^2c are each independently H, -OH, halo, - CN, -S-C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₆ cycloalkyl, -OR ⁷ , or - N(R ⁸ )(R ⁹ ), wherein the aliphatic portions of R ^2a , R ^2b , and R ^2c are each independently optionally substituted with one or more R ¹⁰ groups. In some embodiments, R ^2a , R ^2b , and R ^2c are each independently H, -OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, or C ₃ - C ₆ cycloalkyl, wherein the aliphatic portions of R ^2a , R ^2b , and R ^2c are each independently optionally substituted with one or more R ¹⁰ groups. In some embodiments, R ^2a , R ^2b , and R ^2c are each independently H, -OH, -SCH ₃ , C ₁ -C ₆ alkyl, or -OR ⁷ , wherein the aliphatic portions of R ^2a , R ^2b , and R ^2c are each independently optionally substituted with one or more R ¹⁰ groups. In some embodiments, R ^2a , R ^2b , and R ^2c are each independently H or C ₁ -C ₆ alkyl, wherein the aliphatic portions of R ^2a , R ^2b , and R ^2c are each independently optionally substituted with one or more R ¹⁰ groups. In some embodiments, at least one of R ^2a , R ^2b , and R ^2c is -OH, halo, -CN, -S-C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C ₃ - C ₆ cycloalkyl, -OR ⁷ , or -N(R ⁸ )(R ⁹ ), and the remaining R ^2a , R ^2b , and R ^2c are H, -OH, halo, - CN, -S-C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₆ cycloalkyl, -OR ⁷ , or - N(R ⁸ )(R ⁹ ), wherein the aliphatic portions of R ^2a , R ^2b , and R ^2c are each independently optionally substituted with one or more R ¹⁰ groups. In certain embodiments, one of R ^2a , R ^2b , and R ^2c is -OH, halo, -CN, -S-C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C ₃ - C ₆ cycloalkyl, -OR ⁷ , or -N(R ⁸ )(R ⁹ ), and the remaining R ^2a , R ^2b , and R ^2c are H, wherein the aliphatic portions of R ^2a , R ^2b , and R ^2c are each independently optionally substituted with one or more R ¹⁰ groups. [0077] In other embodiments, one of R ^2a , R ^2b , or R ^2c is taken together with one of R ⁴ and R ⁵ to form a C ₃ -C ₆ cycloalkyl, and the other two of R ^2a , R ^2b , or R ^2c are each independently H, -OH, halo, -CN, -S-C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₆ cycloalkyl, -OR ⁷ , or -N(R ⁸ )(R ⁹ ), wherein the C ₃ -C ₆ cycloalkyl formed by any of R ^2a , R ^2b , R ^2c , R ⁴ , and R ⁵ is optionally substituted with one or more R ¹⁰ groups. In some embodiments, one of R ^2a , R ^2b , and R ^2c is taken together with one of R ⁴ and R ⁵ to form a C _3- C ₆ cycloalkyl, wherein the C ₃ - C ₆ cycloalkyl formed by any of R ^2a , R ^2b , R ^2c , R ⁴ , and R ⁵ is optionally substituted with one or more R ¹⁰ groups, and the other two of R ^2a , R ^2b , or R ^2c are each independently H or C ₁ -C ₆ alkyl. [0078] In other embodiments, one or two of R ^2a , R ^2b , and R ^2c is taken together with R ⁴ and R ⁵ to form a 4- to 6-membered heterocycloalkenyl or a 5- to 6-membered heteroaryl; and the remaining one or two of R ^2a , R ^2b , and R ^2c are each independently H, -OH, halo, -CN, -S- C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₆ cycloalkyl, -OR ⁷ , or - N(R ⁸ )(R ⁹ ), wherein the 4- to 6-membered heterocycloalkenyl or 5- to 6-membered heteroaryl formed by any of R ^2a , R ^2b , R ^2c , R ⁴ , and R ⁵ is optionally substituted with one or more R ¹⁰ groups. In certain embodiments, one or two of R ^2a , R ^2b , and R ^2c is taken together with R ⁴ and R ⁵ to form a 4- to 6-membered heterocycloalkenyl or a 5- to 6-membered heteroaryl; and the remaining one or two of R ^2a , R ^2b , and R ^2c are each independently H or C ₁ -C ₆ alkyl, wherein the 4- to 6-membered heterocycloalkenyl or 5- to 6-membered heteroaryl formed by any of R ^2a , R ^2b , R ^2c , R ⁴ , and R ⁵ is optionally substituted with one or more R ¹⁰ groups. [0079] In some embodiments, R ³ is halo or C ₁ -C ₃ alkyl, wherein the aliphatic portions of R ³ are each independently optionally substituted with one or more R ¹⁰ groups. In some embodiments, R ³ is C ₁ -C ₃ alkyl, wherein the aliphatic portions of R ³ are each independently optionally substituted with one or more R ¹⁰ groups. In certain embodiments, R ³ is methyl optionally substituted with one or more R ¹⁰ groups. In certain other embodiments, R ³ is methyl. In still other embodiments, R ³ is halo. In some embodiments, R ³ is F or Cl. In other embodiments, R ³ is Cl. [0080] In some embodiments, R ⁴ and R ⁵ are each independently H, D, -OH, C ₁ -C ₆ alkyl, or -NHS(O) ₂ C ₁ -C ₆ alkyl. In some embodiments, R ⁴ and R ⁵ are each independently H, D, or - OH. In some embodiments, R ⁴ and R ⁵ are each independently H or -OH. In other embodiments, R ⁴ and R ⁵ are each independently D or -OH. In other embodiments, R ⁴ and R ⁵ are each independently -OH or C ₁ -C ₆ alkyl. In some embodiments, one of R ⁴ and R ⁵ is -OH, and the other of R ⁴ and R ⁵ is H, D, or C ₁ -C ₆ alkyl. In some embodiments, one of R ⁴ and R ⁵ is -OH or C ₁ -C ₆ alkyl, and the other of R ⁴ and R ⁵ is H or D. In certain embodiments, one of R ⁴ and R ⁵ is -OH or C ₁ -C ₆ alkyl, and the other of R ⁴ and R ⁵ is H or D. In other embodiments, one of R ⁴ and R ⁵ is -OH, and the other of R ⁴ and R ⁵ is C ₁ -C ₆ alkyl. In other embodiments, R ⁴ and R ⁵ are H. In yet other embodiments, R ⁴ and R ⁵ are independently C ₁ -C ₆ alkyl. [0081] In other embodiments, R ⁴ and R ⁵ are taken together with the atom to which they are attached to form =O or =N-(OH). In some embodiments, R ⁴ and R ⁵ are taken together with the atom to which they are attached to form =O. In other embodiments, R ⁴ and R ⁵ are taken together with the atom to which they are attached to form =N-(OH). [0082] In yet other embodiments, one of R ⁴ and R ⁵ is taken together with one of R ^2a , R ^2b , and R ^2c to form a C _3- C ₆ cycloalkyl, and the other of R ⁴ and R ⁵ is H, D, OH, C ₁ -C ₆ alkyl, or - NHS(O) ₂ C _1- C ₆ alkyl. In some embodiments, one of R ⁴ and R ⁵ is taken together with one of R ^2a , R ^2b , and R ^2c to form a C ₃ -C ₆ cycloalkyl, and the other of R ⁴ and R ⁵ is H, D, or -OH. In still yet other embodiments, R ⁴ and R ⁵ are taken together with one or two of R ^2a , R ^2b , and R ^2c to form a 4- to 6-membered heterocycloalkenyl or a 5- to 6-membered heteroaryl. [0083] In some embodiments, R ⁶ is H. In some embodiments, R ⁰ is taken together with R ⁶ and the atoms to which they are attached to form a 4- to 6-membered heterocycloalkenyl or a 5- to 6-membered heteroaryl, wherein the aliphatic portions of the 4- to 6-membered heterocycloalkenyl or 5- to 6-membered heteroaryl are optionally substituted with one or more R ¹⁰ groups. [0084] In some embodiments, each R ⁷ is independently H, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl. In some embodiments, each R ⁷ is independently H or C ₁ -C ₆ alkyl. In some embodiments, each R ⁷ is H. In other embodiments, each R ⁷ is independently C ₁ -C ₆ alkyl. In certain embodiments, each R ⁷ is independently methyl or ethyl. [0085] In some embodiments, R ⁸ and R ⁹ are each independently H, C ₁ -C ₆ alkyl, C ₃ - C ₆ cycloalkyl, or C ₁ -C ₆ haloalkyl. R ⁸ and R ⁹ are each independently H or C ₁ -C ₆ alkyl. In some embodiments, R ⁸ and R ⁹ are each independently C ₁ -C ₆ alkyl. In certain embodiments, R ⁸ and R ⁹ are methyl. In some embodiments, R ⁸ and R ⁹ are H. In other embodiments, one of R ⁸ and R ⁹ is H and the other of R ⁸ and R ⁹ is C ₁ -C ₆ alkyl. [0086] In other embodiments, R ⁸ and R ⁹ are taken together with the nitrogen atom to which they are attached to form a 3- to 6-membered heterocycloalkyl, a 4- to 6-membered heterocycloalkenyl, or a 5- to 6-membered heteroaryl. [0087] In some embodiments, each R ¹⁰ is independently halo, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, -OR ⁷ , -CN, -N(R ⁸ )(R ⁹ ), -(C _1- C ₃ alkyl)-N(R ⁸ )(R ⁹ ). In some embodiments, each R ¹⁰ is independently halo, -OR ⁷ , or -(C ₁ -C ₃ alkyl)-N(R ⁸ )(R ⁹ ). In some embodiments, each R ¹⁰ is independently -OR ⁷ . In some embodiments, each R ¹⁰ is independently halo, C ₁ -C ₆ alkyl, or - OR ⁷ . In some embodiments, each R ¹⁰ is independently halo or C ₁ -C ₆ alkyl. In some embodiments, each R ¹⁰ is independently halo. In some embodiments, each R ¹⁰ is independently C ₁ -C ₆ alkyl. [0088] In some embodiments, of formula (I) is , [0089] In some embodiments, of formula (I) is . In certain embodiments, of formula (I) is , , [0090] In some embodiments wherein Y is -C(O)-, the compound of Formula (I) is a compound of Formula (I-1) or a compound of Formula (I-2). In some embodiments wherein Y is absent, the compound of Formula (I) is a compound of Formula (I-3). [0091] In some embodiments, the compound of formula (I) is a compound of formula (I- 1), or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing. In some variations, R ¹⁰ is absent. In other variations, 1-5 R ¹⁰ groups are present. In some embodiments, 1 or 2 R ¹⁰ groups are present. In some embodiments, the moiety _{of Formula (I-1) is} , or [0092] In some embodiments, the compound of formula (I) or compound of Formula (I- 1) is a compound of formula (I-1-a), (I-1-b), (I-1-c), (I-1-d), (I-1-e), (I-1-f), or (I-1-g), or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing:

In some embodiments, X ¹ , X ² , X ³ and X ⁴ are each independently N or C-R ¹ ; each R ¹ is independently H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, -OR ⁷ , -CN, -N(R ⁸ )(R ⁹ ), wherein the aliphatic portions of R ¹ are optionally substituted with one or more R ¹⁰ groups; R ^2a , R ^2b , and R ^2c are each independently H, -OH, -SCH ₃ , C ₁ -C ₆ alkyl, or -OR ⁷ ; wherein the aliphatic portions of R ^2a , R ^2b , and R ^2c are each independently optionally substituted with one or more R ¹⁰ groups; or one or two of R ^2a , R ^2b , and R ^2c is taken together with R ⁴ and R ⁵ to form a 4- to 6- membered heterocycloalkenyl or a 5- to 6-membered heteroaryl; and the remaining one or two of R ^2a , R ^2b , and R ^2c are each independently H, -OH, halo, -CN, -S-C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₆ cycloalkyl, -OR ⁷ , or -N(R ⁸ )(R ⁹ ), wherein the 4- to 6-membered heterocycloalkenyl or 5- to 6-membered heteroaryl formed by any of R ^2a , R ^2b , R ^2c , R ⁴ , and R ⁵ is optionally substituted with one or more R ¹⁰ groups;R ³ is halo, or C ₁ -C ₃ alkyl, wherein the aliphatic portions of R ³ are each independently optionally substituted with one or more R ¹⁰ groups; R ⁴ and R ⁵ are each independently H, D, -OH, C ₁ -C ₆ alkyl, or - NHS(O) ₂ C ₁ -C ₆ alkyl, or R ⁴ and R ⁵ are taken together with the atom to which they are attached to form =O or =N-(OH), or R ⁴ and R ⁵ are taken together with one or two of R ^2a , R ^2b , and R ^2c to form a 4- to 6-membered heterocycloalkenyl or a 5- to 6-membered heteroaryl; R ⁶ is H; each R ⁷ is independently H, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl; R ⁸ and R ⁹ are each independently Hor C ₁ -C ₆ alkyl, or R ⁸ and R ⁹ are taken together with the nitrogen atom to which they are attached to form a 3- to 6-membered heterocycloalkyl, a 4- to 6-membered heterocycloalkenyl, or a 5- to 6-membered heteroaryl; and each R ¹⁰ is independently halo, - OR ⁷ , or -(C ₁ -C ₃ alkyl)-N(R ⁸ )(R ⁹ ). In some embodiments of formula (I-a), (I-b), (I-c), (I-d), (I- e), (I-f), or (I-g), one of X ¹ and X ² is C-R ¹ and the other of X ¹ and X ² is N. [0093] In other embodiments, the compound of formula (I) is a compound of formula (I- 2): or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein R ⁰ is H, C ₁ -C ₃ alkyl, 3- to 6-membered heterocycloalkyl, or - N(R ⁸ )(R ⁹ ), optionally substituted with 1 to 5 independently selected R ¹⁰ groups. In some embodiments of Formula (I-2), R ⁰ is C ₁ -C ₃ alkyl, 3- to 6-membered heterocycloalkyl, or - N(R ⁸ )(R ⁹ ), optionally substituted with 1 to 5 independently selected R ¹⁰ groups. [0094] In other embodiments, the compound of formula (I) or compound of Formula (I-2) is a compound of formula (I-2-a), (I-2-b), (I-2-c), (I-2-d), (I-2-e), or (I-2-f), or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing:

[0095] In some embodiments, X ¹ , X ² , X ³ and X ⁴ are each independently N or C-R ¹ ; R ⁰ is C ₁ - C ₃ alkyl, wherein the aliphatic portions of R ⁰ are optionally substituted with one or more R ¹⁰ groups; each R ¹ is independently H; R ^2a , R ^2b , and R ^2c are each independently H or C ₁ -C ₆ alkyl, or one of R ^2a , R ^2b , and R ^2c is taken together with one of R ⁴ and R ⁵ to form a C ₃ - C ₆ cycloalkyl, and the other two of R ^2a , R ^2b , or R ^2c are each independently H or C ₁ -C ₆ alkyl; wherein the aliphatic portions of R ^2a , R ^2b , and R ^2c are each independently optionally substituted with one or more R ¹⁰ groups; R ³ is C ₁ -C ₃ alkyl, wherein the aliphatic portions of R ³ are each independently optionally substituted with one or more R ¹⁰ groups; R ⁴ and R ⁵ are each independently H, D, or -OH, or one of R ⁴ and R ⁵ is taken together with one of R ^2a , R ^2b , and R ^2c to form a C ₃ -C ₆ cycloalkyl, and the other of R ⁴ and R ⁵ is H, D, or -OH; R ⁶ is H; each R ⁷ is independently H or C ₁ -C ₆ alkyl; and each R ¹⁰ is independently -OR ⁷ . [0096] In some embodiments, the compound of formula (I) is a compound of formula (I- 3): or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing. In some embodiments of Formula (I-3), R ⁰ and R ⁶ are taken together with the atoms to which they are attached to form a 4- to 6-membered heterocycloalkenyl or a 5- to 6-membered heteroaryl, wherein the 4- to 6-membered heterocycloalkenyl or 5- to 6- membered heteroaryl is optionally substituted with one or more R ¹⁰ groups. In other embodiments, R ⁰ is H, C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, 3- to 6-membered heterocycloalkyl, or - N(R ⁸ )(R ⁹ ), wherein the aliphatic portions of R ⁰ are optionally substituted with one or more R ¹⁰ groups; and R ⁶ is H. [0097] In some embodiments, X ¹ , X ² , X ³ and X ⁴ are each independently N or C-R ¹ ; R ⁰ is H or C ₁ -C ₃ alkyl, or R ⁰ is taken together with R ⁶ and the atoms to which they are attached to form a 4- to 6-membered heterocycloalkenyl or a 5- to 6-membered heteroaryl, wherein the 4- to 6-membered heterocycloalkenyl or 5- to 6-membered heteroaryl is optionally substituted with one or more R ¹⁰ groups; each R ¹ is independently H or halo; R ^2a , R ^2b , and R ^2c are each independently H, -OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, or C ₃ - C ₆ cycloalkyl, wherein the aliphatic portions of R ^2a , R ^2b , and R ^2c are each independently optionally substituted with one or more R ¹⁰ groups; R ³ is C ₁ -C ₃ alkyl; R ⁴ and R ⁵ are each independently H or -OH; and R ⁶ is H, or R ⁶ is taken together with R ⁰ and the atoms to which they are attached to form a 4- to 6-membered heterocycloalkenyl or a 5- to 6-membered heteroaryl, wherein the 4- to 6-membered heterocycloalkenyl or 5- to 6-membered heteroaryl is optionally substituted with one or more R ¹⁰ groups. [0098] In other embodiments, the compound of formula (I) or compound of Formula (I-3) is a compound of formula (I-3-a), (I-3-b), (I-3-c), (I-3-d), (I-3-e), or (I-3-f), or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing:

[0099] In some embodiments, provided is a compound selected from the compounds in Table 1, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing. Table 1.

[0100] Although certain compounds described in Table 1 are presented as specific stereoisomers and/or in a non-stereochemical form, it is understood that any or all stereochemical forms, including any enantiomeric or diastereomeric forms, and any tautomers or other forms of any of the compounds of Table 1 are herein described. In some embodiments, the compound described herein is selected from Compound No. 1-193. [0101] This disclosure also includes all salts, such as pharmaceutically acceptable salts, of compounds referred to herein. This disclosure also includes any or all of the stereochemical forms, including any enantiomeric or diastereomeric forms, and any tautomers or other forms, such as N-oxides, solvates, hydrates, or isotopomers, of the compounds described. The present disclosure also includes co-crystals of the compounds described herein. Unless stereochemistry is explicitly indicated in a chemical structure or name, the structure or name is intended to embrace all possible stereoisomers of a compound depicted. In addition, where a specific stereochemical form is depicted, it is understood that other stereochemical forms are also embraced by the invention. All forms of the compounds are also embraced by the invention, such as crystalline or non-crystalline forms of the compounds. Compositions comprising a compound of the invention are also intended, such as a composition of substantially pure compound, including a specific stereochemical form thereof. Compositions comprising a mixture of compounds of the invention in any ratio are also embraced by the invention, including mixtures of two or more stereochemical forms of a compound of the invention in any ratio, such that racemic, non-racemic, enantioenriched and scalemic mixtures of a compound are embraced. [0102] In the descriptions herein, it is understood that every description, variation, embodiment, or aspect of a moiety can be combined with every description, variation, embodiment, or aspect of other moieties the same as if each and every combination of descriptions is specifically and individually listed. For example, every description, variation, embodiment, or aspect provided herein with respect to R ⁰ of formula (I) may be combined with every description, variation, embodiment, or aspect of X ¹ , X ² , X ³ , X ⁴ , Y, R ¹ , R ^2a , R ^2b , R ^2c , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , and/or R ¹⁰ , the same as if each and every combination were specifically and individually listed. It is also understood that all descriptions, variations, embodiments or aspects of formula (I), where applicable, apply equally to other formulae detailed herein, and are equally described, the same as if each and every description, variation, embodiment or aspect were separately and individually listed for all formulae. For example, all descriptions, variations, embodiments, or aspects of formula (I), where applicable, apply equally to any of formulae (I-1), (I-2), (I-3), (I-1-a), (I-1-b), (I-1-c), (I-1-d), (I-1-e), (I-1-f), (I-1-g), (I-2-a), (I-2-b), (I-2-c), (I-2-d), (I-2-e), (I-2-f), (I-3-a), (I-3-b), (I-3-c), (I-3-d), (I-3-e), or (I-3-f), detailed herein, and are equally described, the same as if each and every description, variation, embodiment or aspect were separately and individually listed for all formulae. III. General Synthetic Methods [0103] The compounds of the present disclosure may be prepared by a number of processes as generally described below and more specifically in the Examples hereinafter (such as the schemes provided in the Examples below). In the following process descriptions, the symbols when used in the formulae depicted are to be understood to represent those groups described above in relation to the formulae herein. [0104] The intermediates described in the following preparations may contain a number of nitrogen, hydroxy, and acid protecting groups such as esters. The variable protecting group may be the same or different in each occurrence depending on the particular reaction conditions and the particular transformations to be performed. The protection and deprotection conditions are well known to the skilled artisan and are described in the literature. See e.g., P. G. M. Wuts and T. W. Greene, Greene's Protective Groups in Organic Synthesis 4th edition, Wiley-Interscience, New York, 2006. [0105] Certain stereochemical centers have been left unspecified and certain substituents have been eliminated in the following schemes for the sake of clarity and are not intended to limit the teaching of the schemes in any way. Furthermore, individual isomers, enantiomers, and diastereomers may be separated or resolved by one of ordinary skill in the art at any convenient point in the synthesis of compounds of the invention, by methods such as selective crystallization techniques or chiral chromatography (See e.g., J. Jacques, et al., "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, Inc., 1981, and E.L. Eliel and S.H. Wilen,” Stereochemistry of Organic Compounds”, Wiley-Interscience, 1994). [0106] The compounds of the present invention, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, may be prepared by a variety of procedures known in the art, some of which are illustrated in the Examples below. The specific synthetic steps for each of the routes described may be combined in different ways, to prepare compounds of the present disclosure, or salts thereof. The products of each step can be recovered by conventional methods well known in the art, including extraction, evaporation, precipitation, chromatography, filtration, trituration, and crystallization. The reagents and starting materials are readily available to one of ordinary skill in the art. Others may be made by standard techniques of organic and heterocyclic chemistry which are analogous to the syntheses of known structurally-similar compounds and the procedures described in the Examples which follow including any novel procedures. [0107] Compounds of formula (I), (I-1), (I-2), (I-3), (I-1-a), (I-1-b), (I-1-c), (I-1-d), (I-1- e), (I-1-f), (I-1-g), (I-2-a), (I-2-b), (I-2-c), (I-2-d), (I-2-e), (I-2-f), (I-3-a), (I-3-b), (I-3-c), (I-3- d), (I-3-e), and (I-3-f), can be prepared according to Scheme A, Scheme B, Scheme C, or Scheme D, Scheme E, or Scheme F,wherein X ¹ , X ² , X ³ , X ⁴ , Y, R ⁰ , R ¹ , R ^2a , R ^2b , R ^2c , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , and/or R ¹⁰ , are as defined for formula (I), (I-1), (I-2), (I-3), (I-1-a), (I-1-b), (I-1-c), (I-1-d), (I-1-e), (I-1-f), (I-1-g), (I-2-a), (I-2-b), (I-2-c), (I-2-d), (I-2-e), (I-2-f), (I-3-a), (I-3-b), (I-3-c), (I-3-d), (I-3-e), or (I-3-f), or any applicable variation thereof as detailed herein. [0108] Compounds of formula (I) may be prepared according to the general synthetic scheme shown in Scheme A below. In Scheme A, diethoxyacetimidamides of general formula A-a, wherein X ¹ and X ² are independently selected from the group consisting of N or C-R ¹ , are reacted with H ₂ SO ₄ to yield the corresponding isoquinolin-3-amines of general formula A-b. These are further reacted with heterocyclyl-functionalized boronic acid derivatives of general formula A-c, wherein X ³ and X ⁴ are independently selected from the group consisting of N or C-R ¹ , to form naphthyridines of general formula A-d. These can be reacted with (R ⁰ -Y)-substituted carboxylic acids of general formula A-e to give compounds of formula (I). In scheme A, R ² is a carbon atom substituted with R ^2a , R ^2b , and R ^2c , as defined for Formula (I). [0109] In some variations of Scheme A, the starting material A-a may be substituted by material B-a to form compounds of formula (I) as shown in general synthetic scheme, Scheme B. In Scheme B, functionalized benzene with general formula B-a, is reacted with methyl 2,2-diethoxyacetimidate to form intermediate B-b, which undergoes cyclisation to form the corresponding quinolin-3-amine of B-c. This is further functionalised to form intermediate B-d, which is reacted with a heterocyclyl-substituted boronic acid derivative B- e, to form the resulting substituted quinoline, B-f, wherein R ³ is selected from halo, or C ₁ - ₃ alkyl, and R ² is a carbon atom substituted with R ^2a , R ^2b , and R ^2c and X ³ and X ⁴ are each independently N or C-R ¹ . Intermediate B-f is further reacted with B-g, to give compounds of Formula (I). Scheme B. [0110] Compounds of Formula (I-1) and (I-3) may be prepared according to the general synthetic scheme shown in Scheme C. In Scheme C, intermediate C-a is reacted with bis(pinacolato)diboron to form intermediate C-b. The intermediate C-b is further reacted with a functionalized heterocycle, of general formula C-c to form intermediate C-d. Intermediate C-d can be further reacted with intermediate C-e to form compounds of Formula (I-1), or alternatively Formula (I-2), wherein R is H or alkyl. [0111] In some variations of Scheme A, the starting material A-a may be substituted by material D-e to form compounds of formula (I) as shown in general synthetic scheme, Scheme B. Compounds of Formula (I-1) may be prepared according to the general synthetic scheme shown in Scheme D. In Scheme D, intermediate D-a is functionalized using NaCN to form intermediate D-b. D-b is further functionalized using Grignard reagent to form intermediate D-c, wherein R’ corresponds to -C(R ⁴ )(R ⁵ )-C-(R ^2a )( R ^2b )( R ^2c ). Intermediate D-e is functionalized using tributyltin hydride to form intermediate D-f, which undergoes a Stille reaction to form compounds of Formula (I).

[0112] Alternatively, compounds of Formula (I-1) may be prepared according to the general synthetic scheme shown in Scheme E. In Scheme E, E-a is reacted with a suitable heterocyclyl in an alkylation reaction to form E-b. E-b then undergoes a cyclization reaction to form the naphthyridone portion of E-c. E-c is functionalized using a suitable intermediate of general formula E-d, to form E-e and the compound is reduced to form the naphthyridine of Formula (I-1). This may then undergo further reactions to produce various functionalized groups such as those shown in E-g, and E-h, and in the oxime E-i.

[0113] In some variations of Scheme C, Compounds of Formula (I) may also be prepared according to the general synthetic scheme shown in Scheme F. The intermediate material C-c is reacted with reacted with bis(pinacolato)diboron to form F-a, which is reacted with compounds of general formula C-a, to form compounds of formula (I). In Scheme F, boronic acid derivative F-a can be coupled with a suitable substituted intermediate, such as C-a to form F-b. F-b is then reacted with a Boc-protected secondary amine in a substitution reaction to form F-c. F-c is then substituted using a suitable R ⁰ or R ⁰ -Y moiety substituted with an appropriate leaving group (LG) to form intermediate F-d, and the Boc-protecting group is removed by hydrolysis to form compounds of Formula (I). [0114] It should be recognized that the present disclosure also provides for any intermediates of the compounds and methods for synthesizing the compounds as described herein. In another aspect, provided herein are general intermediates as described in any one of Schemes A through F above, or compound-specific intermediates as described in the examples below. It should be further recognized that the present disclosure also provides for synthetic methods comprising any individual step or combination of individual process steps, or compositions of synthetic intermediates and/or reaction products as described herein. IV. Pharmaceutical Compositions and Formulations [0115] Any of the compounds described herein may be formulated as a pharmaceutically acceptable composition. [0116] Pharmaceutical compositions of any of the compounds detailed herein are embraced by this disclosure. Thus, the present disclosure includes pharmaceutical compositions comprising a compound as detailed herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, and a pharmaceutically acceptable carrier or excipient. In one aspect, the pharmaceutically acceptable salt is an acid addition salt, such as a salt formed with an inorganic or organic acid. Pharmaceutical compositions may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration or a form suitable for administration by inhalation. [0117] A compound as detailed herein may in one aspect be in a purified form and compositions comprising a compound in purified forms are detailed herein. Compositions comprising a compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, as detailed herein are provided, such as compositions of substantially pure compounds. In some embodiments, a composition containing a compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, as detailed herein is in substantially pure form. In one variation, “substantially pure” intends a composition that contains no more than 35% impurity, wherein the impurity denotes a compound other than the compound comprising the majority of the composition or a salt thereof. For example, a composition of a substantially pure compound selected from a compound of Table 1 intends a composition that contains no more than 35% impurity, wherein the impurity denotes a compound other than the compound of Table 1. In one variation, a composition of substantially pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, is provided wherein the composition contains no more than 25% impurity. In another variation, a composition of substantially pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, is provided wherein the composition contains or no more than 20% impurity. In still another variation, a composition of substantially pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, is provided wherein the composition contains or no more than 10% impurity. In a further variation, a composition of substantially pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, is provided wherein the composition contains no more than 5% impurity. In another variation, a composition of substantially pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co- crystal thereof, or a mixture of any of the foregoing, is provided wherein the composition contains no more than 3% impurity. In still another variation, a composition of substantially pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, is provided wherein the composition contains no more than 1% impurity. In a further variation, a composition of substantially pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, is provided wherein the composition contains no more than 0.5% impurity. In yet other variations, a composition of substantially pure compound means that the composition contains no more than 15%, no more than 10%, no more than 5%, no more than 3%, or no more than 1% impurity, which impurity may be the compound in a different stereochemical form. For instance, and without limitation, a composition of substantially pure (S) compound means that the composition contains no more than 15% or no more than 10% or no more than 5% or no more than 3% or no more than 1% of the (R) form of the compound. [0118] In one variation, the compounds herein are synthetic compounds prepared for administration to an individual. In another variation, compositions are provided containing a compound in substantially pure form. In another variation, the present disclosure embraces pharmaceutical compositions comprising a compound detailed herein and a pharmaceutically acceptable carrier. In another variation, methods of administering a compound are provided. The purified forms, pharmaceutical compositions and methods of administering the compounds are suitable for any compound or form thereof detailed herein. In some embodiments, the compounds and compositions as provided herein are sterile. Methods for sterilization known in the art may be suitable for any compounds or form thereof and compositions thereof as detailed herein. [0119] A compound detailed herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, may be formulated for any available delivery route, including an oral, mucosal (e.g., nasal, sublingual, vaginal, buccal or rectal), parenteral (e.g., intramuscular, subcutaneous or intravenous), topical or transdermal delivery form. A compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, may be formulated with suitable carriers to provide delivery forms that include, but are not limited to, tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, cataplasms (poultices), pastes, powders, dressings, creams, solutions, patches, aerosols (e.g., nasal spray or inhalers), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions or water-in-oil liquid emulsions), solutions and elixirs. [0120] A compound detailed herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, can be used in the preparation of a formulation, such as a pharmaceutical formulation, by combining the compound or compounds, or a pharmaceutically acceptable salt, solvate, hydrate, or co- crystal thereof, or a mixture of any of the foregoing, with a pharmaceutically acceptable carrier. Depending on the therapeutic form of the system (e.g., transdermal patch vs. oral tablet), the carrier may be in various forms. In addition, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants. Formulations comprising the compound may also contain other substances which have valuable therapeutic properties. Pharmaceutical formulations may be prepared by known pharmaceutical methods. Suitable formulations can be found, e.g., in Remington’s Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA, 20th ed. (2000), which is incorporated herein by reference. [0121] A compound detailed herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, may be administered to individuals in a form of generally accepted oral compositions, such as tablets, coated tablets, and gel capsules in a hard or in soft shell, emulsions or suspensions. Examples of carriers, which may be used for the preparation of such compositions, are lactose, corn starch or its derivatives, talc, stearate or its salts, etc. Acceptable carriers for gel capsules with soft shell are, for instance, plant oils, wax, fats, semisolid and liquid poly-ols, and so on. In addition, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants. [0122] Any of the compounds, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, described herein can be formulated in a tablet in any dosage form described, for example, a compound as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, can be formulated as a 10 mg tablet. [0123] Compositions comprising a compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, provided herein are also described. In one variation, the composition comprises a compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, and a pharmaceutically acceptable carrier or excipient. I n another variation, a composition of substantially pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, is provided. In some embodiments, the composition is for use as a human or veterinary medicament. In some embodiments, the composition is for use in a method described herein. In some embodiments, the composition is for use in the treatment of a disease or disorder described herein. [0124] Compositions formulated for co-administration of a compound provided herein and one or more additional pharmaceutical agents are also described. The co-administration can be simultaneous or sequential in any order. A compound provided herein may be formulated for co-administration with the one or more additional pharmaceutical agents in the same dosage form (e.g., single tablet or single i.v.) or separate dosage forms (e.g., two separate tablets, two separate i.v., or one tablet and one i.v.). Furthermore, co-administration can be, for example, 1) concurrent delivery, through the same route of delivery (e.g., tablet or i.v.), 2) sequential delivery on the same day, through the same route or different routes of delivery, or 3) delivery on different days, through the same route or different routes of delivery. V. Methods of Use [0125] Compounds and compositions detailed herein, such as a pharmaceutical composition containing a compound of formula (I) or any variation thereof provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, and a pharmaceutically acceptable carrier or excipient, may be used in methods of administration and treatment as provided herein. The compounds and compositions may also be used in in vitro methods, such as in vitro methods of administering a compound or composition to cells for screening purposes and/or for conducting quality control assays. [0126] In one aspect, provided herein are methods of a method of treating a cancer or neoplastic disease in a human in need thereof. In some embodiments, provided herein are methods of treating a disease or disorder mediated by a RAF kinase. RAF Kinase Inhibition [0127] In one aspect, provided herein is a method of inhibiting ARAF, BRAF and CRAF enzymatic activity in a cell, comprising exposing the cell with an effective amount of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing. [0128] The compounds and compositions described herein may be used in a method of treating a disease or disorder mediated by ARAF, BRAF, or CRAF kinase activity. In some embodiments, the compound or composition is administered according to a dosage described herein. [0129] In some embodiments, provided herein is a method for treating a disease or disorder mediated by RAF kinase activity comprising administering to an individual in need of treatment an effective amount of a compound of formula (I) or any variation thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing. In some embodiments, the disease or disorder is a cancer or neoplastic disease. [0130] In still yet another aspect, provided herein is a method of treating a cancer or neoplastic disease in a human in need thereof, comprising administering to the human a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing. RAF Kinase Family [0131] In vertebrates, RAF is comprised of a family of three genetically distinct serine/threonine protein kinases designated ARAF, BRAF and CRAF (sometimes referred to as RAF-1). These family members are highly conserved at the primary sequence level (75% amino acid identity across their entire protein sequence and >87% identity within their respective kinase domains) and exhibit the same overall domain architecture. ARAF, BRAF and CRAF are ubiquitously and differentially expressed across all cell and tissue types. As such, they collectively serve as an essential signaling node of the Ras/Raf/MEK/ERK (MAPK) pathway. Importantly, a substantial proportion of all cancers are driven by genetic alterations in either the RTKs or a particular member of the MAPK pathway especially HRAS, KRAS, NRAS and the RAF isoforms. that then drive aberrant activation of the pathway. Therefore, as an essential node in the MAPK pathway, the RAF kinases represent an important therapeutic intervention point for the treatment of a variety of malignancies whose dysregulated growth and survival rely upon MAPK signaling. Accordingly, multiple RAF kinase inhibitors have been approved for specific indications including melanoma and NSCLC and numerous additional inhibitors are currently undergoing clinical investigation for a variety of other malignancies. RAF function [0132] Upon ligand binding, RTKs homo- or hetero oligomerize with other receptors and auto-phosphorylate key tyrosine residues in trans. These phosphorylated residues then serve as docking sites for downstream effectors, especially adapter proteins involved in the recruitment and activation of RAS (H-, K- and N-RAS) such as Grb2 and SOS, respectively. Activated GTP-bound RAS now binds and recruits RAF thereby inducing conformational changes in the latter to induce its dimerization and concomitant activation. RAF then binds and phosphorylates /activates MEK which then phosphorylates/activates ERK. Activated ERK then redistributes to the cytoplasm, the cytoskeleton and the nucleus to control cell growth/division, differentiation and survival. RAF Structure and Regulation [0133] Grossly, the primary structure of RAF can be divided into two domains; an N- terminal regulatory domain and a C-terminal kinase domain (KD) connected by a linker region. The regulatory domain contains multiple elements including a RAS-binding domain (RBD) followed immediately downstream by a Cysteine-Rich Domain (CRD). A key phosphorylation site resides within the linker region and another at the extreme C-terminus downstream of the KD. In its inactive conformation, RAF is located in the cytoplasm in a monomeric, dual-phosphorylated, autoinhibited state. This autoinhibition is mediated via two cooperative mechanisms: (1) direct interaction between the RBD and the KD and (2) 14-3-3 protein dimers that simultaneously interact with the two phosphorylated residues flanking the KD. The combination of these interactions effectively binds up the KD into the inactive conformation. Upon RAS engagement via interactions with both the RBD and CRD, the RBD-KD interaction is effectively disrupted exposing the phosphorylation site within the linker region to phosphatase action via the MRAS/SHOC2/PP1 complex. Subsequent dephosphorylation of this residue abrogates intramolecular 14-3-3 binding thereby fully relieving autoinhibition and exposing residues critical for interaction with the plasma membrane. RAS-bound hemi-phosphorylated RAF can now dimerize with another RAF protein (homo- or heterodimerization) via intermolecular interactions between their respective KDs as well as 14-3-3 cross-linking between the two adjacent phosphorylated residues at the C-terminus of each protomer. Importantly, this fully active RAF complex functions as an obligate dimer to both bind to and activate MEK, ultimately driving ERK activation to complete the signaling cascade. RAF Mutations and Cancer [0134] Given their critical involvement in the RTK/RAS/RAF/MEK/ERK pathway, it should be no surprise each of the RAF isoforms are bona fide proto-oncogenes. Accordingly, a variety of mutations have been identified in ARAF, BRAF and CRAF that have been functionally linked to tumor formation. Importantly, these mutations fall into distinct classes with discrete mechanisms of kinase activation. [0135] BRAF is the most commonly mutated RAF isoform with alterations reported in approximately 8% of all solid tumors. Melanomas harbor the greatest proportion of BRAF mutations with 40-50% prevalence followed by thyroid, colorectal (CRC) and non-small cell lung cancers (NSCLC). These mutations can be divided into three distinct functional classes based upon how they elicit aberrant activation of RAF kinase activity. Class I mutations render the kinase constitutively active and independent of the requirement for RAS binding or dimerization with another RAF isoform. These mutations are unique to BRAF and are associated with highly specific alterations within the 600 ^th codon leading to the conversion of a valine residue to an aspartate, glutamate, lysine or arginine (V600D/E/K/R). Class II mutations drive aberrant kinase activation by conferring constitutive RAS-independent RAF- dimerization without adversely impacting the intrinsic kinase activity of the mutant. These mutations can be further subdivided into 3 subclasses according to which region within the kinase domain the alteration occurs (designated as Class IIa and IIb) or the formation of a kinase fusion arising from a chromosome translocation event (designated Class IIc) whereby the negative regulatory RBD and CRD domains are removed by deletion and replaced with the fusion partner. The class II mutations include the following: G464V, G469A, G469V, G469R, E586K, K601E, K601N, L597R, L597S, L597Q) These mutations are most common in NSCLC and CRC. Finally, Class III mutants confer enhanced RAS-dependent RAF dimerization to drive pathway activation. These mutations substantially attenuate the intrinsic kinase activity of the mutant such that transactivation of the wildtype RAF dimerization partner is key to aberrant pathway activation. Accordingly, other genetic alterations leading to RAS activation are often found co-occurring with these Class III mutations to facilitate dimerization. The class III mutations include the following: G466R, G466A, G466E, G466V, N581I, N581S, D594E, D594G, D594N, G596C, G596R. [0136] Compared to BRAF, the prevalence of oncogenic mutations within CRAF are relatively rare and found sporadically across a wide array of cancers including melanoma, NSCLC, pancreatic carcinoma, glioma, colorectal and hematological malignancies. There are two distinct mutation types that have been reported for CRAF. The first mutation type consists of point mutations that reside within the linker region effectively disrupting 14-3-3 binding to the linker domain phosphorylation site and conferring a more open confirmation that is now accessible to phosphatase action and subsequent dimerization/activation. These mutations include P261L and P261A. The second CRAF mutation type is analogous to the Class II mutations in BRAF. Specifically, there are reports of point mutations found in regions of the kinase domain analogous to the Class IIa and IIb BRAF mutants in CRAF across multiple cancer types, especially melanomas. These mutations include E478K, R391W, R391S and T491I as well as certain mutations that are also found in a subset of RASopathies; a cluster of diverse genetic diseases whose underlying etiology appears to derive from chronic MAPK pathway activation. There are also multiple reports of Class IIc mutations in RAF (CRAF fusions), which, like the BRAF fusions, possess fusion partners that effectively replace the RBD and CRD domains to relieve autoinhibition and drive dimerization and activation. [0137] To date, only one oncogenic mutation at codon 214 in ARAF has been reported. This mutation results in either a cysteine or phenylalanine for serine substitution (S214C/F) and has been identified in multiple NSCLC patients with an approximate prevalence of 0.5%. Given that no additional oncogenic mutations were identified in these tumors, it is likely that the ARAF mutants are the oncogenic drivers in these cancers. Accordingly, in vitro characterization of cell lines engineered to express an S214F ARAF mutant revealed that the mutant induces MAPK pathway activation and markedly enhances colony formation (a hallmark activity of an oncogene) in a kinase-dependent manner. Given that S214 is the linker region phosphorylation site critical for 14-3-3 binding, it is likely conferring constitutive activation in a manner very similar to the CRAF point mutants described above. RAF Kinase Inhibitors [0138] Given the strong link between genetic alterations in components of the MAPK pathway and the development of cancer in a wide array of tumor types, this pathway represents a key opportunity for the development of targeted therapies to control these proliferative diseases. In particular, inhibitors directed against the RAF family should offer an important treatment option for patients harboring RAF kinase activating mutations found in a number of cancer types including those of the skin, thyroid and lung. Accordingly, over the last 2 decades, numerous small molecule RAF inhibitors have been discovered and several of these have advanced into the clinic and gone on to full regulatory approval. The vast majority of these compounds are ATP-competitive small molecule inhibitors and bind in the kinase active site. They are divided into three types, dependent upon the specific structural conformation they induce within the kinase upon binding. These inhibitor types are designated type 1 inhibitor, type 1.5 inhibitor and type 2 inhibitor. Type 1 Inhibitors

[0139] Type 1 inhibitors bind in the active or ‘closed’ form of the kinase domain which is largely defined by the relative inward orientation of the C-helix and the ‘DFG’ loop which both comprise key structural and functional elements of the active site. This binding mode is designated C-helix-in/DFG-in. These compounds make key interactions with what is known as the hinge (the flexible linker between the amino and carboxyl terminal lobes of the kinase domain) as well as the pocket that normally accommodates the adenine ring of ATP. SB590885 and GDC-0879 are two literature examples of type I RAF inhibitors. Both were demonstrated to be almost exclusively active in BRAF Class 1 mutant cell contexts both in vitro and in vivo. Despite this promising activity, to date, no type I inhibitors have entered clinical development.

Type 2 inhibitors

[0140] Type 2 inhibitors bind to the kinase domain in an open conformation in which the DFG-loop is oriented in an outward or inactive position. This conformation exposes an allosteric, hydrophobic pocket adjacent to the ATP binding site that can be exploited to gain further enhancements in potency and selectivity via hydrogen bonding, Van der Waals and hydrophobic interactions. Accordingly, Type 2 inhibitors consist of functionalities that interact with both the hinge region as well as the allosteric pocket leaving the C-helix in an inward undisturbed orientation. Accordingly, this conformation is denoted as C-helix- in/DFG-out. In the literature, there exist a number of examples of Type 2 RAF inhibitors including several that have undergone clinical evaluation. Unlike the Type 1 inhibitor examples, these molecules as a class are more broadly active, exhibiting activity across a range of mutant contexts including RAS (KRAS, NRAS, HRAS), BRAF (Class 1, II and III) and CRAF. To date, multiple Type 2 inhibitors have entered into clinical development for patients harboring genetic alterations in the MAPK pathway. Importantly, several of these agents have demonstrated clinical activity in both Class I mutant BRAF and RAS mutant contexts. However, the activity has been limited and no Type 2 RAF inhibitor is currently approved for any indication.

Type 1.5 Inhibitors

[0141] Type 1.5 inhibitors bind to both the hinge region as well as the space typically occupied by the adenine moiety of ATP in much the same way as the Type 1 RAF inhibitors. What distinguishes the Type 1.5 inhibitors is that they take advantage of additional interactions at the back of the ATP binding pocket made accessible by the relatively small threonine gatekeeper residue found in all RAF isoforms (T382 in ARAF, T529 in BRAF and T421 in CRAF). Importantly, these back-pocket interactions alter the conformation of the C- helix, forcing it into an outward conformation while the DFG loop is oriented in its active or ‘in’ conformation. This conformation is denoted as C-helix-out/DFG-in. This conformation exerts a significant impact on the affinity of inhibitor for the second protomer of the RAF dimer rendering it markedly less able to bind inhibitor. Consequently, Type 1.5 inhibitors are highly active against BRAF Class I mutants that signal as monomers versus other MAPK pathway mutant contexts and the wildtype state where RAF signals as an obligate dimer. To date, 3 Type 1.5 inhibitors have been approved for the treatment of malignant melanomas harboring Class 1 BRAF mutations: vemurafenib, dabrafenib and encorafenib.

Paradoxical activation

[0142] As described above, ARAF, BRAF and CRAF are primarily regulated at the structural level in which various intra- and inter-molecular protein-protein interactions define both their localization and activity state. Accordingly, the structural changes induced with inhibitor binding exert biological effects beyond simple inhibition of kinase activity and these effects can differ depending upon the genetic context of the cells or tissues being exposed to inhibitor. In addition, dependent upon the inhibitor type, these effects are distinct, having important implications regarding safety as well as sensitivity and resistance to inhibitor treatment.

[0143] In normal cells and tissues in which the RAF isoforms are unmutated, inhibitor binding actually enhances signaling flux through the MAPK pathway in what is known as paradoxical activation. This effect derives from one or more of four distinct yet interdependent mechanisms; (1) attenuation of inhibitory auto-phosphorylation in the linker region, (2) interruption of kinase domain interactions, (3) enhancement of binding to GTP- bound RAS at the plasma membrane and (4) transactivation of the second protomer of the RAF dimer. The first 3 of these mechanisms collectively drive enhanced RAF protomer dimerization and therefore enhance downstream signaling. The fourth mechanism involves inhibitor binding to the first protomer of the RAF dimer to induce a C-helix out conformation that effectively locks the conformation of the active site of the second protomer to the active C-helix-in conformation thereby inducing both its activation and markedly reducing its affinity for inhibitor (negative allostery). The extent and magnitude of activation is dependent upon which of these mechanisms are induced by inhibitor binding and this is ultimately dictated by the binding mode of the inhibitor. Accordingly, Type 1, 2 and 1.5 inhibitors all engage the first 3 mechanisms to induce paradoxical activation. Only the Type 1.5 inhibitors engage the fourth mechanism to further enhance paradoxical activation.

Therapeutic Resistance

[0144] Clinical resistance to Type 1.5 and Type 2 inhibitors has been observed, but with distinct mechanisms of action. Patients with BRAF Class I mutant melanoma that become refractory to or relapse on Type 1.5 inhibitor therapies often exhibit mutations that drive RAF dimerization. These alterations typically involve RAF amplification/overexpression or RAS mutations but can also include aberrant alternative splicing events that remove the RBD and CRD and effectively remove the blockade to dimerization. When the Class I mutant BRAF protomer acts in the context of a dimer rather than its typical monomeric state, it is much less sensitive to Type 1.5 inhibitor treatment. This is due largely to the inhibitor’s impact on the C-helix which, as mentioned in the previous section not only results in transactivation of the unoccupied protomer but it also renders this protomer markedly less able to bind inhibitor such that super-clinical concentrations of inhibitor are required to significantly attenuate MAPK pathway signaling in the resistant tumor. Given the relatively limited clinical data available for the Type 2 RAF inhibitors, only one mechanism of therapeutic resistance has been reported thus far. In the case of belvarafenib, multiple patients that relapsed on therapy exhibited alterations in ARAF. These mutations reside within the kinase domain active site and rendered the kinase resistant not only to belvarafenib but a panel of Type 2 inhibitors.

Mutant coverage

[0145] Because the type 1.5 inhibitors are not effective at inhibiting RAF activity in the context of a dimer, they are only effective at inhibiting Class I BRAF mutants that signal as monomers. Because Type 2 inhibitors can inhibit both monomeric and dimeric RAF, they are able to inhibit Class II and III BRAF mutants that signal as obligate dimers in addition to the Class I mutants.

Clinical Safety

[0146] Paradoxical activation is known to adversely impact the tolerability of these inhibitors in patients, thereby limiting their clinical utility. As mentioned previously, Type 1.5 inhibitors markedly induce paradoxical activation in normal tissues by binding RAF dimers and transactivating the second unbound protomer. Accordingly, in the clinic, Type 1.5 inhibitor treatment is associated with multiple adverse events associated with aberrant MAPK pathway activation particularly involving the skin such as palmoplantar erythrodysaesthesia syndrome and proliferative skin lesions including keratoacanthomas and cutaneous squamous cell carcinomas. MEK inhibitors have been successfully deployed in combination with Type 1.5 RAF inhibitors to effectively manage these toxicities. Specifically, vemurafenib, dabrafenib and encorafenib have been approved in combination with cobimetinib, trametinib and binimetinib, respectively, for patients with BRAF Class I mutant metastatic melanoma. Not only have these combinations improved tolerability by attenuating paradoxical activation in normal tissues but they have also improved therapeutic benefit both in terms of overall response rate and long term survival.

[0147] In contrast, Type 2 inhibitors can bind and inhibit both protomers equally thereby significantly attenuating paradoxical activation and driving full MAPK inhibition, even in normal unmutated tissues. Consequently, the toxicities associated with Type 2 inhibitors are more in keeping with those elicited by MEK inhibitors.

[0148] In still yet another aspect, provided herein is a method of treating a cancer or neoplastic disease in a human in need thereof, comprising administering to the human a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein the cancer or neoplastic disease is associated with one or more genetic alterations that engender elevated RAS/RAF/MEK/ERK pathway activation. In some embodiments, the cancer or neoplastic disease is associated with one or more genetic alterations in KRAS, NRAS, HRAS, ARAF, BRAF or CRAF. In some embodiments, the cancer or neoplastic disease is associated with one or more mutations in KRAS selected from the group consisting of G12D, G12V, G12C, G12S, G12R, G12A, G13D, G13C, GBR, Q61H, Q61K, Q61L, Q61P, Q61R and Q61E. In some embodiments, the cancer or neoplastic disease is associated with one or more mutations in NRAS selected from the group consisting of G12D, G12S, G12C, G12V, G12A, G13D, GBR, G13V, G13C, G13A, G13S, G61R, Q61K Q61H, and G61L. In some embodiments, the cancer or neoplastic disease is associated with one or more mutations in HRAS selected from the group consisting of G12V, G12S, G12D, G12C, G12R, G12A, G13R, G13V, G13D, G13S, G13C, Q61R, Q61L, Q61K, and Q61H. In some embodiments, the cancer or neoplastic disease is associated with one or more mutations in ARAF selected from the group consisting of S214C and S214F. In some embodiments, the cancer or neoplastic disease is associated with one or more mutations in BRAF selected from the group consisting of Class I, Class Ila, Class lib, Class lie, and Class III mutations. In some embodiments, the cancer or neoplastic disease is associated with one or more mutations in CRAF selected from the group consisting of P261 A, P261L, E478K, R391W, R391S and T491I, or is associated with a CRAF fusion. In other embodiments, the cancer or neoplastic disease is associated with one or more genetic lesions resulting in the activation of one or more receptor tyrosine kinases (RTKs). In some embodiments, the one or more genetic lesions is a point mutation, a fusion or any combination thereof. In some embodiments, the one or more receptor tyrosine kinase is selected from the group consistion of ALK, EGFR, ERBB2, LTK, MET, NTRK, RET, and ROSE

[0149] The compounds and compositions of the present disclosure may be suitable for treatment of certain subtypes of cancer or neoplastic diseases, which may also be associated with mutations in KRAS, NRAS, HRAS, ARAF, BRAF or CRAF. In some embodiments, the cancer is is a solid tumor or a hematological malignancy. In some embodiments, the cancer is melanoma, lung cancer, pancreatic carcinoma, glioma, colorectal carcincoma, chronic myeloid leukemia (CML), acute myeloid leukemia (AML), or acute lymphoblastic leukemia (ALL). In certain embodiments, the lung cancer is non-small cell lung cancer (NSCLC). In one aspect, provided herein is a method of treating a solid tumor or a hematological malignancy, comprising administering to the human a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof, or a mixture of any of the foregoing. In some embodiments, the solid tumor or hematological malignancy is melanoma, lung cancer, pancreatic carcinoma, glioma, colorectal carcincoma, chronic myeloid leukemia (CML), acute myeloid leukemia (AML), or acute lymphoblastic leukemia (ALL). In certain embodiments, the lung cancer is non-small cell lung cancer (NSCLC). [0150] In some embodiments of the present aspect, the cancer is a refractory cancer. In certain embodiments of the foregoing, the refractory cancer is associated with a genetic alteration or alterations in KRAS (including mutants G12D, G12V, G12C, G12S, G12R, G12A, G13D, G13C, G13R, Q61H, Q61K, Q61L, Q61P, Q61R and Q61E), NRAS (including mutants G12D, G12S, G12C, G12V, G12A, G13D, G13R, G13V, G13C, G13A, G13S, G61R, Q61K Q61H, G61L), HRAS (including mutants G12V, G12S, G12D, G12C, G12R, G12A, G13R, G13V, G13D, G13S, G13C, Q61R, Q61L, Q61K, Q61H), BRAF (including gene amplification, class II and III mutants [including G464V, G469A, G469V, G469R, E586K, K601E, K601N, G466R, G466A, G466E, G466V, N581I, N581S, D594E, D594G, D594N, G596C, G596R, L597R, L597S, L597Q], BRAF fusions or alternative splicing events that result in the loss of BRAF gene exons 4-10, 4-8, 2-8 or 2-10), RTKs (including ALK, EGFR, ERBB2, LTK, MET, NTRK, RET, ROS1). In still further embodiments of the foregoing, the refractory cancer may be combined with any preceding embodiments of the present aspect, the method further comprises administering one or more pharmaceutical agents including anti-microtubular therapies, topoisomerase inhibitors, alkylating agents, nucleotide synthesis inhibitors, DNA synthesis inhibitors, protein synthesis inhibitors, developmental signaling pathway inhibitors, pro-apoptotic agents, RTK inhibitors (including inhibitors against ALK, EGFR, ERBB2, LTK, MET, NTRK, RET, ROS1), RAF inhibitors representing alternative binding modes (such as Type 1.5 or Type II), MEK1/2 inhibitors, ERK1/2 inhibitors, RSK1/2/3/4 inhibitors, AKT inhibitors, TORC1/2 inhibitors, DNA damage response pathway inhibitors (including ATM, ATR), PI3K inhibitors and/or radiation.

[0151] In some embodiments of the present aspect, the cancer is a refractory BRAF Class I mutant cancer. In some embodiments, the refractory BRAF Class I mutant cancer is associated with a point mutation selected from the group consisting of V600D, V600E, V600K, and V600R. In certain embodiments of the foregoing, the refractory cancer is associated with a genetic alteration in KRAS, NRAS, HRAS or BRAF that drives BRAF dimerization and confers resistance to approved Type 1.5 inhibitors (including vemurafenib, dabrafenib and encorafenib) both alone and in the context of MEK inhibitor (including cobimetinib, trametinib and binimetinib) combinations. In some embodiments, the refractory cancer is associated with one or more mutations in KRAS selected from the group consisting of G12D, G12V, G12C, G12S, G12R, G12A, G13D, G13C, GBR, Q61H, Q61K, Q61L, Q61P, Q61R and Q61E. In some embodiments, the refractory cancer is associated with one or more mutations in NRAS selected from the group consisting of G12D, G12S, G12C, G12V, G12A, G13D, G13R, G13V, G13C, G13A, G13S, G61R, Q61K Q61H, and G61L. In some embodiments, the refractory cancer is associated with one or more mutations in HRAS selected from the group consisting of G12V, G12S, G12D, G12C, G12R, G12A, G13R, G13V, G13D, G13S, G13C, Q61R, Q61L, Q61K, and Q61H. In some embodiments, the refractory cancer is associated with one or more genetic alterations in BRAF selected from the group consisting of gene amplification, point mutation, BRAF fusion, and gene splicing events. In some embodiments, the refractory cancer is associated with one or more Class II or Class III mutations in BRAF. In some embodiments, the refractory cancer is associated with one or more mutations in BRAF selected from the group consisting of G464V, G469A, G469V, G469R, E586K, K601E, K601N, G466R, G466A, G466E, G466V, N581I, N581S, D594E, D594G, D594N, G596C, G596R, L597R, L597S, and L597Q. In some embodiments, the refractory cancer is associated with one or more alternative splicing events that result in the loss of BRAF gene exons 4-10, 4-8, 2-8 or 2-10. In still further embodiments of the foregoing, the method further comprises administering one or more pharmaceutical agents including anti-microtubular therapies, topoisomerase inhibitors, alkylating agents, nucleotide synthesis inhibitors, DNA synthesis inhibitors, protein synthesis inhibitors, developmental signaling pathway inhibitors, pro-apoptotic agents, RTK inhibitors (including inhibitors against ALK, EGFR, ERBB2, LTK, MET, NTRK, RET, ROS1), RAF inhibitors representing alternative binding modes (such as Type 1.5 or Type II), MEK1/2 inhibitors, ERK1/2 inhibitors, RSK1/2/3/4 inhibitors, AKT inhibitors, TORC1/2 inhibitors, DNA damage response pathway inhibitors (including ATM, ATR), PI3K inhibitors and/or radiation.

[0152] In some embodiments, the individual is a mammal. In some embodiments, the individual is a primate, dog, cat, rabbit, or rodent. In some embodiments, the individual is a primate. In some embodiments, the individual is a human. In some embodiments, the human is at least about or is about any of 18, 21, 30, 50, 60, 65, 70, 75, 80, or 85 years old. In some embodiments, the human is a child. In some embodiments, the human is less than about or about any of 21, 18, 15, 10, 5, 4, 3, 2, or 1 years old.

[0153] In some embodiments, the method further comprises administering one or more additional pharmaceutical agents. In some embodiments, the method further comprises administering radiation. In some embodiments, the method further comprises administering one or more additional pharmaceutical agents, including anti -microtubular therapies (e.g. paclitaxel, vincristine), topoisomerase inhibitors (e.g. adriamycin), alylating agents (e.g. busulfan, cyclophosphamide), nucleotide synthesis inhibitors (hyroxyurea), DNA synthesis inhibtiors (e.g. cytarabine), protein synthesis inhibitors (e.g. omacetaxine), developmental signaling pathway inhibitors (e.g. sonidegib, Hedgehog pathway), pro-apoptotic agents (e.g. venetoclax), Abl myristoyl-pocket binding inhibitors (e.g. asciminib), MEK1/2 inhibitors (e.g. trametinib, binimetinib), AKT inhibitors (e.g. ipatasertib), PI3K inhibitors (e.g. apelisib)and radiation.

VI. Dosing and Method of Administration

[0154] The dose of a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, administered to an individual (such as a human) may vary with the particular compound or salt thereof, the method of administration, and the particular cancer, such as type and stage of cancer, being treated. In some embodiments, the amount of the compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, is a therapeutically effective amount.

[0155] The compounds provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, may be administered to an individual via various routes, including, e.g., intravenous, intramuscular, subcutaneous, oral, and transdermal.

[0156] The effective amount of the compound may in one aspect be a dose of between about 0.01 and about 100 mg/kg. Effective amounts or doses of the compounds of the present disclosure may be ascertained by routine methods, such as modeling, dose escalation, or clinical trials, taking into account routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the disease to be treated, the subject’s health status, condition, and weight. An exemplary dose is in the range of about from about 0.7 mg to 7 g daily, or about 7 mg to 350 mg daily, or about 350 mg to 1.75 g daily, or about 1.75 to 7 g daily.

[0157] Any of the methods provided herein may in one aspect comprise administering to an individual a pharmaceutical composition that contains an effective amount of a compound provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, and a pharmaceutically acceptable excipient. [0158] A compound or composition provided herein may be administered to an individual in accordance with an effective dosing regimen for a desired period of time or duration, such as at least about one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer, which in some variations may be for the duration of the individual’s life. In one variation, the compound is administered on a daily or intermittent schedule. The compound can be administered to an individual continuously (for example, at least once daily) over a period of time. The dosing frequency can also be less than once daily, e.g., about a once weekly dosing. The dosing frequency can be more than once daily, e.g., twice or three times daily. The dosing frequency can also be intermittent, including a ‘drug holiday’ (e.g., once daily dosing for 7 days followed by no doses for 7 days, repeated for any 14 day time period, such as about 2 months, about 4 months, about 6 months or more). Any of the dosing frequencies can employ any of the compounds described herein together with any of the dosages described herein.

VII. Articles of Manufacture and Kits

[0159] The present disclosure further provides articles of manufacture comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof, or a mixture of any of the foregoing, a composition described herein, or one or more unit dosages described herein in suitable packaging. In certain embodiments, the article of manufacture is for use in any of the methods described herein. Suitable packaging is known in the art and includes, for example, vials, vessels, ampules, bottles, jars, flexible packaging and the like. An article of manufacture may further be sterilized and/or sealed.

[0160] The present disclosure further provides kits for carrying out the methods of the present disclosure, which comprises one or more compounds described herein or a composition comprising a compound described herein. The kits may employ any of the compounds disclosed herein. In one variation, the kit employs a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, thereof. The kits may be used for any one or more of the uses described herein, and, accordingly, may contain instructions for the treatment of any disease or described herein, for example for the treatment of cancer or neoplastic disease, such as those associated with or mediated by RAF kinase. [0161] In some embodiments, the kit contains instructions for the treatment of a disease or disorder mediated by or associated with RAF kinase activity. In some embodiments, the disease or disorder is associated with one or more genetic alterations in KRAS, NRAS, HR AS, ARAF, BRAF or CRAF.

[0162] The kits optionally further comprise a container comprising one or more additional pharmaceutical agents and which kits further comprise instructions on or in the package insert for treating the subject with an effective amount of the one or more additional pharmaceutical agents.

[0163] Kits generally comprise suitable packaging. The kits may comprise one or more containers comprising any compound described herein. Each component (if there is more than one component) can be packaged in separate containers or some components can be combined in one container where cross-reactivity and shelf-life permit.

[0164] The kits may be in unit dosage forms, bulk packages (e.g., multi-dose packages) or sub-unit doses. For example, kits may be provided that contain sufficient dosages of a compound as disclosed herein and/or an additional pharmaceutically active compound useful for a disease detailed herein to provide effective treatment of an individual for an extended period, such as any of a week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more. Kits may also include multiple unit doses of the compounds and instructions for use and be packaged in quantities sufficient for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies).

[0165] The kits may optionally include a set of instructions, generally written instructions, although electronic storage media (e.g., magnetic diskette or optical disk) containing instructions are also acceptable, relating to the use of component(s) of the methods of the present disclosure. The instructions included with the kit generally include information as to the components and their administration to an individual.

ENUMERATED EMBODIMENTS

[0166] The following enumerated embodiments are representative of some aspects of the invention.

1. A compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein: X ¹ , X ² , X ³ and X ⁴ are each independently N or C-R ¹ ; Y is absent, or is -C(O)-; R ⁰ is H, C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, 3- to 6-membered heterocycloalkyl, or - N(R ⁸ )(R ⁹ ), wherein the aliphatic portions of R ⁰ are optionally substituted with one or more R ¹⁰ groups, or R ⁰ is taken together with R ⁶ and the atoms to which they are attached to form a 4- to 6-membered heterocycloalkenyl or a 5- to 6-membered heteroaryl, wherein the 4- to 6-membered heterocycloalkenyl or 5- to 6-membered heteroaryl is optionally substituted with one or more R ¹⁰ groups; each R ¹ is independently H, halo, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, 5- to 6- membered heteroaryl, -OR ⁷ , -CN, -N(R ⁸ )(R ⁹ ), or -C(O)-N(R ⁸ )(R ⁹ ), wherein R ¹ is optionally substituted with one or more R ¹⁰ groups; R ^2a , R ^2b , and R ^2c are each independently H, -OH, halo, -CN, -S-C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₆ cycloalkyl, -OR ⁷ , or -N(R ⁸ )(R ⁹ ), or one of R ^2a , R ^2b , and R ^2c is taken together with one of R ⁴ and R ⁵ to form a C ₃ - C ₆ cycloalkyl, and the other two of R ^2a , R ^2b , or R ^2c are each independently H, - OH, halo, -CN, -S-C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₆ cycloalkyl, -OR ⁷ , or -N(R ⁸ )(R ⁹ ), or one or two of R ^2a , R ^2b , and R ^2c is taken together with R ⁴ and R ⁵ to form a 4- to 6- membered heterocycloalkenyl or a 5- to 6-membered heteroaryl; and the remaining one or two of R ^2a , R ^2b , and R ^2c are each independently H, -OH, halo, -CN, -S-C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C ₃ - C ₆ cycloalkyl, -OR ⁷ , or -N(R ⁸ )(R ⁹ ), wherein the C ₃ -C ₆ cycloalkyl, 4- to 6-membered heterocycloalkenyl or 5- to 6- membered heteroaryl formed by any of R ^2a , R ^2b , R ^2c , R ⁴ , and R ⁵ is optionally substituted with one or more R ¹⁰ groups; R ³ is halo or C ₁ -C ₃ alkyl, wherein the aliphatic portions of R ³ are each independently optionally substituted with one or more R ¹⁰ groups; R ⁴ and R ⁵ are each independently H, D, -OH, C ₁ -C ₆ alkyl, or -NHS(O) ₂ C ₁ -C ₆ alkyl, or R ⁴ and R ⁵ are taken together with the atom to which they are attached to form =O or =N- (OH), or one of R ⁴ and R ⁵ is taken together with one of R ^2a , R ^2b , and R ^2c to form a C _3- C ₆ cycloalkyl, and the other of R ⁴ and R ⁵ is H, D, OH, C ₁ -C ₆ alkyl, or - NHS(O) ₂ C _1- C ₆ alkyl; R ⁴ and R ⁵ are taken together with one or two of R ^2a , R ^2b , and R ^2c to form a 4- to 6-membered heterocycloalkenyl or a 5- to 6-membered heteroaryl; R ⁶ is H, or R ⁶ is taken together with R ⁰ and the atoms to which they are attached to form a 4- to 6-membered heterocycloalkenyl or a 5- to 6-membered heteroaryl, wherein the 4- to 6-membered heterocycloalkenyl or 5- to 6-membered heteroaryl are optionally substituted with one or more R ¹⁰ groups; each R ⁷ is independently H, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl; R ⁸ and R ⁹ are each independently H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, or C ₁ -C ₆ haloalkyl, or R ⁸ and R ⁹ are taken together with the nitrogen atom to which they are attached to form a 3- to 6-membered heterocycloalkyl, a 4- to 6-membered heterocycloalkenyl, or a 5- to 6-membered heteroaryl; and each R ¹⁰ is independently halo, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, -OR ⁷ , -CN, -N(R ⁸ )(R ⁹ ), - (C _1- C ₃ alkyl)-N(R ⁸ )(R ⁹ ). 2. The compound of embodiment 1, wherein the compound of formula (I) is a compound of formula (I-1): or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof. 3. The compound of embodiment 2, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, wherein the moiety of Formula (I-1) is 4. The compound of any one of embodiments 1 to 3, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, which is a compound of formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), or (I-g):

5. The compound of any one of embodiments 1 to 4, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, wherein: X ¹ , X ² , X ³ and X ⁴ are each independently N or C-R ¹ ; each R ¹ is independently H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, -OR ⁷ , -CN, or -N(R ⁸ )(R ⁹ ), wherein the aliphatic portions of R ¹ are optionally substituted with one or more R ¹⁰ groups; R ^2a , R ^2b , and R ^2c are each independently H, -OH, -SCH ₃ , C ₁ -C ₆ alkyl, or -OR ⁷ , wherein the aliphatic portions of R ^2a , R ^2b , and R ^2c are each independently optionally substituted with one or more R ¹⁰ groups; or one or two of R ^2a , R ^2b , and R ^2c is taken together with R ⁴ and R ⁵ to form a 4- to 6- membered heterocycloalkenyl or a 5- to 6-membered heteroaryl; and the remaining one or two of R ^2a , R ^2b , and R ^2c are each independently H, -OH, halo, -CN, -S-C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C ₃ - C ₆ cycloalkyl, -OR ⁷ , or -N(R ⁸ )(R ⁹ ), wherein the 4- to 6-membered heterocycloalkenyl or 5- to 6-membered heteroaryl formed by any of R ^2a , R ^2b , R ^2c , R ⁴ , and R ⁵ is optionally substituted with one or more R ¹⁰ groups; R ³ is halo or C ₁ -C ₃ alkyl, wherein the aliphatic portions of R ³ are each independently optionally substituted with one or more R ¹⁰ groups; R ⁴ and R ⁵ are each independently H, D, -OH, C ₁ -C ₆ alkyl, or -NHS(O) ₂ C ₁ -C ₆ alkyl, or R ⁴ and R ⁵ are taken together with the atom to which they are attached to form =O or =N- (OH), or R ⁴ and R ⁵ are taken together with one or two of R ^2a , R ^2b , and R ^2c to form a 4- to 6-membered heterocycloalkenyl or a 5- to 6-membered heteroaryl; R ⁶ is H; each R ⁷ is independently H, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl; R ⁸ and R ⁹ are each independently H or C1-C6 alkyl, or R ⁸ and R ⁹ are taken together with the nitrogen atom to which they are attached to form a 3- to 6-membered heterocycloalkyl, a 4- to 6-membered heterocycloalkenyl, or a 5- to 6- membered heteroaryl; and each R ¹⁰ is independently halo, -OR ⁷ , or -(C ₁ -C ₃ alkyl)-N(R ⁸ )(R ⁹ ). 6. The compound of embodiment 5, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, wherein one of X ¹ and X ² is C-R ¹ and the other of X ¹ and X ² is N. 7. The compound of embodiment 1, wherein the compound of formula (I) is a compound of formula (I-2): or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, wherein R ⁰ is H, C ₁ -C ₃ alkyl, 3- to 6-membered heterocycloalkyl, or -N(R ⁸ )(R ⁹ ), optionally substituted with 1 to 5 independently selected R ¹⁰ groups. 8. The compound of embodiment 1 or embodiment 7, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, wherein: X ¹ , X ² , X ³ and X ⁴ are each independently N or C-R ¹ ; R ⁰ is C ₁ -C ₃ alkyl, wherein the aliphatic portions of R ⁰ are optionally substituted with one or more R ¹⁰ groups; each R ¹ is independently H; R ^2a , R ^2b , and R ^2c are each independently H or C ₁ -C ₆ alkyl, wherein the aliphatic portions of R ^2a , R ^2b , and R ^2c are each independently optionally substituted with one or more R ¹⁰ groups; or one of R ^2a , R ^2b , and R ^2c is taken together with one of R ⁴ and R ⁵ to form a C ₃ - C ₆ cycloalkyl, and the other two of R ^2a , R ^2b , or R ^2c are each independently H or C ₁ -C ₆ alkyl, wherein the C ₃ -C ₆ cycloalkyl is optionally substituted with one or more R ¹⁰ groups; R ³ is C ₁ -C ₃ alkyl, wherein the aliphatic portions of R ³ are each independently optionally substituted with one or more R ¹⁰ groups; R ⁴ and R ⁵ are each independently H, D, or -OH, or one of R ⁴ and R ⁵ is taken together with one of R ^2a , R ^2b , and R ^2c to form a C ₃ - C ₆ cycloalkyl, and the other of R ⁴ and R ⁵ is H, D, or -OH; R ⁶ is H; each R ⁷ is independently H or C ₁ -C ₆ alkyl; and each R ¹⁰ is independently -OR ⁷ . 9. The compound of embodiment 1, wherein the compound of formula (I) is a compound of formula (I-3): or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof. 10. The compound of embodiment 1 or embodiment 9, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, wherein: X ¹ , X ² , X ³ and X ⁴ are each independently N or C-R ¹ ; R ⁰ is H or C ₁ -C ₃ alkyl, or R ⁰ is taken together with R ⁶ and the atoms to which they are attached to form a 4- to 6-membered heterocycloalkenyl or a 5- to 6-membered heteroaryl, wherein the 4- to 6-membered heterocycloalkenyl or 5- to 6-membered heteroaryl is optionally substituted with one or more R ¹⁰ groups; each R ¹ is independently H or halo; R ^2a , R ^2b , and R ^2c are each independently H, -OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, or C ₃ -C ₆ cycloalkyl, wherein the aliphatic portions of R ^2a , R ^2b , and R ^2c are each independently optionally substituted with one or more R ¹⁰ groups; R ³ is C ₁ -C ₃ alkyl; R ⁴ and R ⁵ are each independently H or -OH; and R ⁶ is H, or R ⁶ is taken together with R ⁰ and the atoms to which they are attached to form a 4- to 6-membered heterocycloalkenyl or a 5- to 6-membered heteroaryl, wherein the 4- to 6- membered heterocycloalkenyl or 5- to 6-membered heteroaryl is optionally substituted with one or more R ¹⁰ groups. 11. The compound of any one of embodiments 1 to 10, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, wherein:

12. The compound of any one of embodiments 1 to 11, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, wherein: 13. The compound of any one of embodiments 1 to 12, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, wherein R ¹ is H, halo, C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, 5- to 6-membered heteroaryl, -OR ⁷ , -CN, -N(R ⁸ )(R ⁹ ), -C(O)-N(R ⁸ )(R ⁹ ). 14. The compound of any one of embodiments 1 to 13, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, wherein R ¹ is H, F, -CH ₃ , cyclopropyl, -OCH ₃ , O CN, NH ₂ , -C(O)-NHCH ₃ , -C(O)-N(CH ₃ ) ₂ , or 15. The compound of any one of embodiments 1 to 14, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, wherein X ³ and X ⁴ are each CH. 16. A compound, or pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, which is:

17. A pharmaceutical composition comprising the compound of any one of embodiments 1 to 16, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, and one or more pharmaceutically acceptable excipients. 18. A method of inhibiting ARAF, BRAF and CRAF enzymatic activity in a cell, comprising exposing the cell with an effective amount of a compound of any one of embodiments 1 to 16, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a pharmaceutical composition according to embodiment 17. 19. A method of treating a cancer or neoplastic disease in a human in need thereof, comprising administering to the human a compound of any one of embodiments 1 to 16, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a pharmaceutical composition according to embodiment 17. 20. The method of embodiment 19, wherein the cancer or neoplastic disease is associated with one or more genetic alterations that engender elevated RAS/RAF/MEK/ERK pathway activation. 21. The method of embodiment 19 or 20, wherein the cancer or neoplastic disease is associated with one or more genetic alterations in KRAS, NRAS, HRAS, ARAF, BRAF or CRAF. 22. The method of any one of embodiments 19 to 21, wherein the cancer or neoplastic disease is associated with one or more mutations in KRAS selected from the group consisting of G12D, G12V, G12C, G12S, G12R, G12A, G13D, G13C, G13R, Q61H, Q61K, Q61L, Q61P, Q61R and Q61E; or one or more mutations in NRAS selected from the group consisting of G12D, G12S, G12C, G12V, G12A, G13D, G13R, G13V, G13C, G13A, G13S, G61R, Q61K Q61H, and G61L; or one or more mutations in HRAS selected from the group consisting of G12V, G12S, G12D, G12C, G12R, G12A, G13R, G13V, G13D, G13S, G13C, Q61R, Q61L, Q61K, and Q61H; or one or more mutations in ARAF selected from the group consisting of S214C and S214F; or one or more mutations in BRAF selected from the group consisting of Class I, Class IIa, Class IIb, Class IIc, and Class III mutations; or one or more mutations in CRAF selected from the group consisting of P261A, P261L, E478K, R391W, R391S and T491I, or a CRAF fusion. 23. The method of any one of embodiments 19 to 22, wherein the cancer or neoplastic disease is associated with one or more genetic lesions resulting in the activation of one or more receptor tyrosine kinases (RTKs). 24. The method of embodiment 23, wherein the one or more genetic lesions is a point mutation, a fusion or any combination thereof. 25. The method of embodiment 23 or embodiment 24, wherin the one or more receptor tyrosine kinase is selected from the group consistion of ALK, EGFR, ERBB2, LTK, MET, NTRK, RET, and ROS1. 26. The method of any one of embodiments 19 to 25, wherein the cancer is a refractory cancer. 27. The method of any one of embodiments 19 to 26, the refractory cancer is associated with one or more genetic alterations in BRAF selected from the group consisting of gene amplification, point mutation, BRAF fusion, and gene splicing events. 28. The method of any one of embodiments 19 to 27, the cancer is a refractory BRAF Class I mutant cancer. 29. The method of embodiment 28, wherein the refractory BRAF Class I mutant cancer is associated with a point mutation selected from the group consisting of V600D, V600E, V600K, and V600R. 30. The method of any one of embodiments 19 to 29, wherein the refractory cancer is associated with one or more Class II or Class III mutations in BRAF. 31. The method of embodiment 30, wherein the refractory cancer is associated with one or more mutations in BRAF selected from the group consisting of G464V, G469A, G469V, G469R, E586K, K601E, K601N, G466R, G466A, G466E, G466V, N581I, N581S, D594E, D594G, D594N, G596C, G596R, L597R, L597S, and L597Q. 32. The method of embodiment 31, wherein the refractory cancer is associated with one or more alternative splicing events that result in the loss of BRAF gene exons 4-10, 4-8, 2-8 or 2-10. 33. The method of any one of embodiments 19 to 32, wherein the cancer is a solid tumor or a hematological malignancy. 34. The method of embodiment 33, wherein the cancer is melanoma, lung cancer, pancreatic carcinoma, glioma, colorectal carcincoma, chronic myeloid leukemia (CML), acute myeloid leukemia (AML), or acute lymphoblastic leukemia (ALL). 35. The method of embodiment 34, wherein the lung cancer is non-small cell lung cancer (NSCLC). 36. The method of any one of embodiments 19 to 35, further comprising administering one or more pharmaceutical agents including anti-microtubular therapies, topoisomerase inhibitors, alkylating agents, nucleotide synthesis inhibitors, DNA synthesis inhibitors, protein synthesis inhibitors, developmental signaling pathway inhibitors, pro-apoptotic agents, RTK inhibitors, RAF inhibitors representing alternative binding modes, MEK1/2 inhibitors, ERK1/2 inhibitors, RSK1/2/3/4 inhibitors, AKT inhibitors, TORC1/2 inhibitors, DNA damage response pathway inhibitors, PI3K inhibitors and/or radiation. EXAMPLES [0167] It is understood that the present disclosure has been made only by way of example, and that numerous changes in the combination and arrangement of parts can be resorted to by those skilled in the art without departing from the spirit and scope of present disclosure. Synthetic Examples [0168] The chemical reactions in the Examples described can be readily adapted to prepare a number of other compounds disclosed herein, and alternative methods for preparing the compounds of this disclosure are deemed to be within the scope of this disclosure. For example, the synthesis of non-exemplified compounds according to the present disclosure can be successfully performed by modifications apparent to those skilled in the art, e.g., by appropriately protecting interfering groups, by utilizing other suitable reagents known in the art other than those described, or by making routine modifications of reaction conditions, reagents, and starting materials. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds of the present disclosure. [0169] Abbreviations used in the Examples include the following: ACN: acetonitrile; Brettphos: 2-(dicyclohexylphosphino)3,6-dimethoxy-2’,4’,6’-triiso propyl-1,1’-biphenyl; dppf: 1,1’-ferrocenediyl-bis(diphenylphosphine); DCM: dichloromethane; DMF: dimethylformamide; DMSO: dimethyl sulfoxide; EtOAc: ethyl acetate; EtOH: ethanol or ethyl alcohol; ¹ H NMR: proton nuclear magnetic resonance; LCMS: liquid chromatography– mass spectrometry; LiHMDS: lithium hexamethyldisilazide; MeOH: methanol or methyl alcohol; NBS: N-bromosuccinimide; OAc: acetate; Py: pyridine; THF: tetrahydrofuran; and TLC: thin-layer chromatography. Example 1. Synthesis of (R)-N-(6-cyano-7-(6-((R)-1-hydroxypropyl)-4-methylpyridin-3- yl)isoquinolin-3-yl)-2,2-difluorocyclopropane-1-carboxamide (Compound 1) and (R)-N-(6- cyano-7-(6-((S)-1-hydroxypropyl)-4-methylpyridin-3-yl)isoqui nolin-3-yl)-2,2- difluorocyclopropane-1-carboxamide (Compound 2) Step 1: Synthesis of (3-bromo-4-iodophenyl)methanamine: [0170] To a solution of 3-bromo-4-iodobenzonitrile (12.5 g, 40.59 mmol) in THF (20.0 mL) was added BH ₃ (100.0 ml, 1 mol/L) at 0 °C under N ₂ . The resulting mixture was stirred at 65 °C for 2 h. After the reaction was completed, the mixture was diluted with H ₂ O and extracted with CH ₂ Cl ₂ . The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to afford (3-bromo-4-iodophenyl)methanamine (12.5 g, crude) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 311.9. Step 2: Synthesis of N-(3-bromo-4-iodobenzyl)-2,2-diethoxyacetimidamide: [0171] To a solution of (3-bromo-4-iodophenyl)methanamine (12.5 g, crude) in MeOH (125.0 mL) was added methyl 2,2-diethoxyacetimidate (9.6 g, 60.10 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the mixture was diluted with H ₂ O and extracted with CH ₂ Cl ₂ . The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to afford N-(3-bromo-4-iodobenzyl)-2,2- diethoxyacetimidamide (12.5 g, crude) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 441.0. Step 3: Synthesis of 7-bromo-6-iodoisoquinolin-3-amine: [0172] A solution of N-(3-bromo-4-iodobenzyl)-2,2-diethoxyacetimidamide (12.5 g, crude) in conc.H ₂ SO ₄ (100.0 mL) was stirred at 60 °C for 1 h. After the reaction was completed, the mixture was basified to pH=9 with saturated NaOH (aq.). The resulting mixture was extracted with DCM. The combined organic layers were washed with brine and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/CH ₂ Cl ₂ (2/1, v/v) to afford 7-bromo-6-iodoisoquinolin-3-amine (4.0 g, crude) as a brown solid. LCMS (ESI, m/z): [M+H] ⁺ = 348.9. Step 4: Synthesis of 3-amino-7-bromoisoquinoline-6-carbonitrile: [0173] To a solution of 7-bromo-6-iodoisoquinolin-3-amine (3.5 g, crude) in DMF (35.0 mL) was added Zn(CN) ₂ (588.8 mg, 5.01 mmol) and Pd(PPh ₃ ) ₄ (2.3 g, 2.00 mmol) at room temperature under N ₂ . The resulting mixture was stirred at 120 °C for 1 h. After the reaction was completed, the resulting mixture was diluted with H ₂ O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (2/1, v/v) to afford 3-amino- 7-bromoisoquinoline-6-carbonitrile (800.0 mg, 32%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 248.0. Step 5: Synthesis of 3-amino-7-(4-methyl-6-propionylpyridin-3-yl)isoquinoline-6- carbonitrile: [0174] To a mixture of 3-amino-7-bromoisoquinoline-6-carbonitrile (450.0 mg, 1.81 mmol) in dioxane (10.0 mL)/H ₂ O (2.0 mL) was added (4-methyl-6-propionylpyridin-3- yl)boronic acid (525.1 mg, 2.72 mmol), K ₂ CO ₃ (752.0 mg, 5.44 mmol) and Pd(dppf)Cl ₂ (132.7 mg, 0.18 mmol) at room temperature under N ₂ . The resulting mixture was stirred at 100 °C for 2 h. After the reaction was completed, the resulting mixture was diluted with H ₂ O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (10/1, v/v) to afford 3-amino-7-(4-methyl-6-propionylpyridin-3-yl)isoquinoline-6-c arbonitrile (500.0 mg, 87%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 317.1 Step 6: Synthesis of (R)-N-(6-cyano-7-(4-methyl-6-propionylpyridin-3-yl)isoquinol in-3-yl)- 2,2-difluorocyclopropane-1-carboxamide: N [0175] To a mixture of 3-amino-7-(4-methyl-6-propionylpyridin-3-yl)isoquinoline-6- carbonitrile (150.0 mg, 0.47 mmol) in Pyridine (6.0 mL) was added (R)-2,2- difluorocyclopropane-1-carboxylic acid (59.2 mg, 0.56 mmol) and EDCI (272.6 mg, 1.42 mmol) at room temperature. The resulting mixture was stirred at room temperature for 3 h. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (10/1, v/v) to afford (R)-N-(6-cyano-7-(4-methyl-6-propionylpyridin-3-yl)isoquinol in-3-yl)-2,2- difluorocyclopropane-1-carboxamide (110.0 mg, 55%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 421.1. Step 7: Synthesis of (1R)-N-(6-cyano-7-(6-(1-hydroxypropyl)-4-methylpyridin-3- yl)isoquinolin-3-yl)-2,2-difluorocyclopropane-1-carboxamide: [0176] To a solution of (R)-N-(6-cyano-7-(4-methyl-6-propionylpyridin-3-yl)isoquinol in- 3-yl)-2,2-difluorocyclopropane-1-carboxamide (110.0 mg, 0.26 mmol) in THF (4.0 mL)/MeOH (0.8 mL) were added NaBH ₄ (14.8 mg, 0.39 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction mixture was quenched with H ₂ O at 0 °C. The resulting mixture was diluted with H ₂ O and extracted with CH ₂ Cl ₂ . The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (10/1, v/v) to afford (1R)-N-(6-cyano-7-(6-(1-hydroxypropyl)-4-methylpyridin-3- yl)isoquinolin-3-yl)-2,2-difluorocyclopropane-1-carboxamide (80.0 mg, 72%) as a yellow green solid. LCMS (ESI, m/z): [M+H] ⁺ = 423.2. Step 8: Separation of (R)-N-(6-cyano-7-(6-((R)-1-hydroxypropyl)-4-methylpyridin-3- yl)isoquinolin-3-yl)-2,2-difluorocyclopropane-1-carboxamide (Compound 1) and (R)-N-(6- cyano-7-(6-((S)-1-hydroxypropyl)-4-methylpyridin-3-yl)isoqui nolin-3-yl)-2,2- difluorocyclopropane-1-carboxamide (Compound 2): [0177] The product of (1R)-N-(6-cyano-7-(6-(1-hydroxypropyl)-4-methylpyridin-3- yl)isoquinolin-3-yl)-2,2-difluorocyclopropane-1-carboxamide (79.0 mg, 0.18 mmol) was separated by Prep-HPLC with the following conditions (Column: CHIRAL ART Cellulose- SC, 2x25 cm, 5 μm; Mobile Phase A: Hex (0.5% 2M NH ₃ -MeOH)-HPLC, Mobile Phase B: EtOH: DCM=1 : 1— HPLC; Flow rate: 20 mL/min; Gradient: 25% B to 25% B in 20 min; Wave Length: 254/220 nm; RTl(min): 17.54; RT2(min): 19.70) to afford (R)-N-(6-cyano-7- (6-(l-hydroxypropyl)-4-methylpyridin-3-yl)isoquinolin-3-yl)- 2,2-difluorocyclopropane-l- carboxamide Isomer 1 (retention time: 17.54 min, 25.0 mg, 62%) as a white solid and (R)-N- (6-cyano-7-(6-(l-hydroxypropyl)-4-methylpyridin-3-yl)isoquin olin-3-yl)-2,2- difluorocyclopropane-1 -carboxamide Isomer 2 (retention time 19.70 min, 24.1 mg, 60%) as a white solid. The absolute stereochemistry of Isomers 1 and 2 was not assigned. The two isomeric structures that could be obtained from chiral separation of the isomeric mixture as described above are shown as Compounds 1 and 2 in Table 1.

[0178] (R)-N-(6-cyano-7-(6-(l-hydroxypropyl)-4-methylpyridin-3-yl)i soquinolin-3- yl)-2,2-difluorocyclopropane-l-carboxamide Isomer 1: RTl(min): 17.54; LCMS (ESI, m/z): [M+H]+ = 423.1. ¹ H NMR (400 MHz, DMSO-d6): δ 11.35 (s, 1H), 9.33 (s, 1H), 8.78 (s, 1H), 8.64 (s, 1H), 8.41 (s, 1H), 8.26 (s, 1H), 7.54 (s, 1H), 5.39 (d, J = 6.4 Hz, 1H), 4.59 - 4.55 (m, 1H), 3.14 - 3.04 (m, 1H), 2.24 (s, 3H), 2.17 - 2.04 (m, 2H), 1.91 - 1.82 (m, 1H), 1.77 - 1.65 (m, 1H), 0.94 - 0.89 (m, 3H).

[0179] (R)-N-(6-cyano-7-(6-(l-hydroxypropyl)-4-methylpyridin-3-yl)i soquinolin-3- yl)-2,2-difluorocyclopropane-l-carboxamide Isomer 2: RT2(min): 19.70; LCMS (ESI, m/z): [M+H]+ = 423.1. ¹ H NMR (400 MHz, DMSO-d6): δ 11.35 (s, 1H), 9.34 (s, 1H), 8.78 (s, 1H), 8.64 (s, 1H), 8.41 (s, 1H), 8.26 (s, 1H), 7.54 (s, 1H), 5.39 (d, J = 6.4 Hz, 1H), 4.59 - 4.56 (m, 1H), 3.14 - 3.04 (m, 1H), 2.24 (s, 3H), 2.16 - 2.04 (m, 2H), 1.91 - 1.80 (m, 1H), 1.72 - 1.64 (m, 1H), 0.94 - 0.89 (m, 3H).

Example 2. Synthesis of (R)-2,2-difluoro-N-(3-(6-((R)-l-hydroxypropyl-l-d)-4- methylpyridin-3-yl)-1,6-naphthyridin-7-yl)cyclopropane-l-car boxamide (Compound 3) and (R)-2,2-difluoro-N-(3-(6-((S)-l-hydroxypropyl-l-d)-4-methylp yridin-3-yl)-l,6- naphthyridin-7-yl)cyclopropane-1 -carboxamide (Compound 4)

Step 1: Synthesis of (lR)-2,2-difluoro-N-(3-(6-(l-hydroxypropyl-l-d)-4-methylpyri din-3-yl)- 1, 6-naphthyridin- 7 -yl)cyclopropane-l -carboxamide: [0180] To a solution of (lR)-2,2-difluoro-N-[3-(4-methyl-6-propanoylpyridin-3-yl)-l, 6- naphthyridin-7-yl]cyclopropane-l -carboxamide (120.0 mg, 0.30 mmol) in THF (2.0 mL)/CD ₃ OD (0.5 mL) was added NaBD4 (22.9 mg, 0.60 mmol) at 0 °C under N2. The resulting mixture was stirred for 1 h at room temperature. After the reaction was completed, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (7/1, v/v) to afford (lR)-2,2-difluoro-N-(3-(6-(l- hydroxypropyl-l-d)-4-methylpyridin-3-yl)-l,6-naphthyridin-7- yl)cyclopropane-l- carboxamide (50.0 mg, 41%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 400.2.

Step 2: Separation of (R)-2,2-difluoro-N-(3-(6-((R)-l-hydroxypropyl-l-d)-4-methylp yridin-3- yl)-l,6-naphthyridin-7-yl)cyclopropane-l -carboxamide (Compound 3) and (R)-2,2-dijluoro- N-(3-(6-((S)-l-hydroxypropyl-l-d)-4-methylpyridin-3-yl)-l,6- naphthyridin-7- yl)cyclopropane-l -carboxamide (Compound 4)

[0181] The product of (lR)-2,2-difluoro-N-(3-(6-(l-hydroxypropyl-l-d)-4- methylpyridin-3-yl)-l,6-naphthyridin-7-yl)cyclopropane-l-car boxamide (50.0 mg, 0.12 mmol) was separated by Prep-HPLC with the following conditions (Column: CHIRAL ART Cellulose-SC, 2x25 cm, 5 pm; Mobile Phase A: Hex(0.5% 2M NH ₃ -MeOH)-HPLC, Mobile Phase B: MeOH: DCM=1 : 1— HPLC; Flow rate: 20 mL/min; Gradient: 70% B to 70% B in 12.5 min; Wave Length: 254/220 nm; RTl(min): 7.20; RT2(min): 10.30) to afford (R)-2,2- difluoro-N-(3 -(6-(l -hydroxypropyl- 1 -d)-4-methylpyri din-3 -yl)- 1 ,6-naphthyridin-7- yl)cyclopropane-l -carboxamide Isomer 1 (retention time 7.20 minutes, 18.0 mg, 72%) as a white solid and (R)-2,2-difluoro-N-(3-(6-(l-hydroxypropyl-l-d)-4-methylpyrid in-3-yl)-l,6- naphthyridin-7-yl)cyclopropane-l -carboxamide Isomer 2 (retention time 10.30 minutes, 19.6 mg, 78%) as a white solid. The absolute stereochemistry of Isomers 1 and 2 was not assigned. The two isomeric structures that could be obtained from chiral separation of the isomeric mixture as described above are shown as Compounds 3 and 4 in Table 1.

[0182] (R)-2,2-difluoro-N-(3-(6-(l-hydroxypropyl-l-d)-4-methylpyrid in-3-yl)-l,6- naphthyridin-7-yl)cyclopropane-l-carboxamide Isomer 1: RTl(min): 7.20; LCMS (ESI, m/z): [M+H]+ = 400.1. ¹ H NMR (400 MHz, DMSO-d6): δ 11.36 (s, 1H), 9.30 (s, 1H), 9.13 (d, J = 2.4 Hz, 1H), 8.60 - 8.58 (m, 2H), 8.47 (s, 1H), 7.51 (s, 1H), 5.33 (s, 1H), 3.14 - 3.06 (m, 1H), 2.38 (s, 3H), 2.15 - 2.04 (m, 2H), 1.87 - 1.80 (m, 1H), 1.72 - 1.64 (m, 1H), 0.93 - 0.89 (m, 3H).

[0183] (R)-2,2-difluoro-N-(3-(6-(l-hydroxypropyl-l-d)-4-methylpyrid in-3-yl)-l,6- naphthyridin-7-yl)cyclopropane-l-carboxamide Isomer 2: RT2(min): 10.30; LCMS (ESI, m/z): [M+H]+ = 400.2. ¹ H NMR (400 MHz, DMSO-d6): δ 11.36 (s, 1H), 9.30 (s, 1H), 9.13 (d, J = 2.4 Hz, 1H), 8.60 - 8.58 (m, 2H), 8.47 (s, 1H), 7.51 (s, 1H), 5.33 (s, 1H), 3.14 - 3.06 (m, 1H), 2.38 (s, 3H), 2.15 - 2.03 (m, 2H), 1.87 - 1.80 (m, 1H), 1.72 - 1.64 (m, 1H), 0.93 - 0.89 (m, 3H).

Example 3. Synthesis of (R,Z)-N-(6-cyano-7-(6-(l-(hydroxyimino)propyl)-4-methylpyrid in- 3-yl)isoquinolin-3-yl)-2,2-difluorocyclopropane-l-carboxamid e (Compound 5)

Step 1: Synthesis of (R)-N-(6-cyano-7-(4-methyl-6-propionylpyridin-3-yl)isoquinol in-3-yl)- 2, 2-difluorocyclopropane-l -carboxamide : N \/

[0184] To a mixture of 3-amino-7-(4-methyl-6-propionylpyridin-3-yl)isoquinoline-6- carbonitrile (300.0 mg, 0.94 mmol) in pyridine (10.0 mL) was added (R)-2,2- difluorocyclopropane-1 -carboxylic acid (173.6 mg, 1.42 mmol) and EDCI (363.5 mg, 1.89 mmol) at room temperature. The resulting mixture was stirred at room temperature for 3 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (10/1, v/v) to afford (R)-N-(6-cyano-7-(4-methyl-6-propionylpyridin-3-yl)isoquinol in-3-yl)- 2,2-difluorocyclopropane-l -carboxamide (150.0 mg, 37%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 421.1.

Step 2: Synthesis of (R,Z)-N-(6-cyano-7-(6-(l -(hydroxyimino)propyl)-4-methylpyridin-3- yl)isoquinolin-3-yl)-2,2-difluorocyclopropane-l-carboxamide (Compound 5):

[0185] To a solution of (R)-N-(6-cyano-7-(4-methyl-6-propionylpyridin-3-yl)isoquinol in-

3 -yl)-2,2-difluorocyclopropane-l -carboxamide (40.0 mg, 0.09 mmol) in DCM (2.0 mL) and EtOH (2.0 mL) were added NH2OH HCI (13.2 mg, 0.19 mmol) and N aO Ac (15.6 mg, 0.19 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the mixture was concentrated under vacuum. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (10/1, v/v) and then purified by Prep-HPLC with the following conditions: (Column: XBridge Prep OBD C18 Column, 30x150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 34% B to 44% B in 10 min; Wave Length: 254 nm) to afford (R,Z)-N-(6-cyano-7-(6-(l-(hydroxyimino)propyl)-4-methylpyrid in-3- yl)isoquinolin-3-yl)-2,2-difluorocyclopropane-l-carboxamide (Compound 5, 13.1 mg, 32%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 436.1. ¹ H NMR (400 MHz, DMSO-d6 ): δ 11.54 - 11.40 (m, 2H), 9.35 (s, 1H), 8.82 (s, 1H), 8.66 (s, 1H), 8.54 (s, 1H), 8.29 (s, 1H), 7.89 (s, 1H), 3.14 - 3.04 (m, 1H), 2.94 - 2.86 (m, 2H), 2.25 (s, 3H), 2.11 - 2.04 (m, 2H), 1.13 - 1.08 (m, 3H).

Example 4. Synthesis of (lS,2S)-N-(6-cyano-7-(6-((Z)-l-(hydroxyimino)propyl)-4- methylpyridin-3-yl)isoquinolin-3-yl)-2-fluorocyclopropane-l -carboxamide ( Compound 6)

Step 1: Synthesis of (1 S,2S)-N-(6-cyano-7-(4-methyl-6-propionylpyridin-3-yl)isoquin olin-3- yl)-2-fhiorocyclopropane-l-carboxamide: [0186] To a mixture of 3-amino-7-(4-methyl-6-propanoylpyridin-3-yl)isoquinoline-6- carbonitrile (150.0 mg, 0.47 mmol) in Pyridine (5.0 mL) was added (lS,2S)-2- fluorocyclopropane-1 -carboxylic acid (74.0 mg, 0.71 mmol) and EDCI (181.7 mg, 0.94 mmol) at room temperature. The resulting mixture was stirred at room temperature for 3 h. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (10/1, v/v) to afford (lS,2S)-N-[6-cyano-7-(4-methyl-6-propanoylpyridin-3-yl)isoqu inolin-3- yl]-2-fluorocyclopropane-l -carboxamide (100.0 mg, 52%) as a green solid. LCMS (ESI, m/z): [M+H] ⁺ =403.1

Step 2: Synthesis of (lS,2S)-N-(6-cyano-7-(6-((Z)-l-(hydroxyimino)propyl)-4-methy lpyridin- 3-yl)isoquinolin-3-yl)-2-fluorocyclopropane-l -carboxamide ( Compound 6) :

[0187] To a solution of (lS,2S)-N-[6-cyano-7-(4-methyl-6-propanoylpyridin-3- yl)isoquinolin-3-yl]-2-fluorocyclopropane-l-carboxamide (95.0 mg, 0.25 mmol) in DCM (4.0 mL) and EtOH (4.0 mL) were added NH2OHHCI (31.0 mg, 0.44 mmol) and NaOAc (36.6 mg, 0.44 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the mixture was concentrated under vacuum. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (10/1, v/v) and then purified by Prep-HPLC with the following conditions: (Column: XBridge Prep OBD C18 Column, 30x150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 40% B in 10 min; Wave Length: 254 nm) to afford (lS,2S)-N-(6-cyano-7-(6-((Z)-l- (hydroxyimino)propyl)-4-methylpyridin-3-yl)isoquinolin-3-yl) -2-fluorocyclopropane-l- carboxamide (40.9 mg, 40%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 418.1. ¹ H NMR (400 MHz, DMSO-d6 ): δ 11.53 (s, 1H), 11.21 (s, 1H), 9.33 (s, 1H), 8.78 (s, 1H), 8.66 (s, 1H), 8.54 (s, 1H), 8.27 (s, 1H), 7.89 (s, 1H), 5.08 - 4.89 (m, 1H), 2.93 - 2.69 (m, 2H), 2.33 - 2.27 (m, 1H), 2.25 (s, 3H), 1.76 - 1.68 (m, 1H), 1.26 - 1.21 (m, 1H), 1.12 - 1.05 (m, 3H). Example 5. Synthesis of (R)-2,2-difluoro-N-(7-(6-((R)-l-hydroxypropyl-l-d)-4- methylpyridin-3-yl)-2,6-naphthyridin-3-yl)cyclopropane-l-car boxamide (Compound 7) and (R)-2,2-difluoro-N-(7-(6-((S)-l-hydroxypropyl-l-d)-4-methylp yridin-3-yl)-2,6- naphthyridin-3-yl)cyclopropane-l -carboxamide (Compound 8)

Step 1: Synthesis of (lR)-2,2-difluoro-N-(7-(6-(l-hydroxypropyl-l-d)-4-methylpyri din-3-yl)- 2,6-naphthyridin-3-yl)cyclopropane-l-carboxamide:

[0188] To a solution of (R)-2,2-difluoro-N-(7-(4-methyl-6-propionylpyridin-3-yl)-2,6 - naphthyri din-3 -yl)cy cl opropane-1 -carboxamide (332.0 mg, 0.84 mmol) in THF (12.0 mL) and CD3OD (3.0 mL) was added NaBD4 (106.0 mg, 2.80 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the reaction mixture was quenched with H2O at 0 °C and then extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH2Cl2/MeOH (9/1, v/v) to afford (lR)-2,2-difluoro-N- (7-(6-(l-hydroxypropyl-l-d)-4-methylpyridin-3-yl)-2,6-naphth yridin-3-yl)cyclopropane-l- carboxamide (293.0 mg, 87%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 400.2.

