WO2023137223A1

WO2023137223A1 - Pan-kras inhibitors and uses thereof

Info

Publication number: WO2023137223A1
Application number: PCT/US2023/010940
Authority: WO
Inventors: Yi Chen
Original assignee: Newave Pharmaceutical Inc.; Guangzhou Lupeng Pharmaceutical Company Ltd.
Priority date: 2022-01-17
Filing date: 2023-01-17
Publication date: 2023-07-20

Abstract

The disclosure includes compounds of Formula (3) wherein each of Warhead, R1, R2, R3, L1, L2, L3, L4, L5, L6, R0, Q1, Q2, Q3, W1, W2, m, n, and i, are defined herein. Also disclosed is a method for treating a neoplastic disease, autoimmune disease, and inflammatory disorder with these compounds.

Description

PAN-KRAS INHIBITORS AND USES THEREOF

REFERENCE TO RELATED APPLICATIONS

This application claims priority to and the benefit of the filing date of U.S. Provisional Patent Application No. 63/300,181, filed on January 17, 2022, International Patent Application No. PCT/US2022/034523, filed on June 22, 2022, and U.S. Provisional Patent Application No. 63/410,409, filed on September 27, 2022, the entire contents of each of the above applications are incorporated herein by reference.

BACKGROUND OF THE INVENTION

Kirsten 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, GD12R, and G12V. SUMMARY OF THE INVENTION

In one aspect, this invention relates to a compound of Formula (3), 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 (3) or N-oxide thereof:

Formula (3) wherein

Warhead is chemical group that can form a covalent bond with a Cysteine of a target protein; each of Wi, and W2, independently, is N or C(R_a); each of Li, L2, L3, L4, L5, and l_6, independently, is absent, a bond, (CR_aRb)p, N(R_C), 0, S, 0(0), S(0₂), -0(CRaR_b)p-, -N(Rc)(CR_aRb)p-, 00(0), 0(0)0, 0S0₂, S(0₂)0, C(0)S, SC(0), C(0)C(0), C(0)N(Rc), N(Rc)C(0), S(O₂)N(R_C), N(R_C)S(O₂), 00(0)0, 0C(0)S, 0C(0)N(R_c), N(R_c)C(0)0, N(R_c)C(0)S, N(Rc)C(0)N(Rc), (CR_aRb)pN(Rc)(CR_aRb)_q, (CRaRb)pN(R_c)C(O)(CRaRb)_q, OC(O)N(Rc)(CRaRb)p+iN(Rc)(CR_aRb)_q, (CRaRb)pC(O)N(Rc)(CR_aRb)_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; when W1 is C(R_a), the R_a and Li, 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;

Qi is a 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;

Q2 is a 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; Q3 is a 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;

Ro is independently H, D, halo, cyano, nitro, alkyl, alkylene-R_a, alkylene-P(O)RbR_c, alkenyl, alkynyl, C(O)R_a, C(O)NR_bR_c, C(O)OR_a, NH(CH₂)_PR_a, NR_bR_c, NR_bC(O)R_c, =NR_b, NR_bS(O)₂R_c, N=S(O)R_bR_c, OR_a, OC(O)R_a, =0, P(0)R_bR_c, SR_a, S(O)R_a, S(O)(NR_b)R_c, S(O)₂R_a, S(O)₂NR_bR_c, 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; each R1 is independently H, D, halo, cyano, nitro, alkyl, alkylene-R_a, alkylene-P(O)R_bR_c, alkenyl, alkynyl, C(0)R_a, C(0)NR_bR_c, C(0)0R_a, NH(CH₂)_pR_a, NR_bR_c, NR_bC(0)R_c, =NR_b, NR_bS(0)₂R_c, N=S(0)R_bR_c, 0R_a, 0C(0)R_a, =0, P(0)R_bR_c, SR_a, S(0)R_a, S(0)(NR_b)R_c, S(0)₂R_a, S(0)₂NR_bR_c, 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; or two R1, 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 R₂ is independently H, D, halo, cyano, nitro, alkyl, alkylene-R_a, alkylene-P(O)R_bR_c, alkenyl, alkynyl, C(0)R_a, C(0)NR_bR_c, C(0)0R_a, NH(CH₂)_pR_a, NR_bR_c, NR_bC(0)R_c, =NR_b, NR_bS(0)₂R_c, N=S(0)R_bR_c, 0R_a, 0C(0)R_a, =0, P(0)R_bR_c, SR_a, S(0)R_a, S(0)(NR_b)R_c, S(0)₂R_a, S(0)₂NR_bR_c, 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; or 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, alkylene-R_a, alkylene-P(O)R_bR_c, alkenyl, alkynyl, C(0)R_a, C(0)NR_bR_c, C(0)0R_a, NH(CH₂)_pR_a, NR_bR_c, NR_bC(0)R_c, =NR_b, NR_bS(0)₂R_c, N=S(0)R_bR_c, 0R_a, 0C(0)R_a, =0, P(0)R_bR_c, SR_a, S(0)R_a, S(0)(NR_b)R_c, S(0)₂R_a, S(0)₂NR_bR_c, 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; or 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;

R2 and 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; each R_a is independently H, D, halo, cyano, nitro, alkyl, alkylene-P(O)RbR_c, alkenyl, alkynyl, C(O)alkyl, C(O)NHOH, C(O)NH₂, C(O)OH, C(O)O(alkyl), NH₂, NH(alkyl), NH(haloalkyl), NHC(O)alkyl, =NRb, N=S(O)RbR_c, OH, O(alkyl), =0, P(O)RbR_c, S(O)(NRb)R_c, 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 R_e substituents;

R_a and 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; each Rb is independently H, D, halo, cyano, nitro, alkyl, alkylene-P(O)RbR_c, alkenyl, alkynyl, C(O)alkyl, C(O)NHOH, C(O)NH₂, C(0)0H, C(O)O(alkyl), NH₂, NH(alkyl), NH(haloalkyl), NHC(O)alkyl, =NRb, N=S(O)RbR_c, OH, O(alkyl), =0, P(0)RbR_c, S(O)(NRb)R_c, 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 R_e substituents;

R_a and 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 Rd substituents; each R_c is independently H, D, halo, cyano, nitro, alkyl, alkylene-P(O)RbR_c, alkenyl, alkynyl, C(O)alkyl, C(0)NH0H, C(0)NH₂, C(0)0H, C(O)O(alkyl), NH₂, NH(alkyl), NH(haloalkyl), NHC(O)alkyl, =NRb, N=S(0)RbR_c, OH, O(alkyl), =0, P(O)RbR_c, S(O)(NRb)R_c, 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 R_e substituents;

Rb and R_c, 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 Rd is independently H, D, halo, cyano, nitro, alkyl, alkylene-P(O)RbR_c, alkenyl, alkynyl, C(O)alkyl, C(O)NHOH, C(O)NH₂, C(0)0H, C(O)O(alkyl), NH₂, NH(alkyl), NH(haloalkyl), NHC(O)alkyl, =NRb, N=S(O)RbR_c, OH, O(alkyl), =0, P(O)RbR_c, S(O)(NRb)R_c, 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 R_e substituents; or 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 R_e substituents; each R_e is independently H, D, halo, cyano, nitro, alkyl, alkylene-P(O)RbR_c, alkenyl, alkynyl, C(O)alkyl, C(O)NHOH, C(O)NH₂, C(O)OH, C(O)O(alkyl), NH₂, NH(alkyl), NH(haloalkyl), NHC(O)alkyl, =NRb, N=S(O)RbR_c, OH, O(alkyl), =0, P(O)RbR_c, S(O)(NRb)R_c, 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 Rf substituents; or two R_e, 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 Rf substituents; each Rf is independently H, D, halo, cyano, nitro, alkyl, alkylene-P(O)RbR_c, alkenyl, alkynyl, C(O)alkyl, C(O)NHOH, C(O)NH₂, C(0)0H, C(O)O(alkyl), NH₂, NH(alkyl), NH(haloalkyl), NHC(O)alkyl, =NRb, N=S(O)RbR_c, OH, O(alkyl), =0, P(0)RbR_c, S(O)(NRb)R_c, 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 R_g substituents; each R_g is independently H, D, halo, cyano, nitro, alkyl, alkylene-P(O)RbR_c, alkenyl, alkynyl, C(O)alkyl, C(O)NHOH, C(0)NH₂, C(0)0H, C(O)O(alkyl), NH₂, NH(alkyl), NH(haloalkyl), NHC(O)alkyl, =NRb, N=S(O)RbR_c, OH, O(alkyl), =0, P(O)RbR_c, S(O)(NRb)R_c, cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused- heterocyclic, bridged-heterocyclic, aryl, or heteroaryl; i is O, 1 , 2, 3, 4, 5, or 6; m is O, 1 , 2, 3, 4, 5, or 6; n is O, 1 , 2, 3, 4, 5, or 6; p is O, 1 , 2, 3, 4, 5, or 6; and q is O, 1 , 2, 3, 4, 5, or 6.

In preferred embodiments, the compound is represented by Formula (3-A):

wherein

Warhead

R4 is H, D, halo, cyano, alkyl, alkylene-R_a, alkenyl, alkynyl, 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, alkyl, alkylene-R_a, alkenyl, alkynyl, 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, alkyl, alkylene-R_a, alkenyl, alkynyl, 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 and 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 Rd substituents; and

Rz is H, D, halo, cyano, alkyl, alkylene-R_a, alkenyl, alkynyl, 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.

The remaining groups are as defined in Formula (3).

In preferred embodiments, the compound is represented by Formula (3-A1):

Formula (3-Al) wherein

W is C(RaR ), N(R_C), 0, S, or S(0₂).

The remaining groups are as defined in Formula (3) and (3-A).

In preferred embodiments, the compound is represented by Formula (3-B):

Formula (3-B) wherein

QIA is a 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; g is 0, 1, 2, 3, or 4; h is 0, 1, 2, or 3; and g+h=i;

RIA and RIB, independently, is Ri;

W is C(RaR ), N(R_C), 0, S, or S(O₂).

The remaining groups are as defined in Formula (3), Formula (3-A) and (3-A1).

In preferred embodiments, the compound is represented by Formula (3-C):

Formula (3-C) wherein

W is 0, S, or S(0₂).

The remaining groups are as defined in Formula (3), Formulae (3-A), (3-A1) and (3-B).

In preferred embodiments, the compound is represented by Formula (3-J):

Formula (3-J) wherein

W11 is N, or C(R_a);

Z¹¹ is absent, a bond, (CR_aR_b)_P, N(R_C), 0, S, C(0), S(0₂), -O(CR_aR_b)_P-, -N(R_c)(CR_aRb)_P-, 0C(0), C(0)0, 0S0₂, S(0₂)0, C(O)S, SC(O), C(0)C(0), C(O)N(Rc), N(Rc)C(O), S(O₂)N(R_C), N(RC)S(O₂), 0C(0)0, OC(O)S, OC(O)N(RC), N(RC)C(O)O, N(RC)C(O)S, N(RC)C(O)N(RC), (CR_aRb)_PN(R_c)(CR_aRb)_q, (CR_aRb)_PN(R_c)C(O)(CR_aRb)_q, OC(O)N(R_c)(CR_aRb)_P+iN(R_c)(CR_aRb)_q, or (CR_aRb)_PC(O)N(R_c)(CR_aRb)_q; p Is O, 1 , 2, or 3; and q Is O, 1 , 2, or 3.

In preferred embodiments, the compound is represented by Formula (3-K):

Formula (3-K) wherein

Z¹¹ is absent, a bond, (CR_aRb)_P, N(R_C), 0, S, C(0), S(0₂), -O(CR_aRb)_P-, -N(R_c)(CR_aRb)_P-, 0C(0), C(0)0, 0S0₂, S(0₂)0, C(O)S, SC(O), C(O)C(O), C(O)N(Rc), N(Rc)C(O), S(O₂)N(R_C), N(RC)S(O₂), 0C(0)0, OC(O)S, OC(O)N(RC), N(RC)C(O)O, N(RC)C(O)S, N(RC)C(O)N(RC), (CR_aRb)_PN(R_c)(CR_aRb)_q, (CR_aRb)_PN(R_c)C(O)(CR_aRb)_q, OC(O)N(R_c)(CR_aRb)_P+iN(R_c)(CR_aRb)_q, or (CR_aRb)_PC(O)N(R_c)(CR_aRb)_q; p is 0, 1 , 2, or 3; and q is O, 1 , 2, or 3.

In preferred embodiments, the compound is represented by Formula (3-N):

Formula (3-N) wherein

Z¹¹ is absent, a bond, (CR_aRb)_P, N(R_C), 0, S, 0(0), S(0₂), -O(CR_aRb)_P-, -N(R_c)(CR_aRb)_P-, 00(0), 0(0)0, 0S0₂, S(0₂)0, C(O)S, SC(O), C(O)C(O), C(O)N(R_c), N(R_c)C(O), S(O₂)N(R_C), N(RC)S(O₂), 00(0)0, OC(O)S, OC(O)N(RC), N(RC)C(O)O, N(RC)C(O)S, N(RC)C(O)N(RC), (CR_aRb)pN(R_c)(CR_aRb)_q, (CR_aRb)_PN(R_c)C(O)(CR_aRb)_q, OC(O)N(R_c)(CR_aRb)_P+iN(R_c)(CR_aRb)_q, or (CR_aRb)_PC(O)N(Rc)(CR_aRb)_q; p Is O, 1 , 2, or 3; and q Is O, 1 , 2, or 3.

In preferred embodiments, the compound is represented by Formula (3-0):

Formula (3-0)

The remaining groups are as defined in Formula (3), Formulae (3-A), (3-A1) and (3-B). In preferred embodiments, the compound is represented by Formula (3-i):

Formula (3-1) wherein

W3 is N or C(R_a); h is 0, 1, 2, or 3; and 1 +h=i; and

Ric and R , independently, is R1.

The remaining groups are as defined in Formula (3), Formulae (3-A), and (3-A1).

In preferred embodiments, the compound is represented by Formula (3-ii):

Formula (3-ii) wherein

W is 0, S, or S(O₂).

The remaining groups are as defined in Formula (3), Formulae (3-A), Formulae (3-A1), and Formulae(3-i).

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 INVENTION

Exemplary compounds described herein include, but are not limited to, the following:

(S)-N-(1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1 H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3-yl)acrylamide,

(R)-N-(1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1 H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3-yl)acrylamide,

(S)-N-(1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1 H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3-yl)-2-fluoroacrylamide,

(R)-N-(1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1 H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3-yl)-2-fluoroacrylamide,

N-((3S,4R)-4-cyano-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1 H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3-yl)acrylamide,

N-((3S,4S)-4-cyano-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1 H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3-yl)acrylamide,

N-((3R,4R)-4-cyano-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1 H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3-yl)acrylamide, N-((3R,4S)-4-cyano-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1 H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3-yl)acrylamide,

N-((3S,5R)-5-cyano-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1 H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3-yl)acrylamide,

N-((3S,5S)-5-cyano-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1 H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3-yl)acrylamide,

N-((3R,5R)-5-cyano-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1 H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3-yl)acrylamide,

N-((3R,5S)-5-cyano-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1 H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3-yl)acrylamide,

N-((3S,4R)-4-cyano-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1 H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-methylazepan-3-yl)acryl amide,

N-((3S,4S)-4-cyano-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1 H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-methylazepan-3-yl)acryl amide,

N-((3R,4R)-4-cyano-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1 H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-methylazepan-3-yl)acryl amide,

N-((3R,4S)-4-cyano-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1 H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-methylazepan-3-yl)acryl amide,

N-((3S,5S)-5-cyano-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1 H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5-methylazepan-3-yl)acryl amide,

N-((3S,5R)-5-cyano-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1 H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5-methylazepan-3-yl)acryl amide,

N-((3R,5S)-5-cyano-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1 H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5-methylazepan-3-yl)acryl amide,

N-((3R,5R)-5-cyano-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1 H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5-methylazepan-3-yl)acryl amide,

N-((3R,4R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1 H-pyrrolizin-

7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-hydroxy-4-methylazepan-3-yl)acrylamide,

N-((3R,4S)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1 H-pyrrolizin-

N-((3S,4R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1 H-pyrrolizin-

N-((3S,4S)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1 H-pyrrolizin-

N-((3S,5S)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1 H-pyrrolizin-

7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5-hydroxy-5-methylazepan-3-yl)acrylamide, N-((3S,5R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1 H-pyrrolizin-

7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5-hydroxy-5-methylazepan-3-yl)acrylamide,

N-((3R,5S)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1 H-pyrrolizin-

N-((3R,5R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1 H-pyrrolizin-

(S)-N-(1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1 H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4,4-dimethylazepan-3-yl)acrylamide,

(R)-N-(1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1 H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4,4-dimethylazepan-3-yl)acrylamide,

(S)-N-(1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1 H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5,5-dimethylazepan-3-yl)acrylamide,

(R)-N-(1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1 H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5,5-dimethylazepan-3-yl)acrylamide,

(R)-N-(1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1 H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4,4-difluoroazepan-3-yl)acrylamide,

(S)-N-(1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1 H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4,4-difluoroazepan-3-yl)acrylamide,

(S)-N-(1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1 H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5,5-difluoroazepan-3-yl)acrylamide,

(R)-N-(1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1 H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5,5-difluoroazepan-3-yl)acrylamide,

(S)-N-(4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1 H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1 ,1-dioxido-1,4-thiazepan-6-yl)acryl amide,

(R)-N-(4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1 H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1 ,1-dioxido-1,4-thiazepan-6-yl)acryl amide,

(S)-N-(4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1 H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1 ,4-oxazepan-6-yl)acrylamide,

(R)-N-(4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1 H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1 ,4-oxazepan-6-yl)acrylamide,

(S)-N-(4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1 H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1 ,4-oxazepan-6-yl)-2-fluoroacrylamide,

(R)-N-(4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1 H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1 ,4-oxazepan-6-yl)-2-fluoroacrylamide,

(R)-N-(1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1 H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-methyl-1 ,4-diazepan-6-yl)-2-fluoroacrylamide, (S)-N-(1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1 H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-methyl-1 ,4-diazepan-6-yl)-2-fluoroacrylamide,

(R)-N-(1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1 H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-methyl-1 ,4-diazepan-6-yl)acrylamide,

(S)-N-(1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1 H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-methyl-1 ,4-diazepan-6-yl)acrylamide,

(R)-N-(1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1 H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-(tetrahydro-2H-pyran-4-yl)-1 ,4-diazepan-6-yl)acrylamide,

(S)-N-(1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1 H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-(tetrahydro-2H-pyran-4-yl)-1 ,4-diazepan-6-yl)acrylamide,

(S)-N-(1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-

(morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3-yl)acrylamide,

(R)-N-(1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-

(S)-N-(1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-

(morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3-yl)-2-fluoroacrylamide,

(R)-N-(1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-

N-((3S,4R)-4-cyano-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-

N-((3S,4S)-4-cyano-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-

N-((3R,4R)-4-cyano-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-

N-((3R,4S)-4-cyano-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-

N-((3S,5R)-5-cyano-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-

N-((3S,5S)-5-cyano-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-

N-((3R,5R)-5-cyano-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-

N-((3R,5S)-5-cyano-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-

(morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-methylazepan-3-yl)acrylamide, N-((3S,4S)-4-cyano-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-

(morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-methylazepan-3-yl)acrylamide,

(morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5-methylazepan-3-yl)acrylamide,

N-((3R,4R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-

(morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-hydroxy-4-methylazepan-3-yl)acrylamide,

N-((3R,4S)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-

N-((3S,4R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-

N-((3S,4S)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-

N-((3S,5S)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-

(morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5-hydroxy-5-methylazepan-3-yl)acrylamide,

N-((3S,5R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-

N-((3R,5S)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-

N-((3R,5R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-

(S)-N-(1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-

(morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4,4-dimethylazepan-3-yl)acrylamide,

(R)-N-(1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-

(S)-N-(1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-

(morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5,5-dimethylazepan-3-yl)acrylamide, (R)-N-(1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-

(morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5,5-dimethylazepan-3-yl)acrylamide,

(R)-N-(1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-

(morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4,4-difluoroazepan-3-yl)acrylamide,

(S)-N-(1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-

(morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5,5-difluoroazepan-3-yl)acrylamide,

(R)-N-(1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-

(S)-N-(4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-

(morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1 ,1-dioxido-1 ,4-thiazepan-6-yl)acrylamide,

(R)-N-(4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-

(R)-N-(1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-

(morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-methyl-1 ,4-diazepan-6-yl)-2- fluoroacrylamide,

(S)-N-(1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-

(R)-N-(1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-

(morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-methyl-1 ,4-diazepan-6-yl)acrylamide,

(S)-N-(1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-

(R)-N-(1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-

(morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-(tetrahydro-2H-pyran-4-yl)-1 ,4-diazepan-

6-yl)acrylamide,

(S)-N-(1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-

6-yl)acrylamide,

(R)-N-(4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-

(morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1 ,4-oxazepan-6-yl)acrylamide,

(R)-N-(4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-

(morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1 ,4-oxazepan-6-yl)-2-fluoroacrylamide, (R)-N-(4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-

(morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1 ,4-oxazepan-6-yl)-N-methylacrylamide, (R)-N-(4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1- (morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1 ,4-oxazepan-6-yl)-N-(methyl- d3)acryl amide,

(R)-N-(4-(7-(3-cyano-8-ethynyl-7-fluoronaphthalen-1 -yl)-8-fluoro-2-((1- (morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1 ,4-oxazepan-6-yl)acrylamide, (R)-N-(4-(7-(3-(dimethylphosphoryl)-8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-((1- (morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-yl)acrylamide,

(R)-N-(4-(7-(3-acetyl-8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-((1-

(morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1_J4-oxazepan-6-yl)acrylamide_J

N-((R)-4-(7-(8-ethynyl-7-fluoro-3-((S)-1-hydroxyethyl)naphthalen-1-yl)-8-fluoro-2-((1- (morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1_J4-oxazepan-6-yl)acrylamide_J

N-((R)-4-(7-(8-ethynyl-7-fluoro-3-((R)-1-hydroxyethyl)naphthalen-1-yl)-8-fluoro-2-((1- (morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1_J4-oxazepan-6-yl)acrylamide_J (R)-N-(4-(7-(8-ethynyl-7-fluoro-3-(2-hydroxypropan-2-yl)naphthalen-1-yl)-8-fluoro-2-((1- (morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-yl)acrylamide, (R)-N-(4-(7-(8-ethynyl-7-fluoro-3-methoxynaphthalen-1-yl)-8-fluoro-2-((1- (morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-yl)acrylamide,

(R)-N-(4-(7-(8-ethynyl-7-fluoro-3-(methylsulfonyl)naphthalen-1-yl)-8-fluoro-2-((1-

(morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1_J4-oxazepan-6-yl)acrylamide_J (R)-(4-(4-(6-acrylamido-1,4-oxazepan-4-yl)-8-fluoro-2-((1-

(morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-yl)boronic acid,

(R)-N-(4-(7-(8-ethynyl-7-fluoro-3-oxo-2,3-dihydroisoquinolin-1-yl)-8-fluoro-2-((1- (morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-yl)acrylamide,

(R)-N-(4-(7-(5-ethynyl-6-fluoro-2-oxo-1,2-dihydroquinolin-4-yl)-8-fluoro-2-((1-

(morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-yl)acrylamide,

N-((R)-4-(7-((S)-8-ethynyl-7-fluoro-3-hydroxy-3,4-dihydroquinolin-1 (2H)-yl)-8-fluoro-2-((1- (morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-yl)acrylamide,

N-((R)-4-(7-((R)-8-ethynyl-7-fluoro-3-hydroxy-3,4-dihydroquinolin-1 (2H)-yl)-8-fluoro-2-((1- (morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-yl)acrylamide,

N-((R)-4-(7-((S)-8-ethynyl-7-fluoro-3-hydroxy-3-methyl-3,4-dihydroquinolin-1 (2H)-yl)-8-fluoro-2-((1- (morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-yl)acrylamide,

N-((R)-4-(7-((R)-8-ethynyl-7-fluoro-3-hydroxy-3-methyl-3,4-dihydroquinolin-1 (2H)-yl)-8-fluoro-2-((1- (morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-yl)acrylamide,

(R)-N-(4-(7-(5-ethynyl-6-fluoro-2,3-dihydro-4H-benzo[b][1 ,4]oxazin-4-yl)-8-fluoro-2-((1- (morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-yl)acrylamide, (R)-N-(4-(7-(8-ethynyl-7-fluoro-3,4-dihydroquinolin-1 (2H)-yl)-8-fluoro-2-((1- (morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1 ,4-oxazepan-6-yl)acrylamide,

N-((R)-4-(7-((S)-5-ethynyl-6-fluorochroman-4-yl)-8-fluoro-2-((1-

N-((R)-4-(7-((R)-5-ethynyl-6-fluorochroman-4-yl)-8-fluoro-2-((1-

(morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1 ,4-oxazepan-6-yl)acrylamide, N-((R)-4-(7-((S)-8-ethynyl-7-fluoro-1 ,2,3,4-tetrahydronaphthalen-1-yl)-8-fluoro-2-((1-

(morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1 ,4-oxazepan-6-yl)acrylamide, N-((R)-4-(7-((R)-8-ethynyl-7-fluoro-1 ,2,3,4-tetrahydronaphthalen-1-yl)-8-fluoro-2-((1- (morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1 ,4-oxazepan-6-yl)acrylamide,

N-((6R)-4-(7-(8-ethynyl-7-fluoro-3-hydroxy-1 ,2,3,4-tetrahydronaphthalen-1-yl)-8-fluoro-2-((1- (morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1 ,4-oxazepan-6-yl)acrylamide,

N-((6R)-4-(7-(8-ethynyl-7-fluoro-3-hydroxy-3-methyl-1 ,2,3,4-tetrahydronaphthalen-1-yl)-8-fluoro-2-((1- (morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1 ,4-oxazepan-6-yl)acrylamide, (R)-N-(4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-((1-

(morpholinomethyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,4-oxazepan-6- yl)acrylamide,

N-((6R)-4-(7-(8-ethynyl-7-fluoro-1 ,2,3,4-tetrahydronaphthalen-1-yl)-2-((1- (morpholinomethyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3_J4-d]pyrimidin-4-yl)-1 ,4-oxazepan-6- yl)acrylamide,

N-((6R)-4-(7-(8-ethynyl-7-fluoro-3-hydroxy-1 ,2,3,4-tetrahydronaphthalen-1-yl)-2-((1- (morpholinomethyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3_J4-d]pyrimidin-4-yl)-1 ,4-oxazepan-6- yl)acrylamide,

N-((6R)-4-(7-(8-ethynyl-7-fluoro-3-hydroxy-3-methyl-1 ,2,3,4-tetrahydronaphthalen-1-yl)-2-((1- (morpholinomethyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3_J4-d]pyrimidin-4-yl)-1 ,4-oxazepan-6- yl)acrylamide,

N-((6R)-4-(7-(8-ethynyl-7-fluoro-3,4-dihydroquinolin-1 (2H)-yl)-2-((1- (morpholinomethyl)cyclopropyl)methoxy)-5_J6_J7,8-tetrahydroquinazolin-4-yl)-1,4-oxazepan-6-yl)acrylamide, N-((6R)-4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-((1- (morpholinomethyl)cyclopropyl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6- yl)acrylamide,

N-((R)-4-((S)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6-fluoro-3-(1- (morpholinomethyl)cyclopropyl)-2,3-dihydro-[1 ,4]dioxino[2,3-b][1 ,6]naphthyridin-10-yl)-1 ,4-oxazepan-6- yl)acrylamide,

N-((R)-4-((R)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6-fluoro-3-(1- (morpholinomethyl)cyclopropyl)-2,3-dihydro-[1 ,4]dioxino[2,3-b][1 ,6]naphthyridin-10-yl)-1 ,4-oxazepan-6- yl)acrylamide, N-((R)-4-((R)-8-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-9-fluoro-2-(1- (morpholinomethyl)cyclopropyl)-3,4-dihydro-2H-pyrano[2,3-b][1 ,6]naphthyridin-5-yl)-1 ,4-oxazepan-6- yl)acrylamide,

N-((R)-4-((S)-8-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-9-fluoro-2-(1- (morpholinomethyl)cyclopropyl)-3,4-dihydro-2H-pyrano[2,3-b][1 ,6]naphthyridin-5-yl)-1 ,4-oxazepan-6- yl)acrylamide,

N-((R)-4-((S)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6-fluoro-3-(1-

(morphol i nomethy l)cycl opropyl)- 1 , 1 -dioxido-2, 3-d i hydro- [1 ,4]oxathiino[2,3-b][1 , 6] n aphthy ridi n- 10-yl)- 1 ,4- oxazepan-6-yl)acrylamide,

N-((R)-4-((R)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6-fluoro-3-(1-

(morphol i nomethy l)cycl opropyl)- 1 , 1 -dioxido-2, 3-dihy d ro-[1 ,4]oxathiino[2,3-b][1 , 6] n aphthy ridi n- 10-yl)- 1 ,4- oxazepan-6-yl)acrylamide,

N-((R)-4-((2R,4R)-8-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-9-fluoro-4-hydroxy-4-methyl-2-(1- (morpholinomethyl)cyclopropyl)-3,4-dihydro-2H-pyrano[2,3-b][1 ,6]naphthyridin-5-yl)-1 ,4-oxazepan-6- yl)acrylamide,

N-((R)-4-((2R,4S)-8-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-9-fluoro-4-hydroxy-4-methyl-2-(1- (morpholinomethyl)cyclopropyl)-3,4-dihydro-2H-pyrano[2,3-b][1 ,6]naphthyridin-5-yl)-1 ,4-oxazepan-6- yl)acrylamide,

N-((R)-4-((2S,4R)-8-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-9-fluoro-4-hydroxy-4-methyl-2-(1- (morpholinomethyl)cyclopropyl)-3,4-dihydro-2H-pyrano[2,3-b][1 ,6]naphthyridin-5-yl)-1 ,4-oxazepan-6- yl)acrylamide,

N-((R)-4-((2S,4S)-8-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-9-fluoro-4-hydroxy-4-methyl-2-(1- (morpholinomethyl)cyclopropyl)-3,4-dihydro-2H-pyrano[2,3-b][1 ,6]naphthyridin-5-yl)-1 ,4-oxazepan-6- yl)acrylamide,

(R)-4-(4-(6-acrylamido-1,4-oxazepan-4-yl)-8-fluoro-2-((1-

(morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-yl diisopropyl phosphate, neopentyl (((4-(4-((R)-6-acrylamido-1 ,4-oxazepan-4-yl)-8-fluoro-2-((1 -

(morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2- yl)oxy)(phenoxy)phosphoryl)-L-alaninate,

(S)-N-(4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-

(morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1 ,4-oxazepan-6-yl)-2-fluoroacrylamide, (S)-N-(4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-

(morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1 ,4-oxazepan-6-yl)-N-methylacrylamide, (S)-N-(4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-

(morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1 ,4-oxazepan-6-yl)-N-(methyl- d3)acryl amide,

(S)-N-(4-(7-(3-cyano-8-ethynyl-7-fluoronaphthalen-1 -yl)-8-fluoro-2-((1-

(morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1 ,4-oxazepan-6-yl)acrylamide, (S)-N-(4-(7-(3-(dimethylphosphoryl)-8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-((1- (morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-yl)acrylamide,

(S)-N-(4-(7-(3-acetyl-8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-((1-

N-((S)-4-(7-(8-ethynyl-7-fluoro-3-((S)-1-hydroxyethyl)naphthalen-1-yl)-8-fluoro-2-((1-

N-((S)-4-(7-(8-ethynyl-7-fluoro-3-((R)-1-hydroxyethyl)naphthalen-1-yl)-8-fluoro-2-((1-

(morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1_J4-oxazepan-6-yl)acrylamide_J (S)-N-(4-(7-(8-ethynyl-7-fluoro-3-(2-hydroxypropan-2-yl)naphthalen-1-yl)-8-fluoro-2-((1-

(S)-N-(4-(7-(8-ethynyl-7-fluoro-3-methoxynaphthalen-1-yl)-8-fluoro-2-((1-

(S)-N-(4-(7-(8-ethynyl-7-fluoro-3-(methylsulfonyl)naphthalen-1-yl)-8-fluoro-2-((1-

(S)-(4-(4-(6-acrylamido-1,4-oxazepan-4-yl)-8-fluoro-2-((1-

(S)-N-(4-(7-(8-ethynyl-7-fluoro-3-oxo-2,3-dihydroisoquinolin-1-yl)-8-fluoro-2-((1-

(S)-N-(4-(7-(5-ethynyl-6-fluoro-2-oxo-1,2-dihydroquinolin-4-yl)-8-fluoro-2-((1-

N-((S)-4-(7-((S)-8-ethynyl-7-fluoro-3-hydroxy-3,4-dihydroquinolin-1 (2H)-yl)-8-fluoro-2-((1- (morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-yl)acrylamide,

N-((S)-4-(7-((R)-8-ethynyl-7-fluoro-3-hydroxy-3,4-dihydroquinolin-1 (2H)-yl)-8-fluoro-2-((1- (morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-yl)acrylamide,

N-((S)-4-(7-((S)-8-ethynyl-7-fluoro-3-hydroxy-3-methyl-3,4-dihydroquinolin-1 (2H)-yl)-8-fluoro-2-((1- (morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-yl)acrylamide,

N-((S)-4-(7-((R)-8-ethynyl-7-fluoro-3-hydroxy-3-methyl-3,4-dihydroquinolin-1 (2H)-yl)-8-fluoro-2-((1- (morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-yl)acrylamide,

(S)-N-(4-(7-(5-ethynyl-6-fluoro-2,3-dihydro-4H-benzo[b][1 ,4]oxazin-4-yl)-8-fluoro-2-((1-

(morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-yl)acrylamide, (S)-N-(4-(7-(8-ethynyl-7-fluoro-3,4-dihydroquinolin-1 (2H)-yl)-8-fluoro-2-((1- (morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1 ,4-oxazepan-6-yl)acrylamide,

N-((S)-4-(7-((S)-5-ethynyl-6-fluorochroman-4-yl)-8-fluoro-2-((1-

N-((S)-4-(7-((R)-5-ethynyl-6-fluorochroman-4-yl)-8-fluoro-2-((1-

(morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1 ,4-oxazepan-6-yl)acrylamide, N-((S)-4-(7-((S)-8-ethynyl-7-fluoro-1 ,2,3,4-tetrahydronaphthalen-1-yl)-8-fluoro-2-((1-

N-((S)-4-(7-((R)-8-ethynyl-7-fluoro-1 ,2,3,4-tetrahydronaphthalen-1-yl)-8-fluoro-2-((1- (morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1 ,4-oxazepan-6-yl)acrylamide,

N-((6S)-4-(7-(8-ethynyl-7-fluoro-3-hydroxy-1 ,2,3,4-tetrahydronaphthalen-1-yl)-8-fluoro-2-((1- (morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1 ,4-oxazepan-6-yl)acrylamide,

N-((6S)-4-(7-(8-ethynyl-7-fluoro-3-hydroxy-3-methyl-1 ,2,3,4-tetrahydronaphthalen-1-yl)-8-fluoro-2-((1- (morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1 ,4-oxazepan-6-yl)acrylamide,

(S)-N-(4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-((1-

N-((6S)-4-(7-(8-ethynyl-7-fluoro-1 ,2,3,4-tetrahydronaphthalen-1-yl)-2-((1- (morpholinomethyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3_J4-d]pyrimidin-4-yl)-1 ,4-oxazepan-6- yl)acrylamide,

N-((6S)-4-(7-(8-ethynyl-7-fluoro-3-hydroxy-1 ,2,3,4-tetrahydronaphthalen-1-yl)-2-((1- (morpholinomethyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3_J4-d]pyrimidin-4-yl)-1 ,4-oxazepan-6- yl)acrylamide,

N-((6S)-4-(7-(8-ethynyl-7-fluoro-3-hydroxy-3-methyl-1 ,2,3,4-tetrahydronaphthalen-1-yl)-2-((1- (morpholinomethyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydropyrido[3_J4-d]pyrimidin-4-yl)-1 ,4-oxazepan-6- yl)acrylamide,

