Mutant KRAS modulators and uses thereof

Abstract

The disclosure includes compounds of Formula (1) wherein each of R1, R2, R3, R4, R5, R6, R7, Q1, W1, W2, W3, W4, Z1, Z2, L, m, n, and r, are defined herein. Also disclosed is a method for treating a neoplastic disease, autoimmune disease, and inflammatory disorder with these compounds.

Description

MUTANT KRAS MODULATORS AND USES THEREOFREFERENCE TO RELATED APPLICATIONSThis application claims priority to and the benefit of the filing date of U.S. Provisional Patent Application Nos: 63 / 537,810, filed on September 11, 2023; 63 / 611,828, filed on December 19, 2023; 63 / 548,828, filed on February 1, 2024; and 63 / 655,534, filed on June 3, 2024, the entire contents of each of the above applications are incorporated herein by reference.BACKGROUND OF THE INVENTIONKirsten Rat Sarcoma 2 Viral Oncogene Homolog ("KRas”) is a small GTPase and a member of the Ras family of oncogenes. KRas serves as a molecular switch cycling between inactive (GDP-bound) and active (GTP-bound) states to transduce upstream cellular signals received from multiple tyrosine kinases to downstream effectors to regulate a wide variety of processes, including cellular proliferation (e.g., see Alamgeer et al., (2013) Current Opin Pharmcol.13:394-401).

[0003] The role of activated KRas in malignancy was observed over thirty years ago (e.g., see Santos et al., (1984) Science 223:661-664). Aberrant expression of KRas accounts for up to 20% of all cancers and oncogenic KRas mutations that stabilize GTP binding and lead to constitutive activation of KRas and downstream signaling have been reported in 25 -30% of lung adenocarcinomas, (e.g., see Samatar and Poulikakos (2014) Nat Rev Drug Disc 13(12): 928- 942 doi: 10.1038 / nrd428). Single nucleotide substitutions that result in missense mutations at codons 12 and 13 of the KRas primary amino acid sequence comprise approximately 40% of these KRas driver mutations in lung adenocarcinoma. KRAS G12D mutation is present in 25.0% of all pancreatic ductal adenocarcinoma patients, 13.3% of all colorectal carcinoma patients, 10.1% of all rectal carcinoma patients, 4.1% of all non-small cell lung carcinoma patients and 1.7% of all small cell lung carcinoma patients (e.g., see The AACR Project GENIE Consortium, (2017) Cancer Discovery;7(8):818-831. Dataset Version 4).

[0004] The well-known role of KRas in malignancy and the discovery of these frequent mutations in KRas in various tumor types made KRas a highly attractive target of the pharmaceutical industry for cancer therapy. Notwithstanding thirty years of large-scale discovery efforts to develop inhibitors of KRas for treating cancer, no KRas inhibitor has yet demonstrated sufficient safety and / or efficacy to obtain regulatory approval (e.g., see McCormick (2015) Clin Cancer Res.21 (8): 1797-1801).