Step 2: Separation of (R)-2,2-difluoro-N-(7-(6-((R)-l-hydroxypropyl-l-d)-4-methylp yridin-3- yl)-2,6-naphthyridin-3-yl)cyclopropane-l -carboxamide (Compound 7) and (R)-2,2-difluoro- N-(7-( 6-( (S)-l-hydroxypropyl-l-d)-4-methylpyridin-3-yl)-2, 6-naphthyridin-3- yl)cyclopropane-l -carboxamide (Compound 8):

[0189] The product of (lR)-2,2-difluoro-N-(7-(6-(l-hydroxypropyl-l-d)-4- methylpyridin-3-yl)-2,6-naphthyridin-3-yl)cyclopropane-l -carboxamide (100.0 mg, 0.25 mmol) was separated by Prep-Chiral-HPLC with the following conditions (Column: Chiral ART Cellulose-SA, 2x25 cm, 5 pm; Mobile Phase A: Hex (0.5% 2M NH ₃ -MeOH)-HPLC, Mobile Phase B: MeOH: DCM=1 : 1— HPLC; Flow rate: 20 mL/min; Gradient: 40% B to 40% B in 14.5 min; Wave Length: 254/220 nm; RTl(min): 9.13; RT2(min): 11.81) to afford (R)- 2,2-difluoro-N-(7-(6-(l-hydroxypropyl-l-d)-4-methylpyridin-3 -yl)-2,6-naphthyridin-3- yl)cyclopropane-l -carboxamide Isomer 1 (retention time 9.13 min, 29.2 mg, 58%) as a white solid and (R)-2,2-difluoro-N-(7-(6-(l-hydroxypropyl-l-d)-4-methylpyrid in-3-yl)-2,6- naphthyri din-3 -yl)cy cl opropane-1 -carboxamide Isomer 2 (retention time 11.81 min, 30.7 mg, 61%) as a yellow solid. The absolute stereochemistry of Isomers 1 and 2 was not assigned. The two isomeric structures that could be obtained from chiral separation of the isomeric mixture as described above are shown as Compounds 7 and 8 in Table 1.

[0190] (R)-2,2-difluoro-N-(7-(6-(l-hydroxypropyl-l-d)-4-methylpyrid in-3-yl)-2,6- naphthyridin-3-yl)cyclopropane-l-carboxamide Isomer 1: RTl(min): 9.13; LCMS (ESI, m/z): [M+H]+ = 400.2. ¹ H NMR (400 MHz, DMSO-d6): δ 11.38 (s, 1H), 9.52 (s, 1H), 9.35 (s, 1H), 8.67 (s, 1H), 8.59 (s, 1H), 8.19 (s, 1H), 7.47 (s, 1H), 5.32 (s, 1H), 3.13 - 3.05 (m, 1H), 2.46 (s, 3H), 2.13 - 2.04 (m, 2H), 1.88 - 1.79 (m, 1H), 1.73 - 1.64 (m, 1H), 0.95 - 0.82 (m, 3H).

[0191] (R)-2,2-difluoro-N-(7-(6-(l-hydroxypropyl-l-d)-4-methylpyrid in-3-yl)-2,6- naphthyridin-3-yl)cyclopropane-l-carboxamide Isomer 2: RT2(min): 11.81; LCMS (ESI, m/z): [M+H]+ = 400.2. ¹ H NMR (400 MHz, DMSO-d6): δ 11.38 (s, 1H), 9.52 (s, 1H), 9.35 (s, 1H), 8.67 (s, 1H), 8.59 (s, 1H), 8.19 (s, 1H), 7.46 (s, 1H), 5.31 (s, 1H), 3.13 - 3.05 (m, 1H), 2.45 (s, 3H), 2.16 - 2.02 (m, 2H), 1.91 - 1.79 (m, 1H), 1.78 - 1.62 (m, 1H), 0.95 - 0.82 (m, 3H).

Example 6. Synthesis ofN-(3-{2-[(lS)-l-hydroxybutyl]-4-methylpyrimidin-5-yl}-l,6- naphthyridin-7-yl)cyclopropanecarboxamide (Compound 9) and N-(3-{2-[(lR)-l- hydroxybutyl]-4-methylpyrimidin-5-yl}-l,6-naphthyridin-7-yl) cyclopropanecarboxamide (Compound 10)

Step 1: Synthesis of 7-chloro-l ,6-naphthyridin-3-ylboronic acid:

[0192] To a solution of 3-bromo-7-chloro-l,6-naphthyridine (500.0 mg, 2.05 mmol) in dioxane (15.0 mL) were added bis(pinacolato)diboron (1042.9 mg, 4.10 mmol), KOAc (604.6 mg, 6.15 mmol) and Pd(dppf)Ch (150.2 mg, 0.20 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 2 h under N2. After the reaction was completed, the resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (10/1, v/v) to afford 7-chloro-1,6-naphthyridin-3-ylboronic acid (500.0 mg, 93%) as a brown yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 209.0. Step 2: Synthesis of 1-[5-(7-chloro-1,6-naphthyridin-3-yl)-4-methylpyrimidin-2-yl ]butan-1- one: ^{, 2} [0193] To a solution of 7-chloro-1,6-naphthyridin-3-ylboronic acid (300.0 mg, 1.43 mmol) in dioxane (10.0 mL)/H ₂ O (2.5 mL) were added 1-(5-bromo-4-methylpyrimidin-2- yl)butan-1-one (291.6 mg, 1.19 mmol), KOAc (353.1 mg, 3.598 mmol) and Pd(dppf)Cl ₂ (87.7 mg, 0.12 mmol) at room temperature under N ₂ . The resulting mixture was stirred at 100 °C for 2 h under N ₂ . After the reaction was completed, the resulting mixture was diluted with H ₂ O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (10/1, v/v) to afford 1-[5-(7-chloro-1,6-naphthyridin-3-yl)-4- methylpyrimidin-2-yl]butan-1-one (200.0 mg, 51%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 327.1. Step 3: Synthesis of N-[3-(2-butanoyl-4-methylpyrimidin-5-yl)-1,6-naphthyridin-7- yl]cyclopropanecarboxamide: [0194] To a solution of 1-[5-(7-chloro-1,6-naphthyridin-3-yl)-4-methylpyrimidin-2- yl]butan-1-one (190.0 mg, 0.58 mmol) in dioxane (5.0 mL) were added cyclopropanecarboxamide (148.4 mg, 1.74 mmol), Cs ₂ CO ₃ (568.6 mg, 1.74 mmol), BrettPhos (62.4 mg, 0.11 mmol) and BrettPhos Pd G3 (52.7 mg, 0.05 mmol) at room temperature under N ₂ . The resulting mixture was stirred at 100 °C for 1 h under N ₂ . After the reaction was completed, the resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (10/1, v/v) to afford N-[3-(2-butanoyl-4-methylpyrimidin-5-yl)-l,6- naphthyridin-7-yl]cyclopropanecarboxamide (150.0 mg, 68%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 376.2.

Step 4: Synthesis of N-{3-[2-(l-hydroxybutyl)-4-methylpyrimidin-5-yl]-l,6-naphthy ridin-7- yl]cyclopropanecarboxamide :

[0195] To a solution of N-[3-(2-butanoyl-4-methylpyrimidin-5-yl)-l,6-naphthyridin-7- yl]cyclopropanecarboxamide (140.0 mg, 0.37 mmol) in CH ₂ Cl ₂ (2.0 mL)/MeOH (0.5 mL) were added NaBH4 (16.9 mg, 0.44 mmol) at 0 °C under N2. The resulting mixture was stirred at room temperature for 1 h under N2. After the reaction was completed, the resulting mixture concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (10/1, v/v) to afford N-{3-[2-(l-hydroxybutyl)-4- methylpyrimidin-5-yl]-l,6-naphthyridin-7-yl}cyclopropanecarb oxamide (30.0 mg, 21%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 378.2

Step 5: Separation of N-(3-{2-[( IS)- 1 -hydroxybutyl] -4-methylpyrimidin-5-yl}- 1,6- naphthyridin-7-yl)cyclopropanecarboxamide (Compound 9) andN-(3-{2-[(lR)-l- hydroxybutyl]-4-methylpyrimidin-5-yl]-l,6-naphthyridin-7-yl) cyclopropanecarboxamide (Compound 10):

[0196] The racemic mixture of N-{3-[2-(l-hydroxybutyl)-4-methylpyrimidin-5-yl]-l,6- naphthyridin-7-yl}cyclopropanecarboxamide (30.0 mg, 0.07 mmol) was separated by Prep- HPLC with the following conditions (Column: CHIRAL ART Amylose-SA, 2x25 cm, 5 pm; Mobile Phase A: Hex(0.5% 2M NH ₃ -MeOH)-HPLC, Mobile Phase B: MeOH: DCM=1 : 1- HPLC; Flow rate: 20 mL/min; Gradient: 50% B to 50% B in 8.5 min; Wave Length: 254/220 nm; RTl(min): 5.782; RT2(min): 7.639) to afford N-(3-{2-[l-hydroxybutyl]-4- methylpyrimidin-5-yl}-l,6-naphthyridin-7-yl)cyclopropanecarb oxamide Isomer 1 (retention time 5.782 min, 10.5 mg, 70%) as an off-white solid and N-(3-{2-[l-hydroxybutyl]-4- methylpyrimidin-5-yl}-l,6-naphthyridin-7-yl)cyclopropanecarb oxamide Isomer 2 (retention time 7.639 min, 11.2 mg, 74%) as an off-white solid. The absolute stereochemistry of Isomers 1 and 2 was not assigned. The two isomeric structures that could be obtained from chiral separation of the isomeric mixture as described above are shown as Compounds 9 and 10 in Table 1. [0197] (N-(3-{2-[1-hydroxybutyl]-4-methylpyrimidin-5-yl}-1,6-naphth yridin-7- yl)cyclopropanecarboxamide Isomer 1: RT1(min): 5.782, LCMS (ESI, m/z): [M+H] ⁺ = 378.1. ¹ H NMR (400 MHz, DMSO-d ₆ ^^^į^11.18 (s, 1H), 9.28 (s, 1H), 9.16 (d, J = 2.4 Hz, 1H), 8.78 (s, 1H), 8.64 - 8.62 (m, 2H), 5.18 (d, J = 6.0 Hz, 1H), 4.69 - 4.64 (m, 1H), 2.55 (s, 3H), 2.14 - 2.10 (m, 1H), 1.84 - 1.74 (m, 2H), 1.44 - 1.34 (m, 2H), 0.94 - 0.85 (m, 7H). [0198] N-(3-{2-[(1-hydroxybutyl]-4-methylpyrimidin-5-yl}-1,6-naphth yridin-7- yl)cyclopropanecarboxamide Isomer 2: RT2(min): 7.639, LCMS (ESI, m/z): [M+H] ⁺ = 378.2. ¹ H NMR (400 MHz, DMSO-d ₆ ^^^į^11.18 (s, 1H), 9.28 (s, 1H), 9.16 (d, J = 2.4 Hz, 1H), 8.78 (s, 1H), 8.64 - 8.62 (m, 2H), 5.18 (d, J = 6.0 Hz, 1H), 4.69 - 4.64 (m, 1H), 2.55 (s, 3H), 2.14 - 2.10 (m, 1H), 1.84 - 1.74 (m, 2H), 1.44 - 1.33 (m, 2H), 0.94 - 0.85 (m, 7H). Example 7. Synthesis of N-(7-{2-[(1S)-1-hydroxybutyl]-4-methylpyrimidin-5-yl}-2,6- naphthyridin-3-yl)cyclopropanecarboxamide (Compound 11) and N-(7-{2-[(1R)-1- hydroxybutyl]-4-methylpyrimidin-5-yl}-2,6-naphthyridin-3-yl) cyclopropanecarboxamide (Compound 12) Step 1: Synthesis of 5-bromo-4-methylpyrimidine-2-carbonitrile: [0199] To a solution of TEDA (1.0 g, 9.64 mmol) in DMSO (50.0 mL)/H ₂ O (20.0 mL) were added NaCN (2.1 g, 43.3 mmol) at room temperature. Then a solution of 5-bromo-2- chloro-4-methylpyrimidine (9.0 g, 43.3 mmol) in DMSO (50.0 mL) was added dropwise to the mixture at room temperature. The resulting mixture was stirred at room temperature for 16 h. After the reaction was completed, the resulting mixture was diluted with H ₂ O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (1/1, v/v) to afford 5-bromo-4-methylpyrimidine-2-carbonitrile (4.0 g, 46%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 198.0. Step 2: Synthesis of 1-(5-bromo-4-methylpyrimidin-2-yl)butan-1-one: [0200] To a solution of 5-bromo-4-methylpyrimidine-2-carbonitrile (2.0 g, 2.05 mmol) in THF (30.0 mL) were added bromo(propyl)magnesium (7.5 mL, 2 mol/L) at 0 °C under N ₂ . The resulting mixture was stirred at room temperature under N ₂ . After the reaction was completed, the resulting mixture was diluted with H ₂ O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (5/1, v/v) to afford 1-(5- bromo-4-methylpyrimidin-2-yl)butan-1-one (550.0 mg, 22%) as a yellow oil. LCMS (ESI, m/z): [M+H] ⁺ = 243.0 [0201] Step 3: Synthesis of N-[7-(tributylstannyl)-2,6-naphthyridin-3- yl]cyclopropanecarboxamide: [0202] To a solution of N-(7-chloro-2,6-naphthyridin-3-yl)cyclopropanecarboxamide (550.0 mg, 2.22 mmol) in dioxane (15.0 mL) were added hexabutyldistannane (2576.3 mg, 4.44 mmol), tricyclohexylphosphane (249.0 mg, 0.88 mmol) and Pd(OAc) ₂ (99.7 mg, 0.44 mmol) at room temperature under N ₂ . The resulting mixture was stirred at 110 °C for 1 h under N ₂ . After the reaction was completed, the resulting mixture was concentrated under vacuum. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (5/1, v/v) to afford N-[7-(tributylstannyl)-2,6-naphthyridin-3- yl]cyclopropanecarboxamide (500.0 mg, 44%) as a yellow oil. LCMS (ESI, m/z): [M+H] ⁺ = 504.2. Step 4: Synthesis of N-[7-(2-butanoyl-4-methylpyrimidin-5-yl)-2,6-naphthyridin-3- yl]cyclopropanecarboxamide: [0203] To a solution of N-[7-(tributylstannyl)-2,6-naphthyridin-3- yl]cyclopropanecarboxamide (500.0 mg, 0.99 mmol) in toluene (10.0 mL) were added 1-(5- bromo-4-methylpyrimidin-2-yl)butan-l-one (362.9 mg, 1.49 mmol) and Pd(PPh ₃ )4 (115.0 mg, 0.10 mmol) at room temperature under N2. The resulting mixture was stirred at 110 °C for 16 h under N2. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with

CH ₂ Cl ₂ /MeOH (5/1, v/v) to afford N-[7-(2-butanoyl-4-methylpyrimidin-5-yl)-2,6- naphthyridin-3-yl]cyclopropanecarboxamide (170.0 mg, 45%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 376.2.

Step 5: Synthesis ofN-{7-[2-(l-hydroxybutyl)-4-methylpyrimidin-5-yl]-2,6-napht hyridin-3- yl}cyclopropanecarboxamide :

[0204] To a solution of N-[7-(2-butanoyl-4-methylpyrimidin-5-yl)-2,6-naphthyridin-3- yl]cyclopropanecarboxamide (160.0 mg, 0.42 mmol) in CH ₂ Cl ₂ (2.0 mL)/MeOH (0.5 mL) were added NaBH4 (19.3 mg, 0.51 mmol) at 0 °C under N2. The resulting mixture was stirred at room temperature for 1 h under N2. After the reaction was completed, the mixture was quenched with MeOH and then concentrated under vacuum. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (7/1, v/v) to afford N-{7-[2-(l- hydroxybutyl)-4-methylpyrimidin-5-yl]-2,6-naphthyridin-3-yl} cyclopropanecarboxamide (90.0 mg, 55%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 378.2.

Step 6: Separation of N-(7-{2-[( IS)- 1 -hydroxybutyl] -4-methylpyrimidin-5-yl}-2, 6- naphthyridin-3-yl)cyclopropanecarboxamide (Compound 11) and N-(7-{2-[(lR)-l- hydroxybutyl]-4-methylpyrimidin-5-yl}-2,6-naphthyridin-3-yl) cyclopropanecarboxamide (Compound 12):

[0205] The racemic product ofN-{7-[2-(l-hydroxybutyl)-4-methylpyrimidin-5-yl]-2,6- naphthyridin-3-yl] cyclopropanecarboxamide (90.0 mg, 0.23 mmol) was separated by Prep- HPLC with the following conditions (Column: CHIRAL ART Amylose-SA, 2x25 cm, 5 μm; Mobile Phase A: Hex(0.5% 2M NH ₃ -MeOH)..HPLC, Mobile Phase B: MeOH: DCM=1 : 1- HPLC; Flow rate: 20 mL/min; Gradient: 30% B to 30% B in 30 min; Wave Length: 254/220 nm; RTl(min): 17.75; RT2(min): 22.69) to afford N-(7-{2-[l-hydroxybutyl]-4- methylpyrimidin-5-yl}-2,6-naphthyridin-3-yl)cyclopropanecarb oxamide Enantiomer 1 (retention time 17.75 min, 36.2 mg, 80%) as an off-white solid and N-(7-{2-[l- hydroxybutyl]-4-methylpyrimidin-5-yl}-2,6-naphthyridin-3-yl) cyclopropanecarboxamide Enantiomer 2 (retention time 22.69 min, 39.3 mg, 87%) as an off-white solid. The absolute stereochemistry of Enantiomers 1 and 2 was not assigned. The two enantiomeric structures that could be obtained from chiral separation of the enantiomeric mixture as described above are shown as Compounds 11 and 12 in Table 1.

[0206] N-(7-{2-[l-hydroxybutyl]-4-methylpyrimidin-5-yl}-2,6-naphthy ridin-3- yl)cyclopropanecarboxamide Enantiomer 1: RTl(min): 17.75, LCMS (ESI, m/z): [M+H] ⁺ = 378.1. ¹ H NMR (400 MHz, DMSO-D6 ): δ 11.20 (s, 1H), 9.50 (s, 1H), 9.34 (s, 1H), 8.89 (s, 1H), 8.69 (s, 1H), 8.28 (s, 1H), 5.16 (d, J= 6.0 _Hz , 1H), 4.69 - 4.64 (m, 1H), 2.64 (s, 3H), 2.14 - 2.08 (m, 1H), 1.86 - 1.71 (m, 2H), 1.45 - 1.32 (m, 2H), 0.93 - 0.85 (m, 7H).

[0207] N-(7-{2-[l-hydroxybutyl]-4-methylpyrimidin-5-yl}-2,6-naphthy ridin-3- yl)cyclopropanecarboxamide Enantiomer 2: RT2(min): 22.69, LCMS (ESI, m/z): [M+H] ⁺ = 378.1. ¹ H NMR (400 MHz, DMSO-D6 ): δ 11.20 (s, 1H), 9.51 (s, 1H), 9.34 (s, 1H), 8.89 (s, 1H), 8.69 (s, 1H), 8.28 (s, 1H), 5.16 (d, J= 6.0 Hz, 1H), 4.69 - 4.64 (m, 1H), 2.64 (s, 3H), 2.14 - 2.08 (m, 1H), 1.86 - 1.74 (m, 2H), 1.45 - 1.32 (m, 2H), 0.93 - 0.85 (m, 7H).

Example 8. Synthesis of (lS,2S)-2-[(dimethylamino)methyl]-N-(7-{6-[(lS)-l- hydroxybutyl]-4-methylpyridin-3-yl}-2,6-naphthyridin-3-yl)cy clopropane-l-carboxamide (Compound 13), (lS,2S)-2-[(dimethylamino)methyl]-N-(7-{6-[(lR)-l-hydroxybut yl]-4- methylpyridin-3-yl}-2, 6-naphthyridin-3-yl)cyclopropane-l -carboxamide ( Compound 14), (lR,2R)-2-[(dimethylamino)methyl]-N-(7-{6-[(lS)-l-hydroxybut yl]-4-methylpyridin-3-yl}- 2,6-naphthyridin-3-yl)cyclopropane-l-carboxamide (Compound 15) and (lR,2R)-2- [(dimethylamino)methyl]-N-(7-{6-[(lR)-l-hydroxybutyl]-4-meth ylpyridin-3-yl}-2,6- naphthyridin-3-yl)cyclopropane-l -carboxamide (Compound 16)

Step 1: Synthesis of Ethyl (trans)-2-{[7-(6-butanoyl-4-methylpyridin-3-yl)-2,6-naphthyr idin- 3-yl]carbamoyl}cyclopropane-l-carboxylate: [0208] To a solution of 1-[5-(7-amino-2,6-naphthyridin-3-yl)-4-methylpyridin-2- yl]butan-1-one (2.9 g, 9.47 mmol) in pyridine (100.0 mL) was added (trans)-2- (ethoxycarbonyl)cyclopropane-1-carboxylic acid (4.5 g, 28.40 mmol) at 0 °C. Then EDCI (3.6 g, 18.93 mmol) was added to the mixture at room temperature. The mixture was stirred at room temperature for 2 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (61/39, v/v) to afford ethyl (trans)-2-{[7- (6-butanoyl-4-methylpyridin-3-yl)-2,6-naphthyridin-3-yl]carb amoyl}cyclopropane-1- carboxylate (2.3 g, 54%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 447.2 Step 2: Synthesis of (trans)-N-{7-[6-(1-hydroxybutyl)-4-methylpyridin-3-yl]-2,6- naphthyridin-3-yl}-2-(hydroxymethyl)cyclopropane-1-carboxami de: [0209] To a solution of ethyl (trans)-2-{[7-(6-butanoyl-4-methylpyridin-3-yl)-2,6- naphthyridin-3-yl]carbamoyl}cyclopropane-1-carboxylate (2.0 g, 4.48 mmol) in tetrahydrofuran (70.0 mL) was added DIBAl-H (36.0 mL, 1 mol/L) at -40 °C under N ₂ . The mixture was stirred at -40 °C for 1 h under N ₂ . After the reaction was completed, the resulting mixture was quenched with water and then concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (10/1, v/v) to afford (trans)-N-{7-[6-(1-hydroxybutyl)-4-methylpyridin-3-yl]-2,6-n aphthyridin-3-yl}-2- (hydroxymethyl)cyclopropane-1-carboxamide (1.0 g, 54%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 407.2. Step 3: Synthesis of (trans)-N-[7-(6-butanoyl-4-methylpyridin-3-yl)-2,6-naphthyri din-3-yl]-2- formylcyclopropane-1-carboxamide: [0210] To a solution of (trans)-N-{7-[6-(1-hydroxybutyl)-4-methylpyridin-3-yl]-2,6- naphthyridin-3-yl}-2-(hydroxymethyl)cyclopropane-1-carboxami de (1.0 g, 2.46 mmol) in ethyl acetate (60.0 mL) was added IBX (1.2 g, 4.33 mmol) at room temperature. The mixture was stirred at 80 °C for 2 h. After the reaction was completed, the resulting mixture was filtered. The filtrate was concentrated under reduced pressure to afford (trans)-N-[7-(6- butanoyl-4-methylpyridin-3-yl)-2,6-naphthyridin-3-yl]-2-form ylcyclopropane-1-carboxamide (1.0 g, crude) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 403.2. Step 4: Synthesis of (trans)-2-[(dimethylamino)methyl]-N-{7-[6-(1-hydroxybutyl)-4 - methylpyridin-3-yl]-2,6-naphthyridin-3-yl}cyclopropane-1-car boxamide: [0211] To a solution of (trans)-N-[7-(6-butanoyl-4-methylpyridin-3-yl)-2,6-naphthyri din- 3-yl]-2-formylcyclopropane-1-carboxamide (1.0 g, 2.49 mmol) in THF (25.0 mL)/MeOH (5.0 mL) was added dimethylamine hydrochloride (405.2 mg, 4.97 mmol) and NaBH ₃ CN (468.4 mg, 7.46 mmol) at 0 °C under N ₂ . The resulting mixture was stirred at room temperature for 2 h. Then NaBH ₄ (188.0 mg, 4.97 mmol) was added to the above mixture at 0 °C under N ₂ . The resulting mixture was stirred at room temperature for additional 1 h. After the reaction was completed, the resulting mixture was quenched with water and then concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (10/1, v/v) to afford (trans)-2-[(dimethylamino)methyl]- N-{7-[6-(1-hydroxybutyl)-4-methylpyridin-3-yl]-2,6-naphthyri din-3-yl}cyclopropane-1- carboxamide (110.0 mg, 10%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 434.2. Step 5: Separation of (1S,2S)-2-[(dimethylamino)methyl]-N-(7-{6-[(1S)-1-hydroxybut yl]-4- methylpyridin-3-yl}-2,6-naphthyridin-3-yl)cyclopropane-1-car boxamide (Compound 13), (1S,2S)-2-[(dimethylamino)methyl]-N-(7-{6-[(1R)-1-hydroxybut yl]-4-methylpyridin-3-yl}- 2,6-naphthyridin-3-yl)cyclopropane-1-carboxamide (Compound 14), (1R,2R)-2- [ (dimethylamino)methyl ]-N-( 7-{6-[ ( 1S)-1 -hydroxybutyl ]-4-methylpyridin-3-yl}-2, 6- naphthyridin-3-yl)cyclopropane-l -carboxamide (Compound 15) and (lR,2R)-2- [(dimethylamino)methyl]-N-(7-{6-[(lR)-l-hydroxybutyl]-4-meth ylpyridin-3-yl}-2,6- naphthyridin-3-yl)cyclopropane-l-carboxamide (Compound 16):

[0212] The product of (trans)-2-[(dimethylamino)methyl]-N-{7-[6-(l-hydroxybutyl)-4 - methylpyridin-3-yl]-2,6-naphthyridin-3-yl}cyclopropane-l-car boxamide (90.0 mg, 0.21 mmol) was separated by Prep-chiral-HPLC with the following the conditions: (Column: CHIRALPAK IG, 2x25 cm, 5 μm; Mobile Phase A: Hex (0.5% 2M NH ₃ -MeOH)-HPLC, Mobile Phase B: IPA: DCM=1 : 1— HPLC; Flow rate: 20 mL/min; Gradient: 70% B to 70% B in 10 min; Wave Length: 254/220 nm; RTl(min): 4.87; RT2(min): 7.77) to afford the Isomer mixture product A of 2-[(dimethylamino)methyl]-N-(7-{6-[l-hydroxybutyl]-4- methylpyri din-3 -yl} -2, 6-naphthyri din-3 -yl)cy cl opropane-1 -carboxamide Isomer Al & 2- [(dimethylamino)methyl]-N-(7-{6-[l-hydroxybutyl]-4-methylpyr idin-3-yl}-2,6-naphthyridin- 3 -yl)cy cl opropane-1 -carboxamide Isomer A2 (45.0 mg) and the Isomer mixture product B of 2-[(dimethylamino)methyl]-N-(7-{6-[l-hydroxybutyl]-4-methylp yridin-3-yl}-2,6- naphthyri din-3 -yl)cy cl opropane-1 -carboxamide Isomer Bl & 2-[(dimethylamino)methyl]-N- (7-{6-[l-hydroxybutyl]-4-methylpyridin-3-yl}-2,6-naphthyridi n-3-yl)cyclopropane-l- carboxamide Isomer B2 (45.0 mg).

[0213] The absolute stereochemistry of Isomers Al, A2, Bl and B2 was not assigned. The four isomeric structures that could be obtained from chiral separation of the isomeric mixture as described above are shown as Compounds 13, 14, 15 and 16 in Table 1.

[0214] The Isomer mixture product A of 2-[(dimethylamino)methyl]-N-(7-{6-[l- hydroxybutyl]-4-methylpyridin-3-yl}-2,6-naphthyridin-3-yl)cy clopropane-l-carboxamide Isomer Al & 2-[(dimethylamino)methyl]-N-(7-{6-[l-hydroxybutyl]-4-methylp yridin-3-yl}- 2,6-naphthyridin-3-yl)cyclopropane-l -carboxamide Isomer A2 (45.0 mg) was separated by Prep-chiral -HPLC with the following the conditions: (Column: CHIRAL ART Amylose-SA, 2x25 cm, 5 pm; Mobile Phase A: Hex(0.5% 2M NH ₃ -MeOH)-HPLC, Mobile Phase B: MeOH: DCM=1: 1— HPLC; Flow rate: 20 mL/min; Gradient: 50% B to 50% B in 16 min; Wave Length: 254/220 nm; RTl(min): 6.89; RT2(min): 12.60) to afford (lS,2S)-2- [(dimethylamino)methyl]-N-(7-{6-[(lS)-l-hydroxybutyl]-4-meth ylpyridin-3-yl}-2,6- naphthyri din-3 -yl)cy cl opropane-1 -carboxamide Isomer Al (11.9 mg, 52%) as a white solid and (lS,2S)-2-[(dimethylamino)methyl]-N-(7-{6-[(lR)-l-hydroxybut yl]-4-methylpyridin-3- yl}-2,6-naphthyridin-3-yl)cyclopropane-l-carboxamide Isomer A2 (10.8 mg, 48%) as a white solid.

[0215] The Isomer mixture product B of 2-[(dimethylamino)methyl]-N-(7-{6-[l- hydroxybutyl]-4-methylpyridin-3-yl}-2,6-naphthyridin-3-yl)cy clopropane-l-carboxamide Isomer Bl & 2-[(dimethylamino)methyl]-N-(7-{6-[l-hydroxybutyl]-4-methylp yridin-3-yl}- 2,6-naphthyridin-3-yl)cyclopropane-l -carboxamide Isomer B2 (45.0 mg) was separated by Prep-chiral -HPLC with the following the conditions: (Column: CHIRAL ART Amylose-SA, 2x25 cm, 5 pm; Mobile Phase A: Hex(0.5% 2M NH ₃ -MeOH)-HPLC, Mobile Phase B: MeOH: DCM=1: 1— HPLC; Flow rate: 20 mL/min; Gradient: 40% B to 40% B in 20 min; Wave Length: 254/220 nm; RTl(min): 11.35; RT2(min): 15.87) to afford 2- [(dimethylamino)methyl]-N-(7-{6-[l-hydroxybutyl]-4-methylpyr idin-3-yl}-2,6-naphthyridin- 3 -yl)cyclopropane-l -carboxamide Isomer Bl (6.5 mg, 28%) as a white solid and 2- [(dimethylamino)methyl]-N-(7-{6-[l-hydroxybutyl]-4-methylpyr idin-3-yl}-2,6-naphthyridin- 3-yl)cyclopropane-l -carboxamide Isomer B2 (5.7 mg, 25%) as a white solid. [0216] 2-[(dimethylamino)methyl]-N-(7-{6-[l-hydroxybutyl]-4-methylp yridin-3-yl}-2,6- naphthyri din-3 -yl)cy cl opropane-1 -carboxamide Isomer Al : CHIRAL ART Amylose-SA, RTl(min): 4.87; RTl(min): 6.89; LCMS (ESI, m/z): [M+H]+ = 434.2. XH NMR (400 MHz, DMSO-d6): 5 11.22 (s, 1H), 9.48 (s, 1H), 9.33 (s, 1H), 8.67 (s, 1H), 8.57 (s, 1H), 8.17 (s, 1H), 7.46 (s, 1H), 5.34 (d, J = 5.2 Hz, 1H), 4.64 - 4.59 (m, 1H), 2.76 (d, J = 6.8 Hz, 2H), 2.58 - 2.57 (m, 6H), 2.45 (s, 3H), 2.08 - 2.06 (m, 1H), 1.81 - 1.71 (m, 2H), 1.69 - 1.60 (m, 1H), 1.44 - 1.34 (m, 2H), 1.24 - 1.20 (m, 1H), 0.98 - 0.94 (m, 1H), 0.92 - 0.89 (m, 3H).

[0217] 2-[(dimethylamino)methyl]-N-(7-[6-[l-hydroxybutyl]-4-methylp yridin-3-yl}-2,6- naphthyri din-3 -yl)cy cl opropane-1 -carboxamide Isomer A2: CHIRAL ART Amylose-SA, RTl(min): 4.87; CHIRAL ART Amylose-SA; RT2(min): 12.60; LCMS (ESI, m/z): [M+H]+ = 434.2. ¹ H NMR (400 MHz, DMSO-d6): 5 11.22 (s, 1H), 9.48 (s, 1H), 9.33 (s, 1H), 8.67 (s, 1H), 8.57 (s, 1H), 8.17 (s, 1H), 7.46 (s, 1H), 5.34 (d, J = 5.2 Hz, 1H), 4.64 - 4.59 (m, 1H), 2.76 (d, J = 6.8 Hz, 2H), 2.58 - 2.57 (m, 6H), 2.45 (s, 3H), 2.09 - 2.05 (m, 1H), 1.79 - 1.71 (m, 2H), 1.69 - 1.60 (m, 1H), 1.42 - 1.34 (m, 2H), 1.24 - 1.20 (m, 1H), 0.98 - 0.94 (m, 1H), 0.92 - 0.89 (m, 3H).

[0218] 2-[(dimethylamino)methyl]-N-(7-{6-[l-hydroxybutyl]-4-methylp yridin-3-yl}-2,6- naphthyri din-3 -yl)cy cl opropane-1 -carboxamide Isomer Bl : CHIRAL ART Amylose-SA, RT2(min): 7.77; Column: CHIRALPAK IG, CHIRAL ART Amylose-SA; RTl(min): 11.35; LCMS (ESI, m/z): [M+H]+ = 434.2. ¹ H NMR (400 MHz, DMSO-d6): 5 11.22 (s, 1H), 9.48 (s, 1H), 9.33 (s, 1H), 8.67 (s, 1H), 8.57 (s, 1H), 8.17 (s, 1H), 7.46 (s, 1H), 5.34 (d, J = 4.8 Hz, 1H), 4.64 - 4.59 (m, 1H), 2.76 (d, J = 6.8 Hz, 2H), 2.58 - 2.57 (m, 6H), 2.45 (s, 3H), 2.09 - 2.05 (m, 1H), 1.77 - 1.72 (m, 2H), 1.69 - 1.60 (m, 1H), 1.44 - 1.34 (m, 2H), 1.24 - 1.20 (m, 1H), 0.98 - 0.94 (m, 1H), 0.92 - 0.89 (m, 3H).

[0219] 2-[(dimethylamino)methyl]-N-(7-{6-[l-hydroxybutyl]-4-methylp yridin-3-yl}-2,6- naphthyri din-3 -yl)cy cl opropane-1 -carboxamide Isomer B2: CHIRAL ART Amylose-SA, RT2(min): 7.77; CHIRAL ART Amylose-SA; RT2(min): 15.87; LCMS (ESI, m/z): [M+H]+ = 434.2. ¹ H NMR (400 MHz, DMSO-d6): 5 11.22 (s, 1H), 9.48 (s, 1H), 9.33 (s, 1H), 8.67 (s, 1H), 8.57 (s, 1H), 8.17 (s, 1H), 7.46 (s, 1H), 5.34 (d, J = 5.2 Hz, 1H), 4.62 - 4.59 (m, 1H), 2.76 (d, J = 6.8 Hz, 2H), 2.58 - 2.57 (m, 6H), 2.45 (s, 3H), 2.08 - 2.05 (m, 1H), 1.77 - 1.72 (m, 2H), 1.69 - 1.60 (m, 1H), 1.44 - 1.36 (m, 2H), 1.24 - 1.20 (m, 1H), 0.98 - 0.94 (m, 1H), 0.92 - 0.89 (m, 3H). Example 9. Synthesis of (R)-N-(5-cyclopropyl-7-(6-(1-hydroxybutyl)-4-methylpyridin-3 -yl)- 2,6-naphthyridin-3-yl)cyclopropanecarboxamide (Compound 17) and (S)-N-(5- cyclopropyl-7-(6-(1-hydroxybutyl)-4-methylpyridin-3-yl)-2,6- naphthyridin-3- yl)cyclopropanecarboxamide (Compound 8) Step 1: Synthesis of methyl 5-((6-chloro-4-formylpyridin-3-yl)ethynyl)-4-methylpicolinat e: O O [0220] To a solution of methyl 5-ethynyl-4-methylpyridine-2-carboxylate (2.0 g, 11.41 mmol) in DMF (50.0 mL) was added 5-bromo-2-chloroisonicotinaldehyde (2.5 g, 11.42 mmol), CataCXium A Pd G2 (761.0 mg, 1.14 mmol), CuI (220.0 mg, 1.14 mmol), DIEA (4.4 g, 34.22 mmol) and CataCxium A (816.2 mg, 2.28 mmol) at room temperature under N ₂ . The resulting mixture was stirred at 65 °C for 2 h under N ₂ . After the reaction was completed, the resulting mixture was diluted with H ₂ O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (60/40, v/v) to afford methyl 5-((6- chloro-4-formylpyridin-3-yl)ethynyl)-4-methylpicolinate (680.0 mg, 18%) as a brown solid. LCMS (ESI, m/z): [M+H] ⁺ =315.2. Step 2: Synthesis of methyl (E)-5-((6-chloro-4-((hydroxyimino)methyl)pyridin-3-yl)ethyny l)- 4-methylpicolinate: OH [0221] To a solution of methyl 5-((6-chloro-4-formylpyridin-3-yl)ethynyl)-4- methylpicolinate (500.0 mg, 1.58 mmol) in EtOH (5.0 mL) and DCM (5.0 mL) was added AcONa (298.5 mg, 3.04 mmol) and NH ₂ OH.HCl (190.2 mg, 2.74 mmol) at room temperature. The resulting mixture was stirred at room temperature for 4 h. After the reaction was completed, the resulting mixture was filtered. The filtrate was concentrated under reduced pressure to afford methyl (E)-5-((6-chloro-4-((hydroxyimino)methyl)pyridin-3- yl)ethynyl)-4-methylpicolinate (470.0 mg, crude) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =330.1. Step 3: Synthesis of 7-chloro-3-(6-(methoxycarbonyl)-4-methylpyridin-3-yl)-2,6- naphthyridine 2-oxide: OH [0222] To a solution of methyl (E)-5-((6-chloro-4-((hydroxyimino)methyl)pyridin-3- yl)ethynyl)-4-methylpicolinate (1.0 g, crude) in CHCl ₃ (25.0 mL) was added AgNO ₃ (474.1 mg, 2.94 mmol) at room temperature under N ₂ . The resulting mixture was stirred at 80 °C for 3 h. After the reaction was completed, the resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (30/70, v/v) to afford 7-chloro-3-(6- (methoxycarbonyl)-4-methylpyridin-3-yl)-2,6-naphthyridine 2-oxide (400.0 mg, 40%) as a yellow oil. LCMS (ESI, m/z): [M+H] ⁺ =330.2. Step 4: Synthesis of 7-(cyclopropanecarboxamido)-3-(6-(methoxycarbonyl)-4-methylp yridin- 3-yl)-2,6-naphthyridine 2-oxide: [0223] To a solution of 7-chloro-3-(6-(methoxycarbonyl)-4-methylpyridin-3-yl)-2,6- naphthyridine 2-oxide (1.5 g, 4.56 mmol) in 1,4-dioxane (20.0 mL) was added cyclopropanecarboxamide (775.0 mg, 9.12 mmol), Pd ₂ (dba) ₃ (420.9 mg, 0.46 mmol), Xantphos (527.3 mg, 0.92 mmol) and Cs ₂ CO ₃ (4.2 g, 13.68 mmol) at room temperature under N ₂ . The resulting mixture was stirred at 100 °C for 2 h. After the reaction was completed, the mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography with petroleum ether/ethyl acetate (55/45, v/v) to afford 7-(cyclopropanecarboxamido)-3-(6- (methoxycarbonyl)-4-methylpyridin-3-yl)-2,6-naphthyridine 2-oxide (790.0 mg, 49%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 379.1. Step 5: Synthesis of methyl 5-(1-chloro-7-(cyclopropanecarboxamido)-2,6-naphthyridin-3- yl)-4-methylpicolinate: [0224] To a solution of 7-(cyclopropanecarboxamido)-3-(6-(methoxycarbonyl)-4- methylpyridin-3-yl)-2,6-naphthyridine 2-oxide (1.5 g, 3.96 mmol) in CH ₂ Cl ₂ (35.0 mL) was added MsCl (541.7 mg, 4.75 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. After the reaction was completed, the resulting mixture was diluted with H ₂ O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography with petroleum ether/ethyl acetate (40/60, v/v) to afford methyl 5-(1-chloro-7-(cyclopropanecarboxamido)- 2,6-naphthyridin-3-yl)-4-methylpicolinate (800.0 mg, 53%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 397.1. Step 6: Synthesis of methyl 5-(7-(cyclopropanecarboxamido)-1-cyclopropyl-2,6- naphthyridin-3-yl)-4-methylpicolinate: [0225] To a solution of methyl 5-(1-chloro-7-(cyclopropanecarboxamido)-2,6- naphthyridin-3-yl)-4-methylpicolinate (300.0 mg, 0.76 mmol) in 1,4-dioxane (5.0 mL) and H ₂ O (1.0 mL) was added cyclopropylboronic acid (174.4 mg, 2.03 mmol), Pd(dppf)Cl ₂ (59.4 mg, 0.07 mmol) and K ₂ CO ₃ (336.0 mg, 2.44 mmol) at room temperature under N ₂ . The resulting mixture was stirred at 80 °C for 2 h. After the reaction was completed, the mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography with petroleum ether/ethyl acetate (50/50, v/v) to afford Vmethyl 5- (7-(cyclopropanecarboxamido)-1-cyclopropyl-2,6-naphthyridin- 3-yl)-4-methylpicolinate (190.0 mg, 62%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 403.1. Step 7: Synthesis of 5-(7-(cyclopropanecarboxamido)-1-cyclopropyl-2,6-naphthyridi n-3-yl)- 4-methylpicolinic acid: [0226] To a solution of methyl 5-(7-(cyclopropanecarboxamido)-1-cyclopropyl-2,6- naphthyridin-3-yl)-4-methylpicolinate (190.0 mg, 0.47 mmol) in THF (5.0 mL) and H ₂ O (2.0 mL) was added LiOH (112.8 mg, 4.70 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. After the reaction was completed, the resulting mixture was concentrated under vacuum. The pH value of the residue was adjusted to 3.0 with HCl (1.0 mol/L). The mixture was extracted with CH ₂ Cl ₂ . The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by reverse phase flash chromatography with ACN/H ₂ O (70/30, v/v) to afford 5-(7-(cyclopropanecarboxamido)-1-cyclopropyl-2,6- naphthyridin-3-yl)-4-methylpicolinic acid (90.0 mg, 49%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =389.1. Step 8: Synthesis of N-(5-cyclopropyl-7-(4-methyl-6-(morpholine-4-carbonyl)pyridi n-3-yl)- 2,6-naphthyridin-3-yl)cyclopropanecarboxamide: [0227] To a solution of 5-(7-(cyclopropanecarboxamido)-1-cyclopropyl-2,6- naphthyridin-3-yl)-4-methylpicolinic acid (540.0 mg, 1.39 mmol) in DMF (25.0 mL) was added HATU (793.3 mg, 2.08 mmol), DIEA (896.6 mg, 6.95 mmol) and morpholine (177.2 mg, 2.09 mmol) at room temperature. The resulting mixture was stirred at room temperature for 4 h. After the reaction was completed, the resulting mixture was diluted with H ₂ O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography with petroleum ether/ethyl acetate (50/50, v/v) to afford N-(5-cyclopropyl-7-(4-methyl-6-(morpholine-4-carbonyl)pyridi n-3-yl)-2,6- naphthyridin-3-yl)cyclopropanecarboxamide (450.0 mg, 71%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 458.1. Step 9: Synthesis of N-(7-(6-butyryl-4-methylpyridin-3-yl)-5-cyclopropyl-2,6-naph thyridin-3- yl)cyclopropanecarboxamide: [0228] To a solution of N-(5-cyclopropyl-7-(4-methyl-6-(morpholine-4-carbonyl)pyridi n- 3-yl)-2,6-naphthyridin-3-yl)cyclopropanecarboxamide (400.0 mg, 0.87 mmol) in THF (15.0 mL) was added CH ₃ CH ₂ CH ₂ MgBr (0.64 mL, 2.0 mol/L in THF) at 0 °C under N ₂ . The resulting mixture was stirred at 0 °C for 1 h under N ₂ . After the reaction was completed, the resulting mixture was diluted with H ₂ O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (55/45, v/v) to afford N-(7-(6-butyryl-4- methylpyridin-3-yl)-5-cyclopropyl-2,6-naphthyridin-3-yl)cycl opropanecarboxamide (294.3 mg, 81%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ =415.2. Step 10: Synthesis of N-(5-cyclopropyl-7-(6-(1-hydroxybutyl)-4-methylpyridin-3-yl) -2,6- naphthyridin-3-yl)cyclopropanecarboxamide: [0229] To a solution of N-(7-(6-butyryl-4-methylpyridin-3-yl)-5-cyclopropyl-2,6- naphthyridin-3-yl)cyclopropanecarboxamide (300.0 mg, 0.72 mmol) in tetrahydrofuran (15.0 mL) and methanol (3.0 mL) was added NaBH ₄ (41.1 mg, 1.09 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the resulting mixture was diluted with H ₂ O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with dichloromethane/methanol (90/10, v/v) to afford N-(5- cyclopropyl-7-(6-(1-hydroxybutyl)-4-methylpyridin-3-yl)-2,6- naphthyridin-3- yl)cyclopropanecarboxamide (84.0 mg, 28%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺

417.2.

Step 11: Separation of (R)-N-(5-cyclopropyl-7-(6-(l-hydroxybutyl)-4-methylpyridin-3 -yl)~ 2,6-naphthyridin-3-yl)cyclopropanecarboxamide (Compound 17) and (S)-N-(5-cyclopropyl- 7-( 6-( 1 -hydroxybutyl)-4-methylpyridin-3-yl)-2, 6-naphthyridin-3- yl)cyclopropanecarboxamide (Compound 18):

[0230] The racemic mixture of N-(5-cyclopropyl-7-(6-(l-hydroxybutyl)-4-methylpyridin- 3-yl)-2,6-naphthyridin-3-yl)cyclopropanecarboxamide (84.0 mg, 0.18 mmol) was separated by Prep-Chiral-HPLC with the following conditions (Column: CHIRALPAK IG, 2 x 25 cm, 5 pm; Mobile Phase A: Hex (0.5% 2M NH ₃ -MeOH)-HPLC, Mobile Phase B: IPA: DCM=1 : 1 — HPLC; Flow rate: 20 mL/min; Gradient: 30% B to 30% B in 19 min; Wave Length: 254/220 nm; RTl(min): 9.82; RT2(min): 13.87) to afford N-(5-cyclopropyl-7-(6-(l- hydroxybutyl)-4-methylpyridin-3-yl)-2,6-naphthyridin-3-yl)cy clopropanecarboxamide Enantiomer 1 (retention time 9.82 min, 23.3 mg, 55%) as a white solid and N-(5-cyclopropyl- 7-(6-(l-hydroxybutyl)-4-methylpyridin-3-yl)-2,6-naphthyridin -3- yl)cyclopropanecarboxamide Enantiomer 2 (retention time 13.87 min, 22.7 mg, 54%) as a white solid. The absolute stereochemistry of Enantiomers 1 and 2 was not assigned. The two enantiomeric structures that could be obtained from chiral separation of the enantiomeric mixture as described above are shown as Compounds 17 and 18 in Table 1.

[0231] N-(5-cyclopropyl-7-(6-(l-hydroxybutyl)-4-methylpyridin-3-yl) -2,6- naphthyridin-3-yl)cyclopropanecarboxamide Enantiomer 1 _: RTl(min): 9.82; LCMS (ESI, m/z): [M+H] ⁺ = 417.2. ¹ H NMR (400 MHz, DMSO-d ₆ ): 5 11.02 (s, 1H), 9.11 (d, J = 4.8 Hz, 1H), 8.42 - 8.37 (m, 2H), 8.24 - 8.19 (m, 1H), 7.52 - 7.50 (m, 1H), 5.36 - 5.32 (m, 1H), 4.64 - 4.60 (m, 1H), 2.20 (s, 3H), 2.11 - 2.08 (m, 1H), 1.79 - 1.65 (m, 3H), 1.49 - 1.40 (m, 2H), 1.22 - 1.20 (m, 2H), 1.08 - 1.03 (m, 1H), 0.99 - 0.84 (m, 8H).

[0232] N-(5-cyclopropyl-7-(6-(l-hydroxybutyl)-4-methylpyridin-3-yl) -2,6- naphthyridin-3-yl)cyclopropanecarboxamide Enantiomer 2: RT2(min): 13.87; LCMS (ESI, m/z): [M+H] ⁺ = 417.2 ¹ H NMR (400 MHz, DMSO-d ₆ ): 5 11.03 (s, 1H), 9.11 (d, J= 4.4 Hz, 1H), 8.42 - 8.37 (m, 2H), 8.24 - 8.19 (m, 1H), 7.52 - 7.50 (m, 1H), 5.36 - 5.32 (m, 1H), 4.66 - 4.62 (m, 1H), 2.20 (s, 3H), 2.11 - 2.08 (m, 1H), 1.79 - 1.65 (m, 3H), 1.45 - 1.37 (m, 2H), 1.22 - 1.20 (m, 2H), 1.09 - 1.02 (m, 1H), 0.99 - 0.84 (m, 8H). Example 10. Synthesis of (1R,2R)-2-fluoro-N-(7-(6-((Z)-1-(hydroxyimino)propyl)-4- methylpyridin-3-yl)-2,6-naphthyridin-3-yl)cyclopropane-1-car boxamide (Compound 19) Step 1: Synthesis of (1R,2R)-2-fluoro-N-(7-(4-methyl-6-propionylpyridin-3-yl)-2,6 - naphthyridin-3-yl)cyclopropane-1-carboxamide: O [0233] To a solution of 1-(5-(7-amino-2,6-naphthyridin-3-yl)-4-methylpyridin-2- yl)propan-1-one (90.0 mg, 0.31 mmol) in pyridine (5.0 mL) was added (1R,2R)-2- fluorocyclopropane-1-carboxylic acid (32.0 mg, 0.31 mmol) and EDCI (118.0 mg, 0.62 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column with petroleum ether/ethyl acetate (60/40, v/v) to afford (1R,2R)-2-fluoro-N-(7-(4-methyl-6-propionylpyridin-3-yl)-2,6 -naphthyridin-3- yl)cyclopropane-1-carboxamide (78.0 mg, 63%) as a green solid. LCMS (ESI, m/z): [M+H] ⁺ =379.2. Step 2: Synthesis of (1R,2R)-2-fluoro-N-(7-(6-((Z)-1-(hydroxyimino)propyl)-4-meth ylpyridin- 3-yl)-2,6-naphthyridin-3-yl)cyclopropane-1-carboxamide (Compound 19): [0234] To a solution of (1R,2R)-2-fluoro-N-(7-(4-methyl-6-propionylpyridin-3-yl)-2,6 - naphthyridin-3-yl)cyclopropane-1-carboxamide (74.0 mg, 0.20 mmol) in EtOH (50.0 ml) was added pyridine (46.4 mg, 0.59 mmol) and NH ₂ OH.HCl (20.4 mg, 0.29 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 2 h. After the reaction was completed, the resulting mixture was diluted with H ₂ O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: (Column: XBridge Prep OBD C18 Column, 30x150 mm, 5 pm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 40% B in 10 min; Wave Length: 254 nm) to afford (lR,2R)-2-fluoro-N-(7-(6-((Z)-l-(hydroxyimino)propyl)-4-meth ylpyridin-3-yl)-2,6- naphthyri din-3 -yl)cy cl opropane-1 -carboxamide (Compound 19, 12.0 mg, 15%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 394.2. 'H NMR (400 MHz, DMSO-d ₆ ): 5 11.45 (s, 1H), 11.23 (s, 1H), 9.52 (s, 1H), 9.35 (s, 1H), 8.71 - 8.69 (m, 2H), 8.22 (s, 1H), 7.83 (s, 1H), 5.09 - 4.88 (m, 1H), 2.93 - 2.87 (m, 2H), 2.47 (s, 3H), 2.35 - 2.28 (m, 1H), 1.77 - 1.67 (m, 1H), 1.27 - 1.21 (m, 1H), 1.11 - 1.07 (m, 3H).

Example 11. Synthesis of (lS,2S)-2-fluoro-N-(7-(6-((Z)-l-(hydroxyimino)propyl)-4- methylpyridin-3-yl)-2, 6-naphthyridin-3-yl)cyclopropane-l -carboxamide (Compound 20)

Step 1: Synthesis of (lS,2S)-2-fluoro-N-(7-(4-methyl-6-propionylpyridin-3-yl)-2,6 - naphthyridin-3-yl)cyclopropane-l-carboxamide:

[0235] To a solution of l-(5-(7-amino-2,6-naphthyridin-3-yl)-4-methylpyridin-2- yl)propan-l-one (80.0 mg, 0.27 mmol) in pyridine (5.0 mL) was added (l S,2S)-2- fluorocy cl opropane-1 -carboxylic acid (28.5 mg, 0.27 mmol) and EDCI (104.9 mg, 0.55 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column with petroleum ether/ethyl acetate (50/50, v/v) to afford (lS,2S)-2-fluoro-N-(7-(4-methyl-6-propionylpyridin-3-yl)-2,6 -naphthyridin-3- yl)cy cl opropane-1 -carboxamide (84.0 mg, 77%) as a green solid. LCMS (ESI, m/z): [M+H] ⁺ =379.2.

Step 2: Synthesis of (lS,2S)-2-fluoro-N-(7-(6-((Z)-l-(hydroxyimino)propyl)-4-meth ylpyridin- 3-yl)-2, 6-naphthyridin-3-yl)cyclopropane-l -carboxamide (Compound 20):

[0236] To a solution of (lS,2S)-2-fluoro-N-(7-(4-methyl-6-propionylpyridin-3-yl)-2,6 - naphthyri din-3 -yl)cy cl opropane-1 -carboxamide (74.0 mg, 0.20 mmol) in EtOH (3.0 ml) was added pyridine (46.4 mg, 0.59 mmol) and NH2OH.HCI (20.4 mg, 0.29 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 2 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: (Column: XBridge Prep OBD C18 Column, 30x150 mm, 5 pm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 25% B to 35% B in 10 min; Wave Length: 254 nm) to afford (lS,2S)-2-fluoro-N-(7-(6-((Z)-l-(hydroxyimino)propyl)-4-meth ylpyridin-3-yl)-2,6- naphthyri din-3 -yl)cy cl opropane-1 -carboxamide (17.1 mg, 22%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 394.2. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.46 (s, 1H), 11.24 - 11.18 (m, 1H), 9.51 (s, 1H), 9.34 (s, 1H), 8.75 - 8.69 (m, 2H), 8.24 - 8.22 (m, 1H), 7.82 (s, 1H), 5.09 - 4.88 (m, 1H), 2.92 - 2.87 (m, 2H), 2.47 (s, 3H), 2.34 - 2.27 (m, 1H), 1.76 - 1.68 (m, 1H), 1.27 - 1.20 (m, 1H), 1.10 - 1.04 (m, 3H).

Example 12. Synthesis of (R,Z)-2,2-difluoro-N-(7-(6-(l-(hydroxyimino)propyl)-4- methylpyridin-3-yl)-2, 6-naphthyridin-3-yl)cyclopropane-l -carboxamide (Compound 21 )

Step 1: Synthesis of (R)-2,2-difluoro-N-(7-(4-methyl-6-propionylpyridin-3-yl)-2,6 - naphthyridin-3-yl)cyclopropane-l-carboxamide:

[0237] To a solution of l-(5-(7-amino-2,6-naphthyridin-3-yl)-4-methylpyridin-2- yl)propan-l-one (90.0 mg, 0.31 mmol) in pyridine (5.0 mL) was added (R)-2,2- difluorocyclopropane-1 -carboxylic acid (37.6 mg, 0.31 mmol) and EDCI (95.6 mg, 0.62 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column with petroleum ether/ethyl acetate (30/70, v/v) to afford (R)-2,2-difluoro-N-(7-(4-methyl-6-propionylpyridin-3-yl)-2,6 -naphthyridin-3- yl)cyclopropane-l -carboxamide (64.0 mg, 49%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ =397.1.

Step 2: Synthesis of (R,Z)-2,2-difluoro-N-(7-(6-(l-(hydroxyimino)propyl)-4-methyl pyridin-3- yl)-2, 6-naphthyridin-3-yl)cyclopropane-l-carboxamide (Compound 21):

[0238] To a solution of (R)-2,2-difluoro-N-(7-(4-methyl-6-propionylpyridin-3-yl)-2,6 - naphthyri din-3 -yl)cy cl opropane-1 -carboxamide (74.0 mg, 0.20 mmol) in EtOH (10.0 ml) was added pyridine (38.3 mg, 0.48 mmol) and NH2OH.HCI (16.8 mg, 0.24 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 2 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: (Column: XBridge Prep OBD C18 Column, 30x150 mm, 5 pm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 32% B to 42% B in 10 min; Wave Length: 254 nm) to afford (R,Z)-2,2-difluoro-N-(7-(6-(l-(hydroxyimino)propyl)-4-methyl pyridin-3-yl)-2,6- naphthyri din-3 -yl)cy cl opropane-1 -carboxamide (Compound 21, 5.2 mg, 7%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 412.1. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.46 - 11.18 (m, 2H), 9.54 (s, 1H), 9.36 (s, 1H), 8.75 - 8.68 (m, 2H), 8.26 - 8.23 (m, 1H), 7.82 (s, 1H), 3.13 - 3.05 (m, 1H), 2.92 - 2.86 (m, 2H), 2.47 (s, 3H), 2.13 - 2.05 (m, 2H), 1.10 - 1.04 (m, 3H).

Example 13. Synthesis ofN-(3-{4-methyl-6-[(lR)-l-(propane-l- sulfonamido)propyl]pyridin-3-yl}-l,6-naphthyridin-7-yl)cyclo propanecarboxamide (Compound 22) and N-(3-{4-methyl-6-[(lS)-l-(propane-l-sulfonamido)propyl]pyrid in-3- yl}-l, 6-naphthyridin- 7-yl)cyclopropanecarboxamide (Compound 23)

Step 1: Synthesis of N-(3-(4-methyl-6-(l-(propylsulfonamido)propyl)pyridin-3-yl)- l ,6- naphthyridin- 7-yl) cyclopropanecarboxamide : [0239] To a solution of N-[3-(4-methyl-6-propanoylpyridin-3-yl)-l,6-naphthyridin-7- yl]cyclopropanecarboxamide (175.0 mg, 0.49 mmol) in toluene (5.0 mL) was added propane- 1 -sulfonamide (119.6 mg, 0.97 mmol) and Ti(Oi-Pr)4 (207.0 mg, 0.73 mmol) at room temperature. The resulting mixture was stirred at 120 °C for 16 h. After the reaction was completed. The resulting mixture was concentrated under reduced pressure. To the above residue was added DCM/MeOH (8.0 mL/8.0 mL) and NaBH ₄ (73.5 mg, 1.94 mmol) at room temperature. The resulting mixture was stirred at room temperature for additional 2 h. The reaction mixture was quenched with water at room temperature and then extracted with CH2CI2. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with acetonitrile/water (1/2, v/v) to afford N-(3-(4- methyl-6-(l-(propylsulfonamido)propyl)pyridin-3-yl)-l,6-naph thyridin-7- yl)cyclopropanecarboxamide (60.0 mg, 26%) as a light brown oil. LCMS (ESI, m/z): [M+H] ⁺ = 468.3.

Step 2: Separation ofN-(3-{4-methyl-6-[(lR)-l-(propane-l-sulfonamido)propyl]pyr idin-3- yl}-l, 6-naphthyridin-7-yl)cyclopropanecarboxamide (Compound 22)and N-(3-{4-methyl-6- [ ( 1S)-1 -(propane- l-sulfonamido)propyl ]pyridin-3-yl}-l, 6-naphthyridin- 7- yl)cyclopropanecarboxamide (Compound 23):

[0240] The racemic product of N-(3-(4-methyl-6-(l-(propylsulfonamido)propyl)pyri din-

3-yl)-l,6-naphthyridin-7-yl)cyclopropanecarboxamide (60.0 mg) was separated by Prep- Chiral-HPLC with the following conditions (Column: CHIRALPAK IG, 2x25 cm, 5 pm; Mobile Phase A: Hex: DCM=1 : 1(0.5% 2M NH ₃ -MeOH)-HPLC, Mobile Phase B: EtOH— HPLC; Flow rate: 20 mL/min; Gradient: 30% B to 30% B in 15 min; Wave Length: 220/254 nm; RTl(min): 9.89; RT2(min): 13.24) to afford N-(3-{4-methyl-6-[l-(propane-l- sulfonamido)propyl]pyri din-3 -yl } - 1 ,6-naphthyridin-7-yl)cyclopropanecarboxamide Enantiomer 1 (retention time 9.89 min, 13.4 mg, 44%) as a white solid and N-(3-{4-methyl- 6-[l-(propane-l-sulfonamido)propyl]pyridin-3-yl}-l,6-naphthy ridin-7- yl)cyclopropanecarboxamide Enantiomer 2 (retention time 13.24 min 10.0 mg, 33%) as a white solid. The absolute stereochemistry of Enantiomers 1 and 2 was not assigned. The two enantiomeric structures that could be obtained from chiral separation of the enantiomeric mixture as described above are shown as Compounds 22 and 23 in Table 1.

[0241] N-(3-{4-methyl-6-[l-(propane-l-sulfonamido)propyl]pyridin-3- yl}-l,6- naphthyridin-7-yl)cyclopropanecarboxamide Enantiomer 1: RT1 : 9.89 min; LCMS (ESI, m/z): [M+H]+ =468.3. ¹ H NMR (400 MHz, DMSO-d6): δ 11.17 (s, 1H), 9.28 (s, 1H), 9.11 (d, J = 2.4 Hz, 1H), 8.61 - 8.57 (m, 2H), 8.52 (s, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.49 (s, 1H), 4.34 - 4.30 (m, 1H), 2.90 - 2.84 (m, 1H), 2.73 - 2.66 (m, 1H), 2.38 (s, 3H), 2.13 - 2.09 (m, 1H), 1.87 - 1.77 (m, 2H), 1.62 - 1.54 (m, 2H), 0.94 - 0.83 (m, 10H).

[0242] N-(3-{4-methyl-6-[l-(propane-l-sulfonamido)propyl]pyridin-3- yl}-l,6- naphthyridin-7-yl)cyclopropanecarboxamide Enantiomer 2: RT2: 13.24 min; LCMS (ESI, m/z): [M+H]+ = 468.3. ¹ H NMR (400 MHz, DMSO-d6): δ 11.17 (s, 1H), 9.28 (s, 1H), 9.11 (s, 1H), 8.61 - 8.51 (m, 3H), 7.72 (d, J = 7.6 Hz, 1H), 7.49 (s, 1H), 4.34 - 4.30 (m, 1H), 2.90 - 2.84 (m, 1H), 2.73 - 2.66 (m, 1H), 2.38 (s, 3H), 2.13 - 2.09 (m, 1H), 1.87 - 1.77 (m, 2H), 1.62 - 1.54 (m, 2H), 0.94 - 0.83 (m, 10H).

Example 14. Synthesis of (lS)-l-{4-methyl-5-[7-(methylamino)-l,6-naphthyridin-3- yl]pyridin-2-yl}propan-l-ol (Compound 24) and (lR)-l-{4-methyl-5-[7-(methylamino)-l,6- naphthyridin-3-yl]pyridin-2-yl}propan-l-ol (Compound 25)

Step 1: Synthesis of l-[5-(7-chloro-l,6-naphthyridin-3-yl)-4-methylpyridin-2-yl]p ropan-l- one:

[0243] To a solution of 4-methyl-6-propanoylpyridin-3-ylboronic acid (2.2 g, 11.40 mmol) in l,4-dioxane/H2O (24.0 mL/6.0 mL) was added 3-bromo-7-chloro-l,6-naphthyridine (3.1 g, 12.54 mmol), K2CO3 (4.7 g, 34.19 mmol) and Pd(dppf)Ch (834.0 mg, 1.14 mmol) at room temperature under N ₂ . The resulting mixture was stirred at 80 °C for 2 h. After the reaction was completed, the resulting mixture was diluted with H ₂ O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (50/50, v/v) to afford 1-[5-(7-chloro-1,6-naphthyridin-3-yl)-4-methylpyridin-2-yl]p ropan-1-one (1.3 g, 27%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =312.1. Step 2: Synthesis of Tert-butyl N-[3-(4-methyl-6-propanoylpyridin-3-yl)-1,6-naphthyridin-7- yl]carbamate: [0244] To a solution of 1-[5-(7-chloro-1,6-naphthyridin-3-yl)-4-methylpyridin-2- yl]propan-1-one (1.3 g, 4.17 mmol) in 1,4-dioxane (15.0 mL) was added Cs ₂ CO ₃ (4.1 g, 12.51 mmol), Pd(OAc) ₂ (187.2 mg, 0.83 mmol), tert-butyl carbamate (488.5 mg, 4.17 mmol) and XPhos (795.1 mg, 1.67 mmol) at room temperature under N ₂ . The resulting mixture was stirred at 100 °C for 2 h. After the reaction was completed, the resulting mixture was diluted with H ₂ O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (55/45, v/v) to afford tert-butyl N-[3-(4-methyl-6-propanoylpyridin-3-yl)- 1,6-naphthyridin-7-yl]carbamate (950.0 mg, 35%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =393.2. Step 3: Synthesis of Tert-butyl N-methyl-N-[3-(4-methyl-6-propanoylpyridin-3-yl)-1,6- naphthyridin-7-yl]carbamate: [0245] To a solution of tert-butyl N-[3-(4-methyl-6-propanoylpyridin-3-yl)-1,6- naphthyridin-7-yl]carbamate (950.0 mg, 2.42 mmol) in DMF (10.0 mL) was added K ₂ CO ₃ (1.0 g, 7.26 mmol) and CH ₃ I (515.4 mg, 3.63 mmol) at 0 C under N ₂ . The resulting mixture was stirred at 30 °C for 16 h. After the reaction was completed, the resulting mixture was diluted with H ₂ O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford tert-butyl N-methyl-N-[3-(4-methyl-6-propanoylpyridin-3- yl)-1,6-naphthyridin-7-yl]carbamate (400.0 mg, crude) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =407.2. Step 4: Synthesis of tert-butyl N-{3-[6-(1-hydroxypropyl)-4-methylpyridin-3-yl]-1,6- naphthyridin-7-yl}-N-methylcarbamate: [0246] To a solution of tert-butyl N-methyl-N-[3-(4-methyl-6-propanoylpyridin-3-yl)- 1,6-naphthyridin-7-yl]carbamate (380.0 mg, 0.94 mmol) in THF (5.0 mL) was added dropwise DIBAL-H (0.9 mL, 1 mol/L) at -78 C under N ₂ . The resulting mixture was stirred at -78 °C for 1 h. After the reaction was completed, the resulting mixture was quenched with aq. NH ₄ Cl at -78 C and then extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford tert-butyl N-{3-[6-(1-hydroxypropyl)-4- methylpyridin-3-yl]-1,6-naphthyridin-7-yl}-N-methylcarbamate (380.0 mg, crude) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =409.2. Step 5: Synthesis of 1-{4-methyl-5-[7-(methylamino)-1,6-naphthyridin-3-yl]pyridin -2- yl}propan-1-ol: [0247] To a solution of tert-butyl N-{3-[6-(1-hydroxypropyl)-4-methylpyridin-3-yl]-1,6- naphthyridin-7-yl}-N-methylcarbamate (350.0 mg, crude) in CH ₂ Cl ₂ (2.5 mL) was added TFA (2.5 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the resulting mixture was adjusted pH to 7.0 with NH3.H2O and then concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography with CH3CN/H2O (30/70, v/v) to afford l-{4-methyl-5- [7-(methylamino)-l,6-naphthyridin-3-yl]pyridin-2-yl(propan-l -ol (90.0 mg, 34%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =309.2.

Step 6: Separation of (lS)-l-{4-methyl-5-[7-(methylamino)-l,6-naphthyridin-3-yl]py ridin-2- yl}propan-l-ol (Compound 24) and (lR)-l-{4-methyl-5-[7-(methylamino)-l,6-naphthyridin- 3-yl]pyridin-2-yl}propan-l-ol (Compound 25):

[0248] The product l-{4-methyl-5-[7-(methylamino)-l,6-naphthyridin-3-yl]pyridin -2- yl (propan- l-ol (90.0 mg, 0.29 mmol) was separated by Prep-Chiral -HPLC with the following conditions (Column: CHIRAL ART Cellulose-SC, 2x25 cm, 5 pm; Mobile Phase A: Hex: DCM=1 : 1 (0.5% 2M NH ₃ -MeOH)-HPLC, Mobile Phase B: EtOH-HPLC; Flow rate: 20 mL/min; Gradient: 50% B to 50% B in 12.5 min; Wave Length: 220/254 nm; RTl(min): 5.86; RT2(min): 9.26) to afford l-{4-methyl-5-[7-(methylamino)-l,6-naphthyridin-3- yl]pyridin-2-yl (propan- l-ol Enantiomer 1 (retention time 5.86 min, 22.7 mg, 50%) and l-{4- methyl-5-[7-(methylamino)-l,6-naphthyri din-3 -yl]pyridin-2-yl(propan-l-ol Enantiomer 2 (retention time 9.26 min, 21.0 mg, 46%) as a yellow solid. The absolute stereochemistry of Enantiomers 1 and 2 was not assigned. The two enantiomeric structures that could be obtained from chiral separation of the enantiomeric mixture as described above are shown as Compounds 24 and 25 in Table 1.

[0249] l-{4-methyl-5-[7-(methylamino)-l,6-naphthyridin-3-yl]pyridin -2-yl}propan- l-ol Enantiomer 1: RT1=5.86 min; LCMS (ESI, m/z): [M+H] ⁺ =309.1. ¹ H NMR (400 MHz, DMSO-d ₆ ): 5 8.97 (s, 1H), 8.83 (d, J= 2.4 Hz, 1H), 8. 41 (s, 1H), 8.28 (d, J= 2.0 Hz, 1H), 7. 46 (s, 1H), 6.94 - 6.90 (m, 1H), 6.62 (s, 1H), 5.33 (d, J= 5.2 Hz, 1H), 4.56 - 4.52 (m, 1H), 2.87 (d, J= 4.8 Hz, 3H), 2.35 (s, 3H), 1.87 - 1.81 (m, 1H), 1.71 - 1.63 (m, 1H), 0.92 - 0.88 (m, 3H).

[0250] l-{4-methyl-5-[7-(methylamino)-l,6-naphthyridin-3-yl]pyridin -2-yl}propan- l-ol Enantiomer 2: RT2=9.26 min; LCMS (ESI, m/z): [M+H] ⁺ =309.1. ¹ H NMR (400 MHz, DMSO-d ₆ ): 5 8.97 (s, 1H), 8.83 (d, J= 2.4 Hz, 1H), 8.41 (s, 1H), 8.28 (d, J= 2.4 Hz, 1H), 7.46 (s, 1H), 6.94 - 6.90 (m, 1H), 6.62 (s, 1H), 5.33 (d, J = 4.8 Hz, 1H), 4.56 - 4.52 (m, 1H), 2.87 (d, J = 4.8 Hz, 3H), 2.35 (s, 3H), 1.86 - 1.81 (m, 1H), 1.71 - 1.63 (m, 1H), 0.92 - 0.89 (m, 3H). Example 15. Synthesis of (1R)-1-{4-methyl-5-[7-(methylamino)-2,6-naphthyridin-3- yl]pyridin-2-yl}propan-1-ol (Compound 26) and (1S)-1-{4-methyl-5-[7-(methylamino)-2,6- naphthyridin-3-yl]pyridin-2-yl}propan-1-ol (Compound 27) Step 1: Synthesis of tert-butyl methyl(7-(4-methyl-6-propionylpyridin-3-yl)-2,6-naphthyridin - 3-yl)carbamate: [0251] To a mixture of tert-butyl N-(7-chloro-2,6-naphthyridin-3-yl)-N-methylcarbamate (604.24 mg, 2.05 mmol) in 1,4-dioxane/H ₂ O (12.5 mL/2.5 mL) was added 1-(4-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pr opan-1-one (566.0 mg, 2.05 mmol), K ₃ PO ₄ (1309.9 mg, 6.17 mmol), XPhos (196.1 mg, 0.41 mmol) and XPhos Pd G3 (174.1 mg, 0.21 mmol) at room temperature under N ₂ . The resulting mixture was stirred at 60 °C for 2 h. After the reaction was completed, the resulting mixture was diluted with H ₂ O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (5/1, v/v) to afford tert-butyl methyl(7-(4-methyl-6-propionylpyridin-3-yl)-2,6-naphthyridin - 3-yl)carbamate (360.0 mg, 43%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ =407.2. Step 2: Synthesis of Tert-butyl N-{7-[6-(1-hydroxypropyl)-4-methylpyridin-3-yl]-2,6- naphthyridin-3-yl}-N-methylcarbamate: [0252] To a solution of tert-butyl N-methyl-N-[7-(4-methyl-6-propanoylpyridin-3-yl)- 2,6-naphthyridin-3-yl]carbamate (360.0 mg, 0.89 mmol) in THF/CH ₃ OH (27.0 mL/9.0 mL) was added NaBH ₄ (67.0 mg, 1.77 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction mixture was diluted with H ₂ O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with ACN/H ₂ O (2/1, v/v) to afford tert-butyl N-{7-[6-(1-hydroxypropyl)-4- methylpyridin-3-yl]-2,6-naphthyridin-3-yl}-N-methylcarbamate (180.0 mg, 50%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ =409.2. Step 3: Synthesis of 1-{4-methyl-5-[7-(methylamino)-2,6-naphthyridin-3-yl]pyridin -2- yl}propan-1-ol: [0253] To a solution of tert-butyl N-{7-[6-(1-hydroxypropyl)pyridin-3-yl]-2,6- naphthyridin-3-yl}-N-methylcarbamate (160.0 mg, 0. 41 mmol) in CH ₂ Cl ₂ (5.0 mL) was added TFA (5.0 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the mixture was concentrated under reduced pressure. The mixture was diluted with H ₂ O. The pH value of the mixture was adjusted to 7 with aq.NaHCO ₃ . The mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with ACN/H ₂ O (1/5, v/v) to afford 1-{4-methyl-5-[7-(methylamino)- 2,6-naphthyridin-3-yl]pyridin-2-yl}propan-1-ol (120.0 mg, 96%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =309.2. Step 4: Synthesis of (1R)-1-{4-methyl-5-[7-(methylamino)-2,6-naphthyridin-3-yl]py ridin-2- yl}propan-1-ol (Compound 26) and (1S)-1-{4-methyl-5-[7-(methylamino)-2,6-naphthyridin- 3-yl]pyridin-2-yl}propan-1-ol (Compound 27): [0254] The product l-{4-methyl-5-[7-(methylamino)-2,6-naphthyridin-3-yl]pyridin -2- yl (propan- l-ol (120.0 mg, 0. 39 mmol) was separated by Prep-Chiral-HPLC with the following conditions (Column: CHIRALPAK Cellulose- IH, 2x25 cm, 5 um; Mobile Phase A:Hex:DCM=l : l (0.5% 2M NH ₃ -MeOH)-HPLC, Mobile Phase B:EtOH-HPLC; Flow rate:20 mL/min; Gradient:20% B to 20% B in 15 min; 220/254 nm; RTl(min): 7.77; RT2(min): 12.10) to afford l-{4-methyl-5-[7-(methylamino)-2,6-naphthyridin-3-yl]pyridin - 2-yl} propan- l-ol Enantiomer 1 (retention time 7.77 min, 21.9 mg, 36%) as a yellow solid and l-{4-methyl-5-[7-(methylamino)-2,6-naphthyridin-3-yl]pyridin -2-yl (propan- l-ol Enantiomer 2 (retention time 12.10 min, 26.7 mg, 44%) as a yellow solid.

[0255] l-{4-methyl-5-[7-(methylamino)-2,6-naphthyridin-3-yl]pyridin -2-yl}propan- l-ol Enantiomer 1: RTl(min): 7.77; LCMS (ESI, m/z): [M+H] ⁺ =309.0. ¹ H NMR(400 MHz, DMSO-d ₆ ): δ 9.20 (s, 1H), 9.03 (s, 1H), 8.53 (s, 1H), 7.91 (s, 1H), 7.42 (s, 1H), 6.90 - 6.86 (m, 1H), 6.71 (s, 1H), 5.30 (d, J= 5.2 Hz, 1H), 4.56 - 4.52 (m, 1H), 2.87 (s, 3H), 2.43 (s, 3H), 1.89 - 1.78 (m, 1H), 1.73 - 1.69 (m, 1H), 0.91 - 0. 88 (m, 3H).

[0256] l-{4-methyl-5-[7-(methylamino)-2,6-naphthyridin-3-yl]pyridin -2-yl (propan- l-ol

Enantiomer 2: RT2(min): 12.10; LCMS (ESI, m/z): [M+H] ⁺ =309.1. ¹ H NMR(400 MHz, DMSO- ₆ ): δ 9.20 (s, IH), 9.03 (s, IH), 8.53 (s, IH), 7.91 (s, IH), 7.42 (s, IH), 6.90 - 6.86 (m, IH), 6.71 (s, IH), 5.30 (d, J= 5.2 Hz, IH), 4.56 - 4.52 (m, IH), 2.87 (s, 3H), 2.43 (s, 3H), 1.89 - 1.78 (m, IH), 1.73 - 1.64 (m, IH), 0.91 - 0. 88 (m, 3H).

Example 16. Synthesis of (S)-l-(4-methyl-5-(7-(methylamino)-2,6-naphthyridin-3- yl)pyridin-2-yl)butan-l-ol (Compound 29) and (R)-l-(4-methyl-5-(7-(methylamino)-2,6- naphthyridin-3-yl)pyridin-2-yl)butan-l-ol (Compound 30)

Step 1: Synthesis of tert-butyl (7-(6-butyryl-4-methylpyridin-3-yl)-2,6-naphthyridin-3- yl) (methyl) carbamate :

[0257] To a solution of tert-butyl (7-chloro-2,6-naphthyridin-3-yl)(methyl)carbamate (400.0 mg, 1.46 mmol) in l,4-dioxane/H2O (10.0 mL/2.0 mb) was added (6-butyryl-4- methylpyridin-3-yl)boronic acid (281.9 mg, 1.46 mmol), K2CO3 (564.6 mg, 4.39 mmol) and PdAMPhos (96.4 mg, 0.15 mmol) at room temperature under N ₂ . The resulting mixture was stirred at 80 °C for 2 h. After the reaction was completed, the resulting mixture was diluted with H ₂ O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfa1te and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /CH ₃ OH (90/10, v/v) to afford tert-butyl (7-(6-butyryl-4-methylpyridin-3-yl)-2,6- naphthyridin-3-yl)(methyl)carbamate (310.0 mg, 54%) as a brown solid. LCMS (ESI, m/z): [M+H] ⁺ =421.2. Step 2: Synthesis of tert-butyl (7-(6-(1-hydroxybutyl)-4-methylpyridin-3-yl)-2,6-naphthyridi n- 3-yl)(methyl)carbamate: [0258] To a solution of tert-butyl (7-(6-butyryl-4-methylpyridin-3-yl)-2,6-naphthyridin-3- yl)(methyl)carbamate (290.0 mg, 0.69 mmol) in THF/CH ₃ OH (4.0 mL/4.0 mL) was added NaBH ₄ (78.3 mg, 2.07 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the resulting mixture was quenched with H ₂ O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford tert-butyl (7-(6-(1-hydroxybutyl)-4-methylpyridin-3-yl)-2,6- naphthyridin-3-yl)(methyl)carbamate (320.0 mg, crude) as a brown solid. LCMS (ESI, m/z): [M+H] ⁺ =423.2. Step 3: Synthesis of 1-(4-methyl-5-(7-(methylamino)-2,6-naphthyridin-3-yl)pyridin -2- yl)butan-1-ol: [0259] To a solution of tert-butyl (7-(6-(1-hydroxybutyl)-4-methylpyridin-3-yl)-2,6- naphthyridin-3-yl)(methyl)carbamate (300.0 mg, 0.71 mmol) in CH ₂ Cl ₂ (4.0 mL) was added TFA (4.0 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was diluted with H2O. The pH value of the mixture was adjusted to 7 with aq.NaHCO3. The mixture was extracted with CH2CI2. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /CH3OH (87/13, v/v) to afford l-(4-methyl-5-(7-(methylamino)- 2,6-naphthyridin-3-yl)pyridin-2-yl)butan-l-ol (200.0 mg, 87%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =323.2.

Step 4: Separation of (S)-l-(4-methyl-5-(7-(methylamino)-2,6-naphthyridin-3-yl)pyr idin-2- yl)butan-l-ol (Compound 29) and (R)-l-(4-methyl-5-(7-(methylamino)-2,6-naphthyridin-3- yl)pyridin-2-yl)butan-l-ol (Compound 30):

[0260] The racemic product of l-(4-methyl-5-(7-(methylamino)-2,6-naphthyridin-3- yl)pyridin-2-yl)butan-l-ol (200.0 mg, 0.62 mmol) was separated by Prep-Chiral-HPLC with the following conditions (Column: CHIRALPAK IH, 2x25 cm, 5 pm; Mobile Phase A: Hex (0.5% 2M NH ₃ -MeOH)-HPLC, Mobile Phase B: MeOH: EtOH=l : 1-HPLC; Flow rate: 20 mL/min; Gradient: 10% B to 10% B in 24 min; Wave Length: 220/254 nm; RTl(min): 13.20; RT2(min): 18.23) to afford l-(4-methyl-5-(7-(methylamino)-2,6-naphthyridin-3-yl)pyridin -2- yl)butan-l-ol Enantiomer 1 (retention time 13.20 min, 54.8 mg, 54%) as a yellow solid and 1- (4-methyl-5-(7-(methylamino)-2, 6-naphthyri din-3 -yl)pyri din-2 -yl)butan-l-ol Enantiomer 2 (retention time 18.23 min, 55.4 mg, 55%) as a yellow solid. The absolute stereochemistry of Enantiomers 1 and 2 was not assigned. The two enantiomeric structures that could be obtained from chiral separation of the enantiomeric mixture as described above are shown as Compounds 29 and 30 in Table 1.

[0261] l-(4-methyl-5-(7-(methylamino)-2,6-naphthyridin-3-yl)pyridin -2-yl)butan-l- ol Enantiomer 1: RTl(min): 13.20; LCMS (ESI, m/z): [M+H] ⁺ =323.2. 'H NMR (400 MHz, DMSO-d ₆ ): 5 9.19 (s, 1H), 9.03 (s, 1H), 8.53 (s, 1H), 7.90 (s, 1H), 7.42 (s, 1H), 6.90 - 6.86 (m, 1H), 6.70 (s, 1H), 5.30 (d, J= 4.8 Hz, 1H), 4.63 - 4.58 (m, 1H), 2.87 (d, J= 4.8 Hz, 3H), 2.43 (s, 3H), 1.80 - 1.72 (m, 1H), 1.68 - 1.59 (m, 1H), 1.45 - 1.34 (m, 2H), 0.92 - 0.88 (m, 3H). [0262] l-(4-methyl-5-(7-(methylamino)-2,6-naphthyridin-3-yl)pyridin -2-yl)butan-l- ol Enantiomer 2: RT2(min): 18.23; LCMS (ESI, m/z): [M+H] ⁺ =323.2. 'H NMR (400 MHz, DMSO-d ₆ ): 5 9.19 (s, 1H), 9.03 (s, 1H), 8.53 (s, 1H), 7.90 (s, 1H), 7.42 (s, 1H), 6.90 - 6.86 (m, 1H), 6.70 (s, 1H), 5.30 (d, J= 4.8 Hz, 1H), 4.62 - 4.58 (m, 1H), 2.87 (d, J= 4.8 Hz, 3H), 2.43 (s, 3H), 1.78 - 1.72 (m, 1H), 1.68 - 1.59 (m, 1H), 1.44 - 1.34 (m, 2H), 0.92 - 0.89 (m, 3H).

Example 17. Synthesis of (S)-l-(4-methyl-5-(7-(methylamino)-2,6-naphthyridin-3- yl)pyridin-2-yl)butan-l-ol (Compound 31) and (R)-l-(4-methyl-5-(7-(methylamino)-2,6- naphthyridin-3-yl)pyridin-2-yl)butan-l-ol (Compound 32)

Step 1: Synthesis of tert-butyl N-[7-(4-methyl-6-propanoylpyridin-3-yl)-2,6-naphthyridin-3- yl] carbamate:

[0263] To a solution of tert-butyl (7-chloro-2,6-naphthyridin-3-yl)carbamate (1.6 g, 5.70 mmol) in 1,4-dioxane (20.0 mL)/H20 (4.0 mb) was added 4-m ethyl-6-propanoylpyri din-3 - ylboronic acid (1.1 g, 5.70 mmol), XPhos (543.4 mg, 1.14 mmol), K3PO4 (3.6 g, 17.09 mmol) and XPhos Pd G3 (482.4 mg, 0.57 mmol) at room temperature under N2. The resulting mixture was stirred at 80 °C for 4 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (1/1, v/v) to afford tert-butyl N-[7-(4- methyl-6-propanoylpyridin-3-yl)-2,6-naphthyridin-3-yl]carbam ate (670.0 mg, 29%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =393.2.

Step 2: Synthesis of tert-butyl N-{7-[6-(l-hydroxypropyl)-4-methylpyridin-3-yl]-2,6- naphthyridin-3-yl}carbamate: [0264] To a solution of tert-butyl N-[7-(4-methyl-6-propanoylpyridin-3-yl)-2,6- naphthyridin-3-yl]carbamate (360.0 mg, 0.92 mmol) in THF (10.0 mL)/MeOH (5.0 mL) was added NaBH ₄ (34.7 mg, 0.92 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the resulting mixture was quenched with H ₂ O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (1/1, v/v) to afford tert-butyl N-{7-[6-(1-hydroxypropyl)-4- methylpyridin-3-yl]-2,6-naphthyridin-3-yl}carbamate (130.0 mg, 35%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =395.2. Step 3: Synthesis of 1-(5-(7-amino-2,6-naphthyridin-3-yl)-4-methylpyridin-2-yl)pr opan-1-ol: [0265] To a solution of tert-butyl N-{7-[6-(1-hydroxypropyl)-4-methylpyridin-3-yl]-2,6- naphthyridin-3-yl}carbamate (130.0 mg, 0.33 mmol) in DCM (3.0 mL) was add TFA (3.0 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The pH value of the residue was adjusted to 7 with aq.NaHCO ₃ . The mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography with CH ₃ CN/H ₂ O (75/25, v/v) to afford 1-(5-(7-amino-2,6-naphthyridin-3-yl)-4-methylpyridin-2-yl)pr opan-1-ol (60.0 mg, 60%) as a yellow green solid. LCMS (ESI, m/z): [M+H] ⁺ =295.1. Step 4: Separation of (S)-1-(5-(7-amino-2,6-naphthyridin-3-yl)-4-methylpyridin-2-y l)propan- 1-ol (Compound 31) and (R)-1-(5-(7-amino-2,6-naphthyridin-3-yl)-4-methylpyridin-2- yl)propan-1-ol (Compound 32): [0266] The racemic product l-(5-(7-amino-2,6-naphthyridin-3-yl)-4-methylpyridin-2- yl)propan-l-ol (60.0 mg, 0.20 mmol) was separated by Prep-Chiral -HPLC with the following conditions (Column: CHIRALPAK IH, 2x25 cm, 5 pm; Mobile Phase A: Hex (0.5% 2M NH ₃ -MeOH) - HPLC, Mobile Phase B: MeOH: EtOH=l : 1 - HPLC; Flow rate: 20 mL/min; Gradient: 45% B to 45% B in 9 min; Wave Length: 220/254 nm; RTl(min): 4.38; RT2(min): 7.05) to afford l-(5-(7-amino-2,6-naphthyridin-3-yl)-4-methylpyridin-2-yl)pr opan-l-ol Enantiomer l(retention time 4.38 min, 5.9 mg, 20%) as a yellow green solid and l-(5-(7- amino-2,6-naphthyridin-3-yl)-4-methylpyridin-2-yl)propan-l-o l Enantiomer 2 (retention time 7.05 min, 20.0 mg, 66%) as a yellow green solid. The absolute stereochemistry of Enantiomers 1 and 2 was not assigned. The two enantiomeric structures that could be obtained from chiral separation of the enantiomeric mixture as described above are shown as Compounds 31 and 32 in Table 1.

[0267] l-(5-(7-amino-2,6-naphthyri din-3 -yl)-4-methylpyri din-2 -yl)propan-l-ol

Enantiomer 1 : RTl(min): 4.38; LCMS (ESI, m/z): [M+H]+ =295.2. 'H NMR (400 MHz, CD3OD-d4): 5 9.11 (s, IH), 9.00 (s, IH), 8.51 (s, IH), 7.88 (s, IH), 7.53 (s, IH), 6.97 (s, IH), 4.71- 4.68 (m, IH), 2.47 (s, 3H), 1.92 - 1.89 (m, IH), 1.84 - 1.79 (m, IH), 1.02 - 0.98 (m, 3H).

[0268] l-(5-(7-amino-2,6-naphthyri din-3-yl)-4-methylpyri din-2 -yl)propan-l-ol

Enantiomer 2: RT2(min): 7.05; LCMS (ESI, m/z): [M+H]+ =295.2. 'H NMR (400 MHz, DMSO-d6): 5 9.14 (s, 1H), 8.99 (s, 1H), 8.53 (s, 1H), 7.89 (s, 1H), 7.42 (s, 1H), 6.79 (s, 1H), 6.37 (s, 2H), 5.30 (d, J = 4.8 Hz, 1H), 4.56 - 4.52 (m, 1H), 2.43 (s, 3H), 1.87 - 1.80 (m, 1H), 1.71 -1.64 (m, 1H), 0.95 - 0.89 (m, 3H).

Example 18. Synthesis ofN-(7-{6-[(lS)-l-hydroxybutyl]-4-methylpyridin-3-yl}-2,6- naphthyridin-3-yl)cyclopropanecarboxamide (Compound 33) and N-(7-{6-[(lR)-l- hydroxybutyl]-4-methylpyridin-3-yl}-2,6-naphthyridin-3-yl)cy clopropanecarboxamide (Compound 34)

Step 1: Synthesis of N-[7-(6-butanoyl-4-methylpyridin-3-yl)-2,6-naphthyridin-3- yl ] cyclopropanecarboxamide: o [0269] To a mixture of N-(7-chloro-2,6-naphthyridin-3-yl)cyclopropanecarboxamide (1.0 g, 4.04 mmol) in 1,4-dioxane/H ₂ O (24.0 mL/5.0 mL) was added 6-butanoyl-4-methylpyridin- 3-ylboronic acid (0.8 g, 4.04 mmol), K ₂ CO ₃ (1.7 g, 12.11 mmol) and Pd(PPh ₃ ) ₄ (0.5 g, 0.40 mmol) at room temperature under N ₂ . The resulting mixture was stirred at 100 °C for 2 h under N ₂ . After the reaction was completed, the resulting mixture was diluted with H ₂ O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (5/1, v/v) to afford N-[7-(6-butanoyl-4-methylpyridin-3-yl)-2,6-naphthyridin-3- yl]cyclopropanecarboxamide (650.0 mg, 43%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ =375.2. Step 2: Synthesis of N-{7-[6-(1-hydroxybutyl)-4-methylpyridin-3-yl]-2,6-naphthyri din-3- yl}cyclopropanecarboxamide: [0270] To a solution of N-[7-(6-butanoyl-4-methylpyridin-3-yl)-2,6-naphthyridin-3- yl]cyclopropanecarboxamide (300.0 mg, 0.80 mmol) in THF/CH ₃ OH (9.0 mL /3.0 mL) was added NaBH ₄ (60.6 mg, 1.60 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the reaction mixture was diluted with H ₂ O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with ACN/H ₂ O (5/1, v/v) to afford N-{7-[6-(1-hydroxybutyl)-4-methylpyridin-3-yl]-2,6- naphthyridin-3-yl}cyclopropanecarboxamide (173.0 mg, 57 %) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =377.2. Step 3: Separation of N-(7-{6-[(1S)-1-hydroxybutyl]-4-methylpyridin-3-yl}-2,6-naph thyridin- 3-yl)cyclopropanecarboxamide (Compound 33) and N-(7-{6-[(1R)-1-hydroxybutyl]-4- methylpyridin-3-yl}-2,6-naphthyridin-3-yl)cyclopropanecarbox amide (Compound 34):

[0271] The racemic product of N-{7-[6-(l-hydroxybutyl)-4-methylpyridin-3-yl]-2,6- naphthyridin-3-yl} cyclopropanecarboxamide (150.0 mg, 0. 40 mmol) was separated by Prep- Chiral-HPLC with the following conditions (Column: CHIRALPAK IH, 2x25 cm, 5 um; Mobile Phase A:Hex:DCM=l : 1 (0.5% 2M NH ₃ -MeOH)-HPLC, Mobile Phase B:EtOH— HPLC; Flow rate:20 mL/min; Gradient:30% B to 30% B in 16 min; 220/254 nm; RTl(min): 6.42; RT2(min): 11.22) to afford N-(7-{6-[l-hydroxybutyl]-4-methylpyridin-3-yl}-2,6- naphthyridin-3 -yl)cy cl opropanecarboxamide Enantiomer 1 (retention time 6.42 min, 32.0 mg, 42%) as a yellow solid and N-(7-{6-[l-hydroxybutyl]-4-methylpyridin-3-yl}-2,6- naphthyridin-3-yl)cyclopropanecarboxamide Enantiomer 2 (retention time 11.22 min, 40.8 mg, 54%) as a yellow solid. The absolute stereochemistry of Enantiomers 1 and 2 was not assigned. The two enantiomeric structures that could be obtained from chiral separation of the enantiomeric mixture as described above are shown as Compounds 33 and 34 in Table 1.

[0272] N-(7-{6-[l-hydroxybutyl]-4-methylpyridin-3-yl]-2,6-naphthyri din-3- yl)cyclopropanecarboxamide Enantiomer 1 : RTl(min): 6.42; LCMS (ESI, m/z): [M+H]+ =377.2. ¹ H NMR (400 MHz, DMSO-d6): 5 11.17 (s, 1H), 9.47 (s, 1H), 9.33 (s, 1H), 8.67 (s, 1H), 8.57 (s, 1H), 8.16 (s, 1H), 7.46 (s, 1H), 5.33 (d, J = 4.8 Hz, 1H), 4.64 - 4.60 (m, 1H), 2.45 (s, 3H), 2.11 - 2.08 (m, 1H), 1.78 - 1.73 (m, 1H), 1.70 - 1.62 (m, 1H), 1.50 - 1.43 (m, 2H), 0.98 - 0.80 (m, 7H).

[0273] N-(7-[6-[l-hydroxybutyl]-4-methylpyridin-3-yl}-2,6-naphthyri din-3- yl)cyclopropanecarboxamide Enantiomer 2: RT2(min): 11.22; LCMS (ESI, m/z): [M+H]+ =377.2. ¹ H NMR (400 MHz, DMSO-d6): δ 11.17 (s, 1H), 9.47 (s, 1H), 9.33 (s, 1H), 8.67(s, 1H), 8.57 (s, 1H), 8.16 (s, 1H), 7.46 (s, 1H), 5.33 (d, J = 4.8 Hz, 1H), 4.64 - 4.60 (m, 1H), 2.45 (s, 3H), 2.11 - 2.08 (m, 1H), 1.78 - 1.70 (m, 1H), 1.68 - 1.63 (m, 1H), 1.42 -1.39 (m, 2H), 0.92 - 0.86 (m, 7H).

Example 19. Synthesis of (lS)-l-[5-(7-amino-2 ₎ 6-naphthyndin-3-yl)-4-methylpyndin-2- yl]butan-l-ol (Compound 35) and (lR)-l-[5-(7-amino-2,6-naphthyridin-3-yl)-4- methylpyridin-2-yl]butan-l-ol (Compound 36)

Step 1: Synthesis of l-(5-bromo-4-methylpyridin-2-yl)butan-l-one: [0274] To a solution of 5-bromo-N-methoxy-N,4-dimethylpyridine-2-carboxamide (5.0 g, 19.30 mmol) in THF (100.0 mL) was added dropwise bromo(propyl)magnesium (14.5 mL, 28.95 mmol) at 0 °C under N ₂ . The resulting mixture was stirred at room temperature for 2 h under N ₂ . After the reaction was completed, the reaction was quench with aq. NH ₄ Cl and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (90/10, v/v) to afford 1-(5-bromo-4-methylpyridin-2-yl)butan-1-one (2.0 g, 42%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ =242.0. Step 2: Synthesis of 6-butanoyl-4-methylpyridin-3-ylboronic acid: [0275] To a solution of 1-(5-bromo-4-methylpyridin-2-yl)butan-1-one (1.9 g, 7.85 mmol) in dioxane (20.0 mL) was added bis(pinacolato)diboron (3.0 g, 11.77 mmol), KOAc (2.3 g, 23.54 mmol) and Pd(dppf)Cl ₂ (639.3 mg, 0.79 mmol) at room temperature under N ₂ . The resulting mixture was stirred at 80 °C for 2 h. After the reaction was completed, the resulting mixture was diluted with H ₂ O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (90/10, v/v) to afford 6-butanoyl-4- methylpyridin-3-ylboronic acid (1.0 g, 61%) as a brown solid. LCMS (ESI, m/z): [M+H] ⁺ =208.1. Step 3: Synthesis of tert-butyl N-[7-(6-butanoyl-4-methylpyridin-3-yl)-2,6-naphthyridin-3- yl]carbamate: [0276] To a solution of 6-butanoyl-4-methylpyridin-3-ylboronic acid (555.1 mg, 2.68 mmol) in dioxane/H ₂ O (5.0/1.0 mL) was added tert-butyl N-(7-chloro-2,6-naphthyridin-3- yl)carbamate (500.0 mg, 1.79 mmol), K ₃ PO ₄ (1.1 g, 5.36 mmol), XPhos (170.4 mg, 0.36 mmol) and XPhos Pd G3 (151.3 mg, 0.18 mmol) at room temperature under N ₂ . The resulting mixture was stirred at 60 °C for 2 h. After the reaction was completed, the resulting mixture was diluted with H ₂ O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (75/25, v/v) to afford tert-butyl N-[7-(6- butanoyl-4-methylpyridin-3-yl)-2,6-naphthyridin-3-yl]carbama te (500.0 mg, 68%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =407.2. Step 4: Synthesis of tert-butyl N-{7-[6-(1-hydroxybutyl)-4-methylpyridin-3-yl]-2,6- naphthyridin-3-yl}carbamate: [0277] To a solution of tert-butyl N-[7-(6-butanoyl-4-methylpyridin-3-yl)-2,6- naphthyridin-3-yl]carbamate (360.0 mg, 0.89 mmol) in THF (5.0 mL) was added dropwise DIBAL-H (2.0 ml, 1 mol/L) at -78 °C under N ₂ . The resulting mixture was stirred at -78 °C for 1 h. After the reaction was completed, the resulting mixture was quenched with aq. NH ₄ Cl and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford tert-butyl N-{7-[6-(1-hydroxybutyl)-4-methylpyridin-3-yl]-2,6- naphthyridin-3-yl}carbamate (400.0 mg, crude) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =409.2. Step 5: Synthesis of 1-[5-(7-amino-2,6-naphthyridin-3-yl)-4-methylpyridin-2-yl]bu tan-1-ol: OH [0278] To a solution of tert-butyl N-{7-[6-(1-hydroxybutyl)-4-methylpyridin-3-yl]-2,6- naphthyridin-3-yl}carbamate (350.0 mg, crude) in DCM (2.0 mL) was added TFA (2.0 mL) at room temperature. The resulting mixture was stirred at room temperature for 0.5 h. After the reaction was completed, the mixture was concentrated under reduced pressure. The pH value of the residue was adjusted to 8 with aq.NaHCOs. The mixture was extracted with CH2CI2. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography with H2O/CH3OH (40/60, v/v) to afford l-[5-(7-amino-2,6-naphthyridin-3-yl)-4-methylpyridin-2-yl]bu tan-l-ol (150.0 mg, 50%) as a green solid. LCMS (ESI, m/z): [M+H] ⁺ =309.2.

Step 6: Separation of (lS)-l-[5-(7-amino-2,6-naphthyridin-3-yl)-4-methylpyridin-2- yl]butan- l-ol (Compound 35) and (lR)-l-[5-(7-amino-2,6-naphthyridin-3-yl)-4-methylpyridin-2- yl]butan-l-ol (Compound 36):

[0279] The racemic product l-[5-(7-amino-2,6-naphthyridin-3-yl)-4-methylpyridin-2- yl]butan-l-ol (150.0 mg, 0.48 mmol) was separated by Prep-Chiral-HPLC with the following conditions (Column: CHIRALPAK IH, 2x25 cm, 5 pm; Mobile Phase A: Hex (0.5% 2M NH ₃ -MeOH)— HPLC, Mobile Phase B: MeOH: EtOH=l : 1-HPLC; Flow rate: 20 mL/min; Gradient: 20% B to 20% B in 19 min; Wave Length: 220/254 nm; RTl(min): 10.06; RT2(min): 14.10) to afford l-[5-(7-amino-2,6-naphthyridin-3-yl)-4-methylpyridin-2- yl]butan-l-ol Enantiomer 1 (, 36.1 mg, 48%) as a green solid and l-[5-(7-amino-2,6- naphthyridin-3-yl)-4-methylpyridin-2-yl]butan-l-ol Enantiomer 2(retention time 14.10 min, 49.8 mg, 66%) as a green solid. The absolute stereochemistry of Enantiomers 1 and 2 was not assigned. The two enantiomeric structures that could be obtained from chiral separation of the enantiomeric mixture as described above are shown as Compounds 35 and 36 in Table 1.

[0280] l-[5-(7-amino-2,6-naphthyridin-3-yl)-4-methylpyridin-2-yl]bu tan-l-ol

Enantiomer 1: RTl(min): 10.06; LCMS (ESI, m/z): [M+H]+ =309.2. ¹ H NMR (400 MHz, DMSO-d6): δ 9.14 (s, 1H), 8.99 (s, 1H), 8.52 (s, 1H), 7.89 (s, 1H), 7.42 (s, 1H), 6.79 (s, 1H), 6.37 (s, 2H), 5.29 (d, J = 5.2 Hz, 1H), 4.63 - 4.58 (m, 1H), 2.33 (s, 3H), 1.80 - 1.72 (m, 1H), 1.69 - 1.60 (m, 1H), 1.46 - 1.37 (m, 2H), 0.98 - 0.86 (m, 3H).

[0281] l-[5-(7-amino-2,6-naphthyridin-3-yl)-4-methylpyridin-2-yl]bu tan-l-ol

Enantiomer 2: RT2(min): 14.10; LCMS (ESI, m/z): [M+H]+ =309.2. ¹ H NMR (400 MHz, DMSO-d6): δ 9.14 (s, 1H), 8.99 (s, 1H), 8.52 (s, 1H), 7.88 (s, 1H), 7.42 (s, 1H), 6.79 (s, 1H), 6.37 (s, 2H), 5.29 (d, J = 5.2 Hz, 1H), 4.62 - 4.58 (m, 1H), 2.42 (s, 3H), 1.80 - 1.72 (m, 1H), 1.69 - 1.60 (m, 1H), 1.46 - 1.32 (m, 2H), 0.98 - 0.86 (m, 3H).

Example 20. Synthesis of (R)-N-(7-(6-(l-hydroxypropyl)-4-methylpyridin-3-yl)-2,6- naphthyridin-3-yl)cyclopropanecarboxamide (Compound 37) and (S)-N-(7-(6-(l- hydroxypropyl)-4-methylpyridin-3-yl)-2,6-naphthyridin-3-yl)c yclopropanecarboxamide (Compound 38)

Step 1: Synthesis ofN-(7-chloro-2,6-naphthyridin-3-yl)cyclopropanecarboxamide:

[0282] To a solution of 7-chloro-2,6-naphthyridin-3-amine (730.0 mg, 4.06 mmol) in pyridine (10.0 mL) was added cyclopropanecarbonyl chloride (1.3 g, 12.19 mmol) at 0 °C under N2. The resulting mixture was stirred at 0 °C for 2 h. After the reaction was completed, the reaction mixture was diluted with water and then filtered. The solid was collected and dried to afford N-(7-chloro-2,6-naphthyridin-3-yl)cyclopropanecarboxamide (610.0 mg, crude) as a brown solid. LCMS (ESI, m/z): [M+H] ⁺ =248.1.

