Small polycyclic molecular glue degrader of VAV1

Abstract

The disclosure includes compounds of Formula (A), wherein each of R0, R1, R2, R3, R4, RA, L1, L2, Q1, Q2, Z0, Z1, j, k, m, n, and r are defined herein. Also disclosed is a method for treating a neoplastic disease, autoimmune disease, and inflammatory disorder with these compounds.

Description

[0001] 125569-02020

[0002] Molecular Glue Degrader of VAV1 REFERENCE TO RELATED APPLICATIONS

[0003] This application clams the benefit of the filing dates of U. S. provisional patent application Nos.: 63 / 775,966, filed on March 21, 2025; 63 / 781,439, filed on April 1, 2025; 63 / 839,056, filed on July 6, 2025; 63 / 946,023, filed on December 21, 2025, and 63 / 981,919, filed on February 13, 2026, the entire contents of each of the above-referenced applications are hereby incorporated herein by reference.

[0004] BACKGROUND OF THE INVENTION

[0005] The ubiquitin proteasome system can be manipulated with different small molecules to trigger targeted degradation of specific proteins of interest. Promoting the targeted degradation of proteins using small molecule degraders is emerging as a new modality in the treatment of diseases. One such modality relies on redirecting the activity of E3 ligases such as cereblon (a phenomenon known as E3 reprogramming) using low molecular weight compounds, which have been termed molecular glues (also called molecular glue degraders), to promote the poly-ubiquitination and ultimately proteasomal degradation of new protein substrates involved in the development of diseases. Molecular glues bind to both the E3 ligase and the target protein. It is believed that the interaction between the molecular glue and the E3 ligase creates a surface that promotes formation of a complex with the target protein, permitting subsequent degradation of the target protein. Examples of molecular glues for the E3 ligase cereblon include: Thalidomide, Lenalidomide and Pomalidomide, all of which are immunomodulatory imide drugs (IMiDs) approved by the FDA for use in hematological cancers.

[0006] The guanine nucleotide exchange factor (GEF) VAV1, a previously ‘undruggable’ protein integral to T / B lymphocyte antigen-receptor signaling, promotes actin polymerization, immunological synapse formation, T cell activation and differentiation, and cytokine production. Preclinical studies have shown that targeted degradation of VAV1 protein modulates both T- and B-cell receptor-mediated activity have shown promising activity in preclinical models of autoimmune diseases such as inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, and dermatological disorders.

[0007] SUMMARY OF THE INVENTION

[0008] In one aspect, this invention relates to a compound of Formula (A), or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an125569-02020

[0009] isotopic form, or a prodrug of said compound of Formula (A) or N-oxide thereof:

[0010] (R3)nn

[0011] 7°

[0012] R4 Li ^2 H

[0013] NVO

[0014] Ro°

[0015] m(R2) I Q2 T(RA),

[0016] k(Ri)

[0017]

[0018] (A), wherein

[0019] Qi is cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged- carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl;

[0020] Q2 is cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged- carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl;

[0021] Z° is absent, a bond, -(CRaRb)P-, -N(RC)-, -O-, -S-, -C(O)-, -S(O2)-, -O(CRaRb)P-, - N(Rc)(CRaRb)p-, -OC(O)-, -C(O)O-, -OSO2-, -S(O2)O-, -C(O)S-, -SC(O)-, -C(O)C(O)-, - C(O)N(Rc)-, -N(Rc)C(O)-, -S(O2)N(RC)-, -N(RC)S(O2)-, -OC(O)O-, -OC(O)S-, - OC(O)N(Rc)-, -N(Rc)C(O)O-, -N(Rc)C(O)S-, -N(Rc)C(O)N(Rc)-, - (CRaRb)pN(Rc)(CRaRb)q-, -(CRaRb)pN(Rc)C(O)(CRaRb)q-, OC(O)N(Rc)(CRaRb)P+iN(Rc)(CRaRb)q-, -(CRaRb)PC(O)N(Rc)(CRaRb)q-, bivalent alkenyl;

[0022] Zi is absent, a bond, -(CRaRb)P-, -N(RC)-, -O-, -S-, -C(O)-, -S(O2)-, -O(CRaRb)P-, - N(Rc)(CRaRb)p-, -OC(O)-, -C(O)O-, -OSO2-, -S(O2)O-, -C(O)S-, -SC(O)-, -C(O)C(O)-, - C(O)N(Rc)-, -N(Rc)C(O)-, -S(O2)N(RC)-, -N(RC)S(O2)-, -OC(O)O-, -OC(O)S-, - OC(O)N(Rc)-, -N(Rc)C(O)O-, -N(Rc)C(O)S-, -N(Rc)C(O)N(Rc)-, - (CRaRb)pN(Rc)(CRaRb)q-, -(CRaRb)pN(Rc)C(O)(CRaRb)q-, OC(O)N(Rc)(CRaRb)P+iN(Rc)(CRaRb)q-, -(CRaRb)PC(O)N(Rc)(CRaRb)q-, bivalent alkenylene;

[0023] Li is absent, a bond, N(Ra), O, S, C(O), S(O2), OC(O), C(O)O, OSO2, S(O2)O, C(O)S, SC(O), C(O)C(O), C(O)N(Ra), N(Ra)C(O), S(O2)N(Ra), N(Ra)S(O2), OC(O)O, OC(O)S, OC(O)N(Ra), N(Ra)C(O)O, N(Ra)C(O)S, N(Ra)C(O)N(Ra), alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiro- heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, in which each of the aforementioned is optionally substituted with one or more Rd

[0024] L2is absent, a bond, N(Ra), O, S, C(O), S(O2), OC(O), C(O)O, OSO2, S(O2)O, C(O)S, SC(O), C(O)C(O), C(O)N(Ra), N(Ra)C(O), S(O2)N(Ra), N(Ra)S(O2), OC(O)O,125569-02020

[0025] OC(O)S, OC(O)N(Ra), N(Ra)C(O)O, N(Ra)C(O)S, N(Ra)C(O)N(Ra), alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, in which each of the aforementioned is optionally substituted with one or more Rd;

[0026] each Ro is independently H, D, halo, cyano, nitro, alkyl, alkenyl, alkynyl, -alkylene-Ra, =CRaRb, =NRb, =0, -C(0)Ra, -C(0)NRbRc, -C(0)0Ra, -NH(CH2)pRa, -NRbRc, -NRbC(0)Rc, -NRbS(O)2Rc, -N=S(O)RbRc, -0Ra, -0C(0)Ra, -0C(0)0Ra, -0P(0)(0Rb)(0Rc), -0P(0)(0Rb)(NHRc), -0P(0)RbRc, -P(0)RbRc, -alkylene-P(O)RbRc, -SRa, -S(O)Ra, -S(O)(NRb)Rc, -S(O)2Ra, -S(O)2NRbRc, -(CRaRb)PRd, -(CRaRb)PN(Rc)(CRaRb)qRd, -(CRaRb)PO(CRaRb)qRd, -(CRaRb)PC(O)(CRaRb)qRd, -(CRaRb)PC(0)0(CRaRb)qRd, -(CRaRb)P0C(0)(CRaRb)qRd, -(CRaRb)P0C(0)0(CRaRb)qRd, -(CRaRb)PN(Rc)C(O)(CRaRb)qRd, -(CRaRb)PC(O)N(Rc)(CRaRb)qRd, -(CRaRb)POC(O)N(Rc)(CRaRb)qRd, -(CRaRb)PN(Rc)C(O)O(CRaRb)qRd, cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, each of the aforementioned is optionally substituted with one or more independently selected Rd substituents;

[0027] each Ri is independently H, D, halo, cyano, nitro, alkyl, alkenyl, alkynyl, -alkylene-Ra, =CRaRb, =NRb, =0, -C(0)Ra, -C(0)NRbRc, -C(0)0Ra, -NH(CH2)pRa, -NRbRc, -NRbC(0)Rc, -NRbS(0)2Rc, -N=S(0)RbRc, -0Ra, -0C(0)Ra, -0C(0)0Ra, -0P(0)(0Rb)(0Rc), -0P(0)(0Rb)(NHRc), -0P(0)RbRc, -P(0)RbRc, -alkylene-P(O)RbRc, -SRa, -S(O)Ra, -S(0)(NRb)Rc, -S(O)2Ra, -S(0)2NRbRc, -(CRaRb)PRd, -(CRaRb)PN(Rc)(CRaRb)qRd, -(CRaRb)P0(CRaRb)qRd, -(CRaRb)PC(O)(CRaRb)qRd, -(CRaRb)PC(0)0(CRaRb)qRd, -(CRaRb)P0C(0)(CRaRb)qRd, -(CRaRb)P0C(0)0(CRaRb)qRd, -(CRaRb)PN(Rc)C(O)(CRaRb)qRd, -(CRaRb)PC(O)N(Rc)(CRaRb)qRd, -(CRaRb)POC(O)N(Rc)(CRaRb)qRd, -(CRaRb)PN(Rc)C(0)0(CRaRb)qRd, cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, each of the aforementioned is optionally substituted with one or more independently selected Rd substituents;

[0028] two Ri, taken together with the atom(s) to which they are attached, independently form a cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, wherein each of the aforementioned is optionally and125569-02020

[0029] independently substituted with one or more independently selected Rd substituent;

[0030] each R2 is independently H, D, halo, cyano, nitro, alkyl, alkenyl, alkynyl, -alkylene-Ra, =CRaRb, =NRb, =0, -C(O)Ra, -C(O)NRbRc, -C(O)ORa, -NH(CH2)pRa, -NRbRc, -NRbC(O)Rc, -NRbS(O)2Rc, -N=S(O)RbRc, -0Ra, -OC(O)Ra, -OC(O)ORa, -OP(O)(ORb)(ORc), -OP(O)(ORb)(NHRc), -OP(O)RbRc, -P(O)RbRc, -alkylene-P(O)RbRc, -SRa, -S(O)Ra, -S(O)(NRb)Rc, -S(O)2Ra, -S(O)2NRbRc, -(CRaRb)PRd, -(CRaRb)PN(Rc)(CRaRb)qRd, -(CRaRb)PO(CRaRb)qRd, -(CRaRb)PC(O)(CRaRb)qRd, -(CRaRb)PC(O)O(CRaRb)qRd, -(CRaRb)POC(O)(CRaRb)qRd, -(CRaRb)POC(O)O(CRaRb)qRd, -(CRaRb)PN(Rc)C(O)(CRaRb)qRd, -(CRaRb)PC(O)N(Rc)(CRaRb)qRd, -(CRaRb)POC(O)N(Rc)(CRaRb)qRd, -(CRaRb)PN(Rc)C(O)O(CRaRb)qRd, cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, each of the aforementioned is optionally substituted with one or more independently selected Rd substituents;

[0031] Ri and R2, taken together with the atom(s) to which they are attached, independently form a cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, wherein each of the aforementioned is optionally and independently substituted with one or more independently selected Rd substituent;

[0032] two R2, taken together with the atom(s) to which they are attached, independently form a cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, wherein each of the aforementioned is optionally and independently substituted with one or more independently selected Rd substituent;

[0033] each R3 is independently H, D, halo, cyano, nitro, alkyl, alkenyl, alkynyl, -alkylene-Ra, =CRaRb, =NRb, =0, -C(0)Ra, -C(0)NRbRc, -C(0)0Ra, -NH(CH2)pRa, -NRbRc, -NRbC(0)Rc, -NRbS(0)2Rc, -N=S(0)RbRc, -0Ra, -0C(0)Ra, -0C(0)0Ra, -0P(0)(0Rb)(0Rc), -0P(0)(0Rb)(NHRc), -0P(0)RbRc, -P(0)RbRc, -alkylene-P(O)RbRc, -SRa, -S(O)Ra, -S(0)(NRb)Rc, -S(O)2Ra, -S(0)2NRbRc, -(CRaRb)PRd, -(CRaRb)PN(Rc)(CRaRb)qRd, -(CRaRb)P0(CRaRb)qRd, -(CRaRb)PC(O)(CRaRb)qRd, -(CRaRb)PC(0)0(CRaRb)qRd, -(CRaRb)P0C(0)(CRaRb)qRd, -(CRaRb)P0C(0)0(CRaRb)qRd, -(CRaRb)PN(Rc)C(O)(CRaRb)qRd, -(CRaRb)PC(O)N(Rc)(CRaRb)qRd, -(CRaRb)POC(O)N(Rc)(CRaRb)qRd, -(CRaRb)PN(Rc)C(0)0(CRaRb)qRd, cycloalkyl,125569-02020

[0034] 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;

[0035] two R3, taken together with the atom(s) to which they are attached, independently form a cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, wherein each of the aforementioned is optionally and independently substituted with one or more independently selected Rd substituent;

[0036] R2 and R3, taken together with the atom(s) to which they are attached, independently form a cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, wherein each of the aforementioned is optionally and independently substituted with one or more independently selected Rd substituent;

[0037] L2 and R3, taken together with the atom(s) to which they are attached, independently form a cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, wherein each of the aforementioned is optionally and independently substituted with one or more independently selected Rd substituent;

[0038] R4 is H, D, halo, cyano, nitro, alkyl, alkenyl, alkynyl, -alkylene-Ra, =CRaRb, =NRb, =0, -C(0)Ra, -C(0)NRbRc, -C(0)0Ra, -NH(CH2)PRa, -NRbRc, -NRbC(0)Rc, -NRbS(0)2Rc, -N=S(0)RbRc, -0Ra, -0C(0)Ra, -0C(0)0Ra, -0P(0)(0Rb)(0Rc), -0P(0)(0Rb)(NHRc), -0P(0)RbRc, -P(0)RbRc, -alkylene-P(O)RbRc, -SRa, -S(O)Ra, -S(0)(NRb)Rc, -S(O)2Ra, -S(0)2NRbRc, -(CRaRb)PRd, -(CRaRb)PN(Rc)(CRaRb)qRd, -(CRaRb)PO(CRaRb)qRd, -(CRaRb)PC(O)(CRaRb)qRd, -(CRaRb)PC(0)0(CRaRb)qRd, -(CRaRb)POC(O)(CRaRb)qRd, -(CRaRb)P0C(0)0(CRaRb)qRd, -(CRaRb)PN(Rc)C(O)(CRaRb)qRd, -(CRaRb)PC(O)N(Rc)(CRaRb)qRd, -(CRaRb)POC(O)N(Rc)(CRaRb)qRd, -(CRaRb)PN(Rc)C(0)0(CRaRb)qRd, cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, each of the aforementioned is optionally substituted with one or more independently selected Rd substituents;125569-02020

[0039] RA is H, D, or F;

[0040] each Rais independently H, D, alkyl, alkenyl, alkynyl, halo, -CF3, cyano, nitro, -OH, -C(O)NHOH, -C(O)NH2, -C(O)OH, -NH2, =CReRf, =NRe, =0, -C(O)Re, -C(O)NReRf, -C(O)ORe, -NH(CH2)pRe, -NReRf, -NReC(0)Rf, -NReS(O)2Rf, -N=S(O)ReRf, -0Re, -OC(O)Re, -OC(O)ORe, -OP(O)(ORe)(ORf), -OP(O)(ORe)(NHRf), -alkylene-P(O)ReRf, -OP(O)ReRf„ -P(O)ReRf, -SRe, -S(O)Re, -S(O)(NRe)Rf, -S(O)2Re, -S(O)2NReRf, N=S(O)ReRf, -S(O)(NRe)Rf, -(CH2)pRf, -(CH2)pN(Re)(CH2)qRf, -(CH2)pO(CH2)qRf, -(CH2)pC(O)(CH2)qRf, -(CH2)pC(O)O(CH2)b,qRf, -(CH2)pOC(O)(CH2)qRf, -(CH2)pOC(O)O(CH2)qRf, -(CH2)pN(Re)C(O)(CH2)qRf, -(CH2)pC(O)N(Re)(CH2)qRf, -(CH2)pOC(O)N(Re)(CH2)qRf, -(CRaRb)pN(Re)C(O)O(CH2)qRf, cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, each of the aforementioned is optionally and independently substituted with one or more independently selected Rgsubstituents;

[0041] each Rb is independently H, D, alkyl, alkenyl, alkynyl, halo, -CF3, cyano, nitro, -OH, -C(0)NH0H, -C(0)NH2, -C(0)0H, -NH2, =CReRf, =NRe, =0, -C(0)Re, -C(O)NReRf, -C(0)0Re, -NH(CH2)pRe, -NReRf, -NReC(0)Rf, -NReS(0)2Rf, -N=S(O)ReRf, -0Re, -0C(0)Re, -0C(0)0Re, -alkylene-P(O)ReRf, -0P(0)(0Re)(0Rf), -OP(O)(ORe)(NHRf), -OP(O)ReRf, -P(O)ReRf, -SRe, -S(O)Re, -S(O)(NRe)Rf, -S(O)2Re, -S(O)2NReRf, N=S(O)ReRf, -S(O)(NRe)Rf, -(CH2)pRf, -(CH2)pN(Re)(CH2)qRf, -(CH2)pO(CH2)qRf, -(CH2)pC(O)(CH2)qRf, -(CH2)pC(O)O(CH2)b,qRf, -(CH2)pOC(O)(CH2)qRf, -(CH2)pOC(O)O(CH2)qRf, -(CH2)pN(Re)C(O)(CH2)qRf, -(CH2)pC(O)N(Re)(CH2)qRf, -(CH2)pOC(O)N(Re)(CH2)qRf, -(CRaRb)pN(Re)C(O)O(CH2)qRf, cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, each of the aforementioned is optionally and independently substituted with one or more independently selected Rgsubstituents;

[0042] Ra and Rb, taken together with the atom(s) to which they are attached, independently form a cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, wherein each of the aforementioned is optionally and independently substituted with one or more125569-02020

[0043] independently selected Rgsubstituent;

[0044] each Rcis independently H, D, alkyl, alkenyl, alkynyl, halo, -CF3, cyano, nitro, -OH, -C(O)NHOH, -C(O)NH2, -C(O)OH, -NH2, =CReRf, =NRe, =0, -C(O)Re, -C(O)NReRf, -C(O)ORe, -NH(CH2)pRe, -NReRf, -NReC(0)Rf, -NReS(O)2Rf, -N=S(O)ReRf, -0Re, -OC(O)Re, -OC(O)ORe, -alkylene-P(O)ReRf, -OP(O)(ORe)(ORf), -OP(O)(ORe)(NHRf), -OP(O)ReRf, -P(O)ReRf, -SRe, -S(O)Re, -S(O)(NRe)Rf, -S(O)2Re, -S(O)2NReRf, N=S(O)ReRf, -S(O)(NRe)Rf, -(CH2)pRf, -(CH2)pN(Re)(CH2)qRf, -(CH2)pO(CH2)qRf, -(CH2)pC(O)(CH2)qRf, -(CH2)pC(O)O(CH2)qRf, -(CH2)pOC(O)(CH2)qRf, -(CH2)pOC(O)O(CH2)qRf, -(CH2)pN(Re)C(O)(CH2)qRf, -(CH2)pC(O)N(Re)(CH2)qRf, -(CH2)pOC(O)N(Re)(CH2)qRf, -(CRaRb)pN(Re)C(O)O(CH2)qRf, cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, each of the aforementioned is optionally and independently substituted with one or more independently selected Rgsubstituents;

[0045] Rb and Rc, taken together with the atom(s) to which they are attached, independently form a cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, wherein each of the aforementioned is optionally and independently substituted with one or more independently selected Rgsubstituent;

[0046] each Rd is independently H, D, alkyl, alkenyl, alkynyl, halo, -CF3, cyano, nitro, -OH, -C(0)NH0H, -C(0)NH2, -C(0)0H, -NH2, =CReRf, =NRe, =0, -C(0)Re, -C(O)NReRf, -C(0)0Re, -NH(CH2)pRe, -NReRf, -NReC(0)Rf, -NReS(0)2Rf, -N=S(O)ReRf, -0Re, -0C(0)Re, -0C(0)0Re, -alkylene-P(O)ReRf, -0P(0)(0Re)(0Rf), -OP(O)(ORe)(NHRf), -OP(O)ReRf„ -P(O)ReRf, -SRe, -S(O)Re, -S(O)(NRe)Rf, -S(O)2Re, -S(O)2NReRf, N=S(O)ReRf, -S(O)(NRe)Rf, -(CH2)pRf, -(CH2)pN(Re)(CH2)qRf, -(CH2)pO(CH2)qRf, -(CH2)pC(O)(CH2)qRf, -(CH2)pC(O)O(CH2)b,qRf, -(CH2)pOC(O)(CH2)qRf, -(CH2)pOC(O)O(CH2)qRf, -(CH2)pN(Re)C(O)(CH2)qRf, -(CH2)pC(O)N(Re)(CH2)qRf, -(CH2)pOC(O)N(Re)(CH2)qRf, -(CRaRb)pN(Re)C(O)O(CH2)qRf, cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, each of the aforementioned is optionally and independently substituted with one or more125569-02020

[0047] independently selected Rgsubstituents;

[0048] two Rd, taken together with the atom(s) to which they are attached, independently form a cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, wherein each of the aforementioned is optionally and independently substituted with one or more independently selected Rgsubstituent;

[0049] each Reis independently H, D, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxy alkyloxy, alkoxyalkyloxyalkyl, alkylidenyl, alkoxyalkylidenyl, alkylthio, alkylsulfonyl, cyanoalkyl, cyanoalkenyl, cyanoalkynyl, alkylamino, dialkylamino, aminocarbonyl, alkoxycarbonyl, alkylcarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, halo, haloalkyl, haloalkylidenyl, hydroxyalkyl, haloalkoxy, heteroalkyl, hydroxyalkyl, oxoalkyl, -NH2, -OH, -CF3, -Cyano, -Nitro, =CH2, =NH, =0, -C(O)NH2, -C(O)NHOH, -C(O)OH, -C(O)ORg-, -OC(O)Rg-, -OP(O)(OH)(OH), -P(O)(OH)(OH), aralkyl, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkyloxyalkyl, cycloalkylalkyloxyalkyloxy, cycloalkylalkyloxyalkyl, heteroaralkyl, heterocyclylalkyl, heterocyclyloxy, heterocyclyloxyalkyl, heterocyclylalkyloxy, heterocyclylalkyloxyalkyl, cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, each of the aforementioned is optionally and independently substituted with one or more independently selected Rgsubstituents;

[0050] two Re, taken together with the atom(s) to which they are attached, independently form a cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, wherein each of the aforementioned is optionally and independently substituted with one or more independently selected Rgsubstituent;

[0051] each Rf is independently H, D, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxy alkyloxy, alkoxyalkyloxyalkyl, alkylidenyl, alkoxyalkylidenyl, alkylthio, alkylsulfonyl, cyanoalkyl, cyanoalkenyl, cyanoalkynyl, alkylamino, dialkylamino, aminocarbonyl, alkoxycarbonyl, alkylcarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, halo, haloalkyl, haloalkylidenyl, hydroxyalkyl, haloalkoxy, heteroalkyl, hydroxyalkyl, oxoalkyl, -NH2, -OH, -C(0)0Rg-, -0C(0)Rg-,-CF3, -Cyano, -125569-02020

[0052] Nitro, =CH2, =NH, =0, -C(O)NH2, -C(O)NHOH, -C(O)OH,-OP(O)(OH)(OH), -P(O)(OH)(OH), aralkyl, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkyloxyalkyl, cycloalkylalkyloxyalkyloxy, cycloalkylalkyloxyalkyl, heteroaralkyl, heterocyclylalkyl, heterocyclyloxy, heterocyclyloxyalkyl, heterocyclylalkyloxy, heterocyclylalkyloxyalkyl, cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, each of the aforementioned is optionally and independently substituted with one or more independently selected Rgsubstituents;

[0053] two Rf, taken together with the atom(s) to which they are attached, independently form a cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, wherein each of the aforementioned is optionally and independently substituted with one or more independently selected Rgsubstituent;

[0054] each Rgis independently H, D, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxy alkyloxy, alkoxyalkyloxyalkyl, alkylidenyl, alkoxyalkylidenyl, alkylthio, alkylsulfonyl, cyanoalkyl, cyanoalkenyl, cyanoalkynyl, alkylamino, dialkylamino, aminocarbonyl, alkoxycarbonyl, alkylcarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, halo, haloalkyl, haloalkylidenyl, hydroxyalkyl, haloalkoxy, heteroalkyl, hydroxyalkyl, oxoalkyl, -NH2, -OH, -CF3, -Cyano, -Nitro, =CH2, =NH, =0, -C(O)NH2, -C(O)NHOH, -C(O)OH,-OP(O)(OH)(OH), -P(O)(OH)(OH), aralkyl, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkyloxyalkyl, cycloalkylalkyloxyalkyloxy, cycloalkylalkyloxyalkyl, heteroaralkyl, heterocyclylalkyl, heterocyclyloxy, heterocyclyloxyalkyl, heterocyclylalkyloxy, heterocyclylalkyloxyalkyl, cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, each of the aforementioned is optionally and independently substituted with one or more independently selected Rh substituents;

[0055] each Rh is independently H, D, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxy alkyloxy, alkoxyalkyloxyalkyl, alkylidenyl, alkoxyalkylidenyl, alkylthio, alkylsulfonyl, cyanoalkyl, cyanoalkenyl, cyanoalkynyl, alkylamino, dialkylamino, aminocarbonyl, alkoxycarbonyl, alkylcarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, alkylaminocarbonylalkyl,125569-02020

[0056] dialkylaminocarbonylalkyl, halo, haloalkyl, haloalkylidenyl, hydroxyalkyl, haloalkoxy, heteroalkyl, hydroxyalkyl, oxoalkyl, -NH2, -OH, -CF3, -Cyano, -Nitro, =CH2, =NH, =O, -C(O)NH2, -C(O)NHOH, -C(O)OH,-OP(O)(OH)(OH), -P(O)(OH)(OH), aralkyl, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkyloxyalkyl, cycloalkylalkyloxyalkyloxy, cycloalkylalkyloxyalkyl, heteroaralkyl, heterocyclylalkyl, heterocyclyloxy, heterocyclyloxyalkyl, heterocyclylalkyloxy, heterocyclylalkyloxyalkyl, cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl;

[0057] j is 0, 1, 2, 3, 4, 5, or 6;

[0058] k is 0, 1, 2, 3, 4, 5, or 6;

[0059] m is 0, 1, 2, 3, 4, 5, or 6;

[0060] n is 0, 1, 2, 3, 4, 5, or 6;

[0061] p is 0, 1, 2, 3, 4, 5, or 6;

[0062] q is 0, 1, 2, 3, 4, 5, or 6; and

[0063] r is 0, 1, 2, 3, 4, 5, or 6.

[0064] In a further embodiment, the compound is represented by Formula (B):

[0065] (R3)n

[0066]

[0067] wherein

[0068] Q2 is heterocycloalkyl, aryl, or heteroaryl.

[0069] In a further embodiment, the compound is represented by Formula (C):

[0070]

[0071] wherein

[0072] A is C(RaRb), N(Rc), O, or S.

[0073] In a further embodiment, the compound is represented by Formula (D):125569-02020

[0074]

[0075] wherein

[0076] s is 0, 1, 2, 3, 4, 5, or 6.

[0077] In a further embodiment, the compound is represented by Formula (E):

[0078]

[0079] wherein

[0080] Q3 is a cycloalkyl, heterocycloalkyl, or heteroaryl; and t is 0, 1, 2, 3, 4, 5, or 6.

[0081] In a further embodiment, the compound is represented by Formula (F):

[0082]

[0083] wherein

[0084] Q3 is a cycloalkyl.

[0085] In a further embodiment, the compound is represented by Formula (G):

[0086]

[0087] wherein

[0088] Q3 is a heteroaryl.

[0089] In a further embodiment, the compound is represented by Formula (M):125569-02020

[0090]

[0091] In a further embodiment, the compound is represented by Formula (N):

[0092]

[0093] wherein

[0094] w is 0, 1, 2, 3, 4, 5, or 6.

[0095] In a further embodiment, the compound is represented by Formula (O):

[0096]

[0097] wherein

[0098] x is 0, 1, 2, 3, 4, 5, or 6.

[0099] In a further embodiment, the compound is represented by Formula (P):

[0100]

[0101] wherein

[0102] wl is 0, 1, 2, 3, 4, 5, or 6; and x is 0, 1, 2, 3, 4, 5, or 6.

[0103] In a further embodiment, the compound is represented by Formula (Q):

[0104]

[0105] In a further embodiment, the compound is represented by Formula (R):125569-02020

[0106]

[0107] wherein

[0108] Q3 is a cycloalkyl, heterocycloalkyl, or heteroaryl; and

[0109] t is 0, 1, 2, 3, 4, 5, or 6.

[0110] In a further embodiment, the compound is represented by Formula (S):

[0111]

[0112] Compounds of the invention may contain one or more asymmetric carbon atoms.

[0113] 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.

[0114] 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.

[0115] 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.

[0116] 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 / disorder.

[0117] This invention also relates to a method of treating a neoplastic disease, particularly the B-cell malignancy including but not limited to B-cell lymphoma, lymphoma (including Hodgkin's and non-Hodgkin's lymphoma), hairy cell lymphoma, small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL), multiple125569-02020

[0118] myeloma, chronic and acute myelogenous leukemia and chronic and acute lymphocytic leukemia, 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.

[0119] 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.

[0120] 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 / features of the invention (compounds, pharmaceutical compositions, methods of make / 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.

[0121] DETAILED DESCRIPTION OF THE INVENTION

[0122] 3-(2-chloro-3-((S)-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrido[l,2-a]quinolin-8-yl)phenyl)piperidine-2, 6-dione,

[0123] 3-(2-chloro-3-((R)-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrido[l,2-a]quinolin-8-yl)phenyl)piperidine-2, 6-dione,

[0124] 3-(2-chloro-3-((S)-6,6-difluoro-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrido[l,2-a]quinolin-8-yl)phenyl)piperidine-2, 6-dione,

[0125] 3-(2-chloro-3-((R)-6,6-difluoro-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrido[l,2-a]quinolin-8-yl)phenyl)piperidine-2, 6-dione,125569-02020

[0126] 3-(2-chloro-3-((S)-5,5-difluoro-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrido[l,2-a]quinolin-8-yl)phenyl)piperidine-2, 6-dione,

[0127] 3-(2-chloro-3-((R)-5,5-difluoro-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrido[l,2-a]quinolin-8-yl)phenyl)piperidine-2, 6-dione,

[0128] 5-(2-chloro-3-((S)-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrido[l,2-a]quinolin-8-yl)phenyl)- 3,3-difluoropiperidine-2,6-dione,

[0129] 5-(2-chloro-3-((R)-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrido[l,2-a]quinolin-8-yl)phenyl)-3,3-difluoropiperidine-2, 6-dione,

[0130] 3-(2-chloro-3-((S)-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrido[l,2-a]quinolin-8-yl)phenyl)- 4.4-difluoropiperidine-2, 6-dione,

[0131] 3-(2-chloro-3-((R)-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrido[l,2-a]quinolin-8-yl)phenyl)-4,4-difluoropiperidine-2, 6-dione,

[0132] (R)-3-(2-chloro-3-((S)-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrido[l,2-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0133] (S)-3-(2-chloro-3-((S)-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrido[l,2-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0134] (R)-3-(2-chloro-3-((R)-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrido[l,2-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0135] (S)-3-(2-chloro-3-((R)-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrido[l,2-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0136] (S)-3-(2-chloro-3-((S)-l-oxo-2-(propan-2-ylidene)-2,3,4,4a,5,6-hexahydro-lH-pyrido[l,2-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2, 6-dione,125569-02020

[0137] (S)-3-(2-chloro-3-((S, E)-2-ethylidene-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrido[l,2-a] quinolin-8-yl)phenyl)-3-fluoropiperidine-2,6-dione,

[0138] (S)-3-(2-chloro-3-((S, Z)-2-(l-fluoroethylidene)-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrido[l,2-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0139] (S)-3-(2-chloro-3-((S, E)-2-(l-fluoroethylidene)-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrido[l,2-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0140] (S)-3-(2-chloro-3-((R)-2,2-difluoro-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrido[l,2-a] quinolin-8-yl)phenyl)-3-fluoropiperidine-2,6-dione,

[0141] (S)-3-(2-chloro-3-((6aR,7aS,8aS)-9-oxo-5,6,6a,7,7a,8,8a,9-octahydrocyclopropa[4,5]pyrido[l,2-a]quinolin-3-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0142] (S)-3-(2-chloro-3-((R)-8-methyl-ll-oxo-5,6,6a,7,8,ll-hexahydropyrazolo[3',4':4,5]pyrido[l,2-a]quinolin-3-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0143] (S)-3-(2-chloro-3-((S, E)-2-ethylidene-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrido[l,2-a] quinolin-8-yl)phenyl)-3-fluoropiperidine-2,6-dione-4,4,5,5-d4,

[0144] (S)-3-(2-chloro-3-((6aR,7aS,8aS)-9-oxo-5,6,6a,7,7a,8,8a,9-octahydrocyclopropa[4,5]pyrido[l,2-a]quinolin-3-yl)phenyl)-3-fluoropiperidine-2, 6-dione-4,4,5,5-d4,

[0145] (S)-3-(2-chloro-3-((R)-8-methyl-ll-oxo-5,6,6a,7,8,ll-hexahydropyrazolo[3',4':4,5]pyrido[l,2-a]quinolin-3-yl)phenyl)-3-fluoropiperidine-2, 6-dione-4,4,5,5-d4,

[0146] (S)-3-(2-chloro-3-((4aR,5aS)- 1-oxo- 1,2, 3, 4,5a, 6-hexahydro-5H-cyclopropa[b]pyrido[l,2-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0147] (S)-3-(2-chloro-3-((4aR,5aR)-l-oxo-l,2,3,4,5a,6-hexahydro-5H-cyclopropa[b]pyrido[l,2-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2, 6-dione,125569-02020

[0148] (S)-3-(2-chloro-3-((4aS,5aR)- 1-oxo- 1,2, 3, 4,5a, 6-hexahydro-5H-cyclopropa[b]pyrido[l,2-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0149] (S)-3-(2-chloro-3-((4aS,5aS)-l-oxo-l,2,3,4,5a,6-hexahydro-5H-cyclopropa[b]pyrido[l,2-a] quinolin-8-yl)phenyl)-3-fluoropiperidine-2,6-dione,

[0150] (S)-3-(2-chloro-3-((laS,2aS,3aS,10aS)-10-oxo-la,2,3a,4,10,10a-hexahydro-lH,3H-cyclopropa[4,5]pyrido[l,2-a]cyclopropa[b]quinolin-6-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0151] (S)-3-(2-chloro-3-((laR,2aS,3aS,10aR)-10-oxo-la,2,3a,4,10,10a-hexahydro-lH,3H-cyclopropa[4,5]pyrido[l,2-a]cyclopropa[b]quinolin-6-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0152] (S)-3-(2-chloro-3-((laS,2aS,3aR,10aS)-10-oxo-la,2,3a,4,10,10a-hexahydro-lH,3H-cyclopropa[4,5]pyrido[l,2-a]cyclopropa[b]quinolin-6-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0153] (S)-3-(2-chloro-3-((laR,2aS,3aR,10aR)-10-oxo-la,2,3a,4,10,10a-hexahydro-lH,3H-cyclopropa[4,5]pyrido[l,2-a]cyclopropa[b]quinolin-6-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0154] (S)-3-(2-chloro-3-((4aR,5aS, E)-2-ethylidene-l-oxo-l,2,3,4,5a,6-hexahydro-5H-cyclopropa[b]pyrido[l,2-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0155] (S)-3-(2-chloro-3-((4aR,5aR, E)-2-ethylidene-l-oxo-l,2,3,4,5a,6-hexahydro-5H-cyclopropa[b]pyrido[l,2-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0156] (S)-3-(2-chloro-3-((4aR,5aS, Z)-2-(l-fluoroethylidene)-l-oxo-l,2,3,4,5a,6-hexahydro-5H-cyclopropa[b]pyrido[l,2-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0157] (S)-3-(2-chloro-3-((4aR,5aR, Z)-2-(l-fluoroethylidene)-l-oxo-l,2,3,4,5a,6-hexahydro-5H-cyclopropa[b]pyrido[l,2-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0158] (S)-3-(2-chloro-3-((4aR,5aS, E)-2-(l-fluoroethylidene)-l-oxo-l,2,3,4,5a,6-hexahydro- 5H-cyclopropa[b]pyrido[l,2-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2, 6-dione,125569-02020

[0159] (S)-3-(2-chloro-3-((4aR,5aR, E)-2-(l-fluoroethylidene)-l-oxo-l,2,3,4,5a,6-hexahydro-5H-cyclopropa[b]pyrido[l,2-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0160] (S)-3-(2-chloro-3-((4aR,5aS)-2,2-difluoro-l-oxo-l,2,3,4,5a,6-hexahydro-5H-cyclopropa[b]pyrido[l,2-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0161] (S)-3-(2-chloro-3-((4aS,5aR)-2,2-difluoro- 1-oxo- 1,2, 3, 4,5a, 6-hexahydro-5H-cyclopropa[b]pyrido[l,2-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0162] (S)-3-(2-chloro-3-((laR,2aS,3aS,10aR)-10-oxo-la,2,3a,4,10,10a-hexahydro-lH,3H-cyclopropa[4,5]pyrido[l,2-a]cyclopropa[b]quinolin-6-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0163] (S)-3-(2-chloro-3-((laS,2aS,3aS,10aS)-10-oxo-la,2,3a,4,10,10a-hexahydro-lH,3H-cyclopropa[4,5]pyrido[l,2-a]cyclopropa[b]quinolin-6-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0164] (S)-3-(2-chloro-3-((laR,2aR,3aR,10aR)-10-oxo-la,2,3a,4,10,10a-hexahydro-lH,3H-cyclopropa[4,5]pyrido[l,2-a]cyclopropa[b]quinolin-6-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0165] (S)-3-(2-chloro-3-((laS,2aR,3aR,10aS)-10-oxo-la,2,3a,4,10,10a-hexahydro-lH,3H-cyclopropa[4,5]pyrido[l,2-a]cyclopropa[b]quinolin-6-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0166] (S)-3-(2-chloro-3-((4aS,5aS)-3-methyl-12-oxo-4,5a,6,12-tetrahydro-3H,5H-cyclopropa[b]pyrazolo[3',4':4,5]pyrido[l,2-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2,6-dione,

[0167] (S)-3-(2-chloro-3-((4aR,5aR)-3-methyl-12-oxo-4,5a,6,12-tetrahydro-3H,5H-cyclopropa[b]pyrazolo[3',4':4,5]pyrido[l,2-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2,6-dione,

[0168] (S)-3-(2-chloro-3-((4aS,5aS)-2-methyl-12-oxo-2,5a,6,12-tetrahydro-4H,5H-cyclopropa[b]pyrazolo[3',4':4,5]pyrido[l,2-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2,6-dione,125569-02020

[0169] (S)-3-(2-chloro-3-((4aS,5aS)-2-isopropyl-12-oxo-2,5a,6,12-tetrahydro-4H,5H-cyclopropa[b]pyrazolo[3',4':4,5]pyrido[l,2-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2,6-dione,

[0170] (S)-3-(2-chloro-3-((4aR,5aR)-2-methyl-12-oxo-2,5a,6,12-tetrahydro-4H,5H-cyclopropa[b]pyrazolo[3',4':4,5]pyrido[l,2-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2,6-dione,

[0171] (S)-3-(2-chloro-3-((5aS,6aS)-13-oxo-5,6a,7,13-tetrahydro-6H-cyclopropa[b]pyrimido[4',5':4,5]pyrido[l,2-a]quinolin-9-yl)phenyl)-3-fluoropiperidine-2,6-dione,

[0172] (S)-3-(2-chloro-3-((5aR,6aR)-13-oxo-5,6a,7,13-tetrahydro-6H-cyclopropa[b]pyrimido[4',5':4,5]pyrido[l,2-a]quinolin-9-yl)phenyl)-3-fluoropiperidine-2,6-dione,

[0173] (5aS,6aS)-9-(2-chloro-3-((S)-3-fluoro-2,6-dioxopiperidin-3-yl)phenyl)-4-methyl-6a,7-dihydro-6H-cyclopropa[2,3]quinolino[l,2-g][l,6]naphthyridine-3,13(4H,5H)-dione,

[0174] (5aR,6aR)-9-(2-chloro-3-((S)-3-fluoro-2,6-dioxopiperidin-3-yl)phenyl)-4-methyl-6a,7-dihydro-6H-cyclopropa[2,3]quinolino[l,2-g][l,6]naphthyridine-3,13(4H,5H)-dione,

[0175] (S)-3-(2-chloro-3-((4aS,5aS)-12-oxo-5a,6-dihydro-4H,5H,12H-cyclopropa[b]isoxazolo[3',4':4,5]pyrido[l,2-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2,6-dione,

[0176] (S)-3-(2-chloro-3-((4aR,5aR)-12-oxo-5a,6-dihydro-4H,5H,12H-cyclopropa[b]isoxazolo[3',4':4,5]pyrido[l,2-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2,6-dione,

[0177] (S)-3-(2-chloro-3-((4aS,5aS)-3-methyl-12-oxo-4,5a,6,12-tetrahydro-3H,5H-cyclopropa[b]pyrazolo[3',4':4,5]pyrido[l,2-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2,6-dione,125569-02020

[0178] (S)-3-(2-chloro-3-((4aS,5aR)-3-methyl-12-oxo-4,5a,6,12-tetrahydro-3H,5H-cyclopropa[b]pyrazolo[3',4':4,5]pyrido[l,2-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2,6-dione,

[0179] (S)-3-(2-chloro-3-((4aS,5aS)-3-isopropyl-12-oxo-4,5a,6,12-tetrahydro-3H,5H-cyclopropa[b]pyrazolo[3',4':4,5]pyrido[l,2-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2,6-dione,

[0180] (S)-3-(2-chloro-3-((4aS,5aR)-3-isopropyl-12-oxo-4,5a,6,12-tetrahydro-3H,5H-cyclopropa[b]pyrazolo[3',4':4,5]pyrido[l,2-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2,6-dione,

[0181] (S)-3-(2-chloro-3-((4aS,5aS)-12-oxo-4,5a,6,12-tetrahydro-5H-cyclopropa[b]isoxazolo[5',4':4,5]pyrido[l,2-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2,6-dione,

