HK40106339A - Compounds for the treatment of kinase-dependent disorders - Google Patents

Description

Compounds for treating kinase-dependent disorders

This application is a divisional application of the invention patent application filed on January 25, 2009, with application number 201980015066.9 (international application number PCT/US2019/015297) entitled "Compound for treating kinase-dependent diseases".

Technical Field

This invention relates to compounds that regulate cellular activities such as proliferation, differentiation, programmed cell death, migration, and chemical invasion by modulating protein kinase activity. More specifically, this invention relates to compounds that inhibit, regulate, and/or modulate Axl and Mer receptor tyrosine kinases, compositions containing these compounds, methods of using them to treat kinase-dependent diseases and disorders, the synthesis of said compounds, and methods of formulating compounds for pharmaceutical purposes.

Cross-references to related applications

This application claims priority to U.S. Provisional Application Serial No. 62/622,702, filed January 26, 2018 and U.S. Provisional Application Serial No. 62/758,321, filed November 9, 2018, the entire contents of which are incorporated herein by reference.

Background Technology

Human Axl belongs to the TAM subfamily of receptor tyrosine kinases, including Mer. TAM kinases are characterized by an extracellular ligand-binding domain consisting of two immunoglobulin-like domains and two fibronectin type III domains. Axl is overexpressed in many tumor cell types and was originally cloned from patients with chronic myeloid leukemia. When overexpressed, Axl exhibits transformative potential. Axl signaling is believed to induce tumor growth by activating proliferative and anti-apoptotic signaling pathways. Axl has been associated with cancers such as lung cancer, myeloid leukemia, uterine cancer, ovarian cancer, glioma, melanoma, thyroid cancer, renal cell carcinoma, osteosarcoma, gastric cancer, prostate cancer, and breast cancer. Overexpression of Axl leads to poor prognosis in patients with the indicated cancers.

Like Axl, Mer activation leads to downstream signaling pathways in tumor growth and activation. Mer binds to ligands such as the soluble protein Gas-6. Gas-6 binding to Mer induces autophosphorylation of Mer in its intracellular domain, resulting in downstream signal activation. Overexpression of Mer in cancer cells leads to increased metastasis, most likely through the generation of soluble Mer extracellular domain proteins as decoy receptors. Tumor cells secrete soluble forms of extracellular Mer receptors, which reduce the ability of soluble Gas-6 ligands to activate Mer on endothelial cells, thereby contributing to cancer progression.

Therefore, compounds that inhibit TAM receptor tyrosine kinases such as Axl and Mer are needed to treat selected cancers.

Summary of the Invention

In one aspect, the present invention provides compounds of formula I:

Or its pharmaceutically acceptable salt, wherein:

_R1 is selected _from -H, -CN, -CO- _NR5R6 , _-CO2R7 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted _{( C1} - _C6 )alkyl, optionally substituted ( _C3 - _C8 )cycloalkyl, optionally substituted ( _C3 - _C6 ) _{heterocycloalkyl} , _-SO2NR8R9 and -( _{SO2 )} -( _C1 - _C6 )alkyl;

Where _R1 is selected _{from -CN} , -CO- _NR5R6 , _-CO2R7 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted ( _C3 - _C8 )cycloalkyl, optionally substituted ( _C3 - _C6 ) heterocycloalkyl, _-SO2NR8R9 and -( _SO2 )-( _C1 - _C6 )alkyl, _{R2 is -H} , halogroup, _-NR5R6 or optionally substituted _{( C1} - _C6 )alkoxy;

Where _R1 is -H, an optionally substituted ( _C1 - _C6 ) alkyl, or _an optionally substituted ( _C1 - _C6 ) alkoxy, _R2 is -CO- _NR5R6 ; or _{-CO2R7 ;}

Or _R1 and _R2 together with the atoms to which they are attached form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl;

_R3 is selected from -H, optionally substituted (C1 _{- C6} ) alkyl, -CN, and halogroup;

_R4 is -H or a halogenated group;

Optionally substituted with one, two, three or four independently selected groups from halogroups and ( _C1 - _C6 )alkyl groups, wherein the linkage point is indicated;

_R5 and _R6 are each independently -H, optionally substituted ( _C1 - _C6 ) alkyl, or optionally substituted ( _C1 - _C6 ) alkoxy;

_R7 is -H or an optionally substituted ( _C1 - _C6 ) alkyl group.

_R8 and _R9 are each independently -H or optionally substituted ( _C1 - _C6 ) alkyl groups;

Alternatively, _R8 and _R9 can be connected to form an optionally substituted heterocyclic ring; and

Y is selected from O, S, SO, _SO₂ , NH and N-( _C₁ - _C₆ alkyl).

On the other hand, compounds of formula A are provided:

Or its pharmaceutically acceptable salt, wherein

(i) _R1 is selected from ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, ( _C6 - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-10 heteroaryl, 4-10 heterocycloalkyl, -CN, -NHOH, -C(O) ^Ra , -C(O) ^NRaRa , -C(O) ^NHORa , ^-C (O) ^ORa , -C(O)NRaS(O) _2Ra , ^-OC (O) ^NRaRa , ^C (＝ ^NRa ) ^{Ra ,} -C(＝NOH) ^Ra , -C(＝NOH) ^{NRa ,} -C(＝ ^NCN ) ^{NRaRa ,} -C(＝NRa) ^NRaRa , -S(O) ^{NRaRa ,} -S(O) _2NRaC ( ^O ) ^Ra , -P(O)R ^a R ^a , -P(O)(OR ^a )(OR ^a ), -B(OH) ₂ , -B(OR ^a ) ₂ and S(O) ₂ NR ^a R ^a ; and

_R2 is selected from -H, halogenated, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, (C1- _C6 )haloalkyl, (C1 _- C6)haloalkoxy, ( _{C6 - C10} )aryl-( _C1 - _C4 )alkylene-, (C3 _{-C10 )} cycloalkyl-( _C1 - _C4 )alkylene-, (5-14-membered heteroaryl)-( _{C1 - C4} )alkylene-, (4-14-membered heterocycloalkyl)-(C1 _{- C4} )alkylene-, -CN, _-NO2 , ^-ORa , ^-SRa , ^-NHORa , -C(O) ^{Ra ,} -C(O) ^NRaRa , -C(O) ^NHORa , -C(O) ^ORa , -C(O)NR ^a S(O) ₂ R ^a , -OC(O)R ^a , -OC(O)NR ^a R ^a , -NHR ^a , -NR ^a R ^a , -NR ^a C(O)R ^a , -NR ^a C(=NR ^a )R ^a , -NR ^a C(O)OR ^a , -NR ^a C(O)NR ^a R ^a , -C(=NR ^a )R ^a , -C(=NOH)R ^a , -C(=NOH)NR ^a , -C(=NCN)NR ^a R ^a , -NR ^a C(=NCN)NR ^a R ^a , -C(=NR ^a )NR ^a R ^a , -NR ^a C(=NR ^a )NR ^a R ^a , -NR ^a S(O)R ^a , -NR ^a S(O) ₂ R ^a , -NR ^a S(O) ₂ NR ^a R ^a ,-S(O)R ^a -S(O)NR ^aRa , ^-S (O) _2Ra , -S(O) _2NR ^aC (O) ^Ra , -P(O) ^RaRa , -P(O)(OR ^a )( ^{OR a )} , -B ⁽ OH) ₂ , -B(OR ^a ) ₂ and -S(O ^{)2NR aRa} _, ^wherein _R1 or _R2 is a (C1 _{- C6} )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, ( _C6 - _C10 )aryl-( _C1 - _C4 )alkylene-, ( _C3 - _C10 )cycloalkyl-( _C1 - _C4 )alkylene-, (5-14-membered heteroaryl)-(C1 _{- C4} )alkylene- and (4-14-membered heterocycloalkyl)-(C1 _- C ₄ ) Alkylenes – each optionally substituted by 1, 2, 3, 4, or 5 independently selected ^Rb substituents, provided that when _R1 is a 5-7-membered heteroaryl or 5-7-membered heterocyclic alkyl and _R2 is a _C1-6 alkoxy, the 5-7-membered heteroaryl or 5-7-membered heterocyclic alkyl is not connected to the fused benzene ring of the quinoline moiety via a cyclic nitrogen atom; or

(ii) _R1 is selected from -H, halogroup, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, (C2- _C6 )ynyl, ( _C1 - _C6 )haloalkyl, (C1 _{- C6} )haloalkoxy, ( _{C6 - C10} )aryl, ( _C3 - _C10 )cycloalkyl, 5-14-membered heteroaryl, 4-14-membered heterocycloalkyl, ( _C6 - _C10 )aryl-( _{C1- C4} )alkylene-, ( _C3 - _C10 )cycloalkyl-( _{C1- C4} )alkylene-, (5-14-membered heteroaryl)-( _{C1- C4} )alkylene-, (4-14-membered heterocycloalkyl)-( _{C1- C4} )alkylene-, -CN, _-NO2 , ^-ORa , -SR ^a , -NHOR ^a , -C(O)R ^a , -C(O)NR ^a R ^a , -C(O)NHOR ^a , -C(O)OR ^a , -C(O)NR ^a S(O) ₂ R ^a , -OC(O)R ^a , -OC(O)NR ^a R ^a , -NHR ^a , -NR ^a R ^a , -NR ^a C(O)R ^a , -NR ^a C(=NR ^a )R ^a , -NR ^a C(O)OR ^a , -NR ^a C(O)NR ^a R ^a , -C(=NR ^a )R ^a , -C(=NOH)R ^a , -C(=NOH)NR ^a , -C(=NCN)NR ^a R ^a , -NR ^a C(=NCN)NR ^a R ^a , -C(=NR ^a )NR ^a R ^a , -NR ^a C(=NR ^a )NR ^a R ^a , -NR ^a S(O) ^Ra , ^-NRaS (O) _2Ra , -NRaS ₍ O) ^2NRaRa , ^-S (O ₎ ^Ra , -S(O) ^NRaRa , -S(O) ^2Ra , ^-S (O) _2NRaC (O)Ra, ^-P (O) ^RaRa , -P ⁽ O)( ^ORa )( ^ORa ) ^{, -B} (OH) ² , -B( ^ORa ) _{2 and} -S(O) _2NRaRa , wherein _R1 or ^R2 is a ( _C1 - _C6 )alkyl, ( _C2 - _C6 ) ^alkenyl , ( _C2 - _C6 )ynyl, (C6 _{-C10 )} aryl, ( _C3 - _C10 )cycloalkyl, 5-14 heteroaryl, 4-14 heterocycloalkyl, ( _C6 - _{C10 ) ...} The aryl-(C1 _{- C4} )alkylene-, (C3- _C10 )cycloalkyl-( _C1 -C4)alkylene-, (5-14-membered heteroaryl)-( _{C1- C4} )alkylene-, and (4-14-membered heterocycloalkyl)-( _{C1 - C4} )alkylene- are each optionally substituted by 1, 2, 3 _, 4, or 5 independently selected ^Rb substituents; and

R ₂ is selected from (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, -CN, -NHOH, -C(O)R ^a , -C(O)NR ^a R ^a , -C(O)NHOR ^a , -C(O)OR ^a , -C(O)NR ^a S(O) ₂ R ^a , -OC(O)NR ^a R ^a , C(=NR ^a )R ^a , -C(=NOH)R ^a , -C(=NOH)NR ^a , -C(=NCN)NR ^a R ^a , -NR ^a C(=NCN)NR ^a R ^a , -C(=NR ^a )NR ^a R ^a , -S(O)NR ^a R ^a , -S(O) ₂ NR ^a C(O)R ^a , -P(O)R ^a R ^a , -P(O)(OR ^a )(OR ^a ), -B(OH) ₂ , -B(OR ^a ) ₂ and S(O) ₂ NR ^{a Ra} , provided that when R ₁ is a 5-7 membered heteroaryl or a 5-7 membered heterocyclic alkyl and R ₂ is a C _1-6 alkoxy, then the 5-7 membered heteroaryl or 5-7 membered heterocyclic alkyl of R ₁ is not connected to the fused benzene ring of the quinoline moiety through a cyclic nitrogen atom.

(iii) _R1 and _R2 together with the atoms to which they are attached form a fused (C3 _{- C7} ) cycloalkyl ring or a fused 4- to 10-membered heterocyclic alkyl ring, wherein the fused (C3 _{- C7} ) cycloalkyl ring and the fused 4- to 10-membered heterocyclic alkyl ring are each optionally substituted by one, two or three independently selected ^Rb substituents, provided that the compound is not 1-[2-(4-fluorophenyl)-acetyl]-cyclopropanecarboxylic acid [3-fluoro-4-(7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxa-1-aza-cyclododecane[b]naphthalene-4-yloxy)-phenyl]-amide;

_R10 and _R11 are each independently selected from -H, halogroup, ( _C1 - _C6 )alkyl, (C1- _C6 )haloalkyl, ( _{C1 - C6} )haloalkoxy, ( _C6 - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-14-membered heteroaryl, 4-14-membered heterocycloalkyl, ( _C6 - _C10 )aryl-( _C1 - _C4 )alkylene-, ( _C3 - _C10 )cycloalkyl-( _{C1- C4} )alkylene-, (5-14-membered heteroaryl)-( _{C1- C4} )alkylene-, (4-14-membered heterocycloalkyl)-( _{C1- C4} )alkylene-, -CN, _-NO2 ^{, -ORa} , -SRa, ^-NHORa , -C(O) ^Ra , -C(O)NR ^a R ^a , -C(O)OR ^a , -C(O)NR ^a S(O) ₂ R ^a , -OC(O)R ^a , -OC(O)NR ^a R ^a , -NHR ^a , -NR ^a R ^a , -NR ^a C(O)R ^a , -NR ^a C(=NR ^a )R ^a , -NR ^a C(O)OR ^a , -NR ^a C(O)NR ^a R ^a , -C(=NR ^a )R ^a , -C(=NOH)R ^a , -C(=NOH)NR ^a , -C(=NCN)NR ^a R ^a , -NR ^a C(=NCN)NR ^a R ^a , -C(=NR ^a )NR ^a R ^a , -NR ^a C(=NR ^a )NR ^a R ^a , -NR ^a S(O)R ^a , -NR ^a S(O) ₂ R ^a , -NR ^aS (O) ₂ NR ^{a Ra} , -S(O) ^Ra , -S(O)NR ^{a Ra} , -S(O) ₂ ^Ra , -S(O) ₂ NR ^a C(O) Ra, -P(O)Ra ^Ra , -P(O)( ^{OR a} )(OR ^a ), -B( ^OH ) ₂ , -B(OR ^a ) ₂ and S(O) ₂ NR ^{a Ra} , wherein _R1 or _R2 is a ( _{C1-C6)alkyl, (C6} - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-14-membered heteroaryl, 4-14-membered heterocycloalkyl, ( _C6 - _C10 )aryl-(C1-C4)alkylene-, (C3-C10)cycloalkyl-( _C1 - _C4 )alkylene-, (C3- _C10 )cycloalkyl-(C1 _- C4)alkylene-, ( _C3 - _C10 )cycloalkyl-(C1 _- C4 ₎ alkylene-. The alkylene-, (5-14-membered heteroaryl)-(C1 _{- C4} )alkylene- and (4-14-membered heterocyclic alkyl)-(C1 _{- C4} )alkylene- are each optionally substituted by 1, 2, 3, 4 or 5 independently selected ^Rb substituents;

Each _R3 is independently selected from -H, halogroup, -OH, -CN, optionally substituted ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy, ( _C1 - _C6 )haloalkoxy, _-NH2 , -NH( _C1 - _C6 )alkyl, -N( _C1 - _C6 )alkyl) ₂ and ( _C3 - _C6 )cycloalkyl, wherein the ( _C1 -C6)alkoxy, -NH( _C1 - _C6 )alkyl, -N( _C1 - _{C6 )} alkyl) _{2 and} ( _C3 - _C6 )cycloalkyl of R3 are each optionally substituted by 1, 2 or 3 independently selected ^Rg substituents;

Each R ₁₄ is independently selected from halogen, -OH, -NH ₂ , -CN, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )haloalkyl, (C ₁ -C ₆ )haloalkoxy, -COOH, -NH(C ₁ -C ₆ )alkyl, -N(C ₁ -C _6alkyl ) ₂ , phenyl, phenyl-(C _1- C ₂ )alkylene, (C _3- C ₆ )cycloalkyl, (C _3- C ₆ )cycloalkyl-(C _1- C ₄ )alkylene-, 4 to 6-membered heterocycloalkyl, (4 to 6-membered heterocycloalkyl)-(C _1- C ₄ )alkylene-, 5 to 6-membered heteroaryl, (5 to 6-membered heteroaryl)-(C _1- C ₄ )alkylene- and -OR ^e , wherein R _The ( _C1 - _C6 )alkyl, phenyl, phenyl-(C1- _C2 )alkylene, ( _C3- C6)cycloalkyl, ( _{C3- C6} )cycloalkyl-(C1 _{- C4} )alkylene, 4- to ₆ -membered heterocycloalkyl, ( _4- to 6-membered heterocycloalkyl)-(C1 _{- C4} )alkylene, 5- to 6-membered heteroaryl and (5- to 6-membered heteroaryl)-(C1 _{- C4} )alkylene are each optionally substituted by one, two or three independently selected ^Rg substituents.

R ₁₅ is H or C _1-6 alkyl;

Each _R4 is independently selected from -H, halogroup, -OH, -COOR ^e , -CONR ^{e Re} , -CN, -NH ₂ , -NH ((C1 _{- C6} )alkyl), -N ((C1 _{- C6} )alkyl) ₂ , (C1 _{- C6} )alkyl, (C1 _{- C6} )alkoxy, (C1 _{- C6} )haloalkyl, (C1 _{- C6} )haloalkoxy, -CONR ^{a Ra} , -NR ^a COR ^a , -NR ^a CONR ^{a Ra} , -SO ₂ ^Ra , -NR ^a S(O) ₂ ^Ra , -NR ^a S(O) ₂ NR ^{a Ra} , (C3 _{- C6} )cycloalkyl, 4- to 6-membered heterocyclic alkyl, phenyl, 5- or 6-membered heteroaryl, (C3 _{- C6} )cycloalkyl-(C1 _- C4 ₎ R4 is optionally substituted with alkylene-, (4- to 6-membered heterocyclic alkyl)-(C1 _{- C4} )alkylene-, phenyl-(C1 _{- C2} )alkylene-, and (5 or 6-membered heteroaryl)-(C1 _{- C4} )alkylene-, wherein the ( _{C1- C6} )alkyl, ( _{C3- C6} )cycloalkyl, _4- to 6-membered heterocyclic alkyl, phenyl, 5 or 6-membered heteroaryl, ( _{C3- C6} )cycloalkyl-( _{C1- C4} )alkylene-, (4- to 6-membered heterocyclic alkyl)-(C1 _{- C4} )alkylene-, phenyl-(C1 _{- C2} )alkylene-, and (5 or 6-membered heteroaryl)-(C1 _{- C4} )alkylene-, respectively, by 1, 2 or 3 independently selected ^Rf substituents;

Each Ra ^is independently selected from -H, -CN, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )haloalkyl, ( _C2 - _C6 )alkenyl, (C2- _C6 )ynyl, ( _C6 -C10)aryl, ( _C3 - _C10 )cycloalkyl, 5-14-membered heteroaryl, 4-14-membered heterocycloalkyl, ( _{C6 - C10} )aryl-(C1- _C4 )alkylene-, (C3 _{- C10} )cycloalkyl-( _C1 - _C4 )alkylene-, (5-14-membered heteroaryl)-( _{C1- C4} )alkylene-, and (4-14-membered heterocycloalkyl)-( _{C1- C4 )} alkylene-, wherein the ( _C1 - _{C6)alkyl, (C1-C6 )} alkyl, ⁽ _C2 - _C6) alkylene- ... ( _C2 - _C6 )alkenyl, (C2-C6)ynyl, ( _C6 - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-14-membered heteroaryl, 4-14-membered heterocycloalkyl, ( _C6 - _C10 )aryl-( _C1 - _C4 )alkylene-, ( _{C3- C10} )cycloalkyl-( _C1 - _C4 )alkylene-, (5-14-membered heteroaryl)-( _{C1 - C4} )alkylene- and (4-14-membered heterocycloalkyl)-( _{C1 - C4} )alkylene- are each optionally substituted by 1, 2, 3, 4 or 5 independently selected ^Rd substituents;

Each ^Rb is independently selected from halogen, oxo, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, (C1-C6)haloalkyl, ( _{C1 -C6 )} haloalkoxy, ( _C6 - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-10-membered heteroaryl, _4-10 -membered heterocycloalkyl, ( _C6 - _C10 )aryl-( _{C1- C4} )alkylene-, ( _{C3- C10} )cycloalkyl-(C1 _{- C4} )alkylene-, (5-10-membered heteroaryl)-(C1 _{- C4} )alkylene-, (4-10-membered heterocycloalkyl)-(C1 _{- C4} )alkylene-, -CN, -OH, _-NH2 , -NO _2. -NHOR ^c , -OR ^c , -SR ^c , -C(O)R ^c , -C(O)NR ^c R ^c , -C(O)OR ^c , -C(O)NR ^c S(O) ₂ R ^c , -OC(O)R ^c , -OC(O)NR ^c R ^c , -C(=NOH)R ^c , -C(=NOH)NR ^c , -C(=NCN)NR ^c R ^c , -NR ^c C(=NCN)NR ^c R ^c , -C(=NR ^c )NR ^c R ^c , -NR ^c C(=NR ^c )NR ^c R ^c , -NHR ^c , -NR ^c R ^c , -NR ^c C(O)R ^c , -NR ^c C(=NR ^c )R ^c , -NR ^c C(O)OR ^c , -NR ^c C(O)NR ^c R ^c , -NR ^c S(O)R ^c ,-NR ^c S(O) _2Rc ^{, -NRcS} (O) _2NRcRc , ^-S (O) ^Rc , -S(O) ^NRcRc , -S(O) ^2Rc , -S(O) ^2NRcC (O) ^Rc , -Si(Rc) ₃ , -P(O) ^RcRc , ^-P ( ^O ₎ ( ^ORc )(ORc), ^-B (OH) ₂ , ^-B ( ^ORc ) ₂ and -S(O) _2NRcRc , wherein ^Rb is a ⁽ C1-C6) ^alkyl , (C1- ^C6 ) _haloalkyl , ( _C1 - _C6 )haloalkoxy, (C2-C6)alkenyl, ( _C2 - _C6 )alkynyl, ( _C6 - _C10 )aryl, (C3-C10)alkyl, ( _C3 - _C10 )alkyl, ( _C4 - _C5 )alkyl, ( _C6 - _C10 )alkyl, ( _C3- C10)alkyl, (C4 _... ( _C6 - _C10 ) aryl-(C1-C4) alkylene-, (C3-C10) cycloalkyl-( _{C1- C4} ) alkylene-, ( _5-10 ) heteroaryl-( _{C1 - C4} ) alkylene-, and ( _4-10 ) heterocycloalkyl-(C1 _{- C4 )} alkylene- are each optionally further substituted by one, two, or three independently selected ^Rd substituents;

Each ^Rc is independently selected from -H, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )haloalkyl, ( _C2 - _C6 )alkenyl, ( _C2 -C6)ynyl, (C6- _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-10 heteroaryl, 4-10 heterocycloalkyl, ( _C6 - _C10 )aryl-( _C1 - _C4 )alkylene-, (C3 _{- C10} )cycloalkyl-( _C1 - _C4 )alkylene-, (5-10 heteroaryl)-(C1 _{- C4} )alkylene-, and (4-10 heterocycloalkyl)-(C1 _{-C4)alkylene-, wherein the (C1- C6} )alkyl, ( _C2- C6)alkenyl, ( _C3 - _C10 ) alkylene-, ( ^C4 - _C10 ) alkylene-, ( _C6 - _C10 ) alkylene-, (C1 ... ₂ - _C6 ) ynyl, ( _C6 - _C10 ) aryl, ( _C3 - _C10 ) cycloalkyl, 5-10 heteroaryl, 4-10 heterocycloalkyl, (C6- _C10 ) aryl-( _C1 -C4) alkylene-, ( _C3 - _C10 ) cycloalkyl-(C1 _{- C4} ) alkylene-, (5-10 heteroaryl)-( _{C1 - C4} ) alkylene- and (4-10 heterocycloalkyl)-(C1 _{- C4} ) alkylene- are each optionally substituted by 1, 2, 3, ₄ or 5 independently selected R ^f substituents;

Each R d is independently selected from (C <sub>1- C 6  )alkyl, (C <sub>1- C  6 )haloalkyl, haloyl, (C<sub>6-C10)aryl, 5-10 heteroaryl, (C <sub>3- C 10 )cycloalkyl, 4-10 heterocyclic alkyl, (C <sub>6- C 10 )aryl-(C <sub>1- C 4 )alkylene-, (C <sub>3- C 10 )cycloalkyl-(C <sub>1- C 4 )alkylene-, (5-10 heteroaryl)-(C <sub>1- C 4 )alkylene-, (4-10 heterocyclic alkyl)-(C <sub>1- C4 )alkylene-, -CN, -NH 2 , -NHOR e , -OR e , -SRe, -C(O)R  e , -C(O)NReRe , -C(O)OR e -OC(O)R e , -OC(O)NR eR e , -NHR e , -NR eR e , -NR e C(O)R e , -NR e C(O)NR eR e , -NR e C(O)OR e , -C(＝NR e )NR eR e , -NR e C(＝NR e )NR eR e , -NR e C(＝NOH)NR eR e, -NR e C(＝NCN)NR eR e , -S (O)R e , -S(O)NR eR e , -S(O) 2 Re, -NR e S (O) 2 Re , -NR e S(O) 2 NR e Re and -S (O) 2 NR e Re , wherein R d is a (C 1- C 6 ) alkyl , (C 1 - C 6 )haloalkyl, (C 6- C 10 )alkyl, (C 6- C 10 )alkyl, ... )aryl, 5-10 heteroaryl, ( C3- C10 )cycloalkyl, 4-10 heterocycloalkyl, (C6 - C10 )aryl-(C1-C4)alkylene-, (C3 - C10 )cycloalkyl-( C1- C4 )alkylene-, ( 5-10 heteroaryl)-(C1- C4 )alkylene- and (4-10 heterocycloalkyl)-( C1- C4 ) alkylene- are each optionally substituted by 1, 2 or 3 independently selected R f substituents;

Each ^Re is independently selected from -H, (C1 _{- C6} )alkyl, (C3 _{- C6} )cycloalkyl-, (C3 _{- C6} )cycloalkyl-(C1 _{- C4} )alkylene-, (C6- _C10 )aryl, ( _{C6- C10} )aryl-( _{C1 - C4} )alkylene-, 5- or 6-membered heteroaryl, (5- or 6-membered heteroaryl)-(C1 _- C4)alkylene-, 4- or 7-membered heterocycloalkyl, (4- or 7-membered heterocycloalkyl)-(C1 _{- C4} )alkylene-, (C1- _C6 ) haloalkyl, ( _{C1 - C6} ) haloalkoxy, (C2 _{- C4} ) alkenyl, and (C2 _{- C4} ) ynyl, wherein ^the (C1 _{- C4} )alkyl, (C3 _{- C6)...} The cycloalkyl, ( _{C6- C10} ) aryl, 5- or 6-membered heteroaryl, 4- or 7-membered heterocycloalkyl, ( _{C6- or 10} ) aryl-( _{C1- or 4} ) alkylene-, (5- or 6-membered heteroaryl)-( _{C1- or 4} ) alkylene-, (4- or 7-membered heterocycloalkyl)-( _C1- or ₄ ) alkylene-, ( _{C2- or 4} ) alkenyl, and ( _C2- or ₄ ) ynyl groups are each optionally substituted with 1, 2, or 3 ^Rf substituents.

Or any two ^Ra substituents together with the nitrogen atom to which they are attached form a 4, 5, 6, 7, 8, 9 or 10-membered heterocyclic alkyl group, each heterocyclic alkyl group optionally being substituted by 1, 2 or 3 independently selected R ^f substituents;

Alternatively, any two ^Rc substituents together with the nitrogen atom to which they are attached can form a 4, 5, 6, 7, 8, 9, or 10-membered heterocyclic alkyl group, each heterocyclic alkyl group optionally being substituted by one, two, or three independently selected ^Rf substituents.