Step 2: Synthesis ofN-(7-(4-methyl-6-propionylpyridin-3-yl)-2,6-naphthyridin-3 - yl)cyclopropanecarboxamide:

[0283] To a solution of N-(7-chloro-2,6-naphthyridin-3-yl)cyclopropanecarboxamide

(570.0 mg, crude) in dioxane/H2O (5.0 mL/1.0 mL) was added (4-methyl-6-propionylpyridin- 3-yl)boronic acid (488.6 mg, 2.53 mmol), K3PO4 (1.5 g, 6.90 mmol), XPhos (219.4 mg, 0.46 mmol) and XPhos Pd G3 (194.8 mg, 0.23 mmol) at room temperature under N ₂ . The resulting mixture was stirred at 60 °C for 4 h. After the reaction was completed, the resulting mixture was diluted with H ₂ O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (75/25, v/v) to afford N-(7-(4-methyl-6- propionylpyridin-3-yl)-2,6-naphthyridin-3-yl)cyclopropanecar boxamide (500.0 mg, 54%) as a brown solid. LCMS (ESI, m/z): [M+H] ⁺ =361.2. Step 3: Synthesis of N-(7-(6-(1-hydroxypropyl)-4-methylpyridin-3-yl)-2,6-naphthyr idin-3- yl)cyclopropanecarboxamide: [0284] To a solution of N-(7-(4-methyl-6-propionylpyridin-3-yl)-2,6-naphthyridin-3- yl)cyclopropanecarboxamide (251.0 mg, 0.70 mmol) in THF/MeOH (5.0 mL/1.0 mL) was added NaBH ₄ (133.1 mg, 3.52 mmol) at 0 °C under N2. The resulting mixture was stirred at room temperature for 16 h. After the reaction was completed, the resulting mixture was quenched with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography with ACN/H2O (50/50, v/v) to afford N-(7-(6-(1-hydroxypropyl)-4- methylpyridin-3-yl)-2,6-naphthyridin-3-yl)cyclopropanecarbox amide (150.0 mg, 57%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ =363.2. Step 4: Separation of (R)-N-(7-(6-(1-hydroxypropyl)-4-methylpyridin-3-yl)-2,6-naph thyridin- 3-yl)cyclopropanecarboxamide (Compound 37) and (S)-N-(7-(6-(1-hydroxypropyl)-4- methylpyridin-3-yl)-2,6-naphthyridin-3-yl)cyclopropanecarbox amide (Compound 38): [0285] The racemic mixture of N-(7-(6-(1-hydroxypropyl)-4-methylpyridin-3-yl)-2,6- naphthyridin-3-yl)cyclopropanecarboxamide (130.0 mg, 0.36 mmol) was separated by Prep- Chiral-HPLC with the following conditions (Column: CHIRALPAK IH, 2x25 cm, 5 pm; Mobile Phase A: Hex (0.5% 2M NH ₃ -MeOH)-HPLC, Mobile Phase B: MeOH: DCM=1: 1- HPLC; Flow rate: 20 mL/min; Gradient: 40% B to 40% B in 10 min; Wave Length: 220/254 nm; RTl(min): 4.64; RT2(min): 7.79) to afford N-(7-(6-(l-hydroxypropyl)-4-methylpyridin- 3-yl)-2,6-naphthyridin-3-yl)cyclopropanecarboxamide Enantiomer 1 (retention time 4.64 min, 53.0 mg, 81%) as a yellow solid and N-(7-(6-(l-hydroxypropyl)-4-methylpyridin-3-yl)- 2,6-naphthyridin-3-yl)cyclopropanecarboxamide Enantiomer 2 (retention time 7.79 min, 48.9 mg, 75%) as a white solid. The absolute stereochemistry of Enantiomers 1 and 2 was not assigned. The two enantiomeric structures that could be obtained from chiral separation of the enantiomeric mixture as described above are shown as Compounds 37 and 38 in Table 1.

[0286] N-(7-(6-(l-hydroxypropyl)-4-methylpyridin-3-yl)-2,6-naphthyr idin-3- yl)cyclopropanecarboxamide Enantiomer 1 : RTl(min): 4.64; LCMS (ESI, m/z): [M+H]+ =363.2. ¹ H NMR (400 MHz, DMSO-d6): δ 11.17 (s, 1H), 9.47 (s, 1H), 9.32 (s, 1H), 8.67 (s, 1H), 8.58 (s, 1H), 8.16 (s, 1H), 7.46 (s, 1H), 5.34 (d, J = 4.8 Hz, 1H), 4.58 - 4.54 (m, 1H), 2.43 (s, 3H), 2.14 - 2.08 (m, 1H), 1.90 - 1.79 (m, 1H), 1.76 - 1.65 (m, 1H), 0.90 - 0.80 (m, 7H).

[0287] N-(7-(6-(l-hydroxypropyl)-4-methylpyridin-3-yl)-2,6-naphthyr idin-3- yl)cyclopropanecarboxamide Enantiomer 2: RT2(min): 7.79; LCMS (ESI, m/z): [M+H]+ =363.2. ¹ H NMR (400 MHz, DMSO- d6): δ 11.16 (s, 1H), 9.47 (s, 1H), 9.32 (s, 1H), 8.66 (s, 1H), 8.58 (s, 1H), 8.16 (s, 1H), 7.46 (s, 1H), 5.34 (d, J = 4.8 Hz, 1H), 4.58 - 4.54 (m, 1H), 2.45 (s, 3H), 2.12 - 2.08 (m, 1H), 1.88 - 1.81 (m, 1H), 1.72 - 1.65 (m, 1H), 0.95 - 0.86 (m, 7H).

Example 21. Synthesis ofN-methyl-7-(4-methyl-6-propylpyridin-3-yl)-2,6-naphthyridi n-3- amine (Compound 39)

Step 1: Synthesis of 5-bromo-4-methyl-2-propylpyridine:

[0288] To a solution of 2,5-dibromo-4-methylpyridine (5.0 g, 19.93 mmol) in THF (30.0 mL) was added Pd(dppf)Ch (145.8 g, 0.20 mmol) and bromo(propyl)magnesium (20.0 mL, 1 mol/L) at -10 °C under N2. The resulting mixture was stirred at -10 °C for 3.5 h under N2. After the reaction was completed, the reaction mixture was quenched with NH ₄ Cl (aq.) and then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography with petroleum ether/EtOAc (1/1, v/v) to afford 5-bromo-4-methyl-2-propylpyridine (2.0 g, 47%) as a yellow oil. LCMS (ESI, m/z): [M+H] ⁺ =214.0. Step 2: Synthesis of 4-methyl-6-propylpyridin-3-ylboronic acid: [0289] To a solution of 5-bromo-4-methyl-2-propylpyridine (2.0 g, 9.34 mmol) in dioxane (15.0 mL) was added bis(pinacolato)diboron (7.1 g, 28.02 mmol), KOAc (2.8 g, 28.02 mmol) and Pd(dppf)Cl ₂ (683.5 mg, 0.93 mmol) at room temperature under N ₂ . The resulting mixture was stirred at 80 °C for 16 h under N ₂ . After the reaction was completed, the resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography CH ₂ Cl ₂ /MeOH (6/1, v/v) to afford 4- methyl-6-propylpyridin-3-ylboronic acid (260.0 mg, 15%) as a brown solid. LCMS (ESI, m/z): [M+H] ⁺ =180.1. Step 3: Synthesis of tert-butyl N-methyl-N-[7-(4-methyl-6-propylpyridin-3-yl)-2,6- naphthyridin-3-yl]carbamate: [0290] To a solution of 4-methyl-6-propylpyridin-3-ylboronic acid (250.0 mg, 1.40 mmol) in dioxane (5.0 mL)/H ₂ O (1.0 mL) was added tert-butyl N-(7-chloro-2,6-naphthyridin- 3-yl)-N-methylcarbamate (410.2 mg, 1.40 mmol), K ₂ CO ₃ (575.0 mg, 4.19 mmol), XPhos (133.1 mg, 0.28 mmol) and XPhos Pd G ₃ (118.2 mg, 0.14 mmol) at room temperature under N ₂ . The resulting mixture was stirred at 80 °C for 16 h. After the reaction was completed, the resulting mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography with CH3CN/H2O (5/1, v/v) to afford tert-butyl N-methyl-N- [7-(4-methyl-6-propylpyridin-3-yl)-2,6-naphthyridin-3-yl]car bamate (18.0 mg, 3%) as a brown solid. LCMS (ESI, m/z): [M+H] ⁺ =393.2.

Step 4: Synthesis ofN-methyl-7-(4-methyl-6-propylpyridin-3-yl)-2,6-naphthyridi n-3-amine (Compound 39):

[0291] To a solution of tert-butyl N-methyl-N-[7-(4-methyl-6-propylpyridin-3-yl)-2,6- naphthyridin-3-yl]carbamate (18.0 mg, 0.05 mmol) in DCM (2.0 mL) was added TFA (2.0 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, The pH value of the mixture was adjusted to 7 with aq.NaHCO3. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 30x150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 45% B in 8 min; Wave Length: 254 nm) to afford N-methyl-7- (4-methyl-6-propylpyridin-3-yl)-2,6-naphthyridin-3-amine (Compound 39, 2.5 mg, 18%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =293.1. ¹ H NMR (400 MHz, DMSO-d6): δ 9.17 (s, 1H), 9.03 (s, 1H), 8.53 (s, 1H), 7.89 (s, 1H), 7.20 (s, 1H), 6.89 - 6.85 (m, 1H), 6.70 (s, 1H), 2.87 (d, J= 5.2 Hz, 3H), 2.74 - 2.70 (m, 2H), 2.39 (s, 3H), 1.78 - 1.69 (m, 2H), 0.96 - 0.89 (m, 3H).

Example 22. Synthesis of (S)-4,4,4-trifluoro-l-(4-methyl-5-(7-(methylamino)-2,6- naphthyridin-3-yl)pyridin-2-yl)butan-l-ol (Compound 40) and (R)-4,4,4-trifluoro-l-(4- methyl-5- ( 7-(methylamino)-2, 6-naphthyridin-3-yl)pyridin-2-yl) butan-1 -ol ( Compound 41)

Step 1: Synthesis of l-(5-bromo-4-methylpyridin-2-yl)-4,4,4-trifluorobutan-l-one: [0292] To a solution of 5-bromo-N-methoxy-N,4-dimethylpicolinamide (5.0 g, 19.30 mmol) in THF (200.0 mL) was added dropwise chloro(3,3,3-trifluoropropyl)magnesium (77.2 mL, 0.5 mol/L) at 0 °C under N ₂ . The resulting mixture was stirred at 0 °C for 1 h. After the reaction was completed, the reaction mixture was quenched with H ₂ O at 0 °C and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (93/7, v/v) to afford 1-(5-bromo-4-methylpyridin-2-yl)-4,4,4-trifluorobutan-1-one (4.0 g, 70%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ =296.0. Step 2: Synthesis of (4-methyl-6-(4,4,4-trifluorobutanoyl)pyridin-3-yl)boronic acid: [0293] To a solution of 1-(5-bromo-4-methylpyridin-2-yl)-4,4,4-trifluorobutan-1-one (2.0 g, 6.76 mmol) in dioxane (20.0 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2- dioxaborolane) (5.2 g, 20.27 mmol), KOAc (1.3 g, 13.51 mmol) and Pd(dppf)Cl2 (0.5 g, 0.68 mmol) at room temperature under N ₂ . The resulting mixture was stirred at 80 °C for 4 h. After the reaction was completed, the resulting mixture was diluted with H ₂ O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (1/1, v/v) to afford (4-methyl-6-(4,4,4-trifluorobutanoyl)pyridin-3-yl)boronic acid (2.0 g, 86%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =262.1. Step 3: Synthesis of tert-butyl methyl(7-(4-methyl-6-(4,4,4-trifluorobutanoyl)pyridin-3-yl)- 2,6-naphthyridin-3-yl)carbamate: [0294] To a solution of (4-methyl-6-(4,4,4-trifluorobutanoyl)pyridin-3-yl)boronic acid (1.2 g, 4.58 mmol) in dioxane/H ₂ O (15.0 mL/3.0 mL) was added tert-butyl N-(3- chloroisoquinolin-7-yl)-N-methylcarbamate (1.0 g, 3.50 mmol), K ₂ CO ₃ (1.5 g, 10.49 mmol) and Pd(dppf)Cl ₂ (255.9 mg, 0.35 mmol) at room temperature under N ₂ . The resulting mixture was stirred at 80 °C for 4 h. After the reaction was completed, the resulting mixture was diluted with H ₂ O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (3/1, v/v) to afford tert-butyl methyl(7-(4-methyl-6-(4,4,4- trifluorobutanoyl)pyridin-3-yl)-2,6-naphthyridin-3-yl)carbam ate (1.3 g, 78%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =475.2. Step 4: Synthesis of tert-butyl N-methyl-N-{7-[4-methyl-6-(4,4,4-trifluoro-1- hydroxybutyl)pyridin-3-yl]-2,6-naphthyridin-3-yl}carbamate: [0295] To a solution of tert-butyl methyl(7-(4-methyl-6-(4,4,4-trifluorobutanoyl)pyridin- 3-yl)-2,6-naphthyridin-3-yl)carbamate (600.0 mg, 1.26 mmol) in THF (20.0 mL) was added dropwise DIBAL-H (3.8 mL, 1 mol/L) at -65 °C under N ₂ . The resulting mixture was stirred at -65 °C for 1 h under N ₂ . After the reaction was completed, the reaction was quenched with H ₂ O at -65 °C and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography with CH ₃ CN/H ₂ O (54/46, v/v) to afford tert-butyl N-methyl-N-{7-[4-methyl-6-(4,4,4- trifluoro-1-hydroxybutyl)pyridin-3-yl]-2,6-naphthyridin-3-yl }carbamate (120.0 mg, 19%) as a brown solid. LCMS (ESI, m/z): [M+H] ⁺ =477.2. Step 5: Synthesis of 4,4,4-trifluoro-1-(4-methyl-5-(7-(methylamino)-2,6-naphthyri din-3- yl)pyridin-2-yl)butan-1-ol: [0296] To a solution of tert-butyl N-methyl-N-{7-[4-methyl-6-(4,4,4-trifluoro-l- hydroxybutyl)pyridin-3-yl]-2,6-naphthyridin-3-yl}carbamate (150.0 mg, 0.31 mmol) in DCM (5.0 mL) was add TFA (5.0 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with H2O. The pH value of the mixture was adjusted to 7 with aq.NaHCO3. The mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography with CH3CN/H2O (70/30, v/v) to afford 4,4,4-trifluoro-l-(4-methyl-5-(7-(methylamino)-2,6-naphthyri din-3-yl)pyridin-2- yl)butan-l-ol (100.0 mg, 84%) as a yellow green solid. LCMS (ESI, m/z): [M+H] ⁺ =377.2.

Step 6: Separation of (S)-4,4,4-trifluoro-l-(4-methyl-5-(7-(methylamino)-2,6-napht hyridin-3- yl)pyridin-2-yl)butan-l-ol (Compound 40)and (R)-4,4,4-trifluoro-l-(4-methyl-5-(7-

(methylamino)-2, 6-naphthyridin-3-yl)pyridin-2-yl)butan-l-ol (Compound 41):

[0297] The racemic product 4,4,4-trifluoro-l-(4-methyl-5-(7-(methylamino)-2,6- naphthyridin-3-yl)pyridin-2-yl)butan-l-ol (100.0 mg, 0.27 mmol) was separated by Prep- Chiral-HPLC with the following conditions (Column: CHIRALPAK IF, 2x25 cm, 5 pm; Mobile Phase A: Hex (0.5% 2M NH ₃ -MeOH)-HPLC, Mobile Phase B: EtOH-HPLC; Flow rate: 20 mL/min; Gradient: 25% B to 25% B in 20 min; Wave Length: 220/254 nm;

RTl(min): 13.41; RT2(min): 16.85) to afford 4,4,4-trifluoro-l-(4-methyl-5-(7- (methylamino)-2,6-naphthyridin-3-yl)pyridin-2-yl)butan-l-ol Enantiomer 1 (retention time 13.41 min, 25.1 mg, 50%) as a yellow solid and 4,4,4-trifluoro-l-(4-methyl-5-(7- (methylamino)-2,6-naphthyridin-3-yl)pyridin-2-yl)butan-l-ol Enantiomer 2 (retention time 16.85 min, 26.3 mg, 52%) as a yellow solid. The absolute stereochemistry of Enantiomers 1 and 2 was not assigned. The two enantiomeric structures that could be obtained from chiral separation of the enantiomeric mixture as described above are shown as Compounds 40 and 41 in Table 1. [0298] 4, 4, 4-trifluoro-l-(4-methyl-5-(7-(methylamino)-2, 6-naphthyri din-3-yl)pyri din-

2-yl)butan-l-ol Enantiomer 1 : RTl(min): 13.41; LCMS (ESI, m/z): [M+H]+ =377.2. ¹ H NMR (400 MHz, DMSO-d6): δ 9.18 (s, 1H), 9.04 (s, 1H), 8.57 (s, 1H), 7.92 (s, 1H), 7.47 (s, 1H), 6.88 (d, J = 4.4 Hz, 1H), 6.71 (s, 1H), 5.69 (s, 1H), 4.70 (s, 1H), 2.97 - 2.87 (m, 3H), 2.45 - 2.31 (m, 5H), 2.10 - 2.04 (m, 1H), 1.92 - 1.87 (m, 1H).

[0299] 4, 4, 4-trifluoro-l-(4-methyl-5-(7-(methylamino)-2, 6-naphthyri din-3-yl)pyri din-

2-yl)butan-l-ol Enantiomer 2: RT2(min): 16.85; LCMS (ESI, m/z): [M+H]+ =377.2. ¹ H

NMR (400 MHz, DMSO-d6): δ 9.18 (s, 1H), 9.04 (s, 1H), 8.57 (s, 1H), 7.92 (s, 1H), 7.47 (s, 1H), 6.88 (d, J = 5.2 Hz, 1H), 6.71 (s, 1H), 5.67 (d, J = 4.8 Hz, 1H), 4.70 (s, 1H), 2.88 - 2.84 (m, 3H), 2.44 - 2.25 (m, 5H), 2.10 - 2.04 (m, 1H), 1.92 - 1.86 (m, 1H).

Example 23. Synthesis of (lS,2S)-2-fluoro-N-(7-{6-[(lR)-l-hydroxypropyl]-4- methylpyridin-3-yl}-2, 6-naphthyridin-3-yl)cyclopropane-l -carboxamide (Compound 42) and (lS,2S)-2-fluoro-N-(7-{6-[(lS)-l-hydroxypropyl]-4-methylpyri din-3-yl}-2,6- naphthyridin-3-yl)cyclopropane-l-carboxamide (Compound 43)

Step 1: Synthesis of 7-chloro-2,6-naphthyridin-3-amine:

[0300] To a solution of tert-butyl N-(7-chloro-2,6-naphthyridin-3-yl)carbamate (1.0 g, 3.58 mmol) in DCM (12.0 mL) was added TEA (4 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the pH value of the mixture was adjusted to 7 with NaHCO3 (aq). The mixture was extracted with CH2CI2. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 7- chl oro-2, 6-naphthyri din-3 -amine (500.0 mg, crude) as a brown solid. LCMS (ESI, m/z): [M+H] ⁺ =180.0.

Step 2: Synthesis of (lS,2S)-N-(7-chloro-2,6-naphthyridin-3-yl)-2-fluorocycloprop ane-l- carboxamide: [0301] To a solution of 7-chloro-2,6-naphthyridin-3-amine (480.0 mg, crude) in DMF (20.0 mL) was added DIEA (1.7 g, 13.36 mmol), (1S,2S)-2-fluorocyclopropane-1-carboxylic acid (556.3 mg, 5.34 mmol) and HATU (2.2 g, 5.67 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 16 h. After the reaction was completed, the resulting mixture was diluted with H ₂ O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (3/1, v/v) to afford to afford (1S,2S)-N- (7-chloro-2,6-naphthyridin-3-yl)-2-fluorocyclopropane-1-carb oxamide (500.0 mg, 70%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =266.0. Step 3: Synthesis of (1S,2S)-2-fluoro-N-[7-(4-methyl-6-propanoylpyridin-3-yl)-2,6 - naphthyridin-3-yl]cyclopropane-1-carboxamide: [0302] To a solution of (1S,2S)-N-(7-chloro-2,6-naphthyridin-3-yl)-2- fluorocyclopropane-1-carboxamide (480.0 mg, 1.81 mmol) in dioxane/H ₂ O (5.0 mL/1.0 mL) was added 4-methyl-6-propanoylpyridin-3-ylboronic acid (418.5 mg, 2.17 mmol), K ₃ PO ₄ (1.2 g, 5.42 mmol), XPhos (172.3 mg, 0.36 mmol) and XPhos Pd G3 (153.0 mg, 0.18 mmol) at room temperature. The resulting mixture was stirred at 60 °C for 1 h under N ₂ . After the reaction was completed, the resulting mixture was filtered. The filtrate was concentrated under vacuum. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (1/1, v/v) to afford (1S,2S)-2-fluoro-N-[7-(4-methyl-6-propanoylpyridin- 3-yl)-2,6-naphthyridin-3-yl]cyclopropane-1-carboxamide (520.0 mg, 76%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =379.1. Step 4: Synthesis of (1S,2S)-2-fluoro-N-{7-[6-(1-hydroxypropyl)-4-methylpyridin-3 -yl]-2,6- naphthyridin-3-yl}cyclopropane-1-carboxamide: [0303] To a solution of (lS,2S)-2-fhioro-N-[7-(4-methyl-6-propanoylpyridin-3-yl)-2,6 - naphthyri din-3 -yl]cy cl opropane-1 -carboxamide (500.0 mg, 1.32 mmol) in MeOH (20.0 mL) was added NaBH ₄ (100.0 mg, 2.64 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction mixture was quenched with H2O and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (1/9, v/v) to afford (lS,2S)-2-fluoro-N-{7-[6-(l-hydroxypropyl)-4- methylpyri din-3 -yl]-2,6-naphthyri din-3 -yljcy cl opropane-1 -carboxamide (150.0 mg, 30%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =381.2.

Step 5: Separation of (lS,2S)-2-jluoro-N-(7-{6-[(lR)-l-hydroxypropyl]-4-methylpyri din-3- yl}-2,6-naphthyridin-3-yl)cyclopropane-l-carboxamide (Compound 42)and (lS,2S)-2-fluoro- N-(7-{6-[(lS)-l-hydroxypropyl]-4-methylpyridin-3-yl}-2,6-nap hthyridin-3-yl)cyclopropane- 1 -carboxamide (Compound 43):

[0304] The product of (lS,2S)-2-fluoro-N-{7-[6-(l-hydroxypropyl)-4-methylpyridin-3 - yl]-2,6-naphthyridin-3-yl} cyclopropane- 1 -carboxamide (150.0 mg, 0.39 mmol) was separated by Prep-Chiral-HPLC with the following conditions (Column: CHIRAL ART Amylose-SA, 2x25 cm, 5 pm; Mobile Phase A: MtBE (0.5% 2M NH ₃ -MeOH)-HPLC, Mobile Phase B: MeOH: DCM=1 : 1— HPLC; Flow rate: 20 mL/min; Gradient: 60% B to 60% B in 9 min; Wave Length: 220/254 nm; RTl(min): 5.61; RT2(min): 7.69) to afford (1S,2S)- 2-fluoro-N-(7-{6-[l-hydroxypropyl]-4-methylpyridin-3-yl}-2,6 -naphthyri din-3- yl)cy cl opropane-1 -carboxamide Isomer 1 (retention time 5.61 min, 39.6 mg, 52%) as a white solid and (lS,2S)-2-fluoro-N-(7-{6-[l-hydroxypropyl]-4-methylpyridin-3 -yl}-2,6- naphthyri din-3 -yl)cy cl opropane-1 -carboxamide Isomer 2 (retention time 7.69 min, 42.4 mg, 56%) as a white solid. The absolute stereochemistry of Isomers 1 and 2 was not assigned. The two isomeric structures that could be obtained from chiral separation of the isomeric mixture as described above are shown as Compounds 42 and 43 in Table 1.

[0305] (lS,2S)-2-fluoro-N-(7-{6-[l-hydroxypropyl]-4-methylpyridin-3 -yl}-2,6- naphthyridin-3-yl)cyclopropane-l-carboxamide Isomer 1: RTl(min): 5.61; LCMS (ESI, m/z): [M+H]+ =381.2. ¹ H NMR (400 MHz, DMSO-d6): 5 11.24 (s, 1H), 9.50 (s, 1H), 9.34 (s, 1H), 8.69 (s, 1H), 8.59 (s, 1H), 8.18 (s, 1H), 7.47 (s, 1H), 5.37 (d, J = 4.8 Hz, 1H), 5.08 - 4.88 (m, 1H), 4.58 - 4.54 (m, 1H), 2.46 (s, 3H), 2.34 - 2.27 (m, 1H), 1.88 - 1.81 (m, 1H), 1.76 - 1.65 (m, 2H), 1.26 - 1.21 (m, 1H), 0.92 - 0.88 (m, 3H).

[0306] (lS,2S)-2-fluoro-N-(7-{6-[-l-hydroxypropyl]-4-methylpyridin- 3-yl}-2,6- naphthyridin-3-yl)cyclopropane-l-carboxamide Isomer 2: RT2(min): 7.69; LCMS (ESI, m/z): [M+H]+ =381.2. ¹ H NMR (400 MHz, DMSO-d6): 5 11.24 (s, 1H), 9.50 (s, 1H), 9.34 (s, 1H), 8.69 (s, 1H), 8.59 (s, 1H), 8.18 (s, 1H), 7.47 (s, 1H), 5.36 (d, J = 5.2 Hz, 1H), 5.07 - 4.89 (m, 1H), 4.58 - 4.53 (m, 1H), 2.46 (s, 3H), 2.33 - 2.29 (m, 1H), 1.86 - 1.81 (m, 1H), 1.76 - 1.65 (m, 2H), 1.26 - 1.21 (m, 1H), 0.92 - 0.88 (m, 3H).

Example 24. Synthesis of (R)-N-(7-(6-(l-hydroxypropyl)-4-methylpyridin-3-yl)-2,6- naphthyridin-3-yl) acetamide (Compound 44) and (S)-N-(7-(6-(l-hydroxypropyl)-4- methylpyridin-3-yl)-2, 6-naphthyridin-3-yl) acetamide (Compound 45)

Step 1: Synthesis ofN-(7-chloro-2,6-naphthyridin-3-yl)acetamide:

[0307] To a solution of 7-chloro-2,6-naphthyridin-3-amine (500.0 mg, 2.78 mmol) in Pyridine (20.0 mL) was added acetyl chloride (239.7 mg, 3.07 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 0.5 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (50/50, v/v) to afford N-(7-chloro-2,6- naphthyridin-3-yl)acetamide (400.0 mg, 64%) as a brown solid. LCMS (ESI, m/z): [M+H] ⁺ =222.0.

Step 2: Synthesis ofN-[7-(4-methyl-6-propanoylpyridin-3-yl)-2,6-naphthyridin-3 - yl]acetamide:

[0308] To a solution of N-(7-chloro-2,6-naphthyridin-3-yl)acetamide (400.0 mg, 1.80 mmol) in dioxane/ELO (10.0/2.0 mL) was added 4-methyl-6-propanoylpyridin-3-ylboronic acid (418.0 mg, 2.16 mmol), K3PO4 (1.1 g, 5.41 mmol), XPhos (344.1 mg, 0.72 mmol) and XPhos Pd G3 (305.5 mg, 0.36 mmol) at room temperature under N2. The resulting mixture was stirred at 60 °C for 2 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (70/30, v/v) to afford N-[7-(4-methyl-6- propanoylpyridin-3-yl)-2,6-naphthyridin-3-yl]acetamide (400.0 mg, 60%) as an orange oil. LCMS (ESI, m/z): [M+H] ⁺ =335.1.

Step 3: Synthesis ofN-(7-(6-(l-hydroxypropyl)-4-methylpyridin-3-yl)-2,6-naphth yridin-3- yl)acetamide :

[0309] To a solution of N-[7-(4-methyl-6-propanoylpyridin-3-yl)-2,6-naphthyridin-3- yl]acetamide (200.0 mg, 0.60 mmol) in THF/MeOH (4.0/1.0 mL) was added NaBEL (113.1 mg, 2.99 mmol) at room temperature under N2. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction was quenched with H2O at room temperature and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography with petroleum CH3CN/H2O (50/50, v/v) to afford N-(7-(6-(l- hydroxypropyl)-4-methylpyridin-3-yl)-2,6-naphthyridin-3-yl)a cetamide (100.0 mg, 32%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ =337.2. Step 4: Separation of (R)-N-(7-(6-(l-hydroxypropyl)-4-methylpyridin-3-yl)-2,6-naph thyridin- 3 -y I) acetamide (Compound 44) and (S)-N-(7-(6-(l-hydroxypropyl)-4-methylpyridin-3-yl)-2,6- naphthyridin-3-yl)acetamide (Compound 45):

[0310] The racemic mixture of N-(7-(6-(l-hydroxypropyl)-4-methylpyridin-3-yl)-2,6- naphthyri din-3 -yl)acetamide (100.0 mg, 0.22 mmol) was separated by Prep-Chiral-HPLC with the following conditions (Column: CHIRAL ART Amylose-SA, 2x25 cm, 5 pm; Mobile Phase A: Hex (0.5% 2M NH ₃ -MeOH)-HPLC, Mobile Phase B: MeOH: DCM=1 : 1-HPLC; Flow rate: 20 mL/min; Gradient: 30% B to 30% B in 18 min; Wave Length: 220/254 nm; RTl(min): 13.61; RT2(min): 16.61) to afford N-(7-(6-(l-hydroxypropyl)-4-methylpyridin-3- yl)-2,6-naphthyridin-3-yl)acetamide Enantiomer 1 (retention time 13.61 min, 13.3 mg, 26%) as a white solid and N-(7-(6-(l-hydroxypropyl)-4-methylpyridin-3-yl)-2,6-naphthyr idin-3- yl)acetamide Enantiomer 2 (retention time 16.61, 26.5 mg, 53%) as a white solid. The absolute stereochemistry of Enantiomers 1 and 2 was not assigned. The two enantiomeric structures that could be obtained from chiral separation of the enantiomeric mixture as described above are shown as Compounds 44 and 45 in Table 1.

[0311] N-(7-(6-(l-hydroxypropyl)-4-methylpyridin-3-yl)-2,6-naphthyr idin-3- yl)acetamide Enantiomer 1: RTl(min): 13.61; LCMS (ESI, m/z): [M+H]+ =337.2. ¹ H NMR (400 MHz, DMSO-d6): δ 10.88 (s, 1H), 9.51 (s, 1H), 9.32 (s, 1H), 8.67 (s, 1H), 8.58 (s, 1H), 8.17 (s, 1H), 7.46 (s, 1H), 5.35 (d, J = 4.8 Hz, 1H), 4.58 - 4.53 (m, 1H), 2.45 (s, 3H), 2.19 (s, 3H), 1.90 - 1.79 (m, 1H), 1.74 - 1.63 (m, 1H), 0.97 - 0.88 (m, 3H).

[0312] N-(7-(6-(l-hydroxypropyl)-4-methylpyridin-3-yl)-2,6-naphthyr idin-3- yl)acetamide Enantiomer 2: RT2(min): 16.61; LCMS (ESI, m/z): [M+H]+ =337.2. ¹ H NMR (400 MHz, DMSO- d6): δ 10.88 (s, 1H), 9.51 (s, 1H), 9.32 (s, 1H), 8.67 (s, 1H), 8.58 (s, 1H), 8.17 (s, 1H), 7.46 (s, 1H), 5.35 (d, J = 5.2 Hz, 1H), 4.58 - 4.53 (m, 1H), 2.45 (s, 3H), 2.19 (s, 3H), 1.88 - 1.79 (m, 1H), 1.74 - 1.65 (m, 1H), 0.93 - 0.87 (m, 3H).

Example 25. Synthesis of (lR,2R)-2-fluoro-N-(7-(6-((R)-l-hydroxybutyl)-4-methylpyridi n- 3-yl)-2,6-naphthyridin-3-yl)cyclopropane-l-carboxamide (Compound 46) and (lR,2R)-2- fluoro-N-(7-(6-((S)-l-hydroxybutyl)-4-methylpyridin-3-yl)-2, 6-naphthyridin-3- yl)cyclopropane-l-carboxamide (Compound 47)

Step 1: Synthesis of l-(5-(7-amino-2,6-naphthyridin-3-yl)-4-methylpyridin-2-yl)bu tan-l-one:

[0313] To a mixture of tert-butyl (7-(6-butyryl-4-methylpyridin-3-yl)-2,6-naphthyridin-3- yl)carbamate (2.7 g, 6.64 mmol) in DCM (30.0 mL) was added TFA (15.0 mL) at room temperature. The resulting mixture was stirred at room temperature for 0.5 h. After the reaction was completed, the pH value of the resulting mixture was adjusted to 8 with NaHCO3 (aq). The resulting mixture was extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (10/1, v/v) to afford l-(5-(7-amino-2,6-naphthyridin-3- yl)-4-methylpyridin-2-yl)butan-l-one (2.0 g, 98%) as an off-white solid. LCMS (ESI, m/z): [M+H] ⁺ = 307.1.

Step 2: Synthesis of (lR,2R)-N-(7-(6-butyryl-4-methylpyridin-3-yl)-2,6-naphthyrid in-3-yl)-2- fluorocyclopropane-1 -carboxamide:

[0314] To a mixture of l-(5-(7-amino-2,6-naphthyridin-3-yl)-4-methylpyridin-2- yl)butan-l-one (500.0 mg, 1.63 mmol) in pyridine (10.0 mL) was added (lR,2R)-2- fluorocyclopropane-1 -carboxylic acid (339.7 mg, 3.26 mmol) and EDCI (625.7 mg, 3.26 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /CH3OH (10/1, v/v) to afford (lR,2R)-N-(7-(6-butyryl-4-methylpyridin-3-yl)-2,6-naphthyrid in-3-yl)- 2-fluorocyclopropane-l -carboxamide (460.0 mg, 71%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 393.2.

Step 3: Synthesis of (lR,2R)-2-fluoro-N-(7-(6-(l-hydroxybutyl)-4-methylpyridin-3- yl)-2,6- naphthyridin-3-yl)cyclopropane-l-carboxamide:

[0315] To a mixture of (lR,2R)-N-(7-(6-butyryl-4-methylpyridin-3-yl)-2,6-naphthyrid in- 3 -yl)-2-fluorocyclopropane-l -carboxamide (420.0 mg, 1.07 mmol) in THF (5.0 mL) and MeOH (0.5 mL) were added NaBH ₄ (202.4 mg, 5.35 mmol) at 0 °C under N2. The resulting mixture was stirred at room temperature for 4 h. After the reaction was completed, the reaction mixture was quenched with saturated NH4CI (aq.) at 0 °C. The resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH2CI2/CH3OH (10/1, v/v) to afford (lR,2R)-2-fluoro-N-(7-(6-(l-hydroxybutyl)-4- methylpyridin-3-yl)-2,6-naphthyridin-3-yl)cyclopropane-l-car boxamide (200.0 mg, 49%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 381.2.

Step 4: Separation of (lR,2R)-2-fluoro-N-(7-(6-((R)-l-hydroxybutyl)-4-methylpyridi n-3-yl)~ 2, 6-naphthyridin-3-yl)cyclopropane-l -carboxamide (Compound 46) and ( lR,2R)-2-fluoro-N- (7-( 6-( (S)-l-hydroxybutyl)-4-methylpyridin-3-yl)-2, 6-naphthyridin-3-yl)cyclopropane-l- carboxamide (Compound 47):

[0316] The racemic mixture of (lR,2R)-2-fluoro-N-(7-(6-(l-hydroxybutyl)-4- methylpyridin-3-yl)-2,6-naphthyridin-3-yl)cyclopropane-l -carboxamide (100.0 mg, 0.25 mmol) was separated by Prep-Chiral-HPLC with the following conditions (Column:

CHIRAL ART Amylose-SA, 2x25 cm, 5 pm; Mobile Phase A: Hex (0.5% 2M NH ₃ -MeOH)- HPLC, Mobile Phase B: MeOH: DCM=1 : 1-HPLC; Flow rate: 20 mL/min; Gradient: 30% B to 30% B in 23 min; Wave Length: 220/254 nm; RTl(min): 15.79; RT2(min): 19.72) to afford (lR,2R)-2-fluoro-N-(7-{6-[l-hydroxybutyl]-4-methylpyridin-3- yl}-2,6-naphthyridin- 3-yl)cyclopropane-l -carboxamide Isomer 1 (retention time 15.79 min, 21.5 mg, 43%) as a white solid and (lR,2R)-2-fluoro-N-(7-{6-[l-hydroxybutyl]-4-methylpyridin-3- yl}-2,6- naphthyri din-3 -yl)cy cl opropane-1 -carboxamide Isomer 2 (retention time 19.72 min, 22.4 mg, 44%) as a white solid. The absolute stereochemistry of Isomers 1 and 2 was not assigned. The two isomeric structures that could be obtained from chiral separation of the isomeric mixture as described above are shown as Compounds 46 and 47 in Table 1.

[0317] (lR,2R)-2-fluoro-N-(7-(6-(l-hydroxybutyl)-4-methylpyridin-3- yl)-2,6- naphthyridin-3-yl)cyclopropane-l-carboxamide Isomer 1: RTl(min): 15.79; LCMS (ESI, m/z): [M+H]+ = 395.1. ¹ H NMR (400 MHz, DMSO-d6): δ 11.22 (s, 1H), 9.50 (s, 1H), 9.34 (s, 1H), 8.69 (s, 1H), 8.58 (s, 1H), 8.17 (s, 1H), 7.46 (s, 1H), 5.34 (d, J = 5.2 Hz, 1H), 5.08 - 4.90 (m, 1H), 4.64 - 4.60 (m, 1H), 2.46 (s, 3H), 2.32 - 2.29 (m, 1H), 1.79 - 1.64 (m, 3H), 1.43

- 1.37 (m, 2H), 1.26 - 1.21 (m, 1H), 0.93 - 0.89 (m, 3H).

[0318] (lR,2R)-2-fluoro-N-(7-(6-(l-hydroxybutyl)-4-methylpyridin-3- yl)-2,6- naphthyridin-3-yl)cyclopropane-l-carboxamide Isomer 2: RT2(min): 19.72; LCMS (ESI, m/z): [M+H]+ = 395.0. ¹ H NMR (400 MHz, DMSO-d6): δ 11.22 (s, 1H), 9.50 (s, 1H), 9.34 (s, 1H), 8.69 (s, 1H), 8.58 (s, 1H), 8.18 (s, 1H), 7.47 (s, 1H), 5.34 (d, J = 4.8 Hz, 1H), 5.07 - 4.90 (m, 1H), 4.63 - 4.61 (m, 1H), 2.45 (s, 3H), 2.32 - 2.29 (m, 1H), 1.82 - 1.64 (m, 3H), 1.43

- 1.37 (m, 2H), 1.28 - 1.19 (m, 1H), 0.93 - 0.89 (m, 3H).

Example 26. Synthesis of (lR,2R)-2-fluoro-N-(7-(6-((R)-l-hydroxypropyl)-4- methylpyridin-3-yl)-2,6-naphthyridin-3-yl)cyclopropane-l-car boxamide (Compound 48)and (lR,2R)-2-fluoro-N-(7-(6-((S)-l-hydroxypropyl)-4-methylpyrid in-3-yl)-2,6- naphthyridin-3-yl)cyclopropane-l-carboxamide (Compound 49)

Step 1: Synthesis of (lR,2R)-2-fluoro-N-(7-(4-methyl-6-propionylpyridin-3-yl)-2,6 - naphthyridin-3-yl)cyclopropane-l-carboxamide: [0319] To a solution of (lR,2R)-N-(7-chloro-2,6-naphthyridin-3-yl)-2- fluorocyclopropane-1 -carboxamide (380.0 mg, 1.43 mmol) in lA-dioxane/ELO (4.0 mL/1.0 mL) was added l-(4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)p yridin-2- yl)propan-l-one (787.2 mg, 2.86 mmol), K2CO3 (593.0 mg, 4.29 mmol) and Pd(PPh3)4 (165.3 mg, 0.14 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 2 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /CH3OH (10/1, v/v) to afford (lR,2R)-2-fluoro-N-(7-(4-methyl-6-propionylpyridin-3-yl)-2,6 -naphthyri din-3- yl)cyclopropane-l -carboxamide (500.0 mg, 92%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 379.1.

Step 2: Synthesis of (lR,2R)-2-fluoro-N-(7-(6-(l-hydroxypropyl)-4-methylpyridin-3 -yl)-2,6- naphthyridin-3-yl)cyclopropane-l-carboxamide:

[0320] To a solution of (lR,2R)-2-fluoro-N-(7-(4-methyl-6-propionylpyridin-3-yl)-2,6 - naphthyri din-3 -yl)cy cl opropane-1 -carboxamide (500.0 mg, 1.32 mmol) in THF/CH3OH (5.0 mL/1.0 mL) was added NaBH4 (100.0 mg, 2.64 mmol) at 0 °C under N2. The resulting mixture was stirred at room temperature for 0.5 h. After the reaction was completed, the resulting mixture was quenched with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by reverse phase flash column chromatography with H2O/CH3CN (1/1, v/v) to afford (lR,2R)-2-fluoro-N-(7-(6-(l- hydroxypropyl)-4-methylpyridin-3-yl)-2,6-naphthyridin-3-yl)c yclopropane-l-carboxamide (100.0 mg, 19%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 381.2.

Step 3: Separation of (lR,2R)-2-fluoro-N-(7-(6-((R)-l-hydroxypropyl)-4-methylpyrid in-3-yl)~ 2, 6-naphthyridin-3-yl)cyclopropane-l -carboxamide (Compound 48) and ( lR,2R)-2-fluoro-N- (7-( 6-( (S)-l-hydroxypropyl)-4-methylpyridin-3-yl)-2, 6-naphthyridin-3-yl)cyclopropane-l- carboxamide (Compound 49):

[0321] The product of (lR,2R)-2-fluoro-N-(7-(6-(l-hydroxypropyl)-4-methylpyridin-3 - yl)-2, 6-naphthyri din-3 -yl)cy cl opropane-1 -carboxamide (100.0 mg, 0.26 mmol) was separated by Prep-Chiral-HPLC with the following conditions (Column: CHIRAL ART Amylose-SA, 2x25 cm, 5 pm; Mobile Phase A: MtBE (0.5% 2M NH ₃ -MeOH)-HPLC, Mobile Phase B: MeOH: DCM=1 : 1— HPLC; Flow rate: 20 mL/min; Gradient: 20% B to 20% B in 14 min;

Wave Length: 220/254 nm; RTl(min): 9.04; RT2(min): 12.42) to afford (lR,2R)-2-fluoro-N- (7-(6-(l-hydroxypropyl)-4-methylpyridin-3-yl)-2,6-naphthyrid in-3-yl)cyclopropane-l- carboxamide Isomer 1 (retention time 9.04 min, 42.4 mg, 84%) as a yellow solid and (lR,2R)-2-fluoro-N-(7-(6-(l-hydroxypropyl)-4-methylpyridin-3 -yl)-2, 6-naphthyri din-3- yl)cy cl opropane-1 -carboxamide Isomer 2 (retention time 12.42 min, 26.6 mg, 52%) as a white solid. The absolute stereochemistry of Isomers 1 and 2 was not assigned. The two isomeric structures that could be obtained from chiral separation of the isomeric mixture as described above are shown as Compounds 48 and 49 in Table 1.

[0322] (lR,2R)-2-fluoro-N-(7-(6-(l-hydroxypropyl)-4-methylpyridin-3 -yl)-2,6- naphthyridin-3-yl)cyclopropane-l-carboxamide Isomer 1: RTl(min): 9.04; LCMS (ESI, m/z): [M+H]+ = 381.2. ¹ H NMR (400 MHz, DMSO-d6): δ 11.21 (s, 1H), 9.50 (s, 1H), 9.34 (s, 1H), 8.69 (s, 1H), 8.59 (s, 1H), 8.18 (s, 1H), 7.47 (s, 1H), 5.34 (d, J = 4.8 Hz, 1H), 5.09 - 4.88 (m, 1H), 4.58 - 4.54 (m, 1H), 2.46 (s, 3H), 2.35 - 2.28 (m, 1H), 1.88 - 1.82 (m, 1H), 1.80

- 1.65 (m, 2H), 1.28 - 1.19 (m, 1H), 0.93 - 0.89 (m, 3H).

[0323] (lR,2R)-2-fluoro-N-(7-(6-(l-hydroxypropyl)-4-methylpyridin-3 -yl)-2,6- naphthyridin-3-yl)cyclopropane-l-carboxamide Isomer 2: RT2(min): 12.42; LCMS (ESI, m/z): [M+H]+ = 381.2. ¹ H NMR (400 MHz, DMSO- d6): δ 11.21 (s, 1H), 9.50 (s, 1H), 9.34 (s, 1H), 8.69 (s, 1H), 8.59 (s, 1H), 8.18 (s, 1H), 7.47 (s, 1H), 5.34 (d, J = 5.2 Hz, 1H), 5.08 - 4.90 (m, 1H), 4.58 - 4.54 (m, 1H), 2.46 (s, 3H), 2.33 - 2.29 (m, 1H), 1.87 - 1.82 (m, 1H), 1.80

- 1.65 (m, 2H), 1.26 - 1.21 (m, 1H), 0.92 - 0.89 (m, 3H).

Example 27. Synthesis ofN-(7-(6-(2-hydroxyethyl)-4-methylpyridin-3-yl)-2,6-naphthy ridin- 3-yl)cyclopropanecarboxamide (Compound 50) Step 1: Synthesis of Methyl 2-(4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridin-2-yl)acetate:

[0324] To a solution of methyl 2-(5-bromo-4-methylpyridin-2-yl)acetate (1.0 g, 4.09 mmol) in dioxane (10.0 mL) was added bis(pinacolato)diboron (3.1 g, 12.29 mmol), KOAc (2.4 g, 24.58 mmol) and Pd(dppf)C12 (0.6 g, 0.81 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 2 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (1/1, v/v) to afford methyl 2-(4-methyl-5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)ac etate (500.0 mg, 41%) as a brown solid. LCMS (ESI, m/z): [M+H] ⁺ = 292.2.

Step 2: Synthesis of Methyl 2-(5-(7-(cyclopropanecarboxamido)-2,6-naphthyridin-3-yl)-4- methylpyridin-2-y I) acetate :

[0325] To a mixture of methyl 2-(4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridin-2-yl)acetate (500.0 mg, 1.17 mmol) in dioxane (10.0 mL)H2O (2.0 mL) was added N-(7-chloro-2,6-naphthyridin-3-yl)cyclopropanecarboxamide (354.4 mg, 1.43 mmol), K2CO3 (1186.7 mg, 8.58 mmol) and Pd(dppf)C12 (209.4 mg, 0.28 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 2 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (1/1, v/v) to afford methyl 2-(5-(7-(cyclopropanecarboxamido)-2,6-naphthyridin-3-yl)-4-m ethylpyridin-2-yl)acetate (180.0 mg, 33%) as a yellow oil. LCMS (ESI, m/z): [M+H] ⁺ = 377.2. Step 3: Synthesis ofN-(7-(6-(2-hydroxyethyl)-4-methylpyridin-3-yl)-2,6-naphthy ridin-3- yl)cyclopropanecarboxamide (Compound 50):

[0326] To a solution of methyl 2-(5-(7-(cyclopropanecarboxamido)-2,6-naphthyridin-3- yl)-4-methylpyridin-2-yl)acetate (180.0 mg, 0.47 mmol) in THF (10.0 mL) was added DIBAL-H (2.8 mL, 1 mol/L) at 0 °C under N2. The resulting mixture was stirred at room temperature for 1 h under N2. After the reaction was completed, the reaction mixture was quenched with water at 0 °C. The reaction mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: (Column: XBridge Prep OBD C18 Column, 30x150 mm, 5 pm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 20% B to 25% B in 8 min; Wave Length: 254 nm) to afford N-(7-(6-(2-hydroxyethyl)-4-methylpyridin-3-yl)-2,6-naphthyri din-3- yl)cyclopropanecarboxamide (Compound 50, 15.0 mg, 6%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 349.1. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.18 (s, 1H), 9.47 (s, 1H), 9.33 (s, 1H), 8.67 (s, 1H), 8.58 (s, 1H), 8.15 (s, 1H), 7.28 (s, 1H), 4.71 - 4.68 (m, 1H), 3.83 - 3.78 (m, 2H), 2.94 - 2.90 (m, 2H), 2.42 (s, 3H), 2.14 - 2.07 (m, 1H), 0.92 - 0.84 (m, 4H).

Example 28. Synthesis of (lS,2S)-2-fluoro-N-(7-{6-[(lR)-l-hydroxybutyl]-4-methylpyrid in- 3-yl}-2,6-naphthyridin-3-yl)cyclopropane-l-carboxamide (Compound 51) and (lS,2S)-2- fluoro-N-(7-{6-[(lS)-l-hydroxybutyl]-4-methylpyridin-3-yl}-2 ,6-naphthyridin-3- yl) cyclopropane-1 -carboxamide (Compound 52)

Step 1: Synthesis of (lS,2S)-N-[7-(6-butanoyl-4-methylpyridin-3-yl)-2,6-naphthyri din-3-yl]~ 2-fluorocyclopropane-l -carboxamide :

[0327] To a mixture of l-[5-(7-amino-2,6-naphthyridin-3-yl)-4-methylpyridin-2- yl]butan-l-one (480.0 mg, 1.56 mmol) and (lS,2S)-2-fluorocyclopropane-l -carboxylic acid (163.0 mg, 1.56 mmol) in pyridine (10.0 mL) was added EDCI (600.6 mg, 3.13 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography with CH3CN/H2O (60/40, v/v) to afford (lS,2S)-N-[7-(6-butanoyl-4-methylpyridin-3-yl)-2,6-naphthyri din-3- yl]-2-fluorocyclopropane-l -carboxamide (300.0 mg, 48%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 393.2.

Step 2: Synthesis of (lS,2S)-2-fluoro-N-{7-[6-(l-hydroxybutyl)-4-methylpyridin-3- yl]-2,6- naphthyridin-3-yl}cyclopropane-l-carboxamide:

[0328] To a stirred mixture of (lS,2S)-N-[7-(6-butanoyl-4-methylpyridin-3-yl)-2,6- naphthyri din-3 -yl]-2-fluorocy cl opropane-1 -carboxamide (270.0 mg, 0.68 mmol) in THF (10.0 mL) and MeOH (1.0 mL) was added NaBH ₄ (130.1 mg, 3.44 mmol) at 0 °C under N2. The resulting mixture was stirred at room temperature for 4 h. After the reaction was completed, the reaction mixture was quenched with NH4CI (aq.) at 0 °C. The resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /CH3OH (10/1, v/v) to afford (lS,2S)-2-fluoro-N-{7-[6-(l- hydroxybutyl)-4-methylpyridin-3-yl]-2,6-naphthyridin-3-yl}cy clopropane-l-carboxamide (120.0 mg, 44%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 395.2.

Step 3: Separation of (lS,2S)-2-fluoro-N-(7-{6-[(lR)-l-hydroxybutyl]-4-methylpyrid in-3-yl}- 2,6-naphthyridin-3-yl)cyclopropane-l-carboxamide (Compound 51) and (lS,2S)-2-fluoro-N- (7-{6-[(lS)-l-hydroxybutyl]-4-methylpyridin-3-yl}-2,6-naphth yridin-3-yl)cyclopropane-l- carboxamide (Compound 52): [0329] The racemic mixture of (lS,2S)-2-fluoro-N-{7-[6-(l-hydroxybutyl)-4- methylpyri din-3 -yl]-2,6-naphthyri din-3 -yl)cy cl opropane-1 -carboxamide (100.0 mg, 0.25 mmol) was separated by Prep-Chiral-HPLC with the following conditions ( Column: CHIRAL ART Amylose-SA, 2x25 cm, 5 pm; Mobile Phase A: Hex (0.5% 2 M NH ₃ -MeOH)- -HPLC, Mobile Phase B: MeOH: DCM=1 : 1-HPLC; Flow rate: 20 mL/min; Gradient: 50% B to 50% B in 11.5 min; Wave Length: 220/254 nm; RT1 (min): 7.40; RT2 (min): 10.44) to afford (lS,2S)-2-fluoro-N-(7-{6-[l-hydroxybutyl]-4-methylpyridin-3- yl}-2,6-naphthyridin-3- yl)cyclopropane-l -carboxamide Isomer 1 (retention time 7.40 min, 29.9 mg, 59%) as a white solid and (lS,2S)-2-fluoro-N-(7-{6-[l-hydroxybutyl]-4-methylpyridin-3- yl}-2,6- naphthyri din-3 -yl)cy cl opropane-1 -carboxamide (retention time 10.44 min, 25.4 mg, 50%) as a white solid. The absolute stereochemistry of Isomers 1 and 2 was not assigned. The two isomeric structures that could be obtained from chiral separation of the isomeric mixture as described above are shown as Compounds 51 and 52 in Table 1.

[0330] (lS,2S)-2-fluoro-N-(7-{6-[l-hydroxybutyl]-4-methylpyridin-3- yl}-2,6- naphthyridin-3-yl)cyclopropane-l-carboxamide Isomer 1: RT1 (min): 7.40; LCMS (ESI, m/z): [M+H]+ = 395.0. ¹ H NMR (400 MHz, DMSO-d6): δ 11.22 (s, 1H), 9.50 (s, 1H), 9.34 (s, 1H), 8.69 (s, 1H), 8.58 (s, 1H), 8.18 (s, 1H), 7.47 (s, 1H), 5.34 (d, J = 5.2 Hz, 1H), 5.08 - 4.89 (m, 1H), 4.64 - 4.60 (m, 1H), 2.45 (s, 3H), 2.33 - 2.29 (m, 1H), 1.78 - 1.63 (m, 3H), 1.42

- 1.37 (m, 2H), 1.26 - 1.21 (m, 1H), 0.93 - 0.89 (m, 3H).

[0331] (lS,2S)-2-fluoro-N-(7-{6-[l-hydroxybutyl]-4-methylpyridin-3- yl}-2,6- naphthyridin-3-yl)cyclopropane-l-carboxamide Isomer 2: RT2 (min): 10.44; LCMS (ESI, m/z): [M+H]+ = 395.0. ¹ H NMR (400 MHz, DMSO-d6): δ 11.22 (s, 1H), 9.50 (s, 1H), 9.34 (s, 1H), 8.69 (s, 1H), 8.58 (s, 1H), 8.18 (s, 1H), 7.47 (s, 1H), 5.34 (d, J = 2.8 Hz, 1H), 5.08 - 4.88 (m, 1H), 4.65 - 4.60 (m, 1H), 2.46 (s, 3H), 2.35 - 2.28 (m, 1H), 1.78 - 1.64 (m, 3H), 1.45

- 1.35 (m, 2H), 1.27 - 1.19 (m, 1H), 0.94 - 0.89 (m, 3H).

Example 29. Synthesis ofN-{7-[6-(l-hydroxy-2-methylpropan-2-yl)-4-methylpyridin-3- yl]- 2,6-naphthyridin-3-yl}cyclopropanecarboxamide (Compound 53)

Step 1: Synthesis of Methyl 2-(5-bromo-4-methylpyridin-2-yl)acetate: [0332] The solution of (5-bromo-4-methylpyridin-2-yl)acetic acid (16.0 g, 69.55 mmol) in HCl/MeOH (400.0 mL, 4.0 mol/L) was stirred at 80 °C for 5 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (1/1, v/v) to afford methyl 2-(5-bromo-4-methylpyridin-2-yl)acetate (8.0 g, 47%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 244.0.

Step 2: Synthesis of Methyl 2-(5-bromo-4-methylpyridin-2-yl)-2-methylpropanoate:

[0333] To a solution of methyl 2-(5-bromo-4-methylpyridin-2-yl)acetate (3.0 g, 12.29 mmol) in THF (50.0 mL) was added LiHMDS (30.8 mL, 1.0 mol/L) at -78 °C under N2. The resulting mixture was stirred at -78 °C for 1 h under N2. Then a solution of methyl iodide (5.2 g, 36.87 mmol) in THF (10.0 mL) was added dropwise to the above mixture at -78 °C. The mixture was stirred at room temperature for additional 2 h. After the reaction was completed, the reaction mixture was quenched with NH4CI (sat.) solution and then extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (1/1, v/v) to afford methyl 2-(5-bromo-4-methylpyridin-2-yl)-2-methylpropanoate (2.5 g, 74%) as a yellow oil. LCMS (ESI, m/z): [M+H] ⁺ = 272.0.

Step 3: Synthesis of 6-(l-methoxy-2-methyl-l-oxopropan-2-yl)-4-methylpyridin-3-yl boronic acid:

[0334] To a solution of methyl 2-(5-bromo-4-methylpyridin-2-yl)-2-methylpropanoate (500.0 mg, 1.84 mmol) in dioxane (10.0 mL) was added bis(pinacolato)diboron (1.4 g, 5.51 mmol), KOAc (540.9 mg, 5.51 mmol) and Pd(dppf)C12 (134.4 mg, 0.18 mmol) at room temperature under N2. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (1/2, v/v) to afford 6-(l-methoxy-2-m ethyl- l-oxopropan-2-yl)-4-methylpyri din-3 -ylboronic acid (200.0 mg, 45%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 238.1.

Step 4: Synthesis of Methyl 2-[5-(7-cyclopropaneamido-2,6-naphthyridin-3-yl)-4- methylpyridin-2-yl] -2-methylpropanoate :

[0335] To a mixture of 6-(l-methoxy-2-methyl-l-oxopropan-2-yl)-4-methylpyridin-3- ylboronic acid (200.0 mg, 0.84 mmol) in dioxane (10.0 mL/H2O (2.0 mL) was added N-(7- chloro-2,6-naphthyridin-3-yl)cyclopropanecarboxamide (208.9 mg, 0.84 mmol), K2CO3 (349.8 mg, 2.53 mmol) and Pd(dppf)C12 (61.7 mg, 0.08 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 2 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (1/1, v/v) to afford methyl 2-[5-(7-cyclopropaneamido-2,6-naphthyridin-3-yl)-4-methylpyr idin-2-yl]-2- methylpropanoate (110.0 mg, 32%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 405.2.

Step 3: Synthesis ofN-{7-[6-(l-hydroxy-2-methylpropan-2-yl)-4-methylpyridin-3- yl]-2,6- naphthyridin-3-yl}cyclopropanecarboxamide (Compound 53):

[0336] To a solution of methyl 2-[5-(7-cyclopropaneamido-2,6-naphthyridin-3-yl)-4- methylpyridin-2-yl]-2-methylpropanoate (100.0 mg, 0.25 mmol) in THF (20.0 mL) was added DIBAL-H (1.2 mL, 1.0 mol/L) at 0 °C under N2. The resulting mixture was stirred at room temperature for 2 h under N2. After the reaction was completed, the reaction mixture was quenched with water at 0 °C. The reaction mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: (Column: XBridge Prep OBD C18 Column, 30x150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 23% B to 33% B in 8 min; Wave Length: 254 nm) to afford N-{7-[6-(l-hydroxy-2-methylpropan-2-yl)-4-methylpyridin-3-yl ]-2,6- naphthyridin-3-yl} cyclopropanecarboxamide (Compound 53, 10.5 mg, 11%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 377.2. ¹ H NMR (400 MHz, DMSO-d ₆ ): 5 11.16 (s, 1H), 9.47 (s, 1H), 9.32 (s, 1H), 8.66 - 8.61 (m, 2H), 8.14 (s, 1H), 7.39 (s, 1H), 4.71 - 4.67 (m, 1H), 3.63 - 3.60 (m, 2H), 2.43 (s, 3H), 2.14 - 2.08 (m, 1H), 1.32 (s, 6H), 0.92 - 0.81 (m, 4H).

Example 30. Synthesis of (R)-N-(7-(6-(l-hydroxypropan-2-yl)-4-methylpyridin-3-yl)-2,6 - naphthyridin-3-yl)cyclopropanecarboxamide (Compound 54) and (S)-N-(7-(6-(l- hydroxypropan-2-yl)-4-methylpyridin-3-yl)-2,6-naphthyridin-3 - yl)cyclopropanecarboxamide (Compound 55)

Step 1: Synthesis of Methyl 2-(5-bromo-4-methylpyridin-2-yl)propanoate:

[0337] To a solution of methyl 2-(5-bromo-4-methylpyridin-2-yl)acetate (3.0 g, 12.29 mmol) in THF (50.0 mL) was added LiHMDS (30.0 mL, 1 mol/L) at -78 °C under N2. The resulting mixture was stirred at -78 °C for 1 h under N2. Then a solution of methyl iodide (2.6 g, 18.43 mmol) in THF (10.0 mL) was added dropwise to the mixture at -78 °C. The mixture was stirred at room temperature for additional 2 h. After the reaction was completed, the reaction mixture was quenched with NH4CI (sat.) solution and then extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (1/1, v/v) to afford methyl 2-(5-bromo-4-methylpyridin-2-yl)propanoate (950.0 mg, 29%) as a yellow oil. LCMS (ESI, m/z): [M+H] ⁺ = 258.0.

Step 2: Synthesis of (6-(l-methoxy-l-oxopropan-2-yl)-4-methylpyridin-3-yl)boronic acid: ( pp )

[0338] To a solution of methyl 2-(5-bromo-4-methylpyridin-2-yl)propanoate (950.0 mg, 3.68 mmol) in dioxane (20.0 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2- dioxaborolane) (2.8 g, 11.04 mmol), KOAc (2.1 g, 22.08 mmol) and Pd(dppf)C12 (0.2 g, 0.36 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 2 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (1/1, v/v) to afford (6-(l-methoxy-l-oxopropan-2-yl)-4-methylpyridin-3-yl)boronic acid (750.0 mg, 91%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 224.1.

Step 3: Synthesis of Methyl 2-(5-(7-(cyclopropanecarboxamido)-2,6-naphthyridin-3-yl)-4- methylpyridin-2-yl )propanoate :

[0339] To a mixture of (6-(l-methoxy-l-oxopropan-2-yl)-4-methylpyridin-3-yl)boronic acid (750.0 mg, 3.36 mmol) in dioxane (10.0 mL)H2O (2.0 mL) was added N-(7-chloro-2,6- naphthyridin-3-yl)cyclopropanecarboxamide (832.8 mg, 3.36 mmol), K2CO3 (2.7 g, 20.17 mmol) and Pd(dppf)C12 (0.2 g, 0.33 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 2 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (1/1, v/v) to afford methyl 2-(5-(7- (cyclopropanecarboxamido)-2,6-naphthyridin-3-yl)-4-methylpyr idin-2-yl)propanoate (390.0 mg, 29%) as a yellow oil. LCMS (ESI, m/z): [M+H] ⁺ = 391.2

Step 4: Synthesis ofN-(7-(6-(l-hydroxypropan-2-yl)-4-methylpyridin-3-yl)-2,6-n aphthyridin- 3-yl)cyclopropanecarboxamide :

[0340] To a solution of methyl 2-(5-(7-(cyclopropanecarboxamido)-2,6-naphthyridin-3- yl)-4-methylpyridin-2-yl)propanoate (180.0 mg, 0.47 mmol) in THF (10.0 mL) was added DIBAL-H (2.8 mL, 1 mol/L) at 0 °C under N2. The resulting mixture was stirred at room temperature for 1 h under N2. After the reaction was completed, the reaction mixture was quenched with water at 0 °C. The reaction mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (10/1, v/v) to afford N-(7- (6-(l-hydroxypropan-2-yl)-4-methylpyridin-3-yl)-2,6-naphthyr idin-3- yl)cyclopropanecarboxamide (42.0 mg, 22%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =

363.2.

Step 5: Separation of (R)-N-(7-(6-(l-hydroxypropan-2-yl)-4-methylpyridin-3-yl)-2,6 - naphthyridin-3-yl)cyclopropanecarboxamide (Compound 54) and (S)-N-(7-(6-(l- hydroxypropan-2-yl)-4-methylpyridin-3-yl)-2,6-naphthyridin-3 -yl)cyclopropanecarboxamide (Compound 55):

[0341] The racemic product of N-(7-(6-(l-hydroxypropan-2-yl)-4-methylpyridin-3-yl)-

2,6-naphthyridin-3-yl)cyclopropanecarboxamide (42.0 mg, 0.11 mmol) was separated by Prep-Chiral-HPLC with the following conditions: (Column: CHIRAL ART Amylose-SA, 2x25 cm, 5 pm; Mobile Phase A: Hex(0.5% 2M NHs-MeOH)— HPLC, Mobile Phase B: MeOH: DCM=1 : 1— HPLC; Flow rate: 20 mL/min; Gradient: 30% B to 30% B in 19 min;

Wave Length: 220/254 nm; RTl(min): 14.18; RT2(min): 17.07) to afford N-(7-(6-(l- hydroxypropan-2-yl)-4-methylpyridin-3-yl)-2,6-naphthyridin-3 -yl)cyclopropanecarboxamide

Enantiomer 1 (retention time 14.18 min, 14.5 mg, 69%) as a white solid and N-(7-(6-(l- hydroxypropan-2-yl)-4-methylpyridin-3-yl)-2,6-naphthyridin-3 -yl)cyclopropanecarboxamide

Enantiomer 2 (retention time 17.07 min, 13.2 mg, 62%) as a white solid. The absolute stereochemistry of Enantiomers 1 and 2 was not assigned. The two enantiomeric structures that could be obtained from chiral separation of the enantiomeric mixture as described above are shown as Compounds 54 and 55 in Table 1.

[0342] N-(7-(6-(l-hydroxypropan-2-yl)-4-methylpyridin-3-yl)-2,6-nap hthyridin-3- yl)cyclopropanecarboxamide Enantiomer 1: RTl(min): 14.18; LCMS (ESI, m/z): [M+H]+ = 363.1. ¹ H NMR (400 MHz, DMSO-d6): δ 11.16 (s, 1H), 9.46 (s, 1H), 9.32 (s, 1H), 8.66 (s, 1H), 8.59 (s, 1H), 8.14 (s, 1H), 7.25 (s, 1H), 4.67 - 4.64 (m, 1H), 3.72 - 3.58 (m, 2H), 3.05 - 2.96 (m, 1H), 2.42 (s, 3H), 2.14 - 2.08 (m, 1H), 1.25 (d, J = 7.2 Hz, 3H), 0.90 - 0.86 (m, 4H).

[0343] N-(7-(6-(l-hydroxypropan-2-yl)-4-methylpyridin-3-yl)-2,6-nap hthyridin-3- yl)cyclopropanecarboxamide Enantiomer 2: RT2(min): 17.07; LCMS (ESI, m/z): [M+H]+ = 363.1. ¹ H NMR (400 MHz, DMSO-d6): δ 11.16 (s, 1H), 9.47 (s, 1H), 9.32 (s, 1H), 8.67 (s, 1H), 8.59 (s, 1H), 8.15 (s, 1H), 7.26 (s, 1H), 4.67 - 4.64 (m, 1H), 3.77 - 3.70 (m, 1H), 3.63 - 3.56 (m, 1H), 3.04 - 2.99 (m, 1H), 2.42 (s, 3H), 2.11 - 2.01 (m, 1H), 1.26 (d, J = 6.8 Hz, 3H), 0.90 - 0.87 (m, 4H).

Example 31. Synthesis of (S)-N-(7-(6-(l-hydroxypropyl)-4-methylpyridin-3-yl)-2,6- naphthyridin-3-yl)oxetane-3-carboxamide (Compound 56) and (R)-N-(7-(6-(l- hydroxypropyl)-4-methylpyridin-3-yl)-2,6-naphthyridin-3-yl)o xetane-3-carboxamide (Compound 57)

Step 1: Synthesis ofN-(7-(4-methyl-6-propionylpyridin-3-yl)-2,6-naphthyridin-3 -yl)oxetane- 3-carboxamide:

[0344] To a solution of l-(5-(7-amino-2,6-naphthyridin-3-yl)-4-methylpyridin-2- yl)propan-l-one (480.0 mg, 1.64 mmol) in pyridine (6.0 mL) was added oxetane-3- carboxylic acid (335.2 mg, 3.28 mmol) and EDCI (629.5 mg, 3.28 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (10/1, v/v) to afford N-(7- (4-methyl-6-propionylpyridin-3-yl)-2,6-naphthyridin-3-yl)oxe tane-3-carboxamide (600.0 mg, 97%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 377.2. Step 2: Synthesis ofN-(7-(6-(l-hydroxypropyl)-4-methylpyridin-3-yl)-2,6-naphth yridin-3- yl)oxetane-3-carboxamide:

[0345] To a stirred mixture of N-(7-(4-methyl-6-propionylpyridin-3-yl)-2,6-naphthyridin- 3 -yl)oxetane-3 -carboxamide (250.0 mg, 0.66 mmol) in CH3OH (5.0 mL) and THF (0.5 mL) were added NaBH ₄ (125.6 mg, 3.32 mmol) at 0 °C under N2. The resulting mixture was stirred at room temperature for 4 h. After the reaction was completed, the resulting mixture was quenched with water at 0 °C and then extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (10/1, v/v) to afford N-(7-(6-(l-hydroxypropyl)-4- methylpyridin-3-yl)-2,6-naphthyridin-3-yl)oxetane-3-carboxam ide (70.0 mg, 27%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 379.2.

Step 3: Separation of (S)-N-(7-(6-(l-hydroxypropyl)-4-methylpyridin-3-yl)-2,6-naph thyridin-

3-yl)oxetane-3-carboxamide (Compound 56) and (R)-N-(7-(6-(l -hydroxypropyl)-4- methylpyridin-3-yl)-2, 6-naphthyridin-3-yl)oxetane-3-carboxamide (Compound 57):

[0346] The racemic mixture of N-(7-(6-(l-hydroxypropyl)-4-methylpyridin-3-yl)-2,6- naphthyri din-3 -yl)oxetane-3 -carboxamide (70.0 mg, 0.18 mmol) was separated by Prep- Chiral-HPLC with the following conditions (Column: CHIRALPAK IG, 2x25 cm, 5 μm; Mobile Phase A: MeOH (0.5% 2M NH ₃ -MeOH)-HPLC, Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 40% B to 40% B in 15 min; Wave Length: 220/254 nm; RTl(min): 8.02; RT2(min): 10.78) to afford N-(7-(6-(l-hydroxypropyl)-4-methylpyridin-3-yl)-2,6- naphthyri din-3 -yl)oxetane-3 -carboxamide Enantiomer 1 (retention time 8.02 min, 25.0 mg, 71%) as a white solid and N-(7-(6-(l-hydroxypropyl)-4-methylpyridin-3-yl)-2,6- naphthyri din-3 -yl)oxetane-3 -carboxamide Enantiomer 2 (retention time 10.78 min, 21.0 mg, 60%) as a white solid. The absolute stereochemistry of Enantiomers 1 and 2 was not assigned. The two enantiomeric structures that could be obtained from chiral separation of the enantiomeric mixture as described above are shown as Compounds 56 and 57 in Table 1.

[0347] N-(7-(6-(l-hydroxypropyl)-4-methylpyridin-3-yl)-2,6-naphthyr idin-3- yl)oxetane-3-carboxamide Enantiomer 1: RTl(min): 8.02; LCMS (ESI, m/z): [M+H]+ = 379.0 ¹ H NMR (400 MHz, DMSO-d6): δ 10.90 (s, 1H), 9.54 (s, 1H), 9.33 (s, 1H), 8.76 (s, 1H), 8.59 (s, 1H), 8.18 (s, 1H), 7.47 (s, 1H), 5.33 (d, J = 4.8 Hz, 1H), 4.76 - 4.72 (m, 4H), 4.58 - 4.55 (m, 1H), 4.19 - 4.15 (m, 1H), 2.45 (s, 3H), 1.86 - 1.83 (m, 1H), 1.72 - 1.67 (m, 1H), 0.92 - 0.88 (m, 3H).

[0348] N-(7-(6-(l-hydroxypropyl)-4-methylpyridin-3-yl)-2,6-naphthyr idin-3- yl)oxetane-3-carboxamide Enantiomer 2: RT2(min): 10.78; LCMS (ESI, m/z): [M+H]+ = 379.0. ¹ H NMR (400 MHz, DMSO- d6): δ 10.91 (s, 1H), 9.54 (s, 1H), 9.33 (s, 1H), 8.76 (s, 1H), 8.59 (s, 1H), 8.18 (s, 1H), 7.47 (s, 1H), 5.33 (d, J = 4.8 Hz, 1H), 4.77 - 4.72 (m, 4H), 4.58 - 4.53 (m, 1H), 4.21 - 4.14 (m, 1H), 2.45 (s, 3H), 1.88 - 1.81 (m, 1H), 1.79 - 1.72 (m, 1H), 0.92 - 0.89 (m, 3H).

Example 32. Synthesis ofN-(7-{6-[(lR)-l-hydroxypropyl]-4-methylpyridin-3-yl}-2,6- naphthyridin-3-yl)cyclobutanecarboxamide (Compound 58) and N-(7-{6-[(lS)-l- hydroxypropyl]-4-methylpyridin-3-yl}-2,6-naphthyridin-3-yl)c yclobutanecarboxamide (Compound 59)

Step 1: Synthesis of N-[7-(4-methyl-6-propanoylpyridin-3-yl)-2,6-naphthyridin-3- yl (cyclobutanecarboxamide :

[0349] To a solution of l-[5-(7-amino-2,6-naphthyridin-3-yl)-4-methylpyridin-2- yl]propan-l-one (500.0 mg, crude) in THF (10.0 mL) was added cyclobutanecarbonyl chloride (202.8 mg, 1.71 mmol) and TEA (346.2 mg, 3.42 mmol) at room temperature. The mixture was stirred at room temperature for 3 h. After the reaction was completed, the mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated in vacuo to afford N-[7-(4-methyl-6-propanoylpyridin-3-yl)-2,6-naphthyridin-3- yl]cyclobutanecarboxamide (850.0 mg, crude) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 375.2.

Step 2: Synthesis of N-{7-[6-(l-hydroxypropyl)-4-methylpyridin-3-yl]-2,6-naphthyr idin-3- yl}cyclobutanecarboxamide:

[0350] To a solution of N-[7-(4-methyl-6-propanoylpyridin-3-yl)-2,6-naphthyridin-3- yl]cyclobutanecarboxamide (400.0 mg, crude) in MeOH (4.0 mL)/THF (20.0 mL) was added NaBH ₄ (404.1 mg, 10.68 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction mixture was quenched with water at 0 °C and concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (10/1, v/v) to afford N-{7-[6-(l- hy droxypropyl)-4-methylpyri din-3 -yl]-2, 6-naphthyri din-3 -yl} cyclobutanecarboxamide (110.0 mg, 27%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 377.2.

Step 3: Separation ofN-(7-{6-[(lR)-l-hydroxypropyl]-4-methylpyridin-3-yl}-2,6- naphthyridin-3-yl)cyclobutanecarboxamide (Compound 58) andN-(7-{6-[(lS)-l- hydroxypropyl]-4-methylpyridin-3-yl}-2,6-naphthyridin-3-yl)c yclobutanecarboxamide (Compound 59):

[0351] The racemic product ofN-{7-[6-(l-hydroxypropyl)-4-methylpyridin-3-yl]-2,6- naphthyridin-3-yl} cyclobutanecarboxamide (130.0 mg, 0.35 mmol) was separated by Prep- Chiral-HPLC with the following conditions: (Column: CHIRALPAK IG, 2x25 cm, 5 pm; Mobile Phase A: MeOH (0.5% 2M NH ₃ -MeOH)-HPLC, Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 40% B to 40% B in 20 min; Wave Length: 220/254 nm; RTl(min): 10.65; RT2(min): 13.81) to afford N-(7-{6-[l-hydroxypropyl]-4-methylpyridin-3-yl}-2,6- naphthyridin-3 -yl)cy cl obutanecarb oxami de Enantiomer 1 (retention time 10.65 min, 43.5 mg, 79%) as a white solid and N-(7-{6-[l-hydroxypropyl]-4-methylpyridin-3-yl}-2,6- naphthyri din-3 -yl)cy cl obutanecarb oxami de Enantiomer 2 (retention time 13.81 min, 45.4 mg, 82%) as a white solid. The absolute stereochemistry of Enantiomers 1 and 2 was not assigned. The two enantiomeric structures that could be obtained from chiral separation of the enantiomeric mixture as described above are shown as Compounds 58 and 59 in Table 1.

[0352] N-(7-{6-[l-hydroxypropyl]-4-methylpyridin-3-yl}-2,6-naphthyr idin-3- yl)cyclobutanecarboxamide Enantiomer 1: RTl(min): 10.65 ; LCMS (ESI, m/z): [M+H]+ = 377.2. ¹ H NMR (400 MHz, DMSO-d6): δ 10.72 (s, 1H), 9.50 (s, 1H), 9.31 (s, 1H), 8.73 (s, 1H), 8.58 (s, 1H), 8.17 (s, 1H), 7.46 (s, 1H), 5.37 (d, J = 4.8 Hz, 1H), 4.58 - 4.53 (m, 1H), 3.51 - 3.42 (m, 1H), 2.45 (s, 3H), 2.33 - 2.24 (m, 2H), 2.19 - 2.11 (m, 2H), 2.03 - 1.91 (m, 1H), 1.89 - 1.79 (m, 2H), 1.74 - 1.63 (m, 1H), 0.92 - 0.88 (m, 3H).

[0353] N-(7-{6-[l-hydroxypropyl]-4-methylpyridin-3-yl}-2,6-naphthyr idin-3- yl)cyclobutanecarboxamide Enantiomer 2: RT2(min): 13.81; LCMS (ESI, m/z): [M+H]+ =

377.1. ¹ H NMR (400 MHz, DMSO-d6): δ 10.72 (s, 1H), 9.50 (s, 1H), 9.31 (s, 1H), 8.73 (s, 1H), 8.58 (s, 1H), 8.17 (s, 1H), 7.47 (s, 1H), 5.37 (d, J = 5.2 Hz, 1H), 4.58 - 4.53 (m, 1H), 3.51 - 3.42 (m, 1H), 2.45 (s, 3H), 2.33 - 2.24 (m, 2H), 2.19 - 2.11 (m, 2H), 2.03 - 1.91 (m, 1H), 1.89 - 1.81 (m, 2H), 1.74 - 1.63 (m, 1H), 0.92 - 0.88 (m, 3H).

Example 33. Synthesis ofN-(7-{6-[(lR)-l-hydroxypropyl]-4-methylpyridin-3-yl}-2,6- naphthyridin-3-yl)-2-methoxyacetamide (Compound 60) and N-(7-{6-[(lS)-l- hydroxypropyl]-4-methylpyridin-3-yl}-2,6-naphthyridin-3-yl)- 2-methoxyacetamide (Compound 61)

Step 1: Synthesis of tert-butyl N-[7-(4-methyl-6-propanoylpyridin-3-yl)-2,6-naphthyridin-3- yl] carbamate:

[0354] To a stirred mixture of tert-butyl N-(7-chloro-2,6-naphthyridin-3-yl)carbamate (2.0 g, 7.15 mmol) and l-[4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)p yridin- 2-yl]propan-l-one (4.9 g, 17.87 mmol) in 1,4-dioxane (20.0 mL) and H2O (4.0 mL) were added K2CO3 (2.9 g, 21.45 mmol) and Pd(dppf)C12 (1.1 g, 1.43 mmol) at room temperature. The resulting mixture was stirred at 85 °C for 2 h under N2. After the reaction was completed, the mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /CH3OH (10/1, v/v) to afford tert-butyl N-[7-(4-methyl-6- propanoylpyridin-3-yl)-2,6-naphthyridin-3-yl]carbamate (1.5 g, 53%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 393.2.

Step 2: Synthesis of l-[5-(7-amino-2,6-naphthyridin-3-yl)-4-methylpyridin-2-yl]pr opan-l- one:

[0355] A mixture of tert-butyl N-[7-(4-methyl-6-propanoylpyridin-3-yl)-2,6- naphthyridin-3-yl]carbamate (1.4 g, 3.56 mmol) in DCM (10.0 mL) and TFA (5.0 mL) was stirred at room temperature for 1 h. After the reaction was completed, the resulting mixture was neutralized to pH=8 with saturated NaHCO3 (aq). The resulting mixture was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography with CH3CN/H2O (50/50, v/v) to afford l-[5-(7-amino-2,6-naphthyridin-3-yl)-4-methylpyridin-2-yl]pr opan-l-one (1.0 g, 67%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 293.2.

Step 3: Synthesis of 2-methoxy-N-[7-(4-methyl-6-propanoylpyridin-3-yl)-2,6-naphth yridin-3- ylfacetamide:

[0356] To a stirred mixture of l-[5-(7-amino-2,6-naphthyridin-3-yl)-4-methylpyridin-2- yl]propan-l-one (400.0 mg, 1.368 mmol) in pyridine (3.0 mL) was added methoxyacetyl chloride (742.4 mg, 6.84 mmol) and DMAP (33.4 mg, 0.27 mmol) at room temperature. The resulting mixture was stirred at 70 °C for 16 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /CH3OH (10/1, v/v) to afford 2-methoxy-N-[7-(4- methyl-6-propanoylpyridin-3-yl)-2,6-naphthyridin-3-yl]acetam ide (400.0 mg, 80%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 365.2.

Step 4: Synthesis ofN-{7-[6-(l-hydroxypropyl)-4-methylpyridin-3-yl]-2,6-naphth yridin-3-yl}~ 2-methoxyacetamide:

[0357] To a stirred mixture of 2-methoxy-N-[7-(4-methyl-6-propanoylpyridin-3-yl)-2,6- naphthyridin-3-yl]acetamide (300.0 mg, 0.82 mmol) in THF (5.0 mL) and MeOH (0.5 mL) was added NaBH ₄ (155.7 mg, 4.10 mmol) at 0 °C under N2. The resulting mixture was stirred at room temperature for 4 h. After the reaction was completed, the reaction mixture was quenched with H2O and then extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /CH3OH (10/1, v/v) to afford N-{7-[6-(l-hydroxypropyl)-4- methylpyri din-3 -yl]-2, 6-naphthyri din-3 -yl}-2-methoxyacetamide (150.0 mg, 49%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 367.2.

Step 5: Separation ofN-(7-{6-[(lR)-l-hydroxypropyl]-4-methylpyridin-3-yl}-2,6- naphthyridin-3-yl)-2-methoxyacetamide (Compound 60) andN-(7-{6-[(lS)-l- hydroxypropyl]-4-methylpyridin-3-yl}-2,6-naphthyridin-3-yl)- 2-methoxyacetamide (Compound 61):

[0358] The racemic mixture ofN-{7-[6-(l-hydroxypropyl)-4-methylpyridin-3-yl]-2,6- naphthyridin-3-yl}-2-methoxyacetamide (80.0 mg, 0.22 mmol) was separated by Prep- Chiral-HPLC with the following conditions (Column: CHIRAL ART Amylose-SA, 2x25 cm, 5 pm; Mobile Phase A: MtBE (0.1% FA) -HPLC, Mobile Phase B: MeOH: DCM=1 : 1- HPLC; Flow rate: 20 mL/min; Gradient: 20% B to 20% B in 15 min; Wave Length: 254 nm; RT1 (min): 9.72; RT2 (min): 13.61) to afford N-(7-{6-[l-hydroxypropyl]-4-methylpyridin-3- yl}-2,6-naphthyridin-3-yl)-2-methoxyacetamide Enantiomer 1 (retention time 9.72min, 24.1 mg, 60%) as a white solid and N-(7-{6-[l-hydroxypropyl]-4-methylpyridin-3-yl}-2,6- naphthyridin-3-yl)-2-methoxyacetamide Enantiomer 2 (retention time 13.61 min, 29.5 mg, 73%) as a white solid. The absolute stereochemistry of Enantiomers 1 and 2 was not assigned. The two enantiomeric structures that could be obtained from chiral separation of the enantiomeric mixture as described above are shown as Compounds 60 and 61 in Table 1.

[0359] N-(7-{6-[l-hydroxypropyl]-4-methylpyridin-3-yl}-2,6-naphthyr idin-3-yl)-2- methoxyacetamide Enantiomer 1: RT1 (min): 9.72; LCMS (ESI, m/z): [M+H]+ = 367.1. ¹ H NMR (400 MHz, DMSO-d6): δ 10.40 (s, 1H), 9.55 (s, 1H), 9.34 (s, 1H), 8.69 (s, 1H), 8.59 (s, 1H), 8.19 (s, 1H), 7.47 (s, 1H), 5.34 (d, J = 4.4 Hz, 1H), 4.58 - 4.54 (m, 1H), 4.17 (s, 2H), 3.43 (s, 3H), 2.46 (s, 3H), 1.90 - 1.80 (m, 1H), 1.74 - 1.63 (m, 1H), 0.93 - 0.88 (m, 3H).

[0360] N-(7-{6-[l-hydroxypropyl]-4-methylpyridin-3-yl}-2,6-naphthyr idin-3-yl)-2- methoxyacetamide Enantiomer 2: RT2 (min): 13.61; LCMS (ESI, m/z): [M+H]+ = 367.1. ¹ H NMR (400 MHz, DMSO-d6): δ 10.40 (s, 1H), 9.55 (s, 1H), 9.34 (s, 1H), 8.69 (s, 1H), 8.59 (s, 1H), 8.19 (s, 1H), 7.47 (s, 1H), 5.34 (d, J = 5.2 Hz, 1H), 4.58 - 4.54 (m, 1H), 4.17 (s, 2H), 3.43 (s, 3H), 2.46 (s, 3H), 1.90 - 1.80 (m, 1H), 1.74 - 1.63 (m, 1H), 0.93 - 0.88 (m, 3H).

Example 34. Synthesis of (2R)-N-(7-{6-[(lR)-l-hydroxypropyl]-4-methylpyridin-3-yl}-2, 6- naphthyridin-3-yl)oxetane-2-carboxamide (Compound 62) and (2R)-N-(7-{6-[(lS)-l- hydroxypropyl]-4-methylpyridin-3-yl}-2,6-naphthyridin-3-yl)o xetane-2-carboxamide (Compound 63)

Step 1: Synthesis of (2R)-N-[7-(4-methyl-6-propanoylpyridin-3-yl)-2,6-naphthyridi n-3- yl oxetane-2-carboxamide:

[0361] To a solution of l-[5-(7-amino-2,6-naphthyridin-3-yl)-4-methylpyridin-2- yl]propan-l-one (300.0 mg, 1.02 mmol) in Pyridine (10.0 mL) was added (2R)-oxetane-2- carboxylic acid (104.7 mg, 1.02 mmol) and EDCI (393.4 mg, 2.05 mmol) at 0 °C under N2. The resulting mixture was stirred at 0 °C for 3 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography with CH ₂ Cl ₂ /MeOH (10/1, v/v) to afford (2R)-N-[7-(4-methyl-6- propanoylpyridin-3-yl)-2,6-naphthyridin-3-yl]oxetane-2-carbo xamide (300.0 mg, 77%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 377.2

Step 2: Synthesis of (2R)-N-{7-[6-(l-hydroxypropyl)-4-methylpyridin-3-yl]-2,6-nap hthyridin-

3-yl}oxetane-2-carboxamide:

[0362] To a solution of (2R)-N-[7-(4-methyl-6-propanoylpyridin-3-yl)-2,6-naphthyridi n- 3-yl]oxetane-2-carboxamide (260.0 mg, 0.69 mmol) in MeOH (1.0 mL)/THF (4.0 mL) was added NaBH ₄ (52.2 mg, 1.38 mmol) at 0 °C under N2. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography with CH ₂ Cl ₂ /MeOH (5/1, v/v) to afford (2R)-N-{7-[6-(l-hydroxypropyl)-4-methylpyridin-3-yl]-2,6-nap hthyridin- 3-yl}oxetane-2-carboxamide (70.0 mg, 26%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 379.2.

Step 3: Separation of (2R)-N-(7-{6-[(lR)-l-hydroxypropyl]-4-methylpyridin-3-yl}-2, 6- naphthyridin-3-yl)oxetane-2-carboxamide (Compound 62) and (2R)-N-(7-{6-[(lS)-l- hydroxypropyl]-4-methylpyridin-3-yl}-2,6-naphthyridin-3-yl)o xetane-2-carboxamide (Compound 63):

[0363] The racemic mixture of (2R)-N-{7-[6-(l-hydroxypropyl)-4-methylpyridin-3-yl]- 2,6-naphthyridin-3-yl}oxetane-2-carboxamide (70.0 mg, 0.18 mmol) was separated by Prep- Chiral-HPLC with the following conditions (Column: CHIRAL ART Amylose-SA, 2x25 cm, 5 pm; Mobile Phase A: Hex(0.5% 2M NH ₃ -MeOH)-HPLC, Mobile Phase B: MeOH: DCM=1 : 1— HPLC; Flow rate: 20 mL/min; Gradient: 60% B to 60% B in 10 min; Wave Length: 220/254 nm; RTl(min): 6.57; RT2(min): 9.11) to afford (2R)-N-(7-{6-[l- hydroxypropyl]-4-methylpyridin-3-yl}-2,6-naphthyridin-3-yl)o xetane-2-carboxamide Isomer

1 (retention time 6.57 min, 17.6 mg, 50%) as a white solid and (2R)-N-(7-{6-[l- hydroxypropyl]-4-methylpyridin-3-yl}-2,6-naphthyridin-3-yl)o xetane-2-carboxamide Isomer

2 (retention time 9.11 min, 15.2 mg, 42%) as a white solid. The absolute stereochemistry of Isomers 1 and 2 was not assigned. The two isomeric structures that could be obtained from chiral separation of the isomeric mixture as described above are shown as Compounds 62 and 63 in Table 1.

[0364] (2R)-N-(7-{6-[l-hydroxypropyl]-4-methylpyridin-3-yl}-2,6-nap hthyridin-3- yl)oxetane-2-carboxamide Isomer 1: RTl(min): 6.57, LCMS (ESI, m/z): [M+H]+ = 379.1. 1H NMR (400 MHz, DMSO-d6): δ 10.31 (s, 1H), 9.57 (s, 1H), 9.36 (s, 1H), 8.74 (s, 1H),

8.59 (s, 1H), 8.21 (s, 1H), 7.47 (s, 1H), 5.36 (d, J = 4.4 Hz, 1H), 5.31 - 5.27 (m, 1H), 4.71 - 4.68 (m, 2H), 4.57 - 4.53 (m, 1H), 3.05 - 2.96 (m, 1H), 2.77 - 2.68 (m, 1H), 2.46 (s, 3H), 1.90 - 1.80 (m, 1H), 1.74 - 1.63 (m, 1H), 0.92 - 0.89 (m, 3H).

[0365] (2R)-N-(7-{6-[l-hydroxypropyl]-4-methylpyridin-3-yl}-2,6-nap hthyridin-3- yl)oxetane-2-carboxamide Isomer 2: RT2(min): 9.11, LCMS (ESI, m/z): [M+H]+ = 379.0. 1H NMR (400 MHz, DMSO-d6): δ 10.31 (s, 1H), 9.57 (s, 1H), 9.36 (s, 1H), 8.74 (s, 1H),

8.60 (s, 1H), 8.21 (s, 1H), 7.48 (s, 1H), 5.37 (s, 1H), 5.31 - 5.27 (m, 1H), 4.71 - 4.68 (m, 2H), 4.58 - 4.55 (m, 1H), 3.05 - 2.96 (m, 1H), 2.77 - 2.68 (m, 1H), 2.46 (s, 3H), 1.88 - 1.80 (m, 1H), 1.74 - 1.63 (m, 1H), 0.92 - 0.89 (m, 3H).

Example 35. Synthesis of (lS,2S)-2-fluoro-N-(3-{6-[(lS)-l-hydroxybutyl]-4-methylpyrid in- 3-yl}-l,6-naphthyridin-7-yl)cyclopropane-l-carboxamide (Compound 64) and (lS,2S)-2- fluoro-N-(3-{6-[(lR)-l-hydroxybutyl]-4-methylpyridin-3-yl}-l ,6-naphthyridin-7- yl) cyclopropane-1 -carboxamide (Compound 65)

Step 1: Synthesis of (lS,2S)-N-[3-(6-butanoyl-4-methylpyridin-3-yl)-l,6-naphthyri din-7-yl]~ 2-fluorocyclopropane-l -carboxamide : [0366] To a stirred solution of l-[5-(7-chloro-l,6-naphthyridin-3-yl)-4-methylpyridin-2- yl]butan-l-one (600.0 mg, 1.84 mmol) in dioxane (30.0 mL) was added (l S,2S)-2- fluorocyclopropane-1 -carboxamide (417.7 mg, 4.05 mmol), K2CO3 (763.6 mg, 5.53 mmol), XPhos (175.6 mg, 0.37 mmol) and Pd(OAc)2 (41.4 mg, 0.18 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 2 h. After the reaction as completed, the reaction mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The filtarte was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/EtOAc (v/v, 30/70) to afford (lS,2S)-N-[3-(6-butanoyl-4-methylpyridin-3- yl)-l,6-naphthyri din-7-yl]-2-fluorocy cl opropane-1 -carboxamide (270.0 mg, 37%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 393.2.

Step 2: Synthesis of (lS,2S)-2-fluoro-N-{3-[6-(l-hydroxybutyl)-4-methylpyridin-3- yl]-l,6- naphthyridin-7-yl}cyclopropane-l -carboxamide:

[0367] To a stirred solution of (lS,2S)-N-[3-(6-butanoyl-4-methylpyridin-3-yl)-l,6- naphthyridin-7-yl]-2-fluorocyclopropane-l -carboxamide (200.0 mg, 0.51 mmol) in MeOH (4.0 mL) CH ₂ Cl ₂ (20.0 mL) was added NaBH ₄ (28.9 mg, 0.77 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 30 min. After the reaction was completed, the resulting mixture was quenched with water and then concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (v/v, 10/1) to afford (lS,2S)-2-fluoro-N-{3-[6-(l-hydroxybutyl)-4-methylpyridin-3- yl]-l,6-naphthyridin-7- yl} cyclopropane- 1 -carboxamide (60.0 mg, 29%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 395.2.

Step 3: Separation of (lS,2S)-2-fluoro-N-(3-{6-[(lS)-l-hydroxybutyl]-4-methylpyrid in-3-yl}~ If -naphthyridin-7-yl) cyclopropane- 1 -carboxamide (Compound 64) and (lS,2S)-2-fluoro-N- (3-{6-[(lR)-l-hydroxybutyl]-4-methylpyridin-3-yl}-l,6-naphth yridin-7-yl)cyclopropane-l- carboxamide (Compound 65):

[0368] The product of (lS,2S)-2-fluoro-N-{3-[6-(l-hydroxybutyl)-4-methylpyridin-3- yl]- l,6-naphthyridin-7-yl}cyclopropane-l-carboxamide (60.0 mg, 0.15 mmol) was separated by Prep-Chiral-HPLC with the following conditions: (Column: Lux 5um Cellulose-4, 2.12x25 cm, 5 pm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)— HPLC, Mobile Phase B: MeOH: EtOH=l : 1— HPLC; Flow rate: 20 mL/min; Gradient: 50% B to 50% B in 19 min; Wave Length: 254/220 nm; RTl(min): 13.04; RT2(min): 15.79) to afford (lS,2S)-2-fluoro-N-(3-{6- [ 1 -hydroxybutyl]-4-methylpyri din-3 -y 1 } - 1 ,6-naphthyridin-7-yl)cyclopropane- 1 -carboxamide Isomer 1 (retention time 13.04 min, 10.8 mg, 35%) as a white solid and (lS,2S)-2-fhioro-N- (3-{6-[l-hydroxybutyl]-4-methylpyridin-3-yl}-l,6-naphthyridi n-7-yl)cyclopropane-l- carboxamide Isomer 2 (retention time 15.79 min, 11.2 mg, 37%) as a white solid. The absolute stereochemistry of Isomers 1 and 2 was not assigned. The two isomeric structures that could be obtained from chiral separation of the isomeric mixture as described above are shown as Compounds 64 and 65 in Table 1.

[0369] (lS,2S)-2-fluoro-N-(3-{6-[l-hydroxybutyl]-4-methylpyridin-3- yl}-l,6- naphthyridin-7-yl)cyclopropane-l-carboxamide Isomer 1: RTl(min): 13.04; LCMS (ESI, m/z): [M+H]+ = 395.2. ¹ H NMR (400 MHz, DMSO-d6): δ 11.20 (s, 1H), 9.28 (s, 1H), 9.12 (d, J = 2.4 Hz, 1H), 8.62 (s, 1H), 8.57 - 8.55 (m, 1H), 8.46 (s, 1H), 7.51 (s, 1H), 5.35 (d, J = 5.2 Hz, 1H), 5.06 - 4.90 (m, 1H), 4.63 - 4.61 (m, 1H), 2.34 - 2.28 (m, 4H), 1.78 - 1.64 (m, 3H), 1.44 - 1.35 (m, 2H), 1.27 - 1.20 (m, 1H), 0.93 - 0.90 (m, 3H).

[0370] (lS,2S)-2-fluoro-N-(3-{6-[l-hydroxybutyl]-4-methylpyridin-3- yl}-l,6- naphthyridin-7-yl)cyclopropane-l-carboxamide Isomer 2: RT2(min): 15.79; LCMS (ESI, m/z): [M+H]+ = 395.2. ¹ H NMR (400 MHz, DMSO-d6): δ 11.20 (s, 1H), 9.29 (s, 1H), 9.12 (d, J = 2.4 Hz, 1H), 8.62 (s, 1H), 8.57 (d, J = 2.0 Hz, 1H), 8.46 (s, 1H), 7.51 (s, 1H), 5.35 (d, J = 4.8 Hz, 1H), 5.06 - 4.90 (m, 1H), 4.63 - 4.61 (m, 1H), 2.37 - 2.30 (m, 4H), 1.78 - 1.64 (m, 3H), 1.44 - 1.37 (m, 2H), 1.25 - 1.20 (m, 1H), 0.93 - 0.90 (m, 3H).

Example 36. Synthesis (lS,2S)-N-[7-(6-butanoyl-4-methylpyridin-3-yl)-2,6-naphthyri din-3- yl]-2-fluorocyclopropane-l -carboxamide (Compound 66)

[0371] To a solution of (lS,2S)-N-(7-chloro-2,6-naphthyridin-3-yl)-2- fluorocyclopropane-1 -carboxamide (450.0 mg, 1.69 mmol) in dioxane (18.0 mL)/H20 (3.6 mL) was added 6-butanoyl-4-methylpyridin-3-ylboronic acid (491.0 mg, 2.37 mmol), K2CO3 (468.2 mg, 3.39 mmol) and Pd(dppf)C12 (123.9 mg, 0.17 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 1 h under N2. After the reaction was completed, the resulting mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated in vacuo. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (20/1, v/v) to afford (lS,2S)-N-[7-(6-butanoyl-4- methylpyridin-3-yl)-2,6-naphthyridin-3-yl]-2-fluorocycloprop ane-l -carboxamide (Compound 66, 12.8 mg, 1%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 393.3.

NMR (400 MHz, DMSO-d ₆ ): δ 11.25 (s, 1H), 9.53 (s, 1H), 9.36 (s, 1H), 8.82 (s, 1H), 8.70 (s, 1H), 8.27 (s, 1H), 7.96 (s, 1H), 5.09 - 4.88 (m, 1H), 3.20 - 3.17 (m, 2H), 2.53 (s, 3H), 2.37 - 2.28 (m, 1H), 1.78 - 1.64 (m, 3H), 1.28 - 1.16 (m, 1H), 0.98 - 0.94 (m, 3H).

Example 37. Synthesis of (lS,2S)-2-fluoro-N-(7-(6-((S)-l-hydroxybutyl-l-d)-4- methylpyridin-3-yl)-2,6-naphthyridin-3-yl)cyclopropane-l-car boxamide (Compound 67)and (lS,2S)-2-fluoro-N-(7-(6-((R)-l-hydroxybutyl-l-d)-4-methylpy ridin-3-yl)-2,6- naphthyridin-3-yl)cyclopropane-l -carboxamide (Compound 68)

Step 1: Synthesis of (lS,2S)-2-fluoro-N-(7-(6-(l-hydroxybutyl-l-d)-4-methylpyridi n-3-yl)-2,6- naphthyridin-3-yl)cyclopropane-l-carboxamide:

[0372] To a solution of (lS,2S)-N-[7-(6-butanoyl-4-methylpyridin-3-yl)-2,6- naphthyri din-3 -yl]-2-fluorocy cl opropane-1 -carboxamide (270.0 mg, 0.69 mmol) in THF/CD3OD (10.0 mL/2.0 mL) was added NaBD ₄ (577.9 mg, 13.76 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the mixture was quenched with MeOH and then concentrated under vacuum. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (10/1, v/v) and the purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30x 150 mm, 5 pm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 26% B to 36% B in 8 min; Wave Length: 254 nm) to afford (lS,2S)-2-fluoro-N-(7-(6-(l-hydroxybutyl-l-d)-4-methylpyridi n-3-yl)-2,6-naphthyridin-3- yl)cyclopropane-l -carboxamide (45.0 mg, 16%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 396.2.

Step 2: Separation of (lS,2S)-2-fluoro-N-(7-(6-((S)-l-hydroxybutyl-l-d)-4-methylpy ridin-3- yl)-2,6-naphthyridin-3-yl)cyclopropane-l -carboxamide (Compound 67)and ( IS, 2 S) -2 -fluor o- N-(7-( 6-( (R)-l-hydroxybutyl-l-d)-4-methylpyridin-3-yl)-2, 6-naphthyridin-3-yl)cyclopropane- 1 -carboxamide (Compound 68):

[0373] The racemic product of (1 S,2S)-2-fluoro-N-(7-(6-(l-hydroxybutyl-l-d)-4- m ethylpyri din-3 -yl)-2, 6-naphthyri din-3 -yl)cy cl opropane-1 -carboxamide (45.0 mg, 0.11 mmol) was separated by Prep-Chiral-HPLC with the following conditions: (Column: CHIRAL ART Amylose-SA, 2x25 cm, 5 pm; Mobile Phase A: Hex(0.5% 2M NH ₃ -MeOH)- HPLC, Mobile Phase B: MeOH: DCM=1 : 1-HPLC; Flow rate: 20 mL/min; Gradient: 50% B to 50% B in 11 min; Wave Length: 220/254 nm; RTl(min): 6.39; RT2(min): 9.29) to afford (lS,2S)-2-fluoro-N-(7-(6-(l-hydroxybutyl-l-d)-4-methylpyridi n-3-yl)-2,6-naphthyridin-3- yl)cy cl opropane-1 -carboxamide Isomer 1 (retention time 6.39 min, 16.5 mg, 73%) as a white solid and (1 S,2S)-2-fluoro-N-(7-(6-(l-hydroxybutyl-l-d)-4-methylpyridin- 3-yl)-2,6- naphthyri din-3 -yl)cy cl opropane-1 -carboxamide Isomer 2 (retention time 9.29 min, 15.6 mg, 69%) as a white solid. The absolute stereochemistry of Isomers 1 and 2 was not assigned. The two isomeric structures that could be obtained from chiral separation of the isomeric mixture as described above are shown as Compounds 67 and 68 in Table 1.