[0182] (S)-3-(2-chloro-3-((4aS,5aR)-12-oxo-4,5a,6,12-tetrahydro-5H-cyclopropa[b]isoxazolo[5',4':4,5]pyrido[l,2-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2,6-dione,

[0183] (S)-3-(2-chloro-3-((4aS,5aS)-12-oxo-4,5a,6,12-tetrahydro-5H-cyclopropa[b]isothiazolo[5',4':4,5]pyrido[l,2-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2,6-dione,

[0184] (S)-3-(2-chloro-3-((4aS,5aR)-12-oxo-4,5a,6,12-tetrahydro-5H-cyclopropa[b]isothiazolo[5',4':4,5]pyrido[l,2-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2,6-dione,

[0185] (S)-3-(2-chloro-3-((4aR,5aS)-l-oxo-l,2,3,4,5a,6-hexahydro-5H-cyclopropa[b]pyrido[l,2-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2,6-dione-4,4-d2,

[0186] (S)-3-(2-chloro-3-((4aS,5aR)-l-oxo-l,2,3,4,5a,6-hexahydro-5H-cyclopropa[b]pyrido[l,2-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2,6-dione-4,4-d2,125569-02020

[0187] (S)-3-(2-chloro-3-((4aR,5aS)-2,2-difluoro-l-oxo-l,2,3,4,5a,6-hexahydro-5H-cyclopropa[b]pyrido[l,2-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2,6-dione-4,4-d2,

[0188] (S)-3-(2-chloro-3-((4aS,5aR)-2,2-difluoro-l-oxo-l,2,3,4,5a,6-hexahydro-5H-cyclopropa[b]pyrido[l,2-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2,6-dione-4,4-d2,

[0189] (S)-3-(2-chloro-3-((laR,2aS,3aS,10aR)-10-oxo-la,2,3a,4,10,10a-hexahydro-lH,3H-cyclopropa[4,5]pyrido[l,2-a]cyclopropa[b]quinolin-6-yl)phenyl)-3-fluoropiperidine-2, 6-dione- 4,4-d2,

[0190] (S)-3-(2-chloro-3-((laS,2aS,3aS,10aS)-10-oxo-la,2,3a,4,10,10a-hexahydro-lH,3H-cyclopropa[4,5]pyrido[l,2-a]cyclopropa[b]quinolin-6-yl)phenyl)-3-fluoropiperidine-2, 6-dione- 4,4-d2,

[0191] (S)-3-(2-chloro-3-((laR,2aR,3aR,10aR)-10-oxo-la,2,3a,4,10,10a-hexahydro-lH,3H-cyclopropa[4,5]pyrido[l,2-a]cyclopropa[b]quinolin-6-yl)phenyl)-3-fluoropiperidine-2, 6-dione- 4,4-d2,

[0192] (S)-3-(2-chloro-3-((laS,2aR,3aR,10aS)-10-oxo-la,2,3a,4,10,10a-hexahydro-lH,3H-cyclopropa[4,5]pyrido[l,2-a]cyclopropa[b]quinolin-6-yl)phenyl)-3-fluoropiperidine-2, 6-dione- 4,4-d2,

[0193] (S)-3-(2-chloro-3-((4aS,5aS)-3-methyl-12-oxo-4,5a,6,12-tetrahydro-3H,5H-cyclopropa[b]pyrazolo[3',4':4,5]pyrido[l,2-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2,6-dione-4,4-d2,

[0194] (S)-3-(2-chloro-3-((4aR,5aR)-3-methyl-12-oxo-4,5a,6,12-tetrahydro-3H,5H-cyclopropa[b]pyrazolo[3',4':4,5]pyrido[l,2-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2,6-dione-4,4-d2,

[0195] (S)-3-(2-chloro-3-((4aS,5aS)-2-methyl-12-oxo-2,5a,6,12-tetrahydro-4H,5H-cyclopropa[b]pyrazolo[3',4':4,5]pyrido[l,2-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2,6-dione-4,4-d2,125569-02020

[0196] (S)-3-(2-chloro-3-((4aS,5aS)-2-(methyl-d3)-12-oxo-2,5a,6,12-tetrahydro-4H,5H-cyclopropa[b]pyrazolo[3',4':4,5]pyrido[l,2-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2,6-dione-4,4-d2,

[0197] (S)-3-(2-chloro-3-((4aS,5aS)-2-isopropyl-12-oxo-2,5a,6,12-tetrahydro-4H,5H-cyclopropa[b]pyrazolo[3',4':4,5]pyrido[l,2-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2,6-dione-4,4-d2,

[0198] (S)-3-(2-chloro-3-((4aR,5aR)-2-methyl-12-oxo-2,5a,6,12-tetrahydro-4H,5H-cyclopropa[b]pyrazolo[3',4':4,5]pyrido[l,2-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2,6-dione-4,4-d2,

[0199] (S)-3-(2-chloro-3-((5aS,6aS)-13-oxo-5,6a,7,13-tetrahydro-6H-cyclopropa[b]pyrimido[4',5':4,5]pyrido[l,2-a]quinolin-9-yl)phenyl)-3-fluoropiperidine-2,6-dione-4,4-d2,

[0200] (S)-3-(2-chloro-3-((5aR,6aR)-13-oxo-5,6a,7,13-tetrahydro-6H-cyclopropa[b]pyrimido[4',5':4,5]pyrido[l,2-a]quinolin-9-yl)phenyl)-3-fluoropiperidine-2,6-dione-4,4-d2,

[0201] (5aS,6aS)-9-(2-chloro-3-((S)-3-fluoro-2,6-dioxopiperidin-3-yl-4,4-d2)phenyl)-4-methyl-6a, 7 -dihydro-6H-cyclopropa[2,3 ] quinolino [ 1,2-g] [ 1,6] naphthyridine-3, 13 (4H,5H)-dione,

[0202] (5aR,6aR)-9-(2-chloro-3-((S)-3-fluoro-2,6-dioxopiperidin-3-yl-4,4-d2)phenyl)-4-methyl-6a, 7 -dihydro-6H-cyclopropa[2,3 ] quinolino [ 1,2-g] [ 1,6] naphthyridine-3, 13 (4H,5H)-dione,

[0203] (S)-3-(2-chloro-3-((4aS,5aS)-12-oxo-5a,6-dihydro-4H,5H,12H-cyclopropa[b]isoxazolo[3',4':4,5]pyrido[l,2-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2,6-dione-4,4-d2,

[0204] (S)-3-(2-chloro-3-((4aR,5aR)-12-oxo-5a,6-dihydro-4H,5H,12H-cyclopropa[b]isoxazolo[3',4':4,5]pyrido[l,2-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2,6-dione-4,4-d2,125569-02020

[0205] 3-(2-chloro-3-((4aR,5aS)-l-oxo-l,2,3,4,5a,6-hexahydro-5H-cyclopropa[b]pyrido[l,2-a] quinolin-8-yl)phenyl)-3-fluoropiperidine-2,6-dione-4,4,5,5-d4,

[0206] 3-(2-chloro-3-((4aS,5aR)-l-oxo-l,2,3,4,5a,6-hexahydro-5H-cyclopropa[b]pyrido[l,2-a] quinolin-8-yl)phenyl)-3-fluoropiperidine-2,6-dione-4,4,5,5-d4,

[0207] 3-(2-chloro-3-((4aR,5aS)-2,2-difluoro-l-oxo-l,2,3,4,5a,6-hexahydro-5H-cyclopropa[b]pyrido[l,2-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2,6-dione-4,4,5,5-d4,

[0208] 3-(2-chloro-3-((4aS,5aR)-2,2-difluoro-l-oxo-l,2,3,4,5a,6-hexahydro-5H-cyclopropa[b]pyrido[l,2-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2,6-dione-4,4,5,5-d4,

[0209] 3-(2-chloro-3-((laR,2aS,3aS,10aR)-10-oxo-la,2,3a,4,10,10a-hexahydro-lH,3H-cyclopropa[4,5]pyrido[l,2-a]cyclopropa[b]quinolin-6-yl)phenyl)-3-fluoropiperidine-2, 6-dione- 4,4,5,5-d4,

[0210] 3-(2-chloro-3-((laS,2aS,3aS,10aS)-10-oxo-la,2,3a,4,10,10a-hexahydro-lH,3H-cyclopropa[4,5]pyrido[l,2-a]cyclopropa[b]quinolin-6-yl)phenyl)-3-fluoropiperidine-2, 6-dione- 4,4,5,5-d4,

[0211] 3-(2-chloro-3-((laR,2aR,3aR,10aR)-10-oxo-la,2,3a,4,10,10a-hexahydro-lH,3H-cyclopropa[4,5]pyrido[l,2-a]cyclopropa[b]quinolin-6-yl)phenyl)-3-fluoropiperidine-2, 6-dione- 4,4,5,5-d4,

[0212] 3-(2-chloro-3-((laS,2aR,3aR,10aS)-10-oxo-la,2,3a,4,10,10a-hexahydro-lH,3H-cyclopropa[4,5]pyrido[l,2-a]cyclopropa[b]quinolin-6-yl)phenyl)-3-fluoropiperidine-2, 6-dione- 4,4,5,5-d4,

[0213] 3-(2-chloro-3-((4aS,5aS)-3-methyl-12-oxo-4,5a,6,12-tetrahydro-3H,5H-cyclopropa[b]pyrazolo[3',4':4,5]pyrido[l,2-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2,6-dione-4,4,5,5-d4,125569-02020

[0214] 3-(2-chloro-3-((4aR,5aR)-3-methyl-12-oxo-4,5a,6,12-tetrahydro-3H,5H-cyclopropa[b]pyrazolo[3',4':4,5]pyrido[l,2-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2,6-dione-4,4,5,5-d4,

[0215] 3-(2-chloro-3-((4aS,5aS)-2-methyl-12-oxo-2,5a,6,12-tetrahydro-4H,5H-cyclopropa[b]pyrazolo[3',4':4,5]pyrido[l,2-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2,6-dione-4,4,5,5-d4,

[0216] 3-(2-chloro-3-((4aR,5aR)-2-methyl- 12-oxo-2, 5a, 6, 12-tetrahydro-4H, 5H-cyclopropa[b]pyrazolo[3',4':4,5]pyrido[l,2-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2,6-dione-4,4,5,5-d4,

[0217] (S)-3-(2-chloro-3-((5aS,6aS)-13-oxo-5,6a,7,13-tetrahydro-6H-cyclopropa[b]pyrimido[4',5':4,5]pyrido[l,2-a]quinolin-9-yl)phenyl)-3-fluoropiperidine-2,6-dione-4,4,5,5-d4,

[0218] (S)-3-(2-chloro-3-((5aR,6aR)-13-oxo-5,6a,7,13-tetrahydro-6H-cyclopropa[b]pyrimido[4',5':4,5]pyrido[l,2-a]quinolin-9-yl)phenyl)-3-fluoropiperidine-2,6-dione-4,4,5,5-d4,

[0219] (5aS,6aS)-9-(2-chloro-3-((S)-3-fluoro-2,6-dioxopiperidin-3-yl-4,4,5,5-d4)phenyl)-4-methyl-6a,7-dihydro-6H-cyclopropa[2,3]quinolino[l,2-g][l,6]naphthyridine-3,13(4H,5H)-dione,

[0220] (5aR,6aR)-9-(2-chloro-3-((S)-3-fluoro-2,6-dioxopiperidin-3-yl-4,4,5,5-d4)phenyl)-4-methyl-6a,7-dihydro-6H-cyclopropa[2,3]quinolino[l,2-g][l,6]naphthyridine-3,13(4H,5H)-dione,

[0221] (S)-3-(2-chloro-3-((4aS,5aS)-12-oxo-5a,6-dihydro-4H,5H,12H-cyclopropa[b]isoxazolo[3',4':4,5]pyrido[l,2-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2,6-dione-4,4,5,5-d4,

[0222] (S)-3-(2-chloro-3-((4aR,5aR)-12-oxo-5a,6-dihydro-4H,5H,12H-cyclopropa[b]isoxazolo[3',4':4,5]pyrido[l,2-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2,6-dione-4,4,5,5-d4,125569-02020

[0223] (S)-3-(2-chloro-3-((4aR,6aR)-l-oxo-l,2,3,4,5,6,6a,7-octahydrocyclobuta[b]pyrido[l,2-a]quinolin-9-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0224] (S)-3-(2-chloro-3-((4aR,6aS)-l-oxo-l,2,3,4,5,6,6a,7-octahydrocyclobuta[b]pyrido[l,2-a]quinolin-9-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0225] (S)-3-(2-chloro-3-((4aS,6aS)-l-oxo-l,2,3,4,5,6,6a,7-octahydrocyclobuta[b]pyrido[l,2-a]quinolin-9-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0226] (S)-3-(2-chloro-3-((4aS,6aR)-l-oxo-l,2,3,4,5,6,6a,7-octahydrocyclobuta[b]pyrido[l,2-a]quinolin-9-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0227] (S)-3-(2-chloro-3-((laS,2aS,4aR,llaS)-ll-oxo-la,2,3,4,4a,5,ll,lla-octahydro-lH-cyclobuta[b]cyclopropa[4,5]pyrido[l,2-a]quinolin-7-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0228] (S )-3 -(2-chloro-3 -((1 aR,2aS,4aR, 11 aR)- 11 -oxo- la, 2, 3, 4, 4a, 5, 11, 11 a-octahydro- 1 H-cyclobuta[b]cyclopropa[4,5]pyrido[l,2-a]quinolin-7-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0229] (S)-3-(2-chloro-3-((laS,2aS,4aS,l laS)-l l-oxo-la,2,3,4,4a,5,l 1,1 la-octahydro-lH-cyclobuta[b]cyclopropa[4,5]pyrido[l,2-a]quinolin-7-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0230] (S)-3-(2-chloro-3-((laR,2aS,4aS,l laR)-l l-oxo-la,2,3,4,4a,5,l 1,11 a-octahydro- 1H-cyclobuta[b]cyclopropa[4,5]pyrido[l,2-a]quinolin-7-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0231] (S)-3-(2-chloro-3-((4aS,6aR, E)-2-ethylidene-l-oxo-l,2,3,4,5,6,6a,7-octahydrocyclobuta[b]pyrido[l,2-a]quinolin-9-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0232] (S)-3-(2-chloro-3-((4aS,6aS, E)-2-ethylidene-l-oxo-l,2,3,4,5,6,6a,7-octahydrocyclobuta[b]pyrido[l,2-a]quinolin-9-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0233] (S)-3-(2-chloro-3-((4aS,6aR, Z)-2-(l-fluoroethylidene)-l-oxo-l,2,3,4,5,6,6a,7-octahydrocyclobuta[b]pyrido[l,2-a]quinolin-9-yl)phenyl)-3-fluoropiperidine-2, 6-dione,125569-02020

[0234] (S)-3-(2-chloro-3-((4aS,6aS, Z)-2-(l-fluoroethylidene)-l-oxo-l,2,3,4,5,6,6a,7-octahydrocyclobuta[b]pyrido[l,2-a]quinolin-9-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0235] (S)-3-(2-chloro-3-((4aS,6aR, E)-2-(l-fluoroethylidene)-l-oxo-l,2,3,4,5,6,6a,7-octahydrocyclobuta[b]pyrido[l,2-a]quinolin-9-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0236] (S)-3-(2-chloro-3-((4aS,6aS, E)-2-(l-fluoroethylidene)-l-oxo-l,2,3,4,5,6,6a,7-octahydrocyclobuta[b]pyrido[l,2-a]quinolin-9-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0237] (S)-3-(2-chloro-3-((4aS,6aR)-3-methyl-13-oxo-4,5,6,6a,7,13-hexahydro-3H-cyclobuta[b]pyrazolo[3',4':4,5]pyrido[l,2-a]quinolin-9-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0238] (S)-3-(2-chloro-3-((4aS,6aS)-3-methyl-13-oxo-4,5,6,6a,7,13-hexahydro-3H-cyclobuta[b]pyrazolo[3',4':4,5]pyrido[l,2-a]quinolin-9-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0239] (S)-3-(2-chloro-3-((4aS,6aR)-3-isopropyl-13-oxo-4,5,6,6a,7,13-hexahydro-3H-cyclobuta[b]pyrazolo[3',4':4,5]pyrido[l,2-a]quinolin-9-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0240] (S)-3-(2-chloro-3-((4aS,6aS)-3-isopropyl-13-oxo-4,5,6,6a,7,13-hexahydro-3H-cyclobuta[b]pyrazolo[3',4':4,5]pyrido[l,2-a]quinolin-9-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0241] (S)-3-(2-chloro-3-((4aS,6aR)-13-oxo-4,5,6,6a,7,13-hexahydrocyclobuta[b]isoxazolo[5',4':4,5]pyrido[l,2-a]quinolin-9-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0242] (S)-3-(2-chloro-3-((4aS,6aS)-13-oxo-4,5,6,6a,7,13-hexahydrocyclobuta[b]isoxazolo[5',4':4,5]pyrido[l,2-a]quinolin-9-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0243] (S)-3-(2-chloro-3-((4aS,6aR)- 13-0X0-4, 5, 6, 6a, 7,13-hexahydrocyclobuta[b]isothiazolo[5',4':4,5]pyrido[l,2-a]quinolin-9-yl)phenyl)-3-fluoropiperidine-2, 6-dione,125569-02020

[0244] (S)-3-(2-chloro-3-((4aS,6aS)-13-oxo-4,5,6,6a,7,13-hexahydrocyclobuta[b]isothiazolo[5',4':4,5]pyrido[l,2-a]quinolin-9-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0245] (S)-3-(2-chloro-3-((4aR,5aS)-l-oxo-l,2,3,4,5a,6-hexahydro-5H-cyclopropa[j]thieno[3,2-c]quinolizin-8-yl)phenyl)-3-fluoropiperidine-2,6-dione-4,4-d2,

[0246] (S)-3-(2-chloro-3-((laR,2aS,3aS,9aR)-9-oxo-la,2,3a,4,9,9a-hexahydro-lH,3H-dicyclopropa[b,i]thieno[2,3-f]quinolizin-6-yl)phenyl)-3-fluoropiperidine-2,6-dione-4,4-d2,

[0247] (S)-3-(2-chloro-3-((laS,2aS,3aS,9aS)-9-oxo-la,2,3a,4,9,9a-hexahydro-lH,3H-dicyclopropa[b,i]thieno[2,3-f]quinolizin-6-yl)phenyl)-3-fluoropiperidine-2,6-dione-4,4-d2,

[0248] (S)-3-(2-chloro-3-((4aS,5aS)-2-methyl-ll-oxo-2,5a,6,ll-tetrahydro-4H,5H-cyclopropa[i]pyrazolo[3,4-b]thieno[2,3-f]quinolizin-8-yl)phenyl)-3-fluoropiperidine-2, 6-dione- 4,4-d2,

[0249] (S)-3-(2-chloro-3-((4aS,5aS)-3-methyl-ll-oxo-4,5a,6,ll-tetrahydro-3H,5H-cyclopropa[i]pyrazolo[3,4-b]thieno[2,3-f]quinolizin-8-yl)phenyl)-3-fluoropiperidine-2, 6-dione- 4,4-d2,

[0250] (S)-3-(2-chloro-3-((4aS,5aS)-l l-oxo-5a,6-dihydro-4H,5H,l 1H-cyclopropa[i]isoxazolo[3,4-b]thieno[2,3-f]quinolizin-8-yl)phenyl)-3-fluoropiperidine-2, 6-dione- 4,4-d2,

[0251] (S)-3-(2-chloro-3-((5aS,6aS)-12-oxo-5,6a,7,12-tetrahydro-6H-cyclopropa[i]pyrimido[4,5-b]thieno[2,3-f]quinolizin-9-yl)phenyl)-3-fluoropiperidine-2, 6-dione- 4,4-d2,

[0252] (5aS,6aS)-9-(2-chloro-3-((S)-3-fluoro-2,6-dioxopiperidin-3-yl-4,4-d2)phenyl)-4-methyl-6a,7-dihydro-6H-cyclopropa[2,3]thieno[3',2':5,6]pyrido[l,2-g][l,6]naphthyridine-3,12(4H,5H)-dione,125569-02020

[0253] (S)-3-(2-chloro-3-((4aS,5aR)-l-oxo-l,2,3,4,5a,6-hexahydro-5H-cyclopropa[j]thieno[3,2-c]quinolizin-8-yl)phenyl)-3-fluoropiperidine-2,6-dione-4,4-d2,

[0254] (S)-3-(2-chloro-3-((laR,2aR,3aR,9aR)-9-oxo-la,2,3a,4,9,9a-hexahydro-lH,3H-dicyclopropa[b,i]thieno[2,3-f]quinolizin-6-yl)phenyl)-3-fluoropiperidine-2,6-dione-4,4-d2,

[0255] (S)-3-(2-chloro-3-((laS,2aR,3aR,9aS)-9-oxo-la,2,3a,4,9,9a-hexahydro-lH,3H-dicyclopropa[b,i]thieno[2,3-f]quinolizin-6-yl)phenyl)-3-fluoropiperidine-2,6-dione-4,4-d2,

[0256] (S)-3-(2-chloro-3-((4aR,5aR)-2-methyl-ll-oxo-2,5a,6,ll-tetrahydro-4H,5H-cyclopropa[i]pyrazolo[3,4-b]thieno[2,3-f]quinolizin-8-yl)phenyl)-3-fluoropiperidine-2, 6-dione- 4,4-d2,

[0257] (S)-3-(2-chloro-3-((4aR,5aR)-3-methyl-ll-oxo-4,5a,6,ll-tetrahydro-3H,5H-cyclopropa[i]pyrazolo[3,4-b]thieno[2,3-f]quinolizin-8-yl)phenyl)-3-fluoropiperidine-2, 6-dione- 4,4-d2,

[0258] (S)-3-(2-chloro-3-((4aR,5aR)-l l-oxo-5a,6-dihydro-4H,5H,l 1H-cyclopropa[i]isoxazolo[3,4-b]thieno[2,3-f]quinolizin-8-yl)phenyl)-3-fluoropiperidine-2, 6-dione - 4,4-d2,

[0259] (S)-3-(2-chloro-3-((5aR,6aR)-12-oxo-5,6a,7,12-tetrahydro-6H-cyclopropa[i]pyrimido[4,5-b]thieno[2,3-f]quinolizin-9-yl)phenyl)-3-fluoropiperidine-2, 6-dione- 4,4-d2,

[0260] (5aR,6aR)-9-(2-chloro-3-((S)-3-fluoro-2,6-dioxopiperidin-3-yl-4,4-d2)phenyl)-4-methyl-6a,7-dihydro-6H-cyclopropa[2,3]thieno[3',2':5,6]pyrido[l,2-g][l,6]naphthyridine-3,12(4H,5H)-dione,

[0261] (S)-3-(2-chloro-3-((4aR,5aS)-l-oxo-l,2,3,4,5a,6-hexahydro-5H-cyclopropa[j]thieno[3,2-c]quinolizin-8-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0262] (S)-3-(2-chloro-3-((laR,2aS,3aS,9aR)-9-oxo-la,2,3a,4,9,9a-hexahydro-lH,3H-dicyclopropa[b,i]thieno[2,3-f]quinolizin-6-yl)phenyl)-3-fluoropiperidine-2, 6-dione,125569-02020

[0263] (S)-3-(2-chloro-3-((laS,2aS,3aS,9aS)-9-oxo-la,2,3a,4,9,9a-hexahydro-lH,3H-dicyclopropa[b,i]thieno[2,3-f]quinolizin-6-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0264] (S)-3-(2-chloro-3-((4aS,5aS)-2-methyl-ll-oxo-2,5a,6,ll-tetrahydro-4H,5H-cyclopropa[i]pyrazolo[3,4-b]thieno[2,3-f]quinolizin-8-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0265] (S)-3-(2-chloro-3-((4aS,5aS)-3-methyl-ll-oxo-4,5a,6,ll-tetrahydro-3H,5H-cyclopropa[i]pyrazolo[3,4-b]thieno[2,3-f]quinolizin-8-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0266] (S)-3-(2-chloro-3-((4aS,5aS)-l l-oxo-5a,6-dihydro-4H,5H,l 1H-cyclopropa[i]isoxazolo[3,4-b]thieno[2,3-f]quinolizin-8-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0267] (S)-3-(2-chloro-3-((5aS,6aS)-12-oxo-5,6a,7,12-tetrahydro-6H-cyclopropa[i]pyrimido[4,5-b]thieno[2,3-f]quinolizin-9-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0268] (5aS,6aS)-9-(2-chloro-3-((S)-3-fluoro-2,6-dioxopiperidin-3-yl)phenyl)-4-methyl-6a,7-dihydro-6H-cyclopropa[2,3]thieno[3',2':5,6]pyrido[l,2-g][l,6]naphthyridine-3,12(4H,5H)-dione,

[0269] (S)-3-(2-chloro-3-((4aS,5aR)-l-oxo-l,2,3,4,5a,6-hexahydro-5H-cyclopropa[j]thieno[3,2-c]quinolizin-8-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0270] (S)-3-(2-chloro-3-((laR,2aR,3aR,9aR)-9-oxo-la,2,3a,4,9,9a-hexahydro-lH,3H-dicyclopropa[b,i]thieno[2,3-f]quinolizin-6-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0271] (S)-3-(2-chloro-3-((laS,2aR,3aR,9aS)-9-oxo-la,2,3a,4,9,9a-hexahydro-lH,3H-dicyclopropa[b,i]thieno[2,3-f]quinolizin-6-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0272] (S)-3-(2-chloro-3-((4aR,5aR)-2-methyl-ll-oxo-2,5a,6,ll-tetrahydro-4H,5H-cyclopropa[i]pyrazolo[3,4-b]thieno[2,3-f]quinolizin-8-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0273] (S)-3-(2-chloro-3-((4aR,5aR)-3-methyl-ll-oxo-4,5a,6,ll-tetrahydro-3H,5H-cyclopropa[i]pyrazolo[3,4-b]thieno[2,3-f]quinolizin-8-yl)phenyl)-3-fluoropiperidine-2, 6-dione,125569-02020

[0274] (S)-3-(2-chloro-3-((4aR,5aR)-l l-oxo-5a,6-dihydro-4H,5H,l 1H-cyclopropa[i]isoxazolo[3,4-b]thieno[2,3-f]quinolizin-8-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0275] (S)-3-(2-chloro-3-((5aR,6aR)-12-oxo-5,6a,7,12-tetrahydro-6H-cyclopropa[i]pyrimido[4,5-b]thieno[2,3-f]quinolizin-9-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0276] (5aR,6aR)-9-(2-chloro-3-((S)-3-fluoro-2,6-dioxopiperidin-3-yl)phenyl)-4-methyl-6a,7-dihydro-6H-cyclopropa[2,3]thieno[3',2':5,6]pyrido[l,2-g][l,6]naphthyridine-3,12(4H,5H)-dione,

[0277] 3-(2-chloro-3-((S)-2-methyl-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl)phenyl)piperidine-2, 6-dione,

[0278] 3-(2-chloro-3-((R)-2-methyl-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl)phenyl)piperidine-2, 6-dione,

[0279] (R)-3-(2-chloro-3-((S)-2-methyl-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a] quinolin-8-yl)phenyl)-3-fluoropiperidine-2,6-dione,

[0280] (S)-3-(2-chloro-3-((S)-2-methyl-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a] quinolin-8-yl)phenyl)-3-fluoropiperidine-2,6-dione,

[0281] (R)-3-(2-chloro-3-((R)-2-methyl-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a] quinolin-8-yl)phenyl)-3-fluoropiperidine-2,6-dione,

[0282] (S)-3-(2-chloro-3-((R)-2-methyl-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a] quinolin-8-yl)phenyl)-3-fluoropiperidine-2,6-dione,

[0283] 3-(2-chloro-3-((R)-6,6-difluoro-2-methyl-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl)phenyl)piperidine-2, 6-dione,

[0284] 3-(2-chloro-3-((S)-6,6-difluoro-2-methyl-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl)phenyl)piperidine-2, 6-dione,125569-02020

[0285] 3-(2-chloro-3-((R)-5,5-difluoro-2-methyl-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl)phenyl)piperidine-2, 6-dione,

[0286] 3-(2-chloro-3-((S)-5,5-difluoro-2-methyl-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl)phenyl)piperidine-2, 6-dione,

[0287] (S)-3-(2-chloro-3-((7aS,8aR,8bR)-7-methyl-6-oxo-6,7,7a,8,8a,8b,9,10-octahydrocyclopropa[4,5]pyrimido[l,6-a]quinolin-2-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0288] (S)-3-(2-chloro-3-((7aR,8aS,8bR)-7-methyl-6-oxo-6,7,7a,8,8a,8b,9,10-octahydrocyclopropa[4,5]pyrimido[l,6-a]quinolin-2-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0289] (S)-3-(2-chloro-3-((4aR,5aS)-2-methyl-l-oxo-l,2,3,4,5a,6-hexahydro-5H-cyclopropa[b]pyrimido[l,6-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0290] (S)-3-(2-chloro-3-((4aR,5aR)-2-methyl-l-oxo-l,2,3,4,5a,6-hexahydro-5H-cyclopropa[b]pyrimido[l,6-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0291] (S)-3-(2-chloro-3-((4aS,5aS)-2-methyl-l-oxo-l,2,3,4,5a,6-hexahydro-5H-cyclopropa[b]pyrimido[l,6-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0292] (S)-3-(2-chloro-3-((4aS,5aR)-2-methyl-l-oxo-l,2,3,4,5a,6-hexahydro-5H-cyclopropa[b]pyrimido[l,6-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0293] (S)-3-(2-chloro-3-((laR,lbS,2aS,10aS)-10-methyl-9-oxo-la,2a,3,9,10,10a-hexahydro-lH,2H-cyclopropa[4,5]pyrimido[l,6-a]cyclopropa[b]quinolin-5-yl)phenyl)-3-fluoropiperidine-2,6-dione,

[0294] (S)-3-(2-chloro-3-((laS,lbS,2aS,10aR)-10-methyl-9-oxo-la,2a,3,9,10,10a-hexahydro-lH,2H-cyclopropa[4,5]pyrimido[l,6-a]cyclopropa[b]quinolin-5-yl)phenyl)-3-fluoropiperidine-2,6-dione,125569-02020

[0295] (S)-3-(2-chloro-3-((laR,lbS,2aR,10aS)-10-methyl-9-oxo-la,2a,3,9,10,10a-hexahydro-lH,2H-cyclopropa[4,5]pyrimido[l,6-a]cyclopropa[b]quinolin-5-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0296] (S)-3-(2-chloro-3-((laS,lbS,2aR,10aR)-10-methyl-9-oxo-la,2a,3,9,10,10a-hexahydro-lH,2H-cyclopropa[4,5]pyrimido[l,6-a]cyclopropa[b]quinolin-5-yl)phenyl)-3-fluoropiperidine-2,6-dione,

[0297] (S)-3-(2-chloro-3-((4aR,5aS)-2-methyl-l-oxo-l,2,3,4,5a,6-hexahydro-5H-cyclopropa[b]pyrimido[l,6-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0298] (S)-3-(2-chloro-3-((4aR,6aS)-2-methyl-l-oxo-l,2,3,4,5,6,6a,7-octahydrocyclobuta[b]pyrimido[l,6-a]quinolin-9-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0299] (S)-3-(2-chloro-3-((4aS,6aR)-2-methyl-l-oxo-l,2,3,4,5,6,6a,7-octahydrocyclobuta[b]pyrimido[l,6-a]quinolin-9-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0300] (S)-3-(2-chloro-3-((4aS,6aS)-2-methyl-l-oxo-l,2,3,4,5,6,6a,7-octahydrocyclobuta[b]pyrimido[l,6-a]quinolin-9-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0301] (S)-3-(2-chloro-3-((laR,lbS,3aR,llaS)-ll-methyl-10-oxo-la,2,3,3a,4,10,ll,lla-octahydro-lH-cyclobuta[b]cyclopropa[4,5]pyrimido[l,6-a]quinolin-6-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0302] (S)-3-(2-chloro-3-((laS,lbS,3aR,llaR)-ll-methyl-10-oxo-la,2,3,3a,4,10,ll,lla-octahydro-lH-cyclobuta[b]cyclopropa[4,5]pyrimido[l,6-a]quinolin-6-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0303] (S)-3-(2-chloro-3-((laR,lbS,3aS,llaS)-ll-methyl-10-oxo-la,2,3,3a,4,10,ll,lla-octahydro-lH-cyclobuta[b]cyclopropa[4,5]pyrimido[l,6-a]quinolin-6-yl)phenyl)-3-fluoropiperidine-2, 6-dione,125569-02020

[0304] (S)-3-(2-chloro-3-((laS,lbS,3aS,llaR)-ll-methyl-10-oxo-la,2,3,3a,4,10,ll,lla-octahydro-lH-cyclobuta[b]cyclopropa[4,5]pyrimido[l,6-a]quinolin-6-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0305] (S)-3-(2-chloro-3-((R)-2-isopropyl-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a] quinolin-8-yl)phenyl)-3-fluoropiperidine-2,6-dione,

[0306] (S)-3-(2-chloro-3-((7aS,8aR,8bR)-7-isopropyl-6-oxo-6,7,7a,8,8a,8b,9,10-octahydrocyclopropa[4,5]pyrimido[l,6-a]quinolin-2-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0307] (S)-3-(2-chloro-3-((7aR,8aS,8bR)-7-isopropyl-6-oxo-6,7,7a,8,8a,8b,9,10-octahydrocyclopropa[4,5]pyrimido[l,6-a]quinolin-2-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0308] (S)-3-(2-chloro-3-((4aR,5aS)-2-isopropyl-1-oxo-1,2,3,4,5a,6-hexahydro-5H-cyclopropa[b]pyrimido[1,6-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2,6-dione,

[0309] (S)-3-(2-chloro-3-((4aR,5aR)-2-isopropyl-l-oxo-l,2,3,4,5a,6-hexahydro-5H-cyclopropa[b]pyrimido[l,6-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0310] (S)-3-(2-chloro-3-((4aS,5aS)-2-isopropyl-l-oxo-l,2,3,4,5a,6-hexahydro-5H-cyclopropa[b]pyrimido[l,6-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0311] (S)-3-(2-chloro-3-((4aS,5aR)-2-isopropyl-l-oxo-l,2,3,4,5a,6-hexahydro-5H-cyclopropa[b]pyrimido[l,6-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0312] (S)-3-(2-chloro-3-((laR,lbS,2aS,10aS)-10-isopropyl-9-oxo-la,2a,3,9,10,10a-hexahydro-lH,2H-cyclopropa[4,5]pyrimido[l,6-a]cyclopropa[b]quinolin-5-yl)phenyl)-3-fluoropiperidine-2,6-dione,

[0313] (S)-3-(2-chloro-3-((laS,lbS,2aS,10aR)-10-isopropyl-9-oxo-la,2a,3,9,10,10a-hexahydro-lH,2H-cyclopropa[4,5]pyrimido[l,6-a]cyclopropa[b]quinolin-5-yl)phenyl)-3-fluoropiperidine-2,6-dione,125569-02020

[0314] (S)-3-(2-chloro-3-((laR,lbS,2aR,10aS)-10-isopropyl-9-oxo-la,2a,3,9,10,10a-hexahydro-lH,2H-cyclopropa[4,5]pyrimido[l,6-a]cyclopropa[b]quinolin-5-yl)phenyl)-3-fluoropiperidine- 2, 6-dione,

[0315] (S)-3-(2-chloro-3-((1aS,1bS,2aR,10aR)-10-isopropyl-9-oxo-1a,2a,3,9,10,10a-hexahydro-1H,2H-cyclopropa[4,5]pyrimido[1,6-a]cyclopropa[b]quinolin-5-yl)phenyl)-3-fluoropiperidine-2,6-dione,

[0316] (S)-3-(2-chloro-3-((R)-2-methyl-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a] quinolin-8-yl)phenyl)-3-fluoropiperidine-2,6-dione-4,4,5,5-d4,

[0317] (S)-3-(2-chloro-3-((7aS,8aR,8bR)-7-methyl-6-oxo-6,7,7a,8,8a,8b,9,10-octahydrocyclopropa[4,5]pyrimido[l,6-a]quinolin-2-yl)phenyl)-3-fluoropiperidine-2, 6-dione-4,4,5,5-d4,

[0318] (S)-3-(2-chloro-3-((7aR,8aS,8bR)-7-methyl-6-oxo-6,7,7a,8,8a,8b,9,10-octahydrocyclopropa[4,5]pyrimido[l,6-a]quinolin-2-yl)phenyl)-3-fluoropiperidine-2, 6-dione-4,4,5,5-d4,

[0319] (S)-3-(2-chloro-3-((4aR,5aS)-2-methyl-l-oxo-l,2,3,4,5a,6-hexahydro-5H-cyclopropa[b]pyrimido[l,6-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2,6-dione-4,4,5,5-d4,

[0320] (S)-3-(2-chloro-3-((4aR,5aR)-2-methyl-l-oxo-l,2,3,4,5a,6-hexahydro-5H-cyclopropa[b]pyrimido[l,6-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2,6-dione-4,4,5,5-d4,

[0321] (S)-3-(2-chloro-3-((1aR,1bS,2aS,10aS)-10-methyl-9-oxo-1a,2a,3,9,10,10a-hexahydro-1H,2H-cyclopropa[4,5]pyrimido[1,6-a]cyclopropa[b]quinolin-5-yl)phenyl)-3-fluoropiperidine-2,6-dione-4,4,5,5-d4,

[0322] (S)-3-(2-chloro-3-((1aS,1bS,2aS,10aR)-10-methyl-9-oxo-1a,2a,3,9,10,10a-hexahydro-1H,2H-cyclopropa[4,5]pyrimido[1,6-a]cyclopropa[b]quinolin-5-yl)phenyl)-3-fluoropiperidine-2,6-dione-4,4,5,5-d4,125569-02020

[0323] (S)-3-(2-chloro-3-((laR,lbS,2aR,10aS)-10-methyl-9-oxo-la,2a,3,9,10,10a-hexahydro-lH,2H-cyclopropa[4,5]pyrimido[l,6-a]cyclopropa[b]quinolin-5-yl)phenyl)-3-fluoropiperidine-2,6-dione-4,4,5,5-d4,

[0324] (S)-3-(2-chloro-3-((laS,lbS,2aR,10aR)-10-methyl-9-oxo-la,2a,3,9,10,10a-hexahydro-lH,2H-cyclopropa[4,5]pyrimido[l,6-a]cyclopropa[b]quinolin-5-yl)phenyl)-3-fluoropiperidine-2,6-dione-4,4,5,5-d4,

[0325] 3-(2-chloro-3-(l-oxo-5,6-dihydro-lH-pyrido[l,2-a]quinolin-8-yl)phenyl)piperidine-2,6-dione,

[0326] 3-(2-chloro-3-(6,6-difluoro-l-oxo-5,6-dihydro-lH-pyrido[l,2-a]quinolin-8-yl)phenyl)piperidine-2, 6-dione,

[0327] 3-(2-chloro-3-(5,5-difluoro-l-oxo-5,6-dihydro-lH-pyrido[l,2-a]quinolin-8-yl)phenyl)piperidine-2, 6-dione,

[0328] (R)-3-(2-chloro-3-(l-oxo-5,6-dihydro-lH-pyrido[l,2-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0329] (S)-3-(2-chloro-3-(l-oxo-5,6-dihydro-lH-pyrido[l,2-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0330] 5-(2-chloro-3-(l-oxo-5,6-dihydro-lH-pyrido[l,2-a]quinolin-8-yl)phenyl)-3,3-difluoropiperidine-2, 6-dione,

[0331] 3-(2-chloro-3-(l-oxo-5,6-dihydro-lH-pyrido[l,2-a]quinolin-8-yl)phenyl)-4,4-difluoropiperidine-2, 6-dione

[0332] 3-(2-chloro-3-((S)-l-oxo-2-(3-(propan-2-ylidene)cyclobutyl)-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl)phenyl)piperidine-2, 6-dione,125569-02020

[0333] 3-(2-chloro-3-((R)-l-oxo-2-(3-(propan-2-ylidene)cyclobutyl)-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl)phenyl)piperidine-2, 6-dione,

[0334] 3-(2-chloro-3-((S)-l-oxo-2-(3-(tetrahydro-4H-pyran-4-ylidene)cyclobutyl)-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl)phenyl)piperidine-2, 6-dione,

[0335] 3-(2-chloro-3-((R)-l-oxo-2-(3-(tetrahydro-4H-pyran-4-ylidene)cyclobutyl)-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl)phenyl)piperidine-2, 6-dione,

[0336] 3-(2-chloro-3-((S)-l-oxo-2-((lr,3S)-3-(4-(propan-2-ylidene)piperidin-l-yl)cyclobutyl)-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl)phenyl)piperidine-2,6-dione,

[0337] 3-(2-chloro-3-((R)-l-oxo-2-((lr,3R)-3-(4-(propan-2-ylidene)piperidin-l-yl)cyclobutyl)-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl)phenyl)piperidine-2,6-dione,

[0338] 3-(2-chloro-3-((S)-l-oxo-2-((lr,3S)-3-(4-(tetrahydro-4H-pyran-4-ylidene)piperidin-l-yl)cyclobutyl)-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl)phenyl)piperidine-2,6-dione,

[0339] 3-(2-chloro-3-((R)-l-oxo-2-((lr,3R)-3-(4-(tetrahydro-4H-pyran-4-ylidene)piperidin-l-yl)cyclobutyl)-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl)phenyl)piperidine-2,6-dione,

[0340] (R)-3-(2-chloro-3-((S)-l-oxo-2-(3-(propan-2-ylidene)cyclobutyl)-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0341] (S)-3-(2-chloro-3-((S)-l-oxo-2-(3-(propan-2-ylidene)cyclobutyl)-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0342] (R)-3-(2-chloro-3-((R)-l-oxo-2-(3-(propan-2-ylidene)cyclobutyl)-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0343] (S)-3-(2-chloro-3-((R)-l-oxo-2-(3-(propan-2-ylidene)cyclobutyl)-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2, 6-dione,125569-02020

[0344] (R)-3-(2-chloro-3-((S)-l-oxo-2-(3-(tetrahydro-4H-pyran-4-ylidene)cyclobutyl)-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2,6-dione,

[0345] (S)-3-(2-chloro-3-((S)-l-oxo-2-(3-(tetrahydro-4H-pyran-4-ylidene)cyclobutyl)-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2,6-dione,