N-((6S)-4-(7-(8-ethynyl-7-fluoro-3,4-dihydroquinolin-1 (2H)-yl)-2-((1- (morpholinomethyl)cyclopropyl)methoxy)-5_J6_J7,8-tetrahydroquinazolin-4-yl)-1,4-oxazepan-6-yl)acrylamide, N-((6S)-4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-((1- (morpholinomethyl)cyclopropyl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6- yl)acrylamide,

N-((S)-4-((S)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6-fluoro-3-(1- (morpholinomethyl)cyclopropyl)-2,3-dihydro-[1 ,4]dioxino[2,3-b][1 ,6]naphthyridin-10-yl)-1 ,4-oxazepan-6- yl)acrylamide,

N-((S)-4-((R)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6-fluoro-3-(1- (morpholinomethyl)cyclopropyl)-2,3-dihydro-[1 ,4]dioxino[2,3-b][1 ,6]naphthyridin-10-yl)-1 ,4-oxazepan-6- yl)acrylamide, N-((S)-4-((R)-8-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-9-fluoro-2-(1- (morpholinomethyl)cyclopropyl)-3,4-dihydro-2H-pyrano[2,3-b][1 ,6]naphthyridin-5-yl)-1 ,4-oxazepan-6- yl)acrylamide,

N-((S)-4-((S)-8-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-9-fluoro-2-(1- (morpholinomethyl)cyclopropyl)-3,4-dihydro-2H-pyrano[2,3-b][1 ,6]naphthyridin-5-yl)-1 ,4-oxazepan-6- yl)acrylamide,

N-((S)-4-((S)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6-fluoro-3-(1- (morphol i nomethy l)cycl opropyl)- 1 , 1 -dioxido-2, 3-d i hydro- [1 ,4]oxathiino[2,3-b][1 , 6] n aphthy ridi n- 10-yl)- 1 ,4- oxazepan-6-yl)acrylamide,

N-((S)-4-((R)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6-fluoro-3-(1-

N-((S)-4-((2R,4R)-8-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-9-fluoro-4-hydroxy-4-methyl-2-(1- (morpholinomethyl)cyclopropyl)-3,4-dihydro-2H-pyrano[2,3-b][1 ,6]naphthyridin-5-yl)-1 ,4-oxazepan-6- yl)acrylamide,

N-((S)-4-((2R,4S)-8-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-9-fluoro-4-hydroxy-4-methyl-2-(1- (morpholinomethyl)cyclopropyl)-3,4-dihydro-2H-pyrano[2,3-b][1 ,6]naphthyridin-5-yl)-1 ,4-oxazepan-6- yl)acrylamide,

N-((S)-4-((2S,4R)-8-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-9-fluoro-4-hydroxy-4-methyl-2-(1- (morpholinomethyl)cyclopropyl)-3,4-dihydro-2H-pyrano[2,3-b][1 ,6]naphthyridin-5-yl)-1 ,4-oxazepan-6- yl)acrylamide,

N-((S)-4-((2S,4S)-8-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-9-fluoro-4-hydroxy-4-methyl-2-(1- (morpholinomethyl)cyclopropyl)-3,4-dihydro-2H-pyrano[2,3-b][1 ,6]naphthyridin-5-yl)-1 ,4-oxazepan-6- yl)acrylamide,

(S)-4-(4-(6-acrylamido-1,4-oxazepan-4-yl)-8-fluoro-2-((1- (morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-yl diisopropyl phosphate, neopentyl (((4-(4-((S)-6-acrylamido-1 ,4-oxazepan-4-yl)-8-fluoro-2-((1 - (morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2- yl)oxy)(phenoxy)phosphoryl)-L-alaninate,

(R)-N-(4-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-((1-

(morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1 ,4-oxazepan-6-yl)acrylamide, (R)-N-(4-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-((1-

(morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1 ,4-oxazepan-6-yl)-2-fluoroacrylamide, (R)-N-(4-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-((1-

(morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1 ,4-oxazepan-6-yl)-N-methylacrylamide, (R)-N-(4-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-((1-

N-((R)-4-((S)-7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-6-fluoro-3-(1-(morpholinomethyl)cyclopropyl)-2,3- dihydro-[1,4]dioxino[2,3-b][1,6]naphthyridin-10-yl)-1,4-oxazepan-6-yl)acrylamide,

N-((R)-4-((R)-7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-6-fluoro-3-(1-(morpholinomethyl)cyclopropyl)-2,3- dihydro-[1,4]dioxino[2,3-b][1,6]naphthyridin-10-yl)-1,4-oxazepan-6-yl)acrylamide,

N-((R)-4-((R)-8-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-9-fluoro-2-(1-(morpholinomethyl)cyclopropyl)-3,4- dihydro-2H-pyrano[2,3-b][1 ,6]naphthyridin-5-yl)-1 ,4-oxazepan-6-yl)acrylamide,

N-((R)-4-((S)-8-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-9-fluoro-2-(1-(morpholinomethyl)cyclopropyl)-3,4- dihydro-2H-pyrano[2,3-b][1 ,6]naphthyridin-5-yl)-1 ,4-oxazepan-6-yl)acrylamide,

N-((R)-4-((S)-7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-6-fluoro-3-(1-(morpholinomethyl)cyclopropyl)-1 ,1- dioxido-2,3-dihydro-[1 ,4]oxathiino[2,3-b][1 ,6]naphthyridin-10-yl)-1 ,4-oxazepan-6-yl)acrylamide,

N-((R)-4-((R)-7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-6-fluoro-3-(1-(morpholinomethyl)cyclopropyl)-1 ,1- dioxido-2,3-dihydro-[1 ,4]oxathiino[2,3-b][1 ,6]naphthyridin-10-yl)-1 ,4-oxazepan-6-yl)acrylamide,

N-((R)-4-((2R,4R)-8-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-9-fluoro-4-hydroxy-4-methyl-2-(1-

(morpholinomethyl)cyclopropyl)-3,4-dihydro-2H-pyrano[2,3-b][1 ,6]naphthyridin-5-yl)-1 ,4-oxazepan-6- yl)acrylamide,

N-((R)-4-((2R,4S)-8-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-9-fluoro-4-hydroxy-4-methyl-2-(1-

N-((R)-4-((2S,4R)-8-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-9-fluoro-4-hydroxy-4-methyl-2-(1-

N-((R)-4-((2S,4S)-8-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-9-fluoro-4-hydroxy-4-methyl-2-(1-

(S)-N-(4-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-((1-

(morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1 ,4-oxazepan-6-yl)-2-fluoroacrylamide,

(S)-N-(4-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-((1-

(morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1 ,4-oxazepan-6-yl)-N-methylacrylamide,

(S)-N-(4-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-((1-

(morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1 ,4-oxazepan-6-yl)-N-(methyl- d3)acryl amide, N-((S)-4-((S)-7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-6-fluoro-3-(1-(morpholinomethyl)cyclopropyl)-2,3- dihydro-[1,4]dioxino[2,3-b][1,6]naphthyridin-10-yl)-1,4-oxazepan-6-yl)acrylamide,

N-((S)-4-((R)-7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-6-fluoro-3-(1-(morpholinomethyl)cyclopropyl)-2,3- dihydro-[1 ,4]dioxino[2,3-b][1 ,6]naphthyridin-10-yl)-1 ,4-oxazepan-6-yl)acrylamide,

N-((S)-4-((R)-8-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-9-fluoro-2-(1-(morpholinomethyl)cyclopropyl)-3,4- dihydro-2H-pyrano[2,3-b][1 ,6]naphthyridin-5-yl)-1 ,4-oxazepan-6-yl)acrylamide,

N-((S)-4-((S)-8-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-9-fluoro-2-(1-(morpholinomethyl)cyclopropyl)-3,4- dihydro-2H-pyrano[2,3-b][1 ,6]naphthyridin-5-yl)-1 ,4-oxazepan-6-yl)acrylamide,

N-((S)-4-((S)-7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-6-fluoro-3-(1-(morpholinomethyl)cyclopropyl)-1 ,1- dioxido-2,3-dihydro-[1 ,4]oxathiino[2,3-b][1 ,6]naphthyridin-10-yl)-1 ,4-oxazepan-6-yl)acrylamide,

N-((S)-4-((R)-7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-6-fluoro-3-(1-(morpholinomethyl)cyclopropyl)-1 ,1- dioxido-2,3-dihydro-[1 ,4]oxathiino[2,3-b][1 ,6]naphthyridin-10-yl)-1 ,4-oxazepan-6-yl)acrylamide,

N-((S)-4-((2R,4R)-8-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-9-fluoro-4-hydroxy-4-methyl-2-(1- (morpholinomethyl)cyclopropyl)-3,4-dihydro-2H-pyrano[2,3-b][1 ,6]naphthyridin-5-yl)-1 ,4-oxazepan-6- yl)acrylamide,

N-((S)-4-((2R,4S)-8-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-9-fluoro-4-hydroxy-4-methyl-2-(1- (morpholinomethyl)cyclopropyl)-3,4-dihydro-2H-pyrano[2,3-b][1 ,6]naphthyridin-5-yl)-1 ,4-oxazepan-6- yl)acrylamide,

N-((S)-4-((2S,4R)-8-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-9-fluoro-4-hydroxy-4-methyl-2-(1- (morpholinomethyl)cyclopropyl)-3,4-dihydro-2H-pyrano[2,3-b][1 ,6]naphthyridin-5-yl)-1 ,4-oxazepan-6- yl)acrylamide,

N-((S)-4-((2S,4S)-8-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-9-fluoro-4-hydroxy-4-methyl-2-(1-

(R)-N-(4-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-((1-

(S)-N-(4-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-((1-

(R)-N-(4-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-((1-

(morpholinomethyl)cyclopropyl)methoxy)quinazolin-4-yl)-1,4-oxazepan-6-yl)acrylamide,

N-((6R)-4-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-((1- (morpholinomethyl)cyclopropyl)methoxy)quinazolin-4-yl)-1,4-oxazepan-6-yl)acrylamide, N-((6R)-4-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-6,8-difluoro-2-((1- (morpholinomethyl)cyclopropyl)methoxy)quinazolin-4-yl)-1,4-oxazepan-6-yl)acrylamide,

N-((6R)-4-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-6-methyl-2-((1- (morpholinomethyl)cyclopropyl)methoxy)quinazolin-4-yl)-1,4-oxazepan-6-yl)acrylamide, N-((6R)-4-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-6-ethyl-8-fluoro-2-((1 - (morpholinomethyl)cyclopropyl)methoxy)quinazolin-4-yl)-1,4-oxazepan-6-yl)acrylamide,

N-((6R)-4-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-((1-

(morpholinomethyl)cyclopropyl)methoxy)-6-vinylquinazolin-4-yl)-1,4-oxazepan-6-yl)acrylamide,

(S)-N-(4-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-((1-

N-((6S)-4-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-((1-

N-((6S)-4-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-6,8-difluoro-2-((1-

N-((6S)-4-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-6-methyl-2-((1-

N-((6S)-4-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-6-ethyl-8-fluoro-2-((1-

N-((6S)-4-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-((1- (morpholinomethyl)cyclopropyl)methoxy)-6-vinylquinazolin-4-yl)-1,4-oxazepan-6-yl)acrylamide, N-((5aR,6R)-2-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-1-fluoro-12-((1- (morpholinomethyl)cyclopropyl)methoxy)-5,5a,6,7,9,10-hexahydro-4,8-dioxa-3,10a,11,13-tetraazanaphtho[1 ,8- ab]heptalen-6-yl)acrylamide,

N-((5aS,6R)-2-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-1-fluoro-12-((1- (morpholinomethyl)cyclopropyl)methoxy)-5,5a,6,7,9,10-hexahydro-4,8-dioxa-3,10a,11,13-tetraazanaphtho[1 ,8- ab]heptalen-6-yl)acrylamide,

N-((5aR,6S)-2-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-1-fluoro-12-((1- (morpholinomethyl)cyclopropyl)methoxy)-5,5a,6,7,9,10-hexahydro-4,8-dioxa-3,10a,11,13-tetraazanaphtho[1 ,8- ab]heptalen-6-yl)acrylamide,

N-((5aS,6S)-2-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-1-fluoro-12-((1- (morpholinomethyl)cyclopropyl)methoxy)-5,5a,6,7,9,10-hexahydro-4,8-dioxa-3,10a,11,13-tetraazanaphtho[1 ,8- ab]heptalen-6-yl)acrylamide,

N-((5aR,9R)-2-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-1-fluoro-12-((1- (morpholinomethyl)cyclopropyl)methoxy)-5a,6,9, 10-tetrahydro-5H, 8H-4, 7-d ioxa-3, 10a, 11,13- tetraazanaphtho[1,8-ab]heptalen-9-yl)acrylamide,

N-((5aS,9R)-2-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-1-fluoro-12-((1- (morpholinomethyl)cyclopropyl)methoxy)-5a,6,9, 10-tetrahydro-5H, 8H-4, 7-d ioxa-3, 10a, 11,13- tetraazanaphtho[1,8-ab]heptalen-9-yl)acrylamide,

N-((5aR,9S)-2-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-1-fluoro-12-((1- (morpholinomethyl)cyclopropyl)methoxy)-5a,6,9, 10-tetrahydro-5H, 8H-4, 7-d ioxa-3, 10a, 11,13- tetraazanaphtho[1,8-ab]heptalen-9-yl)acrylamide, N-((5aS,9S)-2-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-1-fluoro-12-((1- (morpholinomethyl)cyclopropyl)methoxy)-5a,6,9, 10-tetrahydro-5H, 8H-4, 7-d ioxa-3, 10a, 11,13- tetraazanaphtho[1,8-ab]heptalen-9-yl)acrylamide,

N-(2-(2-amino-3-cyanobenzo[b]thiophen-4-yl)-1-fluoro-12-((1-(morpholinomethyl)cyclopropyl)methoxy)- 5, 5a, 6, 7, 9, 10-hexahydro-4,8-dioxa-3, 10a, 11 , 13-tetraazanaphtho[1 , 8-ab] heptal en-6-y I )acry I am ide,

N-(2-(2-amino-3-cyanobenzo[b]thiophen-4-yl)-1-fluoro-12-((1-(morpholinomethyl)cyclopropyl)methoxy)- 5a,6,9,10-tetrahydro-5H,8H-4,7-dioxa-3, 10a, 11 , 13-tetraazanaphtho[1 ,8-ab]heptalen-9-yl)acrylamide,

N-(2-(2-aminobenzo[d]thiazol-4-yl)-1 -fluoro- 12-((1 -(morpholinomethyl)cyclopropyl)methoxy)- 5, 5a, 6, 7, 9, 10-hexahydro-4,8-dioxa-3, 10a, 11 , 13-tetraazanaphtho[1 , 8-ab] heptal en-6-y I )acry I am ide,

N-(2-(2-aminobenzo[d]thiazol-4-yl)-1 -fluoro- 12-((1 -(morpholinomethyl)cyclopropyl)methoxy)-5a,6,9, 10- tetrahyd ro-5H , 8H-4, 7-d ioxa-3, 10a, 11 , 13-tetraazanaphtho[1 , 8-ab] heptalen-9-y I) aery I ami de,

N-(11 -(2-amino-3-cyanobenzo[b]thiophen-4-yl)-12-ch I oro- 10-fl uoro-8-((1 - (morpholinomethyl)cyclopropyl)methoxy)-1 ,2,4,5, 14,14a-hexahydro-[1,4]oxazepino[5',4':3,4][1 ,4]oxazepino[5,6,7- de]quinazolin-1-yl)acrylamide,

N-(11 -(2-amino-3-cyanobenzo[b]thiophen-4-yl)-12-ch I oro- 10-fl uoro-8-((1 - (morpholinomethyl)cyclopropyl)methoxy)-4,5, 14, 14a-tetrahydro-1 H,3H- [1,4]oxazepino[3',4':3,4][1 ,4]oxazepino[5,6,7-de]quinazolin-4-yl)acrylamide,

N-(11-(2-aminobenzo[d]thiazol-4-yl)-12-chloro-10-fluoro-8-((1-(morpholinomethyl)cyclopropyl)methoxy)- 1,2, 4, 5, 14, 14a-hexahydro-[1 ,4]oxazepino[5',4':3,4][1,4]oxazepino[5,6,7-de]quinazolin-1-yl)acrylamide,

N-(11-(2-aminobenzo[d]thiazol-4-yl)-12-chloro-10-fluoro-8-((1-(morpholinomethyl)cyclopropyl)methoxy)- 4,5, 14, 14a-tetrahydro-1 H,3H-[1 ,4]oxazepino[3',4':3,4][1 ,4]oxazepino[5,6,7-de]quinazolin-4-yl)acrylamide,

(S)-N-(4-(7-(2-amino-3-cyanobenzo[b]thiophen-4-yl)-8-fluoro-2-((1-

(R)-N-(4-(7-(2-amino-3-cyanobenzo[b]thiophen-4-yl)-8-fluoro-2-((1-

N-((6S)-4-(7-(2-amino-3-cyanobenzo[b]thiophen-4-yl)-6-chloro-8-fluoro-2-((1- (morpholinomethyl)cyclopropyl)methoxy)quinazolin-4-yl)-1,4-oxazepan-6-yl)acrylamide,

N-((6R)-4-(7-(2-amino-3-cyanobenzo[b]thiophen-4-yl)-6-chloro-8-fluoro-2-((1-

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 or ²H) is a stable, non-radioactive isotope of hydrogen and has an atomic weight of 2.0144. Hydrogen naturally occurs as a mixture of the isotopes ^XH (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 well known 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.

As used herein, "Acyl” means a carbonyl containing substituent represented by the formula -C(0)-R in which R is H, alkyl, a carbocycle, a heterocycle, carbocycle-substituted alkyl or heterocycle-substituted alkyl wherein the alkyl, alkoxy, carbocycle and heterocycle are as defined herein. Acyl groups include alkanoyl (e.g. acetyl), aroyl (e.g. benzoyl), and heteroaroyl.

"Aliphatic” means a moiety characterized by a straight or branched chain arrangement of constituent carbon atoms and may be saturated or partially unsaturated with one or more double or triple bonds.

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.

The term "alkenyl” refers to a straight or branched hydrocarbon containing 2-20 carbon atoms (e.g., C2- Cw) 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- Cw) 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.

The term "alkylamino” refers to an — N(R)-alkyl in which R can be H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl.

"Alkoxy” means an oxygen moiety having a further alkyl substituent.

"Alkoxycarbonyl” means an alkoxy group attached to a carbonyl group.

"Oxoalkyl” means an alkyl, further substituted with a carbonyl group. The carbonyl group may be an aldehyde, ketone, ester, amide, acid or acid chloride. The term "cycloalkyl” refers to a saturated hydrocarbon ring system having 3 to 30 carbon atoms (e.g., C3-C12, C3-C8, Cs-Ce). 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 more common 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 "heterocycloal kyl” 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 0, 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 be nitrogen, 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.

"Amino” means a nitrogen moiety having two further substituents where each substituent has a hydrogen or carbon atom alpha bonded to the nitrogen. 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.

"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 4n+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)NR_aRb where R_a and 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 -CN.

"Formyl” means the radical -CH=O.

"Formimino” means the radical -HC=NH.

"Halo” means fluoro, chloro, bromo or iodo.

"Halo-substituted alkyl”, as an isolated group or part of a larger group, means "alkyl” substituted by one or more "halo” atoms, as such terms are defined in this Application. Halo-substituted alkyl includes haloalkyl, dihaloalkyl, trihaloalkyl, perhaloalkyl and the like.

"Hydroxy” means the radical -OH.

"Imine derivative” means a derivative comprising the moiety -C(=NR)-, wherein R comprises a hydrogen or carbon atom alpha to the nitrogen.

"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.”

"Nitro” means the radical -NO2.

"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.

"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(O)-. 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.

"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. The specific 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 and Vinorelbine); 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, KDR/VEGFR2, KHS/MAP4K5, LATS1, LATS2, LOK, 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, mTOR/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, TA0K3/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 material near 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 antiinflammatory 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's disease, 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.

An approach to synthesize compounds of

In Scheme (3-C), the starting material 1-B-6 can be prepared by conventional procedures using appropriate compounds and reagent. The starting material 1-B-6 is converted to intermediate 3-C-1 through a SNAr substitution reaction, which can be converted to the intermediate 3-C-2 readily. Finally, 3-C-2 is deprotected to afford 3-C-3, which can react with 1-B-9a to yield the target compound 3-C-4.

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 (3-J).

In Scheme (3-J), the starting material 1-J-4 can be prepared by conventional procedures using appropriate compounds and reagent. The starting material 1-J-4 can be converted to 3-J-2 through a sequence of two-step reaction. After that, the intermediate 3-J-2 is deprotected to afford 3-J-3, which can react with 1-B-9a to yield the target compound 3-J-4.

An approach to synthesize compounds

described in Scheme (3-K).

In Scheme (3-K), the starting material 3-H-1 can be prepared by conventional procedures using appropriate compounds and reagent. The starting material 3-H-1 can be converted to the intermediate 3-K-1. After that, 3-K-1 is reduced to 3-K-2, which can be converted to 3-K-3 via a general coupling reaction. Finally, the intermediate 3-K-3 is deprotected to afford 3-K-4, which can react with 1-B-9a to yield the target compound 3-K-5.

An approach to synthesize compounds

described in Scheme (3-N).

In Scheme (3-N), the starting material 1-C-1 can be prepared by conventional procedures using appropriate compounds and reagent. The starting material 1-C-1 can react with 3-C-1a to give intermediate 3-N- 1, which can be converted to the intermediate 3-N-2 via a coupling reaction. After that, 3-N-2 is deprotected to afford 3-N-3, which can go through a reductive amination reaction to give 3-N-4. Finally, 3-N-4 is deprotected to afford 3-N-5, which can react with 1-B-9a to yield the target compound 3-N-6.

An approach to synthesize compounds

described in Scheme (3-0)

In Scheme (3-0), the starting material 3-N-3 can be prepared by conventional procedures using appropriate compounds and reagent. The starting material 3-N-3 can go through a Buchwald coupling reaction with 1-C-4a to give 3-0-1 . Finally, 3-0-1 is deprotected to afford 3-0-2, which can react with 1-B-9a to yield the target compound 3-0-3.

Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures. The compounds

can be made by the method referred to Scheme 3-C to 3-O, by using different starting material and reagents, or by the conventional organic reactions.

The compounds

can be made by the method referred to Scheme 3-C to 3-0, by using different starting material and reagents, or by the conventional organic reactions.

The compounds

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 mass spectrometer and Shimadzu SCL-10A LC column: Example INT_1 : Preparation of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine

Synthesis of 2-chloro-3-fluoropyridine-4-carboxylic acid: Into a 2000 mL round-bottom flask, were placed methyl 2-chloro-3-fluoropyridine-4-carboxylate (100.0 g, 527.5 mmol, 1.0 eq), THF (500 mL), water (500 mL) and LIOH (50.5 g, 2110.0 mmol, 4.0 eq). The reaction mixture was stirred for 3 hours at 25°C. The resulting mixture was then quenched by the addition of water (400 mL) and adjust to pH=5.0 with HCI (1 M). The resulting mixture was extracted with EtOAc (2x500 mL). The combined organic layers were washed with brine (1000 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum to give 2-chloro-3- fluoropyridine-4-carboxylic acid as a white solid (85.0 g, 91.8%). LC-MS (El, m/z) M+1 : 176.

Synthesis of tert-butyl (2-chloro-3-fluoropyridin-4-yl)carbamate: Into a 2000 mL round-bottom flask, were placed 2-chloro-3-fluoroisonicotinic acid (75.0 g, 427.2 mmol, 1.0 eq), toluene (550 mL), t-BuOH (500 mL), 4A molecular sieve (300 g) and EtsN (129.7 g, 1281.8 mmol, 3.0 eq). The resulting mixture was stirred at 110°C for 0.5 hour under nitrogen, then the mixture was cooled to 25°C. After that, diphenylphosphoryl azide (176.0 g, 640.9 mmol, 1.5 eq) was added at 25°C. The reaction mixture was stirred for 5 hours at 110°C. The resulting mixture was quenched by the addition of water (400 mL) and then extracted with EtOAc (3x500 mL). The combined organic layers were washed with brine (1 L), 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 (2-chloro-3-fluoropyridin-4-yl)carbamate as a white solid (85.0 g, 80.7%). LC-MS (El, m/z) M+1 : 247.

Synthesis of 2-chloro-3-fluoropyridin-4-amine: Into a 1000 mL round-bottom flask, were placed tertbutyl (2-chloro-3-fluoropyridin-4-yl)carbamate (85.0 g, 344.6 mmol, 1.0 eq), MeCN (110 mL) and HCI in dioxane (350 mL, 4 M) at 5°C. The reaction mixture was stirred at 25°C for 4 hours. The resulting mixture was filtered, the filter cake was diluted with saturated NaHCOs solution and 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 to give 2-chloro-3-fluoropyridin-4-amine as a white solid (42.0 g, 83.2%). LC-MS (El, m/z) M+1 : 147.

Synthesis of 2-chloro-3-fluoro-5-iodopyridin-4-amine: Into a 1000 mL round-bottom flask, were placed 2-chloro-3-fluoropyridin-4-amine (42.0 g, 286.6 mmol, 1.0 eq), NIS (77.4 g, 343.9 mmol, 1.2 eq), MeCN (300 mL) and TsOH«H2O (2.5 g, 14.3 mmol, 0.05 eq) at 25°C. The resulting mixture was stirred for 16 hours at 70°C. The reaction mixture was quenched by the addition of water (300 mL) and then extracted with EtOAc (2x500 mL). The combined organic layers were washed with saturated aq. NaHCOs (500 mL), saturated aq. Na2SO3 (500 mL) and brine (500 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum to give 2-chloro-3-fluoro-5-iodopy ridi n-4-ami ne as a yellow solid (90.0 g, crude). LC-MS (El, m/z) M+1 : 273.

Synthesis of ethyl 4-amino-6-chloro-5-fluoronicotinate: Into a 2000 mL pressure tank reactor, were placed 2-chloro-3-fluoro-5-iodopyridin-4-amine (90.0 g, 330.3 mmol, 1.0 eq), EtOH (1700 mL), Pd(PPh3)2Cl2 (23.0 g, 33.0 mmol, 0.1 eq) and TEA (120.0 g, 1189.2 mmol, 3.6 eq). The reaction mixture was stirred for 16 hours at 80°C under CO (5 atm) atmosphere. The reaction mixture was filtered, the filtrate was concentrated under vacuum to give ethyl 4-amino-6-chloro-5-fluoronicotinate as a yellow solid (68.0 g, 94.2%). LC-MS (El, m/z) M+1 : 219.

Synthesis of ethyl 6-chloro-5-fluoro-4-(3-(2,2,2-trichloroacetyl)ureido)nicotinate: Into a 500 mL round-bottom flask, were placed ethyl ethyl 4-amino-6-chloro-5-fluoronicotinate (68.0 g, 311.1 mmol, 1.0 eq), THF (190 mL) and 2,2,2-trichloroacetyl isocyanate (87.9 g, 466.6 mmol, 1.5 eq). The reaction mixture was stirred for 20 min at 25°C. The resulting mixture was concentrated under vacuum. The residue was triturated with MTBE to give ethyl 6-chloro-5-fluoro-4-(3-(2,2,2-trichloroacetyl)ureido)nicotinate as a white solid (77.0 g, 60.8%). LC- MS (El, m/z) M+1 : 406/408.

Synthesis of 7-chloro-8-fluoropyrido[4,3-d]pyrimidine-2,4-diol: Into a 500 mL round-bottom flask, were placed ethyl 6-chloro-5-fluoro-4-(3-(2,2,2-trichloroacetyl)ureido)nicotinate (77.0 g, 189.2 mmol, 1.0 eq) and NH3 (g) in MeOH (77 mL, 20%). The reaction mixture was stirred for 1 hour at 25°C. The resulting mixture was concentrated under vacuum. The residue was triturated with MTBE to give 7-chloro-8-fluoropyrido[4,3- d]pyrimidine-2,4-diol as a white solid (35.0 g, 85.8%). LC-MS (El, m/z) M-1 : 214.

Synthesis of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine: To a stirred solution of POCI3 (406.0 g, 2647.8 mmol, 22.8 eq) was added DIEA (75.0 g, 580.3 mmol, 5.0 eq) dropwise at 5°C. After that, 7-chloro-8- fluoropyrido[4,3-d]pyrimidine-2,4-diol (25.0 g, 116.0 mmol, 1.0 eq) was added in portions at 5°C. The resulting mixture was stirred for additional 3 hours at 100°C. The resulting mixture was concentrated under vacuum and poured onto ice-water (300 mL), and then 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 :5 to give 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine as a yellow solid (16.5 g, 56.3%). ¹HNMR (300 MHz, DMSO-cfe) < 8.92 (s, 1 H).

Example INT_2: Preparation of triisopropyl({2-[6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)naphthalen-1-yl]ethynyl})silane

Synthesis 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)Cl2]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 (El, 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). After that, MOMBr (3.3 g, 26.4 mmol, 1.5 eq) was added dropwise at -40°C under a nitrogen atmosphere. The reaction mixture was stirred at -40°C for 30 mins. The reaction mixture was quenched by the addition of water (20 mL) and then extracted with CH2CI2 (2x200 mL). The combined organic layers 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-(methoxy methoxy)-8-[2-(triisopropy Isi ly l)ethy nyl]naphthalen- 1 -ol as a light yellow solid (5.0 g, 73.8%). LC-MS (El, 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). After that, Tf2<3 (5.5 g, 19.5 mmol, 1.5 eq) was added 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 3-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphthalen-1 -yl trifluoromethanesulfonate as a light yellow solid (4.5 g, 67.0%). LC-MS (El, m/z) M-CF₃SO₂+1 : 384. ¹HNMR (400 MHz, Chloroform-d) 5 7.75- 7.73 (m, 2H), 7.50-7.41 (m, 2H), 7.33 (d, 4=2.4 Hz, 1 H), 5.31 (s, 2H), 3.54 (s, 3H), 1.19 (d, 4 = 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 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 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 (El, m/z) M+1 : 495. ¹HNMR (400 MHz, Chloroform-d) 5 7.74-7.66 (m, 2H), 7.48 (d, 4=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_3: Preparation of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol

Synthesis of ethyl 2-methylene-5-oxotetrahydro-1H-pyrrolizine-7a(5H)-carboxylate: To a stirred mixture of ethyl 5-oxopyrrolidine-2-carboxylate (100.0 g, 636.2 mmol, 1.0 eq) and 3-chloro-2-(chloromethyl)prop- 1-ene (318.1 g, 2544.8 mmol, 4.0 eq) in THF (600 mL) was added LIHMDS (1336 mL, 1336 mmol, 2.1 eq) dropwise at -40°C under nitrogen atmosphere. The resulting mixture was stirred overnight at 25°C under nitrogen atmosphere. The reaction was quenched by the addition of sat. NH4CI (aq.) (100 mL) at 0-5°C. The mixture was neutralized to pH=7 with HCI (1 M), and then extracted with EtOAc (2x800 mL). The combined organic layers were washed with water (1 L) and brine (1 L), 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=2: 1 to give ethyl 2-methylene-5-oxotetrahydro-1 H-pyrrolizine-7a(5H)-carboxylate as a yellow oil (70.0 g, 52.6%). ¹HNMR (400 MHz, DMSO-d₆) 5 5.04 (ddq, >18.2, 3.3, 2.0 Hz, 2H), 4.15 (d, >7.1 Hz, 1 H), 4.15-4.04 (m, 2H), 3.63-3.51 (m, 1 H), 2.91 (dd, >15.4, 1.6 Hz, 1 H), 2.67-2.52 (m, 2H), 2.41 (ddd, >12.7, 9.1 , 1.8 Hz, 1 H), 2.35-2.12 (m, 2H), 1.19 (t, >7.1 Hz, 3H).

Synthesis of ethyl 2,5-dioxotetrahydro-1 H-pyrrolizine-7a(5H)-carboxylate: Into a 2000 mL roundbottom flask purged, were placed ethyl 2-methylidene-5-oxo-tetrahydropyrrolizine-7a-carboxylate (70.0 g, 334.8 mmol, 1.0 eq), MeCN (700 mL), CH2CI2 (700 mL), water (1050 mL) and trichlororuthenium hydrate (3.8 g, 16.7 mmol, 0.05 eq). After that, sodium periodate (286.4 g, 1339 mmol, 4.0 eq) was added in portions at 5°C. The reaction mixture was stirred for additional 6 hours at 25°C. The resulting mixture was basified to pH=9 with saturated NaHCOs (aq.) and then extracted with EtOAc (2x1500 mL). The combined organic layers were washed with brine (1500 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=2: 1 to give ethyl 2,5-dioxotetrahydro-1 H-pyrrolizine-7a(5H)-carboxylate as a colorless oil (40.0 g, 56.6%). LC-MS (El, m/z) M+1 : 212. ¹HNMR (400 MHz, Chloroform-d) 5 4.25 (q, >7.1 Hz, 2H), 4.13 (dd, >18.5, 1.0 Hz, 1 H), 3.57 (dd, >18.5, 1.4 Hz, 1 H), 3.05-2.92 (m, 2H), 2.92-2.75 (m, 1 H), 2.47 (ddd, >16.8, 9.5, 1.4 Hz, 2H), 2.19 (ddd, >13.0, 11.2, 9.5 Hz, 1 H), 1.30 (t, >7.1 Hz, 3H).

Synthesis of ethyl (2S,7aS)-2-hydroxy-5-oxotetrahydro-1H-pyrrolizine-7a(5H)-carboxylate: To a stirred solution of ethyl 2,5-dioxotetrahydro-1 H-pyrrolizine-7a(5H)-carboxylate (20 g, 94.7 mmol, 1.0 eq) in EtOH (100 mL) was added NaBH4 (1.1 g, 28.4 mmol, 0.3 eq) in portions at 5°C. The resulting mixture was stirred at 5°C for 20 min. The reaction mixture was then quenched by the addition of sat. NH4CI (aq.) (20 mL) at 5°C and stirred at this temperature for 30 min. The resulting mixture was concentrated under vacuum. The crude residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether=2: 1 to give ethyl (2S,7aS)-2- hydroxy-5-oxotetrahydro-1 H-pyrrolizine-7a(5H)-carboxylate as a yellow oil (10.0 g, 49.5%). LC-MS (El, m/z) M+1 : 214. ¹HNMR (400 MHz, Chloroform-d) 5 4.63 (d, >2.3 Hz, 1 H), 4.22 (q, >7.1 Hz, 2H), 3.87 (dt, >12.6, 1.7 Hz, 1 H), 3.22 (ddd, >12.5, 4.3, 1.2 Hz, 1 H), 2.87-2.74 (m, 1 H), 2.74-2.64 (m, 1 H), 2.56 (dd, >14.0, 5.5 Hz, 1 H), 2.44 (dd, >16.1 , 9.1 Hz, 1 H), 2.24 (td, >12.1, 9.0 Hz, 1 H), 1.98 (ddd, >14.0, 2.8, 1.5 Hz, 1 H), 1.30 (t, >7.1 Hz, 3H).

Synthesis of ethyl (2R,7aS)-2-fluoro-5-oxotetrahydro-1 H-pyrrolizine-7a(5H)-carboxylate: To a stirred solution of ethyl (2S,7aS)-2-hydroxy-5-oxotetrahydro-1 H-pyrrolizine-7a(5H)-carboxylate (5.0 g, 23.4 mmol, 1 .0 eq) in CH2CI2 (50 mL) was added DAST (4.9 g, 30.4 mmol, 1 .3 eq) dropwise at -78°C under nitrogen atmosphere. The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was quenched by the addition of MeOH (2.0 mL) and water (60 mL) at 5°C, and then extracted with CH2CI2 (3x80mL). The combined organic layers were washed with brine (150 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=2: 1 to give ethyl (2R,7aS)-2-fluoro-5-oxotetrahydro-1 H-pyrrolizine-7a(5H)-carboxylate as a light yellow oil (3.5 g, 69.4%). LC-MS (El, m/z) M+1 : 216.