Or any two ^Re substituents together with the nitrogen atom to which they are attached form a 4, 5, 6, 7, 8, 9 or 10-membered heterocyclic alkyl group, each heterocyclic alkyl group optionally being substituted by 1, 2 or 3 independently selected R ^f substituents;

Each ^Rf is independently selected from halogen, -OH, -CN, -COOH, _-NH2 , -NH-(C1 _{- C6} )alkyl, -N((C1 _{- C6} )alkyl) ₂ , (C1 _{- C6} )alkyl, (C1- _C6 )alkoxy, ( _C1- C6)alkylthio, (C1 _{- C6} )haloalkyl, (C1 _{- C6} )haloalkoxy, phenyl, 5-6-membered heteroaryl, 4-6-membered heterocyclic alkyl, and ( _{C3 - C6} )cycloalkyl, wherein the (C1 _{- C6} )alkyl, phenyl, (C3 _{- C6} )cycloalkyl, 4-6-membered heterocyclic alkyl, and 5-6-membered heteroaryl of ^Rf are each optionally selected by 1, 2, or 3 from halogen, -OH, -CN, -COOH, _-NH2 , (C1 _- C6 ₎ alkyl, -NH- _{( ...} Substituents of alkyl, (C1 _{- C4} )alkoxy, (C1 _{- C4} )haloalkyl, ( _{C1- C4} )haloalkoxy, phenyl, (C3 _{- C10} )cycloalkyl, 5-6-membered heteroaryl and 4-6-membered heterocyclic alkyl groups;

Each R ^g is independently selected from halogenated, -OH, -CN, -COOH, -COO-( _{C1- C4} ) _alkyl , -NH2, -NH-( _{C1- C6} )alkyl, -N((C1 _{- C6} )alkyl) ₂ , ( _{C1- C6} )alkyl, (C1 _{- C6} )alkoxy, (C1- _C6 )alkylthio, ( _{C1- C6 )} haloalkyl, (C1 _{- C6} )haloalkoxy, phenyl, 5-6-membered heteroaryl, 4-6-membered heterocyclic alkyl and (C3 _{- C6} )cycloalkyl;

Y is selected from -O-, -S-, -SO-, _-SO₂- , -NH-, and -N((C₁ _{- C₆} )alkyl)-;

The cyclic nitrogen atom on the quinoline moiety in Formula A may optionally be oxidized;

The subscript n is an integer of 1, 2, 3 or 4;

The subscript m is an integer of 1, 2, 3, 4, or 5; and

The subscript p is an integer of 0, 1, 2, 3 or 4.

On the other hand, it provides a method for treating diseases, symptoms, or syndromes mediated at least in part by modulating the in vivo activity of protein kinases using compounds of Formula I or pharmaceutically acceptable salts thereof.

On the other hand, methods for preparing compounds of formula A and formula I are provided.

These and other aspects, as well as the implementation plan, are described below.

Detailed Implementation

Abbreviations and Definitions

The following abbreviations and terms have a consistent meaning throughout the text:

The symbol "-" represents a single bond, and "=" represents a double bond.

As used in this article, the singular forms “a,” “a,” and “the” include plural references unless the context clearly indicates otherwise.

When a variable is defined generally, it has many possible substituents, and each individual group can be defined as having or not having a bond. For example, if R ^_z can be hydrogen, this can be indicated as "-H" or "H" in the definition of R_^z.

When depicting or describing chemical structures, unless otherwise explicitly stated, it is assumed that all carbon atoms have tetravalent hydrogen substitutions. For example, in the structure on the left of the following diagram, nine hydrogen atoms are implied. Nine hydrogen atoms are depicted in the structure on the right. Sometimes, specific atoms in a structure are described in the textual formula as having one or more hydrogen atoms as substituents (explicitly defined as _hydrogen ), such as _-CH₂CH₂- . Those skilled in the art will understand that the above descriptive techniques are common in the field of chemistry to provide a concise and simple description of other complex structures.

If the group "R" is described as "floating" on the ring system, such as in the following formula:

Unless otherwise defined, the substituent “R” can be located on any atom of the ring system, assuming that a hydrogen atom described, implicit or explicitly defined is replaced from one of the ring atoms, as long as a stable structure is formed.

If the group "R" is described as floating on a fused ring system, such as in the following formula:

Unless otherwise defined, the substituent “R” can be located on any atom in a fused ring system, assuming substitution from one of the ring atoms for a hydrogen atom described (e.g., -NH- in the above formula), an implicit hydrogen atom (e.g., hydrogen not shown in the above formula but to be understood as present), or an explicitly defined hydrogen atom (e.g., “Z” equals =CH- in the above formula), as long as a stable structure is formed. In the example shown, the “R” group can be located on a 5-membered or 6-membered ring in the fused ring system. When the group “R” is described as being present on a ring system containing saturated carbon, for example in the following formula:

In this example, "y" can be more than one, assuming each substitutes for a currently depicted, implicit, or explicitly defined hydrogen atom on the ring; then, unless otherwise defined, two "R"s can be located on the same carbon atom, provided the resulting structure is stable. A simple example is that when R is a methyl group, a geminal dimethyl group can be present on the carbon atom of the ring shown (the "cyclic" carbon). In another example, two Rs (including the carbon atom) on the same carbon atom can form a ring, resulting in a spirocyclic ("spirocyclic" group) structure having a ring as shown, for example, in the following formula:

"Halogen" or "halogenated group" refers to fluorine, chlorine, bromine or iodine.

The term “C _nm ” or “C _n - _{C m} ” indicates a range including the endpoints, where n and m are integers and represent the number of carbons. Examples include C _1-4 , C ₁ -C ₄ , C _1-6 , C ₁ -C ₆ , etc.

"Alkyl" refers to a branched or straight-chain hydrocarbon chain having one to eight carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, and heptyl. ( _C1 - _C6 )alkyl is preferred. The terms "Cn _nm alkyl" or "( _Cn - _Cm )alkyl" refer to an alkyl group having n to m carbon atoms. When optionally substituted, one or more hydrogen atoms of the alkyl group (e.g., 1 to 4, 1 to 2, or 1) may be partially substituted as described in "Optional Substitution" below. In some aspects, the alkyl group is unsubstituted or not optionally substituted.

"alkylene" refers to a divalent saturated aliphatic group having 1 to 10 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 2 carbon atoms with optional substitution. When optionally substituted, one or more hydrogen atoms (e.g., 1 to 4, 1 to 2, or 1) of the alkylene group may be partially substituted as described in "Optional Substitution" below. In some aspects, the alkylene group is unsubstituted or not optionally substituted. The term "Cn-m alkylene" refers to an alkylene group having n to m carbon atoms. Examples of alkylene groups include, but are not limited to, methylene, ethane-1,2-diyl, propane-1,3-diyl, propane-1,2-diyl, butane-1,4-diyl, butane-1,3-diyl, butane-1,2-diyl, 2-methyl-propane-1,3-diyl, etc.

The term "alkenyl" refers to a straight-chain or branched hydrocarbon group corresponding to an alkyl group having one or more carbon-carbon double bonds. An alkenyl group formally corresponds to an alkene in which one of the CH bonds is replaced by the alkenyl group at the junction with the remainder of the compound. The terms "C_{_n}n-alkenyl" or "(C _{_n}-C _{_m} )alkenyl" refer to an alkenyl group having n to m carbon atoms. In some embodiments, the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Exemplary alkenyl groups include, but are not limited to, vinyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, etc.

The term "alkynyl" refers to a straight-chain or branched hydrocarbon group corresponding to an alkyl group having one or more carbon-carbon triple bonds. An alkynyl group formally corresponds to an alkyne in which one of the CH bonds is replaced by an alkyl group at the junction with the remainder of the compound. The terms "C _{_n}nm</sub>alkynyl" or "(C _{_n}-C _{_m} )alkynyl" refer to an alkynyl group having n to m carbon atoms. Exemplary alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl, etc. In some embodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

"Alkoxy" refers to the part of the formula -OR', where R' is a ( _C1 - _C6 ) alkyl moiety as defined herein. The terms "Cn _nm alkoxy" or "( _Cn - _Cm ) alkoxy" refer to an alkoxy group whose alkyl group has n to m carbons. Examples of alkoxy moiety include, but are not limited to, methoxy, ethoxy, isopropoxy, etc.

The alkoxy group may be unsubstituted or optionally substituted. When optionally substituted, one or more hydrogen atoms of the alkoxy group (e.g., 1 to 4, 1 to 2, or 1) may be partially substituted as described in “Optional Substitution” below, provided that the α-hydrogen atom of the ether oxygen is not substituted by a hydroxyl, amino, or thio group. In some aspects, the alkoxy group is unsubstituted or not optionally substituted.

"Alkoxycarbonyl" refers to the group -C(O)-R', where R' is a ( _C1 - _C6 ) alkoxy group as defined herein.

The term "amino" refers to a group with the formula -NH ₂ .

The term "carbamoyl" refers to a group with the formula -C(O)NH ₂ .

The term "carbonyl" used alone or in combination with other terms refers to the -C(=O)- group, which can also be written as C(O).

The term "cyano" or "nitrile" refers to a group with the formula -C≡N, which can also be written as -CN or CN.

The term "oxo" refers to an oxygen atom as a divalent substituent, which, when attached to carbon, forms a carbonyl group, or when attached to a heteroatom, forms a sulfoxide or sulfone group or an N-oxide group. In some embodiments, the heterocyclic group may optionally be substituted by one or two oxo (=O) substituents.

The term "sulfide" refers to a sulfur atom as a divalent substituent, which, when attached to carbon, forms a thiocarbonyl group (C=S).

The term “heteroatoms” as used in this article is intended to include boron, phosphorus, sulfur, oxygen, and nitrogen.

As used herein, the term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms have been replaced by halogen atoms. The term "C _{_n}nm haloalkyl" or (C _{_n}-C_{_m}) haloalkyl refers to a C _{_n} nm alkyl group having n to m carbon atoms and at least one to at most {2(nm)+1} halogen atoms that may be the same or different. In some embodiments, the halogen atom is a fluorine atom. In some embodiments, the haloalkyl group has 1 to 6 or 1 to 4 carbon atoms. Exemplary haloalkyl groups include CF _₃, C _₂F_₅ , CH _{_F2}, CCl _{₃, CHCl₂ ,} C _₂Cl _₅, etc. In some embodiments, the haloalkyl group is a fluoroalkyl group.

The term "haloalkoxy" used alone or in combination with other terms refers to a group of the formula -O-haloalkyl, wherein the haloalkyl group is as defined above. The term "C _{_n}nm</sub>haloalkoxy" or (C _{_n}-C_{_m} )haloalkoxy refers to a haloalkoxy group whose haloalkyl group has n to m carbons. Exemplary haloalkoxy groups include trifluoromethoxy, etc. In some embodiments, the haloalkoxy group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

"Aryl" refers to a monocyclic or dicyclic ring (e.g., having two fused rings) with a monovalent carbon group of six to fourteen members, wherein the monocyclic ring is aromatic and at least one ring in the dicyclic ring is aromatic. The terms "C _{_n}nm</sub>aryl" or "(C _{_n}-C_{_m})aryl" refer to an aryl group having n to m ring carbon atoms. In some embodiments, the aryl group has 6 to about 10 carbon atoms. In some embodiments, the aryl group has 6 carbon atoms. In some embodiments, the aryl group has 10 carbon atoms. Unless otherwise stated, the valence bond of the group may be located on any atom of any ring within the group, where permitted by the valence bond rules. Representative examples include phenyl, naphthyl, and indenyl.

The aryl group may be unsubstituted or optionally substituted. When optionally substituted, one or more hydrogen atoms of the aryl group (e.g., 1 to 5, 1 to 2, or 1) may be partially substituted as described in “Optional Substitution” below. In some aspects, the alkoxy group is unsubstituted or not optionally substituted.

"Arylene" refers to a divalent, six- to fourteen-membered single-carbon or double-carbon ring, wherein the single ring is aromatic and at least one ring in the double ring is aromatic. Representative examples include phenylene, naphthylene, and indenylene.

“Cycloalkyl” refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic, or polycyclic), including cyclic alkyl and alkenyl groups. The terms “C _{_n}nm cycloalkyl” or “(C _{_n}-C_{_m} )cycloalkyl” refer to a cycloalkyl group having n to m ring member carbon atoms. Cycloalkyl groups may include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) groups and spirocyclic groups. Cycloalkyl groups may have 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 cyclic carbons (C _{_3-14}). In some embodiments, the cycloalkyl group has 3 to 14 members, 3 to 10 members, 3 to 6 ring members, 3 to 5 ring members, or 3 to 4 ring members. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl group is a C _{_3-6} monocyclic cycloalkyl group. The cycloalkyl group may optionally be oxidized to form an oxo or thio group. The cycloalkyl group also includes a cycloalkylene group. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cyclohepttrienyl, norbornyl, norpinel, norcarelyl, bicyclo[1.1.1]pentenyl, bicyclo[2.1.1]hexenyl, etc. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, the cycloalkyl group comprises a single saturated carbon ring having three to eight carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The cycloalkyl group may optionally be substituted with one or more substituents (such as one, two, or three substituents). In some embodiments, the cycloalkyl substituent is selected from ( _C1 - _C6 )alkyl, hydroxyl, ( _C1 - _C6 )alkoxy, halo( _C1 - _C6 )alkyl, halo( _C1 - _C6 )alkoxy, halogroup, amino, mono- and di( _C1 - _C6 )alkylamino, hetero( _C1 - _C6 )alkyl, acyl, aryl, and heteroaryl.

The cycloalkyl group may be unsubstituted or optionally substituted. When optionally substituted, one or more hydrogen atoms (e.g., 1 to 4, 1 to 2, or 1) of the cycloalkyl group may be partially substituted as described in “Optional Substitution” below. In some aspects, the substituted cycloalkyl group may be incorporated into an external or internal cycloalkene (e.g., cyclohexyl-2-en-1-yl). In some aspects, the cycloalkyl group is unsubstituted or not optionally substituted.

"Cycloalkoxycarbonyl" means the group -C(O)-OR', where R' is a ( _C3 - _C6 ) cycloalkyl group as defined herein.

"Phenoxycarbonyl" refers to the group -C(O)-O phenyl.

"Heteroaryl" refers to a monocyclic, fused bicyclic, or fused tricyclic monocyclic group of 5 to 14 ring atoms, containing one or more (preferably one, two, three, or four) cyclic heteroatoms independently selected from -O-, -S(O) _n- (n is 0, 1, or 2), -N-, and -N(R')-, and the remaining ring atoms are carbon, wherein the ring containing the monocyclic group is aromatic, and at least one ring in the fused ring containing the bicyclic or tricyclic group is aromatic. One or both ring carbon atoms of any non-aromatic ring containing the bicyclic or tricyclic group may be replaced by a -C(O)-, -C(S)-, or -C(=NH)- group. R' is hydrogen, alkyl, hydroxyl, alkoxy, acyl, or alkylsulfonyl. Unless otherwise specified, the valence bond may be located on any atom of any ring of the heteroaryl group, where permitted by the valence bond rules. In particular, when the valence bond is located on nitrogen, there is no additional nitrogen substituent. More specifically, the term heteroaryl includes, but is not limited to, 1,2,4-triazolyl, 1,3,5-triazolyl, phthalimide, pyridyl, pyrroleyl, imidazolyl, thiophene, furanyl, indoleyl, 2,3-dihydro-1H-indoleyl (including, for example, 2,3-dihydro-1H-indole-2-yl or 2,3-dihydro-1H-indole-5-yl), isoindoleyl, dihydroindoleyl, isoindolelinyl, benzimidazolyl, benzo[a]dioxacyclopenten-4-yl, benzofuranyl, cyclolinyl, indazinyl, diazanaphthyl-3-yl, phthalazin-3-yl, phthalazin-4-yl, pteridinyl, and purineyl. Quinazolinyl, quinoxolinyl, tetrazolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, oxadiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl (including, for example, tetrahydroisoquinolin-4-yl or tetrahydroisoquinolin-6-yl), pyrrolo[3,2-c]pyridinyl (including, for example, pyrrolo[3,2-c]pyridin-2-yl or pyrrolo[3,2-c]pyridin-7-yl), benzopyranyl, thiazolyl, isothiazolyl, thiadiazolyl, benzothiazolyl, benzothiaphenyl, and their derivatives, as well as their N-oxides or protected derivatives.

A five-membered heteroaryl ring is a heteroaryl group having five ring atoms, wherein one or more (e.g., 1, 2, 3, or 4) ring atoms are independently selected from N, O, and S. Exemplary five-membered heteroaryl rings include thiophene, furanyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl.

A six-membered heteroaryl ring is a heteroaryl group having six ring atoms, wherein one or more (e.g., 1, 2, 3, or 4) ring atoms are independently selected from N, O, and S. Exemplary six-membered heteroaryl rings are pyridyl, pyrazinyl, pyrimidinyl, triazinyl, and pyridazinyl.

"Heteroarylene" refers to a divalent group of 5 to 14 ring atoms in a monocyclic, fused bicyclic, or fused tricyclic form, containing one or more (preferably one, two, three, or four) cyclic heteroatoms independently selected from -O-, -S(O) _n- (n is 0, 1, or 2), -N-, and -N(R ¹⁹ )-, and the remaining ring atoms are carbon, wherein the ring containing the monocyclic group is aromatic, and at least one ring in the fused ring containing the bicyclic or tricyclic group is aromatic. One or both ring carbon atoms of any non-aromatic ring containing the bicyclic or tricyclic group may be replaced by a -C(O)-, -C(S)-, or -C(=NH)- group. ^{R 19} is hydrogen, alkyl, or alkenyl. Unless otherwise specified, the valence bond may be located on any atom of any ring of the heteroarylene group, where permitted by the valence bond rules. In particular, when the valence bond is located on nitrogen, there is no additional nitrogen substituent. More specifically, the term heteroaryl includes, but is not limited to, thiophene-diyl, benzo[d]isoxazole-diyl, benzo[d]isothiazol-diyl, 1H-indazole-diyl (optionally substituted at the N1 position with R ¹⁹ ), benzo[d]oxazole-diyl, benzo[d]thiazol-diyl, 1H-benzo[d]imidazol-diyl (optionally substituted at the N1 position with R ¹⁹ ), 1H-benzo[d][1,2,3]triazole-diyl (optionally substituted at the N1 position with R ¹⁹ ), imidazo[1,2-a]pyridine-diyl, cycloline-diyl, quinoline-diyl, pyridine-diyl, 1-oxo-pyridine-diyl, [1,2,4]triazolo[4,3-a]pyridine-diyl and 2,3-dihydroimidazo[1,2-a]pyridine-diyl, etc.

As used herein, “heterocyclic alkyl” or “heterocyclic group” refers to a non-aromatic ring or ring system that optionally contains one or more alkenyl groups as part of a ring structure, has at least one heteroatom ring member independently selected from boron, nitrogen, sulfur, oxygen, and phosphorus, and has 4-14, 4-10, 4-7, or 4-6 ring members. The term “heterocyclic alkyl” includes monocyclic 4-, 5-, 6-, and 7-membered heterocyclic alkyl groups. Heterocyclic alkyl groups may include monocyclic, bicyclic, or polycyclic (e.g., having two or three fused or bridged rings) ring systems or spirocyclic rings. In some embodiments, the heterocyclic alkyl group is a monocyclic group having one, two, or three heteroatoms independently selected from nitrogen, sulfur, and oxygen. The cyclic carbon atom and heteroatom of the heterocyclic alkyl group may optionally be oxidized to form an oxo or thio group or other oxidized bond (e.g., C(O), S(O), C(S), S(O) _₂ , N-oxide, etc.), or the nitrogen atom may be quaternized. The heterocyclic alkyl group may be linked by a cyclic carbon atom or a cyclic heteroatom. In some embodiments, the heterocyclic alkyl group contains 0 to 3 double bonds. In some embodiments, the heterocyclic alkyl group contains 0 to 2 double bonds. The definition of heterocyclic alkyl also includes a portion having one or more aromatic rings fused with (i.e., sharing bonds with) the heterocyclic alkyl ring, such as benzo[a] or thiophene derivatives of piperidine, morpholine, aza, etc. Heterocyclic alkyl groups containing fused aromatic rings may be linked by any cyclic atom, including the cyclic atom of the fused aromatic ring. Examples of heterocyclic alkyl groups include azirrobutyl, azirroheptyl, dihydrobenzofuranyl, dihydropyranyl, morpholino, 3-oxa-9-azaspiro[5.5]undecyl, 1-oxa-8-azaspiro[4.5]decyl, piperidinyl, piperazinyl, oxoperazinyl, pyranyl, pyrrolidinyl, quininecycloyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,4-tetrahydroquinolinyl, scopolyl, 4,5,6,7-tetrahydrothiazo[5,4-c]pyridinyl, and thiomorpholino.

The term "heterocyclic alkyl" or "heterocyclic group" can be unsubstituted or optionally substituted. When optionally substituted, one or more hydrogen atoms of the group (e.g., 1 to 4, 1 to 2, or 1) can be partially substituted independently from fluorine, hydroxyl, alkoxy, amino, alkylamino, acylamino, thio, and alkylthio groups. In some aspects, the substituted heterocyclic group may be incorporated into an external or internal cyclic olefin (e.g., cyclohexyl-2-en-1-yl). In some aspects, the heterocyclic group is unsubstituted or not optionally substituted.

Optional replacement

Unless otherwise expressly stated, groups are optionally substituted herein. The term “optionally substituted” means substituted or unsubstituted. In some embodiments, alkyl, alkenyl, ynyl, carbocycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally substituted. “Optionally substituted” means a group that can be substituted or unsubstituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” ynyl, “substituted” or “unsubstituted” cycloalkyl, “substituted” or “unsubstituted” cycloalkyl, “substituted” or “unsubstituted” heterocycloalkyl, “substituted” or “unsubstituted” aryl, or “substituted” or “unsubstituted” heteroaryl). Generally, the term “substituted” means that at least one hydrogen present on the group is replaced by a permissible substituent, such as a substituent that, after substitution, yields a stable compound (e.g., a compound that does not spontaneously transform, such as through rearrangement, cyclization, elimination, or other reactions). Unless otherwise stated, a “substituted” group has a substituent at one or more substituted positions of the group, and the substituent is either the same or different at each position when more than one position is substituted in any given structure. The term “substituted” contemplates substitution by all permissible substituents of an organic compound, and includes any substituents described herein that result in the formation of a stable compound. The invention contemplates any and all such combinations to obtain a stable compound. For the purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituents described herein that satisfy the valence of the heteroatom and result in the formation of a stable moiety. The invention is not intended to be limited in any way to the exemplary substituents described herein.

Exemplary carbon atom substituents include, but are not limited to, halogens (halogenated groups), -CN, _-NO₂ , _-N₃ , _-SO₂H , _-SO₃H , -OH, -OR ^aa , -ON(R ^bb ) ₂ , -N(R ^bb ) ₂ , -N(R ^bb ) ₃ ⁺ X ^- , -N(OR ^cc )R ^bb , -SH, -SR ^aa , -SSR ^cc , -C(＝O)R ^aa , _-CO₂H , -CHO, -C(OR ^cc ) ₂ , _-CO₂R ^aa , -OC(＝O)R ^aa , _-OCO₂R ^aa , -C(＝O)N(R ^bb ) ₂ , -OC(＝O)N(R ^bb ) ₂ , -NR ^bb C(＝O)R ^aa , -NR ^bb _CO₂R ^aa , -NR ^bb C(=O)N(R ^bb ) ₂ , -C(=NR ^bb )R ^aa , -C(=NR ^bb )OR ^aa , -OC(=NR ^bb )R ^aa , -OC(=NR ^bb )OR ^aa , -C(=NR ^bb )N(R ^bb ) ₂ , -OC(=NR ^bb )N(R ^bb ) ₂ , -NR ^bb C(=NR ^bb )N(R ^bb ) ₂ , -C(=O)NR ^bb SO ₂ R ^aa , -NR ^bb SO ₂ R ^aa , -SO ₂ N(R ^bb ) ₂ , -SO ₂ R ^aa , -SO ₂ OR ^aa , -OSO ₂ R ^aa , -S(=O)R ^aa , -OS(=O)R ^aa , -Si(R ^aa ) ₃ , -OSi(R ^aa ) ₃ -C(=S)N(R ^bb ) ₂ , -C(=O)SR ^aa , -C(=S)SR ^aa , -SC(=S)SR ^aa , -SC(=O)SR ^aa , -OC(=O)SR ^aa , -SC(=O)OR ^aa , -SC(=O)R ^aa , -P(=O) ₂ R ^aa , -OP(=O) ₂ R ^aa , -P(＝O)(R ^aa ) ₂ , -OP(＝O)(R ^aa ) ₂ , -OP(＝O)(OR ^cc ) ₂ , -P(＝O) ₂ N(R ^bb ) ₂ , -OP(＝O) ₂ N(R ^bb ) ₂ , -P(＝O)(NR ^bb ) ₂ , -OP(＝O)(NR ^bb ) ₂ , ^-NRbb P(＝O)(OR ^cc ) ₂ 、 -NR ^bb P(＝O)(NR ^bb ) ₂ 、 -OP(R ^cc ) ₂ 、 -OP(R ^cc ) ₃ 、 -B(OR ^cc ) ₂ 、 -BR ^aa (OR ^cc ), C _1-10 alkyl, C _1-10 perhaloalkyl, C _2-10 alkenyl, C _2-10 ynyl, (C ₃ -C ₁₀ ) carbocycloalkyl, 3-14 membered heterocycloalkyl, (C ₆ -C ₁₄ ) aryl and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R ^dd groups;

Alternatively, the two hydrogen atoms on the carbon atom can be replaced by the groups =O, =S, =NN(R ^bb ) ₂ , =NNR ^bb C(=O)R ^aa , =NNR ^bb C(=O)OR ^aa , =NNR ^bb S(=O) ₂ R ^aa , =NR ^bb or =NOR ^cc ;

Each instance of ^Raa is independently selected from ( _C1 - _C10 ) alkyl, ( _C1 - _C10 ) perhaloalkyl, ( _C2 - _C10 ) alkenyl, ( _C2 - _C10 ) ynyl, ( _C3 - _C10 ) cycloalkyl, 3-14-membered heterocyclic alkyl, ( _C6 - _C14 ) aryl and 5-14-membered heteroaryl, or two ^Raa groups are joined to form a 3-14-membered heterocyclic alkyl or 5-14-membered heteroaryl ring, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic alkyl, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4 or 5 ^Rdd groups;

Each instance of R ^bb is independently selected from hydrogen, ( _C1 - _C10 ) perhaloalkyl, ( _C2 - _C10 ) alkenyl, ( _C2 - _C10 ) ynyl, ( _C3 - _C10 ) cycloalkyl, _C6-14 aryl and 5-14 heteroaryl, or two R ^bb groups are joined to form a 3-14 heterocyclic alkyl or 5-14 heteroaryl ring, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic alkyl, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4 or 5 R ^dd groups;

Each instance of R cc is independently selected from hydrogen, (C <sub>1 -C  10 )alkyl, (C <sub>1 -C 10 ) perhaloalkyl, (C <sub>2 -C 10 )alkenyl, (C <sub>2 -C10 )ynyl, (C<sub>3-C10)cycloalkyl, 3-14-membered heterocyclic alkyl, (C <sub>6 -C14 )aryl and 5-14-membered heteroaryl, or two R cc  groups are joined to form a 3-14-membered heterocyclic alkyl or 5-14-membered heteroaryl ring, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic alkyl, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4 or 5 R dd groups;

Each instance of R dd is independently selected from halogens, -CN, -NO2 , -SO 2 H, -SO 3 H, -OH, -OR ee , -ON(R ff )2, -N(Rff )  2  , -N(Rff) 3  + X- , -N(OR ee )R ff , -SH, -SR ee , -SSRee, -C ( =O)R ee , -CO 2 H, -CO 2 Ree, -OC(=O)R ee , -OCO 2 R ee , -C(=O)N(R ff ) 2 , -OC(=O)N(R ff ) 2 , -NR  ff C(=O)R ee , -NRffCO 2 R ee , -NRff C(=O)N(R ff ) 2 , -C(=NRff  )OR2 ee , -OC(=NR ff )R ee , -OC(=NR ff )OR ee , -C(=NR ff )N(R ff ) 2 , -OC(=NR ff )N(R ff ) 2 , -NR ff C(=NR ff )N(R ff ) 2 , -NR ff SO 2 R ee , -SO 2 N(R ff ) 2 , -SO 2 R ee , -SO 2 OR ee , -OSO 2 R ee , -S(=O)R ee , -Si(R ee ) 3 , -OSi(R ee ) 3 , -C(=S)N(R ff ) 2 , -C(=O)SR ee , -C(=S)SR ee , -SC(=S)SR ee , -P(=O) 2 R ee , -P(＝O)(R ee ) 2 , -OP(＝O)(R ee ) 2 , -OP(＝O)(OR ee ) 2 , (C 1 -C 10 )alkyl, (C 1 -C 10 )perhaloalkyl, (C 2 -C 10 )alkenyl, (C 2 -C 10 )ynyl, (C 3 -C 10 )cycloalkyl, 3-10-membered heterocyclic alkyl, (C 6 -C 10 )aryl, 5-10-membered heteroaryl, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic alkyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R gg groups, or two geminal R dd substituents may be joined to form =O or =S;

Each instance of ^Ree is independently selected from ( _C1 - _C6 )alkyl, ( _C1 - _C6 )perhaloalkyl, ( _C2 - _C6 )alkenyl, (C2-C6)ynyl, ( _C3 - _C10 )cycloalkyl, ( _{C6 - C10} )aryl, 3-10 heterocyclic alkyl, and 3-10 heteroaryl, wherein each alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, cycloalkyl, heterocyclic alkyl, aryl, and heteroaryl is independently substituted by 0, 1, 2, ₃ , 4, or 5 ^Rgg groups;

Each instance of R ff is independently selected from hydrogen, (C <sub>1 -C  6  )alkyl, (C<sub> 1- C6 )perhaloalkyl, (C <sub>2 -C 6 )alkenyl, (C <sub>2- C6 )ynyl, (C <sub>3 -C 10 )cycloalkyl, (C<sub>6-C10)aryl, and 5-10 heteroaryl, or two R ff  groups are joined to form a 3-10 heterocyclic alkyl or 5-10 heteroaryl ring, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic alkyl, aryl, and heteroaryl group is independently substituted by 0, 1, 2, 3, 4, or 5 R gg groups; and

Each instance of R gg  is independently a halogen, -CN, -NO2 , -SO 2 H, -SO 3 H, -OH, -OC 1-6 alkyl, -ON(C 1-6 alkyl) 2 , -N(C  1-6 alkyl) 2  + X - , -NH(C 1-6 alkyl) 2  + X - , -NH2 (C 1-6 alkyl) + X- , -NH 3  + X - , -N(OC 1-6 alkyl)(C  1-6 alkyl), -N(OH)(C1-6alkyl), -NH(OH), -SH, -SC 1-6 alkyl, -SS(C 1-6 alkyl), -C(＝O)(C 1-6 alkyl), -CO2 H, -CO 2 (C1-6alkyl), -OC(＝O)(C 1-6 alkyl), -OCO2 (C 1-6 alkyl), 1-6 alkyl), -C(=O)NH 2 , -C(=O)N(C 1-6 alkyl) 2 , -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -NHCO 2 (C 1-6 alkyl), -NHC(=O)N(C 1-6 alkyl) 2 , -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH 2 , -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1-6 alkyl), -OC(=NH)OC 1-6 alkyl, -C(=NH)N(C 1-6 alkyl) 2 , -C(=NH)NH(C 1-6 alkyl), -C(=NH)NH 2 , -OC(=NH)N(C 1-6 alkyl) 1-6 alkyl) 2 , -OC(NH)NH (C 1-6 alkyl), -OC(NH)NH 2 , -NHC(NH)N (C 1-6 alkyl) 2 , -NHC(＝NH)NH 2 , -NHSO 2 (C 1-6 alkyl), -SO 2N (C 1-6 alkyl) 2 , -SO 2NH (C 1-6 alkyl), -SO 2NH 2 , -SO 2 C 1-6 alkyl, -SO 2 OC 1-6 alkyl, -OSO 2 C 1-6 alkyl, -SOC 1-6 alkyl, -Si (C 1-6 alkyl) 3 , -OSi (C 1-6 alkyl) 3 , -C(＝S)N (C 1-6 alkyl) 2 , C(＝S)NH (C 1-6 alkyl), C(＝S)NH 2 , -C(＝O)S (C 1-6 alkyl) =1-6 alkyl), -C(=S)SC 1-6 alkyl, -SC(=S)SC 1-6 alkyl, -P(=O) 2 (C 1-6 alkyl), -P(=O)(C 1-6 alkyl) 2 , -OP(=O)(C 1-6 alkyl) 2 , -OP(=O)(OC 1-6 alkyl) 2 , (C 1 -C 6 ) alkyl, (C 1 -C 6 ) perhaloalkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) ynyl, (C 3 -C 10 ) cycloalkyl, (C 6 -C 10 ) aryl, 3-10 membered heterocyclic alkyl, 5-10 membered heteroaryl; or two homologous R gg substituents can be joined to form =O or =S; wherein X- is a counter ion.