[0346] (R)-3-(2-chloro-3-((R)-l-oxo-2-(3-(tetrahydro-4H-pyran-4-ylidene)cyclobutyl)-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2,6-dione,

[0347] (S)-3-(2-chloro-3-((R)-l-oxo-2-(3-(tetrahydro-4H-pyran-4-ylidene)cyclobutyl)-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2,6-dione,

[0348] (R)-3-(2-chloro-3-((S)-l-oxo-2-((lr,3S)-3-(4-(propan-2-ylidene)piperidin-l-yl)cyclobutyl)-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0349] (S)-3-(2-chloro-3-((S)-l-oxo-2-((lr,3S)-3-(4-(propan-2-ylidene)piperidin-l-yl)cyclobutyl)-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0350] (R)-3-(2-chloro-3-((R)-l-oxo-2-((lr,3R)-3-(4-(propan-2-ylidene)piperidin-l-yl)cyclobutyl)-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0351] (S)-3-(2-chloro-3-((R)-l-oxo-2-((lr,3R)-3-(4-(propan-2-ylidene)piperidin-l-yl)cyclobutyl)-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0352] (R)-3-(2-chloro-3-((S)-l-oxo-2-((lr,3S)-3-(4-(tetrahydro-4H-pyran-4-ylidene)piperidin-l-yl)cyclobutyl)-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2, 6-dione,125569-02020

[0353] (S)-3-(2-chloro-3-((S)-l-oxo-2-((lr,3S)-3-(4-(tetrahydro-4H-pyran-4-ylidene)piperidin-l-yl)cyclobutyl)-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0354] (R)-3-(2-chloro-3-((R)-l-oxo-2-((lr,3R)-3-(4-(tetrahydro-4H-pyran-4-ylidene)piperidin-l-yl)cyclobutyl)-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0355] (S)-3-(2-chloro-3-((R)-l-oxo-2-((lr,3R)-3-(4-(tetrahydro-4H-pyran-4-ylidene)piperidin-l-yl)cyclobutyl)-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2, 6-dione,

[0356] 5-(2-chloro-3-((S)-2-methyl-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl)phenyl)-3, 3 -difluoropiperidine-2, 6-dione,

[0357] 5-(2-chloro-3-((R)-2-methyl-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl)phenyl)-3, 3 -difluoropiperidine-2, 6-dione,

[0358] 5-(2-chloro-3-((S)-l-oxo-2-(3-(propan-2-ylidene)cyclobutyl)-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl)phenyl)-3,3-difluoropiperidine-2, 6-dione,

[0359] 5-(2-chloro-3-((R)-l-oxo-2-(3-(propan-2-ylidene)cyclobutyl)-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl)phenyl)-3,3-difluoropiperidine-2, 6-dione,

[0360] 5-(2-chloro-3-((S)-l-oxo-2-(3-(tetrahydro-4H-pyran-4-ylidene)cyclobutyl)-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl)phenyl)-3,3-difluoropiperidine-2, 6-dione,

[0361] 5-(2-chloro-3-((R)-l-oxo-2-(3-(tetrahydro-4H-pyran-4-ylidene)cyclobutyl)-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl)phenyl)-3,3-difluoropiperidine-2, 6-dione,

[0362] 5-(2-chloro-3-((S)-l-oxo-2-((lr,3S)-3-(4-(propan-2-ylidene)piperidin-l-yl)cyclobutyl)-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl)phenyl)-3,3-difluoropiperidine-2,6-dione,125569-02020

[0363] 5-(2-chloro-3-((R)-l-oxo-2-((lr,3R)-3-(4-(propan-2-ylidene)piperidin-l-yl)cyclobutyl)-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl)phenyl)-3,3-difluoropiperidine-2,6-dione,

[0364] 5-(2-chloro-3-((S)-l-oxo-2-((lr,3S)-3-(4-(tetrahydro-4H-pyran-4-ylidene)piperidin-l-yl)cyclobutyl)-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl)phenyl)-3,3-difluoropiperidine-2, 6-dione,

[0365] 5-(2-chloro-3-((R)-l-oxo-2-((lr,3R)-3-(4-(tetrahydro-4H-pyran-4-ylidene)piperidin-l-yl)cyclobutyl)-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl)phenyl)-3,3-difluoropiperidine-2, 6-dione,

[0366] 3-(2-chloro-3-((R)-6,6-difluoro-l-oxo-2-(3-(propan-2-ylidene)cyclobutyl)-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl)phenyl)piperidine-2, 6-dione,

[0367] 3-(2-chloro-3-((S)-6,6-difluoro-l-oxo-2-(3-(propan-2-ylidene)cyclobutyl)-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl)phenyl)piperidine-2, 6-dione,

[0368] 3-(2-chloro-3-((R)-6,6-difluoro-l-oxo-2-(3-(tetrahydro-4H-pyran-4-ylidene)cyclobutyl)-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl)phenyl)piperidine-2,6-dione,

[0369] 3-(2-chloro-3-((S)-6,6-difluoro-l-oxo-2-(3-(tetrahydro-4H-pyran-4-ylidene)cyclobutyl)-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl)phenyl)piperidine-2,6-dione,

[0370] 3-(2-chloro-3-((R)-6,6-difluoro-l-oxo-2-((lr,3R)-3-(4-(propan-2-ylidene)piperidin-l-yl)cyclobutyl)-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl)phenyl)piperidine-2,6-dione,

[0371] 3-(2-chloro-3-((S)-6,6-difluoro-l-oxo-2-((lr,3S)-3-(4-(propan-2-ylidene)piperidin-l-yl)cyclobutyl)-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl)phenyl)piperidine-2,6-dione,125569-02020

[0372] 3-(2-chloro-3-((R)-6,6-difluoro-l-oxo-2-((lr,3R)-3-(4-(tetrahydro-4H-pyran-4-ylidene)piperidin-l-yl)cyclobutyl)-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl)phenyl)piperidine-2, 6-dione,

[0373] 3-(2-chloro-3-((S)-6,6-difluoro-l-oxo-2-((lr,3S)-3-(4-(tetrahydro-4H-pyran-4-ylidene)piperidin-l-yl)cyclobutyl)-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl)phenyl)piperidine-2, 6-dione,

[0374] 3-(2-chloro-3-((R)-5,5-difluoro-l-oxo-2-(3-(propan-2-ylidene)cyclobutyl)-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl)phenyl)piperidine-2, 6-dione,

[0375] 3-(2-chloro-3-((S)-5,5-difluoro-l-oxo-2-(3-(propan-2-ylidene)cyclobutyl)-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl)phenyl)piperidine-2, 6-dione,

[0376] 3-(2-chloro-3-((R)-5,5-difluoro-l-oxo-2-(3-(tetrahydro-4H-pyran-4-ylidene)cyclobutyl)-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl)phenyl)piperidine-2,6-dione,

[0377] 3-(2-chloro-3-((S)-5,5-difluoro-l-oxo-2-(3-(tetrahydro-4H-pyran-4-ylidene)cyclobutyl)-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl)phenyl)piperidine-2,6-dione,

[0378] 3-(2-chloro-3-((R)-5,5-difluoro-l-oxo-2-((lr,3R)-3-(4-(propan-2-ylidene)piperidin-l-yl)cyclobutyl)-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl)phenyl)piperidine-2,6-dione,

[0379] 3-(2-chloro-3-((S)-5,5-difluoro-l-oxo-2-((lr,3S)-3-(4-(propan-2-ylidene)piperidin-l-yl)cyclobutyl)-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl)phenyl)piperidine-2,6-dione,

[0380] 3-(2-chloro-3-((R)-5,5-difluoro-l-oxo-2-((lr,3R)-3-(4-(tetrahydro-4H-pyran-4-ylidene)piperidin-l-yl)cyclobutyl)-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl)phenyl)piperidine-2, 6-dione,125569-02020

[0381] 3-(2-chloro-3-((S)-5,5-difluoro-1-oxo-2-((1r,3S)-3-(4-(tetrahydro-4H-pyran-4-ylidene)piperidin-1-yl)cyclobutyl)-2,3,4,4a,5,6-hexahydro-1H-pyrimido[1,6-a]quinolin-8-yl)phenyl)piperidine-2,6-dione

[0382] Compounds of the invention may contain one or more asymmetric carbon atoms.

[0383] 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.

[0384] 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:

[0385] • Prodrug derivatives: prodrugs, upon administration to a subject, will converted in vivo into active compounds of the present invention [Nature Reviews of Drug Discovery, 2008, Volume 7, p255]. It is noted that in many instances, the prodrugs themselves also fall within the scope of the range of compounds according to the present invention. The prodrugs of the compounds of the present invention can be prepared by starndard organic reaction, for example, by reacting with a carbamylating agent (e.g., 1,1- acyloxyalkylcarbonochloridate, para-nitrophenyl carbonate, or the like) or an acylating agent. Further examples of methods and strategies of making prodrugs are described in Bioorganic and Medicinal Chemistry Letters, 1994, Vol. 4, p. 1985.

[0386] • Deuterium-enriched compounds: deuterium (D or2H) is a stable, non-radioactive isotope of hydrogen and has an atomic weight of 2.0144. Hydrogen naturally occurs as a mixture of the isotopesXH (hydrogen or protium), D (2H or deuterium), and T (3H or tritium). The natural abundance of deuterium is 0.015%. One of ordinary skill in the art recognizes that in all chemical compounds with a H atom, the H atom actually represents a mixture of H and D, with about 0.015% being D. Thus, compounds with a level of deuterium that has been enriched to be greater than its natural abundance of 0.015%, should be considered unnatural and, as a result, novel over their nonenriched

[0387] counterparts.125569-02020

[0388] 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.

[0389] 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, methylbenzoate, 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.

[0390] 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,125569-02020

[0391] 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, iso-propylamine, 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.

[0392] 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.

[0393] Compounds of the present invention that comprise tertiary nitrogen-containing groups may be quatemized 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.

[0394] 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 meta-Chloroperoxybenzoic acid (mCPBA) to from amine oxide.

[0395] 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.125569-02020

[0396] 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.

[0397] 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.

[0398] 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, poly anhydrides, polyglycolic acid, collagen, poly orthoesters, 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.

[0399] Additionally, the invention encompasses pharmaceutical compositions comprising any solid or liquid physical form of the compound of the invention. For example, the compounds125569-02020

[0400] 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.

[0401] 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 cosolvents, 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-a-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.

[0402] 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.

[0403] 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.

[0404] As used herein, “Acyl” means a carbonyl containing substituent represented by the formula -C(O)-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.

[0405] “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.125569-02020

[0406] The term “alkyl” refers to a straight or branched hydrocarbon containing 1-20 carbon atoms (e.g., C1-C10). 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.

[0407] The term “alkenyl” refers to a straight or branched hydrocarbon containing 2-20 carbon atoms (e.g., C2-C10) and one or more double bonds. Examples of alkenyl include, but are not limited to, ethenyl, propenyl, and allyl. Preferably, the alkylene group has two to ten carbon atoms. More preferably, the alkylene group has two to four carbon atoms.

[0408] The term “alkynyl” refers to a straight or branched hydrocarbon containing 2-20 carbon atoms (e.g., C2-C10) and one or more triple bonds. Examples of alkynyl include, but are not limited to, ethynyl, 1-propynyl, 1- and 2-butynyl, and l-methyl-2-butynyl. Preferably, the alkynyl group has two to ten carbon atoms. More preferably, the alkynyl group has two to four carbon atoms.

[0409] 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.

[0410] “Alkoxy” means an oxygen moiety having a further alkyl substituent.

[0411] “Alkoxycarbonyl” means an alkoxy group attached to a carbonyl group.

[0412] “Oxoalkyl” means an alkyl, further substituted with a carbonyl group. The carbonyl group may be an aldehyde, ketone, ester, amide, acid or acid chloride.

[0413] The term “cycloalkyl” refers to a saturated hydrocarbon ring system having 3 to 30 carbon atoms (e.g., C3-C12, C3-C8, C3-C6). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The term “cycloalkenyl” refers to a non-aromatic hydrocarbon ring system having 3 to 30 carbons (e.g., C3-C12) and one or more double bonds. Examples include cyclopentenyl, cyclohexenyl, and cycloheptenyl.

[0414] The term “heterocycloalkyl” refers to a nonaromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having one or more heteroatoms (such as O, N, S, P, or Se). Examples of heterocycloalkyl groups include, but are not limited to, piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, and tetrahydrofuranyl.

[0415] The term “cycloalkenyl” refers to a nonaromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having one or more double bonds.

[0416] The term “heterocycloalkenyl” refers to a nonaromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having one or more heteroatoms (such as O, N, S, P, or Se) and one or more double bonds.125569-02020

[0417] 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.

[0418] 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 O, N, S, P, or Se). Examples of heteroaryl groups include pyridyl, furyl, imidazolyl, benzimidazolyl, pyrimidinyl, thienyl, quinolinyl, indolyl, and thiazolyl.

[0419] Spiroalkyl 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:

[0420]

[0421] 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 following125569-02020

[0422] groups:

[0423]

[0424] 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:

[0425]

[0426] 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:

[0427]

[0428] “Amino” means a nitrogen moiety having two further substituents where each125569-02020

[0429] 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, tertbutoxycarbonyl, benzyloxycarbonyl, and the like.

[0430] “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).

[0431] “Carbamoyl” means the radical -OC(O)NRaRb where Raand Rb are each independently two further substituents where a hydrogen or carbon atom is alpha to the nitrogen. It is noted that carbamoyl moieties may include protected derivatives thereof. Examples of suitable protecting groups for carbamoyl moieties include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like. It is noted that both the unprotected and protected derivatives fall within the scope of the invention.

[0432] “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.

[0433] “Carboxy” means the radical -C(O)O-. It is noted that compounds of the invention containing carboxy moieties may include protected derivatives thereof,

[0434]

[0435] where the oxygen is substituted with a protecting group. Suitable protecting groups for carboxy moieties include benzyl, tert-butyl, and the like.

[0436] “Cyano” means the radical -CN.

[0437] “Formyl” means the radical -CH=O.

[0438] “Formimino” means the radical -HC=NH.

[0439] “Halo” means fluoro, chloro, bromo or iodo.

[0440] “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.

[0441] “Hydroxy” means the radical -OH.

[0442] “Imine derivative” means a derivative comprising the moiety -C(=NR)-, wherein R comprises a hydrogen or carbon atom alpha to the nitrogen.

[0443] “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.”125569-02020

[0444] 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.”

[0445] “Nitro” means the radical -NO2.

[0446] “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.

[0447] 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).

[0448] 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.

[0449] “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.

[0450] “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.

[0451] “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.

[0452] “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.125569-02020

[0453] “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).

[0454] “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.

[0455] “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.

[0456] “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.

[0457] “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 (i.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.

[0458] 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 more125569-02020

[0459] charged atoms and / or one or more counter ion.

[0460] “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.

[0461] “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.

[0462] “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.

[0463] “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.

[0464] “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 benefit / 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 sound125569-02020

[0465] 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.

[0466] 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.

[0467] 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.

[0468] “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 antineoplastic 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.

[0469] 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,125569-02020

[0470] 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 (Estramu stine), and retinoids (Bexarotene, Isotretinoin, Tretinoin (ATRA).

[0471] 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 / ACVR1B, ALK5 / TGFBR1, ALK6 / BMPR1B, 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, CAMKla, CAMKlb, CAMKld, CAMKlg, CAMKIIa, CAMKIIb, CAMKIId, CAMKIIg, CAMK4, CAMKK1, CAMKK2, CDC7-DBF4, CDKl-cyclin A, CDKl-cyclin B, CDKl-cyclin E, CDK2-cyclin A, CDK2-cyclin Al, CDK2-cyclin E, CDK3-cyclin E, CDK4-cyclin DI, CDK4-cyclin D3, CDK5-p25, CDK5-p35, CDK6-cyclin DI, CDK6-cyclin D3, CDK7-cyclin H, CDK9-cyclin K, CDK9-cyclin Tl, CHK1, CHK2, CKlal, CKld, CKlepsilon, CKlgl, CKlg2, CKlg3, CK2a, CK2a2, c-KIT, CLK1, CLK2, CLK3, CLK4, c-MER, c-MET, COT1 / MAP3K8, CSK,125569-02020

[0472] c-SRC, CTK / MATK, DAPK1, DAPK2, DCAMKL1, DCAMKL2, DDR1, DDR2, DLK / MAP3K12, DMPK, DMPK2 / CDC42BPG, DNA-PK, DRAK1 / STK17A, DYRK1 / DYRK1A, DYRK1B, 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, LCK, LCK2 / ICK, LKB1, LIMK1, LOK / STK10, LRRK2, LYN, LYNB, MAPKAPK2, MAPKAPK3, MAPKAPK5 / PRAK, MARK1, MARK2 / PAR-lBa, 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 / FRAPl, 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, (pllOa / p85a), PI3Kb, (pllOb / p85a), PI3Kd, (pllOd / p85a), PI3Kg(pl20g), PIM1, PIM2, PIM3, PKA, PKAcb, PKAcg, PKCa, PKCbl, PKCb2, PKCd, PKCepsilon, PKCeta, PKCg, PKCiota, PKCmu / PRKDl, PKCnu / PRKD3, PKCtheta, PKCzeta, PKD2 / PRKD2, PKG la, PKG lb, PKG2 / PRKG2, PKN1 / PRK1, PKN2 / PRK2, PKN3 / PRK3, PLK1, PLK2, PLK3, PLK4 / SAK, PRKX, PYK2, RAFI, RET, RIPK2, RIPK3, RIPK5, ROCK1, ROCK2, RON / MST1R, ROS / ROS1, RSK1, RSK2, RSK3, RSK4, SGK1, SGK2, SGK3 / SGKL, SIK1, SIK2, SLK / STK2, SNARK / NUAK2, SRMS, SSTK / TSSK6, STK16, STK22D / TSSK1, STK25 / YSK1, STK32b / YANK2, STK32c / YANK3, STK33, STK38 / NDR1, STK38L / NDR2, STK39 / STLK3, SRPK1, SRPK2, SYK, TAK1, TAOK1, TAOK2 / TAO1, TAOK3 / JIK, TBK1, TEC, TESK1, TGFBR2, TIE2 / TEK, TLK1, TLK2, TNIK, TNK1, TRKA, TRKB, TRKC, TRPM7 / CHAK1, TSSK2, TSSK3 / STK22C, TTBK1, TTBK2, TTK, TXK, TYK1 / LTK, TYK2, TYRO3 / SKY, ULK1, ULK2, ULK3, VRK1, VRK2, WEE1, WNK1, WNK2, WNK3, YES / YES1,125569-02020

[0473] 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(E41K), 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 / T670I), 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(T341M), 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(V561M), FGFR2(N549H), FGFR3(G697C), FGFR3(K650E), FGFR3(K650M), FGFR4(N535K), FGFR4(V550E), FGFR4(V550E), FLT3(D835Y), FLT3(ITD), JAK2 (V617F), LRRK2 (G2019S), LRRK2 (I2020T), LRRK2 (R1441C), p38a(T106M), PDGFRa(D842V), PDGFRa(T674I), PDGFRa(V561D), RET(E762Q), RET(G691S), RET(M918T), RET(R749T), RET(R813Q), RET(V804E), RET(V804M), RET(Y791F), TIF2(R849W), TIF2(Y897S), and TIF2(Y1108F).

[0474] 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 (HD AC), histone acetyltransferases (HAT), and methyltransferase (e.g histone lysine methyltransferases, histone arginine methyltransferase, DNA methyltransferase, etc).

[0475] 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(e.g brentuximab vedotin, ibritumomab tioxetan), cancer immunotherapy such as Interleukin-2, cancer vaccines(e.g., sipuleucel-T) or monoclonal antibodies (e.g., Bevacizumab, Alemtuzumab, Rituximab, Trastuzumab, etc).

[0476] 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 further125569-02020

[0477] 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.

[0478] 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, antimicrotubule 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.

[0479] 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.

[0480] 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 not125569-02020

[0481] 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.

[0482] In some embodiments, the anti-inflammatory agent is a salicylate. Salicylates include by are not limited to acetylsalicylic acid or aspirin, sodium salicylate, and choline and magnesium salicylates. The anti-inflammatory agent may also be a corticosteroid. For example, the corticosteroid may be cortisone, dexamethasone, methylprednisolone, prednisolone, prednisolone sodium phosphate, or prednisone.

[0483] In additional embodiments the anti-inflammatory agent is a gold compound such as gold sodium thiomalate or auranofin.

[0484] 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.

[0485] Other embodiments of the invention pertain to combinations in which at least one antiinflammatory 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.

[0486] In certain embodiments, the compounds of the invention are administered in combination with one or more immunosuppressant agents.

[0487] 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.

[0488] 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.

[0489] 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's125569-02020

[0490] 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.

[0491] 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.

[0492] 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.

[0493] 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.125569-02020

[0494] H

[0495]

[0496] In Scheme 1, the starting material 1-1 is commercially available. The starting material 1-1 reacts with TMSCN to afford the intermediate 1-2, which reacts with DAST to give 1-3. After that, the intermediate 1-3 reacts with l-3a to provide 1-4. The intermediate 1-4 is hydrolyzed to give 1-5, which is converted to 1-6 through an intramolecular cyclization reaction followed by SFC seperation.

[0497] Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.

[0498]

[0499] In Scheme 2A, the starting material 2A-la can be reduced to intermediate 2A-2a, which can be transformed into 2A-3a via an Appel reaction. At the same time, 2A-1 reacts with TMSCN to afford the intermediate 2A-2, which reacts with DAST to give 2A-3. After that, the125569-02020

[0500] intermediate 2A-3 reacts with 2A-3a to provide 2A-4. The intermediate 2A-4 is hydrolyzed to give 2A-5, which is converted to 2A-6 through an intramolecular cyclization reaction followed by SFC seperation.

[0501] Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.

[0502] HRO^N^O

[0503] Br^XX^(RA)r

[0504] The intermediate o

[0505]

[0506] f A- la wherein RA is H, D, or F can be made by the method similar to Scheme 1, 2A, and 2B by using different starting material, intermediates, and

[0507]

[0508] In Scheme 3, the starting material 3-1 is commercially available. The starting material 3-1 reacts with dimethyl carbonate to intermediate 3-2 in the presence of a suitable base. After that, the intermediate 3-2 reacts with LiAlH4to provide 3-3, which goes through an iridium-catalyzed asymmetric hydrogenation reaction to afford the intermediate 3-4. Finally, the intermediate 3-4 is brominated to give the target compounds 3-5.

[0509] Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.

[0510] The intermediate

[0511]

[0512] of can be made by the Scheme 4 described below.125569-02020

[0513]

[0514] In Scheme 4, the preparation of 3-5 is described in Scheme 3. The starting material 3-5 can be protected with a silyl group to give intermediate 4-1. After that, the intermediate 4-1 reacts with acetyl chloride to provide 4-2. The intermediate 4-2 is deprotected to give 4-3, which is converted to bromine 4-4 through an Appel reaction. Finally, intermediate 4-4 goes through an intramolecular cyclization reaction to give the target compounds 4-5.

[0515] Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.

[0516] RbO

[0517] The intermediate o

[0518]

[0519] f Br can be made by the Scheme 4A described below.

[0520]

[0521] In Scheme 4A, the preparation of 4-6 is described in Scheme 4. The starting material 4-6 reacts with 4-6a to afford the intermediate 4A-1 via an Adol reaction. After that, the intermediate 4A-1 is eliminated to give the target compounds 4A-2.

[0522] Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.

[0523] R O U

[0524] The intermediate o

[0525]

[0526] fbBr can be made by the method similar to Scheme 4A by using different starting material, intermediates, and reagents.

[0527]

[0528] 125569-02020

[0529] made by the Scheme 5 described below.

[0530]

[0531] In Scheme 5, the preparation of 4-6 is described in Scheme 4. The starting material 4-6 reacts with PhSeCl to afford the intermediate 5-1 in the presence of a suitable base. After that, the intermediate 5-1 is oxidized, followed by elimination to provide 5-2. The intermediate 5-2 goes through a cyclopropanation reaction to give the target compounds 5-3a / 3b.

[0532] Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.

[0533]

[0534]

[0535] In Scheme 6, the preparation of 5-2 is described in Scheme 5. The starting material 5-2 goes through a two-step sequene of Cu-catalyzed P-boration and Brown hydroboration to provide the intermediate 6-1. After that, the intermediate 6-1 is oxidized to give 6-2. The intermediate 6-2 reacts with DMF-DMA to afford 6-3, which goes through a cyclization reaction to give the target compounds 6-4.

[0536] Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.

[0537] I O

[0538] The intermediate

[0539]

[0540] of Br (wherein Q2 is a cycloalkyl, heterocycloalkyl, or heteroaryl, in which each of the aforementioned is optionally and independently substituted with one or more independently selected Rgsubstituent) can be made by the method similar to125569-02020

[0541] Scheme 5-6 by using different starting material, intermediates, and reagents.

[0542]

[0543] In Scheme 7, the starting material 7-1 is commercially available. The starting material 7-1 can be alkylated to give intermediate 7-2. After that, the intermediate 7-2 goes through an aza-Claisen rearrangement reaction to provide 7-3. The intermediate 7-3 reacts with 7-3a to give 7-4, which is converted to 7-5 via an intramolecular Kulinkovich reaction and then separated into 7-5a / 5b / 5c / 5d with SFC.

[0544] Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.

[0545] The intermediate

[0546]

[0547] of Br can be made by the Scheme 7A described below.

[0548]

[0549] In Scheme 7A, the preparation of 7-5a is described in Scheme 7. The starting material 7-5a reacts with 4-6a to afford the intermediate 7A-1 via an Adol reaction. After that, the125569-02020

[0550] intermediate 7A-1 is eliminated to give the target compounds 7A-2.

[0551] Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.

[0552] I pri

[0553] RbO

[0554] The intermediate o

[0555]

[0556] f tsrcanbe made by the Scheme 7B described below.

[0557]

[0558] In Scheme 7B, the preparation of 7-5b is described in Scheme 7. The starting material 7-5b reacts with 4-6a to afford the intermediate 7B-1 via an Adol reaction. After that, the intermediate 7B-1 is eliminated to give the target compounds 7B-2.

[0559] Also, the target compounds can be synthesized by alternative methods but not limited to the

[0560]

[0561] In Scheme 8, the preparation of 7-5a is described in Scheme 7. The starting material 7-5a reacts with PhSeCl to afford intermediate 8-1 in the presence of a suitable base. After that, the intermediate 8-1 is oxidized, followed by elimination to provide 8-2. The intermediate 8-2 goes through a cyclopropanation reaction followed by SFC separation to give the target compounds 8-3a / 3b.

[0562] Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.125569-02020

[0563]

[0564] made by the Scheme 9 described below.

[0565]

[0566] In Scheme 9, the preparation of 7-5b is described in Scheme 7. The starting material 7-5b reacts with PhSeCl to afford the intermediate 9-1 in the presence of a suitable base. After that, the intermediate 9-1 is oxidized, followed by elimination to provide 9-2. The intermediate 9-2 goes through a cyclopropanation reaction followed by SFC separation to give the target compounds 9-3a / 3b.

[0567] Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.

[0568] The intermediate

[0569]

[0570] of BrCan be made by the Scheme 10 described below.

[0571]

[0572] In Scheme 10, the preparation of 8-2 is described in Scheme 8. The starting material 8-2 goes through a two-step sequene of Cu-catalyzed P-boration and Brown hydroboration can provide the intermediate 10-1. After that, the intermediate 10-1 is oxidized to provide 10-2. The intermediate 10-2 reacts with DMF-DMA to afford 10-3, which goes through a cyclization reaction to give the target compounds 10-4.

[0573] Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.125569-02020

[0574] The intermediate

[0575]

[0576] of Br can be made by the Scheme 10A described below.

[0577]

[0578] In Scheme 10A, the preparation of 10-3 is described in Scheme 10. The starting material 10-3 goes through a cyclization reaction to give the target compounds 10A-1.

[0579] Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.

[0580] The intermediate

[0581]

[0582] of Br can be made by the Scheme 10B described below.

[0583]

[0584] In Scheme 10B, the preparation of 10-3 is described in Scheme 10. The starting material 10-3 goes through a cyclization reaction to give the target compounds 10B-1.

[0585] Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.

[0586] The intermediate

[0587]

[0588] of Br can be made by the Scheme 10C described below.

[0589]

[0590] 125569-02020

[0591] In Scheme 10C, the preparation of 10-3 is described in Scheme 10. The starting material 10-3 goes through a cyclization reaction can provide the intermediate 10C-1. After that, the intermediate 10C-1 is hydrolyzed to provide 10C-2. The decarboxylation of intermediate 10C-2 in the presence of Cu / quinoline can afford 10C-3.

[0592] Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.

[0593] The intermediate o

[0594]

[0595] f0^'T *> Ircanbe made by the Scheme 10D described below.

[0596]

[0597] In Scheme 10D, the preparation of 10-3 is described in Scheme 10. The starting material 10-3 goes through a cyclization reaction to give the target compounds 10D-1.

[0598] Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.

[0599]

[0600] In Scheme 11, the preparation of 9-2 is described in Scheme 9. The starting material 9-2 goes through a two-step sequene of Cu-catalyzed P-boration and Brown hydroboration to provide the intermediate 11-1. After that, the intermediate 11-1 is oxidized to provide 11-2. The125569-02020

[0601] intermediate 11-2 reacts with DMF-DMA to afford 11-3, which goes through a cyclization reaction to give the target compounds 11-4.

[0602] Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.

[0603] The intermediate

[0604]

[0605] of Br can be made by the Scheme 11A described below.

[0606]

[0607] In Scheme 11A, the preparation of 11-3 is described in Scheme 11. The starting material 11-3 goes through a cyclization reaction to give the target compounds 11A-1.

[0608] Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.

[0609] The intermediate

[0610]

[0611] of Br can be made by the Scheme 11B described below.

[0612]

[0613] In Scheme 11B, the preparation of 11-3 is described in Scheme 11. The starting material 11-3 goes through a cyclization reaction to give the target compounds 11B-1.

[0614] Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.

[0615] The intermediate

[0616]

[0617] of Br can be made by the Scheme 11C described125569-02020

[0618] below.

[0619]

[0620] In Scheme 11C, the preparation of 11-3 is described in Scheme 11. The starting material 11-3 goes through a cyclization reaction can provide the intermediate 11C-1. After that, the intermediate 11C-1 is hydrolyzed to provide 11C-2. The decarboxylation of intermediate 11C-2 in the presence of Cu / quinoline can afford 11C-3.

[0621] Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.

[0622] The intermediate

[0623]

[0624] of Br can be made by the Scheme 11D described below.

[0625]

[0626] In Scheme 11D, the preparation of 11-3 is described in Scheme 11. The starting material 11-3 goes through a cyclization reaction to give the target compounds 11D-1.

[0627] Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.

[0628] t(Rd)

[0629] The intermediate

[0630]

[0631] of Br (wherein Q3 is a cycloalkyl, heterocycloalkyl, or heteroaryl, in which each of the aforementioned is optionally and independently substituted with one or more independently selected Rgsubstituent) can be made by the method similar to Scheme 8 to 11D by using different starting material, intermediates, and reagents.

[0632] Rj I4 L2(Rd)s

[0633] >1

[0634] A

[0635] The intermediate

[0636]

[0637] of o Br (wherein Q3 is a cycloalkyl,125569-02020

[0638] heterocycloalkyl, or heteroaryl, in which each of the aforementioned is optionally and independently substituted with one or more independently selected Rgsubstituent) can be made by the method similar to Scheme 8 to 11D by using different starting material, intermediates, and reagents.

[0639] The intermediate o

[0640]

[0641] f Br can be made by the method similar to Scheme 8 to 11D by using different starting material, intermediates, and reagents.

[0642]

[0643]

[0644] In Scheme 12, the preparation of 4-2 is described in Scheme 4. The starting material 4-2 reacts with BociO to afford the intermediate 12-1. After that, the intermediate 12-1 is deprotected to provide 12-2. The intermediate 12-2 reacts with MS2O to afford 12-3, which is alkylated to give the target compounds 12-4. Finally, the intermediate 12-4 is deprotected to give 12-5, which goes through an intramolecular cyclization to give 12-6.

[0645] Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.

[0646] R 'JL-^ 11NY ON

[0647] The intermediate

[0648]

[0649] of1Br can be made by the method similar to Scheme 12 by using different starting material, intermediates, and reagents.125569-02020

[0650]

[0651]

[0652] In Scheme 13, the preparation of 12-2 is described in Scheme 12. The starting material 12-2 goes through an elimination reaction to afford alkene 13-1. After that, the intermediate 13-1 is transformed into 13-2 via a cyclopropanation reaction, which is reduced to afford the intermediate 13-3. Finally, the intermediate 13-3 goes through an intramolecular cyclization to give 13-4, which is alkylated to give the target compounds 13-5a / 5b.

[0653] Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.

[0654] »(Rg)-^YZ,^|

[0655] , / L2Y T

[0656] T Thhe i ■n.termediat.

[0657]

[0658] e o 4f-R11’ ° Br can be made by the method similar to Scheme 13 by using different starting material, intermediates, and reagents.

[0659]

[0660] 125569-02020

[0661]

[0662] In Scheme 14, the starting material 14-1 is commercially available. The starting material 14-1 is alkylated to give intermediate 14-2, which is converted to 14-3 via an aza-Claisen rearrangement reaction. After that, the intermediate 14-3 reacts with 14-3a to give 14-4, which goes through an intramolecular Kulinkovich reaction to afford 14-5. Next, the intermediate 14-5 is transformed into 14-6. Finally, the intermediate 14-6 is brominated with NBS to afford the intermediate 14-7, which is converted to the target compounds 14-8a / 8b via an intramolecular cyclization reaction.

[0663] Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.

[0664] The intermediate

[0665]

[0666] of can be made by the method similar to Scheme 14 by using different starting material, intermediates, and reagents.

[0667] The intermediate o

[0668]

[0669] f

[0670]

[0671] can be made by the Scheme 15 described below.125569-02020

[0672]

[0673] In Scheme 15, the starting material 15-1 is commercially available. The starting material 15-1 is alkylated to give intermediate 15-2, which is converted to 14-3 via cyclopropanation reaction. After that, the intermediate 15-3 is hydrolyed to give 15-4, which reacts with 14-3 to provide 15-5. The intermediate 15-5 goes through an intramolecular Kulinkovich reaction to afford 15-6. Next, the intermediate 15-6 is deprotected to give 15-7. Finally, the intermediate 15-7 is brominated with NBS to afford the intermediate 15-8a / 8b, which is converted to the target compounds 15-9a / 9b / 9c / 9d via an intramolecular cyclization reaction followed by SFC seperation.

[0674] Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.

[0675]

[0676]

[0677] can be made by the Scheme 16 described below.

[0678]

[0679] In Scheme 16, the preparation of 15-8b is described in Scheme 15. The starting material 15-8b is converted to the target compounds 16-la / lb / lc / ld via an intramolecular cyclization reaction followed by SFC seperation.125569-02020

[0680] Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.

[0681] The intermediate

[0682]

[0683] of can be made by the method similar to Scheme 14 by using different starting material, intermediates, and reagents.

[0684] ,'(S)

[0685] S Br

[0686] The compound

[0687]

[0688] of O can be made by the Scheme 17A described below.

[0689]

[0690] In Scheme 17A, the starting material 17A-1 is commercially available. The starting material 17A-1 is boronated to give intermediate 17A-2, which is converted to 17A-3 via amination reaction. After that, the intermediate 17A-3 is allylated to give 17A-4 via Stille reaction, which reacts with 17A-4a to provide 17A-5. The intermediate 17A-5 goes through an intramolecular Kulinkovich reaction to afford 17A-6. Finally, the intermediate 17A-6 is brominated with NBS to afford the intermediate 17A-7.

[0691] Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.

[0692] / Ch S' ^. Br

[0693] The compound

[0694]

[0695] of O can be made by the Scheme 17B described below.

[0696]

[0697] In Scheme 17B, the preperation of starting material 17A-7 is described in Scheme 17A. The starting material is oxidized to give 17B-1. After that, the intermediate 17B-1 goes through125569-02020

[0698] a cyclopropanation reaction and then followed SFC separation to give the target compounds 17B-2.

[0699] Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.

[0700] ,t(s)

[0701] The compound of xp O can be made by the Scheme 17C described below.

[0702]

[0703] In Scheme 17C, the preperation of starting material 17B-1 is described in Scheme 17B. The starting material 17B-1 goes through a cyclopropanation reaction and then followed SFC separation to give the target compounds 17C-1.

[0704] Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.

[0705]

[0706]

[0707] In Scheme 17D, the preperation of starting material 17B-1 is described in Scheme 17B. The starting material 17B-1 goes through a two-step sequene of Cu-catalyzed P-boration and Brown hydroboration to provide the intermediate 17D-1. After that, the intermediate 17D-1 is oxidized to provide 17D-2. The intermediate 17D-2 reacts with DMF-DMA to afford 17D-3, which goes through a cyclization reaction to give the target compounds 17D-4.

[0708] Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.125569-02020

[0709] (S)

[0710] S Br

[0711] The compound

[0712]

[0713] ofKt|can be made by the Scheme 17E described below.

[0714]

[0715] In Scheme 17E, the preparation of 17D-3 is described in Scheme 17D. The starting material 17D-3 goes through a cyclization reaction to give the target compounds 17E-1.

[0716] Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.

[0717] y(s)

[0718] s Br

[0719] The compound

[0720]

[0721] of O can be made by the Scheme 17F described below.

[0722]

[0723] In Scheme 17F, the preparation of 17D-3 is described in Scheme 17D. The starting material 17D-3 goes through a cyclization reaction to give the target compounds 17F-1.

[0724] Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.

[0725] (3)

[0726] N

[0727] Br

[0728] The compound

[0729]

[0730] of can be made by the Scheme 17G described below.

[0731]

[0732] In Scheme 17G, the preparation of 17D-3 is described in Scheme 17D. The starting material 17D-3 goes through a cyclization reaction to give the target compounds 17G-1.

[0733] Also, the target compounds can be synthesized by alternative methods but not limited to the125569-02020

[0734] above procedures.

[0735] The compound

[0736]

[0737] of can be made by the Scheme 17H described below.

[0738]

[0739] In Scheme 17H, the preparation of 17D-3 is described in Scheme 17D. The starting material 17D-3 goes through a cyclization reaction can provide the intermediate 17H-1. After that, the intermediate 17H-1 is hydrolyzed to provide 17H-2. The decarboxylation of intermediate 17H-2 in the presence of Cu / quinoline can afford 17H-3.

[0740] Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.

[0741] t(Rd)-@WS Br

[0742] The intermediate

[0743]

[0744] of U (wherein Q3 is a cycloalkyl, heterocycloalkyl, or heteroaryl, in which each of the aforementioned is optionally and independently substituted with one or more independently selected Rgsubstituent) can be made by the method similar to Scheme 17A to 17H by using different starting material, intermediates, and reagents.

[0745] (Rd)s

[0746] RpL |~L2\7 \

[0747] t(Rd)^M S- ^Br

[0748] The intermediate o

[0749]

[0750] f O (wherein Q3 is a cycloalkyl, heterocycloalkyl, or heteroaryl, in which each of the aforementioned is optionally and independently substituted with one or more independently selected Rgsubstituent) can be made by the method similar to Scheme 17A to 17H by using different starting material, intermediates, and reagents.

[0751] (Rd)s

[0752] RpL I~L2 W \

[0753] n(R3) S' Br

[0754] The intermediate

[0755]

[0756] of O can be made by the method similar to Scheme 17A to 17H by using different starting material, intermediates, and reagents.125569-02020

[0757] . O

[0758] T(RA)I

[0759] The compound

[0760]

[0761] of can be made by the Scheme A described below.

[0762]

[0763] In Scheme A, the preparation of starting material 4-6 is described in Scheme 4. The starting material 4-6 can be converted into A-l via a Miyaura borylation rection, which reacts with A-la to afford the target compounds A-2 via a Suzuki coupling reaction.

[0764] Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.

[0765] . O

[0766] ±(RA)r

[0767] The compound

[0768]

[0769] of can be made by the Scheme B described below.

[0770]

[0771] In Scheme B, the preparation of starting material 4A-2 is described in Scheme 4A. The starting material 4A-2 can be converted into B-l via a Miyaura borylation rection, which reacts with A-la to afford the target compounds B-2 via a Suzuki coupling reaction.

[0772] Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.

[0773] . O

[0774] ±(RA)r

[0775] The compound

[0776]

[0777] of can be made by the Scheme C described below.125569-02020

[0778]

[0779] In Scheme C, the preparation of starting material 5-3a is described in Scheme 5. The starting material 5-3a can be converted to C-l via a Miyaura borylation rection, which reacts with A-la to afford the target compounds C-2 through a Suzuki coupling reaction.

[0780] Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.

[0781] The compound

[0782]

[0783] of can be made by the Scheme D described below.

[0784]

[0785] In Scheme D, the preparation of starting material 5-3b is described in Scheme 5. The starting material 5-3b can be converted to D-l via a Miyaura borylation rection, which reacts with A-la to afford the target compounds D-2 through a Suzuki coupling reaction.

[0786] Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.

[0787] The compound

[0788]

[0789] of can be made by the Scheme E described below.

[0790]

[0791] In Scheme E, the preparation of starting material 6-4 is described in Scheme 6. The starting material 6-4 can be converted to E-l via a Miyaura borylation rection, which reacts with A-la to afford the target compounds E-2 through a Suzuki coupling reaction.125569-02020

[0792] Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.

[0793] Rd-N

[0794] > (RA)I

[0795] The compound

[0796]

[0797] of can be made by the Scheme F described below.

[0798]

[0799] In Scheme F, the preparation of starting material 10A-1 is described in Scheme 10A. The starting material 10A-1 can be converted to F-l via a Miyaura borylation rection, which reacts with A-la to afford the target compounds F-2 through a Suzuki coupling reaction.

[0800] Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.

[0801] The compound of can be made by the Scheme G described

[0802]

[0803]

[0804] In Scheme G, the preparation of starting material 7-5c is described in Scheme 7. The starting material 7-5c can be converted to G-l via a Miyaura borylation rection, which reacts with A-la to afford the target compounds G-2 through a Suzuki coupling reaction.

[0805] Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.