Synthesis of ethyl (2R,7aS)-2-fluoro-5-oxotetrahydro-1 H-pyrrolizine-7a(5H)-carboxylate: 1.5 g of ethyl (2R,7aS)-2-fluoro-5-oxotetrahydro-1 H-pyrrolizine-7a(5H)-carboxylate was separated by SFC using the following conditions: Column, 5: IC-3 50*3.0mm,3.0um; mobile phase B: EtOH; Flow rate: 3.0 ml/min; Gradient: 10% B to 55% B in 3 min, RT: 0.766 min; Detector, 220nm. Finally, ethyl (2R,7aS)-2-fluoro-5-oxotetrahydro-1 H- pyrrolizine-7a(5H)-carboxylate was obtained as a colorless oil (450 mg, 30%). TR=0.766 min in CHIRAL-SFC, Column: CHIRALPACK IC-3 50*3.0mm,3.0um. mobile phase A: CO2; mobile phase B: EtOH. Method Set: 10% to 50%_B1_2_2200, Oven Temperature: 35°C. ¹HNMR (300 MHz, Chloroform-d) 5 5.4-5.19 (m, 1 H), 4.26-4.18 (m, 3H), 4.20-4.15 (m, 1 H), 3.18 (ddd, 0=33.6, 13.5, 3.4 Hz, 1 H), 2.75-2.62 (m, 2H), 2.44 (ddd, 0=17.6, 8.9, 4.7 Hz, 1 H), 2.33-2.07 (m, 2H), 1.30 (t, 0=7.1 Hz, 3H).

Synthesis of ((2R,7aS)-2-fluorotetrahydro-1 H-pyrrolizin-7a(5H)-yl)methanol: To a stirred solution of ethyl (2R,7aS)-2-fluoro-5-oxotetrahydro-1 H-pyrrolizine-7a(5H)-carboxylate (300 mg, 1.4 mmol, 1.0 eq) in THF (5.0 mL) was added UAIH4 (80 mg, 2.1 mmol, 1.5 eq) in portions at 5°C and stirred at 70°C for 3 hours. The reaction was quenched with I^SO^IO H2O (2.0 g). The resulting mixture was filtered, the filter cake was washed with EtOAc (2x10 mL). The filtrate was concentrated under reduced pressure to afford ((2R,7aS)-2- fluorotetrahydro-1 H-pyrrolizin-7a(5H)-yl)methanol as colorless oil (200 mg, 90.1 %). LC-MS (El, m/z) M+1 : 160.

Example INT_4: Preparation of {2-[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)naphthalen-1-yl]ethynyl}triisopropylsilane

Synthesis of 7-fluoro-8-[2-(triisopropylsilyl)ethynyl]naphthalene-1 ,3-diol : To a solution of 7- fluoronaphthalene-1 ,3-diol (5.0 g, 28.1 mmol, 1.0 eq) and (2-bromoethynyl)triisopropylsilane (8.8 g, 33.7 mmol, 1.2 eq) in dioxane (60 mL) were added AcOK (3.4 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 (El, 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-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphthalen-1-ol: To a solution of 7-fluoro-8-[2-(triisopropylsilyl)ethynyl]naphthalene-1 ,3-diol (7.0 g, 19.5 mmol, 1.0 eq) and DIEA (7.6 g, 58.6 mmol, 3.0 eq) in CH2CI2 (100 mL) was added dropwise bromomethoxymethane (3.7 g, 29.3 mmol, 1.5 eq) at -40°C under N2 atmosphere. The reaction mixture was stirred at -40°C for 30 min. The reaction mixure was quenched by the addition of water (20 mL) and then extracted with CH2CI2 (2x200 mL). The combined organic layers were washed with brine (500 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 :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 (El, m/z) M+1 : 403.

Synthesis of 7-fluoro-3-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphthalen-1-yl trifluoromethanesulfonate: To a stirred mixture of 7-fluoro-3-(methoxymethoxy)-8-[2- (triisopropylsilyl)ethynyl]naphthalen-1 -ol (4.0 g, 9.9 mmol, 1.0 eq) and DIEA (3.9 g, 29.8 mmol, 3.0 eq) in CH2CI2 (60 mL) were added Tf2<3 (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-dioxaborolan-2- yl)naphthalen-1 -yl]ethynyl}triisopropylsilane: Into a 250 mL round-bottom flask were added 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 mixure 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 (El, 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_5: Preparation of ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1- yl)ethynyl)triisopropylsilane

Synthesis of 7-fluoronaphthalen-1-ol: Into a 100 mL 3-necked round-bottom flask, were added 7- fluoro-3,4-dihydronaphthalen-1 (2H)-one (2.0 g, 12.2 mmol, 1.0 eq), AcOH (40 mL), HBr in AcOH (0.2 mL). After that, Br2 (2.1 g, 13.4 mmol, 1.1 eq) was added dropwise at 0 °C. The resulting mixture was stirred for additional 3 hours at 25°C. The reaction was quenched with water (40 mL) and extracted with CH2CI2 (3x40 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum to afford a brown oil, which was dissovled in DMF (15 mL). To the above mixture was added LiBr (1.8 g, 20.7 mmol, 1.7 eq) and U2CO3 (1.5 g, 20.7 mmol, 1.7 eq). The resulting mixture was stirred for additional 3.5 hours at 160°C. The reaction was quenched with water (15 mL) and extracted with EtOAc (3x15 mL). The combined organic layers were 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-fluoronaphthalen-1-ol as a light yellow solid (1.3 g, 65.8%). ¹HNMR (300 MHz, Chloroform-d) 5 7.92 (dd, >10.4, 2.7 Hz, 1 H), 7.34 (dd, >9.3, 5.7 Hz, 1 H), 7.31-7.21 (m, 2H), 7.09 (ddd, >9.3, 8.1, 2.7 Hz, 1 H), 6.95 (d, >7.6 Hz, 1 H).

Synthesis of 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1 -ol : Into a 250 mL round-bottom flask, were placed 7-fluoronaphthalen-1 -ol (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), [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)naphthalen-1-ol as a light yellow solid (7.0 g, 69.6%).

Synthesis of 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1 -yl trifluoromethanesulfonate: Into a 250 mL round bottom flask, were placed 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1 -ol (4.0 g, 9.9 mmol, 1.0 eq), DIEA (3.9 g, 29.8 mmol, 3.0 eq), CH2CI2 (60 mL). After that, Tf2<3 (4.2 g, 14.9 mmol, 1.5 eq) was added 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 with water (100 mL) and 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-8-((triisopropylsilyl)ethynyl)naphthalen-1 -yl trifluoromethanesulfonate as a light yellow solid (5.0 g, 94.1%).

Synthesis of ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1- yl)ethynyl)triisopropylsilane: Into a 250 mL round-bottom flask, were placed 7-fluoro-3-(methoxymethoxy)-8- ((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), 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 was quenched with water (100 mL) and extracted with ethyl acetate (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 ((2-fluoro-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%). ¹HNMR (300 MHz, DMSO-de) 5 8.11-7.97 (m, 2H), 7.79-7.66 (m, 1 H), 7.62-7.52 (m, 2H), 1.35 (s, 12H), 1.13 (d, >4.8 Hz, 21 H). Example INT_6: Preparation of tert-butyl (1 R,5S)-3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate

Synthesis of tert-butyl (1 R,5S)-3-(2,7-d ic hl oro-8-f I uoropyrido[4, 3-d]pyri m idi n-4-yl )-3, 8- diazabicyclo[3.2.1]octane-8-carboxylate: Into a 1000 mL round-bottom flask, were placed 2,4,7-trichloro-8- fluoropyrido[4,3-d]pyrimidine (10.0 g, 39.6 mmol, 1.0 eq) and CH2CI2 (160 mL). After that, DIEA (12.8 g, 99.0 mmol, 2.5 eq) was added dropwise at -40°C. The reaction mixture was stirred at -40°C for 15 min. Then to the mixture was added a solution of tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (8.4 g, 39.6 mmol, 1.0 eq) in CH2CI2 (35 mL) dropwise at -40°C. The resulting mixture was stirred for additional 15 min at -40°C. The reaction mixture was quenched by the addition of water (200 mL), and then 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 give tert-butyl (1 R,5S)-3-(2,7-dichloro-8-fluoropyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow solid (13.6 g, 80.2%). LC-MS (ES, m/z) M+1 : 428.

Example INT_7A&7B: Preparation of tert-butyl N-[(3R)-1-[7-chloro-8-fluoro-2-(hexahydropyrrolizin-7a- ylmethoxy)pyrido[4,3-d]pyrimidin-4-yl]azepan-3-yl]carbamate (assumed) & tert-butyl N-[(3S)-1-[7-chloro- 8-fluoro-2-(hexahydropyrrolizin-7a-ylmethoxy)pyrido[4,3-d]pyrimidin-4-yl]azepan-3-yl]carbamate (assumed)

Synthesis of tert-butyl N-(1-{2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl}azepan-3- yl)carbamate: Into a 100 mL 3-necked round-bottom flask, were placed 2,4,7-trichloro-8-fluoropyrido[4,3- d]pyrimidine (1.0 g, 4.0 mmol, 1.0 eq), CH2CI2 (20 mL). After that, DIEA (1.0 g, 7.9 mmol, 2.0 eq) was added dropwised at -40°C. Then the reaction mixture was stirred at -40°C for 15 min. Then a solution of tert-butyl N- (azepan-3-yl)carbamate (850 mg, 4.0 mmol, 1.0 eq) in CH2CI2 (5 mL) added dropwise at -40°C. The resulting mixture was stirred for additional 45 min at -40°C. The resulting mixture was quenched by the addition of water (50 mL). The mixture was extracted with ethyl acetate (2x50 mL) and washed with brine (2x50 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 :2 to give tert-butyl N-(1- {2, 7-dichloro-8-fl uoropy rido[4,3-d] py rimidin-4-y l}azepan-3-y l)carbamate as a light yellow solid (1 .5 g, 88.0%). ¹HNMR (300 MHz, DMSO-d₆) 5 9.14 (s, 1 H), 7.05 (d, >7.2, 1 H), 4.25, (d, >12.9, 1 H), 3.91-3.73 (m, 4H), 2.06- 1.70 (m, 4H), 1.63-1.45 (m, 2H), 1.41 (s, 9H).

Synthesis of tert-butyl N-{1-[7-chloro-8-fluoro-2-(hexahydropyrrolizin-7a-ylmethoxy)pyrido[4,3- d]pyrimidin-4-yl]azepan-3-yl}carbamate: Into a 100-mL 3-necked round-bottom flask, were placed tert-butyl N- (1 -{2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl}azepan-3-yl)carbamate (1.4 g, 3.3 mmol, 1.0 eq), hexahydropyrrol izin-7a-y Imethanol (460 mg, 3.3 mmol, 1 .0 eq) and THF (20 mL). This was followed by the addition of NaH (267 mg, 6.5 mmol, 2.0 eq, 60%) at 0°C. The resulting solution was stirred for 4 hours at 25°C. The resulting mixture was then quenched by the addition of water (40 mL). The resulting solution was extracted with ethyl acetate (2x40 mL) and washed with brine (2x40 mL) and the organic layers combined. The combined organic layers were 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 dichloromethane/methanol=5:1 to give tert-butyl N-{1-[7-chloro-8-fluoro-2-(hexahydropyrrolizin-7a-ylmethoxy)pyrido[4,3-d]pyrimidin-4-yl]azepan-3- yljcarbamate as a light yellow solid (1 .2 g, 68.9%). LC-MS (El, m/z) M+1 : 535/537.

Synthesis of tert-butyl N-[(3R)-1-[7-chloro-8-fluoro-2-(hexahydropyrrolizin-7a- ylmethoxy)pyrido[4,3-d]pyrimidin-4-yl]azepan-3-yl]carbamate (assumed) & tert-butyl N-[(3S)-1-[7-chloro- 8-fluoro-2-(hexahydropyrrolizin-7a-ylmethoxy)pyrido[4,3-d]pyrimidin-4-yl]azepan-3-yl]carbamate (assumed): 1.0 g of tert-butyl N-{1-[7-chloro-8-fluoro-2-(hexahydropyrrolizin-7a-ylmethoxy)pyrido[4,3- d]pyrimidin-4-yl]azepan-3-yl}carbamate was purified by Chiral-Prep-HPLC using the following conditions: Column: CHIRALPAK IE, 3*25 cm, 5 pm; Mobile Phase A: MTBE (0.1% DEA)-HPLC, Mobile Phase B: IPA- HPLC; Flow rate: 30 mL/min; Gradient: 20% B to 20% B in 16 min; Wave Length: 220/254 nm. Finally, tert-butyl N-[(3R)-1-[7-chloro-8-fluoro-2-(hexahydropyrrolizin-7a-ylmethoxy)pyrido[4,3-d]pyrimidin-4-yl]azepan-3- yl]carbamate (assumed) was obtained as a light yellow oil (430 mg, 43.0%) and tert-butyl N-[(3S)-1-[7-chloro-8- fluoro-2-(hexahydropyrrolizin-7a-ylmethoxy)pyrido[4,3-d]pyrimidin-4-yl]azepan-3-yl]carbamate (assumed) was obtained as a light yellow oil (440 mg, 44.0%). 2A, TR=3.311 min in CHIRAL-HPLC, Column: CHIRALPAK IE-3, 100*4.6mm, 3um IE30CS-XF004, phase A: MTBE (0.5%DEA); mobile phase B: IPA, Cone, of Pump B: 20.0%, Oven Temperature: 25°C. 2B, TR=3.982 min in CHIRAL-HPLC, Column: CHIRALPAK IE-3, 100*4.6mm, 3um IE30CS-XF004, phase A: MTBE(0.5%DEA); mobile phase B: IPA, Cone, of Pump B: 20.0%, Oven Temperature: 25°C.

Example INT_8: Preparation of tert-butyl (1-(aminomethyl)cyclobutyl)(methyl)carbamate

Synthesis of 1-((tert-butoxycarbonyl)(methyl)amino)cyclobutane-1-carboxylic acid: Into a 500 mL 3-necked round-bottom flask, were added 1-[(tert-butoxycarbonyl)amino]cyclobutane-1 -carboxylic acid (10.0 g, 46.4 mmol, 1.0 eq) and tetrahydrofuran (200 mL) at 25°C. To the above mixture was added NaH (2.8 g, 60% in mineral oil, 116.6 mmol, 2.5 eq) in portions at 0°C. The resulting mixture was stirred for additional 30 min at 0°C and then CH3I (9.9 g, 69.7 mmol, 1.5 eq) was added dropwise at 0°C. The resulting mixture was stirred for additional 16 hours at 25°C. The reaction was quenched by the addition of water (200 mL) at 0°C, and acidified to pH=4 with cone. HCI. The resulting mixture was extracted with EtOAc (3x200 mL). The combined organic layers were washed with brine (2x200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum to afford 1-((tert-butoxycarbonyl)(methyl)amino)cyclobutane-1-carboxylic acid as a colorless oil (10.0 g, 93.8%). ¹HNMR (300 MHz, DMSO-d₆) 5 12.40 (s, 1 H), 2.72 (s, 3H), 2.47-2.22 (m, 4H), 2.12 -1.84 (m, 1 H), 1.82-1.67 (m, 1 H), 1.35 (s, 9H).

Synthesis of tert-butyl (1-carbamoylcyclobutyl)(methyl)carbamate: Into a 500 mL 3-necked roundbottom flask, were added 1-((tert-butoxycarbonyl)(methyl)amino)cyclobutane-1 -carboxylic acid (10.0 g, 43.6 mmol, 1.0 eq), DCM (200 mL), NH₄CI (7.0 g, 130.8 mmol, 3.0 eq), DIEA (6.7 g, 52.3 mmol, 1.2 eq) and HATH (19.9 g, 52.3 mmol, 1.2 eq) at 25°C. The resulting mixture was stirred for 16 hours at 30°C. The reaction was quenched by the addition of water (150 mL) and then extracted with CH2CI2 (3x150 mL). The combined organic layers were washed with brine (2x200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum to give tert-butyl (1-carbamoylcyclobutyl)(methyl)carbamate as a brown yellow oil (20.0 g, crude). ¹HNMR (300 MHz, DMSO-d₆) 5 6.91 (d, >34.1 Hz, 1 H), 3.62 (pd, >6.6, 3.8 Hz, 1 H), 3.20-3.06 (m, 1 H), 2.77 (s, 2H), 2.70 (s, 3H), 2.48-2.09 (m, 2H), 1.95- 1.55 (m, 1 H), 1.45-1.16 (m, 9H).

Synthesis of tert-butyl (1-(aminomethyl)cyclobutyl)(methyl)carbamate: Into a 500 mL 3-necked round-bottom flask, were added tert-butyl (1-carbamoylcyclobutyl)(methyl)carbamate (20.0 g, 87.6 mmol, 1.0 eq) and BH3-Me2S (35.0 mL, 350.0 mmol, 4.0 eq) at 25°C. The resulting mixture was stirred for 12 hours at 25°C. The reaction was quenched by the addition of MeOH (50 mL) at 25°C. The resulting mixture was concentrated under vacuum to give tert-butyl (1-(aminomethyl)cyclobutyl)(methyl)carbamate as a brown oil (25.0 g, crude).

Synthesis of tert-butyl (1-((((benzyloxy)carbonyl)amino)methyl)cyclobutyl)(methyl)carbamate:

Into a 500 mL 3-necked round-bottom flask, were added tert-butyl (1-(aminomethyl)cyclobutyl)(methyl)carbamate (25.0 g, 116.6 mmol, 1.0 eq), CH2CI2 (250 mL) and TEA (23.6 g, 233.3 mmol, 2.0 eq) at 25°C. To the above mixture was added Cbz-CI (13.9 g, 81.6 mmol, 0.7 eq) dropwise at 0°C. The resulting mixture was stirred for additional 4 hours at 25°C. The reaction was quenched by the addition of water (100 mL) and then extracted with CH2CI2 (3x100 mL). The combined organic layers were washed with brine (200 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 :1 to afford tert-butyl (1- ((((benzyloxy)carbonyl)amino)methyl)cyclobutyl)(methyl)carbamate as a colorless oil (800 mg, 1.9%). ¹HNMR (300 MHz, DMSO-d₆) 3 7.44-7.20 (m, 5H), 5.02 (s, 2H), 3.36 (d, >6. 6 Hz, 2H), 2.57 (s, 3H), 2.06 (h, >10.5 Hz, 4H), 1.70-1.54 (m, 3H), 1.37 (s, 9H).

Synthesis of tert-butyl (1-(aminomethyl)cyclobutyl)(methyl)carbamate: Into a 100 mL roundbottom flask, were added tert-butyl (1-((((benzyloxy)carbonyl)amino)methyl)cyclobutyl)(methyl)carbamate (800 mg, 2.2 mmol, 1.0 eq), MeOH (10 mL) and Pd/C (50 mg, 0.5 mmol, 0.2 eq) at 25°C. The resulting mixture was stirred for 12 hours at 25°C under H2 (3 atm) atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (2x10 mL). The filtrate was concentrated under vacuum to afford tert-butyl (1- (aminomethyl)cyclobutyl)(methyl)carbamate as a colorless oil (400 mg, 81.2%). ¹HNMR (300 MHz, DMSO-de) 6 2.77 (s, 2H), 2.66 (s, 3H), 2.16-1.91 (m, 4H), 1.67-1.51 (m, 2H), 1.37 (s, 9H).

Example INT_9: Preparation of tert-butyl (1-(aminomethyl)cyclopentyl)(methyl)carbamate Synthesis of 1-((tert-butoxycarbonyl)(methyl)amino)cyclopentane-1-carboxylic acid: Into a 500 mL 3-necked round-bottom flask, were placed 1-((tert-butoxycarbonyl)amino)cyclopentane-1 -carboxylic acid (10.0 g, 43.6 mmol, 1.0 eq) and tetrahydrofuran (200 mL) at 25°C. To the above mixture was added NaH (2.6 g, 60% in mineral oil, 109.0 mmol, 2.5 eq) in portions at 0°C. The resulting mixture was stirred for additional 30 min at 0°C. Then added CH3I (9.3 g, 65.4 mmol, 1.5 eq) dropwise at 0°C. The resulting mixture was stirred for additional 16 hours at 25°C. The reaction was quenched by the addition of water (200 mL) at 0°C. The mixture was acidified pH=4 with cone. HCI. The resulting mixture was extracted with ethyl acetate (3x200 mL). The combined organic layers were washed with brine (2x200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum to afford 1-((tert-butoxycarbonyl)(methyl)amino)cyclopentane-1- carboxylic acid as a light brown oil (11.0 g, crude).¹HNMR (300 MHz, DMSO-de) 5 2.86 (s, 3H), 2.28-2.07 (m, 2H), 1.96-1.80 (m, 2H), 1.74-1.52 (m, 4H), 1.36 (s, 9H).

Synthesis of tert-butyl (1-carbamoylcyclopentyl)(methyl)carbamate: Into a 500 mL 3-necked round-bottom flask, were added 1-((tert-butoxycarbonyl)(methyl)amino)cyclopentane-1-carboxylic acid (11.0 g, 45.2 mmol, 1.0 eq), CH2CI2 (200 mL), NH4CI (7.2 g, 135.6 mmol, 3.0 eq), DIEA (7.0 g, 54.2 mmol, 1.2 eq) and HATU (20.6 g, 54.2 mmol, 1.2 eq) at 25°C. The resulting mixture was stirred for 16 hours at 30°C. The reaction was quenched by the addition of water (150 mL), and then extracted with CH2CI2 (3x150 mL). The combined organic layers were washed with brine (2x200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum to afford tert-butyl (1-carbamoylcyclopentyl)(methyl)carbamate as a brown oil (25.0 g, crude).

Synthesis of tert-butyl (1-(aminomethyl)cyclopentyl)(methyl)carbamate: Into a 500 mL 3-necked round-bottom flask, were added tert-butyl (1-carbamoylcyclopentyl)(methyl)carbamate (25.0 g, 103.1 mmol, 1.0 eq), tetrahydrofuran (100 mL), and BHs-tetrahydrofuran (40 mL, 400.0 mmol, 3.8 eq) at 25°C. The resulting mixture was stirred for 12 hours at 25°C. The reaction was quenched by the addition of MeOH (50 mL) at 25°C. The resulting mixture was concentrated under vacuum to give tert-butyl (1- (aminomethyl)cyclopentyl)(methyl)carbamate as a brown oil (20.0 g, crude).

Synthesis of tert-butyl (1-((((benzyloxy)carbonyl)amino)methyl)cyclopentyl)(methyl)carbamate:

Into a 500 mL 3-necked round-bottom flask, were added tert-butyl (1- (aminomethyl)cyclopentyl)(methyl)carbamate (20.0 g, 87.5 mmol, 1.0 eq), CH2CI2 (200 mL), and TEA (17.7 g, 175.1 mmol, 2.0 eq) at 25°C. To the above mixture was added Cbz-CI (10.4 g, 61.3 mmol, 0.7 eq) dropwise at 0°C. The resulting mixture was stirred for additional 4 hours at 25°C. The reaction was quenched by the addition of water (100 mL), and then extracted with CH2CI2 (3x100 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 :1 to afford to afford tert-butyl (1-((((benzyloxy)carbonyl)amino)methyl)cyclopentyl)(methyl)carbamate as a colorless oil (1.4 g, 4.4%). ¹HNMR (300 MHz, DMSO-d₆) 5 7.35 (s, 5H), 5.02 (s, 2H), 3.27 (d, 7=6.2 Hz, 2H), 2.77 (s, 3H), 1.96 (d, 7=12.6 Hz, 2H), 1.72 (d, 7=11.3 Hz, 2H), 1.67-1.48 (m, 4H), 1.39 (s, 9H).

Synthesis of tert-butyl (1-(aminomethyl)cyclopentyl)(methyl)carbamate: Into a 100 mL roundbottom flask, were added tert-butyl (1-((((benzyloxy)carbonyl)amino)methyl)cyclopentyl)(methyl)carbamate (1.5 g, 4.1 mmol, 1.0 eq), MeOH (30 mL) and Pd/C (0.1 g, 0.8 mmol, 0.2 eq) at 25°C. The resulting mixture was stirred for 12 hours at 25°C under H2(3 atm) atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (2x10 mL). The filtrate was concentrated under vacuum to afford tert-butyl (1- (aminomethyl)cyclopentyl)(methyl)carbamate as a colorless oil (800 mg, 84.6%). ¹HNMR (300 MHz, DMSO-de) 5 2.87 (s, 3H), 2.68 (s, 2H), 2.03-1.87 (m, 2H), 1.84-1.66 (m, 2H), 1.65-1.43 (m, 2H), 1.39 (s,9H). Example INT_10: Preparation of (S)-(1,2-dimethylpyrrolidin-2-yl)methanol

Synthesis of (S)-(1,2-dimethylpyrrolidin-2-yl)methanol: Into a 250 mL 3-necked round-bottom flask, were added (S)-1 -(tert-butoxycarbonyl)-2-methylpyrrolidine-2-carboxylic acid (10 g, 43.6 mmol, 1.0 eq) and tetrahydrofuran (150 mL) at 25°C. To the above mixture was added LIAIFL (5.0 g, 130.8 mmol, 3.0 eq) in portions over 10 min at 0°C. The resulting mixture was stirred for additional 4 hours at 25°C. The reaction was quenched by the addition of H2O (5 mL) at 0°C. The resulting mixture was stirred for 15 min. The resulting mixture was added with 10%NaOH (5 mL). The resulting mixture was stirred for 10 min. The resulting mixture was added with H2O (15 mL). The resulting mixture was filtered, the filter cake was washed with tetrahydrofuran (3x100 mL). The filtrate was concentrated under vacuum. The crude product was purified by distillation under vacuum and the fraction was collected at 80°C to give (S)-(1 ,2-dimethylpyrrolidin-2-yl)methanol as a colorless oil (550 mg, 9.7%). ¹HNMR (400 MHz, Chloroform-d) 5 3.32 (d, >10.2 Hz, 1 H), 3.25 (d, >9.8 Hz, 1 H), 3.05 (dt, >9.2, 5.2 Hz, 1 H), 2.57 (q, >8.7 Hz, 1 H), 2.21 (s, 3H), 2.11-1.97 (m, 1 H), 1.72 (qd, >8.2, 5.2 Hz, 2H), 1.58- 1.41 (m, 1 H), 0.87 (s, 3H).

Example INT_11 A&11B: Preparation of tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-(((2S,4R)-4-fluoro-1,2- dimethylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,4R)-4-fluoro-1,2-dimethylpyrrolidin-2- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

Synthesis of 1 -tert-butyl 2-methyl (4R)-4-fluoro-2-methylpyrrolidine-1,2-dicarboxylate: Into a 500 mL 3-necked round-bottom flask were added 1 -tert-butyl 2-methyl (2S,4R)-4-fluoropyrrolidine-1 ,2-dicarboxylate (10.0 g, 40.4 mmol, 1.0 eq) and THF (200 mL) at 25°C. To the above mixture was added 2 M LiHMDS (40 ml, 80.6 mmol, 2.0 eq) dropwise at -78°C. The resulting mixture was stirred for additional 1 h at -78°C. Then to the above mixture was added Mel (11 .5 g, 81 .0 mmol, 2.0 eq) dropwiser at -78°C. The resulting mixture was stirred for additional 3 h at 25°C. The reaction was quenched by the addition of water (200 mL), and then extracted with EtOAc (3x200 mL). The combined organic layers were washed with brine (200 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 :1 to afford 1-tert-butyl 2-methyl (4R)-4-fluoro-2- methylpyrrolidine-1 ,2-dicarboxylate as a colorless oil (10.0 g, 94.6%). ¹HNMR (400 MHz, DMSO-cfe) 3 5.47-5.01 (m, 1 H), 3.80-3.70 (m, 2H), 3.70-3.57 (m, 3H), 2.49-2.13 (m, 3H), 1.59-1.49 (m, 2H), 1.44-1.27 (m, 9H).

Synthesis of ((4R)-4-fluoro-1,2-dimethylpyrrolidin-2-yl)methanol: Into a 500 mL 3-necked roundbottom flask were added 1-tert-butyl 2-methyl (4R)-4-fluoro-2-methylpyrrolidine-1 ,2-dicarboxylate (10.0 g, 38.2 mmol, 1.0 eq) and THF (200 mL) at 25°C. To the above mixture was added UAIH4 (2.9 g, 76.5 mmol, 2.0 eq) in portions at 0°C. The resulting mixture was stirred for additional 3 hours at 0°C. The reaction was quenched by the addition of water (3 mL) at 0°C, and stirred for 15min. Then added 15% NaOH (3 mL) at 0°C, and stirred for 15min. Then added water (9 mL) at 0°C, and stirred for 15min. The resulting mixture was filtered, the filter cake was washed with THF (2x30mL). The filtrate was concentrated under vacuum. The crude product was purified by distillation under 30 mmHg and the fraction was collected at 60°C to afford ((4R)-4-fluoro-1 ,2- dimethylpyrrolidin-2-yl)methanol as a colorless oil (3.5 g, 62.1%). ¹HNMR (400 MHz, DMSO-de) 5 5.29 - 4.93 (m, 1 H), 4.35 (d, J = 35.1 Hz, 1 H), 3.4-3.12 (m, 2H), 3.09-2.89 (m, 1 H), 2.87-2.63 (m, 1 H), 2.35-2.08 (m, 4H), 2.05- 1.75 (m, 1 H), 0.96 (s, 1 H), 0.84 (s, 2H).

Synthesis of tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-(((2S,4R)-4-fluoro-1,2-dimethylpyrrolidin-2- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and tert-butyl (1 R,5S)-3-(7-chloro-8-fluoro-2-(((2R,4R)-4-fluoro-1,2-dimethylpyrrolidin-2-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: Into a 40 mL vial were added ((4R)-4-fluoro- 1 ,2-dimethylpyrrolidin-2-yl)methanol (516 mg, 3.5 mmol, 1.5 eq) and tetrahydrofuran (20 mL) at 25°C. To the above mixture was added NaH (112 mg, 4.7 mmol, 2.0 eq) in portions over 5 min at 0°C. The resulting mixture was stirred for additional 30 min at 25°C. To the above mixture was added tert-butyl (1 R,5S)-3-(2,7-dichloro-8- fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1 g, 2.3 mmol, 1.0 eq) in portions over 5 min at 25°C. The resulting mixture was stirred for additional 3 hours at 25°C. The reaction was quenched with sat. NH4CI (aq.) at 0°C. The resulting mixture was extracted with ethyl acetate (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 dichloromethane/methanol =10:1. The crude product was purified by Prep-SFC using the following conditions. Finally, tert-butyl (1 R,5S)-3-(7-chloro-8-fl uoro-2-(((2S, 4R)-4-fluoro- 1 , 2-d i methyl pyrrol id i n-2- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1 ]octane-8-carboxylate was obtained as a white solid (180 mg, 14.3%) and tert-butyl (1 R,5S)-3-(7-chloro-8-fluoro-2-(((2R,4R)-4-fluoro-1 ,2-dimethylpyrrolidin-2- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1 ]octane-8-carboxylate was obtained as a white solid (500 mg, 39.7%). A, TR=1.29 min in CHIRAL-SFC, Column: (R, R)-WHELK-O1-Kromasil, 3*25 cm, 5 pm; Mobile Phase A: CO2, Mobile Phase B: CH3OH (0.1% 2M NH3-CH3OH); Flow rate: 80 mL/min; Gradient: isocratic 50% B; Column Temperature(25°C): 35; Back Pressure(bar): 100; Wave Length: 220 nm. B, TR=1.47 min in CHIRAL- SFC, Column: (R, R)-WHELK-O1-Kromasil, 3*25 cm, 5 pm; Mobile Phase A: CO2, Mobile Phase B: CH3OH (0.1% 2M NH3-CH3OH); Flow rate: 80 mL/min; Gradient: isocratic 50% B; Column Temperature(25°C): 35; Back Pressure(bar): 100; Wave Length: 220 nm. LC-MS (ES, m/z) M+1 : 539/541.

Example INT_12: Preparation of ((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methanol

Synthesis of ((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methanol: Into a 500 mL 3-necked roundbottom flask were added 1 -(tert-butyl) 2-methyl (2S,4R)-4-fluoropyrrolidine-1 ,2-dicarboxylate (10.0 g, 40.5 mmol, 1.0 eq) and tetrahydrofuran (200 mL) at 25°C. To the above mixture was added UAIH4 (3.1 g, 80.9 mmol, 2.0 eq) in portions at 0°C. The resulting mixture was stirred for additional 3 hours at 0°C. The reaction was quenched by the addition of water (3 mL) at 0°C and stirred for 15min. Then added 15% NaOH (3 mL) at 0°C, and stirred for 15 min. Then added water (9 mL) at 0°C, and stirred for 15 min. The resulting mixture was filtered, the filter cake was washed with tetrahydrofuran (2x30mL). The filtrate was concentrated under vacuum. The crude product was purified by distillation under 30 mmHg and the fraction was collected at 60°C to afford ((2S,4R)-4-fluoro-1 - methylpyrrolidin-2-yl)methanol as a colorless oil (2.0 g, 37.1%). ¹HNMR (400 MHz, DMSO-de) 5 5.27-4.96 (m, 1 H), 4.59 (s, 1 H), 3.49-3.27 (m, 2H), 2.62-2.45 (m, 2H), 2.34 (dd, 10.2, 3.2 Hz, 1 H), 2.29 (s, 3H), 2.12-1.59 (m, 2H).

Example INT_13: Preparation of (1-(morpholinomethyl)cyclopropyl)methanol

Synthesis 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. To the mixture was added CH2CI2 (150 mL), TEA (52.7 g, 520.4 mmol, 5.0 eq) and morpholine (10.9 g, 124.9 mmol, 1.2 eq) 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 Na2SO4. 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_14A&14B: Preparation of tert-butyl N-[(6S)-4-(7-chloro-8-fluoro-2-{[1-(morpholin-4- ylmethyl)cyclopropyl]methoxy}pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-yl]carbamate (assumed) and tert-butyl N-[(6R)-4-(7-chloro-8-fluoro-2-{[1-(morpholin-4-ylmethyl)cyclopropyl]methoxy}pyrido[4,3- d]pyrimidin-4-yl)-1,4-oxazepan-6-yl]carbamate (assumed)

Synthesis of tert-butyl N-(4-{2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl}-1,4-oxazepan-6- yl)carbamate: Into a 100 round-bottom flask, were placed 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (550 mg, 2.2 mmol, 1.0 eq) and CH2CI2 (10 mL). To the above mixture was added DIEA (704 mg, 5.4 mmol, 2.5 eq) dropwise at -40°C. The reaction mixture was stirred at -40°C for 15 min. To the above mixture was added tertbutyl N-(1 ,4-oxazepan-6-yl)carbamate (471 mg, 2.2 mmol, 1.0 eq) in CH2CI2 (5 mL) dropwise at -40°C. The resulting mixture was stirred for additional 15 min at -40°C. The reaction mixture was then quenched by the addition of water (10 mL). The resulting mixture extracted with EtOAc (2x30 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 :1 to give tert-butyl N-(4-{2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl}-1 ,4-oxazepan-6-yl)carbamate as a yellow solid (700 mg, 74.3%). LC-MS (ES, m/z) M+1 : 432/434.

Synthesis of tert-butyl N-[4-(7-chloro-8-fluoro-2-{[1-(morpholin-4- ylmethyl)cyclopropyl]methoxy}pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-yl]carbamate: Into a 50 mL round-bottom flask, were placed tert-butyl N-(4-{2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl}-1 ,4-oxazepan-6- yl)carbamate (700 mg, 1.6 mmol, 1.0 eq), [1-(morpholin-4-ylmethyl)cyclopropyl]methanol (222 mg, 1.3 mmol, 0.8 eq) and THF (15 mL) at 25°C. To the above mixture was added NaH (130 mg, 3.2 mmol, 2.0 eq, 60%) in portions at 0°C. The resulting mixture was stirred for 1 hour at 0°C. The reaction was quenched with sat. NH4CI (aq.) at 0°C, and then extracted with ethyl acetate (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 dichloromethane/methanol =10:1 to give tertbutyl N-[4-(7-chloro-8-fluoro-2-{[1-(morpholin-4-ylmethyl)cyclopropyl]methoxy}pyrido[4,3-d]pyrimidin-4-yl)-1 ,4- oxazepan-6-yl]carbamate as a white solid (300 mg, 32.7%). LC-MS (ES, m/z) M+1 : 567/569.