[0005] Compounds that inhibit KRas activity are still highly desirable and under investigation, including those that disrupt effectors such as guanine nucleotide exchange factors (e.g., see Sun et al., (2012) Agnew Chem Int Ed Engl.51 (25) :6140-6143 doi: 10.1002 / anie201201358) as well recent advances in the covalent targeting of an allosteric pocket of KRas G12C (e.g., see Ostrem et al., (2013) Nature 503:548-551 and Fell et al., (2018) ACS Med. Chem. Lett.9: 1230-1234). Clearly there remains a continued interest and effort to develop modulators of KRas, particularly the activating KRas mutants, such as KRas G12C, G12D, G12V, and G13D.SUMMARY OF THE INVENTIONIn one aspect, this invention relates to a compound of Formula (1), or an N-oxide thereof, or apharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug of said compound of Formula (1) or N-oxide thereof:whereinQi is aryl, or heteroaryl;Wi to W4 are each independently N or C(Ra);Z1 is absent, a bond, -(CRaRb)P-, -N(RC)-, -O-, or -S-;7-i is absent, a bond, -(CRaRb)P-, -N(RC)-, -O-, -O-(CRaRb)P-, or -S-;L is absent, a bond, -(CRaRb)p-, -N(RC)-, -O-, -S-, -C(O)-, -S(O2)-, -O(CRaRb)P-, -N(Rc)(CRaRb)P-, -OC(O)-, -C(O)O-, -OSO2-, -S(O2)O-, -C(O)S-, -SC(O)-, -C(O)C(O)-, -C(O)N(Rc)-, -N(Rc)C(O)-, - S(O2)N(RC)-, -N(RC)S(O2)-, -OC(O)O-, -OC(O)S-, -OC(O)N(RC)-, -N(RC)C(O)O-, -N(RC)C(O)S-, - N(Rc)C(O)N(Rc)-, -(CRaRb)PN(Rc)(CRaRb)q-, -(CRaRb)PN(Rc)C(O)(CRaRb)q- ,OC(O)N(Rc)(CRaRb)P+iN(Rc)(CRaRb)q-, -(CRaRb)PC(O)N(Rc)(CRaRb)q-, bivalent alkyl, bivalent alkenyl, bivalent alkynyl, bivalent cycloalkyl, bivalent cycloalkenyl, bivalent fused-carbocyclic, bivalent bridged- carbocyclic, bivalent spirocycloalkyl, bivalent heterocycloalkyl, bivalent heterocycloalkenyl, bivalent spiro-heterocyclic, bivalent fused-heterocyclic, bivalent bridged-heterocyclic, bivalent aryl, or bivalent heteroaryl, each of the aforementioned is independently optionally subsitiuted with one or more Rdsubstituents; each R1 is independently H, D, halo, cyano, nitro, alkyl, alkenyl, alkynyl, -alkylene-Ra, =CRaRb, =NRb, =0, -C(0)Ra, -C(0)NRbRc, -C(0)0Ra, -NH(CH2)pRa, -NRbRc, -NRbC(0)Rc, -NRbS(O)2Rc, - N=S(0)RbRc, -0Ra, -0C(0)Ra, -0C(0)0Ra, -0P(0)(0Rb)(0Rc), -OP(O)(ORb)(NHRc), -0P(0)RbRc, - P(0)RbRc, -alkylene-P(O)RbRc, -SRa, -S(0)Ra, -S(0)(NRb)Rc, -S(0)2Ra, -S(0)2NRbRc, -(CRaRb)PRd, - (CRaRb)PN(Rc)(CRaRb)qRd, -(CRaRb)PO(CRaRb)qRd, -(CRaRb)PC(O)(CRaRb)qRd, - (CRaRb)pC(O)O(CRaRb)qRd, -(CRaRb)P0C(0)(CRaRb)qRd, -(CRaRb)P0C(0)0(CRaRb)qRd, - (CRaRb)PN(Rc)C(O)(CRaRb)qRd, -(CRaRb)pC(O)N(Rc)(CRaRb)qRd, -(CRaRb)p0C(0)N(Rc)(CRaRb)qRd, - (CRaRb)pN(Rc)C(O)O(CRaRb)qRd, cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged- carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged- heterocyclic, aryl, or heteroaryl, each of the aforementioned is optionally substituted with one or more independently selected Rdsubstituents; or two R1, taken together with the atom(s) to which they are attached, independently form a cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl, each of theaforementioned is optionally and independently substituted with one or more independently selected Rd substituents; each R2 is independently H, D, halo, cyano, nitro, alkyl, alkenyl, alkynyl, -alkylene-Ra, =CRaRb, =NRb, =0, -C(0)Ra, -C(O)NRbRc, -C(0)0Ra, -NH(CH2)PRa, -NRbRc, -NRbC(O)Rc, -NRbS(O)2Rc, - N=S(O)RbRc, -0Ra, -0C(0)Ra, -0C(0)0Ra, -OP(O)(ORb)(ORc), -OP(O)(ORb)(NHRc), -OP(O)RbRc, - P(O)RbRc, -alkylene-P(O)RbRc, -SRa, -S(O)Ra, -S(O)(NRb)Rc, -S(O)2Ra, -S(O)2NRbRc, -(CRaRb)PRd, - (CRaRb)PN(Rc)(CRaRb)qRd, -(CRaRb)PO(CRaRb)qRd, -(CRaRb)PC(O)(CRaRb)qRd, - (CRaRb)PC(O)O(CRaRb)qRd, -(CRaRb)POC(O)(CRaRb)qRd, -(CRaRb)POC(O)O(CRaRb)qRd, - (CRaRb)pN(Rc)C(O)(CRaRb)qRd, -(CRaRb)pC(O)N(Rc)(CRaRb)qRd, -(CRaRb)p0C(0)N(Rc)(CRaRb)qRd, - (CRaRb)pN(Rc)C(O)O(CRaRb)qRd, cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged- carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged- heterocyclic, aryl, or heteroaryl, each of the aforementioned is optionally substituted with one or more independently selected Rd substituents; two R2, taken together with the atom(s) to which they are attached, independently form a cycloalkyl or heterocycloalkyl, wherein each cycloalkyl or heterocycloalkyl is optionally and independently substituted with one or more independently selected Rd substituents; each R3 is independently H, D, halo, cyano, nitro, alkyl, alkenyl, alkynyl, -alkylene-Ra, =CRaRb, =NRb, =0, -C(0)Ra, -C(0)NRbRc, -C(0)0Ra, -NH(CH2)pRa, -NRbRc, -NRbC(0)Rc, -NRbS(O)2Rc, - N=S(O)RbRc, -0Ra, -0C(0)Ra, -0C(0)0Ra, -0P(0)(0Rb)(0Rc), -OP(O)(ORb)(NHRc), -0P(0)RbRc, - P(0)RbRc, -alkylene-P(O)RbRc, -SRa, -S(O)Ra, -S(O)(NRb)Rc, -S(O)2Ra, -S(O)2NRbRc, -(CRaRb)pRd, - (CRaRb)pN(Rc)(CRaRb)qRd, -(CRaRb)pO(CRaRb)qRd, -(CRaRb)pC(O)(CRaRb)qRd, - (CRaRb)pC(0)0(CRaRb)qRd, -(CRaRb)p0C(0)(CRaRb)qRd, -(CRaRb)p0C(0)0(CRaRb)qRd, - (CRaRb)pN(Rc)C(O)(CRaRb)qRd, -(CRaRb)pC(O)N(Rc)(CRaRb)qRd, -(CRaRb)p0C(0)N(Rc)(CRaRb)qRd, - (CRaRb)pN(Rc)C(0)0(CRaRb)qRd, cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged- carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged- heterocyclic, aryl, or heteroaryl, each of the aforementioned is optionally substituted with one or more independently selected Rdsubstituents; two R3, taken together with the atom(s) to which they are attached, independently form a cycloalkyl or heterocycloalkyl, wherein each cycloalkyl or heterocycloalkyl is optionally and independently substituted with one or more independently selected Rdsubstituents;R4 is H, D, halo, cyano, nitro, alkyl, alkenyl, alkynyl, -alkylene-Ra, =CRaRb, =NRb, =0, -C(0)Ra, -C(0)NRbRc, -C(0)0Ra, -NH(CH2)pRa, -NRbRc, -NRbC(0)Rc, -NRbS(O)2Rc, -N=S(O)RbRc, -0Ra, - 0C(0)Ra, -0C(0)0Ra, -0P(0)(0Rb)(0Rc), -OP(O)(ORb)(NHRc), -0P(0)RbRc, -P(0)RbRc, -alkylene- P(0)RbRc, -SRa, -S(O)Ra, -S(0)(NRb)Rc, -S(O)2Ra, -S(O)2NRbRc, -(CRaRb)pRd, - (CRaRb)pN(Rc)(CRaRb)qRd, -(CRaRb)pO(CRaRb)qRd, -(CRaRb)pC(O)(CRaRb)qRd, - (CRaRb)pC(0)0(CRaRb)qRd, -(CRaRb)p0C(0)(CRaRb)qRd, -(CRaRb)p0C(0)0(CRaRb)qRd, - (CRaRb)pN(Rc)C(O)(CRaRb)qRd, -(CRaRb)pC(O)N(Rc)(CRaRb)qRd, -(CRaRb)p0C(0)N(Rc)(CRaRb)qRd, -(CRaRb)pN(Rc)C(O)O(CRaRb)qRd, cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged- carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged- heterocyclic, aryl, or heteroaryl, each of the aforementioned is optionally substituted with one or more independently selected Rd substituents;Rs is H, D, halo, cyano, nitro, alkyl, alkenyl, alkynyl, -alkylene-Ra, =CRaRb, =NRb, =0, -C(0)Ra, -C(0)NRbRc, -C(0)0Ra, -NH(CH2)PRa, -NRbRc, -NRbC(0)Rc, -NRbS(0)2Rc, -N=S(O)RbRc, -0Ra, - 0C(0)Ra, -0C(0)0Ra, -0P(0)(0Rb)(0Rc), -OP(O)(ORb)(NHRc), -0P(0)RbRc, -P(0)RbRc, -alkylene- P(0)RbRc, -SRa, -S(0)Ra, -S(0)(NRb)Rc, -S(0)2Ra, -S(0)2NRbRc, -(CRaRb)pRd, - (CRaRb)pN(Rc)(CRaRb)qRd, -(CRaRb)PO(CRaRb)qRd, -(CRaRb)PC(O)(CRaRb)qRd, - (CRaRb)pC(O)O(CRaRb)qRd, -(CRaRb)pOC(O)(CRaRb)qRd, -(CRaRb)pOC(O)O(CRaRb)qRd, - (CRaRb)pN(Rc)C(O)(CRaRb)qRd, -(CRaRb)pC(O)N(Rc)(CRaRb)qRd, -(CRaRb)pOC(O)N(Rc)(CRaRb)qRd, - (CRaRb)pN(Rc)C(O)O(CRaRb)qRd, cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged- carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged- heterocyclic, aryl, or heteroaryl, each of the aforementioned is optionally substituted with one or more independently selected Rd substituents;Re is H, D, halo, cyano, nitro, alkyl, alkenyl, alkynyl, -alkylene-Ra, =CRaRb, =NRb, =0, -C(0)Ra, -C(0)NRbRc, -C(0)0Ra, -NH(CH2)pRa, -NRbRc, -NRbC(0)Rc, -NRbS(O)2Rc, -N=S(O)RbRc, -0Ra, - 0C(0)Ra, -0C(0)0Ra, -0P(0)(0Rb)(0Rc), -OP(O)(ORb)(NHRc), -0P(0)RbRc, -P(0)RbRc, -alkylene- P(0)RbRc, -SRa, -S(0)Ra, -S(0)(NRb)Rc, -S(0)2Ra, -S(0)2NRbRc, -(CRaRb)pRd, - (CRaRb)pN(Rc)(CRaRb)qRd, -(CRaRb)PO(CRaRb)qRd, -(CRaRb)PC(O)(CRaRb)qRd, - (CRaRb)pC(O)O(CRaRb)qRd, -(CRaRb)pOC(O)(CRaRb)qRd, -(CRaRb)pOC(O)O(CRaRb)qRd, - (CRaRb)pN(Rc)C(O)(CRaRb)qRd, -(CRaRb)pC(O)N(Rc)(CRaRb)qRd, -(CRaRb)pOC(O)N(Rc)(CRaRb)qRd, - (CRaRb)pN(Rc)C(O)O(CRaRb)qRd, cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged- carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged- heterocyclic, aryl, or heteroaryl, each of the aforementioned is optionally substituted with one or more independently selected Rdsubstituents;Rz is H, D, halo, cyano, nitro, alkyl, alkenyl, alkynyl, -alkylene-Ra, =CRaRb, =NRb, =0, -C(0)Ra, -C(0)NRbRc, -C(0)0Ra, -NH(CH2)pRa, -NRbRc, -NRbC(0)Rc, -NRbS(O)2Rc, -N=S(O)RbRc, -0Ra, - 0C(0)Ra, -0C(0)0Ra, -0P(0)(0Rb)(0Rc), -OP(O)(ORb)(NHRc), -0P(0)RbRc, -P(0)RbRc, -alkylene- P(0)RbRc, -SRa, -S(0)Ra, -S(0)(NRb)Rc, -S(0)2Ra, -S(0)2NRbRc, -(CRaRb)pRd, - (CRaRb)pN(Rc)(CRaRb)qRd, -(CRaRb)PO(CRaRb)qRd, -(CRaRb)PC(O)(CRaRb)qRd, - (CRaRb)pC(O)O(CRaRb)qRd, -(CRaRb)pOC(O)(CRaRb)qRd, -(CRaRb)pOC(O)O(CRaRb)qRd, - (CRaRb)pN(Rc)C(O)(CRaRb)qRd, -(CRaRb)pC(O)N(Rc)(CRaRb)qRd, -(CRaRb)pOC(O)N(Rc)(CRaRb)qRd, - (CRaRb)pN(Rc)C(O)O(CRaRb)qRd, cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged- carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged- heterocyclic, aryl, or heteroaryl, each of the aforementioned is optionally substituted with one or more independently selected Rdsubstituents;Re and Rz, taken together with the atom(s) to which they are attached, independently form a cycloalkyl or heterocycloalkyl, wherein each cycloalkyl or heterocycloalkyl is optionally and independently substituted with one or more independently selected Rdsubstituents; and each Rais independently H, D, alkyl, alkenyl, alkynyl, halo, -CF3, cyano, nitro, -OH, - C(O)NHOH, -C(O)NH2, -C(O)OH, -NH2, =CReRf, =NRe, =0, -C(0)Re, -C(0)NReRf, -C(0)0Re, - NH(CH2)pRe, -NReRf, -NReC(0)Rf, -NReS(O)2Rf, -N=S(O)ReRf, -0Re, -0C(0)Re, -0C(0)0Re, - 0P(0)(0Re)(0Rf), -0P(0)(0Re)(NHRf), -alkylene-P(O)ReRf, -0P(0)ReRf„ -P(0)ReRf, -SRe, -S(O)Re, - S(0)(NRe)Rf, -S(0)2Re, -S(O)2NReRf, N=S(O)ReRf, -S(O)(NRe)Rf, -(CH2)pRf, -(CH2)pN(Re)(CH2)qRf, - (CH2)pO(CH2)qRf, -(CH2)pC(O)(CH2)qRf, -(CH2)pC(O)O(CH2b)qRf, -(CH2)pOC(O)(CH2)qRf, - (CH2)pOC(O)O(CH2)qRf, -(CH2)pN(Re)C(O)(CH2)qRf, -(CH2)pC(O)N(Re)(CH2)qRf, - (CH2)pOC(O)N(Re)(CH2)qRf, -(CRaRb)PN(Re)C(O)O(CH2)qRf, cycloalkyl, cycloalkenyl, spirocycloalkyl, fused -carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused- heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, each of the aforementioned is optionally and independently substituted with one or more independently selected Rgsubstituents; each Rb is independently H, D, alkyl, alkenyl, alkynyl, halo, -CF3, cyano, nitro, -OH, - C(O)NHOH, -C(O)NH2, -C(O)OH, -NH2, =CReRf, =NRe, =0, -C(0)Re, -C(0)NReRf, -C(0)0Re, - NH(CH2)pRe, -NReRf, -NReC(0)Rf, -NReS(O)2Rf, -N=S(O)ReRf, -0Re, -0C(0)Re, -0C(0)0Re, -alkylene- P(O)ReRf, -OP(O)(ORe)(ORf), -OP(O)(ORe)(NHRf), -0P(0)ReRf, -P(0)ReRf, -SRe, -S(O)Re, - S(0)(NRe)Rf, -S(0)2Re, -S(O)2NReRf, N=S(O)ReRf, -S(O)(NRe)Rf, -(CH2)pRf, -(CH2)pN(Re)(CH2)qRf, - (CH2)pO(CH2)qRf, -(CH2)pC(O)(CH2)qRf, -(CH2)pC(O)O(CH2b)qRf, -(CH2)pOC(O)(CH2)qRf, - (CH2)pOC(O)O(CH2)qRf, -(CH2)pN(Re)C(O)(CH2)qRf, -(CH2)pC(O)N(Re)(CH2)qRf, - (CH2)pOC(O)N(Re)(CH2)qRf, -(CRaRb)PN(Re)C(O)O(CH2)qRf, cycloalkyl, cycloalkenyl, spirocycloalkyl, fused -carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused- heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, each of the aforementioned is optionally and independently substituted with one or more independently selected Rgsubstituents;Raand Rb, taken together with the atom(s) to which they are attached, independently form a cycloalkyl or heterocycloalkyl, wherein each cycloalkyl or heterocycloalkyl is optionally and independently substituted with one or more independently selected Rgsubstituents; each Rcis independently H, D, alkyl, alkenyl, alkynyl, halo, -CF3, cyano, nitro, -OH, - C(O)NHOH, -C(O)NH2, -C(O)OH, -NH2, =CReRf, =NRe, =0, -C(0)Re, -C(0)NReRf, -C(0)0Re, - NH(CH2)pRe, -NReRf, -NReC(0)Rf, -NReS(O)2Rf, -N=S(O)ReRf, -0Re, -0C(0)Re, -0C(0)0Re, -alkylene- P(O)ReRf, -OP(O)(ORe)(ORf), -OP(O)(ORe)(NHRf), -0P(0)ReRf, -P(0)ReRf, -SRe, -S(O)Re, - S(0)(NRe)Rf, -S(0)2Re, -S(O)2NReRf, N=S(O)ReRf, -S(O)(NRe)Rf, -(CH2)pRf, -(CH2)pN(Re)(CH2)qRf, - (CH2)pO(CH2)qRf, -(CH2)pC(O)(CH2)qRf, -(CH2)pC(O)O(CH2b)qRf, -(CH2)pOC(O)(CH2)qRf, - (CH2)pOC(O)O(CH2)qRf, -(CH2)pN(Re)C(O)(CH2)qRf, -(CH2)pC(O)N(Re)(CH2)qRf, - (CH2)pOC(O)N(Re)(CH2)qRf, -(CRaRb)PN(Re)C(O)O(CH2)qRf, cycloalkyl, cycloalkenyl, spirocycloalkyl, fused -carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, each of the aforementioned is optionally and independently substituted with one or more independently selected Rgsubstituents;Rb and Rc, taken together with the atom(s) to which they are attached, independently form a cycloalkyl or heterocycloalkyl, wherein each cycloalkyl or heterocycloalkyl is optionally and independently substituted with one or more independently selected Rgsubstituents; each Rd is independently H, D, alkyl, alkenyl, alkynyl, halo, -CF3, cyano, nitro, -OH, - C(O)NHOH, -C(O)NH2, -C(O)OH, -NH2, =CReRf, =NRe, =0, -C(0)Re, -C(0)NReRf, -C(0)0Re, - NH(CH2)pRe, -NReRf, -NReC(0)Rf, -NReS(O)2Rf, -N=S(O)ReRf, -0Re, -0C(0)Re, -0C(0)0Re, -alkylene- P(0)ReRf, -OP(O)(ORe)(ORf), -OP(O)(ORe)(NHRf), -0P(0)ReRf„ -P(0)ReRf, -SRe, -S(O)Re, - S(0)(NRe)Rf, -S(0)2Re, -S(O)2NReRf, N=S(O)ReRf, -S(O)(NRe)Rf, -(CH2)pRf, -(CH2)pN(Re)(CH2)qRf, - (CH2)pO(CH2)qRf, -(CH2)pC(O)(CH2)qRf, -(CH2)pC(O)O(CH2b)qRf, -(CH2)pOC(O)(CH2)qRf, - (CH2)pOC(O)O(CH2)qRf, -(CH2)pN(Re)C(O)(CH2)qRf, -(CH2)pC(O)N(Re)(CH2)qRf, - (CH2)pOC(O)N(Re)(CH2)qRf, -(CRaRb)PN(Re)C(O)O(CH2)qRf, cycloalkyl, cycloalkenyl, spirocycloalkyl, fused -carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused- heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, each of the aforementioned is optionally and independently substituted with one or more independently selected Rgsubstituents; two Rd, taken together with the atom(s) to which they are attached, independently form a cycloalkyl or heterocycloalkyl, wherein each cycloalkyl or heterocycloalkyl is optionally and independently substituted with one or more independently selected Rgsubstituents; each Reis independently H, D, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyalkyloxy, alkoxyalkyloxyalkyl, alkylidenyl, alkoxyalkylidenyl, alkylthio, alkylsulfonyl, cyanoalkyl, cyanoalkenyl, cyanoalkynyl, alkylamino, dialkylamino, aminocarbonyl, alkoxycarbonyl, alkylcarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, halo, haloalkyl, haloalkylidenyl, hydroxyalkyl, haloalkoxy, heteroalkyl, hydroxyalkyl, oxoalkyl, -NH2, -OH, -CF3, -Cyano, -Nitro, =CH2, =NH, =0, -C(0)NH2, -C(O)NHOH, - C(O)OH, -C(0)0Rg-, -0C(0)Rg-, -OP(O)(OH)(OH), -P(O)(OH)(OH), aralkyl, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkyloxyalkyl, cycloalkylalkyloxyalkyloxy, cycloalkylalkyloxyalkyl, heteroaralkyl, heterocyclylalkyl, heterocyclyloxy, heterocyclyloxyalkyl, heterocyclylalkyloxy, heterocyclylalkyloxyalkyl, cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged- carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged- heterocyclic, aryl, or heteroaryl, each of the aforementioned is optionally and independently substituted with one or more independently selected Rgsubstituents; two Re, taken together with the atom(s) to which they are attached, independently form a cycloalkyl or heterocycloalkyl, wherein each cycloalkyl or heterocycloalkyl is optionally and independently substituted with one or more independently selected Rgsubstituents; each Rfis independently H, D, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyalkyloxy, alkoxyalkyloxyalkyl, alkylidenyl, alkoxyalkylidenyl, alkylthio, alkylsulfonyl, cyanoalkyl,cyanoalkenyl, cyanoalkynyl, alkylamino, dialkylamino, aminocarbonyl, alkoxycarbonyl, alkylcarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, halo, haloalkyl, haloalkylidenyl, hydroxyalkyl, haloalkoxy, heteroalkyl, hydroxyalkyl, oxoalkyl, -NH2, -OH, -CF3, -Cyano, -Nitro, =CH2, =NH, =0, -C(0)NH2, -C(O)NHOH, - C(O)OH, -C(0)0Rg-, -0C(0)Rg-, -OP(O)(OH)(OH), -P(O)(OH)(OH), aralkyl, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkyloxyalkyl, cycloalkylalkyloxyalkyloxy, cycloalkylalkyloxyalkyl, heteroaralkyl, heterocyclylalkyl, heterocyclyloxy, heterocyclyloxyalkyl, heterocyclylalkyloxy, heterocyclylalkyloxyalkyl, cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged- carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged- heterocyclic, aryl, or heteroaryl, each of the aforementioned is optionally and independently substituted with one or more independently selected Rgsubstituents; two Rf, taken together with the atom(s) to which they are attached, independently form a cycloalkyl or heterocycloalkyl, wherein each cycloalkyl or heterocycloalkyl is optionally and independently substituted with one or more independently selected Rgsubstituents; each Rgis independently H, D, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyalkyloxy, alkoxyalkyloxyalkyl, alkylidenyl, alkoxyalkylidenyl, alkylthio, alkylsulfonyl, cyanoalkyl, cyanoalkenyl, cyanoalkynyl, alkylamino, dialkylamino, aminocarbonyl, alkoxycarbonyl, alkylcarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, halo, haloalkyl, haloalkylidenyl, hydroxyalkyl, haloalkoxy, heteroalkyl, hydroxyalkyl, oxoalkyl, -NH2, -OH, -CF3, -Cyano, -Nitro, =CH2, =NH, =0, -C(0)NH2, -C(O)NHOH, - C(O)OH,-OP(O)(OH)(OH), -P(O)(OH)(OH), aralkyl, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkyloxyalkyl, cycloalkylalkyloxyalkyloxy, cycloalkylalkyloxyalkyl, heteroaralkyl, heterocyclylalkyl, heterocyclyloxy, heterocyclyloxyalkyl, heterocyclylalkyloxy, heterocyclylalkyloxyalkyl, cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, each of the aforementioned is optionally and independently substituted with one or more independently selected Rhsubstituents; each Rhis independently H, D, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyalkyloxy, alkoxyalkyloxyalkyl, alkylidenyl, alkoxyalkylidenyl, alkylthio, alkylsulfonyl, cyanoalkyl, cyanoalkenyl, cyanoalkynyl, alkylamino, dialkylamino, aminocarbonyl, alkoxycarbonyl, alkylcarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, halo, haloalkyl, haloalkylidenyl, hydroxyalkyl, haloalkoxy, heteroalkyl, hydroxyalkyl, oxoalkyl, -NH2, -OH, -CF3, -Cyano, -Nitro, =CH2, =NH, =0, -C(0)NH2, -C(O)NHOH, - C(O)OH,-OP(O)(OH)(OH), -P(O)(OH)(OH), aralkyl, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkyloxyalkyl, cycloalkylalkyloxyalkyloxy, cycloalkylalkyloxyalkyl, heteroaralkyl, heterocyclylalkyl, heterocyclyloxy, heterocyclyloxyalkyl, heterocyclylalkyloxy, heterocyclylalkyloxyalkyl, cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged-carbocyclic, heterocycloalkyl,heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl; m Is O, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; n Is O, 1, 2, 3, 4, 5, or 6; p Is O, 1, 2, 3, 4, 5, or 6; p1 is 0,1, 2, 3, 4, or 5. q Is O, 1, 2, 3, 4, 5, or 6; and r is O, 1, 2, 3, 4, 5, or 6.In preferred embodiments, the compound is represented by Formula (2):In preferred embodiments, the compound is represented by Formula (3):In preferred embodiments, the compound is represented by Formula (4):In preferred embodiments, the compound is represented by Formula (5):In preferred embodiments, the compound is represented by Formula (6):In preferred embodiments, the compound is represented by Formula (7):whereinW5is N or C(Ra).In preferred embodiments, the compound is represented by Formula (8):In preferred embodiments, the compound is represented by Formula (9):In preferred embodiments, the compound is represented by Formula (10):Compounds of the invention may contain one or more asymmetric carbon atoms. Accordingly, the compounds may exist as diastereomers, enantiomers, or mixtures thereof. Each of the asymmetric carbon atoms may be in the R or S configuration, and both of these configurations are within the scope of the invention.A modified compound of any one of such compounds including a modification having an improved (e.g., enhanced, greater) pharmaceutical solubility, stability, bioavailability, and / or therapeutic index as compared to the unmodified compound is also contemplated. Exemplary modifications include (but are not limited to) applicable prodrug derivatives, and deuterium-enriched compounds.It should be recognized that the compounds of the present invention may be present and optionally administered in the form of salts or solvates. The invention encompasses any pharmaceutically acceptable salts and solvates of any one of the above-described compounds and modifications thereof.Also within the scope of this invention is a pharmaceutical composition containing one or more of the compounds, modifications, and / or salts and thereof described above for use in treating a neoplastic disease, autoimmune disease, and inflammatory disorders, therapeutic uses thereof, and use of the compounds for the manufacture of a medicament for treating the disease I disorder.This invention also relates to a method of treating a neoplastic disease, by administering to a subject in need thereof an effective amount of one or more of the compounds, modifications, and / or salts, and compositions thereof described above.Autoimmune and / or inflammatory diseases that can be affected using compounds and compositions according to the invention include, but are not limited to: psoriasis, allergy, Crohn's disease, irritable bowel syndrome, Sjogren's disease, tissue graft rejection, and hyperacute rejection of transplanted organs, asthma, systemic lupus erythematosus (and associated glomerulonephritis), dermatomyositis, multiple sclerosis, scleroderma, vasculitis (ANCA-associated and other vasculitides), autoimmune hemolytic and thrombocytopenic states, Goodpasture's syndrome (and associated glomerulonephritis and pulmonary hemorrhage), atherosclerosis, rheumatoid arthritis, chronic Idiopathic thrombocytopenic purpura (ITP), Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes, septic shock, and myasthenia gravis.The details of one or more embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and from the claims. It should be understood that all mebodiments I features of the invention (compounds, pharmaceutical compositions, methods of make I use, etc) described herein, including any specific features described in the examples and original claims, can combine with one another unless not applicable or explicitly disclaimed.DETAILED DESCRIPTION OF THE INVENTIONExemplary compounds described herein include, but are not limited to, the following:1-[(4R,7S,8S,9S)-13-(3-amino-8-ethynyl-7-fluoronaphthalen-1-yl)-14-fluoro-9-methyl-17-{[1-(morpholin- 4-yl methyl)cyclopropy I] methoxy }- 10-oxa-2, 12,16,18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]-2-fluoroprop-2-en-1 - one,1 - [(4R.7S, 8S, 9S)- 13-(3-amino-8-ethynyl-7-fluoronaphthalen-1 -yl)-14-fl uoro-9-methy I- 17-{[1 -(morpholin- 4-y I methy l)cy clopropy I] methoxy }- 10-oxa-2, 12,16,18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one, 1-[(4R,7S,8S,9S)-13-(3-amino-8-ethynyl-7-fluoronaphthalen-1-yl)-17-[(2,6-dimethylidene- tetrahy d ropy rrol izi n-7a-y I )methoxy] - 14-f I uoro-9-methy I- 10-oxa-2, 12, 16,18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]-2-fluoroprop-2-en-1 - one,1-[(4R,7S,8S,9S)-13-(3-amino-8-ethynyl-7-fluoronaphthalen-1-yl)-17-[(2,6-dimethylidene- tetrahy d ropy r rol i zi n-7a-y I )methoxy] - 14-f I uoro-9-methy I- 10-oxa-2, 12, 16,18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{ 15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one,1-[(4R,7S,8R)-13-(3-amino-8-ethynyl-7-fluoronaphthalen-1-yl)-17-[(2,6-dimethylidene- tetrahy d ropy rrol i zi n-7a-y I )methoxy] - 14-f I uoro-2, 12, 16, 18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{ 15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one, 1-[(4R,7S,8R,9R)-13-(3-amino-8-ethynyl-7-fluoronaphthalen-1-yl)-17-[(2,6-dimethylidene- tetrahy d ropy rrol i zi n-7a-y I )methoxy] - 14-f I uoro-9-methy I-2, 12,16,18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{ 15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one,1-[(4R,7S,8R,9R, 10R)-13-(3-amino-8-ethynyl-7-fluoronaphthalen-1 -yl)-17-[(2,6-dimethylidene- tetrahydropyrrolizin-7a-yl)methoxy]-14-fluoro-9, 10-dimethyl-2, 12,16, 18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{ 15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one,1-[(4R,7S,8R,9R, 10S)-13-(3-amino-8-ethynyl-7-fluoronaphthalen-1 -yl)-17-[(2,6-dimethylidene- tetrahydropyrrolizin-7a-yl)methoxy]-14-fluoro-9, 10-dimethyl-2, 12,16, 18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one,1-[(4R,7S,8R,9R, 10R)-13-(3-amino-8-ethynyl-7-fluoronaphthalen-1 -yl)-14-fluoro-9, 10-dimethyl-17-{[1 - (mor phol i n-4-y I methy l)cy clopropy I] methoxy }-2, 12, 16,18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one,1-[(4R,7S,8R,9R, 10R)-13-(3-amino-8-ethynyl-7-fluoronaphthalen-1 -yl)-14-fluoro-9, 10-dimethyl-17-{[1 - (mor phol i n -4-yl methy I )cy cl opropy I] methoxy }-2, 12,16, 18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{ 15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]-2-fluoroprop-2-en-1 - one,1-[(4R,7S,8R,9R,10R)-13-(3-amino-8-ethynyl-7-fluoronaphthalen-1-yl)-14-fluoro-9,10-dimethyl-17-[(1- {[(3R)-3-methy I morphol i n-4-y I] methy I }cy clopropy I )methoxy] -2, 12, 16,18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one, 1-[(4R,7S,8R,9R, 10R)-13-(3-amino-8-ethynyl-7-fluoronaphthalen-1 -yl)-14-fluoro-9, 10-dimethyl-17-[(1 - {[(3S)-3-methy I morphol i n-4-y I] methy I }cycl opropyl)methoxy]-2, 12,16, 18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one, 1-[(4R,7S,8R,9R, 10R)-13-(3-amino-8-ethynyl-7-fluoronaphthalen-1 -yl)-14-fluoro-9, 10-dimethyl-17-[(1 - {[(2S)-2-methy I morphol i n-4-y I] methy I }cycl opropyl)methoxy]-2, 12,16, 18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one, 1-[(4R,7S,8R,9R, 10R)-13-(3-amino-8-ethynyl-7-fluoronaphthalen-1 -yl)-14-fluoro-9, 10-dimethyl-17-[(1 - {[(2R)-2-methy I morphol I n -4-yl] methy I }cy clopropy I )methoxy] -2, 12,16, 18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{ 15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one, 1-[(4R,7S,8S)-13-(3-amino-8-ethynyl-7-fluoronaphthalen-1-yl)-17-[(2,6-dimethylidene- tetrahy d ropy r rol I zi n-7a-y I )methoxy] - 14-f I uoro-2, 12, 16, 18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{ 15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one, 1-[(4R,7S,8S,9S)-13-(3-amino-8-ethynyl-7-fluoronaphthalen-1-yl)-17-[(2,6-dimethylidene- tetrahy d ropy r rol I zi n-7a-y I )methoxy] - 14-f I uoro-9-methy I-2, 12,16,18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{ 15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one, 1-[(4R,7S,8S,9S,10R)-13-(3-amino-8-ethynyl-7-fluoronaphthalen-1-yl)-17-[(2,6-dimethylidene- te trahy d ropy r rol I zi n-7a-y I )methoxy] - 14-fl uoro-9, 10-d I methy i-2, 12,16,18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{ 15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one, 1-[(4R,7S,8S,9S, 10S)-13-(3-amino-8-ethynyl-7-fluoronaphthalen-1-yl)-17-[(2,6-dimethylidene- tetrahydropyrrolizin-7a-yl)methoxy]-14-fluoro-9, 10-dimethyl-2, 12,16, 18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one,1 -[(4R,7S,8S,9S)-13- (8-ethy ny l-7-f I uoro-3-hy d roxy n aph th alen- 1 -yl)-14-fl uoro-9-methy I- 17-{[ 1 - (mor phol i n-4-y I methy l)cy clopropy I] methoxy }- 10-oxa-2, 12,16,18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]-2-fluoroprop-2-en-1 - one,1 -[(4R,7S,8S,9S)-13- (8-ethy ny l-7-f I uoro-3-hy d roxy n aph th alen- 1 -yl)-14-fl uoro-9-methy I- 17-{[ 1 - (morpholin-4-ylmethyl)cyclopropyl]methoxy}-10-oxa-2, 12, 16,18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one, 1-[(4R,7S,8S,9S)-17-[(2,6-dimethylidene-tetrahydropyrrolizin-7a-yl)methoxy]-13-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-1 -yl)-14-f I uoro-9-methy I- 10-oxa-2, 12, 16,18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{ 15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]-2-fluoroprop-2-en-1 - one,1-[(4R,7S,8S,9S)-17-[(2,6-dimethylidene-tetrahydropyrrolizin-7a-yl)methoxy]-13-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-1 -yl)-14-f I uoro-9-methy I- 10-oxa-2, 12, 16,18,20-pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{ 15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one,1 - [(4R.7S, 8R, 9R, 10R)- 13-(8-ethy ny l-7-f I uoro-3-hy d roxy n aph th alen- 1 -yl)-14-fluoro-9, 10-dimethy I- 17-{[1 - (mor phol i n-4-y I methy l)cy clopropy I] methoxy }-2, 12, 16,18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one,1 - [(4R.7S, 8R, 9R, 10R)- 13-(8-ethy ny l-7-f I uoro-3-hy d roxy n aph th alen- 1 -yl)-14-fl uoro-9, 10-dimethy I- 17-{[1 - (mor phol i n-4-y I methy l)cy clopropy I] methoxy }-2, 12, 16,18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]-2-fluoroprop-2-en-1 - one,1 - [(4R.7S, 8R, 9R, 10R)- 13-(8-ethy ny l-7-f I uoro-3-hy d roxy n aph th alen- 1 -yl)-14-fl uoro-9, 10-dimethy I- 17-[(1 - {[(3R)-3-methy I mor phol i n -4-y I] methy IJcycl opropy I )me thoxy] -2, 12,16, 18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{ 15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one,1-[(4R,7S,8R,9R,10R)-13-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-14-fluoro-9,10-dimethyl-17-[(1- {[(3S)-3-methy I mor phol i n-4-y I] methy I }cy clopropy I )methoxy] -2, 12, 16,18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{ 15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one,1-[(4R,7S,8R,9R,10R)-13-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-14-fluoro-9,10-dimethyl-17-[(1- {[(2S)-2-methy I mor phol i n-4-y I] methy I }cy clopropy I )methoxy] -2, 12, 16,18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{ 15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one,1-[(4R,7S,8R,9R,10R)-13-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-14-fluoro-9,10-dimethyl-17-[(1- {[(2R)-2-methy I morphol in-4-y l]methy IJcycl opropy l)methoxy]-2, 12, 16, 18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{ 15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one, 1-[(4R,7S,8R)-14-(3-amino-8-ethynyl-7-fluoronaphthalen-1-yl)-18-[(2,6-dimethylidene- tetrahydropyrrolizin-7a-yl)methoxy]-15-fluoro-2, 13,17,19,21- pentaazapentacyclo[10.7.1 .1A{4,7}.0A{2,8}.0A{16,20}]henicosa-1 (19), 12(20), 13, 15, 17-pentaen-21-yl]prop-2-en-1- one,1-[(4R,7S,8R,9R)-14-(3-amino-8-ethynyl-7-fluoronaphthalen-1-yl)-18-[(2,6-dimethylidene- tetrahydropyrrolizin-7a-yl)methoxy]-15-fluoro-9-methyl-2,13, 17, 19,21- pentaazapentacyclo[10.7.1 .1A{4,7}.0A{2,8}.0A{16,20}]henicosa-1 (19), 12(20), 13, 15, 17-pentaen-21-yl]prop-2-en-1- one,1-[(4R,7S,8R,9R, 10S)-14-(3-amino-8-ethynyl-7-fluoronaphthalen-1-yl)-18-[(2,6-dimethylidene- tetrahydropyrrolizin-7a-yl)methoxy]-15-fluoro-9, 10-dimethyl-2, 13, 17, 19,21- pentaazapentacyclo[10.7.1 .1A{4,7}.0A{2,8}.0A{16,20}]henicosa-1 (19), 12(20), 13, 15, 17-pentaen-21-yl]prop-2-en-1- one,1-[(4R,7S,8R,9R, 10R)-14-(3-amino-8-ethynyl-7-fluoronaphthalen-1-yl)-18-[(2,6-dimethylidene- tetrahy d ropy rrol izi n-7a-y I )methoxy] - 15-f I uoro-9, 10-d i methy I -2, 13, 17, 19,21- pentaazapentacyclo[10.7.1 .1A{4,7}.0A{2,8}.0A{16,20}]henicosa-1 (19), 12(20), 13, 15, 17-pentaen-21-yl]prop-2-en-1- one,1-[(4R,7S,8R,9R, 11 R)-14-(3-amino-8-ethynyl-7-fluoronaphthalen-1-yl)-18-[(2,6-dimethylidene-tetrahydropyrrolizin-7a-yl)methoxy]-15-fluoro-9, 11-dimethyl-2, 13, 17, 19,21- pentaazapentacyclo[10.7.1 .1A{4,7}.0A{2,8}.0A{16,20}]henicosa-1 (19), 12(20), 13, 15, 17-pentaen-21-yl]prop-2-en-1- one,1-[(4R,7S,8R,9R, 11 S)-14-(3-amino-8-ethynyl-7-fluoronaphthalen-1-yl)-18-[(2,6-dimethylidene- tetrahydropyrrolizin-7a-yl)methoxy]-15-fluoro-9, 11-dimethyl-2, 13, 17, 19,21- pentaazapentacyclo[10.7.1 .1A{4,7}.0A{2,8}.0A{16,20}]henicosa-1 (19), 12(20), 13, 15, 17-pentaen-21-yl]prop-2-en-1- one,1-[(4R,7S,8R)-14-(3-amino-8-ethynyl-7-fluoronaphthalen-1-yl)-18-[(2,6-dimethylidene- tetrahydropy rrol izin-7 a-y l)methoxy]- 15-fl uoro-11 -oxa-2, 13, 17,19,21- pentaazapentacyclo[10.7.1 .1A{4,7}.0A{2,8}.0A{16,20}]henicosa-1 (19), 12(20), 13, 15, 17-pentaen-21-yl]prop-2-en-1- one,1-[(4R,7S,8R)-14-(3-amino-8-ethynyl-7-fluoronaphthalen-1-yl)-18-[(2,6-dimethylidene- tetrahy d ropy rrol izi n-7a-y I )methoxy] - 15-f I uoro- 11 -methyl-2, 11 ,13,17, 19,21- hexaazapentacyclo[10.7.1 .1A{4,7}.0A{2,8}.0A{16,20}]henicosa-1 (19), 12(20), 13, 15, 17-pentaen-21-yl]prop-2-en-1- one,1 -[(4R,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-14-fluoro-9-methyl-17-{[1 -(morpholin- 4-yl methyl )cycl opropy I] methoxy }- 10-oxa-2, 12, 16, 18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{ 15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one,1-[(4R,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-14-fluoro-9-methyl-17-{[1-(morpholin- 4-yl methyl )cycl opropy I] methoxy }- 10-oxa-2, 12, 16, 18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{ 15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]-2-fluoroprop-2-en-1 - one,1 -[(4R,7S,8S,9S)-13-[5-amino-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl]-14-fluoro-9-methyl-17-{[1 - (morp hoi I n-4-y I methy l)cy clopropy I] methoxy }- 10-oxa-2, 12,16,18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{ 15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]-2-fluoroprop-2-en-1 - one,1-[(2R,4R,7S,8S,9S)-13-[5-amino-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl]-14-fluoro-9-methyl-17- ({[(1 , 4-oxazi n an-4-y I methy l)cy clopropy I] methy I }oxy)- 10-oxa-2, 12, 16,18,20- pentazapentacyclo[9.7.1 .14,7.015, 19.02, 8] icosa- 1 (18), 11 (19), 12, 14, 16-pentaen-20-yl]prop-2-en-1 -one,1-[(4R,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-17-[(2,6-dimethylidene- tetrahydropyrrolizin-7a-yl)methoxy]-14-fluoro-9-methyl-10-oxa-2, 12,16,18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]-2-fluoroprop-2-en-1 - one,1-[(4R,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-17-[(2,6-dimethylidene- tetrahydropyrrolizin-7a-yl)methoxy]-14-fluoro-9-methyl-10-oxa-2, 12,16,18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one,1-[(4R,7S,8R)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-17-[(2,6-dimethylidene-tetrahydropyrrolizin-7a-yl)methoxy]-14-fluoro-2, 12,16,18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one,1-[(4R,7S,8R,9R)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-17-[(2,6-dimethylidene- tetrahydropyrrolizin-7a-yl)methoxy]-14-fluoro-9-methyl-2,12, 16, 18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one,1-[(4R,7S,8R,9R, 10R)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-17-[(2,6-dimethylidene- tetrahydropyrrolizin-7a-yl)methoxy]-14-fluoro-9, 10-dimethyl-2, 12,16, 18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one, 1-[(4R,7S,8R,9R, 10S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-17-[(2,6-dimethylidene- tetrahy d ropy rrol izi n-7a-y I )methoxy] - 14-f I uoro-9, 10-d i methyl -2, 12, 16,18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one,1-[(4R,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-17-[(2,6-dimethylidene- tetrahy d ropy r rol i zi n-7a-y I )methoxy] - 14-f I uoro-9-methy I-2, 12,16,18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{ 15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one,1-[(4R,7S,8R)-14-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-18-[(2,6-dimethylidene- tetrahy d ropy r rol i zi n-7a-y I )methoxy] - 15-f I uoro-2, 13, 17, 19,21- pentaazapentacyclo[10.7.1 .1A{4,7}.0A{2,8}.0A{16,20}]henicosa-1 (19), 12(20), 13, 15, 17-pentaen-21-yl]prop-2-en-1- one,1-[(4R,7S,8R)-14-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-18-[(2,6-dimethylidene- tetrahy d ropy r rol i zi n-7a-y I )methoxy] - 15-f I uoro- 11 -oxa-2, 13,17,19,21- pentaazapentacyclo[10.7.1 .1A{4,7}.0A{2,8}.0A{16,20}]henicosa-1 (19), 12(20), 13, 15, 17-pentaen-21-yl]prop-2-en-1- one,1-[(4R,7S,8R)-14-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-18-[(2,6-dimethylidene- tetrahydropyrrolizin-7a-yl)methoxy]-15-fluoro-11-methyl-2,11,13, 17,19,21- hexaazapentacyclo[10.7.1 .1A{4,7}.0A{2,8}.0A{16,20}]henicosa-1 (19), 12(20), 13, 15, 17-pentaen-21-yl]prop-2-en-1- one,1-[(4R,7S,8R,9R, 10R)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-14-fluoro-9, 10-dimethyl-17-{[1- (mor phol i n-4-y I methy l)cy clopropy I] methoxy }-2, 12, 16,18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one,1-[(4R,7S,8R,9R, 10R)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-14-fluoro-9, 10-dimethyl-17-{[1- (mor phol i n-4-y I methy l)cy clopropy I] methoxy }-2, 12, 16,18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]-2-fluoroprop-2-en-1- one,1-[(4R,7S,8R,9R)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-14-fluoro-9-methyl-17-{[1-(morpholin- 4-yl methy I )cycl opropy I] methoxy }-2, 12,16,18,20-pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}]icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one,(2Z)-1-[(2S,4R,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-14-fluoro-9-methyl-17-({[(1 ,4-oxazinan-4-ylmethyl)cyclopropyl]methyl}oxy)-10-oxa-2, 12,16,18,20- pentazapentacyclo[9.7.1 .14,7.015, 19.02, 8] icosa- 1 (19), 11 (12), 13, 15(16), 17-pentaen-20-yl]-4-methylpent-2-en-1 - one(2Z)-1-[(2R,4R,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-14-fluoro-9-methyl-17-({[(1 ,4- oxazinan-4-ylmethyl)cyclopropyl]methyl}oxy)-10-oxa-2, 12, 16, 18,20- pentazapentacyclo[9.7.1 .14,7.015, 19.02, 8] icosa- 1 (18), 11 (19), 12, 14, 16-pentaen-20-yl]-4-methylpent-2-en-1 -one,(2E)-1-[(2R,4R,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-14-fluoro-9-methyl-17-({[(1 ,4- oxazinan-4-ylmethyl)cyclopropyl]methyl}oxy)-10-oxa-2, 12, 16, 18,20- pentazapentacyclo[9.7.1 .14,7.015, 19.02, 8] icosa- 1 (18), 11 (19), 12, 14, 16-pentaen-20-yl]but-2-en-1 -one,1-[(2R,4R,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-14-fluoro-9-methyl-17-({[(1 ,4- oxazinan-4-ylmethyl)cyclopropyl]methyl}oxy)-10-oxa-2, 12, 16, 18,20- pentazapentacyclo[9.7.1 .14,7.015, 19.02, 8] icosa- 1 (18), 11 (19), 12, 14, 16-pentaen-20-yl]-3-methylbut-2-en-1 -one,1-[(2R,4R,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-14-fluoro-9-methyl-17-({[(1 ,4- oxazinan-4-ylmethyl)cyclopropyl]methyl}oxy)-10-oxa-2, 12, 16, 18,20- pentazapentacyclo[9.7.1 .14,7.015, 19.02, 8] icosa- 1 (18), 11 (19), 12, 14, 16-pentaen-20-yl]-2-fluoro-3-methylbut-2-en- 1-one,(2E)-1-[(2R,4R,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-14-fluoro-9-methyl-17-({[(1 ,4- oxazinan-4-ylmethyl)cyclopropyl]methyl}oxy)-10-oxa-2, 12, 16, 18,20- pentazapentacyclo[9.7.1 .14,7.015,19.02, 8]icosa-1 (18), 11 (19), 12, 14, 16-pentaen-20-yl]-4,4,4-trifluoro-3- methylbut-2-en-1-one,1-[(2R,4R,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-14-fluoro-9-methyl-17-({[(1 ,4- oxazinan-4-ylmethyl)cyclopropyl]methyl}oxy)-10-oxa-2, 12,16,18,20- pentazapentacyclo[9.7.1 .14,7.015, 19.02, 8] icosa- 1 (18), 11 (19), 12, 14, 16-pen taen-20-y I] -2, 3-d i methy I bu t-2-en- 1 - one,1-[(2R,4R,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-14-fluoro-9-methyl-17-({[(1 ,4- oxazinan-4-ylmethyl)cyclopropyl]methyl}oxy)-10-oxa-2, 12, 16, 18,20- pentazapentacyclo[9.7.1 .14,7.015, 19.02, 8] icosa- 1 (18), 11 (19), 12, 14, 16-pentaen-20-yl]-2-(cyclohexylidene)ethan- 1-one,1-[(2R,4R,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-14-fluoro-9-methyl-17-({[(1 ,4- oxazinan-4-ylmethyl)cyclopropyl]methyl}oxy)-10-oxa-2,12,16,18,20-pentazapentacyclo[9.7.1.14’7.015’19.02’8]icosa- 1 (18), 11 (19), 12, 14, 16-pen taen-20-y l]-2-(3, 4, 5, 6-tetrahy d ro-2 H-py ran-4-y I i dene)eth an- 1 -one,(2E)-1-[(2R,4R,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-14-fluoro-9-methyl-17-({[(1,4- oxazinan-4-ylmethyl)cyclopropyl]methyl}oxy)-10-oxa-2,12,16,18,20-pentazapentacyclo[9.7.1.14’7.015’19.02’8]icosa- 1 (18), 11 (19), 12, 14, 16-pen taen-20-y l]-3, 4-d i methy I pen t-2-en- 1 -one,(2E)-1-[(2R,4R,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-14-fluoro-9-methyl-17-({[(1 ,4- oxazinan-4-ylmethyl)cyclopropyl]methyl}oxy)-10-oxa-2, 12,16,18,20-pentazapentacyclo[9.7.1 .147.015’19.02’8]icosa- 1 (18), 11 (19), 12, 14, 16-pen taen-20-yl]-3-(3, 4, 5, 6-tetrahy d ro-2 H-py ran-4-y I) but-2-en- 1 -one,(2E)-1-[(2R,4R,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-14-fluoro-9-methyl-17-({[(1 ,4- ox azi n a n -4-y I methy I )cycl op ropy I] m ethy l}oxy )- 10-oxa-2, 12,16,18,20-pentazapentacyclo[9.7.1 .147.015’19.02’8]icosa- 1 (18), 11 (19), 12, 14, 16-pen taen-20-y l]-3-(3, 3-d if I uorocy clobu ty I) bu t-2-en- 1 -one,(2E)-1-[(2R,4R,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-14-fluoro-9-methyl-17-({[(1 ,4- oxazinan-4-ylmethyl)cyclopropyl]methyl}oxy)-10-oxa-2,12, 16,18,20-pentazapentacyclo[9.7.1.14’7.015’19.02’8]icosa- 1 (18), 11 (19), 12, 14, 16-pen taen-20-y l]-3-(3, 4-d if I uoropheny l)bu t-2-en- 1 -one,(2E)-1-[(2R,4R,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-14-fluoro-9-methyl-17-({[(1 ,4- oxazinan-4-ylmethyl)cyclopropyl]methyl}oxy)-10-oxa-2,12,16,18,20-pentazapentacyclo[9.7.1.14’7.015’19.02’8]icosa- 1 (18), 11 (19), 12, 14, 16-pen taen-20-y l]-3-(py rid i n-2-y I) bu t-2-en- 1 -one,(2E)-1-[(4R,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-14-fluoro-9-methyl-17-{[1-(mor phol i n-4-y I methy l)cy clopropy I] methoxy }- 10-oxa-2, 12,16,18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]-4-methyl-4-[(3S)-3- methylmorpholin-4-yl]pent-2-en-1-one,(2Z)-1-[(4R,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-14-fluoro-9-methyl-17-{[1-(mor phol i n-4-y I methy l)cy clopropy I] methoxy }- 10-oxa-2, 12,16,18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]-4-methyl-4-[(3S)-3- methylmorpholin-4-yl]pent-2-en-1-one,(2E)-1-[(4R,7S,8R,9R)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-14-fluoro-9-methyl-17-{[1-(morp hoi i n-4-y I methy l)cy clopropy I] methoxy }-2, 12,16, 18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{ 15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]-4-methyl-4-[(3S)-3- methylmorpholin-4-yl]pent-2-en-1-one,(2Z)-1-[(4R,7S,8R,9R)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-14-fluoro-9-methyl-17-{[1-(mor phol i n-4-y I methy l)cy clopropy I] methoxy }-2, 12, 16,18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]-4-methyl-4-[(3S)-3- methylmorpholin-4-yl]pent-2-en-1-one,1 -[(4R,7S,8S,9S)-13- [5-am i no-3-ch loro-2-(tr if I uoromethy l)pheny I] - 14-f I uoro-4, 9-d i methy I - 17-{[1 - (mor phol i n-4-y I methy l)cy clopropy I] methoxy }- 10-oxa-2, 12,16,18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one, 1-[(2R,4S,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-14-fluoro-9-methyl-17-({[(1 ,4- oxazi n an-4-y I methy l)cy clopropy I] methy I }oxy)-4-[(1 E)-prop- 1 -eny I]- 10-oxa-2, 12,16,18,20- pentazapentacyclo[9.7.1 .147.015’19.028]icosa-1 (18), 11 (19), 12, 14, 16-pentaen-20-yl]prop-2-en-1 -one,1-[(2R,4S,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-14-fluoro-9-methyl-4-(2- methylprop-1-enyl)-17-({[(1 ,4-oxazinan-4-ylmethyl)cyclopropyl]methyl}oxy)-10-oxa-2,12, 16,18,20- pentazapentacyclo[9.7.1.147.015’19.028]icosa-1 (18),11 (19),12,14,16-pentaen-20-yl]prop-2-en-1-one,1-[(2R,4S,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-14-fluoro-9-methyl-4-(3-methylbut- 2-en-2-y I )- 17-({[(1 , 4-oxazi n an-4-y I methy I )cycl opropy I] methy l}oxy )- 10-oxa-2, 12,16,18,20- pentazapentacyclo[9.7.1 .147.015’19.028]icosa-1 (18), 11 (19), 12, 14, 16-pentaen-20-yl]prop-2-en-1 -one,1-[(2R,4S,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-14-fluoro-9-methyl-4-[(1 E)-3- methyl but- 1 -eny I]- 17-({[( 1 , 4-oxazi n an-4-y I methyl )cyclopropy I] methyl }oxy)- 10-oxa-2, 12, 16,18,20- pentazapentacyclo[9.7.1 .147.015 19.028]icosa-1 (18),11 (19),12,14, 16-pentaen-20-yl]prop-2-en-1-one, 1-[(2R,4S,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-4-[(1 E)-2-cyclopropylvinyl]-14- f I uoro-9-methy I- 17-({[(1 , 4-oxazi n an-4-y I methyl)cyclopropy I] methyl }oxy)- 10-oxa-2, 12, 16,18,20- pentazapentacyclo[9.7.1 .147.015’19.028]icosa-1 (18), 11 (19), 12, 14, 16-pentaen-20-yl]prop-2-en-1 -one, 1-[(2R,4S,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-4-ethynyl-14-fluoro-9-methyl-17- ({[(1 , 4-oxazi n an-4-y I methyl )cycl opropy I] methyljoxy)- 10-oxa-2, 12,16, 18,20- pentazapentacyclo[9.7.1 .147.015 19.028]icosa-1 (18),11 (19),12,14, 16-pentaen-20-yl]prop-2-en-1-one, 1-[(2R,4R,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-4-ethyl-14-fluoro-9-methyl-17- ({[(1 , 4-oxazi n an-4-y I methyl )cycl opropy I] methyljoxy)- 10-oxa-2, 12,16, 18,20- pentazapentacyclo[9.7.1 .147.015 19.028]icosa-1 (18),11 (19),12,14, 16-pentaen-20-yl]prop-2-en-1-one,1-[(4S,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-14-fluoro-4-isopropyl-9-methyl-17-{[1- (mor phol I n-4-y I methy l)cy clopropy I] methoxy }- 10-oxa-2, 12,16,18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one,1-[(2R,4S,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-4-cyclopropyl-14-fluoro-9-methyl- 17-({[( 1 , 4-oxazi nan-4-y I methy l)cy clopropy I] methy I }oxy)- 10-oxa-2, 12,16,18,20- pentazapentacyclo[9.7.1 .147.015 19.028]icosa-1 (18),11 (19),12,14, 16-pentaen-20-yl]prop-2-en-1-one, 1-[(2R,4S,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-14-fluoro-9-methyl-4- (methy I cycl opropy I)- 17-({[(1 , 4-oxazi n an-4-y I methy I )cycl opropy I] methy l}oxy)- 10-oxa-2, 12,16,18,20- pentazapentacyclo[9.7.1 .147.015’19.028]icosa-1 (18), 11 (19), 12, 14, 16-pentaen-20-yl]prop-2-en-1 -one,1-[(2R,4S,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-14-fluoro-4-{[(3S)-3-methyl-1,4- oxazi n an-4-y I] methy I }-9-methy I - 17-({[(1 , 4-oxazi n an-4-y I methy l)cycl opropy I] methy l}oxy)- 10-oxa-2, 12,16, 18,20- pentazapentacyclo[9.7.1 .147.015 19.028]icosa-1 (18),11 (19),12,14, 16-pentaen-20-yl]prop-2-en-1-one,1-[(2R,4S,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-14-fluoro-4-{[(3R)-3-methyl-1,4- oxazi n an-4-y I] methy I }-9-methy I - 17-({[(1 , 4-oxazi n an-4-y I methy l)cycl opropy I] methy l}oxy)- 10-oxa-2, 12,16, 18,20- pentazapentacyclo[9.7.1 .147.015 19.028]icosa-1 (18),11 (19),12,14, 16-pentaen-20-yl]prop-2-en-1-one,1-[(2R,4R,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-14-fluoro-9-methyl-4-[(1S)-1-(1 ,4- oxazi n an-4-y l)ethy I] - 17-({[(1 , 4-oxazi n an-4-y I methy I )cycl opropy I] methy l}oxy)- 10-oxa-2, 12,16,18,20- pentazapentacyclo[9.7.1 .147.015 19.028]icosa-1 (18),11 (19),12,14, 16-pentaen-20-yl]prop-2-en-1-one,1-[(2R,4R,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-14-fluoro-4-[(1 S)-1-[(3S)-3-methyl- 1 ,4-oxazinan-4-yl]ethyl]-9-methyl-17-({[(1 ,4-oxazinan-4-ylmethyl)cyclopropyl]methyl}oxy)-10-oxa-2,12, 16,18,20- pentazapentacyclo[9.7.1 .147.015 19.028]icosa-1 (18),11 (19),12,14, 16-pentaen-20-yl]prop-2-en-1-one,1-[(2R,4R,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-14-fluoro-4-{1-[(3R)-3-methyl-1 ,4- oxazi n an-4-y I] ethy l}-9-methy I- 17-({[( 1 , 4-oxazi nan-4-y I methy l)cy clopropy I] methy I }oxy)- 10-oxa-2, 12,16,18,20- pentazapentacyclo[9.7.1 .147.015’19.028]icosa-1 (18), 11 (19), 12, 14, 16-pentaen-20-yl]prop-2-en-1 -one, 1-[(4R,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-14-fluoro-9-methyl-4-[(3S)-3-methy I morphol i ne-4-carbony I] - 17-{[1 - (morphol i n-4-y I methy l)cy cl opropy I] methoxy }- 10-oxa-2, 12,16, 18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one, 1-[(2R,4R,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-14-fluoro-4-{[(3R)-3-methyl-1 ,4- oxazinan-4-yl]carbonyl}-9-methyl-17-({[( 1 , 4-oxazi n an-4-y I methy I )cy clopropy I] methy l}oxy )- 10-oxa-2, 12,16, 18,20- pentazapentacyclo[9.7.1.14’7.015’19.02’8]icosa-1 (18),11 (19),12,14,16-pentaen-20-yl]prop-2-en-1-one,1 -[(4S,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-14-fluoro-9-methyl-17-{[1 -(morpholin- 4-y Imethy l)cyclopropy l]methoxy }-4-pheny I- 10-oxa-2, 12, 16, 18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one, 1-[(4R,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-14-fluoro-9-methyl-17-{[1-(morpholin-4-y I methy l)cy clopropy I] methoxy }-4-(pyri di n-2-y I )- 10-oxa-2, 12,16, 18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one,1 -[(4S,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-14-fluoro-9-methyl-17-{[1 -(morpholin- 4-y I methy l)cy clopropy I] methoxy }-4-[ 1 - (oxan-4-y I) pi peri d i n -4-y I]- 10-oxa-2, 12,16,18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{ 15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one, 1-[(4S,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-14-fluoro-9-methyl-4-{3-[(3S)-3- methyl morphol in-4-yl]cyclobutyl}-17-{[1 -(morphol i n-4-y I methy l)cycl opropyl] methoxy}- 10-oxa-2, 12, 16, 18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{ 15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one, 1-[(4R,7S,8R,9R)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-14-fluoro-4,9-dimethyl-17-{[1-(morp hoi i n-4-y I methy l)cy clopropy I] methoxy }-2, 12, 16,18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{ 15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one, 1-[(4S,7S,8R,9R)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-14-fluoro-4-isopropyl-9-methyl-17-{[1-(mor phol i n-4-y I methy l)cy clopropy I] methoxy }-2, 12, 16,18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one, 1-[(4S,7S,8R,9R)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-14-fluoro-9-methyl-4-{[(3S)-3- methylmorpholin-4-yl]methyl}-17-{[1-(morpholin-4-ylmethyl)cyclopropyl]methoxy}-2,12, 16, 18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one, 1-[(4R,7S,8R,9R)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-14-fluoro-9-methyl-4-[(3S)-3- methylmorpholine-4-carbonyl]-17-{[1 - (morphol i n-4-y I methy l)cy cl opropy I] methoxy }-2, 12,16,18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one, 1-[(4R,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-17-{[(3S,4S)-4-(difluoromethyl)-1,3- d i methy I pi per id i n-3-y I] methoxy }-14-fl uoro-9-methy I -10-oxa-2, 12,16, 18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{ 15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one, 1-[(4R,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-17-{[(3R,4R)-4-(difluoromethyl)-1,3- d i methy I pi per id i n-3-y I] methoxy }-14-fl uoro-9-methy I -10-oxa-2, 12,16, 18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{ 15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one, 1-[(4R,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-17-{[(3S,4S)-4-(difluoromethyl)-1- isopropyl -3-methy I pi per id i n -3-yl] methoxy }-14-fl uoro-9-methyl- 10-oxa-2, 12, 16,18,20-pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{ 15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one, 1-[(4R,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-17-{[(3S,4S)-4-(difluoromethyl)-3- methy I- 1 -(oxan-4-y I) pi peri d i n-3-y I] methoxy }- 14-fl uoro-9-methy I- 10-oxa-2, 12, 16, 18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one, 1-[(4R,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-17-{[(3S,4S)-4-(difluoromethyl)-3- methyl-1-{7-oxaspiro[3.5]nonan-2-yl}piperidin-3-yl]methoxy}-14-fluoro-9-methyl-10-oxa-2,12, 16,18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one, 1-[(4R,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-17-{[(3S,4S)-4-(difluoromethyl)-1-(7- {4, 4-dimethyl-2H,3H-pyrano[2,3-c]pyridin-8-yl}-7-azaspiro[3.5]nonan-2-yl)-3-methylpiperidin-3-yl] methoxy }-14- f I uoro-9-methy I- 10-oxa-2, 12, 16, 18,20-pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}]icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one, 1-[(4R,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-17-{[(3S,4S)-4-(difluoromethyl)-1-(3- {4,4-dimethyl-8-[(3S)-3-methylmorpholin-4-yl]-2H,3H-pyrano[2,3-c]pyridin-5-yl}cyclobutyl)-3-methylpiperidin-3- yl]methoxy}-14-fluoro-9-methyl-10-oxa-2,12,16,18,20-pentaazapentacyclo[9.7.1 .1A{4,7}.0A{2,8}.0A{15, 19}]icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one,1-[(4R,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-17-{[(3S,4S)-4-(difluoromethyl)-1- ({4,4-dimethyl-8-[(3S)-3-methylmorpholin-4-yl]-2H,3H-pyrano[2,3-c]pyridin-5-yl}methyl)-3-methylpiperidin-3- yl]methoxy}-14-fluoro-9-methyl-10-oxa-2,12,16,18,20-pentaazapentacyclo[9.7.1 .1A{4,7}.0A{2,8}.0A{15, 19}]icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one,1-[(2R,4R,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-14-fluoro-17-({[(3R,4R)-4- (d if I uoromethy l)-3-methy I - 1 - (prop-2-y I )hexahy d ropy r id i n-3-y I] methy l}oxy )-9-methy I - 10-oxa-2, 12,16, 18,20- pentazapentacyclo[9.7.1 .147.015 19.028]icosa-1 (18),11 (19),12,14, 16-pentaen-20-yl]prop-2-en-1-one, 1-[(2R,4R,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-14-fluoro-17-({[(3R,4R)-4- (difluoromethyl)-3-methyl-1-(3,4,5,6-tetrahydro-2H-pyran-4-yl)hexahydropyridin-3-yl]methyl}oxy)-9-methyl-10- oxa-2, 12,16, 18,20-pentazapentacyclo[9.7.1 .14’7.015’19.02’8]icosa-1 (18), 11 (19), 12, 14, 16-pentaen-20-yl]prop-2-en- 1-one,1-[(2R,4R,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-14-fluoro-17-({[(3R,4R)-4- (difluoromethyl)-3-methyl-1-(7-oxaspiro[3.5]nonan-2-yl)hexahydropyridin-3-yl]methyl}oxy)-9-methyl-10-oxa- 2,12, 16,18,20-pentazapentacyclo[13.3.1 .147011’19.02’8]icosa-1 (18), 11 (19), 12, 14, 16-pentaen-20-yl]prop-2-en-1 - one,1-[(2R,4R,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-14-fluoro-17-({[(3R,4R)-4- (difluoromethyl)-1-[7-(4,4-dimethyl-3,4-dihydro-2H-pyrano[2,3-c]pyridin-8-yl)-7-azaspiro[3.5]nonan-2-yl]-3- methy I hexahy d ropy rid i n-3-y I] methy I }oxy )-9-methy I- 10-oxa-2, 12, 16,18,20- pentazapentacyclo[9.7.1 .147.015’19.028]icosa-1 (18), 11 (19), 12, 14, 16-pentaen-20-yl]prop-2-en-1 -one, 1-[(2R,4R,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-14-fluoro-17-({[(3R,4R)-4- (difluoromethyl)-1-(3-{4,4-dimethyl-8-[(3S)-3-methyl-1,4-oxazinan-4-yl]-3,4-dihydro-2H-pyrano[2,3-c]pyridin-5- y I }cy clobu ty I )-3-methy I hexahyd ropy ri di n-3-y I] methy l}oxy )-9-methy I- 10-oxa-2, 12,16,18,20-pen tazapen tacycl o [9.7.1 .147.015’19.028]icosa-1 (18), 11 (19), 12, 14, 16-pentaen-20-yl]prop-2-en-1 -one,1-[(2S,4R,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-14-fluoro-17-({[(3R,4R)-4- (difluoromethyl)-1-({4,4-dimethyl-8-[(3S)-3-methyl-1,4-oxazinan-4-yl]-3,4-dihydro-2H-pyrano[2,3-c]pyridin-5- y I }methy l)-3-methy I hexahyd ropy ri d i n-3-y I] methy I }oxy )-9-methy I- 10-oxa-2, 12, 16, 18,20- pentazapentacyclo[13.3.1 .147.011 19.028]icosa-1 (18),11 (19),12,14, 16-pentaen-20-yl]prop-2-en-1-one,1-[(4R,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-14-fluoro-9-methyl-17-{[(3R)-1- methy I pi perid i n-3-y I] methoxy }- 10-oxa-2, 12,16,18,20-pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}]icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one,1-[(4R,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-14-fluoro-9-methyl-17-{[(3S)-1- methy I pi perid i n-3-y I] methoxy }- 10-oxa-2, 12,16,18,20-pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}]icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one,1-[(4R,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-17-{[(3R)-1 ,3-dimethylpiperidin-3- y I] methoxy }- 14-fl uoro-9-methy I- 10-oxa-2, 12, 16,18,20-pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}]icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one,1-[(4R,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-17-{[(3S)-1 ,3-dimethylpi peridin-3- y I] methoxy }- 14-fl uoro-9-methy I- 10-oxa-2, 12, 