[0806] The compound

[0807]

[0808] of can be made by the Scheme H described below.125569-02020

[0809]

[0810] In Scheme H, the preparation of starting material 7A-2 is described in Scheme 7A. The starting material 7A-2 can be converted to H-l via a Miyaura borylation rection, which reacts with A-la to afford the target compounds H-2 through a Suzuki coupling reaction.

[0811] Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.

[0812] The compound

[0813]

[0814] of can be made by the Scheme I described below.

[0815]

[0816] 1-1

[0817] In Scheme I, the preparation of starting material 8-3a is described in Scheme 8. The starting material 8-3a can be converted to 1-1 via a Miyaura borylation rection, which reacts with A-la to afford the target compounds 1-2 through a Suzuki coupling reaction.

[0818] Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.

[0819] The compound

[0820]

[0821] of can be made by the Scheme J described below.

[0822]

[0823] J-2

[0824] In Scheme J, the preparation of starting material 8-3b is described in Scheme 8. The starting material 8-3b can be converted to J-l via a Miyaura borylation rection, which reacts with A-la to afford the target compounds J-2 through a Suzuki coupling reaction.

[0825] Also, the target compounds can be synthesized by alternative methods but not limited to the125569-02020

[0826] above procedures.

[0827] The compound

[0828]

[0829] of can be made by the Scheme K described below.

[0830]

[0831] In Scheme K, the preparation of starting material 10-4 is described in Scheme 10. The starting material 10-4 can be converted to K-l via a Miyaura borylation rection, which reacts with A-la to afford the target compounds K-2 through a Suzuki coupling reaction.

[0832] Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.

[0833] The compound

[0834]

[0835] of can be made by the Scheme L described below.

[0836]

[0837] In Scheme L, the preparation of starting material 10A-1 is described in Scheme 10A. The starting material 10A-1 can be converted to L-l via a Miyaura borylation rection, which reacts with A-la to afford the target compounds L-2 through a Suzuki coupling reaction.

[0838] Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.

[0839] The compound

[0840]

[0841] of can be made by the Scheme M described below.125569-02020

[0842]

[0843] In Scheme M, the preparation of starting material 10B-1 is described in Scheme 10B. The starting material 10B-1 can be converted to M-l via a Miyaura borylation rection, which reacts with A-la to afford the target compounds M-2 through a Suzuki coupling reaction.

[0844] Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.

[0845] The compound

[0846]

[0847] of can be made by the Scheme N described below.

[0848]

[0849] 10C-3

[0850] In Scheme N, the preparation of starting material 10C-1 is described in Scheme 10C. The starting material 10C-1 can be converted to N-l via a Miyaura borylation rection, which reacts with A-la to afford the target compounds N-2 through a Suzuki coupling reaction.

[0851] Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.

[0852] The compound

[0853]

[0854] of can be made by the Scheme O described below.

[0855]

[0856] In Scheme O, the preparation of starting material 10D-1 is described in Scheme 10D. The starting material 10D-1 can be converted to 0-1 via a Miyaura borylation rection, which reacts125569-02020

[0857] with A-la to afford the target compounds 0-2 through a Suzuki coupling reaction.

[0858] Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.

[0859] t(Rd R O^N^O

[0860] o UfU(RA)r

[0861] The compound

[0862]

[0863] of can be made by the Scheme P described below.

[0864]

[0865] In Scheme P, the starting material P-1 can be made by the method similar to Scheme 8 to 11D by using different starting material, intermediates, and reagents. The starting material P-1 can be converted to P-2 via a Miyaura borylation rection, which reacts with A-la to afford the target compounds P-3 through a Suzuki coupling reaction.

[0866] Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.

[0867] The compounds o

[0868]

[0869] f, wherein RA is H, D, or F; and Q3 is a cycloalkyl, heterocycloalkyl, or heteroaryl, in which each of the aforementioned is optionally and independently substituted with one or more independently selected Rgsubstituent, can be made by the method similar to Scheme G to P by using different starting material, intermediates, and reagents.

[0870] The compounds

[0871]

[0872] of, wherein RA is H, D, or F; and Q3 is a cycloalkyl, heterocycloalkyl, or heteroaryl, in which each of the aforementioned is optionally and independently substituted with one or more independently selected Rgsubstituent, can be made by the method similar to Scheme G to P by using different starting material, intermediates, and reagents.125569-02020

[0873] The compound

[0874]

[0875] of can be made by the Scheme Q described below.

[0876]

[0877] In Scheme Q, the preparation of starting material 12-6 is described in Scheme 12. The starting material 12-6 can be converted to Q-l via a Miyaura borylation rection, which reacts with A-la to afford the target compounds Q-2 through a Suzuki coupling reaction.

[0878] Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.

[0879] The compound

[0880]

[0881] of can be made by the Scheme R described below.

[0882]

[0883] R-2

[0884] In Scheme R, the preparation of starting material 14-8 is described in Scheme 14. The starting material 14-8 can be converted to R-l via a Miyaura borylation rection, which reacts with A-la to afford the target compounds R-2 through a Suzuki coupling reaction.

[0885] Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.

[0886] The compounds

[0887]

[0888] of, wherein RA is H, D, or F can be made by the method similar to Scheme A to R by using different starting material, intermediates, and reagents.125569-02020

[0889] The compound

[0890]

[0891] of can be made by the Scheme SI described below.

[0892] 17A-7

[0893]

[0894] In Scheme SI, the preparation of starting material 17A-7 is described in Scheme 17A. The starting material 17A-7 can be converted to Sl-1 via a Miyaura borylation rection, which reacts with A-la to afford the target compounds Sl-2 through a Suzuki coupling reaction.

[0895] Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.

[0896] D( VN^O

[0897] ZW XUw

[0898] The compound

[0899]

[0900] of °Jcan be made by the Scheme S2 described below.

[0901]

[0902] S2-1 S2-2

[0903] In Scheme S2, the preparation of starting material 17B-2 is described in Scheme 17B. The starting material 17B-2 can be converted to S2-1 via a Miyaura borylation rection, which reacts with A-la to afford the target compounds S2-2 through a Suzuki coupling reaction.

[0904] Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.

[0905] The compound

[0906]

[0907] of can be made by the Scheme S3 described below.

[0908]

[0909] S3-2125569-02020

[0910] In Scheme S3, the preparation of starting material 17C-1 is described in Scheme 17C. The starting material 17C-1 can be converted to S3-1 via a Miyaura borylation rection, which reacts with A-la to afford the target compounds S3-2 through a Suzuki coupling reaction.

[0911] Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.

[0912] H

[0913] ^(RA)1

[0914] The compound

[0915]

[0916] of can be made by the Scheme S4 described below.

[0917]

[0918] S4-2

[0919] In Scheme S4, the preparation of starting material 17D-4 is described in Scheme 17D. The starting material 17D-4 can be converted to S4-1 via a Miyaura borylation rection, which reacts with A-la to afford the target compounds S4-2 through a Suzuki coupling reaction.

[0920] Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.

[0921] The compound

[0922]

[0923] of can be made by the Scheme S5 described below.

[0924] Bpin

[0925]

[0926] S5-1 S5-2

[0927] In Scheme S5, the preparation of starting material 17E-1 is described in Scheme 17E. The starting material 17E-1 can be converted to S5-1 via a Miyaura borylation rection, which reacts with A-la to afford the target compounds S5-2 through a Suzuki coupling reaction.

[0928] Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.

[0929] The compound

[0930]

[0931] of can be made by the Scheme S6125569-02020

[0932] described below.

[0933]

[0934] S6-1

[0935] In Scheme S6, the preparation of starting material 17F-1 is described in Scheme 17F. The starting material 17F-1 can be converted to S6-1 via a Miyaura borylation rection, which reacts with A-la to afford the target compounds S6-2 through a Suzuki coupling reaction.

[0936] Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.

[0937] The compound

[0938]

[0939] of can be made by the Scheme S7 described below.

[0940]

[0941] In Scheme S7, the preparation of starting material 17G-1 is described in Scheme 17G. The starting material 17G-1 can be converted to S7-1 via a Miyaura borylation rection, which reacts with A-la to afford the target compounds S7-2 through a Suzuki coupling reaction.

[0942] Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.

[0943] H

[0944] N^O

[0945] J(RA)r

[0946] The compound

[0947]

[0948] of can be made by the Scheme S8 described below.

[0949]

[0950] S8-2

[0951] In Scheme S8, the preparation of starting material 17H-3 is described in Scheme 17H. The starting material 17H-3 can be converted to S8-1 via a Miyaura borylation rection, which reacts with A-la to afford the target compounds S8-2 through a Suzuki coupling reaction.125569-02020

[0952] Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.

[0953] The compound

[0954]

[0955] of UM can be made by the Scheme S9 described below.

[0956] S'

[0957]

[0958] S9-1 S9-2 S9-3

[0959] In Scheme S9, the starting material S9-1 can be made by the method similar to Scheme 17A to 17H by using different starting material, intermediates, and reagents. The starting material S9-1 can be converted to S9-2 via a Miyaura borylation rection, which reacts with A-la to afford the target compounds S9-3 through a Suzuki coupling reaction.

[0960] Also, the target compounds can be synthesized by alternative methods but not limited to the above procedures.

[0961] The compounds o

[0962]

[0963] f, wherein RA is H, D, or F; and Q3 is a cycloalkyl, heterocycloalkyl, or heteroaryl, in which each of the aforementioned is optionally and independently substituted with one or more independently selected Rgsubstituent, can be made by the method similar to Scheme SI to S9 by using different starting material, intermediates, and reagents.

[0964] 1 I(Ro)j

[0965] The compounds

[0966]

[0967] of0 1, wherein RA is H, D, or F, can be made by the method similar to Scheme SI to S9 by using different starting material, intermediates, and reagents.

[0968] (R3)n

[0969] .z°

[0970] m(R2)l

[0971] k(

[0972] The compounds oR

[0973]

[0974] f, wherein RA is H, D, or F can be made by the method similar to Scheme A to S9 by using different starting material,125569-02020

[0975] intermediates, and reagents.

[0976] The compounds o

[0977]

[0978] f wherein RA is H, D, or F can be made by the method similar to Scheme A to S9 by using different starting material, intermediates, and reagents.

[0979] 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.

[0980] 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:

[0981] Example INT-A-1: Preparation of 3-(2-chloro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)piperidine-2, 6-dione

[0982] Synthesis of l-bromo-3-(bromomethyl)-2-chlorobenzene: Into a 100-mL roundbottom flask, were placed l-bromo-2-chloro-3 -methylbenzene (5.0 g, 24.33 mmol, 1.0 eq), NBS (4.79 g, 26.91 mmol, 1.1 eq), BPO (298 mg, 1.23 mmol, 0.05 eq) and CC14(50 mL), the mixture was stirred at 90°C for 6 hours. The reaction was evaporated to dryness under reduced pressure. The residue was diluted with ethyl acetate (25 mL), filtered and evaporated to dryness under reduced pressure. The residue was purified by a flash column (silica gel, heptane) to afford 1-bromo-3-(bromomethyl)-2-chlorobenzene (4.51 g, 59%) as a colorless liquid. 'HNMR (500 MHz, CDC13) 57.60 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.12 (t, J = 7.8 Hz, 1H), 4.62 (s, 2H).

[0983] Synthesis of 2-(3-bromo-2-chlorophenyl) acetonitrile: To a solution of l-bromo-3-(bromomethyl)-2-chlorobenzene (4.5 g, 15.83 mmol, 1.0 eq) and TMSCN (2.34 mg, 23.59125569-02020

[0984] mmol, 1.5 eq) in DCM (40 mL) was cooled down to 0°C under nitrogen atmosphere. TBAF (27.76 mL, 1 M in THF, 1.5 eq) was added by dropwise. The mixture was stirred for 1.5 hours at 25°C under nitrogen protection. The reaction was extracted with water (3x30 mL), dried over Na₂SO₄, filtered and evaporated to dryness under reduced pressure. The residue was purified by a flash column (silica gel, ethyl acetate / n-hexane =0:1-5:95) to afford 2-(3-bromo-2-chlorophenyl) acetonitrile (3.85 g, 105%) as off-white solidTHNMR (500 MHz, CDCh) 87.65 (d, J = 8.0 Hz, 1H), 7.50 (d, J = 7.7 Hz, 1H), 7.20 (t, J = 7.9 Hz, 1H), 3.89 (s, 2H).

[0985] Synthesis of tert-butyl 4-(3-bromo-2-chlorophenyl)-4-cyanobutanoate: A solution of 2-(3-bromo-2-chlorophenyl) acetonitrile (3.8 g, 16.49 mmol, 1.0 eq) in THF (36 mL) was cooled down to 0°C under nitrogen atmosphere. Sodium methoxide (178.4 mg, 3.3 mmol, 0.2 eq) and tert-butyl acrylate (2.11 g, 16.46 mmol, 1.0 eq) were added. The mixture was stirred for 2.5 hours at 20°C. The reaction was quenched with water (30 mL) and brine (30 mL), extracted with ethyl acetate (2x50 mL). The combined organic phases were washed with brine (2x30 mL), dried over Na₂SO₄. Filtered and evaporated to dryness under reduced pressure. The residue was purified by a flash column (silica gel, EA / n-heptane=0: 1-3:97) to afford tert-butyl 4-(3-bromo-2-chlorophenyl)-4-cyanobutanoate (3.09 g, 52%) as a colorless liquid. 'HNMR (500 MHz, CDCh) 87.64 (dd, 7= 8.0, 1.1 Hz, 1H), 7.52 (dd, 7 = 7.7, 1.0 Hz, 1H), 7.21 (t, 7= 7.9 Hz, 1H), 4.49 (dd, 7 = 8.7, 5.8 Hz, 1H), 2.55 - 2.33 (m, 2H), 2.31 - 2.08 (m, 2H), 1.45 (s, 9H).

[0986] Synthesis of 3-(3-bromo-2-chlorophenyl)piperidine-2, 6-dione: Into a 100-mL roundbottom flask, were placed tert-butyl 4-(3-bromo-2-chlorophenyl)-4-cyanobutanoate (2.8 g, 7.81 mmol, 1.0 eq) and HOAc (16.8 mL), the mixture was stirred at room temperature. Then H2SO4 (3.6 g, 36.7 mmol, 4.7 eq) was added by dropwise, the mixture was stirred at 90°C for 4 hours. The reaction was cooled down to room temperature, dripped into ice water (70 mL), filtered and washed with ice water (2x15 mL) to afford 3-(3-bromo-2-chlorophenyl)piperidine-2, 6-dione (2.0 g, 84.7%) as an off white solid. LC-MS (ESI) [M+Na]+=325.01 / 326.94, tR=4.830 min.

[0987] Synthesis of 3-(2-chloro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)piperidine-2, 6-dione: Into a 50-mL three necked round-bottom flask, were placed 3-(3-bromo-2-chlorophenyl)piperidine-2, 6-dione (2.0 g, 6.61 mmol, 1.0 eq), 1,4-dioxane (32 mL), Bpini (2.01 g, 7.92 mmol, 1.2 eq), KOAc (1.95 g, 19.87 mmol, 3 eq) and Pd(dppf)Cl2, the mixture was stirred at 85°C for 16 hours under nitrogen atmosphere. The reaction was quenched with water (100 mL), extracted with ethyl acetate (2x50 mL). The combined organic phases were washed with brine (2x100 mL), dried over Na₂SO₄. Filtered and evaporated to dryness under reduced pressure. The residue was purified by a flash column (silica gel, EA / n-heptane=0:1-30:70) to afford 3-(2-chloro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-125569-02020

[0988] yl)phenyl)piperidine-2, 6-dione (1.32 g, 57%) as an off white solid. LC-MS (ESI) [M+H]+=350.18, tR=5.601 min.

[0989] Example INT-A-2& A-3: Preparation of (S)-8-bromo-2,3,4,4a,5,6-hexahydro-lH-pyrido[l,2-a]quinolin-l-one and ( / ?)-8-bromo-2,3,4,4a,5,6-hexahydro-lH-pyrido[l,2-a]quinolin-l-one

[0990] Synthesis of l-(tert-butyl) 7-ethyl 3-oxoheptanedioate: To a stirred solution of 2,2-dimethyl-l,3-dioxane-4, 6-dione (1 g, 6.94 mmol, 1.0 eq) in dichloromethane (50 mL) at 0°C was added pridine (1.4 mL, 17.35 mmol, 2.5 eq) dropwise and the reaction was stirred for 15 minutes to give a colorless solution. A solution of ethyl 5-chloro-5-oxopentanoate (1.07 mL, 6.8 mmol, 1.0 eq) in dichloromethane (50 mL) was added dropwise at 0°C over a period of 45 minutes. The mixture was stirred for 1 hour at 0°C and then for 1 hour at 25 °C to give an orange solution. The reaction was diluted with dichloromethane (100 mL) and poured into a mixture of HC1 (2 M) and crushed ice (ca. 150g). The organic phase was separated and the aqueous layer extracted with dichloromethane (2 x 50mL). The combined organic extracts were washed with HC1 (2 M, 2x25mL) and sat. NaCl (40mL), dried (Na₂SO₄), filtered, and concentrated under vacuum to afford the orange oil. This oil was carried forward to the next step without purification. The crude was dissolved in tert-butanol (50 mL) and heated under reflux for 16 hours. The reaction was quenched with water (20 mL) and extracted with EtOAc (3x100 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by a flash column (silica gel, ethyl acetate / petroleum ether=0: 1-1:3) to afford 1 -(tert-butyl) 7-ethyl 3-oxoheptanedioate (310 mg, 17.3%) as a yellow oil. LC-MS (ESI) [M+H+Na]+=281.2.

[0991] 'HNMR (400 MHz, Chloroform-d) 54.12 (q, J= 7.2 Hz, 2H), 3.34 (s, 2H), 2.61 (t, J = 7.2 Hz, 2H), 2.33 (t, J = 7.2 Hz, 2H), 1.91 (t, J = 7.2 Hz, 2H), 1.47 (s, 9H), 1.25 (t, J = 7.2 Hz, 3H).

[0992] Synthesis of ethyl 7-(5-bromo-2-nitrophenyl)-5-oxoheptanoate: A solution of 1 -(tert-butyl) 7-ethyl 3-oxoheptanedioate (7.5 g, 29.03 mmol, 1.0 eq) in tetrahydrofuran (50 mL) at 0°C was treated with NaH (1.16 g, 29.03 mmol, 1.0 eq) and stirred at 0°C for 15 minutes. To the colorless anion was slowly added dropwise 4-bromo-2-(bromomethyl)-l -nitrobenzene (8.56 g, 29.03 mmol, 1.0 eq) in tetrahydrofuran (50 mL). The reaction was stirred with gradual warming to 25°C for 16 hours, and then at 50°C for 1 hour. After cooling, the crude reaction was poured into sat. NH4CI (20 mL) and extracted with ethyl acetate (2x25 mL). The combined organic extracts were washed with brine, dried (MgSCU), filtered, and concentrated under vacuum to give yellow oil. The crude product was dissolved in dichloromethane (50 mL), and then treated125569-02020

[0993] with triethylsilane (5 mL) and trifluoroacetic acid (5 mL) for 5 hours. The solvent was removed under vacuum and the crude product was heated at 130°C for 15 minutes to promote decarboxylation. The residue was purified by a flash column (silica gel, ethyl acetate / petroleum ether=0: 1-1:1) to afford ethyl 7-(5-bromo-2-nitrophenyl)-5-oxoheptanoate (8.33 g, 77.1%) as a brown oil. LC-MS (ESI) [M+H]+=372.0, 374.0.

[0994] Synthesis of ethyl 4-(6-bromo-l,4-dihydroquinolin-2-yl)butanoate: To a solution of ethyl 7-(5-bromo-2-nitrophenyl)-5-oxoheptanoate (7.72 g, 20.74 mmol, 1.0 eq) in EtOH (50 mL) and H2O (50 mL) were added Fe (5.79 g, 103.71 mmol, 5.0 eq) and NH4CI (11.09 g, 207.41 mmol, 10.0 eq). The reaction was stirred for 16 hours at 50°C. The reaction was filtered and concentrated under reduced pressure. The reaction was quenched with water (20 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by a flash column (silica gel, ethyl acetate / petroleum ether=0:2-l: 1) to afford ethyl 4-(6-bromo-l,4-dihydroquinolin-2-yl)butanoate (717 mg, 10.1%) as a white solid.

[0995] LC-MS (ESI) [M+H]+=326.2, 328.0. 'H NMR (400 MHz, CDCl3) 57.11-6.96 (m, 2H), 6.34 (d, J = 8.4 Hz, 1H), 4.14 (q, J = 7.2 Hz, 2H), 3.83 (s, 1H), 3.- 3.18 (m, 1H), 2.84-2.63 (m, 2H), 2.35 (t, J = 7.2 Hz, 2H), 1.98-1.89 (m, 1H), 1.78-1.69 (m, 2H), 1.64-1.56 (m, 1H), 1.55-1.49 (m, 2H), 1.26 (t, 7= 7.2 Hz, 3H).

[0996] Synthesis of 4-(6-bromo-l,2,3,4-tetrahydroquinolin-2-yl)butanoic acid: To a solution of ethyl 4-(6-bromo-l,4-dihydroquinolin-2-yl)butanoate (717 mg, 2.19 mmol, 1.0 eq) in tetrahydrofuran (5 mL) and H2O (5 mL) were added lithium hydroxide hydrate (184.44 mg, 4.39 mmol, 2.0 eq) and stirred for 16 hours at 25°C. The residue was concentrated under reduced pressure. The pH adjusted to ~3 using HC1(2 M). The reaction was extracted with ethyl acetate (3x20 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 4-(6-bromo-l,2,3,4-tetrahydroquinolin-2-yl)butanoic acid (636 mg, 97.1%) as a white solid. LC-MS (ESI) [M+H]+=298.0, 300.0.

[0997] Synthesis of (S)-8-bromo-2,3,4,4a,5,6-hexahydro-lH-pyrido[l,2-a]quinolin-l-one and ( / ?)-8-bromo-2,3,4,4a,5,6-hexahydro-lH-pyrido[l,2-a]quinolin-l-one: To a solution of 4-(6-bromo-l,2,3,4-tetrahydroquinolin-2-yl)butanoic acid (300 mg, 1.01 mmol, 1.0 eq) in N, N-dimethylformamide (3 mL) was added EDCI (212.16 mg, 1.11 mmol, 1.1 eq) and HOBt (149.55 mg, 1.11 mmol, 1.1 eq), and then TEA (0.418mL, 3.02 mmol, 3.0 eq) was added and stirred for 2 hours at 50°C. The reaction was quenched with water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous125569-02020

[0998] sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by a flash column (silica gel, ethyl acetate / petroleum ether=0:2-l:l) and then purified by SFC using the following conditions: Regis Whelk(R, R),40 mm I. D.x250mm, 10pm: mobile phase, Methanol((40% Phase B up to 40% in 24 min); Detector, UV 254 / 214 nm, tR=12.3 min to afford (S)-8-bromo-2,3,4,4a,5,6-hexahydro-l / / -pyrido[l,2-a]quinolin-l-one (75 mg, 26.6%) as a white solid, and tR=20.9 min to afford (R)-8-bromo-2,3,4,4a,5,6-hexahydro-lH-pyrido[l,2-a]quinolin-1-one (75 mg, 26.6%) as a white solid. LC-MS (ESI) [M+H]+=280.0, 282.0.

[0999] Example INT-A-4& A-5: Preparation of (3 / ?)-3-(3-bromo-2-chlorophenyl)-3-fluorohexahydropyridine-2, 6-dione and (3S)-3-(3-bromo-2-chlorophenyl)-3-fluorohexahydropyridine-2, 6-dione

[1000] Synthesis of 2-(3-bromo-2-chlorophenyl)-2-fluoroacetonitrile: To a solution of Znb (0.15 g, 0.456 mmol, 0.02 eq) in dichloromethane (50 mL) were added 3-bromo-2-chlorobenzene-l-carbaldehyde (5.00 g, 22.8 mmol, 1.0 eq) and trimethylsilyl cyanide (2.26 g, 22.8 mmol, 1.0 eq) at 0°C under N2. The resulting mixture was stirred at 25°C for 2 hours under N2. The reaction was added DAST (3.67 g, 22.8 mmol, 1.0 eq) at 0°C under N2. The resulting mixture was stirred for 12 hours at 25°C under N2. The reaction was quenched with water (300 mL) and extracted with dichloromethane (3x350 mL). The combined organic layers was washed with brine (3x300 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by a flash column (silica gel, ethyl acetate / petroleum ether=0:10-l:10) to afford 2-(3-bromo-2-chlorophenyl)-2-fluoroacetonitrile (4.00 g, 70.7%) as a yellow oil. 'HNMR (400 MHz, Chloroform-d) 57.79 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.36-7.28 (m, 1H), 6.43 (d, J = 45.2 Hz, 1H).

[1001] Synthesis of methyl 4-(3-bromo-2-chlorophenyl)-4-cyano-4-fluorobutanoate: To a solution of 2-(3-bromo-2-chlorophenyl)-2-fluoroacetonitrile (3.00 g, 12.1 mmol, 1.0 eq) in dimethyl sulfoxide (30 mL) was added methyl prop-2-enoate (1.04 g, 12.1 mmol, 1.0 eq) and DBU (0.37 g, 2.4 mmol, 0.2 eq) at 25°C. The resulting mixture was stirred for 18 hours at 25°C. The reaction was quenched with water (300 mL) and extracted with ethyl acetate (3x500 mL). The combined organic layers was washed with brine (3x300 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by a flash column (silica gel, ethyl acetate / petroleum ether = 0: 10-1: 10) to afford methyl 4-(3-bromo-2-chlorophenyl)-4-cyano-4-fluorobutanoate (2.2 g, 54.5%) as a yellow oil. 'HNMR (400 MHz, Chloroform-d) 57.70 (dd, J = 8.0, 1.6 Hz, 1H), 7.54-7.43 (m, 1H), 7.22-7.16 (m, 1H), 3.61 (s, 3H), 2.92-2.77 (m, 1H), 2.71-2.56 (m, 2H), 2.53-2.40 (m, 1H).125569-02020

[1002] Synthesis of 3-(3-bromo-2-chlorophenyl)-3-fluorohexahydropyridine-2, 6-dione: To a solution of methyl 4-(3-bromo-2-chlorophenyl)-4-cyano-4-fluorobutanoate (2.20 g, 6.57 mmol, 1.0 eq) in acetic acid (20 mL) was added H2SO4 (0.35 mL, 6.57 mmol, 1.0 eq) at 25°C under N2. The resulting mixture was stirred for 4 hours at 140°C. The residue was purified by a reverse phase column chromatography (MeCN: 0.1% TFA in H2O = 50%~70%) to afford 3-(3-bromo-2-chlorophenyl)-3-fluorohexahydropyridine-2, 6-dione (100 mg, 4.8%) as a yellow solid.

[1003] 'HNMR (400 MHz, dimethyl sulfoxide-^) 5 11.59 (s, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 7.8 Hz, 1H), 7.45 (t, J = 8.0 Hz, 1H), 2.97-2.74 (m, 2H), 2.70-2.58 (m, 1H), 2.35-2.18 (m, 1H).

[1004] Synthesis of (3 / ?)-3-(3-bromo-2-chlorophenyl)-3-fluorohexahydropyridine-2, 6-dione and (3S)-3-(3-bromo-2-chlorophenyl)-3-fluorohexahydropyridine-2, 6-dione: The racemate residue was purified by SFC using the following conditions: Daicel ChiralCel OJ; 40mm I. D.x250mm,10pm; mobile phase, supercritical CO2; and isopropanol(0% Phase B up to 53% in 20 min) Detector, UV 254 / 214 nm, Rt = 5.20 min to afford to obtained (3S)-3-(3-bromo-2-chlorophenyl)-3-fluorohexahydropyridine-2, 6-dione (20 mg, 20.0%) as a yellow solid and Rt = 6.38 min to obtained (3R)-3-(3-bromo-2-chlorophenyl)-3-fluorohexahydropyridine-2, 6-dione (20 mg, 20.0%) as a yellow solid as a yellow solid. Faster peak (Rt = 5.20 mins). 'HNMR (400 MHz, dimethyl sulfoxide-^,) 8 11.53 (s, 1H), 7.89 (dd, J = 8.0, 1.2 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.45 (t, J = 8.0 Hz, 1H), 2.95-2.78 (m, 2H), 2.65-2.58 (m, 1H), 2.33-2.18 (m, 1H). Slower peak (Rt = 6.38 mins). 'HNMR (400 MHz, dimethyl sulfoxide -de 8 11.52 (s, 1H), 7.89 (dd, J = 8.0, 1.2 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.45 (t, J = 8.0 Hz, 1H), 2.99-2.74 (m, 2H), 2.69-2.58 (m, 1H), 2.34-2.17 (m, 1H).

[1005] Example INT-A-7& A-8: Preparation of (4aS)-8-bromo-l-oxo-2-[(lr,3S)-3-[4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutyl]-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinoline and (4a / ?)-8-bromo-l-oxo-2-[(lr,3 / ?)-3-[4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutyl]-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinoline

[1006] Synthesis of 2-methylpropan-2-yl 4-(propan-2-ylidene)hexahydropyridine-l-carboxylate: To a solution of isobutyltriphenylphosphonium bromide (16.27 g, 37.64 mmol, 1.5 eq) in THF (50 mL) was added potassium bis(trimethylsilyl)amide (7.51 g, 37.64 mmol, 1.5 eq) at 0°C under N2. The resulting mixture was stirred at 25°C for 1 hour under N2. The reaction was added 2-methylpropan-2-yl 4-oxohexahydropyridine- 1 -carboxylate (5.00 g, 25.09 mmol, 1.0 eq) at 0°C under N2. The resulting mixture was stirred for 2 hours at 70°C under N2. The reaction was quenched with aq. NH4CI (200 mL) and extracted with ethyl acetate (3x250 mL).125569-02020

[1007] The combined organic layers was washed with brine (3x200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by a flash column (silica gel, ethyl acetate / petroleum ether = 0: 10-1: 10) to afford 2-methylpropan-2-yl 4-(propan-2-ylidene)hexahydropyridine-l -carboxylate (4.00 g, 70.7%) as a yellow oil. 'HNMR (400 MHz, Chloroform-d) 53.30 (t, J = 5.6 Hz, 4H), 2.17 (t, J = 5.6 Hz, 4H), 1.60 (s, 6H), 1.39 (s, 9H).

[1008] Synthesis of methyl 4-(3-bromo-2-chlorophenyl)-4-cyano-4-fluorobutanoate (trifluoroacetic acid salt): To a solution of 2-methylpropan-2-yl 4-(propan-2-ylidene)hexahydropyridine- 1 -carboxylate (3.80 g, 16.86 mmol, 1.0 eq) in dichloromethane (30 mL) was added trifluoroacetic acid (10 mL) at 25°C. The resulting mixture was stirred at 25°C for 3 hours. The reaction was concentrated to afford 4-(propan-2-ylidene)hexahydropyridine trifluoroacetic acid salt (1.91 g, 99.3%) as a yellow solid. LC-MS (ESI) [M+H]+= 126.2.

[1009] Synthesis of 2-methylpropan-2-yl ({3-[4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutyl}amino)methanoate: To a solution of 4-(propan-2-ylidene)hexahydropyridine trifluoroacetic acid (4.50 g, 15.00 mmol, 1.0 eq) in methanol (40 mL) was added 2-methylpropan-2-yl [(3-oxocyclobutyl)amino]methanoate (2.78 g, 15 mmol, 1.0 eq) and sodium acetate (1.23 g, 15 mmol, 1.0 eq) at 25°C. The resulting mixture was stirred for 5 hour at 25°C under N2. The reaction was added sodium triacetoxyborohydride (9.49 g, 44.97 mmol, 3.0 eq) at 25°C under N2. The resulting mixture was stirred for 2 hours at 25°C under N2. The reaction was quenched with H2O (200 mL) and extracted with dichloromethane (3x250 mL). The combined organic layers were washed with brine (3x200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by a flash column (silica gel, methanol / dichloromethane = 0: 10-1: 10) to afford 2-methylpropan-2-yl ({ 3-[4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutyl}amino)methanoate (1.50 g, 34.0%) as a yellow oil. LC-MS (ESI) [M+H]+= 294.8.

[1010] Synthesis of 2-methylpropan-2-yl {[(lr,3r)-3-[4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutyl]amino}methanoate: The residue was purified by a flash column (silica gel, methanol / dichloromethane = 1:15-1:10) to afford 2-methylpropan-2-yl { [( 1 s,3s)-3 - [4-(propan-2-ylidene)hexahydropyridin- 1 -yl] cyclobutyl] amino } methanoate (400 mg, 40.3%) as a yellow solid and 2-methylpropan-2-yl {[(lr,3r)-3-[4-(propan-2-ylidene)hexahydropyridin-l-yl] cyclobutyl] amino} methanoate (300 mg, 30.2%) as a yellow solid.

[1011] Synthesis of (lr,3r)-3-[4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutan-l-amine trifluoroacetic acid: To a solution of 2-methylpropan-2-yl {[(lr,3r)-3-[4-(propan-2-125569-02020

[1012] ylidene)hexahy dropyridin-l-yl] cyclobutyl] amino Jmethanoate (250 mg, 0.85 mmol, 1.0 eq) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL) at 25°C. The resulting mixture was stirred at 25°C for 3 hours. The reaction was filtered and concentrated to afford (lr,3r)-3-[4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutan-l-amine trifluoroacetic acid (200 mg, 76.4%) as a yellow solid. LC-MS (ESI) [M+H]+= 194.7.

[1013] Synthesis of 2-methylpropan-2-yl 6-bromo-2-(2-{[(lr,3r)-3-[4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutyl]amino}ethyl)-l,2,3,4-tetrahydroquinoline-l-carboxylate: To a solution of ( Ir, 3 r)-3-[4-(propan-2-ylidene)hexahy dropyridin-l-yl] cyclobutan-1- amine (220 mg, 1.13 mmol, 1.0 eq) and 2-methylpropan-2-yl 6-bromo-2-(formylmethyl)- 1,2, 3, 4-tetrahydroquinoline-l -carboxylate (400 mg, 1.13 mmol, 1.0 eq) in methanol (5 mL) was added sodium acetate (93 mg, 1.13 mmol, 1.0 eq) at 25°C. The resulting mixture was stirred at 25°C for 12 hours. The reaction was added sodium triacetoxyborohydride (716 mg, 3.40 mmol, 3.0 eq) and stirred at 25°C for 1 hour. The reaction was quenched with aq. NH4CI (100 mL) and extracted with ethyl acetate (3x150 mL). The combined organic layers were washed with brine (3x100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by a flash column (silica gel, methanol / dichloromethane = 1:20 ~ 1:10) to afford 2-methylpropan-2-yl 6-bromo-2-(2-{ [( 1 r,3r)-3- [4-(propan-2-ylidene)hexahydropyridin- 1 -yl] cyclobutyl] amino Jethyl)- 1,2,3,4-tetrahydroquinoline-1 -carboxylate (200 mg, 33.2%) as a yellow solid. LC-MS (ESI) [M+H]+= 532.4.

[1014] Synthesis of 8-bromo-1-oxo-2-[(1r,3r)-3-[4-(propan-2-ylidene)hexahydropyridin-1-yl]cyclobutyl]-2,3,4,4a,5,6-hexahydro-1H-pyrimido[1,6-a]quinoline: To a solution of 6-bromo-2-(2- { [( 1 r,3 r)-3 - [4-(propan-2-ylidene)hexahydropyridin- 1 -yl] cyclobutyl] amino } ethyl)-1,2,3,4-tetrahydroquinoline (100 mg, 0.23 mmol, 1.0 eq) in dichloromethane (3 mL) was added DIEA (0.12 mL, 0.69 mmol, 3.0 eq) and triphosgene (22.64 mg, 0.076 mmol, 0.3 eq) at 0°C under N2. The resulting mixture was stirred for 2 hours at 25°C under N2. The reaction was quenched with aq. NaHCOs (100 mL) and extracted with dichloromethane (3x250 mL). The combined organic layers was washed with brine (3x150 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 8-bromo-l-oxo-2-[(lr,3r)-3-[4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutyl]-2,3,4,4a,5,6-hexahydro-1H-pyrimido[l,6-a]quinoline (100 mg, 94.3%) as a yellow solid. LC-MS (ESI) [M+H]+= 459.2.

[1015] Synthesis of (4aS)-8-bromo-l-oxo-2-[(lr,3S)-3-[4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutyl]-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinoline and (4a / ?)-8-bromo-l-oxo-2-[(lr,3 / ?)-3-[4-(propan-2-125569-02020

[1016] ylidene)hexahydropyridin-l-yl]cyclobutyl]-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a] quinoline: The racemate residue was purified by SFC using the following conditions: Daicel ChiralPak AY; 40 mm I. D.x250 mm, 10 pm; mobile phase, n-Hexane; and 0.1% NH3. H2O Methanol (30% Phase B in 19 min) Detector, UV 254 / 214 nm, RT = 11.0 min to afford to obtained (4aS )- 8-bromo- 1 -oxo-2- [( 1 r,3S)-3 - [4-(propan-2-ylidene)hexahydropyridin- 1 -yl]cyclobutyl]-2,3,4,4a,5,6-hexahydro-1H-pyrimido[l,6-a]quinoline (40mg, 26.7%) as a yellow solid and RT = 14.7 min to obtained(4aR)-8-bromo-l-oxo-2-[(lr,3R)-3-[4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutyl]-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinoline (40 mg, 26.7%) as a yellow solid.

[1017] Example INT-A-9& A-10: Preparation of ( / ?)-8-bromo-2-(3-(propan-2-ylidene)cyclobutyl)-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-l-one and (S)-8-bromo-2-(3-(propan-2-y lidene)cyclobutyl)-2,3.4,4a, 5,6-hexahyd ro- 1 H-py rimidol 1.6-a] quinolin- 1 -one Synthesis of 2-methylpropan-2-yl {[3- (dibromomethylidene)cyclobutyl]amino}methanoate: To a solution of 2-methylpropan-2-yl [(3-oxocyclobutyl)amino]methanoate (25 g, 134.9 mmol, 1.0 eq) and PPI13 (177 g, 674.8 mmol, 5.0 eq) in tetrahydrofuran (500 mL) was added carbon tetrabromide (134.3 g, 404.9 mmol, 3.0 eq) at 0°C, then the reaction mixture was stirred at 25°C for 18 hours. To the reaction mixture was added water (1 L). The resulting mixture was extracted with ethyl acetate (3x200 mL). The combined organic phases were washed with water (500 mL), brine (500 mL), dried over anhydrous sodium sulfate, filtered and concentrated to afford a residue. The residue was purified by flash column on silica gel eluting with (ethyl acetate / petroleum ether= 1:20-1: 10) to afford 2-methylpropan-2-yl {[3-(dibromomethylidene)cyclobutyl]amino}methanoate (1.5 g, 3.2%) as a yellow oil. 'HNMR (400 MHz, Chloroform -d): 54.71 (s, 1H), 4.16-3.93 (m, 1H), 3.03-2.83 (m, 2H), 2.52-2.35 (m, 2H), 1.38 (s, 9H).

[1018] Synthesis of 2-methylpropan-2-yl {[3-(propan-2-ylidene)cyclobutyl]amino}methanoate: To a solution of 2-methylpropan-2-yl { [3-(dibromomethylidene)cyclobutyl] amino Jmethanoate (800 mg, 2.4 mmol, 1.0 eq), methylboranediol (561.6 mg, 9.6 mmol, 4.0 eq) and CS2CO3 (1.5 g, 4.8 mmol, 2.0 eq) in dioxane (10 mL) was added Pd(dppf)Cl2(171.6 mg, 0.24 mmol, 0.1 eq), then the reaction mixture was stirred at 100°C for 18 hours under N2. The residue was purified by a flash column (silica gel, ethyl acetate / petroleum ether = 1:20-1:10) to afford 2-methylpropan-2-yl { [3-(propan-2-ylidene)cyclobutyl]amino}methanoate (450 mg, 90.8%) as a yellow oil. 'HNMR125569-02020

[1019] (400 MHz, Chloroform-d): 54.69 (s, 1H), 4.13-3.89 (m, 1H), 3.00-2.84 (m, 2H), 2.39-2.29 (m, 2H), 1.46-1.43 (m, 6H), 1.37 (s, 9H).

[1020] Synthesis of 3-(propan-2-ylidene)cyclobutan-l-amine: To a solution of 2-methylpropan-2-yl {[3-(propan-2-ylidene)cyclobutyl]amino}methanoate (450 mg, 2.3 mmol, 1.0 eq) in dichloromethane (10 mL) was added trifluoroacetic acid (2.7 g, 23.6 mmol, 1.0 eq), then the reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was neutralized with sat. NaHCCh to pH = 8. To the reaction mixture was added water (10 mL). The resulting mixture was extracted with ethyl acetate (3x10 mL). The combined organic phases were washed with water (10 mL), brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to afford 3-(propan-2-ylidene)cyclobutan-l-amine (230 mg, 87.4%) as a yellow oil. LC-MS (ESI) [M+H]+=112.2.

[1021] Synthesis of 2-methylpropan-2-yl 6-bromo-2-(2-{[3-(propan-2-ylidene)cyclobutyl]amino}ethyl)-l,2,3,4-tetrahydroquinoline-l-carboxylate: To a solution of 2-methylpropan-2-yl 6-bromo-2-(formylmethyl)- 1, 2, 3, 4-tetrahydroquinoline- 1 -carboxylate (200 mg, 0.56 mmol, 1.0 eq) and 3-(propan-2-ylidene)cyclobutan-l-amine (62.7 mg, 0.56 mmol, 1.0 eq) in tetrahydrofuran (5 mL) was added sodium triacetoxyborohydride (238.2 mg, 1.2 mmol, 2.0 eq), then the reaction mixture was stirred at 25°C for 18 hours. To the reaction mixture was added water (10 mL). The resulting mixture was extracted with ethyl acetate (3x10 mL). The combined organic phases were washed with water (10 mL), brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to afford a residue. The residue was purified by a flash column (silica gel, methanol / dichloromethane= 1:20-1: 10) to afford 2-methylpropan-2-yl 6-bromo-2-(2-{[3-(propan-2-ylidene)cyclobutyl]amino}ethyl)-l,2,3,4-tetrahydroquinoline-1 -carboxylate (180 mg, 70.9%) as a yellow oil. LC-MS (ESI) [M+H]+= 451.2.