Synthesis of tert-butyl N-[(6S)-4-(7-chloro-8-fluoro-2-{[1-(morpholin-4- ylmethyl)cyclopropyl]methoxy}pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-yl]carbamate (assumed) and tert-butyl N-[(6R)-4-(7-chloro-8-fluoro-2-{[1-(morpholin-4-ylmethyl)cyclopropyl]methoxy}pyrido[4,3- d]pyrimidin-4-yl)-1,4-oxazepan-6-yl]carbamate (assumed): The residue tert-butyl N-[4-(7-chloro-8-fluoro-2- {[1-(morpholin-4-ylmethyl)cyclopropyl]methoxy}pyrido[4,3-d]pyrimidin-4-yl)-1 ,4-oxazepan-6-yl]carbamate (300 mg, 0.5 mmol, 1.0 eq) was purified by SFC to give tert-butyl N-[(6S)-4-(7-chloro-8-fluoro-2-{[1-(morpholin-4- y I methy l)cy clopropy I] methoxy }py rido [4, 3-d] py ri midin -4-y I)- 1 ,4-oxazepan-6-yl]carbamate (assumed) (80 mg, 26.7%) and tert-butyl N-[(6R)-4-(7-chloro-8-fluoro-2-{[1-(morpholin-4-ylmethyl)cyclopropyl]methoxy}pyrido[4,3- d]pyrimidin-4-yl)-1,4-oxazepan-6-yl]carbamate (assumed) (120 mg, 40.0%) as a white solid, tert-butyl N-[(6S)-4- (7-chloro-8-fluoro-2-{[1-(morpholin-4-ylmethyl)cyclopropyl]methoxy}pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6- yl]carbamate (assumed): RT1= 5.9 min in CHIRAL ART Cellulose-SB, 3x25 cm, 5 pm; Mobile Phase A: CO2; Gradient: isocratic 50% B; Column Temperature: 35°C; Back Pressure: 100 bar; Wave Length: 220 nm; Sample Solvent: MeOH: DCM=2:1; Injection Volume: 3 mL. LC-MS (ES, m/z) M+1 : 567/569. tert-butyl N-[(6R)-4-(7- chloro-8-fluoro-2-{[1-(morpholin-4-ylmethyl)cyclopropyl]methoxy}pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6- yl]carbamate (assumed): RT2= 7.0 min in CHIRAL ART Cellulose-SB, 3x25 cm, 5 pm; Mobile Phase A: CO2; Gradient: isocratic 50% B; Column Temperature: 35°C; Back Pressure: 100 bar; Wave Length: 220 nm; Sample Solvent: MeOH: DCM=2: 1 ; Injection Volume: 3 mL.

Example INT_15: Preparation of tert-butyl N-[(6R)-1-(7-chloro-8-fluoro-2-{[1-(morpholin-4- ylmethyl)cyclopropyl]methoxy}pyrido[4,3-d]pyrimidin-4-yl)-4-methyl-1,4-diazepan-6-yl]carbamate (assumed) & tert-butyl N-[(6S)-1-(7-chloro-8-fluoro-2-{[1-(morpholin-4- ylmethyl)cyclopropyl]methoxy}pyrido[4,3-d]pyrimidin-4-yl)-4-methyl-1,4-diazepan-6-yl]carbamate (assumed)

Synthesis of methyl (benzylcarbamoyl)formate: Into a 1000-mL 3-necked round-bottom flask, were placed 1-phenylmethanamine (26.2 g, 244.9 mmol, 1.2 eq), DCM (400 mL), TEA (62.0 g, 612.2 mmol, 3.0 eq). This was followed by the addition of methyl oxaloch I oridate (25.0 g, 204.1 mmol, 1 .0 eq) at 0°C. The resulting solution was stirred for 2 hours at 25°C. The resulting mixture was then quenched by the addition of water (800 mL), and then extracted with ethyl acetate (2x800 mL). The combined organic layers was washed with brine (2x800 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 (benzylcarbamoyl)formate as a light yellow solid (25.0 g, 63.4%). ¹HNMR (300 MHz, DMSO-de) 5 9.67- 9.33 (m, 1 H), 7.48-7.17 (m, 5H), 4.34 (d, >6.3 Hz, 2H), 3.79 (s, 3H).

Synthesis of N'-benzyl-N-methylethanediamide: Into a 1000-mL 3-necked round-bottom flask, were placed methyl (benzylcarbamoyl)formate (24.0 g, 124.2 mmol, 1.0 eq), methanamine hydrochloride (9.7 g, 310.6 mmol, 2.5 eq), EtOH (300 mL), K2CO3 (51.5 g, 372.7 mmol, 3.0 eq). The resulting solution was stirred for 12 hours at 70°C. The resulting mixture was then quenched by the addition of water (800 mL) and then extracted with DCM (2x1000 mL). The combined organic layers was washed with brine (2x800 mL) and then dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum to give N'-benzy l-N- methylethanediamide as a white solid (20.0 g, 83.8%). ¹HNMR (300 MHz, DMSO-de) 5 9.28 (t, 6.6 Hz, 1 H), 8.73 (d, >5.4 Hz, 1 H), 7.38-7.18 (m, 5H), 4.33 (d, >6.6 Hz, 2H), 2.69 (d, >4.8 Hz, 3H).

Synthesis of benzyl[2-(methylamino)ethyl]amine: Into a 500 mL 3-necked round-bottom flask, were placed N'-benzyl-N-methylethanediamide (15.0 g, 78.0 mmol, 1.0 eq), THF (200 mL). This was followed by the addition of UAIH4 (8.9 g, 234.1 mmol, 3.0 eq) at 0°C. The mixture was stirred at 70°C for 16 hours. The reaction was then quenched by the addition of water (9 mL), 15% NaOH (9 mL), water (27 mL). The resulting solution was stirred for 20 minutes and dried over anhydrous magnesium sulfate. The solids were filtered out. The filtrate was concentrated under vacuum. The crude residue was purified onto a silica gel column and eluted with dichloromethane/methanol=10:1 to give benzyl[2-(methylamino)ethyl]amine as a light yellow oil (6.5 g, 50.7%). ¹HNMR (300 MHz, DMSO-d₆) 6 7.32-7.28 (m, 5H), 3.68 (s, 2H), 2.54 (s, 3H), 2.52-2.50 (m, 2H), 2.26-2.24 (m, 4H).

Synthesis of tert-butyl N-(1,3-dihydroxypropan-2-yl)carbamate: Into a 1000 mL 3-necked roundbottom flask and maintained with an inert atmosphere of nitrogen, were placed methyl 2-[(tert- butoxycarbonyl)amino]-3-hydroxypropanoate (30.0 g, 136.8 mmol, 1.0 eq), MeOH (300 mL). This was followed by the addition of NaBH4 (15.5 g, 410.5 mmol, 3.0 eq) at 0°C. The mixture was stirred at 25°C for 16 hours. The resulting mixture was then quenched by the addition of water (500 mL) and then extracted with dichloromethane (2x800 mL). The combined organic layers was washed with brine (2x500 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 :0 to give tert-butyl N-(1 ,3-dihydroxypropan-2- yl)carbamate as a white solid (21.0 g, 80.3%). ¹HNMR (300 MHz, DMSO-d₆) 5 6.27 (d, 0=6.0 Hz, 1 H), 4.49 (t, 0=5.4 Hz, 2H), 3.43-3.33 (m, 5H), 1.38 (s, 9H).

Synthesis of tert-butyl N-(3-oxoprop-1-en-2-yl)carbamate: Into a 500 mL 3-necked round-bottom flask and maintained with an inert atmosphere of nitrogen, were placed oxalic dichloride (19.9 g, 156.9 mmol, 2.0 eq), DCM (150 mL). This was followed by the addition of DMSO (30.6 g, 392.2 mmol, 5.0 eq) at -70°C. Then the mixture was stirred for 1 hour at -70°C. A solution of tert-butyl N-(1,3-dihydroxypropan-2-yl)carbamate (15.0 g, 78.4 mmol, 1.0 eq) in dichloromethane (50 mL) was added dropwise at -70°C, then the mixture was stirred from -70°C for 30 minutes. This was followed by the addition of TEA (39.7 g, 392.2 mmol, 5.0 eq) at -70°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 DCM (2x500 mL). The combined organic layers was washed with brine (2x500 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 :5 to give tert-butyl N-(3- oxoprop-1-en-2-yl)carbamate as a light yellow oil (7.8 g, 58.1%). ¹HNMR (400 MHz, DMSO-de) 5 9.25 (s, 1 H), 8.01 (s, 1 H), 6.48 (s, 1 H), 5.59 (d, 1.2 Hz, 1 H), 1.44 (s, 9H).

Synthesis of tert-butyl N-(1-benzyl-4-methyl-1,4-diazepan-6-yl)carbamate: Into a 500 mL 3-necked round-bottom flask, were placed tert-butyl N-(3-oxoprop-1-en-2-yl)carbamate (7.8 g, 45.6 mmol, 1.0 eq), MeOH (150 mL), benzyl[2-(methylamino)ethyl]amine (7.5 g, 45.6 mmol, 1.0 eq). Then the reaction mixture was stirred at 25°C for 30 min. This was followed by the addition of NaBH4 (4.3 g, 113.9 mmol, 2.5 eq) at 0°C. The resulting mixture was stirred for additional 2 hours at 25°C. The resulting mixture was then quenched by the addition of water (200 mL) and then extracted with DCM (2x400 mL). The combined organic layers was washed with brine (2x400 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 :0 to give tertbutyl N-(1-benzyl-4-methyl-1,4-diazepan-6-yl)carbamate as a light yellow solid (5.6 g, 38.5%). ¹HNMR (300 MHz, DMSO-de) 6 7.32-7.23 (m, 5H), 6.48 (d, >8.4 Hz, 1 H), 3.69-3.53 (m, 3H), 2.74-2.64 (m, 3H), 2.61-2.50 (m, 5H), 2.28 (s, 3H), 1.34 (s, 9H).

Synthesis of tert-butyl N-(1-methyl-1,4-diazepan-6-yl)carbamate: Into a 100-mL round-bottom flask, were placed tert-butyl N-(1-benzyl-4-methyl-1,4-diazepan-6-yl)carbamate (2.5 g, 7.8 mmol, 1.0 eq), MeOH (30 mL), Pd/C (250 mg). The mixture was stirred at 25°C under 2 atm of hydrogen press for 16 hours. The resulting mixture was filtered. The filtrate was concentrated under vacuum to give tert-butyl N-(1 -methyl-1 ,4-diazepan-6- yl)carbamate as a light yellow oil (1 .4 g, crude).

Synthesis of tert-butyl N-(1 -{2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl}-4-methyl-1 ,4- diazepan-6-yl)carbamate: Into a 100 mL 3-necked round-bottom flask, were placed 2,4,7-trichloro-8- fluoropyrido[4,3-d]pyrimidine (1.2 g, 4.7 mmol, 1.0 eq), DCM (30 mL). This was followed by the addition of DIEA (1 .2 g, 9.5 mmol, 2.0 eq) at -40°C. Then the reaction mixture was stirred at -40°C for 15 min. A solution of tertbutyl N-(1 -methyl-1, 4-diazepan-6-yl)carbamate (1.1 g, 4.8 mmol, 1.0 eq) in CH2CI2 (10 mL) added dropwise at - 40°C. The resulting mixture was stirred for additional 45 min at -40°C. The resulting mixture was then quenched by the addition of water (50 mL). The mixture was extracted with ethyl acetate (2x50 mL) and washed with brine (2x50 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 :0 to give tert-butyl N-(1-{2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl}-4-methyl-1 ,4-diazepan-6- yl)carbamate as a light yellow solid (1.3 g, 61.4%). ¹HNMR (400 MHz, DMSO-d₆) 5 9.12 (s, 1 H), 6.94 (d, 4=6.8 Hz, 1 H), 4.23-4.15 (m, 1 H), 4.09-3.85 (m, 4H), 2.94-2.85 (m, 1 H), 2.84-2.77 (m, 2H), 2.73-2.68 (m, 1 H), 2.32 (s, 3H), 1.39 (s, 9H).

Synthesis of tert-butyl N-[1-(7-chloro-8-fluoro-2-{[1-(morpholin-4- ylmethyl)cyclopropyl]methoxy}pyrido[4,3-d]pyrimidin-4-yl)-4-methyl-1,4-diazepan-6-yl]carbamate: Into a 100-mL 3-necked round-bottom flask, were placed tert-butyl N-(1 -{2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4- yl}-4-methyl-1 ,4-diazepan-6-yl)carbamate (1.3 g, 2.9 mmol, 1.0 eq), [1 -(morpholin-4- ylmethyl)cyclopropyl]methanol (500 mg, 2.9 mmol, 1.0 eq), THF (15 mL). This was followed by the addition of NaH (470 mg, 60%, 4.0 eq) at 0°C. The resulting solution was stirred for 2 hours at 25°C. The resulting mixture was then quenched by the addition of water (40 mL), and then extracted with ethyl acetate (2x50 mL). The combined organic layers was washed with brine (2x50 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 dichloromethane/methanol=20:1 to give tert-butyl N-[1 -(7-chloro-8-fluoro-2-{[1 -(morpholin-4- ylmethyl)cyclopropyl]methoxy}pyrido[4,3-d]pyrimidin-4-yl)-4-methyl-1 ,4-diazepan-6-yl]carbamate as a white solid (650 mg, 38.4%).¹HNMR (400 MHz, DMSO-d₆) 6 8.97 (s, 1 H), 6.90 (d, 4=8.0 Hz, 1 H), 4.32 (s, 2H), 4.21 (dd, 4=13.6, 4.1 Hz, 1 H), 4.06-3.96 (m, 3H), 3.81-3.71 (m, 1 H), 3.53-3.51 (m, 4H), 2.91-2.69 (m, 4H), 2.44-2.36 (m, 4H), 2.32-2.26 (m, 5H), 1.39 (s, 9H), 0.66-0.59 (m, 2H), 0.43-0.40 (m, 2H).

Synthesis of tert-butyl N-[(6R)-1-(7-chloro-8-fluoro-2-{[1-(morpholin-4- ylmethyl)cyclopropyl]methoxy}pyrido[4,3-d]pyrimidin-4-yl)-4-methyl-1,4-diazepan-6-yl]carbamate (assumed) & tert-butyl N-[(6S)-1-(7-chloro-8-fluoro-2-{[1-(morpholin-4- ylmethyl)cyclopropyl]methoxy}pyrido[4,3-d]pyrimidin-4-yl)-4-methyl-1,4-diazepan-6-yl]carbamate (assumed): 700 mg of tert-butyl N-[1-(7-chloro-8-fluoro-2-{[1-(morpholin-4- y I methy l)cy clopropy I] methoxyjpy rido [4, 3-d] py ri midin -4-y l)-4-methy I- 1 ,4-diazepan-6-yl]carbamate was purified by Chiral-Prep-HPLC using the following conditions: Column: CHIRAL ART Cellulose-SB 3*25 cm, 5 pm; Mobile Phase A: CO2, Mobile Phase B: IPA: HEX=1 : 1 (0.1 % 2M NHs-MeOH); Flow rate: 80 mL/min; Gradient: isocratic 45% B; Wave Length: 220/254 nm. Finally, tert-butyl N-[(6R)-1 -(7-chloro-8-fluoro-2-{[1 -(morpholin-4- ylmethyl)cyclopropyl]methoxy}pyrido[4,3-d]pyrimidin-4-yl)-4-methyl-1 ,4-diazepan-6-yl]carbamate (assumed) was obtained as a light yellow solid (320 mg, 45.7%) and tert-butyl N-[(6S)-1 -(7-chloro-8-fluoro-2-{[1 -(morpholin-4- ylmethyl)cyclopropyl]methoxy}pyrido[4,3-d]pyrimidin-4-yl)-4-methyl-1 ,4-diazepan-6-yl]carbamate (assumed) was obtained as a light yellow solid (330 mg, 47.1%). A, TR=2.559 min in CHIRAL-SFC, Column: Cellulose-SB 100x4.6mm 3.0um, phase: IPA (50%Hex)20mMNH3, Cone, of Pump B: 10.0%, Oven Temperature: 35°C. B, TR=2.757 min in CHIRAL-SFC, Column: Cellulose-SB 100x4.6mm 3.0um, phase: IPA (50%Hex)20mMNH3, Cone, of Pump B: 10.0%, Oven Temperature: 35°C. Example 1 : Preparation of 1-[3-(2-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-3- hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]prop-2-en- 1-one

Synthesis of tert-butyl (1 R,5S)-3-(2,7-d ic hl oro-8-f I uoropyrido[4, 3-d]pyri m idi n-4-yl )-3, 8- diazabicyclo[3.2.1]octane-8-carboxylate: 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 CH2CI2 (160 mL) was added DIEA (12.8 g, 99.0 mmol, 2.5 eq) dropwise at -40°C. The reaction mixture was stirred at -40°C for 15 min. After that, a solution of tert-butyl (1 R,5S)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (8.4 g, 39.6 mmol, 1.0 eq) in CH2CI2 (35 mL) was added dropwise at - 40°C. The resulting mixture was stirred for an additional 15 min at -40°C. The reaction mixture was quenched by the addition of water (200 mL) and then 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 give tert-butyl (1 R,5S)-3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate as a yellow solid (13.6 g, 80.2%). LC-MS (El, m/z) M+1 : 428.

Synthesis of tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: Into a 50 mL round-bottom flask, were placed tert-butyl (1 R,5S)-3-{2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl}-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (511 mg, 1.2 mmol, 1.0 eq), [(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a- yl]methanol (190 mg, 1.2 mmol, 1.0 eq) and THF (10 mL). After that, NaH (95 mg, 2.4 mmol, 2.0 eq, 60%) was added in portions at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 1 hour at 25°C. The reaction mixture was quenched by the addition of water/ice (2 mL) and then 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 :1 to afford tert-butyl (1 R,5S)-3-(2-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a- yl]methoxy}-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a colorless oil (160 mg, 24.3%). LC-MS (El, m/z) M+1 : 551.

Synthesis of tert-butyl (1 R,5S)-3-(2-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-8- fluoro-7-[3-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphthalen-1-yl]pyrido[4,3-d]pyrimidin-4-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate: Into a 50 mL round-bottom flask, were placed tert-butyl (1 R,5S)- 3-(2-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl] methoxy }-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3, 8- diazabicyclo[3.2.1]octane-8-carboxylate (160 mg, 0.3 mmol, 1.0 eq), triisopropyl((6-(methoxymethoxy)-8- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)silane (230 mg, 0.5 mmol, 1.6 eq), K2CO3 (120 mg, 0.9 mmol, 3.0 eq), CataCXium Pd G3 (21 mg, 0.03 mmol, 0.1 eq) and Solvents (DME/water=10:1, 4 mL) under nitrogen atmosphere. The resulting mixture was stirred for 4 hours at 80°C under nitrogen atmosphere. The reaction mixture was quenched by the addition of water (10 mL) and then extracted with EtOAc (2x 15 mL). The combined organic layers were washed with brine (15 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 tert-butyl (1 R,5S)-3-(2-{[(2R,7aS)-2-fluoro- hexahydropyrrolizin-7a-yl]methoxy}-8-fluoro-7-[3-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphthalen-1- yl]pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow solid (150 mg, 58.5%). LC- MS (El, m/z) M+1 : 883.

Synthesis of tert-butyl (1 R,5S)-3-(2-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-7-[8- ethynyl-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate: Into an 8 mL sealed tube, were placed tert-butyl (1 R,5S)-3-(2- {[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-8-fluoro-7-[3-(methoxymethoxy)-8-[2- (triisopropylsilyl)ethynyl]naphthalen-1-yl]pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150 mg, 0.17 mmol, 1.0 eq), CsF (258 mg, 1.7 mmol, 10.0 eq) and DMF (3 mL). The resulting mixture was stirred for 2 hours at 25°C. The resulting mixture was quenched by the addition of water (10 mL) and then extracted with EtOAc (2x10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. Finally, tert-butyl (1 R,5S)-3-(2- {[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-7-[8-ethynyl-3-(methoxymethoxy)naphthalen-1-yl]-8- fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate was obtained as a yellow solid (100 mg, 81.0%). LC-MS (El, m/z) M+1 : 727.

Synthesis of 4-(2-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-4-[(1 R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl]-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynylnaphthalen-2-ol: Into an 8 mL sealed tube, were placed tert-butyl (1 R,5S)-3-(2-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-7-[8- ethynyl-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (100 mg, 0.14 mmol, 1.0 eq) and CH2CI2 (2 mL). After that, HCI (gas) in 1 ,4-dioxane (4 M, 0.5 mL, 2.0 mmol, 14.5 eq) was added dropwise at 0°C. The resulting mixture was stirred for 1 hour at 0°C. The mixture was neutralized to pH=8 with NH3 in MeOH (2 M). The resulting mixture was concentrated under vacuum at 0°C. The crude product was purified by Prep-HPLC using the following conditions (Prep-HPLC-006): Column, YMC- Actus Triart C18 ExRS, 30*150 mm, 5pm; mobile phase, water (10 mmol/L NH4HCO3+0.1 % NFL’FLO) and CH3CN (45% CH3CN up to 85% in 10 min) detector, UV 254 nm to afford 4-(2-{[(2R,7aS)-2-fluoro- hexahydropyrrolizin-7a-yl]methoxy}-4-[(1 R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoropyrido[4,3-d]pyrimidin- 7-y l)-5-ethy ny lnaphthalen-2-ol as a yellow solid (20 mg, 25.0%). LC-MS (El, m/z) M+1 : 583. ¹HNMR (400 MHz, DMSO-d₆) 5 10.14 (s, 1 H), 9.03 (s, 1 H), 7.88 (d, >7.9 Hz, 1 H), 7.44 (dt, >15.0, 7.1 Hz, 2H), 7.34 (d, >2.6 Hz, 1 H), 7.12 (d, >2.5 Hz, 1 H), 5.28 (d, >54.2 Hz, 1 H), 4.48 (d, >12.2 Hz, 1 H), 4.30 (d, >12.2 Hz, 1 H), 4.11 (dd, >10.2, 2.6 Hz, 1 H), 4.01 (d, >10.4 Hz, 1 H), 3.65 (s, 1 H), 3.57 (s, 1 H), 3.55 (s, 3H), 3.09 (d, >9.8 Hz, 2H), 3.02 (s, 1 H), 2.84 (s, 1 H), 2.14 (d, >5.1 Hz, 1 H), 2.05 (s, 1 H), 2.01 (s, 1 H), 1.84 (d, J = 13.8 Hz, 1 H), 1.78 (d, J = 9.8 Hz, 2H), 1.66 (s, 4H).

Synthesis of 1-[3-(2-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-3- hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]prop-2-en- 1-one: Into an 8 mL sealed tube were added 4-(2-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-4- [(1 R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynylnaphthalen-2-ol (20 mg, 0.03 mmol, 1.0 eq), CH2CI2 (1 mL) and DIEA (13 mg, 0.09 mmol, 3.0 eq) at 25 °C. After that, acryloyl chloride (3 mg, 0.03 mmol, 1 .0 eq) was added dropwise at 0°C. The resulting mixture was stirred for 2 hours at 25 °C. The reaction mixture was quenched by the addition of water (0.5 mL) and then extracted with CH2CI2 (2x10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in THF (0.5 mL) and water (0.5 mL) and then LiOH (3 mg, 0.14 mmol, 4.0 eq) was added at 25 °C. The reaction mixture was stirred for an additional 3 hours at 25°C. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC using the following conditions (Prep-HPLC-006): Column, YMC-Actus Triart C18 ExRS, 30*150 mm, 5pm; mobile phase, water (10 mmol/L NH₄HCO₃+0.1 % NH₃«H₂O) and CH₃CN (45% CH₃CN up to 85% in 10 min) detector, UV 254 nm to afford 1-[3-(2-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a- yl]methoxy}-7-(8-ethynyl-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octan-8-yl]prop-2-en-1-one as a yellow solid (5.0 mg, 22.88%). LC-MS (El, m/z) M+1 : 637. ¹HNMR (400 MHz, DMSO-d₆) 5 10.15 (s, 1 H), 9.05 (s, 1 H), 7.89 (d, 7=8.0 Hz, 1 H), 7.45-7.43 (m, 2H), 7.35 (s, 1 H), 7.13 (s, 1 H), 6.82 (dd, 7=16.7, 10.3 Hz, 1 H), 6.26 (d, 7=16.6 Hz, 1 H), 5.79 (d, 7=10.4 Hz, 1 H), 5.36-5.22 (m, 1 H), 4.76 (s, 2H), 4.65 (d, 7 = 12.7 Hz, 1 H), 4.44 (s, 1 H), 4.14 (d, 7 = 10.4 Hz, 1 H), 4.04 (d, 7=10.5 Hz, 1 H), 3.69 (d, 7=12.4 Hz, 1 H), 3.60 (s, 2H), 3.10 (d, 7=9.5 Hz, 2H), 3.02 (s, 1 H), 2.84 (s, 1 H), 2.14-2.01 (m, 4H), 1.89-1.75 (m, 6H).

Example 2: Preparation of 1-[(2S)-2-{[(2-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-7-(8- ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4- yl)(methyl)amino]methyl}pyrrolidin-1-yl]prop-2-en-1-one

Synthesis of 1-[(2S)-2-{[(2-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-7- fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino]methyl}pyrrolidin-1- yl]prop-2-en-1-one: Into an 8 mL sealed tube were added 4-(2-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a- yl] methoxy }-8-fluoro-4-{methyl[(2S)-pyrrolidin-2-ylmethyl]amino}pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6- fluoronaphthalen-2-ol (30 mg, 0.05 mmol, 1.0 eq) and DIEA (16 mg, 0.1 mmol, 2.5 eq) at 25 °C. After that, acryloyl chloride (3 mg, 0.03 mmol, 0.7 eq) was added dropwise at 0°C. The reaction mixture was stirred for 1 hour at 0°C. The resulting mixture was quenched by the addition of water (5 mL) and then extracted with CH2CI2 (2x10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC using the following conditions ((Prep-HPLC-006): Column, YMC-Actus Triart C18 ExRS, 30*150 mm, 5pm; mobile phase, water (10 mmol/L NH4HCC₃+0.1 % NHs TfeO) and CH₃CN (45% CH₃CN up to 85% in 10 min) detector, UV 254 nm.) to afford 1-[(2S)-2-{[(2-{[(2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl]methoxy}-7-(8-ethynyl-7-fluoro- 3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)(methyl)amino]methyl}pyrrolidin-1-yl]prop-2-en-1- one as a yellow solid (10 mg, 30.6%). LC-MS (ES, m/z) M+1 : 657. ¹HNMR (400 MHz, DMSO-d₆) 5 10.15 (s, 1 H), 9.34-9.03 (m, 1 H), 7.98 (dd, 7=9.8, 6.0 Hz, 1 H), 7.57-7.32 (m, 2H), 7.32-6.61 (m, 2H), 6.14-6.03 (m, 1 H), 5.69 (q, 7=9.9, 9.1 Hz, 1 H), 5.29 (m, 1 H), 5.09-4.75 (m, 1 H), 4.36-3.91 (m, 5H), 3.85 (d, 7=24.1 Hz, 1 H), 3.62 (d, 7=13.4 Hz, 1 H), 3.22 (d, >11.8 Hz, 1 H), 3.11 (d, >11.9 Hz, 2H), 3.04 (s, 3H), 2.84 (d, >8.5 Hz, 1 H), 2.27-1.93 (m, 6H), 1.92-1.71 (m, 4H).

Example 3: Preparation of 1-((1R,5S)-3-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)prop-2-en-1- one

Synthesis of tert-butyl (1 R,5S)-3-(7-chloro-8-fluoro-2-((tetrahydro-1 H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: Into a 40 mL vial, were added tert-butyl (1 R,5S)-3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate (600 mg, 1.4 mmol, 1.0 eq), dioxane (6 mL), (tetrahydro-1 H-pyrrolizin-7a(5H)-yl)methanol (297 mg, 2.1 mmol, 1.5 eq), CS2CO3 (1369 mg, 4.2 mmol, 3.0 eq). The resulting mixture was stirred for additional 16 hours at 90°C. The reaction was quenched with water (6 mL) and extracted with EtOAc (3x6 mL). The combined organic layers were 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 dichloromethane/methanol=10:1 to give tert-butyl (1 R,5S)-3-(7-chloro-8-fluoro-2-((tetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a white solid (370 mg, 49.6%). LC-MS (ES, m/z) M+1 : 533/535.

Synthesis of tert-butyl (1 R,5S)-3-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1- yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate: Into an 8 mL vial, were added tert-butyl (1 R,5S)-3-(7-chloro-8-fluoro- 2-((tetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (145 mg, 0.3 mmol, 1.0 eq), ((2-fluoro-8-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)naphthalen-1- yl)ethynyl)triisopropylsilane (115 mg, 0.4 mmol, 1.3 eq), DME (2 mL), H2O (0.2 mL), cata CXium A Pd G3 (20 mg, 0.02 mmol, 0.1 eq), K2CO3 (113 mg, 0.8 mmol, 3.0 eq) under nitrogen atmosphere. The resulting mixture was stirred for 3 hours at 80°C under nitrogen atmosphere. The reaction was quenched with water (2 mL) and extracted with EtOAc (3x2mL). The combined organic layers were 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 dichloromethane/methanol=10: 1 to give tert-butyl (1 R,5S)-3-(8-fluoro-7-(7-fluoro-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((tetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin- 4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a light yellow solid (150 mg, 66.9%). LC-MS (ES, m/z) M+1 : 823.

Synthesis of tert-butyl (1 R,5S)-3-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-((tetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: Into an 8 mL vial, were added tert-butyl (1 R,5S)-3-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1 - yl)-2-((tetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (140 mg, 0.2 mmol, 1.0 eq), CsF (259 mg, 1.7 mmol, 10.0 eq), DMF (3 mL). The resulting mixture was stirred for additional 2 hours at 30°C. The reaction was quenched with water (3 mL) and extracted with EtOAc (3x3mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum to afford tert-butyl 3-[7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2- (hexahydropyrrolizin-7a-ylmethoxy)pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a brown solid (95 mg, crude). LC-MS (ES, m/z) M+1 : 667.

Synthesis of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8- fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine HCI salt: Into an 8 mL vial, were added tert-butyl (1 R,5S)-3-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1 H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (80 mg, 0.1 mmol, 1.0 eq), HCI(gas) in 1 ,4-dioxane (2 mL), CH2CI2 (0.5 mL). The resulting mixture was stirred for additional 1 hours at 25°C. The resulting mixture was concentrated under vacuum. Finally, 4-((1 R,5S)-3,8-diazabicyclo[3.2.1 ]octan- 3-yl)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]py rimidine HCI salt was obtained as a brown solid (60 mg, crude). LC-MS (ES, m/z) M+1 : 567.

Synthesis of 1-((1 R,5S)-3-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1 H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)prop-2-en-1- one: Into an 8 mL vial, were added 4-((1 R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7- fluoronaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (50 mg, 0.1 mmol, 1.0 eq), CH2CI2 (1 mL), acryloyl chloride (6 mg, 0.1 mmol, 0.7 eq), DIEA (28 mg, 0.2 mmol, 2.5 eq). The resulting mixture was stirred for additional 1 h at 0°C. The reaction was quenched with water (1 mL) and extracted with CH2CI2 (3x1 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The residue was purified by reverse flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% NHs iW), 10% to 50% gradient in 10 min; detector, UV 254 nm. Finally, 1-((1 R,5S)-3-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2- ((tetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)prop- 2-en-1-one was obtained as a light yellow solid (8 mg, 14.6%). LC-MS (ES, m/z) M+1 : 621. ¹HNMR (400 MHz, DMSO-d₆) 6 9.07 (s, 1 H), 8.30-8.16 (m, 2H), 7.76-7.56 (m, 3H), 6.85-6.74 (m, 1 H), 6.27 (d, >15.9 Hz, 1 H), 5.82- 5.73 (m, 1 H), 4.76 (s, 2H), 4.64 (d, >12.7 Hz, 1 H), 4.46 (t, >13.3 Hz, 1 H), 4.05 (d, >9.1 Hz, 3H), 3.76-3.53 (m, 2H), 2.94 (dt, >10.4, 5.5 Hz, 2H), 2.57 (d, >7.3 Hz, 2H), 1.90 (dt, >11.9, 5.9 Hz, 4H), 1.79-157 (m, 8H).

Example 4: Preparation of 1-((1R,5S)-3-(2-(3-(dimethylamino)azetidin-1-yl)-7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)prop-2-en- 1-one

Synthesis of tert-butyl (1R,5S)-3-(7-chloro-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoropyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: Into a 40 mL vial, were placed tert-butyl (1 R, 5S)-3-(2, 7-d ich loro-8-fluoropy rido [4, 3-d] py ri midin-4-y l)-3, 8-di azabicy clo [3.2.1]octane-8-carboxylate (500 mg, 1.2 mmol, 1.0 eq), N,N-dimethylazetidin-3-amine (117 mg, 1.2 mmol, 1.0 eq), acetonitrile (10 mL) and CS2CO3 (761 mg, 2.3 mmol, 2.0 eq) at 25°C. The resulting mixture was stirred for additional 4 hours at 80°C. The resulting mixture was diluted with H2O (30 mL) and extracted with CH2CI2 (4x10 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 dichloromethane/methanol =10:1 to give tert-butyl (1 R,5S)-3-(7-chloro-2-(3-(dimethylamino)azetidin-1 -yl)-8- fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a white solid (640 mg, 90%). LC-MS (ES, m/z) M+1 : 492/494.

Synthesis of tert-butyl (1 R,5S)-3-(2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate: Into an 8 mL vial, were placed tert-butyl (1 R,5S)-3-(7-chloro-2-(3- (dimethylamino)azetidin-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 0.4 mmol, 1.0 eq), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)naphthalen-1-yl)ethynyl)triisopropylsilane (250 mg, 0.5 mmol, 1.2 eq), dimethoxyethane (4 mL), H2O (0.4 mL), K2CO3 (169 mg, 1.2 mmol, 3.0 eq) and CataCXium A Pd G3 (30 mg, 0.04 mmol, 0.1 eq) at 25°C under nitrogen atmosphere. The resulting mixture was stirred for 4 hours at 80°C under nitrogen atmosphere. The resulting mixture was diluted with H2O (5 mL) and extracted with CH2CI2 (4x5 mL). The combined organic layers were washed with brine (5 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 dichloromethane/methanol =10:1 to give tert-butyl (1R,5S)-3-(2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a white solid (170 mg, 53.4%). LC-MS (ES, m/z) M+1 : 842.

Synthesis of tert-butyl (1 R,5S)-3-(2-(3-(dimethylamino)azetidin-1-yl)-7-(8-ethynyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate: Into an 8 mL vial, were placed tert-butyl (1 R,5S)-3-(2-(3-(dimethylamino)azetidin-1 -yl)-8-fluoro-7- (7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (160 mg, 0.2 mmol, 1.0 eq), CsF (289 mg, 1.9 mmol, 10.0 eq) and DMF (3 mL). The resulting mixture was stirred for 2 hours at 25°C. The resulting mixture was then quenched by the addition of water (5 mL) and extracted with ethyl acetate (4x5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum to give tert-butyl (1 R,5S)-3-(2-(3-(dimethylamino)azetidin-1-yl)-7-(8-ethynyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate as a yellow solid (150 mg, crude). LC-MS (ES, m/z) M+1 : 686.

Synthesis of 4-(4-((1 R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(3-(dimethylamino)azetidin-1-yl)-8- fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol: Into an 8 mL sealed tube, were placed tert-butyl (1R,5S)-3-(2-(3-(dimethylamino)azetidin-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1- yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (140 mg, 0.2 mmol, 1.0 eq) and CH2CI2 (2 mL). After that, HCI(gas) in 1,4-dioxane (1 mL) was added dropwise at 0°C. The resulting mixture was stirred for 1 hour at 0°C. The mixture was neutralized to pH=8 with NH3 in methanol (2 M). The resulting mixture was diluted water (5 mL) and extracted with CH2CI2 (4x5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum at 0°C to give 4-(4-((1 R,5S)-3,8-diazabicyclo[3.2.1 ]octan-3-yl)-2-(3-(dimethylamino)azetidin-1 -yl)-8- fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol as a yellow solid (100 mg, 90.4%). LC-MS (ES, m/z) M+1 : 542.