As mentioned earlier, nitrogen atoms can be substituted or unsubstituted, where valence bonds allow, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, -OH, -OR ^aa , -N(R ^cc ) ₂ , -CN, -C(＝O)R ^aa , -C(＝O)N(R ^cc ) ₂ , -CO _2R ^aa , -SO _2R ^aa , -C(＝NR ^bb )R ^aa , -C(＝NR ^cc )OR ^aa , -C(＝NR ^cc )N(R ^cc ) ₂ , -SO _2N (R ^cc ) ₂ , -SO _2R ^cc , -SO _2OR ^cc , -SOR ^aa , -C(＝S)N(R ^cc ) ₂ , -C(＝O)SR ^cc , -C(＝S)SR ^cc , -P(＝O) _2R ^aa , -P(＝O)(R ^aa ) ₂ , -P(＝O) _2N (R ^cc ) ₂ , -P(＝O)(NR ^cc ) ₂ , (C ₁ -C ₁₀ ) alkyl, (C ₁ -C ₁₀ ) perhaloalkyl, (C ₂ -C ₁₀ ) alkenyl, (C ₂ -C ₁₀ ) ynyl, (C ₃ -C ₁₀ ) cycloalkyl, 3-14-membered heterocyclic alkyl, (C ₆ -C 1 ₄ ) aryl and 5-14-membered heteroaryl, or two R ^cc groups attached to the N atom are joined to form a 3-14-membered heterocyclic alkyl or 5-14-membered heteroaryl ring, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic alkyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R ^dd groups, and wherein ^Raaa , ^Rbb , ^Rcc and ^Rdd are as defined above.

In some embodiments, the substituents present on the nitrogen atom are nitrogen protecting groups (also referred to herein as "amino protecting groups"). Nitrogen-protecting groups include, but are not limited to, -OH, -OR ^aa , -N( ^Rcc ) ₂ , -C(=O)R ^aa , -C(=O)N( ^Rcc ) ₂ , _-CO2R ^aa , -SO2R _aa , -C(= ^NRcc ) ^{R aa ,} -C(= ^NRcc )OR ^aa , -C(=NRcc)N( ^Rcc ) ₂ , -SO2N( ^Rcc )2, _-SO2Rcc , -SO2ORcc, -SOR aa, _-C (= ^S )N( ^Rcc) ₂ , -C(=O ^)SRcc , ^-C (=S)SRcc, ( ^C1 -C10) _alkyl (e.g., aralkyl, heteroaralkyl ⁾ , (C2-C10) ^alkenyl , ( _C2 - _C10 )alkyl, ( _{C1-C10)alkyl, (C2 - C10} )alkyl, ( _C1 -C10)alkyl, _{... The} group may contain alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aralkyl _, aryl, and heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aralkyl, aryl, and heteroaryl group is independently substituted by 0, 1 _{, 2} , 3, 4, or 5 ^Rdd groups, wherein ^Raaa , ^Rbb , ^Rcc , and ^Rdd are as defined herein. Nitrogen protecting groups are well known in the art, including those described in detail in Protecting Groups in Organic Synthesis, TW Greene and PGMWuts, 3rd edition, John Wiley & Sons, 1999 (incorporated herein by reference).

For example, nitrogen-protecting groups such as amide groups (e.g., -C(=O) ^Raa ) include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropionamide, pyridine amide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetylacetamide, (N'-dithiobenzyloxyacetamide)acetamide, 3-(p-hydroxyphenyl)propionamide, 3-(o-nitrophenyl)propionamide, 2-methyl-2-(o-nitrophenoxy)propionamide, 2-methyl-2-(o-phenylazophenoxy)propionamide, 4-chlorobutyramide, 3-methyl-3-nitrobutyramide, o-nitrocinnamamide, N-acetylmethionine derivatives, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

Nitrogen protecting groups such as urethane groups (e.g., -C(=O)OR ^aa ) include, but are not limited to, methyl urethane, ethyl urethane, 9-fluorenyl methyl urethane (Fmoc), 9-(2-sulfonyl)fluorenyl methyl urethane, 9-(2,7-dibromo)fluorenyl methyl urethane, methyl 2,7-di-tert-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothiophene)]urethane (DBD-Tmoc), 4-methoxybenzoyl urethane (Phenoc), 2,2,2-trichloroethyl urethane (Troc), and 2-trimethylsilyl ethyl urethane. 1-(1-adamantyl)-1-methylethylcarbamate (Teoc), 2-phenylethylcarbamate (hZ), 1-(1-adamantyl)-1-methylethylcarbamate (Adpoc), 1,1-dimethyl-2-haloethylcarbamate, 1,1-dimethyl-2,2-dibromoethylcarbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethylcarbamate (TCBOC), ethyl 1-methyl-1-(4-biphenyl)carbamate (Bpoc), 1-(3,5-di-tert-butylphenyl)-1-methyl Ethyl carbamate (t-Bumeoc), ethyl 2-(2'- and 4'-pyridyl)carbamate (Pyoc), ethyl 2-(N,N-dicyclohexylcarboxylamino)carbamate, tert-butyl carbamate (BOC or Boc), 1-adamantane carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinoline carbamate Esters, N-hydroxypiperidinyl carbamates, alkyl dithiocarbamates, benzyl carbamates (Cbz), p-methoxybenzyl carbamates (Moz), p-nitrobenzyl carbamates, p-bromobenzyl carbamates, p-chlorobenzyl carbamates, 2,4-dichlorobenzyl carbamates, 4-methylsulfinylbenzyl carbamates (Msz), 9-anthraylmethyl carbamates, diphenylmethyl carbamates, 2-methylthioethyl carbamates, 2-methylsulfonylethyl carbamates, 2-(p-toluenesulfonyl)ethylcarbamates Esters, [2-(1,3-dithiaalkyl)]carbamate (Dmoc), 4-methylthiophenylcarbamate (Mtpc), 2,4-dimethylphenylthiocarbamate (Bmpc), 2-phosphonoethylcarbamate (Peoc), 2-triphenylphosphonoisopropylcarbamate (Ppoc), 1,1-dimethyl-2-cyanoethylcarbamate, m-chloro-p-acyloxybenzylcarbamate, p-(dihydroxyboryl)benzylcarbamate, 5-benzoxazolylmethylcarbamate, 2-(trifluoromethyl)-6- Tcroc, m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl (o-nitrophenyl)methyl carbamate, tert-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropyl methyl carbamate, p-decoxybenzyl carbamate, 2,2-dimethoxyylvinyl carbamate Ester, o-(N,N-dimethylcarbamoyl)benzylcarbamate, 1,1-dimethyl-3-(N,N-dimethylcarbamoyl)propylcarbamate, 1,1-dimethylpropynylcarbamate, di(2-pyridyl)methylcarbamate, 2-furanylmethylcarbamate, 2-iodoethylcarbamate, isobornylcarbamate, isobutylcarbamate, isonicocyanate, p-(p'-methoxyphenylazo)benzylcarbamate, 1-methylcyclobutylcarbamate, 1-methylcyclohexylcarbamate Ester, 1-methyl-1-cyclopropylmethylcarbamate, ethyl 1-methyl-1-(3,5-dimethoxyphenyl)carbamate, ethyl 1-methyl-1-(p-phenylazophenyl)carbamate, 1-methyl-1-phenylethylcarbamate, 1-methyl-1-(4-pyridyl)ethylcarbamate, phenyl carbamate, p-(benzoazo)benzylcarbamate, 2,4,6-tri-tert-butylphenylcarbamate, 4-(trimethylammonium)benzylcarbamate and 2,4,6-trimethylbenzylcarbamate of carbamate.

Nitrogen protecting groups such as sulfonamide groups (e.g., -S(=O) ₂ Raaa ⁾ This includes, but is not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylbenzodihydropyran-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilyl ethyl sulfonamide (SES), 9-anthracitesulfonamide, 4-(4',8'-dimethoxynaphthyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and benzoylmethanesulfonamide.

Other nitrogen-protecting groups include, but are not limited to, phenothiazinyl-(10)-acyl derivatives, N'-p-toluenesulfonylaminoacyl derivatives, N'-phenylaminothioyl derivatives, N-benzoylphenylpropionyl derivatives, N-acetylmethionine derivatives, 4,5-diphenyl-3-oxazoline-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldimethylsilylazacyclopentane adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexane-2-one, 5-substituted... 1,3-Dibenzyl-1,3,5-triazacyclohexane-2-one, 1-substituted 3,5-dinitro-4-pyridinone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyrrololin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferroceneylmethylamino (Fcm), N-2-pyridinemethylamino N'-oxide, N-1,1-dimethylthiomethyleneamine, N-benzylamine, N-p-methoxybenzylamine, N-diphenylmethyleneamine, N-[(2-pyridyl)trimethylmethyl]methyleneamine, N-(N',N'-dimethylaminomethylene)amine, N,N'-isopropylidenediamine, N-p-nitrobenzylamine, N-salicylamine, N-5-chlorosalicylamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexylamine, N-(5,5-dimethyl-3-oxo-1 -Cyclohexenyl)amine, N-borane derivatives, N-diphenylboronic acid derivatives, N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelate, N-zinc chelate, N-nitrosamine, N-nitrosamine, N-amine oxide, diphenylphosphamide (Dpp), dimethylthiophosphamide (Mpt), diphenylthiophosphamide (Ppt), dialkylaminophosphate, dibenzylaminophosphate, diphenylaminophosphate, benzenesulfinamide, o-nitrobenzenesulfinamide (Nps), 2,4-dinitrobenzenesulfinamide, pentachlorobenzenesulfinamide, 2-nitro-4-methoxybenzenesulfinamide, triphenylmethylsulfinamide, and 3-nitropyridinesulfinamide (Npys).

In some embodiments, the substituents present on the oxygen atom are oxygen protecting groups (also referred to herein as "hydroxy protecting groups"). Oxygen protecting groups include, but are not limited to, ^-Raa , -N( ^Rbb ) ₂ , -C(=O) ^SRaa , -C(=O) ^Raa _, ^-CO2Raa , -C(=O)N( ^Rbb ) ₂ , -C(= ^NRbb ) ^Raa , -C(= ^NRbb ) ^ORaa , -C(= ^NRbb )N( ^Rbb ) ₂ , -S(=O) ^Raa , -SO2Raa, -Si( ^Raa ) _{3 ,} ^-P ( ^Rcc ) ₂ , -P( ^Rcc ) ₃ , -P(=O) _2Raa , -P(=O)( ^Raa ) ₂ , -P(=O)( ^ORcc ) ₂ , -P(=O) _2N ( ^Rbb ) ₂ and -P(=O)(NRbb ^{) 2} ) ₂ , wherein ^Raaa , ^Rbb , and ^Rcc are as defined herein. Oxygen protecting groups are well known in the art, including those described in detail in Protecting Groups in Organic Synthesis, TW Greene and PGM Watts, 3rd edition, John Wiley & Sons, 1999 (incorporated herein by reference).

Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxymethyl (MOM), methylthiomethyl (MTM), tert-butylthiomethyl, (phenyl dimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacol methyl (GUM), tert-butoxymethyl, 4-pentenoxymethyl (POM), silyloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl ( THP), 3-bromotetrahydropyranyl, tetrahydrothiaranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiaranyl, 4-methoxytetrahydrothiaranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP), 1,4-dioxane-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methylenebenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-Methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenoyl)ethyl, tert-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-pyridinemethyl, 4-pyridinemethyl, 3-methyl-2-pyridinemethyl N-oxy, diphenylmethyl, p,p'-dinitrophenylmethyl, 5-dibenzocycloheptyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, Di(p-methoxyphenyl)phenylmethyl, Tri(p-methoxyphenyl)methyl, 4-(4'-bromobenzoyloxyphenyl)diphenylmethyl, 4,4',4”-tris(4,5-dichlorophthalimidephenyl)methyl, 4,4',4”-tris(acetylpropionyloxyphenyl)methyl, 4,4',4”-tris(benzoyloxyphenyl)methyl, 3-(imidazol-1-yl)bis(4',4”-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1'-pyrenemethyl, 9-anthrayl, 9-(9-phenyl)xanthrayl, 9-(9-phenyl-10-oxo)anthrayl, 1,3-benzodithiapentane-2-yl, benzisothiazolyl S,S - Dioxide, Trimethylsilyl (TMS), Triethylsilyl (TES), Triisopropylsilyl (TIPS), Dimethylisopropylsilyl (IPDMS), Diethylisopropylsilyl (DEIPS), Dimethylhexylsilyl, Tert-butyldimethylsilyl (TBDMS), Tert-butyldiphenylsilyl (TBDPS), Tribenzylsilyl, Tri-p-xylylsilyl, Triphenylsilyl, Diphenylmethylsilyl (DPMS), Tert-butylmethoxyphenylsilyl (TBMPS), Formate, Benzoylcarbamate, Acetate, Chloroacetic acid ester, Dichloroacetic acid ester, Trichloroacetic acid ester, Trifluoroacetic acid Esters, methoxyacetic acid esters, triphenylmethoxyacetic acid esters, phenoxyacetic acid esters, p-chlorophenoxyacetic acid esters, 3-phenylpropionate esters, 4-oxovalerate esters (acetylpropionate esters), 4,4-(ethylidene dithio)valerate esters (acetylpropionyl dithioacetal), neovalerate esters, adamantane esters, crotonate esters, 4-methoxycrotonate esters, benzoate esters, p-phenylbenzoate esters, 2,4,6-trimethylbenzoate esters (methanesulfonate esters), methyl carbonate, 9-fluorenyl methyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(benzenesulfonyl)ethyl carbonate (Psec) ), 2-(triphenylphosphino)ethyl carbonate (Peoc), isobutyl carbonate, ethylene carbonate, allyl carbonate, tert-butyl carbonate (BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p-methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzyl thiocarbonate, 4-ethoxy-1-naphthyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylvalerate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl) Benzoate esters, 2,6-dichloro-4-methylphenoxyacetic acid esters, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetic acid esters, 2,4-bis(1,1-dimethylpropyl)phenoxyacetic acid esters, dichlorophenylacetic acid esters, isobutyrate esters, monosuccinate esters, (E)-2-methyl-2-butenoate esters, o-(methoxyyl)benzoate esters, α-naphthyl esters, nitrate esters, N,N,N’,N’-tetramethyldiaminophosphate alkyl esters, N-phenylcarbamate alkyl esters, borate esters, dimethylthiophosphoryl, alkyl 2,4-dinitrobenzenesulfinic acid esters, sulfate esters, methanesulfonates (methanesulfonates), benzyl sulfonates, and toluenesulfonates (Ts).

In some implementations, the substituents present on the sulfur atom are sulfur protecting groups (also known as "thiol protecting groups"). Sulfur protecting groups include, but are not limited to, ^-Raa , -N( ^Rbb ) ₂ , -C(=O) ^SRaa , -C(=O) ^Raa _, ^-CO2Raa , -C(=O)N( ^Rbb ) ₂ , -C(= ^NRbb ) ^Raa , -C(= ^NRbb ) ^ORaa , -C(= ^NRbb )N( ^Rbb ) ₂ , -S(=O) ^Raa , -SO2Raa, -Si( ^Raa ) _{3 ,} ^-P ( ^Rcc ) ₂ , -P( ^Rcc ) ₃ , -P(=O) _2Raa , -P(=O)( ^Raa ) ₂ , -P(=O)( ^ORcc ) ₂ , -P(=O) _2N ( ^Rbb ) ₂ and -P(=O)(NRbb ^{) 2} ) ₂ , wherein ^Raaa , ^Rbb , and ^Rcc are as defined herein. Sulfur protecting groups are well known in the art, including those described in detail in Protecting Groups in Organic Synthesis, TWGreene and PGMWuts, 3rd edition, John Wiley & Sons, 1999 (incorporated herein by reference).

As used herein, “leaving group” (LG) is a term understood in the art as referring to a molecular fragment separated from a pair of electrons in bond heterolytic cleavage, wherein the molecular fragment is an anionic or neutral molecule. As used herein, the leaving group can be an atom or group that can be substituted by a nucleophile. See, for example, Smith, March Advanced Organic Chemistry, 6th edition (501-502). Exemplary leaving groups include, but are not limited to, halogens (e.g., chlorine, bromine, iodine), -OR ^aa (where ^Raaa is as defined herein when the O atom is attached to a carbonyl group), -O(C=O)R ^LG , or -O(SO) _2R ^LG (e.g., toluenesulfonyl, methanesulfonyl, benzenesulfonyl), wherein R ^LG is an optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, the leaving group is a halogen.

The terms defined above are illustrated with specific examples in the embodiments.

The “yield” for each reaction described in this article is expressed as a percentage of the theoretical yield.

For the purposes of this invention, "patient" includes humans and any other animals, particularly mammals and other organisms. Therefore, this method is suitable for human treatment and veterinary applications. In a preferred embodiment, the patient is a mammal, and in the most preferred embodiment, the patient is a human. Examples of preferred mammals include mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, and primates.

"Kinease-dependent diseases or disorders" refer to pathological conditions that depend on the activity of one or more kinases. Kinases directly or indirectly participate in signaling pathways for various cellular activities, including proliferation, adhesion, migration, differentiation, and invasion. Diseases associated with kinase activity include tumor growth, pathological angiogenesis that supports solid tumor growth, and other diseases involving excessive local angiogenesis, such as eye diseases (diabetic retinopathy, age-related macular degeneration, etc.) and inflammation (psoriasis, rheumatoid arthritis, etc.).

"Therapeutic effective amount" is the amount of the compound of the present invention that improves disease symptoms when administered to a patient. The amount of the compound of the present invention constituting the "therapeutic effective amount" will vary depending on the compound, the disease state and its severity, the age of the patient to be treated, etc. Therapeutic effective amount can be conventionally determined by those skilled in the art based on their own knowledge and the content of this disclosure.

"Cancer" refers to a proliferative cellular disease state, including but not limited to: Heart : sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma; Head and neck: squamous cell carcinoma of the head and neck, laryngeal and hypopharyngeal carcinoma, nasal cavity and paranasal sinus carcinoma, nasopharyngeal carcinoma, salivary gland carcinoma, oral cavity and pharyngeal carcinoma; Lung: bronchial carcinoma (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma, non-small cell lung cancer), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Colon: colorectal cancer, adenocarcinoma, gastrointestinal stromal tumor, lymphoma, carcinoid tumor, Turcot syndrome. Syndrome; Gastrointestinal tract : gastric cancer, adenocarcinoma of the esophagogastric junction, esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (cancer, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vasoactive intestinal peptide tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Breast: metastatic breast cancer, ductal carcinoma in situ, invasive ductal carcinoma, tubular carcinoma, medullary carcinoma, mucinous carcinoma, lobular carcinoma in situ, triple-negative breast cancer; Urogenital tract : kidney (adenocarcinoma, Wilms' tumor) Tumors: [Nephroblastoma], lymphoma, leukemia, renal cell carcinoma; bladder and urethra: squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma, urothelial carcinoma; prostate: adenocarcinoma, sarcoma, castration-resistant prostate cancer; testes: seminoma, teratoma, embryonal carcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoid tumor, lipoma; clear cell carcinoma, papillary carcinoma; liver: hepatocellular carcinoma, bile duct carcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; bone: osteoblastoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma. Sarcoma), malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell chordoma, osteochondroma (osteochondrogenic osteoma), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor; Thyroid: medullary thyroid carcinoma, differentiated thyroid carcinoma, papillary thyroid carcinoma, follicular thyroid carcinoma, Hurthle cell carcinoma. Cancer) and undifferentiated thyroid carcinoma; Nervous system : Skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), Meninges (meningioma, meningeal sarcoma, glioma), Brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor [pineal tumor], glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), Spinal cord neurofibroma, meningioma, glioma, sarcoma; Gynecology : Uterus (endometrial cancer), Cervix (cervical cancer, tumor-pre-cervical dysplasia), Ovary (ovarian cancer [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulosa cell-theca cell tumor, Sertoli-Leydig cell tumor) Tumors: dysgerminoma, malignant teratoma; vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma); vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma)); fallopian tube (cancer); hematology : blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma [malignant lymphoma]; skin : malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus dysplasia, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal glands : neuroblastoma. Therefore, the term "cancer cell" as used herein includes cells afflicted by any of the above-identified diseases.

"Pharmaceutically acceptable salts" include "pharmaceutically acceptable acid addition salts" and "pharmaceutical acceptable base addition salts." "Pharmaceutical acceptable acid addition salts" refer to those salts that, when formed with inorganic acids (such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.) and organic acids (such as acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc.), retain the biological validity of the free base and are not biologically or otherwise undesirable.

"Pharmaceutically acceptable base addition salts" include salts derived from inorganic bases, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Exemplary salts are ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, and salts of substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Exemplary organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. (See, for example, S.M. Berge et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977; 66: 1-19, which is incorporated herein by reference.)

As used herein, the term "compound" is intended to include all stereoisomers, geometric isomers, tautomers, and isotopes of the described structure. The term also means the compounds of the present invention, regardless of how they are prepared, such as synthetically, by biological processes (e.g., metabolism or enzymatic conversion), or combinations thereof.

The compounds of the present invention may also include all isotopes of the atoms present in the intermediates or the final compound. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

Any process step or sequence disclosed and/or claimed herein may be performed under an inert gas atmosphere, more particularly under argon or nitrogen. Furthermore, the method of the present invention may be performed as a semi-continuous or continuous method, more preferably as a continuous method.

Furthermore, many of the process steps and sequences described in this article are scalable.

Generally, the nomenclature used in this application is based on the nomenclature conventions adopted by the International Union of Pure and Applied Chemistry (IUPAC). The chemical structures shown herein are prepared using [method name missing]. Any open valence bonds appearing on carbon, oxygen, or nitrogen atoms in the structures herein indicate the presence of hydrogen atoms.

Embodiments of the present invention

On the one hand, compounds of formula A are provided:

Or a pharmaceutically acceptable salt thereof, wherein the variables and substituents in formula A are as defined in the invention summary.

In one embodiment of this aspect, the compound of formula A is a compound of formula A-1.

In another embodiment of this aspect, the compound of formula A is a compound of formula A-2.

In another embodiment of this aspect, the compound of formula A is a compound of formula A-3:

^Ra1 is -H or (C1 _{- C6} ) alkyl.

In another embodiment, _R1 in the compound of formula A-3 is -H.

In another embodiment of this aspect, the compound of formula A is a compound of formula A-4:

The ring A is a 5- to 14-membered heteroaryl group; and the subscript r is 1, 2, 3 or 4.

In this implementation, _R2 is -H.

In another implementation, r in formula A-4 is 1 or 2.

In another embodiment of formula A: _R1 is -H, optionally substituted ( _C1 - _C6 )alkyl, halogroup _, ^-ORa , -NO2, _-NH2 , _-NHRa , ^-NRaRa , ^-SRa , ^-SORa or -S(O) ^2Ra , and ^R2 is selected from ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, ( _C6 - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, ^-CN , -NHORa, -C ⁽ _O ) ^Ra , -C(O) ^{NRaRa ,} -C(O) ^NHORa , -C(O) ^ORa , -C(O) ^NRaS (O) ^2Ra , ^-OC (O) ^NRaRa , ^NRaC (O ₎ ^Ra , ^-NRaC (＝ ^NRa ) ^Ra , ^-NRa C(O)OR ^a , -NR ^a C(O)NR ^a R ^a , -C(=NR ^a )R ^a , -C(=NOH)R ^a , -C(=NOR ^a )R ^a , -C(=NOH)NR ^a , -C(=NCN)NR ^a R ^a , -NR ^a C(=NCN)NR ^a R ^a , -C(=NR ^a )NR ^a R ^a , -NR ^a C(=NR ^a )NR ^a R ^a , -NR ^a S(O)R ^a , -NR ^a S(O) ₂ R ^a , -NR ^a S(O) ₂ NR ^a R ^a , -S(O)R ^a , -S(O)NR ^a R ^a , -S(O) ₂ R ^a , -S(O) ₂ NR ^a C(O)R ^a , -P(O)R ^a R ^a , -P(O)(OR ^a )(OR ^a ), -B(OH) ₂ , -B(OR ^a ) ₂ and -S(O) ₂ NR ^a R ^a .

In one implementation of this scheme, _R1 is -H.

In another embodiment: _R1 is selected from ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, ( _C6 - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-10 heteroaryl, 4-10 heterocycloalkyl, -CN, -NHOR ^a , -C(O)Ra, -C(O) ^{NR aRa} , ^-C (O)NHOR ^a , -C(O)OR ^a , -C(O)NR ^aS (O) _2Ra ^, -OC(O)NR ^aRa , -NR ^aC (O) ^Ra , -NR ^aC (＝NR ^a ) ^{Ra ,} -NR ^aC (O)OR ^a , -NR ^aC (O) ^{NR aRa ,} -C(＝NR ^a ) ^Ra , -C(＝NOH)Ra, -C(＝NOH)NR ^{a ,} -C(＝NOR ^a) )R ^a , -C(=NCN)NR ^a R ^a , -NR ^a C(=NCN)NR ^a R ^a , -C(=NR ^a )NR ^a R ^a , -NR ^a C(=NR ^a )NR ^a R ^a , -NR ^a S(O)R ^a , -NR ^a S(O) ₂ R ^a , -NR ^a S(O) ₂ NR ^a R ^a , -S(O)R ^a , -S(O)NR ^{a and} _​ ^​ _​ ^{​ ​ ​ ​ ​ ​} _​ ^​ _{​ ​} ^{​ ​}

_R2 is -H, optionally substituted ( _C1 - _C6 ) ^alkyl , halogroup, ^-ORa , -NO2, _-NH2 , _-NHRa , ^{-NRaRa , -SRa} , ^-SORa or -S(O) _2Ra ^.

In one implementation of this scheme, _R2 is -H.