[0374] (lS,2S)-2-fluoro-N-(7-(6-(l-hydroxybutyl-l-d)-4-methylpyridi n-3-yl)-2,6- naphthyridin-3-yl)cyclopropane-l-carboxamide Isomer 1: RTl(min): 6.39; LCMS (ESI, m/z): [M+H]+ = 396.1. ¹ H NMR (400 MHz, DMSO-d6): δ 11.22 (s, 1H), 9.50 (s, 1H), 9.34 (s, 1H), 8.69 (s, 1H), 8.58 (s, 1H), 8.18 (s, 1H), 7.47 (s, 1H), 5.31 (s, 1H), 5.07 - 4.90 (m, 1H), 2.45 (s, 3H), 2.33 - 2.29 (m, 1H), 1.78 - 1.61 (m, 3H), 1.43 - 1.36 (m, 2H), 1.26 - 1.21 (m, 1H), 0.93 - 0.89 (m, 3H).

[0375] (lS,2S)-2-fluoro-N-(7-(6-(l-hydroxybutyl-l-d)-4-methylpyridi n-3-yl)-2,6- naphthyridin-3-yl)cyclopropane-l-carboxamide Isomer 2: RT2(min): 9.29; LCMS (ESI, m/z): [M+H]+ = 396.2. ¹ H NMR (400 MHz, DMSO-d6): δ 11.21 (s, 1H), 9.50 (s, 1H), 9.34 (s, 1H), 8.68 (s, 1H), 8.58 (s, 1H), 8.17 (s, 1H), 7.47 (s, 1H), 5.30 (s, 1H), 5.08 - 4.90 (m, 1H), 2.45 (s, 3H), 2.33 - 2.29 (m, 1H), 1.78 - 1.61 (m, 3H), 1.43 - 1.37 (m, 2H), 1.26 - 1.21 (m, 1H), 0.93 - 0.89 (m, 3H).

Example 38. Synthesis of (R)-N-(7-(6-((R)-l-hydroxybutyl)-4-methylpyridin-3-yl)-2,6- naphthyridin-3-yl)-2-methoxypropanamide (Compound 69) and (R)-N-(7-(6-((S)-l- hydroxybutyl)-4-methylpyridin-3-yl)-2,6-naphthyridin-3-yl)-2 -methoxypropanamide (Compound 70)

Step 1: Synthesis of (R)-N-(7-(6-butyryl-4-methylpyridin-3-yl)-2,6-naphthyridin-3 -yl)-2- methoxypropanamide:

[0376] To a solution of (R)-2-methoxypropanoic acid (358.8 mg, 3.44 mmol) in Pyridine (40.0 mL) was added l-(5-(7-amino-2,6-naphthyridin-3-yl)-4-methylpyridin-2-yl)bu tan-l- one (880.0 mg, 2.87 mmol) at 0 °C. Then EDCI (1101.2 mg, 5.74 mmol) was added to the mixture at 0 °C under N2. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (2/1, v/v) to afford (R)-N-(7-(6-butyryl-4-methylpyridin-3-yl)-2,6-naphthyridin-3 -yl)-2- methoxypropanamide (750.0 mg, 66%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 393.2

Step 2: Synthesis of (2R)-N-(7-(6-(l-hydroxybutyl)-4-methylpyridin-3-yl)-2,6-naph thyridin-3- yl)-2-methoxypropanamide:

[0377] To a solution of (R)-N-(7-(6-butyryl-4-methylpyridin-3 -yl)-2, 6-naphthyri din-3 - yl)-2-methoxypropanamide (710.0 mg, 1.80 mmol) in MeOH (2.0 mL)/DCM (20.0 mL) was added NaBH ₄ (342.1 mg, 9.04 mmol) at 0 °C under N2. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction was quenched with water at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (2/1, v/v) to afford (2R)-N-(7-(6-(l -hy droxybutyl)-4-methylpyridin-3-yl)-2, 6-naphthyri din-3-yl)-2- methoxypropanamide (70.0 mg, 9%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 395.2.

Step 3: Separation of (R)-N-(7-(6-((R)-l-hydroxybutyl)-4-methylpyridin-3-yl)-2,6- naphthyridin-3-yl)-2-methoxypropanamide (Compound 69) and (R)-N-(7-(6-((S)-l- hydroxybutyl)-4-methylpyridin-3-yl)-2,6-naphthyridin-3-yl)-2 -methoxypropanamide (Compound 70):

[0378] The product of (2R)-N-(7-(6-(l-hydroxybutyl)-4-methylpyridin-3-yl)-2,6- naphthyridin-3-yl)-2-methoxypropanamide (70.0 mg, 0.17 mmol) was separated by Prep- HPLC with the following conditions (Column: CHIRAL ART Amylose-SA, 2x25 cm, 5 pm; Mobile Phase A: MtBE(0.1% FA)-HPLC, Mobile Phase B: EtOH: DCM=1 : 1-HPLC; Flow rate: 20 mL/min; Gradient: 20% B to 20% B in 16 min; Wave Length: 220/254 nm;

RTl(min): 9.77; RT2(min): 13.31) to afford (R)-N-(7-(6-(l-hydroxybutyl)-4-methylpyridin- 3-yl)-2,6-naphthyridin-3-yl)-2-methoxypropanamide Isomer 1 (retention time 9.77 min, 24.1 mg, 68%) as a white solid and (R)-N-(7-(6-(l-hydroxybutyl)-4-methylpyridin-3-yl)-2,6- naphthyridin-3-yl)-2-methoxypropanamide Isomer 2 (retention time 13.31 min, 23.4 mg, 66%) as a white solid. The absolute stereochemistry of Isomers 1 and 2 was not assigned. The two isomeric structures that could be obtained from chiral separation of the isomeric mixture as described above are shown as Compounds 69 and 70 in Table 1. [0379] (R)-N-(7-(6-(l-hydroxybutyl)-4-methylpyridin-3-yl)-2,6-napht hyridin-3-yl)-2- methoxypropanamide Isomer 1: RTl(min): 9.77; LCMS (ESI, m/z): [M+H]+ = 395.2. ¹ H NMR (400 MHz, DMSO-d6): δ 10.51 (s, 1H), 9.55 (s, 1H), 9.35 (s, 1H), 8.72 (s, 1H), 8.59 (s, 1H), 8.20 (s, 1H), 7.47 (s, 1H), 5.36 (d, J = 4.8 Hz, 1H), 4.64 - 4.60 (m, 1H), 4.15 - 4.10 (m, 1H), 3.35 (s, 3H), 2.46 (s, 3H), 1.81 - 1.73 (m, 1H), 1.69 - 1.60 (m, 1H), 1.45 - 1.36 (m, 5H), 0.93 - 0.89 (m, 3H).

[0380] (R)-N-(7-(6-(l-hydroxybutyl)-4-methylpyridin-3-yl)-2,6-napht hyridin-3-yl)-2- methoxypropanamide Isomer 2: RT2(min): 13.31; LCMS (ESI, m/z): [M+H]+ = 395.2. ¹ H NMR (400 MHz, DMSO-d6): δ 10.51 (s, 1H), 9.55 (s, 1H), 9.35 (s, 1H), 8.72 (s, 1H), 8.58 (s, 1H), 8.20 (s, 1H), 7.47 (s, 1H), 5.36 (d, J = 5.2 Hz, 1H), 4.64 - 4.60 (m, 1H), 4.15 - 4.10 (m, 1H), 3.35 (s, 3H), 2.46 (s, 3H), 1.81 - 1.73 (m, 1H), 1.69 - 1.60 (m, 1H), 1.45 - 1.36 (m, 5H), 0.93 - 0.89 (m, 3H).

Example 39. Synthesis of (R)-N-(7-(6-(l,4-dihydroxybutyl)-4-methylpyridin-3-yl)-2,6- naphthyridin-3-yl)cyclopropanecarboxamide (Compound 71) and (S)-N-(7-(6-(l ,4- dihydroxybutyl)-4-methylpyridin-3-yl)-2,6-naphthyridin-3-yl) cyclopropanecarboxamide (Compound 72)

Step 1: Synthesis of l-(5-bromo-4-methylpyridin-2-yl)-4-hydroxybutan-l-one:

[0381] To a solution of 5-bromo-2-iodo-4-methylpyridine (1.0 g, 3.35 mmol) in THF (10.0 mL) was added i-PrMgCl (2.0 mL, 2.0 mmol/L) at 0 °C under N2. The mixture was stirred at 0 °C for 1 h under N2. Then a solution of dihydrofuran-2(3H)-one (346.7 mg, 4.02 mmol) in THF (1.0 mL) was added dropwise to the above mixture at 0 °C. The mixture was stirred at 0 °C for 1 h. After the reaction was completed, the reaction mixture was quenched with NH4CI (sat.) solution and then extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (1/1, v/v) to afford l-(5-bromo-4- methylpyridin-2-yl)-4-hydroxybutan-l-one (500.0 mg, 57%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 258.0. Step 2: Synthesis of 4-hydroxy-l-(4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaboro lan-2- yl)pyridin-2-yl)butan-l-one:

[0382] To a solution of l-(5-bromo-4-methylpyridin-2-yl)-4-hydroxybutan-l-one (420.0 mg, 1.62 mmol) in 1,4-dioxane (10.0 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'- bi(l,3,2-dioxaborolane) (1.2 g, 4.88 mmol), KO Ac (479.0 mg, 4.88 mmol) and Pd(dppf)C12 (238.1 mg, 0.32 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 2 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to afford 4-hydroxy-l-(4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaboro lan-2-yl)pyridin-2- yl)butan-l-one (1.7 g, crude) as a black solid. LCMS (ESI, m/z): [M+H] ⁺ = 306.2.

Step 3: Synthesis ofN-(7-(6-(4-hydroxybutanoyl)-4-methylpyridin-3-yl)-2,6-naph thyridin-3- yl)cyclopropanecarboxamide:

[0383] To a mixture of 4-hydroxy-l-(4-methyl-5-(4,4,5,5-tetramethyl-l,3,2- di oxaborolan-2-yl)pyri din-2 -yl)butan-l -one (1.5 g, crude) in l,4-dioxane/H2O (15.0 mL/3.0 mL) was added N-(7-chl oro-2, 6-naphthyridin-3-yl)cyclopropanecarboxamide (1.2 g, 4.91 mmol), K2CO3 (2.0 g, 14.74 mmol) and Pd(dppf)C12 (0.7 g, 0.98 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 2 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (1/1, v/v) to afford N-(7-(6- (4-hydroxybutanoyl)-4-methylpyridin-3-yl)-2,6-naphthyridin-3 -yl)cyclopropanecarboxamide (250.0 mg, 13%) as a brown solid. LCMS (ESI, m/z): [M+H] ⁺ = 391.2 Step 4: Synthesis of N-(7-(6-(l ,4-dihydroxybutyl)-4-methylpyridin-3-yl)-2,6-naphthyridin-3- yl)cyclopropanecarboxamide:

[0384] To a solution of N-(7-(6-(4-hydroxybutanoyl)-4-methylpyridin-3-yl)-2,6- naphthyridin-3-yl)cyclopropanecarboxamide (200.0 mg, 0.51 mmol) in THF (8.0 mL) was added DIBAL-H (3.0 mL, 1.0 mol/L) at 0 °C under N2. The resulting mixture was stirred at room temperature for 1 h under N2. After the reaction was completed, the reaction mixture was quenched with water at 0 °C. The reaction mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (10/1, v/v) to afford N-(7- (6-( 1 ,4-dihy droxybutyl)-4-methylpyri din- 3 -yl)-2, 6-naphthyri din-3 - yl)cyclopropanecarboxamide (80.0 mg, 39%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 393.2.

Step 5: Separation of (R)-N-(7-(6-(l,4-dihydroxybutyl)-4-methylpyridin-3-yl)-2,6- naphthyridin-3-yl)cyclopropanecarboxamide (Compound 71) and (S)-N-(7-(6-(l,4- dihydroxybutyl)-4-methylpyridin-3-yl)-2,6-naphthyridin-3-yl) cyclopropanecarboxamide (Compound 72):

[0385] The racemic product of N-(7-(6-(l,4-dihydroxybutyl)-4-methylpyridin-3-yl)-2,6- naphthyridin-3-yl)cyclopropanecarboxamide (80.0 mg, 0.20 mmol) was separated by Prep- Chiral-HPLC with the following conditions: (Column: Lux 5um Cellulose-4, 2.12x25 cm, 5 pm; Mobile Phase A: Hex(0.5% 2M NH ₃ -MeOH)-HPLC, Mobile Phase B: MeOH: EtOH=l : 1— HPLC; Flow rate: 20 mL/min; Gradient: 35% B to 35% B in 29 min; Wave Length: 254/220 nm; RTl(min): 21.13; RT2(min): 24.25) to afford N-(7-(6-(l,4- dihydroxybutyl)-4-methylpyridin-3-yl)-2,6-naphthyridin-3-yl) cyclopropanecarboxamide Enantiomer 1 (retention time 21.13 min, 37.7 mg, 94%) as a white solid and -N-(7-(6-(l,4- dihydroxybutyl)-4-methylpyridin-3-yl)-2,6-naphthyridin-3-yl) cyclopropanecarboxamide Enantiomer 2 (retention time 24.25 min, 35.0 mg, 87%) as a white solid. The absolute stereochemistry of Enantiomers 1 and 2 was not assigned. The two enantiomeric structures that could be obtained from chiral separation of the enantiomeric mixture as described above are shown as Compounds 71 and 72 in Table 1.

[0386] N-(7-(6-(l,4-dihydroxybutyl)-4-methylpyridin-3-yl)-2,6-napht hyridin-3- yl)cyclopropanecarboxamide Enantiomer 1: RTl(min): 21.13; LCMS (ESI, m/z): [M+H]+ = 393.1. ¹ H NMR (400 MHz, DMSO-d6): δ 11.16 (s, 1H), 9.47 (s, 1H), 9.33 (s, 1H), 8.67 (s, 1H), 8.58 (s, 1H), 8.17 (s, 1H), 7.47 (s, 1H), 5.37 (d, J = 4.8 Hz, 1H), 4.63 - 4.61 (m, 1H), 4.39 - 4.37 (m, 1H), 3.44 - 3.40 (m, 2H), 2.45 (s, 3H), 2.12 - 2.09 (m, 1H), 1.90 - 1.80 (m, 1H), 1.74 - 1.61 (m, 1H), 1.55 - 1.51 (m, 2H), 0.90 - 0.87 (m, 4H).

[0387] N-(7-(6-(l,4-dihydroxybutyl)-4-methylpyridin-3-yl)-2,6-napht hyridin-3- yl)cyclopropanecarboxamide Enantiomer 2: RT2(min): 24.25; LCMS (ESI, m/z): [M+H]+ = 393.1. ¹ H NMR (400 MHz, DMSO-d6): δ 11.17 (s, 1H), 9.47 (s, 1H), 9.33 (s, 1H), 8.67 (s, 1H), 8.58 (s, 1H), 8.17 (s, 1H), 7.47 (s, 1H), 5.37 (d, J = 4.8 Hz, 1H), 4.64 - 4.60 (m, 1H), 4.39 - 4.37 (m, 1H), 3.44 - 3.39 (m, 2H), 2.45 (s, 3H), 2.13 - 2.09 (m, 1H), 1.87 - 1.81 (m, 1H), 1.69 - 1.65 (m, 1H), 1.57 - 1.48 (m, 2H), 0.92 - 0.87 (m, 4H).

Example 40. Synthesis of (S)-N-(7-(6-(l-hydroxybutyl)-4-methylpyridin-3-yl)-2,6- naphthyridin-3-yl)acetamide (Compound 73)and (R)-N-(7-(6-(l-hydroxybutyl)-4- methylpyridin-3-yl)-2, 6-naphthyridin-3-yl) acetamide (Compound 74)

Step 1: Synthesis ofN-[7-(6-butanoyl-4-methylpyridin-3-yl)-2,6-naphthyridin-3- yl]acetamide:

[0388] To a stirred mixture of l-[5-(7-amino-2,6-naphthyridin-3-yl)-4-methylpyridin-2- yl]butan-l-one (450.0 mg, 1.47 mmol) and acetyl chloride (345.9 mg, 4.41 mmol) in pyridine (6.0 mL) was added DMAP (35.9 mg, 0.29 mmol) at room temperature under N2. The resulting mixture was stirred at 70 °C for 16 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (10/1, v/v) to afford N-[7-(6-butanoyl-4- methylpyridin-3-yl)-2,6-naphthyridin-3-yl]acetamide (500.0 mg, 97%) as a yellow solid.

LCMS (ESI, m/z): [M+H] ⁺ = 349.1.

Step 2: Synthesis of N-{7-[6-(l-hydroxybutyl)-4-methylpyridin-3-yl]-2,6-naphthyri din-3- yl}acetamide:

[0389] To a stirred solution of N-[7-(6-butanoyl-4-methylpyridin-3-yl)-2,6-naphthyridin- 3-yl]acetamide (500.0 mg, 1.44 mmol) and MeOH (1.0 mL) in THF (10.0 mL) was added NaBH ₄ (271.5 mg, 7.18 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 16 h.

After the reaction was completed, the reaction mixture was quenched with water at 0 °C. The resulting mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography with acetonitrile/water (64/36, v/v) to afford N-{7-[6-(l-hydroxybutyl)-4- m ethylpyri din-3 -yl]-2, 6-naphthyri din-3 -yl} acetamide (180.0 mg, 35%) as a brown solid. LCMS (ESI, m/z): [M+H] ⁺ = 351.1.

Step 3: Separation of (S)-N-(7-(6-(l-hydroxybutyl)-4-methylpyridin-3-yl)-2,6-napht hyridin-3- yl)acetamide (Compound 73)and (R)-N-(7-(6-(l-hydroxybutyl)-4-methylpyridin-3-yl)-2,6- naphthyridin-3-yl)acetamide (Compound 74):

[0390] The racemic mixture ofN-{7-[6-(l-hydroxybutyl)-4-methylpyridin-3-yl]-2,6- naphthyridin-3-yl} acetamide (100.0 mg, 0.28 mmol) was separated by Prep-Chiral-HPLC with the following conditions (Column: CHIRALPAK IH, 2x25 cm, 5 pm; Mobile Phase A: Hex(0.5% 2M NH ₃ -MeOH)-HPLC, Mobile Phase B: EtOH: DCM=1 : 1-HPLC; Flow rate: 20 mL/min; Gradient: 30% B to 30% B in 8.5 min; Wave Length: 220/254 nm; RTl(min): 5.14; RT2(min): 7.07) to afford N-(7-{6-[l-hydroxybutyl]-4-methylpyridin-3-yl}-2,6- naphthyridin-3-yl)acetamide Enantiomer 1 (retention time 5.14 min, 24.7 mg, 49%) as a white solid and N-(7-{6-[l-hydroxybutyl]-4-methylpyridin-3-yl}-2,6-naphthyri din-3- yl)acetamide Enantiomer 2 (retention time 7.07 min, 30.7 mg, 61%) as a white solid. The absolute stereochemistry of Enantiomers 1 and 2 was not assigned. The two enantiomeric structures that could be obtained from chiral separation of the enantiomeric mixture as described above are shown as Compounds 73 and 74 in Table 1.

[0391] N-(7-{6-[l-hydroxybutyl]-4-methylpyridin-3-yl}-2,6-naphthyri din-3- yl)acetamide Enantiomer 1: RTl(min): 5.14; LCMS (ESI, m/z): [M+H]+ = 351.0. ¹ H NMR (400 MHz, DMSO-d6): δ 10.87 (s, 1H), 9.51 (s, 1H), 9.32 (s, 1H), 8.67 (s, 1H), 8.57 (s, 1H), 8.16 (s, 1H), 7.47 (s, 1H), 5.33 (d, J = 4.8 Hz, 1H), 4.64 - 4.60 (m, 1H), 2.45 (s, 3H), 2.19 (s, 3H), 1.81 - 1.73 (m, 1H), 1.70 - 1.61 (m, 1H), 1.45 - 1.33 (m, 2H), 0.93 - 0.89 (m, 3H).

[0392] N-(7-{6-[l-hydroxybutyl]-4-methylpyridin-3-yl}-2,6-naphthyri din-3- yl)acetamide Enantiomer 2: RT2(min): 7.07; LCMS (ESI, m/z): [M+H]+ = 351.0. ¹ H NMR (400 MHz, DMSO-d6): δ 10.87 (s, 1H), 9.51 (s, 1H), 9.32 (s, 1H), 8.67 (s, 1H), 8.57 (s, 1H), 8.16 (s, 1H), 7.47 (s, 1H), 5.33 (d, J = 4.8 Hz, 1H), 4.64 - 4.60 (m, 1H), 2.45 (s, 3H), 2.19 (s, 3H), 1.81 - 1.73 (m, 1H), 1.69 - 1.61 (m, 1H), 1.45 - 1.33 (m, 2H), 0.93 - 0.89 (m, 3H).

Example 41. Synthesis of (lR)-2,2-difluoro-N-(7-{6-[(lS)-l-hydroxybutyl]-4- methylpyridin-3-yl}-2, 6-naphthyridin-3-yl)cyclopropane-l -carboxamide (Compound 75) and (lR)-2,2-difluoro-N-(7-{6-[(lR)-l-hydroxybutyl]-4-methylpyri din-3-yl}-2,6- naphthyridin-3-yl)cyclopropane-l -carboxamide (Compound 76)

Step 1: Synthesis of (lR)-N-[7-(6-butanoyl-4-methylpyridin-3-yl)-2,6-naphthyridin -3-yl]-2,2- difluorocyclopropane-1 -carboxamide:

[0393] To a mixture of l-[5-(7-amino-2,6-naphthyridin-3-yl)-4-methylpyridin-2- yl]butan-l-one (600.0 mg, 1.96 mmol) in pyridine (15.0 mL) was added (lR)-2,2- difluorocyclopropane-1 -carboxylic acid (310.8 mg, 2.55 mmol) at 0 °C under N2. Then EDCI (750.9 mg, 3.92 mmol) was added to the mixture at 0 °C. The mixture was stirred at room temperature for 2 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/EtOAc (1/1, v/v) to afford (lR)-N-[7-(6-butanoyl-4-methylpyridin-3-yl)-2,6- naphthyridin-3-yl]-2,2-difluorocyclopropane-l -carboxamide (260.0 mg, 32%) as a white solid. LCMS (ESI, m/z): [M+H]+ = 411.2.

Step 2: Synthesis of (lR)-2,2-difluoro-N-{7-[6-(l-hydroxybutyl)-4-methylpyridin-3 -yl]-2,6- naphthyridin-3-yl}cyclopropane-l-carboxamide:

[0394] To a solution of (lR)-N-[7-(6-butanoyl-4-methylpyridin-3-yl)-2,6-naphthyridin -3- yl]-2,2-difluorocyclopropane-l -carboxamide (250.0 mg, 0.61 mmol) in CH2CI2 (20.0 mL)/MeOH (4.0 mL) was added NaBH ₄ (230.4 mg, 6.09 mmol) at 0 °C under N2. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the resulting mixture was quenched with methanol and then concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (10/1, v/v) and then purified by Prep-HPLC with the following conditions: (Column: XBridge Shield RP18 OBD Column, 30x150 mm, 5 pm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 36% B to 48% B in 8 min; Wave Length: 254 nm) to afford (lR)-2,2-difluoro-N-{7-[6-(l-hydroxybutyl)-4- methylpyri din-3 -yl]-2,6-naphthyri din-3 -yl)cy cl opropane-1 -carboxamide (70.0 mg, 27%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 413.2.

Step 3: Separation of (lR)-2,2-difluoro-N-(7-{6-[(lS)-l-hydroxybutyl]-4-methylpyri din-3-yl}~ 2, 6-naphthyridin-3-yl)cyclopropane-l -carboxamide (Compound 75) and (lR)-2,2-difluoro-N- (7-{6-[(lR)-l-hydroxybutyl]-4-methylpyridin-3-yl}-2,6-naphth yridin-3-yl)cyclopropane-l- carboxamide (Compound 76):

[0395] The product of (lR)-2,2-difluoro-N-{7-[6-(l-hydroxybutyl)-4-methylpyridin-3 - yl]-2,6-naphthyridin-3-yl} cyclopropane- 1 -carboxamide (70.0 mg, 0.17 mmol) was separated by Prep-Chiral-HPLC with the following conditions: (Column: CHIRAL ART Amylose-SA, 2x25 cm, 5 pm; Mobile Phase A: Hex(0.5% 2M NHs-MeOH)— HPLC, Mobile Phase B: MeOH: DCM=1 : 1— HPLC; Flow rate: 20 mL/min; Gradient: 40% B to 40% B in 15 min; Wave Length: 220/254 nm; RTl(min): 9.54; RT2(min): 12.37) to afford (lR)-2,2-difhioro-N- (7-{6-[l-hydroxybutyl]-4-methylpyridin-3-yl}-2,6-naphthyridi n-3-yl)cyclopropane-l- carboxamide Isomer 1 (retention time 9.54 min, 24.9 mg, 71%) as a white solid and (lR)-2,2- difluoro-N-(7-{6-[l-hydroxybutyl]-4-methylpyridin-3-yl}-2,6- naphthyri din-3- yl)cyclopropane-l -carboxamide Isomer 2 (retention time 12.37 min, 30.9 mg, 88%) as a white solid. The absolute stereochemistry of Isomers 1 and 2 was not assigned. The two isomeric structures that could be obtained from chiral separation of the isomeric mixture as described above are shown as Compounds 75 and 76 in Table 1.

[0396] (lR)-2,2-difluoro-N-(7-{6-[l-hydroxybutyl]-4-methylpyridin-3 -yl}-2,6- naphthyridin-3-yl)cyclopropane-l-carboxamide Isomer 1: RTl(min): 9.54; LCMS (ESI, m/z): [M+H]+ = 413.2. ¹ H NMR (400 MHz, DMSO-d6): δ 11.40 (s, 1H), 9.52 (s, 1H), 9.35 (s, 1H), 8.67 (s, 1H), 8.58 (s, 1H), 8.19 (s, 1H), 7.47 (s, 1H), 5.36 (d, J = 4.8 Hz, 1H), 4.64 - 4.60 (m, 1H), 3.13 - 3.05 (m, 1H), 2.45 (s, 3H), 2.13 - 2.03 (m, 2H), 1.81 - 1.60 (m, 2H), 1.45 - 1.33 (m, 2H), 0.93 - 0.89 (m, 3H).

[0397] (lR)-2,2-difluoro-N-(7-{6-[l-hydroxybutyl]-4-methylpyridin-3 -yl}-2,6- naphthyridin-3-yl)cyclopropane-l-carboxamide Isomer 2: RT2(min): 12.37; LCMS (ESI, m/z): [M+H]+ = 413.1. ¹ H NMR (400 MHz, DMSO-d6): δ 11.40 (s, 1H), 9.53 (s, 1H), 9.36 (s, 1H), 8.68 (s, 1H), 8.58 (s, 1H), 8.20 (s, 1H), 7.47 (s, 1H), 5.36 (d, J = 5.2 Hz, 1H), 4.64 - 4.60 (m, 1H), 3.13 - 3.05 (m, 1H), 2.45 (s, 3H), 2.13 - 2.05 (m, 2H), 1.80 - 1.62 (m, 2H), 1.45 - 1.35 (m, 2H), 0.93 - 0.89 (m, 3H).

Example 42. Synthesis of (R)-2,2-difluoro-N-(3-(6-((S)-l-hydroxybutyl)-4-methylpyridi n-3- yl)-l,6-naphthyridin-7-yl)cyclopropane-l-carboxamide (Compound 77) and (R)-2,2- difluoro-N-(3-(6-((R)-l-hydroxybutyl)-4-methylpyridin-3-yl)- l,6-naphthyridin-7- yl) cyclopropane-1 -carboxamide (Compound 78)

Step 1: Synthesis of l-(5-(7-chloro-l,6-naphthyridin-3-yl)-4-methylpyridin-2-yl)b utan-l-one: [0398] To a solution of 3-bromo-7-chloro-l,6-naphthyridine (2.4 g, 9.85 mmol) in dioxane (60.0 mL)/H20 (12.0 mL) were added (6-butyryl-4-methylpyridin-3-yl)boronic acid (3.0 g, 14.78 mmol), Pd(dppf)C12 (0.7 g, 0.98 mmol) and K2CO3 (8.1 g, 59.14 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 2 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (2/1, v/v) to afford l-(5-(7-chloro-l,6-naphthyridin-3-yl)-4-methylpyridin-2-yl)b utan-l-one (400.0 mg, 12%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 326.1

Step 2: Synthesis of Tert-butyl (3-(6-butyryl-4-methylpyridin-3-yl)-l,6-naphthyridin-7- yl)carbamate :

[0399] To a solution of l-(5-(7-chloro-l,6-naphthyridin-3-yl)-4-methylpyridin-2- yl)butan-l-one (400.0 mg, 1.22 mmol) in dioxane (20.0 mL) were added tert-butyl carbamate (431.4 mg, 3.68 mmol), CS2CO3 (1200.0 mg, 3.68 mmol), XPhos (234.1 mg, 0.49 mmol) and Pd(OAc)2 (55.1 mg, 0.24 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 1 h under N2. After the reaction was completed, the resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (1/1, v/v) to afford tertbutyl (3-(6-butyryl-4-methylpyridin-3-yl)-l,6-naphthyridin-7-yl)ca rbamate (450.0 mg, 90%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 407.2.

Step 3: Synthesis of l-(5-(7-amino-l,6-naphthyridin-3-yl)-4-methylpyridin-2-yl)bu tan-l-one:

[0400] To a solution of tert-butyl (3-(6-butyryl-4-methylpyridin-3-yl)-l,6-naphthyridin-7- yl)carbamate (450.0 mg, 1.10 mmol) in CH ₂ Cl ₂ (10.0 mL) was added TFA (5.6 mL) at room temperature. The resulting mixture was stirred at room temperature for 30 min. After the reaction was completed, the pH value of the mixture was adjusted to 8 with NaHCO3(aq.). The reaction mixture was diluted with H2O and extracted with CH2CI2. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to afford l-(5-(7-amino-l,6-naphthyridin-3-yl)-4- methylpyridin-2-yl)butan-l-one (250.0 mg, crude) as an orange solid. LCMS (ESI, m/z): [M+H] ⁺ = 307.1.

Step 4: Synthesis of (R)-N-(3-(6-butyryl-4-methylpyridin-3-yl)-l,6-naphthyridin-7 -yl)-2,2- difluorocyclopropane- 1 -carboxamide:

[0401] To a solution l-(5-(7-amino-l,6-naphthyridin-3-yl)-4-methylpyridin-2-yl)bu tan-l- one (220.0 mg, crude) in Pyridine (8.0 mL) were added (R)-2,2-difluorocyclopropane-l- carboxylic acid (525.9 mg, 4.30 mmol) and EDCI (275.3 mg, 1.43 mmol) at 0 °C under N2. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (15/1, v/v) to afford (R)-N-(3- (6-butyryl-4-methylpyridin-3-yl)-l,6-naphthyridin-7-yl)-2,2- difluorocyclopropane-l- carboxamide (290.0 mg, 98%) as a yellow solid, LCMS (ESI, m/z): [M+H] ⁺ = 411.2.

Step 5: Synthesis of (lR)-2,2-difluoro-N-(3-(6-(l-hydroxybutyl)-4-methylpyridin-3 -yl)-l,6- naphthyridin-7-yl)cyclopropane-l-carboxamide:

[0402] To a solution of (R)-N-(3-(6-butyryl-4-methylpyridin-3-yl)-l,6-naphthyridin-7 - yl)-2,2-difluorocyclopropane-l -carboxamide (300.0 mg, 0.73 mmol) in CH2CI2 (30.0 mL)/MeOH (6.0 mL) was added NaBH ₄ (55.3 mg, 1.46 mmol) at 0 °C under N2. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (20/1, v/v) to afford (lR)-2,2-difluoro-N- (3-(6-(l-hydroxybutyl)-4-methylpyridin-3-yl)-l,6-naphthyridi n-7-yl)cyclopropane-l- carboxamide (50.0 mg, 16%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 413.2

Step 6: Separation of (R)-2,2-dijluoro-N-(3-(6-((S)-l-hydroxybutyl)-4-methylpyridi n-3-yl)-

If -naphthyridin-7-yl) cyclopropane- 1 -carboxamide (Compound 77) and (R)-2,2-difluoro-N- (3-(6-((R)-l-hydroxybutyl)-4-methylpyridin-3-yl)-l,6-naphthy ridin-7-yl)cyclopropane-l- carboxamide (Compound 78):

[0403] The product of (lR)-2,2-difluoro-N-(3-(6-(l-hydroxybutyl)-4-methylpyridin-3 - yl)-l,6-naphthyridin-7-yl)cyclopropane-l-carboxamide (50.0 mg, 0.11 mmol) was separated by Prep-HPLC with the following conditions (Column: CHIRAL ART Cellulose-SC, 2x25 cm, 5 pm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)— HPLC, Mobile Phase B: EtOH: DCM=1: 1— HPLC; Flow rate: 20 mL/min; Gradient: 90% B to 90% B in 13 min; Wave Length: 220/254 nm; RTl(min): 6.44; RT2(min): 10.46) to afford (R)-2,2-difluoro-N-(3-(6- (l-hydroxybutyl)-4-methylpyridin-3-yl)-l,6-naphthyridin-7-yl )cyclopropane-l-carboxamide Isomer 1 (retention time 6.44 min, 17.6 mg, 70%) as a white solid and (R)-2,2-difluoro-N-(3- (6-(l-hydroxybutyl)-4-methylpyridin-3-yl)-l,6-naphthyridin-7 -yl)cyclopropane-l- carboxamide Isomer 2 (retention time 10.46 min, 16.8 mg, 67%) as a white solid. The absolute stereochemistry of Isomers 1 and 2 was not assigned. The two isomeric structures that could be obtained from chiral separation of the isomeric mixture as described above are shown as Compounds 77 and 78 in Table 1.

[0404] (R)-2,2-difluoro-N-(3-(6-(l-hydroxybutyl)-4-methylpyridin-3- yl)-l,6- naphthyridin-7-yl)cyclopropane-l-carboxamide Isomer 1: RTl(min): 6.44; LCMS (ESI, m/z): [M+H]+ = 413.2. ¹ H NMR (400 MHz, DMSO-d6): δ 11.40 (s, 1H), 9.31 (s, 1H), 9.14 (d, J = 2.4 Hz, 1H), 8.59 (d, J = 2.4 Hz, 2H), 8.47 (s, 1H), 7.52 (s, 1H), 5.40 (s, 1H), 4.65 - 4.61 (m, 1H), 3.14 - 3.05 (m, 1H), 2.37 (s, 3H), 2.15 - 2.05 (m, 2H), 1.81 - 1.73 (m, 1H), 1.69 - 1.60 (m, 1H), 1.45 - 1.35 (m, 2H), 0.93 - 0.90 (m, 3H).

[0405] (R)-2,2-difluoro-N-(3-(6-(l-hydroxybutyl)-4-methylpyridin-3- yl)-l,6- naphthyridin-7-yl)cyclopropane-l-carboxamide Isomer 2: RT2(min): 10.46; LCMS (ESI, m/z): [M+H]+ = 413.2. ¹ H NMR (400 MHz, DMSO-d6): 5 11.40 (s, 1H), 9.31 (s, 1H), 9.14 (d, J = 1.2 Hz, 1H), 8.60 (s, 2H), 8.47 (s, 1H), 7.53 (s, 1H), 5.44 - 5.38 (m, 1H), 4.65 - 4.62 (m, 1H), 3.14 - 3.05 (m, 1H), 2.38 (s, 3H), 2.17 - 2.03 (m, 2H), 1.81 - 1.73 (m, 1H), 1.70 - 1.61 (m, 1H), 1.45 - 1.34 (m, 2H), 0.93 - 0.89 (m, 3H).

Example 43. Synthesis of (lS,2S)-2-fluoro-N-(7-(6-((R)-l-hydroxy-2-(methylthio)ethyl) -4- methylpyridin-3-yl)-2, 6-naphthyridin-3-yl)cyclopropane-l -carboxamide (Compound 79) and (lS,2S)-2-fluoro-N-(7-(6-((S)-l-hydroxy-2-(methylthio)ethyl) -4-methylpyridin-3-yl)- 2, 6-naphthyridin-3-yl) cyclopropane-1 -carboxamide ( Compound 80)

Step 1: Synthesis of 5-bromo-4-methyl-2-vinylpyridine:

[0406] To a mixture of 2,5-dibromo-4-methylpyridine (15.0 g, 59.78 mmol) in dioxane (150.0 mL) and H2O (30.0 mL) was added 4,4,5,5-tetramethyl-2-vinyl-l,3,2-dioxaborolane (18.4 g, 119.56 mmol), K2CO3 (24.7 g, 179.34 mmol) and Pd(dppf)C12 (8.7 g, 11.95 mmol) at room temperature under N2. The resulting mixture was stirred at 85 °C for 2 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (1/1, v/v) to afford 5-bromo-4-methyl-2-vinylpyridine (6.0 g, 50%) as a brown yellow oil. LCMS (ESI, m/z): [M+H] ⁺ = 198.0.

Step 2: Synthesis of 5-bromo-4-methyl-2-(oxiran-2-yl)pyridine :

[0407] To a mixture of 5-bromo-4-methyl-2-vinylpyridine (6.0 g, 30.29 mmol) and NaHCO3 (3.3 g, 39.38 mmol) in DCM (60.0 mL) were added m-CPBA (6.2 g, 36.35 mmol) at room temperature. The resulting mixture was stirred at room temperature for 12 h. After the reaction was completed, the resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (1/1, v/v) to afford 5-bromo-4-methyl-2-(oxiran-2-yl)pyridine (3.6 g, 55%) as a brown solid. LCMS (ESI, m/z): [M+H] ⁺ = 214.0.

Step 3: Synthesis of l-(5-bromo-4-methylpyridin-2-yl)-2-(methylthio)ethan-l-ol:

[0408] To a mixture of 5-bromo-4-methyl-2-(oxiran-2-yl)pyridine (2.4 g, 11.21mmol) in MeOH (25.0 mL) was added CH3NaS (15.7 g, 20% in H2O) at room temperature. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (1/1, v/v) to afford l-(5- bromo-4-methylpyridin-2-yl)-2-(methylthio)ethan-l-ol (1.0 g, 34%) as a brown solid. LCMS (ESI, m/z): [M+H] ⁺ = 262.0.

Step 4: Synthesis of (6-(l-hydroxy-2-(methylthio)ethyl)-4-methylpyridin-3-yl)boro nic acid:

[0409] To a mixture of l-(5-bromo-4-methylpyridin-2-yl)-2-(methylthio)ethan-l-ol (500.0 mg, 1.90 mmol) in dioxane (8.0 mL) were added 4,4,4',4',5,5,5',5'-octamethyl-2,2'- bi(l,3,2-dioxaborolane) (968.6 mg, 3.81 mmol), KOAc (561.5 mg, 5.72 mmol) and Pd(dppf)C12 (279.1 mg, 0.38 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 2 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford (6-(l-hydroxy-2-(methylthio)ethyl)-4- methylpyri din-3 -yl)boronic acid (2.0 g, crude) as an brown solid. LCMS (ESI, m/z): [M+H] ⁺ = 228.1. Step 5: Synthesis of (lS,2S)-2-fluoro-N-(7-(6-(l-hydroxy-2-(methylthio)ethyl)-4- methylpyridin-3-yl)-2,6-naphthyridin-3-yl)cyclopropane-l-car boxamide:

[0410] To a mixture of (6-(l-hydroxy-2-(methylthio)ethyl)-4-methylpyridin-3-yl)boro nic acid (1.0 g, crude) in dioxane (10.0 mL) and H2O (2.0 mL) was added (lS,2S)-N-(7-chloro- 2,6-naphthyridin-3-yl)-2-fluorocyclopropane-l -carboxamide (400.8 mg, 1.50 mmol), K2CO3 (625.6 mg, 4.52 mmol) and Pd(dppf)C12 (220.8 mg, 0.3 mmol) at room temperature under N2. The resulting mixture was stirred at 85 °C for 1 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated in vacuo. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (10/1, v/v) to afford ( 1 S,2S)-2-fluoro-N-(7-(6-( l -hydroxy-2- (methylthio)ethyl)-4-methylpyri din-3 -yl)-2,6-naphthyri din-3 -yl)cy cl opropane-1 -carboxamide (70.0 mg, 18%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 413.1.

Step 6: Separation of (lS,2S)-2-fluoro-N-(7-(6-((R)-l -hydroxy-2 -(methylthio)ethyl)-4- methylpyridin-3-yl)-2,6-naphthyridin-3-yl)cyclopropane-l-car boxamide (Compound 79) and (lS,2S)-2-fluoro-N-(7-(6-((S)-l-hydroxy-2-(methylthio)ethyl) -4-methylpyridin-3-yl)-2,6- naphthyridin-3-yl)cyclopropane-l -carboxamide (Compound 80):

[0411] The product of (lS,2S)-2-fluoro-N-(7-(6-(l-hydroxy-2-(methylthio)ethyl)-4- m ethylpyri din-3 -yl)-2, 6-naphthyri din-3 -yl)cy cl opropane-1 -carboxamide (70.0 mg, 0.17 mmol) was separated by Prep-HPLC with the following conditions (Column: CHIRAL ART Amylose-SA, 2x25 cm, 5 μm; Mobile Phase A: Hex (0.5% 2M NH3-MeOH)— HPLC, Mobile Phase B: MeOH: DCM=1 : 1— HPLC; Flow rate: 20 mL/min; Gradient: 60% B to 60% B in 15 min; Wave Length: 220/254 nm; RTl(min): 6.57; RT2(min): 12.83) to afford (lS,2S)-2- fluoro-N-(7-(6-(l-hydroxy-2-(methylthio)ethyl)-4-methylpyrid in-3-yl)-2, 6-naphthyri din-3- yl)cy cl opropane-1 -carboxamide Isomer 1 (retention time 6.57 min, 17.2 mg, 49%) as a white solid and (lS,2S)-2-fluoro-N-(7-(6-(l-hydroxy-2-(methylthio)ethyl)-4-m ethylpyridin-3-yl)- 2,6-naphthyridin-3-yl)cyclopropane-l-carboxamide Isomer 2 (retention time 12.83 min, 12.9 mg, 36%) as a white solid. The absolute stereochemistry of Isomers 1 and 2 was not assigned. The two isomeric structures that could be obtained from chiral separation of the isomeric mixture as described above are shown as Compounds 79 and 80 in Table 1.

[0412] (lS,2S)-2-fluoro-N-(7-(6-(l-hydroxy-2-(methylthio)ethyl)-4-m ethylpyridin-3- yl)-2,6-naphthyridin-3-yl)cyclopropane-l-carboxamide Isomer 1: RTl(min): 6.57; LCMS (ESI, m/z): [M+H]+ = 413.1. ¹ H NMR (400 MHz, DMSO-d6): δ 11.24 (s, 1H), 9.51 (s, 1H), 9.34 (s, 1H), 8.69 (s, 1H), 8.61 (s, 1H), 8.19 (s, 1H), 7.51 (s, 1H), 5.70 (d, J = 5.2 Hz, 1H), 5.07 - 4.90 (m, 1H), 4.83 - 4.79 (m, 1H), 3.01 - 2.96 (m, 1H), 2.84 - 2.79 (m, 1H), 2.46 (s, 3H), 2.34 - 2.27 (m, 1H), 2.09 (s, 3H), 1.77 - 1.67 (m, 1H), 1.28 - 1.19 (m, 1H).

[0413] (lS,2S)-2-fluoro-N-(7-(6-(l-hydroxy-2-(methylthio)ethyl)-4-m ethylpyridin-3- yl)-2,6-naphthyridin-3-yl)cyclopropane-l-carboxamide Isomer 2: RT2(min): 12.83;

LCMS (ESI, m/z): [M+H]+ = 413.0. ¹ H NMR (400 MHz, DMSO-d6): δ 11.24 (s, 1H), 9.51 (s, 1H), 9.34 (s, 1H), 8.69 (s, 1H), 8.61 (s, 1H), 8.18 (s, 1H), 7.51 (s, 1H), 5.70 (d, J = 5.2 Hz, 1H), 5.08 - 4.89 (m, 1H), 4.83 - 4.79 (m, 1H), 3.01 - 2.96 (m, 1H), 2.84 - 2.79 (m, 1H), 2.46 (s, 3H), 2.32 - 2.28 (m, 1H), 2.08 (s, 3H), 1.76 - 1.68 (m, 1H), 1.26 - 1.20 (m, 1H).

Example 44. Synthesis ofN-{7-[6-(l-hydroxycyclobutyl)-4-methylpyridin-3-yl]-2,6- naphthyridin-3-yl}acetamide (Compound 81)

Step 1: Synthesis of l-(5-bromo-4-methylpyridin-2-yl)cyclobutan-l-ol:

[0414] To a solution of 5-bromo-2-iodo-4-methylpyridine (2.0 g, 6.71 mmol) in THF (100.0 mL) was added dropwise n-BuLi (2.6 mL, 2.5 mol/L) at -78 °C under N2. The resulting mixture was stirred at -78 °C for 5 min. Then cyclobutanone (941.1 mg, 13.43 mmol) was added dropwise to the mixture at -78 °C under N2. The resulting mixture was stirred at -78 °C for additional 2 h. After the reaction was completed, the reaction mixture was quenched with sat. NH4CI (aq.) at -78 °C and extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (3/1, v/v) to afford l-(5-bromo-4- methylpyridin-2-yl)cyclobutan-l-ol (500.0 mg, 30%) as a light yellow oil. LCMS (ESI, m/z): [M+H] ⁺ = 242.1.

Step 2: Synthesis of l- (5-bromo-4-methylpyridin-2-yl)cyclobutyl acetate:

[0415] To a mixture of l-(5-bromo-4-methylpyridin-2-yl)cyclobutan-l-ol (500.0 mg, 2.06 mmol) in pyridine (15.0 mL) was added acetyl chloride (486.3 mg, 6.20 mmol) and DMAP (50.5 mg, 0.41 mmol)at 0 °C under N2. The resulting mixture was stirred at 70 °C for 16 h. After the reaction was completed, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (1/1, v/v) to afford l-(5-bromo-4-methylpyridin-2-yl)cyclobutyl acetate (200.0 mg, 34%) as a light yellow oil. LCMS (ESI, m/z): [M+H] ⁺ = 284.2.

Step 3: Synthesis of l-[3-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl] cyclobutyl acetate:

[0416] To a mixture of l-(5-bromo-4-methylpyridin-2-yl)cyclobutyl acetate (190.0 mg, 0.67 mmol) and bis(pinacolato)diboron (509.4 mg, 2.01 mmol) in dioxane (5.0 mL) was added AcOK (196.9 mg, 2.01 mmol) and Pd(dppf)C12 (97.9 mg, 0.13 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 16 h. After the reaction was completed, the reaction mixture was diluted with H2O and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to afford l-[3-methyl-4-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]cyclobutyl acetate (600.0 mg, crude) as a brown solid. LCMS (ESI, m/z): [M+H] ⁺ = 331.2. Step 4: Synthesis of l-[5-(7-acetamido-2,6-naphthyridin-3-yl)-4-methylpyridin-2- yl]cyclobutyl acetate:

[0417] To a mixture of N-(7-chl oro-2, 6-naphthyri din-3 -yl)acetamide (130.0 mg, 0.59 mmol) and l-[3-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)p henyl]cyclobutyl acetate (581.1 mg, crude) in dioxane (5.0 mL) and H2O (1.0 mL) was added K2CO3 (243.2 mg, 1.76 mmol) and Pd(dppf)C12 (85.8 mg, 0.12 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 2 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (1/1, v/v) to afford l-[5-(7-acetamido-2,6- naphthyridin-3-yl)-4-methylpyridin-2-yl]cyclobutyl acetate (200.0 mg, 87%) as a brown oil. LCMS (ESI, m/z): [M+H] ⁺ = 391.4.

Step 5: Synthesis ofN-{7-[6-(l-hydroxycyclobutyl)-4-methylpyridin-3-yl]-2,6-na phthyridin-3- yl}acetamide (Compound 81):

[0418] To a solution of l-[5-(7-acetamido-2,6-naphthyridin-3-yl)-4-methylpyridin-2- yl]cyclobutyl acetate (160.0 mg, 0.41 mmol) in MeOH (5.0 mL) was added K2CO3 (169.9 mg, 1.23 mmol) at room temperature. The mixture was stirred at room temperature for 2 h. After the reaction was completed, the mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: (Column: XBridge Shield RP18 OBD Column, 30x150 mm, 5 pm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 24% B to 34% B in 10 min; Wave Length: 254 nm) to afford N-{7-[6-(l-hydroxycyclobutyl)- 4-methylpyridin-3-yl]-2,6-naphthyridin-3-yl}acetamide (Compound 81, 4.4 mg, 3%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 349.0. ¹ H NMR (400 MHz, DMSO-d ₆ ): 6 10.89 (s, 1H), 9.52 (s, 1H), 9.32 (s, 1H), 8.68 - 8.64 (m, 2H), 8.18 (s, 1H), 7.56 (s, 1H), 5.80 (s, 1H), 2.64 - 2.58 (m, 2H), 2.44 (s, 3H), 2.26 - 2.22 (m, 2H), 2.19 (s, 3H), 1.98 - 1.89 (m, 1H), 1.88 - 1.82 (m, 1H).

Example 45. Synthesis of (lR,2R)-2-fluoro-N-(3-{6-[(lS)-l-hydroxybutyl]-4-methylpyrid in- 3-yl}-2-methoxy-l,6-naphthyridin-7-yl)cyclopropane-l-carboxa mide (Compound 82) and (lR,2R)-2-fluoro-N-(3-{6-[(lR)-l-hydroxybutyl]-4-methylpyrid in-3-yl}-2-methoxy-l,6- naphthyridin-7-yl)cyclopropane-l -carboxamide (Compound 83)

Step 1: Synthesis of 3-bromo-7 -chlor o-2 -methoxy- 1 ,6-naphthyridine :

[0419] The solution of 3-bromo-2,7-dichloro-l,6-naphthyridine (2.0 g, 14.39 mmol) in MeOH (100.0 mL) was stirred at 85 °C for 4 h. After the reaction was completed, the mixture was concentrated under vacuum. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (8/2, v/v) to afford 3-bromo-7-chloro-2-methoxy-l,6- naphthyridine (1.5 g, 76%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 272.9.

Step 2: Synthesis of l-[5-(7-chloro-2-methoxy-l,6-naphthyridin-3-yl)-4-methylpyri din-2- yl]butan-l-one:

[0420] To a mixture of 3-bromo-7-chloro-2-methoxy-l,6-naphthyridine (1.5 g, 5.48 mmol) in l,4-dioxane/H2O (20.0 mL/4.0 mL) were added 6-butanoyl-4-methylpyri din-3 - ylboronic acid (1.4 g, 6.58 mmol), K2CO3 (1.5 g, 10.97 mmol) and Pd(dppf)C12 (401.3 mg, 0.55 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 2 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (1/1, v/v) to afford l-[5-(7-chloro-2-methoxy-l,6-naphthyridin-3-yl)-4-methylpyri din-2-yl]butan-l-one (1.0 g, 51%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 356.1.

Step 3: Synthesis of (lR,2R)-N-[3-(6-butanoyl-4-methylpyridin-3-yl)-2-methoxy-l,6 - naphthyridin- 7-yl ]-2-fluorocyclopropane-l -carboxamide:

[0421] To a solution of l-[5-(7-chloro-2-methoxy-l,6-naphthyridin-3-yl)-4- methylpyridin-2-yl]butan-l-one (500.0 mg, 1.41 mmol) in 1,4-dioxane (10.0 mL) were added (lR,2R)-2-fluorocyclopropane-l-carboxamide (289.7 mg, 2.81 mmol), CS2CO3 (915.7 mg, 2.81 mmol), Pd2(dba)3 (128.9 mg, 0.14 mmol) and XPhos (134.0 mg, 0.28 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 2 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (10/1, v/v) to afford (lR,2R)-N-[3-(6- butanoyl-4-methylpyridin-3-yl)-2-methoxy- 1 ,6-naphthyridin-7-yl]-2-fluorocyclopropane- 1 - carboxamide (350.0 mg, 58%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 423.2.

Step 4: Synthesis of (lR,2R)-2-fluoro-N-{3-[6-(l-hydroxybutyl)-4-methylpyridin-3- yl]-2- methoxy-l,6-naphthyridin-7-yl}cyclopropane-l -carboxamide:

[0422] To a solution of (lR,2R)-N-[3-(6-butanoyl-4-methylpyridin-3-yl)-2-methoxy-l,6 - naphthyridin-7-yl]-2-fluorocyclopropane-l -carboxamide (300.0 mg, 0.71 mmol) in THF/MeOH (10.0 mL/2.0 mL) was added NaBH ₄ (268.6 mg, 7.10 mmol) at 0 °C under N2. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the mixture was quenched with MeOH and then concentrated under vacuum. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (10/1, v/v) to afford (lR,2R)-2-fluoro-N-{3-[6-(l-hydroxybutyl)-4-methylpyridin-3- yl]-2-methoxy-l,6- naphthyridin-7-yl}cyclopropane-l-carboxamide (100.0 mg, 33%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 425.2.

Step 5: Separation of (lR,2R)-2-fluoro-N-(3-{6-[(lS)-l-hydroxybutyl]-4-methylpyrid in-3-yl}~ 2-methoxy-l,6-naphthyridin-7-yl)cyclopropane-l -carboxamide (Compound 82) and (1R,2R)~ 2-jluoro-N-(3-{6-[(lR)-l-hydroxybutyl]-4-methylpyridin-3-yl} -2-methoxy-l,6-naphthyridin- 7-yl)cyclopropane-l -carboxamide (Compound 83):

[0423] The product of (lR,2R)-2-fluoro-N-{3-[6-(l-hydroxybutyl)-4-methylpyridin-3- yl]-2-methoxy-l,6-naphthyridin-7-yl}cyclopropane-l-carboxami de (100.0 mg, 0.24 mmol) was separated by Prep-Chiral-HPLC with the following conditions: (Column: Lux 5um Cellulose-4, 2.12x25 cm, 5 μm; Mobile Phase A: Hex (0.5% 2M NH ₃ -MeOH)-HPLC, Mobile Phase B: MeOH: EtOH=l : 1— HPLC; Flow rate: 20 mL/min; Gradient: 90% B to 90% B in 12.5 min; Wave Length: 254/220 nm; RTl(min): 6.72; RT2(min): 9.07) to afford (lR,2R)-2-fluoro-N-(3-{6-[l-hydroxybutyl]-4-methylpyridin-3- yl}-2-methoxy-l,6- naphthyridin-7-yl)cyclopropane-l -carboxamide Isomer 1 (retention time 6.72 min, 33.8 mg, 67%) as a white solid and (lR,2R)-2-fluoro-N-(3-{6-[l-hydroxybutyl]-4-methylpyridin-3- yl}-2-methoxy-l,6-naphthyridin-7-yl)cyclopropane-l-carboxami de Isomer 2 (retention time 9.07 min, 28.8 mg, 57%) as a white solid. The absolute stereochemistry of Isomers 1 and 2 was not assigned. The two isomeric structures that could be obtained from chiral separation of the isomeric mixture as described above are shown as Compounds 82 and 83 in Table 1.

[0424] (lR,2R)-2-fluoro-N-(3-{6-[l-hydroxybutyl]-4-methylpyridin-3- yl}-2-methoxy- l,6-naphthyridin-7-yl)cyclopropane-l-carboxamide Isomer 1: RTl(min): 6.72; LCMS (ESI, m/z): [M+H]+ = 425.2. ¹ H NMR (400 MHz, DMSO-d6): δ 11.06 (s, 1H), 9.04 (s, 1H), 8.42 (s, 1H), 8.31 (s, 1H), 8.27 (s, 1H), 7.44 (s, 1H), 5.30 (d, J = 4.8 Hz, 1H), 5.06 - 4.87 (m, 1H), 4.62 - 4.58 (m, 1H), 4.00 (s, 3H), 2.32 - 2.28 (m, 1H), 2.17 (s, 3H), 1.77 - 1.61 (m, 3H), 1.45 - 1.37 (m, 2H), 1.24 - 1.19 (m, 1H), 0.94 - 0.90 (m, 3H).

[0425] (lR,2R)-2-fluoro-N-(3-{6-[l-hydroxybutyl]-4-methylpyridin-3- yl}-2-methoxy- l,6-naphthyridin-7-yl)cyclopropane-l-carboxamide Isomer 2: RT2(min): 9.07; LCMS (ESI, m/z): [M+H]+ = 425.1. ¹ H NMR (400 MHz, DMSO-d6): δ 11.08 (s, 1H), 9.04 (s, 1H), 8.42 (s, 1H), 8.31 - 8.27 (m, 2H), 7.45 (s, 1H), 5.32 (d, J = 4.8 Hz, 1H), 5.06 - 4.88 (m, 1H), 4.62 - 4.58 (m, 1H), 4.00 (s, 3H), 2.33 - 2.26 (m, 1H), 2.17 (s, 3H), 1.79 - 1.61 (m, 3H), 1.46 - 1.37 (m, 2H), 1.26 - 1.19 (m, 1H) 0.94 - 0.90 (m, 3H).

Example 46. Synthesis of (lS,2S)-2-fluoro-N-(3-{6-[(lS)-l-hydroxybutyl]-4-methylpyrid in- 3-yl}-2-methoxy-l,6-naphthyridin-7-yl)cyclopropane-l-carboxa mide (Compound 84) and (lS,2S)-2-fluoro-N-(3-{6-[(lR)-l-hydroxybutyl]-4-methylpyrid in-3-yl}-2-methoxy-l,6- naphthyridin-7-yl)cyclopropane-l -carboxamide (Compound 85)

Step 1: Synthesis of l-[5-(7-chloro-2-methoxy-l,6-naphthyridin-3-yl)-4-methylpyri din-2- yl]butan-l-one:

[0426] To a solution of 3-bromo-7-chloro-2-methoxy-l,6-naphthyridine (1.5 g, 5.48 mmol) in dioxane (20.0 mL/H2O (5.0 mL) were added 6-butanoyl-4-methylpyri din-3 - ylboronic acid (1.1 g, 5.48 mmol), K2CO3 (2.2 g, 16.45 mmol) and Pd(dppf)C12 (0.4 g, 0.54 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 2 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (10/1, v/v) to afford l-[5-(7-chloro-2-methoxy-l,6-naphthyridin-3-yl)-4-methylpyri din-2-yl]butan-l-one (1.0 g, 51%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 356.1

Step 2: Synthesis of (lS,2S)-N-(3-(6-butyryl-4-methylpyridin-3-yl)-2-methoxy-l,6- naphthyridin-7-yl)-2-fluorocyclopropane-l-carboxamide:

[0427] To a solution of l-[5-(7-chloro-2-methoxy-l,6-naphthyridin-3-yl)-4- methylpyridin-2-yl]butan-l-one (500.0 mg, 1.40 mmol) in dioxane (10.0 mL) were added (lS,2S)-2-fluorocyclopropane-l -carboxamide (173.8 mg, 1.68 mmol), CS2CO3 (1373.5 mg, 4.21 mmol), XPhos (66.9 mg, 0.14 mmol) and Pd(0Ac)2 (63.1 mg, 0.28 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 1 h under N2. After the reaction was completed, the resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CELCE/MeOH (1/1, v/v) to afford (lS,2S)-N-(3-(6-butyryl-4-methylpyridin-3-yl)-2- methoxy-l,6-naphthyridin-7-yl)-2-fluorocyclopropane-l-carbox amide (300.0 mg, 54%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 423.2.

Step 3: Synthesis of (lS,2S)-2-fluoro-N-(3-(6-(l-hydroxybutyl)-4-methylpyridin-3- yl)-2- methoxy-l,6-naphthyridin-7-yl)cyclopropane-l-carboxamide:

[0428] To a solution of (lS,2S)-N-(3-(6-butyryl-4-methylpyridin-3-yl)-2-methoxy-l,6- naphthyridin-7-yl)-2-fluorocyclopropane-l -carboxamide (200.0 mg, 0.47 mmol) in THF (4.0 mL)/MeOH (1.0 mL) were added NaBH4 (89.5 mg, 2.36 mmol) at 0 °C under N2. The resulting mixture was stirred at room temperature for 1 h under N2. After the reaction was completed, the resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (5/1, v/v) to afford (lS,2S)-2-fluoro-N-(3-(6-(l-hydroxybutyl)-4-methylpyridin-3- yl)-2- methoxy-l,6-naphthyridin-7-yl)cyclopropane-l-carboxamide (50.0 mg, 24%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 425.2

Step 4: Synthesis of (lS,2S)-2-fluoro-N-(3-{6-[(lS)-l-hydroxybutyl]-4-methylpyrid in-3-yl}-2- methoxy-l,6-naphthyridin-7-yl)cyclopropane-l-carboxamide (Compound 84) and (lS,2S)-2- fluoro-N-(3-{6-[(lR)-l-hydroxybutyl]-4-methylpyridin-3-yl}-2 -methoxy-l,6-naphthyridin-7- yl)cyclopropane-l -carboxamide (Compound 85):

[0429] The racemic mixture of (lS,2S)-2-fluoro-N-(3-(6-(l-hydroxybutyl)-4- methylpyridin-3-yl)-2-methoxy-l,6-naphthyridin-7-yl)cy cl opropane-1 -carboxamide (50.0 mg, 0.11 mmol) was separated by Prep-HPLC with the following conditions (Column: Lux 5um Cellulose-4, 2.12x25 cm, 5 pm; Mobile Phase A: Hex(0.5% 2M NH ₃ -MeOH)-HPLC, Mobile Phase B: MeOH: EtOH=l : 1— HPLC; Flow rate: 20 mL/min; Gradient: 50% B to 50% B in 14 min; Wave Length: 254/220 nm; RTl(min): 8.65; RT2(min): 10.61) to afford (lS,2S)-2-fhioro-N-(3-{6-[l-hydroxybutyl]-4-methylpyridin-3- yl}-2-methoxy-l,6- naphthyridin-7-yl)cyclopropane-l -carboxamide Isomer 1 (retention time 8.65 min, 19.4 mg, 77%) as a white solid and (lS,2S)-2-fluoro-N-(3-{6-[(lR)-l-hydroxybutyl]-4-methylpyrid in- 3-yl}-2-methoxy-l,6-naphthyridin-7-yl)cyclopropane-l-carboxa mide Isomer 2 (retention time 10.61 min, 18.2 mg, 72%) as a white solid. The absolute stereochemistry of Isomers 1 and 2 was not assigned. The two isomeric structures that could be obtained from chiral separation of the isomeric mixture as described above are shown as Compounds 84 and 85 in Table 1.

[0430] (lS,2S)-2-fluoro-N-(3-{6-[l-hydroxybutyl]-4-methylpyridin-3- yl}-2-methoxy- l,6-naphthyridin-7-yl)cyclopropane-l-carboxamide Isomer 1: RTl(min): 8.65, LCMS (ESI, m/z): [M+H]+ = 425.1. ¹ H NMR (400 MHz, DMSO-d6): δ 11.08 (s, 1H), 9.04 (s, 1H), 8.42 (s, 1H), 8.31 (s, 1H), 8.27 (s, 1H), 7.45 (s, 1H), 5.32 (d, J = 4.8 Hz, 1H), 5.06 - 4.88 (m, 1H), 4.62 - 4.58 (m, 1H), 4.00 (s, 3H), 2.33 - 2.27 (m, 1H), 2.17 (s, 3H), 1.78 - 1.62 (m, 3H),

1.45 - 1.38 (m, 2H), 1.24 - 1.19 (m, 1H), 0.94 - 0.90 (m, 3H).

[0431] (lS,2S)-2-fluoro-N-(3-{6-[l-hydroxybutyl]-4-methylpyridin-3- yl}-2-methoxy- l,6-naphthyridin-7-yl)cyclopropane-l-carboxamide Isomer 2: RT2(min): 10.61, LCMS (ESI, m/z): [M+H]+ = 425.2. ¹ H NMR (400 MHz, DMSO-d6): δ 11.08 (s, 1H), 9.04 (s, 1H), 8.42 (s, 1H), 8.31 (s, 1H), 8.27 (s, 1H), 7.45 (s, 1H), 5.31 (d, J = 4.8 Hz, 1H), 5.06 - 4.88 (m, 1H), 4.62 - 4.58 (m, 1H), 4.00 (s, 3H), 2.33 - 2.27 (m, 1H), 2.17 (s, 3H), 1.77 - 1.60 (m, 3H),

1.46 - 1.36 (m, 2H), 1.26 - 1.17 (m, 1H), 0.94 - 0.90 (m, 3H).

Example 47. Synthesis of (lS,2S)-2-fluoro-N-{7-[6-(3-hydroxypentan-3-yl)-4- methylpyridin-3-yl]-2, 6-naphthyridin-3-yl}cyclopropane-l -carboxamide (Compound 86)

[0432] To a stirred mixture of (lS,2S)-2-fluoro-N-[7-(4-methyl-6-propanoylpyridin-3- yl)-2,6-naphthyridin-3-yl]cyclopropane-l -carboxamide (200.0 mg, 0.53 mmol) in THF (6.0 mL) was added ethylmagnesium bromide (0.8 mL, 2 mol/L) at 0 °C under N2.The resulting mixture was stirred at 0 °C for 2 h. After the reaction was completed, the reaction mixture was quenched with sat. NH4CI (aq.) at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (8/1, v/v) and then purified by Prep-HPLC with the following conditions (Column: XBridge Prep Phenyl OBD Column, 19x250 mm, 5 pm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: MeOH— HPLC; Flow rate: 25 mL/min; Gradient: 61% B to 66% B in 10 min; Wave Length: 254 nm) to afford (lS,2S)-2-fhioro-N-{7-[6-(3- hydroxypentan-3-yl)-4-methylpyridin-3-yl]-2,6-naphthyridin-3 -yl}cyclopropane-l- carboxamide (Compound 86, 13.7 mg, 6%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 409.1. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.21 (s, 1H), 9.50 (s, 1H), 9.33 (s, 1H), 8.69 (s, 1H), 8.62 (s, 1H), 8.20 (s, 1H), 7.57 (s, 1H), 5.07 - 4.87 (m, 2H), 2.46 (s, 3H), 2.32 - 2.24 (m, 1H), 1.99 - 1.89 (m, 2H), 1.78 - 1.67 (m, 3H), 1.27 - 1.19 (m, 1H), 0.68 - 0.65 (m, 6H).

Example 48. Synthesis ofN-(7-{6-[(lR)-l-hydroxybutyl]-4-methylpyridin-3-yl}-2,6- naphthyridin-3-yl)-3-methyloxetane-3-carboxamide (Compound 87) and N-(7-{6-[(lS)-l- hydroxybutyl]-4-methylpyridin-3-yl}-2,6-naphthyridin-3-yl)-3 -methyloxetane-3- carboxamide (Compound 88)

Step 1: Synthesis ofN-[7-(6-butanoyl-4-methylpyridin-3-yl)-2,6-naphthyridin-3- yl]-3- methyloxetane-3-carboxamide:

[0433] To a stirred mixture of l-[5-(7-amino-2,6-naphthyridin-3-yl)-4-methylpyridin-2- yl]butan-l-one (1.4 g, 4.57 mmol) and 3 -methyloxetane-3 -carboxylic acid (1.1 g, 9.14 mmol) in pyridine (12.0 mL) was added EDCI (1.8 g, 9.14 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography with acetonitrile/water (64/36, v/v) to afford N- [7-(6-butanoyl-4-methylpyridin-3-yl)-2,6-naphthyridin-3-yl]- 3-methyloxetane-3- carboxamide (500.0 mg, 27%) as a brown solid. LCMS (ESI, m/z): [M+H] ⁺ = 405.1. Step 2: Synthesis ofN-{7-[6-(l-hydroxybutyl)-4-methylpyridin-3-yl]-2,6-naphthy ridin-3-yl}- 3-methyloxetane-3-carboxamide:

[0434] To a stirred mixture of N-[7-(6-butanoyl-4-methylpyridin-3-yl)-2,6-naphthyridin- 3-yl]-3-methyloxetane-3-carboxamide (200.0 mg, 0.49 mmol) in THF (15.0 mL) and MeOH (1.5 mL) was added NaBH ₄ (56.1 mg, 1.48 mmol) at 0 °C under N2. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the reaction mixture was quenched with water at 0 °C and then evaporated in avcuo. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (10/1, v/v) to afford N-{7-[6- (l-hydroxybutyl)-4-methylpyridin-3-yl]-2,6-naphthyridin-3-yl }-3-methyloxetane-3- carboxamide (80.0 mg, 39%) as a light yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 407.2.

Step 3: Separation ofN-(7-{6-[(lR)-l-hydroxybutyl]-4-methylpyridin-3-yl}-2,6-na phthyridin- 3-yl)-3-methyloxetane-3-carboxamide (Compound 87) andN-(7-{6-[(lS)-l-hydroxybutyl]-4- methylpyridin-3-yl}-2, 6-naphthyridin-3-yl)-3-methyloxetane-3-carboxamide (Compound 88):

[0435] The racemic mixture ofN-{7-[6-(l-hydroxybutyl)-4-methylpyridin-3-yl]-2,6- naphthyridin-3-yl} -3 -methyloxetane-3 -carboxamide (80.0 mg, 0.19 mmol) was separated by Prep-Chiral-HPLC with the following conditions (Column: Lux 5um Cellulose-4, 2.12x25 cm, 5 μm; Mobile Phase A: Hex (0.5% 2M NH ₃ -MeOH)-HPLC, Mobile Phase B: MeOH: EtOH=l : 1--HPLC; Flow rate: 20 mL/min; Gradient: 70% B to 70% B in 10.5 min; Wave Length: 254/220 nm; RTl(min): 7.16; RT2(min): 8.86) to afford N-(7-{6-[l-hydroxybutyl]- 4-methylpyridin-3-yl}-2,6-naphthyridin-3-yl)-3 -methyloxetane-3 -carboxamide Enantiomer 1 (retention time 7.16 min, 6.6 mg, 16%) as a yellow solid and N-(7-{6-[l-hydroxybutyl]-4- methylpyridin-3-yl}-2,6-naphthyridin-3-yl)-3-methyloxetane-3 -carboxamide Enantiomer 2 (retention time 8.86 min, 13.3 mg, 33%) as a yellow solid. The absolute stereochemistry of Enantiomers 1 and 2 was not assigned. The two enantiomeric structures that could be obtained from chiral separation of the enantiomeric mixture as described above are shown as Compounds 87 and 88 in Table 1.

[0436] N-(7-{6-[l-hydroxybutyl]-4-methylpyridin-3-yl}-2,6-naphthyri din-3-yl)-3- methyloxetane-3-carboxamide Enantiomer 1: RTl(min): 7.16; LCMS (ESI, m/z): [M+H]+ = 407.1. ¹ H NMR (400 MHz, DMSO-d6): δ 10.93 (s, 1H), 9.54 (s, 1H), 9.35 (s, 1H), 8.73 (s, 1H), 8.59 (s, 1H), 8.19 (s, 1H), 7.47 (s, 1H), 5.34 (d, J = 4.8 Hz, 1H), 4.90 (d, J = 6.4 Hz, 2H), 4.65 - 4.60 (m, 1H), 4.41 (d, J = 6.4 Hz, 2H), 2.46 (s, 3H), 1.82 - 1.75 (m, 1H), 1.68 (s, 3H), 1.66 - 1.61 (m, 1H), 1.47 - 1.35 (m, 2H), 0.94 - 0.89 (m, 3H).

[0437] N-(7-{6-[l-hydroxybutyl]-4-methylpyridin-3-yl}-2,6-naphthyri din-3-yl)-3- methyloxetane-3-carboxamide Enantiomer 2: RT2(min): 8.86; LCMS (ESI, m/z): [M+H]+ = 407.1. ¹ H NMR (400 MHz, DMSO-d6): δ 10.93 (s, 1H), 9.54 (s, 1H), 9.35 (s, 1H), 8.73 (s, 1H), 8.59 (s, 1H), 8.19 (s, 1H), 7.47 (s, 1H), 5.34 (d, J = 5.2 Hz, 1H), 4.90 (d, J = 6.4 Hz, 2H), 4.65 - 4.60 (m, 1H), 4.41 (d, J = 6.4 Hz, 2H), 2.46 (s, 3H), 1.84 - 1.73 (m, 1H), 1.68 (s, 3H), 1.65 - 1.61 (m, 1H), 1.47 - 1.35 (m, 2H), 0.93 - 0.90 (m, 3H).

Example 49. Synthesis of (2S)-N-(7-{6-[(lR)-l-hydroxybutyl]-4-methylpyridin-3-yl}-2,6 - naphthyridin-3-yl)-2-methoxypropanamide (Compound 89) and (2S)-N-(7-{6-[(lS)-l- hydroxybutyl]-4-methylpyridin-3-yl}-2,6-naphthyridin-3-yl)-2 -methoxypropanamid (Compound 90)

Step 1: Synthesis of (2S)-N-[7-(6-butanoyl-4-methylpyridin-3-yl)-2,6-naphthyridin -3-yl]-2- methoxypropanamide:

[0438] To a stirred mixture of l-[5-(7-amino-2,6-naphthyridin-3-yl)-4-methylpyridin-2- yl]butan-l-one (700.0 mg, 2.29 mmol) and (2S)-2-methoxypropanoic acid (951.5 mg, 9.14 mmol) in pyridine (20.0 mL) was added EDCI (876.0 mg, 4.57 mmol) at room temperature under N2. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with dichloromethane/methanol (10/1, v/v) to afford (2S)-N- [7-(6-butanoyl-4-methylpyridin-3-yl)-2,6-naphthyridin-3-yl]- 2-methoxypropanamide (150.0 mg, 16%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 393.5.

Step 2: Synthesis of (2S)-N-{7-[6-(l-hydroxybutyl)-4-methylpyridin-3-yl]-2,6-naph thyridin-3- yl}-2-methoxypropanamide:

[0439] To a stirred mixture of (2S)-N-[7-(6-butanoyl-4-methylpyridin-3-yl)-2,6- naphthyridin-3-yl]-2-methoxypropanamide (130.0 mg, 0.33 mmol) in THF (4.0 mL) and MeOH (0.4 mL) was added NaBH ₄ (37.6 mg, 0.99 mmol) at 0 °C under N2. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the reaction mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with dichloromethane/methanol (10/1, v/v) to afford (2S)-N-{7-[6-(l- hydroxybutyl)-4-methylpyridin-3-yl]-2,6-naphthyridin-3-yl}-2 -methoxypropanamide (60.0 mg, 45%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 395.3.

Step 3 Separation of (2S)-N-(7-{6-[(lR)-l-hydroxybutyl]-4-methylpyridin-3-yl}-2,6 - naphthyridin-3-yl)-2-methoxypropanamide (Compound 89) and (2S)-N-(7-{6-[(lS)-l- hydroxybutyl]-4-methylpyridin-3-yl}-2,6-naphthyridin-3-yl)-2 -methoxypropanamid (Compound 90):

[0440] The product of (2S)-N-{7-[6-(l-hydroxybutyl)-4-methylpyridin-3-yl]-2,6- naphthyridin-3-yl}-2-methoxypropanamide (60.0 mg, 0.15 mmol) was separated by Prep- Chiral-HPLC with the following conditions (Column: CHIRAL ART Amylose-SA, 2x25 cm, 5 pm; Mobile Phase A: MtBE(0.1% FA)-HPLC, Mobile Phase B: EtOH: DCM=1 : 1- HPLC; Flow rate: 20 mL/min; Gradient: 20% B to 20% B in 17 min; Wave Length: 220/254 nm; RTl(min): 10.35; RT2(min): 14.39) to afford (2S)-N-(7-{6-[l-hydroxybutyl]-4- methylpyridin-3-yl}-2,6-naphthyridin-3-yl)-2-methoxypropanam ide Isomer 1 (retention time 10.35 min, 26.8 mg, 89%) as a white solid and (2S)-N-(7-{6-[l-hydroxybutyl]-4- methylpyridin-3-yl}-2,6-naphthyridin-3-yl)-2-methoxypropanam ide Isomer 2 (retention time 14.39 min, 26.0 mg, 87%) as a white solid. The absolute stereochemistry of Isomers 1 and 2 was not assigned. The two isomeric structures that could be obtained from chiral separation of the isomeric mixture as described above are shown as Compounds 89 and 90 in Table 1.

[0441] (2S)-N-(7-{6-[l-hydroxybutyl]-4-methylpyridin-3-yl}-2,6-naph thyridin-3-yl)- 2-methoxypropanamide Isomer 1 : RTl(min): 10.35, LCMS (ESI, m/z): [M+H]+ = 395.1. ¹ H NMR (400 MHz, DMSO-d6): δ 10.46 (s, 1H), 9.54 (s, 1H), 9.35 (s, 1H), 8.71 (s, 1H), 8.59 (s, 1H), 8.20 (s, 1H), 7.47 (s, 1H), 5.34 (d, J = 4.8 Hz, 1H), 4.64 - 4.60 (m, 1H), 4.15 - 4.10 (m, 1H), 3.36 (s, 3H), 2.45 (s, 3H), 1.81 - 1.73 (m, 1H), 1.70 - 1.62 (m, 1H), 1.45 - 1.36 (m, 5H), 0.93 - 0.86 (m, 3H).

[0442] (2S)-N-(7-{6-[l-hydroxybutyl]-4-methylpyridin-3-yl}-2,6-naph thyridin-3-yl)- 2-methoxypropanamide Isomer 2: RT2(min): 14.39, LCMS (ESI, m/z): [M+H]+ = 395.1. ¹ H NMR (400 MHz, DMSO-d6): δ 10.46 (s, 1H), 9.54 (s, 1H), 9.35 (s, 1H), 8.71 (s, 1H), 8.58 (s, 1H), 8.19 (s, 1H), 7.47 (s, 1H), 5.34 (d, J = 4.8 Hz, 1H), 4.65 - 4.60 (m, 1H), 4.14 - 4.09 (m, 1H), 3.36 (s, 3H), 2.45 (s, 3H), 1.82 - 1.73 (m, 1H), 1.70 - 1.61 (m, 1H), 1.45 - 1.36 (m, 5H), 0.93 - 0.89 (m, 3H).

Example 50. Synthesis of (lR,2R)-2-fluoro-N-(7-(6-((S)-l-hydroxybutyl-l-d)-4- methylpyridin-3-yl)-2, 6-naphthyridin-3-yl)cyclopropane-l -carboxamide (Compound 91 ) and (lR,2R)-2-fluoro-N-(7-(6-((R)-l-hydroxybutyl-l-d)-4-methylpy ridin-3-yl)-2,6- naphthyridin-3-yl)cyclopropane-l-carboxamide (Compound 92)

Step 1: Synthesis of (lR,2R)-N-[7-(6-butanoyl-4-methylpyridin-3-yl)-2,6-naphthyri din-3-yl]~ 2-fluorocyclopropane-l -carboxamide :

[0443] To a mixture of l-[5-(7-amino-2,6-naphthyridin-3-yl)-4-methylpyridin-2- yl]butan-l-one (500.0 mg, 1.63 mmol) in pyridine (10.0 mL) was added (lR,2R)-2- fluorocyclopropane-1 -carboxylic acid (509.6 mg, 4.90 mmol) and EDCI (938.6 mg, 4.90 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (1/1, v/v) to afford (lR,2R)-N-[7-(6-butanoyl-4-methylpyridin-3-yl)-2,6-naphthyri din-3-yl]-2- fluorocy cl opropane-1 -carboxamide (327.0 mg, 51%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 393.2

Step 2: Synthesis of (lR,2R)-2-fluoro-N-(7-(6-(l-hydroxybutyl-l-d)-4-methylpyridi n-3-yl)- 2,6-naphthyridin-3-yl)cyclopropane-l-carboxamide:

[0444] To a solution of (lR,2R)-N-[7-(6-butanoyl-4-methylpyridin-3-yl)-2,6- naphthyri din-3 -yl]-2-fluorocy cl opropane-1 -carboxamide (300.0 mg, 0.76 mmol) in CD3OD (2.0 mL) and THF (8.0 mL) was added NaBD4 (144.6 mg, 3.82 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the reaction mixture was quenched with H2O at 0 °C and then extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (9/1, v/v) to afford (lR,2R)-2-fluoro-N- (7-(6-(l-hydroxybutyl-l-d)-4-methylpyridin-3-yl)-2,6-naphthy ridin-3-yl)cyclopropane-l- carboxamide (148.0 mg, 48%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 396.2.

Step 3: Separation of (lR,2R)-2-fluoro-N-(7-(6-((S)-l-hydroxybutyl-l-d)-4-methylpy ridin-3- yl)-2,6-naphthyridin-3-yl)cyclopropane-l -carboxamide (Compound 91) and (lR,2R)-2- fluoro-N-(7-( 6-( (R)-l-hydroxybutyl-l-d)-4-methylpyridin-3-yl)-2, 6-naphthyridin-3- yl)cyclopropane-l -carboxamide (Compound 92):

[0445] The product of (lR,2R)-2-fluoro-N-(7-(6-(l-hydroxybutyl-l-d)-4-methylpyridi n- 3-yl)-2,6-naphthyridin-3-yl)cyclopropane-l-carboxamide (148.0 mg, 0.37 mmol) was separated by Prep-Chiral-HPLC with the following conditions (Column: CHIRAL ART Amylose-SA, 2x25 cm, 5 μm; Mobile Phase A: Hex(0.2% FA)— HPLC, Mobile Phase B: MeOH: DCM=1 : 1— HPLC; Flow rate: 20 mL/min; Gradient: 30% B to 30% B in 22 min; Wave Length: 220\254 nm; RTl(min): 15.16; RT2(min): 18.96) to afford (lR,2R)-2-fluoro- N-(7-(6-(l-hydroxybutyl-l-d)-4-methylpyridin-3-yl)-2,6-napht hyridin-3-yl)cyclopropane-l- carboxamide Isomer 1 (retention time 15.16 min, 31.9 mg, 43%) as a white solid and (lR,2R)-2-fhioro-N-(7-(6-(l-hydroxybutyl-l-d)-4-methylpyridi n-3-yl)-2,6-naphthyri din-3- yl)cyclopropane-l -carboxamide Isomer 2 (retention time 18.96 min, 27.6 mg, 37%) as a white solid. The absolute stereochemistry of Isomers 1 and 2 was not assigned. The two isomeric structures that could be obtained from chiral separation of the isomeric mixture as described above are shown as Compounds 91 and 92 in Table 1.

[0446] (lR,2R)-2-fluoro-N-(7-(6-(l-hydroxybutyl-l-d)-4-methylpyridi n-3-yl)-2,6- naphthyridin-3-yl)cyclopropane-l-carboxamide Isomer 1: RTl(min): 15.16; LCMS (ESI, m/z): [M+H]+ = 396.2. ¹ H NMR (400 MHz, DMSO-d6): δ 11.20 (s, 1H), 9.50 (s, 1H), 9.34 (s, 1H), 8.68 (s, 1H), 8.58 (s, 1H), 8.17 (s, 1H), 7.47 (s, 1H), 5.29 (s, 1H), 5.07 - 4.89 (m, 1H), 2.45 (s, 3H), 2.34 - 2.29 (m, 1H), 1.78 - 1.62 (m, 3H), 1.43 - 1.37 (m, 2H), 1.28 - 1.19 (m, 1H), 0.93 - 0.90 (m, 3H).

[0447] (lR,2R)-2-fluoro-N-(7-(6-(l-hydroxybutyl-l-d)-4-methylpyridi n-3-yl)-2,6- naphthyridin-3-yl)cyclopropane-l-carboxamide Isomer 2: RT2(min): 18.96; LCMS (ESI, m/z): [M+H]+ = 396.1. ¹ H NMR (400 MHz, DMSO-d6): δ 11.20 (s, 1H), 9.50 (s, 1H), 9.34 (s, 1H), 8.68 (s, 1H), 8.58 (s, 1H), 8.17 (s, 1H), 7.47 (s, 1H), 5.29 (s, 1H), 5.07 - 4.89 (m, 1H), 2.45 (s, 3H), 2.34 - 2.29 (m, 1H), 1.78 - 1.62 (m, 3H), 1.45 - 1.35 (m, 2H), 1.28 - 1.19 (m, 1H), 0.93 - 0.90 (m, 3H).

Example 51. Synthesis of (lR,2R)-2-fluoro-N-(3-{6-[(lS)-l-hydroxybutyl]-4-methylpyrid in- 3-yl}-l,6-naphthyridin-7-yl)cyclopropane-l-carboxamide (Compound 93) and (lR,2R)-2- fluoro-N-(3-{6-[(lR)-l-hydroxybutyl]-4-methylpyridin-3-yl}-l ,6-naphthyridin-7- yl) cyclopropane-1 -carboxamide (Compound 94)

Step 1: Synthesis of (lR,2R)-N-[3-(6-butanoyl-4-methylpyridin-3-yl)-l,6-naphthyri din-7-yl]~ 2-fluorocyclopropane-l -carboxamide : [0448] To a solution l-[5-(7-chloro-l,6-naphthyridin-3-yl)-4-methylpyridin-2-yl]b utan-l- one (600.0 mg, 1.84 mmol) in dioxane (30.0 mL) were added (lR,2R)-2-fluorocyclopropane- 1-carboxamide (284.8 mg, 2.76 mmol), CS2CO3 (1800.1 mg, 5.52 mmol), Brettphos (197.7 mg, 0.36 mmol) and Brettphos Pd G3 (166.9 mg, 0.18 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 2 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated in vacuo. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (2/1, v/v) to afford (lR,2R)-N-[3-(6-butanoyl-4- methylpyri din-3 -yl)-l,6-naphthyri din-7-yl]-2-fluorocy cl opropane-1 -carboxamide (400.0 mg, 55%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 393.2

Step 2: Synthesis of (lR,2R)-2-fluoro-N-{3-[6-(l-hydroxybutyl)-4-methylpyridin-3- yl]-l,6- naphthyridin-7-yl}cyclopropane-l -carboxamide:

[0449] To a solution of (lR,2R)-N-[3-(6-butanoyl-4-methylpyridin-3-yl)-l,6- naphthyridin-7-yl]-2-fluorocyclopropane-l -carboxamide (200.0 mg, 0.51 mmol) in THF (2.0 mL) were added DIBAL-H (1.0 mL, 1.0 mmol/L) at room temperature under N2. The resulting mixture was stirred at room temperature for 1.5 h. After the reaction was completed, the reaction mixture was quenched with H2O at 0 °C. The resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (10/1, v/v) to afford (lR,2R)-2-fluoro-N-{3-[6-(l-hydroxybutyl)-4-methylpyridin-3- yl]-l,6- naphthyridin-7-yl}cyclopropane-l-carboxamide (70.0 mg, 34%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 395.2.

Step 3. Separation of (lR,2R)-2-fluoro-N-(3-{6-[(lS)-l-hydroxybutyl]-4-methylpyrid in-3-yl}~ If -naphthyridin-7-yl) cyclopropane- 1 -carboxamide (Compound93) and (lR,2R)-2-fluoro-N- (3-{6-[(lR)-l-hydroxybutyl]-4-methylpyridin-3-yl}-l,6-naphth yridin-7-yl)cyclopropane-l- carboxamide (Compound 94):

[0450] The racemic mixture of (lR,2R)-2-fluoro-N-(3-(6-(l-hydroxybutyl)-4- methylpyridin-3-yl)-l,6-naphthyridin-7-yl)cyclopropane-l-car boxamide (70.0 mg, 0.18 mmoL) was separated by Prep-HPLC with the following conditions (Column: CHIRAL ART Amylose-SA, 2x25 cm, 5 pm; Mobile Phase A: Hex(0.2% FA)— HPLC, Mobile Phase B: MeOH: DCM=1 : 1— HPLC; Flow rate: 20 mL/min; Gradient: 30% B to 30% B in 17 min; Wave Length: 220\254 nm; RTl(min): 12.48; RT2(min): 15.70) to afford (lR,2R)-2-fluoro- N-(3 -(6-( 1 -hydroxybutyl)-4-methylpyri din-3 -yl)- 1 ,6-naphthyridin-7-yl)cyclopropane- 1 - carboxamide Isomer 1 (retention time 12.48 min, 13.4 mg, 38%) as a white solid and (lR,2R)-2-fhioro-N-(3-{6-[l-hydroxybutyl]-4-methylpyridin-3- yl}-l,6-naphthyri din-7- yl)cyclopropane-l -carboxamide Isomer 1 (retention time 15.70 min, 16.2 mg, 46%) as a white solid. The absolute stereochemistry of Isomers 1 and 2 was not assigned. The two isomeric structures that could be obtained from chiral separation of the isomeric mixture as described above are shown as Compounds 93 and 94 in Table 1.

[0451] (lR,2R)-2-fluoro-N-(3-{6-[l-hydroxybutyl]-4-methylpyridin-3- yl}-l,6- naphthyridin-7-yl)cyclopropane-l-carboxamide Isomer 1: RT1 (min): 12.48; LCMS (ESI, m/z): [M+H]+ = 395.2. ¹ H NMR (400 MHz, DMSO-d6): δ 11.20 (s, 1H), 9.29 (s, 1H), 9.12 (d, J = 2.0 Hz, 1H), 8.62 (s, 2H), 8.57 (d, J = 1.6 Hz, 1H), 7.51 (s, 1H), 5.35 (d, J = 5.2 Hz, 1H), 5.07 - 4.89 (m, 1H), 4.64 - 4.60 (m, 1H), 2.37 (s, 3H), 2.35 - 2.30 (m, 1H), 1.78 - 1.64 (m, 3H), 1.44 - 1.38 (m, 2H), 1.26 - 1.20 (m, 1H), 0.94 - 0.90 (m, 3H).

[0452] (lR,2R)-2-fluoro-N-(3-{6-[l-hydroxybutyl]-4-methylpyridin-3- yl}-l,6- naphthyridin-7-yl)cyclopropane-l-carboxamide Isomer 2: RT2(min): 15.70; LCMS (ESI, m/z): [M+H]+ = 395.2. ¹ H NMR (400 MHz, DMSO-d6): δ 11.20 (s, 1H), 9.29 (s, 1H), 9.12 (d, J = 2.4 Hz, 1H), 8.62 (s, 1H), 8.57 (d, J = 2.0 Hz, 1H), 8.46 (s, 1H), 7.51 (s, 1H), 5.35 (d, J = 5.2 Hz, 1H), 5.08 - 4.89 (m, 1H), 4.64 - 4.60 (m, 1H), 2.37 (s, 3H), 2.35 - 2.30 (m, 1H), 1.78 - 1.63 (m, 3H), 1.44 - 1.37 (m, 2H), 1.26 - 1.20 (m, 1H), 0.94 - 0.90 (m, 3H). Example 52. Synthesis of (lR,2R)-2-fluoro-N-(7-{6-[(2R)-2-hydroxypropyl]-4- methylpyridin-3-yl}-2, 6-naphthyridin-3-yl)cyclopropane-l -carboxamide (Compound 95) and (lR,2R)-2-fluoro-N-(7-{6-[(2S)-2-hydroxypropyl]-4-methylpyri din-3-yl}-2,6- naphthyridin-3-yl)cyclopropane-l-carboxamide (Compound 96)

Step 1: Synthesis of l-(5-bromo-4-methylpyridin-2-yl)propan-2-one:

[0453] To a solution of methyl 2-(5-bromo-4-methylpyridin-2-yl)acetate (5.8 g, 23.76 mmol) in THF (50.0 mL) was added dropwise bromo(methyl)magnesium (118.8 mL, 1 mol/L) at 0 °C under N2. The resulting mixture was stirred at room temperature for 3 h under N2. After the reaction was completed, the reaction mixture was quenched by the addition of sat. NH4CI (aq.) at 0 °C. The resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography with petroleum ether/ethyl acetate (5/1, v/v) to afford l-(5- bromo-4-methylpyridin-2-yl)propan-2-one (500.0 mg, 9%) as a yellow oil. LCMS (ESI, m/z): [M+H] ⁺ = 228.0

Step 2: Synthesis of l-(5-bromo-4-methylpyridin-2-yl)propan-2-ol:

[0454] To a solution of l-(5-bromo-4-methylpyridin-2-yl)propan-2-one (500.0 mg, 2.19 mmol) in MeOH (2.0 mL)/THF (8.0 mL) was added NaBH ₄ (331.7 mg, 8.76 mmol) at 0 °C under N2. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography with petroleum ether/ethyl acetate (1/1, v/v) to afford l-(5-bromo-4- methylpyridin-2-yl)propan-2-ol (300.0 mg, 59%) as a yellow oil. LCMS (ESI, m/z): [M+H] ⁺ = 230.0. Step 3: Synthesis of (6-(2-hydroxypropyl)-4-methylpyridin-3-yl)boronic acid:

[0455] To a solution of l-(5-bromo-4-methylpyridin-2-yl)propan-2-ol (300.0 mg, 1.30 mmol) in dioxane (10.0 mL) was added bis(pinacolato)diboron (662.1 mg, 2.60 mmol), KOAc (383.8 mg, 3.91 mmol) and Pd(dppf)C12 (95.4 mg, 0.13 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 2 h under N2. The resulting mixture was filtered. The filtrate was concentrated under vacuum to afford (6-(2-hydroxypropyl)-4- methylpyri din-3 -yl)boronic acid (300.0 mg, crude) as a brown solid. LCMS (ESI, m/z): [M+H] ⁺ = 278.2.

Step 4: Synthesis of ((lR,2R)-2-fluoro-N-{7-[6-(2-hydroxypropyl)-4-methylpyridin- 3-yl]-2,6- naphthyridin-3-yl}cyclopropane-l-carboxamide:

[0456] To a solution of (6-(2-hydroxypropyl)-4-methylpyridin-3-yl)boronic acid (300.0 mg, crude) in dioxane (10.0 mL)/ H20 (2.5 mL) was added (lR,2R)-N-(7-chloro-2,6- naphthyridin-3-yl)-2-fluorocyclopropane-l -carboxamide (191.7 mg, 0.72 mmol), K2CO3 (299.1 mg, 2.16 mmol) and Pd(dppf)C12 (52.8 mg, 0.07 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 2 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (10/1, v/v) to afford (lR,2R)-2-fluoro-N- {7-[6-(2-hydroxypropyl)-4-methylpyridin-3-yl]-2,6-naphthyrid in-3-yl}cyclopropane-l- carboxamide (100.0 mg, 36%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 381.2.

Step 5. Separation of (lR,2R)-2-fluoro-N-(7-{6-[(2R)-2-hydroxypropyl]-4-methylpyri din-3- yl}-2,6-naphthyridin-3-yl)cyclopropane-l-carboxamide (Compound 95) and (lR,2R)-2- fluoro-N-(7-{6-[(2S)-2-hydroxypropyl]-4-methylpyridin-3-yl}- 2,6-naphthyridin-3- yl)cyclopropane-l -carboxamide (Compound 96):

[0457] The racemic mixture of (lR,2R)-2-fluoro-N-{7-[6-(2-hydroxypropyl)-4- methylpyridin-3-yl]-2,6-naphthyridin-3-yl}cyclopropane-l-car boxamide (90.0 mg, 0.23 mmol) was separated by Prep-Chiral-HPLC with the following conditions (Column: CHIRALPAK ID, 2x25 cm, 5 pm; Mobile Phase A: Hex(0.5% 2M NH ₃ -MeOH)-HPLC, Mobile Phase B: EtOH: DCM=1 : 1— HPLC; Flow rate: 20 mL/min; Gradient: 50% B to 50% B in 20 min; Wave Length: 220/254 nm; RTl(min): 12.49; RT2(min): 15.64) to afford (lR,2R)-2-fhioro-N-(7-{6-[2-hydroxypropyl]-4-methylpyridin-3 -yl}-2,6-naphthyri din-3- yl)cyclopropane-l -carboxamide Isomer 1 (retention time 12.49 min, 33.4 mg, 74%)) as a white solid and (lR,2R)-2-fluoro-N-(7-{6-[2-hydroxypropyl]-4-methylpyridin-3 -yl}-2,6- naphthyri din-3 -yl)cy cl opropane-1 -carboxamide Isomer 2 (retention time 15.64 min, 27.8 mg, 61%) as a white solid. The absolute stereochemistry of Isomers 1 and 2 was not assigned. The two isomeric structures that could be obtained from chiral separation of the isomeric mixture as described above are shown as Compounds 95 and 96 in Table 1.

[0458] (lR,2R)-2-fluoro-N-(7-{6-[2-hydroxypropyl]-4-methylpyridin-3 -yl}-2,6- naphthyridin-3-yl)cyclopropane-l-carboxamide Isomer 1: RTl(min): 12.49, LCMS (ESI, m/z): [M+H]+ = 381.1. ¹ H NMR (400 MHz, DMSO-d6): δ 11.21 (s, 1H), 9.49 (s, 1H), 9.33 (s, 1H), 8.68 (s, 1H), 8.59 (s, 1H), 8.16 (s, 1H), 7.25 (s, 1H), 5.08 - 4.88 (m, 1H), 4.71 (d, J = 4.4 Hz, 1H), 4.11 - 4.07 (m, 1H), 2.90 - 2.85 (m, 1H), 2.80 - 2.75 (m, 1H), 2.42 (s, 3H), 2.33 - 2.29 (m, 1H), 1.77 - 1.68 (m, 1H), 1.26 - 1.19 (m, 1H), 1.13 (d, J = 6.4 Hz, 3H).

[0459] (lR,2R)-2-fluoro-N-(7-{6-[2-hydroxypropyl]-4-methylpyridin-3 -yl}-2,6- naphthyridin-3-yl)cyclopropane-l-carboxamide Isomer 2: RTl(min): 15.64; LCMS (ESI, m/z): [M+H]+ = 381.1. ¹ H NMR (400 MHz, DMSO-d6): δ 11.21 (s, 1H), 9.49 (s, 1H), 9.34 (s, 1H), 8.68 (s, 1H), 8.59 (s, 1H), 8.16 (s, 1H), 7.26 (s, 1H), 5.08 - 4.88 (m, 1H), 4.72 (s, 1H), 4.13 - 4.08 (m, 1H), 2.90 - 2.85 (m, 1H), 2.80 - 2.76 (m, 1H), 2.42 (s, 3H), 2.34 - 2.28 (m, 1H), 1.76 - 1.68 (m, 1H), 1.26 - 1.17 (m, 1H), 1.13 (d, J = 6.0 Hz, 3H). Example 53. Synthesis of (S)-N-(3-(6-(l-hydroxybutyl)-4-methylpyridin-3-yl)-l,6- naphthyridin-7-yl) acetamide (Compound 97) and (R)-N-(3-(6-(l-hydroxybutyl)-4- methylpyridin-3-yl)-l, 6-naphthyridin- 7-yl) acetamide ( Compound 98)

Step 1: Synthesis ofN-(3-(6-butyryl-4-methylpyridin-3-yl)-l,6-naphthyridin-7-y l)acetamide:

[0460] To a solution of l-(5-(7-chloro-l,6-naphthyridin-3-yl)-4-methylpyridin-2- yl)butan-l-one (500.0 mg, 1.53 mmol) in dioxane (15.0 mL) was added acetamide (181.3 mg, 3.07 mmol), K2CO3 (636.3 mg, 4.60 mmol), XPhos (146.3 mg, 0.30 mmol) and Pd(OAc)2 (34.4 mg, 0.15 mmol) at room temperature under N2. The mixture was stirred at 100 °C for 2 h under N2. After the reaction was completed, the mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (10/1, v/v) to afford N-(3-(6-butyryl-4-methylpyridin-3-yl)-l,6-naphthyridin-7-yl) acetamide (300.0 mg, 56%) as an orange solid. LCMS (ESI, m/z): [M+H] ⁺ = 349.2.

Step 2: Synthesis of N-(3-(6-(l-hydroxybutyl)-4-methylpyridin-3-yl)-l ,6-naphthyridin-7- yl)acetamide :

[0461] To a solution of N-(3-(6-butyryl-4-methylpyridin-3-yl)-l,6-naphthyridin-7- yl)acetamide (200.0 mg, 0.57 mmol) in CH ₂ Cl ₂ /MeOH (10.0 mL/2.0 mL) was added NaBH ₄ (32.5 mg, 0.86 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the resulting mixture was quenched with methanol and then concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (10/1, v/v) to afford N-(3-(6-(l-hydroxybutyl)-4- methylpyridin-3-yl)-l,6-naphthyridin-7-yl)acetamide (60.0 mg, 29%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 351.2. Step 3: Separation of (S)-N-(3-(6-(l-hydroxybutyl)-4-methylpyridin-3-yl)-l,6-napht hyridin-7- yl)acetamide (Compound 97) and (R)-N-(3-(6-(l-hydroxybutyl)-4-methylpyridin-3-yl)-l ,6- naphthyridin-7-y I) acetamide (Compound 98)

[0462] The racemic product of N-(3-(6-(l-hy droxybutyl)-4-methylpyri din-3 -yl)- 1,6- naphthyridin-7-yl)acetamide (60.0 mg, 0.17 mmol) was separated by Prep-Chiral-HPLC with the following conditions: (Column: Lux 5um Cellulose-4, 2.12x25 cm, 5 pm; Mobile Phase A: Hex(0.5% 2M NH ₃ -MeOH)-HPLC, Mobile Phase B: MeOH: EtOH=l : 1-HPLC; Flow rate: 20 mL/min; Gradient: 50% B to 50% B in 18 min; Wave Length: 220/254 nm;

RTl(min): 11.52; RT2(min): 14.22) to afford N-(3-(6-(l-hydroxybutyl)-4-methylpyridin-3- yl)-l,6-naphthyridin-7-yl)acetamide Enantiomer 1 (retention time 11.52 min, 26.5 mg, 88%) as a white solid and N-(3-(6-(l-hydroxybutyl)-4-methylpyridin-3-yl)-l,6-naphthyri din-7- yl)acetamide Enantiomer 2 (retention time 14.22 min, 26.1 mg, 87%) as a white solid. The absolute stereochemistry of Enantiomers 1 and 2 was not assigned. The two enantiomeric structures that could be obtained from chiral separation of the enantiomeric mixture as described above are shown as Compounds 97 and 98 in Table 1.

[0463] N-(3-(6-(l-hydroxybutyl)-4-methylpyridin-3-yl)-l,6-naphthyri din-7- yl)acetamide Enantiomer 1: RTl(min): 11.52; LCMS (ESI, m/z): [M+H]+ = 351.2. ^T H NMR (400 MHz, DMSO-d6): δ 10.84 (s, 1H), 9.26 (s, 1H), 9.11 (d, J = 2.4 Hz, 1H), 8.62 (s, 1H), 8.55 (d, J = 2.0 Hz, 1H), 8.45 (s, 1H), 7.50 (s, 1H), 5.34 (d, J = 4.8 Hz, 1H), 4.64 - 4.60 (m, 1H), 2.37 (s, 3H), 2.19 (s, 3H), 1.80 - 1.73 (m, 1H), 1.70 - 1.61 (m, 1H), 1.46 - 1.36 (m, 2H), 0.97 - 0.90 (m, 3H).