Synthesis of 1-((1R,5S)-3-(2-(3-(dimethylamino)azetidin-1-yl)-7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)prop-2-en- 1-one: Into an 8 mL sealed tube, were placed 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(3- (dimethylamino)azetidin-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (90 mg, 0.2 mmol, 1.0 eq), CH2CI2 (2 mL) and DIEA (54 mg, 0.4 mmol, 2.5 eq) at 25°C. After that, acryloyl chloride (12 mg, 0.1 mmol, 0.8 eq) was added dropwise at 0°C. The resulting mixture was stirred for 1 hour at 0°C. The reaction was quenched by the addition of water (0.5 mL) at 25°C. The resulting mixture was extracted with CH2CI2 (2x10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (2 mL) and H2O (2 mL). To the above mixture was added LIOH ^20 (28 mg, 0.7 mmol, 4.0 eq) at 25°C. The resulting mixture was stirred for additional 1 hour at 25°C. The resulting mixture was concentrated under vacuum at 0°C. The crude product was purified by Prep-HPLC using the following conditions: Column, YMC-Actus Triart C18 ExRS, 30*150 mm, 5pm; mobile phase, H₂O (10 mmol/L NH₄HCO₃+0.1% NH₃ 'H₂O) and CH₃CN (45% CH₃CN up to 85% in 10 min), Flow rate: 60 mL/min; Detector, 254/220 nm. Finally, 1-((1 R,5S)-3-(2-(3- (dimethylamino)azetidin-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4- yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)prop-2-en-1 -one as a yellow solid (10 mg, 10.3%). LC-MS (ES, m/z) M+1 : 596. ¹HNMR (300 MHz, Chloroform-d) 5 8.72 (s, 1 H), 7.61 (dd, 7=8.1 , 5.7 Hz, 1 H), 7.24-7.04 (m, 3H), 6.65-6.33 (m, 2H), 5.81 (dd, 7=8.7, 2.4 Hz, 1 H), 4.93 (s, 1 H), 4.67-3.99 (m, 6H), 3.61 (dt, 7=9.0, 8.4 Hz, 2H), 3.22 (s, 1 H), 2.82 (s, 1 H), 2.26 (s, 6H), 1.98 (s, 3H), 1.85-1.69 (m, 2H), 1.28 (s, 1 H).

Example 5: Preparation of 1-((1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- ((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8- yl)prop-2-en-1-one

Synthesis of tert-butyl (1 R,5S)-3-(7-chloro-8-fluoro-2-((tetrahydro-1 H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: Into a 100 mL roundbottom flask, were placed tert-butyl 3-{2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl}-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (700 mg, 1.6 mmol, 1.0 eq), hexahydropyrrolizin-7a-ylmethanol (346 mg, 2.5 mmol, 1.5 eq), dioxane (20 mL) and Cs2CO₃ (1598 mg, 4.9 mmol, 3.0 eq) at 25°C. The resulting mixture was stirred for 16 hours at 90°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 (2x20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude residue was applied onto a silica gel column and eluted with CH2Cl2/MeOH=10:1 to afford tert-butyl (1 R,5S)-3- (7-ch I oro-8-f I uoro-2-((tetrahy d ro- 1 H-py rrol i zi n-7a(5H)-y l)methoxy)py rido [4, 3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a white solid (600 mg, 68.9%). LC-MS (ES, m/z) M+1 : 533.

Synthesis of tert-butyl (1 R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: Into a 50 mL round-bottom flask, were placed tert-butyl (1 R,5S)-3-(7-chloro-8-fluoro-2-((tetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300 mg, 0.4 mmol, 1.0 eq), {2-[2-fluoro-6-(methoxymethoxy)-8- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)naphthalen-1-yl]ethynyl}triisopropylsilane (275 mg, 0.5 mmol, 1.3 eq), DME (5 mL), H2O (0.5 mL), K2CO3 (171 mg, 1.2 mmol, 3.0 eq) and CataCXium A Pd G3 (26 mg, 0.04 mmol, 0.1 eq) at 25°C under nitrogen atmosphere. The resulting mixture was stirred for 4 hours at 80°C under nitrogen atmosphere. The reaction mixture was then quenched by the addition of H2O (5 mL). The resulting mixture was extracted with EtOAc (2x15 mL). The combined organic layers were washed with brine (15 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 tert-butyl (1 R,5S)-3-(8-fluoro-7- (7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((tetrahydro-1 H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as an off-white solid (300 mg, 82.3%). LC-MS (ES, m/z) M+1 : 883.

Synthesis of tert-butyl (1 R,5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8- fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate: Into a 40 mL sealed tube, were placed tert-butyl (1 R,5S)-3-(8-fluoro- 7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((tetrahydro-1 H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (280 mg, 0.3 mmol, 1.0 eq), CsF (482 mg, 3.2 mmol, 10.0 eq) and DMF (5 mL). The resulting mixture was stirred for 2 hours at 25°C. The resulting mixture was quenched by the addition of water (10 mL) and then extracted with EtOAc (2x10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum to give tert-butyl (1 R,5S)-3-(7-(8-ethynyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((tetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow oil (200 mg, 86.8%). LC-MS (ES, m/z) M+1 : 727.

Synthesis of 4-(4-((1 R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol: Into an 8 mL sealed tube, were placed tert-butyl (1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2- ((tetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (200 mg, 0.3 mmol, 1.0 eq) and CH2CI2 (2 mL). After that, a solution of HOI (gas) in 1 ,4-dioxane (1 mL) was added dropwise at 0°C. The resulting mixture was stirred for 1 hour at 0°C. The mixture was neutralized to pH=8 with NH3 in MeOH (2 M). The resulting mixture was diluted water (10 mL). The resulting mixture was extracted with CH2CI2 (2x10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum at 0°C to give 4-(4- ((1 R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((tetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]py rimidin-7-y l)-5-ethyny l-6-fluoronaphthalen-2-ol as a yellow solid (100 mg, 62.4%). LC-MS (ES, m/z) M+1 : 583.

Synthesis of 1-((1 R,5S)-3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- ((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8- yl)prop-2-en-1-one: Into an 8 mL sealed tube, were placed 4-(4-((1 R,5S)-3,8-diazabicyclo[3.2.1 ]octan-3-yl)-8- fluoro-2-((tetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2- ol (90 mg, 0.2 mmol, 1.0 eq), CH2CI2 (3 mL) and DIEA (50 mg, 0.4 mmol, 2.5 eq) at 25°C. To the above mixture was added acryloyl chloride (14 mg, 0.2 mmol, 1.0 eq) dropwise at 0°C. The resulting mixture was stirred for 1 hour at 0°C. The reaction was quenched by the addition of water (0.5 mL) at 25°C and then extracted with CH2CI2 (2x10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in THF (2 mL) and H2O (2 mL). To the above mixture was added LIOH TI2O (15 mg, 0.6 mmol, 4.0 eq) at 25°C. The resulting mixture was stirred for additional 1 hour at 25°C. The resulting mixture was concentrated under vacuum at 0°C. The crude product was purified by Prep-HPLC using the following conditions: Column, YMC-Actus Triart C18 ExRS, 30*150 mm, 5pm; mobile phase, H₂O (10 mmol/L NH₄HCO₃+0.1% NH₃ 'H₂O) and CH₃CN (45% CH₃CN up to 85% in 10 min), Flow rate: 60 mL/min; Detector, 254/220 nm. Finally, 1-((1 R,5S)-3-(7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octan-8-yl)prop-2-en-1-one was obtained as a yellow solid (15 mg, 15.3%) . LC-MS (ES, m/z) M+1 : 637. ¹HNMR (400 MHz, DMSO-d₆) 5 10.11 (s, 1 H), 9.05 (s, 1 H), 7.98 (dd, 7=9.1 , 5.8 Hz, 1 H), 7.47 (t, 7=9.0 Hz, 1 H), 7.42-7.37 (m, 1 H), 7.19 (s, 1 H), 6.81 (dd, 7=16.8, 10.4 Hz, 1 H), 6.26 (d, 7=16.7 Hz, 1 H), 5.78 (d, 7=10.5 Hz, 1 H), 4.76 (s, 2H), 4.63 (s, 1 H), 4.45 (t, 7=13.6 Hz, 1 H), 4.06 (s, 2H), 3.95 (s, 1 H), 3.68 (d, 7=11.4 Hz, 1 H), 3.61 (s, 1 H), 2.94 (dt, 7=10.8, 5.6 Hz, 2H), 2.60-2.51 (m, 2H), 1.95-1.69 (m, 10H), 1.59 (dd, 7 = 12.4, 7.1 Hz, 2H).

Example 6: Preparation of 1-((1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)prop-2-en-1- one

Synthesis of tert-butyl (1 R,5S)-3-(7-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: Into a 50 mL roundbottom flask, were placed tert-butyl (1 R,5S)-3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (600 mg, 1.4 mmol, 1.0 eq), (S)-(1-methylpyrrolidin-2-yl)methanol (161 mg, 1.4 mmol, 1.0 eq) and THF (15 mL) at 25°C. After that, NaH (67 mg, 2.8 mmol, 2.0 eq) was added in portions at 0°C. The resulting mixture was stirred for 4 hours at 25°C. The reaction was quenched by the addition of water (5 mL) at 25°C and then 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 reduced pressure. The crude residue was applied onto a silica gel column and eluted with CH2Cl2/MeOH=10:1 to give tert-butyl (1 R,5S)-3-(7-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a white solid (420 mg, 59.1%). LC-MS (ES, m/z) M+1 : 507.

Synthesis of tert-butyl (1 R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: Into a 50 mL round-bottom flask, were placed tert-butyl (1 R,5S)-3-(7-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (420 mg, 0.8 mmol, 1.0 eq), ((2-fluoro-6-(methoxymethoxy)-8-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (552 mg, 1.0 mmol, 1.3 eq), K2CO3 (343 mg, 2.5 mmol, 3.0 eq), DME (10 mL), H2O (1 mL) and CataCXium A Pd G3 (53 mg, 0.1 mmol, 0.1 eq) at 25°C under nitrogen atmosphere. The resulting mixture was stirred for 4 hours at 80°C under nitrogen atmosphere. The reaction mixure was quenched by the addition of H2O (5 mL). The resulting mixture was extracted with EtOAc (2x15 mL). The combined organic layers were washed with brine (15 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 tert-butyl (1 R,5S)-3-(8-fluoro-7- (7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1 ]octane-8-carboxylate as a colorless oil (250 mg, 35.2%). LC-MS (ES, m/z) M+1 : 858.

Synthesis of tert-butyl (1 R,5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8- fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate: Into a 40 mL sealed tube, were placed tert-butyl (1 R,5S)-3-(8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (250 mg, 0.3 mmol, 1.0 eq), CsF (443 mg, 2.9 mmol, 10.0 eq) and DMF (5 mL). The resulting mixture was stirred for 2 hours at 25°C. The resulting mixture was quenched by the addition of water (10 mL) and then extracted with EtOAc (2x10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum to give tert-butyl (1 R,5S)-3-(7-(8-ethynyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((S)-1 -methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate a yellow oil (170 mg, 83.2%). LC-MS (ES, m/z) M+1 : 701.

Synthesis of 4-(4-((1 R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol: Into an 8 mL sealed tube, were placed tert-butyl (1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (170 mg, 0.2 mmol, 1.0 eq) and CH2CI2 (2mL). After that, HCI(gas) in 1,4-dioxane (1 mL) was added dropwise at 0°C. The resulting mixture was stirred for 1 hour at 0°C. The mixture was neutralized to pH=8 with NH3 in MeOH (2 M). The resulting mixture was diluted water (10 mL). The resulting mixture was extracted with CH2CI2 (2x10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum at 0°C to give 4-(4-((1 R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro- 2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol as a yellow solid (80 mg, 59.3%). LC-MS (ES, m/z) M+1: 557.

Synthesis of 1-((1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)prop-2-en-1- one: Into an 8 mL sealed tube, were placed 4-(4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoro-2-{[(2S)-1 - methylpyrrolidin-2-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (80 mg, 0.2 mmol, 1.0 eq), CH2CI2 (3 mL) and DIEA (46 mg, 0.4 mmol, 2.5 eq) at 25°C. After that, acryloyl chloride (13 mg, 0.2 mmol, 1 .0 eq) was added dropwise at 0°C. The resulting mixture was stirred for 1 hour at 0°C. The reaction was quenched by the addition of water (0.5 mL) at 25°C and then extracted with CH2CI2 (2x10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in THF (2 mL) and H2O (2 mL). To the above mixture was added LIOH ^20 (24 mg, 0.6 mmol, 4.0 eq) at 25°C. The resulting mixture was stirred for additional 1 hour at 25°C. The resulting mixture was concentrated under vacuum at 0°C. The crude product was purified by Prep-HPLC using the following conditions: Column, YMC-Actus Triart C18 ExRS, 30*150 mm, 5pm; mobile phase, H₂O (10 mmol/L NH₄HCO₃+0.1% NH₃ 'H₂O) and CH₃CN (45% CH₃CN up to 85% in 10 min), Flow rate: 60 mL/min; Detector, 254/220 nm. Finally, 1-((1 R,5S)-3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)prop-2-en-1- one was obtained as a yellow solid (20 mg, 22.79%). LC-MS (ES, m/z) M+1 : 611 . ¹HNMR (400 MHz, DMSO-de) 5 10.16 (s, 1 H), 9.06 (s, 1 H), 7.99 (dd, >9.2, 5.9 Hz, 1 H), 7.47 (t, >9.0 Hz, 1 H), 7.40 (d, >2.5 Hz, 1 H), 7.19 (s, 1 H), 6.82 (dd, >16.7, 10.3 Hz, 1 H), 6.26 (dd, >16.8, 2.3 Hz, 1 H), 5.79 (d, >10.6 Hz, 1 H), 4.76 (s, 2H), 4.64 (t, >11.9 Hz, 1 H), 4.43 (d, >12.9 Hz, 2H), 4.23 (s, 1 H), 3.96 (s, 1 H), 3.69 (d, >12.5 Hz, 1 H), 3.62 (d, >12.6 Hz, 1 H), 3.03-2.95 (m, 1 H), 2.60-2.55 (m, 1 H), 2.40 (s, 3H), 2.25-2.19 (m, 1 H), 2.03-1.92 (m, 2H), 1.84-1.79 (m, 4H), 1.73-1.68 (m, 3H).

Example 7: Preparation of 1-((1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((S)-1- methylpiperidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)prop-2-en-1- one

Synthesis of tert-butyl (1 R,5S)-3-(7-chloro-8-fluoro-2-(((S)-1-methylpiperidin-2- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylat: Into a 50 mL roundbottom flask, were placed tert-butyl (1 R,5S)-3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (750 mg, 1.8 mmol, 1.0 eq), (S)-(1-methylpiperidin-2-yl)methanol (226 mg, 1.8 mmol, 1.0 eq) and THF (15 mL) at 25°C. After that, NaH (84 mg, 3.6 mmol, 2.0 eq, 60%) was added in portions at 0°C. The resulting mixture was stirred for 4 hours at 25°C. The reaction was quenched by the addition of water (5 mL) at 25°C. 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 MeOH/CH2Cl2=1:10 to give tert-butyl (1 R,5S)-3-(7-chloro-8-fluoro-2-(((S)-1 -methylpiperidin-2- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a white solid (600 mg, 65.8%). LC-MS (ES, m/z) M+1 : 521.

Synthesis of tert-butyl (1 R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((S)-1-methylpiperidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin- 4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: Into a 50 mL round-bottom flask, were placed tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-(((S)-1-methylpiperidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (300 mg, 0.6 mmol, 1.0 eq), {2-[2-fluoro-6-(methoxymethoxy)-8-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)naphthalen-1-yl]ethynyl}triisopropylsilane (354 mg, 0.7 mmol, 1.2 eq), K2CO3 (239 mg, 1.7 mmol, 3.0 eq), DME (10 mL), H2O (1 mL) and CataCXium A Pd G3(37 mg, 0.06 mmol, 0.1 eq) at 25°C under nitrogen atmosphere. The resulting mixture was stirred for 4 hours at 80°C under nitrogen atmosphere. The reaction mixure was then quenched by the addition of water (5 mL). The resulting mixture was extracted with EtOAc (2x15 mL). The combined organic layers were washed with brine (15 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 tert-butyl (1 R,5S)-3-(8-fluoro-7- (7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((S)-1-methylpi peridin-2- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1 ]octane-8-carboxylate as a colorless oil (230 mg, 45.9%). LC-MS (ES, m/z) M+1 : 871.

Synthesis of tert-butyl (1 R,5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8- fluoro-2-(((S)-1-methylpiperidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate: Into a 40 mL sealed tube, were placed tert-butyl (1 R,5S)-3-(8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((S)-1-methylpiperidin-2- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (230 mg, 0.3 mmol, 1.0 eq), CsF (401 mg, 3.0 mmol, 10.0 eq) and DMF (5 mL). The resulting mixture was stirred for 2 hours at 25°C. The resulting mixture was then quenched by the addition of water (10 mL). The resulting mixture was extracted with EtOAc (2x10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum to give tert-butyl (1 R, 5S)-3-(7-(8-ethy ny l-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((S)-1 -methylpiperidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow oil (120 mg, 63.6%). LC-MS (ES, m/z) M+1 : 715.

Synthesis of 4-(4-((1 R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((S)-1-methylpiperidin-2- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol: Into an 8 mL sealed tube, were placed t tert-butyl (1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((S)-1- methylpiperidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (120 mg, 0.2 mmol, 1.0 eq) and CH2CI2 (2mL). After that, HCI(gas) in 1,4-dioxane (1 mL) was added dropwise at 0°C. The resulting mixture was stirred for 1 hour at 0°C. The mixture was neutralized to pH=8 with NH3 in MeOH (2 M). The resulting mixture was diluted water (10 mL). The resulting mixture was extracted with CH2CI2 (2x10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum at 0°C to give 4-(4-((1 R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro- 2-(((S)-1-methylpiperidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol as a yellow solid (60 mg, 62.6%). LC-MS (ES, m/z) M+1 : 571.

Synthesis of 1-((1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((S)-1- methylpiperidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)prop-2-en-1- one: Into an 8 mL sealed tube, were placed 4-(4-((1 R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((S)-1 - methylpiperidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (60 mg, 0.105 mmol, 1 eq), CH2CI2 (2 mL) and DIEA (34 mg, 0.3 mmol, 2.5 eq) at 25°C. After that, acryloyl chloride (10 mg, 0.1 mmol, 1 .0 eq) was added dropwise at 0°C. The resulting mixture was stirred for 1 hour at 0°C. The reaction was quenched by the addition of water (5 mL) at 25°C and then extracted with CH2CI2 (2x10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in THF (1 mL) and H2O (1 mL). After that, LIOH H2O (18 mg, 0.4 mmol, 4.0 eq) was added at 25°C. The resulting mixture was stirred for additional 1 hour at 25°C. The resulting mixture was concentrated under vacuum at 0°C. The crude product was purified by Prep- HPLC using the following conditions: Column, YMC-Actus Triart C18 ExRS, 30*150 mm, 5pm; mobile phase, H₂O (10 mmol/L NH₄HCO₃+0.1% NH₃ 'H₂O) and CH₃CN (45% CH₃CN up to 85% in 10 min), Flow rate: 60 mL/min; Detector, 254/220 nm. Finally, 1-((1 R,5S)-3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((S)-1-methylpiperidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)prop-2-en-1- one was obtained as a yellow solid (20 mg, 30.5%). LC-MS (ES, m/z) M+1 : 625. ¹HNMR (400 MHz, DMSO-de) 5 10.16 (s, 1 H), 9.06 (s, 1 H), 7.99 (dd, 7=9.1 , 5.8 Hz, 1 H), 7.47 (t, 7=9.0 Hz, 1 H), 7.40 (d, 7=2.7 Hz, 1 H), 7.19 (s, 1 H), 6.82 (dd, 7=16.7, 10.3 Hz, 1 H), 6.27 (d, 7=16.6 Hz, 1 H), 5.79 (d, 7=10.6 Hz, 1 H), 4.76 (s, 2H), 4.67 (d, 7=13.6 Hz, 1 H), 4.57-4.28 (m, 3H), 3.96 (s, 1 H), 3.70 (d, 7=12.7 Hz, 1 H), 3.62 (d, 7=12.8 Hz, 1 H), 2.80 (d, 7=10.1 Hz, 1 H), 2.28 (s, 3H), 2.11-2.07(m, 1 H), 1.92-1.68 (m, 7H), 1.63-1.34 (m, 3H), 1.28-1.24 (m, 1 H).

Example 8: Preparation of N-[(3R)-1-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (hexahydropyrrolizin-7a-ylmethoxy)pyrido[4,3-d]pyrimidin-4-yl]azepan-3-yl]prop-2-enamide (assumed)

Synthesis of tert-butyl N-[(3R)-1-{8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-[2- (triisopropylsilyl)ethynyl]naphthalen-1-yl]-2-(hexahydropyrrolizin-7a-ylmethoxy)pyrido[4,3-d]pyrimidin-4- yl}azepan-3-yl]carbamate: Into a 40-mL sealed-tube purged and maintained with an inert atmosphere of nitrogen, were placed tert-butyl N-[(3R)-1 -[7-chloro-8-fluoro-2-(hexahydropyrrolizin-7a-ylmethoxy)pyrido[4,3- d]pyrimidin-4-yl]azepan-3-yl]carbamate (assumed) (250 mg, 0.5 mmol, 1.0 eq), {2-[2-fluoro-6-(methoxymethoxy)- 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl]ethynyl}triisopropylsilane (216 mg, 0.6 mmol, 1.2 eq), K2CO₃ (194 mg, 1.4 mmol, 3.0 eq), DME (5 mL), H2O (0.5 mL), cataCXium A Pd G3 (34 mg, 0.05 mmol, 0.1 eq). The resulting solution was stirred for 2 hours at 80°C in an oil bath. The resulting mixture was quenched by the addition of water (40 mL) and then extracted with ethyl acetate (2x40 mL). The combined organics were dried over Na2SO4, filtered and concentrated under vacuum. The crude residue was purified onto a silica gel column and eluted with dichloromethane/methanol=10:1 to give tert-butyl N-[(3R)-1-{8-fluoro-7-[7-fluoro-3- (methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphthalen-1-yl]-2-(hexahydropyrrolizin-7a- ylmethoxy)pyrido[4,3-d]pyrimidin-4-yl}azepan-3-yl]carbamate (assumed) as a light yellow solid (180 mg, 43.5%). LC-MS (El, m/z) M+1 : 885.

Synthesis of tert-butyl N-[(3R)-1-{7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8- fluoro-2-(hexahydropyrrolizin-7a-ylmethoxy)pyrido[4,3-d]pyrimidin-4-yl}azepan-3-yl]carbamate (assumed): Into a 40-mL sealed tube, were placed tert-butyl N-[(3R)-1 -{8-fluoro-7-[7-fluoro-3- (methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphthalen-1-yl]-2-(hexahydropyrrolizin-7a- ylmethoxy)pyrido[4,3-d]pyrimidin-4-yl}azepan-3-yl]carbamate (assumed) (150 mg, 0.2 mmol, 1.0 eq), DMF (3 mL), CsF (257 mg, 1.7 mmol, 10.0 eq). The resulting solution was stirred for 2 hours at 25°C. The resulting mixture was quenched by the addition of water (40 mL) and then extracted with ethyl acetate (2x40 mL). The combined organics were dried over anhydrous Na2SC>4 filtered and concentrated under vacuum. Finally, tertbutyl N-[(3R)-1-{7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoro-2-(hexahydropyrrolizin-7a- ylmethoxy)pyrido[4,3-d]pyrimidin-4-yl}azepan-3-yl]carbamate (assumed) was obtained as a light yellow solid (140 mg, crude). LC-MS (El, m/z) M+1 : 729.

Synthesis of 4-{4-[(3R)-3-aminoazepan-1-yl]-8-fluoro-2-(hexahydropyrrolizin-7a- ylmethoxy)pyrido[4,3-d]pyrimidin-7-yl}-5-ethynyl-6-fluoronaphthalen-2-ol (assumed): Into a 50 mL 3- necked round-bottom, were placed tert-butyl N-[(3R)-1-{7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1- yl]-8-fluoro-2-(hexahydropyrrolizin-7a-ylmethoxy)pyrido[4,3-d]pyrimidin-4-yl}azepan-3-yl]carbamate (assumed) (130 mg, 0.2 mmol, 1.0 eqJ.CFhC (4 mL). After that, HCI(gas) in 1,4-dioxane (2 mL, 4 M) was added at 0°C. Then the mixture was stirred for 1 hour at 0°C. The mixture neutralized to pH=7-8 with NH3 in MeOH (2 M). The resulting mixture was then quenched by the addition of water (40 mL) and extracted with CH2CI2 (2x40 mL). The combined organics were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum to give 4-{4-[(3R)-3-aminoazepan-1-yl]-8-fluoro-2-(hexahydropyrrolizin-7a-ylmethoxy)pyrido[4,3- d]pyrimidin-7-yl}-5-ethynyl-6-fluoronaphthalen-2-ol (assumed) as light yellow solid (110 mg, crude) .

Synthesis of N-[(3R)-1-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (hexahydropyrrolizin-7a-ylmethoxy)pyrido[4,3-d]pyrimidin-4-yl]azepan-3-yl]prop-2-enamide (assumed): Into a 50 mL 3-necked round-bottom flask, were placed 4-{4-[(3R)-3-aminoazepan-1-yl]-8-fluoro-2- (hexahydropyrrolizin-7a-ylmethoxy)pyrido[4,3-d]pyrimidin-7-yl}-5-ethynyl-6-fluoronaphthalen-2-ol (assumed) (80 mg, 0.1 mmol, 1.0 eq), DIEA (44 mg, 0.3 mmol, 2.5 eq), CH2CI2 (3 mL). This was followed by the addition of acryloyl chloride (15 mg, 0.15 mmol, 1.2 eq) at 0°C. Then the mixture was stirred for 1 hour at 0°C. The resulting mixture was then quenched by the addition of water (30 mL). The mixture was extracted with dichloromethane (2x30 mL) and washed with brine (30 mL). The mixture was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. To the above mixture was added THF (1 mL), H2O (1 mL), LiOH (13 mg, 0.5 mmol, 4.0 eq). The resulting mixture was stirred for additional 1 hour at 25°C. The crude product was purified by Prep-HPLC using the following conditions: Column, SunFire Prep C18 OBD Column, 50*250mm 5um 10nm; mobile phase, Water (0.05% NH4HCO3) and CH3CN (35% Phase B up to 45% in 7 min); Detector, UV 254/220 nm. Finally, N-[(3R)-1-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(hexahydropyrrolizin- 7a-ylmethoxy)pyrido[4,3-d]pyrimidin-4-yl]azepan-3-yl]prop-2-enamide (assumed) was obtained as a light yellow solid (20 mg, 22.9%). LC-MS (El, m/z) M+1 : 639. ¹HNMR (400 MHz, DMSO-d₆) 5 10.17 (s, 1 H), 9.20 (d, 7=4.0 Hz, 1 H), 8.27 (dd, 7=13.0, 7.6 Hz, 1 H), 7.98 (dd, 7=9.2, 6.0 Hz, 1 H), 7.47 (t, 7=9.0 Hz, 1 H), 7.39 (d, 7=2.6 Hz, 1 H), 7.18 (dd, 7=15.2, 2.6 Hz, 1 H), 6.28-6.20 (m, 1 H), 6.13-6.08 (m, 1 H), 5.63-5.58 (m, 1 H), 4.56-4.22 (m, 3H), 4.09-3.83 (m, 5H), 2.92 (dt, 7 = 10.4, 5.6 Hz, 2H), 2.56-2.54 (m, 1 H), 2.06 (br, 1 H), 1.95-1.70 (m, 9H), 1.60-1.50 (m, 4H).

Example 9: Preparation of N-[(3S)-1-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (hexahydropyrrolizin-7a-ylmethoxy)pyrido[4,3-d]pyrimidin-4-yl]azepan-3-yl]prop-2-enamide (assumed)

Synthesis of tert-butyl N-[(3S)-1-{8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-[2- (triisopropylsilyl)ethynyl]naphthalen-1-yl]-2-(hexahydropyrrolizin-7a-ylmethoxy)pyrido[4,3-d]pyrimidin-4- yl}azepan-3-yl]carbamate (assumed): Into a 40-mL sealed-tube purged and maintained with an inert atmosphere of nitrogen, were placed tert-butyl N-[(3S)-1-[7-chloro-8-fluoro-2-(hexahydropyrrolizin-7a- ylmethoxy)pyrido[4,3-d]pyrimidin-4-yl]azepan-3-yl]carbamate (assumed) (250 mg, 0.5 mmol, 1.0 eq), {2-[2-fluoro- 6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl]ethynyl}triisopropylsilane (216 mg, 0.6 mmol, 1.2 eq), K2CO3 (194 mg, 1.4 mmol, 3.0 eq), DME (5 mL), H2O (0.5 mL), cataCXium A Pd G3 (34 mg, 0.05 mmol, 0.1 eq). The resulting solution was stirred for 2 hours at 80°C in an oil bath. The resulting mixture was quenched by the addition of water (40 mL) and then extracted with ethyl acetate (2x40 mL) The combined organic layers were 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 dichloromethane/methanol=10:1 to give tert-butyl N-[(3S)-1-{8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-[2- (triisopropylsilyl)ethynyl]naphthalen-1-yl]-2-(hexahydropyrrolizin-7a-ylmethoxy)pyrido[4,3-d]pyrimidin-4- yl}azepan-3-yl]carbamate (assumed) as a light yellow solid (190 mg, 45.9%). LC-MS (El, m/z) M+1 : 885.

Synthesis of tert-butyl N-[(3S)-1-{7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8- fluoro-2-(hexahydropyrrolizin-7a-ylmethoxy)pyrido[4,3-d]pyrimidin-4-yl}azepan-3-yl]carbamate (assumed): Into a 40-mL sealed tube, were placed tert-butyl N-[(3S)-1-{8-fluoro-7-[7-fluoro-3-(methoxymethoxy)- 8-[2-(triisopropylsilyl)ethynyl]naphthalen-1-yl]-2-(hexahydropyrrolizin-7a-ylmethoxy)pyrido[4,3-d]pyrimidin-4- yl}azepan-3-yl]carbamate (assumed) (160 mg, 0.2 mmol, 1.0 eq), DMF (3 mL), CsF (274 mg, 1.8 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 (40 mL) and then extracted with ethyl acetate (2x40 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum to give tert-butyl N- [(3S)-1-{7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoro-2-(hexahydropyrrolizin-7a- ylmethoxy)pyrido[4,3-d]pyrimidin-4-yl}azepan-3-yl]carbamate (assumed) was obtained as a light yellow solid (150 mg, crude). LC-MS (El, m/z) M+1 : 729. Synthesis of 4-{4-[(3S)-3-aminoazepan-1-yl]-8-fluoro-2-(hexahydropyrrolizin-7a- ylmethoxy)pyrido[4,3-d]pyrimidin-7-yl}-5-ethynyl-6-fluoronaphthalen-2-ol (assumed): Into a 50 mL 3- necked round-bottom, were placed tert-butyl N-[(3S)-1-{7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1- yl]-8-fluoro-2-(hexahydropyrrolizin-7a-ylmethoxy)pyrido[4,3-d]pyrimidin-4-yl}azepan-3-yl]carbamate (assumed) (130 mg, 0.2 mmol, 1.0 eq), CH2CI2 (4 mL). This was followed by the addition of HCI(gas) in 1 ,4-dioxane (2 mL, 4 M) at 0°C. Then the mixture was stirred for 1 hour at 0°C. The mixture was neutralized to pH =7-8 with NH3 in MeOH (2 M). The resulting mixture was quenched by the addition of water (40 mL) and then extracted with CH2CI2 (2x40 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum to give 4-{4-[(3S)-3-aminoazepan-1-yl]-8-fluoro-2-(hexahydropyrrolizin-7a- ylmethoxy)pyrido[4,3-d]pyrimidin-7-yl}-5-ethynyl-6-fluoronaphthalen-2-ol (assumed) as a light yellow solid (110 mg, crude) .

Synthesis of N-[(3S)-1-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (hexahydropyrrolizin-7a-ylmethoxy)pyrido[4,3-d]pyrimidin-4-yl]azepan-3-yl]prop-2-enamide (assumed): Into a 50 mL 3-necked round-bottom flask, were placed 4-{4-[(3S)-3-aminoazepan-1-yl]-8-fluoro-2- (hexahydropyrrolizin-7a-ylmethoxy)pyrido[4,3-d]pyrimidin-7-yl}-5-ethynyl-6-fluoronaphthalen-2-ol (assumed) (80 mg, 0.1 mmol, 1.0 eq), DIEA (44 mg, 0.3 mmol, 2.5 eq), CH2CI2 (3 mL). This was followed by the addition of acryloyl chloride (15 mg, 0.2 mmol, 1.2 eq) at 0°C. Then the mixture was stirred for 1 hour at 0°C. The resulting mixture was then quenched by the addition of water (30 mL) and then extracted with dichloromethane (2x30 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. To the above mixture was added THF (1 mL), H2O (1 mL) and LiOH (13 mg, 0.5 mmol, 4.0 eq). The resulting mixture was stirred for additional 1 hour at 25°C. The crude product was purified by Prep-HPLC using the following conditions: Column, SunFire Prep C18 OBD Column, 50*250mm 5um 10nm; mobile phase, Water (0.05% NH4HCO3) and CH3CN (35% Phase B up to 45% in 7 min); Detector, UV 254/220 nm. Finally, N-[(3S)-1-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(hexahydropyrrolizin-7a- ylmethoxy)pyrido[4,3-d]pyrimidin-4-yl]azepan-3-yl]prop-2-enamide (assumed) was obtained as a light yellow solid (20 mg, 22.9%). LC-MS (El, m/z) M+1 : 639. ¹HNMR (400 MHz, DMSO-d₆) 3 10.22 (s, 1 H), 9.20 (d, 4.0 Hz, 1 H), 8.27 (dd, >13.2, 7.6 Hz, 1 H), 7.97 (dd, >9.2, 6.0 Hz, 1 H), 7.46 (t, >9.0 Hz, 1 H), 7.39 (d, >2.4 Hz, 1 H), 7.18 (dd, >15.2, 2.6 Hz, 1 H), 6.27-6.20 (m, 1 H), 6.13-6.08 (m, 1 H), 5.63-5.59 (m, 1 H), 4.55-4.19 (m, 3H), 4.09-3.58 (m, 5H), 2.91 (dt, J = 10.6, 5.6 Hz, 2H), 2.56-2.53 (m, 1 H), 2.07 (br, 1 H), 1.95-1.69 (m, 9H), 1.59-1.50 (m, 4H).

Example 10: Preparation of N-(1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- ((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)cyclobutyl)-N- methylacrylamide

Synthesis of tert-butyl (1-(((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4- yl)amino)methyl)cyclobutyl)(methyl)carbamate: Into a 40 mL vial, were added 2,4,7-trichloro-8- fluoropyrido[4,3-d]pyrimidine (400 mg, 1.6 mmol, 1.0 eq), CH2CI2 (10 mL) and DIEA (512 mg, 4.0 mmol, 2.5 eq) at -40°C. The resulting mixture was stirred for additional 15 min at -40°C. To the above mixture was added tertbutyl (1-(aminomethyl)cyclobutyl)(methyl)carbamate (340 mg, 1.6 mmol, 1.0 eq) in portions over 5 min at -40°C. The resulting mixture was stirred for additional 1 hour at -40°C. The resulting mixture was diluted with H2O (10 mL) and extracted with CH2CI2 (3x10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude residue was applied onto a silica gel column and eluted with petroleum ether / ethyl acetate =1 :1 to give tert-butyl (1- (((2, 7-dichloro-8-fl uoropy rido[4, 3-d] py rimidin-4-y l)amino)methy l)cyclobutyl)(methy l)carbamate as a yellow solid (500 mg, 76.5%). LC-MS (ES, m/z) M+1 : 430/432.