16,18,20-pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}]icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one,1-[(4R,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-17-{[(3S,4S)-4-(difluoromethyl)-1- methy I pi peri d i n -3-yl] methoxy }- 14-f I uoro-9-methy I- 10-oxa-2, 12,16, 18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{ 15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one,1-[(4R,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-17-{[(3S,4R)-4-(difluoromethyl)-1- methy I pi perid i n-3-y I] methoxy }- 14-f I uoro-9-methy I- 10-oxa-2, 12,16, 18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one, 1-[(4R,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-17-{[(3R,4S)-4-(difluoromethyl)-1- methy I pi perid i n-3-y I] methoxy }- 14-f I uoro-9-methy I- 10-oxa-2, 12,16, 18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one,1-[(4R,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-17-{[(3R,4R)-4-(difluoromethyl)-1- methy I pi perid i n-3-y I] methoxy }- 14-f I uoro-9-methy I- 10-oxa-2, 12,16, 18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one,1-[(4R,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-14-fluoro-9-methyl-17-{[(2S)-4- methylmorpholin-2-yl]methoxy}-10-oxa-2,12,16, 18,20-pentaazapentacyclo[9.7.1 .1A{4,7}.0A{2,8}.0A{15, 19}]icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one,1-[(4R,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-14-fluoro-9-methyl-17-{[(2R)-4- methylmorpholin-2-yl]methoxy}-10-oxa-2,12,16, 18,20-pentaazapentacyclo[9.7.1 .1A{4,7}.0A{2,8}.0A{15, 19}]icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one,1-[(4R,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-17-{[(2S)-1,4-dimethylpiperazin-2- y I] methoxy }- 14-fl uoro-9-methy I- 10-oxa-2, 12, 16,18,20-pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}]icosa-1 (19), 11 , 13, 15, 17-pentaen -20-yl] prop-2-en- 1 -one,1-[(4R,7S,8S,9S)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-17-{[(2R)-1 ,4-dimethylpiperazin-2- y I] methoxy }- 14-fl uoro-9-methy I- 10-oxa-2, 12, 16,18,20-pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}]icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one,1-[(4R,7S,8R,9R)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-17-{[(3S,4S)-4-(difluoromethyl)-1,3- dimethylpiperidin-3-yl]methoxy}-14-fluoro-9-methyl-2,12,16, 18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one,1-[(4R,7S,8R,9R)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-17-{[(3S,4R)-4-(difluoromethyl)-1,3- dimethylpiperidin-3-yl]methoxy}-14-fluoro-9-methyl-2,12,16, 18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one,1-[(4R,7S,8R,9R)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-17-{[(3R,4S)-4-(difluoromethyl)-1,3- dimethylpiperidin-3-yl]methoxy}-14-fluoro-9-methyl-2,12,16, 18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one,1-[(4R,7S,8R,9R)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-17-{[(3R,4R)-4-(difluoromethyl)-1,3- dimethylpiperidin-3-yl]methoxy}-14-fluoro-9-methyl-2,12,16, 18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one, 1-[(4R,7S,8R,9R)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-14-fluoro-9-methyl-17-{[(3R)-1- methyl pi perid i n-3-y I] methoxy }-2, 12, 16,18,20-pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}]icosa-1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one,1-[(4R,7S,8R,9R)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-14-fluoro-9-methyl-17-{[(3S)-1- methyl pi peri d i n -3-yl] methoxy }-2, 12,16,18,20-pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{ 15, 19}]icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one,1-[(4R,7S,8R,9R)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-17-{[(3R)-1 ,3-dimethylpiperidin-3- y I] methoxy }- 14-fl uoro-9-methy I-2, 12,16, 18,20-pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}]icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one,1-[(4R,7S,8R,9R)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-17-{[(3S)-1 ,3-dimethylpi peridin-3- y l]methoxy }- 14-fl uoro-9-methy I-2, 12, 16, 18,20-pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}]icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one,1 -[(4R,7S,8R,9R)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-17-{[(3S,4S)-4-(difluoromethyl)-1 - methyl pi perid i n-3-y I] methoxy }- 14-f I uoro-9-methy I-2, 12,16, 18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one,1 -[(4R,7S,8R,9R)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-17-{[(3S,4R)-4-(difluoromethyl)-1 - methyl pi perid i n-3-y I] methoxy }- 14-f I uoro-9-methy I-2, 12,16, 18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one,1 -[(4R,7S,8R,9R)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-17-{[(3R,4S)-4-(difluoromethyl)-1 - methyl pi perid i n-3-y I] methoxy }- 14-f I uoro-9-methy I-2, 12,16, 18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one,1-[(4R,7S,8R,9R)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-17-{[(3R,4R)-4-(difluoromethyl)-1- methyl pi peri d i n -3-yl] methoxy }- 14-f I uoro-9-methy I-2, 12, 16, 18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{ 15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one, 1-[(4R,7S,8R,9R)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-14-fluoro-9-methyl-17-{[(2S)-4- methyl morphol i n-2-y I] methoxy }-2, 12, 16,18,20-pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}]icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one,1-[(4R,7S,8R,9R)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-14-fluoro-9-methyl-17-{[(2R)-4- methyl morphol i n-2-y I] methoxy }-2, 12, 16,18,20-pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}]icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one,1-[(4R,7S,8R,9R)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-17-{[(2S)-1 ,4-dimethylpi perazin-2- y l]methoxy }- 14-fl uoro-9-methy I-2, 12, 16, 18,20-pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}]icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one,1-[(4R,7S,8R,9R)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-17-{[(2R)-1 ,4-dimethylpiperazin-2- y l]methoxy }- 14-fl uoro-9-methy I-2, 12, 16, 18,20-pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}]icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one,1-[(4R,7S,8R,9R)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-17-{[(3S,4S)-4-(difluoromethyl)-1- isopropyl-3-methylpiperidin-3-yl]methoxy}-14-fluoro-9-methyl-2, 12,16, 18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one,1-[(4R,7S,8R,9R)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-17-{[(3S,4S)-4-(difluoromethyl)-3- methyl-1 -(oxan-4-y I) pi peri d i n-3-y I] methoxy }- 14-fl uoro-9-methy I-2, 12,16, 18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one,1-[(4R,7S,8R,9R)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-17-{[(3S,4S)-4-(difluoromethyl)-3- methyl-1-{7-oxaspiro[3.5]nonan-2-yl}piperidin-3-yl]methoxy}-14-fluoro-9-methyl-2, 12, 16,18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{ 15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one,1-[(4R,7S,8R,9R)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-17-{[(3S,4S)-4-(difluoromethyl)-1-(7- {4, 4-dimethyl-2H,3H-pyrano[2,3-c]pyridin-8-yl}-7-azaspiro[3.5]nonan-2-yl)-3-methylpiperidin-3-yl] methoxy }-14- f I uoro-9-methy I-2, 12,16, 18,20-pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{ 15, 19}] icosa- 1 (19), 11 , 13, 15, 17- pentaen-20-yl]prop-2-en-1 -one,1-[(4R,7S,8R,9R)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-17-{[(3S,4S)-4-(difluoromethyl)-1-(3- {4,4-dimethyl-8-[(3S)-3-methylmorpholin-4-yl]-2H,3H-pyrano[2,3-c]pyridin-5-yl}cyclobutyl)-3-methylpiperidin-3- y l]methoxy }- 14-fl uoro-9-methy I-2, 12, 16, 18,20-pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}]icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one,1-[(4R,7S,8R,9R)-13-[5-amino-3-chloro-2-(trifluoromethyl)phenyl]-17-{[(3S,4S)-4-(difluoromethyl)-1- ({4, 4-dimethyl-8-[(3S)-3-methylmorpholin-4-yl]-2H,3H-pyrano[2,3-c]pyridin-5-yl}methyl)-3-methylpi peridin-3- y l]methoxy }- 14-fl uoro-9-methy i-2, 12, 16, 18,20-pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}]icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one,1-[(4R,7S,8S,9S)-13-[6-amino-2-methyl-3-(trifluoromethyl)pyridin-4-yl]-14-fluoro-9-methyl-17-{[1-(morp holi n-4-y I methy l)cy clopropy I] methoxy }- 10-oxa-2, 12,16,18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one, 1-[(4R,7S,8R,9R)-13-[6-amino-2-methyl-3-(trifluoromethyl)pyridin-4-yl]-14-fluoro-9-methyl-17-{[1- (mor phol i n-4-y I methy l)cy clopropy I] methoxy }-2, 12, 16,18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one,1-[(4R,7S,8S,9S)-13-{5-amino-3-chloro-2-[(1 R,2S)-2-methylcyclopropyl]phenyl}-14-fluoro-9-methyl-17- {[1 - (morphol i n-4-y I methy I )cyclopropy I] methoxy }- 10-oxa-2, 12,16, 18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one, 1-[(4R,7S,8S,9S)-13-{5-amino-3-chloro-2-[(1 R,2R)-2-methylcyclopropyl]phenyl}-14-fluoro-9-methyl-17- {[1 -(morphol in-4-ylmethyl)cyclopropy I] methoxy }-10-oxa-2, 12, 16, 18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{ 15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one, 1-[(4R,7S,8S,9S)-13-{5-amino-3-chloro-2-[(1 S,2S)-2-methylcyclopropyl]phenyl}-14-fluoro-9-methyl-17- {[1 -(morphol in-4-ylmethyl)cyclopropy I] methoxy }-10-oxa-2, 12, 16, 18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{ 15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one,1-[(4R,7S,8S,9S)-13-{5-amino-3-chloro-2-[(1 S,2R)-2-methylcyclopropyl]phenyl}-14-fluoro-9-methyl-17- {[1 -(morphol in-4-ylmethyl)cyclopropy I] methoxy }-10-oxa-2, 12, 16, 18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{ 15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one, 1-[(4R,7S,8S,9S)-13-{5-amino-3-chloro-2-[(1 R,2R)-2-isopropylcyclopropyl]phenyl}-14-fluoro-9-methyl- 17-{[1 - (morp hoi i n-4-y I methy I )cy clopropy I] methoxy }-10-oxa-2, 12, 16,18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one, 1-[(4R,7S,8S,9S)-13-{5-amino-3-chloro-2-[(1 R,2S)-2-isopropylcyclopropyl]phenyl}-14-fluoro-9-methyl- 17-{[1 - (morphol i n-4-y I methy I )cy cl opropy I] methoxy }- 10-oxa-2, 12, 16,18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{ 15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one,1-[(4R,7S,8S,9S)-13-{5-amino-3-chloro-2-[(1 S,2R)-2-isopropylcyclopropyl]phenyl}-14-fluoro-9-methyl- 17-{[1 -(mor phol i n-4-y I methy I )cy clopropy I] methoxy }-10-oxa-2, 12, 16,18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one, 1-[(4R,7S,8S,9S)-13-{5-amino-3-chloro-2-[(1 S,2S)-2-isopropylcyclopropyl]phenyl}-14-fluoro-9-methyl- 17-{[1 -(mor phol i n-4-y I methy I )cy clopropy I] methoxy }-10-oxa-2, 12, 16,18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one, 1-[(4R,7S,8S,9S)-13-{5-amino-3-chloro-2-[(1 R,2S)-2-(trifluoromethyl)cyclopropyl]phenyl}-14-fluoro-9- methyl-17-{[1-(morpholin-4-ylmethyl)cyclopropyl]methoxy}-10-oxa-2, 12, 16, 18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one,1-[(4R,7S,8S,9S)-13-{5-amino-3-chloro-2-[(1 R,2R)-2-(trifluoromethyl)cyclopropyl]phenyl}-14-fluoro-9- methyl-17-{[1 -(morphol i n-4-y I methy l)cycl opropy I] methoxy }- 10-oxa-2, 12, 16,18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{ 15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one,1-[(4R,7S,8S,9S)-13-{5-amino-3-chloro-2-[(1 S,2S)-2-(trifluoromethyl)cyclopropyl]phenyl}-14-fluoro-9- methyl-17-{[1 -(morphol i n-4-y I methy l)cycl opropy I] methoxy }- 10-oxa-2, 12, 16,18,20-pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{ 15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one, 1-[(4R,7S,8S,9S)-13-{5-amino-3-chloro-2-[(1 S,2R)-2-(trifluoromethyl)cyclopropyl]phenyl}-14-fluoro-9- methyl-17-{[1 - (mor phol i n-4-y I methy I )cy clopropy I] methoxy }-10-oxa-2, 12,16, 18,20- pentaazapentacyclo[9.7.1 .1A{4, 7}.0A{2, 8}.0A{15, 19}] icosa- 1 (19), 11 , 13, 15, 17-pentaen-20-yl]prop-2-en-1 -one, 1-[(2R,4R,7S,8S,9S)-13-[(8S)-3-amino-8-methyl-5,6,7,8-tetrahydro-1-naphthyl]-14-fluoro-9-methyl-17-({[(1 , 4-oxazi n an-4-y I methy I )cycl opropy I] methy l}oxy )- 10-oxa-2, 12,16, 18,20- pentazapentacyclo[9.7.1.14’7.015’19.02’8]icosa-1 (18),11 (19),12,14,16-pentaen-20-yl]prop-2-en-1-one,1-[(2R,4R,7S,8S,9S)-13-[(8R)-3-amino-8-methyl-5,6,7,8-tetrahydro-1-naphthyl]-14-fluoro-9-methyl-17- ({[(1 , 4-oxazi n an-4-y I methy I )cycl opropy I] methy l}oxy)- 10-oxa-2, 12, 16,18,20- pentazapentacyclo[9.7.1.147.015’19.02’8]icosa-1 (18),11 (19),12,14,16-pentaen-20-yl]prop-2-en-1-one,1-[(2R,4R,7S,8S,9S)-13-[(8S)-3-amino-8-ethyl-5,6,7,8-tetrahydro-1-naphthyl]-14-fluoro-9-methyl-17-({[(1 , 4-oxazi n an-4-y I methy I )cycl opropy I] methy l}oxy)- 10-oxa-2, 12,16, 18,20- pentazapentacyclo[9.7.1 .147.015’19.028]icosa-1 (18), 11 (19), 12, 14, 16-pentaen-20-yl]prop-2-en-1 -one, 1-[(2R,4R,7S,8S,9S)-13-[(8R)-3-amino-8-ethyl-5,6,7,8-tetrahydro-1-naphthyl]-14-fluoro-9-methyl-17-({[(1 , 4-oxazi n an-4-y I methy I )cycl opropy I] methy l}oxy)- 10-oxa-2, 12,16, 18,20- pentazapentacyclo[9.7.1 .147.015’19.028]icosa-1 (18), 11 (19), 12, 14, 16-pentaen-20-yl]prop-2-en-1 -one,Compounds of the invention may contain one or more asymmetric carbon atoms. Accordingly, the compounds may exist as diastereomers, enantiomers or mixtures thereof. The syntheses of the compounds may employ racemates, diastereomers or enantiomers as starting materials or as intermediates. Diastereomeric compounds may be separated by chromatographic or crystallization methods. Similarly, enantiomeric mixtures may be separated using the same techniques or others known in the art. Each of the asymmetric carbon atoms may be in the R or S configuration and both of these configurations are within the scope of the invention.A modified compound of any one of such compounds including a modification having an improved (e.g., enhanced, greater) pharmaceutical solubility, stability, bioavailability and / or therapeutic index as compared to the unmodified compound is also contemplated. The examples of modifications include but not limited to the prodrug derivatives, and the deuterium-enriched compounds. For example:• Deuterium-enriched compounds: deuterium (D or2H) is a stable, non-radioactive isotope of hydrogen and has an atomic weight of 2.0144. Hydrogen naturally occurs as a mixture of the isotopesXH (hydrogen or protium), D (2H or deuterium), and T (3H or tritium). The natural abundance of deuterium is 0.015%. One of ordinary skill in the art recognizes that in all chemical compounds with a H atom, the H atom actually represents a mixture of H and D, with about 0.015% being D. Thus, compounds with a level of deuterium that has been enriched to be greater than its natural abundance of 0.015%, should be considered unnatural and, as a result, novel over their nonenriched counterparts.It should be recognized that the compounds of the present invention may be present and optionally administered in the form of salts, and solvates. For example, it is within the scope of the present invention to convert the compounds of the present invention into and use them in the form of their pharmaceutically acceptable salts derived from various organic and inorganic acids and bases in accordance with procedures wellknown in the art.When the compounds of the present invention possess a free base form, the compounds can be prepared as a pharmaceutically acceptable acid addition salt by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, e.g., hydrohalides such as hydrochloride, hydrobromide, hydroiodide; other mineral acids such as sulfate, nitrate, phosphate, etc:, and alkyl and monoarylsulfonates such as ethanesulfonate, toluenesulfonate and benzenesulfonate; and other organic acids and their corresponding salts such as acetate, tartrate, maleate, succinate, citrate, benzoate, salicylate and ascorbate. Further acid addition salts of the present invention include, but are not limited to: adipate, alginate, arginate, aspartate, bisulfate, bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate, chloride, chlorobenzoate, cyclopentanepropionate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, fumarate, galacterate (from mucic acid), galacturonate, glucoheptaoate, gluconate, glutamate, glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate, 2-hydroxyethanesulfonate, iodide, isethionate, iso-butyrate, lactate, lactobionate, malonate, mandelate, metaphosphate, methanesulfonate, methyl benzoate, monohydrogenphosphate, 2-naphthalenesulfonate, nicotinate, oxalate, oleate, pamoate, pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphonate and phthalate. It should be recognized that the free base forms will typically differ from their respective salt forms somewhat in physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free base forms for the purposes of the present invention.When the compounds of the present invention possess a free acid form, a pharmaceutically acceptable base addition salt can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base. Examples of such bases are alkali metal hydroxides including potassium, sodium and lithium hydroxides; alkaline earth metal hydroxides such as barium and calcium hydroxides; alkali metal alkoxides, e.g, potassium ethanolate and sodium propanolate; and various organic bases such as ammonium hydroxide, piperidine, diethanolamine and N-methylglutamine. Also included are the aluminum salts of the compounds of the present invention. Further base salts of the present invention include, but are not limited to: copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium and zinc salts. Organic base salts include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, e.g., arginine, betaine, caffeine, chloroprocaine, choline, N, N'-dibenzylethylenediamine (benzathine), dicyclohexylamine, diethanolamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lidocaine, lysine, meglumine, N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethanolamine, triethylamine, trimethylamine, tripropylamine and tris- (hydroxymethyl)-methylamine (tromethamine). It should be recognized that the free acid forms will typically differ from their respective salt forms somewhat in physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free acid forms for the purposes of the present invention.In one aspect, a pharmaceutically acceptable salt is a hydrochloride salt, hydrobromide salt,methanesulfonate, toluenesulfonate, acetate, fumarate, sulfate, bisulfate, succinate, citrate, phosphate, maleate, nitrate, tartrate, benzoate, biocarbonate, carbonate, sodium hydroxide salt, calcium hydroxide salt, potassium hydroxide salt, tromethamine salt, or mixtures thereof.Compounds of the present invention that comprise tertiary nitrogen-containing groups may be quaternized with such agents as (C1-4) alkyl halides, e.g., methyl, ethyl, iso-propyl and tert-butyl chlorides, bromides and iodides; di-(Ci-4) alkyl sulfates, e.g., dimethyl, diethyl and diamyl sulfates; alkyl halides, e.g., decyl, dodecyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; and aryl (C1-4) alkyl halides, e.g., benzyl chloride and phenethyl bromide. Such salts permit the preparation of both water- and oil-soluble compounds of the invention.Amine oxides, also known as amine-N-oxide and N-oxide, of anti-cancer agents with tertiary nitrogen atoms have been developed as prodrugs [Mol Cancer Therapy. 2004 Mar; 3(3):233-44], Compounds of the present invention that comprise tertiary nitrogen atoms may be oxidized by such agents as hydrogen peroxide (H2O2), Caro's acid or peracids like mefa-Chloroperoxybenzoic acid (mCPBA) to from amine oxide.The invention encompasses pharmaceutical compositions comprising the compound of the present invention and pharmaceutical excipients, as well as other conventional pharmaceutically inactive agents. Any inert excipient that is commonly used as a carrier or diluent may be used in compositions of the present invention, such as sugars, polyalcohols, soluble polymers, salts and lipids. Sugars and polyalcohols which may be employed include, without limitation, lactose, sucrose, mannitol, and sorbitol. Illustrative of the soluble polymers which may be employed are polyoxyethylene, poloxamers, polyvinylpyrrolidone, and dextran. Useful salts include, without limitation, sodium chloride, magnesium chloride, and calcium chloride. Lipids which may be employed include, without limitation, fatty acids, glycerol fatty acid esters, glycolipids, and phospholipids.In addition, the pharmaceutical compositions may further comprise binders {e.g., acacia, cornstarch, gelatin, carbomer, ethyl cellulose, guar gum, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone), disintegrating agents {e.g., cornstarch, potato starch, alginic acid, silicon dioxide, croscarmellose sodium, crospovidone, guar gum, sodium starch glycolate, Primogel), buffers {e.g., tris-HCL, acetate, phosphate) of various pH and ionic strength, additives such as albumin or gelatin to prevent absorption to surfaces, detergents {e.g., Tween 20, Tween 80, Pluronic F68, bile acid salts), protease inhibitors, surfactants {e.g., sodium lauryl sulfate), permeation enhancers, solubilizing agents {e.g., glycerol, polyethylene glycerol, cyclodextrins), a glidant {e.g., colloidal silicon dioxide), anti-oxidants {e.g., ascorbic acid, sodium metabisulfite, butylated hydroxyanisole), stabilizers {e.g., hydroxypropyl cellulose, hydroxypropylmethyl cellulose), viscosity increasing agents {e.g., carbomer, colloidal silicon dioxide, ethyl cellulose, guar gum), sweeteners {e.g., sucrose, aspartame, citric acid), flavoring agents {e.g., peppermint, methyl salicylate, or orange flavoring), preservatives {e.g., Thimerosal, benzyl alcohol, parabens), lubricants {e.g., stearic acid, magnesium stearate, polyethylene glycol, sodium lauryl sulfate), flow-aids {e.g., colloidal silicon dioxide), plasticizers {e.g., diethyl phthalate, triethyl citrate), emulsifiers {e.g., carbomer, hydroxypropyl cellulose, sodium lauryl sulfate, methyl cellulose, hydroxyethyl cellulose, carboxymethylcellulose sodium), polymer coatings {e.g., poloxamers or poloxamines), coating and film forming agents {e.g., ethyl cellulose, acrylates, polymethacrylates) and / or adjuvants.In one embodiment, the pharmaceutical compositions are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.Additionally, the invention encompasses pharmaceutical compositions comprising any solid or liquid physical form of the compound of the invention. For example, the compounds can be in a crystalline form, in amorphous form, and have any particle size. The particles may be micronized, or may be agglomerated, particulate granules, powders, oils, oily suspensions or any other form of solid or liquid physical form.When compounds according to the present invention exhibit insufficient solubility, methods for solubilizing the compounds may be used. Such methods are known to those of skill in this art, and include, but are not limited to, pH adjustment and salt formation, using co-solvents, such as ethanol, propylene glycol, polyethylene glycol (PEG) 300, PEG 400, DMA (10-30%), DMSO (10-20%), NMP (10-20%), using surfactants, such as polysorbate 80, polysorbate 20 (1-10%), cremophor EL, Cremophor RH40, Cremophor RH60 (5-10%), Pluronic F68 / Poloxamer 188 (20-50%), Solutol HS15 (20-50%), Vitamin E TPGS, and d-o-tocopheryl PEG 1000 succinate (20-50%), using complexation such as HPpCD and SBEpCD (10-40%), and using advanced approaches such as micelle, addition of a polymer, nanoparticle suspensions, and liposome formation.A wide variety of administration methods may be used in conjunction with the compounds of the present invention. Compounds of the present invention may be administered or coadministered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery (for example by catheter or stent), subcutaneously, intraadiposally, intraarticularly, or intrathecally. The compounds according to the invention may also be administered or coadministered in slow release dosage forms. Compounds may be in gaseous, liquid, semi-liquid or solid form, formulated in a manner suitable for the route of administration to be used. For oral administration, suitable solid oral formulations include tablets, capsules, pills, granules, pellets, sachets and effervescent, powders, and the like. Suitable liquid oral formulations include solutions, suspensions, dispersions, emulsions, oils and the like. For parenteral administration, reconstitution of a lyophilized powder is typically used.The term "alkyl” refers to a straight or branched hydrocarbon containing 1-20 carbon atoms (e.g., Ci- C ). Examples of alkyl include, but are not limited to, methyl, methylene, ethyl, ethylene, n-propyl, i-propyl, n- butyl, i-butyl, and t-butyl. Preferably, the alkyl group has one to ten carbon atoms. More preferably, the alkyl group has one to four carbon atoms.Alkylene means a linear saturated divalent hydrocarbon radical of one to twenty carbon atoms or abranched saturated divalent hydrocarbon radical of three to twenty carbon atoms unless otherwise stated e.g., methylene, ethylene, propylene, 1 -methylpropylene, 2-methylpropylene, butylene, pentylene, and the like.The term "alkenyl” refers to a straight or branched hydrocarbon containing 2-20 carbon atoms {e.g., C2- C10) and one or more double bonds. Examples of alkenyl include, but are not limited to, ethenyl, propenyl, and allyl. Preferably, the alkylene group has two to ten carbon atoms. More preferably, the alkylene group has two to four carbon atoms.The term “alkynyl” refers to a straight or branched hydrocarbon containing 2-20 carbon atoms {e.g., C2- C10) and one or more triple bonds. Examples of alkynyl include, but are not limited to, ethynyl, 1 -propynyl, 1- and 2-butynyl, and 1 -methyl-2-butynyl. Preferably, the alkynyl group has two to ten carbon atoms. More preferably, the alkynyl group has two to four carbon atoms."Alkoxy” means a -OR radical where R is alkyl as defined above, e.g., methoxy, ethoxy, propoxy, or 2- propoxy, n-, iso-, or tert-butoxy, and the like.“Alkoxyalkyl” means a linear monovalent hydrocarbon radical of 1 to 20 carbon atoms or a branched monovalent hydrocarbon radical of 3 to 20 carbons substituted with at least one alkoxy group, such as one or two alkoxy groups, as defined above, e.g., 2-methoxyethyl, 1-, 2-, or 3-methoxy propyl, 2-ethoxyethyl, and the like."Alkoxycarbonyl” means a -C(O)OR radical where R is alkyl as defined above, e.g., methoxycarbonyl, ethoxycarbonyl, and the like."Alkoxy al kyloxy” means a -OR radical where R is alkoxyalkyl as defined above. Examples include, but are not limited to, 2-methoxyethyloxy, 1-, 2-, or 3-methoxypropyloxy, 2-ethoxyethyloxy, and the like.“Alkoxyalkyloxyalkyl” means a -(alkylene)-OR radical where R is alkyloxyalkyl as defined above. Examples include, but are not limited to, 2-methoxyethyloxymethyl, methoxymethoxymethyl, 1-, 2-, or 3- methoxy propyloxy methyl, 2-ethoxyethyloxymethyl, and the like.“Alkylidenyl” means refers to a group of formula R= where R is alkyl as defined above. Examples include, but are not limited to, methylidenyl (H2C=), ethylidenyl(CH3CH=), hexylidenyl(CH3(CH2)4CH=), 2- propylidenyl(=C(CH3)2), and the like.“Alkoxy alky lideny I” means refers to a group of formula =R where R is alkoxyalkyl as defined above. Examples include, but are not limited to, methoxethylidenyl (CH3OCH 2CH=) , ethoxyethylidenyl (C2H5OCH2CH=), 1 -methoxyethylidenyl (=C(CH3)OCH3) , and the like.“Alkylthio” means a -SR radical where R is alkyl as defined above, e.g., methylthio, ethylthio, and the like.“Alkylsulfonyl” means a -SO2R radical where R is alkyl as defined above, e.g., methylsulfonyl, ethylsulfonyl, and the like.“Cyanoalkyl” means a linear monovalent hydrocarbon radical of 1 to 20 carbon atoms or a branched monovalent hydrocarbon radical of 3 to 20 carbons substituted with cyano, e.g., cyanomethyl, cyanoethyl, and the like.“Cy anoalkeny I” means an alkenyl radical as defined above where one of the hydrogen atom in thealkynyl chain is replace by a cyano. Examples include, but are not limited to, -C=C(CN), -CH2C=C(CN) , and the like."Cyanoalkynyl” means an alkynyl radical as defined above where one of the hydrogen atom in the alkynyl chain is replace by a cyano. Examples include, but are not limited to, -C C(CN), -CH2C C(CN) , and the like."Deuterium” mean refers to2H or D."Amino” means a -NH2 radical. Unless indicated otherwise, the compounds of the invention containing amino moieties may include protected derivatives thereof. Suitable protecting groups for amino moieties include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like."Alkylamino” means a -NHR radical where R is alkyl as defined above, e.g., methylamino, ethylamino, and the like.“Dialkylamino” means a -NRR' radical where R and R' are independently alkyl as defined above, e.g., dimethylamino, methylethylamino, and the like.Aminocarbonyl, means a univalent radical -C(O)NH2."Alkoxycarbonyl” means a -C(O)OR radical where R is alkyl as defined above, e.g., methoxycarbonyl, ethoxycarbonyl, and the like.Alkylcarbonyl means a -C(O)-R radical where R is alkyl as defined above.Alkyl ami nocarbonyl means a -C(O)-NHR radical where R is alkyl as defined above.Dialkylaminocarbonyl means a -C(O)-NRR’ radical where R and R' are independently alkyl as defined above above.Aminocarbonylalkyl means a -R-C(O)-NH2 radical where R is alkyl as defined above above.Alkylaminocarbonylalkyl, means a -R-C(O)-NH-R’ radical where R and R' are independently alkyl as defined above above.Dialkylaminocarbonylalkyl, means a -R-C(O)-NR’R” radical where R, R' and R” are independently alkyl as defined above above."Aromatic” means a moiety wherein the constituent atoms make up an unsaturated ring system, all atoms in the ring system are sp2 hybridized and the total number of pi electrons is equal to 4 M+2. An aromatic ring may be such that the ring atoms are only carbon atoms or may include carbon and non-carbon atoms (see Heteroaryl)."Carbamoyl” means the radical -OC(O)NRaRb where Raand Rb are each independently two further substituents where a hydrogen or carbon atom is alpha to the nitrogen. It is noted that carbamoyl moieties may include protected derivatives thereof. Examples of suitable protecting groups for carbamoyl moieties include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like. It is noted that both the unprotected and protected derivatives fall within the scope of the invention."Carbonyl” means the radical -C(O)-. It is noted that the carbonyl radical may be further substituted with a variety of substituents to form different carbonyl groups including acids, acid halides, amides, esters, and ketones."Carboxy” means the radical -C(O)O- It is noted that compounds of the invention containing carboxy moieties may include protected derivatives thereof, i.e., where the oxygen is substituted with a protecting group. Suitable protecting groups for carboxy moieties include benzyl, tert-butyl, and the like."Cyano” means the radical -C N."Formyl” means the radical -CH=O."Formimino” means the radical -HC=NH."Halo” means fluoro, chloro, bromo or iodo, preferably fluoro or chloro."Haloalkyl” means alkyl radical as defined above, which is substituted with one or more halogen atoms, e.g., one to five halogen atoms, such as fluorine or chlorine, including those substituted with different halogens, e.g., -CH2CI, — CF3, -CHF2, -CH2CF3, -CF2CF3, -CF(CH3)2, and the like. When the alkyl is substituted with only fluoro, it can be referred to in this Application as fluoroalkyl.“Haloalkylidenyl” means refers to a group of formula =R where R is haloalkyl as defined above. Examples include, but are not limited to, difluoromethylidenyl (=CF2), 2,2-difluoroethylidenyl (OHCHF2), 1- fluoroethylidenyhCFCHs) , and the like."Haloalkoxy” means a -OR radical where R is haloalkyl as defined above e.g., -OCF3, -OCHF2, and the like. When R is haloalkyl where the alkyl is substituted with only fluoro, it is referred to in this Application as fluoroalkoxy."Hydroxy” means the radical -OH.“Hydroxyalkyl” means a linear monovalent hydrocarbon radical of 1 to 20 carbon atoms or a branched monovalent hydrocarbon radical of 3 to 20 carbons substituted with one or two hydroxy groups, provided that if two hydroxy groups are present they are not both on the same carbon atom. Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxy-ethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1- (hydroxymethyl) -2- methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2, 3-dihydroxypropyl, 1- (hydroxymethyl) -2- hydroxyethyl, 2, 3-dihydroxybutyl, 3, 4-dihydroxybutyl and 2- (hydroxymethyl) -3-hydroxypropyl, preferably 2- hydroxyethyl, 2, 3-dihydroxypropyl, and 1- (hydroxymethyl) -2-hydroxyethyl."Heteroalkyl” mean alkyl radical as defined above wherein one or two carbon atoms are replaced by 0, NR (R is H or alkyl), or S, provided the heteroalkyl group is attached to the remainder of the molecule via a carbon atom, e.g., methoxy methyl, methylethylaminoethyl, and the like."Imine derivative” means a derivative comprising the moiety -C(=NR)-, wherein R comprises a hydrogen or carbon atom alpha to the nitrogen."Nitro” means the radical -NO2."Oxo ” as used herein, alone or in combination, refers to =0 ."Oxoalkyl” means an alkyl, further substituted with a carbonyl group. The carbonyl group may be an aldehyde, ketone, ester, amide, acid or acid chloride."Sulfide” means -S-R wherein R is H, alkyl, carbocycle, heterocycle, carbocycloalkyl or heterocycloalkyl. Particular sulfide groups are mercapto, alkylsulfide, for example methylsulfide (-S-Me); arylsulfide, e.g., phenylsulfide; aralkylsulfide, e.g., benzylsulfide."Sulfinyl” means the radical -S(0)-. It is noted that the sulfinyl radical may be further substituted with a variety of substituents to form different sulfinyl groups including sulfinic acids, sulfinamides, sulfinyl esters, and sulfoxides."Sulfonyl” means the radical -S(O)(O)-. It is noted that the sulfonyl radical may be further substituted with a variety of substituents to form different sulfonyl groups including sulfonic acids, sulfonamides, sulfonate esters, and sulfones."Thiocarbonyl” means the radical -C(S)-. It is noted that the thiocarbonyl radical may be further substituted with a variety of substituents to form different thiocarbonyl groups including thioacids, thioamides, thioesters, and thioketones.The term "cycloalkyl” refers to a saturated hydrocarbon ring system having 3 to 30 carbon atoms (e.g., C3-C12, C3-C8, C3-C6). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.The term "cycloalkenyl” refers to a non-aromatic hydrocarbon ring system having 3 to 30 carbons (e.g., C3-C12) and one or more double bonds. Examples include cyclopentenyl, cyclohexenyl, and cycloheptenyl.Spirocycloalkyl refers to a compound comprising two saturated cyclic alkyl rings sharing only one common atom (also known as a spiro atom), with no heteroatom and no unsaturated bonds on any of the rings. In one embodiment, the spiroalkyl is bicyclic. In another embodiment, the spiroalikyl has more than two cycles. In certain embodiments, the spiroalkyl compound is a polyspiro compound connected by two or more spiroatoms making up three or more rings. In certain embodiments, one of the rings of the bicyclic spiroalkyl has 3, 4, 5, 6, 7, or 8 atoms, including the common spito atom. In one embodiment, the spiroalkyl is a 5 to 20 membered, 5 to 14 membered, or 5 to 10 membered polycyclic spiroalkyl group. Representative examples of spiroalkyl include, but are not limited to the following groups:The term "fused-carbocyclic” refers to a polycyclic cyclyl group, wherein each ring in the group shares an adjacent pair of carbon atoms with another ring in the group, wherein one or more rings can contain one or more double bonds. In certain embodiments, the fused heterocyclyl is bicyclic. In certain embodiments, the fused-carbocyclic contains more than two rings, at least two of which share an adjacent pair of atoms. In one embodiment, the fused-carbocyclic is a 5 to 20 membered, 5 to 16 membered, or 5 to 10 membered polycyclic cyclyl group. Representative examples of fused-carbocyclic include, but are not limited to the following groups:The term "bridged-carbocyclic” refers to a group having at least two rings sharing three or morecommon ring atoms, separating the two bridgehead atoms by a bridge containing at least one atom. The bridgehead atoms are the atoms from which three bonds radiate and where the rings meet. The rings of the bridged carbocyclyl can have one or more double bonds. In one embodiment, the bridged carbocyclyl is bicyclic. In one embodiment, the bridged carbocyclyl is a 5 to 20 membered, 5 to 16 membered, or 5 to 10 membered polycyclic carbocyclyl group. Representative examples of bridged carbocyclyl include, but are not limited to the following groups:The term "heterocycloalkyl” refers to a nonaromatic 5-8 membered monocyclic, 8-12 membered bicyclic, 11-14 membered tricyclic, or 14-20 membered tetracyclic ring system having one or more heteroatoms (such as 0, N, S, P, or Se). Examples of heterocycloalkyl groups include, but are not limited to, piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, and tetrahydrofuranyl.The term "heterocycloalkenyl” refers to a nonaromatic 5-8 membered monocyclic, 8-12 membered bicyclic, 11-14 membered tricyclic, or 14-20 membered tetracyclic ring system having one or more heteroatoms (such as O, N, S, P, or Se) and one or more double bonds.Spiroheterocyclyl refers to a compound comprising two non-saturated rings sharing only one common atom (also known as a spiro atom), with at least one heteroatom on one of the two rings, such as a polycyclic heterocyclyl group with rings connected through one common carbon atom. The common atom can be carbon (C), silicon, or nitrogen (such as a positively charged quaternary nitrogen atom). The heteroatoms can comprise nitrogen, quaternary nitrogen, oxidized nitrogen (e.g., NO), oxygen, silicon, and sulfur, including sulfoxide and sulfone, and the remaining ring atoms are C. In addition, one or more of the rings may contain one or more double bonds. In one embodiment, the spiro heterocyclyl is bicyclic, with heteroatom(s) on either one or both cycles. In certain embodiments, one of the rings of the bicyclic spiro heterocyclyl has 3, 4, 5, 6, 7, or 8 atoms, including the common spito atom. In certain embodiments, the spiro heterocyclic compound is a polyspiro compound connected by two or more spiroatoms making up three or more rings. In one embodiment, the spiro heterocyclyl is a 5 to 20 membered, 5 to 14 membered, or 5 to 10 membered polycyclic heterocyclyl group. Representative examples of spiro heterocyclyl include, but are not limited to the following groups:Fused heterocyclyl refers to a polycyclic heterocyclyl group, wherein each ring in the group shares an adjacent pair of atoms (such as carbon atoms) with another ring in the group, wherein one or more rings can contain one or more double bonds, and wherein said rings have one or more heteroatoms, which can benitrogen, quaternary nitrogen, oxidized nitrogen (e.g., NO), oxygen, and sulfur, including sulfoxide and sulfone, and the remaining ring atoms are C. In certain embodiments, the fused heterocyclyl is bicyclic. In certain embodiments, the fused heterocyclyl contains more than two rings, at least two of which share an adjacent pair of atoms. In one embodiment, the fused heterocyclyl is a 5 to 20 membered, 5 to 16 membered, or 5 to 10 membered polycyclic heterocyclyl group. Representative examples of fused heterocyclyl include, but are not limited to the following groups:Bridged heterocyclyl refers to a compound having at least two rings sharing three or more common ring atoms, separating the two bridgehead atoms by a bridge containing at least one atom, wherein at least one ring atom is a heteroatom. The bridgehead atoms are the atoms from which three bonds radiate and where the rings meet. The rings of the bridged heterocyclyl can have one or more double bonds, and the ring heteroatom(s) can be nitrogen, quaternary nitrogen, oxidized nitrogen (e.g., NO), oxygen, and sulfur, including sulfoxide and sulfone as ring atoms, while the remaining ring atoms are C. In one embodiment, the bridged heterocyclyl is bicyclic. In one embodiment, the bridged heterocyclyl is a 5 to 20 membered, 5 to 16 membered, or 5 to 10 membered polycyclic heterocyclyl group. Representative examples of bridged heterocyclyl include, but are not limited to the following groups:The term "aryl” refers to a 6-carbon monocyclic, 10-carbon bicyclic, 14-carbon tricyclic aromatic ring system. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl.The term "heteroaryl” refers to an aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11 - 14 membered tricyclic ring system having one or more heteroatoms (such as 0, N, S, P, or Se). Examples of heteroaryl groups include pyridyl, furyl, imidazolyl, benzimidazolyl, pyrimidinyl, thienyl, quinolinyl, indolyl, and thiazolyl."Aralkyl” means a- (alkylene)-R radical where R is aryl as defined above. Examples include, but are not limited to, benzyl, phenethyl, and the like."Cycloalkylalkyl” means a- (alkylene) -R radical where R is cycloalkyl as defined above. Examples include, but are not limited to, cyclopropyl methyl cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl, and thelike.“Cycloalkyloxy” or "cycloalkoxy” means a-OR radical where R is cycloalkyl as defined above. Examples include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.Cycloalkylalkyloxy means a-OR radical where R is cycloalkylalkyl as defined above. Examples include, but are not limited to, cyclopropyl methyloxy, cyclobutylmethyloxy, cyclopentylmethyloxy, cyclohexylethyloxy, and the like.“Cycloal kyloxy alky I” or “cycloalkoxy alky I” means a- (alkylene) -OR radical where R is cycloalkyl as defined above. Examples include, but are not limited to, cyclopropyloxymethyl, cyclobutyloxymethyl, and the like.“Cycloalkylalkyloxyalkyloxy” means a-OR radical where R is cycloalkylalkyloxyalkyl as defined above. Examples include, but are not limited to, cyclopropylmethyloxyethyloxy, cyclobutylethyloxyethyloxy, and the like.“Cycloalkylalkyloxyalkyl” means a- (alkylene) -OR radical where R is cycloalkylalkyl as defined above. Examples include, but are not limited to, cyclopropylmethyloxymethyl, cyclobutylmethoxymethyl, and the like.“Heteroaralkyl” means a- (alkylene) -R radical where R is heteroaryl as defined above, e.g., pyridinylmethyl, and the like. When the heteroaryl ring in heteroaralkyl contains 5-or 6 ring atoms it is also referred to herein as 5-or 6-membered heteroaralkyl.“Heterocycly lai ky I” or “heterocycloalky I” means a — (alkylene)-R radical where R is heterocyclyl ring as defined above e.g., tetraydrofuranylmethyl, piperazinylmethyl, morpholinylethyl, and the like.“Heterocyclyloxy” means a -OR radical where R is heterocyclyl as defined above. Examples include, but are not limited to, tetraydrofuranyloxy, pyrrolidinyloxy, piperidinyloxy, piperazinyloxy, morpholinyloxy, and the like.“Heterocycly loxy alky I” means a -(alkylene)-OR radical where R is heterocyclyl as defined above. Examples include, but are not limited to, tetraydrofuranyloxymethyl, pyrrolidinyloxymethyl, pyrrolidinyloxyethyl, piperidinyloxyethyl, piperazinyloxyethyl, morpholinyloxyethyl, and the like.“Heterocyclylalkyloxy” means a -O-R radical where R is heterocyclylalkyl as defined above. Examples include, but are not limited to, tetraydrofuranylmethyloxy, pyrrolidinylmethyloxy, pyrrolidinylethyloxy, piperidinylmethyloxy, piperazinylmethyloxy, morpholinylethyloxy, and the like.“Heterocyclylalkyloxyalkyl” means a -(alkylene)-OR radical where R is heterocyclylalkyl as defined above. Examples include, but are not limited to, tetraydrofuranylmethyloxymethyl, pyrrolidinylmethyloxymethyl, pyrrolidinylethyloxymethyl, piperidinylmethyloxymethyl, piperazinylmethylethyl, morpholinylethyloxymethyl, and the like.“Isomers” mean any compound having identical molecular formulae but differing in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereomers” and stereoisomers that are nonsuperimposable mirror images are termed “enantiomers” or sometimes “optical isomers.” A carbon atom bonded to four nonidentical substituents is termed a “chiral center.” A compound with one chiral center has two enantiomeric forms of opposite chirality. A mixture of the two enantiomeric forms is termed a “racemic mixture.”"Protected derivatives” means derivatives of compounds in which a reactive site are blocked with protecting groups. Protected derivatives are useful in the preparation of pharmaceuticals or in themselves may be active as inhibitors. A comprehensive list of suitable protecting groups can be found in T.W. Greene, Protecting Groups in Organic Synthesis, 3rd edition, Wiley & Sons, 1999.The term "substituted” means that an atom or group of atoms has replaced hydrogen as the substituent attached to another group. For aryl and heteroaryl groups, the term "substituted” refers to any level of substitution, namely mono-, di-, tri-, tetra-, or penta-substitution, where such substitution is permitted. The substituents are independently selected, and substitution may be at any chemically accessible position. The term "unsubstituted” means that a given moiety may consist of only hydrogen substituents through available valencies (unsubstituted).If a functional group is described as being "optionally substituted,” the function group may be either (1) not substituted, or (2) substituted. If a carbon of a functional group is described as being optionally substituted with one or more of a list of substituents, one or more of the hydrogen atoms on the carbon (to the extent there are any) may separately and / or together be replaced with an independently selected optional substituent."Animal” includes humans, non-human mammals (e.g., non-human primates, rodents, mice, rats, hamsters, dogs, cats, rabbits, cattle, horses, sheep, goats, swine, deer, and the like) and non-mammals (e.g., birds, and the like).“Bioavailability” as used herein is the fraction or percentage of an administered dose of a drug or pharmaceutical composition that reaches the systemic circulation intact. In general, when a medication is administered intravenously, its bioavailability is 100%. However, when a medication is administered via other routes (e.g., orally), its bioavailability decreases (e.g., due to incomplete absorption and first-pass metabolism). Methods to improve the bioavailability include prodrug approach, salt synthesis, particle size reduction, complexation, change in physical form, solid dispersions, spray drying, and hot-melt extrusion."Disease” specifically includes any unhealthy condition of an animal or part thereof and includes an unhealthy condition that may be caused by, or incident to, medical or veterinary therapy applied to that animal, i.e., the "side effects” of such therapy."Pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary use as well as human pharmaceutical use."Pharmaceutically acceptable salts” means organic or inorganic salts of compounds of the present invention which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids, or with organic acids. Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases. Exemplary salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate,methanesulfonate "mesylate,” ethanesulfonate, benzenesulfonate, p-toluenesulfonate, pamoate ( / .e., 1,1'- methylene-bis-(2-hydroxy-3-naphthoate)) salts, alkali metal (e.g., sodium and potassium) salts, alkaline earth metal (e.g., magnesium) salts, and ammonium salts. A pharmaceutically acceptable salt may involve the inclusion of another molecule such as an acetate ion, a succinate ion or other counter ion. The counter ion may be any organic or inorganic moiety that stabilizes the charge on the parent compound. Furthermore, a pharmaceutically acceptable salt may have more than one charged atom in its structure. Instances where multiple charged atoms are part of the pharmaceutically acceptable salt can have multiple counter ions. Hence, a pharmaceutically acceptable salt can have one or more charged atoms and / or one or more counter ion."Pharmaceutically acceptable carrier” means a non-toxic solvent, dispersant, excipient, adjuvant, or other material which is mixed with the compounds of the present invention in order to form a pharmaceutical composition, i.e., a dose form capable of administration to the patient. Examples of pharmaceutically acceptable carrier includes suitable polyethylene glycol (e.g., PEG400), surfactant (e.g., Cremophor), or cyclopolysaccharide (e.g., hydroxypropyl-p-cyclodextrin or sulfobutyl ether p-cyclodextrins), polymer, liposome, micelle, nanosphere, etc."Pharmacophore,” as defined by The International Union of Pure and Applied Chemistry, is an ensemble of steric and electronic features that is necessary to ensure the optimal supramolecular interactions with a specific biological target and to trigger (or block) its biological response. For example, Camptothecin is the pharmacophore of the well known drug topotecan and irinotecan. Mechlorethamine is the pharmacophore of a list of widely used nitrogen mustard drugs like Melphalan, Cyclophosphamide, Bendamustine, and so on."Prodrug” means a compound that is convertible in vivo metabolically into an active pharmaceutical according to the present invention. For example, an inhibitor comprising a hydroxyl group may be administered as an ester that is converted by hydrolysis in vivo to the hydroxyl compound."Stability” in general refers to the length of time a drug retains its properties without loss of potency. Sometimes this is referred to as shelf life. Factors affecting drug stability include, among other things, the chemical structure of the drug, impurity in the formulation, pH, moisture content, as well as environmental factors such as temperature, oxidization, light, and relative humidity. Stability can be improved by providing suitable chemical and / or crystal modifications (e.g., surface modifications that can change hydration kinetics; different crystals that can have different properties), excipients (e.g., anything other than the active substance in the dosage form), packaging conditions, storage conditions, etc."Therapeutically effective amount” of a composition described herein is meant an amount of the composition which confers a therapeutic effect on the treated subject, at a reasonable benefi t / risk ratio applicable to any medical treatment. The therapeutic effect may be objective {i.e., measurable by some test or marker) or subjective {i.e., subject gives an indication of or feels an effect). An effective amount of the composition described above may range from about 0.1 mg / kg to about 500 mg / kg, preferably from about 0.2 to about 50 mg / kg. Effective doses will also vary depending on route of administration, as well as the possibility of co-usage with other agents. It will be understood, however, that the total daily usage of the compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. Thespecific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or contemporaneously with the specific compound employed; and like factors well known in the medical arts.As used herein, the term "treating” refers to administering a compound to a subject that has a neoplastic or immune disorder, or has a symptom of or a predisposition toward it, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve, or affect the disorder, the symptoms of or the predisposition toward the disorder. The term "an effective amount” refers to the amount of the active agent that is required to confer the intended therapeutic effect in the subject. Effective amounts may vary, as recognized by those skilled in the art, depending on route of administration, excipient usage, and the possibility of co-usage with other agents.A "subject” refers to a human and a non-human animal. Examples of a non-human animal include all vertebrates, e.g., mammals, such as non-human primates (particularly higher primates), dog, rodent {e.g., mouse or rat), guinea pig, cat, and non-mammals, such as birds, amphibians, reptiles, etc. In a preferred embodiment, the subject is a human. In another embodiment, the subject is an experimental animal or animal suitable as a disease model."Combination therapy” includes the administration of the subject compounds of the present invention in further combination with other biologically active ingredients (such as, but not limited to, a second and different anti neoplastic agent) and non-drug therapies (such as, but not limited to, surgery or radiation treatment). For instance, the compounds of the invention can be used in combination with other pharmaceutically active compounds, or non-drug therapies, preferably compounds that are able to enhance the effect of the compounds of the invention. The compounds of the invention can be administered simultaneously (as a single preparation or separate preparation) or sequentially to the other therapies. In general, a combination therapy envisions administration of two or more drugs / treatments during a single cycle or course of therapy.In one embodiment, the compounds of the invention are administered in combination with one or more of traditional chemotherapeutic agents. The traditional chemotherapeutic agents encompass a wide range of therapeutic treatments in the field of oncology. These agents are administered at various stages of the disease for the purposes of shrinking tumors, destroying remaining cancer cells left over after surgery, inducing remission, maintaining remission and / or alleviating symptoms relating to the cancer or its treatment. Examples of such agents include, but are not limited to, alkylating agents such as Nitrogen Mustards (e.g., Bendamustine, Cyclophosphamide, Melphalan, Chlorambucil, Isofosfamide), Nitrosureas {e.g., Carmustine, Lomustine and Streptozocin), ethylenimines {e.g., thiotepa, hexamethylmelanine), Alkylsulfonates {e.g., Busulfan), Hydrazines and Triazines {e.g., Altretamine, Procarbazine, Dacarbazine and Temozolomide), and platinum based agents {e.g., Carboplatin, Cisplatin, and Oxaliplatin); plant alkaloids such as Podophyllotoxins {e.g., Etoposide and Tenisopide), Taxanes {e.g., Paclitaxel and Docetaxel), Vinca alkaloids {e.g., Vincristine, Vinblastine andVinorelbine); anti-tumor antibiotics such as Chromomycins e.g., Dactinomycin and Plicamycin), Anthracyclines (e.g., Doxorubicin, Daunorubicin, Epirubicin, Mitoxantrone, and Idarubicin), and miscellaneous antibiotics such as Mitomycin and Bleomycin; anti-metabolites such as folic acid antagonists (e.g., Methotrexate), pyrimidine antagonists (e.g., 5-Fluorouracil, Foxuridine, Cytarabine, Capecitabine, and Gemcitabine), purine antagonists (e.g., 6-Mercaptopurine and 6-Thioguanine) and adenosine deaminase inhibitors (e.g., Cladribine, Fludarabine, Nelarabine and Pentostatin); topoisomerase inhibitors such as topoisomerase I inhibitors(Topotecan, Irinotecan), topoisomerase II inhibitors (e.g., Amsacrine, Etoposide, Etoposide phosphate, Teniposide), and miscellaneous anti-neoplastics such as ribonucleotide reductase inhibitors (Hydroxyurea), adrenocortical steroid inhibitor (Mitotane), anti-microtubule agents (Estramustine), and retinoids (Bexarotene, Isotretinoin, Tretinoin (ATRA).In one aspect of the invention, the compounds may be administered in combination with one or more targeted anti-cancer agents that modulate protein kinases involved in various disease states. Examples of such kinases may include, but are not limited ABL1, ABL2 / ARG, ACK1, AKT1, AKT2, AKT3, ALK, ALK1 / ACVRL1, ALK2 / ACVR1, ALK4 / ACVR1 B, ALK5 / TGFBR1, ALK6 / BMPR1 B, AMPK(A1 / B1 / G1), AMPK(A1 / B1 / G2), AMPK(A1 / B1 / G3), AMPK(A1 / B2 / G1), AMPK(A2 / B1 / G1), AMPK(A2 / B2 / G1), AMPK(A2 / B2 / G2), ARAF, ARK5 / NUAK1, ASK1 / MAP3K5, ATM, Aurora A, Aurora B , Aurora C , AXL, BLK, BMPR2, BMX / ETK, BRAF, BRK, BRSK1, BRSK2, BTK, CAMKIa , CAMKIb, CAMKId, CAMKIg , CAMKIla , CAMKIlb, CAMKIld , CAMKIIg , CAMK4, CAMKK1, CAMKK2, CDC7-DBF4, CDK1 -cyclin A, CDK1 -cyclin B, CDK1 -cyclin E, CDK2-cyclin A, CDK2-cyclin A1, CDK2-cyclin E, CDK3-cyclin E, CDK4-cyclin D1, CDK4-cyclin D3, CDK5-p25, CDK5-p35, CDK6-cyclin D1, CDK6-cyclin D3, CDK7-cyclin H, CDK9-cyclin K, CDK9-cyclin T1, CHK1, CHK2, CK1a1 , CK1d , CK1 epsilon , CK1 g1 , CK1g2, CK1g3 , CK2a , CK2a2, c-KIT, CLK1 , CLK2, CLK3, CLK4, c-MER, c-MET, COT1 / MAP3K8, CSK, c-SRC, CTK / MATK, DAPK1, DAPK2, DCAMKL1, DCAMKL2, DDR1, DDR2, DLK / MAP3K12, DMPK, DMPK2 / CDC42BPG, DNA-PK, DRAK1 / STK17A, DYRK1 / DYRK1A, DYRK1 B, DYRK2, DYRK3, DYRK4, EEF2K, EGFR, EIF2AK1, EIF2AK2, EIF2AK3, EIF2AK4 / GCN2, EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHB1, EPHB2, EPHB3, EPHB4, ERBB2 / HER2, ERBB4 / HER4, ERK1 / MAPK3, ERK2 / MAPK1, ERK5 / MAPK7, FAK / PTK2, FER, FES / FPS, FGFR1, FGFR2, FGFR3, FGFR4, FGR, FLT1 / VEGFR1, FLT3, FLT4 / VEGFR3, FMS, FRK / PTK5, FYN, GCK / MAP4K2, GRK1, GRK2, GRK3, GRK4, GRK5, GRK6, GRK7, GSK3a, GSK3b, Haspin, HCK, HGK / MAP4K4, HIPK1, HIPK2, HIPK3, HIPK4, HPK1 / MAP4K1, IGF1R, IKKa / CHUK , IKKb / IKBKB, IKKe / IKBKE, IR, IRAKI, IRAK4, IRR / INSRR, ITK, JAK1, JAK2, JAK3, JNK1 , JNK2 , JNK3, KDRA / EGFR2, KHS / MAP4K5, LATS1, LATS2, LCK, LCK2 / ICK, LKB1 , LIMK1, LOK / STK10, LRRK2, LYN, LYNB, MAPKAPK2, MAPKAPK3, MAPKAPK5 / PRAK, MARK1, MARK2 / PAR- 1 Ba, MARK3, MARK4, MEK1, MEK2, MEKK1, MEKK2, MEKK3, MELK, MINK / MINK1, MKK4, MKK6, MLCK / MYLK, MLCK2 / MYLK2, MLK1 / MAP3K9, MLK2 / MAP3K10, MLK3 / MAP3K11, MNK1, MNK2, MRCKa / , CDC42BPA, MRCKb / , CDC42BPB, MSK1 / RPS6KA5, MSK2 / RPS6KA4, MSSK1 / STK23, MST1 / STK4, MST2 / STK3, MST3 / STK24, MST4, mT0R / FRAP1, MUSK, MYLK3, MYO3b, NEK1, NEK2, NEK3, NEK4, NEK6, NEK7, NEK9, NEK11, NIK / MAP3K14, NLK, OSR1 / OXSR1, P38a / MAPK14, P38b / MAPK11, P38d / MAPK13 , P38g / MAPK12 , P70S6K / RPS6KB1, p70S6Kb / , RPS6KB2, PAK1, PAK2, PAK3, PAK4, PAK5, PAK6, PASK, PBK / TOPK, PDGFRa, PDGFRb, PDK1 / PDPK1, PDK1 / PDHK1, PDK2 / PDHK2 , PDK3 / PDHK3, PDK4 / PDHK4,PHKgl , PHKg2 , PI3Ka, (p110a / p85a), PI3Kb, (p110b / p85a), PI3Kd, (p110d / p85a), PI3Kg(p120g), PIM1, PIM2, PIM3, PKA, PKAcb, PKAcg , PKCa , PKCbl , PKCb2 , PKCd , PKCepsilon, PKCeta, PKCg , PKCiota, PKCmu / PRKD1, PKCnu / PRKD3, PKCtheta, PKCzeta, PKD2 / PRKD2, PKG1a , PKG1b , PKG2 / PRKG2, PKN1 / PRK1, PKN2 / PRK2, PKN3 / PRK3, PLK1, PLK2, PLK3, PLK4 / SAK, PRKX, PYK2, RAF1, RET, RIPK2, RIPK3, RIPK5, ROCK1, ROCK2, RON / MST1R, ROS / ROS1, RSK1, RSK2, RSK3, RSK4, SGK1, SGK2, SGK3 / SGKL, SIK1 , SIK2, SLK / STK2, SNARK / NUAK2, SRMS, SSTK / TSSK6, STK16, STK22D / TSSK1, STK25 / YSK1, STK32b / YANK2, STK32c / YANK3, STK33, STK38 / NDR1, STK38L / NDR2, STK39 / STLK3, SRPK1, SRPK2, SYK, TAK1, TAOK1, TAOK2 / TAO1, TAOK3 / JIK, TBK1 , TEC, TESK1, TGFBR2, TIE2 / TEK, TLK1, TLK2, TNIK, TNK1, TRKA, TRKB, TRKC, TRPM7 / CHAK1, TSSK2, TSSK3 / STK22C, TTBK1, TTBK2, TTK, TXK, TYK1 / LTK, TYK2, TYRO3 / SKY, ULK1, ULK2, ULK3, VRK1, VRK2, WEE1, WNK1, WNK2, WNK3, YES / YES1, ZAK / MLTK, ZAP70, ZIPK / DAPK3, KINASE, MUTANTS, ABL1 (E255K), ABL1 (F317I), ABL1 (G250E), ABL1 (H396P), ABL1 (M351T), ABL1 (Q252H), ABL1 (T315I), ABL1 (Y253F), ALK (C1156Y), ALK(L1196M), ALK (F1174L), ALK (R1275Q), BRAF(V599E), BTK(E41 K), CHK2(I157T), c-Kit(A829P), c-KIT(D816H), c- KIT(D816V), c-Kit(D820E), c-Kit(N822K), C-Kit (T670I), c-Kit(V559D), c-Kit(V559D / V654A), c-Kit(V559D / T670l), C-Kit (V560G), c-KIT(V654A), C-MET(D1228H), C-MET(D1228N), C-MET(F1200I), c-MET(M1250T), C- MET(Y1230A), C-MET(Y1230C), C-MET(Y1230D), C-MET(Y1230H), c-Src(T341 M), EGFR(G719C), EGFR(G719S), EGFR(L858R), EGFR(L861Q), EGFR(T790M), EGFR, (L858R.T790M) , EGFR(d746- 750 / T790M), EGFR(d746-750), EGFR(d747-749 / A750P), EGFR(d747-752 / P753S), EGFR(d752-759), FGFR1 (V561 M), FGFR2(N549H), FGFR3(G697C), FGFR3(K650E), FGFR3(K650M), FGFR4(N535K), FGFR4(V550E), FGFR4(V550L), FLT3(D835Y), FLT3(ITD), JAK2 (V617F), LRRK2 (G2019S), LRRK2 (I2020T), LRRK2 (R1441C), p38a(T106M), PDGFRa(D842V), PDGFRa(T674l), PDGFRa(V561D), RET(E762Q), RET(G691S), RET(M918T), RET(R749T), RET(R813Q), RET(V804L), RET(V804M), RET(Y791 F), TIF2(R849W), TIF2(Y897S), and TIF2(Y1108F).In another aspect of the invention, the subject compounds may be administered in combination with one or more targeted anti-cancer agents that modulate non-kinase biological targets, pathway, or processes. Such targets pathways, or processes include but not limited to heat shock proteins (e.g.HSP90), poly-ADP (adenosine diphosphate)-ribose polymerase (PARP), hypoxia-inducible factors(HIF), proteasome, Wnt / Hedgehog / Notch signaling proteins, TNF-alpha, matrix metalloproteinase, farnesyl transferase, apoptosis pathway (e.g Bcl-xL, Bcl-2, Bcl-w), histone deacetylases (HDAC), histone acetyltransferases (HAT), and methyltransferase (e.g histone lysine methyltransferases, histone arginine methyltransferase, DNA methyltransferase, etc).In another aspect of the invention, the compounds of the invention are administered in combination with one or more of other anti-cancer agents that include, but are not limited to, gene therapy, RNAi cancer therapy, chemoprotective agents {e.g., amfostine, mesna, and dexrazoxane), drug-antibody conjugate^. g brentuximab vedotin, ibritumomab tioxetan), cancer immunotherapy such as lnterleukin-2, cancer vaccines(e.g., sipuleucel-T) or monoclonal antibodies {e.g., Bevacizumab, Alemtuzumab, Rituximab, Trastuzumab, etc).In another aspect of the invention, the subject compounds are administered in combination with radiation therapy or surgeries. Radiation is commonly delivered internally (implantation of radioactive materialnear cancer site) or externally from a machine that employs photon (x-ray or gamma-ray) or particle radiation. Where the combination therapy further comprises radiation treatment, the radiation treatment may be conducted at any suitable time so long as a beneficial effect from the co-action of the combination of the therapeutic agents and radiation treatment is achieved. For example, in appropriate cases, the beneficial effect is still achieved when the radiation treatment is temporally removed from the administration of the therapeutic agents, perhaps by days or even weeks.In certain embodiments, the compounds of the invention are administered in combination with one or more of radiation therapy, surgery, or anti-cancer agents that include, but are not limited to, DNA damaging agents, antimetabolites, topoisomerase inhibitors, anti-microtubule agents, kinase inhibitors, epigenetic agents, HSP90 inhibitors, PARP inhibitors, BCL-2 inhibitor, drug-antibody conjugate, and antibodies targeting VEGF, HER2, EGFR, CD50, CD20, CD30, CD33, etc.In certain embodiments, the compounds of the invention are administered in combination with one or more of abarelix, abiraterone acetate, aldesleukin, alemtuzumab, altretamine, anastrozole, asparaginase, bendamustine, bevacizumab, bexarotene, bicalutamide, bleomycin, bortezombi, brentuximab vedotin, busulfan, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, clomifene, crizotinib, cyclophosphamide, dasatinib, daunorubicin liposomal, decitabine, degarelix, denileukin diftitox, denileukin diftitox, denosumab, docetaxel, doxorubicin, doxorubicin liposomal, epirubicin, eribulin mesylate, erlotinib, estramustine, etoposide phosphate, everolimus, exemestane, fludarabine, fluorouracil, fotemustine, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate, hydroxyurea, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib mesylate, interferon alfa 2a, ipilimumab, ixabepilone, lapatinib ditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, mechlorethamine, melphalan, methotrexate, mitomycin C, mitoxantrone, nelarabine, nilotinib, oxaliplatin, paclitaxel, paclitaxel protein-bound particle, pamidronate, panitumumab, pegaspargase, peginterferon alfa-2b, pemetrexed disodium, pentostatin, raloxifene, rituximab, sorafenib, streptozocin, sunitinib maleate, tamoxifen, temsirolimus, teniposide, thalidomide, toremifene, tositumomab, trastuzumab, tretinoin, uramustine, vandetanib, vemurafenib, vinorelbine, zoledronate, radiation therapy, or surgery.In certain embodiments, the compounds of the invention are administered in combination with one or more anti-inflammatory agent. Anti-inflammatory agents include but are not limited to NSAIDs, non-specific and COX-2 specific cyclooxgenase enzyme inhibitors, gold compounds, corticosteroids, methotrexate, tumor necrosis factor receptor (TNF) receptors antagonists, immunosuppressants and methotrexate. Examples of NSAIDs include, but are not limited to, ibuprofen, flurbiprofen, naproxen and naproxen sodium, diclofenac, combinations of diclofenac sodium and misoprostol, sulindac, oxaprozin, diflunisal, piroxicam, indomethacin, etodolac, fenoprofen calcium, ketoprofen, sodium nabumetone, sulfasalazine, tolmetin sodium, and hydroxychloroquine. Examples of NSAIDs also include COX-2 specific inhibitors such as celecoxib, valdecoxib, lumiracoxib and / or etoricoxib.In some embodiments, the anti-inflammatory agent is a salicylate. Salicylates include by are not limited to acetylsalicylic acid or aspirin, sodium salicylate, and choline and magnesium salicylates. The anti-inflammatory agent may also be a corticosteroid. For example, the corticosteroid may be cortisone, dexamethasone, methylprednisolone, prednisolone, prednisolone sodium phosphate, or prednisone.In additional embodiments the anti-inflammatory agent is a gold compound such as gold sodium thiomalate or auranofin.The invention also includes embodiments in which the anti-inflammatory agent is a metabolic inhibitor such as a dihydrofolate reductase inhibitor, such as methotrexate or a dihydroorotate dehydrogenase inhibitor, such as leflunomide.Other embodiments of the invention pertain to combinations in which at least one anti-inflammatory compound is an anti-C5 monoclonal antibody (such as eculizumab or pexelizumab), a TNF antagonist, such as entanercept, or infliximab, which is an anti-TNF alpha monoclonal antibody.In certain embodiments, the compounds of the invention are administered in combination with one or more immunosuppressant agents.In some embodiments, the immunosuppressant agent is glucocorticoid, methotrexate, cyclophosphamide, azathioprine, mercaptopurine, leflunomide, cyclosporine, tacrolimus, and mycophenolate mofetil, dactinomycin, anthracyclines, mitomycin C, bleomycin, or mithramycin, or fingolimod.The invention further provides methods for the prevention or treatment of a neoplastic disease, autoimmune and / or inflammatory disease. In one embodiment, the invention relates to a method of treating a neoplastic disease, autoimmune and / or inflammatory disease in a subject in need of treatment comprising administering to said subject a therapeutically effective amount of a compound of the invention. In one embodiment, the invention further provides for the use of a compound of the invention in the manufacture of a medicament for halting or decreasing a neoplastic disease, autoimmune and / or inflammatory disease.In one embodiment, the neoplastic disease is a B-cell malignancy includes but not limited to B-cell lymphoma, lymphoma (including Hodgkin's lymphoma and non-Hodgkin's lymphoma), hairy cell lymphoma, small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL), multiple myeloma, chronic and acute myelogenous leukemia and chronic and acute lymphocytic leukemia.The autoimmune and / or inflammatory diseases that can be affected using compounds and compositions according to the invention include, but are not limited to allergy, Alzheimer's disease, acute disseminated encephalomyelitis, Addison's disease, ankylosing spondylitis, antiphospholipid antibody syndrome, asthma, atherosclerosis, autoimmune hemolytic anemia, autoimmune hemolytic and thrombocytopenic states, autoimmune hepatitis, autoimmune inner ear disease, bullous pemphigoid, coeliac disease, chagas disease, chronic obstructive pulmonary disease, chronic Idiopathic thrombocytopenic purpura (ITP), churg-strauss syndrome, Crohn's disease, dermatomyositis, diabetes mellitus type 1, endometriosis, Goodpasture's syndrome (and associated glomerulonephritis and pulmonary hemorrhage), graves' disease, guillain-barre syndrome, hashimoto's disease, hidradenitis suppurativa, idiopathic thrombocytopenic purpura, interstitial cystitis, irritable bowel syndrome, lupus erythematosus, morphea, multiple sclerosis, myasthenia gravis, narcolepsy, neuromyotonia, Parkinson's disease, pemphigus vulgaris, pernicious anaemia, polymyositis, primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, schizophrenia, septic shock, scleroderma, Sjogren'sdisease, systemic lupus erythematosus (and associated glomerulonephritis), temporal arteritis, tissue graft rejection and hyperacute rejection of transplanted organs, vasculitis (ANCA-associated and other vasculitides), vitiligo, and wegener's granulomatosis.It should be understood that the invention is not limited to the particular embodiments shown and described herein, but that various changes and modifications may be made without departing from the spirit and scope of the invention as defined by the claims.The compounds according to the present invention may be synthesized according to a variety of reaction schemes. Necessary starting materials may be obtained by standard procedures of organic chemistry. The compounds and processes of the present invention will be better understood in connection with the following representative synthetic schemes and examples, which are intended as an illustration only and not limiting of the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art and such changes and modifications including, without limitation, those relating to the chemical structures, substituents, derivatives, and / or methods of the invention may be made without departing from the spirit of the invention and the scope of the appended claims.In Scheme (A), the starting material A-1 is commercially available. The starting material A-1 is converted to intermediate A-2 through deoxyfluorination reaction, which can be hydrolyzed to the intermediate A- 3 under an alkaline condition. After that, A-3 is transformed into A-4 via an intramolecular cycalization reaction, which goes through an alkylation reaction and a cyclization / deprotection cascade under thermal conditions to provide A-5. Finally, the intermediate A-5 is reduced to give the target compound A-6.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.An approach to synthesize compounds ofis described in Scheme (B).In Scheme (B), the starting material A-1 is commercially available. The starting material A-1 is converted to intermediate B-1 through an alkylation reaction reaction, which can be hydrolyzed to the intermediate B-2. After that, B-2 is transformed into B-3 via an intramolecular cycalization reaction, which goes through an alkylation reaction and a cyclization / deprotection cascade under thermal conditions to provide B-4. The intermediate B-4 is reduced to give the intermediacte B-5. After that, B-5 react with a silyl protecting reagent to afford B-6, which goes through a two-step sequence of hydrogenation and oxidation reactions to provide B-7. Finally, the intermediate B-7 react with a suitable wittig reagent to afford B-8, which is deprotected to yield the target compounds B-9.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.In Scheme (C), the preparation of the starting material B-7 is described in Scheme (B). The starting material B-7 is converted to intermediate C-1 through a carbonyl olefination reaction, which is deprotected to give the target compounds C-2.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.r \H0An approach to synthesize compounds of V-J is described in Scheme (D).In Scheme (D), the preparation of the starting material B-8 is described in Scheme (B). The starting material B-8 is converted to intermediate D-1 through Simmons-Smith reaction. After that, the catalytic hydrogenation of D-1 over PtC>2 in acetic acid can give D-2, which is deprotected to give the target compounds D-3.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.An approach to synthesize compounds ofis described in Scheme (E).In Scheme (E), the preparation of the starting material B-7 is described in Scheme (B). The starting material B-7 is converted to intermediate E-1 via a two-step sequence of deprotection and acetylation reaction. After that, the intermediate E-1 is transformed into E-2 though a nucleophilic difluorination reaction, which is deacetylated to give the target compounds E-3.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.An approach to synthesize compounds ofis described in Scheme (F).In Scheme (F), the preparation of the starting material B-7 is described in Scheme (B). The starting material B-7 reacts with MeMgBr or MeLi can afford the intermediate F-1 , which is deprotected to give the target compounds F-2.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.In Scheme (G), the preparation of the starting material B-6 is described in Scheme (B). The starting material B-6 can be hydrogenated to give G-1, which is transformed into G-2 via a Mitsunobu reaction. After that, the intermediate G-2 is deprotected to yield G-3, which can be further alkylated to afford the G-4. Finally, the intermediate G-4 is deprotected to provide the target compounds G-5.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.An approach to synthesize compounds ofis described in Scheme (H).In Scheme (H), the starting material H-1 is commercially available. The starting material H-1 is hydrolyzed to give intermediate H-2, which can be deprotected to afford intermediate H-3 under acidic condition. After that, H-3 is transformed into H-4 via an intramolecular cycalization reaction, which goes through an alkylation reaction and a cyclization / deprotection cascade under thermal conditions to provide H-5. The intermediate B-4 is reduced to give the target compound H-6.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.An approach to synthesize compounds ofis described in Scheme (I).In Scheme (I), the starting material 1-1 is commercially available. The starting material 1-1 is transformed into I-2A / B via an intramolecular cycalization reaction, which goes through an oxidation reaction to provide I-3. The intermediate i-3 is reduced to give the alcohols I-4. After that, the intermediate I-4 can be deoxyfluorinated to afford fluoride I-5. Finally, the intermediate I-5 is reduced to provide the target compounds I-6.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.An approach to synthesize compoundsdescribed in Scheme (J).In Scheme (J), the preparation of starting material i-4 is described in Scheme (I). The starting material I- 4 can be transformed into J-1 via a Mitsunobu reaction. After that, the intermediate J-1 is deprotected to yield J- 2, which can be further alkylated to afford the intermediate J-3. Finally, the intermediate J-3 is deprotected to provide the target compounds J-4.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.An approach to synthesize compounds ofis described in Scheme (K).In Scheme (K), the preparation of starting material I-2A is described in Scheme (I). The starting material I-2 is reduced to provide the target compounds K-1 .Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.An approach to synthesize compounds of is described in Scheme (L).In Scheme (L), the preparation of starting material I-2A is described in Scheme (I). The starting material 1-2 can be reduced to give L-1, which is protected with a suitable reagent to afford L-2. After that, L-2 can be converted to L-3 through an olefin metathesis reaction, which is deprotected to afford the target compounds L-4.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.HO-' -<R-*An approach to synthesize compounds ofis described in Scheme (M).In Scheme (M), the preparation of starting material L-2 is described in Scheme (L). The starting material L-2 is converted to intermediate M-1 through Simmons-Smith reaction. After that, the catalytic hydrogenation of M-1 over PtC>2 in acetic acid can give M-2, which is deprotected to give the target compounds M-3.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.An approach to synthesize compounds ofis described in Scheme (N).In Scheme (N), the preparation of starting material 1-3 is described in Scheme (I). The starting material 1-3 is converted to intermediate N-1 via nucleophilic difluorination reaction, which is reduced to give the target compounds N-2.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.In Scheme (0), the preparation of starting material I-3 is described in Scheme (I). The starting material I-3 react with a suitable reagent such as Me2Zn or AIMea to afford intermediate 0-1 , which can be reduced to give the target compounds 0-2.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.In Scheme (P), the starting material P-1 is commercially available. The starting material P-1 can be converted to P-3 via a alkylation reaction, which further undergoes a epoxidation reaction to give intermediate P-3. The intermediate P-3 goes through a 5-exo ring closing reaction to give P-4. After that, the intermediate P-4 can be alkylated to give P-5, which is further reduced to provide the target compounds P-6.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.An approach to synthesize compounds ofis described in Scheme (Q).In Scheme (Q), the preparation of starting material H-4 is described in Scheme (H). The starting material H-4 goes through an alkylation reaction and a cyclization / deprotection cascade under thermal conditions to provide intermediate Q-1, which is reduced to give the target compounds Q-2.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.In Scheme (S), the starting material S-1 is commercially available. The starting material S-1 goes through an two-steps sequence of SNAr reaction to provide intermediate S-2, which is brominated to give S-3. After that, the intermediate S-3 is demethylated to afford S-4, which react with chlorinated reagent such as POCI3 to yield the target compounds S-5.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.In Scheme (S-1 ), the starting material S-1-1 is commercially available. The starting material S-1-1 goes through an two-steps sequence of fluorination and iodization reactions to provide intermediate S-1-3, which is converted to S-1 -4 via an insertion carbonyl reaction. After that, the intermediate S-1 -4 react with 2,2,2- trichloroacetyl isocyanate to afford S-1 -5, and then the condensation of S-1 -5 with ammonia methanol can give the intermediate S-1 -6. Finally, S-1 -6 react with chlorinated reagent such as POCI3 to give S-1 -7, which is converted to the target compounds S-1 -8 in the presence of aqueous NaHCOa.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.An approach to synthesize compoundsdescribed in Scheme (S-2).In Scheme (S-2), the starting material S-2-1 is commercially available. The starting material S-2-1 goes through a bromination reaction to provide intermediate S-2-2, which is converted to S-2-3 via an condensation reaction. After that, the intermediate S-2-3 is transformed into the target compounds S-2-4 in the presence of a suitable organic base.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.BocIn Scheme (T), the starting material T-1 is commercially available. The starting material T-1 goes through an O-methylation reaction to provide intermediate T-2, which heating with methyl nitroacetate to afford T-3. After that, hydrogenation of T-3 resulted in cyclization of the intermediate to afford T-4, which react with BOC2O to yield the target compounds T-5.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.BocAn approach to synthesize compounds odescribed in Scheme (T-1).In Scheme (T-1), the preparation of starting material T-5 is described in Scheme (T). The racemization of intermediate T-5 in the presence of a base (DBU), and then isolated to give the target compound T-1-1.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.An approach to synthesize compounds odescribed in Scheme (T-3).In Scheme (T-3), the preparation of starting material T-1-1 is described in Scheme (T-1). The reduction of intermediate T-1-1 in the presence LiAIF resulted in T-3-1, which is protected to give the target compound T- 3-2.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.In Scheme (T-4), the preparation of starting material T-3-2 is described in Scheme (T-3). The starting material T-3-2 is converted to intermediate T-4-1 via an oxidative reaction, which react with MeMgBr or MeLi to give the intermediate T-4-2. After that, the intermediate T-4-2 is deprotected to yield the target compound T-4-3Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.In Scheme (T-5), the preparation of starting material T-5 is described in Scheme (T). The starting material T-5 react with MeMgBr or MeLi to give the intermediate T-5-1, which is dehydrated to give the intermediate T-5-2. After that, the intermediate T-5-2 is reduced to yield the target compound T-5-3.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.BocAn approach to synthesize compoundsdescribed in Scheme (T-6).In Scheme (T-6), the preparation of the starting material T-3-1 is described in Scheme (T-3). The starting material T-3-1 is converted to intermediate T-6-1, which is further react with benzyl bromide to afford T- 6-2. After that, the alkylation of T-6-2 resulted in T-6-3, the intermediate T-6-3 is deprotected to provide T-6-4. The intermediate T-6-4 is converted to intermediate T-6-5 via an oxidative reaction, which react with MeMgBr or MeLi to give the target compounds T-6-6. Finally, the intermediate T-6-6 is deprotected to yield the target compound T-6-7.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.An approach to synthesize compoundsdescribed in Scheme (T-7).In Scheme (T-7), the preparation of the starting material T-6-3 is described in Scheme (T-6). The carbylation of starting material T-6-3 can give the target compound T-7-1 .Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.An approach to synthesize compounds odescribed in Scheme (T-8).In Scheme (T-8), the preparation of the starting material T-6-3 is described in Scheme (T-6). The carboxylation of starting material T-6-3 can give the target compound T-8-1.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.In Scheme (T-9), the preparation of the starting material T-8-1 is described in Scheme (T-8). The condensation of starting material T-8-1 with ammonia can give the intermediate T-9-1, which is dehydrated to give the target compound T-9-2.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.Boc An approach to synthesize compoundsdescribed in Scheme (T-10).In Scheme (T-10), the preparation of the starting material T-7-1 is described in Scheme (T-7). The starting material T-6-3 can be converted to the target compound T-10-1 using Bestmann-Ohira reagent.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.BocAn approach to synthesize compoundsdescribed in Scheme (T-11).In Scheme (T-11), the preparation of the starting material T-6-3 is described in Scheme (T-6). The alkylation of T-6-3 with Etl can give the target compound T-11-1.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.BocAn approach to synthesize compoundsdescribed in Scheme (T-12).In Scheme (T-12), the preparation of the starting material T-7-1 is described in Scheme (T-7). The starting material T-7-1 can be converted to the target compound T-12-1 via Wittig reaction.Also, the target compounds can be synthesized by alternative methods but not limited to the aboveprocedures.BocSimilarly, the compoundscan be made by the method referred to Scheme T to T12, by using different starting material, intermediates, and reagents, or by the conventional organic reactions.In Scheme (V), the starting material V-1 is commercially available. The starting material V-1 is converted to intermediate V-2 via a C-H bond activation and functionalization reaction, which is selectively protected of the 3-OH to give V-3. After that, the intermediate V-3 react with Tf2O to afford V-4 under basic condition, which goes through a Hosomi-Miyaura borylation reaction to provide the target compound V-5.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.An approach to synthesize compoundsdescribed in Scheme (V-1).In Scheme (V-1 ), the starting material V-1-1 is commercially available. The starting material V-1-1 is converted to intermediate V-1 -2 via a phenylacetylene D-A [4+2] reaction, which can be further transformed into the intermediate V-1 -3 under acidic condition. After that, V-1 -3 react with Tf2O under basic condition to give V-1- 4, which can be converted to V-1 -5 via a C-H bond activation and functionalization reaction. The intermediate V- 1-5 is oxidated to give V-1 -6. Finally, V-1 -6 react with MOMCI to afford V-1 -7, which goes through a Hosomi- Miyaura borylation reaction to provide the target compound V-1 -8.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.In Scheme (V-2), the starting material V-2-1 is commercially available. The starting material V-2-1 is converted to intermediate V-2 via a C-H bond activation and functionalization reaction, which react with Tf2O under alkaline condition to give the intermediate V-2-3. After that, V-2-3 is transformed into V-2-4 through a Buchwald coupling reaction, the intermediate V-2-4 goes through a Hosomi-Miyaura borylation reaction to provide the target compound V-2-5.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.In Scheme (V-3), the preparation of the starting material V-2 is described in Scheme (V). The starting material V-2 react with Tf2<3 under alkaline condition to give intermediate V-3-1 , which is transformed into V-3-2 through a Buchwald coupling reaction. After that, V-3-2 is transformed into V-3-3 via a Hosomi-Miyaura borylation reaction. Finally, V-3-3 is fluorinated to provide the target compound V-3-4.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures. g(R1A)'t LBPinThe compounds of (RiB)hcanbema(jeby the method referred to Scheme V to V-3, by using different starting material, intermediates, and reagents, or by the conventional organic reactions.In Scheme (W), the starting material W-1 is commercially available. The starting material W-1 is converted to intermediate W-2 via a Sandmeyer reaction, which is reduced to give the intermediate W-3. After that, the protection of W-3 resulted in W-4, the intermediate W-4 goes through a trifluoromethylation reaction to provide W-5. Finally, the intermediate W-5 is transformed into the target compound W-6 via a Hosomi-Miyaura borylation reaction.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.In Scheme (W-0), the preparation of the starting material W-5 is described in Scheme (W). The starting material W-5 can be deprotected to afford the intermediate W-0-1, which is converted to the target compound W- 0-2 through Hosomi-Miyaura borylation reaction.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.In Scheme (W-1), the preparation of the starting material W-4 is described in Scheme (V). The starting material W-4 goes through a transition metal catalytic reaction to provide W-1-1, which is transformed into the target compound W-1 -2 via a Hosomi-Miyaura borylation reaction.Also, the target compounds can be synthesized by alternative methods but not limited to the aboveprocedures.In Scheme (W-2), the starting material W-2-1 is commercially available. The starting material W-2-1 is converted to intermediate W-2-2 via a Sandmeyer reaction, which is reduced to give the intermediate W-2-3.After that, the protection of W-2-3 resulted in W-2-4, the intermediate W-2-4 goes through a transition metal catalytic reaction to provide W-2-5. Finally, the intermediate W-2-5 is transformed into the target compound W-2- 6 via a Hosomi-Miyaura borylation reaction.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.An approach to synthesize compoundsdescribed in Scheme (X).In Scheme (X), the preparation of the starting material T-3-2 is described in Scheme (T-3). The starting material T-3-2 is converted to intermediate X-1 via an oxidative reaction, which react with MeMgBr or MeLi to give the intermediate X-2. After that, the deprotection of X-2 resulted in X-3, the intermediate X-3 goes through an SNAr reaction with 2,5,7-trichloro-8-fluoropyrido[4,3-d]pyrimidin-4-ol to provide X-4. Finally, the intermediate X-4 is transformed into the target compound X-5 via an intramolecular cyclization reaction.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.BocIn Scheme (X-0), the preparation of the starting material X-3 is described in Scheme (X). The starting material X-3 is converted to intermediate X-0-1 via an SNAr reaction, which is transformed into the target compound X-0-2 through an intramolecular cyclization reaction.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.An approach to synthesize compoundsdescribed in Scheme (X-1).In Scheme (X-1), the preparation of the starting material X-1 is described in Scheme (X). The starting material X-1 is converted to intermediate X-1 -1 via Wittig reaction, which is deprotected to give the intermediate X-1 -2. After that, the intermediate X-1 -2 goes through an SNAr reaction with 5-bromo-4,7-dichloro-2-(ethylthio)- 8-fluoropyrido[4,3-d]pyrimidine to provide X-1 -3. Finally, the intermediate X-1 -3 is transformed into the target compound X-1 -4 via an intramolecular cyclization reaction.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.An approach to synthesize compoundsdescribed in Scheme (X-2).In Scheme (X-2), the preparation of the starting material X-2-1 has the similar manner with which described in Scheme (X). The starting material X-2-1 is converted to intermediate X-2-2 via an oxidation reaction, which react with methyl-phosphorus ylide to give the intermediate X-2-3. After that, the deprotection of X-2-3 resulted in X-2-4, the intermediate X-2-4 goes through an SNAr reaction with 5-bromo-4,7-dichloro-2- (ethylthio)-8-fluoropyrido[4,3-d]pyrimidine to provide X-2-5. Finally, the intermediate X-2-5 is transformed into the target compound X-2-6 via an intramolecular cyclization reaction.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.An approach to synthesize compoundsdescribed in Scheme (X-3).In Scheme (X-3), the preparation of the starting material X-2-2 is described in Scheme (X-2). The starting material X-2-2 is converted to intermediate X-3-1 via a Wittig reaction. After that, the deprotection of X-3- 1 resulted in X-3-2, the intermediate X-3-2 goes through an SNAr reaction with 5-bromo-4,7-dichloro-2-(ethylthio)-8-fluoropyrido[4,3-d]pyrimidine to provide X-3-3. Finally, the intermediate X-3-3 is transformed into the target compound X-3-4 via an intramolecular cyclization reaction, and then these diastereoisomers is separated to yield the target compound X-3-5.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.In Scheme (X-4), the preparation of the starting material X-3-4 is described in Scheme (X-3). The diastereoisomers mixture of X-3-4 is separated to yield the tartget compound X-4-1 .Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.An approach to synthesize compoundsdescribed in Scheme (X-5).In Scheme (X-5), the preparation of the starting material X-2-2 is described in Scheme (X-2). The starting material X-2-2 is converted to intermediate X-5-1 via a hydroboration-oxidation reaction. After that, theoxidation of X-5-1 resulted in X-5-2, the intermediate X-5-2 goes through a Wittig reaction to provide X-5-3.Finally, the intermediate X-5-3 is transformed into the target compound X-5-4 via an SNAr reaction with 5-bromo- 4,7-dichloro-2-(ethylthio)-8-fluoropyrido[4,3-d]pyrimidine, and then the intermediate X-5-4 goes through a Heck coupling reaction to yield the target compound X-5-5.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.An approach to synthesize compoundsdescribed in Scheme (X-6).In Scheme (X-6), the preparation of starting material X-5-5 is described in Scheme (X-5). The starting material X-5-5 goes through a Simmons-Smith cyclopropanation reaction to yield the target compound X-6-1 .Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.The compoundscan be made by the method referred to Scheme X-1 andScheme X-6, by using different starting material, intermediates, and reagents, or by the conventional organic reactions.An approach to synthesize compoundsdescribed in Scheme (X-7).In Scheme (X-7), the preparation of the starting material X-2 is described in Scheme (X). The starting material X-2 is converted to intermediate X-7-1 via a Wittig reaction. After that, the deprotection of X-7-1 resulted in X-7-2, the intermediate X-7-2 goes through an SNAr reaction with 5-bromo-4,7-dichloro-2-(ethylthio)-8- fluoropyrido[4,3-d]pyrimidine to provide X-7-3. Finally, the intermediate X-7-3 is transformed into the target compound X-7-4 via an intramolecular cyclization reaction, and then these diastereoisomers is separated to yield the target compound X-7-5.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.In Scheme (X-8), the preparation of the starting material X-7 is described in Scheme (X-7). The diastereoisomers mixture of X-7-4 is separated to yield the tartget compound X-8-1 .Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.An approach to synthesize compounds described in Scheme (X-9).In Scheme (X-9), the preparation of the starting material X-1-2 is described in Scheme (X-1). The starting material X-1-2 is converted to intermediate X-9-1 via a hydroboration-oxidation reaction. After that, the oxidation of X-9-1 resulted in X-9-2, the intermediate X-9-2 goes through a Wittig reaction to provide X-9-3. Finally, the intermediate X-9-3 is transformed into the target compound X-9-4 via an SNAr reaction with 5-bromo- 4,7-dichloro-2-(ethylthio)-8-fluoropyrido[4,3-d]pyrimidine, and then the intermediate X-9-4 goes through a Heck coupling reaction to yield the target compound X-9-5.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.An approach to synthesize compoundsdescribed in Scheme (X-10).In Scheme (X-10), the preparation of starting material X-9-5 is described in Scheme (X-9). The starting material X-9-5 goes through a Simmons-Smith cyclopropanation reaction to yield the target compound X-10-1 .Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.The compoundscan be made by the method referred to Scheme X-7 andScheme X-10, by using different starting material, intermediates, and reagents, or by the conventional organicreactions.BocIn Scheme (X-11), the preparation of the starting material X-3 is described in Scheme (X). The starting material X-3 is oxidated to afford intermediate X-11-1, which goes through an SNAr reaction with 5-bromo-4,7- dichloro-2-(ethylthio)-8-fluoropyrido[4,3-d]pyrimidine to provide X-11-2. After that, the intermediate X-11-2 is transformed into X-11-3 via an intramolecular coupling reaction, and then the intermediate X-11-3 goes through a Wittig reaction to yield the target compound X-11-4.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.An approach to synthesize compoundsdescribed in Scheme (X-12).In Scheme (X-12), the preparation of the starting material X-11-3 is described in Scheme (X-11). The starting material X-11-3 goes through a Wittig reaction to afford intermediate X-12-1, which is deprotected under acidic conditions to provide X-12-2. After that, the intermediate X-12-2 is transformed into the target compoundX-12-3 via a nucleophilic difluorination reaction.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.An approach to synthesize compoundsdescribed in Scheme (X-13).In Scheme (X-13), the preparation of the starting material T-4-2 is described in Scheme (T-4). The starting material T-4-2 is oxidated to give intermediate X-13-1, which transfermed into X-13-2 via Wittig reaction. The intermediate X-13-2 is deprotected to give the intermediate X-13-3. After that, the intermediate X-13-3 goes through an SNAr reaction with 5-bromo-4,7-dichloro-2-(ethylthio)-8-fluoropyrido[4,3-d]pyrimidine to provide X-13- 4. Finally, the intermediate X-13-4 is transformed into the target compound X-13-5 via an intramolecular cyclization reaction.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.An approach to synthesize compoundsdescribed in Scheme (X-14).In Scheme (X-14), the preparation of the starting material X-2 is described in Scheme (X). The starting material X-2-1 is converted to intermediate X-14-1 via an oxidation reaction, which react with methyl-phosphorus ylide to give the intermediate X-14-2. After that, the deprotection of X-14-2 resulted in X-14-3, the intermediate X- 14-3 goes through an SNAr reaction with 5-bromo-4,7-dichloro-2-(ethylthio)-8-fluoropyrido[4,3-d]pyrimidine to provide X-14-4. Finally, the intermediate X-14-4 is transformed into the target compound X-14-5 via an intramolecular cyclization reaction.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.An approach to synthesize compoundsdescribed in Scheme (X-15).In Scheme (X-15), the preparation of the starting material X-14-1 is described in Scheme (X-14). The starting material X-14-1 is converted to intermediate X-15-1 via a Wittig reaction. After that, the deprotection ofX-15-1 resulted in X-15-2, the intermediate X-15-2 goes through an SNAr reaction with 5-bromo-4,7-dichloro-2- (ethylthio)-8-fluoropyrido[4,3-d]pyrimidine to provide X-15-3. Finally, the intermediate X-15-3 is transformed into the target compound X-15-4 via an intramolecular cyclization reaction, and then these diastereoisomers is separated to yield the target compound X-15-5.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.BooAn approach to synthesize compoundsdescribed in Scheme (X-16).In Scheme (X-16), the preparation of the starting material X-15-4 is described in Scheme (X-15). The diastereoisomers mixture of X-15-4 is separated to yield the tartget compound X-16-1 .Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.starting material T-3-1 is protected with a silyl group to give intermediate X-17-1 . After that, the intermediate X- 17-1 goes through an SNAr reaction with 5-bromo-4,7-dichloro-2-(ethylthio)-8-fluoropyrido[4,3-d]pyrimidine to provide X-17-2, and then the deprotection of X-17-2 can afford X-17-3. The intermediate X-17-3 is oxidated to give X-17-4. Finally, the intermediate X-17-4 is transformed into the target compound X-17-5 via a reductive amination reaction, which goes through an intramolecular cyclization reaction to yield the target compound X-17- 6.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.BocIn Scheme (X-18), the preparation of the starting material X-3 is described in Scheme (X). The starting material X-3 is protected with a silyl group to give intermediate X-18-1. After that, the intermediate X-18-1 goes through an SNAr reaction with 5-bromo-4,7-dichloro-2-(ethylthio)-8-fluoropyrido[4,3-d]pyrimidine to provide X-18-2, and then the deprotection of X-18-2 can afford X-18-3. The intermediate X-18-3 is oxidated to give X-18-4.Finally, the intermediate X-18-4 is transformed into the target compound X-18-5 via a reductive amination reaction, which goes through an intramolecular cyclization reaction to yield the target compound X-18-6.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.An approach to synthesize compoundsdescribed in Scheme (X-19).In Scheme (X-19), the preparation of the starting material X-19-1 is similar with which is described in Scheme (T-6). The starting material X-19-1 is deprotected to give the intermediate X-19-2. X-19-2 is oxidized to afford X-19-3, which react with MeMgBr or MeLi to give the intermediate X-19-4. After that, the deprotection of X- 19-4 resulted in X-19-5, the intermediate X-19-5 goes through an SNAr reaction to provide X-19-6. Finally, the intermediate X-19-6 is transformed into the target compound X-19-7 via an intramolecular cyclization.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.In Scheme (X-19-1), the preparation of the starting material T-11-1 is described in Scheme (T-11). The starting material T-11-1 is deprotected to give the intermediate X-19-1-2. X-19-1-2 is oxidized to afford X-19-1-3, which react with MeMgBr or MeLi to give the intermediate X-19-1 -4. After that, the deprotection of X-19-1 -4 resulted in X-19-1 -5, the intermediate X-19-1 -5 goes through an SNAr reaction to provide X-19-1 -6. Finally, the intermediate X-19-1-6 is transformed into the target compound X-19-1-7 via an intramolecular cyclization.Also, the target compounds can be synthesized by alternative methods but not limited to the aboveIn Scheme (X-19-2), the preparation of the starting material T-8-1 is described in Scheme (T-8). The starting material T-8-1 is deprotected to give the intermediate X-19-2-2. X-19-2-2 is oxidized to afford X-19-2-3, which react with MeMgBr or MeLi to give the intermediate X-19-2-4. After that, the deprotection of X-19-2-4 resulted in X-19-2-5, the intermediate X-19-2-5 goes through an SNAr reaction to provide X-19-2-6. Finally, the intermediate X-19-2-6 is transformed into X-19-2-7 via an intramolecular cyclization, the intermeidiate X-19-2-7 is reduced to afford the target compound X-19-2-8.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.An approach to synthesize compoundsdescribed in Scheme (X-19-3).In Scheme (X-19-3), the preparation of the starting material X-19-2-7 is described in Scheme (X-19-2).The starting material X-19-2-7 is hydrolyzed to afford the target compound X-19-3-1.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.In Scheme (X-19-4), the preparation of the starting material T-12-1 is described in Scheme (T-12). The starting material T-12-1 is deprotected to give the intermediate X-19-4-2. The intermediate X-19-4-2 is oxidized to afford X-19-4-3, which react with MeMgBr or MeLi to give the intermediate X-19-4-4. After that, the deprotection of X-19-4-4 resulted in X-19-4-5, the intermediate X-19-4-5 goes through an SNAr reaction to provide X-19-4-6. Finally, the intermediate X-19-4-6 is transformed into the target compound X-19-4-7 via an intramolecular cyclization.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.An approach to synthesize compoundsdescribed in Scheme (X-19-5).In Scheme (X-19-5), the preparation of the starting material T-11-1 is described in Scheme (T-10). The starting material T-10-1 is deprotected to give the intermediate X-19-5-2. The intermediate X-19-5-2 is oxidized to afford X-19-5-3, which react with MeMgBr or MeLi to give the intermediate X-19-5-4. After that, the deprotection of X-19-5-4 resulted in X-19-5-5, the intermediate X-19-5-5 goes through an SNAr reaction to provide X-19-5-6. Finally, the intermediate X-19-5-6 is transformed into the target compound X-19-5-7 via an intramolecular cyclization.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.In Scheme (X-19-6), the preparation of the starting material X-19-4-7 is described in Scheme (X-19-4). The starting material X-19-5-7 is converted to give the target compound X-19-6-1 via Wacker oxidation.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.In Scheme (X-19-7), the preparation of the starting material X-19-7-1 is similar with which is described in Scheme (T-12). The starting material X-19-7-1 is deprotected to give the intermediate X-19-7-2. X-19-7-2 is oxidized to afford X-19-7-3, which react with MeMgBr or MeLi to give the intermediate X-19-7-4. After that, the deprotection of X-19-7-4 resulted in X-19-7-5, the intermediate X-19-7-5 goes through an SNAr reaction to provide X-19-7-6. Finally, the intermediate X-19-7-6 is transformed into the target compound X-19-7-7 via an intramolecular cyclization.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.The compoundscan be made by the method referred to Scheme X-19 toScheme X-19-7, by using different starting material, intermediates, and reagents, or by the conventional organic reactions.BocAn approach to synthesize compoundsdescribed in Scheme (X-20).In Scheme (X-20), the preparation of the starting material X-19-5 is similar with which is described inScheme (X-19). The starting material X-19-5 is converted to the intermediate X-20-1 , which is oxidized to affordX-20-2. The intermediate X-20-2 react with Tf2<3 to give the intermediate X-20-3. After that, the intermediate X- 20-3 is transformed into X-20-4 through a Suzuki coupling reaction, which is deprotected to give X-20-5. The intermediate X-20-5 goes through an SNAr reaction to provide X-20-6. Finally, the intermediate X-20-6 is transformed into the target compound X-20-7 via an intramolecular cyclization.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures. cAn approach to synthesize compounds ofis described in Scheme (Y).In Scheme (Y), the preparation of the starting material X-1 is described in Scheme (X). The starting material X-1 is converted to intermediate Y-1 via a hydroboration-oxidation reaction. After that, the oxidation of Y-1 resulted in Y-2, the intermediate Y-2 goes through a Wittig reaction to provide Y-3. Finally, the intermediate Y-3 is transformed into Y-4 via an SNAr reaction with 5-bromo-4,7-dichloro-2-(ethy lthio)-8-fluoropy rido[4, 3-d]pyrimidine, and then the intermediate Y-4 goes through an intramolecular cyclization reaction to yield the target compound Y-5.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.In Scheme (Y-1), the preparation of the starting material X-13-2 is described in Scheme (X-13). The starting material X-13-2 is converted to intermediate Y-1 -1 via a hydroboration-oxidation reaction. After that, the oxidation of Y-1 -1 resulted in Y-1 -2, the intermediate Y-1 -2 goes through a Wittig reaction to provide Y-1 -3. Finally, the intermediate Y-1 -3 is transformed into Y-1 -4 via an SNAr reaction with 5-bromo-4,7-dichloro-2- (ethylthio)-8-fluoropyrido[4,3-d]pyrimidine, and then the intermediate Y-1 -4 goes through an intramolecular cyclization reaction to yield the target compound Y-1 -5.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures. - B cAn approach to synthesize compoundsis described in Scheme (Y-2).In Scheme (Y-2), the preparation of the starting material X-5-4 is described in Scheme (X-5). The starting material X-5-4 goes through an intramolecular cyclization reaction to yield the target compound Y-2-1 .Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.In Scheme (Y-3), the preparation of the starting material Y-1 is described in Scheme (Y). The starting material Y-1 is deprotected to give intermediate Y-3-1 . After that, the hydrogenation of Y-3-1 resulted in Y-3-2, the intermediate Y-3-2 goes through a SNAr reaction with 5-bromo-4,7-dichloro-2-(ethylthio)-8-fluoropyrido[4,3- d] pyrimidine to provide Y-3-3. Finally, the intermediate Y-3-3 is transformed into Y-3-4 via deprotection reaction, and then the intermediate Y-3-4 goes through an intramolecular cyclization reaction to yield the target compound Y-3-5.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.An approach to synthesize compoundsdescribed in Scheme (Y-4).In Scheme (Y-4), the preparation of the starting material Y-3-4 is described in Scheme (Y-3). The starting material Y-3-4 is oxidated to give intermediate Y-4-1. After that, the intermediate Y-4-1 goes through a reductive amination reaction to provide Y-4-2. Finally, the intermediate Y-4-2 goes through an intramolecular cyclization reaction to yield the target compound Y-4-3.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.In Scheme (Z), the starting material Z-1 is commercially available. The starting material Z-1 is reduced to intermediate Z-2, the condensation of Z-2 with chloral and then heating with hydroxylamine hydrochloride to give Z-3. After that, the intramolecular cyclization of Z-3 under acidic condition resulted in Z-4, the intermediate Z-4 goes through a hydrolysis decarboxylation reaction to provide Z-5. The intermediate Z-5 react with amino to give Z-6, which is converted to Z-7 via an intramolecular cyclization reaction. Next, the intermediate Z-7 is transformed into Z-8 via an SNAr reaction. Finally, the intermediate Z-8 is transformed into Z-9 via an intramolecular cyclization reaction, and then the intermediate Z-9 react with EtSH to yield the target compound Z-10.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.In Scheme (Z-1 ), the starting material Z-1-1 is commercially available. The starting material Z-1-1 is reduced to intermediate Z-1 -2, the condensation of Z-1 -2 with chloral and then heating with hydroxylamine hydrochloride to give Z-1 -3. After that, the intramolecular cyclization of Z-1 -3 under acidic condition resulted in Z- 1-4, the intermediate Z-1 -4 goes through a hydrolysis decarboxylation reaction to provide Z-1 -5. The intermediate Z-1 -5 react with amino to give Z-1 -6, which is converted to Z-1 -7 via an intramolecular cyclization reaction. Next, the intermediate Z-1 -7 is transformed into Z-1-8 via an SNAr reaction. Finally, the intermediate Z- 1-8 is transformed into Z-1 -9 via an intramolecular cyclization reaction, and then the intermediate Z-1 -9 react with EtSH to yield the target compound Z-1 -10.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.BocThe compoundscan be made by the method referred to Scheme X toScheme Y-4, by using different starting material, intermediates, and reagents, or by the conventional organic reactions.BocThe compoundscan be made by the method referred to Scheme X toScheme Y-4, by using different starting material, intermediates, and reagents, or by the conventional organic reactions.BocThe compoundscan be made by the method referred to Scheme X toScheme Y-4, by using different starting material, intermediates, and reagents, or by the conventional organic reactions.BocAn approach to synthesize compoundsdescribed in SchemeIn Scheme (AA-1), the preparation of the starting material X-19-7 is described in Scheme (X-19). The starting material X-19-7 is oxidized to afford AA-1-1, which goes through an SNAr reaction to provide AA-1 -2. Finally, the intermediate AA-1 -2 is transformed into the target compound AA-1 -3 via Suzuki coupling reaction.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.BocAn approach to synthesize compoundsdescribed in Scheme(AA-2).In Scheme (AA-2), the preparation of the starting material X-19-1 -7 is described in Scheme (X-19-1).The starting material X-19-1-7 is oxidized to afford AA-2-1, which goes through an SNAr reaction to provide AA- 2-2. Finally, the intermediate AA-2-2 is transformed into the target compound AA-2-3 via Suzuki coupling reaction.