[0464] N-(3-(6-(l-hydroxybutyl)-4-methylpyridin-3-yl)-l,6-naphthyri din-7- yl)acetamide Enantiomer 2: RT2(min): 14.22; LCMS (ESI, m/z): [M+H]+ = 351.2. ¹ H NMR (400 MHz, CD3OD): δ 9.23 (s, 1H), 9.04 (d, J = 2.0 Hz, 1H), 8.76 (s, 1H), 8.52 (d, J = 1.6 Hz, 1H), 8.44 (s, 1H), 7.59 (s, 1H), 4.79 - 4.76 (m, 1H), 2.44 (s, 3H), 2.28 (s, 3H), 1.88 - 1.74 (m, 2H), 1.57 - 1.43 (m, 2H), 1.02 - 0.98 (m, 3H). Example 54. Synthesis of (S)-N-(7-(6-(l-hydroxybutyl-l-d)-4-methylpyridin-3-yl)-2,6- naphthyridin-3-yl)acetamide (Compound 99) and (R)-N-(7-(6-(l-hydroxybutyl-l-d)-4- methylpyridin-3-yl)-2, 6-naphthyridin-3-yl) acetamide (Compound 100)

Step 1: Synthesis ofN-[7-(6-butanoyl-4-methylpyridin-3-yl)-2,6-naphthyridin-3- yl]acetamide:

[0465] To a stirred mixture of N-(7-chloro-2,6-naphthyridin-3-yl)acetamide (200.0 mg, 0.90 mmol) and l-[4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)p yridin-2- yl]butan-l-one (521.9 mg, 1.80 mmol) in dioxane (5.0 mL) and H2O (1.0 mL) were added K2CO3 (374.1 mg, 2.71 mmol) and Pd(dppf)C12 (132.1 mg, 0.18 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 16 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (8/1, v/v) to afford N-[7-(6-butanoyl-4- methylpyridin-3-yl)-2,6-naphthyridin-3-yl]acetamide (240.0 mg, 76%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 349.1.

Step 2: Synthesis ofN-(7-(6-(l-hydroxybutyl-l-d)-4-methylpyridin-3-yl)-2,6-nap hthyridin-3- yl)acetamide :

[0466] To a stirred mixture of N-[7-(6-butanoyl-4-methylpyridin-3-yl)-2,6-naphthyridin- 3-yl]acetamide (220.0 mg, 0.63 mmol) in THF (5.0 mL) and MeOH (0.5 mL) was added NaBD4 (71.7 mg, 1.89 mmol) at 0 °C under N2. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the reaction mixture was quenched with sat. NH4CI (aq.) at 0 °C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CfbCb/MeOH (7/1, v/v) to afford N-(7-(6-(l- hydroxybutyl-l-d)-4-methylpyridin-3-yl)-2,6-naphthyridin-3-y l)acetamide (230.0 mg, 98%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 352.1.

Step 3: Separation of (S)-N-(7-(6-(l-hydroxybutyl-l-d)-4-methylpyridin-3-yl)-2,6- naphthyridin- 3 -y I) acetamide (Compound 99) and (R)-N-(7-(6-(l-hydroxybutyl-l-d)-4- methylpyridin-3-yl)-2, 6-naphthyridin-3-yl)acetamide (Compound 100)

[0467] The product of N-(7-(6-(l-hydroxybutyl-l-d)-4-methylpyridin-3-yl)-2,6- naphthyri din-3 -yl)acetamide (150.0 mg, 0.43 mmol) was separated by Prep-HPLC with the following conditions (Column: CHIRAL ART Amylose-SA, 2x25 cm, 5 pm; Mobile Phase A: Hex (0.2% FA)-HPLC, Mobile Phase B: MeOH: DCM=1 : 1-HPLC; Flow rate: 20 mL/min; Gradient: 30% B to 30% B in 17 min; Wave Length: 220\254 nm; RTl(min): 13.15; RT2(min): 15.35) to afford N-(7-(6-(l-hydroxybutyl-l-d)-4-methylpyridin-3-yl)-2, 6- naphthyri din-3 -yl)acetamide Enantiomer 1 (retention time 13.15 min, 26.6 mg, 36%) as a white solid and N-(7-(6-(l-hydroxybutyl-l-d)-4-methylpyridin-3-yl)-2,6-napht hyridin-3- yl)acetamide Enantiomer 2 (retention time 15.35 min, 33.5 mg, 45%) as a white solid. The absolute stereochemistry of Enantiomers 1 and 2 was not assigned. The two enantiomeric structures that could be obtained from chiral separation of the enantiomeric mixture as described above are shown as Compounds 99 and 100 in Table 1.

[0468] N-(7-(6-(l-hydroxybutyl-l-d)-4-methylpyridin-3-yl)-2,6-napht hyridin-3- yl)acetamide Enantiomer 1 : RTl(min): 13.15; LCMS (ESI, m/z): [M+H]+ = 352.1. ¹ H NMR (400 MHz, DMSO-d6): δ 10.86 (s, 1H), 9.51 (s, 1H), 9.32 (s, 1H), 8.67 (s, 1H), 8.58 (s, 1H), 8.19 - 8.14 (m, 1H), 7.47 (s, 1H), 5.30 (s, 1H), 2.45 (s, 3H), 2.19 (s, 3H), 1.80 - 1.73 (m, 1H), 1.68 - 1.61 (m, 1H), 1.45 - 1.35 (m, 2H), 0.93 - 0.89 (m, 3H).

[0469] N-(7-(6-(l-hydroxybutyl-l-d)-4-methylpyridin-3-yl)-2,6-napht hyridin-3- yl)acetamide Enantiomer 2: RT2(min): 15.35; LCMS (ESI, m/z): [M+H]+ = 352.1. ¹ H NMR (400 MHz, DMSO-d6): 5 10.86 (s, 1H), 9.51 (s, 1H), 9.32 (s, 1H), 8.67 (s, 1H), 8.58 (s, 1H), 8.15 (d, J = 6.0 Hz, 1H), 7.47 (s, 1H), 5.30 (s, 1H), 2.45 (s, 3H), 2.19 (s, 3H), 1.80 - 1.73 (m, 1H), 1.68 - 1.61 (m, 1H), 1.45 - 1.35 (m, 2H), 0.93 - 0.89 (m, 3H).

Example 55. Synthesis of (S)-N-(7-(6-((R)-l-hydroxypropyl)-4-methylpyridin-3-yl)-2,6- naphthyridin-3-yl)oxetane-2-carboxamide (Compound 101) and (S)-N-(7-(6-((S)-l- hydroxypropyl)-4-methylpyridin-3-yl)-2,6-naphthyridin-3-yl)o xetane-2-carboxamide (Compound 102)

Step 1: Synthesis of (S)-N-(7-(4-methyl-6-propionylpyridin-3-yl)-2,6-naphthyridin -3- yl)oxetane-2-carboxamide:

[0470] To a solution of l-(5-(7-amino-2,6-naphthyridin-3-yl)-4-methylpyridin-2- yl)propan-l-one (390.0 mg, 1.34 mmol) in pyridine (10.0 mL) was added (S)-oxetane-2- carboxylic acid (149.0 g, 1.47 mmol) and EDCI (623.1 mg, 4.41 mmol) at 0 °C under N2. The resulting mixture was stirred at room temperature for 5 h. After the reaction was completed, the resulting mixture was diluted with water and extracted with CH ₂ Cl ₂ . The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford (S)-N-(7-(4-methyl-6- propionylpyridin-3-yl)-2,6-naphthyridin-3-yl)oxetane-2-carbo xamide (350.0 mg, crude) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 377.1.

Step 2: Synthesis of (2S)-N-(7-(6-(l-hydroxypropyl)-4-methylpyridin-3-yl)-2,6-nap hthyridin- 3-yl)oxetane-2-carboxamide :

[0471] To a solution of (S)-N-(7-(4-methyl-6-propionylpyri din-3 -yl)-2, 6-naphthyri din-3 - yl)oxetane-2-carboxamide (350.0 mg, 0.93 mmol) in THF (8.0 mL) and MeOH (2.0 mL) was added NaBH ₄ (70.7 mg, 1.86 mmol) at 0 °C under N2. The resulting mixture was stirred at room temperature for 3 h. After the reaction was completed, the resulting mixture was diluted with water and extracted with CH ₂ Cl ₂ . The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with MeOH/ffO (60/40, v/v) to afford (2S)-N-(7-(6-(l-hydroxypropyl)-4-methylpyridin-3-yl)-2,6- naphthyridin-3-yl)oxetane-2-carboxamide (80.0 mg, 23%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 379.1.

Step 3: Separation of (S)-N-(7-(6-((R)-l-hydroxypropyl)-4-methylpyridin-3-yl)-2,6- naphthyridin-3-yl)oxetane-2-carboxamide (Compound 101) and (S)-N-(7-(6-((S)-l- hydroxypropyl)-4-methylpyridin-3-yl)-2,6-naphthyridin-3-yl)o xetane-2-carboxamide (Compound 102)

[0472] The racemic mixture of (2S)-N-(7-(6-(l-hydroxypropyl)-4-methylpyridin-3-yl)- 2,6-naphthyridin-3-yl)oxetane-2-carboxamide (80.0 mg, 0.21 mmol) was separated by Prep- Chiral-HPLC with the following conditions (Column: CHIRALPAK IH, 2x25 cm, 5 pm; Mobile Phase A: Hex (0.2% FA)-HPLC, Mobile Phase B: EtOH: DCM=1 : 1-HPLC; Flow rate: 20 mL/min; Gradient: 30% B to 30% B in 18 min; Wave Length: 220/254 nm;

RTl(min): 7.12; RT2(min): 14.03) to afford (S)-N-(7-(6-(l-hydroxypropyl)-4-methylpyridin- 3-yl)-2,6-naphthyridin-3-yl)oxetane-2-carboxamide Isomer 1 (retention time 7.12 min, 25.0 mg, 62%) as a white solid and (S)-N-(7-(6-(l-hydroxypropyl)-4-methylpyridin-3-yl)-2,6- naphthyridin-3-yl)oxetane-2-carboxamide Isomer 2 (retention time 14.03 min, 21.4 mg, 53%) as a white solid. The absolute stereochemistry of Isomers 1 and 2 was not assigned. The two isomeric structures that could be obtained from chiral separation of the isomeric mixture as described above are shown as Compounds 101 and 102 in Table 1.

[0473] (S)-N-(7-(6-(l-hydroxypropyl)-4-methylpyridin-3-yl)-2,6-naph thyridin-3- yl)oxetane-2-carboxamide Isomer 1: RTl(min): 7.12; LCMS (ESI, m/z): [M+H]+ =379.2. ¹ H NMR (400 MHz, DMSO-d6): δ 10.28 (s, 1H), 9.57 (s, 1H), 9.36 (s, 1H), 8.73 (s, 1H), 8.60 (s, 1H), 8.21 (s, 1H), 7.47 (s, 1H), 5.34 - 5.27 (m, 2H), 4.72 - 4.68 (m, 2H), 4.58 - 4.54 (m, 1H), 3.05 - 2.97 (m, 1H), 2.77 - 2.68 (m, 1H), 2.46 (s, 3H), 1.88 - 1.80 (m, 1H), 1.74 - 1.64 (m, 1H), 0.93 - 0.86 (m, 3H).

[0474] (S)-N-(7-(6-(l-hydroxypropyl)-4-methylpyridin-3-yl)-2,6-naph thyridin-3- yl)oxetane-2-carboxamide Isomer 2: RT2(min): 14.03; LCMS (ESI, m/z): [M+H]+ =379.2. ¹ H NMR (400 MHz, DMSO-d6): δ 10.29 (s, 1H), 9.57 (s, 1H), 9.36 (s, 1H), 8.74 (s, 1H), 8.60 (s, 1H), 8.21 (s, 1H), 7.47 (s, 1H), 5.34 - 5.27 (m, 2H), 4.72 - 4.68 (m, 2H), 4.58 - 4.54 (m, 1H), 3.05 - 2.97 (m, 1H), 2.77 - 2.68 (m, 1H), 2.46 (s, 3H), 1.88 - 1.80 (m, 1H), 1.74 - 1.66 (m, 1H), 0.93 - 0.89 (m, 3H).

Example 56. Synthesis ofN-(7-(6-(2-hydroxy-2-methylpropyl)-4-methylpyridin-3-yl)-2 ,6- naphthyridin-3-yl)cyclopropanecarboxamide (Compound 103)

Step 1: Synthesis of l-(5-bromo-4-methylpyridin-2-yl)-2-methylpropan-2-ol:

[0475] To a solution of l-(5-bromo-4-methylpyridin-2-yl)propan-2-one (1.5 g, 6.57 mmol) in THF (10.0 mL) was added CH3MgBr (3.7 mL, 1.0 mmol/L) at 0 °C under N2. The resulting mixture was stirred at room temperature for 3 h under N2. After the reaction was completed, the reaction mixture was quenched by the addition of sat. NH4CI (aq.) at 0 °C. The resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography with petroleum ether/ethyl acetate (5/1, v/v) to afford l-(5-bromo-4- methylpyridin-2-yl)-2-methylpropan-2-ol (90.0 mg, 5%) as a yellow oil. LCMS (ESI, m/z): [M+H] ⁺ = 244.0

Step 2: Synthesis of 6-(2-hydroxy-2-methylpropyl)-4-methylpyridin-3-ylboronic acid:

[0476] To a solution of l-(5-bromo-4-methylpyridin-2-yl)-2-methylpropan-2-ol (90.0 mg, 0.36 mmol) in dioxane (2.0 mL) was added bis(pinacolato)diboron (187.2 mg, 0.73 mmol), KOAc (108.5 mg, 1.10 mmol) and Pd(dppf)C12 (26.9 mg, 0.03 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 2 h under N2. After the reaction was completed, the reaction mixture was filtered. The filtrate was concentrated under vacuum to afford 6-(2-hydroxy-2-methylpropyl)-4-methylpyridin-3-ylboronic acid (90.0 mg, crude) as a brown solid. LCMS (ESI, m/z): [M+H] ⁺ = 210.1. Step 3. Synthesis ofN-(7-(6-(2-hydroxy-2-methylpropyl)-4-methylpyridin-3-yl)-2 ,6- naphthyridin-3-yl)cyclopropanecarboxamide (Compound 103): [0477] To a solution of 6-(2-hydroxy-2-methylpropyl)-4-methylpyridin-3-ylboronic acid (90.0 mg, crude) in dioxane (2.0 mL)/H20 (0.5 mL) was added N-(7-chloro-2,6-naphthyridin- 3-yl)cyclopropanecarboxamide (56.7 mg, 0.22 mmol), K2CO3 (94.9 mg, 0.68 mmol) and Pd(dppf)Cl2 (16.7 mg, 0.02 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 2 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (10/1, v/v) and then purified by Prep-HPLC with the following conditions: (Column: XBridge Shield RP18 OBD Column, 30x150 mm, 5 pm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 29% B to 39% B in 10 min; Wave Length: 254 nm) to afford N-(7-(6-(2- hydroxy-2-methylpropyl)-4-methylpyridin-3-yl)-2,6-naphthyrid in-3- yl)cyclopropanecarboxamide (Compound 103, 57.0 mg, 63%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 377.1. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.15 (s, 1H), 9.46 (s, 1H), 9.32 (s, 1H), 8.66 (s, 1H), 8.58 (s, 1H), 8.16 (s, 1H), 7.29 (s, 1H), 4.79 (s, 1H), 2.87 (s, 2H), 2.42 (s, 3H), 2.11 - 2.08 (m, 1H), 1.15 (s, 6H), 0.90 - 0.86 (m, 4H).

Example 57. Synthesis of (R)-N-(7-(6-(l-hydroxypropyl)-4-methylpyridin-3-yl)-2,6- naphthyridin-3-yl)bicyclo[l.l.l]pentane-l-carboxamide (Compound 104) and (S)-N-(7-(6- (l-hydroxypropyl)-4-methylpyridin-3-yl)-2, 6-naphthyridin-3-yl)bicyclo[l.1.1 )pentane-1- carboxamide (Compound 105)

Step 1: Synthesis ofN-(7-(4-methyl-6-propionylpyridin-3-yl)-2,6-naphthyridin-3 - yl)bicyclo[ 1.1.1 ] pentane -1 -carboxamide: [0478] To a solution of l-(5-(7-amino-2,6-naphthyridin-3-yl)-4-methylpyridin-2- yl)propan-l-one (460.0 mg, 1.57 mmol) in pyridine (20.0 mL) was added bicyclo[l. l.l]pentane-l -carboxylic acid (194.0 mg, 1.73 mmol) and EDCI (422.3 g, 2.20 mmol) at 0 °C under N2. The resulting mixture was stirred at room temperature for 5 h. After the reaction was completed, the resulting mixture was diluted with water and extracted with CH2CI2. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford N-(7-(4- methyl-6-propionylpyri din-3 -yl)-2,6-naphthyri din-3 -yl)bicyclo[ 1.1. l]pentane-l -carboxamide (510.0 mg, crude) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 387.1

Step 2: Synthesis ofN-(7-(6-(l-hydroxypropyl)-4-methylpyridin-3-yl)-2,6-naphth yridin-3- yl)bicyclo[ 1.1.1 ] pentane -1 -carboxamide:

[0479] To a solution of N-(7-(4-methyl-6-propionylpyridin-3-yl)-2,6-naphthyridin-3- yl)bicyclo[l. l.l]pentane-l -carboxamide (510.0 mg, crude) in THF (8.0 mL) and MeOH (2.0 mL) was added NaBH ₄ (99.8 mg, 2.64 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 3 h. After the reaction was completed, the resulting mixture was diluted with water and extracted with CH ₂ Cl ₂ . The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with MeOH/H2O (80/20, v/v) to afford N-(7-(6-(l-hydroxypropyl)-4-methylpyridin-3-yl)-2,6-naphthyr idin-3- yl)bicyclo[l. l.l]pentane-l -carboxamide (300.0 mg, 67%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 389.1.

Step 3. Separation of (R)-N-(7-(6-(l-hydroxypropyl)-4-methylpyridin-3-yl)-2,6-naph thyridin- 3-yl)bicyclo[l.l.l]pentane-l -carboxamide (Compound 104) and (S)-N-(7-(6-(l- hydroxypropyl)-4-methylpyridin-3-yl)-2, 6-naphthyridin-3-yl)bicyclo[ 1.1.1 ]pentane-l- carboxamide (Compound 105)

[0480] The racemic mixture of N-(7-(6-(l-hydroxypropyl)-4-methylpyridin-3-yl)-2,6- naphthyridin-3-yl)bicyclo[l. l.l]pentane-l-carboxamide (100.0 mg, 0.25 mmol) was separated by Prep-Chiral-HPLC with the following conditions (Column: CHIRALPAK AD- H, 2x25 cm, 5 pm; Mobile Phase A: Hex(0.5% 2M NH ₃ -MeOH)-HPLC, Mobile Phase B: MeOH: EtOH=l : 1— HPLC; Flow rate: 20 mL/min; Gradient: 60% B to 60% B in 16 min; Wave Length: 220/254 nm; RTl(min): 10.51; RT2(min): 13.61) to afford N-(7-(6-(l- hydroxypropyl)-4-methylpyri din-3 -yl)-2,6-naphthyri din-3 -yl)bicyclo[ 1.1. l]pentane-l- carboxamide Enantiomer 1 (retention time 10.51 min, 33.8 mg, 67%) as a white solid and N- (7-(6-(l-hydroxypropyl)-4-methylpyridin-3-yl)-2,6-naphthyrid in-3-yl)bicyclo[l .1. l]pentane- 1 -carboxamide Enantiomer 2 (retention time 13.61 min, 31.4 mg, 62%) as a white solid. The absolute stereochemistry of Enantiomers 1 and 2 was not assigned. The two enantiomeric structures that could be obtained from chiral separation of the enantiomeric mixture as described above are shown as Compounds 104 and 105 in Table 1.

[0481] N-(7-(6-(l-hydroxypropyl)-4-methylpyridin-3-yl)-2,6-naphthyr idin-3- yl)bicyclo[l.l.l]pentane-l-carboxamide Enantiomer 1 : RTl(min): 10.51; LCMS (ESI, m/z): [M+H]+ =389.2. ¹ H NMR (400 MHz, DMSO-d6): δ 10.57 (s, 1H), 9.50 (s, 1H), 9.34 (s, 1H), 8.66 (s, 1H), 8.58 (s, 1H), 8.18 (s, 1H), 7.46 (s, 1H), 5.35 (s, 1H), 4.57 - 4.54 (m, 1H), 2.45 (s, 3H), 2.18 (s, 6H), 1.88 - 1.81 (m, 1H), 1.74 - 1.65 (m, 1H), 0.92 - 0.88 (m, 3H).

[0482] N-(7-(6-(l-hydroxypropyl)-4-methylpyridin-3-yl)-2,6-naphthyr idin-3- yl)bicyclo[l.l.l]pentane-l-carboxamide Enantiomer 2: RT2(min): 13.61; LCMS (ESI, m/z): [M+H]+ =389.2. ¹ H NMR (400 MHz, DMSO-d6): δ 10.59 (s, 1H), 9.50 (s, 1H), 9.34 (s, 1H), 8.66 (s, 1H), 8.58 (s, 1H), 8.18 (s, 1H), 7.46 (s, 1H), 5.36 (s, 1H), 4.57 - 4.54 (m, 1H), 2.45 (s, 3H), 2.17 (s, 6H), 1.87 - 1.79 (m, 1H), 1.72 - 1.65 (m, 1H), 0.92 - 0.88 (m, 3H).

Example 58. Synthesis of (lS,2S)-2-fluoro-N-(3-(6-((R)-l-hydroxybutyl-l-d)-4- methylpyridin-3-yl)-l, 6-naphthyridin- 7-yl)cyclopropane-l -carboxamide (Compound 106) and (lS,2S)-2-fluoro-N-(3-(6-((S)-l-hydroxybutyl-l-d)-4-methylpy ridin-3-yl)-l,6- naphthyridin-7-yl)cyclopropane-l -carboxamide (Compound 107)

Step 1: Synthesis of (lS,2S)-N-(3-(6-butyryl-4-methylpyridin-3-yl)-l,6-naphthyrid in-7-yl)-2- fluorocyclopropane-1 -carboxamide:

[0483] To a solution of l-(5-(7-chloro-l,6-naphthyridin-3-yl)-4-methylpyridin-2- yl)butan-l-one (1.0 g, 3.06 mmol) in dioxane (20.0 mL) were added (lS,2S)-2- fluorocyclopropane-1 -carboxamide (474.6 mg, 4.60 mmol), CS2CO3 (3.0 g, 9.20 mmol), XPhos (292.6 mg, 0.61 mmol) and Pd(OAc)2 (68.9 mg, 0.30 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 2 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (1/2, v/v) to afford (1S,2S)- N-(3-(6-butyryl-4-methylpyridin-3-yl)-l,6-naphthyridin-7-yl) -2-fluorocyclopropane-l- carboxamide (70.0 mg, 5%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 393.2.

Step 2: Synthesis of (lS,2S)-2-fluoro-N-(3-(6-(l-hydroxybutyl-l-d)-4-methylpyridi n-3-yl)-l ,6- naphthyridin-7-yl) cyclopropane- 1 -carboxamide:

[0484] To a solution of (lS,2S)-N-(3-(6-butyryl-4-methylpyridin-3-yl)-l,6-naphthyrid in- 7-yl)-2-fhiorocyclopropane-l-carboxamide (75.0 mg, 0.19 mmol) in THF (2.0 mL)/CD3OD (0.4 mL) were added sodium tetrahydroborate-d4 (12.0 mg, 0.28 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction mixture was quenched with H2O at 0 °C. The resulting mixture was diluted with H2O and extracted with CH2CI2. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (8/1, v/v) to afford (lS,2S)-2-fluoro-N-(3-(6-(l-hydroxybutyl-l-d)-4-methylpyridi n-3-yl)- l,6-naphthyridin-7-yl)cyclopropane-l-carboxamide (36.0 mg, 47%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 396.2.

Step 3. Synthesis of (lS,2S)-2-jluoro-N-(3-(6-((R)-l-hydroxybutyl-l-d)-4-methylpy ridin-3-yl)- If -naphthyridin-7-yl) cyclopropane- 1 -carboxamide (Compound 106) and (lS,2S)-2-jluoro- N-(3-(6-((S)-l-hydroxybutyl-l-d)-4-methylpyridin-3-yl)-l,6-n aphthyridin-7-yl)cyclopropane-

[0485] The product of (lS,2S)-2-fluoro-N-(3-(6-(l-hydroxybutyl-l-d)-4-methylpyridi n-3- yl)-l,6-naphthyridin-7-yl)cyclopropane-l-carboxamide (36.0 mg, 0.09 mmol) was separated by Prep-HPLC with the following conditions (Column: CHIRAL ART Amylose-SA, 2x25 cm, 5 pm; Mobile Phase A: Hex (0.5% 2M NH ₃ -MeOH)-HPLC, Mobile Phase B: MeOH: DCM=1 : 1— HPLC; Flow rate: 20 mL/min; Gradient: 70% B to 70% B in 6 min; Wave Length: 254/220 nm; RTl(min): 3.92; RT2(min): 5.27) to afford (lS,2S)-2-fhioro-N-(3-(6-(l- hydroxybutyl-l-d)-4-methylpyridin-3-yl)-l,6-naphthyridin-7-y l)cyclopropane-l-carboxamide Isomer 1 (retention time 3.92 min, 13.3 mg, 73%) as a white solid and (lS,2S)-2-fluoro-N-(3- (6-( 1 -hydroxybutyl- 1 -d)-4-methylpyri din-3 -yl)- 1 ,6-naphthyridin-7-yl)cyclopropane- 1 - carboxamide Isomer 2 (retention time 5.27 min, 13.4 mg, 74%) as a white solid. The absolute stereochemistry of Isomers 1 and 2 was not assigned. The two isomeric structures that could be obtained from chiral separation of the isomeric mixture as described above are shown as Compounds 106 and 107 in Table 1.

[0486] (lS,2S)-2-fluoro-N-(3-(6-(l-hydroxybutyl-l-d)-4-methylpyridi n-3-yl)-l,6- naphthyridin-7-yl)cyclopropane-l-carboxamide Isomer 1: RTl(min):3.92; LCMS (ESI, m/z): [M+H]+ = 396.1. ¹ H NMR (400 MHz, DMSO-d6): δ 11.20 (s, 1H), 9.28 (d, J = 0.8 Hz, 1H), 9.11 (d, J = 2.4 Hz, 1H), 8.61 - 8.56 (m, 2H), 8.45 (s, 1H), 7.50 (s, 1H), 5.33 (s, 1H), 5.08 - 4.88 (m, 1H), 2.37 (s, 3H), 2.33 - 2.30 (m, 1H), 1.79 - 1.61 (m, 3H), 1.45 - 1.35 (m, 2H), 1.27 - 1.18 (m, 1H), 0.93 - 0.89 (m, 3H).

[0487] (lS,2S)-2-fluoro-N-(3-(6-(l-hydroxybutyl-l-d)-4-methylpyridi n-3-yl)-l,6- naphthyridin-7-yl)cyclopropane-l-carboxamide Isomer 2: RT2(min):5.27; LCMS (ESI, m/z): [M+H]+ =396.1. ¹ H NMR (400 MHz, DMSO-d6): δ 11.20 (s, 1H), 9.28 (d, J = 0.8 Hz, 1H), 9.11 (d, J = 2.4 Hz, 1H), 8.61 - 8.56 (m, 2H), 8.45 (s, 1H), 7.50 (s, 1H), 5.33 (s, 1H), 5.06 - 4.89 (m, 1H), 2.37 (s, 3H), 2.33 - 2.30 (m, 1H), 1.82 - 1.64 (m, 3H), 1.43 - 1.36 (m, 2H), 1.25 - 1.20 (m, 1H), 0.93 - 0.89 (m, 3H).

Example 59. Synthesis of (lS,2S)-2-fluoro-N-(3-(6-((S)-l-hydroxybutyl)-4-methylpyridi n-3- yl)-2-methyl-l,6-naphthyridin-7-yl)cyclopropane-l -carboxamide (Compound 109) and (lS,2S)-2-fluoro-N-(3-(6-((R)-l-hydroxybutyl)-4-methylpyridi n-3-yl)-2-methyl-l,6- naphthyridin-7-yl)cyclopropane-l -carboxamide (Compound 110)

Step 1: Synthesis of (lS,2S)-N-(3-(6-butyryl-4-methylpyridin-3-yl)-2-methyl-l ,6- naphthyridin-7-yl)-2-fluorocyclopropane-l-carboxamide:

[0488] To a solution of l-[5-(7-chloro-2-methyl-l,6-naphthyridin-3-yl)-4-methylpyrid in- 2-yl]butan-l-one (100.0 mg, 0.29 mmol) in 1,4-dioxane (7.0 mL) was added CS2CO3 (287.6 mg, 0.88 mmol), BrettPhos Pd G3 (26.7 mg, 0.03 mmol), (lS,2S)-2-fluorocyclopropane-l- carboxamide (60.7 mg, 0.58 mmol) and BrettPhos (31.6 mg, 0.06 mmol) at room temperature under N2. The resulting mixture was stirred at 80 °C for 2 h under N2. After the reaction was completed, the mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (20/80, v/v) to afford (lS,2S)-N-[3-(6-butanoyl-4-methylpyridin-3-yl)-2-methyl-l,6- naphthyridin-7-yl]-2-fluorocyclopropane-l-carboxamide (60.0 mg, 54%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 407.1.

Step 2: Synthesis of (lS,2S)-2-fluoro-N-(3-(6-(l-hydroxybutyl)-4-methylpyridin-3- yl)-2- methyl-lf -naphthyr idin-7-yl) cyclopropane- 1 -carboxamide:

[0489] To a solution of (lS,2S)-N-[3-(6-butanoyl-4-methylpyridin-3-yl)-2-methyl-l,6- naphthyridin-7-yl]-2-fluorocyclopropane-l-carboxamide (70.0 mg, 0.17 mmol) in THF (5.0 mL) and MeOH (1.0 mL) was added NaBH ₄ (9.8 mg, 0.26 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 3 h. After the reaction was completed, the mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with dichloromethane/methanol (90/10, v/v) to afford (lS,2S)-2-fluoro-N-{3-[6-(l-hydroxybutyl)- 4-methylpyridin-3-yl]-2-methyl-l,6-naphthyridin-7-yl}cyclopr opane-l -carboxamide (40.0 mg, 56%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 409.1.

Step 3. Separation of (lS,2S)-2-jluoro-N-(3-(6-((S)-l-hydroxybutyl)-4-methylpyridi n-3-yl)-2- methyl-l,6-naphthyridin-7-yl)cyclopropane-l-carboxamide (Compound 109) and (lS,2S)-2- jluoro-N-(3-(6-((R)-l-hydroxybutyl)-4-methylpyridin-3-yl)-2- methyl-l,6-naphthyridin-7- yl)cyclopropane-l -carboxamide (Compound 110)

[0490] The product of (lS,2S)-2-fluoro-N-{3-[6-(l-hydroxybutyl)-4-methylpyridin-3- yl]- 2-methyl-l,6-naphthyridin-7-yl]cyclopropane-l-carboxamide (60.0 mg, 0.10 mmol) was separated by Prep-Chiral -HPLC with the following conditions (Column: Lux 5um Cellulose- 4, 2.12 x 25 cm, 5 pm; Mobile Phase A: Hex(0.5% 2M NH ₃ -MeOH)-HPLC, Mobile Phase B: MeOH: EtOH=l : 1--HPLC; Flow rate: 20 mL/min; Gradient: 50% B to 50% B in 15 min; Wave Length: 254/220 nm; RTl(min): 9.20; RT2(min): 11.73) to afford (l S,2S)-2-fhioro-N- (3-(6-(l-hydroxybutyl)-4-methylpyridin-3-yl)-2-methyl-l,6-na phthyridin-7-yl)cyclopropane-

1-carboxamide Isomer 1 (retention time 9.20 min, 9.2 mg, 30%) as a white solid and (1S,2S)-

2-fluoro-N-(3-(6-(l-hydroxybutyl)-4-methylpyridin-3-yl)-2 -methyl-l,6-naphthyri din-7- yl)cyclopropane-l -carboxamide Isomer 2 (retention time 11.73 min, 11.6 mg, 38%) as a white solid. The absolute stereochemistry of Isomers 1 and 2 was not assigned. The two isomeric structures that could be obtained from chiral separation of the isomeric mixture as described above are shown as Compounds 109 and 110 in Table 1.

[0491] (lS,2S)-2-fluoro-N-(3-(6-(l-hydroxybutyl)-4-methylpyridin-3- yl)-2-methyl- l,6-naphthyridin-7-yl)cyclopropane-l-carboxamide Isomer 1: RTl(min): 9.20; LCMS (ESI, m/z): [M+H]+ = 409.2. ¹ H NMR (400 MHz, DMSO-d6): δ 11.12 (s, 1H), 9.16 (d, J = 3.6 Hz, 1H), 8.53 (s, 1H), 8.33 - 8.24 (m, 2H), 7.51 (d, J = 4.8 Hz, 1H), 5.38 - 5.32 (m, 1H), 5.06 - 4.89 (m, 1H), 4.65 - 4.59 (m, 1H), 2.40 (s, 3H), 2.32 - 2.30 (m, 1H), 2.12 (s, 3H), 1.86 - 1.62 (m, 3H), 1.45 - 1.35 (m, 2H), 1.24 - 1.18 (m, 1H), 0.94 - 0.92 (m, 3H). [0492] (lS,2S)-2-fluoro-N-(3-(6-(l-hydroxybutyl)-4-methylpyridin-3- yl)-2-methyl- l,6-naphthyridin-7-yl)cyclopropane-l-carboxamide Isomer 2: RT2(min): 11.73; LCMS (ESI, m/z): [M+H]+ = 409.2. ¹ H NMR (400 MHz, DMSO-d6): δ 11.12 (s, 1H), 9.16 (d, J = 4.8 Hz, 1H), 8.52 (s, 1H), 8.33 - 8.24 (m, 2H), 7.51 (d, J= 6.0 Hz, 1H), 5.38 - 5.32 (m, 1H), 5.06 - 4.89 (m, 1H), 4.65 - 4.59 (m, 1H), 2.40 (s, 3H), 2.34 - 2.27 (m, 1H), 2.12 (s, 3H), 1.86 - 1.62 (m, 3H), 1.42 - 1.38 (m, 2H), 1.26 - 1.19 (m,lH), 0.94 - 0.89 (m, 3H).

Example 60. Synthesis ofN-(7-(2-cyano-6-(l-hydroxybutyl)-4-methylpyridin-3-yl)-2,6 - naphthyridin-3-yl)cyclopropanecarboxamide (Compound 111)

Step 1: Synthesis of 5-bromo-2-butyryl-4-methylpyridine 1-oxide:

[0493] To a stirred mixture of l-(5-bromo-4-methylpyridin-2-yl)butan-l-one (5.0 g, 20.65 mmol) in DCM (50.0 mL) was added m-CPBA (5.3 g, 30.97 mmol) at room temperature. The resulting mixture was stirred at room temperature for 12 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (1/1, v/v) to afford 5-bromo-2-butyryl-4-methylpyridine 1-oxide (1.9 g, 35%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 258.0

Step 2: Synthesis of 3-bromo-6-butyryl-4-methylpicolinonitrile:

[0494] To a stirred mixture of 5-bromo-2-butyryl-4-methylpyridine 1-oxide (500.0 mg, 1.93 mmol) in ACN (5.0 mL) was added TMSCN (768.7 mg, 7.74 mmol) and Me2NC(=O) Cl (621.8 mg, 5.81 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 12 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (3/1, v/v) to afford 3-bromo-6-butyryl-4-methylpicolinonitrile (370.0 mg, 71%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 267.0. Step 3: Synthesis ofN-(7-(tributylstannyl)-2,6-naphthyridin-3-yl)cyclopropanec arboxamide:

[0495] To a mixture of N-(7-chl oro-2, 6-naphthyridin-3-yl)cyclopropanecarboxamide (550.0 mg, 2.22 mmol) and 1,1, 1,2, 2, 2-hexabutyl distannane (2576.3 mg, 4.44 mmol) in dioxane (8.0 mL) were added tricyclohexylphosphane (249.0 mg, 0.88 mmol) and Pd(OAc)2 (99.7 mg, 0.44 mmol) at room temperature under N2. The resulting mixture was stirred at 110 °C for 12 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (5/1, v/v) to afford N-(7-(tributylstannyl)-2,6-naphthyridin-3- yl)cyclopropanecarboxamide (400.0 mg, 35%) as a yellow oil. LCMS (ESI, m/z): [M+H]+ = 504.2.

Step 4: Synthesis ofN-(7-(6-butyryl-2-cyano-4-methylpyridin-3-yl)-2,6-naphthyr idin-3- yl)cyclopropanecarboxamide:

[0496] To a solution of N-(7-(tributylstannyl)-2,6-naphthyridin-3- yl)cyclopropanecarboxamide (150.0 mg, 0.29 mmol) in toluene (4.0 mL) was added 3- bromo-6-butyryl-4-methylpicolinonitrile (79.7 mg, 0.29 mmol) and Pd(PPh3)4 (34.5 mg, 0.03 mmol) at room temperature under N2. The resulting mixture was stirred at 110 °C for 12 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (3/1, v/v) to afford N-(7-(6-butyryl-2-cyano-4-methylpyridin-3-yl)-2,6- naphthyridin-3-yl)cyclopropanecarboxamide (40.0 mg, 33%) as a white solid. LCMS (ESI, m/z): [M+H]+ = 400.2.

Step 5. Synthesis ofN-(7-(2-cyano-6-(l-hydroxybutyl)-4-methylpyridin-3-yl)-2,6 - naphthyridin-3-yl)cyclopropanecarboxamide (Compound 111)

[0497] To a solution of N-(7-(6-butyryl-2-cyano-4-methylpyridin-3-yl)-2,6-naphthyrid in- 3-yl)cyclopropanecarboxamide (40.0 mg, 0.10 mmol) in THF (3.0 mL) and MeOH (0.3 mL) was added NaBH ₄ (11.3 mg, 0.30 mmol) at 0 °C under N2. The resulting mixture was stirred at room temperature for 2 h under N2. After the reaction was completed, the reaction was quenched with H2O at 0 °C and then extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (10/1, v/v) and then purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30x150 mm, 5 pm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 39% B to 47% B in 8 min; Wave Length: 220 nm) to afford N-(7-(2-cyano-6-(l- hydroxybutyl)-4-methylpyridin-3-yl)-2,6-naphthyridin-3-yl)cy clopropanecarboxamide (Compound 111, 2.6 mg, 6%) as a light yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 402.1. NMR (400 MHz, DMSO-d ₆ ): δ 11.25 (s, 1H), 9.54 (s, 1H), 9.37 (s, 1H), 8.73 (s, 1H), 8.27 (s, 1H), 7.83 (s, 1H), 5.62 (d, J= 4.8 Hz, 1H), 4.68 - 4.64 (m, 1H), 2.31 (s, 3H), 2.14 - 2.10 (m, 1H), 1.78 - 1.66 (m, 2H), 1.45 - 1.38 (m, 2H), 0.94 - 0.87 (m, 7H).

Example 61. Synthesis of (lR,2R)-2-fluoro-N-(3-(6-((R)-l-hydroxybutyl-l-d)-4- methylpyridin-3-yl)-l, 6-naphthyridin- 7-yl)cyclopropane-l -carboxamide ( Compound 112) and (lR,2R)-2-fluoro-N-(3-(6-((S)-l-hydroxybutyl-l-d)-4-methylpy ridin-3-yl)-l,6- naphthyridin-7-yl)cyclopropane-l-carboxamide (Compound 113)

Step 1: Synthesis of (lR,2R)-2-fluoro-N-(3-(6-(l -hydroxybutyl- 1 -d)-4-methylpyridin-3-yl)~ 1, 6-naphthyridin- 7 -yl)cyclopropane-l -carboxamide:

[0498] To a solution of (lR,2R)-N-(3-(6-butyryl-4-methylpyridin-3-yl)-l,6-naphthyrid in- 7-yl)-2-fluorocyclopropane-l-carboxamide (200.0 mg, 0.51 mmol) in THF/CD3OD (10.0 mL/2.0 mL) was added NaBD4 (25.6 mg, 0.61 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction mixture was quenched with water at 0 °C. The reaction mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (10/1, v/v) to afford (lR,2R)-2-fhioro-N-(3-(6-(l-hydroxybutyl-l-d)-4-methylpyridi n-3-yl)-l,6-naphthyri din-7- yl)cyclopropane-l -carboxamide (60.0 mg, 39%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺

= 396.2.

Step 2. Separation of (lR,2R)-2-jluoro-N-(3-(6-((R)-l-hydr oxybutyl- l-d)-4-methylpyridin-3- yl)-l,6-naphthyridin-7-yl)cyclopropane-l -carboxamide (Compound 112) and (lR,2R)-2- jluoro-N-(3-(6-((S)-l-hydroxybutyl-l-d)-4-methylpyridin-3-yl )-l,6-naphthyridin-7- yl)cyclopropane-l -carboxamide (Compound 113)

[0499] The product of (lR,2R)-2-fluoro-N-(3-(6-(l-hydroxybutyl-l-d)-4-methylpyridi n- 3-yl)-l,6-naphthyridin-7-yl)cyclopropane-l-carboxamide (60.0 mg, 0.15 mmol) was separated by Prep-Chiral-HPLC with the following conditions: (Column: CHIRAL ART Cellulose-SC, 2x25 cm, 5 μm; Mobile Phase A: Hex(0.5% 2M NH ₃ -MeOH)-HPLC, Mobile Phase B: MeOH: DCM=1 : 1— HPLC; Flow rate: 20 mL/min; Gradient: 80% B to 80% B in 11.8 min; Wave Length: 254/220 nm; RTl(min): 6.42; RT2(min): 10.37) to afford (1R,2R)- 2-fluoro-N-(3 -(6-(l -hydroxybutyl- 1 -d)-4-methylpyri din-3 -yl)- 1 ,6-naphthyridin-7- yl)cyclopropane-l -carboxamide Isomer 1 (retention time 6.42 min, 9.1 mg, 30%) as a white solid and (lR,2R)-2-fluoro-N-(3-(6-(l-hydroxybutyl-l-d)-4-methylpyridi n-3-yl)-l,6- naphthyridin-7-yl)cyclopropane-l -carboxamide Isomer 2 (retention time 10.37 min, 8.3 mg, 27%) as a white solid. The absolute stereochemistry of Isomers 1 and 2 was not assigned. The two isomeric structures that could be obtained from chiral separation of the isomeric mixture as described above are shown as Compounds 112 and 113 in Table 1.

[0500] (lR,2R)-2-fluoro-N-(3-(6-(l-hydroxybutyl-l-d)-4-methylpyridi n-3-yl)-l,6- naphthyridin-7-yl)cyclopropane-l-carboxamide Isomer 1: RTl(min): 6.42; LCMS (ESI, m/z): [M+H]+ = 396.1. ¹ H NMR (400 MHz, DMSO-d6): δ 11.20 (s, 1H), 9.28 (s, 1H), 9.11 (d, J = 2.0 Hz, 1H), 8.61 (s, 1H), 8.56 (d, J = 1.6 Hz, 1H), 8.45 (s, 1H), 7.50 (s, 1H), 5.33 (s, 1H), 5.08 - 4.88 (m, 1H), 2.37 (s, 3H), 2.33 - 2.27 (m, 1H), 1.76 - 1.64 (m, 3H), 1.40 - 1.34 (m, 2H), 1.27 - 1.18 (m, 1H), 0.93 - 0.89 (m, 3H).

[0501] (lR,2R)-2-fluoro-N-(3-(6-(l-hydroxybutyl-l-d)-4-methylpyridi n-3-yl)-l,6- naphthyridin-7-yl)cyclopropane-l-carboxamide Isomer 2: RT2(min): 10.37; LCMS (ESI, m/z): [M+H]+ = 396.4. ¹ H NMR (400 MHz, DMSO-d6): δ 11.20 (s, 1H), 9.28 (s, 1H), 9.11 (d, J = 2.0 Hz, 1H), 8.61 - 8.56 (m, 2H), 8.45 (s, 1H), 7.50 (s, 1H), 5.33 (s, 1H), 5.08 - 4.88 (m, 1H), 2.37 (s, 3H), 2.33 - 2.27 (m, 1H), 1.78 - 1.62 (m, 3H), 1.46 - 1.33 (m, 2H), 1.27 - 1.18 (m, 1H), 0.93 - 0.89 (m, 3H).

Example 62. Synthesis of (R)-2,2-difluoro-N-(7-(6-((S)-l-hydroxypropyl)-4-methylpyrid in- 3-yl)-2,6-naphthyridin-3-yl)cyclopropane-l-carboxamide (Compound 114) and (R)-2,2- difluoro-N-(7-(6-((R)-l -hydroxypropyl)-4-methylpyridin-3-yl)-2, 6-naphthyridin-3- yl) cyclopropane-1 -carboxamide (Compound 115)

Step 1: Synthesis of (R)-2,2-difluoro-N-(7-(4-methyl-6-propionylpyridin-3-yl)-2,6 - naphthyridin-3-yl)cyclopropane-l-carboxamide:

[0502] To a solution l-(5-(7-amino-2,6-naphthyridin-3-yl)-4-methylpyridin-2-yl)pr opan- 1-one (500.0 mg, 1.71 mmol) in pyridine (15.0 mL) were added (R)-2,2- difluorocyclopropane-1 -carboxylic acid (250.5 mg, 2.05 mmol) and EDCI (655.7 mg, 3.42 mmol) at 0 °C under N2. The resulting mixture was stirred at room temperature for 2 h under N2. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (10/1, v/v) to afford (R)-2,2-difluoro-N-(7-(4-methyl-6-propionylpyridin-3-yl)-2,6 - naphthyri din-3 -yl)cy cl opropane-1 -carboxamide (200.0 mg, 44%) as a yellow green solid.

LCMS (ESI, m/z): [M+H] ⁺ = 397.1.

Step 2: Synthesis of (lR)-2,2-difluoro-N-(7-(6-(l-hydroxypropyl)-4-methylpyridin- 3-yl)-2,6- naphthyridin-3-yl)cyclopropane-l-carboxamide:

[0503] To a solution of (R)-2,2-difluoro-N-(7-(4-methyl-6-propionylpyridin-3-yl)-2,6 - naphthyri din-3 -yl)cy cl opropane-1 -carboxamide (200.0 mg, 0.50 mmol) in THF (5.0 mL)/MeOH (1.0 mL) was added NaBH ₄ (28.6 mg, 0.75 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction mixture was quenched with H2O at 0 °C. The resulting mixture was diluted with H2O and extracted with CH2CI2. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (8/1, v/v) to afford (lR)-2,2-difluoro-N-(7-(6-(l-hydroxypropyl)-4-methylpyridin- 3-yl)-2,6-naphthyridin- 3 -yl)cy cl opropane-1 -carboxamide (150.0 mg, 74%) as a yellow green solid. LCMS (ESI, m/z): [M+H] ⁺ = 399.2.

Step 3. Separation of Synthesis of (R)-2,2-difluoro-N-(7-(6-((S)-l-hydroxypropyl)-4- methylpyridin-3-yl)-2, 6-naphthyridin-3-yl)cyclopropane-l-carboxamide (Compound 114) and (R)-2, 2-difluoro-N-(7-( 6-( (R)-l-hydroxypropyl)-4-methylpyridin-3-yl)-2, 6-naphthyridin- 3-yl)cyclopropane-l -carboxamide (Compound 115)

[0504] The racemic mixture of (lR)-2,2-difluoro-N-(7-(6-(l-hydroxypropyl)-4- m ethylpyri din-3 -yl)-2, 6-naphthyri din-3 -yl)cy cl opropane-1 -carboxamide (150.0 mg, 0.37 mmol) was separated by Prep-HPLC with the following conditions (Column: CHIRAL ART Amylose-SA, 2x25 cm, 5 μm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)— HPLC, Mobile Phase B: MeOH: DCM=1 : 1— HPLC; Flow rate: 20 mL/min; Gradient: 35% B to 35% B in 17 min; Wave Length: 254/220 nm; RTl(min): 9.87; RT2(min): 14.08) to afford (R)-2,2- difluoro-N-(7-(6-(l-hydroxypropyl)-4-methylpyridin-3-yl)-2,6 -naphthyridin-3- yl)cyclopropane-l -carboxamide Isomer 1 (retention time 9.87 min, 40.5 mg, 54%) as a white solid and (R)-2,2-difluoro-N-(7-(6-(l-hydroxypropyl)-4-methylpyridin-3 -yl)-2,6- naphthyri din-3 -yl)cy cl opropane-1 -carboxamide Isomer 2 (retention time 14.08 min, 36.7 mg, 48%) as a white solid. The absolute stereochemistry of Isomers 1 and 2 was not assigned. The two isomeric structures that could be obtained from chiral separation of the isomeric mixture as described above are shown as Compounds 114 and 115 in Table 1.

[0505] (R)-2,2-difluoro-N-(7-(6-(l-hydroxypropyl)-4-methylpyridin-3 -yl)-2,6- naphthyridin-3-yl)cyclopropane-l-carboxamide Isomer 1: RTl(min):9.87; LCMS (ESI, m/z): [M+H]+ = 399.1. ¹ H NMR (400 MHz, DMSO-d6): δ 11.40 (s, 1H), 9.52 (s, 1H), 9.35 (s, 1H), 8.67 (s, 1H), 8.59 (s, 1H), 8.20 (s, 1H), 7.47 (s, 1H), 5.35 (d, J = 4.8 Hz, 1H), 4.58 - 4.54 (m, 1H), 3.13 - 3.05 (m, 1H), 2.46 (s, 3H), 2.15 - 2.03 (m, 2H), 1.90 - 1.80 (m, 1H), 1.74

- 1.63 (m, 1H), 0.92 - 0.89 (m, 3H).

[0506] (R)-2,2-difluoro-N-(7-(6-(l-hydroxypropyl)-4-methylpyridin-3 -yl)-2,6- naphthyridin-3-yl)cyclopropane-l-carboxamide Isomer 2: RT2(min): 14.08; LCMS (ESI, m/z): [M+H]+ =399.1. ¹ H NMR (400 MHz, DMSO-d6): δ 11.38 (s, 1H), 9.52 (s, 1H), 9.35 (s, 1H), 8.67 (s, 1H), 8.59 (s, 1H), 8.19 (s, 1H), 7.47 (s, 1H), 5.33 (d, J = 4.8 Hz, 1H), 4.58 - 4.54 (m, 1H), 3.13 - 3.05 (m, 1H), 2.46 (s, 3H), 2.15 - 2.02 (m, 2H), 1.90 - 1.80 (m, 1H), 1.74

- 1.63 (m, 1H), 0.92 - 0.89(m, 3H).

Example 63. Synthesis of (lS,2S)-2-fluoro-N-(7-(6-((S)-2-hydroxybutan-2-yl)-4- methylpyridin-3-yl)-2,6-naphthyridin-3-yl)cyclopropane-l-car boxamide (Compound 116) and (lS,2S)-2-fluoro-N-(7-(6-((R)-2-hydroxybutan-2-yl)-4-methylp yridin-3-yl)-2,6- naphthyridin-3-yl)cyclopropane-l -carboxamide (Compound 117)

Step 1: Synthesis of (lS,2S)-2-fluoro-N-(7-(4-methyl-6-propionylpyridin-3-yl)-2,6 - naphthyridin-3-yl)cyclopropane-l-carboxamide:

[0507] To a s solution of (lS,2S)-N-(7-chloro-2,6-naphthyridin-3-yl)-2- fluorocy cl opropane-1 -carboxamide (600.0 mg, 2.25 mmol) in dioxane (10.0 mL) and H2O (2.0 mL) was added l-(4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)p yridin-2- yl)propan-l-one (1.9 g, 6.77 mmol), K2CO3 (936.3 mg, 6.77 mmol) and Pd(dppf)C12 (330.5 mg, 0.45 mmol) at room temperature under N2. The resulting mixture was stirred at 85 °C for 1 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (10/1, v/v) to afford (lS,2S)-2-fluoro-N-(7-(4-methyl-6-propionylpyridin-3-yl)-2,6 - naphthyri din-3 -yl)cy cl opropane-1 -carboxamide (500.0 mg, 58%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 379.1.

Step 2: Synthesis of (lS,2S)-2-fluoro-N-(7-(6-(2-hydroxybutan-2-yl)-4-methylpyrid in-3-yl)- 2,6-naphthyridin-3-yl)cyclopropane-l-carboxamide:

[0508] To a solution of (lS,2S)-2-fluoro-N-(7-(4-methyl-6-propionylpyridin-3-yl)-2,6 - naphthyri din-3 -yl)cy cl opropane-1 -carboxamide (200.0 mg, 0.52 mmol) in tetrahydrofuran (6.0 mL) was added dropwise bromo(methyl)magnesium (1.6 mL, 1 mol/L in THF) at 0°C under N2. The resulting mixture was 0 °C for 2 h under N2. After the reaction was completed, the reaction mixture was diluted with H2O at 0 °C and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (10/1, v/v) to afford (l S,2S)-2-fluoro-N- (7-(6-(2-hydroxybutan-2-yl)-4-methylpyridin-3-yl)-2,6-naphth yridin-3-yl)cyclopropane-l- carboxamide (50.0 mg, 23%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 395.2.

Step 3. Separation of (lS,2S)-2-jluoro-N-(7-(6-((S)-2-hydroxybutan-2-yl)-4-methylp yridin-3- yl)-2,6-naphthyridin-3-yl)cyclopropane-l -carboxamide (Compound 116) and (lS,2S)-2- fluoro-N-(7-( 6-( (R)-2-hydroxybutan-2-yl)-4-methylpyridin-3-yl)-2, 6-naphthyridin-3- yl)cyclopropane-l -carboxamide (Compound 117)

[0509] The product of (lS,2S)-2-fluoro-N-(7-(6-(2-hydroxybutan-2-yl)-4-methylpyrid in- 3-yl)-2,6-naphthyridin-3-yl)cyclopropane-l-carboxamide (50.0 mg, 0.12 mmol) was separated by Prep-Chiral-HPLC with the following conditions (Column: Lux 5um Cellulose- 4, 2.12x25 cm, 5 pm; Mobile Phase A: Hex(0.5% 2M NH ₃ -MeOH)-HPLC, Mobile Phase B: MeOH: EtOH=l : 1— HPLC; Flow rate: 20 mL/min; Gradient: 30% B to 30% B in 14.5 min; Wave Length: 254/220 nm; RTl(min): 11.06; RT2(min): 12.90) to afford (lS,2S)-2-fluoro- N-(7-(6-(2-hydroxybutan-2-yl)-4-methylpyridin-3-yl)-2,6-naph thyridin-3-yl)cyclopropane-l- carboxamide Isomer 1 (retention time 11.06 min, 15.0 mg, 60%) as a white solid and (1S,2S)- 2-fluoro-N-(7-(6-(2-hydroxybutan-2-yl)-4-methylpyridin-3-yl) -2,6-naphthyri din-3- yl)cyclopropane-l -carboxamide Isomer 2 (retention time 12.90 min, 11.2 mg, 40%) as a white solid. The absolute stereochemistry of Isomers 1 and 2 was not assigned. The two isomeric structures that could be obtained from chiral separation of the isomeric mixture as described above are shown as Compounds 116 and 117 in Table 1.

[0510] (lS,2S)-2-fluoro-N-(7-(6-(2-hydroxybutan-2-yl)-4-methylpyrid in-3-yl)-2,6- naphthyridin-3-yl)cyclopropane-l-carboxamide Isomer 1: RTl(min): 11.06; LCMS (ESI, m/z): [M+H]+ = 395.1 ¹ H NMR (400 MHz, DMSO-d6): δ 11.22 (s, 1H), 9.50 (s, 1H), 9.33 (s, 1H), 8.69 (s, 1H), 8.60 (s, 1H), 8.19 (s, 1H), 7.61 (s, 1H), 5.08 - 4.88 (m, 2H), 2.45 (s, 3H), 2.34 - 2.28 (m, 1H), 1.96 - 1.87 (m, 1H), 1.81 - 1.67 (m, 2H), 1.47 (s, 3H), 1.28 - 1.19 (m, 1H), 0.74 - 0.70 (m, 3H).

[0511] (lS,2S)-2-fluoro-N-(7-(6-(2-hydroxybutan-2-yl)-4-methylpyrid in-3-yl)-2,6- naphthyridin-3-yl)cyclopropane-l-carboxamide Isomer 2: RT2(min): 12.90; LCMS (ESI, m/z): [M+H]+ = 395.1. ¹ H NMR (400 MHz, DMSO- d6): δ 11.22 (s, 1H), 9.50 (s, 1H), 9.33 (s, 1H), 8.69 (s, 1H), 8.60 (s, 1H), 8.18 (s, 1H), 7.61 (s, 1H), 5.10 - 4.89 (m, 2H), 2.46 (s, 3H), 2.35 - 2.27 (m, 1H), 1.95 - 1.86 (m, 1H), 1.81 - 1.68 (m, 2H), 1.47 (s, 3H), 1.28 - 1.19 (m, 1H), 0.74 - 0.71 (m, 3H). Example 64. Synthesis of (lR)-2,2-difluoro-N-(3-{6-[(lS)-l-hydroxypropyl]-4- methylpyridin-3-yl}-l, 6-naphthyridin- 7-yl)cyclopropane-l -carboxamide ( Compound 118) and (lR)-2,2-difluoro-N-(3-{6-[(lR)-l-hydroxypropyl]-4-methylpyr idin-3-yl}-l,6- naphthyridin-7-yl)cyclopropane-l -carboxamide (Compound 119)

Step 1: Synthesis of l-[5-(7-amino-l,6-naphthyridin-3-yl)-4-methylpyridin-2-yl]pr opan-l- one:

[0512] To a solution of tert-butyl N-[3-(4-methyl-6-propanoylpyridin-3-yl)-l,6- naphthyridin-7-yl]carbamate (900.0 mg, 2.29 mmol) in CH ₂ Cl ₂ (10.0 mL) was added TFA (10.0 mL) at room temperature. The mixture was stirred at room temperature for 1 h. After the reaction was completed, the mixture was basified to pH=7 with saturated NaHCO3(aq.). The resulting mixture was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography with CH3CN/H2O (1/1, v/v) to afford l-[5-(7-amino-l,6-naphthyridin-3-yl)- 4-methylpyridin-2-yl]propan-l-one (300.0 mg, 44%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 293.1.

Step 2: Synthesis of (lR)-2,2-difluoro-N-[3-(4-methyl-6-propanoylpyridin-3-yl)-l ,6- naphthyridin- 7-yl cyclopropane- 1 -carboxamide:

[0513] To a solution of l-[5-(7-amino-l,6-naphthyridin-3-yl)-4-methylpyridin-2- yl]propan-l-one (270.0 mg, 0.92 mmol) in pyridine (5.0 mL) were added (lR)-2,2- difluorocyclopropane-1 -carboxylic acid (124.0 mg, 1.01 mmol) and EDCI (354.1 mg, 1.85 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (10/1, v/v) to afford (lR)-2,2-difluoro-N-[3-(4-methyl-6-propanoylpyridin-3-yl)-l, 6- naphthyridin-7-yl]cyclopropane-l -carboxamide (200.0 mg, 54%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 397.1.

Step 3: Synthesis of (lR)-2,2-difluoro-N-{3-[6-(l-hydroxypropyl)-4-methylpyridin- 3-yl]-l ,6- naphthyridin-7-yl}cyclopropane-l -carboxamide:

[0514] To a solution of (lR)-2,2-difluoro-N-[3-(4-methyl-6-propanoylpyridin-3-yl)-l, 6- naphthyridin-7-yl]cyclopropane-l-carboxamide (200.0 mg, 0.51 mmol) in THF/MeOH (10.0 mL/2.0 mL) was added NaBH ₄ (22.9 mg, 0.61 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the mixture was quenched with MeOH and then concentrated under vacuum. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (10/1, v/v) to afford (lR)-2,2-difhioro-N- {3-[6-(l-hydroxypropyl)-4-methylpyridin-3-yl]-l,6-naphthyrid in-7-yl}cyclopropane-l- carboxamide (100.0 mg, 49%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 399.2.

Step 4. Separation of (lR)-2,2-difluoro-N-(3-{6-[(lS)-l-hydroxypropyl]-4-methylpyr idin-3- yl}-l,6-naphthyridin-7-yl)cyclopropane-l-carboxamide (Compound 118) and (lR)-2,2- difluoro-N-(3-{6-[(lR)-l-hydroxypropyl]-4-methylpyridin-3-yl }-l,6-naphthyridin-7- yl)cyclopropane-l -carboxamide (Compound 119)

[0515] The racemic product of (lR)-2,2-difluoro-N-{3-[6-(l-hydroxypropyl)-4- methylpyridin-3-yl]-l,6-naphthyridin-7-yl}cyclopropane-l-car boxamide (90.0 mg, 0.23 mmol) was separated by Prep-Chiral-HPLC with the following conditions: (Column: CHIRAL ART Cellulose-SB, 2x25 cm, 5 pm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)— HPLC, Mobile Phase B: EtOH: DCM=1: 1-HPLC; Flow rate: 20 mL/min; Gradient: 30% B to 30% B in 16 min; Wave Length: 254/220 nm; RTl(min): 10.30; RT2(min): 13.10) to afford (lR)-2,2-difluoro-N-(3-{6-[l-hydroxypropyl]-4-methylpyridin- 3-yl}-l,6-naphthyridin- 7-yl)cyclopropane-l -carboxamide Isomer 1 (retention time 10.30 min, 23.3 mg, 51%) as a white solid and (lR)-2,2-difhioro-N-(3-{6-[l-hydroxypropyl]-4-methylpyridin- 3-yl}-l,6- naphthyridin-7-yl)cyclopropane-l -carboxamide Isomer 2 (retention time 13.10 min, 26.4 mg, 58%) as a white solid. The absolute stereochemistry of Isomers 1 and 2 was not assigned. The two isomeric structures that could be obtained from chiral separation of the isomeric mixture as described above are shown as Compounds 118 and 119 in Table 1.

[0516] (lR)-2,2-difluoro-N-(3-{6-[l-hydroxypropyl]-4-methylpyridin- 3-yl}-l,6- naphthyridin-7-yl)cyclopropane-l-carboxamide Isomer 1: RTl(min): 10.30; LCMS (ESI, m/z): [M+H]+ = 399.1. ¹ H NMR (400 MHz, DMSO-d6): δ 11.39 (s, 1H), 9.30 (s, 1H), 9.14 (d, J = 2.0 Hz, 1H), 8.60 (s, 2H), 8.47 (s, 1H), 7.51 (s, 1H), 5.38 (d, J = 4.8 Hz, 1H), 4.58 - 4.53 (m, 1H), 3.14 - 3.05 (m, 1H), 2.38 (s, 3H), 2.16 - 2.02 (m, 2H), 1.90 - 1.80 (m, 1H), 1.73 - 1.63 (m, 1H), 0.93 - 0.89 (m, 3H).

[0517] (lR)-2,2-difluoro-N-(3-{6-[l-hydroxypropyl]-4-methylpyridin- 3-yl}-l,6- naphthyridin-7-yl)cyclopropane-l-carboxamide Isomer 2: RT2(min): 13.10; LCMS (ESI, m/z): [M+H]+ = 399.1. ¹ H NMR (400 MHz, DMSO-d6): δ 11.37 (s, 1H), 9.30 (s, 1H), 9.13 (d, J = 2.0 Hz, 1H), 8.59 - 8.58 (m, 2H), 8.46 (s, 1H), 7.50 (s, 1H), 5.37 (d, J = 4.8 Hz, 1H), 4.58 - 4.53 (m, 1H), 3.11 - 3.07 (m, 1H), 2.37 (s, 3H), 2.14 - 2.05 (m, 2H), 1.90 - 1.80 (m, 1H), 1.73 - 1.63 (m, 1H), 0.93 - 0.89 (m, 3H).

Example 65. Synthesis of (R)-N-(7-(4-chloro-6-(l-hydroxybutyl)pyridin-3-yl)-2,6- naphthyridin-3-yl)cyclopropanecarboxamide (Compound 120) and (S)-N-(7-(4-chloro-6- (l-hydroxybutyl)pyridin-3-yl)-2,6-naphthyridin-3-yl)cyclopro panecarboxamide (Compound 121)

Step 1: Synthesis of 5-bromo-4-chloro-N-methoxy-N-methylpicolinamide:

[0518] To a solution of N,O-dimethylhydroxylamine hydrochloride (6.2 g, 63.97 mmol) in DMF (150.0 mL) was added 5-bromo-4-chloropicolinic acid (10.0 g, 42.65 mmol), DIEA (27.6 g, 213.24 mmol) and HATU (19.5 g, 51.18 mmol) at 0°C under N2. The reaction mixture was stirred at 0 °C for 1 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /ethyl acetate (70/30, v/v) to afford 5-bromo-4-chloro-N- methoxy-N-methylpicolinamide (9.0 g, 81%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ =279.0.

Step 2: Synthesis of l-(5-bromo-4-chloropyridin-2-yl)butan-l-one:

[0519] To a solution of 5-bromo-4-chloro-N-methoxy-N-methylpicolinamide (9.0 g, 32.20 mmol) in THF (100.0 mL) was added CH ₃ CH ₂ CH ₂ MgBr (24.2 mL, 2.0 mol/L in THF) at 0 °C under N ₂ . The resulting mixture was stirred at 0 °C for 1 h under N ₂ . After the reaction was completed, the resulting mixture was diluted with H ₂ O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (85/15, v/v) to afford l-(5-bromo-4-chloropyridin-2-yl)butan-l-one (1.8 g, 19%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ =262.3.

Step 3: Synthesis of (6-butyryl-4-chloropyridin-3-yl)boronic acid:

[0520] To a solution of l-(5-bromo-4-chloropyridin-2-yl)butan-l-one (500.0 mg, 1.91 mmol) in dioxane (15.0 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2- dioxaborolane) (435.3 mg, 1.72 mmol), Pd(dppf)Cl ₂ (139.4 mg, 0.19 mmol) and KOAc (560.8 mg, 5.72 mmol) at room temperature under N ₂ . The resulting mixture was stirred at 80 °C for 2 h under N ₂ . After the reaction was completed, the resulting was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography with ACN/H ₂ O (45/55, v/v) to afford (6-butyryl-4-chl oropyri din-3 - yl)boronic acid (380.0 mg, 87%) as a black oil. LCMS (ESI, m/z): [M+H] ⁺ =228.1.

Step 4: Synthesis ofN-(7-(6-butyryl-4-chloropyridin-3-yl)-2,6-naphthyridin-3- yl)cyclopropanecarboxamide:

[0521] To a solution of (6-butyryl-4-chloropyridin-3-yl)boronic acid (789.8 mg, 3.47 mmol) in dioxane (15.0 mL) and H2O (3.0 mL) was added N-(7-chloro-2,6-naphthyridin-3- yl)cyclopropanecarboxamide (200.0 mg, 0.81 mmol), Pd(dppf)C12 (255.9 mg, 0.35 mmol) and K2CO3 (334.8 mg, 2.42 mmol) at room temperature under N2. The resulting mixture was stirred at 80 °C for 2 h under N2. After the reaction was completed, the resulting was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (50/50, v/v) to afford N-(7-(6- butyryl-4-chloropyridin-3-yl)-2,6-naphthyridin-3-yl)cyclopro panecarboxamide (107.0 mg, 31%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =395.2.

Step 5: Synthesis ofN-(7-(4-chloro-6-(l-hydroxybutyl)pyridin-3-yl)-2,6-naphthy ridin-3- yl)cyclopropanecarboxamide:

[0522] To a solution of N-(7-(6-butyryl-4-chloropyridin-3-yl)-2,6-naphthyridin-3- yl)cyclopropanecarboxamide (300.0 mg, 0.76 mmol) in MeOH (2.0 mL) and THF (10.0 mL) was added NaBH ₄ (43.3 mg, 1.14 mmol) at 0 °C under N2. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (92/8, v/v) to afford N-(7-(4-chloro-6-(l-hydroxybutyl)pyridin-3-yl)-2,6- naphthyridin-3-yl)cyclopropanecarboxamide (67.0 mg, 22%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =397.2.

Step 6. Separation of (R)-N-(7-(4-chloro-6-( l-hydroxybutyl)pyridin-3-yl)-2, 6-naphthyridin-3- yl)cyclopropanecarboxamide (Compound 120) and (S)-N-(7-(4-chloro-6-(l- hydroxybutyl)pyridin-3-yl)-2,6-naphthyridin-3-yl)cyclopropan ecarboxamide (Compound 121)

[0523] The racemic product of N-(7-(4-chloro-6-(l-hydroxybutyl)pyridin-3-yl)-2,6- naphthyridin-3-yl)cyclopropanecarboxamide (67.0 mg, 0.27 mmol) was separated by Prep- Chiral-SFC with the following conditions (Column: CHIRALPAK IH, 7x25 cm, 10 μm; Mobile Phase A: CO2, Mobile Phase B: IPA: ACN=1: 1 (0.1% 2M NH ₃ -MeOH); Flow rate: 250 mL/min; Gradient: isocratic 25% B; Column Temperature(°C): 35; Back Pressure(bar): 100; Wave Length: 220 nm; RTl(min): 16.01; RT2(min): 21.18) afford N-(7-(4-chloro-6-(l- hydroxybutyl)pyridin-3-yl)-2,6-naphthyridin-3-yl)cyclopropan ecarboxamide Enantiomer 1 (retention time 16.01 min, 15.2 mg, crude) as a white solid and N-(7-(4-chloro-6-(l- hydroxybutyl)pyridin-3-yl)-2,6-naphthyridin-3-yl)cyclopropan ecarboxamide Enantiomer 2 (retention time 21.18 min, 18.5 mg, crude) as a white solid. The absolute stereochemistry of Enantiomers 1 and 2 was not assigned. The two enantiomeric structures that could be obtained from chiral separation of the enantiomeric mixture as described above are shown as Compounds 120 and 121 in Table 1.

[0524] The crude product of N-(7-(4-chloro-6-(l-hydroxybutyl)pyridin-3-yl)-2,6- naphthyridin-3-yl)cyclopropanecarboxamide Enantiomer 1 (15.2 mg, crude) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30x150 mm, 5 μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 16% B in 10 min; Wave Length: 254/220 nm) to afford N-(7-(4- chloro-6-(l-hydroxybutyl)pyridin-3-yl)-2,6-naphthyridin-3-yl )cyclopropanecarboxamide Enantiomer 1 (4.2 mg, 14%) as a white solid. N-(7-(4-chloro-6-(l-hydroxybutyl)pyridin-3- yl)-2,6-naphthyridin-3-yl)cyclopropanecarboxamide Enantiomer 1: RTl(min): 16.01 : LCMS (ESI, m/z): [M+H] ⁺ = 397.1. ¹ H NMR (400.0 MHz, DMSO-d ₆ ): δ 11.18 (s, 1H), 9.50 (s, 1H), 9.34 - 9.30 (m, 2H), 8.71 - 8.67 (m, 2H), 8.58 (d, J= 2.0 Hz, 1H), 5.16 (d, J= 6.8 Hz, 1H), 5.05 - 5.00 (m, 1H), 2.13 - 2.08 (m, 1H), 1.81 - 1.74 (m, 2H), 1.47 - 1.24 (m, 2H), 0.94 - 0.85 (m, 7H).

[0525] The crude product of N-(7-(4-chloro-6-(l-hydroxybutyl)pyridin-3-yl)-2,6- naphthyridin-3-yl)cyclopropanecarboxamide Enantiomer 2 (18.5 mg, crude) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30x150 mm, 5 μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 7% B to 21% B in 10 min; Wave Length: 254/220 nm) to afford N-(7-(4- chloro-6-(l-hydroxybutyl)pyridin-3-yl)-2,6-naphthyridin-3-yl )cyclopropanecarboxamide Enantiomer 2 (4.7 mg, 12%). N-(7-(4-chloro-6-(l-hydroxybutyl)pyridin-3-yl)-2,6- naphthyridin-3-yl)cyclopropanecarboxamide Enantiomer 2: RT2(min): 21.18; LCMS (ESI, m/z): [M+H] ⁺ = 397.3. ¹ H NMR (400 MHz, CD ₃ OD): δ 9.37 (s, 1H), 9.29 - 9.26 (m, 2H), 8.63 - 8.58 (m, 2H), 8.48 (s, 1H), 5.23 - 5.19 (m, 1H), 2.00 - 1.96 (m, 1H), 1.89 - 1.80 (m, 2H), 1.58 - 1.47 (m, 2H), 1.07 - 0.93 (m, 7H).

Example 66. Synthesis of (lR,2R)-2-fluoro-N-(3-(6-((S)-l-hydroxybutyl)-4-methylpyridi n- 3-yl)-2-methyl-l,6-naphthyridin-7-yl)cyclopropane-l-carboxam ide (Compound 122) and (lR,2R)-2-fluoro-N-(3-(6-((R)-l-hydroxybutyl)-4-methylpyridi n-3-yl)-2-methyl-l,6- naphthyridin-7-yl)cyclopropane-l -carboxamide (Compound 123)

Step 1: Synthesis of 3-bromo-7-chloro-2-iodo-l,6-naphthyridine:

[0526] To a stirred mixture of 3-bromo-2,7-dichloro-l,6-naphthyridine (1.0 g, 3.60 mmol) in ACN (20.0 mL) was added Nal (2.2 g, 14.39 mmol) and AcCl (0.3 g, 3.60 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 4 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleumether/ethyl acetate (84/16, v/v) to afford 3-bromo-7-chloro-2-iodo-l,6-naphthyridine (390.0 mg, 29%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 368.8.

Step 2: Synthesis of 3 -bromo-7 -chlor o-2 -methyl- 1 ,6-naphthyridine :

[0527] To a solution of 3-bromo-7-chloro-2-iodo-l,6-naphthyridine (300.0 mg, 0.81 mmol) in dioxane (10.0 mL) and H2O (2.0 mL) was added K2CO3 (337.5 mg, 2.43 mmol), Pd(dppf)C12 (57.0 mg, 0.08 mmol) and methylboronic acid (48.6 mg, 0.81 mmol) at room temperature under N2. The resulting mixture was stirred at 70 °C for 16 h under N2. After the reaction was completed, the reaction mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (35/65, v/v) to afford 3-bromo-7-chloro-2-methyl-l,6-naphthyridine (100.0 mg, 47%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 257.2.

Step 3: Synthesis of l-[5-(7-chloro-2-methyl-l,6-naphthyridin-3-yl)-4-methylpyrid in-2- yl]butan-l-one:

[0528] To a stirred mixture of 3-bromo-7-chloro-2-methyl-l,6-naphthyridine (200.0 mg,

0.78 mmol) in dioxane (8.0 mL) and H2O (2.0 mL) was added K2CO3 (322.0 mg, 2.33 mmol), l-[4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)p yridin-2-yl]butan-l-one (224.6 mg, 0.78 mmol) and Pd(dppf)C12 (63.3 mg, 0.08 mmol) at room temperature under N2. The resulting mixture was stirred at 85 °C for 4 h under N2. After the reaction was completed, the mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with dichloromethane/methanol (93/07, v/v) to afford l-[5-(7-chloro-2-methyl-l,6-naphthyridin-3-yl)-4-methylpyrid in-2- yl]butan-l-one (150.0 mg, 56%) as a light yellow solid. LCMS (ESI, m/z): [M+H]+ = 340.2.

Step 4: Synthesis of (lR,2R)-N-[3-(6-butanoyl-4-methylpyridin-3-yl)-2-methyl-l,6- naphthyridin- 7-yl ]-2-fluorocyclopropane-l -carboxamide:

[0529] To a solution of l-[5-(7-chloro-2-methyl-l,6-naphthyridin-3-yl)-4-methylpyrid in- 2-yl]butan-l-one (200.0 mg, 0.59 mmo) in dioxane (5.0 mL) was added (lR,2R)-2- fluorocyclopropane-1 -carboxamide (121.4 mg, 1.18 mmol), CS2CO3 (575.3 mg, 1.77 mmol), BrettPhos (31.5 mg, 0.06 mmol) and BrettPhos Pd G3 (53.4 mg, 0.06 mmol) at room temperature under N2. The resulting mixture was stirred at 80 °C for 3 h under N2. After the reaction was completed, the reaction mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether /ethyl acetate (10/90, v/v) to afford (lR,2R)-N-[3-(6-butanoyl-4-methylpyridin-3-yl)-2-methyl-l,6- naphthyridin-7-yl]-2- fluorocyclopropane-1 -carboxamide (100.0 mg, 41%) as a yellow oil. LCMS (ESI, m/z): [M+H] ⁺ = 407.2.

Step 5: Synthesis of (lR,2R)-2-fluoro-N-(3-(6-(l-hydroxybutyl)-4-methylpyridin-3- yl)-2- methyl-l,6- aphthyridin-7-yl)cyclopropane-l -carboxamide:

[0530] To a stirred mixture of (lR,2R)-N-[3-(6-butanoyl-4-methylpyridin-3-yl)-2- methyl-l,6-naphthyridin-7-yl]-2-fluorocyclopropane-l-carboxa mide (100.0 mg, 0.25 mmol) in MeOH (1.0 mL) and THF (5.0 mL) was added NaBH4 (46.5 mg, 1.23 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 3 h. After the reaction was completed, the mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with dichloromethane/methanol (90/10, v/v) to afford (lR,2R)-2-fluoro-N- (3-(6-(l-hydroxybutyl)-4-methylpyridin-3-yl)-2-methyl-l,6-na phthyridin-7-yl)cyclopropane- 1 -carboxamide (60.0 mg, 60%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 409.2.

Step 6. Separation of (lR,2R)-2-fluoro-N-(3-(6-((S)-l-hydroxybutyl)-4-methylpyridi n-3-yl)-2- methyl-l,6-naphthyridin-7-yl)cyclopropane-l-carboxamide (Compound 122) and (lR,2R)-2- fluoro-N-(3-(6-((R)-l-hydroxybutyl)-4-methylpyridin-3-yl)-2- methyl-l,6-naphthyridin-7- yl) cyclopropane- 1 -carboxamide (Compound 123) [0531] The product of (lR,2R)-2-fluoro-N-(3-(6-(l-hydroxybutyl)-4-methylpyridin-3- yl)- 2-methyl-l,6-naphthyridin-7-yl)cyclopropane-l-carboxamide (60.0 mg, 0.10 mmol) was separated by Prep-Chiral-HPLC with the following conditions (Column: Lux 5um Cellulose- 4, 2.12x25 cm, 5 pm; Mobile Phase A: Hex (0.5% 2M NH ₃ -MeOH)-HPLC, Mobile Phase B: MeOH: EtOH=l : 1— HPLC; Flow rate: 20 mL/min; Gradient: 90% B to 90% B in 13 min; Wave Length: 220/254 nm; RTl(min): 7.42; RT2(min): 10.53) to afford (lR,2R)-2-fluoro-N- (3-(6-(l-hydroxybutyl)-4-methylpyridin-3-yl)-2-methyl-l,6-na phthyridin-7-yl)cyclopropane- 1-carboxamide Isomer 1 (retention time 7.42 min, 10.7 mg, 35%) as a white solid and (lR,2R)-2-fluoro-N-(3-(6-(l-hydroxybutyl)-4-methylpyridin-3- yl)-2-methyl-l,6- naphthyridin-7-yl)cyclopropane-l -carboxamide Isomer 2 (retention time 10.53 min, 11.5 mg, 38%) as a white solid. The absolute stereochemistry of Isomers 1 and 2 was not assigned. The two isomeric structures that could be obtained from chiral separation of the isomeric mixture as described above are shown as Compounds 122 and 123 in Table 1.

[0532] (lR,2R)-2-fluoro-N-(3-(6-(l-hydroxybutyl)-4-methylpyridin-3- yl)-2-methyl- l,6-naphthyridin-7-yl)cyclopropane-l-carboxamide Isomer 1: RTl(min): 7.42; LCMS (ESI, m/z): [M+H]+ = 409.2. ¹ H NMR (400 MHz, DMSO-d6): 5 11.11 (s, 1H), 9.16 (s, 1H), 8.53 (s, 1H), 8.33 - 8.24 (m, 2H), 7.51 (d, J = 4.4 Hz, 1H), 5.35 - 5.31 (m, 1H), 5.12 - 4.84 (m, 1H), 4.63 - 4.56 (m, 1H), 2.40 (s, 3H), 2.30 - 2.21 (m, 1H), 2.12 (s, 3H), 1.86 - 1.63 (m, 3H), 1.44 - 1.37 (m, 2H), 1.26 - 1.22 (m, 1H), 0.94 - 0.90 (m, 3H).

[0533] (lR,2R)-2-fluoro-N-(3-(6-(l-hydroxybutyl)-4-methylpyridin-3- yl)-2-methyl- l,6-naphthyridin-7-yl)cyclopropane-l-carboxamide Isomer 2: RT2(min): 10.53; LCMS (ESI, m/z): [M+H]+ = 409.2. ¹ H NMR (400 MHz, DMSO-d6): 5 11.10 (s, 1H), 9.16 (s, 1H), 8.53 (s, 1H), 8.32 - 8.24 (m, 2H), 7.51 (d, J = 5.2 Hz, 1H), 5.36 - 5.31 (m, 1H), 5.06 - 4.89 (m, 1H), 4.64 - 4.59 (m, 1H), 2.40 (s, 3H), 2.34 - 2.29 (m, 1H), 2.12 (s, 3H), 1.86 - 1.61 (m, 3H), 1.44 - 1.39 (m, 2H), 1.26 - 1.20 (m, 1H), 0.94 - 0.90 (m, 3H).

Example 67 Synthesis of (R)-N-(7-(6-(l-hydroxybutyl)-4-methylpyridazin-3-yl)-2,6- naphthyridin-3-yl)cyclopropanecarboxamide (Compound 124) and (S)-N-(7-(6-(l- hydroxybutyl)-4-methylpyridazin-3-yl)-2,6-naphthyridin-3-yl) cyclopropanecarboxamide (Compound 125)

Step 1: Synthesis of methyl 6-bromo-5-methylpyridazine-3-carboxylate

[0534] To a solution of 3,6-dibromo-4-methylpyridazine (5.0 g, 20.00 mmol) in MeOH (80.0 mL) was added Pd(dppf)C12 (1.5 g, 1.98 mmol) and K2CO3 (8.3 g, 60.32 mmol) at room temperature under CO. The resulting mixture was stirred at 80 °C for 2 h under CO. After the reaction was completed, the resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /ethyl acetate (90/10, v/v) to afford methyl 6-bromo-5-methylpyridazine-3- carboxylate (3.3 g, 71%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =231.1.

Step 2: Synthesis qf 6-bromo-5-methylpyridazine-3-carboxylic acid:

[0535] To a solution of methyl 6-bromo-5-methylpyridazine-3-carboxylate (3.3 g, 14.34 mmol) in THF (20.0 mL) and CH2Cl2 (20.0 mL) was added potassium trimethylsilanolate (5.6 g, 43.02 mmol) at room temperature. The resulting mixture was stirred at 40 °C for 16 h. After the reaction was completed, the resulting mixture was concentrated under vacuum. The pH value of the residue was adjusted to 3.0 with HC1 (aq). The resulting mixture was extracted with CH2CI2. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography with ACN/H2O (15/85, v/v) to afford 6-bromo-5-methylpyridazine-3-carboxylic acid (1.8 g, 58%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =217.1.

Step 3: Synthesis qf 6-bromo-N-methoxy-N,5-dimethylpyridazine-3-carboxamide: [0536] To a solution of 6-bromo-5-methylpyridazine-3-carboxylic acid (500.0 mg, 2.31 mmol) in DMF (10.0 mL) was added N,O-dimethylhydroxylamine hydrochloride (246.9 mg, 2.54 mmol), DIEA (2.8 g, 22.31 mmol) and HATU (1.3 g, 3.46 mmol) at 0°C under N2. The reaction mixture was stirred at 0 °C for 1 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /ethyl acetate (70/30, v/v) to afford 6-bromo-N-methoxy-N,5- dimethylpyridazine-3-carboxamide (420.3 mg, 70%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ =260.0.

Step 4: Synthesis of l-(6-bromo-5-methylpyridazin-3-yl)butan-l-one:

[0537] To a solution of 6-bromo-N-methoxy-N,5-dimethylpyridazine-3-carboxamide (2.2 g, 8.49 mmol) in THF (60.0 mL) was added CH ₃ CH ₂ CH ₂ MgBr (6.4 mL, 2.0 mol/L in THF) at 0 °C under N ₂ . The resulting mixture was stirred at 0 °C for 1 h under N ₂ . After the reaction was completed, the resulting mixture was diluted with H ₂ O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (85/15, v/v) to afford l-(6-bromo-5-methylpyridazin-3-yl)butan-l-one (789.8 mg, 44%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ =243.3.

Step 5: Synthesis of l-(5-methyl-6-(tributylstannyl)pyridazin-3-yl)butan-l-one:

[0538] To a solution of l-(6-bromo-5-methylpyridazin-3-yl)butan-l-one (789.8 mg, 3.27 mmol) in dioxane (15.0 mL) was added Bis(tributyltin) (2.8 g, 4.91 mmol), Pd(OAc) ₂ (79.1 mg, 0.33 mmol) and Tricyclohexylphosphine (184.8 mg, 0.66 mmol) at room temperature under N ₂ . The resulting mixture was stirred at 80 °C for 5 h under N ₂ . After the reaction was completed, the resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (90/10, v/v) to afford l-(5-methyl-6-(tributylstannyl)pyridazin-3-yl)butan- 1-one (470.0 mg, 31%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =455.2.

Step 6: Synthesis ofN-(7-(6-butyryl-4-methylpyridazin-3-yl)-2,6-naphthyridin-3 - yl)cyclopropanecarboxamide:

[0539] To a solution of l-(5-methyl-6-(tributylstannyl)pyridazin-3-yl)butan-l-one (300.0 mg, 0.76 mmol) in dioxane (8.0 mL) was added N-(7-chloro-2, 6-naphthyri din-3 - yl)cyclopropanecarboxamide (179.5 mg, 0.84 mmol), K2CO3 (305.5 mg, 2.28 mmol) and Pd(OAc)2 (19.4 mg, 0.08 mmol) at room temperature under N2. The resulting mixture was stirred at 80 °C for 5 h under N2. After the reaction was completed, the resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (92/8, v/v) to afford N-(7-(6-butyryl-4- methylpyridazin-3-yl)-2,6-naphthyridin-3-yl)cyclopropanecarb oxamide (148.0 mg, 52%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =376.2.

Step 7: Synthesis ofN-(7-(6-(l-hydroxybutyl)-4-methylpyridazin-3-yl)-2,6-napht hyridin-3- yl)cyclopropanecarboxamide:

[0540] To a solution of N-(7-(6-butyryl-4-methylpyridazin-3-yl)-2,6-naphthyridin-3- yl)cyclopropanecarboxamide (440.0 mg, 1.17 mmol) in MeOH (2.0 mL) and THF (10.0 mL) was added NaBH4 (59.0 mg, 1.23 mmol) at 0 °C under N2. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CELCL/MeOH (90/10, v/v) and then purified by Prep-Achiral with the following conditions: (Column: DAICEL DCpak P4VP, 3x25 cm, 5 pm; Mobile Phase A: CO2, Mobile Phase B: MeOH (0.1% 2M NH3-MeOH); Flow rate: 75 mL/min; Gradient: isocratic 28% B; Column Temperature(°C): 35; Back Pressure(bar): 100; Wave Length: 254 nm) to afford N-(7-(6-(l- hydroxybutyl)-4-methylpyridazin-3-yl)-2,6-naphthyridin-3-yl) cyclopropanecarboxamide (59.0 mg, 13%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =378.2. Step 8. Separation of (R)-N-(7-(6-(l-hydroxybutyl)-4-methylpyridazin-3-yl)-2,6-nap hthyridin-

3-yl)cyclopropanecarboxamide (Compound 124) and (S)-N-(7-(6-(l -hydroxybutyl)-4- methylpyridazin-3-yl)-2, 6-naphthyridin-3-yl)cyclopropanecarboxamide (Compound 125)

[0541] The racemic mixture of N-(7-(6-(l-hydroxybutyl)-4-methylpyridazin-3-yl)-2,6- naphthyridin-3-yl)cyclopropanecarboxamide (59.0 mg, 0.16 mmol) was separated by Prep- Chiral-HPLC with the following conditions (Column: CHIRAL ART Cellulose-SC, 2x25 cm, 5 pm; Mobile Phase A: Hex (0.5% 2M NH ₃ -MeOH)-HPLC, Mobile Phase B: MeOH: DCM=1 : 1— HPLC; Flow rate: 20 mL/min; Gradient: 70% B to 70% B in 8.5 min; Wave Length: 254/220 nm; RTl(min): 6.63; RT2(min): 7.78) to afford N-(7-(6-(l-hydroxybutyl)-4- methylpyridazin-3-yl)-2,6-naphthyridin-3-yl)cyclopropanecarb oxamide Enantiomer 1 (retention time 6.63 min, 8.2 mg, 28%) as a white solid and N-(7-(6-(l-hydroxybutyl)-4- methylpyridazin-3-yl)-2,6-naphthyridin-3-yl)cyclopropanecarb oxamide Enantiomer 2 (retention time 7.78 min, 7.7 mg, 26%) as a white solid. The absolute stereochemistry of Enantiomers 1 and 2 was not assigned. The two enantiomeric structures that could be obtained from chiral separation of the enantiomeric mixture as described above are shown as Compounds 124 and 125 in Table 1.

[0542] N-(7-(6-(l-hydroxybutyl)-4-methylpyridazin-3-yl)-2,6-naphthy ridin-3- yl)cyclopropanecarboxamide Enantiomer 1: RTl(min): 6.63: LCMS (ESI, m/z): [M+H]+ = 378.2. ¹ H NMR (400.0 MHz, DMSO-d6): δ 11.20 (s, 1H), 9.51 (s, 1H), 9.34 (s, 1H), 8.89 (s, 1H), 8.69 (s, 1H), 8.28 (s, 1H), 5.16 (d, J = 6.0 Hz, 1H), 4.69 - 4.64 (m, 1H), 2.64 (s, 3H), 2.14 - 2.08 (m, 1H), 1.86 - 1.72 (m, 2H), 1.45 - 1.32 (m, 2H), 0.93 - 0.85 (m, 7H).

[0543] N-(7-(6-(l-hydroxybutyl)-4-methylpyridazin-3-yl)-2,6-naphthy ridin-3- yl)cyclopropanecarboxamide Enantiomer 2: RT2(min): 7.78; LCMS (ESI, m/z): [M+H]+ = 378.2. ¹ H NMR (400.0 MHz, DMSO-d6): δ 11.20 (s, 1H), 9.51 (s, 1H), 9.34 (s, 1H), 8.89 (s, 1H), 8.69 (s, 1H), 8.28 (s, 1H), 5.16 (d, J = 6.0 Hz, 1H), 4.69 - 4.64 (m, 1H), 2.64 (s, 3H), 2.13 - 2.09 (m, 1H), 1.84 - 1.74 (m, 2H), 1.45 - 1.32 (m, 2H), 0.93 - 0.85 (m, 7H).

Example 68 Synthesis ofN-(7-(6-((lR,2R)-l,2-dihydroxypropyl)-4-methylpyridin-3-yl )-2,6- naphthyridin-3-yl)cyclopropanecarboxamide (Compound 126), N-(7-(6-((lS,2S)-l,2- dihydroxypropyl)-4-methylpyridin-3-yl)-2,6-naphthyridin-3-yl )cyclopropanecarboxamide (Compound 127), N-(7-(6-((1R,2S)-1,2-dihydroxypropyl)-4-methylpyridin-3-yl)- 2,6- naphthyridin-3-yl)cyclopropanecarboxamide (Compound 128) and N-(7-(6-((1S,2R)-1,2- dihydroxypropyl)-4-methylpyridin-3-yl)-2,6-naphthyridin-3-yl )cyclopropanecarboxamide (Compound 129) Step 1: Synthesis of (2R)-2-hydroxy-N-methoxy-N-methylpropanamide [0544] To a solution of ethyl (2R)-2-hydroxypropanoate (8.0 g, 67.72 mmol) in THF (240.0 mL,) was added N,O-dimethylhydroxylamine hydrochloride (16.5 g, 169.30 mmol) at room temperature under N ₂ . Then i-PrMgCl (169.30 mL, 2 mol/L) was added dropwise to the mixture at -20 °C. The resulting mixture was stirred at -20 °C for 2 h under N ₂ . After the reaction was completed, the reaction mixture was quenched with sat. NH ₄ Cl (aq.) at 0 °C. the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford (2R)-2-hydroxy-N-methoxy-N- methylpropanamide (5.0 g, crude) as a yellow oil. LCMS (ESI, m/z): [M+H] ⁺ =134.1 Step 2: (1R)-1-[methoxy(methyl)carbamoyl]ethyl acetate: [0545] To a solution of (2R)-2-hydroxy-N-methoxy-N-methylpropanamide (1.5 g, 11.27 mmol) in DCM (75.0 mL) was added TEA (4.5 g, 45.06 mmol) and acetic anhydride (2.3 g, 22.53 mmol) at room temperature under N ₂ . The resulting mixture was stirred at room temperature for 12 h under N ₂ . After the reaction was completed, the resulting mixture was diluted with H ₂ O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (75/15, v/v) to afford (1R)-1-[methoxy(methyl)carbamoyl]ethyl acetate (1.5 g, 76%) as a yellow oil. LCMS (ESI, m/z): [M+H] ⁺ =176.1. Step 3: Synthesis of (R)-1-(5-bromo-4-methylpyridin-2-yl)-2-hydroxypropan-1-one: ^, [0546] To a solution of 2,5-dibromo-4-methylpyridine (2.8 g, 11.42 mmol) in toluene (80.0 mL) was added dropwise n-BuLi (5.5 mL, 2.5 mol/L) at -78 °C under N ₂ . The resulting mixture was stirred at -78 °C for 1 h under N ₂ . Then (1R)-1- [methoxy(methyl)carbamoyl]ethyl acetate (3.0 g, 17.13 mmol) was added to the mixture at - 78 °C. The resulting mixture was stirred at -78 °C for additional 1 h under N ₂ . After the reaction was completed, the reaction mixture was quenched with sat. NH ₄ Cl (aq.) and then extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified flash column chromatography with petroleum ether/ethyl acetate (70/30, v/v) to afford (R)-1-(5-bromo-4-methylpyridin-2-yl)-2-hydroxypropan-1-one (700.0 mg, 21%) as a yellow oil. LCMS (ESI, m/z): [M+H] ⁺ =244.0. Step 4: Synthesis of (2R)-1-(5-bromo-4-methylpyridin-2-yl)-1-oxopropan-2-yl acetate: [0547] To a solution of (R)-1-(5-bromo-4-methylpyridin-2-yl)-2-hydroxypropan-1-one (600.2 mg, 2.46 mmol) in DCM (30.0 mL) was added acetic anhydride (501.9 mg, 4.92 mmol) and TEA (1.2 g, 12.29 mmol) at 0 °C under N ₂ . The resulting mixture was stirred at room temperature for 12 h under N ₂ . After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (75/15, v/v) to afford (2R)-1-(5-bromo-4- methylpyridin-2-yl)-1-oxopropan-2-yl acetate (300.0 mg, 42%) as a yellow oil. LCMS (ESI, m/z): [M+H] ⁺ =286.0. Step 5: Synthesis of (2R)-1-[4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -yl)pyridin- 2-yl]-1-oxopropan-2-yl acetate: [0548] To a solution of (2R)-1-(5-bromo-4-methylpyridin-2-yl)-1-oxopropan-2-yl acetate (500.0 mg, 1.75 mmol) in 1,4-dioxane (10.0 mL) was added AcOK (514.5 mg, 5.24 mmol), bis(pinacolato)diboron (887.5 mg, 3.49 mmol) and Pd(dppf)Cl ₂ (131.2 mg, 0.18 mmol) at room temperature under N ₂ . The resulting mixture was stirred at 80 °C for 12 h under N ₂ . After the reaction was completed, the resulting mixture was diluted with H ₂ O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with MeCN/H ₂ O (1/5, v/v) to afford (2R)-1-[4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -yl)pyridin-2-yl]-1-oxopropan- 2-yl acetate (180.0 mg, 30%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =334.2. Step 6: Synthesis of 1-[5-(7-cyclopropaneamido-2,6-naphthyridin-3-yl)-4-methylpyr idin-2- yl]-1-oxopropan-2-yl acetate: [0549] To a solution of (2R)-1-[4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 - yl)pyridin-2-yl]-1-oxopropan-2-yl acetate (200.0 mg, 0.60 mmol) in dioxane/H ₂ O (10.0/2.0 mL) was added Pd(dppf)Cl ₂ (43.7 mg, 0.06 mmol), N-(7-chloro-2,6-naphthyridin-3- yl)cyclopropanecarboxamide (148.7 mg, 0.60 mmol) and K ₂ CO ₃ (248.4 mg, 1.80 mmol) at room temperature under N2. The resulting mixture was stirred at 80 °C for 12 h under N2. After the reaction was completed, the resulting mixture was diluted with H ₂ O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (50/50, v/v) to afford 1-[5-(7-cyclopropaneamido-2,6-naphthyridin-3-yl)-4-methylpyr idin-2-yl]-1- oxopropan-2-yl acetate (100.0 mg, 39%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =419.2 Step 7: Synthesis of N-(7-(6-(1,2-dihydroxypropyl)-4-methylpyridin-3-yl)-2,6-naph thyridin-3- yl)cyclopropanecarboxamide: [0550] To a solution of 1-[5-(7-cyclopropaneamido-2,6-naphthyridin-3-yl)-4- methylpyridin-2-yl]-1-oxopropan-2-yl acetate (200.0 mg, 0.48 mmol) in MeOH (20.0 mL) was added NaBH ₄ (108.5 mg, 2.87 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 12 h under N ₂ . After the reaction was completed, the resulting mixture was diluted with H ₂ O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with MeCN/H ₂ O (1/5, v/v) to afford N-(7-(6-(1,2-dihydroxypropyl)-4-methylpyridin-3-yl)- 2,6-naphthyridin-3-yl)cyclopropanecarboxamide (100.0 mg, 55%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =379.2 Step 8. Separation of N-(7-(6-((1R,2R)-1,2-dihydroxypropyl)-4-methylpyridin-3-yl)- 2,6- naphthyridin-3-yl)cyclopropanecarboxamide (Compound 126), N-(7-(6-((1S,2S)-1,2- dihydroxypropyl)-4-methylpyridin-3-yl)-2,6-naphthyridin-3-yl )cyclopropanecarboxamide (Compound 127), N-(7-(6-((1R,2S)-1,2-dihydroxypropyl)-4-methylpyridin-3-yl)- 2,6- naphthyridin-3-yl)cyclopropanecarboxamide (Compound 128) and N-(7-(6-((1S,2R)-1,2- dihydroxypropyl)-4-methylpyridin-3-yl)-2,6-naphthyridin-3-yl )cyclopropanecarboxamide (Compound 129)

[0551] The product of N-(7-(6-(l,2-dihydroxypropyl)-4-methylpyridin-3-yl)-2,6- naphthyridin-3-yl)cyclopropanecarboxamide (200.0 mg, 0.53 mmol) was separated by Prep- chiral-SFC with the following conditions (Column: CHIRALPAK ID, 3x25 cm, 5 pm;

Mobile Phase A: CO2, Mobile Phase B: MeOH: DCM=1 : 1(0.1% 2M NH3-MEOH); Flow rate: 70 mL/min; Gradient: isocratic 50% B; Column Temperature(°C): 35; Back Pressure(bar): 100; Wave Length: 220 nm; RTl(min): 8.87; RT2(min): 10.51) to afford an Isomer mixture A of N-(7-(6-(l,2-dihydroxypropyl)-4-methylpyridin-3-yl)-2,6-naph thyridin- 3-yl)cyclopropanecarboxamide Isomer Al and N-(7-(6-(l,2-dihydroxypropyl)-4- methylpyridin-3-yl)-2,6-naphthyridin-3-yl)cyclopropanecarbox amide Isomer A2 (80.0 mg, 40%) as a yellow solid and an Isomer mixture B of N-(7-(6-(l,2-dihydroxypropyl)-4- methylpyridin-3-yl)-2,6-naphthyridin-3-yl)cyclopropanecarbox amide Isomer Bl and N-(7-(6- (l,2-dihydroxypropyl)-4-methylpyridin-3-yl)-2,6-naphthyridin -3- yl)cyclopropanecarboxamide Isomer B2 (81.0 mg, 81%) as a yellow solid.

[0552] The absolute stereochemistry of Isomers Al, A2, Bl and B2 was not assigned. The four isomeric structures that could be obtained from chiral separation of the isomeric mixture as described above are shown as Compounds 126, 127, 128 and 129 in Table 1. [0553] The Isomer mixture A of N-(7-(6-(l,2-dihydroxypropyl)-4-methylpyridin-3-yl)- 2,6-naphthyridin-3-yl)cyclopropanecarboxamide Isomer Al and N-(7-(6-(l,2- dihydroxypropyl)-4-methylpyridin-3-yl)-2,6-naphthyridin-3-yl )cyclopropanecarboxamide Isomer A2 (80.0 mg, 0.21 mmol) were separated by Prep-Chiral -HPLC with the following conditions (Column: CHIRALPAK IG, 2x25 cm, 5 pm; Mobile Phase A: MtBE(0.5% 2M NH ₃ -MeOH)— HPLC, Mobile Phase B: MeOH: EtOH=l: 1-HPLC; Flow rate: 20 mL/min; Gradient: 15% B to 15% B in 23 min; Wave Length: 220/254 nm; RTl(min): 14.54; RT2(min): 18.08) to afford N-(7-(6-(l,2-dihydroxypropyl)-4-methylpyri din-3 -yl)-2, 6- naphthyridin-3-yl)cyclopropanecarboxamide Isomer Al (19.1 mg, 48%) as an off-white solid and N-(7-(6-((lS,2R)-l,2-dihydroxypropyl)-4-methylpyridin-3-yl)- 2,6-naphthyridin-3- yl)cyclopropanecarboxamide Isomer A2 (10.0 mg, 25%) as an off-white yellow solid.

[0554] The Isomer mixture B of N-(7-(6-(l,2-dihydroxypropyl)-4-methylpyridin-3-yl)- 2,6-naphthyridin-3-yl)cyclopropanecarboxamide Isomer Bl and N-(7-(6-(l,2- dihydroxypropyl)-4-methylpyridin-3-yl)-2,6-naphthyridin-3-yl )cyclopropanecarboxamide Isomer B2 (81.0 mg, 0.21 mmol) were separated by Prep-Chiral -HPLC with the following conditions (Column: CHIRALPAK IG, 2x25 cm, 5 pm; Mobile Phase A: MtBE(0.5% 2M NH ₃ -MeOH)— HPLC, Mobile Phase B: EtOH— HPLC; Flow rate: 20 mL/min; Gradient: 10% B to 10% B in 37 min; Wave Length: 220/254 nm; RTl(min): 24.80; RT2(min): 32.40) to afford N-(7-(6-(l,2-dihydroxypropyl)-4-methylpyridin-3-yl)-2,6-naph thyridin-3- yl)cyclopropanecarboxamide Isomer Bl (19.2 mg, 47%) as an off-white solid and N-(7-(6- (l,2-dihydroxypropyl)-4-methylpyridin-3-yl)-2,6-naphthyridin -3- yl)cyclopropanecarboxamide Isomer B2 (19.8 mg, 49%) as an off-white solid

[0555] N-(7-(6-(l,2-dihydroxypropyl)-4-methylpyridin-3-yl)-2,6-naph thyridin-3- yl)cyclopropanecarboxamide Isomer Al: CHIRALPAK ID, RTl(min): 8.87; CHIRALPAK IG, RTl(min): 14.54. LCMS (ESI, m/z): [M+H]+ =379.1. ¹ HNMR (400 MHz, DMSO-d6): δ 11.15 (s, 1H), 9.46 (s, 1H), 9.32 (s, 1H), 8.66 (s, 1H), 8.59 (s, 1H), 8.16 (s, 1H), 7.46 (s, 1H), 5.34 (d, J = 5.2 Hz, 1H), 4.69 (d, J = 4.8 Hz, 1H), 4.53 - 4.50 (m, 1H), 4.02 - 3.97 (m, 1H), 2.45 (s, 3H), 2.14 - 2.08 (m, 1H), 1.03 (d, J = 6.4 Hz, 3H), 0.89 - 0.81 (m, 4H).