Synthesis of tert-butyl (1-(((7-chloro-8-fluoro-2-((tetrahydro-1 H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)cyclobutyl)(methyl)carbamate: Into a 40 mL vial, were placed (tetrahydro-1 H-pyrrolizin-7a(5H)-yl)methanol (148 g, 1.0 mmol, 1.5 eq) and tetrahydrofuran (6 mL) at 25°C. To the above mixture was added NaH (34 mg, 60% in mineral oil, 1 .4 mmol, 2.0 eq) in portions over 5 min at 0°C. The resulting mixture was stirred for additional 30 min at 25°C. To the above mixture was added tertbutyl (1-(((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)amino)methyl)cyclobutyl)(methyl)carbamate (300 mg, 0.7 mmol, 1 .0 eq) in portions over 5 min at 25°C. The resulting mixture was stirred for additional 4 hours at 25°C. The reaction was quenched with sat. NH4CI (aq.) at 0°C and then extracted with ethyl acetate (3x10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude residue was applied onto a silica gel column and eluted with dichloromethane/methanol =10:1 to give tert-butyl (1 -(((7-chloro-8-fluoro-2-((tetrahydro-1 H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)cyclobutyl)(methyl)carbamate as a white solid (210 mg, 56.2%). LC-MS (ES, m/z) M+1 : 535/537.

Synthesis of tert-butyl (1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((tetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)amino)methyl)cyclobutyl)(methyl)carbamate: Into a 40 mL vial, were placed tert-butyl (1- (((7-chloro-8-fluoro-2-((tetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)amino)methyl)cyclobutyl)(methyl)carbamate (200 mg, 0.4 mmol, 1.0 eq), ((2-fluoro-6-(methoxymethoxy)-8- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (230 mg, 0.4 mmol, 1.2 eq), dimethoxyethane (5 mL), H2O (0.5 mL), K3PO4 (159 mg, 0.7 mmol, 2.0 eq) and CataCXium A Pd G3 (27 mg, 0.04 mmol, 0.1 eq) at 25°C under nitrogen atmosphere. The resulting mixture was stirred for 4 hours at 80°C under nitrogen atmosphere. The resulting mixture was diluted with H2O (5 mL) and extracted with CH2CI2 (4x5 mL). The combined organic layers were washed with brine (5 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 dichloromethane/methanol =10:1 to give tert-butyl (1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((tetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin- 4-yl)amino)methyl)cyclobutyl)(methyl)carbamate as a brown solid (180 mg, 54.4%). LC-MS (ES, m/z) M+1 : 885/887. Synthesis of tert-butyl (1-(((7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2- ((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)amino)methyl)cyclobutyl)(methyl)carbamate: Into a 8 mL vial, were placed tert-butyl (1 -(((8-fluoro-7-(7- fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((tetrahydro-1 H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)cyclobutyl)(methyl)carbamate (170 mg, 0.2 mmol, 1.0 eq), CsF (292 mg, 1.9 mmol, 10.0 eq) and DMF (4 mL). The resulting mixture was stirred for 2 hours at 25°C. The resulting mixture was then quenched by the addition of water (5 mL) and extracted with ethyl acetate (4x5 mL). The combined organic layers were washed with brine (5 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 dichloromethane/methanol =10:1 to give tert-butyl (1-(((7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1- yl)-8-fluoro-2-((tetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)amino)methyl)cyclobutyl)(methyl)carbamate as a brown solid (110 mg, 78.5%). LC-MS (ES, m/z) M+1 : 729/731.

Synthesis of 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1-(methylamino)cyclobutyl)methyl)amino)-2- ((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol: Into a 8 mL vial, were placed tert-butyl (1-(((7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((tetrahydro-1 H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)cyclobutyl)(methyl)carbamate (100 mg, 0.1 mmol, 1.0 eq) and CH2CI2 (2 mL). To the above mixture was added HCI(gas) in 1,4-dioxane (0.5 mL) dropwise at 0°C. The resulting mixture was stirred for 1 hour at 0°C. The mixture was neutralized to pH=8 with NH3 in methanol (2 M). The resulting mixture was diluted water (5 mL) and extracted with CH2CI2 (4x5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum at 0°C to give 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1 - (methylamino)cyclobutyl)methyl)amino)-2-((tetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol as a brown solid (80 mg, crude). LC-MS (ES, m/z) M+1 : 585.

Synthesis of N-(1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)cyclobutyl)-N-methylacrylamide: Into a 8 mL sealed tube, were placed 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1 - (methylamino)cyclobutyl)methyl)amino)-2-((tetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol (70 mg, 0.1 mmol, 1.0 eq), CH2CI2 (2 mL) and DIEA (39 mg, 0.3 mmol, 2.5 eq) at 25°C. To the above mixture was added acryloyl chloride (9 mg, 0.1 mmol, 0.8 eq) dropwise at 0°C. The resulting mixture was stirred for 1 hour at 0°C. The reaction was quenched by the addition of water (4 mL) and extracted with CH2CI2 (3x5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (1 mL) and H2O (1 mL). To the above mixture was added UOH.H2O (20 mg, 0.5 mmol, 4.0 eq) at 25°C. The resulting mixture was stirred for additional 1 hour at 25°C. The resulting mixture was concentrated under vacuum at 0°C. The crude product was purified by Prep-HPLC using the following conditions: Column, YMC-Actus Triart C18 ExRS, 30*150 mm, 5pm; mobile phase, H2O (0.1 %FA) and CH3CN (5% CH3CN up to 100% in 10 min), Flow rate: 60 mL/min; Detector, 254/220 nm. Finally, N-(1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8- fluoro-2-((tetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)cyclobutyl)-N- methylacrylamide was obtained as a yellow solid (15 mg, 17.0%). LC-MS (ES, m/z) M+1 : 639. ¹HNMR (300 MHz, DMSO-c/₆) 3 10.59 (s, 1H), 9.36 (d, 0=2.4 Hz, 1 H), 7.99 (dd, 0=9.0, 5.7 Hz, 1 H), 7.57-6.96 (m, 4H), 6.77- 6.33 (m, 1 H), 6.07-5.83 (m, 1H), 5.72-5.29 (m, 1 H), 4.55 (s, 2H), 4.10 (d, 0=9.6 Hz, 2H), 3.95 (s, 1 H), 3.55-3.45 (m, 1 H), 3.22 (s, 2H), 2.81 (d, 0=4.2 Hz, 3H), 2.42-1.55 (m, 15H).

Example 11 : Preparation of N-(1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- ((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)cyclopentyl)-N- methylacrylamide

Synthesis of tert-butyl (1 -(((2, 7-dichloro-8-fl uoropyrido[4,3-d]pyri midin-4- yl)amino)methyl)cyclopentyl)(methyl)carbamate: Into a 40 mL vial, were placed 2,4,7-trichloro-8- fluoropyrido[4,3-d]pyrimidine (400 mg, 1.6 mmol, 1.0 eq) and CH2CI2 (5 mL). To the above mixture was added DIEA (512 mg, 4.0 mmol, 2.5 eq) dropwise at -40°C. The reaction mixture was stirred at -40°C for 15 min. To the above mixture was added tert-butyl (1-(aminomethyl)cyclopentyl)(methyl)carbamate (362 mg, 1.6 mmol, 1.0 eq) in CH2CI2 (5 mL) dropwise at -40°C. The resulting mixture was stirred for additional 1 hour at -40°C. The reaction mixture was then quenched by the addition of water (10 mL) and extracted with ethyl acetate (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 ethyl acetate/petroleum ether=1 :1 to give tert-butyl (1-(((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4- yl)amino)methyl)cyclopentyl)(methyl)carbamate as a white solid (500 mg, 71.0%). LC-MS (ES, m/z) M+1 : 444/446.

Synthesis of tert-butyl (1-(((7-chloro-8-fluoro-2-((tetrahydro-1 H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)cyclopentyl)(methyl)carbamate: Into a 40 mL vial, were placed (tetrahydro-1 H-pyrrolizin-7a(5H)-yl)methanol (143 g, 1.0 mmol, 1.5 eq) and tetrahydrofuran (6 mL) at 25°C. To the above mixture was added NaH (32 mg, 60% in mineral oil, 1 .4 mmol, 2.0 eq) in portions over 5 min at 0°C. The resulting mixture was stirred for additional 30 min at 25°C. To the above mixture was added tertbutyl (1-(((2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)amino)methyl)cyclopentyl)(methyl)carbamate (300 mg, 0.7 mmol, 1 .0 eq) in portions over 5 min at 25°C. The resulting mixture was stirred for additional 4 hours at 25°C. The reaction was quenched with sat. NH4CI (aq.) at 0°C. The resulting mixture was extracted with ethyl acetate (3x10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude residue was applied onto a silica gel column and eluted with dichloromethane/methanol =10:1 to give tert-butyl (1-(((7-chloro-8-fluoro-2- ((tetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)amino)methyl)cyclopentyl)(methyl)carbamate as a white solid (220 mg, 59.2%). LC-MS (ES, m/z) M+1 : 549. Synthesis of tert-butyl (1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)amino)methyl)cyclopentyl)(methyl)carbamate: Into a 40 mL vial, were placed tert-butyl (1- (((7-chloro-8-fluoro-2-((tetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)amino)methyl)cyclopentyl)(methyl)carbamate (200 mg, 0.4 mmol, 1.0 eq), ((2-fluoro-6-(methoxymethoxy)-8- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (224 mg, 0.4 mmol, 1.2 eq), dimethoxyethane (5 mL), H2O (0.5 mL), K2CO3 (101 mg, 0.7 mmol, 2.0 eq) and CataCXium A Pd G3 (27 mg, 0.04 mmol, 0.1 eq) at 25°C under nitrogen atmosphere. The resulting mixture was stirred for 4 hours at 80°C under nitrogen atmosphere. The resulting mixture was diluted with H2O (5 mL) and extracted with CH2CI2 (4x5 mL). The combined organic layers were washed with brine (5 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 dichloromethane/methanol =10:1 to give tert-butyl (1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)- 8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((tetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)amino)methyl)cyclopentyl)(methyl)carbamate as a brown solid (160 mg, 48.8%). LC-MS (ES, m/z) M+1 : 899.

Synthesis of tert-butyl (1-(((7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2- ((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)amino)methyl)cyclopentyl)(methyl)carbamate: Into a 8 mL vial, were placed tert-butyl (1-(((8-fluoro-7-(7- fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((tetrahydro-1 H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)cyclopentyl)(methyl)carbamate (150 mg, 0.2 mmol, 1.0 eq), CsF (253mg, 1.7 mmol, 10.0 eq) and DMF (2 mL). The resulting mixture was stirred for 2 hours at 25°C. The resulting mixture was then quenched by the addition of water (5 mL) and extracted with ethyl acetate (4x5 mL). The combined organic layers were washed with brine (5 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 dichloromethane/methanol =10:1 to give tert-butyl (1-(((7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1- yl)-8-fluoro-2-((tetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)amino)methyl)cyclopentyl)(methyl)carbamate as a brown solid (100 mg, 80.7%). LC-MS (ES, m/z) M+1 : 743/745.

Synthesis of 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1-(methylamino)cyclopentyl)methyl)amino)-2- ((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol: Into a 8 mL vial, were placed tert-butyl (1-(((7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((tetrahydro-1 H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)cyclopentyl)(methyl)carbamate (100 mg, 0.1 mmol, 1.0 eq) and CH2CI2 (2 mL). To the above mixture was added HCI(gas) in 1,4-dioxane (0.5 mL) dropwise at 0°C. The resulting mixture was stirred for 1 hour at 0°C. The mixture was neutralized to pH=8 with NH3 in MeOH (2 M). The resulting mixture was diluted water (5 mL) and then extracted with CH2CI2 (2x5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum at 0°C to give 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1 - (methylamino)cyclopentyl)methyl)amino)-2-((tetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin- 7-y I )n aphth alen-2-ol as a brown solid (60 mg, crude). LC-MS (ES, m/z) M+1 : 599.

Synthesis of N-(1-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)cyclopentyl)-N-methylacrylamide: Into a 8 mL sealed tube, were placed 5-ethynyl-6-fluoro-4-(8-fluoro-4-(((1 - (methylamino)cyclopentyl)methyl)amino)-2-((tetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin- 7-yl)naphthalen-2-ol (50 mg, 0.08 mmol, 1.0 eq), CH2CI2 (2 mL) and DIEA (27 mg, 0.2 mmol, 2.5 eq) at 25°C. To the above mixture was added acryloyl chloride (6 mg, 0.07 mmol, 0.8 eq) dropwise at 0°C. The resulting mixture was stirred for 1 hour at 0°C. The reaction was quenched by the addition of water (4 mL) and then extracted with CH2CI2 (3x5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (1 mL) and H2O (1 mL). To the above mixture was added UOH.H2O (14 mg, 0.3 mmol, 4.0 eq) at 25°C. The resulting mixture was stirred for additional 1 hour at 25°C. The resulting mixture was concentrated under vacuum at 0°C. The crude product was purified by Prep-HPLC using the following conditions: Column, YMC-Actus Triart C18 ExRS, 30*150 mm, 5pm; mobile phase, H2O (0.1% FA) and CH3CN (5% CH3CN up to 100% in 10 min), Flow rate: 60 mL/min; Detector, 254/220 nm. Finally, N-(1-(((7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)amino)methyl)cyclopentyl)-N-methylacrylamide was obtained as a yellow solid (15 mg, 27.5%). LC-MS (ES, m/z) M+1 : 653. ¹HNMR (300 MHz, DMSO-d₆) 5 9.23 (s, 1 H), 9.08 (s, 1 H), 8.26 (s, 1 H), 7.98 (dd, >9.0, 6.0 Hz, 1 H), 7.59-7.30 (m, 2H), 7.18 (d, >2.4 Hz, 1 H), 6.63 (dd, >9.3, 6.6 Hz, 1 H), 5.94 (dd, >10.2, 3.6 Hz, 1 H), 5.58 (dd, >10.2, 2.4 Hz, 1 H), 4.09 (s, 2H), 3.96 (d, >9.6 Hz, 3H), 3.01 (d, >8.1 Hz, 5H), 2.65 (t, >7.2 Hz, 2H), 2.28 (s, 2H), 2.03-1.44 (m, 14H).

Example 12: Preparation of 1-((1R,5S)-3-(2-(((S)-1,2-dimethylpyrrolidin-2-yl)methoxy)-7-(8-ethynyl-7- fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8- yl)prop-2-en-1-one

Synthesis of tert-butyl (1R,5S)-3-(7-chloro-2-(((S)-1,2-dimethylpyrrolidin-2-yl)methoxy)-8- fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: Into a 40 mL vial, were placed (S)-(1 ,2-dimethylpyrrolidin-2-yl)methanol (181 mg, 1.4 mmol, 1.5 eq) and tetrahydrofuran (8 mL) at 25°C. To the above mixture was added NaH (45 mg, 1.9 mmol, 2.0 eq) in portions over 5 min at 0°C. The resulting mixture was stirred for additional 30 min at 25°C. To the above mixture was added tert-butyl (1 R,5S)-3-(2,7- dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (400 mg, 0.9 mmol, 1.0 eq) in portions over 5 min at 25°C. The resulting mixture was stirred for additional 3 hours at 25°C. The reaction was quenched by the addition of sat. NH4CI (aq.) at 0°C. The resulting mixture was extracted with ethyl acetate (3x10 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 dichloromethane/methanol =10:1 to give tert-butyl (1 R,5S)-3-(7-chloro-2-(((S)-1 ,2-dimethylpyrrolidin- 2-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a white solid (330 mg, 67.7%). LC-MS (ES, m/z) M+1 : 521.

Synthesis of tert-butyl (1R,5S)-3-(2-(((S)-1,2-dimethylpyrrolidin-2-yl)methoxy)-8-fluoro-7-(7- fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate: Into a 40 mL vial were added tert-butyl (1 R,5S)-3-(7-chloro-2-(((S)- 1 ,2-dimethylpyrrolidin-2-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (250 mg, 0.5 mmol, 1.0 eq), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (295 mg, 0.6 mmol, 1.2 eq), K3PO4 (204 mg, 1.0 mmol, 2.0 eq), dimethoxyethane (10 mL), H2O (1 mL) and CataCXium A Pd G3 (35 mg, 0.05 mmol, 0.1 eq) at 25°C under nitrogen atmosphere. The resulting mixture was stirred for 4 hours at 80°C under nitrogen atmosphere. The resulting mixture was diluted with H2O (10 mL) and extracted with CH2CI2 (4x10 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 dichloromethane/methanol =10:1 to give tert-butyl (1 R,5S)-3-(2-(((S)-1 ,2-dimethylpyrrolidin-2-yl)methoxy)-8- fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a brown solid (260 mg, 62.2%). LC-MS (ES, m/z) M+1 : 871.

Synthesis of tert-butyl (1R,5S)-3-(2-(((S)-1,2-dimethylpyrrolidin-2-yl)methoxy)-7-(8-ethynyl-7- fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate: Into a 40 mL vial, were placed tert-butyl (1R,5S)-3-(2-(((S)-1,2- dimethylpyrrolidin-2-yl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen- 1 -yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (250 mg, 0.3 mmol, 1.0 eq), CsF (436 mg, 3.0 mmol, 10.0 eq) and DMF (5 mL). The resulting mixture was stirred for 2 hours at 25°C. The resulting mixture was then quenched by the addition of water (5 mL) and extracted with ethyl acetate (4x5 mL). The combined organic layers were washed with brine (5 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 dichloromethane/methanol =10:1 to give tert-butyl (1 R,5S)-3-(2-(((S)-1 ,2-dimethylpyrrolidin-2-yl)methoxy)-7-(8- ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate as a brown solid (180 mg, 87.7%). LC-MS (ES, m/z) M+1 : 715.

Synthesis of 4-(4-((1 R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((S)-1,2-dimethylpyrrolidin-2- yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol: Into a 8 mL sealed tube, were placed tert-butyl (1R,5S)-3-(2-(((S)-1 ,2-dimethylpyrrolidin-2-yl)methoxy)-7-(8-ethynyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (170 mg, 0.2 mmol, 1 eq) and CH2CI2 (2 mL). To the above mixture was added HCI(gas) in 1,4- dioxane (0.5 mL) dropwise at 0°C. The resulting mixture was stirred for 1 hour at 0°C. The mixture was neutralized to pH 8 with NH3 in methanol (2N). The resulting mixture was diluted water (5 mL) and extracted with CH2CI2 (4x5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum at 0°C to give 4-(4-((1 R,5S)-3, 8- diazabicyclo[3.2.1]octan-3-yl)-2-(((S)-1 ,2-dimethylpyrrolidin-2-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5- ethynyl-6-fluoronaphthalen-2-ol as a white solid (170 mg, crude). LC-MS (ES, m/z) M+1 : 571.

Synthesis of 1-((1R,5S)-3-(2-(((S)-1,2-dimethylpyrrolidin-2-yl)methoxy)-7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)prop-2-en- 1-one: Into a 8 mL sealed tube, were placed 4-(4-((1 R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((S)-1 ,2- dimethylpyrrolidin-2-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (170 mg, 0.3 mmol, 1.0 eq), CH2CI2 (4 mL) and DIEA (96 mg, 0.7 mmol, 2.5 eq) at 25°C. To the above mixture was added acryloyl chloride (22 mg, 0.2 mmol, 0.8 eq) dropwise at 0°C. The resulting mixture was stirred for 1 hour at 0°C. The reaction was quenched by the addition of water (4 mL) and then extracted with CH2CI2 (3x5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The residue was dissolved in tetrahydrofuran (2 mL) and H2O (2 mL). To the above mixture was added UOH.H2O (50.0 mg, 1.2 mmol, 4.0 eq) at 25°C. The resulting mixture was stirred for additional 1 hour at 25°C. The resulting mixture was concentrated under vacuum at 0°C. The crude product was purified by Prep-HPLC using the following conditions: Column, YMC-Actus Triart C18 ExRS, 30*150 mm, 5pm; mobile phase, H₂O (10 mmol/L NH₄HCO₃+0.1 % NH3.H2O) and CH3CN (45% CH3CN up to 85% in 10 min), Flow rate: 60 mL/min; Detector, 254/220 nm. Finally, 1-((1 R,5S)-3-(2-(((S)-1 ,2-dimethylpyrrolidin-2-yl)methoxy)-7-(8- ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8- yl)prop-2-en-1-one was obtained as a yellow solid (13 mg, 6.9%). LC-MS (ES, m/z) M+1 : 625. ¹HNMR (300 MHz, Chloroform-d) 5 8.88 (d, 7=11.8 Hz, 1 H), 7.62 (t, 7=4.5 Hz, 1 H), 7.25-7.11 (m, 3H), 6.55-6.39 (m, 2H), 5.80 (dd, 7=8.1 , 3.9 Hz, 1 H), 4.89 (s, 1 H), 4.56 (m, 2H), 4.33 (m, 3H), 3.88-3.62 (m, 1 H), 3.53 (m, 1 H), 3.07 (s, 1 H), 2.76 (d, 7=7.2 Hz, 1 H), 2.67 (t, 7=8.4 Hz, 1 H), 2.43 (m, 3H), 2.20-2.01 (m, 1 H), 2.02-1.54 (m, 8H), 1.17 (s, 3H).

Example 13: Preparation of 1-((1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2S,4R)-4-fluoro-1,2-dimethylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octan-8-yl)prop-2-en-1-one

Synthesis of tert-butyl (1R,5S)-3-(8-fluoro-2-(((2S,4R)-4-fluoro-1,2-dimethylpyrrolidin-2- yl)methoxy)-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: Into a 8 mL vial, were placed tert-butyl (1 R,5S)-3-(7-chloro-8-fluoro-2-(((2S,4R)-4-fluoro-1,2-dimethylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (160 mg, 0.3 mmol, 1.0 eq), ((2-fluoro-6-(methoxymethoxy)-8- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (183 mg, 0.4 mmol, 1.2 eq), dimethoxyethane (4 mL), H2O (0.4 mL), K2CO3 (82 mg, 0.6 mmol, 2.0 eq) and CataCXium A Pd G3 (22 mg, 0.03 mmol, 0.1 eq) at 25°C under nitrogen atmosphere. The resulting mixture was stirred for 16 hours at 80°C under nitrogen atmosphere. The resulting mixture was diluted with H2O (5 mL) and extracted with CH2CI2 (4x5 mL). The combined organic layers were washed with brine (5 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 dichloromethane/methanol=10: 1 to give tert-butyl (1 R,5S)-3-(8-fluoro-2-(((2S,4R)-4-fluoro-1 ,2- dimethylpyrrolidin-2-yl)methoxy)-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1- yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a brown solid (100 mg, 37.8%). LC- MS (ES, m/z) M+1 : 889/891.

Synthesis of tert-butyl (1 R,5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8- fluoro-2-(((2S,4R)-4-fluoro-1,2-dimethylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate: Into a 8 mL vial, were placed tert-butyl (1 R,5S)-3-(8-fluoro-2- (((2S,4R)-4-fluoro-1,2-dimethylpyrrolidin-2-yl)methoxy)-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (90 mg, 0.1 mmol, 1.0 eq), CsF (154 mg, 1.0 mmol, 10.0 eq) and DMF (2 mL). The resulting mixture was stirred for 2 hours at 25°C. The resulting mixture was then quenched by the addition of water (5 mL) and extracted with ethyl acetate (4x5 mL). The combined organic layers were washed with brine (5 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 give tert-butyl (1 R,5S)-3-(7-(8-ethynyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2S,4R)-4-fluoro-1,2-dimethylpyrrolidin-2-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a brown solid (60 mg, 80.8%). LC-MS (ES, m/z) M+1 : 733/735.

Synthesis of 4-(4-((1 R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2S,4R)-4-fluoro-1,2- dimethylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol: Into a 8 mL vial, were placed tert-butyl (1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2- (((2S,4R)-4-fluoro-1,2-dimethylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate (55 mg, 0.08 mmol, 1.0 eq) and CH2CI2 (2 mL). To the above mixture was added HCI (gas) in 1,4- dioxane (0.2 mL) dropwise at 0°C. The resulting mixture was stirred for 1 hour at 0°C. The mixture was neutralized to pH 8 with NH3 in methanol (2 M). The resulting mixture was diluted water (5 mL) and extracted with CH2CI2 (4x5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under vacuum at 0°C to give 4-(4-((1 R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2S,4R)-4-fluoro-1 ,2-dimethylpyrrolidin-2-yl)methoxy)pyrido[4,3- d]py rimidin-7-y l)-5-ethyny l-6-fluoronaphthalen-2-ol as a yellow solid (60 mg, crude). LC-MS (ES, m/z) M+1 : 589.

Synthesis of 1-((1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2S,4R)-4- fluoro-1,2-dimethylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8- yl)prop-2-en-1-one: Into a 8 mL sealed tube, were placed 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8- fluoro-2-(((2S,4R)-4-fluoro-1,2-dimethylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6- fluoronaphthalen-2-ol (50 mg, 0.1 mmol, 1.0 eq), CH2CI2 (2 mL) and DIEA (27 mg, 0.2 mmol, 2.5 eq) at 25°C. To the above mixture was added acryloyl chloride (6 mg, 0.07 mmol, 0.8 eq) dropwise at 0°C. The resulting mixture was stirred for 1 hour at 0°C. The reaction was quenched by the addition of water (4 mL) and extracted with CH2CI2 (3x5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The residue was dissolved in tetrahydrofuran (1 mL) and H2O (1 mL). To the above mixture was added UOH.H2O (14 mg, 0.3 mmol, 4.0 eq) at 25°C. The resulting mixture was stirred for additional 1 hour at 25°C. The resulting mixture was concentrated under vacuum at 0°C. The crude product was purified by Prep-HPLC using the following conditions: Column, YMC-Actus Triart C18 ExRS, 30*150 mm, 5pm; mobile phase, H2O (0.1% FA) and CH3CN (5% CH3CN up to 100% in 10 min), Flow rate: 60 mL/min; Detector, 254/220 nm. Finally, 1-((1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8- fluoro-2-(((2S,4R)-4-fluoro-1,2-dimethylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octan-8-yl)prop-2-en-1-one was obtained as a yellow solid (5 mg, 9.1%). LC-MS (ES, m/z) M+1 : 643. ¹HNMR (300 MHz, Chloroform-d) 5 8.91 (s, 1 H), 8.33 (s, 1 H), 7.62 (dd, >9.0, 5.7 Hz, 1 H), 7.24-7.02 (m, 3H), 6.48 (s, 2H), 5.82 (s, 1 H), 5.30 (d, >6.3 Hz, 1 H), 4.92 (s, 1 H), 4.72-4.45 (m, 4H), 3.77 (s, 2H), 3.55 (t, >11.7 Hz, 1 H), 3.08 (dd, >7.2, 5.1 Hz, 1 H), 2.79 (d, >8.4 Hz, 1 H), 2.58 (d, >10.2 Hz, 4H), 2.30-1.56 (m, 6H), 1.39 (d, >9.0 Hz, 3H).

Example 14: Preparation of 1-((1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,4R)-4-fluoro-1,2-dimethylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octan-8-yl)prop-2-en-1-one

Synthesis of tert-butyl (1R,5S)-3-(8-fluoro-2-(((2R,4R)-4-fluoro-1,2-dimethylpyrrolidin-2- yl)methoxy)-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: Into a 40 mL vial, were placed tert-butyl (1 R,5S)-3-(7-chloro-8-fluoro-2-(((2R,4R)-4-fluoro-1,2-dimethylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300 mg, 0.6 mmol, 1 eq), {2-[2-fluoro-6-(methoxymethoxy)-8- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl]ethynyl}triisopropylsilane (342 mg, 0.7 mmol, 1.2 eq), dimethoxyethane (10 mL), H2O (1 mL), K3PO4 (236 mg, 1.1 mmol, 2.0 eq) and CataCXium A Pd G3 (41 mg, 0.06 mmol, 0.1 eq) at 25°C under nitrogen atmosphere. The resulting mixture was stirred for 16 hours at 80°C under nitrogen atmosphere. The resulting mixture was diluted with H2O (10 mL) and extracted with CH2CI2 (4x10 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 dichloromethane/methanol =10:1 to give tert-butyl (1 R,5S)-3-(8-fluoro-2-(((2R,4R)-4-fluoro-1 ,2- dimethylpyrrolidin-2-yl)methoxy)-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1- yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a brown solid (400 mg, 80.8%). LC- MS (ES, m/z) M+1 : 889/891 .

Synthesis of tert-butyl (1 R,5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8- fluoro-2-(((2R,4R)-4-fluoro-1,2-dimethylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate: Into a 40 mL vial, were placed tert-butyl (1 R,5S)-3-(8-fluoro-2- (((2R,4R)-4-fluoro-1,2-dimethylpyrrolidin-2-yl)methoxy)-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300 mg, 0.3 mmol, 1.0 eq), CsF (513 mg, 3.3 mmol, 10.0 eq) and DMF (6 mL). The resulting mixture was stirred for 2 hours at 25°C. The resulting mixture was then quenched by the addition of water (6 mL) and extracted with ethyl acetate (4x6 mL). The combined organic layers were washed with brine (6 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 give tert-butyl (1 R,5S)-3-(7-(8-ethynyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,4R)-4-fluoro-1 ,2-dimethylpyrrolidin-2-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a brown solid (180 mg, 72.8%). LC-MS (ES, m/z) M+1 : 733/735.

Synthesis of 4-(4-((1 R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,4R)-4-fluoro-1,2- dimethylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol: Into a 8 mL vial, were placed tert-butyl (1 R,5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2- (((2R,4R)-4-fluoro-1 ,2-dimethylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate (170 mg, 0.2 mmol, 1 eq) and CH2CI2 (2 mL). To the above mixture was added HCI(gas) in 1 ,4- dioxane (0.5 mL) dropwise at 0°C. The resulting mixture was stirred for 1 hour at 0°C. The mixture was neutralized to pH=8 with NH3 in methanol (2 M). The resulting mixture was diluted water (5 mL) and extracted with CH2CI2 (4x5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under vacuum at 0°C to give 4-(4-((1 R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,4R)-4-fluoro-1 ,2-dimethylpyrrolidin-2-yl)methoxy)pyrido[4,3- d]py rimidin-7-y l)-5-ethyny l-6-fluoronaphthalen-2-ol as a yellow solid (150 mg, crude). LC-MS (ES, m/z) M+1 : 589.

Synthesis of 1-((1 R,5S)-3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,4R)-4- fluoro-1,2-dimethylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8- yl)prop-2-en-1-one: Into a 8 mL vial, were placed 4-(4-((1 R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- (((2R,4R)-4-fluoro-1 ,2-dimethylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen- 2-ol (140 mg, 0.2 mmol, 1.0 eq), CH2CI2 (2 mL) and DIEA (77 mg, 0.6 mmol, 2.5 eq) at 25°C. To the above mixture was added acryloyl chloride (17 mg, 0.2 mmol, 0.8 eq) dropwise at 0°C. The resulting mixture was stirred for 1 hour at 0°C. The reaction was quenched by the addition of water (4 mL) and then extracted with CH2CI2 (3x5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The residue was dissolved in tetrahydrofuran (1 mL) and H2O (1 mL). To the above mixture was added LiOH.hkO (40 mg, 1.0 mmol, 4.0 eq) at 25°C. The resulting mixture was stirred for additional 1 hour at 25°C. The resulting mixture was concentrated under vacuum at 0°C. The crude product was purified by Prep-HPLC using the following conditions: Column, YMC-Actus Triart C18 ExRS, 30*150 mm, 5pm; mobile phase, H₂O (10 mmol/L NH₄HCO₃+0.1% NH3.H2O) and CH3CN (45% CH3CN up to 85% in 10 min), Flow rate: 60 mL/min; Detector, 254/220 nm. Finally, 1-((1 R,5S)-3-(7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,4R)-4-fluoro-1,2-dimethylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin- 4-yl)-3,8-diazabicyclo[3.2.1 ]octan-8-yl)prop-2-en-1 -one was obtained as a yellow solid (35 mg, 19.9%). LC-MS (ES, m/z) M+1 : 643. ¹HNMR (300 MHz, Chloroform-d) 5 8.92 (d, >9.3Hz, 1 H), 7.72-7.47 (m, 1 H), 7.24-7.02 (m, 3H), 6.60-6.35 (m, 2H), 5.91-5.61 (m, 1 H), 5.15 (d, 4.5 Hz, 1 H), 4.92 (s, 1 H), 4.80-4.16 (m, 5H), 3.77 (t, >5.4 Hz, 1 H), 3.53 (s, 1 H), 3.27 (dd, >11.7, 7.5 Hz, 1 H), 2.95 (dd, >12.0, 10.2 Hz, 1 H), 2.78 (s, 1 H), 2.60-2.27 (m, 5H), 2.24-1.52 (m, 5H), 1.19 (s, 3H).

Example 15: Preparation of 4-(4-((1R,5S)-8-acryloyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-yl isobutyrate

Synthesis of 4-(4-((1 R,5S)-8-acryloyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-yl isobutyrate:

Into a 8 mL vial, were added 1-((1 R,5S)-3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)prop-2-en-1-one (50 mg, 0.08 mmol, 1.0 eq), CH2CI2 (1 mL) and DIEA (26 mg, 0.2 mmol, 2.5 eq) at 25°C. The resulting mixture was stirred for additional 15 min at 25°C. To the above mixture was added propanoyl chloride, isobutyryl chloride (7 mg, 0.07 mmol, 0.8 eq) dropwise over 1 min at 0°C. The resulting mixture was stirred for additional 1 hour at 0°C. The resulting mixture was diluted with water (2 mL). The resulting mixture was extracted with CH2CI2 (4x5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC using the following conditions: Column, YMC-Actus Triart C18 ExRS, 30*150 mm, 5pm; mobile phase, H2O (0.05% FA) and CH3CN (45% CH3CN up to 85% in 10 min), Flow rate: 60 mL/min; Detector, 254/220 nm. Finally, 4-(4- ((1 R,5S)-8-acryloyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-yl isobutyrate was obtained as a white solid (11.5 mg, 20.6%). LC-MS (ES, m/z) M+1 : 681. ¹HNMR (400 MHz, Acetonitrile-cfe) 3 9.05 (s, 1 H), 8.10 (dd, >9.2, 5.8 Hz, 1 H), 7.86 (d, >2.4 Hz, 1 H), 7.58-7.40 (m, 2H), 6.72 (dd, >10.8, 9.4 Hz, 1 H), 6.33 (dd, >11.8, 2.2 Hz, 1 H), 5.78 (dd, >10.4, 2.2 Hz, 1 H), 4.83 (s, 1 H), 4.74 (s, 1 H), 4.61 (s, 1 H), 4.53 (dt, >11.3, 4.5 Hz, 2H), 4.47-4.32 (m, 1 H), 3.76 (dd, >12.0, 10.6 Hz, 1 H), 3.63 (dd, >10.4, 6.6 Hz, 1 H), 3.28 (s, 1 H), 3.13 (t, >7.8 Hz, 1 H), 2.98-2.79 (m, 2H), 2.51 (s, 3H), 2.38-2.22 (m, 2H), 2.17-2.01 (m, 2H), 1.94-1.71 (m, 5H), 1.34 (d, >7.0 Hz, 6H).