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.An approach to synthesize compoundsdescribed in Scheme(AA-3).In Scheme (AA-3), the preparation of the starting material X-19-2-7 is described in Scheme (X-19-2).The starting material X-19-2-7 is oxidized to afford AA-3-1, which goes through an SNAr reaction to provide AA- 3-2. Finally, the intermediate AA-3-2 is transformed into the target compound AA-3-3 via Suzuki coupling reaction.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.An approach to synthesize compoundsdescribed in Scheme(AA-4).In Scheme (AA-4), the preparation of the starting material AA-3-3 is described in Scheme (AA-3). The starting material AA-3-3 is reduced to give the target compound AA-4-1 .Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.BocAn approach to synthesize compoundsdescribed in SchemeIn Scheme (AA-5), the preparation of the starting material AA-4-1 is described in Scheme (AA-4). The starting material AA-4-1 is converted to the target compound AA-4-1 via Wittig reaction.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.BocAn approach to synthesize compoundswherein X is Br or I is described in Scheme (AA-6).In Scheme (AA-6), the preparation of the starting material AA-4-1 is described in Scheme (AA-4). The starting material AA-4-1 is converted to the target compound AA-6-1 via Takai-Utimoto olefination.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.An approach to synthesize compoundsdescribed inScheme (AA-7).In Scheme (AA-7), the preparation of the starting material AA-6-1 is described in Scheme (AA-6). The starting material AA-6-1 is converted to the target compound AA-7-1 via Hosomi-Miyaura borylation.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.BocAn approach to synthesize compoundsdescribed in Scheme(AA-8).In Scheme (AA-8), the preparation of the starting material AA-4-1 is described in Scheme (AA-4). The starting material AA-4-1 reacts with Bestmann-Ohira Reagent to provide the target compound AA-8-1 .Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.BocThe compoundscan be made by the method referred to SchemeAA-1 to Scheme AA-8, by using different starting material, intermediates, and reagents, or by the conventional organic reactions.BocThe compoundscan be made by the method referred to Scheme AA-1 to Scheme AA-8, by using different starting material, intermediates, and reagents, or by the conventional organic reactions.BocThe compoundscan be made by the method referred to SchemeAA-1 to Scheme AA-8, by using different starting material, intermediates, and reagents, or by the conventional organic reactions.can be made by the method referred to SchemeAA-1 to Scheme AA-8, by using different starting material, intermediates, and reagents, or by the conventional organic reactions.can be made by the method referred to SchemeAA-1 to Scheme AA-8, by using different starting material, intermediates, and reagents, or by the conventional organic reactions.An approach to synthesize compoundsdescribed in Scheme (1).In Scheme (1), the preparation of the starting material X-5 is described in Scheme (X). The startingmaterial X-5 is converted to intermediate 1-1 via a SNAr reaction. After that, the intermediate 1-1 is converted to 1-2 through Suzuki coupling reaction. Finally, the intermediate 1-2 is deprotected to give 1-3, and the condensation of 1-3 with suitable acryloyl chloride analogues to yield the target compounds 1-4.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.An approach to synthesize compoundsdescribed in Scheme (2).In Scheme (2), the preparation of the starting material X-1-4 is described in Scheme (X-1). The starting material X-1-4 is converted to intermediate 2-1 via an oxidation reaction. After that, the intermediate 2-1 goes through an SNAr reaction to provide 2-2. The intermediate 2-2 is transformed into 2-3 through a Suzuki coupling reaction. Finally, the intermediate 2-3 is deprotected to give the target compound 2-4, and the condensation of 2- 4 with suitable acryloyl chloride analogues to yield the target compounds 2-5.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.An approach to synthesize compoundsIn Scheme (3), the preparation of the starting material X-2-6 is described in Scheme (X-2). The starting material X-2-6 is converted to intermediate 3-1 via an oxidation reaction. After that, the intermediate 3-1 goes through an SNAr reaction to provide 3-2. The intermediate 3-2 is transformed into 3-3 through a Suzuki coupling reaction. Finally, the intermediate 3-3 is deprotected to give the target compound 3-4, and the condensation of 3- 4 with suitable acryloyl chloride analogues to yield the target compounds 3-5.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.An approach to synthesize compoundsdescribed in Scheme (4).In Scheme (4), the preparation of the starting material X-3-5 is described in Scheme (X-3). The starting material X-3-5 is converted to intermediate 4-1 via an oxidation reaction. After that, the intermediate 4-1 goes through an SNAr reaction to provide 4-2. The intermediate 4-2 is transformed into 4-3 through a Suzuki coupling reaction. Finally, the intermediate 4-3 is deprotected to give the target compound 4-4, and the condensation of 4- 4 with suitable acryloyl chloride analogues to yield the target compounds 4-5.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.An approach to synthesize compoundsdescribed in Scheme (5).In Scheme (5), the preparation of the starting material X-4-1 is described in Scheme (X-4). The starting material X-4-1 is converted to intermediate 5-1 via an oxidation reaction. After that, the intermediate 5-1 goes through an SNAr reaction to provide 5-2. The intermediate 5-2 is transformed into 5-3 through a Suzuki coupling reaction. Finally, the intermediate 5-3 is deprotected to give the target compound 5-4, and the condensation of 5- 4 with suitable acryloyl chloride analogues to yield the target compounds 5-5.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.An approach to synthesize compoundsdescribed in Scheme (6).In Scheme (6), the preparation of the starting material X-5-5 is described in Scheme (X-5). The starting material X-5-5 is converted to intermediate 6-1 via an oxidation reaction. After that, the intermediate 6-1 goes through an SNAr reaction to provide 6-2. The intermediate 6-2 is transformed into 6-3 through a Suzuki coupling reaction. Finally, the intermediate 6-3 is deprotected to give the target compound 6-4, and the condensation of 6- 4 with suitable acryloyl chloride analogues to yield the target compounds 6-5.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.An approach to synthesize compoundsdescribed in Scheme (7).In Scheme (7), the preparation of the starting material X-6-1 is described in Scheme (X-6). The starting material X-6-1 is converted to intermediate 7-1 via an oxidation reaction. After that, the intermediate 7-1 goes through an SNAr reaction to provide 7-2. The intermediate 7-2 is transformed into 7-3 through a Suzuki coupling reaction. Finally, the intermediate 7-3 is deprotected to give the target compound 7-4, and the condensation of 7- 4 with suitable acryloyl chloride analogues to yield the target compounds 7-5.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.can be made by the method referred to Scheme 1-7, by using different starting material, intermediates, and reagents, or by the conventional organic reactions.An approach to synthesize compoundsdescribed in Scheme (8).In Scheme (8), the preparation of the starting material X-7-5 is described in Scheme (X-7). The starting material X-7-5 is converted to intermediate 8-1 via an oxidation reaction. After that, the intermediate 8-1 goes through an SNAr reaction to provide 8-2. The intermediate 8-2 is transformed into 8-3 through a Suzuki coupling reaction. Finally, the intermediate 8-3 is deprotected to give the target compound 8-4, and the condensation of 8- 4 with suitable acryloyl chloride analogues to yield the target compounds 8-5.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.An approach to synthesize compoundsdescribed in Scheme (9).In Scheme (9), the preparation of the starting material X-8-1 is described in Scheme (X-8). The starting material X-8-1 is converted to intermediate 9-1 via an oxidation reaction. After that, the intermediate 9-1 goes through an SNAr reaction to provide 9-2. The intermediate 9-2 is transformed into 9-3 through a Suzuki coupling reaction. Finally, the intermediate 9-3 is deprotected to give the target compound 9-4, and the condensation of 9- 4 with suitable acryloyl chloride analogues to yield the target compounds 9-5.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.An approach to synthesize compoundsdescribed in Scheme (10).In Scheme (10), the preparation of the starting material X-9-5 is described in Scheme (X-9). The starting material X-9-5 is converted to intermediate 10-1 via an oxidation reaction. After that, the intermediate 10- 1 goes through an SNAr reaction to provide 10-2. The intermediate 10-2 is transformed into 10-3 through a Suzuki coupling reaction. Finally, the intermediate 10-3 is deprotected to give the target compound 10-4, and the condensation of 10-4 with suitable acryloyl chloride analogues to yield the target compounds 10-5.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.An approach to synthesize compoundsdescribed in Scheme (11).In Scheme (11), the preparation of the starting material X-10-1 is described in Scheme (X-10). The starting material X-10-1 is converted to intermediate 11-1 via an oxidation reaction. After that, the intermediate11-1 goes through an SNAr reaction to provide 11-2. The intermediate 11-2 is transformed into 11-3 through aSuzuki coupling reaction. Finally, the intermediate 11-3 is deprotected to give the target compound 11-4, and the condensation of 11 -4 with suitable acryloyl chloride analogues to yield the target compounds 11 -5.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.can be made by the method referred to Scheme 8-11, by using different starting material, intermediates, and reagents, or by the conventional organic reactions.An approach to synthesize compoundsdescribed in Scheme (12).In Scheme (12), the preparation of the starting material X-11-4 is described in Scheme (X-11). The starting material X-11-4 is converted to intermediate 12-1 via an oxidation reaction. After that, the intermediate 12-1 goes through an SNAr reaction to provide 12-2. The intermediate 12-2 is transformed into 12-3 through a Suzuki coupling reaction. Finally, the intermediate 12-3 is deprotected to give the target compound 12-4, and the condensation of 12-4 with suitable acryloyl chloride analogues to yield the target compounds 12-5.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.An approach to synthesize compoundsdescribed in Scheme (13).In Scheme (13), the preparation of the starting material X-12-3 is described in Scheme (X-12). The starting material X-12-3 is converted to intermediate 13-1 via an oxidation reaction. After that, the intermediate 13-1 goes through an SNAr reaction to provide 13-2. The intermediate 13-2 is transformed into 13-3 through a Suzuki coupling reaction. Finally, the intermediate 13-3 is deprotected to give the target compound 13-4, and the condensation of 13-4 with suitable acryloyl chloride analogues to yield the target compounds 13-5.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.An approach to synthesize compoundsdescribed in Scheme (14).In Scheme (14), the preparation of the starting material X-13-5 is described in Scheme (X-13). The starting material X-13-5 is converted to intermediate 14-1 via an oxidation reaction. After that, the intermediate14-1 goes through an SNAr reaction to provide 14-2. The intermediate 14-2 is transformed into 14-3 through aSuzuki coupling reaction. Finally, the intermediate 14-3 is deprotected to give the target compound 14-4, and the condensation of 14-4 with suitable acryloyl chloride analogues to yield the target compounds 14-5.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.An approach to synthesize compoundsIn Scheme (15), the preparation of the starting material X-14-5 is described in Scheme (X-14). The starting material X-14-5 is converted to intermediate 15-1 via an oxidation reaction. After that, the intermediate 15-1 goes through an SNAr reaction to provide 15-2. The intermediate 15-2 is transformed into 15-3 through a Suzuki coupling reaction. Finally, the intermediate 15-3 is deprotected to give the target compound 15-4, and the condensation of 15-4 with suitable acryloyl chloride analogues to yield the target compounds 15-5.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.An approach to synthesize compoundsdescribed in Scheme (16).In Scheme (16), the preparation of the starting material X-16-1 is described in Scheme (X-16). The starting material X-16-1 is converted to intermediate 16-1 via an oxidation reaction. After that, the intermediate 16-1 goes through an SNAr reaction to provide 16-2. The intermediate 16-2 is transformed into 16-3 through a Suzuki coupling reaction. Finally, the intermediate 16-3 is deprotected to give the target compound 16-4, and the condensation of 16-4 with suitable acryloyl chloride analogues to yield the target compounds 16-5.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.An approach to synthesize compoundsdescribed in Scheme (17).In Scheme (17), the preparation of the starting material X-15-5 is described in Scheme (X-15). The starting material X-15-5 is converted to intermediate 17-1 via an oxidation reaction. After that, the intermediate 17-1 goes through an SNAr reaction to provide 17-2. The intermediate 17-2 is transformed into 17-3 through a Suzuki coupling reaction. Finally, the intermediate 17-3 is deprotected to give the target compound 17-4, and the condensation of 17-4 with suitable acryloyl chloride analogues to yield the target compounds 17-5.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.An approach to synthesize compoundsdescribed in Scheme (18).In Scheme (18), the preparation of the starting material X-17-6 is described in Scheme (X-17). The starting material X-17-6 is converted to intermediate 18-1 via an oxidation reaction. After that, the intermediate18-1 goes through an SNAr reaction to provide 18-2. The intermediate 18-2 is transformed into 18-3 through aSuzuki coupling reaction. Finally, the intermediate 18-3 is deprotected to give the target compound 18-4, and the condensation of 18-4 with suitable acryloyl chloride analogues to yield the target compounds 18-5.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.An approach to synthesize compoundsdescribed in Scheme (19).In Scheme (19), the preparation of the starting material X-18-6 is described in Scheme (X-18). The starting material X-18-6 is converted to intermediate 19-1 via an oxidation reaction. After that, the intermediate 19-1 goes through an SNAr reaction to provide 19-2. The intermediate 19-2 is transformed into 19-3 through a Suzuki coupling reaction. Finally, the intermediate 19-3 is deprotected to give the target compound 19-4, and the condensation of 19-4 with suitable acryloyl chloride analogues to yield the target compounds 19-5.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.An approach to synthesize compoundsdescribed in Scheme (20).In Scheme (20), the preparation of the starting material Y-5 is described in Scheme (Y). The starting material Y-5 is converted to intermediate 20-1 via an oxidation reaction. After that, the intermediate 20-1 goes through an SNAr reaction to provide 20-2. The intermediate 20-2 is transformed into 20-3 through a Suzuki coupling reaction. Finally, the intermediate 20-3 is deprotected to give the target compound 20-4, and the condensation of 20-4 with suitable acryloyl chloride analogues to yield the target compounds 20-5.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.An approach to synthesize compoundsdescribed in Scheme (21).In Scheme (21), the preparation of the starting material Y-2-1 is described in Scheme (Y-2). The starting material Y-2-1 is converted to intermediate 21-1 via an oxidation reaction. After that, the intermediate 21- 1 goes through an SNAr reaction to provide 21-2. The intermediate 21-2 is transformed into 21-3 through a Suzuki coupling reaction. Finally, the intermediate 21-3 is deprotected to give the target compound 21-4, and the condensation of 21-4 with suitable acryloyl chloride analogues to yield the target compounds 21-5.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.An approach to synthesize compoundsdescribed in Scheme (22).In Scheme (22), the preparation of the starting material Y-3-5 is described in Scheme (Y-3). The starting material Y-3-5 is converted to intermediate 22-1 via an oxidation reaction. After that, the intermediate 22- 1 goes through an SNAr reaction to provide 22-2. The intermediate 22-2 is transformed into 22-3 through a Suzuki coupling reaction. Finally, the intermediate 22-3 is deprotected to give the target compound 22-4, and the condensation of 22-4 with suitable acryloyl chloride analogues to yield the target compounds 22-5.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.An approach to synthesize compoundsdescribed in Scheme (23).In Scheme (23), the preparation of the starting material Y-4-3 is described in Scheme (Y-4). The starting material Y-4-3 is converted to intermediate 23-1 via an oxidation reaction. After that, the intermediate 23- 1 goes through an SNAr reaction to provide 23-2. The intermediate 23-2 is transformed into 23-3 through a Suzuki coupling reaction. Finally, the intermediate 23-3 is deprotected to give the target compound 23-4, and the condensation of 23-4 with suitable acryloyl chloride analogues to yield the target compounds 23-5.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.In Scheme (24), the preparation of the starting material Y-1-5 is described in Scheme (Y-1). The- I l l -starting material Y-1-5 is converted to intermediate 24-1 via an oxidation reaction. After that, the intermediate 24- 1 goes through an SNAr reaction to provide 24-2. The intermediate 24-2 is transformed into 24-3 through a Suzuki coupling reaction. Finally, the intermediate 24-3 is deprotected to give 24-4, and the condensation of 24-4 with suitable acryloyl chloride analogues to yield the target compounds 24-5.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.In Scheme (25), the preparation of the starting material X-19-7 is described in Scheme (X-19). The starting material X-19-7 is converted to intermediate 25-1 via an oxidation reaction. After that, the intermediate 25-1 goes through an SNAr reaction to provide 25-2. The intermediate 25-2 is transformed into 25-3 through a Suzuki coupling reaction. Finally, the intermediate 25-3 is deprotected to give 25-4, and the condensation of 25-4 with suitable acryloyl chloride analogues to yield the target compounds 25-5.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.In Scheme (26), the preparation of the starting material X-19-1-7 is described in Scheme (X-19-1). The starting material X-19-1-7 is converted to intermediate 26-1 via an oxidation reaction. After that, the intermediate 26-1 goes through an SNAr reaction to provide 26-2. The intermediate 26-2 is transformed into 26-3 through a Suzuki coupling reaction. Finally, the intermediate 26-3 is deprotected to give 26-4, and the condensation of 26-4 with suitable acryloyl chloride analogues to yield the target compounds 26-5.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.An approach to synthesize compoundsdescribed in Scheme (27).In Scheme (27), the preparation of the starting material X-19-2-7 is described in Scheme (X-19-2). The starting material X-19-2-7 is converted to intermediate 27-1 via an oxidation reaction. After that, the intermediate 27-1 goes through an SNAr reaction to provide 27-2. The intermediate 27-2 is transformed into 27-3 through a Suzuki coupling reaction. Next, the intermediate 27-3 is reduced to provide 27-4, which is converted to 27-5 via Wittig reaction. Finally, the intermediate 27-5 is deprotected to give 27-6, and the condensation of 27-6 with suitable acryloyl chloride analogues to yield the target compounds 27-7.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.In Scheme (29), the preparation of the starting material 27-4 is described in Scheme (27). The starting material 27-4 reacts with Ohira-Bestmann reagent to give intermediate 29-1. Finally, the intermediate 29-1 is deprotected to give 29-2, and the condensation of 29-2 with suitable acryloyl chloride analogues to yield thetarget compounds 29-3.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.In Scheme (31), the preparation of the starting material 27-3 is described in Scheme (27). The starting material 27-3 is converted to intermediate 31-1 via condensation reaction. Finally, the intermediate 31-1 is deprotected to give 31-2, and the condensation of 31-2 with suitable acryloyl chloride analogues to yield the target compounds 31-3.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.In Scheme (32), the preparation of the starting material 31-2 is described in Scheme (31). The starting material 31-2 is reduced to give intermediate 32-1 and the condensation of 32-1 with suitable acryloyl chloride analogues to yield the target compounds 32-2.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.In Scheme (33), the preparation of the starting material X-0-2 is described in Scheme (X-0). The starting material X-0-2 is converted to intermediate 33-1 via an oxidation reaction. After that, the intermediate 33- 1 goes through an SNAr reaction to provide 33-2. The intermediate 33-2 is transformed into 33-3 through a Suzuki coupling reaction. Finally, the intermediate 33-3 is deprotected to give 33-4, and the condensation of 33-4 with suitable acryloyl chloride analogues to yield the target compounds 33-5.Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.Similarly, the compoundscan be made by the method referred toScheme 25-33, by using different starting material, intermediates, and reagents, or by the conventional organic reactions.Similarly, the compoundscan be made by the method referred toScheme 25-33, by using different starting material, intermediates, and reagents, or by the conventional organic reactions.Similarly, the compoundscan be made by the method referred toScheme 1-33, by using different starting material, intermediates, and reagents, or by the conventional organic reactions.Similarly, the compoundscan be made by the method referred toScheme 1-33, by using different starting material, intermediates, and reagents, or by the conventional organic reactions.Similarly, the compoundsScheme 1-33, by using different starting material, intermediates, and reagents, or by the conventional organic reactions.Similarly, the compoundscan be made by the method referred toScheme 1-33, by using different starting material, intermediates, and reagents, or by the conventional organic reactions.Similarly, the compoundscan be made by the method referred toScheme 1-33, by using different starting material, intermediates, and reagents, or by the conventional organic reactions.Similarly, the compoundscan be made by the method referred toScheme 1-33, by using different starting material, intermediates, and reagents, or by the conventional organic reactions.referred to Scheme 1-33, by using different starting material, intermediates, and reagents, or by the conventional organic reactions.referred to Scheme 1-33, by using different starting material, intermediates, and reagents, or by the conventional organic reactions.Similarly, the compoundscan be made by the method referred to Scheme 1-33, by using different starting material, intermediates, and reagents, or by the conventional organic reactions.The compounds and processes of the present invention will be better understood in connection with the following examples, which are intended as an illustration only and not limiting of the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art and such changes and modifications including, without limitation, those relating to the chemical structures, substituents, derivatives, formulations and / or methods of the invention may be made without departing from the spirit of the invention and the scope of the appended claims.Where NMR data are presented,1H spectra were obtained on XL400 (400 MHz) and are reported as ppm down field from Me4Si with number of protons, multiplicities, and coupling constants in Hertz indicated parenthetically. Where HPLC data are presented, analyses were performed using an Agilent 1100 system. Where LC / MS data are presented, analyses were performed using an Applied Biosystems API-100 massspectrometer and Shimadzu SCL-10A LC column:Example INT_A-1 : Preparation of {2-[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)naphthalen-1-yl]ethynyl}triisopropylsilaneSynthesis of 7-fluoro-8-[2-(triisopropylsilyl)ethynyl]naphthalene-1 ,3-diol: Into a 250 mL round-bottom flask, were placed 7-fluoronaphthalene-1 ,3-diol (5.0 g, 28.1 mmol, 1.0 eq), (2-bromoethynyl)triisopropylsilane (8.8 g, 33.7 mmol, 1 .2 eq), dioxane (60 mL), AcOK (5.5 g, 56.1 mmol, 2.0 eq) and [Ru(p-Cymene)Cl2]2 (1 .7 g, 2.8 mmol, 0.1 eq). The resulting mixture was stirred for 12 hours at 110°C under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The crude residue was applied onto a silica gel column and eluted with ethyl acetate / petroleum ether=4: 1 to give 7-fluoro-8-[2-(triisopropylsilyl)ethynyl]naphthalene-1 ,3-diol as a light yellow solid (7.0 g, 69.6%). LC-MS (ES, m / z) M-1 : 357.1HNMR (400 MHz, DMSO-d6) 5 10.04 (s, 1 H), 9.58 (s, 1 H), 7.63 (dd, J=9.1 , 5.7 Hz, 1 H), 7.25 (t, >9.0 Hz, 1 H), 6.62 (dd, >18.3, 2.4 Hz, 2H), 1.17-1.13 (m, 21 H).Synthesis of 7-fluoro-3-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphthalen-1 -ol: Into a 250 mL round bottom flask, were placed 7-fluoro-8-[2-(triisopropylsilyl)ethynyl]naphthalene-1 ,3-diol (7.0 g, 19.5 mmol, 1.0 eq), DIEA (7.6 g, 58.6 mmol, 3.0 eq) and CH2CI2 (100 mL). To the above mixture was added bromo(methoxy)methane (3.7 g, 29.3 mmol, 1.5 eq) dropwise at -40°C under N2 atmosphere. The reaction mixture was stirred at -40°C for 30 min. The reaction mixture was then quenched by the addition of water (20 mL). The resulting mixture was extracted with CH2CI2 (2x200 mL). The combined organic extracts were washed with brine (500 mL), dried over anhydrous Na2SC>4, and concentrated under vacuum. The crude residue was applied onto a silica gel column and eluted with ethyl acetate / petroleum ether=1 :3 to give 7-fluoro-3- (methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphthalen-1-ol as a light yellow solid (4.0 g, 50.9%). LC-MS (ES, m / z) M+1 : 403.Synthesis of 7-fluoro-3-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphthalen-1-yl trifluoromethanesulfonate: Into a 250 mL round bottom flask, were placed 7-fluoro-3-(methoxymethoxy)-8-[2- (triisopropylsilyl)ethynyl]naphthalen-1 -ol (4.0 g, 9.9 mmol, 1.0 eq), DIEA (3.9 g, 29.8 mmol, 3.0 eq) and CH2CI2 (60 mL). To the above mixture was added Tf20 (4.2 g, 14.9 mmol, 1.5 eq) dropwise at -40°C under nitrogen atmosphere. The resulting mixture was stirred for 1 hour at -40°C under nitrogen atmosphere. The reaction was quenched by the addition of water (10 mL) at -40°C, and then extracted with CH2CI2 (2x100 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The crude residue was applied onto a silica gel column and eluted with ethyl acetate / petroleum ether=1 :5 to give 7-fluoro-3-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphthalen-1 -yl trifluoromethanesulfonate as a light yellow solid (5.0 g, 94.1%).1HNMR (400 MHz, Chloroform-d) 5 7.72 (dd, >9.1, 5.4 Hz, 1 H), 7.44 (d, >2.4 Hz, 1 H), 7.40-7.29 (m, 2H), 5.30 (s, 2H), 3.54 (s, 3H), 1.31-1.23 (m, 3H), 1.20- 1.18 (m, 18H).Synthesis of {2-[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1 , 3, 2-dioxaborol an-2- yl)naphthalen-1-yl]ethynyl}triisopropylsilane: Into a 250 mL round-bottom flask, were placed 7-fluoro-3-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphthalen-1 -yl trifluoromethanesulfonate (5.0 g, 9.4 mmol, 1.0 eq), bis(pinacolato)diboron (3.6 g, 14.0 mmol, 1.5 eq), Toluene (100 mL), Pd(dppf)Cl2 (760 mg, 0.9 mmol, 0.1 eq) and KOAc (3.2 g, 32.7 mmol, 3.5 eq) at 25°C. The resulting mixture was stirred for 16 hours at 100°C under nitrogen atmosphere. The reaction mixture was quenched by the addition of water (100 mL), and then extracted with EtOAc (2x100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under vacuum. The crude residue was applied onto a silica gel column and eluted with ethyl acetate / petroleum ether=1 :20 to give {2-[2-fluoro-6-(methoxymethoxy)-8- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl]ethynyl}triisopropylsilane as a yellow solid (2.0 g, 41.7%). LC-MS (ES, m / z) M+1: 513.1HNMR (400 MHz, Chloroform-d) 5 7.68 (dd, >9.0, 5.6 Hz, 1 H), 7.52 (d, >2.6 Hz, 1 H), 7.39 (d, >2.6 Hz, 1 H), 7.24 (t, >8.8 Hz, 1 H), 5.29 (s, 2H), 3.52 (s, 3H), 1.45 (s, 12H), 1.29 (s, 3H), 1.19-1.17 (m, 18H).Example INT_A-2: Preparation of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5- ((triisopropylsilyl)ethynyl)naphthalen-2-amineSynthesis of 8-((triisopropylsilyl)ethynyl)naphthalene-1 ,3-diol: Into a 250 mL round-bottom flask, were placed naphthalene-1 ,3-diol (4.5 g, 28.1 mmol, 1.0 eq), (2-bromoethynyl)triisopropylsilane (8.8 g, 33.7 mmol, 1.2 eq), dioxane (60 mL), AcOK (5.5 g, 56.1 mmol, 2.0 eq) and [Ru(p-Cymene)Cl2]2 (1.7 g, 2.8 mmol, 0.1 eq). The resulting mixture was stirred for 12 hours at 110°C under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The crude residue was applied onto a silica gel column and eluted with ethyl acetate / petroleum ether=4: 1 to give 8-((triisopropylsilyl)ethynyl)naphthalene-1 ,3-diol as a light yellow solid (6.6 g, 69.6%).1HNMR (400 MHz, DMSO-d6) 5 9.95 (s, 1 H), 9.60 (s, 1 H), 7.57 (dd, >8.2, 1.4 Hz, 1 H), 7.33 (dd, >7.1 , 1.4 Hz, 1 H), 7.25 (dd, >8.1, 7.1 Hz, 1 H), 6.60 (d, >2.3 Hz, 1 H), 6.54 (d, >2.3 Hz, 1 H), 1.13 (s, 21 H).Synthesis of 8-((triisopropylsilyl)ethynyl)naphthalene-1 ,3-diyl bis(trifluoromethanesulfonate): Into a 250 mL round bottom flask, were placed 8-((triisopropylsilyl)ethynyl)naphthalene-1 ,3-diol (11.5 g, 33.5 mmol, 1.0 eq), DIEA (25.9 g, 200.8 mmol, 6.0 eq) and CH2CI2 (150 mL). To the above mixture was added triflic anhydride (37.8 g, 133.9 mmol, 4.0 eq) dropwise at 0°C. The reaction mixture was stirred at 25°C for 4 hours. The reaction mixture was then quenched by the addition of water (100 mL), and then extracted with CH2CI2 (2x200 mL). The combined organic extracts were washed with brine (200 mL), dried over anhydrous Na2SC>4, and concentrated under vacuum. The crude residue was applied onto a silica gel column and eluted with ethyl acetate / petroleum ether=1 :10 to give 8-((triisopropylsilyl)ethynyl)naphthalene-1 ,3-diyl bis(trifluoromethanesulfonate) as a light yellow solid (10.0 g, 48.0%).1HNMR (400 MHz, DMSO-» 5 8.51 (d, >2.5 Hz, 1 H), 8.29 (dd, >8.5, 1.2 Hz, 1 H), 8.08-7.98 (m, 2H), 7.80 (dd, >8.3, 7.3 Hz, 1 H), 1.19-1.09 (m, 21 H).Synthesis of 3-((diphenylmethylene)amino)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate: Into a 250 mL round bottom flask, were placed 8- ((triisopropylsilyl)ethynyl)naphthalene-1,3-diyl bis(trifluoromethanesulfonate) (10.0 g, 16.1 mmol, 1.0 eq), diphenylmethanimine (5.8 g, 32.1 mmol, 2.0 eq), Pd2(dba)3 (1 .5 g, 1 .6 mmol, 0.1 eq), XantPhos (1.9 g, 3.2 mmol, 0.2 eq), CS2CO3 (15.7 g, 48.2 mmol, 3.0 eq) and toluene (100 mL) under nitrogen atmosphere. The resultingmixture was stirred for 14 hours at 100°C under nitrogen atmosphere. The resulting mixture was diluted with H2O (200 mL). The resulting mixture was extracted with CH2CI2 (200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The crude residue was applied onto a silica gel column and eluted with ethyl acetate / petroleum ether=1 :10 to give 3-((diphenylmethylene)amino)-8-((triisopropylsilyl)ethynyl)naphthalen-1 -yl trifluoromethanesulfonate as a light brown solid (8.0 g, 76.2%).Synthesis of 1 ,1-diphenyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)methanimine: Into a 100 mL round bottom flask, were placed 3- ((diphenylmethylene)amino)-8-((triisopropylsilyl)ethynyl)naphthalen-1 -yl trifluoromethanesulfonate (6.0 g, 9.2 mmol, 1.0 eq), 4,4,5-trimethyl-2-(4,4,5-trimethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,3,2-dioxaborolane (4.2 g, 18.2 mmol, 2.0 eq), KOAc (2.8 g, 27.4 mmol, 3.0 eq), Pd(dppf)Cl2-CH2Cl2 (0.8 g, 1.0 mmol, 0.1 eq) and toluene (60 mL) under nitrogen atmosphere. The resulting mixture was stirred for 18 hours at 110°C under nitrogen atmosphere. The resulting mixture was diluted with H2O (100 mL), and then extracted with CH2CI2 (200 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The crude residue was applied onto a silica gel column and eluted with ethyl acetate / petroleum ether=1 : 10 to give 1 ,1-diphenyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5- ((triisopropylsilyl)ethynyl)naphthalen-2-yl)methanimine as a white solid (3.0 g, 51.7 %) .Synthesis of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2- amine: Into an 8 mL vial, were placed 1 , 1 -diphenyl-N-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-5- ((triisopropylsilyl)ethynyl)naphthalen-2-yl)methanimine (2.1 g, 3.5 mmol, 1.0 eq) and HCI (gas) in EA (1 M, 20 mL). The reaction mixture was stirred at 25°C for 4 hours. The precipitated solids were collected by filtration and washed with Et2<3 (10 mL). Finally, 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-5- ((tri isopropy Isi ly l)ethy ny l)naphthalen-2-ami ne was obtained as a white solid (1 .0 g, 67.6%).1HNMR (300 MHz, Chloroform-d) 5 8.15 (d, 2.1 Hz, 1 H), 7.97-7.78 (m, 3H), 7.48 (t, >7.8 Hz, 1 H), 1.44 (s, 11 H), 1.17 (s, 22H).Example INT_A-3: Preparation of 6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-[2- (triisopropylsilyl)ethynyl]naphthalen-2-amineSynthesis of 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1 ,3-diol: Into a 250 mL round-bottom flask, were placed 7-fluoronaphthalene-1 ,3-diol (5.0 g, 28.1 mmol, 1.0 eq), (2-bromoethynyl)triisopropylsilane (8.8 g, 33.7 mmol, 1 .2 eq), dioxane (60 mL), AcOK (5.5 g, 56.1 mmol, 2.0 eq) and [Ru(p-Cymene)Cl2]2 (1 .7 g, 2.8 mmol, 0.1 eq). The resulting mixture was stirred for 12 hours at 110°C under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The crude residue was applied onto a silica gel column and eluted with ethyl acetate / petroleum ether=4: 1 to give 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1 ,3-diol as a light yellow solid (7.0 g, 69.6%). LC-MS (ES, m / z) M-1 : 357.1HNMR (400 MHz, DMSO-d6) 5 10.04 (s, 1 H), 9.58 (s, 1 H), 7.63 (dd, >9.1, 5.7 Hz, 1 H), 7.25 (t, >9.0 Hz, 1 H), 6.62 (dd, >18.3, 2.4 Hz, 2H), 1.17-1.13 (m, 21 H).Synthesis of 7-fluoro-3-(trifluoromethanesulfonyloxy)-8-[2-(triisopropylsilyl)ethynyl]naphthalen-1-yl trifluoromethanesulfonate: Into a 250 mL round bottom flask, were placed 7-fluoro-8-[2- (triisopropylsilyl)ethynyl]naphthalene-1 ,3-diol (12.0 g, 33.5 mmol, 1.0 eq), DIEA (25.9 g, 200.8 mmol, 6.0 eq) and CH2CI2 (150 mL). To the above mixture was added triflic anhydride (37.8 g, 133.9 mmol, 4.0 eq) dropwise at 0°C. The reaction mixture was stirred at 25°C for 4 hours. The reaction mixture was quenched by the addition of water (100 mL), and then extracted with CH2CI2 (2x200 mL). The combined organic extracts were washed with brine (200 mL), dried over anhydrous Na2SO4, and concentrated under vacuum. The crude residue was applied onto a silica gel column and eluted with ethyl acetate / petroleum ether=1 : 10 to give 7-fluoro-3- (trifluoromethanesulfonyloxy)-8-[2-(triisopropylsilyl)ethynyl]naphthalen-1 -yl trifluoromethanesulfonate as a light yellow solid (10.0 g, 48.0%).Synthesis of 3-[(diphenylmethylidene)amino]-7-fluoro-8-[2-(triisopropylsilyl)ethynyl]naphthalen-1-yl trifluoromethanesulfonate: Into a 250 mL round bottom flask, were placed 7-fluoro-3- (trifluoromethanesulfonyloxy)-8-[2-(triisopropylsilyl)ethynyl]naphthalen-1-yl trifluoromethanesulfonate (10.0 g, 16.1 mmol, 1.0 eq), diphenylmethanimine (5.8 g, 32.1 mmol, 2.0 eq), Pd2(dba)a (1.5 g, 1.6 mmol, 0.1 eq), XantPhos (1.9 g, 3.2 mmol, 0.2 eq), CS2CO3 (15.7 g, 48.2 mmol, 3.0 eq) and toluene (100 mL) under nitrogen atmosphere. The resulting mixture was stirred for 14 hours at 100°C under nitrogen atmosphere. The resulting mixture was diluted with H2O (200 mL), and then extracted with CH2CI2 (200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The crude residue was applied onto a silica gel column and eluted with ethyl acetate / petroleum ether=1 : 10 to give 3-[(diphenylmethylidene)amino]-7-fluoro-8-[2-(triisopropylsilyl)ethynyl]naphthalen-1-yl trifluoromethanesulfonate as a light brown solid (8.0 g, 76.2%). LC-MS (ES, m / z) M+1 : 654.Synthesis of N-[6-fluoro-4-(4,4,5, 5-tetramethy I- 1 , 3,2-dioxaborolan-2-y l)-5- [2- (triisopropylsilyl)ethynyl]naphthalen-2-yl]-1 ,1 -diphenylmethanimine: Into a 100 mL round bottom flask, were placed 3-[(diphenylmethylidene)amino]-7-fluoro-8-[2-(triisopropylsilyl)ethynyl]naphthalen-1-yl trifluoromethanesulfonate (3.0 g, 4.6 mmol, 1.0 eq), 4,4,5-trimethyl-2-(4,4,5-trimethyl-1 ,3,2-dioxaborolan-2-yl)-1.3.2-dioxaborolane (2.1 g, 9.1 mmol, 2.0 eq), KOAc (1.4 g, 13.7 mmol, 3.0 eq), Pd(dppf)Cl2-CH2Cl2 (0.4 g, 0.5 mmol, 0.1 eq) and toluene (60 mL) under nitrogen atmosphere. The resulting mixture was stirred for 18 hours at 110°C under nitrogen atmosphere. The resulting mixture was diluted with H2O (100 mL), and then extracted with CH2CI2 (200 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The crude residue was applied onto a silica gel column and eluted with ethyl acetate / petroleum ether=1 :10 to give N-[6-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-5-[2-(triisopropylsilyl)ethynyl]naphthalen-2-yl]-1, 1 -diphenylmethanimine as a white solid (1.0 g, 34.5%).1HNMR (300 MHz, Chloroform-d) 5 7.81 (d, >7.5 Hz, 2H), 7.63-7.40 (m, 4H), 7.33-7.11 (m, 8H), 1.35 (s, 12H), 1.17 (s, 21 H).Synthesis of 6-fl uoro-4-(4, 4, 5, 5-tetramethy 1-1 , 3, 2-dioxaborolan-2-y I )-5-[2- (triisopropylsilyl)ethynyl]naphthalen-2-amine: Into an 8 mL vial, were placed N-[6-fluoro-4-(4,4,5,5-tetramethyl-1.3.2-dioxaborolan-2-yl)-5-[2-(triisopropylsilyl)ethynyl]naphthalen-2-yl]-1 ,1 -diphenylmethanimine (300 mg, 0.5mmol, 1.0 eq) and HCI(gas) in EA (1 M, 1.0 mL). The reaction mixture was stirred at 25°C for 4 hours. The precipitated solids were collected by filtration and washed with Et20 (3 mL). This resulted in 6-fluoro-4-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-5-[2-(triisopropylsilyl)ethynyl]naphthalen-2-amine as a white solid (150 mg, 67.6%).Example INT_A-4: Preparation of tert-butyl (1-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5- ((triisopropylsilyl)ethynyl)naphthalen-2-yl)carbamateSynthesis of tert-butyl N-(1-fluoro-4-hydroxynaphthalen-2-yl)carbamate: Into a 250 mL 3-necked roundbottom flask were added tert-butyl N-(4-bromo-1-fluoronaphthalen-2-yl)carbamate (10 g, 29.4 mmol, 1.0 eq), Pd(dba)2 (0.9 g, 1.5 mmol, 0.05 eq) , t-BuXPhos (1.9 g, 4.4 mmol, 0.15 eq), KOH (6.6 g, 117.6 mmol, 4 eq) and Dioxane (80 mL), H2O (67 mL) at 25°C under nitrogen atmosphere. The resulting mixture was stirred for additional 6 hours at 100°C. The mixture was allowed to cool down to 25°C. Then the reaction was quenched with water, and then extracted with EtOAc (3x100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography and eluted with petroleum ether / ethyl acetate=10:1 to give tertbutyl N-(1-fluoro-4-hydroxynaphthalen-2-yl)carbamate as a brown solid (5.0 g, 61.3%). LC-MS (ES, m / z) M-1 : 276.1HNMR (300 MHz, DMSO-d6) 5 10.15 (s, 1 H), 9.08 (s, 1 H), 8.06 (d, 8.4 Hz, 1 H), 7.87 (d, >8.3 Hz, 1 H), 7.55 (ddd, >8.3, 6.8, 1.3 Hz, 1 H), 7.43 (ddd, >8.2, 6.8, 1.2 Hz, 1 H), 7.24 (d, >6.4 Hz, 1 H), 1.49 (s, 9H).Synthesis of tert-butyl (1 -fluoro-4-hydroxy-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)carbamate: Into a 100 mL round-bottom flask, were placed tert-butyl (1-fluoro-4-hydroxynaphthalen-2-yl)carbamate (3.0 g, 10.8 mmol, 1.0 eq), (2-bromoethynyl)triisopropylsilane (3.7 g, 14.0 mmol, 1.3 eq), dioxane (30 mL), AcOK (2.2 g, 21.6 mmol, 2.0 eq) and [Ru(P-Cymene)Cl2]2 (530 mg, 1.1 mmol, 0.1 eq). The resulting mixture was stirred for 14 hours at 110°C under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The crude residue was applied onto a silica gel column and eluted with ethyl acetate / petroleum ether=4: 1 to give tert-butyl (1 -fluoro-4-hydroxy-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)carbamate as a light brown solid (2.0 g, 40.8%). LC-MS (ES, m / z) M-1 : 456.1HNMR (300 MHz, Chloroform-d) 5 8.97 (s, 1 H), 7.96 (d, >8.5 Hz, 1 H), 7.85 (d, >7.1 Hz, 1 H), 7.60-7.51 (m, 1H), 7.39 (dd, >8.5, 7.2 Hz, 1 H), 6.85-6.78 (m, 1 H), 1.57 (s, 9H), 1.19 (d, >4.5 Hz, 21 H).Synthesis of 3-((tert-butoxycarbonyl)amino)-4-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate: Into a 100 mL round bottom flask, were placed tert-butyl (1 -fluoro-4-hydroxy-5- ((triisopropylsilyl)ethynyl)naphthalen-2-yl)carbamate (2.0 g, 4.4 mmol, 1.0 eq), DIEA (1.7 g, 13.2 mmol, 3.0 eq) and CH2CI2 (20 mL). To the above mixture was added Tf20 (1 .9 g, 6.6 mmol, 1 .5 eq) dropwise at -40°C under nitrogen atmosphere. The resulting mixture was stirred for 1 hour at -40°C under nitrogen atmosphere. The reaction was quenched by the addition of water (10 mL) at -40°C. The resulting mixture was extracted with CH2CI2 (2x100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The crude residue was applied onto a silica gel column and eluted with ethyl acetate / petroleum ether=1 :5 to give 3-((tert-butoxycarbonyl)amino)-4-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate as a light yellow solid (1.6 g, 62.3%).1HNMR (300 MHz, Chloroform-d) 5 8.56 (d, >6.7 Hz, 1 H), 8.01 (d, >8.5 Hz, 1 H), 7.82 (d, >7.2 Hz, 1 H), 7.58-7.47 (m, 1 H), 6.90 (s, 1 H), 1.58 (s, 9H), 1.22-1.17 (m, 21 H).Synthesis of tert-butyl (1 -fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)carbamate: Into an 8 mL sealed tube were placed 3-((tert- butoxycarbonyl)amino)-4-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate (200 mg, 0.3 mmol, 1.0 eq), bis(pinacolato)diboron (173 mg, 0.7 mmol, 2.0 eq), Dioxane (2 mL), Pd(dppf)Cl2 (35 mg, 0.03 mmol, 0.1 eq) and KOAc (100 mg, 1.0 mmol, 3.0 eq) at 25°C. The resulting mixture was stirred for 16 hours at 100°C under nitrogen atmosphere. The reaction mixture was quenched by the addition of H2O (1 mL). The resulting mixture was extracted with ethyl acetate (2x10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The crude residue was applied onto a silica gel column and eluted with ethyl acetate / petroleum ether=1 :20 to give tert-butyl (1-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2- yl)carbamate as a yellow solid (100 mg, 52.1 %).1HNMR (300 MHz, Chloroform-d) 5 8.49 (d, >8.3 Hz, 1 H), 7.99 (d, >8.4 Hz, 1 H), 7.77 (dd, >7.2, 1.3 Hz, 1 H), 7.43 (t, >7.8 Hz, 1 H), 6.74 (s, 1 H), 1.57 (s, 9H), 1.45 (s, 12H),1.29 (s, 3H), 1.17 (d, >2.5 Hz, 18H).Example INT_A-5: Preparation of 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1 -yl)-4,4,5,5-tetramethyl-1.3.2-dioxaborolaneSynthesis of 2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1 ,3,2- dioxaborolane: Into a 20 mL sealed tube, were placed ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1.3.2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (100 mg, 0.2 mmol, 1.0 eq), DMF (3 mL), CsF (304 mg, 2.0 mmol, 10.0 eq). The resulting solution was stirred for 2 hours at 25°C. The resulting mixture was then quenched by the addition of water (50 mL), and then extracted with ethyl acetate (2x50 mL). The combined organic layer was washed with brine (2x50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum to give 2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolane as an off white solid (80 mg, crude). LC-MS (ES, m / z) M+1 : 357.1H NMR (300 MHz, Chloroform-d) 5 7.74 (dd, >9.1 , 5.8 Hz, 1 H), 7.50 (d, >2.6 Hz, 1 H), 7.42 (d, >2.6 Hz, 1 H), 7.28 (s, 1 H),5.30 (s, 2H), 3.70 (s, 1 H), 3.53 (s, 3H), 1.46 (s, 12H).Synthesis of 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1 ,3,2- dioxaborolane: To a solution of 2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1 -yl)-4,4,5,5-tetramethyl-1.3.2-dioxaborolane (80 mg, 0.2 mmol, 1.0 eq) in 10 mL THF was added Pd / C (10%, 8 mg) in a 50-mL roundbottom flask. The mixture was stirred at 25°C for 2 hours under hydrogen atmosphere (2 atm), filtered through a Celite pad and concentrated under vacuum to give 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)- 4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane. The crude product mixture was used in the next step directly without further purification. LC-MS (ES, m / z) M+1 : 361.1HNMR (300 MHz, DMSO-d6) 5 7.77 (dd, >9.0, 6.0 Hz, 1 H),7.54 (d, >2.7 Hz, 1 H), 7.38 (t, >9.3 Hz, 1 H), 7.28 (d, >2.6 Hz, 1 H), 5.31 (s, 2H), 3.66-3.55 (m, 2H), 3.42 (s, 3H), 1.84-1.69 (m, 3H), 1.43-1.33 (m, 12H).Example INT_A-6: Preparation of 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)naphthalen-2- amineSynthesis of 5-ethynyl-6-fluoro-4-(4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)naphthalen-2-amine: Into an 8-mL sealed tube, were placed 6-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-5- ((triisopropylsilyl)ethynyl)naphthalen-2-amine (500 mg, 1.1 mmol, 1.1 eq), DMF (5 mL), CsF (1.6 g, 10.7 mmol, 10.0 eq). The resulting solution was stirred for 2 hours at 25°C. The resulting mixture was then quenched by the addition of water (60 mL), and then extracted with ethyl acetate (2x60 mL). The combined organic layer was washed with brine (2x60 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum to give 5-ethynyl-6-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)naphthalen-2-amine as a light yellow solid(300 mg, 90.1%). LC-MS (ES, m / z) M+1 : 312.Synthesis of 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-amine: Into an 8 mL vial were added5-ethynyl-6-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)naphthalen-2-amine (350 mg, 1.1 mmol, 1.0 eq), MeOH (5 mL) and Pd / C (35 mg, 0.3 mmol, 0.3 eq). The resulting mixture was stirred for 2 hours at 25°C under H2 atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (3x10 mL). The filtrate was concentrated under reduced pressure. The crude residue was purified onto a silica gel column and eluted with ethyl acetate / petroleum ether=1 : 1 to give 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)naphthalen-2-amine as an orange solid(210 mg, 59.2%). LC-MS (ES, m / z) M+1 : 316.Example INT_A-7: Preparation of 5-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-amineSynthesis of 5-ethynyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)naphthalen-2-amine: Into an 8-mL sealed tube, were placed 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen- 2-amine (500 mg, 1.1 mmol, 1.0 eq), DMF (5 mL), CsF (1.6 g, 11.1 mmol, 10.0 eq). The resulting solution was stirred for 2 hours at 25°C. The resulting mixture was then quenched by the addition of water (60 mL), and then extracted with ethyl acetate (2x60 mL). The combined organic layer was washed with brine (2x60 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum to give 5-ethynyl-4-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)naphthalen-2-amine as a light yellow solid(300 mg, 92.0%). LC-MS (ES, m / z) M+1 : 294.Synthesis of 5-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-amine: Into an 8 mL vial were added 5-ethynyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)naphthalen-2-amine (300 mg, 1.0 mmol, 1.0 eq), MeOH (5 mL) and Pd / C (30 mg, 0.28 mmol, 0.28 eq). The resulting mixture was stirred for 2 hours at 25°C under H2 atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (3x10 mL). The filtrate was concentrated under reduced pressure. The crude residue was purified onto a silica gel column and eluted with ethyl acetate / petroleum ether=1 : 1 to give 5-ethyl-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)naphthalen-2-amine as an orange solid (230 mg, 75.6%). LC-MS (ES, m / z) M+1 : 298.Example INT_A-8: Preparation of triisopropyl({2-[6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)naphthalen-1-yl]ethynyl})silaneSynthesis of 8-[2-(triisopropylsilyl)ethynyl]naphthalene-1 ,3-diol: Into a 250 mL round-bottom flask purged, were placed naphthalene-1 ,3-diol (5.0 g, 31.2 mmol, 1.0 eq), (2-bromoethynyl)triisopropylsilane (9.8 g, 37.4 mmol, 1.2 eq), dioxane (60 mL), AcOK (6.1 g, 62.4 mmol, 2.0 eq) and [Ru(p-Cymene)CI2]2 (1.9 g, 3.1 mmol, 0.1 eq). The reaction mixture was stirred for 12 hours at 110 °C under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The crude residue was applied onto a silica gel column and eluted with ethyl acetate / petroleum ether=1 :4 to give 8-[2-(triisopropylsilyl)ethynyl]naphthalene-1 ,3-diol as a light yellow solid (6.0 g, 56.4%). LC-MS (ES, m / z) M-1 : 339.Synthesis of 3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol: Into a 200-mL round bottom flask, were placed 8-[2-(triisopropylsilyl)ethynyl]naphthalene-1,3-diol (6.0 g, 17.6 mmol, 1.0 eq), DIEA (6.8 g, 52.9 mmol, 3.0 eq) and CH2CI2 (100 mL). To the above mixture was added dropwise MOMBr (3.3 g, 26.4 mmol, 1.5 eq) at -40°C under a nitrogen atmosphere. The reaction mixture was stirred at -40°C for 30 mins. The reaction mixure was then quenched by the addition of water (20 mL). The resulting mixure was extracted with CH2CI2 (2x200 mL). The combined organic extracts were washed with brine (500 mL)., dried over anhydrous Na2SC>4, and concentrated under vacuum. The crude residue was applied onto a silica gel column and eluted with ethyl acetate / petroleum ether=1 :3 to give 3-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphthalen-1 -ol as a light yellow solid (5.0 g, 73.8%). LC-MS (ES, m / z) M+1 : 385.Synthesis of 3-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphthalen-1-yl trifluoromethanesulfonate: Into a 250 mL round-bottom flask were placed 3-(methoxymethoxy)-8-[2- (triisopropylsilyl)ethynyl]naphthalen-1 -ol (5.0 g, 13.0 mmol, 1.0 eq), DIEA (5.0 g, 39.0 mmol, 3.0 eq) and CH2CI2 (100 mL). To the above mixture were added Tf20 (5.5 g, 19.5 mmol, 1.5 eq) dropwise at -40°C under nitrogen atmosphere. The resulting mixture was stirred for 1 hour at -40°C under nitrogen atmosphere. The reaction was quenched by the addition of water (10 mL) at -40°C. The resulting mixture was extracted with CH2CI2 (2x100 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The crude residue was applied onto a silica gel column and eluted with ethyl acetate / petroleum ether=1 :5 to give 3-(methoxymethoxy)-8-[2- (triisopropylsilyl)ethynyl]naphthalen-1-yl trifluoromethanesulfonate as a light yellow solid (4.5 g, 67.0%). LC-MS (ES, m / z) M-CF3SO2+I : 384.1HNMR (400 MHz, Chloroform-d) 5 7.75-7.73 (m, 2H), 7.50-7.41 (m, 2H), 7.33 (d, >2.4 Hz, 1 H), 5.31 (s, 2H), 3.54 (s, 3H), 1.38-1.20 (m, 3H), 1.19 (d, J = 5.8 Hz, 18H), 0.94 - 0.82 (m, 3H).Synthesis of triisopropyl({2-[6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)naphthalen-1-yl]ethynyl})silane: Into a 250 mL round-bottom flask, were placed 3-(methoxymethoxy)-8-[2- (triisopropylsilyl)ethynyl]naphthalen-1-yl trifluoromethanesulfonate (4.5 g, 8.7 mmol, 1.0 eq) , bis(pinacolato)diboron (4.4 g, 17.4 mmol, 2.0 eq) , Toluene (100 mL) ,Pd(dppf)Cl2.CH2Cl2 (0.7 g, 0.9 mmol, 0.1 eq) and KOAc (3.0 g, 30.5 mmol, 3.5 eq). The resulting mixture was stirred for 16 hours at 110°C under nitrogen atmosphere. The reaction mixure was then quenched by the addition of H2O (100 mL). The resulting mixturewas extracted with EtOAc (2x100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The crude residue was applied onto a silica gel column and eluted with ethyl acetate / petroleum ether=1 :20 to give triisopropyl({2-[6- (methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl]ethynyl})silane as a yellow solid (3.0 g, 69.7%). LC-MS (ES, m / z) M+1 :495.1HNMR (400 MHz, Chloroform-d) 5 7.74-7.66 (m, 2H), 7.48 (d, >2.6 Hz, 1 H), 7.42-7.32 (m, 2H), 5.30 (s, 2H), 3.52 (s, 3H), 1.45 (s, 12H), 1.18-1.17 (m, 18H), 1.17-1.16 (m, 3H).Example INT_A-9: Preparation of tert-butyl (3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4- (trifluoromethyl)phenyl)carbamateSynthesis of 1-bromo-3-chloro-2-iodo-5-nitrobenzene: Into a 250 mL 3-necked round-bottom flask were added 2-bromo-6-chloro-4-nitroaniline (10.0 g, 39.8 mmol, 1.0 eq) and AcOH (100 mL) at 25°C. To a stirred solution was added H2SO4 (40.0 g, 407.9 mmol, 10.0 eq) dropwise at 0°C. To the above mixture was added NaNC>2 (4.1 g, 59.7 mmol, 1.5 eq) in 16 mL of H2O dropwise over 10 mins at 0°C. The resulting mixture was stirred for additional 30 minutes at 0°C. To the above mixture was added KI (10.0 g, 59.7 mmol, 1.5 eq) in 16 mL H2O dropwise over 10 minutes at 0°C. The resulting mixture was stirred for additional 30 minutes at 25°C. The resulting mixture was diluted with water (1000 mL). The product was precipitated by the addition of water. The precipitated solids were collected by filtration and washed with water (3x100 mL). The resulting solid was dried under infrared light to give 1-bromo-3-chloro-2-iodo-5-nitrobenzene as a brown solid (9.0 g, 62.5%).1HNMR (400 MHz, DMSO-d6) 5 8.40 (d, >2.4 Hz, 1 H), 8.34 (d, >2.4 Hz, 1 H).Synthesis of 3-bromo-5-chloro-4-iodoaniline: Into a 100 mL round-bottom flask were added 1-bromo-3- chloro-2-iodo-5-nitrobenzene (10.0 g, 27.6 mmol, 1.0 eq), NH4CI (5.9 g, 110.4 mmol, 4.0 eq), iron (6.2 g, 110.4 mmol, 4.0 eq), EtOH (50 mL) and H2O (10 mL) at 25°C. The resulting mixture was stirred for additional 2 hours at 70°C. The mixture was allowed to cool down to 25°C. The resulting mixture was filtered, the filter cake was washed with EtOH (3x100 mL). The filtrate was concentrated under vacuum to give 3-bromo-5-chloro-4- iodoaniline as a light brown solid (8.0 g, 87.2%).1HNMR (300 MHz, DMSO-» 5 6.90 (d, >2.4 Hz, 1 H), 6.76 (d, >2.4 Hz, 1 H), 5.80 (s, 2H).Synthesis of tert-butyl (3-bromo-5-chloro-4-iodophenyl)carbamate: Into a 50 mL round-bottom flask were added 3-bromo-5-chloro-4-iodoaniline (1.0 g, 3.0 mmol, 1.0 eq), DMAP (400 mg, 0.3 mmol, 0.1 eq), (BOC)2O (2.0 g, 9.0 mmol, 3.0 eq) and THF (10 mL) at 25°C. The resulting mixture was stirred for additional 12 hours at 80°C. The reaction was quenched with water at 25°C. The resulting mixture was extracted with EtOAc (3x50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum pressure to give the crude product. Into a 50 mL roundbottom flask were added the crude product, K2CO3 (1.3 g, 9.0 mmol, 3.0 eq) and MeOH (10 mL) at 25°C. The resulting mixture was stirred for additional 2 hours at 70°C. The reaction was quenched with water at 25°C. The resulting mixture was extracted with CH2CI2 (3x50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum pressure. Theresidue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate=5:1 to give tert-butyl N-(3-bromo-5-chloro-4-iodophenyl)carbamate as a light