[0556] N-(7-(6-(l,2-dihydroxypropyl)-4-methylpyridin-3-yl)-2,6-naph thyridin-3- yl)cyclopropanecarboxamide Isomer Bl: CHIRALPAK ID, RT2(min): 18.08; CHIRALPAK IG, RTl(min): 20.80. LCMS (ESI, m/z): [M+H]+ =379.1. ¹ H NMR (400 MHz, DMSO-d6): δ 11.16 (s, 1H), 9.47 (s, 1H), 9.32 (s, 1H), 8.66 (s, 1H), 8.59 (s, 1H), 8.16 (s, 1H), 7.46 (s, 1H), 5.33 (d, J = 4.8 Hz, 1H), 4.68 (d, J = 4.8 Hz, 1H), 4.53 - 4.50 (m, 1H), 4.01 - 3.97 (m, 1H),

2.45 (s, 3H), 2.11 - 2.07 (m, 1H), 1.03 (d, J = 6.4 Hz, 3H), 0.93 - 0.84 (m, 4H).

[0557] N-(7-(6-(l,2-dihydroxypropyl)-4-methylpyridin-3-yl)-2,6-naph thyridin-3- yl)cyclopropanecarboxamide Isomer B2: CHIRALPAK ID, RT2(min): 18.08; CHIRALPAK IG, RT2(min): 32.40. LCMS (ESI, m/z): [M+H]+ =379.1. ¹ H NMR (400 MHz, DMSO-d6): δ 11.15 (s, 1H), 9.47 (s, 1H), 9.33 (s, 1H), 8.66 (s, 1H), 8.59 (s, 1H), 8.16 (s, 1H), 7.45 (s, 1H), 5.30 (d, J = 5.6 Hz, 1H), 4.54 (d, J = 5.6 Hz, 1H), 4.43 - 4.40 (m, 1H), 3.95 - 3.90 (m, 1H),

2.45 (s, 3H), 2.14 - 2.08 (m, 1H), 1.06 (d, J = 6.4 Hz, 3H), 0.95 - 0.82 (m, 4H).

[0558] N-(7-(6-(l,2-dihydroxypropyl)-4-methylpyridin-3-yl)-2,6-naph thyridin-3- yl)cyclopropanecarboxamide Isomer A2: CHIRALPAK ID, RTl(min): 8.87; CHIRALPAK IG, RT2(min): 18.08. LCMS (ESI, m/z): [M+H]+ =379.1. ¹ H NMR (400 MHz, DMSO-d6): δ 11.15 (s, 1H), 9.46 (s, 1H), 9.32 (s, 1H), 8.66 (s, 1H), 8.59 (s, 1H), 8.15 (s, 1H), 7.45 (s, 1H), 5.31 (d, J = 5.2 Hz, 1H), 4.55 (d, J = 5.2 Hz, 1H), 4.43 - 4.40 (m, 1H), 3.99 - 3.91 (m, 1H),

2.45 (s, 3H), 2.11 - 2.01 (m, 1H), 1.06 (d, J = 6.4 Hz, 3H), 0.92 - 0.82 (m, 4H).

Example 69. Synthesis of (S)-N-(7-(6-(l-hydroxybutyl)-4-methylpyridin-3-yl)-5-methyl- 2,6- naphthyridin-3-yl)acetamide (Compound 130) and (R)-N-(7-(6-(l-hydroxybutyl)-4- methylpyridin-3-yl)-5-methyl-2,6-naphthyridin-3-yl)acetamide (Compound 131)

Step 1: Synthesis of methyl 5-bromo-4-methylpyridine-2-carboxylate

[0559] To a solution of 5-bromo-4-methylpyridine-2-carboxylic acid (42.0 g, 194.41 mmol) in MeOH (800.0 mL) was added dropwise cone. H2SO4 (60.0 mL) at 0 °C. The resulting mixture was stirred at 80 °C for 3 h. After the reaction was completed, the resulting mixture was cooled to room temperature and then poured into ice water. The mixture was filtered. The solid was collected and dried to afford methyl 5-bromo-4-methylpyridine-2- carboxylate (43.0 g, crude) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ =230.2.

Step 2: Synthesis of methyl 4-methyl-5-[2-(trimethylsilyl)ethynyl]pyridine-2-carboxylate : S [0560] To a solution of methyl 5-bromo-4-methylpyridine-2-carboxylate (12.0 g, 52.16 mmol) in DMF (280.00 mL) was added trimethylsilylacetylene (30.7 g, 312.96 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (3.7 g, 5.21 mmol), CuI (993.4 mg, 5.21 mmol) and TEA (15.8 g, 156.48 mmol) at room temperature under N ₂ . The resulting mixture was stirred at 100 °C for 3 h under N ₂ . After the reaction was completed, the resulting mixture was diluted with H ₂ O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (85/15, v/v) to afford methyl 4-methyl-5-[2-(trimethylsilyl)ethynyl]pyridine-2-carboxylate (7.1 g, 55%) as a brown oil. LCMS (ESI, m/z): [M+H] ⁺ =248.2. Step 3: Synthesis of methyl 5-ethynyl-4-methylpyridine-2-carboxylate: [0561] To a solution of methyl 4-methyl-5-[2-(trimethylsilyl)ethynyl]pyridine-2- carboxylate (8.6 g, 34.76 mmol) in MeOH (150.0 mL) was added K ₂ CO ₃ (14.4 g, 104.28 mmol) at room temperature. The resulting mixture was stirred at room temperature for 4 h. After the reaction was completed, the resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (45/55, v/v) to afford methyl 5-ethynyl-4- methylpyridine-2-carboxylate (4.3 g, 60%) as a brown oil. LCMS (ESI, m/z): [M+H] ⁺ =176.2. Step 4: Synthesis of methyl 5-[2-(4-acetyl-6-chloropyridin-3-yl)ethynyl]-4-methylpyridin e-2- carboxylate: [0562] To a solution of methyl 5-ethynyl-4-methylpyridine-2-carboxylate (2.0 g, 11.41 mmol) in DMF (50.00 mL) was added 1-(5-bromo-2-chloropyridin-4-yl)ethanone (2.7 g, 11.42 mmol), CataCXium A Pd G2 (761.0 mg, 1.14 mmol), CuI (220.0 mg, 1.14 mmol), DIEA (4.4 g, 34.22 mmol) and CataCxium A (816.2 mg, 2.28 mmol) at room temperature under N ₂ . The resulting mixture was stirred at 65 °C for 3 h under N ₂ . After the reaction was completed, the resulting mixture was diluted with H ₂ O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (50/50, v/v) to afford methyl 5-[2-(4-acetyl-6-chloropyridin-3-yl)ethynyl]-4-methylpyridin e-2-carboxylate (680.0 mg, 18%) as a brown solid. LCMS (ESI, m/z): [M+H] ⁺ =329.2. Step 5: Synthesis of methyl (E)-5-((6-chloro-4-(1-(hydroxyimino)ethyl)pyridin-3-yl)ethyn yl)- 4-methylpicolinate: [0563] To a of methyl 5-[2-(4-acetyl-6-chloropyridin-3-yl)ethynyl]-4-methylpyridin e-2- carboxylate (500.0 mg, 1.52 mmol) in EtOH (5.0 mL) and DCM (5.0 mL) was added AcONa (298.5 mg, 3.04 mmol) and NH ₂ OH.HCl (190.2 mg, 2.74 mmol) at room temperature. The resulting mixture was stirred at room temperature for 4 h. After the reaction was completed, the resulting mixture was filtered. The filtrate was concentrated under reduced pressure to afford methyl (E)-5-((6-chloro-4-(1-(hydroxyimino)ethyl)pyridin-3-yl)ethyn yl)-4- methylpicolinate (470.0 mg, crude) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =344.2. Step 6: Synthesis of 7-chloro-3-(6-(methoxycarbonyl)-4-methylpyridin-3-yl)-1-meth yl-2,6- naphthyridine 2-oxide: [0564] To a solution of methyl 5-(2-{6-chloro-4-[(1E)-1-(hydroxyimino)ethyl]pyridin-3- yl}ethynyl)-4-methylpyridine-2-carboxylate (1.0 g, crude) in CHCl ₃ (25.0 mL) was added AgNO ₃ (494.1 mg, 2.90 mmol) at room temperature under N ₂ . The resulting mixture was stirred at 80 °C for 3 h under N ₂ . After the reaction was completed, the resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (30/70, v/v) to afford 7- chloro-3-(6-(methoxycarbonyl)-4-methylpyridin-3-yl)-1-methyl -2,6-naphthyridine 2-oxide (400.0 mg, 40%) as a yellow oil. LCMS (ESI, m/z): [M+H] ⁺ =344.2. Step 7: Synthesis of methyl 5-(7-chloro-1-methyl-2,6-naphthyridin-3-yl)-4-methylpicolina te: [0565] To a solution of 7-chloro-3-(6-(methoxycarbonyl)-4-methylpyridin-3-yl)-1- methyl-2,6-naphthyridine 2-oxide (1.0 g, 2.92 mmol) in dioxane (30.0 mL) was added bis(pinacolato)diboron (3.69 g, 14.53 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 16 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (60/40, v/v) to afford methyl 5-(7-chloro- 1-methyl-2,6-naphthyridin-3-yl)-4-methylpicolinate (680.0 mg, 70%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =328.0. Step 8: Synthesis of 1-(5-(7-chloro-1-methyl-2,6-naphthyridin-3-yl)-4-methylpyrid in-2- yl)butan-1-one: O O [0566] To a solution of methyl 5-(7-chloro-1-methyl-2,6-naphthyridin-3-yl)-4- methylpicolinate (760.0 mg, 2.32 mmol) in THF (15.0 mL) was added CH ₃ CH ₂ CH ₂ MgBr (1.7 mL, 2.0 mol/L in THF) at 0 °C under N ₂ . The resulting mixture was stirred at 0 °C for 1 h under N ₂ . After the reaction was completed, the resulting mixture was diluted with H ₂ O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (55/45, v/v) to afford 1-(5-(7-chloro-1-methyl-2,6-naphthyridin-3-yl)-4-methylpyrid in-2- yl)butan-1-one (220.3 mg, 27%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ =340.3. Step 9: Synthesis of N-(7-(6-butyryl-4-methylpyridin-3-yl)-5-methyl-2,6-naphthyri din-3- yl)acetamide: [0567] To a solution of 1-(5-(7-chloro-1-methyl-2,6-naphthyridin-3-yl)-4-methylpyrid in- 2-yl)butan-1-one (50.0 mg, 0.14 mmol) in dioxane (3.0 mL) was added acetamide (26.1 mg, 0.44 mmol), Cs ₂ CO ₃ (143.8 mg, 0.44 mmol), Brettphos (15.8 mg, 0.03 mmol) and Brettphos Pd G3 (13.3 mg, 0.01 mmol) at room temperature under N ₂ . The resulting mixture was stirred at 80 °C for 3 h under N ₂ . After the reaction was completed, the resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (77/23, v/v) to afford N-(7- (6-butyryl-4-methylpyridin-3-yl)-5-methyl-2,6-naphthyridin-3 -yl)acetamide (40.0 mg, 75%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =363.2. Step 10: Synthesis of N-(7-(6-(1-hydroxybutyl)-4-methylpyridin-3-yl)-5-methyl-2,6- naphthyridin-3-yl)acetamide: [0568] To a solution of N-(7-(6-butyryl-4-methylpyridin-3-yl)-5-methyl-2,6- naphthyridin-3-yl)acetamide (200.0 mg, 0.56 mmol) in THF (6.0 mL) and MeOH (1.0 mL) was added NaBH ₄ (31.2 mg, 0.84 mmol) at 0 °C under N ₂ . The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the resulting mixture was diluted with H ₂ O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (90/10, v/v) to afford N-(7-(6-(l-hydroxybutyl)-4-methylpyridin-3-yl)-5- methyl-2,6-naphthyridin-3-yl)acetamide (39.0 mg, 19%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ =365.2.

Step 11. Separation of (S)-N-(7-(6-( l-hydroxybutyl)-4-methylpyridin-3-yl)-5-methyl-2, 6- naphthyridin-3-yl)acetamide (Compound 130) and (R)-N-(7-(6-(l-hydroxybutyl)-4- methylpyridin-3-yl)-5-methyl-2, 6-naphthyridin-3-yl)acetamide (Compound 131)

[0569] The racemic mixture of N-(7-(6-(l-hydroxybutyl)-4-methylpyridin-3-yl)-5- methyl-2,6-naphthyridin-3-yl)acetamide (39.0 mg, 0.10 mmol) was separated by Prep-Chiral- SFC with the following conditions (Column: Lux 5um Cellulose-4, 3x25 cm, 5 pm; Mobile Phase A: CO2, Mobile Phase B: MeOH: ACN=1 : 1 (0.1% 2M NH ₃ -MeOH); Flow rate: 120 mL/min; Gradient: isocratic 55% B; Column Temperature(°C): 35; Back Pressure(bar): 100; Wave Length: 220 nm; RT1 (min): 6.17; RT2 (min): 7.70) afford N-(7-(6-(l-hydroxybutyl)- 4-methylpyridin-3-yl)-5-methyl-2,6-naphthyridin-3-yl)acetami de Enantiomer 1 (retention time 6.17 min, 6.3 mg, 32%) as a white solid and N-(7-(6-(l-hydroxybutyl)-4-methylpyridin- 3-yl)-5-methyl-2,6-naphthyridin-3-yl)acetamide Enantiomer 2 (retention time 7.70 min, 5.9 mg, 30%) as a white solid. The absolute stereochemistry of Enantiomers 1 and 2 was not assigned. The two enantiomeric structures that could be obtained from chiral separation of the enantiomeric mixture as described above are shown as Compounds 130 and 131 in Table 1.

[0570] N-(7-(6-(l-hydroxybutyl)-4-methylpyridin-3-yl)-5-methyl-2,6- naphthyridin-3- yl)acetamide Enantiomer 1: RTl(min): 6.17: LCMS (ESI, m/z): [M+H]+ = 365.2. ¹ H NMR (400.0 MHz, DMSO-d6): δ 10.82 (s, 1H), 8.70 (s, 1H), 8.54 (s, 1H), 8.26 - 8.21 (m, 1H), 8.00 (s, 1H), 7.40 (s, 1H), 5.28 (d, J = 5.2 Hz, 1H), 4.60 - 4.56 (m, 1H), 3.61 (s, 3H), 2.20 - 2.17 (m, 6H), 1.79 - 1.61 (m, 2H), 1.58 - 1.42 (m, 2H), 0.93 - 0.90 (m, 3H).

[0571] N-(7-(6-(l-hydroxybutyl)-4-methylpyridin-3-yl)-5-methyl-2,6- naphthyridin-3- yl)acetamide Enantiomer 2: RT2(min): 7.70; LCMS (ESI, m/z): [M+H]+ = 365.2. ¹ H NMR (400.0 MHz, DMSO-d6): δ 10.82 (s, 1H), 8.70 (s, 1H), 8.52 (s, 1H), 8.26 - 8.21 (m, 1H), 8.00 (s, 1H), 7.40 (s, 1H), 5.28 (d, J = 5.2 Hz, 1H), 4.60 - 4.56 (m, 1H), 3.61 (s, 3H), 2.20 - 2.17 (m, 6H), 1.79 - 1.61 (m, 2H), 1.58 - 1.42 (m, 2H), 0.93 - 0.90 (m, 3H). Example 70. Synthesis of N-(3-{6-[(1R)-1-hydroxypropyl]-4-methylpyridin-3-yl}-1,6- naphthyridin-7-yl)cyclopropanecarboxamide (Compound 132) and N-(3-{6-[(1S)-1- hydroxypropyl]-4-methylpyridin-3-yl}-1,6-naphthyridin-7-yl)c yclopropanecarboxamide (Compound 133) Step 1: Synthesis of 1-[5-(7-chloro-1,6-naphthyridin-3-yl)-4-methylpyridin-2-yl]p ropan-1- one: [0572] To a solution of 4-methyl-6-propanoylpyridin-3-ylboronic acid (600.0 mg, 3.11 mmol) in 1,4 - dioxane/H ₂ O (20.0 mL/4.0 mL) was added 3-bromo-7-chloro-1,6- naphthyridine (756.9 mg, 3.11 mmol), K ₂ CO ₃ (859.3 mg, 6.22 mmol) and Pd(dppf)Cl ₂ ^. CH ₂ Cl ₂ (253.2 mg, 0.31 mmol) at room temperature under N ₂ . The resulting mixture was stirred at 80 ^o C for 2 h. After the reaction was completed, the resulting mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (7/3, v/v) to afford 1-[5-(7-chloro-1,6- naphthyridin-3-yl)-4-methylpyridin-2-yl]propan-1-one (310.0 mg, 31%) as a light yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =312.1. Step 2: Synthesis of N-[3-(4-methyl-6-propanoylpyridin-3-yl)-1,6-naphthyridin-7- yl]cyclopropanecarboxamide: [0573] To a solution of 1-[5-(7-chloro-1,6-naphthyridin-3-yl)-4-methylpyridin-2- yl]propan-1-one (200.0 mg, 0.64 mmol) in 1,4-dioxane (10.0 mL) was added cyclopropanecarboxamide (273.0 mg, 3.21 mmol), BrettPhos (68.9 mg, 0.13 mmol), Cs ₂ CO ₃ (627.0 mg, 1.92 mmol) and BrettPhos Pd G3 (58.2 mg, 0.06 mmol) at room temperature under N ₂ . The resulting mixture was stirred at 100 ^o C for 16 h. After the reaction was completed, the resulting mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (2/3, v/v) to afford N-[3-(4- methyl-6-propanoylpyridin-3-yl)-l,6-naphthyridin-7-yl]cyclop ropanecarboxamide (130.0 mg, 56%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =361.2.

Step 3: Synthesis ofN-{3-[6-( l-hydroxypropyl)-4-methylpyridin-3-yl]-l, 6-naphthyridin-7- yl}cyclopropanecarboxamide :

[0574] To a solution of N-[3-(4-methyl-6-propanoylpyridin-3-yl)-l,6-naphthyridin-7- yl]cyclopropanecarboxamide (130.0 mg, 0.36 mmol) in THF (5.0 mL) was added dropwise DIBAL-H (0.5 mL, 1.0 mol/L) at -78 °C under N2. The resulting mixture was stirred at -78 °C for 30 min. After the reaction was completed, the reaction mixture was quenched by the addition of MeOH at -78 °C. The mixture was purified by reverse phase flash chromatography with CH3OH/H2O (1/3, v/v) to afford N-{3-[6-(l-hydroxypropyl)-4- methylpyridin-3-yl]-l,6-naphthyridin-7-yl}cyclopropanecarbox amide (95.0 mg, 72%) as a light brown oil. LCMS (ESI, m/z): [M+H] ⁺ =363.2.

Step 4. Separation ofN-(3-{6-[(lR)-l-hydroxypropyl]-4-methylpyridin-3-yl}-l,6- naphthyridin-7-yl)cyclopropanecarboxamide (Compound 132) andN-(3-{6-[(lS)-l- hydroxypropyl]-4-methylpyridin-3-yl}-l,6-naphthyridin-7-yl)c yclopropanecarboxamide (Compound 133)

[0575] The product N-{3-[6-(l-hydroxypropyl)-4-methylpyridin-3-yl]-l,6-naphthyr idin- 7-yl}cyclopropanecarboxamide (95.0 mg) was separated by Prep-Chiral-HPLC with the following conditions (Column: CHIRAL ART Amylose-SA, 2x25 cm, 5 pm; Mobile Phase A: Hex: DCM=3: 1 (0.5% 2M NH ₃ -MeOH)-HPLC, Mobile Phase B: EtOH-HPLC; Flow rate: 20 mL/min; Gradient: 50% B to 50% B in 16 min; Wave Length: 220/254 nm;

RTl(min): 8.24; RT2(min): 12.96) to afford N-(3-{6-[l-hydroxypropyl]-4-methylpyridin-3- yl}-l,6-naphthyridin-7-yl)cyclopropanecarboxamide Enantiomer 1 (retention time 8.24 min, 16.0 mg, 33%) as a white solid and N-(3-{6-[l-hydroxypropyl]-4-methylpyridin-3-yl}-l,6- naphthyridin-7-yl)cyclopropanecarboxamide Enantiomer 2 (retention time 12.96 min, 35.2 mg, 74%) as a white solid. The absolute stereochemistry of Enantiomers 1 and 2 was not assigned. The two enantiomeric structures that could be obtained from chiral separation of the enantiomeric mixture as described above are shown as Compounds 132 and 133 in Table 1.

[0576] N-(3-{6-[l-hydroxypropyl]-4-methylpyridin-3-yl}-l,6-naphthyr idin-7- yl)cyclopropanecarboxamide Enantiomer 1 : RT1=8.24 min; LCMS (ESI, m/z): [M+H]+ =363.3. ¹ H NMR (400 MHz, DMSO-d6): δ 11.16 (s, 1H), 9.27 (s, 1H), 9.10 (d, J = 2.4 Hz, 1H), 8.61 (s, 1H), 8.56 (d, J = 1.6 Hz, 1H), 8.46 (s, 1H), 7.50 (s, 1H), 5.37 (d, J = 4.8 Hz, 1H), 4.58 - 4.53 (m, 1H), 2.37 (s, 3H), 2.13 - 2.08 (m, 1H), 1.88 - 1.82 (m, 1H), 1.72 - 1.63 (m, 1H). 0.98 - 0.83 (m, 7H).

[0577] N-(3-[6-[l-hydroxypropyl]-4-methylpyridin-3-yl}-l,6-naphthyr idin-7- yl)cyclopropanecarboxamide Enantiomer 2: RT2=12.96 min; LCMS (ESI, m/z): [M+H]+ = 363.3. ¹ H NMR (400 MHz, DMSO-d6): δ 11.16 (s, 1H), 9.27 (s, 1H), 9.10 (d, J = 2.0 Hz, 1H), 8.61 (s, 1H), 8.55 (d, J = 2.0 Hz, 1H), 8.46 (s, 1H), 7.50 (s, 1H), 5.34 (d, J = 4.2 Hz, 1H), 4.58 - 4.54 (m, 1H), 2.37 (s, 3H), 2.15 - 2.09 (m, 1H), 1.89 - 1.80 (m, 1H), 1.74 - 1.64 (m, 1H). 0.98 - 0.83 (m, 7H).

Example 71. Synthesis of l-(4-methyl-5-(7-(methylamino)-2,6-naphthyridin-3-yl)pyridin -2- yl)propan-2-ol (Compound 134)

Step 1: Synthesis of (5-bromo-4-methylpyridin-2-yl)methanol

[0578] To a solution of 5-bromo-4-methylpyridine-2-carboxylic acid (2.0 g, 9.23 mmol) in THF (100.0 mL) was added BH3.THF (37.2 mL, 1.0 mol/L) at 0 °C under N2. The reaction mixture was stirred at room temperature for 16 h After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with dichloromethane/methanol (90/10, v/v) to afford (5-bromo-4- methylpyridin-2-yl)methanol (1.1 g, 59%) as a light yellow oil. LCMS (ESI, m/z): [M+H] ⁺ = 202.2. Step 2: Synthesis of 5-bromo-2-(chloromethyl)-4-methylpyridine: [0579] To a solution of (5-bromo-4-methylpyridin-2-yl)methanol (18.0 g, 89.08 mmol) in CH ₂ Cl ₂ (200.0 mL) was added thionyl chloride (26.5 g, 222.71 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (50/50, v/v) to afford 5- bromo-2-(chloromethyl)-4-methylpyridine (16.0 g, 81%) as yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 220.2 Step 3: Synthesis of 2-(5-bromo-4-methylpyridin-2-yl)acetonitrile: [0580] To a solution of 5-bromo-2-(chloromethyl)-4-methylpyridine (16.0 g, 72.55 mmol) in DMSO (200.0 mL) was added NaCN (9.5 g, 145.13 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. After the reaction was completed, the resulting mixture was diluted with H ₂ O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with dichloromethane/methanol (90/10, v/v) to afford 2-(5- bromo-4-methylpyridin-2-yl)acetonitrile (12.0 g, 78%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 211.2. Step 4: Synthesis of (5-bromo-4-methylpyridin-2-yl)acetic acid: [0581] To a solution of 2-(5-bromo-4-methylpyridin-2-yl)acetonitrile (1.0 g, 4.73 mmol) in H ₂ O (20.0 mL) was added HCl (5.0 mL, 6.0 mol/L) at room temperature. The resulting mixture was stirred at 95 °C for 4 h. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography with ACN/H ₂ O (50/50, v/v) to afford (5-bromo-4-methylpyridin-2-yl)acetic acid (980.0 mg, 90%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 230.2. Step 5: Synthesis of 2-(5-bromo-4-methylpyridin-2-yl)-N-methoxy-N-methylacetamide : [0582] To a solution of (5-bromo-4-methylpyridin-2-yl)acetic acid (300.0 mg, 1.30 mmol) in DMF (5.0 mL) was added N,O-dimethylhydroxylamine hydrochloride (139.9 mg, 1.43 mmol), HATU (545.4 mg, 1.43 mmol) and DIEA (842.6 mg, 6.52 mmol) at 0 °C under N _2. The reaction mixture was stirred at room temperature for 2 h _. After the reaction was completed, the resulting mixture was diluted with H ₂ O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with dichloromethane/methanol (95/5, v/v) to afford 2-(5- bromo-4-methylpyridin-2-yl)-N-methoxy-N-methylacetamide (280.0 mg, 78%) as a yellow ^{oil. LCMS (ESI, m/z): [M+H]+} _{= 273.2.} Step 6: Synthesis of 1-(5-bromo-4-methylpyridin-2-yl)propan-2-one: [0583] To a solution of 2-(5-bromo-4-methylpyridin-2-yl)-N-methoxy-N- methylacetamide (2.2 g, 8.08 mmol) in THF (60.0 mL) was added CH ₃ MgBr (12.1 mL, 1.0 mol/L in THF) at 0 °C under N ₂ . The resulting mixture was stirred at 0 °C for 1 h under N ₂ . After the reaction was completed, the resulting mixture was diluted with H ₂ O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (85/15, v/v) to afford 1-(5-bromo-4-methylpyridin-2-yl)propan-2-one (359.8 mg, 16%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ =228.3. Step 7: Synthesis of 1-(5-bromo-4-methylpyridin-2-yl)propan-2-ol: [0584] To a solution of 1-(5-bromo-4-methylpyridin-2-yl)propan-2-one (3.3 g, 14.5 mmol) in MeOH (50.0 mL) was added NaBH ₄ (1.4 g, 36.25 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 4 h _. After the reaction was completed, the resulting mixture was diluted with H ₂ O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with dichloromethane/methanol (90/10, v/v) to afford 1-(5-bromo-4- methylpyridin-2-yl)propan-2-ol (2.8 g, 85%) as a yellow oil. LCMS (ESI, m/z): [M+H] ⁺ = 230.2. Step 8: Synthesis of 5-bromo-2-(2-((tert-butyldimethylsilyl)oxy)propyl)-4-methylp yridine: [0585] To a solution of 1-(5-bromo-4-methylpyridin-2-yl)propan-2-ol (2.8 g, 12.30 mmol) in CH ₂ Cl ₂ (45.0 mL) was added TBSCl (2.8 g, 18.45 mmol) and imidazole (2.5 g, 36.90 mmol) at 0 °C under N ₂ . The reaction mixture was stirred at 40 ^o C for 16 h _. After the reaction was completed, the resulting mixture was diluted with H ₂ O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (45/55, v/v) to afford 5-bromo-2-(2-((tert-butyldimethylsilyl)oxy)propyl)-4-methylp yridine (2.4 g, 57%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 344.3 Step 9: Synthesis of (6-(2-((tert-butyldimethylsilyl)oxy)propyl)-4-methylpyridin- 3-yl)boronic acid: ^O [0586] To a solution of 5-bromo-2-(2-((tert-butyldimethylsilyl)oxy)propyl)-4- methylpyridine (2.4 g, 6.9 mmol) in dioxane (40.0 mL) was added 4,4,4',4',5,5,5',5'- octamethyl-2,2'-bi(1,3,2-dioxaborolane) (2.5 g, 10.35 mmol), Pd(dppf)Cl ₂ (504.4 mg, 0.69 mmol) and KOAc (2.0 g, 20.7 mmol) at room temperature under N ₂ . The resulting mixture was stirred at 80 °C for 4 h under N ₂ . After the reaction was completed, the resulting was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography with ACN/H ₂ O (45/55, v/v) to afford (6-(2- ((tert-butyldimethylsilyl)oxy)propyl)-4-methylpyridin-3-yl)b oronic acid (904.0 mg, 41%) as a brown oil. LCMS (ESI, m/z): [M+H] ⁺ = 310.0. Step 10: Synthesis of tert-butyl (7-(6-(2-((tert-butyldimethylsilyl)oxy)propyl)-4-methylpyrid in- 3-yl)-2,6-naphthyridin-3-yl)(methyl)carbamate: _{, ,} [0587] To a solution of (6-(2-((tert-butyldimethylsilyl)oxy)propyl)-4-methylpyridin- 3- yl)boronic acid (904.0 mg, 2.9 mmol) in dioxane (15.0 mL) and H ₂ O (3.0 mL) was added tert-butyl (7-chloro-2,6-naphthyridin-3-yl)(methyl)carbamate (942.9 mg, 3.22 mmol), Pd(dppf)Cl ₂ (211.9 mg, 0.29 mmol) and K ₂ CO ₃ (1.2 g, 8.7 mmol) at room temperature under N ₂ . The reaction mixture was irradiated with microwave radiation at 85 ^o C for 2 h under N ₂ . After the reaction was completed, the resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (15/85, v/v) to afford tert-butyl (7-(6-(2- ((tert-butyldimethylsilyl)oxy)propyl)-4-methylpyridin-3-yl)- 2,6-naphthyridin-3- yl)(methyl)carbamate (140.0 mg, 9%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 523.3 Step 11. Synthesis of 1-(4-methyl-5-(7-(methylamino)-2,6-naphthyridin-3-yl)pyridin -2- yl)propan-2-ol (Compound 134) [0588] To a solution of tert-butyl (7-(6-(2-((tert-butyldimethylsilyl)oxy)propyl)-4- methylpyridin-3-yl)-2,6-naphthyridin-3-yl)(methyl)carbamate (140.0 mg, 0.26 mmol) in CH ₂ Cl ₂ (2.0 mL) was added TFA (0.5 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the mixture was concentrated under reduced pressure. The pH value of the residue was adjusted to 7.0 with saturated NaHCO3 (aq.). The mixture was extracted with CH2Cl2. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: (Column: Xselect CSH C18 OBD Column 30x150 mm, 5 μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 20% B to 50% B in 8 min; Wave Length: 254 nm) to afford l-(4-methyl-5-(7-(methylamino)-2,6- naphthyridin-3-yl)pyridin-2-yl)propan-2-ol (Compound 134, 10.4 mg, 13%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 309.2. ¹ H NMR (400 MHz, DMSO-d6 ): δ 8.18 (s, 1H), 9.03 (s, 1H), 8.54 (s, 1H), 7.91 (s, 1H), 7.42 (s, 1H), 6.90 - 6.86 (m, 1H), 6.71 (s, 1H), 5.31 (d, J= 4.8 Hz, 1H), 4.56 - 4.52 (m, 1H), 2.87 (d, J= 4.8 Hz, 3H), 2.51 (s, 3H), 0.91 - 0.86 (m, 3H).

Example 72. Synthesis of (lS)-2-cyclopropyl-l-{4-methyl-5-[7-(methylamino)-2,6- naphthyridin-3-yl]pyridin-2-yl}ethanol (Compound 135) and (lR)-2-cyclopropyl-l-{4- methyl-5-[7-(methylamino)-2,6-naphthyridin-3-yl]pyridin-2-yl }ethanol (Compound 136)

Step 1: Synthesis of l-(5-bromo-4-methylpyridin-2-yl)-2-cyclopropylethanone: g

[0589] To a solution of 2,5-dibromo-4-methylpyridine (6.0 g, 23.9 mmol) in toluene (70.0 mL) was added dropwise i-PrMgCl (35.9 mL, 1 mol/L) at 0 °C under N2. The resulting mixture was stirred at 0 °C for 10 min under N2. Then a solution of 2-cyclopropyl-N- methoxy-N-methylacetamide (3.4 g, 23.9 mmol) in toluene (17.0 mL) was added dropwise to the mixture at 0 °C under N2. The resulting mixture was stirred at 0 °C for 3 h under N2. After the reaction was completed, the reaction mixture was quench with aq. NH4CI at 0 °C and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography with petroleum CH3CN/H2O (85/15, v/v) to afford l-(5-bromo-4-methylpyridin-2-yl)-2- cyclopropylethanone (1.5 g, 22%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =254.0

Step 2: Synthesis of 6-(2-cyclopropylacetyl)-4-methylpyridin-3-ylboronic acid: [0590] To a solution of 1-(5-bromo-4-methylpyridin-2-yl)-2-cyclopropylethanone (1.5 g, 5.93 mmol) in dioxane (60.0 mL) was added bis(pinacolato)diboron (4.5 g, 17.79 mmol), KOAc (1.7 g, 17.79 mmol) and Pd(dppf)Cl ₂ (967.8 mg, 1.19 mmol) at room temperature under N ₂ . The resulting mixture was stirred at 100 °C for 2 h. After the reaction was completed, the resulting mixture was diluted with H ₂ O and extracted with CH ₂ Cl ₂ . The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography with CH ₃ CN/H ₂ O (40/60, v/v) to afford 6-(2- cyclopropylacetyl)-4-methylpyridin-3-ylboronic acid (430.0 mg, 30%) as a brown solid. LCMS (ESI, m/z): [M+H] ⁺ =220.1. Step 3: Synthesis of tert-butyl N-{7-[6-(2-cyclopropylacetyl)-4-methylpyridin-3-yl]-2,6- naphthyridin-3-yl}-N-methylcarbamate: C O [0591] To a solution of 6-(2-cyclopropylacetyl)-4-methylpyridin-3-ylboronic acid (390.0 mg, 1.78 mmol) in 1,4-dioxane/H ₂ O (10.0/2.0 mL) was added tert-butyl N-(7-chloro-2,6- naphthyridin-3-yl)-N-methylcarbamate (523.0 mg, 1.78 mmol), K ₃ PO ₄ (1.1 g, 5.34 mmol), XPhos (169.8 mg, 0.36 mmol) and XPhos Pd G3 (150.7 mg, 0.18 mmol) at room temperature under N2. The resulting mixture was stirred at 60 °C for 2 h. After the reaction was completed, the resulting mixture was diluted with H ₂ O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (50/50, v/v) to afford tert- butyl N-{7-[6-(2-cyclopropylacetyl)-4-methylpyridin-3-yl]-2,6-naph thyridin-3-yl}-N- methylcarbamate (400.0 mg, 51%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =433.2. Step 4: Synthesis of tert-butyl N-{7-[6-(2-cyclopropyl-1-hydroxyethyl)-4-methylpyridin-3-yl] - 2,6-naphthyridin-3-yl}-N-methylcarbamate: [0592] To a solution of tert-butyl N-{7-[6-(2-cyclopropylacetyl)-4-methylpyridin-3-yl]- 2,6-naphthyridin-3-yl}-N-methylcarbamate (400.0 mg, 0.92 mmol) in THF (10.0 mL) was added dropwise DIBAl-H (3.70 mL, 1 mol/L) at -78 °C under N ₂ . The resulting mixture was stirred at -78 °C for 1 h. After the reaction was completed, the resulting mixture was quenched with water at -78 °C under N ₂ and then extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford tert-butyl N-{7-[6-(2-cyclopropyl- 1-hydroxyethyl)-4-methylpyridin-3-yl]-2,6-naphthyridin-3-yl} -N-methylcarbamate (400.0 mg, crude) as a brown solid. LCMS (ESI, m/z): [M+H] ⁺ =435.2. Step 5: Synthesis of 2-cyclopropyl-1-(4-methyl-5-(7-(methylamino)-2,6-naphthyridi n-3- yl)pyridin-2-yl)ethan-1-ol [0593] To a solution of tert-butyl N-{7-[6-(2-cyclopropyl-1-hydroxyethyl)-4- methylpyridin-3-yl]-2,6-naphthyridin-3-yl}-N-methylcarbamate (400.0 mg, crude) in DCM (4.0 mL) was added TFA (4.0 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The pH value of the residue was adjusted to 8 with aq. NaHCO ₃ . The mixture was extracted with CH ₂ Cl ₂ . The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography with CH ₃ CN/H ₂ O (40/60, v/v) to afford 2-cyclopropyl-1-(4-methyl-5-(7- (methylamino)-2,6-naphthyridin-3-yl)pyridin-2-yl)ethan-1-ol (200.0 mg, 50%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =335.2. Step 6: Separation of (lS)-2-cyclopropyl-l-(4-methyl-5-[7-(methylamino)-2,6-naphth yridin-

3-yl]pyridin-2-yl}ethanol (Compound 135) and (lR)-2-cyclopropyl-l-{4-methyl-5-[7-

(methylamino)-2, 6-naphthyridin-3-yl]pyridin-2-yl}ethanol (Compound 136)

[0594] The racemic mixture of 2-cyclopropyl-l-(4-methyl-5-(7-(methylamino)-2,6- naphthyridin-3-yl)pyridin-2-yl)ethan-l-ol (200.0 mg, 0.60 mmol) was separated by Prep- Chiral-HPLC with the following conditions (Column: CHIRALPAK IH, 2x25 cm, 5 μm; Mobile Phase A: Hex (0.5% 2M NH ₃ -MeOH)-HPLC, Mobile Phase B: EtOH-HPLC; Flow rate: 20 mL/min; Gradient: 20% B to 20% B in 17 min; Wave Length: 220/254 nm; RTl(min): 7.73; RT2(min): 12.73) to afford 2-cyclopropyl-l-{4-methyl-5-[7-(methylamino)- 2,6-naphthyridin-3-yl]pyridin-2-yl} ethanol Enantiomer 1 (retention time 7.73 min, 36.5 mg, 36%) as a yellow solid and 2-cyclopropyl-l-{4-methyl-5-[7-(methylamino)-2,6-naphthyridi n- 3 -yl]pyridin-2-yl} ethanol Enantiomer 2 (retention time 12.73 min, 46.9 mg, 46%) as a yellow solid. The absolute stereochemistry of Enantiomers 1 and 2 was not assigned. The two enantiomeric structures that could be obtained from chiral separation of the enantiomeric mixture as described above are shown as Compounds 135 and 136 in Table 1.

[0595] 2-cyclopropyl-l-{4-methyl-5-[7-(methylamino)-2,6-naphthyridi n-3- yl]pyridin-2-yl} ethanol Enantiomer 1: RTl(min): 7.73; LCMS (ESI, m/z): [M+H]+ =335.2 1H NMR (400 MHz, DMSO-d6): δ 9.18 (s, 1H), 9.03 (s, 1H), 8.52 (s, 1H), 7.90 (s, 1H), 7.44 (s, 1H), 6.87 (d, J = 4.8 Hz, 1H), 6.71 (s, 1H), 5.35 - 5.33 (m, 1H), 4.67 - 4.65 (m, 1H), 2.87 (d, J = 4.0 Hz, 3H), 2.43 (s, 3H), 1.75 - 1.68 (m, 1H), 1.57 - 1.51 (m, 1H), 0.87 - 0.84 (m, 1H), 0.43 - 0.37 (m, 2H), 0.04 - 0.01 (m, 2H).

[0596] 2-cyclopropyl-l-{4-methyl-5-[7-(methylamino)-2,6-naphthyridi n-3- yl]pyridin-2-yl} ethanol Enantiomer 2: RT2(min): 12.73; LCMS (ESI, m/z): [M+H]+ =335.2. ¹ H NMR (400 MHz, DMSO- d6): δ 9.17 (d, J = 3.6 Hz, 1H), 9.03 (d, J =3.2 Hz, 1H), 8.52 (d, J = 2.4 Hz, 1H), 7.89 (d, J = 3.6 Hz, 1H), 7.43 (s, 1H), 6.87 (s, 1H), 6.70 (d, J = 4.0 Hz, 1H), 5.34 (s, 1H), 4.66 (d, J = 3.6 Hz, 1H), 2.87 (s, 3H), 2.43 (s, 3H), 1.72 - 1.62 (m, 1H), 1.55 - 1.46 (m, 1H), 0.92 - 0.85 (m, 1H), 0.46 - 0.31 (m, 2H), 0.03 - 0.01 (m, 2H). Example 73. Synthesis of (S)-1-(3-fluoro-4-methyl-5-(7-(methylamino)-2,6-naphthyridin -3- yl)pyridin-2-yl)propan-1-ol (Compound 137) and (R)-1-(3-fluoro-4-methyl-5-(7- (methylamino)-2,6-naphthyridin-3-yl)pyridin-2-yl)propan-1-ol (Compound 138) Step 1: Synthesis of 2,5-dibromo-3-fluoro-4-methylpyridine: [0597] The solution of 2,5-dibromo-3-fluoropyridine (10.0 g, 39.23 mmol) in THF (500.0 mL) was added dropwise LDA (29.4 mL, 2 mol/L) at - 65 °C under N ₂ . The resulting mixture was stirred at -65 °C for 0.5 h under N ₂ . Then CH ₃ I (6.7 g, 47.08 mmol) was added to the mixture at -65 °C under N ₂ . The resulting mixture was stirred at - 65 °C for 1 h. After the reaction was completed, the reaction mixture was quenched with sat. NH ₄ Cl (aq.) at -65 °C and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with acetonitrile/water (2/1, v/v) to afford 2,5-dibromo-3-fluoro-4-methylpyridine (6.5 g, 62%) as a light brown solid. LCMS (ESI, m/z): [M+H] ⁺ =267.9. Step 2: Synthesis of 1-(5-bromo-3-fluoro-4-methylpyridin-2-yl)propan-1-ol: [0598] To a solution of 2,5-dibromo-3-fluoro-4-methylpyridine (1.0 g, 3.72 mmol) in THF (15.0 mL) was added dropwise n-BuLi (1.5 mL, 2.5 mol/L) at - 65 °C under N ₂ . The resulting mixture was stirred at - 65 °C for 0.5 h. Then propionaldehyde (647.9 mg, 11.16 mmol) was added to the mixture at -65 °C under N ₂ . The resulting mixture was stirred at - 65 °C for 0.5 h under N ₂ . After the reaction was completed, the reaction mixture was quenched with sat. NH ₄ Cl (aq.) at -65 °C and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (7/1, v/v) to afford 1-(5-bromo-3-fluoro- 4-methylpyridin-2-yl)propan-1-ol (350.0 mg, 37%) as a colorless oil. LCMS (ESI, m/z): [M+H] ⁺ =248.0. Step 3: Synthesis of 1-(3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol an-2- yl)pyridin-2-yl)propan-1-ol: [0599] To a solution of 1-(5-bromo-3-fluoro-4-methylpyridin-2-yl)propan-1-ol (445.0 mg, 1.79 mmol) in 1,4 -dioxane (30.0 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'- bi(1,3,2-dioxaborolane) (1.3 g, 5.38 mmol), KOAc (528.1 mg, 5.38 mmol) and Pd(dppf)Cl ₂ (146.1 mg, 0.18 mmol) at room temperature under N ₂ . The resulting mixture was stirred at 80 °C for 16 h. After the reaction was completed, the resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with acetonitrile/water (1/1, v/v) to afford 1-(3-fluoro-4-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pr opan-1-ol (125.0 mg, 33%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ =296.2. Step 4: Synthesis of tert-butyl (7-(5-fluoro-6-(1-hydroxypropyl)-4-methylpyridin-3-yl)-2,6- naphthyridin-3-yl)(methyl)carbamate: _{, ,} [0600] To a solution of 1-(3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol an- 2-yl)pyridin-2-yl)propan-1-ol (160.0 mg, 0.75 mmol) in 1,4-dioxane/H ₂ O (5.0 mL/1.0 mL) was added tert-butyl (7-chloro-2,6-naphthyridin-3-yl)(methyl)carbamate (220.6 mg, 0.75 mmol), K ₃ PO ₄ (478.3 mg, 2.25 mmol), XPhos (71.6 mg, 0.15 mmol) and XPhos Pd G3 (63.6 mg, 0.08 mmol) at room temperature under N ₂ . The resulting mixture was stirred at 80 °C for 16 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (1/1, v/v) to afford tert-butyl (7-(5-fluoro-6-(1-hydroxypropyl)-4- methylpyridin-3-yl)-2,6-naphthyridin-3-yl)(methyl)carbamate (275.0 mg, 85%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =427.2. Step 5: Synthesis of l-(3-fluoro-4-methyl-5-(7-(methylamino)-2,6-naphthyridin-3-y l)pyridin- 2-yl)propan-l-ol

[0601] The solution of tert-butyl (7-(5-fluoro-6-(l-hydroxypropyl)-4-methylpyridin-3- yl)-2,6-naphthyridin-3-yl)(methyl)carbamate (235.0 mg, 0.55 mmol) in HCl/l,4-di oxane (7.0 mL, 4 mol/L) was stirred at room temperature for 1 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The pH value of the residue was adjusted to 7 with aq.NaHCO3. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with acetonitrile/water (2/3, v/v) to afford l-(3-fluoro-4-methyl-5-(7- (methylamino)-2,6-naphthyridin-3-yl)pyridin-2-yl)propan-l-ol (102.0 mg, 56%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =327.2.

Step 6: Separation of (S)-l-(3-jluoro-4-methyl-5-(7-(methylamino)-2,6-naphthyridin -3- yl)pyridin-2-yl)propan-l-ol (Compound 137) and (R)-l-(3-fluoro-4-methyl-5-(7-

(methylamino)-2, 6-naphthyridin-3-yl)pyridin-2-yl)propan-l-ol (Compound 138)

[0602] The racemic mixture l-(3-fluoro-4-methyl-5-(7-(methylamino)-2,6-naphthyridin- 3-yl)pyridin-2-yl)propan-l-ol (102.0 mg, 0.31 mmol) was separated by Prep-Chiral-HPLC with the following conditions (Column: CHIRAL ART Cellulose-SC, 2x25 cm, 5 pm;

Mobile Phase A: Hex (0.5% 2M NH ₃ -MeOH)-HPLC, Mobile Phase B: MeOH: EtOH=l : 1- HPLC; Flow rate: 20 mL/min; Gradient: 50% B to 50% B in 12 min; Wave Length: 220/254 nm; RTl(min): 9.48; RT2(min): 11.25) to afford l-(3-fluoro-4-methyl-5-(7-(methylamino)- 2, 6-naphthyri din-3 -yl)pyri din-2 -yl)propan-l-ol Enantiomer 1 (retention time 9.48 min, 35.2 mg, 34%) as a yellow solid and l-(3-fluoro-4-methyl-5-(7-(methylamino)-2,6-naphthyridin- 3-yl)pyridin-2-yl)propan-l-ol Enantiomer 2 (retention time 11.25 min, 33.0 mg, 32%) as a green solid. The absolute stereochemistry of Enantiomers 1 and 2 was not assigned. The two enantiomeric structures that could be obtained from chiral separation of the enantiomeric mixture as described above are shown as Compounds 137 and 138 in Table 1.

[0603] l-(3-fluoro-4-methyl-5-(7-(methylamino)-2,6-naphthyridin-3-y l)pyridin-2- yl)propan-l-ol Enantiomer 1: RTl(min): 9.48; LCMS (ESI, m/z): [M+H]+ =327.2. ¹ H NMR (400 MHz, DMSO-d6): δ 9.20 (s, 1H), 9.05 (s, 1H), 8.50 (s, 1H), 7.97 (s, 1H), 6.95 - 6.91 (m, 1H), 6.72 (s, 1H), 5.19 (d, J = 6.0 Hz, 1H), 4.81 - 4.76 (m, 1H), 2.88 (d, J = 5.2 Hz, 3H), 2.35 (s, 3H), 1.90 - 1.78 (m, 2H), 0.92 - 0.85 (m, 3H).

[0604] l-(3-fluoro-4-methyl-5-(7-(methylamino)-2,6-naphthyridin-3-y l)pyridin-2- yl)propan-l-ol Enantiomer 2: RT2(min): 11.25; LCMS (ESI, m/z): [M+H]+ =327.2. ¹ H NMR (400 MHz, DMSO-d6): δ 9.20 (s, 1H), 9.05 (s, 1H), 8.50 (s, 1H), 7.96 (s, 1H), 6.93 (d, J = 4.8 Hz, 1H), 6.72 (s, 1H), 5.19 (d, J = 6.0 Hz, 1H), 4.80 - 4.76 (m, 1H), 2.98 (d, J = 5.2 Hz, 3H), 2.35 (d, J = 1.2 Hz, 3H), 1.90 - 1.78 (m, 2H), 0.92 - 0.85 (m, 3H).

Example 74. Synthesis of (lS)-l-{4-methyl-5-[7-(methylamino)-2,6-naphthyridin-3- yl]pyridin-2-yl}pent-4-en-l-ol (Compound 139) and (lR)-l-{4-methyl-5-[7-(methylamino)~ 2, 6-naphthyridin-3-yl]pyridin-2-yl}pent-4-en-l -ol ( Compound 140)

Step 1: Synthesis of l-(5-bromo-4-methylpyridin-2-yl)pent-4-en-l-one:

[0605] To a solution of 5-bromo-N-methoxy-N,4-dimethylpyridine-2-carboxamide (5.0 g, 19.30 mmol) in THF (50.0 mL) was added dropwise bromo(cyclopropylmethyl)magnesium (19.3 mL, 1 mol/L) at 0 °C under N2. The resulting mixture was stirred at 0 °C for 2 h. After the reaction was completed, the reaction mixture was quenched with aq. NH4CI and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (80/20, v/v) to afford l-(5-bromo-4- methylpyridin-2-yl)pent-4-en-l-one (3.4 g, 69%) as a white solid. LCMS: (ESI, m/z): [M+H] ⁺ =254.0.

Step 2: Synthesis of 4-methyl-6-(pent-4-enoyl)pyridin-3-ylboronic acid: _, [0606] To a solution of 1-(5-bromo-4-methylpyridin-2-yl)pent-4-en-1-one (3.3 g, 12.99 mmol) in dioxane (30.0 mL) was added bis(pinacolato)diboron (4.9 g, 19.48 mmol), KOAc (3.8 g, 38.96 mmol) and Pd(dppf)Cl ₂ (1.1 g, 1.30 mmol) at room temperature under N ₂ . The resulting mixture was stirred at 80 °C for 2 h. After the reaction was completed, the resulting mixture was diluted with H ₂ O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (90/10, v/v) to afford 4-methyl-6-(pent-4- enoyl)pyridin-3-ylboronic acid (3.0 g, 95%) as a brown solid. LCMS (ESI, m/z): [M+H] ⁺ =220.1. Step 3: Synthesis of tert-butyl N-methyl-N-{7-[4-methyl-6-(pent-4-enoyl)pyridin-3-yl]-2,6- naphthyridin-3-yl}carbamate: [0607] To a solution of 4-methyl-6-(pent-4-enoyl)pyridin-3-ylboronic acid (1.0 g, 4.57 mmol) in dioxane (10.0 mL) was added K ₃ PO ₄ (2.9 g, 13.70 mmol), tert-butyl N-(7-chloro- 2,6-naphthyridin-3-yl)-N-methylcarbamate (1.3 g, 4.57 mmol), XPhos (435.3 mg, 0.91 mmol) and XPhos Pd G3 (386.4 mg, 0.46 mmol) at room temperature under N ₂ . The resulting mixture was stirred at 60 °C for 2 h under N ₂ . After the reaction was completed, the resulting mixture was diluted with H ₂ O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (50/50, v/v) to afford tert-butyl N-methyl- N-{7-[4-methyl-6-(pent-4-enoyl)pyridin-3-yl]-2,6-naphthyridi n-3-yl}carbamate (900.0 mg, 45%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ =433.2. Step 4: Synthesis of tert-butyl N-{7-[6-(1-hydroxypent-4-en-1-yl)-4-methylpyridin-3-yl]-2,6- naphthyridin-3-yl}-N-methylcarbamate: [0608] To a solution of tert-butyl N-methyl-N-{7-[4-methyl-6-(pent-4-enoyl)pyridin-3- yl]-2,6-naphthyridin-3-yl}carbamate (800.0 mg, 1.85 mmol) in THF (10.0 mL) was added dropwise DIBAL-H (7.4 mL, 1 mol/L) at -78 °C under N ₂ . The resulting mixture was stirred at -78 °C for 1 h. After the reaction was completed, the resulting mixture was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford tert-butyl N-{7-[6-(1-hydroxypent-4-en-1-yl)-4-methylpyridin-3-yl]-2,6- naphthyridin-3-yl}-N-methylcarbamate (800.0 mg, crude) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ =435.2. Step 5: Synthesis of 1-{4-methyl-5-[7-(methylamino)-2,6-naphthyridin-3-yl]pyridin -2-yl}pent- 4-en-1-ol [0609] To a solution of tert-butyl N-{7-[6-(1-hydroxypent-4-en-1-yl)-4-methylpyridin-3- yl]-2,6-naphthyridin-3-yl}-N-methylcarbamate (800.0 mg, 1.84 mmol) in DCM (10.0 mL) was added TFA (10.0 mL) at room temperature. The resulting mixture was stirred at room temperature for 0.5 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was diluted with H ₂ O. The pH value of the mixture was adjusted to 8 with aq. NaHCO ₃ . The mixture was extracted with CH ₂ Cl ₂ . The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography with H ₂ O/CH ₃ OH (40/60, v/v) to afford 1-{4- methyl-5-[7-(methylamino)-2,6-naphthyridin-3-yl]pyridin-2-yl }pent-4-en-1-ol (200.0 mg, 50%) as a green solid. LCMS (ESI, m/z): [M+H] ⁺ =335.2. Step 6: Separation of (lS)-l-{4-methyl-5-[7-(methylamino)-2,6-naphthyridin-3-yl]py ridin-2- yl}pent-4-en-l-ol (Compound 139) and (lR)-l-{4-methyl-5-[7-(methylamino)-2,6- naphthyridin-3-yl]pyridin-2-yl}pent-4-en-l-ol (Compound 140)

[0610] The racemic product of l-{4-methyl-5-[7-(methylamino)-2,6-naphthyridin-3- yl]pyridin-2-yl}pent-4-en-l-ol (200.0 mg, 0.60 mmol) was separated by Prep-Chiral-HPLC with the following conditions (Column: CHIRALPAK IH, 2x25 cm, 5 pm; Mobile Phase A: Hex (0.5% 2M NH ₃ -MeOH)-HPLC, Mobile Phase B: EtOH-HPLC; Flow rate: 20 mL/min; Gradient: 15% B in 20 min; Wave Length: 220/254 nm; RTl(min): 9.88; RT2(min): 15.71) to afford l-{4-methyl-5-[7-(methylamino)-2,6-naphthyridin-3-yl]pyridin -2-yl}pent-4-en-l-ol Enantiomer l(retention time 9.88 min, 13.8 mg, 13%) as a green solid and l-{4-methyl-5-[7- (methylamino)-2,6-naphthyridin-3-yl]pyridin-2-yl}pent-4-en-l -ol Enantiomer 2 (retention time 15.71 min, 18.8 mg, 18%) as a green solid. The absolute stereochemistry of Enantiomers 1 and 2 was not assigned. The two enantiomeric structures that could be obtained from chiral separation of the enantiomeric mixture as described above are shown as Compounds 139 and 140 in Table 1.

[0611] l-{4-methyl-5-[7-(methylamino)-2,6-naphthyridin-3-yl]pyridin -2-yl}pent-4- en-l-ol Enantiomer 1: RTl(min): 9.88; LCMS (ESI, m/z): [M+H]+ =335.1 ¹ H NMR (400 MHz, DMSO-d6): δ 9.20 (s, IH), 9.03 (s, IH), 8.54 (s, IH), 7.91 (s, IH), 7.44 (s, IH), 6.90 - 6.86 (m, IH), 6.71 (s, IH), 5.92 - 5.82 (m, IH), 5.39 (d, J = 4.8 Hz, IH), 5.06 - 4.95 (m, 2H), 4.64 - 4.61 (m, IH), 2.87 (d, J = 4.8 Hz, 3H), 2.44 (s, 3H), 2.17 - 2.12 (m, 2H), 1.93 - 1.85 (m, IH), 1.77 - 1.70 (m,lH).

[0612] l-{4-methyl-5-[7-(methylamino)-2,6-naphthyridin-3-yl]pyridin -2-yl}pent-4- en-l-ol Enantiomer 2: RT2(min): 15.71; LCMS (ESI, m/z): [M+H]+ =335.2. ¹ H NMR (400 MHz, DMSO- d6): δ 9.19 (s, IH), 9.03 (s, IH), 8.54 (s, IH), 7.91 (s, IH), 7.44 (s, IH), 6.90 - 6.86 (m, IH), 6.71 (s, IH), 5.92 - 5.82 (m, IH), 5.39 (d, J = 4.8 Hz, IH), 5.06 - 4.95 (m, 2H), 4.64 - 4.60 (m, IH), 2.87 (d, J = 5.2 Hz, 3H), 2.43 (s, 3H), 2.17 - 2.12 (m, 2H), 1.92 - 1.84 (m, IH), 1.77 - 1.70 (m, IH). Example 75. Synthesis of (1S)-1-{5-[7-(ethylamino)-2,6-naphthyridin-3-yl]-4- methylpyridin-2-yl}propan-1-ol (Compound 141) and (1R)-1-{5-[7-(ethylamino)-2,6- naphthyridin-3-yl]-4-methylpyridin-2-yl}propan-1-ol (Compound 142) Step 1: Synthesis of Tert-butyl N-(7-chloro-2,6-naphthyridin-3-yl)-N-ethylcarbamate [0613] To a solution of tert-butyl N-(7-chloro-2,6-naphthyridin-3-yl)carbamate (500.0 mg, 1.79 mmol) in DMF (10.0 mL) was added NaH (143.3 mg, 60%) at 0 °C under N ₂ . The resulting mixture was stirred at 0 °C for 1 h. To the above mixture was added ethyl iodide (335.4 mg, 2.15 mmol) at 0 °C. The resulting mixture was stirred at room temperature for another 1 h. After the reaction was completed, the resulting mixture was diluted with H ₂ O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (4/1, v/v) to afford tert-butyl N-(7-chloro-2,6-naphthyridin-3-yl)-N- ethylcarbamate (300.0 mg, 55%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =308.1 Step 2: Synthesis of Tert-butyl N-ethyl-N-[7-(4-methyl-6-propanoylpyridin-3-yl)-2,6- naphthyridin-3-yl]carbamate: O [0614] To a solution of 4-methyl-6-propanoylpyridin-3-ylboronic acid (200.0 mg, 1.04 mmol) in dioxane/H ₂ O (10.0 mL/2.0 mL) was added tert-butyl N-(7-chloro-2,6-naphthyridin- 3-yl)-N-ethylcarbamate (319.3 mg, 1.04 mmol), K3PO4 (660.0 mg, 3.11 mmol), XPhos (99.4 mg, 0.21 mmol) and XPhos Pd G3 (88.3 mg, 0.10 mmol) at room temperature. The resulting mixture was stirred at 60 °C for 1 h under N ₂ . After the reaction was completed, the resulting mixture was concentrated under vacuum. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (5/1, v/v) to afford tert-butyl N-ethyl-N- [7-(4-methyl-6-propanoylpyridin-3-yl)-2,6-naphthyridin-3-yl] carbamate (280.0 mg, 64%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =421.2 Step 3: Synthesis of tert-butyl N-ethyl-N-{7-[6-(1-hydroxypropyl)-4-methylpyridin-3-yl]-2,6- naphthyridin-3-yl}carbamate: [0615] To a solution of tert-butyl N-ethyl-N-[7-(4-methyl-6-propanoylpyridin-3-yl)-2,6- naphthyridin-3-yl]carbamate (260.0 mg, 0.62 mmol) in MeOH/THF (5.0 mL/5.0 mL) was added NaBH ₄ (47.4 mg, 1.24 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (10/1, v/v) to afford tert-butyl N-ethyl-N-{7-[6-(1-hydroxypropyl)-4- methylpyridin-3-yl]-2,6-naphthyridin-3-yl}carbamate (200.0 mg, 77%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =423.2 Step 4: Synthesis of 1-{5-[7-(ethylamino)-2,6-naphthyridin-3-yl]-4-methylpyridin- 2- yl}propan-1-ol: [0616] To a solution of tert-butyl N-ethyl-N-{7-[6-(1-hydroxypropyl)-4-methylpyridin-3- yl]-2,6-naphthyridin-3-yl}carbamate (180.0 mg, 0.43 mmol) in DCM (3.0 mL) was added TFA (1.0 mL) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the pH value of the mixture was adjusted to 7 with NaHCO ₃ (aq.). The mixture was extracted with CH ₂ Cl ₂ . The combined organic layers were washed with brine and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography with CH ₃ CN/H ₂ O (1/1, v/v) to afford 1-{5-[7-(ethylamino)-2,6- naphthyridin-3-yl]-4-methylpyridin-2-yl}propan-1-ol (100.0 mg, 73%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =323.2 Step 5: Separation of (lS)-l-{5-[7-(ethylamino)-2,6-naphthyridin-3-yl]-4-methylpyr idin-2- yl}propan-l-ol (Compound 141) and (lR)-l-{5-[7-(ethylamino)-2,6-naphthyridin-3-yl]-4- methylpyridin-2-yl}propan-l-ol (Compound 142)

[0617] The racemic product of l-{5-[7-(ethylamino)-2,6-naphthyridin-3-yl]-4- methylpyri din-2 -yl (propan- l-ol (100.0 mg, 0.31 mmol) was separated by Prep-Chiral-HPLC with the following conditions (Column: CHIRALPAK IH, 2x25 cm, 5 pm; Mobile Phase A: Hex (0.5% 2M NH ₃ -MeOH)-HPLC, Mobile Phase B: MeOH: DCM=1 : 1-HPLC; Flow rate: 20 mL/min; Gradient: 30% B to 30% B in 10 min; Wave Length: 220/254 nm; RTl(min): 4.41; RT2(min): 7.91) to afford l-{5-[7-(ethylamino)-2,6-naphthyridin-3-yl]-4- methylpyri din-2 -yl (propan- l-ol Enantiomer 1 (retention time 4.41 min, 51.0 mg, 51%) as a green solid and l-{5-[7-(ethylamino)-2,6-naphthyridin-3-yl]-4-methylpyridin- 2-yl(propan-l- ol Enantiomer 2 (retention time 7.91 min, 49.7 mg, 50%) as a green solid. The absolute stereochemistry of Enantiomers 1 and 2 was not assigned. The two enantiomeric structures that could be obtained from chiral separation of the enantiomeric mixture as described above are shown as Compounds 141 and 142 in Table 1.

[0618] l-{5-[7-(ethylamino)-2,6-naphthyridin-3-yl]-4-methylpyridin- 2-yl}propan-l- ol Enantiomer 1: RTl(min): 4.41; LCMS (ESI, m/z): [M+H]+ =323.2. ¹ H NMR (400 MHz, DMSO-d6): δ 9.16 (s, 1H), 9.03 (s, 1H), 8.53 (s, 1H), 7.89 (s, 1H), 7.42 (s, 1H), 6.88 - 6.85 (m, 1H), 6.74 (s, 1H), 5.30 (d, J = 4.8 Hz, 1H), 4.56 - 4.52 (m, 1H), 3.32 - 3.28 (m, 2H), 2.43 (s, 3H), 1.88 - 1.78 (m, 1H), 1.71 - 1.64 (m, 1H), 1.25 - 1.09 (m, 3H), 0.91 - 0.88 (m, 3H).

[0619] l-{5-[7-(ethylamino)-2,6-naphthyridin-3-yl]-4-methylpyridin- 2-yl}propan-l- ol Enantiomer 2: RT2(min): 7.91; LCMS (ESI, m/z): [M+H]+ =323.2. ¹ H NMR (400 MHz, DMSO-d6): δ 9.16 (s, IH), 9.03 (s, IH), 8.53 (s, IH), 7.89 (s, IH), 7.42 (s, IH), 6.88 - 6.85 (m, IH), 6.74 (s, IH), 5.30 (d, J = 4.8 Hz, IH), 4.56 - 4.52 (m, IH), 3.32 - 3.28 (m, 2H), 2.43 (s, 3H), 1.88 - 1.80 (m, IH), 1.73 - 1.65 (m, IH), 1.25 - 1.08 (m, 3H), 0.91 - 0.85 (m, 3H).

Example 76. Synthesis of (lR,2R)-N-(2-cyano-3-(6-((S)-l-hydroxybutyl)-4-methylpyridin - 3-yl)-l, 6-naphthyridin- 7-yl)-2-fluorocyclopropane-l -carboxamide formate ( Compound 143) and (1R,2R)-N-(2-cyano-3-(6-((R)-1-hydroxybutyl)-4-methylpyridin -3-yl)-1,6- naphthyridin-7-yl)-2-fluorocyclopropane-1-carboxamide formate (Compound 144) Step 1: Synthesis of 3-bromo-7-chloro-1,6-naphthyridine-2-carbonitrile [0620] To a solution of 3-bromo-2,7-dichloro-1,6-naphthyridine (500.0 mg, 18.11 mmol) in DMF (100.0 mL) was added KCN (1.3 g, 19.92 mmol) at room temperature. The final reaction mixture was irradiated with microwave radiation at 100 °C for 3 h. The reaction was repeated 9 times. After the reaction was completed, the resulting mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by flash column chromatography with petroleum ether/CH ₂ Cl ₂ (10/90, v/v) to afford 3-bromo-7-chloro-1,6-naphthyridine-2-carbonitrile (1.1 g, 23%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 268.1. Step 2: Synthesis of 3-(6-butyryl-4-methylpyridin-3-yl)-7-chloro-1,6-naphthyridin e-2- carbonitrile: ( pp) [0621] To a solution of 3-bromo-7-chloro-1,6-naphthyridine-2-carbonitrile (150.0 mg, 0.50 mmol) in dioxane (5.0 mL) and H ₂ O (1.0 mL) was added 1-(4-methyl-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)butan-1-one (146.2 mg, 0.50 mmol), K ₂ CO ₃ (209.7 mg, 1.51 mmol) and Pd(dppf)Cl ₂ (82.4 mg, 0.10 mmol) at room temperature under N ₂ . The reaction mixture was stirred at 80 °C for 2 h. After the reaction was completed, the mixture was filtered. The filtrate was concentrated under vacuum. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (25/75, v/v) to afford 3- (6-butyryl-4-methylpyridin-3-yl)-7-chloro-1,6-naphthyridine- 2-carbonitrile (104.0 mg, 59%) as a light yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 351.0. Step 3: Synthesis of (1R,2R)-N-(3-(6-butyryl-4-methylpyridin-3-yl)-2-cyano-1,6-na phthyridin- 7-yl)-2-fluorocyclopropane-1-carboxamide: ^{p , p 3} [0622] To a solution of 3-(6-butyryl-4-methylpyridin-3-yl)-7-chloro-1,6-naphthyridin e-2- carbonitrile (110.0 mg, 0.29 mmol) in dioxane (5.0 mL) was added (1R,2R)-2- fluorocyclopropane-1-carboxamide (42.2 mg, 0.87 mmol), BrettPhos (31.1 mg, 0.06 mmol), BrettPhos Pd G3 (26.3 mg, 0.03 mmol) and Cs ₂ CO ₃ (283.8 mg, 0.44 mmol) at room temperature under N ₂ . The reaction mixture was stirred at 90 °C for 16 h under N ₂ . After the reaction was completed, the mixture was filtered. The filtrate was concentrated under vacuum. The residue was purified by flash column chromatography with DCM/MeOH (92/8, v/v) to afford (1R,2R)-N-(3-(6-butyryl-4-methylpyridin-3-yl)-2-cyano-1,6-na phthyridin-7- yl)-2-fluorocyclopropane-1-carboxamide (72.0 mg, 59%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 418.2. Step 4: Synthesis of (1R,2R)-N-(2-cyano-3-(6-(1-hydroxybutyl)-4-methylpyridin-3-y l)-1,6- naphthyridin-7-yl)-2-fluorocyclopropane-1-carboxamide: [0623] To a solution of (1R,2R)-N-(3-(6-butyryl-4-methylpyridin-3-yl)-2-cyano-1,6- naphthyridin-7-yl)-2-fluorocyclopropane-1-carboxamide (144.0 mg, 0.34 mmol) in THF (5.0 mL) was added DIBAL-H (0.37 mL, 1.0 mol/L in THF) at 0 ^o C under N ₂ . The reaction mixture was stirred at 0 ^o C for 3 h. After the reaction was completed, the resulting mixture was diluted with H ₂ O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (90/10, v/v) to afford (1R,2R)-N-(2-cyano-3-(6-(1-hydroxybutyl)-4- methylpyridin-3-yl)-1,6-naphthyridin-7-yl)-2-fluorocycloprop ane-1-carboxamide (74.0 mg, 51%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 420.2. Step 5: Separation of (lR,2R)-N-(2-cyano-3-(6-((S)-l-hydroxybutyl)-4-methylpyridin -3-yl)- l,6-naphthyridin-7-yl)-2-fluorocyclopropane-l-carboxamide formate (Compound 143) and (lR,2R)-N-(2-cyano-3-(6-((R)-l-hydroxybutyl)-4-methylpyridin -3-yl)-l,6-naphthyridin-7-yl)- 2 fluorocyclopropane- 1 -carboxamide formate (Compound 144)

[0624] The product of (lR,2R)-N-(2-cyano-3-(6-(l-hydroxybutyl)-4-methylpyridin-3-y l)- l,6-naphthyridin-7-yl)-2-fluorocyclopropane-l-carboxamide (74.0 mg, 0.18 mmol) was separated by Prep-Chiral-SFC with the following conditions: (CHIRALPAK IH, 3x25 cm, 5 pm; Mobile Phase A: CO2, Mobile Phase B: IPA: ACN: DCM=2: 2: 1 (0.1% DEA); Flow rate: 100 mL/min; Gradient: isocratic 40% B; Column Temperature (°C): 35; Back Pressure(bar): 100; Wave Length: 220 nm; RTl(min): 3.73; RT2(min): 4.72) to afford (lR,2R)-N-(2-cyano-3-(6-(l-hydroxybutyl)-4-methylpyridin-3-y l)-l,6-naphthyridin-7-yl)-2- fluorocy cl opropane-1 -carboxamide Isomer 1 (retention time 3.73 min, 27.4 mg, crude) as a white solid and (lR,2R)-N-(2-cyano-3-(6-(l-hydroxybutyl)-4-methylpyridin-3-y l)-l,6- naphthyridin-7-yl)-2-fluorocyclopropane-l -carboxamide Isomer 2 (retention time 4.72 min, 28.5 mg, crude) as a white solid. The absolute stereochemistry of Isomers 1 and 2 was not assigned. The two isomeric structures that could be obtained from chiral separation of the isomeric mixture as described above are shown as Compounds 143 and 144 in Table 1.

[0625] The product of (lR,2R)-N-(2-cyano-3-(6-(l-hydroxybutyl)-4-methylpyridin-3-y l)-

1,6-naphthyri din-7-yl)-2-fluorocy cl opropane-1 -carboxamide Isomer 1 (27.4 mg, crude) was purified by Prep-HPLC with the following conditions: (Column: Xselect CSH C18 OBD Column 30x150 mm 5 pm, n; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 11% B to 21% B in 10 min, 21% B to 21% B in 14 min; Wave Length: 254/220 nm) to afford (lR,2R)-N-(2-cyano-3-(6-(l-hydroxybutyl)-4- methylpyridin-3-yl)-l,6-naphthyridin-7-yl)-2-fluorocycloprop ane-l -carboxamide formate Isomer 1 (11.3 mg, 31%) as a white solid.

[0626] The product of (lR,2R)-N-(2-cyano-3-(6-(l-hydroxybutyl)-4-methylpyridin-3-y l)- l,6-naphthyridin-7-yl)-2-fluorocy cl opropane-1 -carboxamide Isomer 2 (28.5 mg, crude) was purified by Prep-HPLC with the following conditions: (Column: Xselect CSH C18 OBD Column 30x150 mm 5 pm, n; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 13% B to 23% B in 10 min; Wave Length: 254/220 nm) to afford (1R,2R)-N-(2-cyano-3-(6-(1-hydroxybutyl)-4-methylpyridin-3-y l)-1,6-naphthyridin-7- yl)-2-fluorocyclopropane-1-carboxamide formate Isomer 2 (10.4 mg, 28%) as a white solid. Example 77. Synthesis of (R)-N-(2-amino-3-(6-((R)-1-hydroxypropyl)-4-methylpyridin-3- yl)-1,6-naphthyridin-7-yl)-2,2-difluorocyclopropane-1-carbox amide (Compound 145) and (R)-N-(2-amino-3-(6-((S)-1-hydroxypropyl)-4-methylpyridin-3- yl)-1,6-naphthyridin-7-yl)- 2,2-difluorocyclopropane-1-carboxamide (Compound 146) Step 1: Synthesis of 3-bromo-2,7-dichloro-1,6-naphthyridine [0627] To a stirred solution of 3-bromo-7-chloro-1H-1,6-naphthyridin-2-one (24.0 g, 92.41 mmol) in SOCl ₂ (300.0 mL) was dropwise added POCl ₃ (100.0 mL) and DMF (4.0 mL) at room temperature. The resulting mixture was stirred at 85 °C for 4 h. After the reaction was completed, the resulting mixture was concentrated under vacuum. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /petroleum ether (95/5, v/v) to afford 3-bromo-2,7-dichloro-1,6-naphthyridine (15.0 g, 60%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 277.0. Step 2: Synthesis of 3-bromo-7-chloro-N,N-bis[(4-methoxyphenyl)methyl]-1,6-naphth yridin- 2-amine: [0628] To a solution of 3-bromo-2,7-dichloro-1,6-naphthyridine (10.0 g, 35.98 mmol) in dioxane (200.0 mL) was added TEA (36.41 g, 359.80 mmol) and bis[(4- methoxyphenyl)methyl]amine (27.7 g, 107.94 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 16 h. After the reaction was completed, the resulting mixture was diluted with H ₂ O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford 3-bromo-7-chloro-N,N-bis[(4- methoxyphenyl)methyl]-1,6-naphthyridin-2-amine (7.7 g, crude) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 498.1. Step 3: Synthesis of 1-[5-(2-{bis[(4-methoxyphenyl)methyl]amino}-7-chloro-1,6- naphthyridin-3-yl)-4-methylpyridin-2-yl]propan-1-one: ^{( )} [0629] To a solution of 3-bromo-7-chloro-N,N-bis[(4-methoxyphenyl)methyl]-1,6- naphthyridin-2-amine (5.0 g, crude) in dioxane (100.0 mL) and H ₂ O (20.0 mL) was added 1- [4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyr idin-2-yl]propan-1-one (3.3 g, 11.5 mmol), K ₂ CO ₃ (2.7 g, 20.40 mmol) and Pd(dppf)Cl ₂ (767.6 mg, 1.06 mmol) at room temperature under N ₂ . The reaction mixture was stirred at 80 °C for 2 h under N ₂ . After the reaction was completed, the resulting mixture was diluted with H ₂ O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (40/60, v/v) to afford 1-[5-(2-{bis[(4-methoxyphenyl)methyl]amino}-7-chloro-1,6-nap hthyridin-3-yl)-4- methylpyridin-2-yl]propan-1-one (2.1 g, 35%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 567.2. Step 4: Synthesis of tert-butyl N-(2-{bis[(4-methoxyphenyl)methyl]amino}-3-(4-methyl-6- propanoylpyridin-3-yl)-1,6-naphthyridin-7-yl)carbamate: [0630] To a solution of 1-[5-(2-{bis[(4-methoxyphenyl)methyl]amino}-7-chloro-1,6- naphthyridin-3-yl)-4-methylpyridin-2-yl]propan-1-one (8.0 g, 14.10 mmol) in dioxane (100.0 mL) was added tert-butyl carbamate (4.9 g, 42.32 mmol), Pd ₂ (dba) ₃ (1.2 g, 1.44 mmol), XPhos (1.3 g, 28.21 mmol) and Cs ₂ CO ₃ (9.2 g, 28.14 mmol) at room temperature under N ₂ . The reaction mixture was stirred at 100 °C for 2 h under N ₂ . After the reaction was completed, the resulting mixture was diluted with H ₂ O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (35/65, v/v) to afford tert- butyl N-(2-{bis[(4-methoxyphenyl)methyl]amino}-3-(4-methyl-6-propa noylpyridin-3-yl)- 1,6-naphthyridin-7-yl)carbamate (6.0 g, 65%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 648.3. Step 5: Synthesis of 1-[5-(7-amino-2-{bis[(4-methoxyphenyl)methyl]amino}-1,6- naphthyridin-3-yl)-4-methylpyridin-2-yl]propan-1-one: [0631] To a solution of tert-butyl N-(2-{bis[(4-methoxyphenyl)methyl]amino}-3-(4- methyl-6-propanoylpyridin-3-yl)-1,6-naphthyridin-7-yl)carbam ate (1.5 g, 2.31 mmol) in CH ₂ Cl ₂ (20.0 mL) was added TFA (5.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. After the reaction was completed, the resulting mixture was concentrated under vacuum. The pH value of the residue was adjusted to 8.0 with sat. NaHCO ₃ . The mixture was extracted with CH ₂ Cl ₂ . The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to afford 1-[5-(7-amino-2-{bis[(4-methoxyphenyl)methyl]amino}-1,6- naphthyridin-3-yl)-4-methylpyridin-2-yl]propan-1-one (1.3 g, crude) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 548.3. Step 6: Synthesis of (1R)-N-(2-{bis[(4-methoxyphenyl)methyl]amino}-3-(4-methyl-6- propanoylpyridin-3-yl)-1,6-naphthyridin-7-yl)-2,2-difluorocy clopropane-1-carboxamide: [0632] To a solution of 1-[5-(7-amino-2-{bis[(4-methoxyphenyl)methyl]amino}-1,6- naphthyridin-3-yl)-4-methylpyridin-2-yl]propan-1-one (1.3 g, crude) in pyridine (20.0 mL) was added (1R)-2,2-difluorocyclopropane-1-carboxylic acid (370.0 mg, 3.01 mmol) and EDCI (2.1 g, 10.95 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 h. After the reaction was completed, the resulting mixture was diluted with H ₂ O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (95/5, v/v) to afford (1R)-N-(2-{bis[(4-methoxyphenyl)methyl]amino}-3-(4- methyl-6-propanoylpyridin-3-yl)-1,6-naphthyridin-7-yl)-2,2-d ifluorocyclopropane-1- carboxamide (1.0 g, 51%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 652.3. Step 7: Synthesis of (1R)-N-[2-amino-3-(4-methyl-6-propanoylpyridin-3-yl)-1,6- naphthyridin-7-yl]-2,2-difluorocyclopropane-1-carboxamide: [0633] The solution of (1R)-N-(2-{bis[(4-methoxyphenyl)methyl]amino}-3-(4-methyl-6- propanoylpyridin-3-yl)-1,6-naphthyridin-7-yl)-2,2-difluorocy clopropane-1-carboxamide (400.0 mg, 0.63 mmol) in TFA (10.0 mL) was stirred at 100 °C for 2 h. After the reaction was completed, the resulting mixture was concentrated under vacuum. The pH value of the residue was adjusted to 8.0 with sat. NaHCO ₃ . The mixture was extracted with CH ₂ Cl ₂ . The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (90/10, v/v) to afford (1R)-N-[2-amino-3-(4- methyl-6-propanoylpyridin-3-yl)-1,6-naphthyridin-7-yl]-2,2-d ifluorocyclopropane-1- carboxamide (200.0 mg, 70%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 412.2. Step 8: Synthesis of (1R)-N-{2-amino-3-[6-(1-hydroxypropyl)-4-methylpyridin-3-yl] -1,6- naphthyridin-7-yl}-2,2-difluorocyclopropane-1-carboxamide: [0634] To a solution of (1R)-N-[2-amino-3-(4-methyl-6-propanoylpyridin-3-yl)-1,6- naphthyridin-7-yl]-2,2-difluorocyclopropane-1-carboxamide (150.0 mg, 0.37 mmol) in THF (5.0 mL) and MeOH (1.0 mL) was added NaBH ₄ (20.6 mg, 0.54 mmol) at room temperature. The reaction mixture was stirred at room temperature for 30 min. After the reaction was completed, the resulting mixture was diluted with H ₂ O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (90/10, v/v) to afford (lR)-N-{2-amino-3- [6-(l-hydroxypropyl)-4-methylpyridin-3-yl]-l,6-naphthyridin- 7-yl}-2,2- difluorocyclopropane-1 -carboxamide (64.0 mg, 43%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 414.2.

Step 9: Separation of (R)-N-(2-amino-3-(6-((R)-l-hydroxypropyl)-4-methylpyridin-3- yl)-l,6- naphthyridin-7-yl)-2,2-difluorocyclopropane-l -carboxamide (Compound 145) and (R)-N-(2- amino-3-( 6-((S)-l -hydroxypropyl)-4-methylpyridin-3-yl)-l , 6-naphthyridin- 7-yl)-2, 2- dijluorocyclopropane-1 -carboxamide (Compound 146)

[0635] The product of (lR)-N-{2-amino-3-[6-(l-hydroxypropyl)-4-methylpyridin-3-yl] - l,6-naphthyridin-7-yl}-2,2-difluorocyclopropane-l-carboxamid e (90.0 mg, 0.24 mmol) was separated by Prep-Chiral-HPLC with the following conditions: (Column: CHIRAL ART Cellulose-SC, 2x25 cm, 5 pm; Mobile Phase A: Hex (0.5% 2M NH ₃ -MeOH)-HPLC, Mobile Phase B: EtOH: DCM=1 : 1— HPLC; Flow rate: 20 mL/min; Gradient: 80% B to 80% B in 14.5 min; Wave Length: 254/220 nm; RTl(min): 8.16; RT2(min): 12.01) to afford (R)-N-(2- amino-3-(6-(l-hydroxypropyl)-4-methylpyridin-3-yl)-l,6-napht hyridin-7-yl)-2,2- difluorocyclopropane- 1 -carboxamide Isomer 1 (retention time 8.16 min, 21.6 mg, 46%) as a white solid and (R)-N-(2-amino-3-(6-(l-hydroxypropyl)-4-methylpyridin-3-yl)- l,6- naphthyridin-7-yl)-2,2-difluorocyclopropane-l -carboxamide Isomer 2 (retention time 12.01 min, 21.7 mg, 46%) as a white solid. The absolute stereochemistry of Isomers 1 and 2 was not assigned. The two isomeric structures that could be obtained from chiral separation of the isomeric mixture as described above are shown as Compounds 145 and 146 in Table 1.

[0636] (R)-N-(2-amino-3-(6-(l-hydroxypropyl)-4-methylpyridin-3-yl)- l,6-naphthyridin- 7-yl)-2,2-difluorocyclopropane-l -carboxamide Isomer 1 : RTl(min): 8.16; LCMS (ESI, m/z): [M+H]+ = 414.2. ¹ H NMR (400 MHz, DMSO-d6): 5 10.97 (s, 1H), 8.72 (d, J = 3.2 Hz, 1H), 8.28 (s, 1H), 8.07 (s, 1H), 7.87 - 7.82 (m, 1H), 7.45 (d, J = 9.2 Hz, 1H), 6.59 (s, 2H), 5.29 (d, J = 4.4 Hz, 1H), 4.56 - 4.52 (m, 1H), 3.09 - 2.97 (m, 1H), 2.18 (s, 3H), 2.10 - 1.98 (m, 2H), 1.89 - 1.82 (m, 1H), 1.75 - 1.64 (m, 1H), 0.97 - 0.88 (m, 3H). [0637] (R)-N-(2-amino-3-(6-(l-hydroxypropyl)-4-methylpyridin-3-yl)- l,6-naphthyridin- 7-yl)-2,2-difluorocyclopropane-l-carboxamide Isomer 2: RT2(min): 12.01; LCMS (ESI, m/z): [M+H]+ = 414.2. ¹ H NMR (400 MHz, DMSO-d6): δ 10.97 (s, 1H), 8.72 (d, J= 3.2 Hz, 1H), 8.28 (d, J= 7.6 Hz, 1H), 8.07 (s, 1H), 7.87 - 7.82 (m, 1H), 7.45 (d, J= 7.6 Hz, 1H), 6.59 (s, 2H), 5.29 (d, J= 5.2 Hz, 1H), 4.56 - 4.52 (m, 1H), 3.09 - 2.97 (m, 1H), 2.18 (s, 3H), 2.10 - 1.98 (m, 2H), 1.89 - 1.82 (m, 1H), 1.75 - 1.64 (m, 1H), 0.97 - 0.88 (m, 3H).

Example 78. Synthesis of (S)-l-ethyl-3-(3-(6-(l-hydroxypropyl)-4-methylpyridin-3-yl)- l,6- naphthyridin-7-yl)urea (Compound 147) and (R)-l-ethyl-3-(3-(6-(l-hydroxypropyl)-4- methylpyridin-3-yl)-l,6-naphthyridin-7-yl)urea (Compound 148)

Step 1: Synthesis of l-(5-(7-chloro-l,6-naphthyridin-3-yl)-4-methylpyridin-2-yl)p ropan-l-one

[0638] To a solution of 3-bromo-7-chloro-l,6-naphthyridine (500.0 mg, 2.05 mmol) in dioxane (20.0 mL) and H2O (4.0 mL) was added l-(4-methyl-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridin-2-yl)propan-l-one (594.5 mg, 3.08 mmol), K2CO3 (851.4 mg, 6.16 mmol) and Pd(dppf)C12 (150.2 mg, 0.21 mmol) at room temperature under N2. The resulting mixture was stirred at 80 °C for 2 h under N2. After the reaction was completed, the mixture was cooled to room temperature and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (95/5, v/v) to afford l-[5-(7-chloro-l,6-naphthyridin-3-yl)-4-methylpyridin-2- yl]propan-l-one (400.0 mg, 62%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 312.1.

Step 2: Synthesis of l-ethyl-3-(3-(4-methyl-6-propionylpyridin-3-yl)-l,6-naphthyr idin-7- yl)urea:

[0639] To a solution of l-[5-(7-chloro-l,6-naphthyridin-3-yl)-4-methylpyridin-2- yl]propan-l-one (350.0 mg, 1.12 mmol) in 1,4-dioxane (6.0 mL) was added ethylurea (197.8 mg, 2.25 mmol), CS2CO3 (1097.3 mg, 3.37 mmol), BrettPhos (120.5 mg, 0.23 mmol) and BrettPhos Pd G3 (101.8 mg, 0.11 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 16 h under N2. After the reaction was completed, the mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (10/90, v/v) to afford 1- ethyl-3-(3-(4-methyl-6-propionylpyridin-3-yl)-l,6-naphthyrid in-7-yl)urea (300.0 mg, 73%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 364.1.

Step 3: Synthesis of l-ethyl-3-(3-(6-(l-hydroxypropyl)-4-methylpyridin-3-yl)-l,6- naphthyridin- 7-yl) urea:

[0640] To a solution of l-ethyl-3-(3-(4-methyl-6-propionylpyridin-3-yl)-l,6- naphthyridin-7-yl)urea (150.0 mg, 0.41 mmol) in MeOH (1.0 mL) and THF (5.0 mL) was added NaBH4 (5.7 mg, 0.41 mmol) at room temperature. The resulting mixture was stirred at room temperature for 3 h. After the reaction was completed, the resulting mixture was diluted with water and then extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (5/95, v/v) to afford l-ethyl-3-(3-(6-(l-hydroxypropyl)-4-methylpyridin-3- yl)-l,6-naphthyridin-7-yl)urea (60.0 mg, 39%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 366.1.

Step 4: Separation of (S)-l-ethyl-3-(3-(6-(l-hydroxypropyl)-4-methylpyridin-3-yl)- l,6- naphthyridin-7-yl)urea (Compound 147) and (R)-l-ethyl-3-(3-(6-(l-hydroxypropyl)-4- methylpyridin-3-yl)-l,6-naphthyridin-7-yl)urea (Compound 148)

[0641] The racemic product of l-ethyl-3-(3-(6-(l-hydroxypropyl)-4-methylpyridin-3-yl)- l,6-naphthyridin-7-yl)urea (60.0 mg, 0.16 mmol) was separated by Prep-Chiral-HPLC with the following conditions: (Column: CHIRAL ART Cellulose-SC, 2 x 25 cm, 5 pm; Mobile Phase A: Hex (0.5% 2M NH ₃ -MeOH)-HPLC, Mobile Phase B: EtOH: DCM=1 : 1-HPLC; Flow rate: 20 mL/min; Gradient: 80% B to 80% B in 14 min; Wave Length: 254/220 nm; RTl(min): 8.16; RT2(min): 12.01) to afford l-ethyl-3-(3-(6-(l-hydroxypropyl)-4- methylpyridin-3-yl)-l,6-naphthyridin-7-yl)urea Enantiomer 1 (retention time 8.16 min, 15.8 mg, 53%) as a white solid and l-ethyl-3-(3-(6-(l-hydroxypropyl)-4-methylpyridin-3-yl)-l,6- naphthyridin-7-yl)urea Enantiomer 2 (retention time 12.01 min, 11.6 mg, 38%) as a white solid. The absolute stereochemistry of Enantiomers 1 and 2 was not assigned. The two enantiomeric structures that could be obtained from chiral separation of the enantiomeric mixture as described above are shown as Compounds 147 and 148 in Table 1.

[0642] l-ethyl-3-(3-(6-(l-hydroxypropyl)-4-methylpyridin-3-yl)-l,6- naphthyridin-7- yl)urea Enantiomer 1: RTl(min): 8.16; LCMS (ESI, m/z): [M+H]+ = 366.2. ¹ H NMR (400 MHz, DMSO-d6): δ 9.28 (s, 1H), 9.15 (s, 1H), 9.03 (d, J = 2.0 Hz, 1H), 8.49 - 8.44 (m, 2H), 8.23 (s, 1H), 7.49 (s, 1H), 7.06 - 7.03 (m, 1H), 5.36 (d, J = 4.8 Hz, 1H), 4.57 - 4.52 (m, 1H), 3.22 - 3.18 (m, 2H), 2.36 (s, 3H), 1.87 - 1.81 (m, 1H), 1.71 - 1.64 (m, 1H), 1.13 - 1.09 (m, 3H), 0.93 - 0.88 (m, 3H).

[0643] l-ethyl-3-(3-(6-(l-hydroxypropyl)-4-methylpyridin-3-yl)-l,6- naphthyridin-7- yl)urea Enantiomer 2: RT2(min): 12.01; LCMS (ESI, m/z): [M+H]+ = 366.1. ¹ H NMR (400 MHz, DMSO-d6): δ 9.30 (s, 1H), 9.16 (s, 1H), 9.04 (d, J = 2.0 Hz, 1H), 8.49 - 8.44 (m, 2H), 8.23 (s, 1H), 7.49 (s, 1H), 7.06 - 7.04 (m, 1H), 5.39 (d, J = 4.8 Hz, 1H), 4.57 - 4.53 (m, 1H), 3.40 - 3.20 (m, 2H), 2.36 (s, 3H), 1.87 - 1.82 (m, 1H), 1.71 - 1.64 (m, 1H), 1.11 - 1.09 (m, 3H), 0.92 - 0.88 (m, 3H).

Example 79. Synthesis of (lR,2R)-N-(6-cyano-7-(6-((Z)-l-(hydroxyimino)propyl)-4- methylpyridin-3-yl)isoquinolin-3-yl)-2-fluorocyclopropane-l- carboxamide (Compound 149)

Step 1: Synthesis of (lR,2R)-N-(6-cyano-7-(4-methyl-6-propionylpyridin-3-yl)isoqu inolin-3- yl)-2-fluorocyclopropane-l-carboxamide

[0644] To a mixture of 3-amino-7-(4-methyl-6-propionylpyridin-3-yl)isoquinoline-6- carbonitrile (150.0 mg, 0.47 mmol) in Pyridine (6.0 mb) was added (lR,2R)-2- fluorocyclopropane-1 -carboxylic acid (59.2 mg, 0.56 mmol) and EDCI (272.6 mg, 1.42 mmol) at room temperature. The resulting mixture was stirred at room temperature for 3 h. After the reaction was completed, the mixture was concentrated under vacuum. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (10/1, v/v) to afford (lR,2R)-N-(6-cyano-7-(4-methyl-6-propionylpyridin-3-yl)isoqu inolin-3-yl)-2- fluorocyclopropane-1 -carboxamide (80.0 mg, 41%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =403.1.

Step 2: Synthesis of (lR,2R)-N-(6-cyano-7-(6-((Z)-l-(hydroxyimino)propyl)-4-methy lpyridin- 3-yl)isoquinolin-3-yl)-2-fluorocyclopropane-l -carboxamide (Compound 149):

[0645] To a solution of (lR,2R)-N-(6-cyano-7-(4-methyl-6-propionylpyridin-3- yl)isoquinolin-3-yl)-2-fluorocyclopropane-l-carboxamide (80.0 mg, 0.19 mmol) in DCM/EtOH (10.0 mL/2.0 mL) was added H ₂ NOH-HC1 (27.6 mg, 0.39 mmol) and NaOAc (32.6 mg, 0.39 mmol) at room temperature. The resulting mixture was stirred at room temperature for 3 h. After the reaction was completed, the mixture was concentrated under vacuum. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (10/1, v/v) and then purified by Prep-Achiral SFC with the following conditions: (Column: YMC-Actus Triart Diol-HILIC, 3x25 cm, 5 pm; Mobile Phase A: CO2, Mobile Phase B: MeOH(0.1% 2M NH3-MEOH); Flow rate: 75 mL/min; Gradient: isocratic 25% B; Column Temperature(°C): 35; Back Pressure(bar): 100; Wave Length: 254 nm) to afford (1R,2R)-N- (6-cyano-7-(6-((Z)-l-(hydroxyimino)propyl)-4-methylpyridin-3 -yl)isoquinolin-3-yl)-2- fluorocyclopropane-1 -carboxamide (Compound 149, 18.1 mg, 21%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 418.1. ¹ H NMR (400 MHz, DMSO-d ₆ ): 5 11.52 (s, 1H), 11.21 (s, 1H), 9.33 (s, 1H), 8.78 (s, 1H), 8.67 (s, 1H), 8.54 (s, 1H), 8.27 (s, 1H), 7.89 (s, 1H), 5.09 - 4.88 (m, 1H), 2.93 - 2.71 (m, 2H), 2.35 - 2.30 (m, 1H), 2.25 (s, 3H), 1.77 - 1.67 (m, 1H), 1.28 - 1.19 (m, 1H), 1.12 - 1.05 (m, 3H).

Example 80. Synthesis of 3-ethyl-l-(7-{6-[(lS)-l-hydroxypropyl]-4-methylpyridin-3-yl} -2,6- naphthyridin-3-yl)urea (Compound 150) and 3-ethyl-l-(7-{6-[(lR)-l-hydroxypropyl]-4- methylpyridin-3-yl}-2,6-naphthyridin-3-yl)urea (Compound 151) Step 1: Synthesis of 3-ethyl-l-[7-(4-methyl-6-propanoylpyridin-3-yl)-2,6-naphthyr idin-3- yl]urea

[0646] To a solution of l-[5-(7-amino-2,6-naphthyridin-3-yl)-4-methylpyridin-2- yl]propan-l-one (340.0 mg, 1.16 mmol) in Pyridine (10.0 mL) was added isocyanatoethane (413.3 mg, 5.81 mmol) at room temperature under N2. The mixture was stirred at 50 °C for 20 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with CELCh/MeOH (10/1, v/v) to afford 3-ethyl-l-[7-(4-methyl-6-propanoylpyridin-3-yl)-2,6-naphthyr idin-3- yl]urea (200.0 mg, 47%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 364.2.

Step 2: Synthesis of 3-ethyl-l-{7-[6-(l-hydroxypropyl)-4-methylpyridin-3-yl]-2,6- naphthyridin-3-yl}urea:

[0647] To a solution of 3-ethyl-l-[7-(4-methyl-6-propanoylpyridin-3-yl)-2,6- naphthyri din-3 -yl]urea (190.0 mg, 0.52 mmol) in DCM (4.0 mL)/MeOH (1.0 mL) was added NaBEL (39.5 mg, 1.04 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the mixture was quenched with MeOH and then concentrated under vacuum. The residue was purified by flash column chromatography with CEECE/MeOH (10/1, v/v) to afford 3-ethyl-l-{7-[6-(l-hydroxypropyl)-4-methylpyridin-3- yl]-2,6-naphthyridin-3-yl}urea (60.0 mg, 31%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺

= 366.2.

Step 3: Separation of 3-ethyl-l-(7-{6-[(lS)-l-hydroxypropyl]-4-methylpyridin-3-yl} -2,6- naphthyridin-3-yl)urea (Compound 150) and 3-ethyl-l-(7-{6-[(lR)-l-hydroxypropyl]-4- methylpyridin-3-yl}-2,6-naphthyridin-3-yl)urea (Compound 151)

[0648] The racemic product of 3-ethyl-l-{7-[6-(l-hydroxypropyl)-4-methylpyridin-3-yl]- 2,6-naphthyridin-3-yl}urea (60.0 mg, 0.16 mmol) was separated by Prep-Chiral-HPLC with the following conditions: (Column: Chiral ART Cellulose-SA, 2x25 cm, 5 pm; Mobile Phase A: Hex(0.5% 2M NH ₃ -MeOH)-HPLC, Mobile Phase B: MeOH: DCM=1 : 1-HPLC; Flow rate: 20 mL/min; Gradient: 40% B to 40% B in 15 min; Wave Length: 254/220 nm; RTl(min): 8.94; RT2(min): 13.70) to afford 3-ethyl-l-(7-{6-[l-hydroxypropyl]-4- m ethylpyri din-3 -yl} -2, 6-naphthyri din-3 -yl)urea Enantiomer 1 (retention time 8.94 min, 21.9 mg, 73%) as an off-white solid and 3-ethyl-l-(7-{6-[l-hydroxypropyl]-4-methylpyridin-3- yl}-2,6-naphthyridin-3-yl)urea Enantiomer 2 (retention time 13.70 min, 27.5 mg, 91%) as an off-white solid. The absolute stereochemistry of Enantiomers 1 and 2 was not assigned. The two enantiomeric structures that could be obtained from chiral separation of the enantiomeric mixture as described above are shown as Compounds 150 and 151 in Table 1.

[0649] 3-ethyl-l-(7-{6-[l-hydroxypropyl]-4-methylpyridin-3-yl}-2,6- naphthyridin-3- yl)urea Enantiomer 1: RTl(min): 8.94; LCMS (ESI, m/z): [M+H]+ = 366.2. ¹ H NMR (400 MHz, DMSO-d6): δ 9.40 (s, 1H), 9.29 (s, 1H), 9.21 (s, 1H), 8.57 (s, 1H), 8.32 (s, 1H), 8.09 (s, 1H), 7.45 (s, 1H), 6.90 - 6.87 (m, 1H), 5.33 (d, J = 4.8 Hz, 1H), 4.57 - 4.53 (m, 1H), 3.24 - 3.17 (m, 2H), 2.45 (s, 3H), 1.87 - 1.79 (m, 1H), 1.73 - 1.63 (m, 1H), 1.13 - 1.10 (m, 3H), 0.92 - 0.88 (m, 3H).

[0650] 3-ethyl-l-(7-{6-[l-hydroxypropyl]-4-methylpyridin-3-yl}-2,6- naphthyridin-3- yl)urea Enantiomer 2 : RT2(min): 13.70; LCMS (ESI, m/z): [M+H]+ = 366.1. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.40 (s, 1H), 9.29 (s, 1H), 9.21 (s, 1H), 8.57 (s, 1H), 8.32 (s, 1H), 8.09 (s, 1H), 7.45 (s, 1H), 6.90 - 6.87 (m, 1H), 5.33 (d, J= 4.8 Hz, 1H), 4.57 - 4.53 (m, 1H), 3.24 - 3.17 (m, 2H), 2.45 (s, 3H), 1.87 - 1.81 (m, 1H), 1.72 - 1.62 (m, 1H), 1.13 - 1.09 (m, 3H), 0.92 - 0.88 (m, 3H).

Example 81. Synthesis of (R)-l-(4-methyl-5-(7H-pyrrolo[2,3-h][l,6]naphthyridin-3- yl)pyridin-2-yl)propan-l-ol (Compound 152) and (S)-l-(4-methyl-5-(7H-pyrrolo[2,3- h][l,6]naphthyridin-3-yl)pyridin-2-yl)propan-l-ol (Compound 153) Step 1: Synthesis of 3-bromo-7 -chloro- 1 ,6-naphthyridine

[0651] To a solution of 4-amino-6-chloropyridine-3-carbaldehyde (14.0 g, 89.42 mmol) in ACN (140.0 mL) was added 2-bromo- 1,1 -dimethoxy ethane (45.3 g, 268.21 mmol) and Yb(OTf)3 (11.1 g, 17.88 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 16 h. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (5/1, v/v) to afford 3-bromo-7-chloro-l,6-naphthyridine (10.0 g, 45%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 242.9.

Step 2: Synthesis of 3-bromo-N-[(4-methoxyphenyl)methyl]-l,6-naphthyridin-7 -amine

[0652] To a solution of 3-bromo-7-chloro-l,6-naphthyridine (10.0 g, 41.07 mmol) in NMP (500.0 mL) was added (4-methoxyphenyl)methanamine (33.8 g, 246.41 mmol) and DIEA (31.9 g, 246.41 mmol) at room temperature. The resulting mixture was stirred at 130 °C for 16 h. After the reaction was completed, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with H2O/ACN (1/1, v/v) to afford 3-bromo-N-[(4-methoxyphenyl)methyl]-l,6-naphthyridin-7-amine (3.0 g, 21%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 344.0.

Step 3: Synthesis of l-[5-(7-{[(4-methoxyphenyl)methyl]amino}-l,6-naphthyridin-3- yl)-4- methylpyridin-2-yl]propan-l-one [0653] To a solution of 3-bromo-N-[(4-methoxyphenyl)methyl]-l,6-naphthyridin-7- amine (5.0 g, 14.53 mmol) in dioxane/ELO (300.0 mL/60.0 mL) was added l-[4-methyl-5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl]pr opan-l-one (4.8 g, 17.43 mmol), Pd(dppf)C12 CH2CI2 (1.2 g, 1.45 mmol) and K2CO3 (6.0 g, 43.58 mmol) at room temperature under N2. The resulting mixture was stirred at 80 °C for 4 h under N2. After the reaction was completed, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography with ethyl acetate/petroleum ether (1/1, v/v) to afford l-[5-(7-{[(4- methoxyphenyl)methyl]amino}-l,6-naphthyridin-3-yl)-4-methylp yridin-2-yl]propan-l-one (1.6 g, 26%) as a brown solid. LCMS (ESI, m/z): [M+H] ⁺ = 413.2.