In another implementation scheme:

_R1 represents ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, ( _C6 - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-10 heteroaryl, 4-10 heterocycloalkyl, -CN, -NHOR ^a , -C(O)Ra, -C(O)NR ^aRa , -C(O) ^{NHOR a ,} -C(O)OR ^a , -C(O)NR ^aS (O) _2Ra , -OC(O)NR ^aRa , -NR ^aC (O) ^Ra , -NR ^aC (＝NR ^a ) ^{Ra ,} -NR ^aC (O)OR ^a , -NR ^aC (O)NR ^aRa , -C(＝NR ^a ) ^{Ra , -C} (＝NOH) ^Ra , -C(＝NOR ^a ) ^Ra , -C(＝NOH)NR ^a , -C(=NCN)NR ^a R ^a , -NR ^a C(=NCN)NR ^a R ^a , -C(=NR ^a )NR ^a R ^a , -NR ^a C(=NR ^a )NR ^a R ^a , -NR ^a S(O)R ^a , -NR ^a S(O) ₂ R ^a , -NR ^a S(O) ₂ NR ^a R ^a , -S(O)R ^a , -S(O)NR ^a R ^a , -S(O) ₂ R ^a , -S(O) ₂ NR ^a C(O)R ^a , -P(O)R ^a R ^a , -P(O)(OR ^a )(OR ^a ), -B(OH) ₂ , -B(OR ^a ) ₂ or -S(O) ₂ NR ^a R ^a ; and

_R2 is selected from -H, halogenated, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, (C1- _C6 )haloalkyl, (C1 _- C6)haloalkoxy, (C6 _{- C10} )aryl-( _C1 - _C4 )alkylene-, (C3 _{-C10 )} cycloalkyl-( _{C1 - C4} )alkylene-, (5-14-membered heteroaryl)-( _{C1 - C4} )alkylene-, (4-14-membered heterocycloalkyl)-(C1 _{- C4} )alkylene-, -CN, _-NO2 , ^-ORa , ^-SRa , ^-NHORa , -C(O) ^{Ra ,} -C(O) ^NRaRa , -C(O) ^NHORa , -C(O) ^ORa , -C(O)NR ^a S(O) ₂ R ^a , -OC(O)R ^a , -OC(O)NR ^a R ^a , -NHR ^a , -NR ^a R ^a , -NR ^a C(O)R ^a , -NR ^a C(=NR ^a )R ^a , -NR ^a C(O)OR ^a , -NR ^a C(O)NR ^a R ^a , -C(=NR ^a )R ^a , -C(=NOH)R ^a , -C(=NOH)NR ^a , -C(=NOR ^a )R ^a , -C(=NCN)NR ^a R ^a , -NR ^a C(=NCN)NR ^a R ^a , -C(=NR ^a )NR ^a R ^a , -NR ^a C(=NR ^a )NR ^a R ^a , -NR ^a S(O)R ^a , -NR ^a S(O) ₂ R ^a , -NR ^a S(O) ₂ NR ^a R ^a , -S(O)R ^a , -S(O)NR ^a R ^a , -S(O) ₂ R ^a , -S(O) ₂ NR ^a C(O)R ^a , -P(O)R ^a R ^a , -P(O)(OR ^a )(OR ^a ), -B(OH) ₂ , -B(OR ^a ) ₂ ; and -S(O) ₂ NR ^a R ^a .

In one implementation of this scheme, _R2 is -H.

In another implementation scheme:

_R1 is selected from -H, halogroup, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, (C1-C6)haloalkyl, (C1 _{- C6} )haloalkoxy, ( _{C6 - C10} )aryl, ( _C3 - _{C10 )} cycloalkyl, 5-14-membered heteroaryl, 4-14-membered heterocycloalkyl, ( _C6 - _C10 )aryl-( _C1 - _C4 )alkylene-, ( _C3 - _C10 )cycloalkyl-(C1- _C4 )alkylene-, (5-14-membered heteroaryl)-( _{C1- C4 )} alkylene-, (4-14-membered heterocycloalkyl)-(C1 _{- C4} )alkylene-, -CN, _-NO2 , ^-ORa , -SR ^a , -NHOR ^a , -C(O)R ^a , -C(O)NR ^a R ^a , -C(O)NHOR ^a , -C(O)OR ^a , -C(O)NR ^a S(O) ₂ R ^a , -OC(O)R ^a , -OC(O)NR ^a R ^a , -NHR ^a , -NR ^a R ^a , -NR ^a C(O)R ^a , -NR ^a C(=NR ^a )R ^a , -NR ^a C(O)OR ^a , -NR ^a C(O)NR ^a R ^a , -C(=NR ^a )R ^a , -C(=NOH)R ^a , -C(= ^NOH )R ^a , -C(=NOH)NR ^a , -C(=NCN)NR ^a R ^a , -NR ^a C(=NCN)NR ^a R ^a , -C(=NR ^a )NR ^a R ^a , -NR ^a C(=NR ^a )NR ^a R ^a , -NR ^a S(O)R ^a , -NR ^a S(O) ₂ R ^a , -NR ^a S(O) ₂ NR ^a R ^a , -S(O)R ^a , -S(O)NR ^a R ^a , -S(O) ₂ R ^a , -S(O) ₂ NR ^a C(O)R ^a , -P(O)R ^a R ^a , -P(O)(OR ^a )(OR ^a ), -B(OH) ₂ , -B(OR ^a ) ₂ and -S(O) ₂ NR ^a R ^a ; and

In one implementation of this scheme, _R1 is -H.

In another alternative implementation:

_R1 and _R2, together with the atoms to which they are attached, form a fused (C3 _{- C7} ) cycloalkyl ring or a fused 4- to 10-membered heterocyclic alkyl ring; wherein each of the fused (C3 _{- C7} ) cycloalkyl ring or the fused 4- to 10-membered heterocyclic alkyl ring is optionally substituted by one, two or three independently selected ^Rb substituents, provided that the compound is not 1-[2-(4-fluoro-phenyl)-acetyl]-cyclopropanecarboxylic acid [3-fluoro-4-(7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxa-1-aza-cyclododecane[b]naphthalene-4-yloxy)-phenyl]-amide.

In another embodiment: _R1 and _R2, together with the atoms to which they are attached, form a fused (C3 _{- C7} ) cycloalkyl ring or a fused 4- to 10-membered heterocyclic alkyl ring, wherein each of the fused ( _{C3- C7} ) cycloalkyl ring or the fused 4- to 10-membered heterocyclic alkyl ring is optionally substituted by one, two, or three independently selected ^Rb substituents, provided that the compound is not a compound having the following formula:

Wherein ring E is a fused 4- to 10-membered heterocyclic alkyl group.

In another embodiment, _R1 in the compounds of formula A, A-1, A-3, or A-4 is selected from -H, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, -C(=NO-(C1 _{- C6} )alkyl) ^Ra , ^-CN , -C(O)ORa, -C(O) ^NRaRa , ^-C (O) ^NHORa , -S(O ^{) 2NRaRa} , phenyl, _5- to 6-membered heteroaryl, (C3 _{- C6} )cycloalkyl, and 4- to 6-membered heterocyclic alkyl.

In another embodiment, _R1 is selected from -H, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, -C(=NO-(C1 _{- C6} )alkyl) ^Ra , -CN, -C(O) ^ORa , ^{-C(O)NRaRa, -C(O)NHORa, -S(O)2NRaRa , phenyl ,} _5- ^to 6-membered heteroaryl, (C3 _{- C6} )cycloalkyl, and 4- to 6-membered heterocycloalkyl; and

_R2 is H, an optional substituted ( _C1 - _C6 ) ^alkyl group, ^a halogroup, ^-ORa , -NO2, _-NH2 , _-NHRa , ^-NRaRa , ^-SRa , ^-SORa , or -S(O) _2Ra ^.

In another embodiment, _R1 is selected from -H, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, -C(=NO-(C1 _{- C6} )alkyl) ^Ra , -CN, -C(O) ^ORa , ^{-C(O)NRaRa, -C(O)NHORa, -S(O)2NRaRa , phenyl ,} _5- ^to 6-membered heteroaryl, (C3 _{- C6} )cycloalkyl, and 4- to 6-membered heterocycloalkyl; and

_R2 is selected from -H, halogroup, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, (C1- _C6 )haloalkyl, (C1 _- C6)haloalkoxy, ( _{C6 - C10} )aryl, ( _{C3-C10)cycloalkyl, (C6 - C10 )} aryl-( _C1 - _C4 )alkylene-, ( _C3 - _C10 )cycloalkyl-( _{C1 - C4} )alkylene-, (5-14-membered heteroaryl)-(C1 _{- C4} )alkylene-, (4-14-membered heterocycloalkyl)-( _{C1- C4} )alkylene-, -CN, _-NO2 , ^-ORa , ^-SRa , ^-NHORa , -C(O) ^Ra , -C(O)NR ^a R ^a , -C(O)NHOR ^a , -C(O)OR ^a , -C(O)NR ^a S(O) ₂ R ^a , -OC(O)R ^a , -OC(O)NR ^a R ^a , -NHR ^a , -NR ^a R ^a , -NR ^a C(O)R ^a , -NR ^a C(=NR ^a )R ^a , -NR ^a C(O)OR ^a , -NR ^a C(O)NR ^a R ^a , -C(=NR ^a )R ^a , -C(=NOH)R ^a , -C(=NOH)NR ^a , -C(=NOR ^a )R ^a , -C(=NCN)NR ^a R ^a , -NR ^a C(=NCN)NR ^a R ^a , -C(=NR ^a )NR ^a R ^a , -NR ^a C(=NR ^a )NR ^a R ^a , -NR ^a S(O)R ^a , -NR ^a S(O) ₂ R ^a , -NR ^a S(O) ₂ NR ^a R ^a , -S(O)R ^a , -S(O)NR ^a R ^a , -S(O) ₂ R ^a , -S(O) ₂ NR ^a C(O)R ^a , -P(O)R ^a R ^a , -P(O)(OR ^a )(OR ^a ), -B(OH) ₂ , -B(OR ^a ) ₂ ; and -S(O) ₂ NR ^a R ^a .

In another embodiment, _R1 is selected from -H, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, -C(=NO-(C1 _{- C6} )alkyl) ^Ra , -CN, -C(O) ^ORa , -C(O) ^NRaRa , -C( ^O ) ^NHORa , -S(O) _2NRaRa ^{, phenyl} , 5- to 6-membered heteroaryl, -( _{C3- C6} )cycloalkyl, and 4- to 6-membered heterocycloalkyl; and

R ₂ is (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, -CN, -NHOR ^a , -C(O)R ^a , -C(O)NR ^a R ^a , -C(O)NHOR ^a , -C(O)OR ^a , -C(O)NR ^a S(O) ₂ R ^a , -OC(O)NR ^a R ^a , -NR ^a C(O)R ^a , -NR ^a C(=NR ^a )R ^a , -NR ^a C(O)OR ^a , -NR ^a C(O)NR ^a R ^a , -C(=NR ^a )R ^a , -C(=NOH)R ^a , -C(=NOH)NR ^a , -C(=NOR ^a )R ^a , -C(=NCN)NR ^a R ^a , -NR ^a C(=NCN)NR ^a R ^a , -C(=NR ^a )NR ^a R ^a , -NR ^a C(＝NR ^a )NR ^a R ^a , -NR ^a S(O)R ^a , -NR ^a S(O) ₂ R ^a , -NR ^a S(O) ₂ NR ^a R ^a , -S(O)R ^a , -S(O)NR ^a R ^a , -S(O) ₂ R ^a , -S(O) ₂ NR ^a C(O)R ^a , -P(O)R ^a R ^a , -P(O)(OR ^a )(OR ^a ), -B(OH) ₂ , -B(OR ^a ) ₂ or -S(O) ₂ NR ^a R ^a .

In another embodiment, _R1 is -H, ^RaNHC (O)-, ^RaOC (O)-, (C1 _{- C6} )alkyl, (C1 _{- C6} )alkoxy, or -C(=NO- _CH3 ) ^Ra , and _R2 is selected from 2-methoxyethylamino, aziridine-1-yl, methylamino, 3-morpholinopropoxy, 2-methoxyethoxy, 2-hydroxyethoxy, propoxy, 2-hydroxypropoxy, methoxycarbonyl, carboxyl, carbamoyl, methylcarbamoyl, (2-hydroxyethoxy)carbamoyl, (2,2-dihydroxyethoxy)carbamoyl, (oxetane-3-yloxy)carbamoyl, methoxycarbamoyl, 2-trimethylsilylethynyl, aminosulfonyl, acetyl, and -C(= _NOCH3 ) _CH3 .

In another embodiment of formulas A and A-2, _R2 is selected from -H, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, -C(=NO-( _C1 - _C6 )alkyl) ^Ra , -CN, -C(O) ^ORa , -C( ^O ) ^NRaRa , -C(O) ^NHORa and ^-S (O) _2NRaRa ^.

In another embodiment, _R1 is -H, optionally substituted ( _C1 - _C6 ) alkyl, halogroup, ^-ORa , _-NO2 , _-NH2 , ^-NHRa , ^-NRaRa , ^-SRa , ^{-SORa ,} or S(O) _2Ra , ^and

_R2 is selected from -H, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, -C(=NO-(C1 _{- C6} )alkyl) ^Ra , -CN, -C(O) ^ORa , -C(O) ^NRaRa , -C(O) ^NHORa , -S( ^{O )} _2NRaRa , ^phenyl , and (C3 _{- C6} )cycloalkyl.

In another embodiment, _R1 is selected from -H, optionally substituted ( _C1 - _C6 ) alkyl, halogroup, ^-ORa , _-NO2 , _-NH2 , ^-NHRa , ^-NRaRa , ^-SRa , ^{-SORa and} -S(O) _2Ra , ^and

_R2 is selected from -H, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, -C(＝NO-(C1 _{- C6} )alkyl) ^Ra , -CN, -C(O) ^ORa , -C(O) ^{NRaRa ,} -C(O) ^NHORa , _-S (O ^{) 2NRaRa} .

In another embodiment, _R1 is selected from ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, ( _C6 - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-10 heteroaryl, 4-10 heterocycloalkyl, -CN, -NHOR ^a , -C(O)Ra, -C(O) ^{NR aRa} , ^-C (O)NHOR ^a , -C(O)OR ^a , -C(O)NR ^aS (O) _2Ra ^, -OC(O)NR ^aRa , -NR ^aC (O) ^Ra , -NR ^aC (＝NR ^a ) ^{Ra ,} -NR ^aC (O)OR ^a , -NR ^aC (O) ^{NR aRa ,} -C(＝NR ^a ) ^Ra , -C(＝NOH)Ra, -C(＝NOH)NR ^{a ,} -C(＝NOR ^a) )R ^a , -C(=NCN)NR ^a R ^a , -NR ^a C(=NCN)NR ^a R ^a , -C(=NR ^a )NR ^a R ^a , -NR ^a C(=NR ^a )NR ^a R ^a , -NR ^a S(O)R ^a , -NR ^a S(O) ₂ R ^a , -NR ^a S(O) ₂ NR ^a R ^a , -S(O)R ^a , -S(O)NR ^{a and} _​ ^​ _​ ^{​ ​ ​ ​ ​ ​} _​ ^​ _{​ ​} ^{​ ​}

_R2 is selected from -H, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, -C(＝NO-(C1 _{- C6} )alkyl) ^Ra , -CN, -C(O) ^ORa , -C(O) ^{NRaRa ,} -C(O) ^NHORa , _-S (O ^{) 2NRaRa} .

In another embodiment, _R1 is selected from -H, halogroup, ( _C1 - _C6 )alkyl, (C2- _C6 )alkenyl, ( _C2 - _C6 )ynyl, ( _C1 - _C6 )haloalkyl, ( _{C1 - C6} )haloalkoxy, ( _C6 - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-14-membered heteroaryl, 4-14-membered heterocycloalkyl, ( _C6 - _C10 )aryl-( _C1 - _C4 )alkylene-, ( _C3 - _C10 )cycloalkyl-(C1 _{- C4} )alkylene-, (5-14-membered heteroaryl)-( _C1 - _C4 )alkylene-, (4-14-membered heterocycloalkyl)-(C1 _{- C4} )alkylene-, -CN, _-NO2 , ^-ORa , -SR ^a , -NHOR ^a , -C(O)R ^a , -C(O)NR ^a R ^a , -C(O)NHOR ^a , -C(O)OR ^a , -C(O)NR ^a S(O) ₂ R ^a , -OC(O)R ^a , -OC(O)NR ^a R ^a , -NHR ^a , -NR ^a R ^a , -NR ^a C(O)R ^a , -NR ^a C(=NR ^a )R ^a , -NR ^a C(O)OR ^a , -NR ^a C(O)NR ^a R ^a , -C(=NR ^a )R ^a , -C(=NOH)R ^a , -C(=NOR ^a )R ^a , -C(=NOH)NR ^a , -C(=NCN)NR ^a R ^a , -NR ^a C(=NCN)NR ^a R ^a , -C(=NR ^a )NR ^a R ^a ,-NR ^a C(=NR ^a )NR ^a R ^a , -NR ^a S(O)R ^a , -NR ^a S(O) ₂ R ^a , -NR ^a S(O) ₂ NR ^a R ^a , -S(O)R ^a , -S(O)NR ^a R ^a , -S(O) ₂ R ^a , -S(O) ₂ NR ^a C(O)R ^a , -P(O)R ^a R ^a , -P(O)(OR ^a )(OR ^a ), -B(OH) ₂ , -B(OR ^a ) ₂ and -S(O) ₂ NR ^a R ^a ; and

_R2 is selected from -H, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, -C(＝NO-(C1 _{- C6} )alkyl) ^Ra , -CN, -C(O) ^ORa , -C(O) ^{NRaRa ,} -C(O) ^NHORa , _-S (O ^{) 2NRaRa} .

In another embodiment, _R1 is selected from 2-methoxyethylamino, aziridine-1-yl, methylamino, 3-morpholinopropoxy, 2-methoxyethoxy, 2-hydroxyethoxy, propoxy, 2-hydroxypropoxy, methoxycarbonyl, carboxyl, carbamoyl, methylcarbamoyl, 2-oxazolyl, pyrazol-3-yl, pyrazol-4-yl, 4-isooxazolyl, 3,5-dimethylisooxazol-4-yl, 1-methyl-pyrazol-4-yl, 2-methyl-pyrazol-3-yl, 2-ethyl-pyrazol-3-yl, 2-(2-hydroxyethyl)-pyrazol-3-yl, 2-(2,2,2-trifluoroethyl)-pyrazol-3-yl, 2-(2-fluoroethyl) -pyrazol-3-yl, 2-(2,2-difluoroethyl)-pyrazol-3-yl, 2-trifluoromethyl-pyrazol-3-yl, 2-difluoromethyl-pyrazol-3-yl, 1-methyl-imidazol-4-yl, 1-methyl-imidazol-2-yl, 1H-imidazol-2-yl, (2-hydroxyethoxy)carbamoyl, (2,2-dihydroxyethoxy)carbamoyl, (oxetane-3-yloxy)carbamoyl, methoxycarbamoyl, 2-trimethylsilylethynyl, ethynyl, 1,3,4-oxadiazol-3-yl, 1H-1,2,3-triazol-5-yl, aminosulfonyl, acetyl, and -C(＝ _NOCH3 ) _CH3 ; and

_R2 is -H, ^-RaNHC (O)-, ^-RaOC (O)-, (C1 _{- C6} )alkyl, (C1 _{- C6} )alkoxy, or -C(=NO- _CH3 ) ^Ra .

In another embodiment of formula A-4, the subscript r is 1 or 2.

In another embodiment of the above aspects and implementation scheme, R ₁₀ and R ₁₁ are each -H.

In another embodiment of the above aspects and implementation scheme, the subscript n is 1.

In another embodiment of the above aspects and implementation scheme, the subscript m is 1.

In another embodiment of the above aspects and implementation scheme, the subscript p is 1.

In another embodiment, compound A is a compound of formula B:

Or a pharmaceutically acceptable salt thereof, wherein _R1 and _R2 are as defined by (i), (ii) or (iii) of formula A; and _R3 , _R10 , _R11 , _R14 , _R4 , n, p, m and Y are defined as follows:

Each _R3 is independently selected from -H, halogroup, -OH, -CN, optionally substituted ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy, ( _C1 - _C6 )haloalkoxy, _-NH2 , -NH( _C1 - _C6 )alkyl, -N( _C1 - _C6 )alkyl) ₂ and ( _C3 - _C6 )cycloalkyl, wherein ( _C1 - _C6 )alkoxy, -NH( _C1 - _C6 )alkyl, -N( _C1 - _C6 )alkyl) ₂ and ( _C3 - _C6 )cycloalkyl are each optionally substituted;

Each of _R10 and _R11 is independently selected from -H, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy, and ( _C1 - _C6 )haloalkoxy.

Each R ₁₄ is independently selected from -halogroup, -OH, _-NH2 , -CN, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy, (C1- _C6 )haloalkyl, ( _C1 - _C6 )haloalkoxy, -COOH, -NH( _C1 - _C6 )alkyl, -N( _C1 - _C6alkyl ) ₂ , phenyl, phenyl-( _{C1 - C2} )alkylene, ( _{C3- C6} )cycloalkyl, (C3- _C6 )cycloalkyl-( _{C1- C4 )} alkylene-, 4- to 6-membered heterocycloalkyl, (4- to 6-membered heterocycloalkyl)-( _{C1- C4} )alkylene-, 5- to 6-membered heteroaryl, (5- to 6-membered heteroaryl)-(C1 _{- C4} )alkylene- and ^-ORe , wherein R _The ( _C1 - _C6 )alkyl, phenyl, phenyl-(C1 _{- C2} )alkylene, (C3- _C6 )cycloalkyl, (C3 _{- C6} )cycloalkyl-(C1 _{- C4} )alkylene, 4- to 6-membered heterocycloalkyl, ( _4- to 6-membered heterocycloalkyl)-(C1 _{- C4} )alkylene, 5- to 6-membered heteroaryl and (5- to 6-membered heteroaryl)-(C1 _{- C4} )alkylene are each optionally substituted;

Each _R4 is independently selected from -H, halogroup, -OH, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy, ( _C1 - _C6 )haloalkyl, and ( _C1 - _C6 )haloalkoxy, wherein the ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy, ( _C1 - _C6 )haloalkyl, and ( _C1 - _C6 )haloalkoxy are each optionally substituted independently;

Each ^Ra is independently selected from -H, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )haloalkyl, ( _C6 - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-14-membered heteroaryl, 4-14-membered heterocycloalkyl, ( _C6 - _C10 )aryl-( _C1 - _C4 )alkylene-, ( _C3 - _C10 )cycloalkyl-( _C1 - _C4 )alkylene-, (5-14-membered heteroaryl)-(C1 _{- C4} )alkylene-, and (4-14-membered heterocycloalkyl)-(C1 _{- C4} )alkylene-, wherein ( _C1 - _C6 )alkyl, ( _C1 - _C6 )haloalkyl, ( _C6 - _C10 )aryl, ( _C3 - _C10)... ( _C6 - _C10 ) aryl-(C1-C4) alkylene-, (C3-C10) cycloalkyl-( _C1 - _C4 ) alkylene-, (5-14) heteroaryl-( _C1 - _C4 ) alkylene-, and (4-14 ₎ heterocycloalkyl-( _{C1 - C4 )} alkylene- can each be substituted independently _;

n, p, and m are each an independent integer from 0 to 3; and

Y is selected from -O-, -S-, -SO-, _-SO2- , -NH- and -N((C1 _{- C6} )alkyl)-.

In one implementation of formulas A and B:

(i)R ₁ is selected from:

( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, (C6- _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-10 heteroaryl, and 4-10 heterocycloalkyl, wherein the ( _{C2 - C6} )alkenyl, ( _C2 - _C6 )ynyl, ( _C6 - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-10 heteroaryl, and 4-10 heterocycloalkyl are each optionally substituted independently by the following:

-CN, -P(O)R ^a R ^a ,P(O)(OR ^a ) ₂ , B(OH) ₂ , B(OR ^a ) ₂ ,

X ₂ ^Ra , where X ₂ is -NHO-, -NH-S(O)-, -N-( _C1 - _C6 )alkyl-S(O)-, -NH-S(O) _2- , -N-( _C1 - _C6 )alkyl-S(O) ₂ ^Ra- , -NH-S(O)-NH-, -N-( _C1 - _C6 )alkyl-S(O)NH-, -NH-S(O) ₂ NH-, -N-( _C1 - _C6 )alkyl-S(O) ₂ NH-, -S(O) ₂ NHC(O)-, and

Where represents the connection point, and:

_Y1 is absent, or is -NH-, -N-( _C1 - _C6 )alkyl-, or -O-.

_Y2 is absent, or is -O-, -NH-, -NHO-, -N-( _C1 - _C6 )alkyl-, _-N2H2- , -NH-S(O ₎ -, or -NH-S(O) _2- ; or

_Y2 represents the optional substitution, where A is a 3-, 4-, 5-, 6-, or 7-membered ring; and

^Z1 is O, NH, N-( _C1 - _C6 )alkyl, NOH, NO-( _C1 - _C6 )alkyl, or NCN; and

_R2 is:

-H or a group selected from the following:

( _C1 - _C6 )alkyl, halogroup ^, _-NO2 , and _X1Ra , wherein _X1 is –O-, -S-, -SO-, -SO2-, -SO2NH-, ^-SO2NRa- , _{-NH- and -N-} ( _C1 - _C6 )alkyl-, wherein ( _C1 - _C6 )alkyl is optionally substituted.

In another implementation of formulas A and B:

(ii)R ₁ is selected from:

( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, (C6- _C10 )aryl, ( _{C3 - C10} )cycloalkyl, 5-10 heteroaryl, and 4-10 heterocycloalkyl, wherein the ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, ( _C6 - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-14 heteroaryl, and 4-14 heterocycloalkyl are each optionally substituted independently by the following:

P(O)R ^a R ^a , P(O)(OR ^a )(OR ^a ) , B(OH) ₂ , B(OR ^a ) ₂ , CN,

X ₂ ^Ra , where X ₂ is -NHO-, -NH-S(O)-, -N-( _C1 - _C6 )alkyl-S(O)-, -NH-S(O) _2- , -N-( _C1 - _C6 )alkyl-S(O) ₂ ^Ra- , -NH-S(O)-NH-, -N-( _C1 - _C6 )alkyl-S(O)NH-, -NH-S(O) ₂ NH-, -N-( _C1 - _C6 )alkyl-S(O) ₂ NH-, -S(O)-, -S(O) _2- , -S(O) ₂ NHC(O), and

in:

_Y1 is absent, or is -NH-, -N-( _C1 - _C6 )alkyl-, or -O-.

_Y2 is absent, or is -O-, -NH-, -NHO-, -N-( _C1 - _C6 )alkyl-, _-N2H2- , _-NH -S(O)- or -NH-S(O) ₂ , or

_Y2 represents the connection point of any optional substitution, where ring A is a 3, 4, 5, 6 or 7-membered ring;

^Z1 is -O-, -NH-, -N-( _C1 - _C6 )alkyl-, -NOH-, -NO-( _C1 - _C6 )alkyl-, or –NCN-; and

_R2 is selected from

H, halogenated, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, (C2- _C6 )ynyl, ( _C1 - _C6 )haloalkyl, (C1 _- C6)haloalkoxy, ( _C6 - _C10 )aryl-(C1 _{- C4} )alkylene-, (C3 _{- C10} )cycloalkyl-( _{C1 - C4} )alkylene-, ( _5-14 -membered heteroaryl)-(C1 _{- C4} )alkylene-, and (4-14-membered heterocycloalkyl)-(C1 _{- C4} )alkylene-, wherein ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, ( _C1 - _C6 )haloalkyl, (C1 _{- C6} )haloalkoxy, ( _C6 - _C10) The aryl, ( _C3 - _C10 )cycloalkyl, (C6- _C10 )aryl-( _C1 -C4)alkylene-, ( _C3 - _C10 )cycloalkyl-( _C1 - _C4 )alkylene-, (5-14-membered heteroaryl)-( _{C1- C4 )} alkylene-, and (4-14-membered heterocycloalkyl)-(C1 _{- C4} )alkylene- are each independently _and optionally substituted with the following:

CN, NO ₂ , P(O)R ^a R ^a , P(O)(OR ^a )(OR ^a ), B(OH) ₂ , B(OR ^a ) ₂ ,

_X1 ^Ra substitution, wherein _X1 is –O-, -S-, -NH- or -N-( _C1 - _C6 )-, -NHO-, -NH-S(O)-, -N-(C1-C6)alkyl-S(O)-, -NH-S(O)2-, -N-( _C1 - _C6 )alkyl-S(O) _2- , -NH-S(O)-NH-, -N-( _C1 - _C6 )alkyl-S(O)NH-, -NH-S(O) _2NH- , -N-(C1- _C6 )alkyl-S(O)2NH-, -S(O) _2NHC (O)-, -NH-S(O)Ra-, -N-(C1-C6)alkyl-S(O) _Ra- , -NH-S(O)2Ra-, -N-( _C1 - _C6 )alkyl-S(O) _2NH- , -N-(C1-C6)alkyl-S(O) _2NH- , -N-(C1-C6)alkyl- ^S (O)2NH-, -N-( _C1 - _C6 )alkyl-S(O) ^2Ra- , -N-(C1-C6)alkyl-S(O)2Ra-, -N-(C1-C6) ^alkyl -S(O) _2NH ... ₁ - _C6 )alkyl-S(O) _2Ra- ^and

in:

_Y1 is absent or is -NH-, -N-( _C1 - _C6 )alkyl- or -O-;

_Y2 is absent, or is -O-, -NH-, -NHO-, -N-( _C1 - _C6 )alkyl-, _-N2H2- , _-NH -S(O)- or -NH-S(O) _2- , or

_Y2 is an optional substitution in which ring A is a 3, 4, 5, 6, or 7-membered ring, and where represents the connection point; and

^Z1 can be O, NH, N-( _C1 - _C6 )alkyl, NOH, NO-( _C1 - _C6 )alkyl, or NCN.