yellow solid (600 mg, 46.1%).1HNMR (300 MHz, Chloroform-d) 5 7.64 (d, 7=2.4 Hz, 1 H), 7.54 (d, 7=2.4 Hz, 1 H), 6.50 (s, 1 H), 1.54 (s, 9H).Synthesis of tert-butyl (3-bromo-5-chloro-4-(trifluoromethyl)phenyl)carbamate: Into a 50 mL 3-necked round-bottom flask were added tert-butyl N-(3-bromo-5-chloro-4-iodophenyl)carbamate (400 mg, 0.9 mmol, 1.0 eq), methyl 2,2-difluoro-2-sulfoacetate (355 mg, 1.9 mmol, 2.0 eq), Cui (53 mg, 0.3 mmol, 0.3 eq) and NMP (5 mL). The resulting mixture was stirred for additional 16 hours at 80°C under nitrogen atmosphere. The reaction was quenched with water at 25°C. The resulting mixture was extracted with EtOAc (3x50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The crude residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate=5:1 to give tert-butyl [3-bromo-5-chloro-4-(trifluoromethyl)phenyl]carbamate as a light yellow solid (200 mg, 57.7%). LC-MS (ES, m / z) M+1 : 374.1HNMR (300 MHz, Chloroform-d) 5 7.71 (d, 7=2.2 Hz, 1 H), 7.59 (d, 7=2.3 Hz, 1 H), 6.63 (bs, 1 H), 1.55 (s, 9H).Synthesis of tert-butyl (3-ch I oro-5-(4,4, 5, 5-tetramethy I -1 , 3, 2-dioxaborol an-2-y I )-4- (trifluoromethyl)phenyl)carbamate: Into a 25 mL round bottom flask, were placed tert-butyl [3-bromo-5-chloro-4- (trifluoromethyl)phenyl]carbamate (200 mg, 0.5 mmol, 1.0 eq), 4,4,5,5-trimethyl-2-(4,4,5,5-trimethyl-1 ,3,2- dioxaborolan-2-yl)-1,3,2-dioxaborolane (241 mg, 1.0 mmol, 2.0 eq), AcOK (140 mg, 1.4 mmol, 3.0 eq), Pd(dppf)Cl2'CH2Cl2 (39 mg, 0.05 mmol, 0.1 eq) and 1,4-dioxane (5 mL) under nitrogen atmosphere. The resulting mixture was stirred for 5 hours at 80°C under nitrogen atmosphere. The resulting mixture was diluted with H2O (10 mL). The resulting mixture was extracted with CH2CI2 (3x20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The crude residue was applied onto a silica gel column and eluted with petroleum ether / ethyl acetate=10:1 to give tert-butyl (3-chloro-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-4- (trifluoromethyl)phenyl)carbamate as an off white solid (110 mg, 48.9%). LC-MS (ES, m / z) M-1 : 420.1HNMR (300 MHz, Chloroform-d) 5 7.88 (s, 1 H), 7.09 (s, 1 H), 6.86 (s, 1 H), 1.38 (s, 9H), 1.28 (d, 7=2.5 Hz, 6H), 1.26 (s, 6H).Example INT_A-10: Preparation of tert-butyl (2-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4- (trifluoromethyl)phenyl)carbamateSynthesis of 5-bromo-2-fluoro-1-methyl-3-nitrobenzene: Into a 50 mL round-bottom flask were added 2- fluoro-1-methyl-3-nitrobenzene (5.0 g, 32.2 mmol, 1.0 eq) and H2SO4 (10 mL). To the above mixture was added NBS (6.9 g, 38.7 mmol, 1.2 eq) in portions at 60°C. The resulting mixture was stirred for 8 hours at 60°C. The mixture was allowed to cool down to 25°C. The reaction was poured into water / ice (100 mL) at 0°C. The resulting mixture was extracted with CH2CI2 (2x50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The crude residue was applied onto a silica gel column and eluted with ethyl acetate / petroleum ether=1 :5 to give 5-bromo-2-fluoro-1-methyl-3-nitrobenzene as a yellow solid (4.0 g, 53.0%).1HNMR (400 MHz, Chloroform-d) 5 7.99 (dd, >6.2, 2.4 Hz, 1 H), 7.63 (dd, >5.8, 2.4 Hz, 1 H), 2.39 (d, J =2.7 Hz, 3H).Synthesis of 5-bromo-2-fluoro-3-methylaniline: Into a 50 mL round-bottom flask were added 5-bromo-2- fluoro-1-methyl-3-nitrobenzene (3.8 g, 16.2 mmol, 1.0 eq), EtOH (4 mL), H2O (4 mL), Fe (4.5 g, 81.2 mmol, 5.0 eq) and NH4CI (4.3 g, 81.2 mmol, 5.0 eq) at 25°C. The resulting mixture was stirred for 3 hours at 70°C. The resulting mixture was filtered, the filter cake was washed with EtOH (2x10 mL). The filtrate was concentrated under vacuum. This resulted in 5-bromo-2-fluoro-3-methylaniline as a yellow solid (1.6 g, 48.3%). LC-MS (ES, m / z) M+1 : 204 / 206.Synthesis of 5-bromo-2-fluoro-4-iodo-3-methylaniline: Into a 50 mL round-bottom flask were added 5- bromo-2-fluoro-3-methylaniline (1.5 g, 7.4 mmol, 1.0 eq), MeCN (15 mL) and NIS (1.7 g, 7.4 mmol, 1.0 eq) at 25°C. The resulting mixture was stirred for 5 hours at 25°C. The resulting mixture was concentrated under vacuum. The residue was dissolved in EtOAc (20 mL) and H2O (20 mL). The resulting mixture was extracted with EtOAc (2x20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The crude residue was applied onto a silica gel column and eluted with ethyl acetate / petroleum ether=1 :5 to give 5-bromo-2-fluoro-4-iodo-3-methylaniline a yellow solid (1.3 g, 53.6%). LC-MS (ES, m / z) M+42: 371 / 373.Synthesis of tert-butyl N-(5-bromo-2-fluoro-4-iodo-3-methylphenyl)carbamate: Into a 50 mL roundbottom flask were added 5-bromo-2-fluoro-4-iodo-3-methylaniline (1.2 g, 3.6 mmol, 1.0 eq), THF (20 mL), DMAP (40 mg, 0.4 mmol, 0.1 eq) and BOC2O (2.5 g, 10.9 mmol, 3.0 eq) at 25°C. The resulting mixture was stirred for 16 hours at 80°C. The reaction was quenched by the addition of water (10 mL) at 25°C. The resulting mixture was extracted with EtOAc (2x20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The residue was dissolved in MeOH (20 mL). To the above mixture was added K2CO3 (1.5 g, 10.9 mmol, 3.0 eq). The resulting mixture was stirred for additional 5 hours at 70°C. The resulting mixture was concentrated under vacuum. The residue was dissolved in EtOAc (20 mL) and H2O (20 mL). The resulting mixture was extracted with EtOAc (2x20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The crude residue was applied onto a silica gel column and eluted with ethyl acetate / petroleum ether=1 :5 to give tert-butyl N-(5-bromo-2-fluoro-4-iodo-3-methylphenyl)carbamate as a white solid (1.0 g, 63.9%). LC-MS (ES, m / z) M-1 : 428 / 430.Synthesis of tert-butyl N-[5-bromo-2-fluoro-3-methyl-4-(trifluoromethyl)phenyl]carbamate: Into a 50 mL round-bottom flask were added tert-butyl N-(5-bromo-2-fluoro-4-iodo-3-methylphenyl)carbamate (900 mg, 2.1 mmol, 1.0 eq), NMP (10 mL), Cui (120 mg, 0.6 mmol, 0.3 eq) and methyl 2,2-difluoro-2-sulfoacetate (804 mg, 4.2 mmol, 2.0 eq) at 25°C. The resulting mixture was stirred for 16 hours at 80°C. The reaction was quenched by the addition of water (10 mL) at 25°C. The resulting mixture was extracted with EtOAc (2x20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The crude residue was applied onto a silica gel column and eluted withethyl acetate / petroleum ether=1 :5 to give tert-butyl N-[5-bromo-2-fluoro-3-methyl-4- (trifluoromethyl)phenyl]carbamate as a white solid (700 mg, 89.9%). LC-MS (ES, m / z) M-1: 370 / 372.Synthesis of tert-butyl (2-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-4- (trifluoromethyl)phenyl)carbamate: Into a 20 mL sealed tube were added tert-butyl N-[5-bromo-2-fluoro-3-methyl- 4-(trifluoromethyl)phenyl]carbamate (500 mg, 1.3 mmol, 1.0 eq), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2- dioxaborolane) (512 mg, 2.0 mmol, 1.5 eq), DMF (5 mL), KOAc (396 mg, 4.0 mmol, 3.0 eq) and Pd(dppf)Cl2.CH2Cl2 (109 mg, 0.1 mmol, 0.1 eq) at 25°C. The resulting mixture was stirred for 16 hours at 80°C under nitrogen atmosphere. The reaction was quenched by the addition of water (10 mL) at 25°C. The resulting mixture was extracted with EtOAc (2x10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The crude residue was applied onto a silica gel column and eluted with ethyl acetate / petroleum ether=1 : 10 to give tert-butyl (2- fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)phenyl)carbamate as a colorless oil (240 mg, 42.6%). LC-MS (ES, m / z) M-1 : 418.Example INT_A-12: Preparation of 3-chloro-4-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)aniline Synthesis of 1-bromo-3-chloro-2-methyl-5-nitrobenzene: Into a 50 mL round bottom flask, were placed2-chloro-4-ni trotoluene (1 .0 g, 5.8 mmol, 1 .0 eq), n-Heptane (5 mL), sulfuric acid (5 mL), NBS (1 .3 g, 7.0 mmol, 1.2 eq). The resulting mixture was diluted with H2O (50 mL). The resulting mixture was extracted with ethyl acetate (2x80 mL). The combined organic layers were washed with brine (80 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The crude residue was applied onto a silica gel column and eluted with ethyl acetate / petroleum ether=1 :5 to give 1-bromo-3-chloro-2-methyl-5-nitrobenzene as a light yellow solid (900 mg, 61.6%).1HNMR (400 MHz, DMSO-d6) 5 8.38 (d, >2.4 Hz, 1 H), 8.30 (d, 2.4 Hz, 1 H), 2.56 (s, 3H).Synthesis of 3-bromo-5-chloro-4-methylaniline: Into a 50 mL round bottom flask, were placed 1-bromo-3-chloro-2-methyl-5-nitrobenzene (850 mg, 3.4 mmol, 1.0 eq), MeOH (5 mL), H2O (5 mL), Fe (948 mg, 17.0 mmol, 5.0 eq), ammonium chloride (908 mg, 17.0 mmol, 5.0 eq). The resulting mixture was filtered, the filter cake was washed with MeOH (3x50 mL). The filtrate was concentrated under vacuum. The crude residue was applied onto a silica gel column and eluted with ethyl acetate / petroleum ether=1 :5 to give 3-bromo-5-chloro-4- methylaniline as a light yellow solid (600 mg, 80.2%).1HNMR (300 MHz, DMSO-» 5 6.79 (d, >2.4 Hz, 1 H), 6.65 (d, >2.4 Hz, 1 H), 5.44 (s, 2H), 2.26 (s, 3H).Synthesis of 3-chloro-4-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)aniline: Into a 20-mL sealed-tube purged and maintained with an inert atmosphere of nitrogen, were placed 3-bromo-5-chloro-4- methylaniline (600 mg, 2.7 mmol, 1.0 eq), DMF (6 mL), 4,4,5,5-tetramethyl-2-(tetramethyl-1 ,3,2-dioxaborolan-2- yl)-1 ,3,2-dioxaborolane (1.4 g, 5.4 mmol, 2.0 eq), AcOK (801 mg, 8.2 mmol, 3.0 eq), Pd(dppf)Cl2 (223 mg, 0.3 mmol, 0.1 eq). The resulting solution was stirred for 16 hours at 80°C in an oil bath. The resulting mixture was then quenched by the addition of water (80 mL), and then extracted with ethyl acetate (2x80 mL). The combined organic layer was washed with brine (2x80 mL), dried over anhydrous Na2SO4. After filtration, the filtrate wasconcentrated under vacuum. The crude residue was purified onto a silica gel column and eluted with petroleum ether / ethyl acetate=3:1 to give 3-chloro-4-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)aniline as a light yellow solid (400 mg, 84.9%).1HNMR (400 MHz, DMSO-d6) 5 6.89 (d, 2.4 Hz, 1 H), 6.71 (d, >2.4 Hz, 1 H), 5.14 (s, 2H), 2.33 (s, 3H), 1.29 (s, 12H).Example INT_A-13: Preparation of 2-(3-chloro-2-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane Synthesis of 2-(3-chloro-2-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane: Into a 100 mL round bottom flask, were placed 1 -bromo-3-chloro-2-(trifluoromethyl)benzene (1.0 g, 4.4 mmol, 1.0 eq), 4,4,5,5-trimethyl-2-(4,4,5,5-trimethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,3,2-dioxaborolane (2.3 g, 8.8 mmol, 2.0 eq), KOAc (0.6 g, 13.2 mmol, 3.0 eq), Pd(dppf)Cl2-CH2Cl2 (100 mg, 0.4 mmol, 0.1 eq) and Dioxane (10 mL) under nitrogen atmosphere. The resulting mixture was stirred for 5 hours at 100°C under nitrogen atmosphere. The resulting mixture was diluted with H2O (80 mL). The resulting mixture was extracted with EtOAc (3x100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The crude residue was applied onto a silica gel column and eluted with petroleum ether / ethyl acetate=5:1 to give 2-(3-chloro-2-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1 ,3,2- dioxaborolane as an off white solid (1.1 g, 40.2%).1HNMR (400 MHz, Chloroform-d) 5 7.52-7.33 (m, 3H), 1.27 (s, 12H).Example INT_A-14: Preparation of N, N-bis(4-methoxybenzyl)-6-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-5-(trifluoromethyl)pyridin-2-amineSynthesis of 4-bromo-N,N-bis(4-methoxybenzyl)-6-methylpyridin-2-amine: Into a 250 mL 3-necked round-bottom flask were added 4-bromo-6-methylpyridin-2-amine (5.0 g, 39.8 mmol, 1.0 eq), DMF (80 mL) at 0°C. To a stirred solution was added NaH (2.6 g, 99.5 mmol, 2.5 eq) in portions over 10 minutes at 0°C. To a stirred solution was added 1-(chloromethyl)-4-methoxybenzene (9.2 g, 79.6 mmol, 2.2 eq) in portions over 10 minutes at 0°C. The resulting mixture was stirred for additional 6 hours at 25°C. The reaction was poured into sat. NH4CI (aq.) at 25°C. The resulting mixture was extracted with EtOAc (3x300 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum pressure. The crude residue was applied onto a silica gel column and eluted with petroleum ether / ethyl acetate=10:1 to give 4-bromo-N,N-bis(4-methoxybenzyl)-6-methylpyridin-2-amine as an off white solid (7.0 g, 53.8%).1HNMR (400 MHz, Chloroform-d) 5 7.22-7.13 (m, 4H), 6.92-6.82 (m, 4H), 6.64 (d, >1.3 Hz, 1 H), 6.50 (s, 1 H), 4.72 (s, 4H), 3.82 (s, 6H), 2.45 (s, 3H).Synthesis of 4-bromo-5-iodo-N,N-bis(4-methoxybenzyl)-6-methylpyridin-2-amine: Into a 250 mL roundbottom flask were added 4-bromo-N,N-bis(4-methoxybenzyl)-6-methylpyridin-2-amine (7.0 g, 27.6 mmol, 1.0 eq), NIS (4.26 g, 27.6 mmol, 1.0 eq) and acetic acid (80 mL) at 25°C. The resulting mixture was stirred for 1 hour at 25°C. The resulting mixture was diluted with water (500 mL) at 25°C. The resulting mixture was extracted with EtOAc (3x400 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum pressure. The crude residue wasapplied onto a silica gel column and eluted with petroleum ether / ethyl acetate=10:1 to give 4-bromo-5-iodo-N,N- bis(4-methoxybenzyl)-6-methylpyridin-2-amine as an off white solid (7.0 g, 58.8%).1HNMR (400 MHz, Chloroform-d) 5 7.22-7.13 (m, 4H), 6.92-6.82 (m, 4H), 6.64 (d, 1.3 Hz, 1 H), 4.72 (s, 4H), 3.82 (s, 6H), 2.45 (s, 3H).Synthesis of 4-bromo-N,N-bis(4-methoxybenzyl)-6-methyl-5-(trifluoromethyl)pyridin-2-amine: Into a 250 mL round-bottom flask were added 4-bromo-5-iodo-N,N-bis(4-methoxybenzyl)-6-methylpyridin-2-amine (7.0 g, 0.9 mmol, 1.0 eq), methyl 2,2-difluoro-2-sulfoacetate (24.0 g, 9.0 mmol, 10.0 eq), Cui (24.0 mg, 9.02 mmol, 10.0 eq) and DMF (80 mL). The resulting mixture was stirred for additional 2 hours at 90°C. The reaction was quenched with water (100 mL) at 25°C. The resulting mixture was extracted with EtOAc (3x300 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The crude residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate=5:1 to give 4-bromo-N,N-bis(4-methoxybenzyl)-6-methyl-5- (trifluoromethyl)pyridin-2-amine as a white solid (6.0 g, 47.7%).1HNMR (400 MHz, Chloroform-d) 5 7.16-7.13 (m, 4H), 6.88-6.82 (m, 4H), 6.66 (d, >1.3 Hz, 1 H), 4.72 (s, 4H), 3.82 (s, 6H), 2.65 (s, 3H).Synthesis of N,N-bis(4-methoxybenzyl)-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5- (trifluoromethyl)pyridin-2-amine: Into a 100 mL round bottom flask, were placed 4-bromo-N,N-bis(4- methoxybenzyl)-6-methyl-5-(trifluoromethyl)pyridin-2-amine (6.0 g, 4.4 mmol, 1.0 eq), 4,4,5,5-trimethyl-2- (4,4,5,5-trimethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,3,2-dioxaborolane (8.3 g, 8.8 mmol, 2.0 eq), KOAc (3.3 g, 13.2 mmol, 3.0 eq), Pd(dppf)Cl2-CH2Cl2 (600 mg, 0.4 mmol, 0.1 eq) and Dioxane (80 mL) under nitrogen atmosphere. The resulting mixture was stirred for 5 hours at 100°C under nitrogen atmosphere. The resulting mixture was diluted with H2O (80 mL). The resulting mixture was extracted with EtOAc (3x100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The crude residue was applied onto a silica gel column and eluted with petroleum ether / ethyl acetate=5: 1 to give N, N-bis(4-methoxybenzyl)-6-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)-5-(trifluoromethyl)pyridin-2-amine as an off white solid (3.1 g, 40.2%).1HNMR (400 MHz, Chloroform-d) 5 7.22-7.13 (m, 4H), 6.92-6.82 (m, 4H), 6.64 (d, >1.3 Hz, 1 H), 4.72 (s, 4H), 3.82 (s, 6H), 2.45 (s, 3H), 1.25 (s, 12H).Example INT_A-15: Preparation of 3-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-4- (trifluoromethyl)anilineSynthesis of 3-bromo-N,N-bis(4-methoxybenzyl)-5-methylaniline: Into a 250 mL 3-necked round-bottom flask were added 3-bromo-5-methylaniline (5.0 g, 39.8 mmol, 1.0 eq), DMF (80 mL) at 0°C. To a stirred solution was added NaH (2.6 g, 99.5 mmol, 2.5 eq) in portions over 10 minutes at 0°C. To a stirred solution was added 1-(chloromethyl)-4-methoxybenzene (9.2 g, 79.6 mmol, 2.2 eq) in portions over 10 minutes at 0°C. The resulting mixture was stirred for additional 6 hours at 25°C. The reaction was poured into sat. NH4CI (aq.) at 25°C. The resulting mixture was extracted with EtOAc (3x300 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum pressure.The crude residue was applied onto a silica gel column and eluted with petroleum ether / ethyl acetate=10: 1 to give 3-bromo-N,N-bis(4-methoxybenzyl)-5-methylaniline as an off white solid (7.0 g, 53.8%).1HNMR (300 MHz, Chloroform-d) 5 7.14 (d, 7=8.5 Hz, 4H), 6.95-6.83 (m, 4H), 6.72 (d, 7=14.7 Hz, 2H), 6.54-6.48 (m, 1 H), 4.52 (s, 4H), 3.82 (s, 6H), 2.22 (s, 3H).Synthesis of 3-bromo-4-iodo-N,N-bis(4-methoxybenzyl)-5-methylaniline: Into a 250 mL round-bottom flask were added 3-bromo-N,N-bis(4-methoxybenzyl)-5-methylaniline (7.0 g, 27.6 mmol, 1.0 eq), NIS (5.26 g, 27.6 mmol, 1 .0 eq), TsOH (0.34 g, 27.6 mmol, 0.2 eq) and DMF (80 mL.) at 25°C. The resulting mixture was stirred for 1 hour at 25°C. The resulting mixture was diluted with Na2S20a (aq.) at 25°C. The resulting mixture was extracted with EtOAc (3x400 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum pressure. The crude residue was applied onto a silica gel column and eluted with petroleum ether / ethyl acetate=10: 1 to give 3-bromo-4-iodo- N,N-bis(4-methoxybenzyl)-5-methylaniline as an off white solid (4.0 g, 38.8%).1HNMR (300 MHz, Chloroform-d) 5 7.14 (d, 7=8.5 Hz, 4H), 7.02 (d, 7=14.7 Hz, 1 H), 6.95-6.83 (m, 4H), 6.54-6.48 (m, 1 H), 4.52 (s, 4H), 3.82 (s, 6H), 2.22 (s, 3H).Synthesis of 3-bromo-N,N-bis(4-methoxybenzyl)-5-methyl-4-(trifluoromethyl)aniline: Into a 250 mL round-bottom flask were added 3-bromo-4-iodo-N,N-bis(4-methoxybenzyl)-5-methylaniline (4.0 g, 1.8 mmol, 1.0 eq), methyl 2,2-difluoro-2-sulfoacetate (7.0 g, 9.0 mmol, 5.0 eq), Cui (1.4 mg, 9.02 mmol, 5.0 eq) and DMF (80 mL). The resulting mixture was stirred for additional 2 hours at 90°C. The reaction was quenched with water (500 mL) at 25°C. The resulting mixture was extracted with EtOAc (3x300 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The crude residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate=5:1 to give 3-bromo-N,N-bis(4-methoxybenzyl)-5-methyl-4-(trifluoromethyl)aniline as a white solid (3.5 g, 57.7%).1HNMR (300 MHz, Chloroform-d) 5 7.14 (d, 7=8.5 Hz, 4H), 6.98 (d, 7=14.7 Hz, 1 H), 6.95- 6.83 (m, 4H), 6.54-6.48 (m, 1 H), 4.52 (s, 4H), 3.82 (s, 6H), 2.22 (s, 3H).Synthesis of N,N-bis(4-methoxybenzyl)-3-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-4- (trifluoromethyl)aniline: Into a 100 mL round bottom flask, were placed 3-bromo-N,N-bis(4-methoxybenzyl)-5- methyl-4-(trifluoromethyl)aniline (3.5 g, 4.4 mmol, 1.0 eq), 4,4,5,5-trimethyl-2-(4,4,5,5-trimethyl-1,3,2- dioxaborolan-2-yl)-1 ,3,2-dioxaborolane (4.3 g, 8.8 mmol, 2.0 eq), KOAc (1.3 g, 13.2 mmol, 3.0 eq), Pd(dppf)Cl2- CH2CI2 (300 mg, 0.4 mmol, 0.1 eq) and DMF (40 mL) under nitrogen atmosphere. The resulting mixture was stirred for 5 hours at 80°C under nitrogen atmosphere. The resulting mixture was diluted with water (80 mL). The resulting mixture was extracted with EtOAc (3x100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The crude residue was applied onto a silica gel column and eluted with petroleum ether / ethyl acetate=5:1 to give N,N- bi s(4-methoxy benzy l)-3-methy l-5-(4, 4, 5,5-tetramethyl- 1 , 3, 2-dioxaborol an-2-y I )-4-(trifl uoromethy l)an i I ine as an off white solid (1.1 g, 40.2%).1HNMR (300 MHz, Chloroform-d) 5 7.14 (d, 7=8.5 Hz, 4H), 6.95-6.83 (m, 4H), 6.54- 6.48 (m, 2H), 4.52 (s, 4H), 3.82 (s, 6H), 2.22 (s, 3H), 1.28 (s, 12H).Synthesis of 3-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline: To a solution of N,N-bis(4-methoxybenzyl)-3-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-4- (trifluoromethyl)aniline (800 mg, 40.9 mmol, 1.0 eq) in MeOH (200 mL) was added Pd / C (10%, 200 mg) in a pressure tank. The mixture was hydrogenated at 70°C under 10 atm hydrogen pressure for 4 hours, filtered through a Celite pad and concentrated under vacuum to give 3-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)-4-(trifluoromethyl)aniline as a colorless oil (120 mg, 33.2%).1H NMR (300 MHz, DMSO-de) 5 6.48 (s, 1 H), 6.42 (s, 1 H), 5.67 (s, 2H), 2.26 (d, J = 2.1 Hz, 3H), 1.27 (s, 12H).Example I NT_A-17: Preparation of 3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline Synthesis of 3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline: Into a 100 mL round bottom flask, were placed 3-bromo-4-(trifluoromethyl)aniline (2.0 g, 4.4 mmol, 1.0 eq), 4,4,5,5-trimethyl-2- (4,4,5,5-trimethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,3,2-dioxaborolane (4.3 g, 8.8 mmol, 2.0 eq), KOAc (2.3 g, 13.2 mmol, 3.0 eq), Pd(dppf)Cl2-CH2Cl2 (200 mg, 0.4 mmol, 0.1 eq) and Dioxane (20 mL) under nitrogen atmosphere. The resulting mixture was stirred for 5 hours at 80°C under nitrogen atmosphere. The resulting mixture was diluted with H2O (80 mL). The resulting mixture was extracted with EtOAc (3x100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The crude residue was applied onto a silica gel column and eluted with petroleum ether / ethyl acetate=5: 1 to give 3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline as an off white solid (0.7 g, 20.2%).1HNMR (300 MHz, Chloroform-d) 5 7.55 (d, 8.4 Hz, 1 H), 7.22 (s, 1 H), 7.01 (d, >7.4 Hz, 1 H), 1.38 (s, 12H).Example INT_B-1 : Preparation of (2,6-dimethylenetetrahydro-1 H-pyrrolizin-7a(5H)-yl)methanolSynthesis of 1 -(tert-butyl) 2-methyl (2S,4R)-4-((tert-butyldiphenylsilyl)oxy)pyrrolidine-1 ,2-dicarboxylate: Into a 2 L 4-necked round-bottom flask, were added 1 -tert-butyl 2-methyl (2S,4R)-4-hydroxypyrrolidine-1 ,2- dicarboxylate (70.0 g, 285.4 mmol, 1.0 eq), Imidazole (58.3 g, 856.2 mmol, 3.0 eq) and DMF (700 mL) at 25°C. To the above mixture was added TBDPS-CI (94.1 g, 342.5 mmol, 1.2 eq) at 0°C. The resulting mixture was stirred for 16 hours at 25°C. The reaction was quenched by the addition of water (500 mL) at 0°C and then extracted with EtOAc (2x500 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The crude residue was applied onto a silica gel column and eluted with ethyl acetate / petroleum ether=1 : 1 to give 1 -(tert-butyl) 2-methyl (2S,4R)- 4-((tert-butyldiphenylsilyl)oxy)pyrrolidine-1 ,2-dicarboxylate as a white solid (110.0 g, 79.7%).1HNMR (300 MHz, DMSO-d6) 5 7.64-7.34 (m, 10H), 4.46-4.24 (m, 2H), 3.61-3.59 (m, 3H), 3.36-3.19 (m, 3H), 2.21-2.18 (m, 1 H), 1.90-1.85 (m, 1 H), 1.35-1.32 (m, 9H), 1.00 (s, 9H).Synthesis of 1 -(tert-butyl) 2-methyl (2R,4R)-4-((tert-butyldiphenylsilyl)oxy)-2-(2- (chloromethyl)allyl)pyrrolidine-1 ,2-dicarboxylate: Into a 3000 mL 4-necked round-bottom flask, were placed 1- (tert-butyl) 2-methyl (2S,4R)-4-((tert-butyldiphenylsilyl)oxy)pyrrolidine-1 ,2-dicarboxylate (90.0 g, 186.1 mmol, 1.0 eq), THF (1000 mL). This was followed by the addition of LIHMDS (279 mL, 1 M in n-hexane, 1.5 eq) at -45°C.Then the reaction mixture was stirred at -45°C for 1 hour. After that a solution of 3-chloro-2-(chloromethyl)prop- 1-ene (27.9 g, 223.3 mmol, 1.2 eq) in THF (400 mL) was added dropwise at -45°C. The resulting mixture was stirred for additional 16 hours at 25°C. The reaction mixture was quenched by the addition of water (1500 mL), and then extracted with ethyl acetate (2500 mL). The combined organic layers was washed with brine (2000 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The crude residue was purified onto a silica gel column and eluted with ethyl acetate / petroleum ether=1 :5 to give 1-(tert- butyl) 2-methyl (2R,4R)-4-((tert-butyldiphenylsilyl)oxy)-2-(2-(chloromethyl)allyl)pyrrolidine-1 ,2-d I carboxyl ate as a light yellow solid (105.0 g, 98.6%).1HNMR (400 MHz, DMSO-» 5 7.61-7.34 (m, 10H), 5.11 -5.04 (m, 1 H), 4.90- 4.83 (m, 1 H), 4.19 (p, >6.8, 6.2 Hz, 1 H), 3.91-3.86 (m, 1 H), 3.81 -3.74 (m, 1 H), 3.70-3.64 (m, 3H), 3.36 (dd, >10.6, 6.2 Hz, 1 H), 3.21 (ddd, >9.8, 6.8, 2.6 Hz, 1 H), 3.06-2.92 (m, 1 H), 2.46-2.42 (m, 1 H), 2.30-2.17 (m, 1 H), 2.15-2.02 (m, 1 H), 1.36 (d, >10.0 Hz, 9H), 0.98 (d, >11.8 Hz, 9H).Synthesis of methyl (2R,4R)-4-((tert-butyldiphenylsilyl)oxy)-2-(2-(chloromethyl)allyl)pyrrolidine-2- carboxylate hydrochloride: Into a 3000 mL 3-necked round-bottom, were placed 1 -(tert-butyl) 2-methyl (2R,4R)- 4-((tert-butyldiphenylsilyl)oxy)-2-(2-(chloromethyl)allyl)pyrrolidine-1 ,2-dicarboxylate (105.0 g, 183.5 mmol, 1.0 eq), CH2CI2 (1000 mL) . This was followed by the addition of HCI (gas)in 1 ,4-dioxane (500 mL) at 0°C. Then the mixture was stirred for 4 hours at 25°C. The resulting mixture was concentrated under vacuum to give methyl (2R,4R)-4-((tert-butyldiphenylsilyl)oxy)-2-(2-(chloromethyl)allyl)pyrrolidine-2-carboxylate hydrochloride as a light yellow solid (90.0 g, crude).Synthesis of methyl (2R, 7aR)-2-((tert-buty Idi phenylsily l)oxy)-6-methylenetetrahydro-1 H-py rrol izine- 7a(5H)-carboxylate: Into a 1000-mL 3-necked round-bottom flask, were placed methyl (2R,4R)-4-((tert- butyldiphenylsilyl)oxy)-2-(2-(chloromethyl)allyl)pyrrolidine-2-carboxylate hydrochloride (90.0 g, 177.0 mmol, 1.0 eq), ACN (1000 mL), TEA (89.5 g, 884.9 mmol, 5.0 eq). The resulting solution was stirred for 16 hours at 25°C. The reaction mixture was concentrated under vacuum, diluted with water (1500 mL), and then extracted with ethyl acetate (2500 mL). The combined organic layer was washed with brine (2500 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The crude residue was purified onto a silica gel column and eluted with ethyl acetate / petroleum ether=1 :2 to give methyl (2R,7aR)-2-((tert- butyldiphenylsilyl)oxy)-6-methylenetetrahydro-1 H-pyrrolizine-7a(5H)-carboxylate as a light yellow solid (60.0 g, 77.8%).1HNMR (400 MHz, DMSO-d6) 5 7.60-7.57 (m, 4H), 7.51-7.38 (m, 6H), 4.87-4.81 (m, 2H), 4.42 (tt, >5.2, 2.7 Hz, 1 H), 3.64-3.62 (m, 1 H), 3.61 (s, 3H), 3.10-3.05 (m, 1 H), 2.98 (dd, >10.8, 2.6 Hz, 1 H), 2.69-2.66 (m, 1 H), 2.65-2.62 (m, 1 H), 2.49-2.40 (m, 2H), 1.86 (dd, >13.4, 5.4 Hz, 1 H), 0.97 (s, 9H).Synthesis of methyl (2R,7aR)-2-hydroxy-6-methylenetetrahydro-1 H-pyrrolizine-7a(5H)-carboxylate: Into a 500-mL round-bottom flask, were placed methyl (2R,7aR)-2-((tert-butyldiphenylsilyl)oxy)-6- methylenetetrahydro-1 H-pyrrolizine-7a(5H)-carboxylate (60.0 g, 137.7 mmol, 1.0 eq), MeOH (600 mL), CsF (209.0 g, 1.4 mmol, 10.0 eq). The resulting solution was stirred for 18 hours at 70°C. The reaction mixture was concentrated under vacuum. The crude residue was purified onto a silica gel column and eluted with dichloromethane / methanol=10: 1 to give methyl (2R,7aR)-2-hydroxy-6-methylenetetrahydro-1 H-pyrrolizine- 7a(5H)-carboxylate as a light yellow oil (16.0 g, 58.9%).1HNMR (400 MHz, DMSO-d6) 5 4.93-4.83 (m, 2H), 4.69(d, >4.0 Hz, 1 H), 4.28 (ddt, 10.0, 5.8, 4.2 Hz, 1 H), 3.63-3.55 (m, 1 H), 3.58 (s, 3H), 3.17 (dt, >14.2, 2.0 Hz, 1 H), 2.90-2.82 (m, 1 H), 2.77-2.67 (m, 2H), 2.52-2.43 (m, 1 H), 2.19 (dd, >13.2, 4.4 Hz, 1 H), 2.02 (dd, >13.2, 6.0 Hz, 1 H).Synthesis of methyl (R)-2-methylene-6-oxotetrahydro-1 H-pyrrolizine-7a(5H)-carboxylate: Into a 500 mL 3-necked round-bottom flask and maintained with an inert atmosphere of nitrogen, were placed (COCI)2 (20.6 g, 162.2 mmol, 2.0 eq), CH2CI2 (160 mL). This was followed by the addition of DMSO (31.7 g, 405.6 mmol, 5.0 eq) at -78°C. Then the mixture was stirred for 1 hour at -78°C. A solution of methyl (2R,7aR)-2-hydroxy-6- methylenetetrahydro-1 H-pyrrolizine-7a(5H)-carboxylate (16.0 g, 81.1 mmol, 1.0 eq) in CH2CI2 (20 mL) was added dropwise at -78°C, the resulting mixture was stirred for 30 minutes. This was followed by the addition of TEA (41.0 g, 405.6 mmol, 5.0 eq) at -78°C. The mixture was stirred at 25°C for 1 hour. The resulting mixture was then quenched by the addition of water (400 mL), and extracted with CH2CI2 (2x450 mL). The combined organic layer was washed with brine (2x450 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The crude residue was purified onto a silica gel column and eluted with ethyl acetate / petroleum ether=1 : 1 to give methyl (R)-2-methylene-6-oxotetrahydro-1 H-pyrrolizine-7a(5H)-carboxylate as a light yellow oil (10.0 g, 63.1%).1HNMR (400 MHz, DMSO-d6) 5 5.03-4.94 (m, 2H), 3.80-3.71 (m, 1 H), 3.63 (s, 3H), 3.42-3.32 (m, 2H), 3.19-3.10 (m, 1 H), 3.12-3.02 (m, 1 H), 2.77-2.65 (m, 2H), 2.61-2.56 (m, 1 H).Synthesis of methyl 2,6-dimethylenetetrahydro-1 H-pyrrolizine-7a(5H)-carboxylate: Into a 100 mL 3- necked round-bottom flask and maintained with an inert atmosphere of nitrogen, were placed methyltriphenylphosphanium bromide (27.5 g, 76.8 mmol, 1.5 eq), THF (100 mL). This was followed by the addition of t-BuOK (10.4 g, 92.2 mmol, 1.8 eq) at 0°C. Then the mixture was stirred for 2 hours at 25°C. A solution of methyl (R)-2-methylene-6-oxotetrahydro-1 H-pyrrolizine-7a(5H)-carboxylate (10.0 g, 51.2 mmol, 1.0 eq) in THF (20 mL) added dropwise at 0°C, Then the mixture was stirred for 2 hours at 25°C and warmed up to 50°C for 16 hours. The resulting mixture was then quenched by the addition of water (200 mL), and then extracted with ethyl acetate (2x200 mL). The combined organic layers was washed with brine (2x200 mL). The mixture was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The crude residue was purified onto a silica gel column and eluted with ethyl acetate / petroleum ether=1 :1 to give methyl 2,6-di methy lenetetrahydro- 1 H-py rrol izine-7a(5H)-carboxyl ate as a light yellow oil (4.5 g, 45.5%).1HNMR (300 MHz, DMSO-d6) 5 5.00-4.87 (m, 4H), 3.65-3.63 (m, 1 H), 3.61 (s, 3H), 3.60-3.58 (m, 1 H), 3.22-3.15 (m, 2H), 2.94- 2.80 (m, 2H), 2.58-2.55 (m, 1 H), 2.52-2.50 (m, 1 H).Synthesis of (2,6-dimethylenetetrahydro-1 H-pyrrolizin-7a(5H)-yl)methanol: Into a 100-mL 3-necked round-bottom flask, were placed methyl 2,6-dimethylenetetrahydro-1 H-pyrrolizine-7a(5H)-carboxylate (4.5 g, 23.3 mmol, 1 .0 eq), THF (50 mL). This was followed by the addition of Li Al H4 (1 .8 g, 46.6 mmol, 2.0 eq) at 0°C. The resulting solution was stirred for 1 hour at 0°C. The reaction was then quenched by the addition of H2O (1.8 mL), 15% NaOH (1.8 mL), H2O (5.4 mL). The resulting solution was stirred for 20 minutes and dried over anhydrous magnesium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum to give (2,6-dimethy lenetetrahydro- 1 H-py rrol izin-7a(5H)-y l)methanol as a light yellow oil (2.4 g, 62.4%).1HNMR (300 MHz, DMSO-d6) 5 4.92-4.87 (m, 4H), 4.57-4.53 (m, 1 H), 3.56-3.50 (m, 2H), 3.17-3.09 (m, 4H), 2.55-2.53 (m, 1 H), 2.49-2.47 (m, 1 H), 2.34-2.19 (m, 2H).Example I NT_B-2: Preparation of (1-(morpholinomethyl)cyclopropyl)methanolSynthesis of methyl 1-(morpholine-4-carbonyl)cyclopropane-1 -carboxylate: Into a 250 mL 3-necked round-bottom flask, were added 1-(methoxycarbonyl)cyclopropane-1 -carboxylic acid (15.0 g, 104.1 mmol, 1.0 eq), CH2CI2 (150 mL) and N,N-dimethylformamide (0.4 mL, 5.2 mmol, 0.05 eq). To the above mixture was added (COCI)2 (53.0 g, 416.3 mmol, 4.0 eq) dropwise over 10 min at 0°C. The resulting mixture was stirred for additional 15 min at 0°C. The resulting mixture was stirred for additional 3 hours at 35°C. The resulting mixture was concentrated under vacuum. The resulting mixture was diluted with CH2CI2 (150 mL), and then TEA (52.7 g, 520.4 mmol, 5.0 eq) and morpholine (10.9 g, 124.9 mmol, 1.2 eq) were added at 0°C. The resulting mixture was stirred for additional 3 hours at 35°C. The resulting mixture was diluted with H2O (200 mL) and extracted with CH2CI2 (3x100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under vacuum. The crude residue was applied onto a silica gel column and eluted with ethyl acetate to give methyl 1-(morpholine-4-carbonyl)cyclopropane-1 -carboxylate as a brown oil (10.0 g, 45.0%).1HNMR (300 MHz, Chloroform-d) 5 3.72 (s, 3H), 3.65 (t, 4.8 Hz, 8H), 1.56-1.42 (m, 2H), 1.37-1.23 (m, 2H).Synthesis of (1-(morpholinomethyl)cyclopropyl)methanol: Into a 250 mL 3-necked round-bottom flask, were added methyl 1 -(morpholine-4-carbonyl)cyclopropane-1 -carboxylate (5.0 g, 23.4 mmol, 1.0 eq), tetrahydrofuran (100 mL). To the above mixture was added UAIH4 (1.8 g, 46.9 mmol, 2.0 eq) in portions at 0°C. The resulting mixture was stirred for additional 2 hours at 25°C. The reaction was quenched by the addition of H2O (2 mL), 15% NaOH (2 mL) and H2O (6 mL) in sequence at 0°C. The resulting mixture was filtered, the filter cake was washed with tetrahydrofuran (3x50 mL), dried over anhydrous MgSC After filtration, the filtrate was concentrated under vacuum to give (1-(morpholinomethyl)cyclopropyl)methanol as a colorless oil (3.0 g, 74.7%).1HNMR (400 MHz, Chloroform-d) 3.68 (t, >4.8 Hz, 4H), 3.64-3.57 (m, 1 H), 3.50 (s, 2H), 2.56 (s, 4H), 2.45 (s, 2H), 0.55-0.41 (m, 2H), 0.41 -0.26 (m, 2H).Example INT_B-4: Preparation of ((2R,7aS)-2-fluoro-6-methylenetetrahydro-1 H-pyrrolizin-7a(5H)-yl)methanolSynthesis of 1 -(tert-butyl) 2-methyl (2R,4R)-4-fluoropyrrolidine-1 ,2-dicarboxylate: Into a 3 L 3-necked round-bottom flask were added 1 -(tert-butyl) 2-methyl (2R,4S)-4-hydroxypyrrolidine-1 ,2-dicarboxylate (60.0 g, 244.6 mmol, 1.0 eq), Pyridine (23.2 g, 293.5 mmol, 1.2 eq) and DCM (900 mL). To the above mixture was added Tf2<3 (75.9 g, 269.1 mmol, 1.1 eq) dropwise at -10°C. The resulting mixture was stirred for 30 min at -10°C. The reaction was quenched by the addition of HCI (aq., 1 N, 480 mL) at 0°C. The resulting mixture was stirred for an additional 60 min. The organic layer was separated and concentrated to 600 mL under vacuum. It was subsequently added to TEA.3HF (86.8 g, 538.2 mmol, 2.2 eq) and TEA (24.8 g, 244.7mmol, 1.0 eq) at 25°C. The reaction was stirred for 5 hours at 25°C and quenched with 10% aq. Na2COa (50 mL). The organic layer was separated and washed with 0.5 N aq. HCI (480 mL). To the organic layer was added KMnO4 (19.3 g, 122.3mmol, 0.5 eq) in H2O (300 mL), and the mixture was stirred for 90 min at 25°C. The resulting mixture was cooled to 10°C and quenched with NaHSOa (12.7 g, 122.3 mmol, 0.5 eq) in H2O (300 mL) while maintaining an internal temperature of around 10°C. The resultant white precipitate was removed via filtration, and the organic layer was separated and concentrated to provide 1 -(tert-butyl) 2-methyl (2R,4R)-4-fluoropyrrolidine-1,2-dicarboxylate as a colorless oil (50.0 g, 82.7%).1HNMR (400 MHz, DMSO-d6) 5 5.27 (dq, >55.2, 3.8 Hz, 1 H), 4.48-4.29 (m, 1 H), 3.65 (d, >9.6 Hz, 3H), 3.61-3.48 (m, 2H), 2.51 (dt, >3.5, 1.7 Hz, 1 H), 2.34-2.14 (m, 1 H), 1.39-1.37 (m, 9H).19FNMR (376 MHz, DMSO) 5 -171.78, -172.05.Synthesis of 1 -(tert-butyl) 2-methyl (2S,4R)-2-(2-(chloromethyl)allyl)-4-fluoropyrrolidine-1 ,2- di carboxyl ate: Into a 2000 mL 3-necked round-bottom flask were added 1 -(tert-butyl) 2-methyl (2R,4R)-4- fluoropyrrolidine-1 ,2-dicarboxylate (45.0 g, 182.0 mmol, 1.0 eq), 3-chloro-2-(chloromethyl)prop-1-ene (27.3 g, 218.4 mmol, 1.2 eq) and THF (900 mL) at 25°C. To the above mixture was added LiHMDS (273mL, 273.0 mmol, 1 N in THF, 1.5 eq) dropwise over 40 min at -40°C. The resulting mixture was stirred for 16 hours at 25°C. The reaction was quenched by the addition of sat. NH4CI (aq.) (1000 mL) at 0°C. The resulting mixture was extracted with EtOAc (2x1000 mL). The combined organic layers were washed with brine (1000 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The crude residue was applied onto a silica gel column and eluted with ethyl acetate / petroleum ether=1 : 1 to afford 1 -(tert-butyl) 2- methyl (2S,4R)-2-(2-(chloromethyl)allyl)-4-fluoropyrrolidine-1 ,2-dicarboxylate (35.0 g, 57.3%) as a colorless oil.1HNMR (400 MHz, Chloroform-d) 5 5.44 (s, 1 H), 5.18-4.95 (m, 2H), 4.05-3.94 (m, 2H), 3.76 (d, >6.7 Hz, 3H), 3.65-3.44 (m, 1 H), 3.28 (d, >14.6 Hz, 1 H), 2.72 (dd, >19.4, 14.6 Hz, 1 H), 2.65-2.36 (m, 2H), 1.49-1.47 (m, 9H).19FNMR (376 MHz, CDCI3) 5 -173.08, -173.88.Synthesis of methyl (2S, 4R)-2-(2-(chloromethy l)ally l)-4-fl uoropy rrolidi ne-2-carboxy late hydrochloride: Into a 2000 mL round-bottom flask were added 1 -(tert-butyl) 2-methyl (2S,4R)-2-(2-(chloromethyl)allyl)-4- fluoropyrrolidine-1 ,2-dicarboxylate (40.0 g, 119.1 mmol, 1.0 eq), DCM (350 mL) and HCI(gas)in 1 ,4-dioxane (250 mL) at 25°C. The resulting mixture was stirred for 3 hours at 25°C. The resulting mixture was concentrated under vacuum. This resulted in methyl (2S,4R)-2-(2-(chloromethyl)allyl)-4-fluoropyrrolidine-2-carboxylate hydrochloride as a white solid (35 g, crude).1HNMR (400 MHz, DMSO-» 5 11.50 (s, 1 H), 9.92 (s, 1 H), 5.61- 5.04 (m, 3H), 4.24 (d, >12.4 Hz, 1 H), 4.15-4.02 (m, 1 H), 3.81 (s, 1 H), 3.76 (s, 3H), 3.16-3.12 (m, 1 H), 3.02-3.00 (m, 1 H), 2.79 (ddd, >17.2, 15.0, 1.9 Hz, 1 H), 2.38-2.28 (m, 1 H).19FNMR (376 MHz, DMSO) 5 -170.03.Synthesis of methyl (2R,7aS)-2-fluoro-6-methylenetetrahydro-1 H-pyrrolizine-7a(5H)-carboxylate: Into a 1000 mL round-bottom flask were added methyl (2S,4R)-2-(2-(chloromethyl)allyl)-4-fluoropyrrolidine-2- carboxylate hydrochloride (32.0 g, 135.8 mmol, 1.0 eq), TEA (68.7 g, 678.9 mmol, 5.0 eq) and CH3CN (400 mL) at 25°C. The resulting mixture was stirred for 16 hours at 25°C. The reaction was quenched by the addition of water (200 mL) at 25°C. The resulting mixture was extracted with EtOAc (2x300 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The crude residue was applied onto a silica gel column and eluted with ethyl acetate / petroleum ether=1 :1 to afford methyl (2R,7aS)-2-fluoro-6-methylenetetrahydro-1 H-pyrrolizine-7a(5H)- carboxylate as a colorless oil (20.0 g, 73.9%).1HNMR (400 MHz, Chloroform-d) 5 5.34-5.23 (m, 1 H), 5.15 (ddt,>5.1, 4.2, 1.1 Hz, 1 H), 5.00-4.89 (m, 2H), 3.86-3.82 (m, 1 H), 3.74 (s, 3H), 3.49-3.45 (m, 1 H), 3.27-3.15 (m, 1 H), 2.97-2.74 (m, 2H), 2.52-2.49 (m, 1 H), 2.17-1.95 (m, 1 H).19FNMR (376 MHz, CDCI3) 5 -174.47.Synthesis of ((2R,7aS)-2-fluoro-6-methylenetetrahydro-1 H-pyrrolizin-7a(5H)-yl)methanol: Into a 50 mL 3-necked round-bottom flask were added methyl (2R,7aS)-2-fluoro-6-methylenetetrahydro-1 H-pyrrolizine- 7a(5H)-carboxylate (500 mg, 2.5 mmol, 1.0 eq) and THF (10 mL) at 25°C. To the above mixture was added LIAIH4 (123.8 mg, 3.3 mmol, 1.3 eq) in portions at O°C. The resulting mixture was stirred for 2 hours at 25°C. The reaction was quenched by the addition of saturated aqueous solution of 10H2O.Na2SO4 at 0°C. The resulting mixture was filtered, the filter cake was washed with ethyl acetate (2x10 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under vacuum. The crude residue was applied onto a silica gel column and eluted with dichloromethane / methanol=10:1 to afford ((2R,7aS)-2-fluoro-6-methylenetetrahydro- 1 H-pyrrolizin-7a(5H)-yl)methanol as a colorless oil (350 mg, 81.5%).Example INT_B-5: Preparation of methyl (3S,4S)-4-(difluoromethyl)-1,3-dimethylpiperidine-3-carboxylate (c / s racemates)Synthesis of 1 -tert-butyl 3-methyl 3-methyl-4-oxopiperidine-1 ,3-dicarboxylate: Into a 500 mL 3-necked round-bottom flask were added 1 -tert-butyl 3-methyl 4-oxopiperidine-1 ,3-dicarboxylate (25.0 g, 97.2 mmol, 1.0 eq) and K2CO3 (40.3 g, 291.5 mmol, 3.0 eq) in 250 mL MeCN at 25°C. To the above mixture was added methyl iodide (27.6 g, 194.3 mmol, 2.0 eq) dropwise over 10 min at 0°C. The resulting mixture was stirred at 40°C for additional 12 hours. The mixture was allowed to cool down to 25°C. The reaction was quenched with sat. NH4CI (aq.) at 25°C. The resulting mixture was extracted with EtOAc (3x200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with ethyl acetate / petroleum ether=1 : 10 to give 1 -tert-butyl 3-methyl 3-methyl-4-oxopiperidine-1,3-dicarboxylate as a white solid (25.0 g, 94.8%).1HNMR (300 MHz, Chloroform-d) 5 4.53-4.39 (m, 1 H), 4.08 (q, >6.4, 5.9 Hz, 1 H), 3.69 (s, 3H), 3.30 (ddd, >13.7, 10.1, 4.5 Hz, 1 H), 3.05 (d, >13.7 Hz, 1 H), 2.73 (s, 1 H), 2.45 (dt, >14.9, 4.5 Hz, 1 H), 1.45 (s, 9H), 1.27 (s, 3H).Synthesis of 1 -(tert-butyl) 3-methyl 4-(difluoromethylene)-3-methylpiperidine-1 ,3-dicarboxylate: Into a 500 mL 3-necked round-bottom flask were added 1 -tert-butyl 3-methyl 3-methyl-4-oxopiperidine-1 ,3- dicarboxylate (20.0 g, 73.7 mmol, 1.0 eq) and 2-difluoromethanesulfonylpyridine (21.4 g, 110.6 mmol, 1.5 eq) in 200 mL DMF at 25°C under nitrogen atmosphere. To the above mixture was added t-BuOK(1.0 M in THF) (75 mL, 1 .8 eq) dropwise over 20 min at -60°C. The resulting mixture was stirred at 25°C for additional 5 hours. The reaction was quenched with sat. NH4CI (aq.) at 25°C. The resulting mixture was extracted with EtOAc (3x200 mL). The combined organic layers were washed with brine (2x100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with ethyl acetate / petroleum ether=1 :5 to give 1 -(tert-butyl) 3-methyl 4- (difluoromethylene)-3-methylpiperidine-1,3-dicarboxylate as a light yellow solid (9.0 g, 40.0%).1HNMR (300MHz, Chloroform-d) 5 4.01-3.88 (m, 1 H), 3.68 (s, 3H), 3.61-3.48 (m, 1 H), 3.27 (dt, >12.8, 6.3 Hz, 1 H), 3.15 (d, >13.4 Hz, 1 H), 2.29 (d, >6.5 Hz, 2H), 1.43 (s, 9H), 1.36 (d, >3.4 Hz, 3H).Synthesis of 1 -(tert-butyl) 3-methyl (3S,4S)-4-(difluoromethyl)-3-methylpiperidine-1,3-dicarboxylate (c / s racemates): To a solution of 1 -(tert-butyl) 3-methyl 4-(difluoromethylene)-3-methylpiperidine-1 ,3-dicarboxylate (7.0 g, 22.9 mmol, 1.0 eq) in 140 mL MeOH was added Pd / C (10%, 700 mg) in a pressure tank. The mixture was hydrogenated at 30°C under 10 atm of hydrogen pressure for 12 hours, filtered through a Celite pad and concentrated under vacuum to give 1 -(tert-butyl) 3-methyl (3S,4S)-4-(difluoromethyl)-3-methylpiperidine-1 ,3- dicarboxylate (c / s racemates) as a light yellow solid (6.0 g, 85.2%).1HNMR (300 MHz, Chloroform-d) 5 6.40- 5.89 (m, 1 H), 4.30 (s, 1 H), 4.07 (s, 1 H), 3.66 (s, 3H), 2.78 (t, >11.9 Hz, 1 H), 2.60 (s, 1 H), 1.89-1.62 (m, 3H), 1.42 (s, 9H), 1.27 (d, >3.1 Hz, 3H).Synthesis of methyl (3S,4S)-4-(difluoromethyl)-3-methylpiperidine-3-carboxylate hydrochloride (c / s racemates): Into a 250 mL 3-necked round-bottom flask were added 1 -(tert-butyl) 3-methyl (3S,4S)-4- (difluoromethyl)-3-methylpiperidine-1 ,3-dicarboxylate (c / s racemates) (6.0 g, 19.5 mmol, 1.0 eq) and HCI in 1 ,4- dioxane (4.0 M) at 25°C. The resulting mixture was stirred at 25°C for additional 1 hour. The resulting mixture was concentrated under vacuum to give methyl (3S,4S)-4-(difluoromethyl)-3-methylpiperidine-3-carboxylate hydrochloride (c / s racemates) as an off-white solid (4.0 g, 98.9%).1HNMR (300 MHz, Methanol-^) 5 6.23 (m, 1 H), 3.81 (s, 3H), 3.60 (d, >13.3 Hz, 1 H), 3.50 (dt, >13.2, 3.5 Hz, 1 H), 3.12 (td, >12.9, 3.6 Hz, 1 H), 2.99 (d, >13.3 Hz, 1 H), 2.42-2.22 (m, 1 H), 2.05 (dq, >14.9, 3.4 Hz, 1 H), 1.87 (dtd, >14.7, 12.8, 4.4 Hz, 1 H), 1.43 (d, >1.5 Hz, 3H).Synthesis of methyl (3S,4S)-4-(difluoromethyl)-1 ,3-dimethylpiperidine-3-carboxylate (c / s racemates): Into a 250 mL 3-necked round-bottom flask were added methyl (3S,4S)-4-(difluoromethyl)-3-methylpiperidine-3- carboxylate hydrochloride (c / s racemates) (5.0 g, 24.1 mmol, 1.0 eq) and formaldehyde solution (2.2 g, 72.4 mmol, 3.0 eq) at 25°C. The resulting mixture was stirred at 25°C for additional 30 min. To the above mixture was added Sodium cyanoborohydride (1.8 g, 29.0 mmol, 1.2 eq). The resulting mixture was stirred at 25°C for additional 2 hours. The reaction was quenched with water at 25°C. The resulting mixture was extracted with EtOAc (3x50 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with ethyl acetate / petroleum ether=1 :5 to give methyl (3S,4S)-4-(difluoromethyl)-1 ,3- dimethylpiperidine-3-carboxylate (c / s racemates) as an off-white solid (3.5 g, 65.6%).1HNMR (300 MHz, Chloroform-d) 5 6.32 (m, 1 H), 3.72 (s, 3H), 3.12 (dt, >11.6, 1.7 Hz, 1 H), 2.97-2.80 (m, 1 H), 2.23 (s, 3H), 1.99- 1 .84 (m, 2H), 1 .76 (t, >11 .3 Hz, 2H), 1 .67-1 .52 (m, 1 H), 1 .27 (d, >3.6 Hz, 3H).Example INT_C-2: Preparation of 2,5,7-trichloro-8-fluoropyrido[4,3-d]pyrimidin-4-olSynthesis of 2,6-dichloro-3-fluoropyridin-4-amine: Into a 2000 mL round-bottom flask, were placed 2,6- dichloropyridin-4-amine (90.0 g, 286.6 mmol, 1.0 eq), select-F (107.4 g, 343.9 mmol, 1.2 eq), MeCN (450 mL) and DMF (450 ml) at 25°C. The resulting mixture was stirred for 1 hour at 80°C. The reaction mixture was quenched by the addition of water (1000 mL), and then extracted with ethyl acetate (3x1000 mL). The combinedorganic extracts were washed with brine (1000 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The crude product was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% TFA), 10% to 80% gradient in 15 min; detector, UV 254 nm. Finally, 2,6-dichloro-3-fluoropyridin-4-amine was obtained as a yellow solid (26.8 g, 26.1%).Synthesis of 2,6-dichloro-3-fluoro-5-iodopyridin-4-amine: to a 1000 mL round-bottom flask, were placed 2,6-dichloro-3-fluoropyridin-4-amine (25.0 g, 286.6 mmol, 1.0 eq), NIS (30.4 g, 343.9 mmol, 1.2 eq), MeCN (300 mL) and TsOH.F O (1.5 g, 14.3 mmol, 0.05 eq) at 25°C. The resulting mixture was stirred for 1 hour at 70°C. The reaction mixture was quenched by the addition of water (500 mL), and then extracted with ethyl acetate (2x500 mL). The combined organic layers were washed with saturated NaHCOa solution (500 mL), saturated NaaSOa solution (500 mL) and brine (500 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum to give 2, 6-dichloro-3-fl uoro-5-iodopy ridi n-4-amine as a yellow solid (38.0 g, crude). HNMR (300 MHz, Chloroform-d) 5 7.05 (s, 2H).Synthesis of methyl 4-amino-2,6-dichloro-5-fluoronicotinate: to a 1000 mL pressure tank reactor, were placed 2,6-dichloro-3-fluoro-5-iodopyridin-4-amine (38.0 g, 330.3 mmol, 1.0 eq), MeOH (700 mL), Pd(dppf)Cl2 (13.0 g, 33.0 mmol, 0.1 eq) and TEA (52.0 g, 1189.2 mmol, 3.6 eq). The reaction mixture was stirred for 12 hours at 60°C under CO (5 atm) atmosphere. The reaction mixture was filtered, the filtrate was concentrated under vacuum to remove 70% of MeOH and the residue was filtered. The filter cake was dried under vacuum to give methyl 4-amino-2,6-dichloro-5-fluoronicotinate as a yellow solid (17.0 g, 64.2%). HNMR (300 MHz, Chloroform-d) 5 6.20 (s, 2H), 3.99 (s, 3H).Synthesis of methyl 2,6-dichloro-5-fluoro-4-(3-(2,2,2-trichloroacetyl)ureido)nicotinate: Into a 250 mL round-bottom flask, were placed ethyl methyl 4-amino-2,6-dichloro-5-fluoronicotinate (17.0 g, 311.1 mmol, 1.0 eq), tetrahydrofuran (80 mL) and 2,2,2-trichloroacetyl isocyanate (32.9 g, 466.6 mmol, 1.5 eq). The reaction mixture was stirred for 1 hour at 25°C. The resulting mixture was concentrated under vacuum. The residue was purified by trituration with MTBE to give methyl 2,6-dichloro-5-fluoro-4-(3-(2,2,2-trichloroacetyl)ureido)nicotinate as a white solid (15.0 g, 40.8%).1HNMR (300 MHz, Chloroform-d) 5 10.39 (s, 1 H), 8.69 (s, 1 H), 4.04 (s, 3H).Synthesis of 5,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine-2,4-diol : Into a 250 mL round-bottom flask, were placed methyl 2,6-dichloro-5-fluoro-4-(3-(2,2,2-trichloroacetyl)ureido)nicotinate (15.0 g, 189.2 mmol, 1.0 eq) and NHa(g) in methanol (40 mL, 20%). The reaction mixture was stirred for 3 hours at 25°C. The resulting mixture was concentrated under vacuum. The residue was purified by trituration with MTBE to give 5, 7-dichloro- 8-fluoropyrido[4,3-d]pyrimidine-2,4-diol as a white solid (8.0 g, 55.8%). LC-MS (ES, m / z) M-1 : 248 / 250.Synthesis of 2,4,5, 7-tetrachloro-8-fluoropyrido[4,3-d]pyrimidine: Into a 250 mL round-bottom flask, were placed 5,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine-2,4-diol (5.0 g, 20.0 mmol, 1.0 eq), POCI3 (100 mL). To the above mixture was added DIEA (10.3 g, 79.9 mmol, 4.0 eq) in portions at 5°C. The resulting mixture was stirred for additional 4 hours at 90°C. The resulting mixture was concentrated under vacuum and poured into NaHCOa (aq.) (100 mL). The resulting mixture was extracted with CH2CI2 (2x100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated undervacuum. The crude residue was applied onto a silica gel column and eluted with ethyl acetate / petroleum ether=1 :5 to give 2,4,5,7-tetrachloro-8-fluoropyrido[4,3-d]pyrimidine as an off-white solid (3.0 g, 52.3%).Synthesis of 2,5,7-trichloro-8-fluoropyrido[4,3-d]pyrimidin-4-ol: Into a 250 mL 3-necked round-bottom, were placed 2,4,5,7-tetrachloro-8-fluoropyrido[4,3-d]pyrimidine (2.2 g, 7.7 mmol, 1.0 eq), THF (40 mL). This was followed by the addition of NaHCOa (23 mL, 1 M) at 0°C. Then the mixture was stirred for 1 hour at 0°C. The mixture neutralized to pH=5-6 with HCI (1 M). The resulting mixture was quenched by the addition of water (80 mL), and then extracted with ethyl acetate (2x150 mL). The combined organic layer was washed with brine (150 mL), dried over anhydrous NaaSC . After filtration, the filtrate was concentrated under vacuum. The crude residue was purified onto a silica gel column and eluted with ethyl acetate / petroleum ether=1 :0 to give 2,5,7- trichloro-8-fluoropyrido[4,3-d]pyrimidin-4-ol as an off-white solid (1.2 g, 58.3%). LC-MS (ES, m / z) M-1 : 266 / 268.Example I NT_C-3: Preparation of 5-bromo-4,7-dichloro-2-(ethylthio)-8-fluoropyrido[4,3-d]pyrimidineSynthesis of 7-chloro-2-(ethylthio)-8-fluoro-4-methoxypyrido[4,3-d]pyrimidine: To a stirred solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (10.0 g, 39.6 mmol, 1.0 eq) in 2-methyl-THF (150 mL) was added NaOMe (8.6 g, 39.6 mmol, 1.0 eq, 25% in MeOH) dropwise at -20°C under nitrogen atmosphere. The resulting mixture was stirred for 15 min at -20°C under nitrogen atmosphere. To the above mixture was added ethanethiol (7.4 g, 118.8mmol, 3.0 eq) dropwise at -20°C. The resulting mixture was stirred for additional 2 min at -20°C. To the above mixture was added DIEA (16.4 g, 126.8 mmol, 3.2 eq) dropwise at -20°C. The resulting mixture was stirred for additional 15 min at -20°C. The resulting mixture was warmed up to 25°C and stirred for 20 minutes. The resulting mixture was stirred for 16 hours at 70°C under nitrogen atmosphere. The reaction was quenched by the addition of water (100 mL), and then extracted with EtOAc (2x100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The crude residue was applied onto a silica gel column and eluted with ethyl acetate / petroleum ether=1 :10 to afford 7-chloro-2-(ethylthio)-8-fluoro-4-methoxypyrido[4,3-d]pyrimidine as a yellow solid (6.0 g, 55.3%).1HNMR (400 MHz, Chloroform-d) 5 8.97 (s, 1 H), 4.23 (s, 3H), 3.30 (q, 7.4 Hz, 2H), 1.48 (t, >7.4 Hz, 3H).Synthesis of 5-bromo-7-chloro-2-(ethylthio)-8-fluoro-4-methoxypyrido[4,3-d]pyrimidine: To a stirred solution of 7-chloro-2-(ethylthio)-8-fluoro-4-methoxypyrido[4,3-d]pyrimidine (6.0 g, 21.9 mmol, 1.0 eq) in THF (60 mL) was added TEMPO-MgCl-LICI (83 mL, 83.3 mmol, 3.8 eq 1 M in THF) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 1 hour at 0°C under nitrogen atmosphere. To the above mixture was added 1 ,2-dibromo-1 ,1 ,2,2-tetrachloroethane (28.6 g, 87.7 mmol, 4.0 eq) in THF (60 mL) dropwise over 10 min at 0°C. The resulting mixture was stirred for additional 2 hours at 0°C. The reaction was quenched by the addition of sat. NH4CI (aq.) (100 mL), and then extracted with EtOAc (2x100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The crude residue was applied onto a silica gel column and eluted with ethyl acetate / petroleum ether=1 : 10 to afford 5-bromo-7-chloro-2-(ethylthio)-8-fluoro-4-methoxypyrido[4,3-d]pyrimidineas a white solid (4.0 g, 51.8%).1HNMR (400 MHz, Chloroform-d) 5 4.23 (s, 3H), 3.28 (q, 7.4 Hz, 2H), 1.48 (t, >7.4 Hz, 3H).Synthesis of 5-bromo-7-chloro-2-(ethylthio)-8-fluoropyrido[4,3-d]pyrimidin-4(3H)-one: Into a 250 mL round-bottom flask were added 5-bromo-7-chloro-2-(ethylthio)-8-fluoro-4-methoxypyrido[4,3-d]pyrimidine (4.0 g, 11 .3 mmol, 1 .0 eq), AcOH (60 mL) and Nal (8.5 g, 56.7 mmol, 5.0 eq) at 25°C. The resulting mixture was stirred for 3 hours at 80°C. The reaction was quenched by the addition of water (100 mL), and then extracted with EtOAc (2x100 mL). The combined organic layers were washed with Na2SOa (aq) (100 mL), brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The crude residue was applied onto a silica gel column and eluted with ethyl acetate / petroleum ether=1 : 1 to afford 5-bromo-7-chloro-2- (ethylthio)-8-fluoropyrido[4,3-d]pyrimidin-4(3H)-one as a white solid (1.9 g, 49.5%).1HNMR (400 MHz, DMSO-de) 5 13.27 (br, 1 H), 3.23 (q, >7.3 Hz, 2H), 1.36 (t, >7.3 Hz, 3H).Synthesis of 5-bromo-4,7-dichloro-2-(ethylthio)-8-fluoropyrido[4,3-d]pyrimidine: To a stirred solution of 5-bromo-7-chloro-2-(ethylthio)-8-fluoropyrido[4,3-d]pyrimidin-4(3H)-one (300 mg, 0.9 mmol, 1.0 eq) and POCI3 (4 mL) was added DIEA (229 mg, 1.8 mmol, 2.0 eq) dropwise at 25°C. The resulting mixture was stirred for 10 min at 60°C. The resulting mixture was concentrated under vacuum. The crude product was used in the next step directly without further purification.Example INT_C-4: Preparation of 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-olSynthesis of 4-Bromo-2,6-dichloro-5-fluoronicotinic acid: At -78°C, Methyl lithium (47.6 mL, 76.19 mmol, 1.6 M) was added dropwise to 2,6-dichloro-5-fluoronicotinic acid (8.0 g, 38.095 mmol) in dry tetrahydrofuran (150 mL). After the addition, the mixture was stirred at -20°C for 2 hours. The reaction mixture was cooled to -78°C again. A solution of 1 ,2-dibromo-1 , 1 ,2,2-tetrachloroethane (12.405 g, 38.095 mmol) in tetrahydrofuran (30 mL) was added dropwise within 30 minutes. The reaction was carried out at 0°C for 1 .5 hours. After that, the reaction solution was poured into ice water (500 mL), wash with chloroform (100 mL). The aqueous phase was adjusted to pH=3 with hydrochloric acid (3 M), the aqueous phase was concentrated under reduced pressure. The crude product was purified by column chromatography to give 4-Bromo-2,6-dichloro-5- fluoronicotinic acid (7.6 g, 88%) as a brown solid.Synthesis of Methyl (4-bromo-2,6-dichloro-5-fluoronicotinoyl)carbamoyliminothioate: 4-Bromo-2,6- dichloro-5-fluoronicotinic acid (6.0 g, 20.90 mmol) was dissolved in thionyl chloride (40.0 mL) at 25°C, and 1 drops of N,N-dimethylformamide is added to the above mixture, The reaction system was stirred at 100°C for 1 hour. After 1 hour, the solvent was concentrated under reduced pressure. The crude product was added to tetrahydrofuran (100 mL) at 0 °C and saturated sodium bicarbonate (100 mL) mixed solvent. Finally, carbamoylimidothiomethyl (12.91 g, 68.607 mmol) was added, the reaction was stirred at this temperature for 30 minutes. The reaction was then extracted with ethyl acetate (200 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. Finally, Methyl (4-bromo-2,6-dichloro-5- fluoronicotinoy l)carbamoy II minothioate (2.23 g, 29.8%) was obtained as a yellow solid.Synthesis of 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol: To a solution of methyl (4- bromo-2,6-dichloro-5-fhioronicotinoyl)carbamimidothioate (6.00 g, 1.0 eq) in dioxane (40 mL) was added DIEA (6.44 g, 3.0 eq). The reaction was stirred at 100 °C for 12 hours. The mixture was diluted with water (50 mL) and extracted with EtOAc (3x50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and purified with column chromatography to afford 5,7-dichloro-8- fl uoro-2-(methy lthio)py rido[4, 3-d]py rimidin-4-ol (5.00 g, 93% yield) as yellow solid. LC-MS (ES, m / z) M+1 : 280.0.Example INT_D-2: Preparation of 8-tert-butyl 2-methyl (1 S,5R)-4-oxo-3,8-diazabicyclo[3.2.1]octane-2,8- d I carboxyl ateSynthesis of methyl (2R)-5-methoxy-3,4-dihydro-2H-pyrrole-2-carboxylate: Into a 3500 mL 3-necked round-bottom flask were added methyl (2R)-5-oxopyrrolidine-2-carboxylate (100.0 g, 698.6 mmol, 1.0 eq) and CH2CI2 (1000 mL). To the above mixture was added tetrafluoroboranuide (155.0 g...