[1022] Synthesis of 6-bromo-2-(2-{[3-(propan-2-ylidene)cyclobutyl]amino}ethyl)-l, 2,3,4-tetrahydroquinoline: To a solution of 2-methylpropan-2-yl 6-bromo-2-(2-{[3-(propan-2-ylidene)cyclobutyl]amino}ethyl)-l,2,3,4-tetrahydroquinoline-l-carboxylate (180 mg, 0.45 mmol, 1.0 eq) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL), then the reaction mixture was stirred at 25°C for 2 hours. The resulting mixture was concentrated to afford a residue. The residue was purified by a flash column (silica gel, methanol / dichloromethane= 1:20-1:10) to afford 6-bromo-2-(2-{[3-(propan-2-ylidene)cyclobutyl] amino} ethyl)- 1, 2, 3, 4-tetrahydroquinoline (150 mg, 96.5%) as a yellow oil.

[1023] LC-MS (ESI) [M+H]+= 351.2.125569-02020

[1024] Synthesis of 8-bromo-l-oxo-2-[3-(propan-2-ylidene)cyclobutyl]-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinoline: To a solution of 6-bromo-2-(2-{[3-(propan-2-ylidene)cyclobutyl]amino}ethyl)-l,2,3,4-tetrahydroquinoline (150 mg, 0.43 mmol, 1.0 eq) in dichloromethane (2 mL) was added DIEA (0.3 mL, 2.1 mmol, 5.0 eq) and triphosgene (38.2mg, 0.13 mmol, 0.3 eq), then the reaction mixture was stirred at 25°C for 1 hour. To the reaction mixture was added water (5 mL). The resulting mixture was extracted with ethyl acetate (3×5 mL). The combined organic phases were washed with water (5 mL), brine (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated to afford a residue. The residue was purified by a flash column (silica gel, ethyl acetate / petroleum ether= 1:20- 1:10) to afford 8-bromo-l-oxo-2-[3-(propan-2-ylidene)cyclobutyl]-2,3,4,4a,5,6-hexahydro-l / / -pyrimido[l,6-a]quinoline (80 mg, 49.6%) as a yellow oil. LC-MS (ESI) [M+H]+= 375.2.

[1025] Synthesis of ( / ?)-8-bromo-2-(3-(propan-2-ylidene)cyclobutyl)-2,3,4,4a,5,6-hexahydro- IH-py rimidol 1.6-a]quinolin- 1 -one and (S)-8-bromo-2-(3-(propan-2-ylideneicyclobutyl )-2,3, 4,4a, 5,6-hexahydro- 1 H-py rimidol 1.6-a | quinolin- 1 -one: 8-bromo- 1 -oxo-2-[3-(propan-2-ylidene)cyclobutyl]-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinoline (80 mg) was separated by SFC (Column: Column: ChiralPak AD-H Daicel chemical Industries, Ltd, 250*30 mm I. D., 5um; Mobile phase A: Supercritical CO2, Mobile phase B: Ethanol (0.1%NH3. H2O); A: B = 70:30, Flow Rate: 50 mL / min; Nozzle Pressure: lOOBar; Column Temperature: 38°C; Wavelength: 220 nm) to afford (R)-8-bromo-2-(3-(propan-2-ylidene)cyclobutyl)-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-l-one (22 mg, 35.0% yield) and (S)-8-bromo-2-(3-(propan-2-ylidene)cyclobutyl)-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-l-one (20 mg, 34.4% yield) as a white solid.

[1026] Example INT-A-11& A-12: Preparation of (4aS)-8-bromo-l-oxo-2-[3-(3,4,5,6-tetrahydro-2H-pyran-4-ylidene)cyclobutyl]-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinoline as a yellow solid and (4a / ?)-8-bromo-l-oxo-2-[3-(3,4,5,6-tetrahydro-2H-pyran-4-y lidene)cyclobutyl]-2,3.4,4a, 5,6-hexahyd ro- 1 H-py rimidol 1.6-a ] quinoline

[1027] Synthesis of 3-(3,4,5,6-tetrahydro-2H-pyran-4-ylidene)cyclobutan-l-amine: To a solution of 2-methylpropan-2-yl {[3-(3,4,5,6-tetrahydro-2 / Z-pyran-4-ylidene)cyclobutyl] amino Jmethanoate (180 mg, 0.71 mmol, 1.0 eq) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL) at 25°C. The resulting mixture was stirred at 25°C for 1 hour. The reaction was filtered and concentrated to afford 3-(3,4,5,6-tetrahydro-2H-pyran-4-ylidene)cyclobutan-l -amine (170 mg, 95.7%, TFA salt) as a yellow solid. LC-MS (ESI) [M+H]+= 154.2.125569-02020

[1028] Synthesis of 2-methylpropan-2-yl 6-bromo-2-(2-{ [3-(3,4,5,6-tetrahydro-2H-pyran-4-ylidene)cyclobutyl]amino}ethyl)-l,2,3,4-tetrahydroquinoline-l-carboxylate: To a solution of 3-(3,4,5,6-tetrahydro-2 / Z-pyran-4-ylidene)cyclobutan-l-amine TFA salt (170 mg, 0.65 mmol, 1.0 eq) in tetrahydro furan (1 mL) and isopropyl alcohol (1 mL) was added 2-methylpropan-2-yl 6-bromo-2-(formylmethyl)- 1, 2, 3, 4-tetrahydroquinoline- 1 -carboxylate (231 mg, 0.65 mmol, 1.0 eq) and titanium tetraisopropanolate (370 mg, 1.30 mmol, 2.0 eq) at 25°C. The resulting mixture was stirred at 25°C for 17 hours. The reaction was added Sodium Triacetoxyborohydride (412 mg, 1.95 mmol, 3.0 eq) and stirred at 25°C for 1 hour. The reaction was quenched with aq. NH4CI (40 mL), filtered and extracted with ethyl acetate (3x50 mL). The combined organic layers was washed with brine (3x50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by a flash column (silica gel, Methanol / Dichloromethane = 1:10 - 1:5) to afford 2-methylpropan-2-yl 6-bromo-2-(2-{[3-(3, 4, 5, 6-tetrahydro-2 / Z-pyran-4-ylidene)cyclobutyl] amino} ethyl)- 1,2, 3, 4-tetrahydroquinoline- 1-carboxylate (100 mg, 31.2%) as a yellow solid. LC-MS (ESI) [M+H]+= 491.2.

[1029] Synthesis of 6-bromo-2-(2-{[3-(3,4,5,6-tetrahydro-2H-pyran-4-ylidene)cyclobutyl]amino}ethyl)-l, 2, 3, 4-tetrahydroquinoline TFA salt: To a solution of 2-methylpropan-2-yl 6-bromo-2-(2-{[3-(3,4,5,6-tetrahydro-2H-pyran-4-ylidene)cyclobutyl]amino}ethyl)-l,2,3,4-tetrahydroquinoline-l-carboxylate (150 mg, 0.31 mmol, 1.0 eq) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL) at 25°C. The resulting mixture was stirred at 25°C for 1 hour. The reaction was filtered and concentrated to afford 6-bromo-2-(2-{[3-(3,4,5,6-tetrahydro-2 / Z-pyran-4-ylidene)cyclobutyl]amino}ethyl)-1,2, 3, 4-tetrahydroquinoline TFA salt (119 mg, 99.6%) as a yellow solid. LC-MS (ESI) [M+H]+= 393.2.

[1030] Synthesis of 8-bromo-l-oxo-2-[3-(3,4,5,6-tetrahydro-2H-pyran-4-ylidene)cyclobutyl]-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinoline: To a solution of 6-bromo-2-(2-{[3-(3,4,5,6-tetrahydro-2 / Z-pyran-4-ylidene)cyclobutyl]amino}ethyl)-l,2,3,4-tetrahydroquinoline (110 mg, 0.28 mmol, 1.0 eq) in dichloromethane (5 mL) was added EthyldiisopropylaMine (0.140 mL, 0.84 mmol, 3.0 eq) and Triphosgene (29.19 mg, 0.09 mmol, 0.35 eq) at 0°C under N2. The resulting mixture was stirred for 2 hours at 25°C under N2. The reaction was quenched with aq. NaHCO₃ (100 mL) and extracted with DCM (3×250 mL). The combined organic layers was washed with brine (3×150 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 8-bromo-l-oxo-2-[3-(3,4,5,6-tetrahydro-2H-pyran-4-ylidene)cyclobutyl]-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinoline (100 mg, 85.3%) as a yellow solid. LC-MS (ESI) [M+H]+= 417.3. 'HNMR (400125569-02020

[1031] MHz, Chloroform-d) 57.60-7.51 (m, 1H), 7.16-7.12 (m, 1H), 7.12-7.10 (m, 1H), 4.91-4.76 (m, 1H), 3.63-3.55 (m, 5H), 3.36-3.25 (m, 2H), 2.89-2.79 (m, 2H), 2.75-2.65 (m, 4H), 2.23-2.16 (m, 1H), 2.06-2.01 (m, 4H), 1.78-1.65 (m, 3H).

[1032] Synthesis of (4aS)-8-bromo-l-oxo-2-[3-(3,4,5,6-tetrahydro-2H-pyran-4-ylidene)cyclobutyl]-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinoline as a yellow solid and (4a / ?)-8-bromo-l-oxo-2-[3-(3,4,5,6-tetrahydro-2H-pyran-4-ylidene)cyclobutyl]-2,3, 4,4a, 5,6-hexahydro-lH-py rimidol l,6-a| quinoline: The residue was purified by SFC using the following conditions: Daicel ChiralCel OZ, 40 mm I. D.x250 mm, 10 pm; mobile phase, Supercritical CO2; and Methanol (60% Phase B in 15 min) Detector, UV 254 / 214 nm, Rt = 7.05 min to afford to obtained (4a5')-8-bromo-l-oxo-2-[3-(3,4,5,6-tetrahydro-2 / Z-pyran-4-ylidene)cyclobutyl]-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinoline (20 mg, 0.048 mmol, 20.0%) as a yellow solid and Rt = 11.32 min to obtained(4aR)-8-bromo-l-oxo-2-[3-(3,4,5,6-tetrahydro-2 / Z-pyran-4-ylidene)cyclobutyl]-2,3,4,4a,5,6-hexahydro-1H-pyrimido[l,6-a]quinoline (20 mg, 0.048 mmol, 20.0%)as a yellow solid.

[1033] Example INT-A-13& A-14: Preparation of 2-[(2S)-6-bromo- l,2,3,4-tetrahydroquinolin-2-yl]ethan-l-ol and 2-[(2 / ?)-6-bromo-l,2,3,4-tetrahydroquinolin-2-yl]ethan-l-ol Synthesis of 2-[(2S)-6-bromo-l,2,3,4-tetrahydroquinolin-2-yl]ethan-l-ol and 2-[(2 / f)-6-bromo-l,2,3,4-tetrahydroquinolin-2-yl]ethan-l-ol: The compound of 2-(6-bromo- 1.2.3.4-tetrahydroquinolin-2-yl)ethan-l-ol (2 g, 7.81 mmol, 1.0 eq) was purified by SFC using the following conditions: Regis Whelk(R, R),50 mm I. D.x250mm, 10pm: mobile phase, Supercritical CO2 and methanol (0% Phase B up to 50% in 6 min); Detector, UV 254 / 214 nm, tR=2.5 min to afford 2-[(2S)-6-bromo-l,2,3,4-tetrahydroquinolin-2-yl]ethan-l-ol (1.1 g, 55.0%) as a yellow solid and tR=3.5 min to afford 2-[(2R)-6-bromo-l,2,3,4-tetrahydroquinolin-2-yl]ethan-l-ol (0.9 g, 45.0%) as a yellow solid.

[1034] Example INT-A-15: Preparation of 2-methylpropan-2-yl 6-bromo-2-(formylmethyl)- 1.2.3.4-tetrahydroquinoline-l-carboxylate

[1035] Synthesis of 6-bromo-2-(4, 4,5, 5-tetramethyl-3-oxa-4-silahex-l-yl)-l, 2,3,4-tetrahydroquinoline: To a solution of 2-(6-bromo-l,2,3,4-tetrahydroquinolin-2-yl)ethan-l-ol (5 g, 19.52 mmol, 1.0 eq) in dichloromethane (50 mL) was added TBSC1 (4.41 g, 29.28 mmol, 1.5 eq) and imidazole (2.66 g, 39.04 mmol, 2.0 eq)at 25°C under nitrogen atmosphere. Then the reaction was stirred at 25°C for 3 hours under nitrogen atmosphere. The residue was purified by a flash column (silica gel, ethyl acetate / petroleum ether=0: 100-5:95) to afford 6-bromo-2-125569-02020

[1036] (4,4,5,5-tetramethyl-3-oxa-4-silahex-l-yl)-l,2,3,4-tetrahydroquinoline (5.2 g, 71.9%) as a yellow oil. LC-MS (ESI) [M+H]+= 370.0. 'HNMR (400 MHz, Chloroform-d) 57.06-6.96 (m, 2H), 6.29 (d, J = 8.4 Hz, 1H), 4.81 (s, 1H), 3.89-3.75 (m, 2H), 3.45-3.35 (m, 1H), 2.89-2.74 (m, 1H), 2.72-2.62 (m, 1H), 1.95-1.83 (m, 1H), 1.80-1.60 (m, 3H), 0.95-0.90 (m, 9H), 0.09 (s, 6H).

[1037] Synthesis of 2-methylpropan-2-yl 6-bromo-2-(4,4,5,5-tetramethyl-3-oxa-4-silahex-l-yl)-l,2,3,4-tetrahydroquinoline-l-carboxylate: The solution of 6-bromo-2-(4, 4,5,5-tetramethyl-3-oxa-4-silahex-l-yl)-l,2,3,4-tetrahydroquinoline (5.2 g, 14.04 mmol, 1.0 eq) in ditert-butyl dicarbonate (64.50 mL, 280.77 mmol, 20.0 eq) was stirred for 48 hours at 60°C under nitrogen protection. The reaction was concentrated under reduced pressure. The residue was purified by a flash column (silica gel, ethyl acetate / petroleum ether=0: 100-5:95) to afford 2-methylpropan-2-yl 6-bromo-2-(4,4,5,5-tetramethyl-3-oxa-4-silahex-l-yl)-l,2,3,4-tetrahydroquinoline-1 -carboxylate (7 g, 95.3%) as a yellow oil. LC-MS (ESI) [M-Boc+H]+= 370.0. 'HNMR (400 MHz, Chloroform-d) 57.45-7.37 (m, 1H), 7.23 (d, J = 9.2 Hz, 2H), 4.70-4.57 (m, 1H), 3.68-3.53 (m, 2H), 2.75-2.65 (m, 2H), 2.17-2.06 (m, 1H), 1.77-1.69 (m, 2H), 1.56 (s, 1H), 1.49 (s, 9H), 0.87 (s, 9H), 0.02 (d, J = 4.0 Hz, 6H).

[1038] Synthesis of 2-methylpropan-2-yl 6-bromo-2-(2-hydroxyethyl)-l, 2,3,4-tetrahydroquinoline-l-carboxylate: The solution of 2-methylpropan-2-yl 6-bromo-2-(4, 4,5,5-tetramethyl-3-oxa-4-silahex-l-yl)-l,2,3,4-tetrahydroquinoline-l-carboxylate (7 g, 14.88 mmol, 1.0 eq) in TBAF in tetrahydrofuran(l M, 30mL) and tetrahydrofuran (30 mL) was stirred for 3 hours at 25°C under nitrogen protection. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (3x50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by a flash column (silica gel, ethyl acetate / petroleum ether =0: 100-30:70) to afford 2-methylpropan-2-yl 6-bromo-2-(2-hydroxyethyl)- 1,2,3, 4-tetrahydroquinoline-1 -carboxylate (4.9 g, 92.45%) as a colorless oil. LC-MS (ESI) [M+H]+= 358.0. 'HNMR (400 MHz, Chloroform-d) 57.26-7.22 (m, 3H), 4.77-4.67 (m, 1H), 3.58 (dd, J = 8.0, 3.2 Hz, 2H), 2.66 (t, J = 6.8 Hz, 2H), 2.36-2.24 (m, 1H), 1.73-1.56 (m, 3H), 1.50 (s, 9H), 1.46-1.38 (m, 1H).

[1039] Synthesis of 2-methylpropan-2-yl 6-bromo-2-(formylmethyl)-l, 2,3,4-tetrahydroquinoline-l-carboxylate: To a solution of 2-methylpropan-2-yl 6-bromo-2-(2-hydroxy ethyl)- 1,2, 3, 4-tetrahydroquinoline-l -carboxylate (500 mg, 1.40 mmol, 1.0 eq) in dichloromethane (5 mL) was added dess-martin periodinane (655 mg, 1.54 mmol, 1.1 eq) at 0°C under nitrogen atmosphere. Then the reaction was stirred at 0°C for 1 hour under nitrogen atmosphere. The reaction mixture was quenched with sodium bicarbonate solution (10 mL) and extracted with dichloromethane (3x20 mL). The combined organic layers were washed with125569-02020

[1040] water (3x10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by a flash column (silica gel, ethyl acetate / petroleum ether=0: 100-30:70) to afford 2-methylpropan-2-yl 6-bromo-2-(formylmethyl)- 1,2, 3, 4-tetrahydroquinoline-l -carboxylate (400 mg, 80.4%) as a yellow oil. LC-MS (ESI) [M+H]+= 300.0. 'HNMR (400 MHz, Chloroform-d) 59.79-9.74 (m, 1H), 7.41-7.31 (m, 1H), 7.29-7.26 (m, 1H), 7.25-7.23 (m, 1H), 5.02-4.93 (m, 1H), 2.70-2.61 (m, 3H), 2.53-2.45 (m, 1H), 2.32 (dd, J = 13.6, 7.2 Hz, 1H), 1.66-1.59 (m, 1H), 1.49 (s, 9H).

[1041] Example INT-A-16: Preparation of (R)-8-bromo-4,4a,5,6-tetrahydro-lH-pyrido[l,2-a]quinolin-l-one

[1042] Synthesis of methyl 2-(quinolin-2-yl)acetate: To a solution of 2-methylquinoline (50.0 g, 349.2 mmol, 1.0 eq) and Dimethyl carbonate (116.4 g, 1.29 mol, 3.7 eq) in THF (500 mL) was added LDA (2.0 M in THF / hexane, Energy Seal, 977.8 mmol, 2.8 eq) dropwise at -78°C, the reaction mixture was stirred at -78 °C for 1 h. After the reaction was completed, saturated NH4CI solution (800 mL) was added and the reaction mixture was extracted by ethyl acetate (3x1000 mL), washed with brine (2x1000 mL), dried over Na₂SO₄, filtered and concentrated in vacuo to give a crude. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether =1:20-1:5) to afford compound methyl 2-(quinolin-2-yl) acetate (batch with 50.0 g to give 140.0 g, 99.6%) as a yellow oil. LC-MS (ESI) [M+H]+=202.1. 'HNMR (400 MHz, Dimethylsulfoxide-<76) 88.38 - 8.28 (m, 1H), 8.00 - 7.89 (m, 2H), 7.80 - 7.69 (m, 1H), 7.61 - 7.56 (m, 1H),7.54 - 7.49 (m, 1H), 4.05 (s, 2H), 3.64 (s, 3H).

[1043] Synthesis of 2-(quinolin-2-yl)ethan-l-ol: To a solution of methyl 2-(quinolin-2-yl)acetate (65.0 g, 323.0 mmol, 1.0 eq) in THF (75 mL) was added DIBAL-H (1.0 M in hexane, 969.0 mmol, 3.0 eq) at -10°C, the reaction was stirred at -10°C for 2 h. After the reaction was completed, the reaction mixture was poured into ice-water (3000 mL), and the mixture was stirred at room temperature for 15 min. The mixture was filtered, the filter cake was washed with ethyl acetate (2x1000 mL), the filtrate was extracted by ethyl acetate (3x400 mL), washed with brine (4x500 mL), dried over Na₂SO₄, filtered and concentrated in vacuo to give a crude. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether =1:2-2:1) to afford compound 2-(quinolin-2-yl)ethan-l-ol (75.0 g ) as a brown solid. LC-MS (ESI) [M+H]+=174.0. 'HNMR (400 MHz, Dimethylsulfoxide-d6) 88.29 - 8.20 (m, 1H), 7.99 - 7.88 (m, 2H), 7.75 - 7.67 (m, 1H), 7.58 - 7.51 (m, 1H), 7.49 - 7.42 (m, 1H), 4.75 - 4.61 (m, 1H), 3.92 - 3.78 (m, 2H), 3.11 - 3.01 (m, 2H).125569-02020

[1044] Synthesis of (R)-2-(l,2,3,4-tetrahydroquinolin-2-yl)ethan-l-ol: 2-(Quinolin-2-yl)ethan-l-ol (18.3 g, 105.6 mmol, 1.0 eq), (S, S)-2 (4.7 g, 5% eq), trifluoroacetic acid (1.2 g, 10.5 mmol, 0.1 eq) and ethanol (210 mL) were added to the reactor in sequence. Then introduce hydrogen into the reactor and allow the reaction to proceed at 0.7 MPa at room temperature for 22 hours. The reaction system was purified by silica gel column chromatography (ethyl acetate / petroleum ether =1:20-1:5) to afford compound (R)-2-( 1,2,3, 4-tetrahydroquinolin-2-yl)ethan-l-ol (15.8 g, 84.4%) as a yellow oil. LC-MS (ESI) [M+H]+=178.1.

[1045] Synthesis of (R)-2-(6-bromo-l,2,3,4-tetrahydroquinolin-2-yl)ethan-l-ol: To a solution of (R)-2-(l,2,3,4-tetrahydroquinolin-2-yl)ethan-l-ol (20.0 g, 112.9 mmol, 1.0 eq) in DMF (200 mL) was added NBS (20.1 g, 112.9 mmol, 1.0 eq) at 0°C under nitrogen atmosphere, the reaction was stirred at 0°C for 1 hour under nitrogen atmosphere. The reaction mixture was quenched with water (200 mL) and extracted with ethyl acetate (3x200 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by a flash column (silica gel, ethyl acetate / petroleum ether =0:100-50:50) to afford (R)-2-(6-bromo-l,2,3,4-tetrahydroquinolin-2-yl)ethan-l-ol (23.0 g, 79.9%) as a yellow oil. LC-MS (ESI) [M+H]+=256.0, 258.0. 'HNMR (400 MHz, CDCh) 5 7.06 - 7.01 (m, 2H), 6.36 (d, J = 8.4 Hz, 1H), 3.94 - 3.89 (m, 1H), 3.85 - 3.79 (m, 1H), 3.49 -3.43 (m, 1H), 2.85 - 2.76 (m, 1H), 2.73 - 2.67 (m, 1H), 1.95 - 1.89 (m, 1H), 1.76 (q, J = 6.0 Hz, 2H), 1.69 - 1.65 (m, 1H).

[1046] Synthesis of (R)-6-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-l, 2,3,4-tetrahydroquinoline: To a solution of (R)-2-(6-bromo- 1,2,3, 4-tetrahydroquinolin-2-yl)ethan-l-ol (23.0 g, 90.2 mmol, 1.0 eq) in dichloromethane (410 mL) was added TBSC1 (20.4 g, 135.3 mmol, 1.5 eq) and imidazole (12.3 g, 180.4 mmol, 2.0 eq) at 25°C under nitrogen atmosphere, the reaction was stirred at 25°C for 3 hours under nitrogen atmosphere. The residue was purified by a flash column (silica gel, ethyl acetate / petroleum ether =0:100-5:95) to afford (R)-6-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-l,2,3,4-tetrahydroquinoline (10.0 g, 30.1%) as a yellow solid. LC-MS (ESI) [M+H]+=370.1, 372.1.

[1047] Synthesis of (R) - 1 - (6-bromo-2- (2- ((tert-butyldimethylsilyl)oxy)ethyl) -3,4-dihydroquinolin-l(2H)-yl)ethan-l-one: To a solution of (R)-6-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-l,2,3,4-tetrahydroquinoline (20.0 g, 54.1 mmol, 1.0 eq) in pyridine (370 mL) was added acetyl chloride (8.5 g, 108.2 mmol, 2.0 eq) dropwise at 0°C. After strring for 1 h at room temperature, the solvent was evaporated under reduced pressure. The residue was taken up with ethyl acetate (1000 mL), and washed with IN HC1 (3x500 mL) and brine (2x500 mL). The organic layer was dried (Na₂SO₄) and concentrated in vacuo to give 23.8125569-02020

[1048] g (crude) of (R)-l-(6-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3,4-dihydroquinolin-l(2H)-yl)ethan- 1-one as a yellow oil. LC-MS (ESI) [M+H]+=412.1, 414.1.

[1049] Synthesis of (R)-l-(6-bromo-2-(2-hydroxyethyl)-3,4-dihydroquinolin-l(2H)-yl)ethan-l-one: To a solution of (R)-l-(6-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3,4-dihydroquinolin-l(2H)-yl)ethan-l-one (22.3 g, 54.1 mmol, 1.0 eq) in tetrahydrofuran (220 mL) was added TBAF (IM in tetrahydrofuran, 66 mL), the resulting solution was stirred at 25°C for 1 hour under nitrogen protection. The reaction was quenched with water (200 mL) and extracted with ethyl acetate (3x200 mL). The organic layer was dried (Na₂SO₄) and concentrated in vacuo to give 22.8 g (crude) of (R)-1-(6-bromo-2-(2-hydroxyethyl)-3,4-dihydroquinolin-1(2H)-yl)ethan-1-one as a yellow oil. LC-MS (ESI) [M+H]+=298.0, 300.0.

[1050] Synthesis of (R)-l-(6-bromo-2-(2-iodoethyl)-3,4-dihydroquinolin-l(2H)-yl)ethan-l-one: To a mixture of THF (300 mL) and PPhs (21.2 g, 81.0 mmol, 1.5 eq) placed on an ice-bath was added iodine (20.4 g, 81.0 mmol, 1.5 eq), imidazole (7.4 g, 108.0 mmol, 2.0 eq) and (R)-l-(6-bromo-2-(2-hydroxyethyl)-3,4-dihydroquinolin-l(2H)-yl)ethan-l-one (16.0 g, 54.0 mmol, 1.0 eq) at 5 min intervals. After the ice batch was removed, the mixture was stirred for 1 h, then water (500 mL) was added to the mixture to stop the reaction. Then, the reaction was extracted with ethyl acetate (3x300 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by a flash column (silica gel, ethyl acetate / petroleum ether =1:20-1:5) to afford (R)-l-(6-bromo-2-(2-iodoethyl)-3,4-dihydroquinolin-l(2H)-yl)ethan-l-one (11.0 g, 59.5% for three steps) as a yellow solid. LC-MS (ESI) [M-CF3COOH+H]+=408.0, 409.9.

[1051] Synthesis of (S)-8-bromo-2,3,4,4a,5,6-hexahydro-lH-pyrido[l,2-a]quinolin-l-one:

[1052] Under N2 protection, (R)-l-(6-bromo-2-(2-iodoethyl)-3,4-dihydroquinolin-l(2H)-yl)ethan-l-one (11.0 g, 27.0 mmol, 1.0 eq) was dissolved in THF (440 mL). At -78°C, LiHMDS was slowly added dropwise, and the reaction mixture was allowed to react at this temperature for 1 hour. Then water (250mL) was added to the mixture to stop the reaction. Then, the reaction was extracted with ethyl acetate (3x400 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by a flash column (silica gel, ethyl acetate / petroleum ether =1:20-1:5) to afford (S)-8-bromo-2,3,4,4a,5,6-hexahydro-lH-pyrido[l,2-a]quinolin-l-one (7.0 g, 92.6%) as a yellow solid.

[1053] Synthesis of (4aR)-8-bromo-2-(phenylselanyl)-2,3,4,4a,5,6-hexahydro-lH-pyrido[l,2-a]quinolin-l-one: To a solution of (S)-8-bromo-2,3,4,4a,5,6-hexahydro-lH-pyrido[l,2-a]quinolin-l-one (300 mg, 1.07 mmol, 1.0 eq) in THF (6 mL) was added LiHMDS (1.0 M in THF, Energy Seal, 1.18 mmol, 1.1 eq) dropwise at -78°C, the reaction mixture was125569-02020

[1054] stirred at -78°C for 1 h. PhSeCl (204.9 mg, 1.07 mmol, 1.0 eq) in THF (6 mL) was added dropwise at -78°C, the reaction mixture was stirred at 0°C for 0.5 h. After the reaction was completed, the reaction mixture was added saturated NH4CI solution (10 mL), extracted by ethyl acetate (3x10 mL), washed with brine (2x10 mL), dried over Na₂SO₄, filtered and concentrated in vacuo to give a crude. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether =1:50-1:20) to afford compound (4aR)-8-bromo-2-(phenylselanyl)-2,3,4,4a,5,6-hexahydro-lH-pyrido[l,2-a]quinolin-l-one (241 mg, 51.7%) as a yellow oil. LC-MS (ESI) [M+H]+=436.0, 438.0.

[1055] Synthesis of (R)-8-bromo-4,4a,5,6-tetrahydro-lH-pyrido[l,2-a]quinolin-l-one: To a solution of m-CPBA (168.7 mg, 0.98 mmol, 1.5 eq) in DCM (15 mL) was added (4aR)-8-bromo-2-(phenylselanyl)-2,3,4,4a,5,6-hexahydro-lH-pyrido[l,2-a]quinolin-l-one (241 mg, 0.55 mmol, 1.0 eq) in DCM (20 mL) at OoC, the reaction was heated at room temperature for 3 h. After the reaction was completed, the reaction mixture was added H₂O (20 mL), extracted by ethyl acetate (3x40 mL), washed with brine (2x30 mL), dried over Na₂SO₄, filtered and concentrated in vacuo to give a crude. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether =1:20-1:50) to afford compound (R)-8-bromo-4,4a,5,6-tetrahydro-lH-pyrido[l,2-a]quinolin-l-one (118 mg, 76.6%) as a yellow oil. LC-MS (ESI) [M+H]+=278.0, 280.1. 'HNMR (400 MHz, Chloroform-d) 57.98 (d, J = 9.2 Hz, 1H), 7.29 (dd, J = 8.8, 2.3 Hz, 1H), 7.22 (d, J = 2.4 Hz, 1H), 6.72-6.67 (m, 1H), 6.08 (d, J = 9.9 Hz, 1H), 4.00-3.92 (m, 1H), 2.79- 2.66 (m, 2H), 2.45 - 2.41 (m, 2H), 2.09 - 2.02 (m, 1H), 1.87-1.77 (m, 1H).

[1056] Example INT-A-17a & INT-A-17b: Preparation of (4aS,5aR)-8-bromo-3,4,5a,6-tetrahydro-5H-cyclopropa[b]pyrido[l,2-a]quinolin-l(2H)-one and (4aR,5aS)-8-bromo-3,4,5a,6-tetrahydro-5H-cyclopropa[b]pyrido[l,2-a]quinolin-l(2H)-one

[1057] Synthesis of N-allyl-4-bromoaniline: To a solution of 4-bromoaniline (65.0 g, 377.9 mmol, 1.0 eq) in DMF (1.3 L) was added allyl bromide (45.7 g, 377.9 mmol, 1.0 eq) and K2CO3 (125.3 g, 906.9 mmol, 2.4 eq), the reaction mixture was stirred at 60°C for 16 h. After the reaction was completed, the reaction mixture was quenched with water (600 mL) and extracted with ethyl acetate (2x600 mL). The combined organic layer was washed with brine (3x600 mL), dried over Na₂SO₄, filtered and concentrated in vacuo to give a crude. The residue was purified by silica gel column chromatography (100% petroleum ether) to afford compound N-allyl-4-bromoaniline (42.5 g, 53.0%) as a yellow oil. LC-MS (ESI) [M+H]+=212.1, 214.1.125569-02020

[1058] 'HNMR (400 MHz, Dimethylsulfoxide-d6) 87.23 - 7.12 (m, 2H), 6.56 - 6.46 (m, 2H), 6.04 (t, J = 5.6 Hz, 1H), 5.95 - 5.77 (m, 1H), 5.27 - 5.02 (m, 2H), 3.71 - 3.60 (m, 2H).

[1059] Synthesis of 2-allyl-4-bromoaniline: To a solution of N-allyl-4-bromoaniline (28.0 g, 132.0 mmol, 1.0 eq) in chlorobenzene (168 mL) was added BF₃•Et₂O(50.1 mL, 198.0 mmol, 1.5 eq), the reaction mixture was stirred at 130°C for 48 h. After the reaction was completed. The reaction mixture poured into 15% NaOH (aq.) (200 mL) and extracted with ethyl acetate (2x200 mL). The combined organic layer was washed with brine (2x200 mL), dried over Na₂SO₄, filtered and concentrated in vacuo to give a crude. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether =1:20-1:10) to afford compound 2-allyl-4-bromoaniline (18.0 g, 64.3%) as a yellow oil. LC-MS (ESI) [M+H]+=212.1, 214.1.

[1060] 'HNMR (300 MHz, Chloroform-d) 57.20 - 7.12 (m, 2H), 6.60 - 6.51 (m, 1H), 6.00 - 5.83 (m, 1H), 5.25 - 5.02 (m, 2H), 5.67 (brs, 2H), 3.25 (d, J = 6.0 Hz, 2H).

[1061] Synthesis of 5-((2-allyl-4-bromophenyl)amino)-5-oxopentanoic acid: To a solution of 2-allyl-4-bromoaniline (15.0 g, 70.7 mmol, 1.0 eq) in toluene (150 mL) was added glutaric anhydrid (8.1 g, 70.7 mmol, 1.0 eq), the reaction mixture was stirred at 120°C for 2 h. After the reaction was completed, the reaction mixture was cooled to room temperature and diluted with hexane (150 mL). The precipitated solid was filtered and washed with hexane (50 mL) and dried under vacuum to afford compound 5-((2-allyl-4-bromophenyl)amino)-5-oxopentanoic acid (batch with 3.0 g to give 32.0 g, crude) as a white solid. LC-MS (ESI) [M+H]+=326.0, 328.0.

[1062] Synthesis of l-(2-allyl-4-bromophenyl)piperidine-2, 6-dione: To a solution of 5-((2allyl-4-bromophenyl)amino)-5-oxopentanoic acid (29.0 g, 88.9 mmol, 1.0 eq) in AciO (150 mL) was added AcONa (10.9 g, 133.4 mmol, 1.5 eq), the reaction mixture was stirred at 120°C for 2 h. After the reaction was completed, the reaction mixture poured into NaHCCh (sat.) (200 mL) and extracted with ethyl acetate (2x200 mL). The combined organic layer was washed with NaHCO3(sat.) (2x200 mL) and brine (2x200 mL), dried over Na₂SO₄, filtered and concentrated in vacuo to give a crude. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether =1:10-1:3) to afford compound 1-(2-allyl-4-bromophenyl)piperidine-2,6-dione (batch with 3.0 g to give 18.0 g, 68.5% for two steps) as a white solid. LC-MS (ESI) [M+H]+=308.0, 310.0. 'HNMR (400 MHz, Chloroform-d) 57.49 - 7.40 (m, 2H), 6.87 (d, J = 8.2 Hz, 1H), 5.88 - 5.69 (m, 1H), 5.16 - 5.02 (m, 2H), 3.13 (d, J = 6.8 Hz, 2H), 2.84 - 2.75 (m, 4H), 2.14 - 2.05 (m, 2H).

[1063] Synthesis of 8-bromo-3,4,5a,6-tetrahydro-5H-cyclopropa[b]pyrido[l,2-a]quinolin-l(2H)-one: Under N2, to a solution of l-(2-allyl-4-bromophenyl)piperidine-2, 6-dione (1.7 g, 5.5125569-02020

[1064] mmol, 1.0 eq) in THF (51 mL) was added MeTi(Oi-Pr)₃ (1.0 M in THF) (11.0 mL, 11.0 mmol, 2.0 eq) and cyclopentylmagnesium chloride (2.0 M in THF) (5.5 mL, 11.0 mmol, 2.0 eq), the reaction mixture was stirred at room temperature for 2 h, and added BF₃•Et₂O (4.25 mL, 16.5 mmol, 3.0 eq). Then the reaction mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction mixture poured into water (25 mL) and extracted with ethyl acetate (2x25 mL). The combined organic layer was washed with brine (2x25 mL), dried over Na₂SO₄, filtered and concentrated in vacuo to give a crude. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether =1:10-1:3) to afford compound 8-bromo-3,4,5a,6-tetrahydro-5H-cyclopropa[b]pyrido[1,2-a]quinolin-1(2H)-one (batch with 300 mg to give 800 mg, 42.2%) as a yellow solid. LC-MS (ESI) [M+H]+=292.1, 294.1. 'HNMR (400 MHz, Chloroform-7) 57.50 (d, J = 8.7 Hz, 1H), 7.31 (dd, J = 8.7, 1.9 Hz, 1H), 7.15 (d, J = 1.6 Hz, 1H), 3.13 (dd, J = 15.6, 3.6Hz, 1H), 2.85 (dd, J = 15.6, 2.4 Hz, 1H), 2.75 - 2.58 (m, 2H), 2.04 - 1.88 (m, 3H), 1.85 - 1.74 (m, 1H), 1.46 - 1.37 (m, 1H), 0.84 (t, J = 6.0 Hz, 1H), 0.54 (dd, J = 8.7, 6.5 Hz, 1H).

[1065] Synthesis of (4aS,5aR)-8-bromo-3,4,5a,6-tetrahydro-5H-cyclopropa[b]pyrido[l,2-a]quinolin-l(2H)-one and (4aR,5aS)-8-bromo-3,4,5a,6-tetrahydro-5H-cyclopropa[b]pyrido[l,2-a]quinolin-l(2H)-one: 8-bromo-3,4,5a,6-tetrahydro-5H-cyclopropa[b]pyrido[l,2-a]quinolin-l(2H)-one (800 mg) was purified by SFC separation to afford (4aS,5aR)-8-bromo-3,4,5a,6-tetrahydro-5H-cyclopropa[b]pyrido[l,2-a]quinolin-l(2H)-one (230 mg) and (4aR,5aS)-8-bromo-3,4,5a,6-tetrahydro-5H-cyclopropa[b]pyrido[l,2-a]quinolin-l(2H)-one (260 mg) (61.3%) both of which are yellow solids. B48571-P1-LC-MS (ESI) [M+H]+=292.1, 294.1. 'HNMR (300 MHz, Chloroform-7) 57.50 (d, J = 8.7 Hz, 1H), 7.31 (dd, 7=8.7, 1.9 Hz, 1H), 7.15 (s, 1H), 3.13 (dd, 7= 15.6, 3.4 Hz, 1H), 2.85 (dd, 7= 15.6, 2.1 Hz, 1H), 2.75-2.58 (m, 2H), 2.05-1.74 (m, 4H), 1.46-1.37 (m, 1H), 0.84 (t, 7 = 5.8 Hz, 1H), 0.54 (dd, J = 8.8, 6.5 Hz, 1H). B48571-P2-LC-MS (ESI) [M+H]+=292.1, 294.1.

[1066] Example 5: Preparation of 3-(2-chloro-3-((S)-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrido[l,2-a]quinolin-8-yl)phenyl)piperidine-2, 6-dione

[1067] Synthesis of 3-(2-chloro-3-((S)-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrido[l,2-a]quinolin-8-yl)phenyl)piperidine-2, 6-dione: To a solution of (S)-8-bromo-2,3,4,4a,5,6-hexahydro-l / Z-pyrido[l,2-a] quinolin- 1 -one (30 mg, 0.11 mmol, 1.0 eq) and 3-(2-chloro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione (37.44 mg, 0.11 mmol, 1.0 eq) in dioxane (2 mL) was added K3PO4 (68.19 mg, 0.32 mmol, 3.0 eq) and125569-02020

[1068] Pd(dppf)Cl2(15.67 mg, 0.02 mmol, 0.2 eq) under N2, and stirred for 6 hours at 100°C. The reaction was quenched with water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified Prep-HPLC using the following conditions: Column, SunFire JB-C235-01, Prime C18, 21.2*250 mm, 5 um; mobile phase, 0.1% FA) and CH3CN ((31% Phase B up to 61% in 1 h); Detector, UV 254 / 214 nm, tR=16.5 min; to afford 3-(2-chloro-3-((S)-l-oxo-2,3,4,4a,5,6-hexahydro-l / Z-pyrido[l,2-a]quinolin-8-yl)phenyl)piperidine-2, 6-dione (5.39 mg, 33.12%) as a white solid. LC-MS (ESI) [M+H]+=423.0. 'HNMR (400 MHz, Chloroform-d) 57.96 (d, J = 8.8 Hz, 1H), 7.95-7.92 (m, 1H), 7.35-7.27 (m, 2H), 7.23-7.15 (m, 3H), 4.38-4.24 (m, 1H), 3.80-3.68 (m, 1H), 3.01-2.87 (m, 2H), 2.86-2.62 (m, 3H), 2.58-2.44 (m, 1H), 2.40-2.24 (m, 2H), 2.23-2.13 (m, 1H), 2.12-2.03 (m, 1H), 2.01-1.80 (m, 3H), 1.78-1.65 (m, 1H).

[1069] Example 6: Preparation of 3-(2-chloro-3-(( / ?)-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrido[l,2-a]quinolin-8-yl)phenyl)piperidine-2, 6-dione

[1070] Synthesis of 3-(2-chloro-3-(( / ?)-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrido[l,2-a]quinolin-8-yl)phenyl)piperidine-2, 6-dione: To a solution of (7?)-8-bromo-2,3,4,4a,5,6-hexahydro-1H-pyrido[1,2-a] quinolin- 1 -one (30 mg, 0.11 mmol, 1.0 eq) and 3-(2-chloro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione (37.44 mg, 0.11 mmol, 1.0 eq) in dioxane (2 mL) were added K3PO4 (68.19 mg, 0.32 mmol, 3.0 eq) and Pd(dppf)Cl2(15.67 mg, 0.02 mmol, 0.2 eq) under N2, and stirred for 6 hours at 100°C. The reaction was quenched with water (20 mL) and extracted with ethyl acetate (3x20 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by Prep-HPLC using the following conditions: Column, SunFire JB-C235-01, Prime C18, 21.2*250 mm, 5 um; mobile phase, 0.1% FA) and CH3CN ((31% Phase B up to 61% in 1 h); Detector, UV 254 / 214 nm, tR=15 min; to afford 3-(2-chloro-3-((7?)-l-oxo-2,3,4,4a,5,6-hexahydro-l / Z-pyrido[l,2-a]quinolin-8-yl)phenyl)piperidine-2, 6-dione (5.44 mg, 33.12%). LC-MS (ESI) [M+H]+=423.0.