In another implementation of formulas A and B:

(iii) _R1 and _R2 together with the atoms to which they are attached form a 4-10 membered heterocyclic alkyl ring optionally substituted with 1, 2 or 3 independently selected from the following groups: halogroup, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )haloalkyl, ( _C1 - _C6 )haloalkoxy, -CN, -OH, _-NH2 , provided that the compound is not 1-[2-(4-fluoro-phenyl)-acetyl]-cyclopropanecarboxylic acid [3-fluoro-4-(7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxa-1-aza-cyclododecano[b]naphthalene-4-yloxy)-phenyl]-amide.

In another embodiment of the compounds of formulas A and B:

_R1 can be -H, -CN, ( _C1 - _C6 )alkyl, ( _C3 - _C10 )cycloalkyl, ( _C6 - _C10 )aryl, 4-10 heterocyclic alkyl, 5-10 heteroaryl, -S(O ^)2NHRa _, -P(O) ^RaRa , ^{-ORa , or}

Where represents the connection point, and:

_Y1 is absent or is -NH-, -N-( _C1 - _C6 )alkyl- or -O-;

_Y2 is absent, or is -O-, -NH-, -NHO-, -N-( _C1 - _C6 )alkyl-, -NH-NH-, -NH-S(O)-, or NH-S(O) ₂ ; and

^Z1 is -O, -NH, -N-( _C1 - _C6 )alkyl, -N-OH or -NO( _C1 - _C6 )alkyl.

In another implementation of formulas A and B:

_R2 is -H, a ^halogroup , _-X1Ra , ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, or

Where represents the connection point, and:

_Y1 is absent, or is NH, N-( _C1 - _C6 ) alkyl, or O;

_Y2 is absent, or is O, NH, NHO, N-( _{C1 - C6} )alkyl, _N2H2 , NH-S(O) or NH-S(O) ₂ ; and

^Z1 is -O, -NH, -N-( _C1 - _C6 )alkyl, -NOH-, or -NO( _C1 - _C6 )alkyl.

In another embodiment of formulas A and B, _R3 is -H or a halogenated group.

In another embodiment of formulas A and B, _R4 is -H or a halogenated group.

In another embodiment of formulas A and B, _R14 is -H or a halogenated group.

In another implementation of formulas A and B, Y is -O-.

In another embodiment, the compound of B is a compound of formula B-1 or B-2:

               

Or its pharmaceutically acceptable salt.

In one implementation of formula B-1:

^Ra1 is an optionally substituted ( _C1 - _C6 ) alkyl group;

_R1 is -H, -CN, optionally substituted 3-6 membered cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 membered heterocycloalkyl, optionally substituted 5-6 membered heteroaryl, _-SO2- ( _C1 - _C6 )alkyl, -SO2NH2, _{-SO2 -} NH( _C1 - _C6 )alkyl, P ₍ O)(( _C1 - _C6 )alkyl) ₂ , or

Where represents the connection point, and:

_Y1 does not exist;

_Y2 is absent, or is -O-, -NH-, -NHO-, -NH-NH-, -N-( _C1 - _C6 )alkyl-; or

_Y2 is an optional substitution in which ring A is a 3, 4, 5, 6 or 7-membered ring, where represents the connection point;

^Z1 is O, NH, N-( _C1 - _C6 )alkyl, NHO, or NO-( _C1 - _C6 )alkyl; and

Ra ^can be -H, -( _C1 - _C6 )alkyl, 4-6 membered heterocyclic alkyl, 3-6 membered cycloalkyl, -( _C2 - _C6 )alkylene-OH, _-CH2CHOH- ( _C2 - _C6 )alkylene-OH, -( _C2 - _C6 )alkylene- _NH2 , -( _C2 - _C6 )alkylene-NH(C1- _C6 ), -( _C2 - _C6 )alkylene-N( _C1 - _C6 ) ₂ or -( _C2 - _C6 )alkylene-N-( _4-6 membered heterocyclic alkyl);

In another embodiment of formula B-1:

^Ra1 is a ( _C1 - _C6 ) alkyl group;

_R1 is -H, -CN, optionally substituted cyclopropyl, optionally substituted phenyl, optionally substituted 4-6 membered azacyclic butyl, optionally substituted pyrrolyl, optionally substituted piperidinyl, optionally substituted oxazolyl, optionally substituted pyridinyl, optionally substituted imidazolyl, optionally substituted pyrrolyl, optionally substituted furanyl, optionally substituted pyrazolyl, optionally substituted oxadiazolyl, _-SO₂- ( _C₁ - _C₆ )alkyl, _-SO₂NH₂ , _{-SO₂ -} NH( _C₁ - _C₆ )alkyl, or P(O)(( _C₁ - _C₆ )alkyl) _₂ ; or

_R1 is where:

_Y1 does not exist;

_Y2 is O, NH, NHO, NH-NH, or N-( _C1 - _C6 ) alkyl; or

_Y2 is an optionally substituted nitrogen-containing heterocyclic butyl group;

^Z1 is an O, NH, or N-( _C1 - _C6 ) alkyl group; and

Ra ^can be H, ( _C1 - _C6 )alkyl, -( _C2 - _C6 )alkylene-OH, _-CH2CHOH- ( _C2 - _C6 )alkylene-OH, -( _C2 - _C6 )alkylene- _NH2 , -( _C2 - _C6 )alkylene-NH( _C1 - _C6 )alkyl, -( _C2 - _C6 )alkylene-N(( _C1 - _C6 )alkyl) ₂ , -( _C2 - _C6 )alkylene-heterocyclic alkyl) or 4-6 membered heterocyclic alkyl, wherein the heterocyclic alkyl is optionally substituted.

In one implementation of formula B-2:

^Ra2 is an optionally substituted ( _C1 - _C6 ) alkyl group;

_R2 represents the connection point, where:

_Y1 does not exist;

_Y2 either does not exist or is -O- or -NH-; and

^Z1 is 0; and

^Ra is -H or -( _C1 - _C6 ) alkyl.

In another implementation of formula B-2:

^Ra2 is a ( _C1 - _C6 ) alkyl group;

_R2 represents the connection point, where:

_Y1 does not exist;

_Y2 either does not exist or is -O- or -NH-; and

^Z1 is an O or NO-( _C1 - _C6 ) alkyl group; and

^Ra is -H or -( _C1 - _C6 ) alkyl.

In another embodiment of formula B-1, ^Ra1 is a methoxy group.

In another embodiment of formula B-2, ^Ra2 is a methoxy group.

In another embodiment, the compound of formula B is a compound of formula B-3 or formula B-4:

Or its pharmaceutically acceptable salt.

In one implementation of formula B-3:

_R1 is -H or ( _C1 - _C6 ) alkyl; and _Y1 is absent;

_Y2 is absent or is -O-, -NHO- or -NH-; and ^Z1 is O or NO-( _C1 - _C6 )alkyl; and ^Ra is -H or -( _C1 - _C6 )alkyl.

In another implementation of formula B-3:

_R1 is –H or methyl;

_Y1 does not exist;

_Y2 is nonexistent or is -O-, -NHO-, or -NH-; and ^Z1 is O or NO-Me; and ^Ra is -H or Me.

In another implementation of formula B-3:

_R1 and ^Ra together with the atoms they are attached to form

4-6 membered heterocyclic alkyl rings optionally substituted with a halogroup, ( _C1 - _C6 )alkyl or ( _C1 - _C6 )haloalkyl.

In one implementation of formula B-4:

_Y1 does not exist;

_Y2 is O, NH, NHO, NH-NH, or N-( _C1 - _C6 ) alkyl; or

_Y2 is an optionally substituted nitrogen-containing heterocyclic butyl group;

^Z1 is O, NH, NO-( _C1 - _C6 )alkyl or N-( _C1 - _C6 )alkyl; and

Ra ^can be H, ( _C1 - _C6 )alkyl, -( _C2 - _C6 )alkylene-OH, _-CH2CHOH- ( _C2 - _C6 )alkylene-OH, -( _C2 - _C6 )alkylene- _NH2 , -( _C2 - _C6 )alkylene-NH( _C1 - _C6 )alkyl, -( _C2 - _C6 )alkylene-N(( _C1 - _C6 )alkyl) ₂ , -( _C2 - _C6 )alkylene-optionally substituted 4-6 membered heterocyclic alkyl) or optionally substituted 4-6 membered heterocyclic alkyl;

_R2 can be -H, -F, -Cl, -Br, -( _C1 - _C6 )alkoxy, -O-( _C2 - _C6 )alkylene-OH, -O-( _C2 - _C6 )alkylene-O-( _C1 - _C6 alkyl), ( _C2 - _C6 )alkylene-O-( _C1 - _C6 )alkyl, _-NH2 , -NH-(C1- _C6 alkyl), -NH-( _C1 - _C6 )alkylene-(optionally substituted 4-6 membered heterocyclic alkyl) or –NH-( _{C2 - C6} )alkylene-O-( _C1 - _C6 alkyl).

In another implementation of formula B-4:

_Y1 does not exist;

_Y2 is O, NH, NHO, NH-NH, or N-( _C1 - _C6 ) alkyl; or

_Y2 is an optionally substituted nitrogen-containing heterocyclic butyl group;

^Z1 is O, NH, NO-( _C1 - _C6 )alkyl, or N-( _C1 - _C6 )alkyl; and

^Ra can be -H, methyl, ethyl, -( _C2 - _C6 )alkylene-OH, _-CH2CHOH- ( _C2 - _C6 )alkylene-OH, -( _C2 - _C6 )alkylene- _NH2 , -( _C2 - _C6 )alkylene-NHMe, -( _C2 - _C6 )alkylene-N(Me) ₂ , -( _C1 - _C6 )alkylene-morpholinyl), -( _C1 - _C6 )alkylene-piperidinyl), ( _C1 - _C6 )alkylene-(optionally substituted pyrrolidinyl), optionally substituted azahexacyclic butyl or optionally substituted oxohexacyclic butyl;

_R2 is -H, -F, -Cl, -Br, methoxy, -O-( _C2 - _C6 )alkylene-OH, -O-( _C2 - _C6 )alkylene-OMe, _-NH2 , -NH-( _C1 - _C6 alkyl), -NH-( _C2 - _C6 )alkylene-OMe, -NH-( _C2 - _C6 )alkylene-(optionally substituted morpholino) or -NH-( _C2 - _C6 )alkylene-O-( _C1 - _C6 alkyl).

In another implementation of formula B-4:

_R2 and ^Ra, together with the atoms they are attached to, form 4-6 membered heterocyclic alkyl rings that are optionally substituted with halogen groups, ( _C1 - _C6 )alkyl groups, or ( _C1 - _C6 )haloalkyl groups.

In another embodiment, the compound of formula B is a compound of formula B-5:

Or a pharmaceutically acceptable salt thereof, wherein ring A in formula B-5 is an optionally substituted 5-6 membered heteroaryl or aryl.

In one implementation of formula B-5:

Ring A is optionally substituted ( _C6 - _C10 ) aryl, optionally substituted ( _C3 - _C10 ) cycloalkyl, optionally substituted 5-10 heteroaryl, or optionally substituted 4-10 heterocycloalkyl; and

_R2 is H, or ( _C1 - _C6 )alkoxy.

In another implementation of formula B-5:

Ring A is optionally substituted with phenyl, optionally substituted with cyclopropyl, optionally substituted with pyridyl, optionally substituted with imidazolyl, optionally substituted with pyrrole, optionally substituted with furanyl, optionally substituted with pyrazolyl, optionally substituted with oxazolyl, optionally substituted with aziridine or optionally substituted with oxacyclobutane; and

_R2 is H or methoxy.

Another embodiment of the compounds of formulas A and B is the compound of formula C:

Or its pharmaceutically acceptable salt, wherein:

_Y1 does not exist;

_Y2 is O, NH, NHO, NH-NH, or N-( _C1 - _C6 ) alkyl; or

_Y2 is an optionally substituted nitrogen-containing heterocyclic butyl group;

Z can be O, NH, NO-( _C1 - _C6 )alkyl or N-( _C1 - _C6 )alkyl;

Ra ^can be -H, ( _C1 - _C6 )alkyl, -( _C2 - _C6 )alkylene-OH, _-CH2CHOH- ( _C2 - _C6 )alkylene-OH, -( _C2 - _C6 )alkylene- _NH2 , -( _C2 - _C6 )alkylene-NH( _C1 - _C6 )alkyl, -( _C2 - _C6 )alkylene-N(( _C1 - _C6 )alkyl) ₂ , -( _C2 - _C6 )alkylene-optionally substituted 4-6 membered heterocyclic alkyl) or optionally substituted 4-6 membered heterocyclic alkyl;

_R2 can be -H, -F, -Cl, -Br, -( _C1 - _C6 )alkoxy, -O-( _C2 - _C6 )alkylene-OH, -O-( _C2 - _C6 )alkylene-O-( _C1 - _C6 alkyl), ( _C2 - _C6 )alkylene-O-( _C1 - _C6 )alkyl, _-NH2 , -NH-(C1- _C6 alkyl), -NH-( _C1 - _C6 )alkylene-(optionally substituted 4-6 membered heterocyclic alkyl), -NH-( _{C2 - C6} )alkylene-O-( _C1 - _C6 alkyl); and

n and m are each an independent integer from 0 to 3.

In another implementation of formula C:

_Y1 does not exist;

_Y2 is O, NH, NHO, NH-NH, or N-( _C1 - _C6 ) alkyl; or

_Y2 is an optionally substituted nitrogen-containing heterocyclic butyl group;

^Z1 is O, NH, NO-( _C1 - _C6 )alkyl or N-( _C1 - _C6 )alkyl;

^Ra can be -H, methyl, ethyl, -( _C2 - _C6 )alkylene-OH, _-CH2CHOH- ( _C2 - _C6 )alkylene-OH, -( _C2 - _C6 )alkylene- _NH2 , -( _C2 - _C6 )alkylene-NHMe, -( _C2 - _C6 )alkylene-N(Me) ₂ , -( _C1 - _C6 )alkylene-morpholinyl), -( _C1 - _C6 )alkylene-piperidinyl), ( _C1 - _C6 )alkylene-(optionally substituted pyrrolidinyl), optionally substituted azahexacyclic butyl or optionally substituted oxohexacyclic butyl;

_R2 is -H, -F, -Cl, -Br, methoxy, -O-( _C2 - _C6 )alkylene-OH, -O-( _C2 - _C6 )alkylene-OMe, _-NH2 , -NH-( _C1 - _C6 alkyl), -NH-( _C2 - _C6 )alkylene-OMe, -NH-( _C2 - _C6 )alkylene-(optionally substituted morpholino) or -NH-( _C2 - _C6 )alkylene-O-( _C1 - _C6 alkyl); and

And n and m are each 0 or 1.

In another implementation of formula C:

_R2 and ^Ra, together with the atoms they are attached to, form 4-6 membered heterocyclic alkyl rings optionally substituted with halogroups, ( _C1 - _C6 )alkyl groups, and ( _C1 - _C6 ) haloalkyl groups; and

n and m are each an independent integer from 0 to 3.

Another embodiment of formula C is a compound of formula C-1.

Or its pharmaceutically acceptable salt, wherein:

_Y2 is O, NH, NHO, NH-NH, or N-( _C1 - _C6 ) alkyl; or

_Y2 is an optionally substituted nitrogen-containing heterocyclic butyl group;

^Z1 is O, NH, NO-( _C1 - _C6 )alkyl or N-( _C1 - _C6 )alkyl;

^Ra can be -H, methyl, ethyl, -( _C2 - _C6 )alkylene-OH, _-CH2CHOH- ( _C2 - _C6 )alkylene-OH, -( _C2 - _C6 )alkylene- _NH2 , -( _C2 - _C6 )alkylene-NHMe, -( _C2 - _C6 )alkylene-N(Me) ₂ , -( _C1 - _C6 )alkylene-morpholinyl), -( _C1 - _C6 )alkylene-piperidinyl), ( _C1 - _C6 )alkylene-(optionally substituted pyrrolidinyl), optionally substituted azahexacyclic butyl or optionally substituted oxohexacyclic butyl;

_R2 is -H, -F, -Cl, -Br, methoxy, -O-( _C2 - _C6 )alkylene-OH, -O-( _C2 - _C6 )alkylene-OMe, _-NH2 , -NH-( _C1 - _C6 alkyl), -NH-( _C2 - _C6 )alkylene-OMe, -NH-( _C2 - _C6 )alkylene-(optionally substituted morpholino) or -NH-( _C2 - _C6 )alkylene-O-( _C1 - _C6 alkyl); and

Furthermore, n and m are each independently 0 or 1.

Another embodiment of formulas A and B is a compound of formula D:

In one implementation of formula D:

_R1 is -H or ( _C1 - _C6 ) alkyl; and

_Y1 does not exist;

_Y2 either does not exist or is -O-, -NHO-, or -NH-; and

^Z1 is O or NO-( _C1 - _C6 ) alkyl;

^Ra is -H or -( _C1 - _C6 ) alkyl; and

n and m are each an independent integer from 0 to 3.

In another implementation of formula D:

_R1 is –H or methyl;

_Y1 does not exist;

_Y2 either does not exist or is -O-, -NHO-, or -NH-; and

^Z1 is O or NO-Me; and

R ^_a can be either -H or -Me.

n and m are each an independent integer between 0 and 1.

In another implementation of formula D:

_R1 and ^Ra together with the atoms they are attached to form

4-6 membered heterocyclic alkyl rings optionally substituted with a halogroup, ( _C1 - _C6 )alkyl, or ( _C1 - _C6 )haloalkyl; and

n and m are each an independent integer between 0 and 1.

Another embodiment of formula D is a compound of formula D-1.

Another embodiment of formulas A and B is a compound of formula E:

Or its pharmaceutically acceptable salt, wherein:

Ring A is optionally substituted ( _C6 - _C10 ) aryl, optionally substituted ( _C3 - _C10 ) cycloalkyl, optionally substituted 5-10 heteroaryl, or optionally substituted 4-10 heterocycloalkyl; and

_R2 is H or ( _C1 - _C6 ) alkoxy.

In another implementation of formula E:

Ring A is optionally substituted with phenyl, optionally substituted with cyclopropyl, optionally substituted with pyridyl, optionally substituted with imidazolyl, optionally substituted with pyrrole, optionally substituted with furanyl, optionally substituted with pyrazolyl, optionally substituted with oxazolyl, optionally substituted with aziridine or optionally substituted with oxacyclobutane; and

_R2 is H or methoxy.

Another embodiment of formulas A and B is a compound of formula F:

Or its pharmaceutically acceptable salt, wherein

^Ra1 is an optionally substituted ( _C1 - _C6 ) alkyl group;

_R1 is -H, -CN, optionally substituted 3-6 membered cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 membered heterocycloalkyl, optionally substituted 5-6 membered heteroaryl, _-SO2- ( _C1 - _C6 )alkyl, _-SO2NH2 , _-SO2 - _NH ( _C1 - _C6 )alkyl, or P(O)(( _C1 - _C6 )alkyl) ₂ , or

Where represents the connection point, and:

_Y1 does not exist;

_Y2 is absent, or is -O-, -NH-, -NHO-, -NH-NH-, -N-( _C1 - _C6 )alkyl-; or

_Y2 is an optional substitution in which ring A is a 3, 4, 5, 6 or 7-membered ring, where represents the connection point;

^Z1 is O, NH, N-( _C1 - _C6 )alkyl, NHO, or NO-( _C1 - _C6 )alkyl; and

Ra ^can be -H, -( _C1 - _C6 )alkyl, 4-6 membered heterocyclic alkyl, 3-6 membered cycloalkyl, -( _C2 - _C6 )alkylene-OH, _-CH2CHOH- ( _C2 - _C6 )alkylene-OH, -( _C2 - _C6 )alkylene- _NH2 , -( _C2 - _C6 )alkylene-NH(C1- _C6 ), -( _C2 - _C6 )alkylene-N( _{C1 - C6} ) ₂ , -( _C2 - _C6 )alkylene-N-(4-6 membered heterocyclic alkyl);

In another implementation of formula F:

^Ra1 is a methyl group;

_R1 is -H, -CN, optionally substituted cyclopropyl, optionally substituted phenyl, optionally substituted 4-6 membered azacyclic butyl, optionally substituted pyrrolyl, optionally substituted piperidinyl, optionally substituted oxazolyl, optionally substituted pyridinyl, optionally substituted imidazolyl, optionally substituted pyrrolyl, optionally substituted furanyl, optionally substituted pyrazolyl, optionally substituted oxadiazolyl, _-SO₂- ( _C₁ - _C₆ )alkyl, _-SO₂NH₂ , _{-SO₂ -} NH( _C₁ - _C₆ )alkyl, or P(O)(( _C₁ - _C₆ )alkyl) _₂ ; or

_R1 is where:

_Y1 does not exist;

_Y2 is O, NH, NHO, NH-NH, or N-( _C1 - _C6 ) alkyl; or

_Y2 is an optionally substituted nitrogen-containing heterocyclic butyl group;

^Z1 is an O, NH, or N-( _C1 - _C6 ) alkyl group; and

Ra ^can be H, ( _C1 - _C6 )alkyl, -( _C2 - _C6 )alkylene-OH, _-CH2CHOH- ( _C2 - _C6 )alkylene-OH, -( _C2 - _C6 )alkylene- _NH2 , -( _C2 - _C6 )alkylene-NH( _C1 - _C6 )alkyl, -( _C2 - _C6 )alkylene-N(( _C1 - _C6 )alkyl) ₂ , -( _C2 - _C6 )alkylene-heterocyclic alkyl) and 4-6 membered heterocyclic alkyl, wherein the heterocyclic alkyl is optionally substituted.

Another embodiment of formulas A and B is a compound of formula G:

Or its pharmaceutically acceptable salt, wherein:

^Ra1 is an optionally substituted ( _C1 - _C6 ) alkyl group;

_R2 represents the connection point, where:

_Y1 does not exist;

_Y2 either does not exist or is -O- or -NH-; and

^Z1 is 0; and

^Ra is -H or -( _C1 - _C6 ) alkyl.

In another implementation of formula G:

^Ra2 is a methyl group;

_R2 represents the connection point, where:

_Y1 does not exist;

_Y2 either does not exist or is -O- or -NH-; and

^Z1 is an O or NO-( _C1 - _C6 ) alkyl group; and

^Ra is –H or -( _C1 - _C6 )alkyl.

Another embodiment of formulas A and B is a compound for regulating kinase activity according to formula H:

Or its pharmaceutically acceptable salt, wherein:

_R1 is selected _from -H, -CN, -CO- _NR5R6 , _-CO2R7 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted _{( C1} - _C6 )alkyl, optionally substituted ( _C3 - _C8 )cycloalkyl, optionally substituted ( _C3 - _C6 ) _{heterocycloalkyl} , _-SO2NR8R9 or -( _{SO2 )} -( _C1 - _C6 )alkyl;

Where _R1 is selected _{from -CN} , -CO- _NR5R6 , _-CO2R7 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted ( _C3 - _C8 )cycloalkyl, optionally substituted ( _C3 - _C6 ) heterocycloalkyl, _-SO2NR8R9 and -( _SO2 )-( _C1 - _C6 )alkyl, _{R2 is} H, _halogroup , _-NR5R6 or optionally substituted _{( C1} - _C6 )alkoxy;

Where _R1 is -H, an optionally substituted ( _C1 - _C6 ) alkyl, or _an optionally substituted ( _C1 - _C6 ) alkoxy, _R2 is -CO- _NR5R6 or _{-CO2R7 ;}

Or _R1 and _R2 together with the atoms to which they are attached form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl;

_R3 is selected from -H, optionally substituted (C1 _{- C6} ) alkyl, -CN, and halogroup;

_R4 is -H or a halogenated group;

Optionally substituted with one, two, three or four independently selected groups from halogroups and ( _C1 - _C6 )alkyl groups, wherein the linkage point is indicated;

_R5 and _R6 are each independently -H, optionally substituted ( _C1 - _C6 ) alkyl or optionally substituted _C1 - _C6 alkoxy;

_R7 is -H or an optionally substituted ( _C1 - _C6 ) alkyl group;

_R8 and _R9 are each independently -H or optionally substituted ( _C1 - _C6 ) alkyl; or

_R8 and _R9 can be connected to form an optionally substituted heterocyclic ring; and

Y is selected from O, S, SO, _SO₂ , NH and N-(( _C₁ - _C₆ )alkyl).

In one embodiment of the compound of formula I, Y is O.

In another implementation, _R3 is -H.

In another implementation, it was not replaced.

In another implementation, _R4 is a halogenated group.

In another embodiment, _R4 is parafluorine.

In another embodiment, _R2 is -H, a halogroup, or an optionally substituted ( _C1 - _C6 )-alkoxy group.

In another implementation, _R1 is -CN.

In another implementation, _R1 is _-CO2H .

In another implementation, _R1 is _-CO2 -Me.

In another implementation, _R1 is -CO-NHR ₆ .

In another implementation, _R1 is -CO-NH2.

In another implementation, _R1 is -CO- _NMeR6 .

In another embodiment, _R3 is -H or a halogenated group.

In another embodiment, _R1 is selected from -CN, -( _SO2 ) _NH2 , -OMe, and -( _SO2 ) _CH3.

Where is the connection point.

In one implementation, _R1 is selected as a connection point.

In another implementation, _R1 is selected as the connection point.

In another implementation, _R2 is selected from -H, -CN, -Br, -F, -Cl, -OMe,

-CH ₂ NH ₂ 、NH ₂ 、NHMe, where is the connection point.

In another embodiment, _R1 is -H, methyl, or methoxy.

In another implementation, _R2 is _-CO2H .

In another implementation, _R1 is _-CO2 -Me.

In another implementation, _R1 is -CO-NHR ₆ .

In another implementation, _R1 is -CO- _NH2 .

In another implementation, _R1 is -CO- _NMeR6 .

In another implementation, _R1 is selected from

In another implementation, _R1 and _R2 together form

In another embodiment, the compound of formula I is the compound of formula I-1:

              

Wherein _R6 is (C1 _{- C6} )alkyl, _R2 is (C1 _{- C6} )alkoxy, _R3 is -H or a halogroup, and _R4 is a halogroup.

In another aspect, the present invention provides compounds of formula A or formula A-I provided in Table 1 below.

Table 1: Specific compounds of the present invention

Or its pharmaceutically acceptable salt.

General application

The application of the compounds of the present invention, either in their pure form or in suitable pharmaceutical compositions, or of their pharmaceutically acceptable salts, can be carried out by any acceptable mode of administration or agent for providing similar efficacy. Thus, administration can be, for example, in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms (such as tablets, suppositories, pills, soft and hard gelatin capsules, powders, solutions, suspensions, aerosols, etc.), preferably in unit dosage forms suitable for simple administration of precise dosage, orally, nasally, parenterally (intravenously, intramuscularly, or subcutaneously), topically, transdermally, intravaginally, intravesically, intracisionally, or rectally.

The composition will comprise a conventional pharmaceutical carrier or excipient and the compound of the present invention as an active agent, and may further include other pharmaceutical agents, pharmaceutical reagents, carriers, adjuvants, etc. The compositions of the present invention can be used in combination with anticancer agents or other agents commonly administered to cancer-treated patients. Adjuvants include preservatives, wetting agents, suspending agents, sweeteners, flavoring agents, aromatizers, emulsifiers, and dispersants. Prevention of microbial action can be ensured by various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, etc. Isotonic agents, such as sugars, sodium chloride, etc., may also be desired. Prolonged absorption of injectable drug forms can be achieved by using agents with delayed absorption, such as aluminum monostearate and gelatin.

If necessary, the pharmaceutical compositions of the present invention may also contain small amounts of excipients, such as wetting agents or emulsifiers, pH buffers, antioxidants, etc., for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylated hydroxytoluene, etc.

Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or mediators include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, etc.), suitable mixtures thereof, vegetable oils (e.g., olive oil), and injectable organic esters such as ethyl oleate. Appropriate flowability may be maintained, for example, by using coatings such as lecithin, by maintaining the desired particle size in the case of dispersions, and by using surfactants.