Step 4: Synthesis of l-[5-(7-amino-l,6-naphthyridin-3-yl)-4-methylpyridin-2-yl]pr opan-l-one

[0654] The solution of l-[5-(7-{[(4-methoxyphenyl)methyl]amino}-l,6-naphthyridin-3- yl)-4-methylpyridin-2-yl]propan-l-one (380.0 mg, 0.92 mmol) in TFA (10.0 mL) was stirred at 80 °C for 2 h. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with H2O (10% NH4HCO3)/ACN (1/2, v/v) to afford l-[5-(7-amino-l,6-naphthyridin-3-yl)-4- methylpyridin-2-yl]propan-l-one (100.0 mg, 37%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 293.1.

Step 5: Synthesis of l-[5-(7-amino-8-iodo-l,6-naphthyridin-3-yl)-4-methylpyridin- 2- yl ]propan-l-one

[0655] To a solution of l-[5-(7-amino-l,6-naphthyridin-3-yl)-4-methylpyridin-2- yl]propan-l-one (1.0 g, 3.49 mmol) in DMF (30.0 mL) was added NIS (0.8 g, 3.49 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography with ethyl acetate/petroleum ether (1/1, v/v) to afford l-[5- (7-amino-8-iodo-l,6-naphthyridin-3-yl)-4-methylpyridin-2-yl] propan-l-one (257.0 mg, 17%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 419.0.

[0656] Step 6: Synthesis of l-(5-{7-amino-8-[(E)-2-ethoxyethenyl]-l, 6-naphthyridin-3- yl}-4-methylpyridin-2-yl)propan-l-one

[0657] To a solution of l-[5-(7-amino-8-iodo-l,6-naphthyridin-3-yl)-4-methylpyridin- 2- yl]propan-l-one (1.2 g, 2.87 mmol) in dioxane/ELO (80.0 mL/20.0 mL) was added 2-[(E)-2- ethoxyethenyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1.7 g, 8.61 mmol), XPhos (0.3 g, 0.58 mmol), K3PO4 (1.8 g, 8.61 mmol) and XPhos Pd G3 (0.2 g, 0.29 mmol) at room temperature under N2. The resulting mixture was stirred at 60 °C for 4 h. After the reaction was completed, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with H2O/CH3OH (1/1, v/v) to afford l-(5-{7-amino- 8-[(E)-2-ethoxy ethenyl]- l,6-naphthyridin-3-yl}-4-methylpyridin-2-yl)propan-l -one (300.0 mg, 28%) as a brown solid. LCMS (ESI, m/z): [M+H] ⁺ = 363.2.

Step 7: Synthesis of l-(4-methyl-5-{7H-pyrrolo[2,3-h]l,6-naphthyridin-3-yl}pyridi n-2- yl)propan-l-one

[0658] The solution of l-(5-{7-amino-8-[(E)-2-ethoxyethenyl]-l,6-naphthyridin-3-yl} -4- methylpyridin-2-yl)propan-l-one (250.0 mg, 0.69 mmol) in HC1 (10.0 mL, 1 mol/L) was stirred at 100 °C for 4 h. After the reaction was completed, the pH value of the mixture was adjusted to 8 with NaHCOs (aq.). The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford l-(4-methyl-5-{7H- pyrrolo[2,3-h]l,6-naphthyridin-3-yl}pyridin-2-yl)propan-l-on e (177.0 mg, crude) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 317.1

Step 8: Synthesis of l-(4-methyl-5-{7H-pyrrolo[2,3-h] l,6-naphthyridin-3-yl}pyridin-2- yl)propan-l-ol

[0659] To a solution of l-(4-methyl-5-{7H-pyrrolo[2,3-h]l,6-naphthyridin-3-yl}pyridi n- 2-yl)propan-l-one (154.0 mg, 0.49 mmol) in THF/CH3OH (5.0 mL/1.0 mL) was added NaBH4 (77.1 mg, 2.10 mmol) at 0 °C under N2. The resulting mixture was stirred at room temperature for 30 min. After the reaction was completed, the reaction mixture was quenched with water and then extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography with petroleum ether/ethyl acetate (1/8, v/v) to afford l-(4-methyl-5-{7H-pyrrolo[2,3-h]l,6- naphthyridin-3-yl}pyridin-2-yl)propan-l-ol (30.0 mg, 19%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 319.1 Step 9: Separation of (R)-l-(4-methyl-5-(7H-pyrrolo[2,3-h] [l,6]naphthyridin-3-yl)pyridin-2- yl)propan-l-ol (Compound 152) and (S)-l-(4-methyl-5-(7H-pyrrolo[2,3-h][l,6]naphthyridin- 3-yl)pyridin-2-yl)propan-l-ol (Compound 153)

[0660] The product of l-(4-methyl-5-{7H-pyrrolo[2,3-h] l,6-naphthyridin-3-yl]pyridin-2- yl)propan-l-ol (30.0 mg, 0.09 mmol) was separated by Prep-Chiral-HPLC with the following conditions (Column: CHIRAL ART Cellulose-SC, 2x25 cm, 5 um; Mobile Phase A:

HEX (0.5% 2M NH ₃ -MeOH)-HPLC, Mobile Phase B: EtOH: DCM=1 : 1-HPLC; Flow rate: 20 mL/min; Gradient: 70% B to 70% B in 12 min; Wave Length: 220/254 nm;

RTl(min): 6.32; RT2(min): 9.49) to afford l-(4-methyl-5-(7H-pyrrolo[2,3- h][l,6]naphthyridin-3-yl)pyridin-2-yl)propan-l-ol Enantiomer 1 (retention time 6.32 min, 1.1 mg, 7%) as a white solid and (S)-l-(4-methyl-5-(7H-pyrrolo[2,3-h][l,6]naphthyridin-3- yl)pyridin-2-yl)propan-l-ol Enantiomer 2 (retention time 9.49 min, 1.4 mg, 9%) as a white solid. The absolute stereochemistry of Enantiomers 1 and 2 was not assigned. The two enantiomeric structures that could be obtained from chiral separation of the enantiomeric mixture as described above are shown as Compounds 152 and 153 in Table 1.

[0661] l-(4-methyl-5-(7H-pyrrolo[2,3-h][l,6]naphthyridin-3-yl)pyrid in-2-yl)propan- l-ol Enantiomer 1: RTl(min): 6.32; LCMS (ESI, m/z): [M+H] ⁺ = 319.2. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.29 (s, 1H), 9.11 (d, J = 2.0 Hz, 1H), 9.03 (s, 1H), 8.67 (d, J= 2.0 Hz, 1H), 8.50 (s, 1H), 7.60 - 7.55 (m, 2H), 7.12 - 7.10 (m, 1H), 5.41 (s, 1H), 4.61 - 4.58 (m, 1H), 2.40 (s, 3H), 1.90 - 1.83 (m, 1H), 1.74 - 1.66 (m, 1H), 0.94 - 0.92 (m, 3H).

[0662] l-(4-methyl-5-(7H-pyrrolo[2,3-h][l,6]naphthyridin-3-yl)pyrid in-2-yl)propan- l-ol Enantiomer 2: RT2(min): 9.49; LCMS (ESI, m/z): [M+H] ⁺ = 319.2. ¹ H NMR (400 MHz, DMSO-d ₆ ): 6 12.28 (s, 1H), 9.11 (d, J = 2.0 Hz, 1H), 9.03 (s, 1H), 8.67 (s, 1H), 8.49 (s, 1H), 7.59 - 7.53 (m, 2H), 7.12 - 7.10 (m, 1H), 5.41 (s, 1H), 4.58 - 4.53 (m, 1H), 2.40 (s, 3H), 1.89 - 1.83 (m, 1H), 1.73 - 1.66 (m, 1H), 0.94 - 0.92 (m, 3H).

Example 82. Synthesis of (lS,2S)-N-(2-cyano-3-(6-((S)-l-hydroxybutyl)-4-methylpyridin -3- yl)-lf-naphthyridin-7-yl)-2-fluorocyclopropane-l -carboxamide formate (Compound 154) and (lS,2S)-N-(2-cyano-3-(6-((R)-l-hydroxybutyl)-4-methylpyridin -3-yl)-l,6-naphthyridin- 7-yl)-2-fluorocyclopropane-l -carboxamide formate (Compound 155)

Step 1: Synthesis of (lS,2S)-N-(3-(6-butyryl-4-methylpyridin-3-yl)-2-cyano-l,6-na phthyridin- 7-yl)-2-fluorocyclopropane-l-carboxamide

[0663] To a solution of 3-(6-butyryl-4-methylpyridin-3-yl)-7-chloro-l,6-naphthyridin e-2- carbonitrile (150.0 mg, 0.43 mmol) in dioxane (5.0 mL) was added (lS,2S)-2- fluorocyclopropane-1 -carboxamide (66.2 mg, 0.64 mmol), BrettPhos (35.8 mg, 0.08 mmol), BrettPhos Pd G3 (29.7 mg, 0.04 mmol) and CS2CO3 (326.8 mg, 0.86 mmol) at room temperature under N2. The reaction mixture was stirred at 90 °C for 4 h under N2. After the reaction was completed, the mixture was filtered. The filtrate was concentrated under vacuum. The residue was purified by flash column chromatography with ethyl acetate/petroleum ether (90/10, v/v) to afford (lS,2S)-N-(3-(6-butyryl-4-methylpyridin-3-yl)- 2-cyano-l,6-naphthyridin-7-yl)-2-fluorocyclopropane-l-carbox amide (72.0 mg, 59%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 418.2.

Step 2: Synthesis of (lS,2S)-N-(2-cyano-3-(6-(l-hydroxybutyl)-4-methylpyridin-3-y l)-l,6- naphthyridin-7-yl)-2-fluorocyclopropane-l-carboxamide:

[0664] To a solution of (lS,2S)-N-(3-(6-butyryl-4-methylpyridin-3-yl)-2-cyano-l,6- naphthyridin-7-yl)-2-fluorocyclopropane-l -carboxamide (73.0 mg, 0.17 mmol) in THF (5.0 mL) and MeOH (1.0 mL) was added NaBH4 (12.9 mg, 0.34 mmol) at 0 °C under N2. The reaction mixture was stirred at room temperature for 1.5 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (90/10, v/v) to afford (lS,2S)-N-(2-cyano-3-(6-(l- hydroxybutyl)-4-methylpyridin-3-yl)-l,6-naphthyridin-7-yl)-2 -fluorocyclopropane-l- carboxamide (47.0 mg, 64%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 420.2.

Step 3: Separation of (lS,2S)-N-(2-cyano-3-(6-((S)-l-hydroxybutyl)-4-methylpyridin -3-yl)- l,6-naphthyridin-7-yl)-2-jluorocyclopropane-l-carboxamide formate (Compound 154) and (lS,2S)-N-(2-cyano-3-(6-((R)-l-hydroxybutyl)-4-methylpyridin -3-yl)-l,6-naphthyridin-7-yl)- 2 luorocyclopropane- 1 -carboxamide formate (Compound 155)

[0665] The product of (lS,2S)-N-(2-cyano-3-(6-(l-hydroxybutyl)-4-methylpyridin-3-y l)-

1.6-naphthyridin-7-yl)-2-fluorocyclopropane-l-carboxamide (68.0 mg, 0.17 mmol) was separated by Prep-Chiral-SFC with the following conditions: (Column: Lux 5um Celluloes-3, 3x25 cm, 5 pm; Mobile Phase A: CO2, Mobile Phase B: MEOH (0.1% 2M NH3-MEOH); Flow rate: 100 mL/min; Gradient: isocratic 10% B; Column Temperature(°C): 35; Back Pressure (bar): 100; Wave Length: 220 nm; RTl(min): 6.85; RT2(min): 8.18) to afford (lS,2S)-N-(2-cyano-3-(6-(l-hydroxybutyl)-4-methylpyridin-3-y l)-l,6-naphthyridin-7-yl)-2- fluorocyclopropane-1 -carboxamide Isomer 1 (retention time 6.85 min, 25.2 mg, crude) as a white solid and (lS,2S)-N-(2-cyano-3-(6-(l-hydroxybutyl)-4-methylpyridin-3-y l)-l,6- naphthyridin-7-yl)-2-fluorocyclopropane-l -carboxamide Isomer 2 (retention time 8.18 min, 25.8 mg, crude) as a white solid. The absolute stereochemistry of Isomers 1 and 2 was not assigned. The two isomeric structures that could be obtained from chiral separation of the isomeric mixture as described above are shown as Compounds 154 and 155 in Table 1.

[0666] The product of (lS,2S)-N-(2-cyano-3-(6-(l-hydroxybutyl)-4-methylpyridin-3-y l)-

1.6-naphthyri din-7-yl)-2-fluorocy cl opropane-1 -carboxamide Isomer 1 (25.2 mg, crude) was purified by Prep-HPLC with the following conditions: (Column: Xselect CSH C18 OBD Column 30x150 mm 5 μm; Mobile Phase A: ACN, Mobile Phase B: Water (0.1% FA); Flow rate: 60 mL/min; Gradient: 12% B to 22% B in 10 min, 22% B to 22% B in 12 min; Wave Length: 254/220 nm) to afford (lS,2S)-N-(2-cyano-3-(6-(l-hydroxybutyl)-4-methylpyridin- 3-yl)-l,6-naphthyridin-7-yl)-2-fluorocyclopropane-l-carboxam ide formate Isomer 1 (6.4 mg, 18%) as a white solid. RTl(min): 6.85; LCMS (ESI, m/z): [M+H]+ = 420.2. ¹ H NMR (400 MHz, DMSO-d6): δ 11.18 (s, 1H), 9.29 (s, 1H), 9.12 (d, J = 2.0 Hz, 1H), 8.62 - 8.57 (m, 2H), 8.46 (s, 1H), 7.51 (s, 1H), 5.35 (d, J = 5.2 Hz, 1H), 5.07 - 4.90 (m, 1H), 4.64 - 4.60 (m, 1H), 2.37 (s, 3H), 2.35 - 2.30 (m, 1H), 1.78 - 1.64 (m, 3H), 1.44 - 1.38 (m, 2H), 1.26 - 1.20 (m, 1H), 0.94 - 0.90 (m, 3H).

[0667] The product of (lS,2S)-N-(2-cyano-3-(6-(l-hydroxybutyl)-4-methylpyridin-3-y l)-

I,6-naphthyri din-7-yl)-2-fluorocy cl opropane-1 -carboxamide Isomer 2 (25.8 mg, crude) was purified by Prep-HPLC with the following conditions: (Column: Xselect CSH C18 OBD Column 30x150 mm, 5 pm; Mobile Phase A: ACN, Mobile Phase B: Water (0.1% FA); Flow rate: 60 mL/min; Gradient: 14% B to 24% B in 10 min; Wave Length: 254/220 nm) to afford (lS,2S)-N-(2-cyano-3-(6-(l-hydroxybutyl)-4-methylpyridin-3-y l)-l,6-naphthyridin-7-yl)-2- fluorocy cl opropane-1 -carboxamide formate Isomer 2 (5.8 mg, 17%) as a white solid.

RT2(min): 8.18; LCMS (ESI, m/z): [M+H]+ = 420.3. ¹ H NMR (400 MHz, DMSO-d6): δ

I I.13 (s, 1H), 9.29 (s, 1H), 9.12 (d, J = 2.4 Hz, 1H), 8.62 - 8.57 (m, 2H), 8.46 (s, 1H), 7.51 (s, 1H), 5.35 (d, J = 5.2 Hz, 1H), 5.08 - 4.90 (m, 1H), 4.64 - 4.60 (m, 1H), 2.37 (s, 3H), 2.35 - 2.30 (m, 1H), 1.78 - 1.63 (m, 3H), 1.44 - 1.37 (m, 2H), 1.26 - 1.20 (m, 1H), 0.94 - 0.90 (m, 3H).

Example 83. Synthesis of (R)-2,2-difluoro-N-(3-(6-((S)-l-hydroxyethyl)-4-methylpyridi n-3- yl)-l,6-naphthyridin-7-yl)cyclopropane-l-carboxamide (Compound 156) and (R)-2,2- difluoro-N-(3-(6-((R)-l-hydroxyethyl)-4-methylpyridin-3-yl)- l,6-naphthyridin-7- yl) cyclopropane-1 -carboxamide (Compound 157)

Step 1: Synthesis of l-(5-bromo-4-methylpyridin-2-yl)ethanone

[0668] To a solution of 4-(5-bromo-4-methylpyridine-2-carbonyl)morpholine (5.0 g, 17.54 mmol) in THF (50.0 mL) was dropwise added bromo(methyl)magnesium (26.4 mL, 1 mol/L in THF) at 0 °C under N2. The resulting mixture was stirred at 0 °C for 0.5 h under N2. After the reaction was completed, the reaction mixture was quenched with H2O at 0 °C and then extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (9/1, v/v) to afford l-(5-bromo-4-methylpyridin-2-yl)ethanone (2.5 g, 66%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 214.0. Step 2: Synthesis of l-[4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)p yridin-2- yl] ethanone:

[0669] To a stirred solution of l-(5-bromo-4-methylpyridin-2-yl)ethanone (2.4 g, 11.21 mmol) in dioxane (30.0 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2- dioxaborolane) (5.7 g, 22.42 mmol), KOAc (3.3 g, 33.64 mmol) and Pd(dppf)C12 (820.4 mg, 1.12 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 1 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with ethyl acetate/petroleum ether (1/1, v/v) to afford l-[4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)p yridin-2- yl]ethanone (1.5 g, 51%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 262.2.

Step 3: Synthesis of l-[5-(7-chloro-l,6-naphthyridin-3-yl)-4-methylpyridin-2-yl]e thanone:

[0670] To a solution of 3-bromo-7-chloro-l,6-naphthyridine (1.4 g, 5.75 mmol) in dioxane (15.0 mL) and H2O (3.0 mL) was added l-[4-methyl-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridin-2-yl]ethanone (1.8 g, 6.90 mmol), Pd(dppf)C12 (0.8 g, 1.15 mmol) and K2CO3 (2.4 g, 17.25 mmol) at room temperature under N2. The resulting mixture was stirred at 85 °C for 2 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (9/1, v/v) to afford l-[5-(7-chloro-l,6-naphthyridin-3-yl)-4-methylpyridin-2- yl]ethanone (1.3 g, 75%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 298.1.

Step 4: Synthesis of tert-butyl (3-(6-acetyl-4-methylpyridin-3-yl)-l,6-naphthyridin-7- yl)carbamate :

[0671] To a solution of l-[5-(7-chloro-l,6-naphthyridin-3-yl)-4-methylpyridin-2- yl]ethanone (1.3 g, 4.20 mmol) in dioxane (15.0 mL) was added tert-butyl carbamate (1.5 g, 12.59 mmol), Pd2(dba)3 (0.8 g, 0.84 mmol), XPhos (0.8 g, 1.68 mmol) and K2CO3 (1.2 g, 8.40 mmol) at room temperature under N2. The resulting mixture was stirred at 85 °C for 16 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with ethyl acetate/petroleum ether (1/1, v/v) to afford tert-butyl (3-(6-acetyl-4-methylpyridin-3-yl)-l,6-naphthyridin-7- yl)carbamate (820.0 mg, 51%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 379.2.

Step 5: Synthesis of l-[5-(7-amino-l,6-naphthyridin-3-yl)-4-methylpyridin-2-yl]et hanone:

[0672] To a solution of tert-butyl N-[3-(6-acetyl-4-methylpyri din-3 -yl)-l,6-naphthyridin-

7-yl]carbamate (820.0 mg, 2.17 mmol) in DCM (5.0 mL) was added TFA (5.0 mL) at room temperature. The mixture was stirred at room temperature for 1 h. After the reaction was completed, the resulting mixture was neutralized to pH = 7 with saturated NaHCO3 (aq). The resulting mixture was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH2C12/MeOH (9/1, v/v) to afford l-[5-(7-amino-l,6-naphthyridin-3-yl)-4-methylpyridin-2- yl]ethanone (300.0 mg, 49%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 279.1.

Step 6: Synthesis of (R)-N-(3-(6-acetyl-4-methylpyridin-3-yl)-l,6-naphthyridin-7- yl)-2,2- difluorocyclopropane-1 -carboxamide:

[0673] To a solution of l-[5-(7-amino-l,6-naphthyridin-3-yl)-4-methylpyridin-2- yl]ethanone (278.0 mg, 1.00 mmol) in pyridine (8.0 mL) was added (R)-2,2- difluorocyclopropane-1 -carboxylic acid (182.9 mg, 1.50 mmol) and EDCI (957.4 mg, 5.00 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (1/1, v/v) to afford (R)-N-(3-(6-acetyl-4-methylpyridin-3-yl)-l,6-naphthyridin-7- yl)-2,2- difluorocyclopropane-1 -carboxamide (250.0 mg, 65%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 383.1.

Step 7: Synthesis of (lR)-2,2-difluoro-N-(3-(6-(l-hydroxyethyl)-4-methylpyridin-3 -yl)-l ,6- naphthyridin-7-yl) cyclopropane- 1 -carboxamide:

[0674] To a stirred solution of (R)-N-(3-(6-acetyl-4-methylpyri din-3 -yl)- 1,6- naphthyridin-7-yl)-2,2-difluorocyclopropane-l -carboxamide (150.0 mg, 0.39 mmol) in THF (4.0 mL) was added DIBAL-H (1.2 mL, 1 mol/L in hexane) at - 40 °C under N2. The resulting mixture was stirred at -40 °C for 2 h under N2. After the reaction was completed, the reaction mixture was quenched with H2O at 0 °C and then extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CELCL/MeOH (9/1, v/v) to afford (lR)-2,2-difluoro-N- (3 -(6-(l -hydroxy ethyl)-4-methylpyri din-3 -yl)- 1 ,6-naphthyridin-7-yl)cy clopropane- 1 - carboxamide (80.0 mg, 53%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 385.1.

Step 8: Separation of (R)-2,2-difluoro-N-(3-(6-((S)-l-hydroxyethyl)-4-methylpyridi n-3-yl)-

If -naphthyridin-7-yl) cyclopropane- 1 -carboxamide (Compound 156) and (R)-2,2-difluoro-N- (3-(6-((R)-l-hydroxyethyl)-4-methylpyridin-3-yl)-l,6-naphthy ridin-7-yl)cyclopropane-l- carboxamide (Compound 157)

[0675] The product of (lR)-2,2-difluoro-N-(3-(6-(l-hydroxyethyl)-4-methylpyridin-3 - yl)-l,6-naphthyridin-7-yl)cyclopropane-l-carboxamide (80.0 mg, 0.21 mmol) was separated by Prep-Chiral-HPLC with the following conditions (Column: CHIRAL ART Amylose-SA, 2x25 cm, 5 pm; Mobile Phase A: Hex (0.5% 2M NH3-MeOH)— HPLC, Mobile Phase B: MeOH: DCM=1 : 1— HPLC; Flow rate: 20 mL/min; Gradient: 50% B to 50% B in 9.5 min; Wave Length: 254/220 nm; RTl(min): 6.33; RT2(min): 7.71) to afford (R)-2,2-difluoro-N- (3 -(6-(l -hydroxy ethyl)-4-methylpyri din-3 -yl)- 1 ,6-naphthyridin-7-yl)cy clopropane- 1 - carboxamide Isomer 1 (retention time 6.33 min, 26.0 mg, 65%) as a white solid and (R)-2,2- difluoro-N-(3 -(6-(l -hydroxy ethyl)-4-methylpyri din-3 -yl)- 1 ,6-naphthyridin-7- yl)cyclopropane-l -carboxamide Isomer 2 (retention time 7.71 min, 30.4 mg, 76%) as a white solid. The absolute stereochemistry of Isomers 1 and 2 was not assigned. The two isomeric structures that could be obtained from chiral separation of the isomeric mixture as described above are shown as Compounds 156 and 157 in Table 1.

[0676] (R)-2,2-difluoro-N-(3-(6-(l-hydroxyethyl)-4-methylpyridin-3- yl)-l,6- naphthyridin-7-yl)cyclopropane-l-carboxamide Isomer 1: RTl(min): 6.33; LCMS (ESI, m/z): [M+H]+ = 385.1. ¹ H NMR (400 MHz, DMSO-d6): δ 11.39 (s, 1H), 9.30 (s, 1H), 9.13 (d, J = 2.0 Hz, 1H), 8.60 - 8.58 (m, 2H), 8.46 (s, 1H), 7.54 (s, 1H), 5.45 (d, J = 4.8 Hz, 1H), 4.81 - 4.75 (m, 1H), 3.13 - 3.05 (m, 1H), 2.37 (s, 3H), 2.14 - 2.04 (m, 2H), 1.42 (d, J = 6.4 Hz, 3H).

[0677] (R)-2,2-difluoro-N-(3-(6-(l-hydroxyethyl)-4-methylpyridin-3- yl)-l,6- naphthyridin-7-yl)cyclopropane-l-carboxamide Isomer 2: RT2(min): 7.71; LCMS (ESI, m/z): [M+H] ⁺ = 385.1. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.39 (s, 1H), 9.30 (s, 1H), 9.13 (d, J= 1.2 Hz, 1H), 8.60 - 8.46 (m, 3H), 7.54 (s, 1H), 5.45 (d, J= 4.8 Hz, 1H), 4.81 - 4.75 (m, 1H), 3.13 - 3.05 (m, 1H), 2.37 (s, 3H), 2.14 - 2.04 (m, 2H), 1.42 (d, J= 6.4 Hz, 3H). Example 84. Synthesis of (lR,2R)-2-fluoro-N-(3-(6-((Z)-l-(hydroxyimino)propyl)-4- methylpyridin-3-yl)-l, 6-naphthyridin- 7-yl)cyclopropane-l -carboxamide (Compound 158)

Step 1: Synthesis of (lR,2R)-2-fluoro-N-(3-(4-methyl-6-propionylpyridin-3-yl)-l ,6- naphthyridin-7-yl)cyclopropane-l-carboxamide

[0678] To a solution of l-(5-(7-chloro-l,6-naphthyridin-3-yl)-4-methylpyridin-2- yl)propan-l-one (290.0 mg, 0.93 mmol) in 1,4-dioxane (5.0 mL) were added (lR,2R)-2- fluorocyclopropane-1 -carboxamide (143.8 mg, 1.40 mmol), CsCCL (909.2 mg, 2.79 mmol), Xphos (88.6 mg, 0.19 mmol) and Pd(OAc)2 (20.8 mg, 0.09 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 2 h. After the reaction was completed, the mixture was filtered. The filtrate was concentrated under vacuum. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (1/1, v/v) to afford (lR,2R)-2-fhjoro-N-(3-(4-methyl-6-propionylpyridin-3-yl)-l,6 -naphthyridin-7- yl)cyclopropane-l -carboxamide (135.0 mg, 38%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 379.1.

Step 2: Synthesis of (lR,2R)-2-fluoro-N-(3-(6-((Z)-l-(hydroxyimino)propyl)-4-meth ylpyridin- 3-yl)-l, 6-naphthyridin-7-yl)cyclopropane-l -carboxamide (Compound 158):

[0679] To a solution of (lR,2R)-2-fluoro-N-(3-(4-methyl-6-propionylpyridin-3-yl)-l,6 - naphthyridin-7-yl)cyclopropane-l -carboxamide (125.0 mg, 0.33 mmol) in DCM (2.0 mL)/EtOH (2.0 mL) were added NH2OHHCI (45.9 mg, 0.66 mmol) and NaOAc (54.2 mg, 0.66 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the mixture was concentrated under vacuum. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (5/1, v/v) and then purified by Prep-HPLC with the following conditions: (Column: XBridge Prep OBD C18 Column, 30x150 mm, 5 pm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 31% B to 39% B in 8 min; Wave Length: 220/254 nm) to afford (lR,2R)-2-fluoro-N-(3-(6-((Z)-l-(hydroxyimino)propyl)-4-meth ylpyridin-3- yl)-l,6-naphthyridin-7-yl)cyclopropane-l-carboxamide (4.8 mg, 3%) as an off white solid. LCMS (ESI, m/z): [M+H] ⁺ = 394.1. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.50 (s, 1H), 11.23 (s, 1H), 9.29 (s, 1H), 9.15 (d, J= 2.4 Hz, 1H), 8.63 - 8.59 (m, 3H), 7.86 (s, 1H), 5.09 - 4.88 (m, 1H), 2.94 - 2.88 (m, 2H), 2.39 (s, 3H), 2.33 - 2.25 (m, 1H), 1.76 - 1.67 (m, 1H), 1.27 - 1.23 (m, 1H), 1.10 - 1.06 (m, 3H).

Example 85. Synthesis of (lS,2S)-2-fluoro-N-(3-{6-[(lZ)-l-(hydroxyimino)propyl]-4- methylpyridin-3-yl}-l,6-naphthyridin-7-yl)cyclopropane-l-car boxamide (Compound 159)

Step 1: Synthesis of (lS,2S)-2-fluoro-N-(3-(4-methyl-6-propionylpyridin-3-yl)-l,6 - naphthyridin-7-yl) cyclopropane- 1 -carboxamide

[0680] To a solution of l-(5-(7-chloro-l,6-naphthyridin-3-yl)-4-methylpyridin-2- yl)propan-l-one (270.0 mg, 0.86 mmol) in dioxane (12.0 mL) were added (lS,2S)-2- fluorocyclopropane-1 -carboxamide (133.9 mg, 1.29 mmol), CS2CO3 (846.5 mg, 2.59 mmol), XPhos (82.5 mg, 0.17 mmol) and Pd(OAc)2 (19.4 mg, 0.08 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 2 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (10/1, v/v) to afford (l S,2S)-2-fluoro-N- (3-(4-methyl-6-propionylpyridin-3-yl)-l,6-naphthyridin-7-yl) cyclopropane-l-carboxamide (100.0 mg, 30%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 379.1.

Step 2: Synthesis of (lS,2S)-2-fluoro-N-(3-{6-[(lZ)-l-(hydroxyimino)propyl]-4- methylpyridin-3-yl}-l , 6-naphthyridin-7-yl)cyclopropane-l-carboxamide (Compound 159):

[0681] To a solution of (lS,2S)-2-fluoro-N-(3-(4-methyl-6-propionylpyridin-3-yl)-l,6 - naphthyridin-7-yl)cyclopropane-l -carboxamide (95.0 mg, 0.25 mmol) in DCM (4.0 mL)/EtOH (4.0 mL) were added NH2OH.HC1 (34.8 mg, 0.50 mmol) and NaOAc (41.1 mg, 0.50 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the mixture was concentrated under vacuum. The residue was purified by flash column chromatography with CH2C12/MeOH (10/1, v/v) and then purified by Prep-HPLC with the following conditions: (Column: XBridge Prep OBD C18 Column, 30x150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 25% B to 35% B in 10 min; Wave Length: 254 nm) to afford (lS,2S)-2-fluoro-N-(3-{6-[(lZ)-l-(hydroxyimino)propyl]-4-met hylpyridin- 3-yl}-l,6-naphthyridin-7-yl)cyclopropane-l-carboxamide (Compound 159, 29.9 mg, 29%) as a white solid. LCMS (ESI, m/z): [M+H]+ = 394.1. ¹ H NMR (400 MHz, DMSO-d6): δ 11.46 (s, 1H), 11.19 (s, 1H), 9.29 (s, 1H), 9.15 (d, J = 3.2 Hz, 1H), 8.62 - 8.59 (m, 3H), 7.86 (s, 1H), 5.11 - 4.86 (m, 1H), 2.93 - 2.86 (m, 2H), 2.39 (s, 3H), 2.34 - 2.30 (m, 1H), 1.79 - 1.68 (m, 1H), 1.29 - 1.17 (m, 1H), 1.12 - 1.07 (m, 3H).

Example 86. Synthesis of (lR)-2,2-difluoro-N-(3-{6-[(lZ)-l-(hydroxyimino)propyl]-4- methylpyridin-3-yl}-l,6-naphthyridin-7-yl)cyclopropane-l-car boxamide (Compound 160)

[0682] To a solution of (lR)-2,2-difluoro-N-[3-(4-methyl-6-propanoylpyridin-3-yl)-l, 6- naphthyridin-7-yl]cyclopropane-l -carboxamide (150.0 mg, 0.37 mmol) in DCM (2.0 mL)/EtOH (2.0 mL) were added NH2OHHCI (52.5 mg, 0.75 mmol) and NaOAc (62.0 mg, 0.75 mmol) at room temperature under N2. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the mixture was concentrated under vacuum. The residue was purified by flash column chromatography with C^CL/MeOH (10/1, v/v) and then purified by Prep-HPLC with the following conditions: (Column: XBridge Prep OBD C18 Column, 30x150 mm, 5 pm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 14% B to 24% B in 10 min; Wave Length: 254 nm) to afford (lR)-2,2-difhioro-N-(3-{6-[(lZ)-l- (hydroxyimino)propyl]-4-methylpyridin-3-yl}-l,6-naphthyridin -7-yl)cyclopropane-l- carboxamide (Compound 160, 33.1 mg, 21%) as an off-white solid. LCMS (ESI, m/z): [M+H] ⁺ = 412.1. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.49 (s, 1H), 11.39 (s, 1H), 9.31 (s, 1H), 9.16 (d, J= 2.0 Hz, 1H), 8.62 - 8.59 (m, 3H), 7.86 (s, 1H), 3.14 - 3.06 (m, 1H), 2.92 - 2.87 (m, 2H), 2.39 (s, 3H), 2.17 - 2.05 (m, 2H), 1.11 - 1.07 (m, 3H).

Example 87. Synthesis of (lR)-2,2-difluoro-N-(7-{6-[(S)-l-hydroxypropyl]-4- methylpyridin-3-yl}isoquinolin-3-yl)cyclopropane-l-carboxami de (Compound 161) and (lR)-2,2-difluoro-N-(7-{6-[(R)-l-hydroxypropyl]-4-methylpyri din-3-yl}isoquinolin-3- yl) cyclopropane-1 -carboxamide (Compound 162)

Step 1: Synthesis of l-[5-(3-chloroisoquinolin-7-yl)-4-methylpyridin-2-yl]propan- l-one

[0683] To a solution of 7-bromo-3-chloroisoquinoline (1.0 g, 4.12 mmol) in 1,4- dioxane/H2O (16.0 mL/4.0 mL) was added 4-methyl-6-propanoylpyridin-3-ylboronic acid (1.1 g, 6.18 mmol), K2CO3 (1.7 g, 12.37 mmol) and Pd(dppf)C12 (301.7 mg, 0.41 mmol) at room temperature under N2. The mixture was stirred at 100 °C for 2 h. After the reaction was completed, the mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (10/1, v/v) to afford l-[5-(3-chloroisoquinolin-7-yl)-4- methylpyridin-2-yl]propan-l-one (800.0 mg, 62%) as an off-white solid. LCMS (ESI, m/z): [M+H] ⁺ = 311.1.

Step 2: Synthesis of tert-butyl [7-(4-methyl-6-propionylpyridin-3-yl)isoquinolin-3- yl] carbamate:

[0684] To a solution of l-[5-(3 -chi oroisoquinolin-7-yl)-4-methylpyri din-2 -yl]propan-l- one (760.0 mg, 2.44 mmol) in 1,4-dioxane (15.0 mL) was added tert-butyl carbamate (572.9 mg, 4.89 mmol), CS2CO3 (2.3 g, 7.33 mmol), Brettphos (262.5 mg, 0.48 mmol) and Brettphos Pd G3 (221.6 mg, 0.24 mmol) at room temperature under N2. The mixture was stirred at 100 °C for 2 h. After the reaction was completed, the mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (10/1, v/v) to afford tert-butyl [7-(4-methyl-6-propionylpyridin-3-yl)isoquinolin-3-yl]carbam ate (300.0 mg, 31%) as a light yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 392.2.

Step 3: Synthesis of l-[5-(3-aminoisoquinolin-7-yl)-4-methylpyridin-2-yl]propan-l -one:

[0685] To a solution of tert-butyl [7-(4-methyl-6-propionylpyridin-3-yl)isoquinolin-3- yl]carbamate (300.0 mg, 0.76 mmol) in CH2CI2 (10.0 mL) was added TFA (5.0 mL) at room temperature. The mixture was stirred at room temperature for 2 h. After the reaction was completed, the mixture was basified to Ph=8 with saturated NaHCO3(aq.). The resulting mixture was extracted with CH ₂ Cl ₂ . The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford l-[5-(3-aminoisoquinolin-7-yl)-4-methylpyridin-2-yl]propan-l - one (110.0 mg, crude) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 292.1.

Step 4: Synthesis of (lR)-2,2-difluoro-N-[7-(4-methyl-6-propionylpyridin-3-yl)iso quinolin-3- yl]cyclopropane-l-carboxamide: [0686] To a solution of l-[5-(3-aminoisoquinolin-7-yl)-4-methylpyridin-2-yl]propan-l - one (110.0 mg, crude) in pyridine (8.0 mL) were added (lR)-2,2-difluorocyclopropane-l- carboxylic acid (75.4 mg, 0.61 mmol) and EDCI (157.9 mg, 0.82 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (10/1, v/v) to afford (lR)-2,2- difluoro-N-[7-(4-methyl-6-propionylpyridin-3-yl)isoquinolin- 3-yl]cyclopropane-l- carboxamide (80.0 mg, 53%) as a light yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 396.1.

Step 5: Synthesis of (lR)-2,2-difluoro-N-{7-[6-(l-hydroxypropyl)-4-methylpyridin- 3- yl]isoquinolin-3-yl}cyclopropane-l-carboxamide:

[0687] To a solution of (lR)-2,2-difluoro-N-[7-(4-methyl-6-propionylpyridin-3- yl)isoquinolin-3-yl]cyclopropane-l-carboxamide (80.0 mg, 0.20 mmol) in CH ₂ Cl ₂ /MeOH (5.0 mL/1.0 mL) was added NaBH4 (11.4 mg, 0.30 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the mixture was quenched with H2O and then concentrated under vacuum. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (10/1, v/v) to afford (lR)-2,2-difluoro-N-{7-[6- (l-hydroxypropyl)-4-methylpyridin-3-yl]isoquinolin-3-yl}cycl opropane-l-carboxamide (68.0 mg, 76%) as an off-white solid. LCMS (ESI, m/z): [M+H] ⁺ = 398.2.

Step 6: Separation of (lR)-2,2-difluoro-N-(7-{6-[(S)-l-hydroxypropyl]-4-methylpyri din-3- yl}isoquinolin-3-yl)cyclopropane-l-carboxamide (Compound 161) and (lR)-2,2-difluoro-N-

(7-{6-[(R)-l-hydroxypropyl]-4-methylpyridin-3-yl}isoquino lin-3-yl)cyclopropane-l- carboxamide (Compound 162)

[0688] The product of (lR)-2,2-difluoro-N-{7-[6-(l-hydroxypropyl)-4-methylpyridin- 3- yl]isoquinolin-3-yl}cyclopropane-l-carboxamide (68.0 mg, 0.17 mmol) was separated by Prep-Chiral-HPLC with the following conditions: (Column: CHIRALPAK AD-H, 2x25 cm, 5 pm; Mobile Phase A: Hex(0.5% 2M NH ₃ -MeOH)-HPLC, Mobile Phase B: EtOH-HPLC; Flow rate: 20 mL/min; Gradient: 70% B to 70% B in 20 min; Wave Length: 254/220 nm; RTl(min): 5.84; RT2(min): 7.85) to afford (lR)-2,2-difhioro-N-(7-{6-[l-hydroxypropyl]-4- methylpyridin-3-yl}isoquinolin-3-yl)cyclopropane-l-carboxami de Isomer 1 (retention time 7.85 min, 19.5 mg, 60%) as an off-white solid and (lR)-2,2-difluoro-N-(7-{6-[l- hydroxypropyl]-4-methylpyridin-3-yl}isoquinolin-3-yl)cyclopr opane-l -carboxamide Isomer 2 (retention time 7.85 min, 18.2 mg, 53%) as an off-white solid. The absolute stereochemistry of Isomers 1 and 2 was not assigned. The two isomeric structures that could be obtained from chiral separation of the isomeric mixture as described above are shown as Compounds 161 and 162 in Table 1.

[0689] (lR)-2,2-difluoro-N-(7-{6-[l-hydroxypropyl]-4-methylpyridin- 3- yl}isoquinolin-3-yl)cyclopropane-l-carboxamide Isomer 1: RTl(min): 5.84; LCMS (ESI, m/z): [M+H]+ = 398.2. ¹ H NMR (400 MHz, DMSO-d6): δ 11.17 (s, 1H), 9.22 (s, 1H), 8.52 (s, 1H), 8.40 (s, 1H), 8.11 (s, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.47 (s, 1H), 5.32 (d, J = 4.8 Hz, 1H), 4.57 - 4.52 (m, 1H), 3.11 - 3.03 (m, 1H), 2.34 (s, 3H), 2.11 - 2.02 (m, 2H), 1.88 - 1.80 (m, 1H), 1.72 - 1.65 (m, 1H), 0.93 - 0.89 (m, 3H).

[0690] (lR)-2,2-difluoro-N-(7-{6-[l-hydroxypropyl]-4-methylpyridin- 3- yl}isoquinolin-3-yl)cyclopropane-l-carboxamide Isomer 2: RT2(min): 7.85; LCMS (ESI, m/z): [M+H]+ = 398.1. ¹ H NMR (400 MHz, DMSO-d6): δ 11.17 (s, 1H), 9.22 (s, 1H), 8.52 (s, 1H), 8.40 (s, 1H), 8.11 (s, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.47 (s, 1H), 5.32 (d, J = 4.8 Hz, 1H), 4.57 - 4.52 (m, 1H), 3.11 - 3.03 (m, 1H), 2.34 (s, 3H), 2.11 - 2.02 (m, 2H), 1.88 - 1.80 (m, 1H), 1.72 - 1.65 (m, 1H), 0.93 - 0.89 (m, 3H).

Example 88. Synthesis of (S)-l-(4-methyl-5-(7H-pyrrolo[2,3-c][2,6]naphthyridin-3- yl)pyridin-2-yl)propan-l-ol (Compound 163) and (R)-l-(4-methyl-5-(7H-pyrrolo[2,3- c][2, 6]naphthyridin-3-yl)pyridin-2-yl)propan-l-ol (Compound 164)

Step J: Synthesis of 7-chloro-4-[2-(trimethylsilyl)ethynyl]-2,6-naphthyridin-3-am ine

[0691] To a solution of 7-chloro-4-iodo-2,6-naphthyridin-3-amine (1.2 g, 3.93 mmol) in

DMF (12.0 mL) was added trimethylsilylacetylene (1.2 g, 11.78 mmol), TEA (1.2 g, 11.78 mmol), Cui (74.8 mg, 0.39 mmol) and Pd(PPh3)2Cl2 (275.7 mg, 0.39 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 2 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography with CH3CN/H2O (90/10, v/v) to afford 7-chloro-4-[2-(trimethylsilyl)ethynyl]-2,6-naphthyridin-3-am ine (660.0 mg, 60%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ =276.1

Step 2: Synthesis ofN-{7-chloro-4-[2-(trimethylsilyl)ethynyl]-2,6-naphthyridin -3- yl}acetamide

[0692] To a solution of 7-chloro-4-[2-(trimethylsilyl)ethynyl]-2,6-naphthyridin-3-am ine (660.0 mg, 2.39 mmol) in DCM (15.0 mL) was added Pyridine (378.6 mg, 4.79 mmol) and AcCl (375.7 mg, 4.79 mmol) at 0 °C under N2. The resulting mixture was stirred at 0 °C for 2 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (50/50, v/v) to afford N-{7-chloro-4-[2-(trimethylsilyl)ethynyl]-2,6-naphthyridin-3 -yl}acetamide (300.0 mg, 39%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ =318.1

Step 3: Synthesis of 3-chloro-7H-pyrrolo[2,3-c]2,6-naphthyridine

[0693] To a solution of N-{7-chloro-4-[2-(trimethylsilyl)ethynyl]-2,6-naphthyridin-3 - yl)acetamide (300.0 mg, 0.94 mmol) in THF (5.0 mL) was added TBAF (494.0 mg, 1.88 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 1 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford 3-chloro- 7H-pyrrolo[2,3-c]2,6-naphthyridine (270.0 mg, crude) as a brown solid. LCMS (ESI, m/z): [M+H] ⁺ =204.0

Step 4: Synthesis of l-(4-methyl-5-{7H-pyrrolo[2,3-c]2,6-naphthyridin-3-yl}pyridi n-2- yl)propan-l-one

[0694] To a solution of 3-chloro-7H-pyrrolo[2,3-c]2,6-naphthyridine (270.0 mg, 1.33 mmol) in dioxane/ELO (4.0 mL / 0.8 mL) was added 4-methyl-6-propanoylpyri din-3 - ylboronic acid (511.8 mg, 2.65 mmol), K2CO3 (549.8 mg, 4.00 mmol) and Pd(dppf)C12 (108.0 mg, 0.13 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 2 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (40/60, v/v) to afford l-(4-methyl-5-{7H-pyrrolo[2,3-c]2,6-naphthyridin-3-yl}pyridi n-2- yl)propan-l-one (170.0 mg, 40%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =317.1.

Step 5: Synthesis of l-(4-methyl-5-(7H-pyrrolo[2,3-c][2,6]naphthyridin-3-yl)pyrid in-2- yl)propan-l-ol

[0695] To a solution of l-(4-methyl-5-{7H-pyrrolo[2,3-c]2,6-naphthyridin-3-yl}pyridi n- 2-yl)propan-l-one (170.0 mg, 0.54 mmol) in CH3OH/THF (2.0 mL/0.4 mL) was added NaBH ₄ (40.9 mg, 1.08 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the resulting mixture was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography with CH3OH/H2O (60/40, v/v) to afford l-(4-methyl-5-(7H-pyrrolo[2,3-c][2,6]naphthyridin- 3-yl)pyridin-2-yl)propan-l-ol (90.0 mg, 52%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =319.1.

Step 6: Separation of (S)-l-(4-methyl-5-(7H-pyrrolo[2,3-c] [2,6]naphthyridin-3-yl)pyridin-2- yl)propan-l-ol (Compound 163) and (R)-l-(4-methyl-5-(7H-pyrrolo[2,3-c][2,6]naphthyridin- 3-yl)pyridin-2-yl)propan-l-ol (Compound 164)

[0696] The racemic product of l-(4-methyl-5-(7H-pyrrolo[2,3-c][2,6]naphthyridin-3- yl)pyridin-2-yl)propan-l-ol (90.0 mg, 0.28 mmol) was separated by Prep-Chiral-HPLC with the following conditions (Column: CHIRAL ART Amylose-SA, 2x25 cm, 5 μm; Mobile Phase A: Hex (0.5% 2M NH ₃ -MeOH)-HPLC, Mobile Phase B: MeOH: DCM=1 : 1-HPLC; Flow rate: 20 mL/min; Gradient: 40% B to 40% B in 11.5 min; Wave Length: 220/254 nm; RTl(min): 8.27; RT2(min): 10.02) to l-(4-methyl-5-(7H-pyrrolo[2,3-c][2,6]naphthyridin-3- yl)pyridin-2-yl)propan-l-ol Enantiomer 1 (retention time 8.27 min, 22.5 mg, 50%) as a white solid and l-(4-methyl-5-(7H-pyrrolo[2,3-c][2,6]naphthyridin-3-yl)pyrid in-2-yl)propan-l-ol Enantiomer 2 (retention time 10.02 min, 23.0 mg, 51%) as a white solid. The absolute stereochemistry of Enantiomers 1 and 2 was not assigned. The two enantiomeric structures that could be obtained from chiral separation of the enantiomeric mixture as described above are shown as Compounds 163 and 164 in Table 1.

[0697] l-(4-methyl-5-(7H-pyrrolo [2,3-c] [2,6] naphthyridin-3-yl)pyridin-2-yl)propan- l-ol Enantiomer 1: RTl(min): 8.27; LCMS (ESI, m/z): [M+H] ⁺ =319.0 ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.39 - 12.36 (br, 1H), 9.90 (s, 1H), 9.06 (s, 1H), 8.62 (s, 1H), 8.28 (s, 1H), 7.70 - 7.68 (m, 1H), 7.49 (s, 1H), 7.27 (d, J= 1.2 Hz, 1H), 5.37 (s, 1H), 4.60 - 4.57 (m, 1H), 2.51 (s, 3H), 1.89 - 1.81 (m, 1H), 1.75 - 1.65 (m, 1H), 0.93 - 0.90 (m, 3H).

[0698] l-(4-methyl-5-(7H-pyrrolo [2,3-c] [2,6] naphthyridin-3-yl)pyridin-2-yl)propan- l-ol Enantiomer 2: RT2(min): 10.02; LCMS (ESI, m/z): [M+H] ⁺ =318.9. ¹ H NMR (400 MHz, DMSO- d ₆ ) 5 12.37 (s, 1H), 9.90 (s, 1H), 9.06 (s, 1H), 8.61 (s, 1H), 8.27 (s, 1H), 7.69 - 7.66 (m, 1H), 7.47 (s, 1H), 7.27 (s, 1H), 5.35 - 5.29 (m, 1H), 4.62 - 4.57 (m, 1H), 2.47 (s, 3H), 1.89 - 1.83 (m, 1H), 1.73 - 1.68 (m, 1H), 1.05 - 0.85 (m, 3H)

Example 89. Synthesis of (S)-l-(5-(3H-imidazo[4,5-c][2,6]naphthyridin-7-yl)-4- methylpyridin-2-yl)propan-l-ol (Compound 165) and (R)-l-(5-(3H-imidazo[4,5- c][2, 6]naphthyridin- 7-yl)-4-methylpyridin-2-yl)propan-l -ol ( Compound 166)

Step 1: Synthesis of 7-chloro-4-nitro-2,6-naphthyridin-3-amine

[0699] To a solution of 7-chloro-2,6-naphthyridin-3-amine (4.0 g, 22.27 mmol) in H2SO4 (40.0 mL) was added KNO3 (2.2 g, 22.28 mmol) at 0 °C under N ₂ . The resulting mixture was stirred at room temperature for 0.5 h. Then the resulting mixture was stirred at 55 °C for additional 1 h. After the reaction was completed, the resulting mixture was adjusted to pH=8.0 with aq. NaHCOs and then extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford 7-chloro-4-nitro-2,6-naphthyridin-3-amine (2.3 g, crude) as a brown solid. LCMS (ESI, m/z): [M+H] ⁺ = 225.0.

Step 2: Synthesis of 7-chloro-2,6-naphthyridine-3,4-diamine

[0700] To a solution of 7-chloro-4-nitro-2,6-naphthyridin-3-amine (2.3 g, 10.24 mmol) in CH3OH/H2O (40.0 mL/10.0 mL) was added Fe (1.7 g, 30.72 mmol) and NH ₄ Cl (1.7 g, 30.72 mmol) at 80 °C. The resulting mixture was stirred at 80 °C for 2 h. After the reaction was completed, the resulting mixture was filtered. The filtrate was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford 7- chloro-2,6-naphthyridine-3,4-diamine (750.0 mg, crude) as a dark red solid. LCMS (ESI, m/z): [M+H] ⁺ = 195.0.

Step 3: Synthesis of 7-chloro-3H-imidazo[4,5-c] [2,6]naphthyridine

[0701] To a solution of 7-chloro-2,6-naphthyridine-3,4-diamine (750.0 mg, 3.85 mmol) in triethoxy methane (8.0 mL) was added CH3COOH (1.8 g, 29.84 mmol) at room temperature. The resulting mixture was stirred at 110 °C for 2 h. After the reaction was completed, the mixture was concentrated under reduced pressure to afford 7-chloro-3H- imidazo[4,5-c][2,6]naphthyridine (700.0 mg, crude) as a red solid. LCMS (ESI, m/z): [M+H] ⁺ = 205.0.

Step 4: Synthesis of 7-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo [4,5- c] [2,6]naphthyridine

[0702] To a solution of 7-chloro-3H-imidazo[4,5-c][2,6]naphthyridine (700.0 mg, 3.42 mmol) in THF (20.0 mL) was added NaH (684.0 mg, 60%) at 0 °C under N2. The resulting mixture was stirred at 0 °C for 1 h under N2. Then SEM-C1 (1.7 g, 10.26 mmol) was added to the mixture at 0 °C. The resulting mixture was stirred at 0 °C for additional 1 h. After the reaction was completed, the resulting mixture was quenched with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (1/1, v/v) to afford 7-chl oro-3 -((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-c] [2, 6]naphthyri dine (360.0 mg, 31%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 335.1

Step 5: Synthesis of l-(4-methyl-5-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imida zo[4,5- c] [2,6 ] naphthyr idin- 7-yl)pyridin-2-yl)propan-l-one

[0703] To a solution of 7-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5 - c][2,6]naphthyridine (260.0 mg, 0.78 mmol) in 1.d-dioxane/H2O (4.0 mL/1.0 mL) was added (4-methyl-6-propionylpyridin-3-yl)boronic acid (299.7 mg, 1.55 mmol), K2CO3 (321.9 mg, 2.33 mmol) and Pd(PPh3)4 (89.7 mg, 0.08 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 2 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /CH3OH (10/1, v/v) to afford l-(4-methyl-5-(3-((2- (trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-c][2,6]naphthy ridin-7-yl)pyridin-2-yl)propan- 1-one (250.0 mg, 71%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 448.2.

Step 6: Synthesis of l-(5-(3H-imidazo[4,5-c] [2,6]naphthyridin-7-yl)-4-methylpyridin-2- yl)propan-l-one

[0704] To a solution of l-(4-methyl-5-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H- imidazo[4,5-c][2,6]naphthyridin-7-yl)pyridin-2-yl)propan-l-o ne (250.0 mg, 0.56 mmol) in DCM (2.0 mL) was added TFA (2.0 mL) at room temperature. The resulting mixture was stirred at room temperature for 0.5 h. After the reaction was completed, the resulting mixture concentrated under reduced pressure. The resulting mixture was basified to pH=8.0 with aq. NaHCCL and then extracted with CH2CI2. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford l-(5-(3H-imidazo[4,5-c][2,6]naphthyridin-7-yl)-4-methylpyrid in- 2-yl)propan-l-one (150.0 mg, crude) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 318.1.

Step 7: Synthesis of l-(5-(3H-imidazo[4,5-c] [2,6]naphthyridin-7-yl)-4-methylpyridin-2- yl)propan-l-ol

[0705] To a solution of l-(5-(3H-imidazo[4,5-c][2,6]naphthyridin-7-yl)-4-methylpyrid in- 2-yl)propan-l-one (130.0 mg, crude) in THF/CH3OH (5.0 mL/1.0 mL) was added NaBH ₄ (31.0 mg, 0.82 mmol) at 0 °C under N2. The resulting mixture was stirred at room temperature for 0.5 h. After the reaction was completed, the resulting mixture was quenched with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated in vacuo. The residue was purified by reverse phase flash column chromatography with H2O/CH3CN (1/1, v/v) to afford l-(5-(3H-imidazo[4,5-c][2,6]naphthyridin-7-yl)-4-methylpyrid in-2- yl)propan-l-ol (60.0 mg, 45%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 320.1.

Step 8: Separation of (S)-l-(5-(3H-imidazo[4,5-c][2,6]naphthyridin-7-yl)-4-methylp yridin-2- yl)propan-l-ol (Compound 165) and (R)-l-(5-(3H-imidazo[4,5-c][2,6]naphthyridin-7-yl)-4- methylpyridin-2-yl)propan-l-ol (Compound 166)

[0706] The product of l-(5-(3H-imidazo[4,5-c][2,6]naphthyridin-7-yl)-4-methylpyrid in- 2-yl)propan-l-ol (60.0 mg, 0.19 mmol) was separated by Prep-Chiral-HPLC with the following conditions (Column: CHIRAL ART Amylose-SA, 2x25 cm, 5 pm; Mobile Phase A: MtBE (0.1% FA)-HPLC, Mobile Phase B: MeOH: EtOH=l : 1-HPLC; Flow rate: 20 mL/min; Gradient: 20% B to 20% B in 13 min; Wave Length: 220/254 nm; RTl(min): 8.48; RT2(min): 11.48) to afford l-(5-(3H-imidazo[4,5-c][2,6]naphthyridin-7-yl)-4-methylpyrid in- 2-yl)propan-l-ol Enantiomer 1 (retention time 8.48 min, 7.4 mg, 24%) as a yellow solid and l-(5-(3H-imidazo[4,5-c][2,6]naphthyridin-7-yl)-4-methylpyri din-2 -yl)propan-l-ol Enantiomer 2 (retention time 11.48 min, 5.1 mg, 17%) as a white solid. The absolute stereochemistry of Enantiomers 1 and 2 was not assigned. The two enantiomeric structures that could be obtained from chiral separation of the enantiomeric mixture as described above are shown as Compounds 165 and 166 in Table 1.

[0707] l-(5-(3H-imidazo[4,5-c][2,6]naphthyridin-7-yl)-4-methylpyrid in-2-yl)propan- l-ol Enantiomer 1: RTl(min): 8.48; LCMS (ESI, m/z): [M+H] ⁺ = 320.2. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 13.88 - 13.75 (m, 1H), 9.96 - 9.90 (m, 1H), 9.27 - 9.24 (m, 1H), 8.62 (s, 2H), 8.39 (s, 1H), 7.48 (s, 1H), 5.36 (d, J= 4.8 Hz, 1H), 4.62 - 4.54 (m, 1H), 2.47 (s, 3H), 1.90 - 1.81 (m, 1H), 1.74 - 1.65 (m, 1H), 0.98 - 0.85 (m, 3H).

[0708] l-(5-(3H-imidazo[4,5-c][2,6]naphthyridin-7-yl)-4-methylpyrid in-2-yl)propan- l-ol Enantiomer 2: RT2(min): 11.48; LCMS (ESI, m/z): [M+H] ⁺ =320.1. ¹ H NMR (300 MHz, DMSO-d ₆ ): 6 13.79 - 13.77 (m, 1H), 9.94 (s, 1H), 9.25 (s, 1H), 8.62 - 8.61 (m, 2H), 8.39 (s, 1H), 7.48 (s, 1H), 5.35 (s, 1H), 4.63 - 4.54 (m, 1H), 2.47 (s, 3H), 1.92 - 1.81 (m, 1H), 1.79 - 1.71 (m, 1H), 0.95 - 0.85 (m, 3H).

Example 90. Synthesis of (R)-l-(4-methyl-5-(7H-pyrrolo[2,3-c][2,6]naphthyridin-3- yl)pyridin-2-yl)butan-l-ol (Compound 167) and (S)-l-(4-methyl-5-(7H-pyrrolo[2,3- c][2, 6]naphthyridin-3-yl)pyridin-2-yl)butan-l-ol (Compound 168)

Step 1: Synthesis of l-(4-methyl-5-(7H-pyrrolo[2,3-c] [2,6]naphthyridin-3-yl)pyridin-2- yl)butan-l-one

[0709] To a solution of 3-chloro-7H-pyrrolo[2,3-c][2,6]naphthyridine (1.0 g, 4.91 mmol) in dioxane (10.0 mL) and H2O (2.0 mL) were added (6-butyryl-4-methylpyridin-3-yl)boronic acid (3.0 g, 14.73 mmol), K2CO3 (2.0 g, 14.73 mmol) and Pd(dppf)C12 (0.4 g, 0.49 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 2 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (50/50, v/v) to afford l-(4-methyl-5-(7H-pyrrolo[2,3-c][2,6]naphthyridin-3-yl)pyrid in-2-yl)butan-l-one (500.0 mg, 30%) as a light yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 331.1.

Step 2: Synthesis of l-(4-methyl-5-(7H-pyrrolo[2,3-c] [2,6]naphthyridin-3-yl)pyridin-2- yl)butan-l-ol

[0710] To a solution of l-(4-methyl-5-(7H-pyrrolo[2,3-c][2,6]naphthyridin-3-yl)pyrid in- 2-yl)butan-l-one (200.0 mg, 0.60 mmol) in THF (5.0 mL) and CH3OH (0.5 mL) was added NaBH ₄ (114.5 mg, 3.02 mmol) at 0 °C under N2. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (10/1, v/v) to afford l-(4-methyl-5-(7H-pyrrolo[2,3-c][2,6]naphthyridin-3-yl)pyrid in-2- yl)butan-l-ol (70.0 mg, 34%) as a light yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 333.1.

Step 3: Separation of (R)-l-(4-methyl-5-(7H-pyrrolo[2,3-c] [2,6]naphthyridin-3-yl)pyridin-2- yl)butan-l-ol (Compound 167 ) and (S)-l-(4-methyl-5-(7H-pyrrolo[2,3-c] [2,6]naphthyridin- 3-yl)pyridin-2-yl)butan-l-ol (Compound 168)

[0711] The racemic product of l-(4-methyl-5-(7H-pyrrolo[2,3-c][2,6]naphthyridin-3- yl)pyridin-2-yl)butan-l-ol (70.0 mg, 0.21 mmol) was separated by Prep- Chiral-HPLC with the following conditions (Column: CHIRAL ART Amylose-SA, 2x5 cm, 5 pm; Mobile Phase A: Hex(0.5% 2M NH ₃ -MeOH)-HPLC, Mobile Phase B: MeOH: DCM=1 : 1-HPLC; Flow rate: 20 mL/min; Gradient: 30% B to 30% B in 18 min; Wave Length: 220/254 nm;

RTl(min): 11.68; RT2(min): 15.03) to afford l-(4-methyl-5-(7H-pyrrolo[2,3- c][2,6]naphthyridin-3-yl)pyridin-2-yl)butan-l-ol Enantiomer 1 (retention time 11.68 min, 28.0 mg, 80%) as a white solid and l-(4-methyl-5-(7H-pyrrolo[2,3-c][2,6]naphthyridin-3- yl)pyridin-2-yl)butan-l-ol Enantiomer 2 (retention time 15.03 min, 20.0 mg, 57%) as an off- white solid. The absolute stereochemistry of Enantiomers 1 and 2 was not assigned. The two enantiomeric structures that could be obtained from chiral separation of the enantiomeric mixture as described above are shown as Compounds 167 and 168 in Table 1.

[0712] l-(4-methyl-5-(7H-pyrrolo [2,3-c] [2,6] naphthyridin-3-yl)pyridin-2-yl)butan-l- ol Enantiomer 1: RTl(min): 11.68; LCMS (ESI, m/z): [M+H] ⁺ = 333.1 ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.37 (s, 1H), 9.90 (s, 1H), 9.06 (s, 1H), 8.60 (s, 1H), 8.26 (s, 1H), 7.69 - 7.67 (m, 1H), 7.47 (s, 1H), 7.28 - 7.26 (m, 1H), 5.32 (d, J= 4.8 Hz, 1H), 4.65 - 4.60 (m, 1H), 2.46 (s, 3H), 1.82 - 1.74 (m, 1H), 1.70 - 1.63 (m, 1H), 1.46 - 1.35 (m, 2H), 0.94 - 0.90 (m, 3H).

[0713] l-(4-methyl-5-(7H-pyrrolo [2,3-c] [2,6] naphthyridin-3-yl)pyridin-2-yl)butan-l- ol Enantiomer 2: RT2(min): 15.03; LCMS (ESI, m/z): [M+H] ⁺ = 333.1. ¹ H NMR (400 MHz, DMSO- d ₆ ) 5 12.37 (s, 1H), 9.89 (s, 1H), 9.06 (s, 1H), 8.60 (s, 1H), 8.26 (s, 1H), 7.69

- 7.67 (m, 1H), 7.47 (s, 1H), 7.28 - 7.26 (m, 1H), 5.32 (d, J= 4.8 Hz, 1H), 4.65 - 4.60 (m, 1H), 2.47 (s, 3H), 1.82 - 1.73 (m, 1H), 1.70 - 1.63 (m, 1H), 1.45 - 1.37 (m, 2H), 0.94 - 0.89 (m, 3H).

Example 91. Synthesis of l-(4-methyl-5-(3H-pyrazolo[3,4-c][2,6]naphthyridin-7-yl)pyri din- 2-yl)propan-l-ol (Compound 28)

Step 1: Synthesis of 7-chloro-2,6-naphthyridin-3-amine

[0714] To a solution of tert-butyl (7-chloro-2,6-naphthyridin-3-yl)carbamate (4.0 g, 14.30 mmol) in DCM (40.0 mL) was added TFA (20.0 mL) at room temperature. The resulting mixture was stirred at room temperature for 0.5 h. After the reaction was completed, the mixture was concentrated under reduced pressure. The pH value of the residue was adjusted to 8.0 with aq. NaHCOs. The mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford 7-chloro-2,6-naphthyridin-3-amine (2.2 g, crude) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 180.0.

Step 2: Synthesis of 7-chloro-4-iodo-2, 6-naphthyridin-3-amine

[0715] To a solution of 7-chloro-2,6-naphthyridin-3-amine (2.0 g, 11.14 mmol) in THF (20.0 mL) was added NIS (2.5 g, 11.14 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 2 h. After the reaction was completed, the mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (49/51, v/v) to afford 7-chloro-4-iodo-2,6-naphthyridin-3-amine (2.2 g, 64%) as yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 305.9.

Step 3: Synthesis of 7-chloro-4-vinyl-2, 6-naphthyridin-3-amine

[0716] To a solution of 7-chloro-4-iodo-2,6-naphthyridin-3-amine (2.0 g, 6.55 mmol) in dioxane/ELO (20.0 mL/4.0 mL) was added 2-ethenyl-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1.5 g, 9.82 mmol), K2CO3 (2.7 g, 19.64 mmol) and Pd(dppf)C12 (0.9 g, 1.31 mmol) at room temperature under N2. The mixture was stirred at 100 °C for 16 h under N2. After the reaction was completed, the mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (70/30, v/v) to afford 7- chloro-4-vinyl-2,6-naphthyridin-3-amine (800.0 mg, 59%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 206.0

Step 4: Synthesis of 7 -chlor o-3 fluor o-4-vinyl-2, 6-naphthyridine

[0717] To a solution of 7-chloro-4-vinyl-2,6-naphthyridin-3-amine (800.0 mg, 3.89 mmol) in BMIM.BF4 (12.0 mL) was added NO.BF4 (681.6 mg, 5.84 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (80/20, v/v) to afford 7-chloro-3-fluoro-4- vinyl-2,6-naphthyridine (256.0 mg, 31%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 209.0.

Step 5: Synthesis of 7-chloro-3-fluoro-2, 6-naphthyridine-4-carbaldehyde

[0718] To a solution of 7-chloro-3-fluoro-4-vinyl-2,6-naphthyridine (250.0 mg, 1.20 mmol) in dioxane/H2O (10.0 mL/3.0 mL) was added 2,6-lutidine (256.7 mg, 2.40 mmol), K2OSO4 (22.1 mg, 0.06 mmol) and NalO4 (256.3 mg, 1.20 mmol) at 0 °C under N2. The resulting mixture was stirred at room temperature for 16 h under N2. After the reaction was completed, the mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (85/15, v/v) to afford 7-chloro-3-fluoro- 2,6-naphthyridine-4-carbaldehyde (110.0 mg, 43%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 211.0.

Step 6: Synthesis of 7-chloro-3H-pyrazolo[3,4-c] [2,6]naphthyridine

[0719] To a solution of 7-chloro-3-fluoro-2,6-naphthyridine-4-carbaldehyde (100.0 mg, 0.48 mmol) in THF (3.0 mL) was added hydrazine hydrate (0.1 mL, 80%) at at room temperature. The resulting mixture was stirred at 60 °C for 16 h. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with DCM/MeOH (10/1, v/v) to afford 7-chloro-3H- pyrazolo[3,4-c][2,6]naphthyridine (90.0 mg, 91%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 205.0.

Step 7: Synthesis of 7-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-pyrazolo[3, 4- c] [2,6]naphthyridine

[0720] To a solution of 7-chloro-3H-pyrazolo[3,4-c][2,6]naphthyridine (80.0 mg, 0.39 mmol) in THF (3.0 mL) was added NaH (14.1 mg, 60%) at 0 °C under N2. The resulting mixture was stirred at 0 °C for 30 min under N2. Then [2- (chloromethoxy)ethyl]trimethylsilane (78.2 mg, 0.47 mmol) was added to the mixture at 0 °C under N2. The resulting mixture was stirred at 0° C for additional 2 h under N2. After the reaction was completed, the reaction mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (7/3, v/v) to afford 7-chl oro-3 -((2-(trimethylsilyl)ethoxy)methyl)-3H-pyrazolo[3,4-c][2,6]n aphthyridine (110.0 mg, 84%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 335.1.

Step 8: Synthesis of l-(4-methyl-5-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-pyraz olo[3,4- c] [2,6]naphthyridin- 7-yl)pyridin-2-yl)propan-l-one

[0721] To a solution of 7-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-pyrazolo[3, 4- c][2,6]naphthyridine (100.0 mg, 0.30 mmol) in dioxane/ELO (5.0 mL / 0.5 mL) was added 4- methyl-6-propanoylpyridin-3-ylboronic acid (86.5 mg, 0.50 mmol), Pd(dppf)C12.CH2C12 (48.7 mg, 0.06 mmol) and K2CO3 (123.8 mg, 0.90 mmol) at room temperature under N2. The resulting mixture was stirred at 85 °C for 16 h under N2. After the reaction was completed, the resulting mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ ethyl acetate (1/2, v/v) to afford l-(4-methyl-5-(3-((2- (trimethylsilyl)ethoxy)methyl)-3H-pyrazolo[3,4-c][2,6]naphth yridin-7-yl)pyridin-2- yl)propan-l-one (100.0 mg, 74%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 448.2.

Step 9: Synthesis of l-(4-methyl-5-(3H-pyrazolo[3,4-c] [2,6]naphthyridin-7-yl)pyridin-2- yl)propan-l-one

[0722] To a solution of l-(4-methyl-5-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H- pyrazolo[3,4-c][2,6]naphthyridin-7-yl)pyridin-2-yl)propan-l- one (100.0 mg, 0.22 mmol) in DCM (2.0 mL) was added TFA (1.0 mL) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the resulting mixture was adjusted pH to 8.0 with aq. NaHCO3 and then extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (10/1, v/v) to afford l-(4-methyl-5-(3H-pyrazolo[3,4- c][2,6]naphthyridin-7-yl)pyridin-2-yl)propan-l-one (60.0 mg, 84%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 318.1.

Step 10: Synthesis of l-(4-methyl-5-(3H-pyrazolo[3,4-c] [2,6]naphthyridin-7-yl)pyridin-2- yl)propan-l-ol (Compound 28)

[0723] To a solution of l-(4-methyl-5-(3H-pyrazolo[3,4-c][2,6]naphthyridin-7- yl)pyridin-2-yl)propan-l-one (50.0 mg, 0.16 mmol) in MeOH/THF (1.5 mL/1.5 mL) was added NaBH ₄ (7.2 mg, 0.19 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: (Column: XBridge Shield RP18 OBD Column, 30x150 mm, 5 pm; Mobile Phase A: Water(10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 18% B to 30% B in 8 min; Wave Length: 254 nm) to afford l-(4-methyl-5-{3H-pyrazolo[3,4- c]2,6-naphthyridin-7-yl}pyridin-2-yl)propan-l-ol (Compound 28) (2.7 mg, 5%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ =320.2. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 14.25 (s, 1H), 9.95 (s, 1H), 9.34 (s, 1H), 8.82 (s, 1H), 8.61 (s, 1H), 8.40 (s, 1H), 7.49 (s, 1H), 5.37 (d, J= 4.8 Hz, 1H), 4.59 - 4.55 (m, 1H), 2.47 (s, 3H), 1.89 - 1.80 (m, 1H), 1.75 - 1.64 (m, 1H), 0.93 - 0.81 (m, 3H).

Example 92. Synthesis of 7-((R)-2,2-difluorocyclopropane-l-carboxamido)-3-(6-((S)-l- hydroxypropyl)-4-methylpyridin-3-yl)-l, 6-naphthyridine-2-carboxamide (Compound 169) and 7-((R)-2,2-difluorocyclopropane-l-carboxamido)-3-(6-((R)-l -hydroxy propyl)-4- methylpyridin-3-yl)-l,6-naphthyridine-2-carboxamide (Compound 170)

Step 1: Synthesis of 7-chloro-3-(4-methyl-6-propionylpyridin-3-yl)-l ,6-naphthyridine-2- carbonitrile

[0724] To a solution of 3-bromo-7-chloro-l,6-naphthyridine-2-carbonitrile (5.0 g, 18.72 mmol) in dioxane (75.0 mL) and H2O (15.0 mL) was added 1 -(4-methyl-5-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)propan-l-on e (5.1 g, 18.75 mmol), K2CO3 (7.5 g, 54.36 mmol) and Pd(dppf)C12 (2.9 g, 3.60 mmol) at room temperature under N2. The reaction mixture was stirred at 80 °C for 2 h under N2. After the reaction was completed, the mixture was filtered. The filtrate was concentrated under vacuum. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (35/65, v/v) to afford 7- chl oro-3 -(4-methyl-6-propionylpyri din-3 -yl)-l,6-naphthyridine-2-carbonitrile (1.6 g, 25%) as a light brown solid. LCMS (ESI, m/z): [M+H] ⁺ = 337.0.

Step 2: Synthesis of methyl 7-chloro-3-(4-methyl-6-propionylpyridin-3-yl)-l,6-naphthyrid ine- 2-carboxylate and 7-chloro-3-(4-methyl-6-propionylpyridin-3-yl)-l , 6-naphthyridine-2- carboxylic acid

[0725] A mixture of 7-chloro-3-(4-methyl-6-propionylpyridin-3-yl)-l,6-naphthyrid ine-2- carbonitrile (4.0 g, 11.87 mmol) in HCl/MeOH (45.0 mL, 4.0 mol/L) was stirred at 60 °C for 3 h. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography with ACN /H2O (10/90, v/v) to afford 7-chloro-3-(4-methyl-6-propionylpyridin-3-yl)-l,6-naphthyrid ine-2- carboxylic acid (900.0 mg, 45%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 356.1. And ACN/H2O (60/40, v/v) to afford methyl 7-chloro-3-(4-methyl-6-propionylpyridin-3-yl)-l,6- naphthyridine-2-carboxylate (700.0 mg, 35%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 370.1.

Step 3: Synthesis of methyl 7-[(tert-butoxycarbonyl)amino]-3-(4-methyl-6-propanoylpyridi n- 3-yl)-l,6-naphthyridine-2-carboxylate

[0726] To a solution of methyl 7-chloro-3-(4-methyl-6-propionylpyridin-3-yl)-l,6- naphthyridine-2-carboxylate (200.0 mg, 0.54 mmol) in dioxane (8.0 mL) was added BocNH2 (63.4 mg, 0.54 mmol), CS2CO3 (528.6 mg, 1.62 mmol), Pd(OAc)2 (24.3 mg, 0.11 mmol) and XPhos (103.1 mg, 0.22 mmol) at room temperature under N2. The resulting mixture was stirred at 80 °C for 2 h under N2. After the reaction was completed, the mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with dichloromethane/methanol (83/17, v/v) to afford methyl 7-[(tert-butoxycarbonyl)amino]-3-(4-methyl-6- propanoylpyri din-3 -yl)-l,6-naphthyridine-2-carboxylate (179.0 mg, 73%) as a brown solid. LCMS (ESI, m/z): [M+H] ⁺ = 451.1.

Step 4: Synthesis of methyl 7-amino-3-(4-methyl-6-propanoylpyridin-3-yl)-l,6-naphthyridi ne-

[0727] To a solution of methyl 7-[(tert-butoxycarbonyl)amino]-3-(4-methyl-6- propanoylpyri din-3 -yl)-l,6-naphthyridine-2-carboxylate (160.0 mg, 0.36 mmol) in DCM (4.0 mL) was added TFA (2.0 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The pH value of the residue was adjusted to 8.0 with saturated NaHCCL (aq.). The mixture was extracted with CH2CI2. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to afford methyl 7-amino-3-(4-methyl-6-propanoylpyridin-3-yl)- l,6-naphthyridine-2-carboxylate (120.0 mg, crude) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 351.1.

Step 5: Synthesis of 7-amino-3-(4-methyl-6-propionylpyridin-3-yl)-l,6-naphthyridi ne-2- carboxamide

[0728] A solution of methyl 7-amino-3-(4-methyl-6-propanoylpyridin-3-yl)-l,6- naphthyridine-2-carboxylate (240.0 mg, 0.68 mmol) in NHVMeOH (8.0 mL, 7.0 mol/L) was stirred at 80 °C for 16 h. After the reaction was completed, the mixture was cooled to room temperature and then concentrated under reduced pressure to afford 7-amino-3-(4-methyl-6- propionylpyridin-3-yl)-l,6-naphthyridine-2-carboxamide (167.0 mg, crude) as a yellow solid LCMS (ESI, m/z): [M+H] ⁺ = 336.1.

Step 6: Synthesis of (R)-7-(2,2-difluorocyclopropane-l-carboxamido)-3-(4-methyl-6 - propionylpyridin-3-yl)-l,6-naphthyridine-2-carboxamide

[0729] To a solution of 7-amino-3-(4-methyl-6-propionylpyridin-3-yl)-l,6-naphthyridi ne- 2-carboxamide (167.0 mg, crude) in pyridine (9.0 mL) was added (lR)-2,2- difluorocyclopropane-1 -carboxylic acid (90.6 mg, 0.74 mmol) and EDCI (1422.5 mg, 7.42 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (90/10, v/v) to afford (R)-7- (2,2-difluorocyclopropane-l-carboxamido)-3-(4-methyl-6-propi onylpyridin-3-yl)-l,6- naphthyridine-2-carboxamide (88.0 mg, 53%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =

440.1.

Step 7: Synthesis of 7-((R)-2,2-difluorocyclopropane-l-carboxamido)-3-(6-(l- hydroxypropyl)-4-methylpyridin-3-yl)-l,6-naphthyridine-2-car boxamide

[0730] To a solution of (R)-7-(2,2-difluorocyclopropane-l-carboxamido)-3-(4-methyl-6 - propionylpyridin-3-yl)-l,6-naphthyridine-2-carboxamide (164.0 mg, 0.37 mmol) in THF (5.0 mL) and MeOH (1.0 mL) was added NaBH ₄ (7.8 mg, 0.74 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (93/7, v/v) to afford 7-((R)-2,2-difluorocyclopropane-l- carboxamido)-3-(6-(l-hydroxypropyl)-4-methylpyridin-3-yl)-l, 6-naphthyridine-2- carboxamide (64.0 mg, 39%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 442.1.

Step 8: Separation of 7-((R)-2,2-difluorocyclopropane-l-carboxamido)-3-(6-((S)-l- hydroxypropyl)-4-methylpyridin-3-yl)-l, 6-naphthyridine-2-carboxamide (Compound 169) and 7-( R)-2, 2-difluorocyclopropane-l-carboxamido)-3-( 6-( (R)-l-hydroxypropyl)-4- methylpyridin-3-yl)-l, 6-naphthyridine-2-carboxamide (Compound 170)

[0731] The product of 7-((R)-2,2-difluorocyclopropane-l-carboxamido)-3-(6-(l- hydroxypropyl)-4-methylpyri din-3 -yl)-l,6-naphthyridine-2-carboxamide (77.0 mg, 0.18 mmol) was separated by Prep-Chiral-SFC with the following conditions: (Column: Lux 5um Cellulose-4, 3x25 cm, 5 μm; Mobile Phase A: CO2, Mobile Phase B: IPA: ACN=1 : 1 (0.1% 2M NH3-MeOEl); Flow rate: 100 mL/min; Gradient: isocratic 50% B; Column Temperature (°C): 35; Back Pressure(bar): 100; Wave Length: 220 nm; RTl(min): 5.28; RT2(min): 6.6) to afford 7-((R)-2,2-difluorocyclopropane-l-carboxamido)-3-(6-(l-hydro xypropyl)-4- methylpyridin-3-yl)-l,6-naphthyridine-2-carboxamide Isomer 1 (retention time 5.28 min, 5.8 mg, 15%) as a white solid and 7-((R)-2,2-difluorocyclopropane-l-carboxamido)-3-(6-((R)-l- hydroxypropyl)-4-methylpyridin-3-yl)-l,6-naphthyridine-2-car boxamide Isomer 2 (retention time 6.60 min, 5.6 mg, 14%) as a white solid. The absolute stereochemistry of Isomers 1 and 2 was not assigned. The two isomeric structures that could be obtained from chiral separation of the isomeric mixture as described above are shown as Compounds 169 and 170 in Table 1.

[0732] 7-((R)-2,2-difluorocyclopropane-l-carboxamido)-3-(6-(l-hydro xypropyl)-4- methylpyridin-3-yl)-l,6-naphthyridine-2-carboxamide Isomer 1: RTl(min): 5.28; LCMS (ESI, m/z): [M+H] ⁺ = 442.1. ¹ H NMR (400 MHz, DMSO ): δ 11.42 (s, 1H), 9.30 (s, 1H), 8.62 (s, 1H), 8.50 (s, 1H), 8.26 (s, 1H), 8.19 (s, 1H), 7.61 (s, 1H), 7.41 (s, 1H), 5.34 (s, 1H), 4.55 - 4.53 (m, 1H), 3.11 - 3.06 (m, 1H), 2.16 (s, 3H), 2.12 - 2.04 (m, 2H), 1.87 - 1.84 (m, 1H), 1.70 - 1.66 (m, 1H), 0.93 - 0.89 (m, 3H).

[0733] 7-((R)-2,2-difluorocyclopropane-l-carboxamido)-3-(6-(l-hydro xypropyl)-4- methylpyridin-3-yl)-l,6-naphthyridine-2-carboxamide Isomer 2: RT2(min): 6.60; LCMS (ESI, m/z): [M+H] ⁺ = 442.1. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.41 (s, 1H), 9.30 (s, 1H), 8.62 (s, 1H), 8.50 (s, 1H), 8.26 (s, 1H), 8.18 (s, 1H), 7.60 (s, 1H), 7.41 (s, 1H), 5.33 - 5.31 (m, 1H), 4.54 - 4.52 (m, 1H), 3.12 - 3.08 (m, 1H), 2.16 (s, 3H), 2.12 - 2.04 (m, 2H), 1.87 - 1.81 (m, 1H), 1.70 - 1.63 (m, 1H), 0.93 - 0.89 (m, 3H).

Example 93. Synthesis of 7-((R)-2,2-difluorocyclopropane-l-carboxamido)-3-(6-((S)-l- hydroxypropyl)-4-methylpyridin-3-yl)-N-methyl-l,6-naphthyrid ine-2-carboxaniide (Compound 171) and 7-((R)-2,2-difluorocyclopropane-l-carboxamido)-3-(6-((R)-l- hydroxypropyl)-4-methylpyridin-3-yl)-N-methyl-l,6-naphthyrid ine-2-carboxamide (Compound 172)

Step 1: Synthesis of 7-amino-N-methyl-3-(4-methyl-6-propionylpyridin-3-yl)-l ,6- naphthyridine-2-carboxamide

[0734] A solution of methyl 7-amino-3-(4-methyl-6-propionylpyridin-3-yl)-l,6- naphthyridine-2-carboxylate (100.0 mg, crude) in CH3NH2/MeOH (10.0 mL, 2.0 mol/L) was stirred at 80 °C for 16 h. After the reaction was completed, the mixture was cooled to room temperature and then concentrated under reduced pressure to afford 7-amino-N-methyl-3-(4- methyl-6-propionylpyri din-3 -yl)-l,6-naphthyridine-2-carboxamide (80.0 mg, crude) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 350.1.

Step 2: Synthesis of (R)-7-(2,2-difluorocyclopropane-l-carboxamido)-N-methyl-3-(4 -methyl-

6-propionylpyridin-3-yl)-l,6-naphthyridine-2-carboxamide

[0735] To a solution of 7-amino-N-methyl-3-(4-methyl-6-propionylpyridin-3-yl)-l,6- naphthyridine-2-carboxamide (200.0 mg, crude) in pyridine (10.0 mL) was added (lR)-2,2- difluorocyclopropane-1 -carboxylic acid (104.8 mg, 0.85 mmol) and EDCI (970.5 mg, 4.25 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (90/10, v/v) to afford (R)-7- (2,2-difluorocyclopropane-l-carboxamido)-N-methyl-3-(4-methy l-6-propionylpyridin-3-yl)- l,6-naphthyridine-2-carboxamide (137.0 mg, 60%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 454.1.

Step 3: Synthesis of 7-((R)-2,2-difluorocyclopropane-l-carboxamido)-3-(6-(l- hydroxypropyl)-4-methylpyridin-3-yl)-N-methyl-l,6-naphthyrid ine-2-carboxamide

[0736] To a solution of (R)-7-(2,2-difluorocyclopropane-l-carboxamido)-N-methyl-3-(4 - methyl-6-propionylpyri din-3 -yl)-l,6-naphthyridine-2-carboxamide (154.0 mg, 0.34 mmol) in THF (5.0 mL) and MeOH (1.0 mL) was added NaBH ₄ (7.2 mg, 0.68 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with C^CL/MeOH (88/12, v/v) to afford 7-((R)-2,2-difluorocyclopropane-

1-carboxamido)-3-(6-(l-hydroxypropyl)-4-methylpyri din-3 -yl)-N-methyl-l, 6-naphthyridine-

2-carboxamide (64.0 mg, 39%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 456.1.

Step 4: Separation of 7-((R)-2,2-dijluorocyclopropane-l-carboxamido)-3-(6-((S)-l- hydroxypropyl)-4-methylpyridin-3-yl)-N-methyl-l,6-naphthyrid ine-2-carboxamide (Compound 171) and 7-((R)-2,2-dijluorocyclopropane-l-carboxamido)-3-(6-((R)-l- hydroxypropyl)-4-methylpyridin-3-yl)-N-methyl-l,6-naphthyrid ine-2-carboxamide (Compound 172)

[0737] The product of 7-((R)-2,2-difluorocyclopropane-l-carboxamido)-3-(6-(l- hydroxypropyl)-4-methylpyri din-3 -yl)-N-methyl-l,6-naphthyridine-2-carboxamide (74.0 mg, 0.16 mmol) was separated by Prep-Chiral-SFC with the following conditions: (Column: Lux 5um Cellulose-4, 3x25 cm, 10 pm; Mobile Phase A: CO2, Mobile Phase B: MeOH: ACN=1 : 1 (0.1% 2M NH3-MeOH); Flow rate: 100 mL/min; Gradient: isocratic 35% B; Column Temperature(°C): 35; Back Pressure(bar): 100; Wave Length: 220 nm; RTl(min): 11.33; RT2(min): 14.67) to afford 7-((R)-2,2-difluorocyclopropane-l-carboxamido)-3-(6-(l- hydroxypropyl)-4-methylpyridin-3-yl)-N-methyl-l,6-naphthyrid ine-2-carboxamide Isomer 1 (retention time 11.33 min, 3.3 mg, 9%) as a white solid and 7-((R)-2,2-difluorocyclopropane- 1-carboxamido)-3-(6-(l-hydroxypropyl)-4-methylpyri din-3 -yl)-N-methyl-l,6-naphthyridine-

2-carboxamide Isomer 2 (retention time 14.67 min, 2.9 mg, 8%) as a white solid. The absolute stereochemistry of Isomers 1 and 2 was not assigned. The two isomeric structures that could be obtained from chiral separation of the isomeric mixture as described above are shown as Compounds 171 and 172 in Table 1.

[0738] 7-((R)-2,2-difluorocyclopropane-l-carboxamido)-3-(6-(l-hydro xypropyl)-4- methylpyridin-3-yl)-N-methyl-l,6-naphthyridine-2-carboxamide Isomer 1: RTl(min):

11.33; LCMS (ESI, m/z): [M+H] ⁺ = 456.1. ¹ H NMR (400.0 MHz, DMSO-d ₆ ): 5 11.17 (s, 1H), 9.22 (s, 1H), 8.52 (s, 1H), 8.40 (s, 1H), 8.11 (s, 1H), 8.00 (d, J= 8.4 Hz, 1H), 7.78 (d, J = 8.8 Hz, 1H), 5.32 (d, J= 4.8 Hz, 1H), 4.55 - 4.53 (m, 1H), 3.31 (s, 3H), 3.12 - 3.04 (m, 1H), 2.34 (s, 3H), 2.07 - 2.04 (m, 2H), 1.90 - 1.81 (m, 1H), 1.70 - 1.65 (m, 1H), 0.93 - 0.89 (m, 3H).

[0739] 7-((R)-2,2-difluorocyclopropane-l-carboxamido)-3-(6-(l-hydro xypropyl)-4- methylpyridin-3-yl)-N-methyl-l,6-naphthyridine-2-carboxamide Isomer 2: RT2(min):

14.67; LCMS (ESI, m/z): [M+H] ⁺ = 456.1. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.17 (s, 1H), 9.22 (s, 1H), 8.52 (s, 1H), 8.40 (s, 1H), 8.11 (s, 1H), 8.00 (d, J= 8.4 Hz, 1H), 7.78 (d, J= 8.8 Hz, 1H), 5.32 (d, J= 4.8 Hz, 1H), 4.56 - 4.53 (m, 1H), 3.31 (s, 3H), 3.12 - 3.06 (m, 1H), 2.34 (s, 3H), 2.07 - 2.04 (m, 2H), 1.90 - 1.81 (m, 1H), 1.74 - 1.68 (m, 1H), 0.93 - 0.89 (m, 3H).

Example 94. Synthesis of 7-((R)-2,2-difluorocyclopropane-l-carboxamido)-3-(6-((S)-l- hydroxypropyl)-4-methylpyridin-3-yl)-N,N-dimethyl-l,6-naphth yridine-2-carboxamide (Compound 173) and 7-((R)-2,2-difluorocyclopropane-l-carboxamido)-3-(6-((R)-l- hydroxypropyl)-4-methylpyridin-3-yl)-N,N-dimethyl-l,6-naphth yridine-2-carboxamide (Compound 174)

Step 1: Synthesis of 7-chloro-N,N-dimethyl-3-(4-methyl-6-propionylpyridin-3-yl)-l ,6- naphthyridine-2-carboxamide

[0740] To a solution of 7-chloro-3-(4-methyl-6-propionylpyridin-3-yl)-l,6-naphthyrid ine-

2-carboxylic acid (700.0 mg, 1.97 mmol) in pyridine (20.0 mL) was added dimethylamine hydrochloride (239.3 mg, 2.96 mmol) and EDCI (1422.5 mg, 7.42 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (90/10, v/v) to afford 7-chloro-N,N- dimethyl-3-(4-methyl-6-propionylpyridin-3-yl)-l,6-naphthyrid ine-2-carboxamide (450.0 mg, 59%) as a light yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 383.0.

Step 2: Synthesis of tert-butyl (2-(dimethylcarbamoyl)-3-(4-methyl-6-propionylpyridin-3-yl)~ 1, 6-naphthyridin- 7 -y I) carbamate

[0741] To a solution of 7-chloro-N,N-dimethyl-3-(4-methyl-6-propionylpyridin-3-yl)- l,6-naphthyridine-2-carboxamide (450.0 mg, 1.18 mmol) in dioxane (25.0 mL) was added BocNH ₂ (194.7 mg, 1.77 mmol), Cs ₂ CO ₃ (1057.2 mg, 3.24 mmol), Pd(OAc) ₂ (25.3 mg, 0.12 mmol) and XPhos (104.1 mg, 0.24 mmol) at room temperature under N2. The resulting mixture was stirred at 80 °C for 2 h under N2. After the reaction was completed, the mixture was cooled to room temperature and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with di chloromethane /methanol (92/8, v/v) to afford tert-butyl (2-(dimethylcarbamoyl)-3-(4- methyl-6-propionylpyridin-3-yl)-l,6-naphthyridin-7-yl)carbam ate (280.0 mg, 62%) as a brown solid. LCMS (ESI, m/z): [M+H] ⁺ = 464.1.

Step 3: Synthesis of 7-amino-N,N-dimethyl-3-(4-methyl-6-propionylpyridin-3-yl)-l, 6- naphthyridine-2-carboxamide

[0742] To a solution of tert-butyl (2-(dimethylcarbamoyl)-3-(4-methyl-6- propionylpyridin-3-yl)-l,6-naphthyridin-7-yl)carbamate (280.0 mg, 0.60 mmol) in DCM (6.0 mL) was added TFA (2.0 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The pH value of the residue was adjusted to 8.0 with saturated NaHCO3 (aq.). The mixture was extracted with CH2CI2. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to afford 7-amino-N,N-dimethyl-3-(4-methyl-6- propionylpyridin-3-yl)-l,6-naphthyridine-2-carboxamide (220.0 mg, crude) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 364.1.

Step 4: Synthesis of (R)-7-(2,2-dijluorocyclopropane-l-carboxamido)-N,N-dimethyl- 3-(4- methyl-6-propionylpyridin-3-yl)-l,6-naphthyridine-2-carboxam ide

[0743] To a solution of 7-amino-N,N-dimethyl-3-(4-methyl-6-propionylpyridin-3-yl)-l, 6- naphthyridine-2-carboxamide (220.0 mg, crude) in pyridine (12.0 mL) was added (lR)-2,2- difluorocyclopropane-1 -carboxylic acid (89.6 mg, 0.72 mmol) and EDCI (711.5 mg, 3.71 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (87/13, v/v) to afford (R)-7- (2,2-difluorocyclopropane-l-carboxamido)-N,N-dimethyl-3-(4-m ethyl-6-propionylpyridin-3- yl)-l,6-naphthyridine-2-carboxamide (140.0 mg, 63%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 468.1.

Step 5: Synthesis of 7-((R)-2,2-dijluorocyclopropane-l-carboxamido)-3-(6-(l- hydroxypropyl)-4-methylpyridin-3-yl)-N,N-dimethyl-l,6-naphth yridine-2-carboxamide

[0744] To a solution of (R)-7-(2,2-difluorocyclopropane-l-carboxamido)-N,N-dimethyl- 3-(4-methyl-6-propionylpyridin-3-yl)-l,6-naphthyridine-2-car boxamide (140.0 mg, 0.29 mmol) in THF (5.0 mL) and MeOH (1.0 mL) was added NaBH ₄ (6.1 mg, 0.58 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (93/7, v/v) to afford 7-((R)-2,2-difluorocyclopropane-l- carboxamido)-3-(6-(l-hydroxypropyl)-4-methylpyridin-3-yl)-N, N-dimethyl-l,6- naphthyridine-2-carboxamide (50.0 mg, 36%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 470.1.

Step 6: Separation of 7-((R)-2,2-dijluorocyclopropane-l-carboxamido)-3-(6-((S)-l- hydroxypropyl)-4-methylpyridin-3-yl)-N,N-dimethyl-l,6-naphth yridine-2-carboxamide (Compound 173) and 7-((R)-2,2-difluorocyclopropane-l-carboxamido)-3-(6-((R)-l- hydroxypropyl)-4-methylpyridin-3-yl)-N,N-dimethyl-l,6-naphth yridine-2-carboxamide (Compound 174)

[0745] The product of 7-((R)-2,2-difluorocyclopropane-l-carboxamido)-3-(6-(l- hydroxypropyl)-4-methylpyri din-3 -yl)-N,N-dimethyl-l,6-naphthyridine-2-carboxamide (55.3 mg, 0.12 mmol) was separated by Prep-Chiral-SFC with the following conditions: (Lux 5um Cellulose-4, 3x25 cm, 5 pm; Mobile Phase A: CO2, Mobile Phase B: IP A; Flow rate: 200 mL/min; Gradient: isocratic 25% B; Column Temperature(°C): 35; Back Pressure(bar): 100; Wave Length: 220 nm; RTl(min): 8.17; RT2(min): 11.04) to afford 7-((R)-2,2- difluorocyclopropane-l-carboxamido)-3-(6-(l-hydroxypropyl)-4 -methylpyri din-3 -yl)-N,N- dimethyl-l,6-naphthyridine-2-carboxamide Isomer 1 (retention time 8.17 min, 4.3 mg, 16%) as a white solid and 7-((R)-2,2-difluorocyclopropane-l-carboxamido)-3-(6-(l- hydroxypropyl)-4-methylpyridin-3-yl)-N,N-dimethyl-l,6-naphth yridine-2-carboxamide Isomer 2 (retention time 11.04 min, 3.8 mg, 14%) as a white solid. The absolute stereochemistry of Isomers 1 and 2 was not assigned. The two isomeric structures that could be obtained from chiral separation of the isomeric mixture as described above are shown as Compounds 173 and 174 in Table 1.

[0746] 7-((R)-2,2-difluorocyclopropane-l-carboxamido)-3-(6-(l-hydro xypropyl)-4- methylpyridin-3-yl)-N,N-dimethyl-l,6-naphthyridine-2-carboxa mide Isomer 1 : RTl(min): 8.17; LCMS (ESI, m/z): [M+H] ⁺ = 470.2. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.19 (s, 1H), 9.49 (s, 1H), 8.92 (s, 1H), 8.86 (s, 1H), 8.64 (s, 1H), 7.49 (s, 1H), 5.38 (d, J= 4.8 Hz, 1H), 4.59 - 4.55 (m, 1H), 3.47 - 3.42 (m, 1H), 3.17 (s, 6H), 2.45 (s, 3H), 2.15 - 2.06 (m, 2H), 1.91 - 1.65 (m, 2H), 0.95 - 0.88 (m, 3H).

[0747] 7-((R)-2,2-difluorocyclopropane-l-carboxamido)-3-(6-(l-hydro xypropyl)-4- methylpyridin-3-yl)-N,N-dimethyl-l,6-naphthyridine-2-carboxa mide Isomer 2: RT2(min): 11.04; LCMS (ESI, m/z): [M+H] ⁺ = 470.2. ¹ H NMR (400 MHz, DMSO-d6 δ 11.19 (s, 1H), 9.50 (s, 1H), 8.92 (s, 1H), 8.86 (s, 1H), 8.65 (s, 1H), 7.50 (s, 1H), 5.40 - 5.37 (m, 1H), 4.59 - 4.56 (m, 1H), 3.47 - 3.41 (m, 1H), 3.17 (s, 6H), 2.45 (s, 3H), 2.15 - 2.07 (m, 2H), 1.89 - 1.71 (m, 2H), 0.95 - 0.88 (m, 3H).

Example 95. Synthesis of (lR,2R)-2-fluoro-N-(3-(6-((S)-l-hydroxybut-3-en-l-yl)-4- methylpyridin-3-yl)-l,6-naphthyridin-7-yl)cyclopropane-l-car boxamide (Compound 175) and (lR,2R)-2-fluoro-N-(3-(6-((R)-l-hydroxybut-3-en-l-yl)-4-meth ylpyridin-3-yl)-l,6- naphthyridin-7-yl)cyclopropane-l -carboxamide (Compound 176)

Step 1: Synthesis of (lR,2R)-N-(3-(6-(l-((tert-butyldimethylsilyl)oxy)but-3-en-l- yl)-4- methylpyridin-3-yl)-l,6-naphthyridin-7-yl)-2-fluorocycloprop ane-l-carboxamide [0748] To a stirred mixture of 3-(6-(1-((tert-butyldimethylsilyl)oxy)but-3-en-1-yl)-4- methylpyridin-3-yl)-7-chloro-1,6-naphthyridine (350.0 mg, 0.79 mmol) and (1R,2R)-2- fluorocyclopropane-1-carboxamide (123.0 mg, 1.19 mmol) in 1,4-dioxane (10.0 mL) were added K ₂ CO ₃ (219.8 mg, 1.59 mmol), Pd ₂ (dba) ₃ (145.7 mg, 0.16 mmol) and XPhos (151.7 mg, 0.32 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 16 h under N ₂ . After the reaction was completed, the resulting mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (73/27, v/v) to afford (1R,2R)-N-(3-(6-(1-((tert-butyldimethylsilyl)oxy)but-3-en-1- yl)-4-methylpyridin-3- yl)-1,6-naphthyridin-7-yl)-2-fluorocyclopropane-1-carboxamid e (300.0 mg, 74%) as a light yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 507.7. Step 2: Synthesis of (1R,2R)-2-fluoro-N-(3-(6-(1-hydroxybut-3-en-1-yl)-4-methylpy ridin-3- yl)-1,6-naphthyridin-7-yl)cyclopropane-1-carboxamide [0749] To a stirred mixture of (1R,2R)-N-(3-(6-(1-((tert-butyldimethylsilyl)oxy)but-3-en- 1-yl)-4-methylpyridin-3-yl)-1,6-naphthyridin-7-yl)-2-fluoroc yclopropane-1-carboxamide (300.0 mg, 0.59 mmol) in THF (10.0 mL)was added TBAF (300.9 mg, 1.18 mmol) at room temperature. The resulting mixture was stirred at 40 °C for 4 h under N ₂ . After the reaction was completed, the mixture was diluted with H ₂ O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (10/1, v/v) to afford (1R,2R)-2-fluoro-N- (3-(6-(1-hydroxybut-3-en-1-yl)-4-methylpyridin-3-yl)-1,6-nap hthyridin-7-yl)cyclopropane-1- carboxamide (80.0 mg, 34%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 393.4 Step 3: Separation of (1R,2R)-2-fluoro-N-(3-(6-((S)-1-hydroxybut-3-en-1-yl)-4- methylpyridin-3-yl)-1,6-naphthyridin-7-yl)cyclopropane-1-car boxamide (Compound 175) and (1R,2R)-2-fluoro-N-(3-(6-((R)-1-hydroxybut-3-en-1-yl)-4-meth ylpyridin-3-yl)-1,6- naphthyridin-7-yl)cyclopropane-1-carboxamide (Compound 176) [0750] The product of (1R,2R)-2-fluoro-N-(3-(6-(1-hydroxybut-3-en-1-yl)-4- methylpyridin-3-yl)-1,6-naphthyridin-7-yl)cyclopropane-1-car boxamide (80.0 mg, 0.20 mmol) was separated by Prep-Chiral-HPLC with the following conditions (Column: CHIRALPAK IE, 2×25 cm, 5 ^m; Mobile Phase A: Hex(0.1% 2M NH ₃ -MeOH)--HPLC, Mobile Phase B: EtOH: DCM=1: 1--HPLC; Flow rate: 20 mL/min; Gradient: 50% B to 50% B in 32 min; Wave Length: 220/254 nm; RT1(min): 15.37; RT2(min): 18.42) to afford (1R,2R)-2-fluoro-N-(3-(6-(1-hydroxybut-3-en-1-yl)-4-methylpy ridin-3-yl)-1,6-naphthyridin- 7-yl)cyclopropane-1-carboxamide Isomer 1 (retention time 15.37 min, 8.5 mg, 41%) as a white solid and (1R,2R)-2-fluoro-N-(3-(6-(1-hydroxybut-3-en-1-yl)-4-methylpy ridin-3-yl)- 1,6-naphthyridin-7-yl)cyclopropane-1-carboxamide Isomer 2 (retention time 18.42 min, 6.3 mg, 31%) as a light yellow solid. The absolute stereochemistry of Isomers 1 and 2 was not assigned. The two isomeric structures that could be obtained from chiral separation of the isomeric mixture as described above are shown as Compounds 175 and 176 in Table 1. [0751] (1R,2R)-2-fluoro-N-(3-(6-(1-hydroxybut-3-en-1-yl)-4-methylpy ridin-3-yl)-1,6- naphthyridin-7-yl)cyclopropane-1-carboxamide Isomer 1: RT1(min): 15.37; LCMS (ESI, m/z): [M+H] ⁺ = 393.1. ¹ H NMR (400 MHz, DMSO-d ₆ ): į 11.21 (s, 1H), 9.29 (s, 1H), 9.12 (d, J = 2.4 Hz, 1H), 8.62 - 8.57 (m, 2H), 8.48 (s, 1H), 7.52 (s, 1H), 5.91 - 5.84 (m, 1H), 5.52 (d, J = 4.8 Hz, 1H), 5.10 - 4.88 (m, 3H), 4.71 - 4.67 (m, 1H), 2.65 - 2.60 (m, 1H), 2.49 - 2.42 (m, 1H), 2.38 (s, 3H), 2.34 - 2.28 (m, 1H), 1.78 - 1.68 (m, 1H), 1.27 - 1.20 (m, 1H). [0752] (1R,2R)-2-fluoro-N-(3-(6-(1-hydroxybut-3-en-1-yl)-4-methylpy ridin-3-yl)-1,6- naphthyridin-7-yl)cyclopropane-1-carboxamide Isomer 2: RT2(min): 18.42; LCMS (ESI, m/z): [M+H] ⁺ = 393.0. ¹ H NMR (400 MHz, DMSO-d ₆ ): į 11.26 (s, 1H), 9.32 (s, 1H), 9.18 (s, 1H), 8.70 - 8.64 (m, 3H), 7.94 (s, 1H), 5.90 - 5.81 (m, 1H), 5.18 - 5.03 (m, 4H), 4.93 - 4.90 (m, 1H), 2.71 - 2.64 (m, 1H), 2.60 - 2.52 (m, 3H), 2.37 - 2.30 (m, 1H), 1.78 - 1.68 (m, 1H), 1.28 - 1.20 (m, 1H).