[1071] 'HNMR (400 MHz, Chloroform-d) 58.02-7.90 (m, 2H), 7.34-7.26 (m, 2H), 7.24-7.15 (m, 3H), 4.38-4.25 (m, 1H), 3.80-3.66 (m, 1H), 2.98-2.87 (m, 2H), 2.85-2.61 (m, 3H), 2.59-2.45 (m, 1H), 2.41-2.24 (m, 2H), 2.23-2.14 (m, 1H), 2.13-2.04 (m, 1H), 2.01-1.79 (m, 3H), 1.78-1.64 (m, 1H).

[1072] Example 10: Preparation of (3S)-3-{2-chloro-3-[(4aS)-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrido[l,2-a]quinolin-8-yl]phenyl}-3-fluorohexahydropyridine-2, 6-dione125569-02020

[1073] Synthesis of (3S)-3-{2-chloro-3-[(4aS)-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrido[l,2-a]quinolin-8-yl]phenyl}-3-fluorohexahydropyridine-2, 6-dione: To a solution of (4aS)-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,3,4,4a,5,6-hexahydro-lH-pyrido[l,2-a]quinolin-1-one (15 mg, 0.05 mmol, 1.0 eq) in dioxane (2 mL) and H2O (0.2 mL) were added (3S)-3-(3-bromo-2-chlorophenyl)-3-fluorohexahydropyridine-2, 6-dione (15 mg, 0.05 mmol, 1.0 eq), Pd(dppf)Cl2(5 mg, 0.005 mmol, 0.1 eq) and K3PO4 (29 mg, 0.14 mmol, 3.0 eq) at 25°C under N2. The resulting mixture was stirred at 100°C for 2 hours under N2. The reaction was concentrated to give a residue, which was purified by Prep-HPLC (Instrument: Shimadzu LH-40 Liquid Handler, Shimadzu LC-20AP Pump, Shimadzu, SPD-20APUV Detector, Column: Ultimate XB-C18, 50 x 250 mm x 10 pm; Mobile phase A: H2O with 0.1%FA; Mobile phase B: CH3CN; Gradient: B from 35% to 65% in 30 min; Flow Rate: 60 mL / min; Rt = 15.0 min, Column Temperature: 30 °C; Wavelength: 214 nm, 254 nm) to afford (35)-3-{2-chloro-3-[(4aS)-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrido[l,2-a]quinolin-8-yl]phenyl}-3-fluorohexahydropyridine-2, 6-dione (1.96 mg, 9.70%) as a white solid. LC-MS (ESI) [M+H]+= 441.2. 'HNMR (400 MHz, Chloroform-d) 58.25 (s, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.46-7.42 (m, 1H), 7.37 (dd, J = 7.6, 1.6 Hz, 1H), 7.21-7.15 (m, 1H), 7.14 (s, 1H), 3.78-3.66 (m, 1H), 3.13-2.96 (m, 2H), 2.92-2.87 (m, 2H), 2.81-2.64 (m, 2H), 2.57-2.47 (m, 1H), 2.36-2.26 (m, 1H), 2.22-2.14 (m, 1H), 2.11-2.03 (m, 1H), 2.01-1.78 (m, 4H), 1.76-1.66 (m, 1H).

[1074] Example 11: Preparation of (3R)-3-{2-chloro-3-[(4aS)-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrido[l,2-a]quinolin-8-yl]phenyl}-3-fluorohexahydropyridine-2, 6-dione

[1075] Synthesis of (3R)-3-{2-chloro-3-[(4aS)-l-oxo-2,3,4,4a,5,6-hexahydro-l / Z-pyrido[l,2-a]quinolin-8-yl]phenyl}-3-fluorohexahydropyridine-2, 6-dione: To a solution of (4aS)-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,3,4,4a,5,6-hexahydro-lH-pyrido[l,2-a]quinolin-1-one (20 mg, 0.06 mmol, 1.0 eq) in dioxane (2 mL) and H2O (0.2mL) were added (3R)-3-(3-bromo-2-chlorophenyl)-3-fluorohexahydropyridine-2, 6-dione (20 mg, 0.06 mmol, 1.0 eq), Pd(dppf)Cl2(5 mg, 0.006 mmol, 0.1 eq) and K3PO4 (39 mg, 0.18 mmol, 3.0 eq) at 25°C under N2. The resulting mixture was stirred at 100°C for 2 hours under N2. The reaction was concentrated to give a residue, which was purified by Prep-HPLC (Instrument: Shimadzu LH-40 Liquid Handler, Shimadzu LC-20AP Pump, Shimadzu, SPD-20APUV Detector, Column: Ultimate XB-C18, 50 x 250 mm x 10 pm; Mobile phase A: H2O with 0.1%FA; Mobile phase B: CH3CN; Gradient: B from 35% to 65% in 30 min; Flow Rate: 60 mL / min; Rt = 15.0 min, Column Temperature: 30°C; Wavelength: 214 nm, 254 nm) to afford (3R)-3-{2-chloro-3-[(4aS)-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrido[l,2-a]quinolin-8-yl]phenyl}-3-125569-02020

[1076] fluorohexahydropyridine-2, 6-dione (8.34 mg, 31.0%) as a white solid. LC-MS (ESI) [M+H]+= 441.2. 'HNMR (400 MHz, Chloroform-d) 58.30 (s, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.48-7.40 (m, 1H), 7.40-7.34 (m, 1H), 7.22-7.01 (m, 2H), 3.82-3.62 (m, 1H), 3.18-2.95 (m, 2H), 2.93-2.83 (m, 2H), 2.81-2.63 (m, 2H), 2.57-2.46 (m, 1H), 2.38-2.26 (m, 1H), 2.22-2.13 (m, 1H), 2.12 - 2.03 (m, 1H), 1.98-1.80 (m, 3H), 1.78-1.63 (m, 1H).

[1077] Examplel2: Preparation of 3-{2-chloro-3-[(4a / ?)-2-methyl-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl]phenyl}hexahydropyridine-2, 6-dione

[1078] Synthesis of 2-(l,2,3,4-tetrahydroquinolin-2-yl)ethan-l-ol: 2-(quinolin-2-yl)ethan-l-ol (25 g, 144.33 mmol, 1.0 eq) and nickel chloride (3.74 g, 28.87 mmol, 0.2 eq) were dissolved in methanol (250 mL). Then the mixture was cooled to 0°C and NaBH4 (21.84 g, 577.32 mmol, 4.0 eq) was slowly added within 30 minutes. The reaction mixture was allowed to warm to 25°C and stirred for 1 h, then the solvent was distilled off and the residue was dissolved in HC1 (2 M) and neutralized with saturated potassium carbonate solution. The reaction mixture was extracted with dichloromethane (3x200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 2-(l,2,3,4-tetrahydroquinolin-2-yl)ethan-l-ol (25 g, 97.7%) as a yellow oil. LC-MS (ESI) [M+H]+= 178.4. 'HNMR (400 MHz, Chloroform-d) 5 6.97 (t, J = 7.6 Hz, 2H), 6.63 (t, J = 7.6 Hz, 1H), 6.50 (d, J = 8.0 Hz, 1H), 4.22 (s, 1H), 3.96-3.87 (m, 1H), 3.86-3.77 (m, 1H), 3.54-3.43 (m, 1H), 2.90-2.80 (m, 1H), 2.79 -2.70 (m, 1H), 1.97-1.92 (m, 1H), 1.81-1.71 (m, 3H).

[1079] Synthesis of 2-(6-bromo-l,2,3,4-tetrahydroquinolin-2-yl)ethan-l-ol: To a solution of 2-(l,2,3,4-tetrahydroquinolin-2-yl)ethan-l-ol (24 g, 135.4 mmol, 1.0 eq) in N, N-dimethylformamide (200 mL) was added NBS (24.1 g, 135.4 mmol, 1.0 eq) at 0°C under nitrogen atmosphere. Then the reaction was stirred at 0°C for 1 hour under nitrogen atmosphere. The reaction mixture was quenched with water (200 mL) and extracted with ethyl acetate (3x200 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by a flash column (silica gel, ethyl acetate / petroleum ether=0: 100-50:50) to afford 2-(6-bromo- 1,2,3, 4-tetrahydroquinolin-2-yl)ethan-l-ol (30 g, 86.50%) as a yellow oil. LC-MS (ESI) [M+H]+= 256.4. 'HNMR (400 MHz, Chloroform-d) 57.09-6.98 (m, 2H), 6.37 (d, J = 8.4 Hz, 1H), 3.92 (dt, J = 10.8, 5.6 Hz, 1H), 3.83 (dt, J = 10.8, 6.0 Hz, 1H), 3.52-3.43 (m, 1H), 2.86-2.78 (m, 1H), 2.74-2.66 (m, 1H), 1.97-1.90 (m, 1H), 1.77 (q, J = 6.0 Hz, 2H), 1.72-1.61 (m, 1H).

[1080] Synthesis of 6-bromo-2-(2-chloroethyl)-l,2,3,4-tetrahydroquinoline: To a solution of 2-(6-bromo-l,2,3,4-tetrahydroquinolin-2-yl)ethan-l-ol (2.0 g, 7.81 mmol, 1.0 eq) in125569-02020

[1081] dichloromethane (20 mL) was added pyridine (0.63 mL, 195.20 mmol, 25.0 eq) and SOCl2(1.13 mL, 15.62 mmol, 2.0 eq) at 0°C under nitrogen atmosphere. Then the reaction was stirred at 25°C for 5 hours. Then tert-butyl methyl ether (20 mL) was added and the mixture was filtered. The filtrate was washed with water (20 mL) and the aqueous layer was extracted with tert-butyl methyl ether (3x20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by a flash column (silica gel, ethyl acetate / petroleum ether=0: 100-20:80) to afford 6-bromo-2-(2-chloroethyl)-l,2,3,4-tetrahydroquinoline (750 mg, 34.9%) as a yellow solid. LC-MS (ESI) [M+H]+= 274.0.

[1082] 'HNMR (400 MHz, Chloroform-d) 57.11-7.01 (m, 2H), 6.39 (d, J = 8.4 Hz, 1H), 3.75-3.63 (m, 2H), 3.61-3.51 (m, 1H), 2.83-2.66 (m, 2H), 2.03-1.93 (m, 3H), 1.73-1.60 (m, 2H).

[1083] Synthesis of 6-bromo-2-[2-(methylamino)ethyl]-l,2,3,4-tetrahydroquinoline: To a solution of 6-bromo-2-(2-chloroethyl)-l,2,3,4-tetrahydroquinoline (750 mg, 2.73 mmol, 1.0 eq) in N,N-dimethylformamide (10 mL) was added monomethylamine in tetrahydrofuran (1 mol / L) (27.3 mL, 27.31 mmol, 10.0 eq), KI (4.53 g, 27.31mmol, 10.0 eq) and Cs2CO3(2.67 g, 8.19 mmol, 3.0 eq) at 25°C under nitrogen atmosphere. Then the reaction was stirred at 40°C for 18 hours under nitrogen atmosphere. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (3x20 mL). The combined organic layers were washed with water (3x20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by a flash column (silica gel, ethyl acetate / petroleum ether=0: 100-30:70) to afford 6-bromo-2-[2-(methylamino)ethyl]-l, 2,3,4-tetrahydroquinoline (180 mg, 24.4%) as a yellow oil. LC-MS (ESI) [M+H]+= 271.0. 'HNMR (400 MHz, Chloroform-d) 57.06-6.98 (m, 2H), 6.37 (d, J = 8.4 Hz, 1H), 3.43-3.35 (m, 1H), 2.93-2.88 (m, 1H), 2.84-2.75 (m, 2H), 2.72-2.67 (m, 1H), 2.51 (s, 3H), 1.93-1.84 (m, 1H), 1.84-1.50 (m, 4H).

[1084] Synthesis of 8-bromo-2-methyl-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinoline: To a solution of 6-bromo-2-[2-(methylamino)ethyl]-l,2,3,4-tetrahydroquinoline (180 mg, 0.67 mmol, 1.0 eq) in dichloromethane (2 mL) was added N,N-diisopropylethylamine (0.33 mL, 2.01 mmol, 3.0 eq) and triphosgene (79 mg, 0.27 mmol, 0.4 eq) at 25°C under nitrogen atmosphere. Then the reaction was stirred at 25°C for 3 hours under nitrogen atmosphere. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (3x10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by a flash column (silica gel, methanol / dichloromethane=0: 100-30:70) to afford 8-bromo-2-methyl-l-oxo-125569-02020

[1085] 2,3,4,4a,5,6-hexahydro-1H-pyrimido[l,6-a]quinoline (80 mg, 40.5%) as a yellow oil. LC-MS (ESI) [M+H]+= 295.0.

[1086] Synthesis of (4a / ?)-8-bromo-2-methyl-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolone: The compound of 8-bromo-2-methyl-l-oxo-2,3,4,4a,5,6-hexahydro-1H-pyrimido[l,6-a]quinoline (80 mg, 0.27 mmol, 1.0 eq) was purified by SFC using the following conditions: Regis Whelk(R, R),40 mm I. D.x250mm, 10pm: mobile

[1087] phase, Supercritical CO2 and methanol((0% Phase B up to 45% in 11 min); Detector, UV 254 / 214 nm, tR=7.2 min to afford (4aR)-8-bromo-2-methyl-l-oxo-2,3,4,4a,5,6-hexahydro-1H-pyrimido[l,6-a]quinoline (5 mg, 6.2%) as a white solid and (4aS)-8-bromo-2-methyl-l-oxo-2,3,4,4a,5,6-hexahydro-1H-pyrimido[l,6-a]quinoline (10 mg, 12.5%) as a white solid.

[1088] Synthesis of 3-{2-chloro-3-[(4a / ?)-2-methyl-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl]phenyl}hexahydropyridine-2, 6-dione: To a solution of 3-[2-chloro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]hexahydropyridine-2,6-dione (6 mg, 0.02 mmol, 1.0 eq) in dioxane (1 mL) and water (0.1 mL) was added (4aR)-8-bromo-2-methyl-l-oxo-2,3,4,4a,5,6-hexahydro-1H-pyrimido[l,6-a]quinoline (5 mg, 0.02 mmol, 1.0 eq), K3PO4 (11 mg, 0.06 mmol, 3.0 eq) and Pd(dppf)Cl2(2 mg, 0.01 mmol, 0.1 eq) at 25°C under nitrogen atmosphere. Then the reaction was stirred at 100°C for 3 hours under nitrogen atmosphere. The reaction mixture was quenched with sodium bicarbonate solution (10 mL) and extracted with ethyl acetate (3x20 mL). The combined organic layers were washed with water (3x10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC using the following conditions: Column, SunFire JB-C235-31, Prime C18, 21.2*250 mm, 5 um; mobile phase, water (0.1% FA) and CH3CN (30% Phase B up to 60% in 30 min); Detector, UV 254 / 214 nm, tR=18.8 min; to afford 3-{2-chloro-3-[(4aR)-2-methyl-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl]phenyl}hexahydropyridine-2, 6-dione (0.8 mg, 10.7%) as a white solid. LC-MS (ESI) [M+H]+= 438.2. 'HNMR (400 MHz, Dimethylsulfoxide-d6) 5 10.91 (s, 1H), 7.74 (d, J = 9.2 Hz, 1H), 7.40-7.24 (m, 3H), 7.11-7.04 (m, 2H), 4.33 (dd, J = 12.0, 5.2 Hz, 1H), 3.78-3.61 (m, 1H), 2.90 (s, 3H), 2.83-2.72 (m, 3H), 2.57-2.53 (m, 1H), 2.35-2.30 (m, 1H), 2.23-2.16 (m, 1H), 2.11-2.06 (m, 1H), 2.03-1.97 (m, 2H), 1.87-1.78 (m, 1H), 1.70-1.58 (m, 1H), 1.53-1.38 (m, 1H).

[1089] Example 13: Preparation of 3-{2-chloro-3-[(4aS)-2-methyl-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl]phenyl}hexahydropyridine-2, 6-dione125569-02020

[1090] Synthesis of 3-{2-chloro-3-[(4aS)-2-methyl-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl]phenyl}hexahydropyridine-2, 6-dione: To a solution of 3-[2-chloro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]hexahydropyridine-2,6-dione (12 mg, 0.03 mmol, 1.0 eq) in dioxane (1 mL) and water (0.1 mL) was added (4aS)-8-bromo-2-methyl-l-oxo-2,3,4,4a,5,6-hexahydro-1H-pyrimido[l,6-a]quinoline (10 mg, 0.03 mmol, 1.0 eq), K3PO4 (22 mg, 0.10 mmol, 3.0 eq) and Pd(dppf)Cl2(3 mg, 0.01 mmol, 0.1 eq) at 25°C under nitrogen atmosphere. Then the reaction was stirred at 100°C for 3 hours under nitrogen atmosphere. The reaction mixture was quenched with sodium bicarbonate solution (10 mL) and extracted with ethyl acetate (3x20 mL). The combined organic layers were washed with water (3x10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC using the following conditions: Column, SunFire JB-C235-35, Prime C18, 21.2*250 mm, 5 um; mobile phase, water (0.1% FA) and CH3CN(30% Phase B up to 60% in 27 min); Detector, UV 254 / 214 nm, tR=16 min; to afford 3-{2-chloro-3-[(4aS)-2-methyl-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl]phenyl}hexahydropyridine-2, 6-dione (2.04 mg, 13.7%) as a white solid. LC-MS (ESI) [M+H]+= 438.2. 'HNMR (400 MHz, Dimethylsulfoxide-d6) 8 10.91 (s, 1H), 7.77-7.72 (m, 1H), 7.39-7.33 (m, 1H), 7.33-7.26 (m, 2H), 7.10-7.06 (m, 2H), 4.33 (dd, J = 12.0, 5.2 Hz, 1H), 3.78-3.59 (m, 1H), 2.90 (s, 3H), 2.81-2.72 (m, 3H), 2.58-2.52 (m, 1H), 2.36-2.30 (m, 1H), 2.21-2.14 (m, 1H), 2.12-2.07 (m, 1H), 2.06-1.95 (m, 2H), 1.86-1.76 (m, 1H), 1.69-1.59 (m, 1H), 1.49-1.28 (m, 1H).

[1091] Example 14: Preparation of 3-{2-chloro-3-[(4aS)-l-oxo-2-[(lr,3S)-3-[4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutyl]-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl]phenyl}hexahydropyridine-2, 6-dione

[1092] Synthesis of 2-methylpropan-2-yl 6-bromo-2-(2-{[(lr,3r)-3-[4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutyl]amino}ethyl)-l,2,3,4-tetrahydroquinoline-l-carboxylate: To a solution of (lr,3r)-3-[4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutan-l- amine (220 mg, 1.13 mmol, 1.0 eq) and 2-methylpropan-2-yl 6-bromo-2-(formylmethyl)- 1,2, 3, 4-tetrahydroquinoline-l -carboxylate (400 mg, 1.13 mmol, 1.0 eq) in methanol (5 mL) was added sodium acetate (93 mg, 1.13 mmol, 1.0 eq) at 25°C. The resulting mixture was stirred at 25°C for 12 hours. The reaction was added sodium triacetoxyborohydride (716 mg, 3.40 mmol, 3.0 eq) and stirred at 25°C for 1 hour. The reaction was quenched with aq. NH4CI (100 mL) and extracted with ethyl acetate (3x150 mL). The combined organic layers was washed with brine (3x100 mL), dried over anhydrous sodium sulfate, filtered and125569-02020

[1093] concentrated under reduced pressure. The residue was purified by a flash column (silica gel, methanol / dichloromethane = 1:20 ~ 1:10) to afford 2-methylpropan-2-yl 6-bromo-2-(2-{ [( 1 r,3r)-3- [4-(propan-2-ylidene)hexahydropyridin- 1 -yl] cyclobutyl] amino Jethyl)- 1,2,3,4-tetrahydroquinoline-1 -carboxylate (200 mg, 33.2%) as a yellow solid. LC-MS (ESI) [M+H]+= 532.4.

[1094] Synthesis of 8-bromo-l-oxo-2-[(lr,3r)-3-[4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutyl]-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinoline: To a solution of 6-bromo-2-(2- { [( 1 r,3 r)-3 - [4-(propan-2-ylidene)hexahydropyridin- 1 -yl] cyclobutyl] amino } ethyl)-1,2,3,4-tetrahydroquinoline (100 mg, 0.23 mmol, 1.0 eq) in dichloromethane (3 mL) was added DIEA (0.12 mL, 0.69 mmol, 3.0 eq) and triphosgene (22.64 mg, 0.076 mmol, 0.3 eq) at 0°C under N2. The resulting mixture was stirred for 2 hours at 25°C under N2. The reaction was quenched with aq. NaHCO3(100 mL) and extracted with dichloromethane (3x250 mL). The combined organic layers was washed with brine (3x150 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 8-bromo-l-oxo-2-[(lr,3r)-3-[4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutyl]-2,3,4,4a,5,6-hexahydro-1H-pyrimido[l,6-a]quinoline (100 mg, 94.3%) as a yellow solid. LC-MS (ESI) [M+H]+= 459.2.

[1095] Synthesis of 8-bromo-1-oxo-2-[(1r,3r)-3-[4-(propan-2-ylidene)hexahydropyridin-1-yl]cyclobutyl]-2,3,4,4a,5,6-hexahydro-1H-pyrimido[1,6-a]quinoline: The residue was purified by SFC using the following conditions: Daicel ChiralPak AY; 40 mm I. D.x250 mm, 10 pm; mobile phase, n-Hexane; and 0.1% NH3. H2O Methanol(30% Phase B in 19 min) Detector, UV 254 / 214 nm, Rt = 11.0 min to afford to obtained (4aS)-8-bromo-l-oxo-2-[(lr,3S)-3-[4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutyl]-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinoline (40mg, 26.7%) as a yellow solid and Rt = 14.7 min to obtained(4aR)-8-bromo-l-oxo-2-[(lr,3R)-3-[4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutyl]-2,3,4,4a,5,6-hexahydro-1H-pyrimido[l,6-a]quinoline (40 mg, 26.7%) as a yellow solid.

[1096] Synthesis of 3-{2-chloro-3-[(4aS)-1-oxo-2-[(1r,3S)-3-[4-(propan-2-ylidene)hexahydropyridin-1-yl]cyclobutyl]-2,3,4,4a,5,6-hexahydro-1H-pyrimido[1,6-a]quinolin-8-yl]phenyl}hexahydropyridine-2,6-dione: To a solution of (4aS)-8-bromo-l-oxo-2-[(lr,3S)-3-[4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutyl]-2,3,4,4a,5,6-hexahydro- 1H-pyrimido[1,6-a]quinoline (20 mg, 0.044 mmol, 1.0 eq) in dioxane (2 mL) and water (0.2mL) was added 3-[2-chloro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]hexahydropyridine-2, 6-dione (15.25 mg, 0.044 mmol, 1.0 eq), Pd(dppf)Cl2(3.19 mg, 0.004 mmol, O.leq) and K3PO4 (27.78 mg, 0.131 mmol, 3.0 eq) at 25°C under N2. The resulting mixture was stirred at 100°C for 2 hours under N2. The reaction was concentrated to give a125569-02020

[1097] residue, which was purified by Prep-HPLC (Instrument: Shimadzu LH-40 Liquid Handler, Shimadzu LC-20AP Pump, Shimadzu, SPD-20APUV Detector, Column: Xtimate C18, 21.2*250 mm, 5 um; Mobile phase A: H2O with 0.1%FA; Mobile phase B: CH3CN; Gradient: B from 25% to 55% in 30 min; Flow Rate: 20 mL / min; RT = 11.2 min, Column Temperature: 30 °C; Wavelength: 214 nm, 254 nm) to afford 3-{2-chloro-3-[(4aS)-l-oxo-2-[(lr,3S)-3-[4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutyl]-2,3,4,4a,5,6-hexahydro-17 / -pyrimido[l,6-a]quinolin-8-yl]phenyl}hexahydropyridine-2, 6-dione (2.09 mg, 8.0%) as a white solid. LC-MS (ESI) [M+H]+= 601.4. 'HNMR (400 MHz, Chloroform-d) 58.13 (s, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.33-7.27 (m, 2H), 7.21 - 7.13 (m, 2H), 7.11 (s, 1H), 4.86 (s, 1H), 4.38-4.24 (m, 1H), 3.80-3.59 (m, 1H), 3.47-3.33 (m, 2H), 2.97-2.89 (m, 1H), 2.88-2.81 (m, 2H), 2.80-2.67 (m, 2H), 2.55-2.45 (m, 2H), 2.40-2.31 (m, 10H), 2.30-2.25 (m, 2H), 2.15-2.08 (m, 1H), 1.84-1.77 (m, 3H), 1.67 (s, 6H).

[1098] Example 15: Preparation of 3-{2-chloro-3-[(4aR)-1-oxo-2-[(1r,3R)-3-[4-(propan-2-ylidene)hexahydropyridin-1-yl]cyclobutyl]-2,3,4,4a,5,6-hexahydro-1H-pyrimido[1,6-a]quinolin-8-yl]phenyl}hexahydropyridine-2,6-dione

[1099] Synthesis of 3-{2-chloro-3-[(4aR)-1-oxo-2-[(1r,3R)-3-[4-(propan-2-ylidene)hexahydropyridin-1-yl]cyclobutyl]-2,3,4,4a,5,6-hexahydro-1H-pyrimido[1,6-a]quinolin-8-yl]phenyl}hexahydropyridine-2,6-dione: To a solution of (4aR)-8-bromo-l-oxo-2-[(lr,37?)-3-[4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutyl]-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinoline (20 mg, 0.044 mmol, 1.0 eq) in dioxane (2 mL) and water (0.2 mL) was added 3-[2-chloro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]hexahydropyridine-2, 6-dione (15.3 mg, 0.044 mmol, 1.0 eq), Pd(dppf)Cl2(3.19 mg, 0.004 mmol, 0.1 eq) and K3PO4 (27.78 mg, 0.131 mmol, 3.0 eq) at 25°C under N2. The resulting mixture was stirred at 100°C for 2 hours under N2. The reaction was concentrated to give a residue, which was purified by Prep-HPLC (Instrument: Shimadzu LH-40 Liquid Handler, Shimadzu LC-20AP Pump, Shimadzu, SPD-20APUV Detector, Column: Xtimate C18, 21.2*250 mm, 5 um; Mobile phase A: H2O with 0.1 %FA; Mobile phase B: CH3CN; Gradient: B from 25% to 55% in 30 min; Flow Rate: 20 mL / min; RT = 11.2 min, Column Temperature: 30 °C; Wavelength: 214 nm, 254 nm) to afford 3-{2-chloro-3-[(4aR)-l-oxo-2-[(lr,37?)-3-[4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutyl]-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl]phenyl}hexahydropyridine-2, 6-dione (5.61 mg, 21.4%) as a white solid. LC-MS (ESI) [M+H]+= 601.4. 'HNMR (400 MHz, Chloroform-d) 58.16 (s, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.33-7.27 (m, 2H), 7.20-7.13 (m, 2H), 7.11 (s, 1H), 4.74 (s, 1H), 4.41-4.22 (m, 1H),125569-02020

[1100] 3.77-3.59 (m, 1H), 3.47-3.33 (m, 2H), 3.14-2.98 (m, 1H), 2.90-2.81 (m, 2H), 2.80-2.64 (m, 2H), 2.60-2.49 (m, 2H), 2.48-2.34 (m, 10H), 2.31-2.26 (m, 2H), 2.13-2.10 (m, 1H), 1.92-1.75 (m, 3H), 1.67 (s, 6H).

[1101] Example 16: Preparation of (3 / ?)-3-{2-chloro-3-[(4a / ?)-l-oxo-2-[3-(propan-2-ylidene)cyclobutyl]-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl]phenyl}-3-fluorohexahydropyridine-2, 6-dione

[1102] Synthesis of (4a / ?)-l-oxo-2-[3-(propan-2-ylidene)cyclobutyl]-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinoline: To a solution of (4aR)-8-bromo-l-oxo-2-[3-(propan-2-ylidene)cyclobutyl]-2,3,4,4a,5,6-hexahydro- 1H-pyrimido[1,6-a]quinoline (20 mg, 0.05 mmol, 1.0 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (40.6 mg, 0.15 mmol, 3.0 eq) and potassium acetate (15.7 mg, 0.15 mmol, 3.0 eq) in dioxane (2 mL) was added Pd(dppf)Cl2(3.9 mg, 0.005 mmol, 0.1 eq), then the reaction mixture was stirred at 100°C for 18 hours under N2. The resulting mixture was concentrated to afford a residue. The residue was purified by a flash column (silica gel, ethyl acetate / petroleum ether= 1:20-7: 10) to afford (4aR)-l-oxo-2-[3-(propan-2-ylidene)cyclobutyl]-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinoline (12 mg, 53.3%) as a yellow oil. LC-MS (ESI) [M+H]+= 423.4.

[1103] Synthesis of (3R)-3-{2-chloro-3-[(4aR)-1-oxo-2-[3-(propan-2-ylidene)cyclobutyl]-2,3,4,4a,5,6-hexahydro-1H-pyrimido[1,6-a]quinolin-8-yl]phenyl}-3-fluorohexahydropyridine-2,6-dione: To a solution of (4aR)-l-oxo-2-[3-(propan-2-ylidene)cyclobutyl]-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,3,4,4a,5,6-hexahydro- 1H-pyrimido[1,6-a]quinoline (10 mg, 0.02 mmol, 1.0 eq), (3R)-3-(3-bromo-2-chlorophenyl)-3-fluorohexahydropyridine-2, 6-dione (7.6 mg, 0.02 mmol, 1.0 eq) and Potassium phosphate tribasic (15.1 mg, 0.06 mmol, 3.0 eq) in dioxane (1 mL) were added H2O (0.2 mL) and Pd(dppf)Cl2(1.7 mg, 0.002 mmol, 0.1 eq), then the reaction mixture was stirred at 100°C for 2 hours under N2. The crude product was purified by prep-HPLC (Instrument: Shimadzu LH-40 Liquid Handler, Shimadzu LC-20AP Pump, Shimadzu, SPD-20APUV Detector, Column:

[1104] Ultimate XB-C18, 50 x 250 mm x 10 pm; Mobile phase A: H2O with FA (0.1% / L); Mobile phase B: CH3CN; Gradient: B from 40% to 80% in 30 min, hold 100% B for 3 min; Flow Rate: 70 mL / min; Rt = 16.5 min, Column Temperature: 30°C; Wavelength: 214 nm, 254 nm) to afford (3R)-3-{2-chloro-3-[(4aR)-l-oxo-2-[3-(propan-2-ylidene)cyclobutyl]-2,3,4,4a,5,6-hexahydro-1H-pyrimido[l,6-a]quinolin-8-yl]phenyl}-3-fluorohexahydropyridine-2, 6-dione (1.75 mg,125569-02020

[1105] 13.5%)as a white solid. LC-MS (ESI) [M+H]+= 536.2. 'HNMR (400 MHz,

[1106] Dimethylsulfoxide-d6) 5 11.51 (s, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.56-7.51 (m, 1H), 7.46-7.42 (m, 1H), 7.11-7.05 (m, 2H), 4.82-4.71 (m, 1H), 3.69-3.60 (m, 1H), 3.07-2.84 (m, 3H), 2.83-2.74 (m, 6H), 2.65-2.59 (m, 1H), 2.52 (s, 1H), 2.31-2.22 (m, 2H), 2.13-2.06 (m, 1H), 1.76-1.62 (m, 2H), 1.53 (s, 6H).

[1107] Example 17: Preparation of (3 / ?)-3-{2-chloro-3-[(4aS)-l-oxo-2-[3-(propan-2-ylidene)cyclobutyl]-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl]phenyl}-3-fluorohexahydropyridine-2, 6-dione

[1108] Synthesis of (4aS)-l-oxo-2-[3-(propan-2-ylidene)cyclobutyl]-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinoline: To a solution of (4aS)-8-bromo-l-oxo-2-[3-(propan-2-ylidene)cyclobutyl]-2,3,4,4a,5,6-hexahydro- 1H-pyrimido[1,6-a]quinoline (20 mg, 0.05 mmol, 1.0 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (40.6 mg, 0.15 mmol, 3.0 eq) and potassium acetate (15.7 mg, 0.15 mmol, 3.0 eq) in dioxane (2 mL) was added Pd(dppf)Cl2(3.9 mg, 0.005 mmol, 0.1 eq), then the reaction mixture was stirred at 100°C for 18 hours under N2. The resulting mixture was concentrated to afford a residue. The residue was purified by a flash column (silica gel, ethyl acetate / petroleum ether=0:10-3:10) to afford (4aS)-l-oxo-2-[3-(propan-2-ylidene)cyclobutyl]-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,3,4,4a,5,6-hexahydro- 1H-pyrimido[1,6-a]quinoline (10 mg, 52.4%) as a yellow oil. LC-MS (ESI) [M+H]+= 423.4.

[1109] Synthesis of (3R)-3-{2-chloro-3-[(4aS)-1-oxo-2-[3-(propan-2-ylidene)cyclobutyl]-2,3,4,4a,5,6-hexahydro-1H-pyrimido[1,6-a]quinolin-8-yl]phenyl}-3-fluorohexahydropyridine-2,6-dione: To a solution of (4aS)-l-oxo-2-[3-(propan-2-ylidene)cyclobutyl]-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,3,4,4a,5,6-hexahydro- 1H-pyrimido[1,6-a]quinoline (10 mg, 0.02 mmol, 1.0 eq), (3R)-3-(3-bromo-2-chlorophenyl)-3-fluorohexahydropyridine-2, 6-dione (7.6 mg, 0.02 mmol, 1.0 eq) and potassium phosphate tribasic (15.1 mg, 0.06 mmol, 3.0 eq) in dioxane (1 mL) were added H2O (0.2 mL) and Pd(dppf)Cl2(1.7 mg, 0.002 mmol, 0.1 eq), then the reaction mixture was stirred at 100°C for 2 hours under N2. The crude product was purified by prep-HPLC (Instrument: Shimadzu LH-40 Liquid Handler, Shimadzu LC-20AP Pump, Shimadzu, SPD-20APUV Detector, Column:

[1110] Ultimate XB-C18, 50 x 250 mm x 10 pm; Mobile phase A: H2O with FA (0.1% / L); Mobile phase B: CH3CN; Gradient: B from 40% to 80% in 30 min, hold 100% B for 3 min; Flow Rate: 70 mL / min; Rt = 17.2 min, Column Temperature: 30°C; Wavelength: 214 nm, 254 nm) to afford (3R)-3-{2-chloro-3-[(4aS)-l-oxo-2-[3-(propan-2-ylidene)cyclobutyl]-2,3,4,4a,5,6-hexahydro-125569-02020

[1111] 1H-pyrimido[l,6-a]quinolin-8-yl]phenyl}-3-fluorohexahydropyridine-2, 6-dione (2.06 mg, 13.8%)as a white solid. LC-MS (ESI) [M+H]+= 536.2. 'HNMR (400 MHz, Dimethylsulfoxide-d6) 5 11.50 (s, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.66-7.62 (m, 1H), 7.56-7.52 (m, 1H), 7.46-7.43 (m, 1H), 7.11-7.05 (m, 2H), 4.86-4.72 (m, 1H), 3.67-3.59 (m, 1H), 3.04-2.85 (m, 3H), 2.83-2.73 (m, 6H), 2.66-2.60 (m, 1H), 2.33-2.23 (m, 2H), 2.14-1.93 (m, 2H), 1.76-1.62 (m, 2H), 1.53 (s, 6H).

[1112] Example 18: Preparation of (3 / ?)-3-{2-chloro-3-[(4a / ?)-l-oxo-2-[3-(3,4,5,6-tetrahydro-2H-pyran-4-ylidene)cyclobutyl]-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl]phenyl}-3-fluorohexahydropyridine-2, 6-dione

[1113] Synthesis of (4a / ?)-l-oxo-2-[3-(3,4,5,6-tetrahydro-2H-pyran-4-ylidene)cyclobutyl]-8-(4,4,5-trimethyl-l,3,2-dioxaborolan-2-yl)-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinoline: To a solution of (4aR)-8-bromo-l-oxo-2-[3-(3,4,5,6-tetrahydro-2 / Z-pyran-4-ylidene)cyclobutyl]-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinoline (15 mg, 0.04 mmol, 1.0 eq) in dioxane (1 mL) was added 4,4,5-trimethyl-2-(4,4,5-trimethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (24.36 mg, 0.11 mmol, 3.0 eq), KOAc (10.58 mg, 0.11 mmol, 3.0 eq) and [l,r-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (5.26 mg, 0.01 mmol, 0.2 eq) at 25°C. The resulting mixture was stirred at 110°C under N2 for 12 hours. The reaction was quenched with H2O (3x20 mL) and extracted with ethyl acetate (3x30 mL). The combined organic layers was washed with brine (3x20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford (4aR)-l-oxo-2-[3-(3,4,5,6-tetrahydro-2 / Z-pyran-4-ylidene)cyclobutyl]-8-(4,4,5-trimethyl-l,3,2-dioxaborolan-2-yl)-2,3,4,4a,5,6-hexahydro-1H-pyrimido[l,6-a]quinoline (15 mg, 92.7%) as a yellow solid. LC-MS (ESI) [M+H]+= 465.1.

[1114] Synthesis of (3 / ?)-3-{2-chloro-3-[(4a / ?)-l-oxo-2-[3-(3,4,5,6-tetrahydro-2H-pyran-4-ylidene)cyclobutyl]-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl]phenyl}-3-fluorohexahydropyridine-2, 6-dione: To a solution of (4aR)-l-oxo-2-[3-(3,4,5,6-tetrahydro-2 / Z-pyran-4-ylidene)cyclobutyl]-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,3,4,4a,5,6-hexahydro-1H-pyrimido[1,6-a]quinoline (15 mg, 0.03 mmol, 1.0 eq) in dioxane - water (1 mL) was added (3R)-3-(3-bromo-2-chlorophenyl)-3-fluorohexahydropyridine-2, 6-dione (10.35 mg, 0.03 mmol, 1.0 eq), [l,r-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (4.73 mg, 0.01 mmol, 0.2 eq) and K3PO4 (20.57 mg, 0.09 mmol, 3.0 eq) at 25°C under N2. The resulting mixture was stirred at 100°C for 1 hour under N2. The reaction was concentrated to give a residue, which was purified by Prep-HPLC (Instrument: Shimadzu LH-40 Liquid Handler,125569-02020

[1115] Shimadzu LC-20AP Pump, Shimadzu, SPD-20APUV Detector, Column: Xtimate C18, 21.2*250 mm, 5 um; Mobile phase A: H2O with 0.1 %FA; Mobile phase B: CH3CN; Gradient: B from 45% to 70% in 28 min; Flow Rate: 20 mL / min; tR = 17.7 min, Column Temperature: 30 °C; Wavelength: 214 nm, 254 nm) to afford (3R)-3-{2-chloro-3-[(4aR)-l-oxo-2-[3-(3,4,5,6-tetrahydro-2 / 7-pyran-4-ylidene)cyclobutyl]-2,3,4,4a,5,6-hexahydro-1H-pyrimido[l,6-a]quinolin-8-yl]phenyl}-3-fluorohexahydropyridine-2, 6-dione (1.65 mg, 8.8%) as a white solid.

[1116] LC-MS (ESI) [M+H]+= 578.5. 'HNMR (400 MHz, Chloroform-d) δ 8.00 (s, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.38-7.29 (m, 2H), 7.07 (d, J = 8.8 Hz, 1H), 7.02 (s, 1H), 5.11 – 4.70 (m, 1H), 3.72-3.50 (m, 5H), 3.40-3.20 (m, 2H), 3.11-2.95 (m, 1H), 2.95-2.82 (m, 3H), 2.82-2.60 (m, 5H), 2.30-2.18 (m, 2H), 2.14-1.97 (m, 5H), 1.80-1.72 (m, 2H).

[1117] Example 19: Preparation of (3 / ?)-3-{2-chloro-3-[(4aS)-l-oxo-2-[3-(3,4,5,6-tetrahydro-2H-pyran-4-ylidene)cyclobutyl]-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl]phenyl}-3-fluorohexahydropyridine-2, 6-dione

[1118] Synthesis of (4aS)-l-oxo-2-[3-(3,4,5,6-tetrahydro-2H-pyran-4-ylidene)cyclobutyl]-8-(4,4,5-trimethyl-l,3,2-dioxaborolan-2-yl)-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinoline: To a solution of (4aS)-8-bromo-l-oxo-2-[3-(3,4,5,6-tetrahydro-2H-pyran-4-ylidene)cyclobutyl]-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinoline (15 mg, 0.04 mmol, 1.0 eq) in dioxane (1 mL) was added 4,4,5-trimethyl-2-(4,4,5-trimethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (24.36 mg, 0.11 mmol, 3.0 eq), KOAc (10.58 mg, 0.11 mmol, 3.0 eq) and [l,r-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (5.26 mg, 0.01 mmol, 0.2 eq) at 25°C. The resulting mixture was stirred at 110°C under N2 for 12 hours. The reaction was quenched with H2O (20 mL) and extracted with ethyl acetate (3x30 mL). The combined organic layers was washed with brine (3x20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford (4a5')-l-oxo-2-[3-(3,4,5,6-tetrahydro-2 / Z-pyran-4-ylidene)cyclobutyl]-8-(4,4,5-trimethyl-l,3,2-dioxaborolan-2-yl)-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinoline (15 mg, 92.7%) as a yellow solid. LC-MS (ESI) [M+H]+= 465.6.