A preferred route of administration is oral, with a convenient daily dosage regimen that can be adjusted according to the severity of the disease state being treated.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with: at least one inert conventional excipient (or carrier), such as sodium citrate or dicalcium phosphate, or (a) a filler or extender, such as starch, lactose, sucrose, glucose, mannitol and silica, (b) a binder, such as cellulose derivatives, starch, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic, (c) a humectant, such as glycerin, (d) a disintegrant, such as agar, calcium carbonate, potato or cassava starch, alginate, croscarmellose sodium, complex silicates and sodium carbonate, (e) a solution retarder, such as paraffin, (f) an absorption enhancer, such as a quaternary ammonium compound, (g) a wetting agent, such as cetyl alcohol and glyceryl monostearate, magnesium stearate, etc., (h) an adsorbent, such as kaolin and bentonite, and (i) a lubricant, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate or mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also contain buffers.

Solid dosage forms as described above can be prepared using coatings and shells such as enteric coatings and other coatings well known in the art. They may contain soothing agents and may also have compositions in which they release one or more active compounds in a delayed manner at a portion of the intestine. Examples of usable embedding compositions are polymeric substances and waxes. If suitable, the active compounds may also be present in microencapsulated form together with one or more of the excipients described above.

Orally administered liquid dosage forms include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. Such dosage forms are prepared, for example, by dissolving, dispersing, etc., the compounds of the present invention or their pharmaceutically acceptable salts and optionally adjuvants in a carrier, such as water, saline solution, aqueous glucose solution, glycerol, ethanol, etc.; solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, and dimethylformamide; oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil; glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitol; or mixtures of these substances, thereby forming a solution or suspension.

In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar and tragacanth gum, or mixtures of these substances.

Compositions for rectal administration are, for example, suppositories, which can be prepared by mixing the compounds of the present invention with, for example, suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or suppository waxes, which are solid at room temperature but liquid at body temperature and thus melt and release the active component therein when in a suitable body cavity.

Dosage forms for topical application of the compounds of this invention include ointments, powders, sprays, and inhalers. The active ingredient is mixed under aseptic conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required. Ophthalmic preparations, ointments, powders, and solutions are also contemplated within the scope of this invention.

Typically, depending on the intended route of administration, a pharmaceutically acceptable composition will contain about 1% to about 99% by weight of the compound of the present invention or a pharmaceutically acceptable salt thereof, and 99% to 1% by weight of a suitable pharmaceutical excipient. In one example, the composition will contain between about 5% and about 75% by weight of the compound of the present invention or a pharmaceutically acceptable salt thereof, with the remainder being a suitable pharmaceutical excipient.

The actual methods for preparing such dosage forms are known or obvious to those skilled in the art; see, for example, Remington's Pharmaceutical Sciences, 18th edition (Mack Publishing Company, Easton, Pa., 1990). In any case, the composition to be administered will contain a therapeutically effective amount of the compound of the invention or a pharmaceutically acceptable salt thereof for treating the disease state taught according to the invention.

The compounds of the present invention, or pharmaceutically acceptable salts thereof, are administered in therapeutically effective amounts, which will vary depending on a variety of factors, including the activity of the specific compound used, the metabolic stability and duration of action of the compound, age, weight, general health condition, sex, diet, administration pattern and time, excretion rate, drug combination, severity of the specific disease state, and the host receiving treatment. The compounds of the present invention can be administered to patients at dose levels ranging from about 0.1 mg to about 1,000 mg per day. For a normal adult weighing about 70 kg, the dose range is, for example, from about 0.01 mg to about 100 mg per kg of body weight per day. However, the specific dose used can vary. For example, the dose can depend on many factors, including the patient's needs, the severity of the disease to be treated, and the pharmacological activity of the compound used. Determining the optimal dose for a particular patient is well known to those skilled in the art.

Combination therapy

The compounds disclosed herein may be administered as a monotherapy or in combination with one or more additional therapies (“co-administration”) for the treatment of diseases or conditions, such as those associated with excessive proliferation, such as cancer. Therapies that may be used in combination with the compounds disclosed herein include: (i) surgery; (ii) radiation therapy (e.g., gamma rays, neutron beam radiation therapy, electron beam radiation therapy, proton therapy, brachytherapy, and whole-body radioisotopes); (iii) endocrine therapy; (iv) adjuvant therapy, immunotherapy, CAR T-cell therapy; and (v) other chemotherapeutic agents.

The term "co-administration" ("co-administration") refers to the simultaneous or sequential administration of a compound of formula I' or a salt thereof and one or more other active pharmaceutical ingredients (including cytotoxic agents and radiotherapy). If the administration is not simultaneous, the compounds are administered at close intervals. Furthermore, it is irrelevant whether the compounds are administered in the same dosage form; for example, one compound may be administered topically and another may be administered orally.

Generally, any agent active in treating a disease or ailment may be administered together. Examples of such agents used for cancer treatment can be found, for example, at https://www.cancer.gov/about-cancer/treatment/drugs (last accessed January 22, 2019) and in publicly available sources such as Cancer Principles and Practice of Oncology, 11th edition (2018), by VTDevita and S. Hellman (eds.), Lippincott Williams & Wilkins. It will be useful for those skilled in the art to be able to identify which combination of agents is appropriate based on the specific properties of the drugs and the disease being treated.

In one implementation, the treatment method includes co-administration of a compound as disclosed herein or a pharmaceutically acceptable salt thereof, and at least one immunotherapy. Immunotherapy (also known as biological response modulator therapy, biologic therapy, biological agent therapy, immune therapy, or biological therapy) is a therapy that uses a part of the immune system to fight disease. Immunotherapy can help the immune system recognize cancer cells or enhance the response to cancer cells. Immunotherapy includes active and passive immunotherapy. Active immunotherapy stimulates the body's own immune system, while passive immunotherapy typically uses components of the immune system produced outside the body.

Examples of active immunotherapy include, but are not limited to, vaccines, including cancer vaccines, tumor cell vaccines (autologous or allogeneic), dendritic cell vaccines, antigen vaccines, anti-idiotypic vaccines, DNA vaccines, viral vaccines, or tumor-infiltrating lymphocyte (TIL) vaccines with interleukin-2 (IL-2) or lymphokine-activated killer (LAK) cell therapy.

Examples of passive immunotherapy include, but are not limited to, monoclonal antibodies and targeted therapies containing toxins. Monoclonal antibodies include naked antibodies and conjugated monoclonal antibodies (also known as labeled, tagged, or loaded antibodies). Naked monoclonal antibodies do not have a drug or radioactive substance attached to them, while conjugated monoclonal antibodies are attached to, for example, chemotherapeutic drugs (chemically labeled), radioactive particles (radiolabeled), or toxins (immunotoxins). Examples of these naked monoclonal antibody drugs include, but are not limited to: rituximab (Rituxan), an antibody against the CD20 antigen used to treat, for example, B-cell non-Hodgkin lymphoma; trastuzumab (Herceptin), an antibody against the HER2 protein used to treat, for example, advanced breast cancer; alemtuzumab (Campath), an antibody against the CD52 antigen used to treat, for example, B-cell chronic lymphocytic leukemia (B-CLL); cetuximab (Erbitux), an antibody against the EGFR protein used, for example, in combination with irinotecan, to treat, for example, advanced colorectal cancer and head and neck cancer; and bevacizumab (Avastin), an anti-angiogenic therapy that acts on the VEGF protein and is used, for example, in combination with chemotherapy to treat, for example, metastatic colorectal cancer. Examples of conjugated monoclonal antibodies include, but are not limited to: the radiolabeled antibody teimozumab (Zevalin), which delivers radioactivity directly to cancerous B lymphocytes and is used to treat, for example, B-cell non-Hodgkin lymphoma; the radiolabeled antibody tosimomumab (Bexxar), which is used to treat, for example, certain types of non-Hodgkin lymphoma; and the immunotoxin gemtuzumab ozomicin (Mylotarg), which contains calcineurin and is used to treat, for example, acute myeloid leukemia (AML). BL22 is a conjugated monoclonal antibody used to treat, for example, hairy cell leukemia; an immunotoxin used to treat, for example, leukemia, lymphoma, and brain tumors; and radiolabeled antibodies (such as OncoScint for colorectal and ovarian cancer and ProstaScint for prostate cancer).

Other examples of therapeutic antibodies that may be used include, but are not limited to: HERCEPTIN ^™ (trastuzumab) (Genentech, Calif.), a humanized anti-HER2 monoclonal antibody for the treatment of patients with metastatic breast cancer; REOPRO.RTM. (abciximab) (Centocor), an anti-glycoprotein IIb/IIIa receptor on platelets to prevent clot formation; ZENAPAX ^™ (dalizumab) (Roche Pharmaceuticals, Switzerland), an immunosuppressive humanized anti-CD25 monoclonal antibody for the prevention of acute renal allogeneic transplant rejection; PANOREX ^™ , a mouse anti-17-IA cell surface antigen IgG2a antibody (Glaxo Wellcome/Centocor); BEC2, a mouse anti-idiotype (GD3 epitope) IgG antibody (ImClone System); IMC-C225, a chimeric anti-EGFR IgG antibody (ImClone System); VITAXIN ^™ This product is a humanized anti-αVβ3 integrin antibody (Applied Molecular Evolution/Medlmmune); Camppath 1H/LDP-03 is a humanized anti-CD52 IgG1 antibody (Leukosite); Smart M195 is a humanized anti-CD33 IgG antibody (Protein Design Lab/Kanebo); RITUXAN ^™ is a chimeric anti-CD20 IgG1 antibody (IDEC Pharm/Genentech, Roche/Zettyaku); LYMPHOCIDE ^™ is a humanized anti-CD22 IgG antibody (Immunomedics); LYMPHOCIDE ^™ Y-90 (Immunomedics); Lymphoscan (Tc-99m labeling; radiographic imaging; Immunomedics); Nuvion (targeting CD3; Protein Design Labs); CM3 is a humanized anti-ICAM3 antibody (ICOS). IDEC-114 is a primate-derived anti-CD80 antibody (IDEC Pharm/Mitsubishi); ZEVALIN ^™ is a radiolabeled mouse anti-CD20 antibody (IDEC/Schering AG); IDEC-131 is a humanized anti-CD40L antibody (IDEC/Eisai); IDEC-151 is a primate-derived anti-CD4 antibody (IDEC); IDEC-152 is a primate-derived anti-CD23 antibody (IDEC/Seikagaku); SMART anti-CD3 is a humanized anti-CD3 IgG (Protein Design Lab); 5G1.1 is a humanized anti-complement factor 5 (C5) antibody (AlexionPharm); D2E7 is a humanized anti-TNF-α antibody (CAT/BASF); CDP870 is a humanized anti-TNF-α antibody. Fab fragment (Celltech); IDEC-151 is a primate-modified anti-CD4 IgG1 antibody (IDEC Pharm/SmithKline Beecham); MDX-CD4 is a human anti-CD4 IgG antibody (Medarex/Eisai/Genmab); CD20-streptomycin protein (+Biotin-Yttrium 90; NeoRx); CDP571 is a human-modified anti-TNF-α IgG4 antibody (Celltech); LDP-02 is a human-modified anti-α4β7 antibody (LeukoSite/Genentech); OrthoClone OKT4A is a human-modified anti-CD4 IgG antibody (Ortho Biotech); ANTOVA™ is a human-modified anti-CD40L IgG antibody (Biogen); ANTEGREN ^™ is a human-modified anti-VLA-4 IgG antibody (Elan); CAT-152 is a human anti-TGF- _β2 antibody (Cambridge Ab Tech). Others are provided in later paragraphs.

Immunotherapy that can be used in combination with the compounds disclosed herein includes adjuvant immunotherapy. Examples include cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte-macrophage colony-stimulating factor (G-CSF), macrophage inflammatory protein (MIP)-1-α, interleukins (including IL-1, IL-2, IL-4, IL-6, IL-7, IL-12, IL-15, IL-18, IL-21, and IL-27), tumor necrosis factor (including TNF-α), and interferons (including IFN-α, IFN-β, and IFN-γ); aluminum hydroxide (alum); BCG; keyhole hemocyanin (KLH); Freund's incomplete adjuvant (IFA); QS-21; DETOX; levamisole; and dinitrophenyl (DNP), as well as combinations thereof, such as interleukins (e.g., IL-2) combined with other cytokines (such as IFN-α).

In various implementations, immunotherapies or immunotherapeutic agents may include one or more of the following: adoptive cell transfer, angiogenesis inhibitors, BCG therapy, biochemotherapy, cancer vaccines, chimeric antigen receptor (CAR) T-cell therapy, cytokine therapy, gene therapy, immune checkpoint modulators, immune conjugates, radioconjugates, oncolytic virus therapy, or targeted drug therapy. The function or at least one of the functions of immunotherapies or immunotherapeutic agents is collectively referred to herein as "immunotherapeutic agents".

This disclosure provides a method for preventing, treating, reducing, inhibiting, or controlling tumor formation, tumors, or cancer in a subject of need, the method comprising administering a therapeutically effective amount of a combination of a compound containing formula I' and an immunotherapeutic agent. In one non-limiting embodiment, the method comprises administering a therapeutically effective amount of a combination of a compound containing formula I' and an immunotherapeutic agent. In various embodiments, when treated with the combination, the combination provides a synergistic, additive, or additive effect in reducing the number of cancer cells compared to each treatment alone. In some embodiments, administration of a therapeutically effective amount of a combination of a compound containing formula I' and an immunotherapeutic agent produces synergistic antitumor activity and/or more potent antitumor activity than the additive effect of administering the compound of formula I' or the immunotherapeutic agent alone.

Human cancers exhibit numerous genetic and epigenetic alterations, generating neoantigens that can be recognized by the immune system (Sjoblom et al. (2006) Science 314:268-74). The adaptive immune system, composed of T and B lymphocytes, possesses potent anti-cancer potential, exhibiting a broad capacity and fine specificity to respond to a variety of tumor antigens. Furthermore, the immune system displays considerable plasticity and a memory component. Successfully utilizing all these properties of the adaptive immune system will make immunotherapy unique among all cancer treatment modalities.

This disclosure provides combinations of compounds of formula I' and immunotherapeutic agents. These exemplary combinations can be used to treat subjects with cancer. In various embodiments, immunotherapeutic agents found to be usable in the compositions, formulations, and methods of the present invention may include one or more agents or therapies, including: adoptive cell transfer, angiogenesis inhibitors, BCG therapy, biochemotherapy, cancer vaccines, chimeric antigen receptor (CAR) T-cell therapy, cytokine therapy, gene therapy, immune checkpoint modulators such as immune checkpoint inhibitors, immune conjugates, radioconjugates, oncolytic virus therapy, or targeted drug therapy.

In some embodiments of this disclosure, the therapeutically effective combination comprises a compound of formula I' and an immunotherapeutic agent. In various related embodiments, the compound of formula I' enhances the activity of the immunotherapeutic agent.

In certain embodiments of each of the foregoing aspects, as well as in other aspects and embodiments described elsewhere herein, the immunotherapeutic agent enhances the activity of compound I'.

In certain embodiments of each of the foregoing aspects, and in other aspects and embodiments described elsewhere herein, the compounds of formula I' and the immunotherapeutic agents act synergistically. In the various embodiments described herein, exemplary immunotherapeutic agents are immune cell (e.g., T cells, dendritic cells, natural killer cells, etc.) modulators selected from co-stimulatory molecules that act as agonists or activators, wherein the modulator is a monoclonal antibody, a bispecific antibody comprising one or more immune checkpoint antigen-binding moieties, a trispecific antibody, or an immune cell-binding multivalent antibody/fusion protein/construct known in the art. In some embodiments, the immunotherapeutic agent may be an antibody that modulates co-stimulatory molecules, binding to antigens on the surface of immune cells or cancer cells. In each of these different implementations, the antibody modulator can be a monoclonal antibody, a polyclonal antibody, a bispecific antibody, a trispecific or multispecific antibody, a fusion protein or a fragment thereof, such as a double-stranded antibody, a single-stranded (sc)-double-stranded antibody (scFv)2, a microantibody, a microbody, Barnase-barstar, scFv-Fc, sc(Fab)2, a trimer antibody construct, a triabody antibody construct, a trimer antibody construct, a tribody antibody construct, a collagen scaffold antibody construct, or a (scFv-TNFa)3 or F(ab)3/DNL antibody construct.

In certain embodiments of each of the foregoing aspects, and in other aspects and embodiments described elsewhere herein, the immunotherapeutic agent is an agent that modulates the immune response, such as a checkpoint inhibitor or checkpoint agonist. In some embodiments, the immunotherapeutic agent is an agent that enhances the antitumor immune response. In some embodiments, the immunotherapeutic agent is an agent that increases cell-mediated immunity. In some embodiments, the immunotherapeutic agent is an agent that increases T cell activity. In some embodiments, the immunotherapeutic agent is an agent that increases cytolytic T cell (CTL) activity. In some embodiments, the immunotherapeutic agent is an antibody modulator that targets PD-1, PD-L1, PD-L2, CEACAM (e.g., CEACAM-1, -3, and/or -5), CTLA-4, TIM-3, LAG-3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, TGFβ, OX40, 41BB, LIGHT, CD40, GITR, TGF-β, TIM-3, SIRP-α, VSIG8, BTLA, SIGLEC7, SIGLEC9, ICOS, B7H3, B7H4, FAS, and/or BTNL2, as well as other antibodies known in the art. In some embodiments, the immunotherapeutic agent is an agent that increases the activity of natural killer (NK) cells. In some embodiments, the immunotherapeutic agent is an agent that inhibits the suppression of the immune response. In some embodiments, the immunotherapeutic agent is an agent that inhibits the activity of suppressor cells or suppressor cell activity. In some embodiments, the immunotherapeutic agent is an agent or therapy that inhibits Treg activity. In some embodiments, the immunotherapeutic agent is an agent that inhibits the activity of inhibitory immune checkpoint receptors. In some embodiments, the combinations of this disclosure comprise a compound of formula I' and an immunotherapeutic agent, wherein the immunotherapeutic agent comprises a T-cell modulator selected from agonists or activators of co-stimulatory molecules. In one embodiment, the agonist of the co-stimulatory molecule is selected from GITR, OX40, ICOS, SLAM (e.g., SLAMF7), HVEM, LIGHT, CD2, CD27, CD28, CDS, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), 4-1BB (CD137), CD30, CD40, BAFFR, CD7, NKG2C, NKp80, CD160, B7-H3, or CD83 ligands (e.g., agonist antibodies or their antigen-binding fragments, or soluble fusions). In other embodiments, the effector cell combination includes a bispecific T cell adaptor (e.g., a bispecific antibody molecule that binds to CD3 and tumor antigens (e.g., EGFR, PSCA, PSMA, EpCAM, HER2, etc.)).

In some implementations, the immunotherapeutic agent is a modulator of PD-1 activity, PD-L1 activity, PD-L2 activity, CTLA-4 activity, CD28 activity, CD80 activity, CD86 activity, 4-1BB activity, OX40 activity, KIR activity, Tim-3 activity, LAG3 activity, CD27 activity, CD40 activity, GITR activity, TIGIT activity, or CD20 activity. Modulators of various activities, including CD96, IDO1, SIRP-α, TIGIT, VSIG8, BTLA, SIGLEC7, SIGLEC9, ICOS, B7H3, B7H4, FAS, BTNL2, cytokines, chemokines, interferons, interleukins, lymphokines, tumor necrosis factor (TNF) family members, and immunostimulatory oligonucleotides. In some embodiments, the immunotherapeutic agent is an immune checkpoint modulator (e.g., an immune checkpoint inhibitor, such as an inhibitor of PD-1 activity, a modulator of PD-L1 activity, a modulator of PD-L2 activity, a modulator of CTLA-4, or a CD40 agonist (e.g., an anti-CD40 antibody molecule), (xi)OX40 agonist (e.g., an anti-OX40 antibody molecule), or (xii)CD27 agonist (e.g., an anti-CD27 antibody molecule). In one embodiment, the immunomodulator is PD-1, PD-L1 Inhibitors of PD-L2, CTLA-4, TIM-3, LAG-3, CEACAM (e.g., CEACAM-1, -3, and/or -5), VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, and/or TGFβ. In one embodiment, the inhibitors of immune checkpoint molecules inhibit PD-1, PD-L1, LAG-3, TIM-3, CEACAM (e.g., CEACAM-1, -3, and/or -5), CTLA-4, or any combination thereof.

Inhibition of inhibitory molecules can occur at the DNA, RNA, or protein level. In some embodiments, inhibitory nucleic acids (e.g., dsRNA, siRNA, or shRNA) can be used to inhibit the expression of inhibitory molecules. In other embodiments, the inhibitor of the inhibitory signal is a peptide, such as a soluble ligand (e.g., PD-1-Ig or CTLA-4Ig); or an antibody or an antigen-binding fragment thereof, such as a monoclonal antibody, a bispecific antibody containing one or more immune checkpoint antigen-binding moieties, a trispecific antibody; or an immune cell-conjugating multivalent antibody/fusion protein/construct known in the art that binds to an inhibitory molecule; for example, an antibody or fragment thereof (also referred to herein as an "antibody molecule") that binds to PD-1, PD-L1, PD-L2, CEACAM (e.g., CEACAM-1, -3, and/or -5), CTLA-4, TIM-3, LAG-3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, TGFβ, or combinations thereof.

In some embodiments, the combination comprises a compound of formula I' and an immunotherapeutic agent, wherein the immunotherapeutic agent is a monoclonal antibody or a bispecific antibody. For example, the monoclonal or bispecific antibody may specifically bind to a member of the c-Met pathway and/or an immune checkpoint modulator (e.g., a bispecific antibody that binds both the hepatocyte growth factor receptor (HGFR) and the immune checkpoint modulator described herein, such as antibodies that bind to PD-1, PD-L1, PD-L2, or CTLA-4, LAG-3, OX40, 41BB, LIGHT, CD40, GITR, TGF-β, TIM-3, SIRP-α, TIGIT, VSIG8, BTLA, SIGLEC7, SIGLEC9, ICOS, B7H3, B7H4, FAS, BTNL2, or CD27). In a specific embodiment, the bispecific antibody specifically binds to the human HGFR protein and one of PD-1, PD-L1, and CTLA-4.

In some embodiments, the immunotherapeutic agent is a cytokine, such as a chemokine, interferon, interleukin, lymphokine, or a member of the tumor necrosis factor family. In some embodiments, the cytokine is IL-2, IL-15, or interferon-γ.

In some embodiments of any of the foregoing aspects or those described elsewhere herein, the cancer is selected from lung cancer, pancreatic cancer, breast cancer, colon cancer, colorectal cancer, melanoma, gastrointestinal cancer, stomach cancer, kidney cancer, ovarian cancer, liver cancer, endometrial cancer, kidney cancer, prostate cancer, thyroid cancer, neuroblastoma, glioma, glioblastoma multiforme, cervical cancer, stomach cancer, bladder cancer, head and neck cancer, and liver cancer.

In some implementations of any of the foregoing aspects or those described elsewhere herein, the subject's cancer or tumor does not respond to immune checkpoint inhibition (e.g., to any immune checkpoint inhibitor described herein, such as a PD-1 antagonist or a PD-L1 antagonist), or the subject's cancer or tumor has progressed after an initial response to immune checkpoint inhibition (e.g., to any immune checkpoint inhibitor described herein, such as a PD-1 antagonist or a PD-L1 antagonist).

In some implementations of any of the foregoing aspects or those described elsewhere herein, the subject is a human being.

Checkpoint inhibitors can be any molecule, agent, treatment, and/or method that has the following effects: inhibiting immune checkpoints, and/or promoting immune checkpoint inhibitors, for example, by promoting intrinsic immune checkpoint inhibitors; inhibiting transcription factors involved in immune checkpoint expression; and/or by acting in synergy with some additional extrinsic factors. For example, checkpoint inhibitors may include treatments that inhibit transcription factors involved in the expression of immune checkpoint genes or promote the expression of transcription factors of tumor suppressor genes such as BACH2 (Luan et al., (2016). Transcription Factors and Checkpoint Inhibitor Expression with Age: Markers of Immunosenescence. Blood, 128(22), 5983). In addition, checkpoint inhibitors can inhibit: transcription of immune checkpoint genes; modification and/or processing of immune checkpoint mRNAs; translation of immune checkpoint proteins; and/or activation of molecules involved in the immune or immune checkpoint pathways, such as PD-1 transcription factors like HIF-1, STAT3, NF-κB, and AP-1, or common oncogenic pathways such as JAK/STAT, RAS/ERK, or PI3K/AKT/mTOR (Zerdes et al., Genetic, transcriptional and post-translational regulation of the programmed death protein ligand 1 in cancer: biology and clinical correlations, Oncogene, Vol. 37, pp. 4639-4661 (2018), the full text of which is incorporated herein by reference).

Checkpoint inhibitors can include therapies, molecules, agents, and/or methods that regulate immune checkpoints at the transcriptional level, such as using co-inhibition of RNA interference pathways and/or post-transcriptional gene silencing (PTGS) (e.g., microRNAs, miRNAs; silenced RNAs, small interfering RNAs, or short interfering RNAs (siRNAs)). Transcriptional regulation of checkpoint molecules has been shown to involve mir-16, which has been shown to target the 3'UTR of checkpoint mRNAs CD80, CD274 (PD-L1), and CD40 (Leibowitz et al., Post-transcriptional regulation of immune checkpoints). oint genes by mir-16 in melanoma, Annals of Oncology (2017) 28; v428-v448). Mir-33a has also been shown to be involved in regulating PD-1 expression in lung adenocarcinoma cases (Boldini et al., Role of microRNA-33a in regulating the expression of PD-1 in lung adenocarcinoma, Cancer Cell Int. 2017; 17:105, the full text of which is cited in this article).

T-cell specific aptamer-siRNA chimeras have been proposed as a highly specific method for inhibiting molecules in the immune checkpoint pathway (Hossain et al., The aptamer–siRNA conjugates: reprogramming T cells for cancer therapy, Ther. Deliv., January 2015; 6(1):1–4, the full text of which is cited in this paper).

Alternatively, treatments affecting related pathways (e.g., metabolism) can be used to suppress members of the immune checkpoint pathway. For example, CAD macrophages oversupply pyruvate, a glycolytic intermediate, in mitochondria, promoting PD-L1 expression via the induction of the bone morphogenetic protein 4/phosphorylated SMAD1/5/IFN regulator 1 (BMP4/p-SMAD1/5/IRF1) signaling pathway. Thus, implementing treatments that regulate metabolic pathways can lead to subsequent regulation of the immunosuppressive PD-1/PD-L1 checkpoint pathway (Watanabe et al., Pyruvate controls the checkpoint inhibitor PD-L1 and suppresses T cell immunity, J Clin Invest., 30 June 2017; 127(7):2725–2738).

Checkpoint immunity can be regulated by oncolytic viruses that selectively replicate within tumor cells and induce an acute immune response in the tumor microenvironment. This is achieved by acting as genetic vectors carrying agents specific to cancer cells (e.g., antibodies, miRNAs, siRNAs, etc.) and influencing their oncolytic activity, as well as the secretion of cytokines and chemokines, in synergistic effects with immune checkpoint inhibition (Shi et al., Cancer Immunotherapy: A Focus on the Regulation of Immune Checkpoints, Int J Mol Sci., May 2018; 19(5):1389). Currently, ongoing clinical trials utilize the following viruses as checkpoint inhibitors: poliovirus, measles virus, adenovirus, poxvirus, herpes simplex virus (HSV), Coxsackievirus, reovirus, Newcastle disease virus (NDV), T-VEC (herpesvirus encoded by GM-CSF (granulocyte-macrophage colony-stimulating factor)) and H101 (Shi et al., ibid.).

Checkpoint inhibitors can act at the translational level of checkpoint immunity. Translation from mRNA to protein represents a key event in gene expression regulation; therefore, inhibiting immune checkpoint translation is a method to suppress the immune checkpoint pathway.

Inhibition of the immune checkpoint pathway can occur at any stage of the immune checkpoint translation process. For example, drugs, molecules, agents, treatments, and/or methods can inhibit the initiation process (whereby the 40S ribosomal subunit is recruited to the 5' end of the mRNA and scans the 5'UTR of the mRNA toward its 3' end). Inhibition can occur by targeting the anticodon of the initiator methionyl transfer RNA (tRNA) (Met-tRNAi, which pairs with the start codon) or by recruiting the 60S subunit to begin elongation and sequentially adding amino acids in the translation of immune checkpoint-specific genes. Alternatively, checkpoint inhibitors can inhibit checkpoints at the translational level by preventing the formation of the ternary complex (TC), namely eukaryotic initiation factor (eIF)2 (or one or more of its α, β, and γ subunits), GTP, and Met-tRNAi.

Checkpoint inhibition can occur through the destabilizing effect of eIF2α, i.e., by preventing its phosphorylation via protein kinase R (PKR), PERK, GCN2, or HRI, or by preventing TC from binding to the 40S ribosome and/or other initiation factors, thereby preventing the formation of the pre-initiation complex (PIC); and by inhibiting the eIF4F complex and/or its cap-binding protein eIF4E, scaffold protein eIF4G, or eIF4A helicase. Methods for translational control in cancer are discussed in Truitt et al., New frontiers intranslational control of the cancer genome, Nat Rev Cancer., April 26, 2016; 16(5):288–304, the full text of which is incorporated herein by reference.