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula (1), or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug of said compound of Formula (1) or N-oxide thereof:whereinQi is aryl, or heteroaryl;Wi to W4 are each independently N or C(Ra);Z1 is absent, a bond, -(CRaRb)P-, -N(RC)-, -O-, or -S-;Z2 is absent, a bond, -(CRaRb)P-, -N(RC)-, -O-, -O-(CRaRb)P-, or -S-;L is absent, a bond, -(CRaRb)P-, -N(RC)-, -O-, -S-, -C(O)-, -S(O2)-, -O(CRaRb)P-, -N(Rc)(CRaRb)P-, -OC(O)-, -C(O)O-, -OSO2-, -S(O2)O-, -C(O)S-, -SC(O)-, -C(O)C(O)-, -C(O)N(Rc)-, -N(Rc)C(O)-, - S(O2)N(RC)-, -N(RC)S(O2)-, -OC(O)O-, -OC(O)S-, -OC(O)N(RC)-, -N(RC)C(O)O-, -N(RC)C(O)S-, - N(Rc)C(O)N(Rc)-, -(CRaRb)PN(Rc)(CRaRb)q-, -(CRaRb)PN(Rc)C(O)(CRaRb)q- ,OC(O)N(Rc)(CRaRb)P+iN(Rc)(CRaRb)q-, -(CRaRb)PC(O)N(Rc)(CRaRb)q-, bivalent alkyl, bivalent alkenyl, bivalent alkynyl, bivalent cycloalkyl, bivalent cycloalkenyl, bivalent fused-carbocyclic, bivalent bridged- carbocyclic, bivalent spirocycloalkyl, bivalent heterocycloalkyl, bivalent heterocycloalkenyl, bivalent spiro-heterocyclic, bivalent fused-heterocyclic, bivalent bridged-heterocyclic, bivalent aryl, or bivalent heteroaryl, each of the aforementioned is independently optionally subsitiuted with one or more Rd substituents; each R1 is independently H, D, halo, cyano, nitro, alkyl, alkenyl, alkynyl, -alkylene-Ra, =CRaRb, =NRb, =0, -C(0)Ra, -C(0)NRbRc, -C(0)0Ra, -NH(CH2)PRa, -NRbRc, -NRbC(0)Rc, -NRbS(0)2Rc, - N=S(O)RbRc, -0Ra, -0C(0)Ra, -0C(0)0Ra, -0P(0)(0Rb)(0Rc), -OP(O)(ORb)(NHRc), -0P(0)RbRc, - P(0)RbRc, -alkylene-P(O)RbRc, -SRa, -S(0)Ra, -S(0)(NRb)Rc, -S(0)2Ra, -S(0)2NRbRc, -(CRaRb)PRd, - (CRaRb)pN(Rc)(CRaRb)qRd, -(CRaRb)PO(CRaRb)qRd, -(CRaRb)PC(O)(CRaRb)qRd, - (CRaRb)PC(O)O(CRaRb)qRd, -(CRaRb)P0C(0)(CRaRb)qRd, -(CRaRb)P0C(0)0(CRaRb)qRd, - (CRaRb)PN(Rc)C(O)(CRaRb)qRd, -(CRaRb)pC(O)N(Rc)(CRaRb)qRd, -(CRaRb)p0C(0)N(Rc)(CRaRb)qRd, - (CRaRb)PN(Rc)C(O)O(CRaRb)qRd, cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged- carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged- heterocyclic, aryl, or heteroaryl, each of the aforementioned is optionally substituted with one or moreindependently selected Rd substituents; or two Ri, taken together with the atom(s) to which they are attached, independently form a cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl, each of the aforementioned is optionally and independently substituted with one or more independently selected Rd substituents; each R2 is independently H, D, halo, cyano, nitro, alkyl, alkenyl, alkynyl, -alkylene-Ra, =CRaRb, =NRb, =0, -C(0)Ra, -C(0)NRbRc, -C(0)0Ra, -NH(CH2)PRa, -NRbRc, -NRbC(0)Rc, -NRbS(O)2Rc, - N=S(O)RbRc, -0Ra, -0C(0)Ra, -0C(0)0Ra, -0P(0)(0Rb)(0Rc), -OP(O)(ORb)(NHRc), -0P(0)RbRc, - P(0)RbRc, -alkylene-P(O)RbRc, -SRa, -S(O)Ra, -S(0)(NRb)Rc, -S(O)2Ra, -S(O)2NRbRc, -(CRaRb)pRd, - (CRaRb)pN(Rc)(CRaRb)qRd, -(CRaRb)PO(CRaRb)qRd, -(CRaRb)PC(O)(CRaRb)qRd, - (CRaRb)pC(O)O(CRaRb)qRd, -(CRaRb)p0C(0)(CRaRb)qRd, -(CRaRb)p0C(0)0(CRaRb)qRd, - (CRaRb)pN(Rc)C(O)(CRaRb)qRd, -(CRaRb)pC(O)N(Rc)(CRaRb)qRd, -(CRaRb)p0C(0)N(Rc)(CRaRb)qRd, - (CRaRb)pN(Rc)C(O)O(CRaRb)qRd, cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged- carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged- heterocyclic, aryl, or heteroaryl, each of the aforementioned is optionally substituted with one or more independently selected Rd substituents; two R2, taken together with the atom(s) to which they are attached, independently form a cycloalkyl or heterocycloalkyl, wherein each cycloalkyl or heterocycloalkyl is optionally and independently substituted with one or more independently selected Rdsubstituents; each R3 is independently H, D, halo, cyano, nitro, alkyl, alkenyl, alkynyl, -alkylene-Ra, =CRaRb, =NRb, =0, -C(0)Ra, -C(0)NRbRc, -C(0)0Ra, -NH(CH2)pRa, -NRbRc, -NRbC(0)Rc, -NRbS(O)2Rc, - N=S(O)RbRc, -0Ra, -0C(0)Ra, -0C(0)0Ra, -0P(0)(0Rb)(0Rc), -OP(O)(ORb)(NHRc), -0P(0)RbRc, - P(0)RbRc, -alkylene-P(O)RbRc, -SRa, -S(O)Ra, -S(O)(NRb)Rc, -S(O)2Ra, -S(O)2NRbRc, -(CRaRb)pRd, - (CRaRb)pN(Rc)(CRaRb)qRd, -(CRaRb)pO(CRaRb)qRd, -(CRaRb)pC(O)(CRaRb)qRd, - (CRaRb)pC(O)O(CRaRb)qRd, -(CRaRb)p0C(0)(CRaRb)qRd, -(CRaRb)p0C(0)0(CRaRb)qRd, - (CRaRb)pN(Rc)C(O)(CRaRb)qRd, -(CRaRb)pC(O)N(Rc)(CRaRb)qRd, -(CRaRb)p0C(0)N(Rc)(CRaRb)qRd, - (CRaRb)pN(Rc)C(O)O(CRaRb)qRd, cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged- carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged- heterocyclic, aryl, or heteroaryl, each of the aforementioned is optionally substituted with one or more independently selected Rdsubstituents; two R3, taken together with the atom(s) to which they are attached, independently form a cycloalkyl or heterocycloalkyl, wherein each cycloalkyl or heterocycloalkyl is optionally and independently substituted with one or more independently selected Rd substituents;R4 is H, D, halo, cyano, nitro, alkyl, alkenyl, alkynyl, -alkylene-Ra, =CRaRb, =NRb, =0, -C(0)Ra, -C(0)NRbRc, -C(0)0Ra, -NH(CH2)pRa, -NRbRc, -NRbC(0)Rc, -NRbS(O)2Rc, -N=S(O)RbRc, -0Ra, - 0C(0)Ra, -0C(0)0Ra, -0P(0)(0Rb)(0Rc), -OP(O)(ORb)(NHRc), -0P(0)RbRc, -P(0)RbRc, -alkylene- P(0)RbRc, -SRa, -S(O)Ra, -S(0)(NRb)Rc, -S(O)2Ra, -S(O)2NRbRc, -(CRaRb)pRd, -(CRaRb)pN(Rc)(CRaRb)qRd, -(CRaRb)PO(CRaRb)qRd, -(CRaRb)PC(O)(CRaRb)qRd, - (CRaRb)PC(O)O(CRaRb)qRd, -(CRaRb)POC(O)(CRaRb)qRd, -(CRaRb)POC(O)O(CRaRb)qRd, - (CRaRb)PN(Rc)C(O)(CRaRb)qRd, -(CRaRb)PC(O)N(Rc)(CRaRb)qRd, -(CRaRb)POC(O)N(Rc)(CRaRb)qRd, - (CRaRb)PN(Rc)C(O)O(CRaRb)qRd, cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged- carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged- heterocyclic, aryl, or heteroaryl, each of the aforementioned is optionally substituted with one or more independently selected Rd substituents;Rs is H, D, halo, cyano, nitro, alkyl, alkenyl, alkynyl, -alkylene-Ra, =CRaRb, =NRb, =0, -C(0)Ra, -C(0)NRbRc, -C(0)0Ra, -NH(CH2)PRa, -NRbRc, -NRbC(0)Rc, -NRbS(0)2Rc, -N=S(O)RbRc, -0Ra, - 0C(0)Ra, -0C(0)0Ra, -0P(0)(0Rb)(0Rc), -OP(O)(ORb)(NHRc), -0P(0)RbRc, -P(0)RbRc, -alkylene- P(0)RbRc, -SRa, -S(0)Ra, -S(0)(NRb)Rc, -S(0)2Ra, -S(0)2NRbRc, -(CRaRb)PRd, - (CRaRb)pN(Rc)(CRaRb)qRd, -(CRaRb)PO(CRaRb)qRd, -(CRaRb)PC(O)(CRaRb)qRd, - (CRaRb)PC(O)O(CRaRb)qRd, -(CRaRb)P0C(0)(CRaRb)qRd, -(CRaRb)P0C(0)0(CRaRb)qRd, - (CRaRb)PN(Rc)C(O)(CRaRb)qRd, -(CRaRb)PC(O)N(Rc)(CRaRb)qRd, -(CRaRb)P0C(0)N(Rc)(CRaRb)qRd, - (CRaRb)PN(Rc)C(O)O(CRaRb)qRd, cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged- carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged- heterocyclic, aryl, or heteroaryl, each of the aforementioned is optionally substituted with one or more independently selected Rdsubstituents;Re is H, D, halo, cyano, nitro, alkyl, alkenyl, alkynyl, -alkylene-Ra, =CRaRb, =NRb, =0, -C(0)Ra, -C(0)NRbRc, -C(0)0Ra, -NH(CH2)pRa, -NRbRc, -NRbC(0)Rc, -NRbS(O)2Rc, -N=S(O)RbRc, -0Ra, - 0C(0)Ra, -0C(0)0Ra, -0P(0)(0Rb)(0Rc), -OP(O)(ORb)(NHRc), -0P(0)RbRc, -P(0)RbRc, -alkylene- P(0)RbRc, -SRa, -S(0)Ra, -S(0)(NRb)Rc, -S(0)2Ra, -S(0)2NRbRc, -(CRaRb)PRd, - (CRaRb)PN(Rc)(CRaRb)qRd, -(CRaRb)PO(CRaRb)qRd, -(CRaRb)PC(O)(CRaRb)qRd, - (CRaRb)PC(O)O(CRaRb)qRd, -(CRaRb)P0C(0)(CRaRb)qRd, -(CRaRb)P0C(0)0(CRaRb)qRd, - (CRaRb)PN(Rc)C(O)(CRaRb)qRd, -(CRaRb)PC(O)N(Rc)(CRaRb)qRd, -(CRaRb)P0C(0)N(Rc)(CRaRb)qRd, - (CRaRb)PN(Rc)C(O)O(CRaRb)qRd, cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged- carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged- heterocyclic, aryl, or heteroaryl, each of the aforementioned is optionally substituted with one or more independently selected Rdsubstituents;Rz is H, D, halo, cyano, nitro, alkyl, alkenyl, alkynyl, -alkylene-Ra, =CRaRb, =NRb, =0, -C(0)Ra, -C(0)NRbRc, -C(0)0Ra, -NH(CH2)pRa, -NRbRc, -NRbC(0)Rc, -NRbS(O)2Rc, -N=S(O)RbRc, -0Ra, - 0C(0)Ra, -0C(0)0Ra, -0P(0)(0Rb)(0Rc), -OP(O)(ORb)(NHRc), -0P(0)RbRc, -P(0)RbRc, -alkylene- P(0)RbRc, -SRa, -S(0)Ra, -S(0)(NRb)Rc, -S(0)2Ra, -S(0)2NRbRc, -(CRaRb)PRd, - (CRaRb)PN(Rc)(CRaRb)qRd, -(CRaRb)PO(CRaRb)qRd, -(CRaRb)PC(O)(CRaRb)qRd, - (CRaRb)pC(O)O(CRaRb)qRd, -(CRaRb)P0C(0)(CRaRb)qRd, -(CRaRb)P0C(0)0(CRaRb)qRd, - (CRaRb)PN(Rc)C(O)(CRaRb)qRd, -(CRaRb)PC(O)N(Rc)(CRaRb)qRd, -(CRaRb)P0C(0)N(Rc)(CRaRb)qRd, - (CRaRb)pN(Rc)C(O)O(CRaRb)qRd, cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged- heterocyclic, aryl, or heteroaryl, each of the aforementioned is optionally substituted with one or more independently selected Rdsubstituents;Re and Rz, taken together with the atom(s) to which they are attached, independently form a cycloalkyl or heterocycloalkyl, wherein each cycloalkyl or heterocycloalkyl is optionally and independently substituted with one or more independently selected Rdsubstituents; and each Rais independently H, D, alkyl, alkenyl, alkynyl, halo, -CF3, cyano, nitro, -OH, - C(O)NHOH, -C(O)NH2, -C(O)OH, -NH2, =CReRf, =NRe, =0, -C(0)Re, -C(0)NReRf, -C(0)0Re, - NH(CH2)pRe, -NReRf, -NReC(0)Rf, -NReS(O)2Rf, -N=S(O)ReRf, -0Re, -0C(0)Re, -0C(0)0Re, - 0P(0)(0Re)(0Rf), -0P(0)(0Re)(NHRf), -alkylene-P(O)ReRf, -0P(0)ReRf„ -P(0)ReRf, -SRe, -S(O)Re, - S(0)(NRe)Rf, -S(0)2Re, -S(O)2NReRf, N=S(O)ReRf, -S(O)(NRe)Rf, -(CH2)pRf, -(CH2)pN(Re)(CH2)qRf, - (CH2)pO(CH2)qRf, -(CH2)pC(O)(CH2)qRf, -(CH2)pC(O)O(CH2b)qRf, -(CH2)pOC(O)(CH2)qRf, - (CH2)pOC(O)O(CH2)qRf, -(CH2)pN(Re)C(O)(CH2)qRf, -(CH2)pC(O)N(Re)(CH2)qRf, - (CH2)pOC(O)N(Re)(CH2)qRf, -(CRaRb)PN(Re)C(O)O(CH2)qRf, cycloalkyl, cycloalkenyl, spirocycloalkyl, fused -carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused- heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, each of the aforementioned is optionally and independently substituted with one or more independently selected Rgsubstituents; each Rbis independently H, D, alkyl, alkenyl, alkynyl, halo, -CF3, cyano, nitro, -OH, - C(O)NHOH, -C(O)NH2, -C(O)OH, -NH2, =CReRf, =NRe, =0, -C(0)Re, -C(0)NReRf, -C(0)0Re, - NH(CH2)pRe, -NReRf, -NReC(0)Rf, -NReS(O)2Rf, -N=S(O)ReRf, -0Re, -0C(0)Re, -0C(0)0Re, -alkylene- P(O)ReRf, -OP(O)(ORe)(ORf), -OP(O)(ORe)(NHRf), -0P(0)ReRf, -P(0)ReRf, -SRe, -S(O)Re, - S(0)(NRe)Rf, -S(0)2Re, -S(O)2NReRf, N=S(O)ReRf, -S(O)(NRe)Rf, -(CH2)pRf, -(CH2)pN(Re)(CH2)qRf, - (CH2)pO(CH2)qRf, -(CH2)pC(O)(CH2)qRf, -(CH2)pC(O)O(CH2b)qRf, -(CH2)pOC(O)(CH2)qRf, - (CH2)pOC(O)O(CH2)qRf, -(CH2)pN(Re)C(O)(CH2)qRf, -(CH2)pC(O)N(Re)(CH2)qRf, - (CH2)pOC(O)N(Re)(CH2)qRf, -(CRaRb)pN(Re)C(O)O(CH2)qRf, cycloalkyl, cycloalkenyl, spirocycloalkyl, fused -carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused- heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, each of the aforementioned is optionally and independently substituted with one or more independently selected Rgsubstituents;Raand Rb, taken together with the atom(s) to which they are attached, independently form a cycloalkyl or heterocycloalkyl, wherein each cycloalkyl or heterocycloalkyl is optionally and independently substituted with one or more independently selected Rgsubstituents; each Rcis independently H, D, alkyl, alkenyl, alkynyl, halo, -CF3, cyano, nitro, -OH, - C(O)NHOH, -C(O)NH2, -C(O)OH, -NH2, =CReRf, =NRe, =0, -C(0)Re, -C(0)NReRf, -C(0)0Re, - NH(CH2)pRe, -NReRf, -NReC(0)Rf, -NReS(O)2Rf, -N=S(O)ReRf, -0Re, -0C(0)Re, -0C(0)0Re, -alkylene- P(O)ReRf, -OP(O)(ORe)(ORf), -OP(O)(ORe)(NHRf), -0P(0)ReRf, -P(0)ReRf, -SRe, -S(O)Re, - S(0)(NRe)Rf, -S(0)2Re, -S(O)2NReRf, N=S(O)ReRf, -S(O)(NRe)Rf, -(CH2)pRf, -(CH2)pN(Re)(CH2)qRf, - (CH2)pO(CH2)qRf, -(CH2)pC(O)(CH2)qRf, -(CH2)pC(O)O(CH2)qRf, -(CH2)pOC(O)(CH2)qRf, -(CH2)POC(O)O(CH2)qRf, -(CH2)pN(Re)C(O)(CH2)qRf, -(CH2)pC(O)N(Re)(CH2)qRf, - (CH2)pOC(O)N(Re)(CH2)qRf, -(CRaRb)pN(Re)C(O)O(CH2)qRf, cycloalkyl, cycloalkenyl, spirocycloalkyl, fused -carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused- heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, each of the aforementioned is optionally and independently substituted with one or more independently selected Rgsubstituents;Rb and Rc, taken together with the atom(s) to which they are attached, independently form a cycloalkyl or heterocycloalkyl, wherein each cycloalkyl or heterocycloalkyl is optionally and independently substituted with one or more independently selected Rgsubstituents; each Rdis independently H, D, alkyl, alkenyl, alkynyl, halo, -CF3, cyano, nitro, -OH, - C(O)NHOH, -C(O)NH2, -C(O)OH, -NH2, =CReRf, =NRe, =0, -C(0)Re, -C(0)NReRf, -C(0)0Re, - NH(CH2)pRe, -NReRf, -NReC(0)Rf, -NReS(O)2Rf, -N=S(O)ReRf, -0Re, -0C(0)Re, -0C(0)0Re, -alkylene- P(0)ReRf, -OP(O)(ORe)(ORf), -OP(O)(ORe)(NHRf), -0P(0)ReRf„ -P(0)ReRf, -SRe, -S(O)Re, - S(0)(NRe)Rf, -S(0)2Re, -S(O)2NReRf, N=S(O)ReRf, -S(O)(NRe)Rf, -(CH2)pRf, -(CH2)pN(Re)(CH2)qRf, - (CH2)pO(CH2)qRf, -(CH2)pC(O)(CH2)qRf, -(CH2)pC(O)O(CH2b)qRf, -(CH2)pOC(O)(CH2)qRf, - (CH2)pOC(O)O(CH2)qRf, -(CH2)pN(Re)C(O)(CH2)qRf, -(CH2)pC(O)N(Re)(CH2)qRf, - (CH2)pOC(O)N(Re)(CH2)qRf, -(CRaRb)PN(Re)C(O)O(CH2)qRf, cycloalkyl, cycloalkenyl, spirocycloalkyl, fused -carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused- heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, each of the aforementioned is optionally and independently substituted with one or more independently selected Rgsubstituents; two Rd, taken together with the atom(s) to which they are attached, independently form a cycloalkyl or heterocycloalkyl, wherein each cycloalkyl or heterocycloalkyl is optionally and independently substituted with one or more independently selected Rgsubstituents; each Reis independently H, D, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyalkyloxy, alkoxyalkyloxyalkyl, alkylidenyl, alkoxyalkylidenyl, alkylthio, alkylsulfonyl, cyanoalkyl, cyanoalkenyl, cyanoalkynyl, alkylamino, dialkylamino, aminocarbonyl, alkoxycarbonyl, alkylcarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, halo, haloalkyl, haloalkylidenyl, hydroxyalkyl, haloalkoxy, heteroalkyl, hydroxyalkyl, oxoalkyl, -NH2, -OH, -CF3, -Cyano, -Nitro, =CH2, =NH, =0, -C(0)NH2, -C(O)NHOH, - C(O)OH, -C(0)0Rg-, -0C(0)Rg-, -OP(O)(OH)(OH), -P(O)(OH)(OH), aralkyl, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkyloxyalkyl, cycloalkylalkyloxyalkyloxy, cycloalkylalkyloxyalkyl, heteroaralkyl, heterocyclylalkyl, heterocyclyloxy, heterocyclyloxyalkyl, heterocyclylalkyloxy, heterocyclylalkyloxyalkyl, cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged- carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged- heterocyclic, aryl, or heteroaryl, each of the aforementioned is optionally and independently substituted with one or more independently selected Rgsubstituents; two Re, taken together with the atom(s) to which they are attached, independently form a cycloalkyl or heterocycloalkyl, wherein each cycloalkyl or heterocycloalkyl is optionally andindependently substituted with one or more independently selected Rgsubstituents; each Rfis independently H, D, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyalkyloxy, alkoxyalkyloxyalkyl, alkylidenyl, alkoxyalkylidenyl, alkylthio, alkylsulfonyl, cyanoalkyl, cyanoalkenyl, cyanoalkynyl, alkylamino, dialkylamino, aminocarbonyl, alkoxycarbonyl, alkylcarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, halo, haloalkyl, haloalkylidenyl, hydroxyalkyl, haloalkoxy, heteroalkyl, hydroxyalkyl, oxoalkyl, -NH2, -OH, -C(O)ORg-, -OC(O)Rg-,-CF3, -Cyano, -Nitro, =CH2, =NH, =0, - C(0)NH2, -C(O)NHOH, -C(O)OH,-OP(O)(OH)(OH), -P(O)(OH)(OH), aralkyl, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkyloxyalkyl, cycloalkylalkyloxyalkyloxy, cycloalkylalkyloxyalkyl, heteroaralkyl, heterocyclylalkyl, heterocyclyloxy, heterocyclyloxyalkyl, heterocyclylalkyloxy, heterocyclylalkyloxyalkyl, cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged- carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged- heterocyclic, aryl, or heteroaryl, each of the aforementioned is optionally and independently substituted with one or more independently selected Rgsubstituents; two Rf, taken together with the atom(s) to which they are attached, independently form a cycloalkyl or heterocycloalkyl, wherein each cycloalkyl or heterocycloalkyl is optionally and independently substituted with one or more independently selected Rgsubstituents; each Rgis independently H, D, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyalkyloxy, alkoxyalkyloxyalkyl, alkylidenyl, alkoxyalkylidenyl, alkylthio, alkylsulfonyl, cyanoalkyl, cyanoalkenyl, cyanoalkynyl, alkylamino, dialkylamino, aminocarbonyl, alkoxycarbonyl, alkylcarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, halo, haloalkyl, haloalkylidenyl, hydroxyalkyl, haloalkoxy, heteroalkyl, hydroxyalkyl, oxoalkyl, -NH2, -OH, -CF3, -Cyano, -Nitro, =CH2, =NH, =0, -C(0)NH2, -C(O)NHOH, - C(O)OH,-OP(O)(OH)(OH), -P(O)(OH)(OH), aralkyl, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkyloxyalkyl, cycloalkylalkyloxyalkyloxy, cycloalkylalkyloxyalkyl, heteroaralkyl, heterocyclylalkyl, heterocyclyloxy, heterocyclyloxyalkyl, heterocyclylalkyloxy, heterocyclylalkyloxyalkyl, cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, each of the aforementioned is optionally and independently substituted with one or more independently selected Rhsubstituents; each Rh is independently H, D, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyalkyloxy, alkoxyalkyloxyalkyl, alkylidenyl, alkoxyalkylidenyl, alkylthio, alkylsulfonyl, cyanoalkyl, cyanoalkenyl, cyanoalkynyl, alkylamino, dialkylamino, aminocarbonyl, alkoxycarbonyl, alkylcarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, halo, haloalkyl, haloalkylidenyl, hydroxyalkyl, haloalkoxy, heteroalkyl, hydroxyalkyl, oxoalkyl, -NH2, -OH, -CF3, -Cyano, -Nitro, =CH2, =NH, =0, -C(0)NH2, -C(O)NHOH, - C(O)OH,-OP(O)(OH)(OH), -P(O)(OH)(OH), aralkyl, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy,cycloalkyloxyalkyl, cycloalkylalkyloxyalkyloxy, cycloalkylalkyloxyalkyl, heteroaralkyl, heterocyclylalkyl, heterocyclyloxy, heterocyclyloxyalkyl, heterocyclylalkyloxy, heterocyclylalkyloxyalkyl, cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl; m is O, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; n is O, 1, 2, 3, 4, 5, or 6; p is O, 1, 2, 3, 4, 5, or 6; p1 is 0,1, 2, 3, 4, or 5. q is O, 1, 2, 3, 4, 5, or 6; and r is O, 1, 2, 3, 4, 5, or 6.