Example 96. Synthesis of (R)-2,2-difluoro-N-(3-(6-((S)-l-hydroxybut-3-en-l-yl)-4- methylpyridin-3-yl)-l, 6-naphthyridin- 7-yl)cyclopropane-l-carboxamide(Compound 177) and (R)-2,2-difluoro-N-(3-(6-((R)-l-hydroxybut-3-en-l-yl)-4-meth ylpyridin-3-yl)-l,6- naphthyridin-7-yl)cyclopropane-l -carboxamide (Compound 178)

Step 1: Synthesis of 2-(l-((tert-butyldimethylsilyl)oxy)but-3-en-l-yl)-4-methyl-5 -(4, 4,5,5- tetramethyl-1, 3, 2-dioxaborolan-2-yl)pyridine

[0753] To a mixture of 5-bromo-2-(l-((tert-butyldimethylsilyl)oxy)but-3-en-l-yl)-4- methylpyridine (5.0 g, 14.03 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2- dioxaborolane) (10.7 g, 42.09 mmol) in 1,4-dioxane (50.0 mL) was added KOAc (4.1 g, 42.09 mmol) and Pd(dppf)C12 (1.0 g, 1.40 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 2 h under N2. After the reaction was completed, the resulting mixture was cooled to room temperature and filtered. The filtrate was concentrated under vacuum. The residue was purified by flash column chromatography with CH2CI2/CH3OH (92/8, v/v) and petroleum ether/ethyl acetate (68/32, v/v) to afford 2-(l- ((tert-butyldimethylsilyl)oxy)but-3-en-l-yl)-4-methyl-5-(4,4 ,5,5-tetramethyl-l,3,2-

dioxaborolan-2-yl)pyridine (4.4 g, 77%) as a light yellow oil. LCMS (ESI, m/z): [M+H] ⁺ = 404.2.

Step 2: Synthesis of 3-(6-(l-((tert-butyldimethylsilyl)oxy)but-3-en-l-yl)-4-methy lpyridin-3- yl) -7 -chlor o-l, 6-naphthyridine

[0754] To a mixture of 2-(l-((tert-butyldimethylsilyl)oxy)but-3-en-l-yl)-4-methyl-5 - (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (2.2 g, 5.54 mmol) and 3-bromo-7- chloro-1, 6-naphthyridine (1.4 g, 5.54 mmol) in 1,4-dioxane (30.0 mL) and H2O (6.0 mL) was added K2CO3 (1.5 g, 11.09 mmol) and Pd(dppf)C12 (405.7 mg, 0.55 mmol) at room temperature under N2. The resulting mixture was stirred at 80 °C for 2 h. After the reaction was completed, the resulting mixture was cooled to room temperature and filtered. The filtrate was concentrated under vacuum. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (72/28, v/v) to afford 3-(6-(l-((tert- butyldimethylsilyl)oxy)but-3-en-l-yl)-4-methylpyridin-3-yl)- 7-chl oro-1, 6-naphthyridine (1.4 g, 57%) as a light yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 440.2.

Step 3: Synthesis of tert-butyl (3-(6-(l-((tert-butyldimethylsilyl)oxy)but-3-en-l-yl)-4- methylpyridin-3-yl)-l , 6-naphthyridin- 7 -yl) carbamate

[0755] To a mixture of 3-(6-(l-((tert-butyldimethylsilyl)oxy)but-3-en-l-yl)-4- methylpyridin-3-yl)-7-chloro-l, 6-naphthyridine (600.0 mg, 1.36 mmol) and tert-butyl carbamate (479.2 mg, 4.09 mmol) in 1,4-dioxane (20.0 mL) was added CS2CO3 (888.5 mg, 2.73 mmol), XPhos (195.0 mg, 0.41 mmol) and Pd(OAc)2 (45.9 mg, 0.20 mmol) at room temperature under N2. The resulting mixture was stirred at 80 °C for 2 h under N2. After the reaction was completed, the resulting mixture was cooled to room temperature and filtered. The filtrate was concentrated under vacuum. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (70/30, v/v) to afford tert-butyl (3-(6-(l - ((tert-butyldimethylsilyl)oxy)but-3-en-l-yl)-4-methylpyridin -3-yl)-l,6-naphthyridin-7- yl)carbamate (700.0 mg, 98%) as a light yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 521.3

Step 4: Synthesis of 3-(6-(l-((tert-butyldimethylsilyl)oxy)but-3-en-l-yl)-4-methy lpyridin-3- yl)-l, 6-naphthyridin-7 -amine

[0756] To a solution of tert-butyl (3-(6-(l-((tert-butyldimethylsilyl)oxy)but-3-en-l-yl)-4- methylpyridin-3-yl)-l,6-naphthyridin-7-yl)carbamate (650.0 mg, 1.25 mmol) in CH2CI2 (12.0 mL) was added TFA (3.0 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the resulting mixture was adjusted to pH = 7.0 with saturated NaHCCL (aq). The resulting mixture was extracted with CH ₂ Cl ₂ . The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /CH3OH (87/13, v/v) to afford 3-(6-(l-((tert- butyldimethylsilyl)oxy)but-3-en-l-yl)-4-methylpyridin-3-yl)- l,6-naphthyridin-7-amine (460.0 mg, 87%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 421.2.

Step 5: Synthesis of (lR)-N-(3-(6-(l-((tert-butyldimethylsilyl)oxy)but-3-en-l-yl) -4- methylpyridin-3-yl)-l , 6-naphthyridin- 7-yl)-2, 2-difluorocyclopropane-l -carboxamide

[0757] To a mixture of 3-(6-(l-((tert-butyldimethylsilyl)oxy)but-3-en-l-yl)-4- methylpyridin-3-yl)-l,6-naphthyridin-7-amine (300.0 mg, 0.71 mmol) and (R)-2,2- difluorocyclopropane-1 -carboxylic acid (130.6 mg, 1.07 mmol) in pyridine (5.0 mL) was added EDCI (683.6 mg, 3.56 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the resulting mixture was concentrated under vacuum. The residue was purified by flash column chromatography with CH2CI2/CH3OH (97/3, v/v) to afford (lR)-N-(3-(6-(l-((tert-butyldimethylsilyl)oxy)but-3-en- 1 -yl)-4-methylpyri din-3 -yl)- 1 ,6-naphthyridin-7-yl)-2,2-difluorocyclopropane- 1 -carboxamide (220.0 mg, 52%) as a light yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 525.2.

Step 6: Synthesis of (lR)-2,2-difluoro-N-(3-(6-(l-hydroxybut-3-en-l-yl)-4-methylp yridin-3- yl)-l, 6-naphthyridin- 7 -yl)cyclopropane-l -carboxamide

[0758] To a solution of (lR)-N-(3-(6-(l-((tert-butyldimethylsilyl)oxy)but-3-en-l-yl) -4- methylpyri din-3 -yl)-l,6-naphthyri din-7-yl)-2,2-difluorocy cl opropane-1 -carboxamide (220.0 mg, 0.42 mmol) in THF (5.0 mL) was added TBAF (219.3 mg, 0.84 mmol) at room temperature under N2. The resulting mixture was stirred at room temperature for 4 h under N2. After the reaction was completed, the resulting mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by flash column chromatography with CH2CI2/CH3OH (94/6, v/v) to afford (lR)-2,2-difluoro-N-(3-(6-(l-hydroxybut-3-en-l-yl)-4-methylp yri din-3 -yl)- 1,6- naphthyridin-7-yl)cyclopropane-l -carboxamide (120.0 mg, 69%) as a light yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 411.2.

Step 7: Separation of (R)-2,2-difluoro-N-(3-(6-((S)-l-hydroxybut-3-en-l-yl)-4-meth ylpyridin- 3-yl)-l,6-naphthyridin-7-yl)cyclopropane-l-carboxamide (Compound 177) and (R)-2,2- difluoro-N-(3-(6-((R)-l-hydroxybut-3-en-l-yl)-4-methylpyridi n-3-yl)-l,6-naphthyridin-7- yl)cyclopropane-l -carboxamide (Compound 178)

[0759] The product of (lR)-2,2-difluoro-N-(3-(6-(l-hydroxybut-3-en-l-yl)-4- methylpyridin-3-yl)-l,6-naphthyridin-7-yl)cyclopropane-l-car boxamide (120.0 mg, 0.29 mmol) was separated by Prep-Chiral-HPLC with the following conditions (Column: CHIRALPAK IE, 2x25 cm, 5 μm; Mobile Phase A: Hex (0.1% 2M NH ₃ -MeOH)-HPLC, Mobile Phase B: EtOH: DCM=1 : 1— HPLC; Flow rate: 20 mL/min; Gradient: 50% B to 50% B in 21 min; Wave Length: 220\254 nm; RTl(min): 10.171; RT2(min): 14.467) to afford (R)- 2,2-difluoro-N-(3-(6-(l-hydroxybut-3-en-l-yl)-4-methylpyridi n-3-yl)-l,6-naphthyridin-7- yl)cyclopropane-l -carboxamide Isomer 1 (retention time 10.171 min, 20.8 mg, 34%) as a white solid and (R)-2,2-difluoro-N-(3-(6-((l-hydroxybut-3-en-l-yl)-4-methylp yridin-3-yl)- 1,6-naphthyri din-7-yl)cy cl opropane-1 -carboxamide Isomer 2 (retention time 14.467 min, 16.2 mg, 27%) as a light yellow solid. The absolute stereochemistry of Isomers 1 and 2 was not assigned. The two enantiomeric structures that could be obtained from chiral separation of the enantiomeric mixture as described above are shown as Compounds 177 and 178 in Table 1.

[0760] (R)-2,2-difluoro-N-(3-(6-(l-hydroxybut-3-en-l-yl)-4-methylpy ridin-3-yl)-l,6- naphthyridin-7-yl)cyclopropane-l-carboxamide Isomer 1: RT1 (min): 10.171; LCMS (ESI, m/z): [M+H] ⁺ = 411.1. ¹ H NMR (400 MHz, DMSO-d6): δ 11.37 (s, 1H), 9.31 (s, 1H), 9.14 (s, 1H), 8.60 (s, 2H), 8.49 (s, 1H), 7.54 (s, 1H), 5.93 - 5.82 (m, 1H), 5.53 (s, 1H), 5.10 - 5.02 (m, 2H), 4.74 - 4.70 (m, 1H), 3.14 - 3.06 (m, 1H), 2.64 - 2.59 (m, 1H), 2.45 - 2.39 (m, 4H), 2.15 - 2.08 (m, 2H).

[0761] (R)-2,2-difluoro-N-(3-(6-(l-hydroxybut-3-en-l-yl)-4-methylpy ridin-3-yl)-l,6- naphthyridin-7-yl)cyclopropane-l-carboxamide Isomer 2: RT2 (min): 14.467; LCMS (ESI, m/z): [M+H] ⁺ = 411.1. ¹ H NMR (400 MHz, DMSO-d6): δ 11.37 (s, 1H), 9.30 (s, 1H), 9.13 (d, J= 2.0 Hz, 1H), 8.60 (s, 2H), 8.48 (s, 1H), 7.52 (s, 1H), 5.93 - 5.82 (m, 1H), 5.51 (d, J= 4.4 Hz, 1H), 5.10 - 5.01 (m, 2H), 4.70 - 4.68 (m, 1H), 3.14 - 3.06 (m, 1H), 2.66 - 2.59 (m, 1H), 2.47 - 2.42 (m, 1H), 2.38 (s, 3H), 2.15 - 2.05 (m, 2H).

Example 97. Synthesis of l-(5-(9,9-dimethyl-8,9-dihydro-7H-pyrrolo[2,3- c][2, 6]naphthyridin-3-yl)-4-methylpyridin-2-yl)propan-l-ol (Compound 108)

Step 1: Synthesis of 7-chloro-4-iodo-2,6-naphthyridin-3-amine

[0762] To a solution of 7-chloro-2,6-naphthyridin-3-amine (1.3 g, 7.57 mmol) in MeOH (10.0 mL) was added NIS (1.9 g, 8.32 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 1 h. After the reaction was completed, the resulting mixture was diluted with water and extracted with CH2Cl2. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column with CH ₂ Cl ₂ /MeOH (95/5, v/v) to afford 7-chloro-4- iodo-2,6-naphthyridin-3-amine (1.9 g, 82%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =306.2. Step 2: Synthesis of 7-chloro-4-iodo-N-(2-methylallyl)-2,6-naphthyridin-3-amine [0763] To a solution of 7-chloro-4-iodo-2,6-naphthyridin-3-amine (420.0 mg, 1.60 mmol) in THF (15.0 mL) was added 3-bromo-2-methylprop-1-ene (316.0 mg, 2.40 mmol) and t- BuOK (537.6 mg, 4.80 mmol) at room temperature. The resulting mixture was stirred at 30 °C for 16 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column with dichloromethane/methanol (85/15, v/v) to afford 7-chloro-4-iodo-N-(2-methylallyl)-2,6- naphthyridin-3-amine (500.0 mg, 74%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 360.1. Step 3: Synthesis of 3-chloro-9,9-dimethyl-8,9-dihydro-7H-pyrrolo[2,3-c][2,6]naph thyridine [0764] To a solution of 7-chloro-4-iodo-N-(2-methylallyl)-2,6-naphthyridin-3-amine (260.0 mg, 0.72 mmol) in methylbenzene (10.0 mL) were added HCO ₂ K (72.9 mg, 0.86 mmol), Bu ₄ NHCl (241.1 mg, 0.86 mmol), Et ₃ N (219.5 mg, 2.16 mmol) and Pd(OAc) ₂ (32.4 mg, 0.14 mmol) at room temperature under N ₂ . The resulting mixture was stirred at 60 °C for 16 h. After the reaction was completed, the resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column with CH ₂ Cl ₂ /MeOH (94/6, v/v) to afford 3-chloro-9,9-dimethyl-8,9-dihydro-7H-pyrrolo[2,3- c][2,6]naphthyridine (100.0 mg, 59%) as an orange solid. LCMS (ESI, m/z): [M+H] ⁺ = 234.1. Step 4: Synthesis of 1-(5-(9,9-dimethyl-8,9-dihydro-7H-pyrrolo[2,3-c][2,6]naphthy ridin-3- yl)-4-methylpyridin-2-yl)propan-1-one

[0765] To a solution of 3-chloro-9,9-dimethyl-8,9-dihydro-7H-pyrrolo[2,3- c][2,6]naphthyridine (100.0 mg, 0.42 mmol) in 1,4-dioxane (10.0 mL) and water (2.0 mL) was added (4-methyl-6-propionylpyridin-3-yl)boronic acid (99.1 mg, 0.51 mmol), Pd(dppf)Ch (62.6 mg, 0.08 mmol) and K2CO3 (177.4 mg, 1.28 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 16 h. After the reaction was completed, the resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column with CH ₂ Cl ₂ /MeOH (97/3, v/v) to afford l-(5-(9,9-dimethyl-8,9-dihydro-7H-pyrrolo[2,3-c][2,6]naphthy ridin-3-yl)-4-methylpyri din-2- yl)propan-l-one (80.0 mg, 38%) as a yellow oil. LCMS (ESI, m/z): [M+H] ⁺ = 347.1.

Step 5: Synthesis of l-(5-(9,9-dimethyl-8,9-dihydro-7H-pyrrolo[2,3-c] [2,6]naphthyridin-3- yl)-4-methylpyridin-2-yl)propan-l-ol (Compound 108)

[0766] To a solution of l-(5-(9,9-dimethyl-8,9-dihydro-7H-pyrrolo[2,3- c][2,6]naphthyridin-3-yl)-4-methylpyridin-2-yl)propan-l-one (116.0 mg, 0.33 mmol) in THF (3.0 mL) and MeOH (1.0 mL) was added NaBHj (25.3 mg, 0.67 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (85/15, v/v) and then purified by reverse phase flash column chromatography with ACN/H2O (70/30, v/v) to afford l-(5-(9,9- dimethyl-8,9-dihydro-7H-pyrrolo[2,3-c][2,6]naphthyridin-3-yl )-4-methylpyridin-2- yl)propan-l-ol (10.7 mg, 9%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 349.1. ¹ H NMR (400 MHz, DMSO-d6 ): 5 9.45 (s, 1H), 8.87 (s, 1H), 8.53 (s, 1H), 7.94 (s, 1H), 7.42 (s, 1H), 6.75 (s, 1H), 5.30 (d, J= 4.8 Hz, 1H), 4.56 - 4.52 (m, 1H), 3.38 (d, J= 1.2 Hz, 2H), 2.45 (s, 3H), 1.87 - 1.80 (m, 1H), 1.71 - 1.64 (m, 1H), 1.59 (s, 6H), 0.92 - 0.88 (m, 3H).

Example 98. Synthesis of (lS,2S)-N-(6-cyano-7-(6-((lZ)-l-(hydroxyimino)propyl)-4- methylpyridin-3-yl)isoquinolin-3-yl)-2-fluorocyclopropane-l -carboxamide ( Compound 6) and (lS,2S)-N-(6-cyano-7-{6-[(lE)-l-(hydroxyimino)propyl]-4-meth ylpyridin-3- yl}isoquinolin-3-yl)-2-fluorocyclopropane-l -carboxamide (Compound 179)

Step 1: Synthesis of (1 S,2S)-N-(6-cyano-7-(4-methyl-6-propionylpyridin-3-yl)isoquin olin-3- yl)-2-fluorocyclopropane-l -carboxamide

[0767] To a mixture of 3-amino-7-(4-methyl-6-propanoylpyridin-3-yl)isoquinoline-6- carbonitrile (150.0 mg, 0.47 mmol) in pyridine (5.0 mL) was added (lS,2S)-2- fluorocyclopropane-1 -carboxylic acid (74.0 mg, 0.71 mmol) and EDCI (181.7 mg, 0.94 mmol) at room temperature. The resulting mixture was stirred at room temperature for 3 h. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (10/1, v/v) to afford (lS,2S)-N-[6-cyano-7-(4-methyl-6-propanoylpyridin-3-yl)isoqu inolin-3- yl]-2-fluorocyclopropane-l -carboxamide (100.0 mg, 52%) as a green solid. LCMS (ESI, m/z): [M+H] ⁺ =403.1

Step 2: Synthesis of (1 S,2S)-N-(6-cyano-7-(6-(( lZ)-l-(hydroxyimino)propyl)-4-methylpyridin- 3-yl)isoquinolin-3-yl)-2-fluorocyclopropane-l-carboxamide (Compound 6) and (1S,2S)-N~(6- cyano-7-{6-[(lE)-l-(hydroxyimino)propyl]-4-methylpyridin-3-y l}isoquinolin-3-yl)-2- fluorocyclopropane-1 -carboxamide (Compound 179)

[0768] To a solution of (lS,2S)-N-[6-cyano-7-(4-methyl-6-propanoylpyridin-3- yl)isoquinolin-3-yl]-2-fluorocyclopropane-l-carboxamide (95.0 mg, 0.25 mmol) in DCM (4.0 mL) and EtOH (4.0 mL) were added NH2OH.HCI (31.0 mg, 0.44 mmol) and NaOAc (36.6 mg, 0.44 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the mixture was concentrated under vacuum. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (10/1, v/v) and then purified by Prep-HPLC with the following conditions: (Column: XBridge Prep OBD C18 Column, 30x150 mm, 5 pm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 40% B in 10 min; Wave Length: 254 nm; RTl(min): 10, RT2(min): 12) to afford (lS,2S)-N-(6-cyano-7- (6-(l-(hydroxyimino)propyl)-4-methylpyridin-3-yl)isoquinolin -3-yl)-2-fluorocyclopropane- 1-carboxamide Isomer 1 (retention time 12 min, 40.9 mg, 40%) as a white solid and (1S,2S)- N-(6-cy ano-7- { 6- [ 1 -(hy droxyimino)propyl] -4-methylpyri din-3 -yl } i soquinolin-3 -yl)-2- fluorocyclopropane-1 -carboxamide Isomer 2 (retention time 10 min, 4.9 mg, 5%) as a white solid. The absolute stereochemistry of Isomers 1 and 2 was not assigned. The two isomeric structures that could be obtained from separation of the isomeric mixture as described above are shown as Compounds 6 and 179 in Table 1.

[0769] (lS,2S)-N-(6-cyano-7-(6-(l-(hydroxyimino)propyl)-4-methylpyr idin-3- yl)isoquinolin-3-yl)-2-fluorocyclopropane-l-carboxamide Isomer 1: RT2(min): 12;

LCMS (ESI, m/z): [M+H]+ = 418.1. ¹ H NMR (400 MHz, DMSO-d6): δ 11.53 (s, 1H), 11.21 (s, 1H), 9.33 (s, 1H), 8.78 (s, 1H), 8.66 (s, 1H), 8.54 (s, 1H), 8.27 (s, 1H), 7.89 (s, 1H), 5.08 - 4.89 (m, 1H), 2.93 - 2.69 (m, 2H), 2.33 - 2.27 (m, 1H), 2.25 (s, 3H), 1.76 - 1.68 (m, 1H), 1.26 - 1.21 (m, 1H), 1.12 - 1.05 (m, 3H).

[0770] (lS,2S)-N-(6-cyano-7-{6-[l-(hydroxyimino)propyl]-4-methylpyr idin-3- yl}isoquinolin-3-yl)-2-fluorocyclopropane-l-carboxamide Isomer 2: RTl(min): 10;

LCMS (ESI, m/z): [M+H]+ = 418.1. ¹ H NMR (400 MHz, DMSO-d6): δ 11.53 - 11.21 (m, 2H), 9.33 (s, 1H), 8.79 (s, 1H), 8.66 (s, 1H), 8.54 (s, 1H), 8.27 (d, J = 6.4 Hz, 1H), 7.89 (d, J = 6.8 Hz, 1H), 5.08 - 4.89 (m, 1H), 2.91 - 2.89 (m, 1H), 2.72 - 2.68 (m, 1H), 2.33 - 2.28 (m, 1H), 2.25 (s, 3H), 1.77 - 1.69 (m, 1H), 1.28 - 1.20 (m, 1H), 1.16 - 1.05 (m, 3H).

Example 99. Synthesis of (R)-N-(3-(6-(4,5-dihydro-lH-pyrazol-3-yl)-4-methylpyridin-3- yl)~ l,6-naphthyridin-7-yl)-2,2-difluorocyclopropane-l -carboxamide (Compound 180)

Step 1: Synthesis of l-(5-bromo-4-methylpyridin-2-yl)prop-2-en-l-one

[0771] To a solution of 5-bromo-4-methylpicolinoyl chloride (5.0 g, crude) in THF (100.0 mL) was dropwise added vinylmagnesium bromide (22.9 mL, 1.0 mol/L in THF) at 0 °C under N2. The resulting mixture was stirred at 0 °C for 3 h. After the reaction was completed, the mixture was diluted with water and extracted with dichloromethane. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by flash chromatography with petroleum ether/ethyl acetate (40/60, v/v) to afford l-(5-bromo-4- methylpyridin-2-yl)prop-2-en-l-one (2.7 g, 54%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 226.0.

Step 2: Synthesis of 5-bromo-2-(4,5-dihydro-lH-pyrazol-3-yl)-4-methylpyridine

[0772] To a solution of l-(5-bromo-4-methylpyridin-2-yl)prop-2-en-l-one (3.3 g, 14.7 mmol) in EtOH (30.0 mL) was added NH2NH2 (14.7 mL, 1.0 mol/L in EtOH) at room temperature. The resulting mixture was stirred at 80 °C for 4 h. After the reaction was completed, the mixture was concentrated under vacuum. The residue was purified by reverse phase flash chromatography with acetonitrile/water (50/50, v/v) to afford 5-bromo-2-(4,5- dihydro-lH-pyrazol-3-yl)-4-methylpyridine (1.6 g, 44%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 240.0.

Step 3: Synthesis of 5-bromo-2-(l-(4-methoxybenzyl)-4,5-dihydro-lH-pyrazol-3-yl)- 4- methylpyridine

[0773] To a solution of 5-bromo-2-(4,5-dihydro-lH-pyrazol-3-yl)-4-methylpyridine (984.0 mg, 4.14 mmol) in DMF (18.0 mL) was added NaH (165.5 mg, 60% purity) at 0 °C under N2. The mixture was stirred at 0 °C for 30 min. Then PMB-C1 (645.8 mg, 4.15 mmol) was added to the mixture at 0°C under N2. The mixture was stirred at room temperature for additional 16 h. After the reaction was completed, the mixture was diluted with water and extracted with dichloromethane. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by flash chromatography with petroleum ether/ethyl acetate (80/20, v/v) to afford 5-bromo-2-(l -(4-methoxybenzyl)-4,5-dihydro-lH-pyrazol-3-yl)-4-methylpyri dine (244.1 mg, 16%) as a brown oil. LCMS (ESI, m/z): [M+H] ⁺ = 360.1.

Step 4: Synthesis of 7-chloro-3-(6-(l-(4-methoxybenzyl)-4,5-dihydro-lH-pyrazol-3- yl)-4- methylpyridin-3-yl)-l, 6-naphthyridine

[0774] To a solution of 5-bromo-2-(l-(4-methoxybenzyl)-4,5-dihydro-lH-pyrazol-3-yl)- 4-methylpyridine (1.3 g, 2.98 mmol) in 1,4-dioxane (14.0 mL) and water (3.5 mL) was added 7-chloro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,6 -naphthyridine (866.7 mg, 2.98 mmol), Pd(dppf)2C12 (218.3 mg, 0.30 mmol) and K2CO3 (1.2 g, 8.68 mmol) at room temperature under N2. The resulting mixture was stirred at 80 °C for 2 h. After the reaction was completed, the mixture was cooled to room temperature and filtered. The filtrate was concentrated under vacuum. The residue was purified by flash chromatography with petroleum ether/ethyl acetate (55/45, v/v) to afford 7-chloro-3-(6-(l-(4-methoxybenzyl)-4,5- dihydro-lH-pyrazol-3-yl)-4-methylpyridin-3-yl)-l,6-naphthyri dine (764.0 mg, 50%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 444.2.

Step 5: Synthesis of tert-butyl (3-(6-(l-(4-methoxybenzyl)-4,5-dihydro-lH-pyrazol-3-yl)-4- methylpyridin-3-yl)-l , 6-naphthyridin- 7 -yl) carbamate [0775] To a solution of 7-chloro-3-(6-(l-(4-methoxybenzyl)-4,5-dihydro-lH-pyrazol-3- yl)-4-methylpyri din-3 -yl)-l,6-naphthyri dine (764.0 mg, 1.72 mmol) in 1,4-dioxane (15.0 mL) was added NH2B0C (1.0 g, 8.59 mmol), CS2CO3 (2.1 g, 6.44 mmol), Pd(OAc)2 (96.5 mg, 0.43 mmol) and XPhos (409.7 mg, 0.86 mmol) at room temperature under N2. The resulting mixture was stirred at 80 °C for 3 h. After the reaction was completed, the mixture was cooled to room temperature and filtered. The filtrate was concentrated under vacuum. The residue was purified by flash chromatography with petroleum ether/ethyl acetate (30/70, v/v) to afford tert-butyl (3-(6-(l-(4-methoxybenzyl)-4,5-dihydro-lH-pyrazol-3-yl)-4- methylpyridin-3-yl)-l,6-naphthyridin-7-yl)carbamate (414.0 mg, 54%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 525.3.

Step 6: Synthesis of 3-(6-(l-(4-methoxybenzyl)-4,5-dihydro-lH-pyrazol-3-yl)-4- methylpyridin-3-yl)-l, 6-naphthyridin- 7 -amine

3-yl)-4-methylpyridin-3-yl)-l,6-naphthyridin-7-yl)carbama te (414.0 mg, 0.79 mmol) in dichloromethane (15.0 mL) was added TFA (3.0 mL) at room temperature. The mixture was stirred at room temperature for 4 h. After the reaction was completed, the mixture was concentrated under vacuum. The pH value of the residue was adjusted to 8.0 with saturated NaHCO3 (aq.). The mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to afford 3-(6-(l-(4-methoxybenzyl)-4,5-dihydro-lH-pyrazol-3- yl)-4-methylpyridin-3-yl)-l,6-naphthyridin-7-amine (300.0 mg, crude) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =425.2.

Step 7: Synthesis of (R)-2,2-difluoro-N-(3-(6-(l-(4-methoxybenzyl)-4,5-dihydro-lH -pyrazol- 3-yl)-4-methylpyridin-3-yl)-l,6-naphthyridin-7-yl)cyclopropa ne-l-carboxamide

[0777] To a solution of 3-(6-(l-(4-methoxybenzyl)-4,5-dihydro-lH-pyrazol-3-yl)-4- methylpyridin-3-yl)-l,6-naphthyridin-7-amine (300.0 mg, crude) in pyridine (10.0 mL) was added (R)-2,2-difluorocyclopropane-l -carboxylic acid (241.4 mg, 1.98 mmol) and EDCI (1.9 g, 9.89 mmol) at room temperature. The resulting mixture was stirred at 40 °C for 16 h. After the reaction was completed, the mixture was diluted with water and extracted with dichloromethane. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by flash chromatography with petroleum ether/ethyl acetate (5/95, v/v) to afford (R)- 2,2-difluoro-N-(3-(6-(l-(4-methoxybenzyl)-4,5-dihydro-lH-pyr azol-3-yl)-4-methylpyri din-3- yl)-l,6-naphthyridin-7-yl)cyclopropane-l-carboxamide (252.0 mg, 75%) as a yellow solid.

LCMS (ESI, m/z): [M+H] ⁺ = 529.2.

Step 8: Synthesis of (R)-N-(3-(6-(4,5-dihydro-lH-pyrazol-3-yl)-4-methylpyridin-3- yl)-l,6- naphthyridin-7-yl)-2,2-difluorocyclopropane-l-carboxamide (Compound 180)

[0778] A solution of (R)-2,2-difluoro-N-(3-(6-(l-(4-methoxybenzyl)-4,5-dihydro-lH - pyrazol-3-yl)-4-methylpyridin-3-yl)-l,6-naphthyridin-7-yl)cy clopropane-l -carboxamide (250.0 mg, 0.48 mmol) in TFA (5.0 mL) was stirred at 100 °C for 4 h. After the reaction was completed, the mixture was concentrated under vacuum. The pH value of the residue was adjusted to 8.0 with sat. NaHCCE. The mixture was extracted with CH2CI2. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions: (Column: XBridge Prep OBD C18 Column, 30 x 150 mm, 5 pm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 40% B to 60% B in 15 min; Wave Length: 220/254 nm) to afford (R)-N- (3-(6-(4,5-dihydro-lH-pyrazol-3-yl)-4-methylpyridin-3-yl)-l, 6-naphthyridin-7-yl)-2,2- difluorocyclopropane- 1 -carboxamide (Compound 180) (12.4 mg, 5%) as a white solid.

LCMS (ESI, m/z): [M+H] ⁺ = 409.1. ¹ H NMR (400 MHz, DMSO-d6 ): 5 11.50 (s, 1H), 9.31 (s, 1H), 9.10 (s, 1H), 8.68 (s, 1H), 8.37 - 8.34 (m, 1H), 8.26 - 8.23 (m, 1H), 8.20 (s, 1H), 7.07 - 7.04 (m, 1H), 3.09 - 2.84 (m, 3H), 2.35 - 2.30 (m, 5H), 1.76 - 1.67 (m, 1H), 1.32 - 1.24 (m, 1H).

Example 100. Synthesis of (R)-2,2-difluoro-N-(3-(4-methyl-6-(lH-pyrazol-3-yl)pyridin-3 - yl)-l, 6-naphthyridin-7-yl)cyclopropane-l -carboxamide (Compound 181)

Step 1: Synthesis of 5-bromo-4-methyl-2-( lH-pyrazol-3-yl)pyridine

[0779] To a solution of 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (1.0 g, 5.15 mmol) in 1,4-dioxane (15.0 mL) and water (3.0 mL) was added 5-bromo-2-iodo-4- methylpyridine (1.5 g, 5.18 mmol), Pd(dppf)2C12 (380.3 mg, 0.52 mmol) and K2CO3 (1.9 g, 15.44 mmol) at room temperature under N2. The resulting mixture was stirred at 80 °C for 2 h. After the reaction was completed, the mixture was cooled to room temperature and then filtered. The filtrate was concentrated under vacuum. The residue was purified by flash chromatography with petroleum ether/ethyl acetate (55/45, v/v) to afford 5-bromo-4-methyl- 2-(lH-pyrazol-3-yl)pyridine (764.0 mg, 65%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 238.2.

Step 2: Synthesis of 5-bromo-2-(l-(4-methoxybenzyl)-lH-pyrazol-3-yl)-4-methylpyri dine

[0780] To a solution of 5-bromo-4-methyl-2-(lH-pyrazol-3-yl)pyridine (984.0 mg, 4.14 mmol) in DMF (18.0 mL) was added NaH (165.5 mg, 60% purity) at 0°C under N2. The mixture was stirred at 0 °C for 30 min. Then PMB-C1 (645.8 mg, 4.15 mmol) was added to the mixture at 0 °C under N2. The mixture was stirred at room temperature for additional 16 h. After the reaction was completed, the mixture was diluted with water and extracted with dichloromethane. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by flash chromatography with petroleum ether/ethyl acetate (80/20, v/v) to afford 5- bromo-2-(l-(4-methoxybenzyl)-lH-pyrazol-3-yl)-4-methylpyridi ne (544.1 mg, 32%) as a brown oil. LCMS (ESI, m/z): [M+H] ⁺ = 358.1.

Step 3: Synthesis of 7-chloro-3-(6-(l-(4-methoxybenzyl)-lH-pyrazol-3-yl)-4-methyl pyridin-3- yl)-l, 6-naphthyridine

[0781] To a solution of 5-bromo-2-(l-(4-methoxybenzyl)-lH-pyrazol-3-yl)-4- methylpyridine (1.3 g, 2.98 mmol) in 1,4-dioxane (15.0 mL) and water (3.0 mL) was added (7-chloro-l,6-naphthyridin-3-yl)boronic acid (866.7 mg, 2.98 mmol), Pd(dppf)2C12 (218.3 mg, 0.30 mmol) and K2CO3 (1.2 g, 8.68 mmol) at room temperature under N2. The resulting mixture was stirred at 80 °C for 2 h. After the reaction was completed, the mixture was cooled to room temperature and filtered. The filtrate was concentrated under vacuum. The residue was purified by flash chromatography with petroleum ether/ethyl acetate (55/45, v/v) to afford 7-chl oro-3 -(6-( 1 -(4-methoxybenzyl)- lH-pyrazol-3 -yl)-4-methylpyridin-3-yl)- 1 ,6- naphthyridine (764.0 mg, 50%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 442.2.

Step 4: Synthesis of tert-butyl 3-(6-(l-(4-methoxybenzyl)-lH-pyrazol-3-yl)-4-methylpyridin-3 -

[0782] To a solution of 7-chloro-3-(6-(l-(4-methoxybenzyl)-lH-pyrazol-3-yl)-4- methylpyri din-3 -yl)-l, 6-naphthyridine (764.0 mg, 1.72 mmol) in 1,4-dioxane (15.0 mL) was added NH2B0C (1.0 g, 8.59 mmol), CS2CO3 (2.1 g, 6.44 mmol), Pd(OAc)2 (96.5 mg, 0.43 mmol) and XPhos (409.7 mg, 0.86 mmol) at room temperature under N2. The resulting mixture was stirred at 80 °C for 3 h. After the reaction was completed, the mixture was cooled to room temperature and filtered. The filtrate was concentrated under vacuum. The residue was purified by flash chromatography with petroleum ether/ethyl acetate (30/70, v/v) to afford tert-butyl (3-(6-(l-(4-methoxybenzyl)-lH-pyrazol-3-yl)-4-methylpyridin- 3-yl)-l,6- naphthyridin-7-yl)carbamate (414.0 mg, 54%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 523.3.

Step 5: Synthesis of 3-(6-(l-(4-methoxybenzyl)-lH-pyrazol-3-yl)-4-methylpyridin-3 -yl)-l,6- naphthyridin- 7 -amine

[0783] To a solution of tert-butyl 3-(6-(l-(4-methoxybenzyl)-lH-pyrazol-3-yl)-4- methylpyridin-3-yl)-l,6-naphthyridin-7-ylcarbamate (300.0 mg, 0.57 mmol) in CH ₂ Cl ₂ (3.0 mL) was added TFA (1.0 mL). The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the resulting mixture was diluted with H2O. The pH value of the mixture was adjusted to 7.0 with saturated NaHCO3 (aq.). The mixture was extracted with CH ₂ Cl ₂ . The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to afford 3-(6-(l-(4- methoxybenzyl)-lH-pyrazol-3-yl)-4-methylpyridin-3-yl)-l,6-na phthyridin-7-amine (300.0 mg, crude) as a yellow oil. LCMS (ESI, m/z): [M+H] ⁺ = 423.1.

Step 6: Synthesis of (R)-2,2-difluoro-N-(3-(6-(l-(4-methoxybenzyl)-lH-pyrazol-3-y l)-4- methylpyridin-3-yl)-l,6-naphthyridin-7-yl)cyclopropane-l-car boxamide

[0784] To a solution of 3-(6-(l-(4-methoxybenzyl)-lH-pyrazol-3-yl)-4-methylpyridin-3 - yl)-l,6-naphthyridin-7-amine (300.0 mg, crude) in pyridine (5.0 mL) was added (lR)-2,2- difluorocyclopropane- 1 -carboxylic acid (108.0 mg, 0.89 mmol) and EDCI (283.0 mg, 1.48 mmol) at room temperature. The resulting mixture was stirred at room temperature for 4 h. After the reaction was completed, the resulting mixture was diluted with of H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by flash chromatography with CH ₂ Cl ₂ /MeOH (90/10, v/v) to afford (R)- 2,2-difluoro-N-(3-(6-(l-(4-methoxybenzyl)-lH-pyrazol-3-yl)-4 -methylpyridin-3-yl)-l,6- naphthyridin-7-yl)cyclopropane-l -carboxamide (148.0 mg, 40%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 527.1.

Step 7: Synthesis of (R)-2,2-dijluoro-N-(3-(4-methyl-6-(lH-pyrazol-3-yl)pyridin-3 -yl)-l,6- naphthyridin-7-yl)cyclopropane-l -carboxamide (Compound 181)

[0785] A solution of (R)-2,2-difluoro-N-(3-(6-(l-(4-methoxybenzyl)-lH-pyrazol-3-y l)-4- methylpyridin-3-yl)-l,6-naphthyridin-7-yl)cyclopropane-l-car boxamide (250.0 mg, 0.48 mmol) in TFA (5.0 mL) was stirred at 100 °C for 4 h. After the reaction was completed, the mixture was concentrated under vacuum. The pH value of the residue was adjusted to 8.0 with sat. NaHCCE. The mixture was extracted with CH ₂ Cl ₂ . The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions: (Column: XBridge Prep OBD C18 Column, 30 x 150 mm, 5 pm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 40% B to 60% B in 15 min; Wave Length: 220/254 nm) to afford (R)-2,2-difluoro-N-(3-(4- methyl-6-(lH-pyrazol-3-yl)pyridin-3-yl)-l,6-naphthyridin-7-y l)cyclopropane-l-carboxamide (Compound 181) (6.2 mg, 2%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 407.2. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.63 (s, 1H), 11.50 (s, 1H), 9.31 (s, 1H), 9.10 (s, 1H), 8.68 (s, 1H), 8.37 - 8.34 (m, 1H), 8.26 - 8.23 (m, 1H), 8.20 - 8.11 (m, 2H), 7.07 - 7.04 (m, 1H), 3.08 - 3.02 (m, 1H), 2.35 (s, 3H), 1.76 - 1.67 (m, 1H), 1.32 - 1.24 (m, 1H). Example 101. Synthesis of (lR,2R)-N-(2-(azetidine-l-carbonyl)-3-(6-((S)-l- hydroxypropyl)-4-methylpyridin-3-yl)-l,6-naphthyridin-7-yl)- 2-fluorocyclopropane-l- carboxamide (Compound 182) and (lR,2R)-N-(2-(azetidine-l-carbonyl)-3-(6-((R)-l- hydroxypropyl)-4-methylpyridin-3-yl)-l, 6-naphthyridin- 7-yl)-2-fluorocyclopropane-l - carboxamide (Compound 183)

Step 1: Synthesis of azetidin-l-yl(3-bromo-7-chloro-l,6-naphthyridin-2-yl)methano ne

[0786] To a solution of 3-bromo-7-chloro-l,6-naphthyridine-2-carboxylic acid (3.0 g, 10.48 mmol) in pyridine (45.0 mL) was added azetidine hydrochloride (1.3 g, 12.57 mmol) and EDCI (2.9 g, 15.20 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. After the reaction was completed, the mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with ethyl acetate /petroleum ether (55/45, v/v) to afford azetidin-l-yl(3-bromo-7-chloro-l,6-naphthyridin-2- yl)methanone (1.9 g, 55%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 326.1.

Step 2: Synthesis of l-(5-(2-(azetidine-l-carbonyl)-7-chloro-l,6-naphthyridin-3-y l)-4- methylpyridin-2-yl)propan-l-one

[0787] To a solution of azetidin-l-yl(3-bromo-7-chloro-l,6-naphthyridin-2-yl)methano ne (1.9 g, 5.82 mmol) in dioxane (45.0 mL) and H2O (9.0 mL) was added l-[4-methyl-5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl]pr opan-l-one (1.8 g, 6.51 mmol), Pd(AMphos)C12 (417.2 mg, 0.63 mmol) and K2CO3 (4.9 g, 35.63 mmol) at room temperature under N2. The resulting mixture was stirred at 80 °C for 2 h under N2. After the reaction was completed, the mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with ethyl acetate/petroleum ether (70/30, v/v) to afford l-(5-(2-(azetidine- l-carbonyl)-7-chloro-l,6-naphthyridin-3-yl)-4-methylpyridin- 2-yl)propan-l-one (820.0 mg, 34%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 395.1.

Step 3: Synthesis of (lR,2R)-N-(2-(azetidine-l-carbonyl)-3-(4-methyl-6-propionylp yridin-3- yl)-l,6-naphthyridin-7-yl)-2-fluorocyclopropane-l -carboxamide

[0788] To a solution of l-(5-(2-(azetidine-l-carbonyl)-7-chloro-l,6-naphthyridin-3-y l)-4- methylpyridin-2-yl)propan-l-one (400.0 mg, 1.02 mmol) in dioxane (13.0 mL) was added (lR,2R)-2-fluorocyclopropane-l-carboxamide (158.7 mg, 1.53 mmol), CS2CO3 (1003.2 mg, 3.09 mmol), BrettPhos (253.9 mg, 0.42 mmol) and BrettPhos Pd G3 (186.2 mg, 0.21 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 2 h under N2. After the reaction was completed, the mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with dichloromethane/methanol (87/13, v/v) to afford (lR,2R)-N-(2- (azetidine-l-carbonyl)-3-(4-methyl-6-propionylpyridin-3-yl)- l,6-naphthyridin-7-yl)-2- fluorocyclopropane-1 -carboxamide (272.0 mg, 57%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 462.2.

Step 4: Synthesis of (lR,2R)-N-(2-(azetidine-l-carbonyl)-3-(6-(l-hydroxypropyl)-4 - methylpyridin-3-yl)-l,6-naphthyridin-7-yl)-2-fluorocycloprop ane-l-carboxamide

[0789] To a solution of (lR,2R)-N-(2-(azetidine-l-carbonyl)-3-(4-methyl-6- propionylpyridin-3-yl)-l,6-naphthyridin-7-yl)-2 -fluorocyclopropane-1 -carboxamide (340.0 mg, 0.73 mmol) in THF (10.0 mL) and MeOH (2.0 mL) was added NaBH ₄ (48.1 mg, 1.31 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with dichloromethane/methanol (85/15, v/v) and then purified by Prep-HPLC with the following conditions (Column: XBridge Prep Phenyl OBD Column, 19x250 mm, 5 pm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 20% B to 30% B in 15 min, 30% B; Wave Length: 254 nm) to afford (lR,2R)-N-(2-(azetidine-l-carbonyl)-3-(6-(l-hydroxypropyl)-4 -methylpyridin-3- yl)-l,6-naphthyridin-7-yl)-2-fluorocyclopropane-l-carboxamid e (77.8 mg, 22%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 464.1.

Step 5: Separation of (lR,2R)-N-(2-(azetidine-l-carbonyl)-3-(6-((S)-l-hydroxypropy l)-4- methylpyridin-3-yl)-l,6-naphthyridin-7-yl)-2-jluorocycloprop ane-l-carboxamide (Compound 182) and (1R, 2R)-N-(2-(azetidine-l-carbonyl)-3-( 6-( (R)-l -hydroxypropyl) -4-methylpyridin- 3-yl)-l, 6-naphthyridin-7-yl)-2-jluorocyclopropane-l -carboxamide (Compound 183)

[0790] The product of (lR,2R)-N-(2-(azetidine-l-carbonyl)-3-(6-(l-hydroxypropyl)-4 - methylpyridin-3-yl)-l,6-naphthyridin-7-yl)-2-fluorocy cl opropane-1 -carboxamide (76.0 mg, 0.16 mmol) was separated by Prep-Chiral-HPLC with the following conditions: (Column: CHIRAL ART Cellulose-SC, 2x25 cm, 5 pm; Mobile Phase A: Hex (0.5% 2M NH ₃ -MeOH)- -HPLC, Mobile Phase B: EtOH: DCM=1 : 1-HPLC; Flow rate: 20 mL/min; Gradient: 55% B to 55% B in 9.5 min; Wave Length: 254/220 nm; RTl(min): 7.38; RT2(min): 8.65) to afford ( 1 R,2R)-N-(2-(azetidine- 1 -carbonyl)-3 -(6-( 1 -hydroxypropyl)-4-methylpyri din-3 -y 1 ) - 1 , 6 - naphthyridin-7-yl)-2-fluorocyclopropane-l -carboxamide Isomer 1 (retention time 7.38 minutes, 14.3 mg, 39%) as a white solid and (lR,2R)-N-(2-(azetidine-l-carbonyl)-3-(6-(l- hydroxypropyl)-4-methylpyridin-3-yl)-l,6-naphthyridin-7-yl)- 2-fluorocycl opropane-1 - carboxamide Isomer 2 (retention time 8.65 minutes, 12.8 mg, 40%) as a white solid. The absolute stereochemistry of Isomers 1 and 2 was not assigned. The two isomeric structures that could be obtained from chiral separation of the isomeric mixture as described above are shown as Compounds 182 and 183 in Table 1.

[0791] (lR,2R)-N-(2-(azetidine-l-carbonyl)-3-(6-(l-hydroxypropyl)-4 - methylpyridin-3-yl)-l,6-naphthyridin-7-yl)-2-fluorocycloprop ane-l-carboxamide

Isomer 1: RTl(min): 7.38; LCMS (ESI, m/z): [M+H] ⁺ = 464.2. ¹ H NMR (400 MHz, DMSO- d ₆ ) 5 11.45 (s, 1H), 9.23 (s, 1H), 9.07 (s, 1H), 8.69 (s, 1H), 8.19 (s, 1H), 7.51 (s, 1H), 5.37 (d, J= 4.8 Hz, 1H), 5.10 - 4.93 (m, 1H), 4.59 - 4.55 (m, 1H), 3.96 - 3.85 (m, 4H), 2.36 - 2.30 (m, 1H), 2.28 (s, 3H), 1.88 - 1.82 (m, 1H), 1.78 - 1.68 (m, 2H), 1.29 - 1.24 (m, 1H), 0.95 - 0.91 (m, 3H).

[0792] (lR,2R)-N-(2-(azetidine-l-carbonyl)-3-(6-((l-hydroxypropyl)- 4- methylpyridin-3-yl)-l,6-naphthyridin-7-yl)-2-fluorocycloprop ane-l-carboxamide

Isomer 2: RT2 (min): 8.65; LCMS (ESI, m/z): [M+H] ⁺ = 464.2. ¹ H NMR (400 MHz, DMSO-d ₆ ): 5 11.47 (s, 1H), 9.23 (s, 1H), 9.07 (s, 1H), 8.69 (s, 1H), 8.19 (s, 1H), 7.51 (s, 1H), 5.37 (d, J= 4.8 Hz, 1H), 5.12 - 4.92 (m, 1H), 4.58 - 4.55 (m, 1H), 3.96 - 3.85 (m, 4H), 2.36 - 2.30 (m, 1H), 2.28 (s, 3H), 1.88 - 1.80 (m, 1H), 1.78 - 1.66 (m, 2H), 1.31 - 1.24 (m, 1H), 0.95 - 0.86 (m, 3H).

Example 102. Synthesis of (lR,2R)-2-fluoro-N-(3-(6-((S)-l-hydroxypropyl)-4- methylpyridin-3-yl)-2-(morpholine-4-carbonyl)-l,6-naphthyrid in-7-yl)cyclopropane-l- carboxamide (Compound 184) and (lR,2R)-2-fluoro-N-(3-(6-((R)-l-hydroxypropyl)-4- methylpyridin-3-yl)-2-(morpholine-4-carbonyl)-l,6-naphthyrid in-7-yl)cyclopropane-l- carboxamide (Compound 185)

Step 1: Synthesis of l-(5-(7-chloro-2-(morpholine-4-carbonyl)-l,6-naphthyridin-3- yl)-4- methylpyridin-2-yl)propan-l-one

[0793] To a solution of 7-chl oro-3 -(4-methyl-6-propionylpyri din-3 -yl)- 1,6- naphthyridine-2-carboxylic acid (700.0 mg, 1.97 mmol) in Pyridine (20.0 mL) was added morpholine (239.3 mg, 2.75 mmol) and EDCI (1422.5 mg, 7.42 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (90/10, v/v) to afford l-(5-(7-chloro-2- (morpholine-4-carbonyl)-l, 6-naphthyridin-3-yl)-4-methylpyri din-2 -yl)propan-l -one (450.0 mg, 53%) as a light yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 425.0.

Step 2: Synthesis of tert-butyl (3-(4-methyl-6-propionylpyridin-3-yl)-2-(morpholine-4- carbonyl)-l,6-naphthyridin-7-yl) carbamate

[0794] To a solution of l-(5-(7-chloro-2-(morpholine-4-carbonyl)-l,6-naphthyridin-3- yl)- 4-methylpyridin-2-yl)propan-l-one (930.0 mg, 2.18 mmol) in dioxane (25.0 mL) was added B0CNH2 (389.7 mg, 3.55 mmol), CS2CO3 (2.1 g, 6.48 mmol), Pd(OAc)2 (50.6 mg, 0.24 mmol) and XPhos (208.1 mg, 0.48 mmol) at room temperature under N2. The resulting mixture was stirred at 80 °C for 2 h under N2. After the reaction was completed, the mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with dichloromethane /methanol (92/8, v/v) to afford tert-butyl (3-(4-methyl-6-propionylpyridin-3-yl)-2- (morpholine-4-carbonyl)-l,6-naphthyridin-7-yl)carbamate (452.0 mg, 41%) as a brown solid. LCMS (ESI, m/z): [M+H] ⁺ = 506.1.

Step 3: Synthesis of l-(5-(7-amino-2-(morpholine-4-carbonyl)-l,6-naphthyridin-3-y l)-4- methylpyridin-2-yl)propan-l-one [0795] To a solution of tert-butyl (3-(4-methyl-6-propionylpyridin-3-yl)-2-(morpholine- 4-carbonyl)-l,6-naphthyridin-7-yl)carbamate (714.0 mg, 1.41 mmol) in DCM (10.0 mL) was added TFA (2.0 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The pH value of the residue was adjusted to 8.0 with saturated NaHCCL (aq.). The mixture was extracted with CH2CI2. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to afford l-(5-(7-amino-2-(morpholine-4-carbonyl)-l,6- naphthyridin-3-yl)-4-methylpyridin-2-yl)propan-l-one (650.0 mg, crude) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 406.1.

Step 4: Synthesis of (lR,2R)-2-fluoro-N-(3-(4-methyl-6-propionylpyridin-3-yl)-2- (morpholine-4-carbonyl)-l,6-naphthyridin-7-yl)cyclopropane-l -carboxamide

[0796] To a solution of l-(5-(7-amino-2-(morpholine-4-carbonyl)-l,6-naphthyridin-3-y l)- 4-methylpyridin-2-yl)propan-l-one (610.0 mg, crude) in pyridine (12.0 mL) was added (lR,2R)-2-fluorocyclopropane-l -carboxylic acid (268.8 mg, 2.16 mmol) and EDCI (2.1 g, 11.13 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (87/13, v/v) to afford (lR,2R)-2-fluoro-N-(3-(4-methyl-6-propionylpyridin-3-yl)-2-( morpholine-4- carbonyl)-l,6-naphthyridin-7-yl)cyclopropane-l-carboxamide (204.0 mg, 33%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 492.1.

Step 5: Synthesis of (lR,2R)-2-fluoro-N-(3-(6-(l-hydroxypropyl)-4-methylpyridin-3 -yl)-2- (morpholine-4-carbonyl)-l,6-naphthyridin-7-yl)cyclopropane-l -carboxamide

[0797] To a solution of (lR,2R)-2-fluoro-N-(3-(4-methyl-6-propionylpyridin-3-yl)-2- (morpholine-4-carbonyl)-l,6-naphthyridin-7-yl)cyclopropane-l -carboxamide (184.0 mg, 0.37 mmol) in MeOH (1.0 mL) and THF (5.0 mL) was added NaBHj (20.5 mg, 0.55 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by flash chromatography with C^CL/MeOH (85/15, v/v) to afford (lR,2R)-2-fluoro-N-(3-(6-(l- hydroxypropyl)-4-methylpyridin-3-yl)-2-(morpholine-4-carbony l)-l,6-naphthyri din-7- yl)cy cl opropane-1 -carboxamide (50.0 mg, 67%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 494.2.

Step 6: Separation of (lR,2R)-2-jluoro-N-(3-(6-((S)-l-hydroxypropyl)-4-methylpyrid in-3-yl)- 2-(morpholine-4-carbonyl)-l,6-naphthyridin-7-yl)cyclopropane -l-carboxamide (Compound 184) and (1R, 2R)-2-jluoro-N-( 3-( 6-( (R)-l-hydroxypropyl)-4-methylpyridin-3-yl)-2- (morpholine-4-carbonyl) -l,6-naphthyridin-7-y I) cyclopropane- 1 -carboxamide (compound

185)

[0798] The product of (lR,2R)-2-fluoro-N-(3-(6-(l-hydroxypropyl)-4-methylpyridin-3 - yl)-2-(morpholine-4-carbonyl)-l,6-naphthyridin-7-yl)cy cl opropane-1 -carboxamide (83.0 mg, 0.17 mmol) was separated by Prep-Chiral-HPLC with the following conditions (Column: CHIRAL ART Cellulose-SC, 2x25 cm, 5 pm; Mobile Phase A: Hex (0.5% 2M NH ₃ -MeOH)- HPLC, Mobile Phase B: MeOH: DCM=1: 1-HPLC; Flow rate: 20 mL/min; Gradient: 60% B to 60% B in 14 min; Wave Length: 254/220 nm; RTl(min): 10.14; RT2(min): 12.75) to afford (lR,2R)-2-fluoro-N-(3-(6-(l-hydroxypropyl)-4-methylpyridin-3 -yl)-2-(morpholine-4- carbonyl)-l,6-naphthyridin-7-yl)cyclopropane-l-carboxamide Isomer 1 (retention time 10.14 minutes, 13.6 mg, 33%) as a white solid and (lR,2R)-2-fluoro-N-(3-(6-(l-hydroxypropyl)-4- methylpyridin-3-yl)-2-(morpholine-4-carbonyl)-l,6-naphthyrid in-7-yl)cyclopropane-l- carboxamide Isomer 2 (retention time 12.75 minutes, 13.5 mg, 33%) as a white solid. The absolute stereochemistry of Isomers 1 and 2 was not assigned. The two isomeric structures that could be obtained from chiral separation of the isomeric mixture as described above are shown as Compounds 184 and 185 in Table 1.

[0799] (lR,2R)-2-fluoro-N-(3-(6-(l-hydroxypropyl)-4-methylpyridin-3 -yl)-2- (morpholine-4-carbonyl)-l,6-naphthyridin-7-yl)cyclopropane-l -carboxamide Isomer 1:

RTl(min): 10.14; LCMS (ESI, m/z): [M+H] ⁺ = 494.2. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ

11.26 (s, 1H), 9.31 (s, 1H), 8.63 - 8.61 (m, 2H), 8.40 (s, 1H), 7.63 (s, 1H), 5.09 - 4.88 (m, 1H), 4.67 - 4.64 (m, 1H), 3.44 - 3.41 (m, 8H), 2.36 - 2.29 (m, 4H), 1.89 - 1.80 (m, 1H), 1.78 - 1.66 (m, 2H), 1.28 - 1.19 (m, 1H), 0.91 - 0.87 (m, 3H).

[0800] (lR,2R)-2-fluoro-N-(3-(6-(l-hydroxypropyl)-4-methylpyridin-3 -yl)-2- (morpholine-4-carbonyl)-l,6-naphthyridin-7-yl)cyclopropane-l -carboxamide Isomer 2:

RT2(min): 12.75; LCMS (ESI, m/z): [M+H] ⁺ = 494.2. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ

11.27 (s, 1H), 9.31 (s, 1H), 8.63 - 8.61 (m, 2H), 8.41 (s, 1H), 7.63 (s, 1H), 5.09 - 4.89 (m, 1H), 4.68 - 4.64 (m, 1H), 3.43 - 3.40 (m, 8H), 2.34 - 2.29 (m, 4H), 1.88 - 1.82 (m, 1H), 1.78 - 1.69 (m, 2H), 1.28 - 1.20 (m, 1H), 0.91 - 0.87 (m, 3H).

Example 103. Synthesis of (lR,2R)-2-fluoro-N-(3-(6-((S)-l-hydroxypropyl)-4- methylpyridin-3-yl)-2-(l-methyl-lH-imidazol-2-yl)-l,6-naphth yridin-7-yl)cyclopropane-l- carboxamide (Compound 186) and (lR,2R)-2-fluoro-N-(3-(6-((R)-l-hydroxypropyl)-4- methylpyridin-3-yl)-2-(l-methyl-lH-imidazol-2-yl)-l,6-naphth yridin-7-yl)cyclopropane-l- carboxamide (Compound 187)

Step 1: Synthesis of 3-bromo-7-chloro-2-(l-methyl-lH-imidazol-2-yl)-l,6-naphthyri dine [0801] To a mixture of 3-bromo-7-chloro-2-iodo-l,6-naphthyridine (1.4 g, 3.79 mmol) in DMF (10 mL) was added l-methyl-2-(tributylstannyl)-lH-imidazole (1.6 g, 4.55 mmol), KF (1.1 g, 18.95 mmol) and Pd(dppf)C12.CH2C12 (271.3 mg, 0.37 mmol) at room temperature under N2. The resulting mixture was stirred for at 60 °C for 12 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (50/50, v/v) to afford 3- bromo-7-chloro-2-(l-methyl-lH-imidazol-2-yl)-l,6-naphthyridi ne (600.0 mg, 48%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 323.0.

Step 2: Synthesis of l-(5-(7-chloro-2-(l-methyl-lH-imidazol-2-yl)-l,6-naphthyridi n-3-yl)-4- methylpyridin-2-yl)propan-l-one

[0802] To a mixture of 3-bromo-7-chloro-2-(l-methyl-lH-imidazol-2-yl)-l,6- naphthyridine (600.0 mg, 1.85 mmol) in dioxane (5.0 mL) and H2O (1.0 mL) was added l-(4- methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridi n-2-yl)propan-l-one (765.3 mg, 2.78 mmol), K2CO3 (76.8 mg, 0.55 mmol) and Pd(dppf)C12 (271.3 mg, 0.37 mmol) at room temperature under N2. The resulting mixture was stirred at 80 °C for 2 h under N2. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (50/50, v/v) to afford l-(5-(7-chloro-2-(l-methyl-lH-imidazol-2-yl)-l,6-naphthyridi n-3-yl)- 4-methylpyridin-2-yl)propan-l-one (200.0 mg, 27%) as a light yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 392.1.

Step 3: Synthesis of (lR,2R)-2-fluoro-N-(2-(l-methyl-lH-imidazol-2-yl)-3-(4-methy l-6- propionylpyridin-3-yl)-l,6-naphthyridin-7-yl)cyclopropane-l- carboxamide

[0803] To a mixture of l-(5-(7-chloro-2-(l-methyl-lH-imidazol-2-yl)-l,6-naphthyridi n- 3-yl)-4-methylpyridin-2-yl)propan-l-one (160.0 mg, 0.40 mmol) in dioxane (3.0 mL) was added (lR,2R)-2-fluorocyclopropane-l -carboxamide (210.4 mg, 2.04 mmol), K2CO3 (76.8 mg, 0.55 mmol) and Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (68.6 mg, 0.08 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 12 h under N2. After the reaction was completed, the resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (50/50, v/v) to afford (lR,2R)-2-fluoro- N-(2-(l -methyl- lH-imidazol-2-yl)-3-(4-methyl-6-propionylpyridin-3-yl)-l,6-n aphthyri din-7- yl)cyclopropane-l -carboxamide (100.0 mg, 53%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 459.2.

Step 4: Synthesis of (lR,2R)-2-jluoro-N-(3-(6-(l-hydroxypropyl)-4-methylpyridin-3 -yl)-2-(l- methyl-lH-imidazol-2-yl)-l,6-naphthyridin-7-yl)cyclopropane- l-carboxamide

[0804] To a solution of (lR,2R)-2-fluoro-N-(2-(l-methyl-lH-imidazol-2-yl)-3-(4-methy l- 6-propionylpyridin-3-yl)-l,6-naphthyridin-7-yl)cyclopropane- l-carboxamide (90.0 mg, 0.19 mmol) in THF (3.0 mL) and MeOH (0.3 mL) were added NaBH4 (14.8 mg, 0.39 mmol) at 0 °C under N2. The resulting mixture was stirred at 0 °C for 2 h under N2. After the reaction was completed, the reaction mixture was quenched with H2O at 0 °C. The resulting mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /MeOH (10/1, v/v) to afford (lR,2R)-2-fluoro-N-(3-(6-(l-hydroxypropyl)-4-methylpyridin-3 -yl)-2- (1-methyl-lH-imidazol -2 -yl)-l,6-naphthyri din-7-yl)cy cl opropane-1 -carboxamide (50.0 mg, 55%) as a light yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 461.2.

Step 5: Separation of (lR,2R)-2-jluoro-N-(3-(6-((S)-l-hydroxypropyl)-4-methylpyrid in-3-yl)- 2-( 1 -methyl- lH-imidazol-2-yl)-l, 6-naphthyridin- 7 -yl)cyclopropane-l -carboxamide (Compound 186) and (lR,2R)-2-jluoro-N-(3-(6-((R)-l-hydroxypropyl)-4-methylpyrid in-3-yl)- 2-( 1 -methyl- lH-imidazol-2-yl)-l, 6-naphthyridin- 7 -yl)cyclopropane-l -carboxamide (Compound 187)

[0805] The product of (lR,2R)-2-fluoro-N-(3-(6-(l-hydroxypropyl)-4-methylpyridin-3 - yl)-2-(l -methyl- IH-imidazol -2 -yl)-l,6-naphthyridin-7-yl)cy cl opropane-1 -carboxamide (50.0 mg, 0.25 mmol) was separated by Prep-Chiral-HPLC with the following conditions (Column: CHIRALPAK IC, 2x25 cm, 5 pm; Mobile Phase A: Hex (0.5% 2M NH ₃ -MeOH), Mobile Phase B: MEOH: DCM=1 : 1— HPLC; Flow rate: 20 mL/min; Gradient: 30% B to 30% B in 28 min; Wave Length: 220/254 nm; RTl(min): 17.75; RT2(min): 21.5) to afford (lR,2R)-2- fluoro-N-(3-(6-(l-hydroxypropyl)-4-methylpyridin-3-yl)-2-(l- methyl-lH-imidazol-2-yl)-l,6- naphthyridin-7-yl)cyclopropane-l -carboxamide Isomer 1 (retention time 17.75 minutes, 6.4 mg, 25%) as a white solid and (lR,2R)-2-fluoro-N-(3-(6-(l-hydroxypropyl)-4-methylpyridin- 3-yl)-2-(l -methyl- IH-imidazol -2 -yl)-l,6-naphthyridin-7-yl)cy cl opropane-1 -carboxamide Isomer 2 (retention time 21.5 minutes, 6.7 mg, 26%) as a white solid. The absolute stereochemistry of Isomers 1 and 2 was not assigned. The two isomeric structures that could be obtained from chiral separation of the isomeric mixture as described above are shown as Compounds 186 and 187 in Table 1.

[0806] (lR,2R)-2-fluoro-N-(3-(6-(l-hydroxypropyl)-4-methylpyridin-3 -yl)-2-(l- methyl-lH-imidazol-2-yl)-l,6-naphthyridin-7-yl)cyclopropane- l-carboxamide Isomer 1:

RTl(min): 17.75; LCMS (ESI, m/z): [M+H] ⁺ = 461.1. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.18 (s, 1H), 9.21 (d, J= 5.2 Hz, 1H), 8.59 (s, 1H), 8.45 - 8.36 (m, 2H), 7.79 (s, 1H), 7.42 (s, 1H), 6.18 - 6.13 (m, 1H), 5.42 - 5.32 (m, 1H), 5.07 - 4.88 (m, 1H), 4.59 - 4.57 (m, 1H), 4.02 (s, 3H), 2.35 - 2.30 (m, 1H), 1.98 - 1.96 (m, 3H), 1.88 - 1.80 (m, 1H), 1.75 - 1.66 (m, 2H), 1.29 - 1.20 (m, 1H), 0.92 - 0.85 (s, 3H). [0807] (lR,2R)-2-fluoro-N-(3-(6-(l-hydroxypropyl)-4-methylpyridin-3 -yl)-2-(l- methyl-lH-imidazol-2-yl)-l,6-naphthyridin-7-yl)cyclopropane- l-carboxamide Isomer 2: RT2(min):21.5; LCMS (ESI, m/z): [M+H] ⁺ = 461.2. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.18 (s, 1H), 9.21 (d, J= 6.0 Hz, 1H), 8.60 (s, 1H), 8.44 - 8.36 (m, 2H), 7.79 (s, 1H), 7.43 - 7.41 (m, 1H), 6.18 - 6.13 (m, 1H), 5.41 - 5.32 (m, 1H), 5.08 - 4.88 (m, 1H), 4.58 - 4.55 (m, 1H), 4.03 (s, 3H), 2.34 - 2.30 (m, 1H), 1.98 - 1.96 (m, 3H), 1.87 - 1.80 (m, 1H), 1.77 - 1.65 (m, 2H), 1.28 - 1.19 (m, 1H), 0.92 - 0.85 (m, 3H).

Example 104. Synthesis of (lR,2R)-2-fluoro-N-(3-(6-((S)-l-hydroxypropyl)-4- methylpyridin-3-yl)-2-(4-methyl-4H-l,2,4-triazol-3-yl)-l,6-n aphthyridin-7-yl)cyclopropane- 1 -carboxamide (Compound 188) and (lR,2R)-2-fluoro-N-(3-(6-((R)-l-hydroxypropyl)-4- methylpyridin-3-yl)-2-(4-methyl-4H-l,2,4-triazol-3-yl)-l,6-n aphthyridin-7-yl)cyclopropane- 1 -carboxamide (Compound 189)

Step 1: Synthesis of 3-bromo-4-methyl-4H-l,2,4-triazole

[0808] To a solution of 4-methyl-4H-l,2,4-triazole (10.0 g, 119.04 mmol) in CHCh (150.0 mL) was added NBS (16.9 g, 95.23 mmol) at room temperature, the resulting mixture was stirred at room temperature for 16 h. After the reaction was completed, the mixture was diluted with H2O and extracted with CHCh. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with ethyl acetate/petroleum ether (55/45, v/v) AND THEN purified by Prep-Achiral-SFC with the following conditions: (Column: GreenSep Basic, 3x15 cm, 5 pm; Mobile Phase A: CO2, Mobile Phase B: MeOH (0.1% 2M NH3-MEOH); Flow rate: 65 mL/min; Gradient: isocratic 31% B; Column Temperature (°C): 35; Back Pressure(bar): 100; Wave Length: 220 nm) to afford 3-bromo-4-methyl-4H-l,2,4-triazole (1.4 g, 7%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 162.1.

Step 2: Synthesis of 4-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-4H- l,2,4- triazole

[0809] To a solution of 3-bromo-4-methyl-4H-l,2,4-triazole (1.4 g, 8.60 mmol) in dioxane (40.0 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (3.3 g, 12.92 mmol), Pd(dppf)C12 (0.8 g, 0.97 mmol) and KOAc (2.6 g, 25.84 mmol) at room temperature under N2. The resulting mixture was stirred at 90 °C for 2 h under N2. After the reaction was completed, the mixture was cooled to room temperature and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with ethyl acetate/petroleum ether (50/50, v/v) to afford 4-methyl-3-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-4H-l,2,4-triazole (1.1 g, 65%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 210.1.

Step 3: Synthesis of 3-bromo-7-chloro-2-(4-methyl-4H-l,2,4-triazol-3-yl)-l,6-naph thyridine

[0810] To a solution of 3-bromo-7-chloro-2-iodo-l,6-naphthyridine (1.5 g, 4.85 mmol) in dioxane (25.0 mL) and H2O (5.0 mL) was added 4-methyl-3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-4H-l,2,4-triazole (890.4 mg, 4.24 mmol), Pd(dppf)C12 (321.6 mg, 0.44 mmol) and K2CO3 (2.0 g, 14.54 mmol) at room temperature under N2. The resulting mixture was stirred at 80 °C for 2 h under N2. After the reaction was completed, the mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether /ethyl acetate (45/55, v/v) to afford 3-bromo-7-chloro-2-(4-methyl-4H-l,2,4-triazol-3-yl)-l,6- naphthyridine (424.0 mg, 26%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 324.1.

Step 4: Synthesis of l-(5-(7-chloro-2-(4-methyl-4H-l,2,4-triazol-3-yl)-l,6-naphth yridin-3-yl)~ 4-methylpyridin-2-yl)propan-l-one

[0811] To a solution of 3-bromo-7-chloro-2-(4-methyl-4H-l,2,4-triazol-3-yl)-l,6- naphthyridine (1.1 g, 3.40 mmol) in dioxane (20.0 mL) and H2O (4.0 mL) was added l-(4- methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridi n-2-yl)propan-l-one (1.0 g, 5.33 mmol), Pd(AMphos)C12 (226.7 mg, 0.33 mmol) and K2CO3 (2.0 g, 14.54 mmol) at room temperature under N2. The resulting mixture was stirred at 80 °C for 2 h under N2. After the reaction was completed, the mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (25/75, v/v) to afford l-(5-(7-chloro-2-(4- methyl-4H-l,2,4-triazol-3-yl)-l,6-naphthyridin-3-yl)-4-methy lpyridin-2-yl)propan-l-one (556.0 mg, 39%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 393.1.

Step 5: Synthesis of (lR,2R)-2-jluoro-N-(2-(4-methyl-4H-l,2,4-triazol-3-yl)-3-(4- methyl-6- propionylpyridin-3-yl)-l,6-naphthyridin-7-yl)cyclopropane-l- carboxamide

[0812] To a solution of l-(5-(7-chloro-2-(4-methyl-4H-l,2,4-triazol-3-yl)-l,6- naphthyridin-3-yl)-4-methylpyridin-2-yl)propan-l-one (600.0 mg, 1.59 mmol) in dioxane (12.0 mL) was added (lR,2R)-2-fluorocyclopropane-l-carboxamide (245.1 mg, 2.38 mmol), K2CO3 (1552.2 mg, 4.76 mmol), Pd(OAc)2 (71.3 mg, 0.32 mmol) and XPhos (302.8 mg, 0.64 mmol) at room temperature under N2. The resulting mixture was stirred at 80 °C for 2 h under N2. After the reaction was completed, the mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether /ethyl acetate (20/80, v/v) to afford (lR,2R)-2-fluoro-N-(2-(4-methyl-4H-l,2,4-triazol-3-yl)-3-(4- methyl-6-propionylpyridin-3- yl)-l,6-naphthyridin-7-yl)cyclopropane-l-carboxamide (204.0 mg, 27%) as a yellow solid.

LCMS (ESI, m/z): [M+H] ⁺ = 460.0.

Step 6: Synthesis of (lR,2R)-2-fluoro-N-(3-(6-(l-hydroxypropyl)-4-methylpyridin-3 -yl)-2-(4- methyl-4H-l, 2, 4-triazol-3-yl)-l, 6-naphthyridin- 7 -yl)cyclopropane-l -carboxamide

[0813] To a solution of (lR,2R)-2-fluoro-N-(2-(4-methyl-4El-l,2,4-triazol-3-yl)-3-(4 - methyl-6-propionylpyridin-3-yl)-l,6-naphthyridin-7-yl)cy cl opropane-1 -carboxamide (204.0 mg, 0.44 mmol) in THF (10.0 mL) and MeOH (2.0 mL) was added NaBH4 (28.5 mg, 0.75 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the resulting mixture was diluted with of H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by flash column chromatography with dichloromethane/methanol (85/15, v/v) to afford (lR,2R)-2-fluoro-N-(3-(6-(l-hydroxypropyl)-4-methylpyridin-3 -yl)-2-(4-methyl-4H- l,2,4-triazol-3-yl)-l,6-naphthyridin-7-yl)cyclopropane-l-car boxamide (70.2 mg, 34%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 462.1.

Step 7: Separation of (lR,2R)-2-fluoro-N-(3-(6-((S)-l-hydroxypropyl)-4-methylpyrid in-3-yl)~ 2-(4-methyl-4H-l,2,4-triazol-3-yl)-l,6-naphthyridin-7-yl)cyc lopropane-l-carboxamide (Compound 188) and (lR,2R)-2fhioro-N-(3-(6-((R)-l-hydroxypropyl)-4-methylpyridi n-3-yl)- 2-(4-methyl-4H-l,2,4-triazol-3-yl)-l,6-naphthyridin-7-yl)cyc lopropane-l-carboxamide

(Compound 189)

[0814] The product of (lR,2R)-2-fluoro-N-(3-(6-(l-hydroxypropyl)-4-methylpyridin-3 - yl)-2-(4-methyl-4H- 1 ,2,4-triazol-3 -yl)- 1 ,6-naphthyridin-7-yl)cyclopropane- 1 -carboxamide (70.2 mg, 0.15 mmol) was separated by Prep-Chiral-HPLC with the following conditions: (Column: CHIRAL ART Cellulose-SC, 2x25 cm, 5 m; Mobile Phase A: Hex (0.5% 2M NH ₃ -MeOH)- HPLC, Mobile Phase B: EtOH: DCM=1 : 1-HPLC; Flow rate: 20 mL/min; Gradient: 80% B to 80% B in 14.5 min; Wave Length: 254/220 nm; RTl(min): 8.16;

RT2(min): 12.01) to afford (lR,2R)-2-fluoro-N-(3-(6-(l-hydroxypropyl)-4-methylpyridin-3 - yl)-2-(4-methyl-4H- 1 ,2,4-triazol-3 -yl)- 1 ,6-naphthyridin-7-yl)cyclopropane- 1 -carboxamide Isomer 1 (retention time 8.16 minutes, 15.5 mg, 44%) as a yellow solid and (lR,2R)-2- fluoro-N-(3-(6-(l-hydroxypropyl)-4-methylpyridin-3-yl)-2-(4- methyl-4H-l,2,4-triazol-3-yl)- 1,6-naphthyri din-7-yl)cy cl opropane-1 -carboxamide Isomer 2 (retention time 12.01 minutes, 14.1 mg, 40%) as a yellow solid. The absolute stereochemistry of Isomers 1 and 2 was not assigned. The two isomeric structures that could be obtained from chiral separation of the isomeric mixture as described above are shown as Compounds 188 and 189 in Table 1.

[0815] (lR,2R)-2-fluoro-N-(3-(6-(l-hydroxypropyl)-4-methylpyridin-3 -yl)-2-(4- methyl-4H-l,2,4-triazol-3-yl)-l,6-naphthyridin-7-yl)cyclopro pane-l-carboxamide

Isomer 1: RTl(min): 8.16; LCMS (ESI, m/z): [M+H] ⁺ = 462.2. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.47 (s, 1H), 9.23 (s, 1H), 9.07 (s, 1H), 8.69 (s, 1H), 8.50 (s, 1H), 8.19 (s, 1H), 7.51 (s, 1H), 5.37 (d, J= 4.8 Hz, 1H), 5.10 - 4.93 (m, 1H), 4.59 - 4.55 (m, 1H), 3.95 (s, 3H), 2.36 - 2.30 (m, 1H), 2.28 (s, 3H), 1.88 - 1.84 (m, 1H), 1.78 - 1.68 (m, 2H), 1.29 - 1.24 (m, 1H), 0.95 - 0.91 (m, 3H).

[0816] (lR,2R)-2-fluoro-N-(3-(6-(l-hydroxypropyl)-4-methylpyridin-3 -yl)-2-(4- methyl-4H-l,2,4-triazol-3-yl)-l,6-naphthyridin-7-yl)cyclopro pane-l-carboxamide

Isomer 2: RT2(min): 12.01; LCMS (ESI, m/z): [M+H] ⁺ = 462.2. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.44 (s, 1H), 9.23 (s, 1H), 9.07 (s, 1H), 8.69 (s, 1H), 8.50 (s, 1H), 8.19 (s, 1H), 7.51 (s, 1H), 5.37 (d, J= 4.8 Hz, 1H), 5.12 - 4.92 (m, 1H), 4.58 - 4.55 (m, 1H), 3.96 (s, 3H), 2.36 - 2.30 (m, 1H), 2.28 (s, 3H), 1.88 - 1.80 (m, 1H), 1.78 - 1.66 (m, 2H), 1.31 - 1.24 (m, 1H), 0.95 - 0.86 (m, 3H).

Example 105. Synthesis of (lR)-2,2-difluoro-N-(3-{6-[(lS)-l-hydroxypropyl]-4- methylpyridin-3-yl}-2-(pyrazol-l-yl)-l,6-naphthyridin-7-yl)c yclopropane-l-carboxamide (Compound 190) and (lR)-2,2-difluoro-N-(3-{6-[(lR)-l-hydroxypropyl]-4-methylpyr idin-3- yl}-2-(pyrazol-l -yl)-l, 6-naphthyridin- 7-yl)cyclopropane-l -carboxamide ( Compound 191)

Step 1: Synthesis of 3-bromo-7 -chlor o-2-(pyr azol- l-yl)-l,6-naphthyridine

[0817] To a solution of 3-bromo-7-chloro-2-iodo-l,6-naphthyridine (4.0 g, 10.83 mmol) in dioxane (80.0 mL) was added pyrazole (884.7 mg, 12.99 mmol), BrettPhos (581.3 mg, 1.08 mmol), CS2CO3 (10.6 g, 32.49 mmol) and BrettPhos Pd G3 (1963.3 mg, 2.17 mmol) at room temperature under N2. The resulting mixture was stirred at 90 °C for 2 h under N2. After the reaction was completed, the mixture was cooled to room temperature and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with ethyl acetate/petroleum ether (50/50, v/v) to afford 3- bromo-7-chloro-2-(pyrazol-l-yl)-l,6-naphthyridine (3.3 g, 98%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 309.1.

Step 2: Synthesis of l-{5-[7-chloro-2-(pyrazol-l-yl)-l,6-naphthyridin-3-yl]-4-met hylpyridin- 2-yl}propan-l-one

[0818] To a solution of 3-bromo-7-chloro-2-(pyrazol-l-yl)-l,6-naphthyridine (1.5 g, 4.85 mmol) in dioxane (15.0 mL) and H2O (3.0 mL) was added l-(4-methyl-5-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)propan-l-on e (1.0 g, 5.33 mmol), Pd(dppf)C12 (0.8 g, 0.97 mmol) and K2CO3 (2.0 g, 14.54 mmol) at room temperature under N2. The resulting mixture was stirred at 80 °C for 2 h under N2. After the reaction was completed, the mixture was cooled to room temperature and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether /ethyl acetate (45/55, v/v) to afford l-{5-[7-chloro-2- (pyrazol-l-yl)-l,6-naphthyridin-3-yl]-4-methylpyridin-2-yl}p ropan-l-one (300.0 mg, 16%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 378.1. Step 3: Synthesis of tert-butyl N-[3-(4-methyl-6-propanoylpyridin-3-yl)-2-(pyrazol-l-yl)-l,6 - naphthyridin- 7-yl ] carbamate

[0819] To a solution of l-{5-[7-chloro-2-(pyrazol-l-yl)-l,6-naphthyridin-3-yl]-4- methylpyridin-2-yl}propan-l-one (600.0 mg, 1.59 mmol) in dioxane (12.0 mL) was added NH ₂ Boc (279.1 mg, 2.38 mmol), Cs ₂ CO ₃ (1552.2 mg, 4.76 mmol), Pd(OAc) ₂ (71.3 mg, 0.32 mmol) and XPhos (151.4 mg, 0.32 mmol) at room temperature under N ₂ . The resulting mixture was stirred at 80 °C for 2 h under N ₂ . After the reaction was completed, the mixture was cooled to room temperature and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether /ethyl acetate (20/80, v/v) to afford tert-butyl N-[3-(4-methyl-6-propanoylpyri din-3 -yl)- 2-(pyrazol-l-yl)-l,6-naphthyridin-7-yl]carbamate (530.0 mg, 72%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 459.2.

Step 4: Synthesis of l-{5-[7-amino-2-(pyrazol-l-yl)-l,6-naphthyridin-3-yl]-4-meth ylpyridin- 2-yl}propan-l-one

[0820] To a solution of tert-butyl N-[3-(4-methyl-6-propanoylpyri din-3 -yl)-2-(pyrazol-l- yl)-l,6-naphthyridin-7-yl]carbamate (550.0 mg, 1.20 mmol) in DCM (10.0 mL) was added TFA (5.0 mL) at room temperature, the resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The pH value of the residue was adjusted to 7.0 with saturated NaHCO ₃ (aq.). The mixture was extracted with CH ₂ C1 ₂ . The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to afford l-{5-[7-amino-2-(pyrazol-l-yl)-l,6-naphthyridin-3-yl]-4-meth ylpyridin-2- yl} propan- 1 -one (490.0 mg, crude) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 359.1. Step 5: Synthesis of (lR)-2,2-difluoro-N-[3-(4-methyl-6-propanoylpyridin-3-yl)-2- (pyrazol-l- yl)-l, 6-naphthyridin-7-yl ] cyclopropane- 1 -carboxamide

[0821] To a solution of l-{5-[7-amino-2-(pyrazol-l-yl)-l,6-naphthyridin-3-yl]-4- methylpyridin-2-yl}propan-l-one (430.0 mg, crude) in pyridine (15.0 mL) was added (1R)- 2,2-difluorocyclopropane-l -carboxylic acid (175.8 mg, 1.44 mmol) and EDCI (3449.9 mg, 18.00 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. After the reaction was completed, the resulting mixture was diluted with H2O and then extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by flash column chromatography with CH2CI2/CH3OH (93/7, v/v) to afford (lR)-2,2-difluoro-N-[3-(4-methyl-6-propanoylpyridin-3-yl)-2- (pyrazol-l-yl)-l,6- naphthyridin-7-yl]cyclopropane-l -carboxamide (340.0 mg, 61%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 463.1.

Step 6: Synthesis of (lR)-2,2-difluoro-N-{3-[6-(l-hydroxypropyl)-4-methylpyridin- 3-yl]-2- (pyrazol-l-yl)-lf-naphthyridin-7-yl}cyclopropane-l -carboxamide

[0822] To a solution of (lR)-2,2-difluoro-N-[3-(4-methyl-6-propanoylpyridin-3-yl)-2- (pyrazol-l-yl)-l,6-naphthyridin-7-yl]cyclopropane-l-carboxam ide (290.0 mg, 0.63 mmol) in THF (10.0 mL) and MeOH (2.0 mL) was added NaBH4 (28.5 mg, 0.75 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by flash column chromatography with CH ₂ Cl ₂ /CH3OH (83/17, v/v) to afford (lR)-2,2-difluoro-N-{3-[6-(l- hydroxypropyl)-4-methylpyri din-3 -yl]-2-(pyrazol- 1 -yl)- 1 ,6-naphthyridin-7-yl } cyclopropane- 1-carboxamide (90.0 mg, 31%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 465.1.

Step 7: Separation of (lR)-2,2-dijluoro-N-(3-{6-[(lS)-l-hydroxypropyl]-4-methylpyr idin-3- yl}-2-(pyrazol-l -yl)-l , 6-naphthyridin-7-yl)cyclopropane-l-carboxamide (Compound 190) and (lR)-2,2-dijluoro-N-(3-{6-[(lR)-l-hydroxypropyl]-4-methylpyr idin-3-yl}-2-(pyrazol-l- yl)-l, 6-naphthyridin-7-yl)cyclopropane-l-carboxamide (Compound 191)

[0823] The product of (lR)-2,2-difluoro-N-{3-[6-(l-hydroxypropyl)-4-methylpyridin- 3- yl]-2-(pyrazol-l-yl)-l,6-naphthyridin-7-yl}cyclopropane-l-ca rboxamide (90.0 mg, 0.22 mmol) was separated by Prep-Chiral-HPLC with the following conditions: (Column: CHIRAL ART Cellulose-SC, 2x25 cm, 5 pm; Mobile Phase A: Hex (0.5% 2M NH ₃ -MeOH)- -HPLC, Mobile Phase B: MeOH: DCM=1: 1-HPLC; Flow rate: 20 mL/min; Gradient: 50% B to 50% B in 16.5 min; Wave Length: 254/220 nm; RTl(min): 9.25; RT2(min): 13.29) to afford (lR)-2,2-difluoro-N-(3-{6-[l-hydroxypropyl]-4-methylpyridin- 3-yl}-2-(pyrazol-l-yl)- l,6-naphthyridin-7-yl)cy cl opropane-1 -carboxamide Isomer 1 (retention time 9.25 minutes, 25.6 mg, 56%) as a white solid and (lR)-2,2-difhioro-N-(3-{6-[l-hydroxypropyl]-4- methylpyri din-3 -yl } -2-(pyrazol- 1 -yl)- 1 ,6-naphthyridin-7-yl)cyclopropane- 1 -carboxamide Isomer 2 (retention time 13.29 minutes, 32.8 mg, 72%) as a white solid. The absolute stereochemistry of Isomers 1 and 2 was not assigned. The two isomeric structures that could be obtained from chiral separation of the isomeric mixture as described above are shown as Compounds 190 and 191 in Table 1.

[0824] (lR)-2,2-difluoro-N-(3-{6-[l-hydroxypropyl]-4-methylpyridin- 3-yl}-2- (pyrazol-l-yl)-l,6-naphthyridin-7-yl)cyclopropane-l-carboxam ide Isomer 1: RTl(min):

9.25; LCMS (ESI, m/z): [M+H] ⁺ = 465.2. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.43 (s, 1H), 9.28 (s, 1H), 8.64 - 8.56 (m, 3H), 8.27 (s, 1H), 7.55 - 7.51 (m, 1H), 7.33 (s, 1H), 6.52 (s, 1H), 5.36 - 5.26 (m, 1H), 4.55 - 4.52 (m, 1H), 3.15 - 3.07 (m, 1H), 2.17 - 2.03 (m, 2H), 1.87 - 1.79 (m, 4H), 1.71 - 1.62 (m, 1H), 0.89 - 0.84 (m, 3H).

[0825] (lR)-2,2-difluoro-N-(3-{6-[l-hydroxypropyl]-4-methylpyridin- 3-yl}-2- (pyrazol-l-yl)-l,6-naphthyridin-7-yl)cyclopropane-l-carboxam ide Isomer 2: RT2(min): 13.29; LCMS (ESI, m/z): [M+H] ⁺ = 465.2. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.43 (s, 1H), 9.28 (s, 1H), 8.63 - 8.56 (m, 3H), 8.27 (s, 1H), 7.55 - 7.51 (m, 1H), 7.33 (s, 1H), 6.52 (s, 1H), 5.36 - 5.26 (m, 1H), 4.55 - 4.52 (m, 1H), 3.15 - 3.07 (m, 1H), 2.17 - 2.03 (m, 2H), 1.87 - 1.81 (m, 4H), 1.71 - 1.62 (m, 1H), 0.94 - 0.87 (m, 3H).

Example 106. Synthesis of 7-((lR,2R)-2-fluorocyclopropane-l-carboxamido)-3-(6-((S)-l- hydroxypropyl)-4-methylpyridin-3-yl)-N,N-dimethyl-l,6-naphth yridine-2-carboxamide (Compound 192) and 7-((lR,2R)-2-fluorocyclopropane-l-carboxamido)-3-(6-((R)-l- hydroxypropyl)-4-methylpyridin-3-yl)-N,N-dimethyl-l,6-naphth yridine-2-carboxamide (Compound 193)

Step 1: Synthesis of 3 -bromo-7 -chlor o-2 -methyl- 1 ,6-naphthyridine

[0826] To a solution of 4-amino-6-chloropyridine-3-carbaldehyde (10.0 g, 63.87 mmol) in ACN (100.0 mL) was added l-bromo-2,2-dimethoxypropane (2.3 g, 127.74 mmol) and Yb(OTf)3 (9.9 g, 15.97 mmol) at room temperature under N2. The resulting mixture was stirred at 80 °C for 4 h under N2. After the reaction was completed, the resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography with petroleum ether/ethyl acetate (90/10, v/v) to afford 3-bromo-7- chloro-2-methyl-l,6-naphthyridine (10.0 g, 60%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 257.0.

Step 2: Synthesis of 3 -bromo-7 -chlor o-l ,6-naphthyridine-2-carboxylic acid

[0827] To a solution of 3-bromo-7-chloro-2-methyl-l,6-naphthyridine (5.0 g, 19.42 mmol) in dioxane (150.0 mL) was added SeO2 (2.1 g, 20.55 mmol). The resulting mixture was stirred at 80 °C for 4 h. The resulting mixture was diluted with DCM and filtered. The filtrate was concentrated under reduced pressure. To a mixture of the residue in HCOOH (50.0 mL) was added H2O2 (3.0 mL, 30%) at 0 °C. The final reaction mixture was stirred at 0 °C for additional 4 h. After the reaction was completed, the resulting mixture was diluted with MeCN and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography with ACN /H2O (30/70, v/v) to afford 3-bromo-7-chloro-l,6-naphthyridine-2-carboxylic acid (2.6 g, 47%) as a brown oil. LCMS (ESI, m/z): [M+H] ⁺ = 287.1.

Step 3: Synthesis of 3-bromo-7-chloro-N,N-dimethyl-l ,6-naphthyridine-2-carboxamide

[0828] To a solution of 3-bromo-7-chloro-l,6-naphthyridine-2-carboxylic acid (3.0 g, 10.48 mmol) in pyridine (45.0 mL) was added dimethylamine hydrochloride (1.2 g, 15.22 mmol) and EDCI (2.9 g, 15.20 mmol) at room temperature, the resulting mixture was stirred at room temperature for 16 h. After the reaction was completed, the mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with ethyl acetate/petroleum ether (75/25, v/v) to afford 3-bromo-7-chloro-N,N-dimethyl-l,6- naphthyridine-2-carboxamide (2.0 g, 60%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 314.1.

Step 4: Synthesis of 7-chloro-N,N-dimethyl-3-(4-methyl-6-propionylpyridin-3-yl)-l ,6- naphthyridine-2-carboxamide

[0829] To a solution of 3-bromo-7-chloro-N,N-dimethyl-l,6-naphthyridine-2- carboxamide (400.0 mg, 1.27 mmol) in dioxane (12.0 mL) and H2O (3.0 mL) was added 1- [4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyr idin-2-yl]propan-l-one (398.0 mg, 1.5 mmol), Pd(PPh3)4 (159.6 mg, 0.14 mmol) and K2CO3 (1.1 g, 7.91 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 2 h under N2. After the reaction was completed, the mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with ethyl acetate/petroleum ether (90/10, v/v) to afford 7-chloro-N,N- dimethyl-3-(4-methyl-6-propionylpyridin-3-yl)-l,6-naphthyrid ine-2-carboxamide (224.0 mg, 46%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 383.1.

Step 5: Synthesis of 7-((lR,2R)-2-fluorocyclopropane-l-carboxamido)-N,N-dimethyl- 3-(4- methyl-6-propionylpyridin-3-yl)-l,6-naphthyridine-2-carboxam ide

[0830] To a solution of 7-chloro-N,N-dimethyl-3-(4-methyl-6-propionylpyridin-3-yl)- l,6-naphthyridine-2-carboxamide (164.0 mg, 0.43 mmol) in dioxane (8.0 mL) was added (lR,2R)-2-fluorocyclopropane-l-carboxamide (78.9 mg, 0.77 mmol), CS2CO3 (582.0 mg, 1.55 mmol), BrettPhos (52.1 mg, 0.08 mmol) and BrettPhos Pd G3 (43.2 mg, 0.04 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 2 h under N2. After the reaction was completed, the mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with dichloromethane/methanol (92/8, v/v) to afford 7-((lR,2R)-2- fluorocy cl opropane-1 -carboxamido)-N,N-dimethyl-3-(4-methyl-6-propionylpyri din-3 -yl)- l,6-naphthyridine-2-carboxamide (101.0 mg, 52%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 450.2.

Step 6: Synthesis of 7-((lR,2R)-2-fluorocyclopropane-l-carboxamido)-3-(6-(l- hydroxypropyl)-4-methylpyridin-3-yl)-N,N-dimethyl-l,6-naphth yridine-2-carboxamide

[0831] To a solution of 7-((lR,2R)-2-fluorocyclopropane-l-carboxamido)-N,N-dimethyl- 3-(4-methyl-6-propionylpyridin-3-yl)-l,6-naphthyridine-2-car boxamide (81.0 mg, 0.18 mmol) in THF (3.0 mL) and MeOH (0.6 mL) was added NaBH4 (9.3 mg, 0.25 mmol) at 0 °C. The resulting solution was stirred at room temperature for 1 h. After the reaction was completed, the mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with dichloromethane/methanol (85/15, v/v) to afford 7-((lR,2R)-2- fluorocy cl opropane-l-carboxamido)-3-(6-(l-hydroxypropyl)-4-methylpyri din-3 -yl)-N,N- dimethyl-l,6-naphthyridine-2-carboxamide (54.2 mg, 67%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 452.1.

Step 7: Separation of7-((lR,2R)-2-fluorocyclopropane-l-carboxamido)-3-(6-((S)-l - hydroxypropyl)-4-methylpyridin-3-yl)-N,N-dimethyl-l,6-naphth yridine-2-carboxamide (Compound 192) and 7-((lR,2R)-2-fluorocyclopropane-l-carboxamido)-3-(6-((R)-l- hydroxypropyl)-4-methylpyridin-3-yl)-N,N-dimethyl-l,6-naphth yridine-2-carboxamide (Compound 193)

[0832] The product of 7-((lR,2R)-2-fluorocyclopropane-l-carboxamido)-3-(6-(l- hydroxypropyl)-4-methylpyri din-3 -yl)-N,N-dimethyl-l,6-naphthyridine-2-carboxamide (54.0 mg, 0.12 mmol) was separated by Prep-Chiral-SFC with the following conditions: (Lux 5um Cellulose-4, 3x25 cm, 5 pm; Mobile Phase A: CO2, Mobile Phase B: IP A; Flow rate: 20 mL/min; Gradient: isocratic 25% B; Column Temperature (°C): 35; Back Pressure(bar): 100; Wave Length: 220 nm; RTl(min): 8.17; RT2(min): 11.04) to afford 7-((lR,2R)-2- fluorocy cl opropane-l-carboxamido)-3-(6-(l-hydroxypropyl)-4-methylpyri din-3 -yl)-N,N- dimethyl-l,6-naphthyridine-2-carboxamide Isomer 1 (retention time 8.17 minutes, 7.6 mg, 28%) as a white solid and 7-((lR,2R)-2-fluorocyclopropane-l-carboxamido)-3-(6-(l- hydroxypropyl)-4-methylpyridin-3-yl)-N,N-dimethyl-l,6-naphth yridine-2-carboxamide Isomer 2 (retention time 11.04 minutes, 5.0 mg, 18%) as a white solid. The absolute stereochemistry of Isomers 1 and 2 was not assigned. The two isomeric structures that could be obtained from chiral separation of the isomeric mixture as described above are shown as Compounds 192 and 193 in Table 1.

[0833] 7-((lR,2R)-2-fluorocyclopropane-l-carboxamido)-3-(6-(l-hydro xypropyl)-4- methylpyridin-3-yl)-N,N-dimethyl-l,6-naphthyridine-2-carboxa mide Isomer 1 : RTl(min): 8.17; LCMS (ESI, m/z): [M+H] ⁺ = 452.2. ¹ H NMR (400.0 MHz, DMSO-d ₆ ): δ 11.35 (s, 1H), 9.07 (s, 1H), 8.79 (s, 1H), 8.53 (s, 1H), 8.45 (s, 1H), 7.48 (s, 1H), 5.35 (d, J = 4.8 Hz, 1H), 5.10 - 4.90 (m, 1H), 4.57 - 4.55 (m, 1H), 2.96 (s, 6H), 2.33 - 2.29 (m, 1H), 2.25 (s, 3H), 1.90 - 1.83 (m, 1H), 1.77 - 1.66 (m, 2H), 1.29 - 1.24 (m, 1H), 0.95 - 0.91 (m, 3H).

[0834] 7-((lR,2R)-2-fluorocyclopropane-l-carboxamido)-3-(6-(l-hydro xypropyl)-4- methylpyridin-3-yl)-N,N-dimethyl-l,6-naphthyridine-2-carboxa mide Isomer 2: RT2(min): 11.04; LCMS (ESI, m/z): [M+H] ⁺ = 452.1 ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.34 (s, 1H), 9.07 (s, 1H), 8.79 (s, 1H), 8.53 (s, 1H), 8.45 (s, 1H), 7.48 (s, 1H), 5.35 (d, J= 4.8 Hz, 1H), 5.10 - 4.92 (m, 1H), 4.58 - 4.54 (m, 1H), 2.96 - 2.93 (m, 6H), 2.36 - 2.29 (m, 1H), 2.25 (s, 3H), 1.88 - 1.85 (m, 1H), 1.77 - 1.68 (m, 2H), 1.27 - 1.24 (m, 1H), 0.94 - 0.91 (m, 3H).

Biological Examples

Example Bl. Cell Viability Assays

[0835] Cell viability was measured in the following MAPK pathway mutant cancer cell lines: A375 (BRAF V600E), HepG2 (NRAS Q61L), SK-MEL-30 (NRAS Q61K), and OCI- AML-2 (MBNL1-CRAF fusion), and K562.

[0836] A375, HepG2, SK-MEL-30, OCI-AML-2, and K562 cells were grown in the appropriate growth medium as described in Table 2 below, and harvested at 50-80% confluence. Cells were counted and seeded at their appropriate density (see Table 2) in a 384- well plate (Coming 3570). A375, HepG2 and SK-MEL-30 were allowed to adhere overnight prior to treatment and the OCI-AML-2 were treated immediately for the indicated drug treatment times (Table 2). Table 2 provides the growth media, number of cells seeded per well and drug treatment times for the each cell line.

Table 2.

[0837] Compounds were dissolved in DMSO and serially diluted. Serially-diluted compound or a DMSO only control (high control, “HC”) was added to the plated cells in each well. Compounds were tested at concentrations of about 10 pM to 0.51 nM, using threefold dilutions. The final proportion of DMSO never exceeded 0.1%.

[0838] Plates were placed in a 37°C, 5% CO2 incubator for the indicated treatment times (Table Bl). Plates were then removed from the incubator and equilibrated for 15 minutes at room temperature. 40 μl of CellTiter Gio reagent (Promega) was added to measure the relative level of metabolically active cells by quantifying intracellular ATP concentrations. Plates were incubated for 30 minutes at room temperature, and luminescence was measured. Percent viability was normalized to a vehicle control only using the following formula: % viability = 100 x (Lumsampie - LumLC) / (LumHC - LumLC ). IC50 values were calculated using XLFit software or Prism (GraphPad Software), as shown in Table 3, below. Graphical curves were fitted using a nonlinear regression model with a sigmoidal dose response.

Table 3.

Example B2. Detection of phosphorylated ERK (pERK)

[0839] A375 cells were counted and seeded at 10,000 cells/well in 384 well plates

(Coming 3764) and allowed to adhere overnight.

[0840] Compounds were dissolved and serially diluted in DMSO. The compounds were then added, mixed, and incubated for four hours at 37°C, 5% CO2. Compounds were added using four-fold dilutions at final concentrations ranging from 10 μM to 0.01 nM. DMSO only and lOuM staurosporine were added as high and low controls. [0841] Following the four-hour incubation with compounds, cell lysates were prepared and AlphaLISA assay measuring phosphorylated ERK was performed. Media was removed using the Apricot Designs pipettor. Lysis buffer was made from IX AlphaLISA SureFire Assay Kit (AlphaLISA SureFire Ultra pERK U (Thr202/Tyr204) ALSU-PERK-A50K) lysis buffer with protease and phosphatase inhibitors. Cells were lysed by adding lOuL to all the wells and mixed for 40 minutes on a plate shaker. lOuL cell lysate was transferred to a new Optiplate (PerkinElmer 6007290) and incubated with 5uL IX acceptor mix for 2 hours in the dark. 5uL of IX donor mix was added to all wells and mixed by shaking followed by overnight incubation in the dark.

[0842] pERK AlphaLISA signal was read on the Envision using standard AlphaLISA settings. Percent inhibition of ERK phosphorylation was calculated by %Inhibition = 100 x (LumHC - LumSample) / (LumHC -LumLC). The low and high controls (LC/HC) are generated from lysate from wells with cells treated with DMSO or 10 mM Staurosporine (BioAustralis, cat # BIA-S1086), respectively. IC50 values were calculated by fitting the Curve using XLfit (v5.3.1.3), equation 201 : Y = Bottom + (Top - Bottom)/(1 + 10 ^A ((LogIC50 - X)*HillSlope)). The IC50 values are shown in Table 4 below.

Table 4.

[0843] All publications, including patents, patent applications, and scientific articles, mentioned in this specification are herein incorporated by reference in their entirety for all purposes to the same extent as if each individual publication, including patent, patent application, or scientific article, were specifically and individually indicated to be incorporated by reference.

[0844] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it is apparent to those skilled in the art that certain minor changes and modifications will be practiced in light of the above teaching. Therefore, the description and examples should not be construed as limiting the scope of the invention.