Checkpoint inhibitors may also include, for example, therapies, molecules, agents, and/or methods that modulate immune checkpoints at the cellular and/or protein level by inhibiting immune checkpoint receptors. Inhibition of checkpoints can occur through the use of antibodies, antibody fragments, antigen-binding fragments, small molecules, and/or other drugs, agents, therapies, and/or methods.

Immune checkpoints are inhibitory pathways within the immune system responsible for maintaining self-tolerance and modulating the immune response to minimize damage to peripheral tissues. However, tumor cells can also activate immune system checkpoints, reducing the effectiveness of the immune response against tumor tissue (“blocking” the immune response). Unlike most anticancer agents, checkpoint inhibitors do not directly target tumor cells but rather lymphocyte receptors or their ligands to enhance the endogenous antitumor activity of the immune system (Pardoll, 2012, Nature Reviews Cancer 12:252-264).

Until recently, cancer immunotherapy has largely focused on enhancing antitumor immune responses through adoptive transfer of activated effector cells, immunization against relevant antigens, or the delivery of nonspecific immunostimulants such as cytokines. However, in the past decade, significant efforts to develop specific immune checkpoint pathway inhibitors have begun to offer novel immunotherapies for cancer treatment, including the development of the antibody (Ab) ipilimumab (YERVOY.RTM.) which binds to and inhibits CTLA-4 for the treatment of patients with advanced melanoma (Hodi et al., (2010) N Engl J Med 363:711-23) and antibodies that specifically bind to the programmed death-1 (PD-1) receptor and block the inhibitory PD-1/PD-1 ligand pathway, such as nivolumab and pembrolizumab (formerly known as lambolizumab; USAN Council Statement (2013) Pembrolizumab: Statement on a nonproprietary name adopted). Developed by the USAN Council (ZZ-165), November 27, 2013 (Topalian et al. (2012a) N Engl J Med 366:2443-54; Topalian et al. (2012b) Curr Opin Immunol 24:207-12; Topalian et al. (2014) J Clin Oncol 32(10):1020-30; Hamid et al. (2013) N Engl J Med 369:134-144; Hamid and Carvajal (2013) Expert Opin Biol Ther 13(6):847-61; McDermott and Atkins (2013) Cancer Med 2(5):662-73).

PD-1 is a key immune checkpoint receptor expressed by activated T and B cells and mediates immunosuppression. Nivolumab (formerly known as 5C4, BMS-936558, MDX-1106, or ONO-4538) is a fully human IgG4 (S228P) PD-1 immune checkpoint inhibitor antibody that selectively prevents interaction with PD-1 ligands (PD-L1 and PD-L2), thereby blocking the downregulation of anti-tumor T cell function (US Patent No. 8,008,449; Wang et al. (2014) In vitro characterization of the anti-PD-1 antibody nivolumab, BMS-936558, and in vivo toxicology in non-human primates). Nivolumab has been approved for the treatment of patients with unresectable or metastatic melanoma who have progressed after ipilimumab treatment, and if BRAF V600 mutation is positive, BRAF inhibitors used to treat squamous non-small cell lung cancer are used.

Recent data suggest a secondary mechanism of anti-CTLA-4 antibodies that may occur within the tumor itself. CTLA-4 has been found to be expressed at higher levels on regulatory T cells (also referred to herein as "Treg cells") in tumors compared to effector T cells (also referred to herein as "Teff cells"), leading to the hypothesis that anti-CTLA-4 preferentially affects Treg cells. (See "Therapeutic use of anti-CTLA-4 antibodies," Christian U. Blank and Alexander Enk, International Immunology, Vol. 27, No. 1, pp. 3-10). Recent studies of the combination of PD-1 and CTLA-4 have shown that combined blocking of the CTLA-4 and PD-1 pathways also synergistically increases the ratio of Teff cells to regulatory T cells and MDSCs, thereby reducing suppression and promoting inflammation in the tumor microenvironment. "Combination of CTLA-4 and PD-1 blockade expands infiltrating T-cells and reduces regulatory T and myeloid cells within B16 melanoma tumors," Curran et al., PNAS | March 2, 2010; Vol. 107 (No. 9); pp. 4275-4280, the full text of which is incorporated herein by reference. Combinations of checkpoint inhibitors and other therapeutic agents can enhance or prolong the antitumor response of checkpoint inhibitors and/or the effects of therapeutic agents. In this regard, WO 2015/069770 discloses combination therapies based on activating adaptive immune responses for the treatment of cancer, particularly combinations of CTLA-4 and PD-1 inhibitors. The full text of the disclosure of WO 2015/069770 is incorporated herein by reference.

One mechanism by which checkpoint blocking anti-CTLA-4 antibodies mediate antitumor effects is through the reduction of regulatory T cells. Due to the unique mechanism of action of anti-CTLA-4 antibodies, they can be successfully combined with anti-PD1 checkpoint blocking antibodies to exert their effects by releasing inhibitory signaling conferred on effector T cells. The dual blocking combination of these antibodies has been shown to improve antitumor responses in preclinical (ProcNatl Acad Sci USA 2010, 107, 4275-4280) and clinical (N Engl J Med 2013, 369, 122-133; N Engl J Med 2015, 372, 2006-2017).

CTLA-4 attenuates early activation of naive and memory T cells through interactions with its ligands B7-1 (CD80) and B7-2 (CD86). PD-1 is a receptor expressed on the surface of activated mature T cells, activated NK cells, B cells, monocytes, and various normal tissues, and plays a key role in maintaining peripheral tolerance [20-21]. In contrast to CTLA-4, PD-1 functions through its interaction with its ligand PD-L1 (also known as B7-H1 or CD274) and is primarily involved in regulating T cell activity in peripheral tissues and providing key immune resistance mechanisms within the tumor microenvironment.

In some implementations, the immunotherapeutic agent is a modulator of PD-1 activity, a modulator of PD-L1 activity, a modulator of PD-L2 activity, a modulator of CTLA-4 activity, a modulator of CD28 activity, a modulator of CD80 activity, a modulator of CD86 activity, a modulator of 4-1BB activity, a modulator of OX40 activity, a modulator of KIR activity, a modulator of Tim-3 activity, a modulator of LAG3 activity, a modulator of CD27 activity, a modulator of CD40 activity, a modulator of GITR activity, a modulator of TIGIT activity, a modulator of CD20 activity, a modulator of CD96 activity, a modulator of IDO1 activity, a cytokine, a chemokine, an interferon, an interleukin, a lymphokine, a member of the tumor necrosis factor (TNF) family, or an immunostimulatory oligonucleotide. In some implementations, the immune checkpoint modulator is, for example, an inhibitor or antagonist, or an activator or agonist, such as a CD28 modulator, a 4-1BB modulator, an OX40 modulator, a CD27 modulator, a CD80 modulator, a CD86 modulator, a CD40 modulator, or a GITR modulator, a Lag-3 modulator, a 41BB modulator, a LIGHT modulator, a CD40 modulator, a GITR modulator, a TGF-β modulator, a TIM-3 modulator, a SIRP-α modulator, a TIGIT modulator, a VSIG8 modulator, a BTLA modulator, a SIGLEC7 modulator, a SIGLEC9 modulator, an ICOS modulator, a B7H3 modulator, a B7H4 modulator, a FAS modulator, and/or a BTNL2 modulator. In some embodiments, the immunotherapeutic agent is an immune checkpoint modulator as described above (e.g., an immune checkpoint modulator antibody, which may be a monoclonal antibody, a bispecific antibody containing one or more immune checkpoint antigen-binding moieties, a trispecific antibody, or in the form of an immune cell-conjugating multivalent antibody/fusion protein/construct known in the art).

Combination therapy with immune checkpoint inhibitor immunotherapies can include antibodies that specifically target immune system checkpoints such as CTLA4, PD1, and PD-L1, representing one of the most promising new avenues for immunotherapy in cancer and other diseases. Additional checkpoint targets such as TIM-3, LAG-3, various B-7 ligands, CHK1 and CHK2 kinases, BTLA, and A2aR are also under investigation. Currently, three checkpoint inhibitors have received fast-track approval from the U.S. Food and Drug Administration for cancer treatment: ipilimumab, a CTLA-4 inhibitor, and pembrolizumab and nivolumab, both PD-1 inhibitors. Several other checkpoint inhibitors are also in clinical trials.

Programmed cell death protein 1 (PD-1 or CD279), a 55-kD type I transmembrane protein, is a member of the CD28 family of T cell costimulatory receptors, which includes immunoglobulin superfamily members CD28, CTLA-4, inducible costimulatory factor (ICOS), and BTLA. PD-1 is highly expressed on activated T cells and B cells. PD-1 expression can also be detected on memory T cell subsets with variable expression levels. Two PD-1-specific ligands have been identified: programmed death ligand 1 (PD-L1, also known as B7-H1 or CD274) and PD-L2 (also known as B7-DC or CD273). In both mouse and human systems, PD-L1 and PD-L2 show downregulation of T cell activation upon binding to PD-1 (Okazaki et al., Int Immunol., 2007; 19:813-824). The interaction between PD-1 and its ligands PD-L1 and PD-L2 (expressed on antigen-presenting cells (APCs) and dendritic cells (DCs) transmits negative regulatory stimuli, downregulating the activated T cell immune response. Blocking PD-1 inhibits this negative signaling and amplifies the T cell response.

Numerous studies have shown that the cancer microenvironment manipulates the PD-L1-/PD-1 signaling pathway, and the induction of PD-L1 expression is associated with the suppression of the immune response against cancer, thereby enabling cancer progression and metastasis. The PD-L1/PD-1 signaling pathway is a major mechanism for cancer immune escape for several reasons. First, and most importantly, this pathway is involved in the negative regulation of the immune response of activated T effector cells found in the periphery. Second, PD-L1 is upregulated in the cancer microenvironment, while PD-1 is also upregulated on activated tumor-infiltrating T cells, potentially enhancing the vicious cycle of suppression. Third, this pathway is complexly involved in the regulation of both innate and adaptive immunity through bidirectional signaling. These factors make the PD-1/PD-L1 complex a central point through which cancer can manipulate the immune response and promote its own progression.

CTLA-4 (also known as cytotoxic T-lymphocyte-associated protein 4, CTLA4, CTLA-4, CD152, differentiation cluster 152; ALPS5, CD, CELIAC3, GRD4, GSE, and IDDM12) is a 24.6-kDa single-pass type I membrane protein that plays an inhibitory role in T cell function. CTLA-4 was initially identified by differential screening of a mouse cytotoxic T cell cDNA library; see Brunet et al., A new member of the immunoglobulin superfamily--CTLA-4, Nature., July 16-22, 1987; 328(6127):267-70. CTLA-4 has been shown to interact with b7 family ligands CD80 (also known as differentiation cluster 80 and B7-1) and CD86 (also known as differentiation cluster 86 or B7-2). See Linsley et al., CTLA-4 is a second receptor for the B cell activation antigen B7, J Exp Med., 1 Sep 1991; 174(3):561-9. Sequence comparison between the human CTLA-4 DNA coding region and the CD28 DNA coding region revealed significant homology between the two sequences, with the greatest similarity between the juxtamembranous and cytoplasmic regions; therefore, CTLA-4 is associated with the elimination/reduction of T cell activity and antagonism of CD28 activity. Mice lacking CTLA-4 have been shown to exhibit extensive lymphoproliferation. Chambers et al., Lymphoproliferation in CTLA-4-deficient mice is mediated by costimulation-dependent activation of CD4+ T cells, Immunity., Dec 1997; 7(6):885-95. It has been reported that CTLA-4 blockade enhances T cell responses, induces autoimmune diseases, and exacerbates antitumor immunity both in vitro and in vivo. (See Luhder, J. Exp. Med. 1998; 187:427-432; Walunas et al., Immunity. 1994; 1:405-413; Kearney, J. Immunol. 1995; 155:1032-1036; Leach, Science 1996; 271:1734-1736). CTLA-4 has also been reported to have alternative and/or additional effects on the initial characteristics of T-cell immune responses (Chambers, Curr. Opin. Immunol. 1997; 9:396-404; Bluestone, J. Immunol. 1997; 158:1989-1993; Thompson, Immunity 1997; 7:445-450).

The first immune checkpoint inhibitor to be tested in clinical trials is Yervoy (Bristol-Myers Squibb), a CTLA-4 mAb. CTLA-4 belongs to the receptor immunoglobulin superfamily, which also includes PD-1, BTLA, TIM-3, and T cell activation V-domain immunoglobulin inhibitor (VISTA). Anti-CTLA-4 mAbs are potent checkpoint inhibitors that remove “breakdowns” from naïve cells and antigen-treated cells. The therapy enhances the anti-tumor function of CD8+ T cells, increases the ratio of CD8+ T cells to Foxp3+ T regulatory cells, and inhibits the suppressive function of T regulatory cells. The main drawback of anti-CTLA-4 mAb therapy is autoimmune toxicity due to the on-target effects of an overactive immune system that has lost its self-regulation. It has been reported that up to 25% of patients treated with ipilimumab experienced serious grade 3-4 adverse events/autoimmune side effects, including dermatitis, enterocolitis, hepatitis, endocrine disorders (including hypophysitis, thyroiditis, and adrenalitis), arthritis, uveitis, nephritis, and aseptic meningitis. In contrast to the experience with anti-CTLA-4 therapy, anti-PD-1 therapy appears to be better tolerable and induces a relatively low rate of autoimmune side effects.

In some embodiments, the immunotherapy agent is an agent that inhibits PD-1 activity. In some embodiments, the immunotherapy agent is an agent that inhibits PD-L1 and/or PD-L2 activity. In some embodiments, the immunotherapy agent is an agent that inhibits CTLA-4 activity. In some embodiments, the immunotherapy agent is an agent that inhibits CD80 and/or CD86 activity. In some embodiments, the immunotherapy agent is an agent that inhibits TIGIT activity. In some embodiments, the immunotherapy agent is an agent that inhibits KIR activity. In some embodiments, the immunotherapy agent is an agent that enhances or stimulates the activity of activated immune checkpoint receptors.

In some embodiments of the methods described herein, the immunotherapeutic agent is a PD-1 antagonist, PD-L1 antagonist, PD-L2 antagonist, CTLA-4 antagonist, CD80 antagonist, CD86 antagonist, KIR antagonist, Tim-3 antagonist, LAG3 antagonist, TIGIT antagonist, CD20 antagonist, CD96 antagonist, or IDO1 antagonist.

In some implementations, the PD-1 antagonist is an antibody that specifically binds to PD-1. In some implementations, the PD-1-binding antibody is pembrolizumab (MK-3475; Merck), pidilizumab (CT-011; Curetech Ltd.), nivolumab (BMS-936558, MDX-1106; Bristol Myer Squibb), MEDI0680 (AMP-514; AstraZenenca/MedImmune), REGN2810 (Regeneron Pharmaceuticals), BGB-A317 (BeiGene Ltd.), PDR-001 (Novartis), or STI-A1110 (Sorrento Therapeutics). In some embodiments, antibodies binding to PD-1 are described in PCT Publication WO2014/179664, for example, antibodies identified as APE2058, APE1922, APE1923, APE1924, APE 1950, or APE1963 (Anaptysbio), or antibodies containing the CDR region of any of these antibodies. In other embodiments, the PD-1 antagonist is a fusion protein including the extracellular domain of PD-L1 or PD-L2, such as AMP-224 (AstraZeneca/MedImmune). In other embodiments, the PD-1 antagonist is a peptide inhibitor, such as AUNP-12 (Aurigene).

In some embodiments, the PD-L1 antagonist is an antibody that specifically binds to PD-L1. In some embodiments, the antibody binding to PD-L1 is atezolizumab (RG7446, MPDL3280A; Genentech), MEDI4736 (AstraZeneca/MedImmune), BMS-936559 (MDX-1105; Bristol Myers Squibb), avelumab (MSB0010718C; Merck KGaA), KD033 (Kadmon), an antibody fraction of KD033, or STI-A1014 (Sorrento Therapeutics). In some implementations, antibodies binding to PD-L1 are described in PCT Publication WO 2014/055897, such as Ab-14, Ab-16, Ab-30, Ab-31, Ab-42, Ab-50, Ab-52, Ab-55, or antibodies containing the CDR region of any of these antibodies, the entire contents of which are incorporated herein by reference.

In some embodiments, the CTLA-4 antagonist is an antibody that specifically binds to CTLA-4. In some embodiments, the antibody binding to CTLA-4 is ipilimumab (Bristol Myer Squibb) or tremelimumab (CP-675,206; Pfizer). In some embodiments, the CTLA-4 antagonist is a CTLA-4 fusion protein or a soluble CTLA-4 receptor, such as KARR-102 (Kahr Medical Ltd.).

In some embodiments, the LAG3 antagonist is an antibody that specifically binds to LAG3. In some embodiments, the LAG3-binding antibody is IMP701 (Prima BioMed), IMP731 (Prima BioMed/GlaxoSmithKline), BMS-986016 (Bristol Myer Squibb), LAG525 (Novartis), and GSK2831781 (GlaxoSmithKline). In some embodiments, the LAG3 antagonist comprises a soluble LAG3 receptor, such as IMP321 (Prima BioMed).

In some embodiments, the KIR antagonist is an antibody that specifically binds to a KIR. In some embodiments, the KIR-binding antibody is lirilumab (Bristol Myer Squibb/Innate Pharma).

In some embodiments, the immunotherapeutic agents used in the combinations disclosed herein (e.g., combinations with compounds of formula I') are activators or agonists of co-stimulatory molecules. In one embodiment, the agonist of the co-stimulatory molecule is selected from agonists of OX40, CD2, CD27, CD28, CDS, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3, or CD83 ligands (e.g., agonist antibodies or their antigen-binding fragments, or soluble fusions).

In some embodiments, the OX40 agonist comprises an OX40 ligand or its OX40-binding moiety. For example, the OX40 agonist may be MEDI6383 (AstraZeneca). In some embodiments, the OX40 agonist is an antibody that specifically binds to OX40. In some embodiments, the antibody binding to OX40 is MEDI6469 (AstraZeneca/MedImmune), MEDI0562 (AstraZeneca/MedImmune), or MOXR0916 (RG7888; Genentech). In some embodiments, the OX40 agonist is a vector capable of expressing the OX40 ligand (e.g., an expression vector or a virus, such as adenovirus). In some embodiments, the vector expressing OX40 is Delta-24-RGDOX (DNAtrix) or DNX2401 (DNAtrix).

In some embodiments, the 4-1BB (CD137) agonist is a binding molecule, such as an anticalin. In some embodiments, the anti-carrier protein is PRS-343 (Pieris AG). In some embodiments, the 4-1BB agonist is an antibody that specifically binds to 4-1BB. In some embodiments, the antibody that binds to 4-1BB is PF-2566 (PF-05082566; Pfizer) or urelumab (BMS-663513; Bristol Myer Squibb).

In some embodiments, the CD27 agonist is an antibody that specifically binds to CD27. In some embodiments, the antibody that binds to CD27 is varlilumab (CDX-1127; Celldex).

In some embodiments, the GITR agonist comprises a GITR ligand or its GITR-binding moiety. In some embodiments, the GITR agonist is an antibody that specifically binds to GITR. In some embodiments, the antibody that binds to GITR is TRX518 (GITR, Inc.), MK-4166 (Merck), or INBRX-110 (Five Prime Therapeutics/Inhibrx).

TIM-3 has been identified as another important inhibitory receptor expressed by exhausted CD8+ T cells. In mouse models of cancer, it has been shown that the most dysfunctional tumor-infiltrating CD8+ T cells actually co-express PD-1 and TIM-3.

LAG-3 is another recently identified inhibitory receptor that limits effector T cell function and increases the inhibitory activity of regulatory T cells. It has recently been revealed that PD-1 and LAG-3 are widely co-expressed by tumor-infiltrating T cells in mice, and that combined blockade of PD-1 and LAG-3 elicits a potent synergistic antitumor immune response in a mouse cancer model.

PD-1 pathway blockade can be combined with vaccines or other I’ antibody compounds to enhance therapeutic efficacy (Hirano, F. et al., Cancer Res., 65(3):1089-1096 (2005); Li, B. et al., Clin. Cancer Res., 15:1507-1509 (2009); and Curran, M.A. et al., Proc. Natl. Acad. Set, 107(9):4275-4280 (2010)).

In some embodiments, the immunotherapeutic agent used in the compositions and methods described herein may include a monoclonal antibody, a bispecific antibody comprising one or more immune checkpoint antigen-binding moieties, a trispecific antibody, or an immune cell-conjugating multivalent antibody/fusion protein/construct known in the art that specifically targets both PD-1 and its ligand PD-L1.

PD-1 (also known as programmed death 1, CD279, or PDCD1) is a cell surface receptor that plays a crucial role in regulating the balance between stimulatory and inhibitory signals in the immune system and maintaining peripheral tolerance (Ishida, Y et al., 1992 EMBO J.11 3887; Kier, Mary E et al., 2008 Annu Rev Immunol 26 677-704; Okazaki, Taku et al., 2007 International Immunology 19 813-824). PD-1 is an inhibitory member of the immunoglobulin superfamily, homologous to CD28. PD-1 is a monomeric type 1 transmembrane protein consisting of an immunoglobulin-variable extracellular domain and cytoplasmic domains containing an immunoreceptor tyrosine-based inhibitory motif (ITIM) and an immunoreceptor tyrosine-based switch motif (ITSM). PD-1 expression is inducible on T cells, B cells, natural killer (NK) cells, and monocytes, for example, after activation of lymphocytes via T cell receptor (TCR) or B cell receptor (BCR) signaling (Kier, Mary E et al., 2008 Annu Rev Immunol 26 677-704; Agata, Y et al., 1996 Int Immunol 8 765-72). PD-1 is the receptor for ligands CD80, CD86, PD-L1 (B7-H1, CD274), and PD-L2 (B7-DC, CD273), which are cell surface expression members of the B7 family (Freeman, Gordon et al., 2000 J Exp Med 1921027; Latchman, Y et al., 2001 Nat Immunol 2 261). Upon ligand binding, PD-1 recruits phosphatases such as SHP-1 and SHP-2 to their intracellular tyrosine motifs, subsequently dephosphorylating effector molecules activated by TCR or BCR signaling (Chemnitz, J et al., 2004 J Immunol 173 945-954; Riley, James L 2009 Immunological Reviews 229 114-125). Thus, PD-1 transduces inhibitory signals to T cells and B cells only when simultaneously bound to TCR or BCR.

PD-1 has been shown to downregulate effector T cell responses through both intrinsic and extracellular functional mechanisms. Inhibitory signaling by PD-1 induces a non-responsive state in T cells, resulting in clonal expansion or failure to produce optimal levels of effector cytokines. PD-1 can also induce T cell apoptosis through its ability to inhibit survival signals from co-stimuli, leading to decreased expression of key anti-apoptotic molecules such as Bcl-XL (Kier, Mary E et al., 2008 Annu Rev Immunol 26 677-704). In addition to these direct effects, recent publications have suggested that PD-1 participates in effector cell suppression by promoting the induction and maintenance of regulatory T cells (TREGs). For example, PD-L1 expressed on dendritic cells has been shown to synergize with TGF-β to promote the induction of CD4+FoxP3+ TREGs with enhanced inhibitory function (Francisco, Loise M et al., 2009 J Exp Med 206 3015-3029).

TIM-3 (also known as T cell immunoglobulin and mucin-containing domain-3, TIM-3, hepatitis A virus cell receptor 2, HAVCR2, HAVcr-2, KIM-3, TIMD-3, TIMD3, Tim-3 and CD366) is a 33.4-kDa single-pass type I membrane protein involved in the immune response (Sanchez-Fueyo et al., Tim-3 inhibits T helper type 1-mediated auto- and alloimmune responses and promotes immune tolerance, Nat. Immunol. 4:1093-1101 (2003)).

TIM-3 is selectively expressed on Th1 cells and phagocytes (e.g., macrophages and dendritic cells). Lowering human expression using siRNA or blocking antibodies leads to increased secretion of interferon-γ (IFN-γ) from CD4-positive T cells, suggesting an inhibitory role of TIM-3 in human T cells. Analysis of clinical samples from patients with autoimmune diseases showed no TIM-3 expression in CD4-positive cells. In particular, T-cell clones derived from the cerebrospinal fluid of multiple sclerosis patients showed lower levels of TIM-3 expression and higher levels of IFN-γ secretion compared to clones derived from healthy individuals (Koguchi K et al., JExp Med. 203:1413-8. (2006)).

TIM-3 is the receptor for galactoglobulin-9, a ligand of a member of the galactoglobulin family, which is a molecule universally expressed in multiple cell types and binds to the following molecules: β-galactoside; phosphatidylserine (PtdSer) (DeKryff et al., T cell/transmembrane, Ig, and mucin-3 allelelic variants differentially recognize phosphatidylserine and immediate phagocytosis of apoptotic cells, J Immunol., 15 Feb 2010; 184(4):1918-30); high-mobility group box 1 (also known as HMGB1, HMG1, HMG3, SBP-1, HMG-1 and high-mobility group box 1) (Chiba et al., Tumor-i Filtrating DCs suppresses nucleic acid-mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1, Nat Immunol., Sep 2012; 13(9):832-42); and carcinoembryonic antigen-associated cell adhesion molecule 1 (also known as CEACAM1, BGP, BGP1, BGPI, carcinoembryonic antigen-associated cell adhesion molecule 1) (Huang et al., CEACAM1 regulates TIM-3-mediated tolerance and exhaustion, Nature., Jan 15 2015; 517(7534):386-90).

BTLA (also known as B- and T-lymphocyte attenuators, BTLA1, CD272, and B- and T-lymphocyte-associated) is a 27.3-kDa single-pass type I membrane protein involved in lymphocyte suppression during the immune response. BTLA is constitutively expressed in both B cells and T cells. BTLA interacts with HVEM (herpesvirus entry mediator), a member of the tumor necrosis factor receptor (TNFR) family (Gonzalez et al., Proc. Natl. Acad. Sci. USA, 2005, 102:1116-21). The interaction between BTLA (belonging to the CD28 family of immunoglobulins) and HVEM (co-stimulatory tumor necrosis factor (TNF) receptor (TNFR)) is unique because it defines crosstalk between these two receptor families. BTLA contains an inhibitory motif (ITIM) based on the tyrosine residues of proximal immunoreceptors and a switch motif (ITSM) based on the tyrosine residues of distal immunoreceptors. Disruption of ITIM or ITSM abolishes BTLA's ability to recruit SHP1 or SHP2, indicating that BTLA recruits SHP1 and SHP2 in a different manner than PD-1 and requires two tyrosine motifs to block T cell activation. The BTLA cytoplasmic tail also contains a third conserved tyrosine motif within its cytoplasmic domain, with a sequence similar to the Grb-2 recruitment site (YXN). Furthermore, phosphorylated peptides containing this BTLA N-terminal tyrosine motif can interact with the p85 subunit of GRB2 and PI3K in vitro, although the functional effects of this interaction in vivo have not been explored (Gavrieli et al., Bioochem. Biophysi Res Commun, 2003, 312, 1236-43). BTLA is a receptor for ligands PTPN6/SHP-1, PTPN11/SHP-2, TNFRSF14/HVEM, and B7H4.

VISTA (also known as the V-domain Ig repressor of T-cell activation VSIR, B7-H5, B7H5, GI24, PP2135, SISP1, DD1α, VISTA, C10orf54, chromosome 10 open reading frame 54, PD-1H, and V-set immunomodulatory receptor) is a 33.9-kDa single-pass type I membrane protein involved in T-cell inhibitory responses, embryonic stem cell differentiation inhibited via BMP4 signaling, and MMP14-mediated MMP2 activation (Yoon et al., Control of signaling-mediated clearance of apoptotic cells by the tumor suppressor p53, Science., July 31, 2015; 349(6247):1261669). VISTA interacts with its ligand VSIG-3 (Wang et al., VSIG-3 as a ligand of VISTA inhibits human T-cell function, Immunology., January 2019; 156(1):74-85)

LAG-3 (also known as lymphocyte activation gene 3, LAG3, CD223, and lymphocyte activation 3) is a 57.4-kDa single-pass type I membrane protein involved in lymphocyte activation and binding to HLA class II antigens. LAG-3 is a member of the immunoglobulin superfamily and is expressed on activated T cells (Huard et al., 1994, Immunogenetics 39:213), NK cells (Triebel et al., 1990, J. Exp. Med. 171:1393-1405), regulatory T cells (Huang et al., 2004, Immunity 21:503-513; Camisaschi et al., 2010, J Immunol. 184:6545-6551; Gagliani et al., 2013, Nat Med 19:739-746), and plasmacytoid dendritic cells (DCs) (Workman et al., 2009, J Immunol 182:1885-1891). LAG-3 is a membrane protein encoded by a gene located on chromosome 12 and is structurally and genetically associated with CD4. Similar to CD4, LAG-3 can interact with MHC class II molecules on the cell surface (Baixeras et al., 1992, J. Exp. Med. 176:327-337; Huad et al., 1996, Eur. J. Immunol. 26:1180-1186). Direct binding of LAG-3 to MHC class II molecules has been shown to play a role in downregulating antigen-dependent stimulation of CD4+ T lymphocytes (Huard et al., 1994, Eur. J. Immunol. 24:3216-3221), and LAG-3 blockade has also been shown to restore CD8+ lymphocyte viability in tumor or autoantigen (Gross et al., 2007, J Clin Invest. 117:3383-3392) and viral models (Blackburn et al., 2009, Nat. Immunol. 10:29-37). Furthermore, the intracytoplasmic region of LAG-3 can interact with LAP (LAG-3-associated protein), a signal transduction molecule involved in the downregulation of the CD3/TCR activation pathway (Iouzalen et al., 2001, Eur. J. Immunol. 31:2885-2891). In addition, CD4+CD25+ regulatory T cells (Tregs) have been shown to express LAG-3 upon activation, which contributes to the inhibitory activity of Treg cells (Huang, C. et al., 2004, Immunity 21:503-513). LAG-3 can also negatively regulate T cell homeostasis through Tregs via T cell-dependent and T cell-independent mechanisms (Workman, C. J. and Vignali, D. A., 2005, J. Immunol. 174:688-695).