Example 16: Preparation of 4-(4-((1R,5S)-8-acryloyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-yl isopropyl carbonate

Synthesis of 4-(4-((1 R,5S)-8-acryloyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-yl isopropyl carbonate: Into a 8 mL vial, were added 1-((1 R,5S)-3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro- 2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)prop-2-en-1- one (50 mg, 0.08 mmol, 1.0 eq), CH2CI2 (2 mL) and DIEA (26 mg, 0.2 mmol, 2.5 eq) at 25°C. The resulting mixture was stirred for additional 15 min at 25°C. To the above mixture was added isopropyl carbonochloridate (4 mg, 0.03 mmol, 0.4 eq) dropwise over 2 min at 0°C. The resulting mixture was stirred for additional 1 hour at 0°C. The resulting mixture was stirred for additional 1 hour at 0°C. The resulting mixture was diluted with water (2 mL) and then extracted with CH2CI2 (4x5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC using the following conditions: Column, YMC-Actus Triart C18 ExRS, 30*150 mm, 5pm; mobile phase, H2O (0.05% FA) and CH3CN (45% CH3CN up to 85% in 10 min), Flow rate: 60 mL/min; Detector, 254/220 nm. Finally, 4-(4-((1 R,5S)-8-acryloyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-yl isopropyl carbonate (13 mg, 22.79%) as a white solid (13 mg, 22.7%). LC-MS (ES, m/z) M+1 : 697. ¹HNMR (400 MHz, Acetonitrile- d₃) 5 9.06 (s, 1 H), 8.12 (t, >7.8 Hz, 1 H), 7.95 (s, 1 H), 7.65-7.43 (m, 2H), 6.73 (dd, >10.2, 8.4 Hz, 1 H), 6.33 (d, >11.8 Hz, 1 H), 5.78 (d, >10.6 Hz, 1 H), 4.99 (p, >6.3 Hz, 1 H), 4.79 (d, >10.8 Hz, 2H), 4.67-4.47 (m, 3H), 4.42 (s, 1 H), 3.92-3.50 (m, 2H), 3.29 (s, 1 H), 3.16 (s, 1 H), 2.88 (s, 1 H), 2.62-2.57 (m, 1 H), 2.54 (s, 3H), 2.17-2.03 (m, 2H), 1.81 (d, >9.8 Hz, 6H), 1.39 (d, >6.2 Hz, 6H).

Example 17: Preparation of 4-(4-((1R,5S)-8-acryloyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-yl dimethylcarbamate

Synthesis of 4-(4-((1 R,5S)-8-acryloyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-yl dimethylcarbamate: Into a 8 mL vial, were added 1-{3-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8- fluoro-2-{[(2S)-1-methylpyrrolidin-2-yl] methoxy }pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl}prop- 2-en-1-one (100 mg, 0.2 mmol, 1.0 eq), K2COs (34 mg, 0.2 mmol, 1.5 eq), CH3CN (4 mL) and dimethylcarbamyl chloride (26 mg, 0.2 mmol, 1.5 eq) at 25°C. The resulting mixture was stirred for additional 12 hours at 40°C. The resulting mixture was diluted with H2O (5 mL) extracted with CH2CI2 (4x5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC using the following conditions: Column, YMC- Actus Triart C18 ExRS, 30*150 mm, 5pm; mobile phase, H2O (0.05% FA) and CH3CN (45% CH3CN up to 85% in 10 min), Flow rate: 60 mL/min; Detector, 254/220 nm. Finally, 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2S)-1 - methylpyrrolidin-2-yl] methoxy }-4-[8-(prop-2-enoyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-yl N,N-dimethylcarbamate was obtained as a yellow solid (16 mg, 14.3%). LC-MS (ES, m/z) M+1 : 682. ¹HNMR (400 MHz, Acetonitrile-cfe) 3 9.05 (s, 1 H), 8.09 (dd, >9.2, 5.8 Hz, 1 H), 7.85 (d, >2.4 Hz, 1 H), 7.56-7.40 (m, 2H), 6.72 (dd, >10.8, 8.4 Hz, 1 H), 6.33 (dd, >11.8, 2.2 Hz, 1 H), 5.78 (dd, >10.4, 2.2 Hz, 1 H), 4.83 (s, 1 H), 4.74 (d, >12.8 Hz, 1 H), 4.60 (s, 1 H), 4.54 (dt, >10.2, 5.0 Hz, 2H), 4.41 (ddd, >8.2, 5.5, 2.8 Hz, 1 H), 3.82-3.70 (m, 1 H), 3.70-3.54 (m, 1 H), 3.27 (dd, >2.2, 1.2 Hz, 1 H), 3.14 (s, 4H), 2.99 (s, 3H), 2.94-2.82 (m, 1 H), 2.53 (s, 3H), 2.42 (d, >8.5 Hz, 1 H), 2.17-2.00 (m, 2H), 1.90-1.83 (m, 2H), 1.80-1.72 (m, 4H). Example 18: Preparation of 1-((1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octan-8-yl)prop-2-en-1-one

Synthesis of tert-butyl (1 R,5S)-3-(7-chloro-8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: Into a 40 mL vial, were added ((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methanol (311 mg, 2.3 mmol, 2.0 eq) and tetrahydrofuran (10 mL) at 25°C. To the above mixture was added NaH (94 mg, 2.3 mmol, 2.0 eq) in portions over 2 min at 0°C. The resulting mixture was stirred for additional 15 min at 25°C. To the above mixture was added tert-butyl (1 R, 5S)-3-(2, 7-d ich loro-8-fluoropy rido [4, 3-d] py ri midin-4-y l)-3, 8-di azabicy clo [3.2.1 ]octane-8-carboxy I ate (500 mg, 1.2 mmol, 1.0 eq) in portions over 10 min at 0°C. The resulting mixture was stirred for additional 4 hours at 25°C. The reaction was quenched with sat. NH4CI (aq.) at 0°C. The resulting mixture was extracted with ethyl acetate (3x20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude residue was applied onto a silica gel column and eluted with dichloromethane/methanol =10:1 to give tert-butyl (1 R,5S)-3-(7-chloro-8-fluoro-2- (((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate as a white solid (350 mg, 57.1 %). LC-MS (ES, m/z) M+1 : 525/527.

Synthesis of tert-butyl (1 R,5S)-3-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)- 7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate: Into a 40 mL vial, were added tert-butyl (1 R,5S)-3-(7-chloro-8- fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (300 mg, 0.6 mmol, 1.0 eq), ((2-fluoro-6-(methoxymethoxy)-8-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (351.46 mg, 0.685 mmol, 1.2 eq), dimethoxyethane (4 mL), H2O (0.4 mL), K2CO3 (158 mg, 1.1 mmol, 2.0 eq) and CataCXium A Pd G3 (42 mg, 0.06 mmol, 0.1 eq) at 25°C under nitrogen atmosphere. The resulting mixture was stirred for 4 hours at 80°C under nitrogen atmosphere. The resulting mixture was diluted with H2O (10 mL) and extracted with CH2CI2 (4x10 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 dichloromethane/methanol =10:1 to give tert-butyl (1 R,5S)-3-(8-fluoro-2-(((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1- yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a brown solid (250 mg, 49.9%). LC- MS (ES, m/z) M+1 : 875/877.

Synthesis of tert-butyl (1 R,5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8- fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate: Into a 40 mL vial, were added tert-butyl (1 R,5S)-3-(8-fluoro-2- (((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (290 mg, 0.3 mmol, 1.0 eq), CsF (503 mg, 3.3 mmol, 10.0 eq) and DMF (8 mL) at 25°C. The resulting mixture was stirred for additional 2 hours at 25°C. The resulting mixture was then quenched by the addition of water (10 mL) and extracted with ethyl acetate (4x10 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 dichloromethane/methanol =10:1 to give tert-butyl (1 R,5S)-3-(7- (8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1 ]octane-8-carboxylate as a brown solid (200 mg, 83.9%). LC-MS (ES, m/z) M+1 : 719/721.

Synthesis of 4-(4-((1 R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2S,4R)-4-fluoro-1- methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol: Into a 40 mL vial, were added tert-butyl (1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2- (((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (190 mg, 0.3 mmol, 1.0 eq) and CH2CI2 (5 mL) at 25°C. To the above mixture was added HCI(gas) in 1,4-dioxane (1.0 mL) dropwise at 0°C. The resulting mixture was stirred for 1 hour at 0°C. The mixture was neutralized to pH=8 with NH3 in methanol (2 M). The resulting mixture was diluted water (10 mL) and extracted with CH2CI2 (4x10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under vacuum at 0°C to give 4-(4-((1 R, 5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol as a brown solid (140 mg, crude). LC-MS (ES, m/z) M+1 : 575/577.

Synthesis of 1-((1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2S,4R)-4- fluoro-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8- yl)prop-2-en-1-one: Into a 40 mL vial, were added 4-(4-((1 R,5S)-3,8-diazabicyclo[3.2.1 ]octan-3-yl)-8-fluoro-2- (((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (130 mg, 0.2 mmol, 1.0 eq), CH2CI2 (4 mL) and DIEA (73 mg, 0.6 mmol, 2.5 eq) at 25°C. To the above mixture was added acryloyl chloride (16 mg, 0.2 mmol, 0.8 eq) dropwise over 2 min at 0°C. The resulting mixture was stirred for additional 1 hour at 0°C. The reaction was quenched by the addition of water (5 mL) and extracted with CH2CI2 (4x5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (2 mL) and H2O (2 mL). To the above mixture was added UOH.H2O (64 mg, 1.5 mmol, 4.0 eq) at 25°C. The resulting mixture was stirred for additional 1 hour at 25°C. The resulting mixture was concentrated under vacuum at 0°C. The crude product was purified by Prep-HPLC using the following conditions: Column, YMC-Actus Triart C18 ExRS, 30*150 mm, 5pm; mobile phase, H2O (0.1 %FA) and CH3CN (5% CH3CN up to 100% in 10 min), Flow rate: 60 mL/min; Detector, 254/220 nm. Finally, 1-((1 R,5S)-3-(7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)prop-2-en-1-one was obtained as a yellow solid (15 mg, 12.0%). LC-MS (ES, m/z) M+1 : 629/631. ¹HNMR (400 MHz, Acetonitrile-cfe) 3 9.02 (d, 4=1.2 Hz, 1 H), 7.91 (dd, 4=9.1, 5.8 Hz, 1 H), 7.46-7.30 (m, 2H), 7.25 (d, 4=2.6 Hz, 1 H), 6.72 (dd, 4=10.8, 6.4 Hz, 1 H), 6.33 (dd, 4=11.8, 2.2 Hz, 1 H), 5.78 (dd, >10.4, 2.2 Hz, 1 H), 5.20 (d, >5.8 Hz, 1 H), 4.82 (s, 1 H), 4.75 (d, >10.7 Hz, 1 H), 4.59 (s, 1 H), 4.51 (td, >10.4, 9.7, 4.7 Hz, 2H), 4.43 (dt, >10.9, 5.1 Hz, 1 H), 3.88-3.38 (m, 4H), 3.19 (s, 1 H), 3.04 (dq, >10.6, 4.9 Hz, 1 H), 2.62 (dt, >11 .6, 1 .8 Hz, 1 H), 2.58-2.51 (m, 1 H), 2.50-2.30 (m, 3H), 2.23 (ddd, >11 .4, 8.2, 6.4 Hz, 1 H), 2.05 (ddd, >10.2,7.4, 4.8 Hz, 2H), 1.91 (d, >10.0 Hz, 2H).

Example 19: Preparation of 1-{3-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[1- (morpholin-4-ylmethyl)cyclopropyl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8- yl}prop-2-en-1-one

Synthesis of tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-((1- (morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate: Into a 40 mL vial, were added (1-(morpholinomethyl)cyclopropyl)methanol (300 mg, 1.6 mmol, 1.5 eq) and tetrahydrofuran (10 mL). To the above mixture was added NaH (56 mg, 2.3 mmol, 2.0 eq) in portions over 2 min at 0°C. The resulting mixture was stirred for additional 15 min at 25°C. To the above mixture was added tert-butyl (1 R,5S)-3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (500 mg, 1.2 mmol, 1.0 eq) in portions over 10 min at 0°C. The resulting mixture was stirred for additional 4 hours at 25°C. The reaction was quenched with sat. NH4CI (aq.) at 0°C. The resulting mixture was extracted with ethyl acetate (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 dichloromethane/methanol =10:1 to give tert-butyl (1 R,5S)-3-(7-chloro-8- fluoro-2-((1-(morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate as a white solid (300 mg, 45.6%). LC-MS (ES, m/z) M-1 : 563/565.

Synthesis of tert-butyl 3-{8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-[2- (triisopropylsilyl)ethynyl]naphthalen-1-yl]-2-{[1-(morpholin-4-ylmethyl)cyclopropyl]methoxy}pyrido [4,3- d]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: Into a 40-mL sealed-tube purged and maintained with an inert atmosphere of nitrogen, were placed tert-butyl 3-(7-chloro-8-fluoro-2-{[1 -(morpholin-4- ylmethyl)cyclopropyl]methoxy}pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (700 mg, 1.2 mmol, 1.0 eq), {2-[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1- yl]ethynyl}triisopropylsilane (765 mg, 1.5 mmol, 1.2 eq), DME (10 mL), H2O (1 mL), K2CO3 (344 mg, 2.5 mmol, 2.0 eq), cata cxium A Pd G3 (91 mg, 0.1 mmol, 0.1 eq). The resulting solution was stirred for overnight at 40°C in an oil bath. The resulting mixture was then quenched by the addition of water (100 mL). The resulting solution was extracted with ethyl acetate (2x100 mL) and washed with brine (2x100 mL) and the organic layers combined. 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=2: 1 to give tert-butyl 3-{8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphthalen- 1-yl]-2-{[1-(^morpholin-4-ylmethyl)cyclopropyl]methoxy}pyrido[4,3-d]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate as a light yellow solid (300 mg, 26.4%). LC-MS (ES, m/z) M+1 : 914. Synthesis of tert-butyl 3-{7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoro-2- {[1-(morpholin-4-ylmethyl)cyclopropyl]methoxy}pyrido[4,3-d]pyrimidin-4-yl}-3,8- diazabicyclo[3.2.1]octane-8-carboxylate: Into a 40-mL sealed tube, were placed tert-butyl 3-{8-fluoro-7-[7- fluoro-3-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphthalen-1-yl]-2-{[1-(morpholin-4- ylmethyl)cyclopropyl]methoxy}pyrido[4,3-d]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (250 mg, 0.3 mmol, 1.0 eq), DMF (3 mL), CsF (416 mg, 2.7 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 (40 mL) and extracted with ethyl acetate (2x40 mL). The combined organic layers was washed with brine (2x40 mL) and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under vacuum to give tert-butyl 3-{7-[8-ethy ny l-7-fl uoro-3- (methoxymethoxy)naphthalen-1-yl]-8-fluoro-2-{[1-(morpholin-4-ylmethyl)cyclopropyl]methoxy}pyrido[4,3- d]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow solid (180 mg, crude). LC-MS (ESI, m/z) M+1 : 757.

Synthesis of 4-(4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoro-2-{[1-(morpholin-4- ylmethyl)cyclopropyl]methoxy}pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol: Into a 50 mL 3-necked round-bottom, were placed tert-butyl 3-{7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]- 8-fluoro-2-{[1-(morpholin-4-ylmethyl)cyclopropyl]methoxy}pyrido [4,3-d]pyrimidin-4-yl}-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (160 mg, 0.2 mmol, 1.0 eq), DCM (4 mL). This was followed by the addition of HCI (gas) in 1,4-dioxane (2 mL, 4N) at 0°C. Then the mixture was stirred for 1 hour at 0°C. The mixture neutralized to pH=7-8 with NH3 in MeOH (2 M). The resulting mixture was then quenched by the addition of water (40 mL) and extracted with CH2CI2 (2x40 mL). The combined organic layers was washed with brine (40 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum to give 4-(4-{3,8- diazabicyclo[3.2.1]octan-3-yl}-8-fluoro-2-{[1-(morpholin-4-ylmethyl)cyclopropyl]methoxy}pyrido[4,3-d]pyrimidin-7- yl)-5-ethynyl-6-fluoronaphthalen-2-ol as a light yellow solid (140 mg, crude). LC-MS (ESI, m/z) M+1 : 613.

Synthesis of 1-{3-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[1-(morpholin-4- ylmethyl)cyclopropyl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl}prop-2-en-1- one: Into a 50 mL 3-necked round-bottom flask, were placed 4-(4-{3,8-diazabicyclo[3.2.1 ]octan-3-yl}-8-fluoro-2- {[1-(morpholin-4-ylmethyl)cyclopropyl]methoxy}pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (120 mg, 0.2 mmol, 1.0 eq), DCM (3 mL), DIEA (63 mg, 0.5 mmol, 2.5 eq). This was followed by the addition of acryloyl chloride (27 mg, 0.3 mmol, 1.5 eq) at 0°C. Then the mixture was stirred for 1 hour at 0°C. The resulting mixture was then quenched by the addition of water (30 mL) and extracted with dichloromethane (2x30 mL). The combined organic layers was washed with brine (30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. To the above mixture was added THF (2 mL), H2O (2 mL), LiOH (19 mg, 0.8 mmol, 4.0 eq). The resulting mixture was stirred for additional 1 hour at 25°C. The crude product was purified by Prep-HPLC using the following conditions: Column, SunFire Prep C18 OBD Column, 50*250mm 5um 10nm; mobile phase, Water (0.05% FA) and CH3CN (40% Phase B up to 50% in 7 min); Detector, UV 254/220 nm. Finally, 1-{3-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[1-(morpholin-4- ylmethyl)cyclopropyl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl}prop-2-en-1-one was obtained as a light yellow solid (25 mg, 19.1%). LC-MS (ESI, m/z) M+1 : 667. ¹HNMR (400 MHz, Acetonitrile-cfe) 5 9.02 (s, 1 H), 7.92 (dd, 7=9.2, 5.8 Hz, 1 H), 7.42-7.33 (m, 2H), 7.25 (d, 7=2.6 Hz, 1 H), 6.75-6.68 (m, 1 H), 6.35- 6.30 (m, 1 H), 5.78 (dd, 7=10.4, 2.2 Hz, 1 H), 4.83 (s, 1 H), 4.74 (d, 7=12.4 Hz, 1 H), 4.60 (s, 1 H), 4.48 (d, 7=12.4 Hz, 1 H), 4.37 (s, 2H), 3.80-3.71 (m, 1 H), 3.59 (t, 7=4.8 Hz, 5H), 3.20 (s 1 H) 2.45 (s, 2H), 2.43-2.32 (m, 3H), 2.04- 1.91 (m, 6H), 0.72-0.65 (m, 2H), 0.52-0.45 (m, 2H).

Example 20: Preparation of N-[(6S)-4-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[1- (morpholin-4-ylmethyl)cyclopropyl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-1,4-oxazepan-6-yl]prop-2- enamide (assumed)

Synthesis of tert-butyl N-[(6S)-4-{8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-[2- (triisopropylsilyl)ethynyl]naphthalen-1-yl]-2-{[1-(morpholin-4-ylmethyl)cyclopropyl]methoxy}pyrido[4,3- d]pyrimidin-4-yl}-1,4-oxazepan-6-yl]carbamate (assumed): Into a 8 mL round-bottom flask, were placed tertbutyl N-[(6S)-4-(7-chloro-8-fluoro-2-{[1-(morpholin-4-ylmethyl)cyclopropyl]methoxy}pyrido[4,3-d]pyrimidin-4-yl)- 1 ,4-oxazepan-6-yl]carbamate (assumed) (75 mg, 0.1 mmol, 1.0 eq), {2-[2-fluoro-6-(methoxymethoxy)-8-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)naphthalen-1-yl]ethynyl}triisopropylsilane (102 mg, 0.2 mmol, 1.5 eq), DME (2 mL), H2O (200 uL), K2CO3 (55 mg, 0.4 mmol, 3.0 eq) and CataCXium A Pd G3 (10 mg, 0.01 mmol, 0.1 eq) at 25°C under nitrogen atmosphere. The resulting mixture was stirred for 3 hours at 80°C under nitrogen atmosphere. The reaction mixture was quenched by the addition of H2O (10 mL) and then 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 : 1 to give tert-butyl N-[(6S)-4-{8-fluoro-7-[7-fluoro-3- (methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphthalen-1-yl]-2-{[1-(morpholin-4- ylmethyl)cyclopropyl]methoxy}pyrido[4,3-d]pyrimidin-4-yl}-1 ,4-oxazepan-6-yl]carbamate (assumed) as an off- white solid (70 mg, 57.7%). LC-MS (ES, m/z) M+1 : 917.

Synthesis of tert-butyl N-[(6S)-4-{7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8- fluoro-2-{[1-(morpholin-4-ylmethyl)cyclopropyl]methoxy}pyrido[4,3-d]pyrimidin-4-yl}-1,4-oxazepan-6- yl]carbamate (assumed): Into a 8 mL sealed tube, were placed tert-butyl N-[(6S)-4-{8-fluoro-7-[7-fluoro-3- (methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphthalen-1-yl]-2-{[1-(morpholin-4- ylmethyl)cyclopropyl]methoxy}pyrido[4,3-d]pyrimidin-4-yl}-1 ,4-oxazepan-6-yl]carbamate (assumed) (70 mg, 0.1 mmol, 1 eq), CsF (116 mg, 0.8 mmol, 10.0 eq) and DMF (2 mL). The resulting mixture was stirred for 1 hour at 25°C. The resulting mixture was quenched by the addition of water (10 mL) and then extracted with EtOAc (2x10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum to give tert-butyl N-[(6S)-4-{7-[8-ethy ny l-7-fl uoro-3- (methoxymethoxy)naphthalen-1-yl]-8-fluoro-2-{[1-(morpholin-4-ylmethyl)cyclopropyl]methoxy}pyrido[4,3- d]pyrimidin-4-yl}-1 ,4-oxazepan-6-yl]carbamate (assumed) as a yellow oil (45 mg, 77.5%). LC-MS (ESI, m/z) M+1 : 761. Synthesis of 4-{4-[(6S)-6-amino-1,4-oxazepan-4-yl]-8-fluoro-2-{[1-(morpholin-4- ylmethyl)cyclopropyl]methoxy}pyrido[4,3-d]pyrimidin-7-yl}-5-ethynyl-6-fluoronaphthalen-2-ol (assumed): Into a 8 mL sealed tube, were placed tert-butyl N-[(6S)-4-{7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen- 1-yl]-8-fluoro-2-{[1-(morpholin-4-ylmethyl)cyclopropyl]methoxy}pyrido[4,3-d]pyrimidin-4-yl}-1,4-oxazepan-6- yl]carbamate (assumed) (45 mg, 0.06 mmol, 1.0 eq) and CH2CI2 (2 mL). To the above mixture was added HCI(gas) in 1,4-dioxane (1 mL) dropwise at 0°C. The resulting mixture was stirred for 1 hour at 0°C. The mixture was neutralized to pH=8 with NH3 in MeOH (2 M). The resulting mixture was diluted water (10 mL). The resulting mixture was extracted with CH2CI2 (2x10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum at 0°C to give 4-{4- [(6S)-6-amino-1 ,4-oxazepan-4-yl]-8-fluoro-2-{[1-(morpholin-4-ylmethyl)cyclopropyl]methoxy}pyrido[4,3- d]pyrimidin-7-yl}-5-ethynyl-6-fluoronaphthalen-2-ol (assumed) as a yellow solid (20 mg, 54.8%). LC-MS (ESI, m/z) M+1 : 617.

Synthesis of N-[(6S)-4-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[1- (morpholin-4-ylmethyl)cyclopropyl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-1,4-oxazepan-6-yl]prop-2- enamide (assumed): Into a 8 mL sealed tube were added 4-{4-[(6S)-6-amino-1,4-oxazepan-4-yl]-8-fluoro-2-{[1- (morpholin-4-ylmethyl)cyclopropyl]methoxy}pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (assumed) (20 mg, 0.03 mmol, 1.0 eq), DCM (1 mL) and DIEA (10 mg, 0.08 mmol, 2.5 eq) at 25°C. To the above mixture was added acryloyl chloride (3 mg, 0.03 mmol, 1.0 eq) dropwise at 0°C. The resulting mixture was stirred for 1 hour at 0°C. The reaction was quenched by the addition of water (0.5 mL) and then extracted with CH2CI2 (2x10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under vacuum. The residue was dissolved in THF (1 mL) and H2O (1 mL), to the above mixture was added UOH.H2O (5 mg, 0.1 mmol, 4.0 eq) at 25°C. The resulting mixture was stirred for additional 1 hour at 25°C. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC using the following conditions ((Prep-HPLC-006): Column, YMC-Actus Triart C18 ExRS, 30*150 mm, 5pm; mobile phase, H₂O (10 mmol/L NH₄HCO₃+0.1 % NH3.H2O) and CH3CN (45% CH3CN up to 85% in 10 min) detector, UV 254 nm.) to afford N-[(6S)-4-[7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoro-2-{[1-(morpholin-4-ylmethyl)cyclopropyl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]- 1 ,4-oxazepan-6-yl]prop-2-enamide (assumed) as a white solid (10 mg, 46.0%). LC-MS (ESI, m/z) M+1 : 671. ¹HNMR (400 MHz, DMSO-d₆) 3 10.17 (s, 1 H), 9.18 (d, >7.0 Hz, 1 H), 8.39 (dd, >14.2, 7.7 Hz, 1 H), 7.99 (dd, >9.2, 5.9 Hz, 1 H), 7.47 (t, >9.0 Hz, 1 H), 7.40 (d, >2.5 Hz, 1 H), 7.18 (dd, >11.3, 2.5 Hz, 1 H), 6.27-6.23 (m, 1 H), 6.16-6.03 (m, 1 H), 5.66-5.57 (m, 1 H), 4.44-4.32 (m, 2H), 4.32-4.23 (m, 2H), 4.19-3.63 (m, 8H), 3.55-3.50 (m, 4H), 2.39-2.37 (m, 4H), 2.36-2.24 (m, 2H), 0.67-0.59 (m, 2H), 0.44-0.38 (m, 2H). Example 21 : Preparation of N-[(6R)-4-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[1- (morpholin-4-ylmethyl)cyclopropyl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-1,4-oxazepan-6-yl]prop-2- enamide (assumed)

Synthesis of tert-butyl N-[(6R)-4-{8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-[2- (triisopropylsilyl)ethynyl]naphthalen-1-yl]-2-{[1-(morpholin-4-ylmethyl)cyclopropyl]methoxy}pyrido[4,3- d]pyrimidin-4-yl}-1,4-oxazepan-6-yl]carbamate (assumed): Into a 8 mL round-bottom flask, were placed tertbutyl N-[(6R)-4-(7-chloro-8-fluoro-2-{[1-(morpholin-4-ylmethyl)cyclopropyl]methoxy}pyrido[4,3-d]pyrimidin-4-yl)- 1,4-oxazepan-6-yl]carbamate (assumed) (75 mg, 0.1 mmol, 1.0 eq), {2-[2-fluoro-6-(methoxymethoxy)-8-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)naphthalen-1-yl]ethynyl}triisopropylsilane (102 mg, 0.2 mmol, 1.5 eq), DME (2 mL), H2O (200 uL), K2CO3 (55 mg, 0.4 mmol, 3.0 eq) and CataCXium A Pd G3 (10 mg, 0.01 mmol, 0.1 eq) at 25°C under nitrogen atmosphere. The resulting mixture was stirred for 3 hours at 80°C under nitrogen atmosphere. The reaction mixture was then quenched by the addition of H2O (2 mL) and then 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 :1 to give tert-butyl N-[(6R)-4-{8-fluoro-7-[7-fluoro-3- (methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphthalen-1-yl]-2-{[1-(morpholin-4- ylmethyl)cyclopropyl]methoxy}pyrido[4,3-d]pyrimidin-4-yl}-1 ,4-oxazepan-6-yl]carbamate (assumed) as an off- white solid (70 mg, 57.7%). LC-MS (ES, m/z) M+1 : 917.

Synthesis of tert-butyl N-[(6R)-4-{7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8- fluoro-2-{[1-(morpholin-4-ylmethyl)cyclopropyl]methoxy}pyrido[4,3-d]pyrimidin-4-yl}-1,4-oxazepan-6- yl]carbamate (assumed): Into a 8 mL sealed tube, were placed tert-butyl N-[(6R)-4-{8-fluoro-7-[7-fluoro-3- (methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphthalen-1-yl]-2-{[1-(morpholin-4- ylmethyl)cyclopropyl]methoxy}pyrido[4,3-d]pyrimidin-4-yl}-1 ,4-oxazepan-6-yl]carbamate (assumed) (70 mg, 0.1 mmol, 1 eq), CsF (116 mg, 0.8 mmol, 10.0 eq) and DMF (2 mL). The resulting mixture was stirred for 1 hour at 25°C. The resulting mixture was then quenched by the addition of water (2 mL) and extracted with EtOAc (2x10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum to give tert-butyl N-[(6R)-4-{7-[8-ethy ny l-7-fl uoro-3- (methoxymethoxy)naphthalen-1-yl]-8-fluoro-2-{[1-(morpholin-4-ylmethyl)cyclopropyl]methoxy}pyrido[4,3- d]pyrimidin-4-yl}-1,4-oxazepan-6-yl]carbamate (assumed) as a yellow oil (45 mg, 77.5%). LC-MS (ESI, m/z) M+1 : 761.

Synthesis of 4-{4-[(6R)-6-amino-1,4-oxazepan-4-yl]-8-fluoro-2-{[1-(morpholin-4- ylmethyl)cyclopropyl]methoxy}pyrido[4,3-d]pyrimidin-7-yl}-5-ethynyl-6-fluoronaphthalen-2-ol (assumed): Into a 8 mL sealed tube, were placed tert-butyl N-[(6R)-4-{7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen- 1-yl]-8-fluoro-2-{[1-(morpholin-4-ylmethyl)cyclopropyl]methoxy}pyrido[4,3-d]pyrimidin-4-yl}-1,4-oxazepan-6- yl]carbamate (assumed) (45 mg, 0.06 mmol, 1.0 eq) and CH2CI2 (2 mL). To the above mixture was added HCI(gas) in 1,4-dioxane (1 mL) dropwise at 0°C. The resulting mixture was stirred for 1 hour at 0°C. The mixture was neutralized to pH 8 with NH3 in MeOH (2 M). The resulting mixture was diluted water (10 mL) and then extracted with CH2CI2 (2x10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum at 0°C to give 4-{4-[(6R)-6-amino- 1 ,4-oxazepan-4-yl]-8-fluoro-2-{[1-(morpholin-4-ylmethyl)cyclopropyl]methoxy}pyrido[4,3-d]pyrimidin-7-yl}-5- ethynyl-6-fluoronaphthalen-2-ol (assumed) as a yellow solid (20 mg, 54.8%). LC-MS (ESI, m/z) M+1 : 617.

Synthesis of N-[(6R)-4-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[1- (morpholin-4-ylmethyl)cyclopropyl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-1,4-oxazepan-6-yl]prop-2- enamide (assumed): Into a 8 mL sealed tube were added 4-{4-[(6R)-6-amino-1 ,4-oxazepan-4-yl]-8-fluoro-2-{[1- (morpholin-4-ylmethyl)cyclopropyl]methoxy}pyrido[4,3-d]pyrimidin-7-yl}-5-ethynyl-6-fluoronaphthalen-2-ol (assumed) (20 mg, 0.03 mmol, 1.0 eq), DCM (1 mL) and DIEA (10 mg, 0.08 mmol, 2.5 eq) at 25°C. To the above mixture was added acryloyl chloride (3 mg, 0.03 mmol, 1.0 eq) dropwise at 0°C. The resulting mixture was stirred for 1 hour at 0°C. The reaction was quenched by the addition of water (5 mL) and then extracted with CH2CI2 (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 residue was dissolved in THF (1 mL) and H2O (1 mL), To the above mixture was added UOH.H2O (5 mg, 0.1 mmol, 4.0 eq) at 25°C. The resulting mixture was stirred for additional 1 hour at 25°C. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC using the following conditions ((Prep-HPLC-006): Column, YMC-Actus Triart C18 ExRS, 30*150 mm, 5pm; mobile phase, H₂O (10 mmol/L NH₄HCO₃+0.1% NH3.H2O) and CH3CN (45% CH3CN up to 85% in 10 min) detector, UV 254 nm.) to afford N-[(6R)-4-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)- 8-fluoro-2-{[1-(morpholin-4-ylmethyl)cyclopropyl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-1 ,4-oxazepan-6-yl]prop-2- enamide (assumed) as a white solid (10 mg, 46.0%). LC-MS (ESI, m/z) M+1 : 671. ¹HNMR (400 MHz, DMSO-cfe) 5 10.17 (s, 1 H), 9.18 (d, >7.0 Hz, 1 H), 8.39 (dd, >14.2, 7.7 Hz, 1 H), 7.99 (dd, >9.2, 5.9 Hz, 1 H), 7.47 (t, >9.0 Hz, 1 H), 7.40 (d, >2.5 Hz, 1 H), 7.18 (dd, >11.3, 2.5 Hz, 1 H), 6.27-6.23 (m, 1 H), 6.16-6.03 (m, 1 H), 5.66-5.57 (m, 1 H), 4.44-4.32 (m, 2H), 4.32-4.23 (m, 2H), 4.19-3.63 (m, 8H), 3.55-3.50 (m, 4H), 2.39-2.37 (m, 4H), 2.36- 2.24 (m, 2H), 0.67-0.59 (m, 2H), 0.44-0.38 (m, 2H).

Example 22: Preparation of 4-(4-((1R,5S)-8-acryloyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- ((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoro-2- naphthonitrile

Synthesis of 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1 ,3-diol : Into a 250 mL roundbottom 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), KOAc (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 6-fluoro-4-hydroxy-5-[2-(triisopropylsilyl)ethynyl]naphthalen-2-yl trifluoromethanesulfonate: Into a 500 mL 3-necked round-bottom flask were placed 7-fluoro-8-[2- (triisopropylsilyl)ethynyl]naphthalene-1 ,3-diol (13.0 g, 36.3 mmol, 1.0 eq), DIEA (9.4 g, 72.5 mmol, 2.0 eq) and CH2CI2 (200 mL) at 25°C. To the above mixture was added triflic anhydride (10.2 g, 36.3 mmol, 1.0 eq) dropwise at -40°C. The resulting mixture was stirred for 30 min at -40°C. The reaction was quenched by the addition of water (50 mL). 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 reduced pressure. The crude residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether=1 :5 to give 6-fluoro-4-hydroxy-5-[2-(triisopropylsilyl)ethynyl]naphthalen-2-yl trifluoromethanesulfonate as a colorless oil (6.0 g, 33.7%). ¹HNMR (400 MHz, DMSO-de) 5 11.14 (s, 1 H), 8.05 (dd, >9.1 , 5.7 Hz, 1 H), 7.60 (d, >2.5 Hz, 1 H), 7.57 (t, >9.0 Hz, 1 H), 6.93 (d, >2.6 Hz, 1 H), 1.13-1.11 (m, 21 H).

Synthesis of 6-fluoro-4-hydroxy-5-[2-(triisopropylsilyl)ethynyl]naphthalene-2-carbonitrile: Into a 50 mL round-bottom flask were placed 6-fluoro-4-hydroxy-5-[2-(triisopropylsilyl)ethynyl]naphthalen-2-y I trifluoromethanesulfonate (1.0 g, 2.0 mmol, 1.0 eq), Zn(CN)2 (720 mg, 6.1 mmol, 3.0 eq), Pd(PPh3)4 (240 mg, 0.2 mmol, 0.1 eq), Zn (70 mg, 1.0 mmol, 0.5 eq) and DMF (20 mL) at 25°C. The resulting mixture was stirred for 4 hours at 100°C under nitrogen atmosphere. The reaction was quenched by the addition of water (10 mL). The resulting mixture was extracted with EtOAc (2x50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether=1 :2 to give 6- fluoro-4-hydroxy-5-[2-(triisopropylsilyl)ethynyl]naphthalene-2-carbonitrile as a colorless oil (650 mg, 86.8%). LC- MS (ES, m/z) M-1 : 366.

Synthesis of 3-cyano-7-fluoro-8-[2-(triisopropylsilyl)ethynyl]naphthalen-1-yl trifluoromethanesulfonate: Into a 50 mL 3-necked round-bottom flask were added 6-fluoro-4-hydroxy-5-[2- (triisopropylsilyl)ethynyl]naphthalene-2-carbonitrile (750 mg, 2.0 mmol, 1.0 eq), Pyridine (646 mg, 8.2 mmol, 4.0 eq) and DCM (15 mL). To the above mixture was added Tf2<3 (864 mg, 3.1 mmol, 1.5 eq) dropwise at -20°C. The resulting mixture was stirred for additional 4 hours at 25°C. The reaction was quenched by the addition of water (10 mL). The resulting mixture was extracted with CH2CI2 (2x30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether=1 :1 to give 3-cyano-7-fluoro-8-[2-(triisopropylsilyl)ethynyl]naphthalen-1-yl trifluoromethanesulfonate as a colorless oil (800 mg, 78.5%). ¹HNMR (400 MHz, DMSO-d₆) 5 8.89 (d, >1.6 Hz, 1 H), 8.36 (dd, >9.2, 5.6 Hz, 1 H), 8.21 (d, >1.5 Hz, 1 H), 7.89 (t, >9.0 Hz, 1 H), 1.25-1.06 (m, 21 H).