[1119] Synthesis of (3 / ?)-3-{2-chloro-3-[(4aS)-l-oxo-2-[3-(3,4,5,6-tetrahydro-2H-pyran-4-y lidene)cyclobutyl|-2,3, 4,4a, 5,6-hexahyd ro- IH-py rimidol 1.6-a| quinolin-8-yl| phenyl }-3-fluorohexahydropyridine-2, 6-dione: To a solution of (4a. S')-l-oxo-2-[3-(3,4,5,6-tctrahydro-2 / 7-pyran-4-ylidene)cyclobutyl]-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,3,4,4a,5,6-hexahydro- 1H-pyrimido[l,6-a]quinoline (10 mg, 0.02 mmol) in dioxane (1 mL) and H2O (0.1 mL) was added (3R)-3-(3-bromo-2-chlorophenyl)-3-fluorohexahydropyridine-2, 6-dione (20.71 mg, 0.07 mmol), K3PO4 (13.71 mg, 0.07 mmol)and [1,1'-125569-02020

[1120] Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (3.15 mg, 0.01 mmol) at 25°C. The resulting mixture was stirred at 100°C under N2 for 2 hours. The reaction was quenched with H2O (20 mL) and extracted with ethyl acetate (3x30 mL). The combined organic layers was washed with brine (3x20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford a residue, which was purified by Prep-HPLC (Instrument: Shimadzu LH-40 Liquid Handler, Shimadzu LC-20AP Pump, Shimadzu, SPD-20APUV Detector, Column: Xtimate C18, 21.2*250 mm, 5 um; Mobile phase A: H2O with 0.1%FA; Mobile phase B: CH3CN; Gradient: B from 45% to 70% in 28 min; Flow Rate: 20 mL / min; Rt = 17.7 min, Column Temperature: 30 °C; Wavelength: 214 nm, 254 nm) to afford (37?)-3-{2-chloro-3-[(4aS)-l-oxo-2-[3-(3,4,5,6-tetrahydro-27 / -pyran-4-ylidene)cyclobutyl]-2,3,4,4a,5,6-hexahydro-17 / -pyrimido[l,6-a]quinolin-8-yl]phenyl}-3-fluorohexahydropyridine-2, 6-dione (1.97 mg, 15.8%) as a white solid. LC-MS (ESI) [M+H]+= 578.4. 'HNMR (400 MHz, CDCl3-d) δ 8.03 (d, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.46-7.40 (m, 1H), 7.40-7.35 (m, 1H), 7.14 (d, J = 8.8 Hz, 1H), 7.09 (s, 1H), 5.18-4.74 (m, 1H), 3.78-3.57 (m, 5H), 3.47-3.31 (m, 2H), 3.16-3.03 (m, 1H), 3.01-2.89 (m, 3H), 2.87-2.70 (m, 5H), 2.36-2.24 (m, 2H), 2.20-2.04 (m, 5H), 1.87-1.78 (m, 2H).

[1121] Example 20: Preparation of (3R)-3-{2-chloro-3-[(4aS)-l-oxo-2-[(lr,3S)-3-[4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutyl]-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl]phenyl}-3-fluorohexahydropyridine-2, 6-dione

[1122] Synthesis of 2-methylpropan-2-yl 6-bromo-2-(2-{[(lr,3r)-3-[4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutyl]amino}ethyl)-l,2,3,4-tetrahydroquinoline-l-carboxylate: To a solution of (lr,3r)-3-[4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutan-l -amine (274.3 mg, 1.41 mmol, 2.0 eq) and 2-methylpropan-2-yl 6-bromo-2-(formylmethyl)- 1,2, 3, 4-tetrahydroquinoline-l -carboxylate (250 mg, 0.71 mmol, 2.0 eq) in tetrahydrofuran (5 mL) was added sodium triacetoxyborohydride (297.7 mg, 1.41 mmol, 2.0 eq), then the reaction mixture was stirred at 25°C for 18 hours. To the reaction mixture was added water (10 mL). The resulting mixture was extracted with ethyl acetate (3x10 mL). The combined organic phases were washed with water (10 mL), brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to afford a residue. The residue was purified by a flash column (silica gel, methanol / dichloromethane= 1: 10-3: 10) to afford 2-methylpropan-2-yl 6-bromo-2-(2-{[(lr,3r)-3-[4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutyl]amino}ethyl)-l,2,3,4-tetrahydroquinoline-l-carboxylate (200 mg, 53.21%) as a yellow oil. LC-MS (ESI) [M+H]+=532.4.125569-02020

[1123] Synthesis of (2S)-6-bromo-2-(2-{[(lr,3S)-3-[4-(propan-2-ylidene)hexahydropyridin- 1-yl]cyclobutyl]amino}ethyl)-l,2,3,4-tetrahydroquinoline: To a solution of 2-methylpropan- 2-yl (2S)-6-bromo-2-(2-{[(lr,3S)-3-[4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutyl]amino}ethyl)-l,2,3,4-tetrahydroquinoline-l-carboxylate (170 mg, 0.32 mmol, 1.0 eq) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL), then the reaction mixture was stirred at 25°C for 2 hours. The resulting mixture was concentrated to afford (2S)-6-bromo-2-(2-{[(lr,3S)-3-[4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutyl]amino}ethyl)-l,2,3,4-tetrahydroquinoline (120 mg, 86.9%) as a yellow oil. LC-MS (ESI) [M+H]+= 432.2.

[1124] Synthesis of (4aS)-8-bromo-l-oxo-2-[(lr,3R)-3-[4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutyl]-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinoline: To a solution of (2S)-6-bromo-2-(2-{[(lr,3R)-3-[4-(propan-2-y lidene)hexahy dropyridin- 1 -y 1] cyclobutyl] amino } ethyl)- 1,2,3,4-tetrahy droquinoline (100 mg, 0.23 mmol, 1.0 eq) and DIEA (0.19 mL, 1.16 mmol, 5.0 eq) in dichloromethane (3mL) was added triphosgene (20.58 mg, 0.07 mmol, 0.3 eq), then the reaction mixture was stirred at 25°C for 1 hours. To the reaction mixture was added water (5 mL). The resulting mixture was extracted with ethyl acetate (3×5 mL). The combined organic phases were washed with water (5 mL), brine (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated to afford a residue. The residue was purified by a flash column (silica gel, ethyl acetate / petroleum ether = 0:10-3:10) to afford (4aS)-8-bromo-l-oxo-2-[(lr,3R)-3-[4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutyl]-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinoline (70 mg, 66.0%) as a yellow. LC-MS (ESI) [M+H]+= 458.2.

[1125] Synthesis of (4aS)-l-oxo-2-[(lr,3S)-3-[4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutyl]-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinoline: To a solution of (4aS)-8-bromo-l-oxo-2-[(lr,3S)-3-[4-(propan-2-ylidene)hexahy dropyridin- 1 -yl] cyclobutyl] -2,3,4, 4a, 5,6-hexahydro- 1 H-pyrimido [1,6-a]quinoline (10 mg, 0.02 mmol, 1.0 eq) in dioxane (1 mL) was added Bis(pinacolato)diboron (16.62 mg, 0.07 mmol, 3.0 eq), KOAc (6.42 mg, 0.07 mmol, 3.0 eq) and [1,1’-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (3.19 mg, 0.01 mmol, 0.2 eq) at 25°C. The resulting mixture was stirred at 110°C under N2 for 12 hours. The reaction was quenched with H2O (20 mL) and extracted with ethyl acetate (3x30 mL). The combined organic layers were washed with brine (3x20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford (4aR)-l-oxo-2-[(lr,3R)-3-[4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutyl]-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-125569-02020

[1126] 2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinoline (20 mg, 90.6%) as a yellow solid. LC-MS (ESI) [M+H]+= 506.3.

[1127] Synthesis of (3R)-3-{2-chloro-3-[(4aS)-l-oxo-2-[(lr,3S)-3-[4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutyl]-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl]phenyl}-3-fluorohexahydropyridine-2, 6-dione: To a solution of (4aS)-l-oxo-2-[(lr,3S)-3-[4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutyl]-8-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-2,3,4,4a,5,6-hexahydro-1H-pyrimido[1,6-a]quinoline (10 mg, 0.02 mmol, 1.0 eq) in dioxane (1 mL) and H2O (0.1 mL) was added (3R)-3-(3-bromo-2-chlorophenyl)-3-fluorohexahydropyridine-2,6-dione (6.34 mg, 0.02 mmol, 1.0 eq), [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.89 mg, 0.01 mmol, 0.2 eq) and K3PO4 (12.60 mg, 0.06 mmol, 3.0 eq) at 25°C under N2. The resulting mixture was stirred at 100°C for 2 hours under N2. The reaction was concentrated to give a residue, which was purified by Prep-HPLC (Instrument: Shimadzu LH-40 Liquid Handler, Shimadzu LC-20AP Pump, Shimadzu, SPD-20APUV Detector, Column: Xtimate C18, 21.2*250 mm, 5 um; Mobile phase A: H2O with 0.1%FA; Mobile phase B: CH3CN; Gradient: B from 18% to 48% in 30 min; Flow Rate: 20 mL / min; tR = 17.1 min, Column Temperature: 30°C; Wavelength: 214 nm, 254 nm) to afford (3R)-3-{2-chloro-3-[(4aS)-l-oxo-2-[(lr,3S)-3-[4-(propan-2-ylidene)hexahydropyridin- 1 -yl] cyclobutyl] -2,3,4, 4a, 5,6-hexahydro- 1 H-pyrimido [1,6-a]quinolin-8-yl]phenyl}-3-fluorohexahydropyridine-2, 6-dione (2.29 mg, 18.7%) as a white solid. LC-MS (ESI) [M+H]+= 619.4. 'HNMR (400 MHz, Chloroform-d) δ 8.29 (s, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.49-7.39 (m, 1H), 7.39-7.32 (m, 1H), 7.16 (d, J = 8.4 Hz, 1H), 7.08 (s, 1H), 4.49 (s, 1H), 3.76-3.59 (m, 1H), 3.43-3.35 (m, 2H), 3.18-2.88 (m, 3H), 2.86-2.75 (m, 4H), 2.68-2.61 (m, 2H), 2.56-2.46 (m, 4H), 2.32-2.23 (m, 2H), 2.20-2.02 (m, 2H), 1.89 -1.74 (m, 6H), 1.67 (s, 6H).

[1128] Example 21: Preparation of (3R)-3-{2-chloro-3-[(4aR)-1-oxo-2-[(1r,3R)-3-[4-(propan-2-ylidene)hexahydropyridin-1-yl]cyclobutyl]-2,3,4,4a,5,6-hexahydro-1H-pyrimido[1,6-a]quinolin-8-yl]phenyl}-3-fluorohexahydropyridine-2,6-dione

[1129] Synthesis of (3 / ?)-3-{2-chloro-3-[(4a / ?)-l-oxo-2-[(lr,3 / ?)-3-[4-(propan-2-y lidenelhexahyd ropy ridin-l-yl|cyclobutyl|-2,3, 4,4a, 5.6-hexahydro-lH-py rimidol 1.6-a]quinolin-8-yl]phenyl}-3-fluorohexahydropyridine-2, 6-dione: To a solution of (4aR)-l-oxo-2-[(lr,3R)-3-[4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutyl]-8-(4,4,5,5-tetramethyl- 1.3.2-dioxaborolan-2-yl)-2,3,4,4a,5,6-hexahydro-1H-pyrimido[l,6-a]quinoline (60.16 mg, 0.12 mmol, 1.0 eq) in dioxane (2 mL) and H2O (0.2 mL) was added (3R)-3-(3-bromo-2-125569-02020

[1130] chlorophenyl)-3-fluorohexahydropyridine-2, 6-dione (38.14mg, 0.12 mmol, 1.0 eq), K3PO4 (75.78 mg, 0.36 mmol, 3.0 eq)and [l,r-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (8.71 mg, 0.01 mmol, 0.1 eq) at 25°C. The resulting mixture was stirred at 100°C under N2 for 2 hours. The reaction was quenched with H2O (50 mL) and extracted with ethyl acetate (3x50 mL). The combined organic layers was washed with brine (3x50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressureto afford a residue, which was purified by Prep-HPLC (Instrument: Shimadzu LH-40 Liquid Handler, Shimadzu LC-20AP Pump, Shimadzu, SPD-20APUV Detector, Column: Xtimate C18, 21.2*250 mm, 5 um; Mobile phase A: H2O with 0.1%FA; Mobile phase B: CH3CN; Gradient: B from 45% to 70% in 28 min; Flow Rate: 20 mL / min; tR = 17.7 min, Column Temperature: 30°C; Wavelength: 214 nm, 254 nm) to afford (3R)-3-{2-chloro-3-[(4aR)-l-oxo-2-[(lr,3R)-3-[4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutyl]-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl]phenyl}-3-fluorohexahydropyridine-2, 6-dione (27.28 mg, 37.0%) as a white solid. LC-MS (ESI) [M+H]+= 619.4. 'HNMR (400 MHz, Chloroform-d) δ 8.17 (s, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.51-7.42 (m, 1H), 7.41-7.35 (m, 1H), 7.16 (d, J = 8.4 Hz, 1H), 7.10 (s, 1H), 4.92-4.48 (m, 1H), 3.77-3.60 (m, 1H), 3.49-3.33 (m, 2H), 3.22-3.08 (m, 1H), 3.07-2.92 (m, 2H), 2.90-2.83 (m, 2H), 2.82-2.67 (m, 2H), 2.59-2.46 (m, 5H), 2.38 -2.25 (m, 3H), 2.23-2.03 (m, 2H), 1.96-1.75 (m, 6H), 1.69 (s, 6H).

[1131] Example 22: Preparation of (3S)-3-{2-chloro-3-[(4aR)-1-oxo-2-[(1r,3R)-3-[4-(propan-2-ylidene)hexahydropyridin-1-yl]cyclobutyl]-2,3,4,4a,5,6-hexahydro-1H-pyrimido[1,6-a]quinolin-8-yl]phenyl}-3-fluorohexahydropyridine-2,6-dione

[1132] Synthesis of (3S)-3-{2-chloro-3-[(4a / ?)-l-oxo-2-[(lr,3 / ?)-3-[4-(propan-2-y lidenelhexahyd ropy ridin-l-yl|cyclobutyl|-2,3, 4,4a, 5.6-hexahydro-lH-py rimidol 1.6-a]quinolin-8-yl]phenyl}-3-fluorohexahydropyridine-2, 6-dione: To a solution of (4aR)-l-oxo-2-[(lr,3R)-3-[4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutyl]-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,3,4,4a,5,6-hexahydro-1H-pyrimido[l,6-a]quinoline (20 mg, 0.04 mmol, 1.0 eq) in dioxane (2 mL) and H2O (0.2 mL)was added (3S)-3-(3-bromo-2-chlorophenyl)-3-fluorohexahydropyridine-2, 6-dione (12.68 mg, 0.04 mmol, 1.0 eq), K3PO4 (75.78 mg, 0.36 mmol, 3.0 eq) and [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (8.71 mg, 0.01 mmol, 0.3 eq) at 25°C. The resulting mixture was stirred at 100°C under N2 for 2 hours. The reaction was quenched with H2O (50 mL) and extracted with ethyl acetate (3x50 mL). The combined organic layers was washed with brine (3x50 mL), dried over anhydrous sodium sulfate, filtered and125569-02020

[1133] concentrated under reduced pressureto afford a residue, which was purified by Prep-HPLC (Instrument: Shimadzu LH-40 Liquid Handler, Shimadzu LC-20AP Pump, Shimadzu, SPD-20APUV Detector, Column: Xtimate C18, 21.2*250 mm, 5 um; Mobile phase A: H2O with 0.1%FA; Mobile phase B: CH3CN; Gradient: B from 45% to 70% in 28 min; Flow Rate: 20 mL / min; tR = 17.7 min, Column Temperature: 30°C; Wavelength: 214 nm, 254 nm) to afford (35)-3-{2-chloro-3-[(4aR)-l-oxo-2-[(lr,3R)-3-[4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutyl]-2,3,4,4a,5,6-hexahydro-1H-pyrimido[l,6-a]quinolin-8-yl]phenyl}-3-fluorohexahydropyridine-2, 6-dione (14.83 mg, 60.5%) as a white solid. LC-MS (ESI) [M+H]+= 619.4. 'HNMR (400 MHz, Chloroform-d) δ 8.17 (s, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.51-7.42 (m, 1H), 7.41-7.35 (m, 1H), 7.16 (d, J = 8.4 Hz, 1H), 7.10 (s, 1H), 4.92-4.48 (m, 1H), 3.77-3.60 (m, 1H), 3.49-3.33 (m, 2H), 3.22-3.08 (m, 1H), 3.07-2.92 (m, 2H), 2.90-2.83 (m, 2H), 2.82-2.67 (m, 2H), 2.59-2.46 (m, 5H), 2.38-2.25 (m, 3H), 2.23-2.03 (m, 2H), 1.96-1.75 (m, 6H), 1.69 (s, 6H).

[1134] Example 23: Preparation of3-{3-[(4aS)-2-[(lS,3R)-3-[(2R)-2-methyl-4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutyl]-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl]-2-chlorophenyl}hexahydropyridine-2, 6-dione

[1135] Synthesis of 2-methylpropan-2-yl (2S)-2-[2-({3-[(2R)-2-methyl-4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutyl}amino)ethyl]-6-bromo-l, 2,3,4-tetrahydroquinoline-l-carboxylate: To a solution of 2-methylpropan-2-yl (2S)-6-bromo-2-(formylmethyl)- 1,2, 3, 4-tetrahydroquinoline-l -carboxylate (250 mg, 706 pmol, 1.0 eq) in methanol (3 mL) were added (lS,3s)-3-[(2R)-2-methyl-4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutan-l -amine (294 mg, 1412 pmol, 2.0 eq) and acetic acid (4.17 mg, 70.6 pmol, 0.1 eq) at 25°C under nitrogen protection. The resulting mixture was stirred at 50°C for 6 hours. Then sodium cyanoborohydride (66 mg, 1059 pmol, 1.5 eq) was added at 50°C. The resulting mixture was stirred at 50°C for 18 hours. The reaction was concentrated under reduced pressure. The residue was purified by a flash column (silica gel, methanol / dichloromethane =0: 10-1: 10) to afford 2-methylpropan-2-yl (2S)-2-(2-{[(lS,3R)-3-[(2R)-2-methyl-4-(propan-2-ylidene)hexahydropyridin- 1-yl] cyclobutyl] amino }ethyl)-6-bromo- 1,2,3, 4-tetrahydroquinoline-1-carboxylate (100 mg, 25.9%) as a yellow oil. LC-MS (ESI) [M+H]+= 546.4.

[1136] Synthesis of (2S)-2-(2-{[(lS,3R)-3-[(2R)-2-methyl-4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutyl]amino}ethyl)-6-bromo-l, 2,3,4-tetrahydroquinoline 2,2,2-trifluoroacetic acid: The solution of 2-methylpropan-2-yl (2S)-2-(2-{[(lS,3R)-3-[(2R)-2-methyl-4-(propan-2ylidene)hexahydropyridin-l-125569-02020

[1137] yl]cyclobutyl]amino}ethyl)-6-bromo-l,2,3,4-tetrahydroquinoline-l-carboxylate (100 mg, 0.18 mmol, 1.0 eq) in trifluoroacetic acid (1 mL) and dichloromethane (3 mL) was stirred at 25°C for 1 hour under nitrogen protection. The reaction was concentrated under reduced pressure to afford (2S)-2-(2-{[(lS,3R)-3-[(2R)-2-methyl-4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutyl]amino}ethyl)-6-bromo-l,2,3,4-tetrahydroquinoline 2,2,2-trifluoroacetic acid (100 mg, 97.5%) as a yellow solid. LC-MS (ESI) [M+H]+= 446.3.

[1138] Synthesis of ((4aS)-2-[(lS,3R)-3-[(2R)-2-methyl-4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutyl]-8-bromo-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinoline: To a solution of (2S)-2-(2-{[(lS,3R)-3-[(2R)-2-methyl-4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutyl]amino}ethyl)-6-bromo-l,2,3,4-tetrahydroquinoline 2,2,2-trifluoroacetic acid (100 mg, 0.18 mmol, 1.0 eq) in dichloromethane (1 mL) were added DIEA (0.089 mL, 0.54 mmol, 3.0 eq) and triphosgene (21 mg, 0.07 mmol, 0.4 eq) at 0°C under nitrogen atmosphere. Then the reaction was stirred at 0°C for 2 hours under nitrogen atmosphere. The residue was purified by prep-HPLC using the following conditions: Column, SunFire JB-C235-35, Xtimate Cl 8, 21.2*250 mm, 5 um; mobile phase, water (0.1% TFA) and CH3CN (40% Phase B up to 60% in 28 min); Detector, UV 254 / 214 nm, tR=20 min; to afford (4aS)-2-[(lS,3R)-3-[(2R)-2-methyl-4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutyl]-8-bromo-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinoline (30 mg, 35.5%) as a white solid. LC-MS (ESI) [M+H]+= 472.2.

[1139] Synthesis of3-{3-[(4aS)-2-[(lS,3R)-3-[(2R)-2-methyl-4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutyl]-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl]-2-chlorophenyl}hexahydropyridine-2, 6-dione: To a solution of (4aS)-2-[( 1 S,3R)-3-[(2R)-2-methyl-4-(propan-2-ylidene)hexahydropyridin- 1 -yl]cyclobutyl] -8-bromo- 1 -oxo-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinoline (25 mg, 0.05 mmol, 1.0 eq) in dioxane (1 mL) and water (0.1 mL) were added 3-[2-chloro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]hexahydropyridine-2, 6-dione (37 mg, 0.10 mmol, 2.0 eq), Pd(dppf)Cl2. CH2C12 (4 mg, 5pmol, 0.1 eq) and K3PO4 (34 mg, 0.15 mmol, 3.0 eq) at 25°C under nitrogen protection. The resulting mixture was stirred at 100°C for 2 hours. The residue was purified by prep-HPLC using the following conditions: Column, SunFire JB-C235-31, Xtimate Cl 8, 21.2*250 mm, 5 um; mobile phase, water (0.1% TFA) and CH3CN (30% Phase B up to 50% in 15.4min); Detector, UV 254 / 214 nm, tR=15.4 min; to afford 3-{3-[(4aS)-2-[( 1 S,3R)-3-[(2R)-2-methyl-4-(propan-2-ylidene)hexahydropyridin- 1 -yl]cyclobutyl] - 1 -oxo-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl]-2-chlorophenyl}hexahydropyridine-2, 6-dione (0.31 mg, 0.9%) as a white solid. LC-MS (ESI) [M+H]+= 615.4. 'HNMR (400125569-02020

[1140] MHz, Chloroform-d) δ 7.99 (s, 1H), 7.78-7.65 (m, 1H), 7.32-7.28 (m, 2H), 7.20-7.14 (m, 2H), 7.13-7.10 (m, 1H), 5.20-4.79 (m, 1H), 4.36-4.28 (m, 1H), 4.12-3.88 (m, 1H), 3.85-3.62 (m, 2H), 3.62-2.95 (m, 7H), 2.93-2.43 (m, 9H), 2.43-2.27 (m, 3H), 2.18-2.08 (m, 1H), 2.02-1.80 (m, 5H), 1.68-1.52 (m, 6H).

[1141] Example 24: Preparation of 3-{2-chloro-3-[(4a / ?)-l-oxo-2-[3-(3,4,5,6-tetrahydro-2H-pyran-4-ylidene)cyclobutyl]-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl]phenyl}hexahydropyridine-2, 6-dione

[1142] Synthesis of (4a / ?)-8-bromo-l-oxo-2-[3-(3,4,5,6-tetrahydro-2H-pyran-4-ylidene)cyclobutyl]-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinoline: To a solution of (4a7?)-8-bromo-2-(3-methylidenecyclobutyl)-l-oxo-2,3,4,4a,5,6-hexahydro-l / / -pyrimido[l,6-a]quinoline (170 mg, 0.49 mmol, 1.0 eq) and 4-methylidenetetrahydropyran (480 mg, 4.90 mmol, 10.0 eq) in dichloromethane (5 mL) was added TZovey da- Grubbs (17 mg, 0.02 mmol, 0.05 eq) at 25°C under nitrogen atmosphere. Then the reaction was stirred at 40°C for 18 hours under nitrogen atmosphere. The residue was concentrated under reduced pressure and purified by a flash column (silica gel, ethyl acetate / petroleum ether=0:l-3:10) to afford (4a7?)-8-bromo-l-oxo-2-[3-(3,4,5,6-tetrahydro-27 / -pyran-4-ylidene)cyclobutyl]-2,3,4,4a,5,6-hexahydro-177-pyrimido[l,6-a]quinoline (35 mg, 17.1%) as a yellow solid. LC-MS (ESI) [M+H]+= 417.0.

[1143] Synthesis of3-{2-chloro-3-[(4a / ?)-l-oxo-2-[3-(3,4,5,6-tetrahydro-2H-pyran-4-ylidene)cyclobutyl]-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl]phenyl}hexahydropyridine-2, 6-dione: To a solution of (4aR)-8-bromo-l-oxo-2-[3-(3,4,5,6-tetrahydro-27 / -pyran-4-ylidene)cyclobutyl]-2,3,4,4a,5,6-hexahydro-17 / -pyrimido[l,6-a]quinoline (35 mg, 0.08 mmol, 1.0 eq) in dioxane (2 mL) and water (0.2 mL) were added 3-[2-chloro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]hexahydropyridine-2,6-dione (58 mg, 0.16 mmol, 2.0 eq), K3PO4 (53 mg, 0.24 mmol, 3.0 eq) and Pd(dppf)Cl2(6 mg, 8 pmol, 0.1 eq) at 25°C under nitrogen protection. The resulting mixture was stirred at 100°C for 2 hours. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (3x20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC using the following conditions: Column, SunFire JB-C235-35, Xtimate Cl 8, 21.2*250 mm, 5 um; mobile phase, water (0.1% FA) and CH3CN (40% Phase B up to 70% in 30 min); Detector, UV 254 / 214 nm, tR=17 min; to afford 3-{2-chloro-3-[(4aR)-l-oxo-2-[3-(3,4,5,6-tetrahydro-27 / -pyran-4-ylidene)cyclobutyl]-2,3,4,4a,5,6-hexahydro-17 / -pyrimido[l,6-a]quinolin-8-yl]phenyl}hexahydropyridine-2, 6-dione (14.62 mg, 31.1%) as a white solid. LC-MS (ESI)125569-02020

[1144] [M+H]+= 560.2. 'HNMR (400 MHz, Chloroform-d) δ 8.07 (s, 1H), 7.81 (d, J = 8.6 Hz, 1H), 7.32-7.27 (m, 2H), 7.20-7.13 (m, 2H), 7.13-7.09 (m, 1H), 5.00-4.88 (m, 1H), 4.36-4.27 (m, 1H), 3.79-3.59 (m, 5H), 3.47-3.31 (m, 2H), 2.99-2.68 (m, 8H), 2.37-2.23 (m, 3H), 2.19-2.06 (m, 5H), 1.89-1.77 (m, 2H).

[1145] Example 25: Preparation of3-{3-[(4aR)-2-[(lR,3R)-3-[(2R)-2-methyl-4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutyl]-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl]-2-chlorophenyl}hexahydropyridine-2, 6-dione

[1146] Synthesis of (lR,3r)-3-[(2R)-2-methyl-4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutan-l-amine: The solution of 2-methylpropan-2-yl {[(lR,3r)-3-[(2R)-2-methyl-4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutyl]amino}methanoate (657 mg, 2.13 mmol, 1.0 eq) in trifluoroacetic acid (1 mL) and dichloromethane (3 mL) was stirred at 25°C for 1 hour under nitrogen protection. The reaction was quenched with saturated potassium carbonate solution (20 mL). The reaction mixture extracted with ethyl acetate (3x20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford (lR,3r)-3-[(2R)-2-methyl-4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutan-l -amine (400 mg, 90.1%) as a yellow solid. LC-MS (ESI) [M+H]+= 209.4.

[1147] Synthesis of 2-methylpropan-2-yl (2R)-2-(2-{[(lR,3R)-3-[(2R)-2-methyl-4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutyl]amino}ethyl)-6-bromo-l, 2,3,4-tetrahydroquinoline-l-carboxylate: To a solution of (lR,3r)-3-[(2R)-2-methyl-4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutan-l -amine (176 mg, 0.84 mmol, 2.0 eq) in methanol (2 mL) were added 2-methylpropan-2-yl (2R)-6-bromo-2-(formylmethyl)-l,2,3,4-tetrahydroquinoline-1 -carboxylate (150 mg, 0.42 mmol, 1.0 eq) and acetic acid (2.50 mg, 42 pmol, 0.1 eq) at 25°C under nitrogen protection. The resulting mixture was stirred at 50°C for 6 hours. Then sodium cyanoborohydride (53 mg, 0.84 mmol, 2.0 eq) was added at 50°C. The resulting mixture was stirred for 18 hours at 50°C. The residue was purified by a flash column (silica gel, methanol / dichloromethane=0:1-1:10) to afford 2-methylpropan-2-yl (2R)-2-(2-{[(lR,3R)-3-[(2R)-2-methyl-4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutyl]amino}ethyl)-6-bromo-l,2,3,4-tetrahydroquinoline-l-carboxylate (100 mg, 43.2%) as a yellow solid. LC-MS (ESI) [M+H]+= 546.3.

[1148] Synthesis of (2R)-2-(2-{[(lR,3R)-3-[(2R)-2-methyl-4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutyl]amino}ethyl)-6-bromo-l, 2,3,4-tetrahydroquinoline 2,2,2-trifluoroacetic acid: The solution of 2-methylpropan-2-yl (2R)-2-125569-02020

[1149] (2-{[(lR,3R)-3-[(2R)-2-methyl-4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutyl]amino}ethyl)-6-bromo-l,2,3,4-tetrahydroquinoline-l-carboxylate (100 mg, 0.18 mmol, 1.0 eq) in trifluoroacetic acid (1 mL) and dichloromethane (3 mL) was stirred at 25°C for 1 hour under nitrogen protection. The reaction was concentrated under reduced pressure to afford (2R)-2-(2-{[(lR,3R)-3-[(2R)-2-methyl-4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutyl]amino}ethyl)-6-bromo-l,2,3,4-tetrahydroquinoline 2,2,2-trifluoroacetic acid (100 mg, 97.5%) as a yellow solid. LC-MS (ESI) [M+H]+= 446.3.

[1150] Synthesis of (4aR)-2-[(lR,3R)-3-[(2R)-2-methyl-4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutyl]-8-bromo-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinoline: To a solution of (2R)-2-(2-{[(lR,3R)-3-[(2R)-2-methyl-4-(propan-2-ylidene)hexahydropyridin- 1 -yl]cyclobutyl] amino }ethyl)-6-bromo- 1,2,3,4-tetrahydroquinoline 2,2,2-trifluoroacetic acid (100 mg, 0.18 mmol, 1.0 eq) and DIEA (0.09 mL, 0.54 mmol, 3.0 eq) in dichloromethane (2 mL) was added triphosgene (17 mg, 0.06 mmol, 0.33 eq) at 0°C under nitrogen protection. The resulting mixture was stirred at 0°C for 2 hours. The reaction mixture was quenched with water (10 mL) and extracted with dichloromethane (3x20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by a flash column (silica gel, methanol / dichloromethane=0:1-1:10) to afford (4aR)-2-[(lR,3R)-3-[(2R)-2-methyl-4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutyl]-8-bromo-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinoline (70 mg, 83.0%) as a yellow solid. LC-MS (ESI) [M+H]+= 474.2.

[1151] Synthesis of3-{3-[(4aR)-2-[(lR,3R)-3-[(2R)-2-methyl-4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutyl]-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl]-2-chlorophenyl}hexahydropyridine-2, 6-dione: To a solution of (4aR)-2-[(lR,3R)-3-[(2R)-2-methyl-4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutyl]-8-bromo-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinoline (70 mg, 0.15 mmol, 1.0 eq) in dioxane (1 mL) and water (0.1 mL) were added 3-[2-chloro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]hexahydropyridine-2, 6-dione (104 mg, 0.30 mmol, 2.0 eq), K₃PO₄ (94 mg, 0.45 mmol, 3.0 eq) and Pd(dppf)Cl2. CH2C12 (12 mg, 15 pmol, 0.1 eq) at 25°C under nitrogen protection. The resulting mixture was stirred at 100°C for 2 hours. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (3x20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC using the following conditions:

[1152] Column, SunFire JB-C235-35, Xtimate C18, 21.2*250 mm, 5 um; mobile phase, water (0.1% FA) and CH₃CN (22% Phase B up to 52% in 28 min); Detector, UV 254 / 214 nm, tR=13.5 min;125569-02020

[1153] to afford 3 - { 3 - [(4aR)-2- [( 1 R,3R)-3 - [(2R)-2-methyl-4-(propan-2-ylidene)hexahydropyridin- 1 -yl]cyclobutyl]-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl]-2-chlorophenyl}hexahydropyridine-2, 6-dione (18.66 mg, 20.4%) as a white solid. LC-MS (ESI) [M+H]+= 615.4. 'HNMR (400 MHz, Dimethylsulfoxide-d6) 5 10.91 (s, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.39-7.33 (m, 1H), 7.33-7.25 (m, 2H), 7.13-7.03 (m, 2H), 4.90-4.78 (m, 1H), 4.38-4.27 (m, 1H), 3.67-3.60 (m, 1H), 3.52-3.43 (m, 2H), 3.10-2.92 (m, 2H), 2.83-2.74 (m, 3H), 2.60-2.52 (m, 1H), 2.42-2.15 (m, 11H), 2.11-2.01 (m, 3H), 1.78-1.69 (m, 1H), 1.68-1.61 (m, 7H), 0.82 (d, J = 6.4 Hz, 3H).

[1154] Example 26: Preparation of 3-{3-[(4aR)-2-[(lS,3S)-3-[(2R)-2-methyl-4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutyl]-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl]-2-chlorophenyl}hexahydropyridine-2, 6-dione

[1155] Synthesis of (lS,3s)-3-[(2R)-2-methyl-4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutan-l-amine: The solution of 2-methylpropan-2-yl {[(lS,3s)-3-[(2R)-2-methyl-4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutyl]amino}methanoate (2 g, 6.48 mmol, 1.0 eq) in trifluoroacetic acid (10 mL) and dichloromethane (30 mL) was stirred for 1 hour at 25°C under nitrogen protection. The reaction was quenched with saturated potassium carbonate solution (20 mL). The reaction mixture extracted with ethyl acetate (3x20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford (lS,3s)-3-[(2R)-2-methyl-4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutan-l -amine (1.3 g, 96.2%) as a yellow solid. LC-MS (ESI) [M+H]+= 209.4.

[1156] Synthesis of 2-methylpropan-2-yl (2R)-2-(2-{[(lR,3R)-3-[(2R)-2-methyl-4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutyl]amino}ethyl)-6-bromo-l, 2,3,4-tetrahydroquinoline-l-carboxylate: To a solution of (lS,3s)-3-[(2R)-2-methyl-4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutan-l -amine (117 mg, 564 pmol, 2.0 eq) in methanol (1 mL) were added 2-methylpropan-2-yl (2R)-6-bromo-2-(formylmethyl)-l,2,3,4-tetrahydroquinoline-1 -carboxylate (100 mg, 282 μmol, 1.0 eq) and acetic acid (1.587 μL, 28.2 μmol, 0.1 eq) at 25°C under nitrogen protection. The resulting mixture was stirred for 6 hours at 50°C. Then sodium cyanoborohydride (35 mg, 564 μmol, 2.0 eq) was added at 50°C. The resulting mixture was stirred at 50°C for 18 hours. The reaction was concentrated under reduced pressure. The residue was purified by a flash column (silica gel, methanol / dichloromethane =0:1-1:10) to afford 2-methylpropan-2-yl (2R)-2-(2-{[(lS,3S)-3-[(2R)-2-methyl-4-(propan-2-ylidene)hexahydropyridin- 1-yl] cyclobutyl] amino }ethyl)-6-bromo- 1,2,3, 4-tetrahydroquinoline-125569-02020

[1157] 1 -carboxylate (80 mg, 51.8%) as a yellow solid. LC-MS (ESI) [M+H]+ = 546.3.

[1158] Synthesis of (2R)-2-(2-{[(lS,3S)-3-[(2R)-2-methyl-4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutyl]amino}ethyl)-6-bromo-l, 2,3,4-tetrahydroquinoline 2,2,2-trifluoroacetic acid: The solution of 2-methylpropan-2-yl (2R)-2-(2- { [( 1 S,3 S )-3 - [(2R)-2-methyl-4-(propan-2-ylidene)hexahydropyridin- 1 -yl]cyclobutyl]amino}ethyl)-6-bromo-l,2,3,4-tetrahydroquinoline-l-carboxylate (80 mg, 0.15 mmol, 1.0 eq) in trifluoroacetic acid (1 mL) and dichloromethane (3 mL) was stirred at 25°C for 1 hour under nitrogen protection. The reaction was concentrated under reduced pressure to afford (2R)-2-(2- { [( 1 S,3S)-3- [(2R)-2-methyl-4-(propan-2-ylidene)hexahydropyridin- 1 -yl]cyclobutyl]amino}ethyl)-6-bromo-l,2,3,4-tetrahydroquinoline 2,2,2-trifluoroacetic acid (80 mg, 97.5%) as a yellow solid. LC-MS (ESI) [M+H]+= 446.2.

[1159] Synthesis of (4aR)-2-[(lS,3S)-3-[(2R)-2-methyl-4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutyl]-8-bromo-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinoline: To a solution of (2R)-2-(2-{[(lS,3S)-3-[(2R)-2-methyl-4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutyl]amino}ethyl)-6-bromo-l,2,3,4-tetrahydroquinoline 2,2,2-trifluoroacetic acid (80 mg, 143 μmol, 1.0 eq) and DIEA (0.071 mL, 429 μmol, 3.0 eq) in dichloromethane (2 mL) was added triphosgene (14 mg, 47.2 μmol, 0.33 eq) at 0°C under nitrogen protection. The resulting mixture was stirred at 0°C for 2 hours. The reaction mixture was quenched with water (10 mL) and extracted with dichloromethane (3x20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by a flash column (silica gel, methanol / dichloromethane=0:1-1:10) to afford (4aR)-2-[(lS,3S)-3-[(2R)-2-methyl-4-(propan- 2-ylidene)hexahydropyridin-l-yl]cyclobutyl]-8-bromo-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinoline (35 mg, 51.9%) as a yellow solid. LC-MS (ESI) [M+H]+= 472.2.

[1160] Synthesis of3-{3-[(4aR)-2-[(lS,3S)-3-[(2R)-2-methyl-4-(propan-2-ylidene)hexahydropyridin-l-yl]cyclobutyl]-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl]-2-chlorophenyl}hexahydropyridine-2, 6-dione: To a solution of (4aR)-2-[( 1 S,3 S )-3 - [(2R)-2-methyl-4-(propan-2-ylidene)hexahydropyridin- 1 -yl] cyclobutyl] - 8-bromo- 1 -oxo-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinoline (30 mg, 63 μmol, 1.0 eq) in dioxane (1 mL) and water (0.1 mL) were added 3-[2-chloro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]hexahydropyridine-2, 6-dione (44 mg, 126 μmol, 2.0 eq), K₃PO₄ (40 mg, 189 μmol, 3.0 eq)and Pd(dppf)Cl₂·CH₂Cl₂ (5 mg, 6 μmol, 0.1 eq) at 25°C under nitrogen protection. The resulting mixture was stirred at 100°C for 2 hours. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (3x20 mL). The combined organic layers were125569-02020

[1161] dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC using the following conditions: Column, SunFire JB-C235-35, Xtimate Cl 8, 21.2*250 mm, 5 um; mobile phase, water (0.1% FA) and CH₃CN (20% Phase B up to 50% in 30 min); Detector, UV 254 / 214 nm, tR=15 min; to afford 3-{3-[(4aR)-2-[( 1 S,3 S )-3 - [(2R)-2-methyl-4-(propan-2-ylidene)hexahydropyridin- 1 -yl] cyclobutyl] - 1 -oxo-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl]-2-chlorophenyl}hexahydropyridine-2, 6-dione (10.73 mg, 27.4%) as a white solid. LC-MS (ESI) [M+H]+= 615.3. 'HNMR (400 MHz, Dimethylsulfoxide-d6) 8 10.91 (s, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.40-7.34 (m, 1H), 7.33-7.26 (m, 2H), 7.12-7.06 (m, 2H), 4.51-4.40 (m, 1H), 4.37-4.29 (m, 1H), 3.67-3.57 (m, 1H), 3.43-3.35 (m, 2H), 3.27-3.19 (m, 2H), 2.85-2.73 (m, 4H), 2.59-2.54 (m, 1H), 2.41-2.14 (m, 9H), 2.11-1.98 (m, 4H), 1.77-1.69 (m, 1H), 1.67-1.58 (m, 7H), 1.01-0.81 (m, 3H).

[1162] Example 27: Preparation of3-{2-chloro-3-[(4aR)-l-oxo-2-{3-[l-(3,4,5,6-tetrahydro-2H-pyran-4-yl)hexahydropyridin-4-ylidene]cyclobutyl}-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl]phenyl}hexahydropyridine-2, 6-dione

[1163] Synthesis of 3-methylidenecyclobutan-l-amine: To the solution of 2-methylpropan-2-yl [(3-methylidenecyclobutyl)amino]methanoate (3 g, 16.3 mmol, 1.0 eq) in dichloromethane (30 mL) was added trifluoroacetic acid (10 mL). The reaction mixture was stirred at 25 °C for 1 hour under N2. The reaction was quenched with saturated sodium bicarbonate (10 mL), filtered and extracted with dichloromethane (3x10 mL). The combined organic layers was washed with brine (3x10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 3-methylidenecyclobutan-l-amine (300 mg, 22.0%) as a colorless oil, the crude was used for next step without further purification. LC-MS (ESI) [M+H]+= 84.0.

[1164] Synthesis of 2-methylpropan-2-yl (2R)-6-bromo-2-{2-[(3-methylidenecyclobutyl)amino]ethyl}-l,2,3,4-tetrahydroquinoline-l-carboxylate: To the solution of 3-methylidenecyclobutan-l-amine (281 mg, 3.38 mmol, 1.0 eq) and 2-methylpropan-2-yl (2R)-6-bromo-2-(formylmethyl)- 1, 2, 3, 4-tetrahydroquinoline- 1 -carboxylate (1.2 g, 3.38 mmol, 1.0 eq) in methanol (12 mL) was added acetic acid (203 mg, 3.38 mmol, 1.0 eq), the mixture was stirred at 25°C for 17 hours, then sodium cyanoborohydride (426 mg, 6.77 mmol, 2.0 eq) was added to the mixture at 25°C, then the mixture was stirred at 25°C for 1 hour. The reaction mixture was added water (100 mL) and extracted with dichloromethane (3x100 mL). The combined organic layers were washed with brine (3x100 mL), dried over anhydrous NaiSCL, filtered and concentrated under vacuum. The reside was purified by column chromatography on silica gel (eluted with methanol / dichloromethane =1:20) to give the title125569-02020

[1165] compound 2-methylpropan-2-yl (2R)-6-bromo-2-{2-[(3-methylidenecyclobutyl)amino]ethyl}-1, 2, 3, 4-tetrahydroquinoline- 1 -carboxylate (300 mg, 21.0%) as white solid. LC-MS (ESI) [M+H]+= 422.2.