2. The compound according to claim 1, or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug thereof, wherein the compound is represented by Formula (2):

3. The compound according to claim 2, or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug thereof, wherein the compound is represented by Formula (3):

4. The compound according to claim 3, or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug thereof, wherein the compound is represented by Formula (4):The compound according to claim 4, or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug thereof, wherein the compound is represented by Formula (5):

6. The compound according to claim 5, or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug thereof, wherein the compound is represented by Formula (6):The compound according to claim 6, or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug thereof, wherein the compound is represented by Formula (7):whereinW5is N or C(Ra).The compound according to claim 7, or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug thereof, wherein the compound is represented by Formula (8):

9. The compound according to claim 8, or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug thereof, wherein the compound is represented by Formula (9):

10. The compound according to claim 9, or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug thereof, wherein the compound is represented by Formula (10):

11. A pharmaceutical composition comprising a compound or an N-oxide thereof as defined in any one of claims 1-10, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug of said compound or N-oxide thereof, and a pharmaceutically acceptable diluent or carrier.

12. A method of treating a neoplastic disease, autoimmune disease, and inflammatory disorder, comprising administering to a subject in need thereof an effective amount of a compound or an N-oxide thereof asdefined in any one of claims 1-10, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug of said compound or N-oxide thereof.

13. Use of a compound or an N-oxide thereof as defined in any one of claims 1-10, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug of said compound or N-oxide thereof, in the manufacture of a medicament for treating a neoplastic disease, autoimmune disease, and inflammatory disorder in a subject in need thereof.

14. A a compound or an N-oxide thereof as defined in any one of claims 1-10, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug of said compound or N-oxide thereof, for use in treating a neoplastic disease, autoimmune disease, and inflammatory disorder in a subject in need thereof.

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