Synthesis of 6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-[2- (triisopropylsilyl)ethynyl]naphthalene-2-carbonitrile: Into a 50 mL round-bottom flask, were placed 3-cyano- 7-fluoro-8-[2-(triisopropylsilyl)ethynyl]naphthalen-1-yl trifluoromethanesulfonate (700 mg, 1.4 mmol, 1.0 eq), bis(pinacolato)diboron (712 mg, 2.8 mmol, 2.0 eq), KOAc (481 mg, 4.9 mmol, 3.5 eq), Pd(dppf)Cl2 (114 mg, 0.1 mmol, 0.1 eq) and Toluene (15 mL) at 25°C. The resulting mixture was stirred for 16 hours at 100°C under nitrogen atmosphere. The reaction mixture was then quenched by the addition of H2O (10 mL), and then extracted with ethyl acetate (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 :20 to give 6-fluoro-4-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-5-[2-(triisopropylsilyl)ethynyl]naphthalene-2-carbonitrile as a yellow solid (300 mg, 44.8%). ¹HNMR (300 MHz, Chloroform-d) 5 8.22 (d, 1.8 Hz, 1 H), 7.91 (d, >1.7 Hz, 1 H), 7.86 (dd, >9.0, 5.6 Hz, 1 H), 7.41 (t, >8.7 Hz, 1 H), 1.46 (s, 12H), 1.18-1.16 (m, 21 H).

Synthesis of tert-butyl (1R,5S)-3-(7-(3-cyano-7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1- yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate: Into a 8 mL round-bottom flask, were placed tert-butyl (1 R,5S)-3-(7- chloro-8-fluoro-2-((tetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 0.4 mmol, 1.0 eq), 6-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-5-[2-(triisopropylsilyl)ethynyl]naphthalene-2-carbonitrile (215 mg, 0.5 mmol, 1.2 eq), K2CO3 (156 mg, 1.1 mmol, 3.0 eq), XPhos Pd G3 (32 mg, 0.04 mmol, 0.1 eq), DME (4 mL) and H2O (200 uL) at 25°C under nitrogen atmosphere. The resulting mixture was stirred for 4 hours at 80°C under nitrogen atmosphere. The reaction mixture was then quenched by the addition of H2O (10 mL) and then 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 : 1 to give tert-butyl (1R,5S)-3-(7-(3-cyano-7-fluoro-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-fluoro-2-((tetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as an off-white solid (100 mg, 31.4%). LC-MS (ES, m/z) M+1 : 848.

Synthesis of tert-butyl (1R,5S)-3-(7-(3-cyano-8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2- ((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate: Into a 8 mL sealed tube, were placed tert-butyl (1R,5S)-3-(7-(3-cyano-7-fluoro-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-fluoro-2-((tetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (95 mg, 0.1 mmol, 1.0 eq), CsF (170 mg, 1.1 mmol, 10.0 eq) and DMF (2 mL). The resulting mixture was stirred for 2 hours at 25°C. The resulting mixture was then quenched by the addition of water (2 mL). The resulting mixture was extracted with EtOAc (2x10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum to give tert-butyl (1 R,5S)-3-(7-(3-cyano-8-ethynyl-7-fluoronaphthalen-1 - yl)-8-fluoro-2-((tetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate as a yellow oil (70 mg, 90.3%). LC-MS (ES, m/z) M+1 : 692.

Synthesis of 4-(4-((1 R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoro-2-naphthonitrile: Into a 8 mL sealed tube, were placed tert-butyl (1R,5S)-3-(7-(3-cyano-8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1 H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (70 mg, 0.1 mmol, 1.0 eq) and CH2CI2 (2 mL). To the above mixture was added HCI(gas) in 1 ,4-dioxane (1 mL) dropwise at 0°C. The resulting mixture was stirred for 1 hour at 0°C. The mixture was neutralized to pH=8 with NH3 in MeOH (2 M). The resulting mixture was diluted water (10 mL). The resulting mixture was extracted with CH2CI2 (2x10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum at 0°C to give 4-(4-((1 R,5S)-3,8-diazabicyclo[3.2.1 ]octan-3- yl)-8-fluoro-2-((tetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoro-2- naphthonitrile as a yellow solid (50 mg, 83.5%). LC-MS (ES, m/z) M+1 : 592.

Synthesis of 4-(4-((1 R,5S)-8-acryloyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((tetrahydro-1 H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoro-2-naphthonitrile: Into a 8 mL sealed tube were added 4-(4- 8-fluoro-2-(hexahydropyrrolizin-7a-ylmethoxy)pyrido[4,3-d]pyrimidin-7-yl)-5- ethynyl-6-fluoronaphthalene-2-carbonitrile (50 mg, 0.1 mmol, 1.0 eq), DCM (1 mL) and DIEA (22 mg, 0.2 mmol, 2.0 eq) at 25°C. To the above mixture was added acryloyl chloride (8 mg, 0.1 mmol, 1.0 eq) dropwise at 0°C. The resulting mixture was stirred for 1 hour at 0°C.The reaction was quenched by the addition of water (0.5 mL) at 25°C. The resulting mixture was extracted with CH2CI2 (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 product was purified by Prep-HPLC using the following conditions: Column, YMC-Actus Triart C18 ExRS, 30*150 mm, 5pm; mobile phase, H₂O (10 mmol/L NH₄HCO₃+0.1% NH3.H2O) and CH3CN (45% CH3CN up to 85% in 10 min) detector, UV 254 nm.) to afford 4-(4-((1 R,5S)-8-acryloyl-3,8-diazabicyclo[3.2.1]octan-3-yl)- 8-fluoro-2-((tetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoro-2- naphthonitrile as a white solid (17 mg, 31.2%). LC-MS (ES, m/z) M+1 : 646. ¹HNMR (400 MHz, DMSO-d₆) 5 9.08 (s, 1 H), 8.89 (d, >1.8 Hz, 1 H), 8.38 (dd, >9.2, 5.9 Hz, 1 H), 8.01 (s, 1 H), 7.81 (t, >9.0 Hz, 1 H), 6.82 (dd, >16.7, 10.4 Hz, 1 H), 6.27 (dd, >16.7, 2.3 Hz, 1 H), 5.79 (dd, >10.3, 2.3 Hz, 1 H), 4.77 (s, 2H), 4.64 (d, >13.0 Hz, 1 H), 4.44 (t, >13.7 Hz, 1 H), 4.18 (s, 1 H), 4.07 (s, 2H), 3.71 (d, >10.9 Hz, 1 H), 3.62 (t, >11.1 Hz, 1 H), 2.94 (dt, >10.8, 5.6 Hz, 2H), 2.59-2.53 (m, 2H), 1.96-1.71 (m, 10H), 1.59 (dt, >12.0, 7.5 Hz, 2H).

Example 23: Preparation of N-[(6R)-1-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[1- (morpholin-4-ylmethyl)cyclopropyl]methoxy}pyrido [4,3-d]pyrimidin-4-yl]-4-methyl-1,4-diazepan-6- yl]prop-2-enamide (assumed)

Synthesis of tert-butyl N-[(6R)-1-{8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-[2- (triisopropylsilyl)ethynyl]naphthalen-1-yl]-2-{[1-(morpholin-4-ylmethyl)cyclopropyl]methoxy}pyrido [4,3- d]pyrimidin-4-yl}-4-methyl-1,4-diazepan-6-yl]carbamate (assumed): Into a 40-mL sealed-tube purged and maintained with an inert atmosphere of nitrogen, were placed tert-butyl N-[(6R)-1-(7-chloro-8-fluoro-2-{[1- (morpholin-4-ylmethyl)cyclopropyl]methoxy}pyrido[4,3-d]pyrimidin-4-yl)-4-methyl-1 ,4-diazepan-6-yl]carbamate (assumed) (200 mg, 0.3 mmol, 1.0 eq), {2-[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)naphthalen-1-yl]ethynyl} triisopropylsilane (177 mg, 0.3 mmol, 1.0 eq), K2CO3 (143 mg, 1.0 mmol, 3.0 eq), DME (4 mL), H2O (0.4 mL), cataCXium A Pd G3 (13 mg, 0.02 mmol, 0.05 eq). The resulting solution was stirred for 2 hours at 80°C in an oil bath. The resulting mixture was then quenched by the addition of water (40 mL) and then extracted with ethyl acetate (2x40 mL). The combined organic layers washed with brine (2x40 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 dichloromethane/methanol=15:1 to give tertbutyl N-[(6R)-1-{8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphthalen-1-yl]-2-{[1- (morpholin-4-ylmethyl)cyclopropyl]methoxy}pyrido [4,3-d]pyrimidin-4-yl}-4-methyl-1 ,4-diazepan-6-yl]carbamate (assumed) as a light yellow solid (210 mg, 65.5%).

Synthesis of tert-butyl N-[(6R)-1-{7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8- fluoro-2-{[1-(morpholin-4-ylmethyl) cyclopropyl]methoxy}pyrido[4,3-d]pyrimidin-4-yl}-4-methyl-1,4- diazepan-6-yl]carbamate (assumed): Into a 40-mL sealed tube, were placed tert-butyl N-[(6R)-1-{8-fluoro-7-[7- fluoro-3-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphthalen-1-yl]-2-{[1-(morpholin-4- ylmethyl)cyclopropyl]methoxy}pyrido [4,3-d]pyrimidin-4-yl}-4-methyl-1 ,4-diazepan-6-yl]carbamate (assumed) (180 mg, 0.2 mmol, 1.0 eq), DMF (3 mL), CsF (294 mg, 1.9 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 (40 mL). The resulting solution was extracted with ethyl acetate (2x40 mL) and washed with brine (2x40 mL) and the organic layers combined. The mixture was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum to give tert-butyl N-[(6R)-1-{7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoro-2-{[1- (morpholin-4-ylmethyl) cyclopropyl]methoxy}pyrido[4,3-d]pyrimidin-4-yl}-4-methyl-1,4-diazepan-6-yl]carbamate (assumed) as a yellow solid (150 mg, crude). LC-MS (ESI, m/z) M+1 : 774.

Synthesis of 4-{4-[(6R)-6-amino-4-methyl-1,4-diazepan-1-yl]-8-fluoro-2-{[1-(morpholin-4- ylmethyl)cyclopropyl]methoxy}pyrido [4,3-d]pyrimidin-7-yl}-5-ethynyl-6-fluoronaphthalen-2-ol (assumed): Into a 50 mL 3-necked round-bottom, were placed tert-butyl N-[(6R)-1-{7-[8-ethynyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl]-8-fluoro-2-{[1-(morpholin-4-ylmethyl)cyclopropyl]methoxy}pyrido [4,3- d]pyrimidin-4-yl}-4-methyl-1 ,4-diazepan-6-yl]carbamate (assumed) (120 mg, 0.2 mmol, 1.0 eq), CH2CI2 (4 mL). This was followed by the addition of HCI (gas) in 1 ,4-dioxane (2 mL, 4 M) at 0°C. Then the mixture was stirred for 1 hour at 0°C. The mixture neutralized to pH=7-8 with NH3 in MeOH (2 M). The resulting mixture was then quenched by the addition of water (30 mL) and extracted with CH2CI2 (2x30 mL). The combined organic layers was washed with brine (30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum to give 4-{4-[(6R)-6-amino-4-methyl-1,4-diazepan-1-yl]-8-fluoro-2-{[1-(morpholin-4- ylmethyl)cyclopropyl]methoxy}pyrido [4,3-d]pyrimidin-7-yl}-5-ethynyl-6-fluoronaphthalen-2-ol (assumed) as a light yellow solid (100 mg, crude). LC-MS (ESI, m/z) M+1 : 630.

Synthesis of N-[(6R)-1-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[1- (morpholin-4-ylmethyl)cyclopropyl]methoxy}pyrido [4,3-d]pyrimidin-4-yl]-4-methyl-1,4-diazepan-6- yl]prop-2-enamide (assumed): Into a 50 mL 3-necked round-bottom flask, were placed 4-{4-[(6R)-6-amino-4- methyl-1,4-diazepan-1-yl]-8-fluoro-2-{[1-(morpholin-4-ylmethyl)cyclopropyl]methoxy}pyrido[4,3-d]pyrimidin-7-yl}- 5-ethynyl-6-fluoronaphthalen-2-ol (assumed) (80 mg, 0.1 mmol, 1.0 eq), DIEA (41 mg, 0.3 mmol, 2.5 eq), DCM (2 mL). This was followed by the addition of acryloyl chloride (14 mg, 0.2 mmol, 1.2 eq) at 0°C. Then the mixture was stirred for 1 hour at 0°C. The resulting mixture was then quenched by the addition of water (50 mL) and extracted with dichloromethane (2x50 mL). The combined organic layers was washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. To the above mixture was added THF (1 mL), H2O (1 mL), LiOH (12 mg, 0.5 mmol, 4.0 eq). The resulting mixture was stirred for additional 1 hour at 25°C. The crude product was purified by Prep-HPLC using the following conditions: Column, SunFire Prep C18 OBD Column, 50*250mm 5um 10nm; mobile phase, Water (0.05% NH3.H2O) and CH3CN (50% Phase B up to 60% in 7 min); Detector, UV 254/220 nm. Finally, N-[(6R)-1-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen- 1-yl)-8-fluoro-2-{[1-(morpholin-4-ylmethyl)cyclopropyl] methoxy}pyrido[4,3-d]pyrimidin-4-yl]-4-methyl-1,4- diazepan-6-yl]prop-2-enamide (assumed) was obtained as a light yellow solid (20 mg, 23.0%). LC-MS (ESI, m/z) M+1 : 684. ¹HNMR (400 MHz, DMSO-d₆) 5 10.15 (s, 1 H), 9.15 (d, >7.6 Hz, 1 H), 8.30-8.21 (m, 1 H), 7.98 (dd, >9.2, 6.0 Hz, 1 H), 7.47 (t, >9.0 Hz, 1 H), 7.40 (d, >2.6 Hz, 1 H), 7.18 (dd, >12.4, 2.4 Hz, 1 H), 6.32-6.24 (m, 1 H), 6.13-6.04 (m, 1 H), 5.66-5.56 (m, 1 H), 4.41-4.35 (m, 2H), 4.34-4.18 (m, 3H), 4.07-3.80 (m, 3H), 3.54 (t, >4.6 Hz, 4H), 2.96-2.91 (m, 2H), 2.81-2.74 (m, 1 H), 2.68-2.58 (m, 1 H), 2.40-2.28 (m, 9H), 0.64-0.59 (m, 2H), 0.42-0.40 (m, 2H).

Example 24: Preparation of N-[(6S)-1-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[1- (morpholin-4-ylmethyl)cyclopropyl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-4-methyl-1,4-diazepan-6- yl]prop-2-enamide (assumed)

Synthesis of tert-butyl N-[(6S)-1-{8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-[2- (triisopropylsilyl)ethynyl]naphthalen-1-yl]-2-{[1-(morpholin-4-ylmethyl)cyclopropyl]methoxy}pyrido [4,3- d]pyrimidin-4-yl}-4-methyl-1,4-diazepan-6-yl]carbamate (assumed): Into a 40-mL sealed-tube purged and maintained with an inert atmosphere of nitrogen, were placed tert-butyl N-[(6S)-1-(7-chloro-8-fluoro-2-{[1- (morpholin-4-ylmethyl)cyclopropyl]methoxy}pyrido[4,3-d]pyrimidin-4-yl)-4-methyl-1,4-diazepan-6-yl]carbamate (assumed) (200 mg, 0.3 mmol, 1.0 eq), {2-[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)naphthalen-1-yl]ethynyl} triisopropylsilane (177 mg, 0.3 mmol, 1.0 eq), K2CO3 (143 mg, 1.0 mmol, 3.0 eq), DME (4 mL), H2O (0.4 mL), cataCXium A Pd G3 (13 mg, 0.01 mmol, 0.05 eq). The resulting solution was stirred for 2 hours at 80°C in an oil bath. The resulting mixture was then quenched by the addition of water (40 mL) and extracted with ethyl acetate (2x40 mL). The combined organic layers was washed with brine (2x40 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 dichloromethane/methanol=15:1 to give tertbutyl N-[(6S)-1-{8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphthalen-1-yl]-2-{[1- (morpholin-4-ylmethyl)cyclopropyl]methoxy}pyrido [4,3-d]pyrimidin-4-yl}-4-methyl-1,4-diazepan-6-yl]carbamate (assumed) as a light yellow solid (190 mg, 59.2%).

Synthesis of tert-butyl N-[(6S)-1-{7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8- fluoro-2-{[1-(morpholin-4-ylmethyl) cyclopropyl]methoxy}pyrido[4,3-d]pyrimidin-4-yl}-4-methyl-1,4- diazepan-6-yl]carbamate (assumed): Into a 40-mL sealed tube, were placed tert-butyl N-[(6S)-1-{8-fluoro-7-[7- fluoro-3-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphthalen-1-yl]-2-{[1-(morpholin-4- ylmethyl)cyclopropyl]methoxy}pyrido [4,3-d]pyrimidin-4-yl}-4-methyl-1 ,4-diazepan-6-yl]carbamate (assumed) (160 mg, 0.2 mmol, 1.0 eq), DMF (3 mL), CsF (261 mg, 1.7 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 (40 mL) and extracted with ethyl acetate (2x40 mL). The combined organic layers was washed with brine (2x40 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum to give tert-butyl N-[(6S)-1-{7-[8- ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoro-2-{[1-(morpholin-4-ylmethyl) cyclopropyl]methoxy}pyrido[4,3-d]pyrimidin-4-yl}-4-methyl-1 ,4-diazepan-6-yl]carbamate (assumed) as a yellow solid (130 mg, crude). LC-MS (ESI, m/z) M+1 : 774.

Synthesis of 4-{4-[(6S)-6-amino-4-methyl-1,4-diazepan-1-yl]-8-fluoro-2-{[1-(morpholin-4- ylmethyl)cyclopropyl]methoxy}pyrido [4,3-d]pyrimidin-7-yl}-5-ethynyl-6-fluoronaphthalen-2-ol (assumed): Into a 50 mL 3-necked round-bottom, were placed tert-butyl N-[(6S)-1-{7-[8-ethynyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl]-8-fluoro-2-{[1-(morpholin-4-ylmethyl)cyclopropyl]methoxy}pyrido [4,3- d]pyrimidin-4-yl}-4-methyl-1 ,4-diazepan-6-yl]carbamate (assumed) (100 mg, 0.1 mmol, 1.0 eq), CH2CI2 (4 mL). This was followed by the addition of HCI (gas) in 1 ,4-dioxane (2 mL, 4 M) at 0°C. Then the mixture was stirred for 1 hour at 0°C. The mixture neutralized to pH=7-8 with NH3 in MeOH (2 M). The resulting mixture was then quenched by the addition of water (30 mL). The resulting solution was extracted with CH2CI2 (2x30 mL) and washed with brine (30 mL) and the organic layers combined. The mixture was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum to give 4-{4-[(6S)-6-amino-4-methyl-1,4-diazepan-1- yl]-8-fluoro-2-{[1-(morpholin-4-ylmethyl)cyclopropyl]methoxy}pyrido [4,3-d]pyrimidin-7-yl}-5-ethynyl-6- fluoronaphthalen-2-ol (assumed) as a light yellow solid (80 mg, crude). LC-MS (ESI, m/z) M+1 : 630.

Synthesis of N-[(6S)-1-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[1- (morpholin-4-ylmethyl)cyclopropyl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-4-methyl-1,4-diazepan-6- yl]prop-2-enamide (assumed): Into a 50 mL 3-necked round-bottom flask, were placed 4-{4-[(6S)-6-amino-4- methyl-1,4-diazepan-1-yl]-8-fluoro-2-{[1-(morpholin-4-ylmethyl)cyclopropyl]methoxy}pyrido[4,3-d]pyrimidin-7-yl}- 5-ethynyl-6-fluoronaphthalen-2-ol (assumed) (60 mg, 0.1 mmol, 1.0 eq), DIEA (31 mg, 0.2 mmol, 2.5 eq), DCM (2 mL). This was followed by the addition of acryloyl chloride (10 mg, 0.1 mmol, 1.2 eq) at 0°C. Then the mixture was stirred for 1 hour at 0°C. The resulting mixture was then quenched by the addition of water (30 mL) and then extracted with dichloromethane (2x30 mL). The combined organic layers was washed with brine (30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. To the above mixture was added THF (1 mL), H2O (1 mL), LiOH (9 mg, 0.4 mmol, 4.0 eq). The resulting mixture was stirred for additional 1 hour at 25°C. The crude product was purified by Prep-HPLC using the following conditions: Column, SunFire Prep C18 OBD Column, 50*250mm 5um 10nm; mobile phase, Water (0.05% NH3.H2O) and CH3CN (50% Phase B up to 60% in 7 min); Detector, UV 254/220 nm. Finally, N-[(6S)-1-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen- 1-yl)-8-fluoro-2-{[1-(morpholin-4-ylmethyl)cyclopropyl]methoxy}pyrido [4,3-d]pyrimidin-4-yl]-4-methyl-1,4- diazepan-6-yl]prop-2-enamide (assumed) was obtained as a light yellow solid (15 mg, 23.0%). LC-MS (ESI, m/z) M+1 : 684. ¹HNMR (400 MHz, DMSO-d₆) 5 10.14 (d, 2.4 Hz, 1 H), 9.15 (d, >7.8 Hz, 1 H), 8.31-8.21 (m, 1 H), 7.98 (dd, >9.2, 6.0 Hz, 1 H), 7.47 (t, >9.0 Hz, 1 H), 7.40 (d, >2.6 Hz, 1 H), 7.18 (dd, >12.4, 2.6 Hz, 1 H), 6.32- 6.24 (m, 1 H), 6.15-6.02 (m, 1 H), 5.63-5.58 (m, 1 H), 4.42-4.35 (m, 2H), 4.34-4.14 (m, 3H), 4.07-3.78 (m, 3H), 3.54 (t, 4.8 Hz, 4H), 2.96-2.91 (m, 2H), 2.81-2.75 (m, 1 H), 2.68-2.67 (m, 1 H), 2.38-2.25 (m, 9H), 0.67-0.58 (m, 2H), 0.42-0.39 (m, 2H).

Biological Example 1 : KRas G12C Binding Assay

HIS-KRAS (G12C, aa 2-185, Sino biological) was diluted to 5uM in EDTA buffer (20 mM HEPES, pH 7.4, 50 mM NaCI, 10 mM EDTA, 0.01% (v/v) Tween-20) and incubated for 30 min at 25°C. The EDTA pretreated HIS-KRAS (G12C) was diluted to 12 nM in assay buffer (25 mM HEPES, pH 7.4, 120 mM NaCI, 5 mM MgCI 2, 1 mM DTT, 0.01 % (v/v) Tween 20, 0.1% (w/v) BSA) containing 120 nM GDP (Sigma) and MAb Anti 6HIS-Tb cryptate Gold (Cisbio) and incubated for 1 hour at 25°C to prepare GDP-loaded HIS-KRAS (G12C). The GDP- loaded HIS-KRAS (G12C) was pre-incubation with diluted compounds in a 384-well plate (Greiner) for 1 hour, then purified SCSI ExD (Flag tag, aa 564-1049) and BODIPY TM FL GTP (Invitrogen) were added to the assay wells (Final concentration: 3 nM HIS-KRAS (G12C), 2 uM SCSI ExD, 80 nM BODIPY TM FL GTP, 21 ng/mL MAb Anti 6HI S-Tb cryptate Gold) and incubated for 4 hours at 25°C. TR-FRET signals were then read on Tecan Spark multimode microplate reader. The parameters were F486: Excitation 340 (35) nm, Emission 486 (10) nm, Lag time 100 ps, Integration time 200 ps; F515: Excitation 340 (35) nm, Emission 515 (10) nm, Lag time 100 ps, Integration time 200 ps. TR-FRET ratios for each individual wells were calculated by equation: TR-FRET ratio = (Signal F515/Signal F486) *10000. Then the data were analyzed using a 4-parameter logistic model to calculate IC50 values. The following table lists the IC50 values of certain compounds of the invention.

Biological Example 2: KRas G12C In vitro Covalent MS-based Assay

GDP-loaded, histidine-tagged, truncated (1-169) KRAS proteins (G12C, WT, G13D, as indicated) at 2uM final concentration were incubated with the test compounds at the doses and time points indicated in a buffer containing 20 mmol/L HEPES pH 7.5, 150 mmol/L NaCI, 1 mmol/L MgCI 2 , and 1 mmol/L DTT. Reactions were quenched by adding formic acid to 0.2%. Samples were buffer exchanged and analyzed by denaturing SEC-MS (Orbitrap Eclipse), Mobile phase: 30% ACN, 0.1% formic acid, 0.02% TFA. Raw data were analyzed by charge state deconvolution with BioPharma Finder 4.1 Intact Mass, ReSpect and Sliding Window algorithms. The masses were calculated via software for KRAS_G12C theoretical sequence and experimental compounds. The follow table shows the result.

Biological Example 3: KRas G12V Binding Assay

HIS-KRAS G12V was diluted to 5uM in EDTA buffer (20 mM HEPES, pH 7.4, 50 mM NaCI, 10 mM EDTA, 0.01% (v/v) Tween-20) and incubated for 30 min at 25°C. The EDTA pretreated HIS-KRAS (G12V) was diluted to 12 nM in assay buffer (25 mM HEPES, pH 7.4, 120 mM NaCI, 5 mM MgCI 2, 1 mM DTT, 0.01% (v/v) Tween 20, 0.1% (w/v) BSA) containing 120 nM GDP (Sigma) and MAb Anti 6HIS-Tb cryptate Gold (Cisbio) and incubated for 1 hour at 25°C to prepare GDP-loaded HIS-KRAS (G12V). The GDP-loaded HIS-KRAS (G12V) was pre-incubation with diluted compounds in a 384-well plate (Greiner) for 1 hour, then purified SCSI ExD (Flag tag, aa 564-1049) and BODIPY TM FL GTP (Invitrogen) were added to the assay wells (Final concentration: 3 nM HIS-KRAS (G12V), 2 uM SCSI ExD, 80 nM BODIPY TM FL GTP, 21 ng/mL MAb Anti 6HI S-Tb cryptate Gold) and incubated for 4 hours at 25°C. TR-FRET signals were then read on Tecan Spark multimode microplate reader. The parameters were F486: Excitation 340 (35) nm, Emission 486 (10) nm, Lag time 100 ps, Integration time 200 ps; F515: Excitation 340 (35) nm, Emission 515 (10) nm, Lag time 100 ps, Integration time 200 ps. TR- FRET ratios for each individual wells were calculated by equation: TR-FRET ratio = (Signal F515/Signal F486) *10000. Then the data were analyzed using a 4-parameter logistic model to calculate IC50 values. The following table lists the I C50 values of certain compounds of the invention.

can not only covalently inhibit the Kras G12C, but also reversibly inhibit other Kras mutations such as G12D, G12R, or G12V.

Biological Example 4: In vitro Anti-proliferation Assay in cancer cell line with Kras mutation

Cell antiproliferation was assayed by PerkinElmer ATPIite™ Luminescence Assay System. Briefly, the various test cancer cell lines were plated at a density of about 1 x 10⁴ cells per well in Costar 96-well plates, and were incubated with different concentrations of compounds for about 72 hours in medium supplemented with 5% FBS or 10% normal human serum(NHS). One lyophilized substrate solution vial was then reconstituted by adding 5 mL of substrate buffer solution, and was agitated gently until the solution was homogeneous. About 50 pL of mammalian cell lysis solution was added to 100 pL of cell suspension per well of a microplate, and the plate was shaken for about five minutes in an orbital shaker at -700 rpm. This procedure was used to lyse the cells and to stabilize the ATP. Next, 50 pL substrate solution was added to the wells and microplate was shaken for five minutes in an orbital shaker at -700 rpm. Finally, the luminescence was measured by a PerkinElmer TopCount® Microplate Scintillation Counter. Such assays, carried out with a range of doses of test compounds, allowed the determination of the cellular anti-antiproliferative I C50 of the compounds of the present invention.

Biological Example 5: mice PK study

The pharmacokinetics of compounds were evaluated in CD-1 mouse via Intravenous and Oral Administration. The IV dose was administered as a slow bolus in the Jugular vein, and oral doses were administered by gavage. The fomulaltion for IV dosing was 5% DMSO in 20% HPBCD in water, and the PC formulation was 2.5% DMSO, 10% EtOH, 20% Cremphor EL, 67.5% D5W. The PK time point for the IV arm was 5, 15, 30 min, 1, 2, 4, 6, 8, 12, 24 hours post dose, and for PO arm was 15, 30 min, 1, 2, 4, 6, 8, 12, 24 hours post dose. Approximately 0.03 mL blood was collected at each time point. Blood of each sample was transferred into plastic micro centrifuge tubes containing EDTA-K2 and collect plasma within 15 min by centrifugation at 4000 g for 5 minutes in a 4°C centrifuge. Plasma samples were stored in polypropylene tubes. The samples were stored in a freezer at -75±15°C prior to analysis. Concentrations of compounds in the plasma samples were analyzed using a LC-MS/MS method. WinNonlin (Phoenix™, version 6.1) or other similar software was used for pharmacokinetic calculations. The following pharmacokinetic parameters were calculated, whenever possible from the plasma concentration versus time data: IV administration: Co, CL, Vd, T1/2, AUCinf, AUCiast, MRT, Number of Points for Regression; PO administration: C_max, T_max, T1/2, AUCinf, AUCiast, F%, Number of Points for Regression. The pharmacokinetic data was described using descriptive statistics such as mean, standard deviation. Additional pharmacokinetic or statistical analysis was performed at the discretion of the contributing scientist, and was documented in the data summary.

Biological Example 6: In vivo Xenograft Studies

Typically, athymic nude mice (CD-1 nu/nu) or SCID mice are obtained at age 6-8 weeks from vendors and acclimated for a minimum 7-day period. The cancer cells are then implanted into the nude mice. Depending on the specific tumor type, tumors are typically detectable about two weeks following implantation. When tumor sizes reach -100-200 mm³, the animals with appreciable tumor size and shape are randomly assigned into groups of 8 mice each, including one vehicle control group and treatment groups. Dosing varies depending on the purpose and length of each study, which typically proceeds for about 3-4 weeks. Tumor sizes and body weight are typically measured three times per week. In addition to the determination of tumor size changes, the last tumor measurement is used to generate the tumor size change ratio (T/C value), a standard metric developed by the National Cancer Institute for xenograft tumor evaluation. In most cases, %T/C values are calculated using the following formula: % T/C = 100 x AT/AC if AT > 0. When tumor regression occurred (AT < 0), however, the following formula is used: % T/T0 = 100 x AT/T0. Values of <42% are considered significant.

Claims

WHAT IS CLAIMED IS:

1 . A compound of Formula (3), 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 (3) or N-oxide thereof:

R_c _m(R₃) ^-Warhead r Q3 ) n j o N

Formula (3) wherein

Warhead is chemical group that can form a covalent bond with a Cysteine of a target protein; each of W1, and W2, independently, is N or C(R_a); each of Li, L2, L3, L4, L5, and Le, independently, is absent, a bond, (CR_aRb)_P, N(R_C), 0, S, C(O), S(O₂), -0(CR_aRb)_P-, -N(R_c)(CR_aRb)p-, OC(O), C(O)O, OSO₂, S(O₂)O, C(0)S, SC(0), C(0)C(0), C(0)N(R_c), N(R_c)C(0), S(O₂)N(R_C), N(R_C)S(O₂), OC(O)O, 0C(0)S, 0C(0)N(R_C), N(R_C)C(0)0, N(R_c)C(0)S, N(Rc)C(0)N(R_c), (CR_aRb)_PN(R_c)(CR_aRb)_q, (CR_aRb)_PN(R_c)C(O)(CR_aRb)_q, OC(O)N(Rc)(CR_aRb)p₊iN(R_c)(CR_aRb)_q, (CR_aRb)_PC(O)N(R_c)(CR_aRb)_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; when W1 is C(R_a), the R_a and Li, 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;

Q2 is a 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;

- I l l - Q3 is a heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged- heterocyclic, or heteroaryl, each of the aforementioned is optionally substituted with one or more independently selected Rd substituents;

Rb and R_c, 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 Rd is independently H, D, halo, cyano, nitro, alkyl, alkylene-P(O)RbR_c, alkenyl, alkynyl, C(O)alkyl, C(O)NHOH, C(O)NH₂, C(0)0H, C(O)O(alkyl), NH₂, NH(alkyl), NH(haloalkyl), NHC(O)alkyl, =NRb, N=S(O)RbR_c, OH, O(alkyl), =0, P(O)RbR_c, S(O)(NRb)R_c, 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 R_e substituents; or 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 R_e substituents; each R_e is independently H, D, halo, cyano, nitro, alkyl, alkylene-P(O)RbR_c, alkenyl, alkynyl, C(O)alkyl, C(O)NHOH, C(O)NH₂, C(O)OH, C(O)O(alkyl), NH₂, NH(alkyl), NH(haloalkyl), NHC(O)alkyl, =NRb, N=S(O)RbR_c, OH, O(alkyl), =0, P(O)RbR_c, S(O)(NRb)R_c, 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 Rf substituents; or two R_e, 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 Rf substituents; each Rf is independently H, D, halo, cyano, nitro, alkyl, alkylene-P(O)RbR_c, alkenyl, alkynyl, C(O)alkyl, C(O)NHOH, C(O)NH₂, C(0)0H, C(O)O(alkyl), NH₂, NH(alkyl), NH(haloalkyl), NHC(O)alkyl, =NRb, N=S(O)RbR_c, OH, O(alkyl), =0, P(0)RbR_c, S(O)(NRb)R_c, 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 R_g substituents; each R_g is independently H, D, halo, cyano, nitro, alkyl, alkylene-P(O)RbR_c, alkenyl, alkynyl, C(O)alkyl, C(O)NHOH, C(0)NH₂, C(0)0H, C(O)O(alkyl), NH₂, NH(alkyl), NH(haloalkyl), NHC(O)alkyl, =NRb, N=S(O)RbR_c, OH, O(alkyl), =0, P(O)RbR_c, S(O)(NRb)R_c, cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused- heterocyclic, bridged-heterocyclic, aryl, or heteroaryl; i is O, 1 , 2, 3, 4, 5, or 6; m is O, 1 , 2, 3, 4, 5, or 6; n is O, 1 , 2, 3, 4, 5, or 6; p is O, 1 , 2, 3, 4, 5, or 6; and q is O, 1 , 2, 3, 4, 5, or 6. 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 (3-A):

(Rl)i Formula (3-A) wherein

Warhead

Rz is H, D, halo, cyano, alkyl, alkylene-R_a, alkenyl, alkynyl, 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. 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-A1):

Formula (3-Al) wherein

W is C(RaR ), N(R_C), 0, S, or S(O₂).

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 (3-B):

Formula (3-B) wherein

QIA is a 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; g is 0, 1 , 2, 3, or 4; h is 0, 1 , 2, or 3; and g+h=i;

RIA and RIB, independently, is Ri;

W is C(RaR ), N(R_C), 0, S, or S(O₂). 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 (3-C):

Formula (3-C) wherein

W is 0, S, or S(O₂).

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 (3-i):

wherein

W3 is N or C(R_a); h is 0, 1, 2, or 3; and 1 +h=i; and

Ric and R , independently, is R1.

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 (3-ii):

Formula (3-ii) wherein

W is 0, S, or S(0₂). A pharmaceutical composition comprising a compound of Formula (3) or an N-oxide thereof as defined in any one of claim 1-7, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug of said compound of Formula (3) or an N-oxide thereof, and a pharmaceutically acceptable diluent or carrier. 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 of Formula (3) or an N- oxide thereof as defined in any one of claims 1-7, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug of said compound of Formula (3) or an N-oxide thereof.