[1166] Synthesis of (2R)-6-bromo-2-{2-[(3-methylidenecyclobutyl)amino]ethyl}-l, 2,3,4-tetrahydroquinoline 2,2,2-trifluoroacetic acid: To the solution of 2-methylpropan-2-yl (2R)-6-bromo-2- {2- [(3 -methylidenecyclobutyl)amino] ethyl } - 1,2,3, 4-tetrahydroquinoline- 1 -carboxylate (350 mg, 0.83 mmol, 1.0 eq) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL). The reaction mixture was stirred at 25°C for 1 hour under N2. The reaction was concentrated under reduced pressure to afford (2R)-6-bromo-2-{2-[(3-methylidenecyclobutyl)amino]ethyl}- 1,2, 3, 4-tetrahydroquinoline 2,2,2-trifluoroacetic acid (300 mg, 77.4%) as colorless oil. The crude was used for next step without further purification. LC-MS (ESI) [M+H]+= 323.2.

[1167] Synthesis of (4aR)-8-bromo-2-(3-methylidenecyclobutyl)-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinoline: To a solution of (2R)-6-bromo-2-(2-{[3-(3,4,5,6-tetrahydro-2H-pyran-4-ylidene)cyclobutyl]amino}ethyl)- 1,2, 3, 4-tetrahydroquinoline 2,2,2-trifluoroacetic acid (280 mg, 0.64 mmol, 1.0 eq) in dichloromethane (3 mL) was added DIEA (0.21 mL, 1.28 mmol, 2.0 eq) and triphosgene (62.9 mg, 0.21 mmol, 0.33 eq) at 0°C under N2. The resulting mixture was stirred at 0°C for 1 hour under N2. The reaction was quenched with aq. NaHCO3(100 mL) and extracted with dichloromethane (3x10 mL). The combined organic layers was washed with brine (3x10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by a flash column (silica gel, methanol / dichloromethane = 1:20) to afford (4aR)-8-bromo-2-(3-methylidenecyclobutyl)-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinoline (120 mg, 53.7%) as a white solid. LC-MS (ESI) [M+H]+= 347.2.

[1168] Synthesis of 2-methylpropan-2-yl 4-{3-[(4aR)-8-bromo-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-2-yl]cyclobutylidene}hexahydropyridine-l-carboxylate: To the solution of (4aR)-8-bromo-2-(3-methylidenecyclobutyl)-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinoline (30 mg, 86 μmol, 1.0 eq) in dichloromethane (0.1 mL) was added 2-methylpropan-2-yl 4-methylidenehexahydropyridine-l-carboxylate (51.1mg, 259 μmol, 3.0 eq) and Hoveyda-Grubbs (1.02 mg, 4 μmol, 0.05 eq) at 25°C. The reaction mixture was stirred at 40°C for 18 hours under N2. The reaction mixture was added water (10 mL) and extracted with dichloro methane (3x10 mL). The combined organic layers were washed with brine (3x10 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The reside was purified by column chromatography on silica gel125569-02020

[1169] (eluted with methanol / dichloromethane =1:20 ) to give the title compound 2-methylpropan-2-yl 4-{3-[(4aR)-8-bromo-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-2-yl]cyclobutylidene}hexahydropyridine-l -carboxylate (40 mg, 22.4%) as a white solid. LC-MS (ESI) [M+H]+= 516.2.

[1170] Synthesis of (4aR)-8-bromo-2-[3-(hexahydropyridin-4-ylidene)cyclobutyl]-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinoline 2,2,2-trifluoroacetic acid: To a solution of 2-methylpropan-2-yl 4-{3-[(4aR)-8-bromo-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-2-yl]cyclobutylidene}hexahydropyridine-l-carboxylate (53 mg, 0.10 mmol, 1.0 eq) in dichloromethane (0.6 mL) was added trifluoroacetic acid (0.2 mL) at 25°C. The resulting mixture was stirred at 25°C for 1 hour. The reaction was filtered and concentrated to afford (4aR)-8-bromo-2-[3-(hexahydropyridin-4-ylidene)cyclobutyl]-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinoline 2,2,2-trifluoroacetic acid (30 mg, 55.1%) as a colorless oil. LC-MS (ESI) [M+H]+= 416.2.

[1171] Synthesis of (4aR)-8-bromo-l-oxo-2-{3-[l-(3,4,5,6-tetrahydro-2H-pyran-4-yl)hexahydropyridin-4-ylidene]cyclobutyl}-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinoline: To the solution of (4aR)-8-bromo-2-[3-(hexahydropyridin-4-ylidene)cyclobutyl]- 1-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinoline 2,2,2-trifluoroacetic acid (25 mg, 60 pmol, 1.0 eq) and tetrahydropyran-4-one (60 mg, 600 μmol 10.0 eq) in methanol (0.5 mL) was added sodium acetate (9.85 mg, 120 μmol, 2.0 eq), the mixture was stirred at 25°C for 17 hours, then sodium cyanoborohydride (7.57 mg, 120 μmol, 2.0 eq) was added to the mixture at 25°C, then the mixture was stirred at 25°C for 1 hour. The reaction mixture was added water (10 mL) and extracted with dichloromethane (3x10 mL). The combined organic layers were washed with brine (3x10 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The reside was purified by column chromatography on silica gel (eluted with methanol / dichloromethane =1:5) to give the title compound (4aR)-8-bromo-l-oxo-2-{3-[l-(3,4,5,6-tetrahydro-2H-pyran-4-yl)hexahydropyridin-4-ylidene]cyclobutyl}-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinoline (15 mg, 49.9%) as white solid. LC-MS (ESI) [M+H]+= 502.2.

[1172] Synthesis of3-{2-chloro-3-[(4aR)-l-oxo-2-{3-[l-(3,4,5,6-tetrahydro-2H-pyran-4-yl)hexahydropyridin-4-ylidene]cyclobutyl}-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl]phenyl}hexahydropyridine-2, 6-dione: To a solution of (4aR)-8-bromo-l-oxo- 2- { 3- [ 1 -(3,4,5,6-tetrahydro-2H-pyran-4-yl)hexahydropyridin-4-ylidene] cyclobutyl } -2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinoline (13 mg, 26 pmol, 1.0 eq) in dioxane / water (0.2 mL / 0.02 mL) was added 3-[2-chloro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]hexahydropyridine-2, 6-dione (18.1 mg, 52 pmol, 2.0 eq), [1,1’-125569-02020

[1173] Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.90 mg, 2.6 μmol, 0.1 eq) and K₃PO₄ (11 mg, 52 μmol, 2.0 eq) at 25°C under N₂. The resulting mixture was stirred at 100°C for 1 hour under N2. The reaction was concentrated to give a residue, which was purified by Prep-HPLC (Instrument: Shimadzu LH-40 Liquid Handler, Shimadzu LC-20AP Pump, Shimadzu, SPD-20APUV Detector, Column: Xtimate C18, 21.2*250 mm, 5 um; Mobile phase A: H₂O with 0.1% TFA; Mobile phase B: CH₃CN; Gradient: B from 25% to 45% in 25 min; Flow Rate: 20 mL / min; Rt = 17.0 min, Column Temperature: 30°C; Wavelength: 214 nm, 254 nm) to afford 3 - { 2-chloro-3 - [(4aR)- 1 -oxo-2- { 3 - [ 1 -(3,4,5,6-tetrahydro-2H-pyran-4-yl)hexahydropyridin-4-ylidene]cyclobutyl}-2,3,4,4a,5,6-hexahydro-lH-pyrimido[l,6-a]quinolin-8-yl]phenyl}hexahydropyridine-2, 6-dione (2.12 mg, 12.6%) as a white solid. LC-MS (ESI) [M+H]+= 643.2. 'HNMR (400 MHz, Chloroform-d) 58.04 (s, 1H), 7.81-7.73 (m, 1H), 7.42-7.35 (m, 1H), 7.31-7.30 (m, 1H), 7.23-7.18 (m, 2H), 7.16-7.14 (m, 1H), 5.30-4.70 (m, 1H), 4.45-4.24 (m, 2H), 4.19-4.10 (m, 2H), 3.78-3.70 (m, 1H), 3.55-3.36 (m, 7H), 2.95-2.70 (m, 12H), 2.47-2.28 (m, 7H), 2.21-2.10 (m, 4H).

[1174] Example 28: Preparation of (S)-3-(2-chloro-3-((S)-l-oxo-2-(propan-2-ylidene)-2,3,4,4a,5,6-hexahydro-lH-pyrido[l,2-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2, 6-dione Synthesis of (4aS)-8-bromo-2-(2-hydroxypropan-2-yl)-2,3,4,4a,5,6-hexahydro-lH-pyrido[l,2-a]quinolin-l-one: To a solution of (S)-8-bromo-2,3,4,4a,5,6-hexahydro-lH-pyrido[l,2-a]quinolin-l-one (700 mg, 2.5 mmol, 1.0 eq) in THF (500 mL) was added LDA (2.0 M in THF / hexane, Energy Seal, 6.25 mmol, 2.5 eq) dropwise at -78°C, the reaction mixture was stirred at -78°C for 0.5 h. Acetone (290 mg, 5.0 mmol, 2.0 eq) was added dropwise at -78 °C, the reaction mixture was stirred at -78 °C for 1.5 h. After the reaction was completed, saturated NH4CI solution (20 mL) was added and the reaction mixture was extracted by ethyl acetate (3x30 mL), washed with brine (2x30 mL), dried over Na₂SO₄, filtered and concentrated in vacuo to give a crude. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether =1:5- 1:2) to afford compound (4aS)-8-bromo-2-(2-hydroxypropan-2-yl)-2,3,4,4a,5,6-hexahydro-lH-pyrido[l,2-a]quinolin-l-one (710 mg, 84.0%) as a yellow oil. LC-MS (ESI) [M+H]+=338.1, 340.1.

[1175] Synthesis of (S)-8-bromo-2-(propan-2-ylidene)-2,3,4,4a,5,6-hexahydro-lH-pyrido[l,2-a] quinolin- 1 -one: To a solution of (4aS)-8-bromo-2-(2-hydroxypropan-2-yl)-2,3,4,4a,5,6-hexahydro-lH-pyrido[l,2-a]quinolin-l-one (700 mg, 2.1 mmol, 1.0 eq) in toluene (55 mL) was added TsOH (178 mg, 1.05 mmol, 0.5 eq), the reaction mixture was stirred at 100°C for 2 h. After the reaction was completed, H₂O (10 mL) was added and the reaction125569-02020

[1176] mixture was extracted by ethyl acetate (3x20 mL), washed with brine (2x20 mL), dried over Na₂SO₄, filtered and concentrated in vacuo to give a crude. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether =1:15) to afford compound (S)-8-bromo-2-(propan-2-ylidene)-2,3,4,4a,5,6-hexahydro-lH-pyrido[l,2-a]quinolin-l-one (280 mg, 42.3%) as a yellow solid. LC-MS (ESI) [M+H]+=320.1, 322.0.

[1177] Synthesis of (S)-2-(propan-2-ylidene)-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,3,4,4a,5,6-hexahydro-lH-pyrido[l,2-a]quinolin-l-one: To a solution of (S)-8-bromo-2-(propan-2-ylidene)-2,3,4,4a,5,6-hexahydro-lH-pyrido[l,2-a]quinolin-l-one (100 mg, 0.31 mmol, 1.0 eq) in dioxane (2 mL) was added B2(Pin)2 (238 mg, 0.93 mmol, 3.0 eq), Pd(dppf)Cl2(23 mg, 0.03 mmol, 0.1 eq) and KO Ac (92 mg, 0.93 mmol, 3.0 eq) at room temperature, the reaction was heated at 100°C for 2 h. After the reaction was completed, H₂O (10 mL) was added and the reaction mixture was extracted by ethyl acetate (3x20 mL), washed with brine (2x20 mL), dried over Na₂SO₄, filtered and concentrated in vacuo to give a crude. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether =1: 10) to afford compound (S)-2-(propan-2-ylidene)-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,3,4,4a,5,6-hexahydro-lH-pyrido[l,2-a]quinolin-l-one (100 mg, 87.2%) as a yellow solid. LC-MS (ESI) [M+H]+=368.2.

[1178] Synthesis of (S)-3-(2-chloro-3-((S)-l-oxo-2-(propan-2-ylidene)-2,3,4,4a,5,6-hexahydro-lH-pyrido[l,2-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2, 6-dione: To a solution of (S)-2-(propan-2-ylidene)-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,3,4,4a,5,6-hexahydro-lH-pyrido[l,2-a]quinolin-l-one (70 mg, 0.19 mmol, 1.0 eq) in DMF (6 mL) was added (S)-3-(3-bromo-2-chlorophenyl)-3-fluoropiperidine-2, 6-dione (61 mg, 0.19 mmol, 1.0 eq), Pd(dppf)Cl2(42 mg, 0.057 mmol, 0.3 eq) and K₃PO₄ (162 mg, 0.76 mmol, 4.0 eq) at room temperature, the reaction was heated at lOOoC for 2 h. After the reaction was completed, H₂O (10 mL) was added and the reaction mixture was extracted by ethyl acetate (3x20 mL), washed with brine (2x20 mL), dried over Na₂SO₄, filtered and concentrated in vacuo to give a crude. The residue was purified by prep-TLC (ethyl acetate / petroleum ether =1:1) to afford compound (S)-3-(2-chloro-3-((S)-l-oxo-2-(propan-2-ylidene)-2,3,4,4a,5,6-hexahydro-lH-pyrido[l,2-a]quinolin-8-yl)phenyl)-3-fluoropiperidine-2, 6-dione (10.1 mg, 11.0%) as a white solid. LC-MS (ESI) [M+H]+=481.1. 'HNMR (400 MHz, Dimethylsulfoxide-d6) 8 11.52 (s, 1H), 8.00 (d, J = 9.2 Hz, 1H), 7.70 - 7.60 (m, 1H), 7.59 - 7.50 (m, 1H), 7.48 - 7.40 (m, 1H), 7.19 - 7.09 (m, 2H), 3.77 - 3.53 (m, 1H), 3.03 - 2.80 (m, 2H), 2.80 - 2.70 (m, 2H), 2.68 - 2.53 (m, 2H), 2.46 - 2.38 (m, 1H), 2.35 - 2.23 (m, 1H), 2.13 - 2.00 (m, 5H), 1.81 (s, 3H), 1.75 - 1.61 (m, 2H).125569-02020

[1179] Example 30: Preparation of (S)-3-(2-chloro-3-((R)-2,2-difluoro-l-oxo-2,3,4,4a,5,6-hexahydro-lH-pyrido[l,2-a] quinolin-8-yl)phenyl)-3-fluoropiperidine-2, 6-dione Synthesis of (R)-8-bromo-2,2-difluoro-2,3,4,4a,5,6-hexahydro-lH-pyrido[l,2-a]quinolin-l-one: To a solution of (S)-8-bromo-2,3,4,4a,5,6-hexahydro-lH-pyrido[l,2-a] quinolin- 1 -one (100 mg, 0.36 mmol, 1.0 eq) in THF (2 mL) was added LiHMDS (2.0 M in THF, 0.72 mmol, 2.0 eq) dropwise at -78°C, the reaction mixture was stirred at -78°C for 2 h. NFSI (449 mg, 1.42 mmol, 4.0 eq) in THF (2 mL) was added dropwise at -78°C. Then the reaction mixture was stirred at room temperature for 2 h. After the reaction was completed, saturated NH4CI solution (20 mL) was added and the reaction mixture was extracted by ethyl acetate (3x20 mL), washed with brine (2x20 mL), dried over Na₂SO₄, filtered and concentrated in vacuo to give a crude. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether =1:20-1:5) to afford compound (R)-8-bromo-2,2-difluoro-2,3,4,4a,5,6-hexahydro-lH-pyrido[l,2-a] quinolin- 1 -one (batch with 60 mg to give 60 mg, 33.2%) as a yellow oil. LC-MS (ESI) [M+H]+=316.0, 318.0.

[1180] Synthesis of (R)-2,2-difluoro-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,3,4,4a,5,6-hexahydro-lH-pyrido[l,2-a]quinolin-l-one: To a solution of (R)-8-bromo-2,2-difluoro-2,3,4,4a,5,6-hexahydro-lH-pyrido[l,2-a]quinolin-l-one (50 mg, 0.16 mmol, 1.0 eq) in dioxane (2 mL) was added B2(Pin)2 (120 mg, 0.47 mmol, 3.0 eq), Pd(dppf)Cl2(13 mg, 0.016 mmol, 0.1 eq) and KO Ac (46 mg, 0.47 mmol, 3.0 eq) at room temperature, the reaction was heated at 100°C for 2 h. After the reaction was completed, the reaction mixture was added H2O (10 mL), extracted by ethyl acetate (3x20 mL), washed with brine (2x20 mL), dried over Na₂SO₄, filtered and concentrated in vacuo to give a crude. The residue was purified by prep-TLC (ethyl acetate / petroleum ether =1:1) to afford compound (R)-2,2-difluoro-8-(4, 4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-2,3,4, 4a, 5,6-hexahydro- 1 H-pyrido [ 1,2-a] quinolin- 1 -one (batch with 10 mg to give 60 mg, 68.9%) as a white solid. LC-MS (ESI) [M+H]+=364.2.

[1181] Synthesis of (S)-3-(2-...

Claims

125569-02020WHAT IS CLAIMED IS:

1. A compound of Formula (A), 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 (A) or N-oxide thereof:whereinQi is cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged- carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl;Q2 is cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged- carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl;Z° is absent, a bond, -(CRaRb)P-, -N(RC)-, -O-, -S-, -C(O)-, -S(O2)-, -O(CRaRb)P-, - N(Rc)(CRaRb)p-, -OC(O)-, -C(O)O-, -OSO2-, -S(O2)O-, -C(O)S-, -SC(O)-, -C(O)C(O)-, - C(O)N(Rc)-, -N(Rc)C(O)-, -S(O2)N(RC)-, -N(RC)S(O2)-, -OC(O)O-, -OC(O)S-, - OC(O)N(Rc)-, -N(Rc)C(O)O-, -N(Rc)C(O)S-, -N(Rc)C(O)N(Rc)-, - (CRaRb)pN(Rc)(CRaRb)q-, -(CRaRb)pN(Rc)C(O)(CRaRb)q-, OC(O)N(Rc)(CRaRb)P+iN(Rc)(CRaRb)q-, -(CRaRb)PC(O)N(Rc)(CRaRb)q-, bivalent alkenyl;Zi is absent, a bond, -(CRaRb)P-, -N(RC)-, -O-, -S-, -C(O)-, -S(O2)-, -O(CRaRb)P-, - N(Rc)(CRaRb)p-, -OC(O)-, -C(O)O-, -OSO2-, -S(O2)O-, -C(O)S-, -SC(O)-, -C(O)C(O)-, - C(O)N(Rc)-, -N(Rc)C(O)-, -S(O2)N(RC)-, -N(RC)S(O2)-, -OC(O)O-, -OC(O)S-, - OC(O)N(Rc)-, -N(Rc)C(O)O-, -N(Rc)C(O)S-, -N(Rc)C(O)N(Rc)-, - (CRaRb)pN(Rc)(CRaRb)q-, -(CRaRb)pN(Rc)C(O)(CRaRb)q-, OC(O)N(Rc)(CRaRb)P+iN(Rc)(CRaRb)q-, -(CRaRb)PC(O)N(Rc)(CRaRb)q-, bivalent alkenylene;Li is absent, a bond, N(Ra), O, S, C(O), S(O2), OC(O), C(O)O, OSO2, S(O2)O, C(O)S, SC(O), C(O)C(O), C(O)N(Ra), N(Ra)C(O), S(O2)N(Ra), N(Ra)S(O2), OC(O)O, OC(O)S, OC(O)N(Ra), N(Ra)C(O)O, N(Ra)C(O)S, N(Ra)C(O)N(Ra), alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiro-125569-02020heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, in which each of the aforementioned is optionally substituted with one or more Rd;L2is absent, a bond, N(Ra), O, S, C(O), S(O2), OC(O), C(O)O, OSO2, S(O2)O, C(O)S, SC(O), C(O)C(O), C(O)N(Ra), N(Ra)C(O), S(O2)N(Ra), N(Ra)S(O2), OC(O)O, OC(O)S, OC(O)N(Ra), N(Ra)C(O)O, N(Ra)C(O)S, N(Ra)C(O)N(Ra), alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, in which each of the aforementioned is optionally substituted with one or more Rd;each Ro is independently H, D, halo, cyano, nitro, alkyl, alkenyl, alkynyl, -alkylene-Ra, =CRaRb, =NRb, =0, -C(0)Ra, -C(0)NRbRc, -C(0)0Ra, -NH(CH2)pRa, -NRbRc, -NRbC(0)Rc, -NRbS(O)2Rc, -N=S(O)RbRc, -0Ra, -0C(0)Ra, -0C(0)0Ra, -0P(0)(0Rb)(0Rc), -0P(0)(0Rb)(NHRc), -0P(0)RbRc, -P(0)RbRc, -alkylene-P(O)RbRc, -SRa, -S(O)Ra, -S(O)(NRb)Rc, -S(O)2Ra, -S(O)2NRbRc, -(CRaRb)PRd, -(CRaRb)PN(Rc)(CRaRb)qRd, -(CRaRb)PO(CRaRb)qRd, -(CRaRb)PC(O)(CRaRb)qRd, -(CRaRb)PC(0)0(CRaRb)qRd, -(CRaRb)P0C(0)(CRaRb)qRd, -(CRaRb)P0C(0)0(CRaRb)qRd, -(CRaRb)PN(Rc)C(O)(CRaRb)qRd, -(CRaRb)PC(O)N(Rc)(CRaRb)qRd, -(CRaRb)POC(O)N(Rc)(CRaRb)qRd, -(CRaRb)PN(Rc)C(O)O(CRaRb)qRd, cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, each of the aforementioned is optionally substituted with one or more independently selected Rd substituents;each Ri is independently H, D, halo, cyano, nitro, alkyl, alkenyl, alkynyl, -alkylene-Ra, =CRaRb, =NRb, =0, -C(0)Ra, -C(0)NRbRc, -C(0)0Ra, -NH(CH2)pRa, -NRbRc, -NRbC(0)Rc, -NRbS(0)2Rc, -N=S(0)RbRc, -0Ra, -0C(0)Ra, -0C(0)0Ra, -0P(0)(0Rb)(0Rc), -0P(0)(0Rb)(NHRc), -0P(0)RbRc, -P(0)RbRc, -alkylene-P(O)RbRc, -SRa, -S(O)Ra, -S(0)(NRb)Rc, -S(O)2Ra, -S(0)2NRbRc, -(CRaRb)PRd, -(CRaRb)PN(Rc)(CRaRb)qRd, -(CRaRb)PO(CRaRb)qRd, -(CRaRb)PC(O)(CRaRb)qRd, -(CRaRb)PC(0)0(CRaRb)qRd, -(CRaRb)P0C(0)(CRaRb)qRd, -(CRaRb)P0C(0)0(CRaRb)qRd, -(CRaRb)PN(Rc)C(O)(CRaRb)qRd, -(CRaRb)PC(O)N(Rc)(CRaRb)qRd, -(CRaRb)POC(O)N(Rc)(CRaRb)qRd, -(CRaRb)PN(Rc)C(O)O(CRaRb)qRd, cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, each of the aforementioned is optionally substituted with one or more independently selected Rd substituents;125569-02020two Ri, taken together with the atom(s) to which they are attached, independently form a cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, wherein each of the aforementioned is optionally and independently substituted with one or more independently selected Rd substituent;each R2 is independently H, D, halo, cyano, nitro, alkyl, alkenyl, alkynyl, -alkylene-Ra, =CRaRb, =NRb, =0, -C(0)Ra, -C(0)NRbRc, -C(0)0Ra, -NH(CH2)pRa, -NRbRc, -NRbC(0)Rc, -NRbS(0)2Rc, -N=S(0)RbRc, -0Ra, -0C(0)Ra, -0C(0)0Ra, -0P(0)(0Rb)(0Rc), -0P(0)(0Rb)(NHRc), -0P(0)RbRc, -P(0)RbRc, -alkylene-P(O)RbRc, -SRa, -S(O)Ra, -S(0)(NRb)Rc, -S(O)2Ra, -S(0)2NRbRc, -(CRaRb)PRd, -(CRaRb)PN(Rc)(CRaRb)qRd, -(CRaRb)P0(CRaRb)qRd, -(CRaRb)PC(O)(CRaRb)qRd, -(CRaRb)PC(0)0(CRaRb)qRd, -(CRaRb)P0C(0)(CRaRb)qRd, -(CRaRb)P0C(0)0(CRaRb)qRd, -(CRaRb)PN(Rc)C(O)(CRaRb)qRd, -(CRaRb)PC(O)N(Rc)(CRaRb)qRd, -(CRaRb)POC(O)N(Rc)(CRaRb)qRd, -(CRaRb)PN(Rc)C(0)0(CRaRb)qRd, cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, each of the aforementioned is optionally substituted with one or more independently selected Rd substituents;Ri and R2, taken together with the atom(s) to which they are attached, independently form a cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, wherein each of the aforementioned is optionally and independently substituted with one or more independently selected Rd substituent;two R2, taken together with the atom(s) to which they are attached, independently form a cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, wherein each of the aforementioned is optionally and independently substituted with one or more independently selected Rd substituent;each R3 is independently H, D, halo, cyano, nitro, alkyl, alkenyl, alkynyl, -alkylene-Ra, =CRaRb, =NRb, =0, -C(0)Ra, -C(0)NRbRc, -C(0)0Ra, -NH(CH2)pRa, -NRbRc, -NRbC(0)Rc, -NRbS(0)2Rc, -N=S(0)RbRc, -0Ra, -0C(0)Ra, -0C(0)0Ra, -0P(0)(0Rb)(0Rc), -0P(0)(0Rb)(NHRc), -0P(0)RbRc, -P(0)RbRc, -alkylene-P(O)RbRc, -SRa, -S(O)Ra, -S(0)(NRb)Rc, -S(O)2Ra, -S(0)2NRbRc, -(CRaRb)PRd, -125569-02020(CRaRb)PN(Rc)(CRaRb)qRd, -(CRaRb)pO(CRaRb)qRd, -(CRaRb)pC(O)(CRaRb)qRd, -(CRaRb)pC(O)O(CRaRb)qRd, -(CRaRb)pOC(O)(CRaRb)qRd, -(CRaRb)pOC(O)O(CRaRb)qRd, -(CRaRb)pN(Rc)C(O)(CRaRb)qRd, -(CRaRb)PC(O)N(Rc)(CRaRb)qRd, -(CRaRb)pOC(O)N(Rc)(CRaRb)qRd, -(CRaRb)PN(Rc)C(O)O(CRaRb)qRd, cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, each of the aforementioned is optionally substituted with one or more independently selected Rd substituents;two R3, taken together with the atom(s) to which they are attached, independently form a cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, wherein each of the aforementioned is optionally and independently substituted with one or more independently selected Rd substituent;R2 and R3, taken together with the atom(s) to which they are attached, independently form a cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, wherein each of the aforementioned is optionally and independently substituted with one or more independently selected Rd substituent;L2 and R3, taken together with the atom(s) to which they are attached, independently form a cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, wherein each of the aforementioned is optionally and independently substituted with one or more independently selected Rd substituent;R4 is H, D, halo, cyano, nitro, alkyl, alkenyl, alkynyl, -alkylene-Ra, =CRaRb, =NRb, =0, -C(0)Ra, -C(0)NRbRc, -C(0)0Ra, -NH(CH2)PRa, -NRbRc, -NRbC(0)Rc, -NRbS(0)2Rc, -N=S(0)RbRc, -0Ra, -0C(0)Ra, -0C(0)0Ra, -0P(0)(0Rb)(0Rc), -0P(0)(0Rb)(NHRc), -0P(0)RbRc, -P(0)RbRc, -alkylene-P(O)RbRc, -SRa, -S(O)Ra, -S(0)(NRb)Rc, -S(O)2Ra, -S(0)2NRbRc, -(CRaRb)PRd, -(CRaRb)pN(Rc)(CRaRb)qRd, -(CRaRb)pO(CRaRb)qRd, -(CRaRb)pC(O)(CRaRb)qRd, -(CRaRb)PC(0)0(CRaRb)qRd, -(CRaRb)pOC(O)(CRaRb)qRd, -(CRaRb)P0C(0)0(CRaRb)qRd, -(CRaRb)pN(Rc)C(O)(CRaRb)qRd, -(CRaRb)pC(O)N(Rc)(CRaRb)qRd, -(CRaRb)pOC(O)N(Rc)(CRaRb)qRd, -(CRaRb)pN(Rc)C(O)O(CRaRb)qRd, cycloalkyl,125569-02020cycloalkenyl, 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;RA is H, D, or F;each Rais independently H, D, alkyl, alkenyl, alkynyl, halo, -CF3, cyano, nitro, -OH, -C(O)NHOH, -C(O)NH2, -C(O)OH, -NH2, =CReRf, =NRe, =0, -C(0)Re, -C(O)NReRf, -C(0)0Re, -NH(CH2)pRe, -NReRf, -NReC(0)Rf, -NReS(0)2Rf, -N=S(O)ReRf, -0Re, -0C(0)Re, -0C(0)0Re, -OP(O)(ORe)(ORf), -OP(O)(ORe)(NHRf), -alkylene-P(O)ReRf, -OP(O)ReRf„ -P(O)ReRf, -SRe, -S(O)Re, -S(O)(NRe)Rf, -S(O)2Re, -S(O)2NReRf, N=S(O)ReRf, -S(0)(NRe)Rf, -(CH2)pRf, -(CH2)pN(Re)(CH2)qRf, -(CH2)pO(CH2)qRf, -(CH2)pC(O)(CH2)qRf, -(CH2)pC(O)O(CH2)b,qRf, -(CH2)pOC(O)(CH2)qRf, -(CH2)pOC(O)O(CH2)qRf, -(CH2)pN(Re)C(O)(CH2)qRf, -(CH2)pC(O)N(Re)(CH2)qRf, -(CH2)pOC(O)N(Re)(CH2)qRf, -(CRaRb)pN(Re)C(O)O(CH2)qRf, cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, each of the aforementioned is optionally and independently substituted with one or more independently selected Rgsubstituents;each Rb is independently H, D, alkyl, alkenyl, alkynyl, halo, -CF3, cyano, nitro, -OH, -C(0)NH0H, -C(0)NH2, -C(0)0H, -NH2, =CReRf, =NRe, =0, -C(0)Re, -C(O)NReRf, -C(0)0Re, -NH(CH2)pRe, -NReRf, -NReC(0)Rf, -NReS(0)2Rf, -N=S(O)ReRf, -0Re, -0C(0)Re, -0C(0)0Re, -alkylene-P(O)ReRf, -0P(0)(0Re)(0Rf), -OP(O)(ORe)(NHRf), -OP(O)ReRf, -P(O)ReRf, -SRe, -S(O)Re, -S(O)(NRe)Rf, -S(O)2Re, -S(O)2NReRf, N=S(O)ReRf, -S(0)(NRe)Rf, -(CH2)pRf, -(CH2)pN(Re)(CH2)qRf, -(CH2)pO(CH2)qRf, -(CH2)pC(O)(CH2)qRf, -(CH2)pC(O)O(CH2)b,qRf, -(CH2)pOC(O)(CH2)qRf, -(CH2)pOC(O)O(CH2)qRf, -(CH2)pN(Re)C(O)(CH2)qRf, -(CH2)pC(O)N(Re)(CH2)qRf, -(CH2)pOC(O)N(Re)(CH2)qRf, -(CRaRb)pN(Re)C(O)O(CH2)qRf, cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, each of the aforementioned is optionally and independently substituted with one or more independently selected Rgsubstituents;Ra and Rb, taken together with the atom(s) to which they are attached,125569-02020independently form a cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, wherein each of the aforementioned is optionally and independently substituted with one or more independently selected Rgsubstituent;each Rcis independently H, D, alkyl, alkenyl, alkynyl, halo, -CF3, cyano, nitro, -OH, -C(O)NHOH, -C(O)NH2, -C(O)OH, -NH2, =CReRf, =NRe, =0, -C(0)Re, -C(O)NReRf, -C(0)0Re, -NH(CH2)pRe, -NReRf, -NReC(0)Rf, -NReS(0)2Rf, -N=S(O)ReRf, -0Re, -0C(0)Re, -0C(0)0Re, -alkylene-P(O)ReRf, -0P(0)(0Re)(0Rf), -OP(O)(ORe)(NHRf), -OP(O)ReRf, -P(O)ReRf, -SRe, -S(O)Re, -S(O)(NRe)Rf, -S(O)2Re, -S(O)2NReRf, N=S(O)ReRf, -S(O)(NRe)Rf, -(CH2)pRf, -(CH2)pN(Re)(CH2)qRf, -(CH2)pO(CH2)qRf, -(CH2)pC(O)(CH2)qRf, -(CH2)pC(O)O(CH2)qRf, -(CH2)pOC(O)(CH2)qRf, -(CH2)pOC(O)O(CH2)qRf, -(CH2)pN(Re)C(O)(CH2)qRf, -(CH2)pC(O)N(Re)(CH2)qRf, -(CH2)pOC(O)N(Re)(CH2)qRf, -(CRaRb)pN(Re)C(O)O(CH2)qRf, cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, each of the aforementioned is optionally and independently substituted with one or more independently selected Rgsubstituents;Rb and Rc, taken together with the atom(s) to which they are attached, independently form a cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, wherein each of the aforementioned is optionally and independently substituted with one or more independently selected Rgsubstituent;each Rd is independently H, D, alkyl, alkenyl, alkynyl, halo, -CF3, cyano, nitro, -OH, -C(0)NH0H, -C(0)NH2, -C(0)0H, -NH2, =CReRf, =NRe, =0, -C(0)Re, -C(O)NReRf, -C(0)0Re, -NH(CH2)pRe, -NReRf, -NReC(0)Rf, -NReS(0)2Rf, -N=S(O)ReRf, -0Re, -0C(0)Re, -0C(0)0Re, -alkylene-P(O)ReRf, -0P(0)(0Re)(0Rf), -OP(O)(ORe)(NHRf), -OP(O)ReRf„ -P(O)ReRf, -SRe, -S(O)Re, -S(O)(NRe)Rf, -S(O)2Re, -S(O)2NReRf, N=S(O)ReRf, -S(O)(NRe)Rf, -(CH2)pRf, -(CH2)pN(Re)(CH2)qRf, -(CH2)pO(CH2)qRf, -(CH2)pC(O)(CH2)qRf, -(CH2)pC(O)O(CH2)b,qRf, -(CH2)pOC(O)(CH2)qRf, -(CH2)pOC(O)O(CH2)qRf, -(CH2)pN(Re)C(O)(CH2)qRf, -(CH2)pC(O)N(Re)(CH2)qRf, -(CH2)pOC(O)N(Re)(CH2)qRf, -125569-02020(CRaRb)pN(Re)C(O)O(CH2)qRf, cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, each of the aforementioned is optionally and independently substituted with one or more independently selected Rgsubstituents;two Rd, taken together with the atom(s) to which they are attached, independently form a cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, wherein each of the aforementioned is optionally and independently substituted with one or more independently selected Rgsubstituent;each Reis independently H, D, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxy alkyloxy, alkoxyalkyloxyalkyl, alkylidenyl, alkoxyalkylidenyl, alkylthio, alkylsulfonyl, cyanoalkyl, cyanoalkenyl, cyanoalkynyl, alkylamino, dialkylamino, aminocarbonyl, alkoxycarbonyl, alkylcarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, halo, haloalkyl, haloalkylidenyl, hydroxyalkyl, haloalkoxy, heteroalkyl, hydroxyalkyl, oxoalkyl, -NH2, -OH, -CF3, -Cyano, -Nitro, =CH2, =NH, =0, -C(O)NH2, -C(O)NHOH, -C(O)OH, -C(O)ORg-, -OC(O)Rg-, -OP(O)(OH)(OH), -P(O)(OH)(OH), aralkyl, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkyloxyalkyl, cycloalkylalkyloxyalkyloxy, cycloalkylalkyloxyalkyl, heteroaralkyl, heterocyclylalkyl, heterocyclyloxy, heterocyclyloxyalkyl, heterocyclylalkyloxy, heterocyclylalkyloxyalkyl, cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, each of the aforementioned is optionally and independently substituted with one or more independently selected Rgsubstituents;two Re, taken together with the atom(s) to which they are attached, independently form a cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, wherein each of the aforementioned is optionally and independently substituted with one or more independently selected Rgsubstituent;each Rf is independently H, D, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxy alkyloxy, alkoxyalkyloxyalkyl, alkylidenyl, alkoxyalkylidenyl, alkylthio, alkylsulfonyl, cyanoalkyl, cyanoalkenyl, cyanoalkynyl, alkylamino,125569-02020dialkylamino, aminocarbonyl, alkoxycarbonyl, alkylcarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, halo, haloalkyl, haloalkylidenyl, hydroxyalkyl, haloalkoxy, heteroalkyl, hydroxyalkyl, oxoalkyl, -NH2, -OH, -C(O)ORg-, -OC(O)Rg-,-CF3, -Cyano, -Nitro, =CH2, =NH, =0, -C(O)NH2, -C(O)NHOH, -C(O)OH,-OP(O)(OH)(OH), -P(O)(OH)(OH), aralkyl, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkyloxyalkyl, cycloalkylalkyloxyalkyloxy, cycloalkylalkyloxyalkyl, heteroaralkyl, heterocyclylalkyl, heterocyclyloxy, heterocyclyloxyalkyl, heterocyclylalkyloxy, heterocyclylalkyloxyalkyl, cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, each of the aforementioned is optionally and independently substituted with one or more independently selected Rgsubstituents;two Rf, taken together with the atom(s) to which they are attached, independently form a cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, wherein each of the aforementioned is optionally and independently substituted with one or more independently selected Rgsubstituent;each Rgis independently H, D, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxy alkyloxy, alkoxyalkyloxyalkyl, alkylidenyl, alkoxyalkylidenyl, alkylthio, alkylsulfonyl, cyanoalkyl, cyanoalkenyl, cyanoalkynyl, alkylamino, dialkylamino, aminocarbonyl, alkoxycarbonyl, alkylcarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, halo, haloalkyl, haloalkylidenyl, hydroxyalkyl, haloalkoxy, heteroalkyl, hydroxyalkyl, oxoalkyl, -NH2, -OH, -CF3, -Cyano, -Nitro, =CH2, =NH, =0, -C(O)NH2, -C(O)NHOH, -C(O)OH,-OP(O)(OH)(OH), -P(O)(OH)(OH), aralkyl, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkyloxyalkyl, cycloalkylalkyloxyalkyloxy, cycloalkylalkyloxyalkyl, heteroaralkyl, heterocyclylalkyl, heterocyclyloxy, heterocyclyloxyalkyl, heterocyclylalkyloxy, heterocyclylalkyloxyalkyl, cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, each of the aforementioned is optionally and independently substituted with one or more independently selected Rh substituents;each Rh is independently H, D, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl,125569-02020alkoxycarbonyl, alkoxy alkyloxy, alkoxyalkyloxyalkyl, alkylidenyl, alkoxyalkylidenyl, alkylthio, alkylsulfonyl, cyanoalkyl, cyanoalkenyl, cyanoalkynyl, alkylamino, dialkylamino, aminocarbonyl, alkoxycarbonyl, alkylcarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, halo, haloalkyl, haloalkylidenyl, hydroxyalkyl, haloalkoxy, heteroalkyl, hydroxyalkyl, oxoalkyl, -NH2, -OH, -CF3, -Cyano, -Nitro, =CH2, =NH, =O, -C(O)NH2, -C(O)NHOH, -C(O)OH,-OP(O)(OH)(OH), -P(O)(OH)(OH), aralkyl, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkyloxyalkyl, cycloalkylalkyloxyalkyloxy, cycloalkylalkyloxyalkyl, heteroaralkyl, heterocyclylalkyl, heterocyclyloxy, heterocyclyloxyalkyl, heterocyclylalkyloxy, heterocyclylalkyloxyalkyl, cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged- heterocyclic, aryl, or heteroaryl;j is 0, 1, 2, 3, 4, 5, or 6;k is 0, 1, 2, 3, 4, 5, or 6;m is 0, 1, 2, 3, 4, 5, or 6;n is 0, 1, 2, 3, 4, 5, or 6;p is 0, 1, 2, 3, 4, 5, or 6;q is 0, 1, 2, 3, 4, 5, or 6; andr is 0, 1, 2, 3, 4, 5, or 6.

2. The compound according to claim 1 or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug thereof, wherein the compound is represented by Formula (B):" N Z°T r Zim(R2)lQ2k(RlfwhereinQ2 is heterocycloalkyl, aryl, or heteroaryl.

3. The compound according to claim 2 or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a125569-02020prodrug thereof, wherein the compound is represented by Formula (C):whereinA is C(RaRb), N(Rc), O, orS.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 (D):whereins is 0, 1, 2, 3, 4, 5, or 6.

5. 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 (E):(E),whereinQ3 is a cycloalkyl, heterocycloalkyl, or heteroaryl; andt is 0, 1, 2, 3, 4, 5, or 6.

6. The compound according to claim 5 or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug thereof, wherein the compound is represented by Formula (F):125569-02020whereinQ3 is a cycloalkyl.

7. The compound according to claim 5 or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug thereof, wherein the compound is represented by Formula (G):whereinQ3 is a heteroaryl.

8. A pharmaceutical composition comprising a compound 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 or N-oxide thereof, and a pharmaceutically acceptable diluent or carrier.

9. A method of treating a neoplastic disease, autoimmune disease, and inflammatory disorder, comprising administering to a subject in need thereof an effective amount of a compound or an N-oxide thereof 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 or N-oxide thereof.

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