LAG-3 has been shown to interact with MHC class II molecules (Huard et al., CD4/majorhistocompatibility complex class II interaction analyzed with CD4-and lymphocyte activation gene-3 (LAG-3)-Ig fusion proteins, Eur J Immunol., Sep 1995; 25(9):2718-21).

In addition, several kinases are known to be checkpoint inhibitors. For example, CHEK-1, CHEK-2, and A2aR.

CHEK-1 (also known as CHK1 kinase, CHK1, and checkpoint kinase 1) is a serine/threonine protein kinase of approximately 54.4 kDa that is involved in checkpoint-mediated cell cycle arrest and in response to DNA damage and/or DNA repair of non-replicated DNA.

CHEK-2 (also known as CHK2 kinase, CDS1, CHK2, HuCds1, LFS2, PP1425, RAD53, hCds1, and checkpoint kinase 2) is a serine/threonine protein kinase of approximately 60.9 kDa involved in checkpoint-mediated cell cycle arrest, DNA repair activation, and double-strand break-mediated apoptosis.

A2aR (also known as adenosine A2A receptor, ADORA2A, adenosine A2a receptor, A2aR, ADORA2, and RDC8) is a 44.7-kDa multi-membrane receptor for adenosine and other ligands.

In various embodiments, immunotherapeutic agents may comprise antibodies or antigen-binding fragments thereof. Within this definition, immune checkpoint inhibitors include bispecific antibodies and immune cell-binding multivalent antibodies/fusion proteins/constructs known in the art. In some embodiments, immunotherapeutic agents comprising bispecific antibodies may include bivalent antibodies that bind to the same epitope of an immune checkpoint molecule, two different epitopes of the same immune checkpoint molecule, or different epitopes of two different immune checkpoints.

Those skilled in the art can realize several bispecific antibody forms known in the art to target CTLA4, PD1, PD-L1, TIM-3, LAG-3, various B-7 ligands, B7H3, B7H4, CHK1 and CHK2 kinases, BTLA, A2aR, OX40, 41BB, LIGHT, CD40, GITR, TGF-β, SIRP-α, TIGIT, VSIG8, SIGLEC7, SIGLEC9, ICOS, FAS, BTNL2, and one or more others used in the combinations described herein.

In various implementations, immunotherapeutic agents may include immune cell-conjugated multivalent antibodies/fusion proteins/constructs.

In one embodiment of this disclosure, a checkpoint inhibitor is combined with a compound of formula I' to reduce or inhibit the metastasis of a primary tumor or cancer to other sites, or the formation or establishment of a metastatic tumor or cancer at other sites distant from the primary tumor or cancer, thereby inhibiting or reducing the recurrence or progression of the tumor or cancer.

In another embodiment of this disclosure, a combination therapy for treating cancer is provided, comprising a compound of formula I' and a checkpoint inhibitor having the potential to elicit an effective and durable immune response and enhance therapeutic benefits and more controllable toxicity.

In another embodiment of this disclosure, a combination therapy for treating cancer is provided, the combination therapy comprising a compound of formula I' and an immune checkpoint inhibitor. In one embodiment of this disclosure, a method for treating cancer and/or preventing metastasis is provided by using a checkpoint inhibitor that synergizes with a compound of formula I'.

In another embodiment, the methods of this disclosure include one or more of the following: 1) reducing or inhibiting the growth, proliferation, migration, or invasion of tumors or cancer cells that may or have metastasized; 2) reducing or inhibiting the formation or establishment of metastases from the primary tumor or cancer to one or more other sites, locations, or regions different from the primary tumor or cancer; 3) reducing or inhibiting the growth or proliferation of metastases at one or more other sites, locations, or regions different from the primary tumor or cancer after metastasis has formed or been established; 4) reducing or inhibiting the formation or establishment of additional metastases after metastasis has formed or been established; 5) prolonging overall survival; 6) prolonging progression-free survival; or 7) stabilizing the disease.

In one embodiment of this disclosure, administration of an immunotherapeutic agent in combination with a compound of formula I' provides a detectable or measurable improvement in a given subject's condition, such as relief or improvement of one or more adverse (physical) symptoms or consequences associated with the presence of cell proliferation or cell hyperproliferation, tumor formation, tumor or cancer, or metastasis, i.e., therapeutic benefit or beneficial effect.

A therapeutic benefit or beneficial effect is any objective or subjective, temporary or long-term improvement in a disease or pathology, or a reduction in the onset, severity, duration, or frequency of adverse symptoms associated with or caused by cell proliferation or cell hyperproliferative disorders such as tumor formation, tumor or cancer, or metastasis. It can lead to improved survival. For example, a satisfactory clinical endpoint of the treatment method according to this disclosure is achieved when the severity, duration, or frequency of one or more associated pathologies, adverse symptoms, or complications gradually or partially decreases, or when one or more of the physiological, biochemical, or cellular manifestations or characteristics of cell proliferation or cell hyperproliferative disorders such as tumor formation, tumor or cancer, or metastasis are inhibited or reversed. Therefore, a therapeutic benefit or improvement can be, but is not limited to, the destruction of target proliferating cells (e.g., tumor formation, tumor or cancer, or metastasis) or the elimination of one, most, or all of the pathologies, adverse symptoms, or complications associated with or caused by cell proliferation or cell hyperproliferative disorders such as tumor formation, tumor or cancer, or metastasis. However, the benefits or improvements of treatment do not necessarily involve curing or completely destroying all target proliferating cells (e.g., tumor formation, tumor or cancer, or metastasis) or eliminating all pathologies, adverse symptoms, or complications associated with or caused by conditions of cell proliferation or excessive cell proliferation, such as tumor formation, tumor or cancer, or metastasis. For example, partially destroying a tumor or cancer mass by inhibiting its progression or worsening, or stabilizing the tumor or cancer mass, size, or cell number, can reduce mortality and prolong life, even if only for days, weeks, or months, although some or most of the tumor or cancer mass, size, or cells remain.

Specific, non-limiting examples of therapeutic benefits include a reduction in tumor formation, tumor or cancer, or metastatic volume (size or cell mass) or cell number; inhibition or prevention of tumor formation, tumor or cancer volume increase (e.g., stabilization); slowing or inhibiting tumor formation, tumor or cancer progression, worsening or metastasis; or inhibiting tumor formation, tumor or cancer proliferation, growth or metastasis.

In one embodiment of this disclosure, administration of an immunotherapeutic agent in combination with a compound of formula I' provides a detectable or measurable improvement or overall response based on irRC (e.g., derived from time-point response assessment and based on tumor burden), including one or more of the following: (i) irCR – complete disappearance of all lesions, whether or not measurable, and no new lesions (confirmed by repeated, continuous assessment for at least 4 weeks from the date of first recording), (ii) irPR – a reduction of .gtoreq. 50% in tumor burden relative to baseline (confirmed by continuous assessment for at least 4 weeks after the date of first recording).

Optionally, any of the methods described herein may not be immediately effective. For example, tumor formation, the number or quality of tumors or cancer cells may increase after treatment, but over time, the quality, size or number of tumor cells in a given subject may eventually stabilize or decrease.

Other adverse symptoms and complications associated with tumor formation, tumors, cancer, and metastasis that can be suppressed, reduced, decreased, delayed, or prevented include, for example, nausea, loss of appetite, somnolence, pain, and malaise. Therefore, a partial or complete reduction or decrease in the severity, duration, or frequency of adverse symptoms or complications associated with or caused by cell hyperproliferative disorders, and improvements in the subject's quality of life and/or well-being, such as increased energy, appetite, and psychological well-being, are specific, non-limiting examples of therapeutic benefits.

Therefore, treatment benefits or improvements may also include a subjective improvement in the quality of life of the treated subject. In another embodiment, a method prolongs or extends the lifespan (survival) of the subject. In yet another embodiment, a method improves the quality of life of the subject.

In one implementation, administration of an immunotherapeutic agent in combination with a compound of formula I' results in a clinically relevant improvement in one or more biomarkers of disease status and progression selected from one or more of the following: (i): overall survival, (ii): progression-free survival, (iii): overall response rate, (iv): reduction in metastatic disease, (v): circulating levels of tumor antigens such as carbohydrate antigen 19.9 (CA19.9) and carcinoembryonic antigen (CEA) or other tumor-dependent antigens, (vii) nutritional status (weight, appetite, serum albumin), (viii): pain control or analgesic use, and (ix): CRP/albumin ratio.

Combining compounds of formula I' with immunotherapeutic agents produces more complex immunity, including not only the development of innate and type 1 immunity, but also immune regulation that more effectively restores appropriate immune function.

In various exemplary methods, checkpoint inhibitor antibodies (monoclonal or polyclonal, bispecific, trispecific, or immune cell-conjugating multivalent antibodies/fusion proteins/constructs) targeting checkpoint molecules of interest (e.g., PD-1) can be sequenced, and the polynucleotide sequence can then be cloned into a vector for expression or propagation. The sequence encoding the antibody of interest or its antigen-binding fragment can be held in a vector within host cells, which can then be amplified and frozen for future use. Production of recombinant monoclonal antibodies in cell cultures can be performed by cloning antibody genes from B cells using methods known in the art. See, for example, Tiller et al., 2008, J. Immunol. Methods 329,112; U.S. Patent No. 7,314,622.

In some embodiments, the method for generating recombinant antibodies may include the step of culturing host cells containing isolated nucleic acids encoding antibodies of the present disclosure. The method for culturing host cells containing isolated nucleic acids encoding antibodies of the present disclosure may be carried out in various ways depending on the nature of the antibody. In some embodiments, where the antibody of the present disclosure is a full-length conventional antibody, for example, the heavy chain variable region and light chain variable region are included under conditions that allow for the generation and isolation of the antibody.

Typically, nucleic acids encoding antibodies or antigen-binding fragments thereof are provided. Such polynucleotides encode both variable and constant regions of each of the heavy and light chains, but other combinations are also contemplated in this disclosure. Oligonucleotide fragments derived from the disclosed polynucleotides and nucleic acid sequences complementary to these polynucleotides are also contemplated in this disclosure.

Polynucleotides can be in the form of RNA, DNA, cDNA, genomic DNA, nucleic acid analogs, and synthetic DNA. DNA can be double-stranded or single-stranded, and if single-stranded, it can be a coding (sense) strand or a non-coding (antisense) strand. The coding sequence of a polypeptide can be the same as or different from the coding sequence, even if the sequence encodes the same polypeptide due to redundancy or degeneracy of the genetic code.

In some embodiments, a nucleic acid encoding an antibody disclosed herein is bound to an expression vector, which may be extrachromosomal or designed to integrate into the genome of the host cell to which it is introduced. The expression vector may contain any number of suitable regulatory sequences (including, but not limited to, transcription and translation control sequences, promoters, ribosome binding sites, enhancers, origins of replication, etc.) or other components (selection genes, etc.), all of which are operatively linked as is well known in the art. In some cases, two nucleic acids are used and placed in separate expression vectors (e.g., the heavy chain in a first expression vector and the light chain in a second expression vector), or alternatively, they may be placed in the same expression vector. Those skilled in the art will understand that the design of the expression vector (including the selection of regulatory sequences) can depend on factors such as the choice of host cell and the desired protein expression level.

Typically, nucleic acids and/or expression can be introduced into suitable host cells to generate recombinant host cells using any method suitable for the selected host cells (e.g., transformation, transfection, electroporation, infection), such that the nucleic acid molecules are operatively linked to one or more expression control elements (e.g., in a vector, in a construct generated through a process within the cell, or integrated into the host cell genome). The resulting recombinant host cells can be maintained under conditions suitable for expression (e.g., in the presence of an inducer, in a suitable non-human animal, in a suitable culture medium supplemented with appropriate salts, growth factors, antibiotics, nutritional supplements, etc.), thereby producing the encoded polypeptide. In some cases, the heavy chain is produced in one cell while the light chain is produced in another cell.

Mammalian cell lines suitable as expression hosts are known in the art and include many immortalized cell lines purchased from American Type Culture Collection (ATCC), Manassas, VA, USA, including but not limited to Chinese hamster ovary (CHO) cells, HEK 293 cells, NSO cells, HeLa cells, baby hamster kidney (BHK) cells, monkey kidney cells (COS) cells, human hepatocellular carcinoma cells (e.g., Hep G2), and many other cell lines. Non-mammalian cells, including but not limited to bacteria, yeast, insects, and plants, can also be used to express recombinant antibodies. In some embodiments, the antibody may be produced in transgenic animals such as cattle or chickens.

Exemplary and illustrative recombinant methods for antibody molecular biology, expression, purification, and screening are described in, for example, Antibody Engineering, edited by Kontermann & Dubel, Springer, Heidelberg, 2001 and 2010, Hayhurst & Georgiou, 2001, Curr. Opin. Chem. Biol. 5:683-689; Maynard & Georgiou, 2000, Annu. Rev. Biomed. Eng. 2:339-76; and Morrison, S. (1985) Science 229:1202, the full text of which is incorporated herein by reference.

In various implementations, the polynucleotide sequences encoding the selected variable heavy and light chains can be genetically manipulated to humanize the antibody or improve its affinity or other characteristics. Antibodies can also be customized for use in, for example, dogs, cats, primates, horses, and cattle.

In some implementations, fully human antibodies can be obtained using commercially available mice engineered to express specific human immunoglobulins. Transgenic animals designed to produce a more desired (e.g., fully human antibody) or stronger immune response can also be used to generate humanized or human antibodies. Examples of such technologies are Xenomouse ^™ from Abgenix, Inc. (Fremont, Calif.) and HuMAb- and TC Mouse ^™ from Medarex, Inc. (Princeton, NJ).

The immune checkpoint modulator antibodies disclosed herein can be recombinantly prepared by first isolating antibodies and antibody-producing cells from a host animal, obtaining the gene sequence, and using the gene sequence to recombinantly express the antibody in host cells (e.g., CHO cells). Another approach is to express the antibody sequence in plant (e.g., tobacco) or yeast cells (e.g., Pichia pastoris or Saccharomyces cerevisiae). Methods for recombinantly expressing antibodies in plants or yeast have been disclosed. See, for example, Peeters et al., Vaccine 19:2756, 2001; Lonberg, N. and D. Huszar Int. Rev. Immunol 13:65, 1995; and Horwitz, A.H. et al., Proc. Natl. Acad. Sci. 85:8678-8682; the full text of these publications is incorporated herein by reference. Methods for preparing antibody derivatives (e.g., domains, single chains, etc.) are known in the art.

Immunoassays and flow cytometry sorting techniques, such as fluorescence activated cell sorting (FACS), can also be used to isolate antibodies specific to checkpoint molecules.

In some embodiments, the polynucleotide comprises a sequence encoding a heavy chain and/or light chain variable region encoding a checkpoint inhibitor antibody or an antigen-binding fragment thereof disclosed herein. The sequence encoding the antibody of interest or its antigen-binding fragment may be held in a vector within a host cell, which can then be amplified and frozen for future use. Vectors (including expression vectors) and host cells are further described herein.

This disclosure includes affinity-matured checkpoint regulator antibodies. For example, affinity-matured antibodies can be produced by procedures known in the art (Marks et al., 1992, Bio/Technology, 10:779-783; Barbas et al., 1994, Proc Nat. Acad. Sci. USA 91:3809-3813). A method for characterizing antibody CDRs and/or altering (such as improving) the binding affinity of peptides such as antibodies is called “library scanning mutagenesis”. An exemplary method for providing affinity-matured antibody and antigen-binding fragments may include replacing one or more amino acid positions in the CDR with two or more amino acids (such as 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) using methods recognized in the art. A clonal library is generated, each clone having the complexity of two or more members (if two or more amino acids are substituted at each position). Typically, the library also includes clones containing native (unsubstituted) amino acids. A small number of clones from each library (e.g., approximately 20-80 clones, depending on the complexity of the library) are screened for binding affinity to the target peptide (or other binding target) and candidates with increased, identical, decreased, or no binding are identified. Methods for determining binding affinity are well known in the art. Binding affinity can be determined using, for example, Biacore™ surface plasmon resonance analysis (which detects approximately 2-fold or greater differences in binding affinity), biosensors, scintillation affinity assays, ELISA, immunoassays, fluorescence quenching, fluorescence transfer, and/or yeast display. Binding affinity can also be screened using suitable bioassays. Biacore™ is particularly useful when the starting antibody has already bound with relatively high affinity (e.g., approximately 10 nM or lower KD). The clonal library can then be recombined into the selection construct using any methods known in the art for selection, including phage display, yeast display, and ribosome display.

Antibodies can also be modified, for example, in variable domains of the heavy and/or light chains, to alter the antibody's binding properties. Changes in the variable regions can alter binding affinity and/or specificity. In some embodiments, no more than one to five conserved amino acid substitutions are made within the CDR domain. In other embodiments, no more than one to three conserved amino acid substitutions are made within the CDR domain. For example, mutations can be made in one or more CDR regions to increase or decrease the KD of the antibody against the checkpoint molecule, increase or decrease the KON, or alter the antibody's binding specificity. Site-directed mutagenesis is well known in the art. See, for example, Sambrook et al. and Ausubel et al.

Pharmaceutical compositions containing compounds of formula I' according to this disclosure will comprise an effective amount of the compound of formula I', an immunotherapeutic agent, and/or both, typically dispersed in a pharmaceutically acceptable carrier. The phrase "pharmaceutically or pharmacologically acceptable" means a molecular entity and composition that does not produce adverse, allergic, or other adverse reactions when properly administered to animals, such as humans. The preparation of pharmaceutical compositions containing compounds of formula I' according to this disclosure is known to those skilled in the art, as exemplified in Remington's Pharmaceutical Sciences, 18th edition, Mack Printing Company, 1990. Furthermore, for animal (e.g., human) administration, it should be understood that the formulation should meet standards of sterility, pyrogenicity, general safety, and purity. Specific examples of pharmaceutically acceptable carriers for use in combination compositions containing compounds of formula I' mixed with immunotherapeutic agents as described herein are borate buffers or sterile saline solutions (0.9% NaCl).

Formulations of immunotherapeutic agents, such as immune checkpoint modulator antibodies used according to this disclosure, can be prepared by mixing an antibody of desired purity with an optional pharmaceutically acceptable carrier, excipient, or stabilizer as well described and illustrated in Remington's Pharmaceutical Sciences, 16th edition, Osol, A.Ed. [1980], for storage in the form of a lyophilized formulation or an aqueous solution and/or suspension. Acceptable carriers, excipients, buffers, or stabilizers are non-toxic to the recipient at the doses and concentrations employed and include suitable aqueous and/or non-aqueous excipients that can be used in the pharmaceutical compositions of this disclosure, such as water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate). For example, appropriate flowability can be maintained by using coating materials such as lecithin, by maintaining the desired particle size in the case of dispersions, and by using surfactants, buffers such as phosphates, citrates, and other organic acids. It may include antioxidants, such as (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, etc.; and (3) metal chelating agents, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.; preservatives (such as octadecane-dimethylbenzylammonium chloride; hexamethylammonium chloride; benzalkonium chloride; benzyl chloride; phenol, butanol or benzyl alcohol; alkyl esters of p-hydroxybenzoate such as methyl p-hydroxybenzoate or propyl p-hydroxybenzoate; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues). Other exemplary pharmaceutically acceptable excipients may include peptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers, such as polyvinylpyrrolidone; amino acids, such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrin; chelating agents, such as EDTA; sugars, such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions, such as sodium; metal complexes (e.g., Zn-protein complexes); and/or nonionic surfactants, such as TWEENTM, PLURONICS™, or polyethylene glycol (PEG).

In one illustrative embodiment, the pharmaceutical composition may optionally contain pharmaceutically acceptable excipients such as pH adjusters and buffers, and toxicity modifiers, such as sodium acetate, sodium chloride, potassium chloride, calcium chloride, and sodium lactate, to approximate physiological conditions. In some embodiments, the checkpoint inhibitor antibody or its antigen-binding fragment of the present disclosure is formulated and may be lyophilized for storage, and reconstituted in a suitable excipient according to lyophilization and reconstitution techniques known in the art prior to use. In an exemplary pharmaceutical composition containing one or more checkpoint inhibitor antibodies or their antigen-binding fragments, the composition is formulated as a sterile, preservative-free solution of one or more checkpoint inhibitor antibodies or their antigen-binding fragments for intravenous or subcutaneous administration. The formulation may be provided as a single-use pre-filled pen, a single-use glass syringe, for example, containing about 1 mL of pre-filled material, or a single-use institutional vial. Preferably, the pharmaceutical composition containing the checkpoint inhibitor antibody or its antigen-binding fragment is clear and colorless, with a pH of about 6.9-5.0, preferably 6.5-5.0, and even more preferably about 6.0 to about 5.0. In various embodiments, when reconstituted and administered to a subject, the formulation comprising the pharmaceutical composition may contain about 500 mg to about 10 mg, or about 400 mg to about 20 mg, or about 300 mg to about 30 mg, or about 200 mg to about 50 mg per mL of solution of a checkpoint inhibitor antibody or an antigen-binding fragment thereof. Exemplary injectable or infusion excipients may include mannitol, citrate monohydrate, disodium hydrogen phosphate dihydrate, disodium hydrogen phosphate monohydrate, polysorbate 80, sodium chloride, sodium citrate, and water for parenteral administration (e.g., intravenous, intramuscular, intraperitoneal, or subcutaneous).

In another exemplary embodiment, one or more immunotherapeutic agents or antigen-binding fragments thereof are formulated into a sterile aqueous solution for intravenous or subcutaneous administration, containing 1-75 mg/mL, or more preferably about 5-60 mg/mL, or even more preferably about 10-50 mg/mL, or even more preferably about 10-40 mg/mL, of an antibody, as well as sodium acetate, polysorbate 80, and sodium chloride, with a pH range of about 5-6. Preferably, the intravenous or subcutaneous formulation is a sterile aqueous solution containing 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 mg/mL of an immunotherapeutic agent (e.g., an immune checkpoint inhibitor antibody or its antigen-binding fragment), 20 mM sodium acetate, 0.2 mg/mL polysorbate 80, and 140 mM sodium chloride, with a pH of 5.5. In addition, solutions containing checkpoint inhibitor antibodies or their antigen-binding fragments may, among other compounds, contain histidine, mannitol, sucrose, trehalose, glycine, polyethylene glycol, EDTA, methionine, and any combination thereof, as well as many other compounds known in the relevant art.

In one embodiment, the pharmaceutical composition of this disclosure comprises the following components: 5-500 mg of the immunotherapeutic agent of this disclosure or its antigen-binding fragment, 10 mM histidine, 5% sucrose, and 0.01% polysorbate 80, at pH 5.8, with or without a compound of formula I'. The composition may be provided in lyophilized powder form. When the powder is reconstituted at its full volume, the composition retains the same formulation. Alternatively, the powder may be reconstituted at half volume, in which case the composition comprises 10-500 mg of the immunotherapeutic agent of this disclosure or its antigen-binding fragment, 20 mM histidine, 10% sucrose, and 0.02% polysorbate 80, at pH 5.8.

In one embodiment, a portion of the dose is administered via intravenous bolus injection, while the remainder is administered via infusion of the immunotherapeutic agent formulation. For example, an intravenously administered immunotherapeutic agent or its antigen-binding fragment may be given in bolus injection at doses of about 0.001 to about 200 mg/kg, such as about 0.001 mg/kg to about 100 mg/kg, or about 0.001 mg/kg to about 50 mg/kg, or about 0.001 mg/kg to about 10 mg/kg, and the remaining antibody dose may be administered via intravenous injection. The predetermined dose of the immunotherapeutic agent or its antigen-binding fragment may be administered, for example, over a period of one to two to five hours.

In another embodiment, a portion of the dose is administered via subcutaneous injection and/or infusion in the form of a bolus, with the remainder administered via infusion of the immunotherapy formulation. In some exemplary dosages, the immunotherapy formulation may be administered subcutaneously via intravenous injection of the immunotherapy agent or its antigen-binding fragment in the range of about 0.001 to about 200 mg/kg, for example, about 0.001 mg/kg to about 100 mg/kg, or about 0.001 mg/kg to about 50 mg/kg, or about 0.001 mg/kg to about 10 mg/kg. In some embodiments, the dose may be given as a bolus, and the remaining immunotherapy dose may be administered via subcutaneous or intravenous injection. The predetermined dose of the immunotherapy agent or its antigen-binding fragment may be administered, for example, over a period of one to two to five hours.

The formulation described herein may also contain one or more active compounds necessary for the specific indication to be treated, preferably those having complementary activities that do not adversely affect each other. For example, it may be desirable to provide one or more immunotherapeutic agents with other specificities. Alternatively or in addition, the composition may comprise anti-inflammatory agents, chemotherapeutic agents, cytotoxic agents, cytokines, growth inhibitors, and/or small molecule antagonists. Such molecules are suitably present in a combination of amounts effective for the intended purpose.

Preparations intended for internal administration should be sterile or near-sterile. This can be easily achieved through filtration using a sterile filter membrane.

In various embodiments, exemplary formulations of the pharmaceutical compositions described herein can be prepared using methods widely known in the field of pharmaceutical formulation. Typically, such preparation methods may include the steps of conjugating an active ingredient with a carrier or one or more other auxiliary ingredients, and then, if desired, packaging the product into desired single-dose or multi-dose units.

In some embodiments, compositions containing compounds of formula I' may also be delivered in vesicles, and immunotherapeutic agents may be delivered in the same liposomal formulation or in a separate formulation compatible with a liposomal formulation containing compounds of formula I'. In some illustrative examples, the liposomes contain liposomal surface portions, such as polyethylene glycol, antibodies, and antibody fragments thereof, that are selectively transported to specific cells or organs to target one or more desired tumor surface antigens, receptors, growth factors, glycoproteins, glycolipids, or neoantigens, thereby enhancing targeted drug delivery.

In another embodiment, the compound of formula I' can be delivered in vesicles, particularly in liposomes (see Langer, Science 249:1527-1533 (1990); Treat et al., Liposomes in the Therapy of Fifenaciodessesase and Cancer, Lopez-Berestein and Fidler (eds.), Liss, N.Y., pp. 353-365 (1989); Lopez-Berestein, ibid., pp. 317-327; see general sources ibid.).

In another embodiment, the compound of formula I', or a combination containing the composition, or a composition containing an immunotherapeutic agent, may be delivered in a controlled-release system. In one embodiment, a pump may be used (see Langer, ibid.; Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321:574 (1989)). In another embodiment, the controlled release of the compound of formula I' may include a polymeric material to provide sustained, intermediate, pulsed, or alternating release (see MEDICAL APPLICATIONS OF CONTROLLED RELEASE, Langer and Wise (eds.), CRC Pres., Boca Raton, Fla. (1974); CONTROLLED DRUG BIOAVAILABILITY, DRUG PRODUCT DESIGN AND PERFORM). ANCE, Smolen and Ball (eds.), Wiley, New York (1984); Ranger and Peppas, J. Macromol. Sci. Rev. Macromol. Chem. 23:61 (1983); see also Levy et al., Science 228:190 (1985); During et al., Ann. Neurol. 25:351 (1989); Howard et al., J. Neurosurg. 71:105 (1989)). Other controlled release systems discussed in Ranger's review (Science 249:1527-1533 (1990)) may be used.

The optimal concentration of the active ingredient in the selected medium can be determined empirically according to procedures well known to those skilled in the art, and will depend on the desired final pharmaceutical formulation and the intended use.

This disclosure also provides a pharmaceutical package or kit comprising one or more containers filled with one or more of the components of a pharmaceutical composition of this disclosure, the pharmaceutical composition comprising at least a compound of formula I' as described herein and one or more checkpoint inhibitor antibodies or antigen-binding fragments thereof. In other embodiments, the kit may contain one or more additional containers providing pharmaceutically acceptable excipients (e.g., diluents). In one embodiment, the kit may comprise at least one container wherein the container may include a compound of formula I' of this disclosure, a checkpoint inhibitor antibody, or an antigen-binding fragment thereof. The kit may also include a set of instructions for preparing and administering the final pharmaceutical composition to a subject in need of treating a checkpoint molecule-mediated disease or condition.

In some embodiments of this disclosure, the immunotherapeutic agent is a population of immune cells that can be administered in combination with a compound of formula I' to treat a subject with cancer. In some embodiments, the immunotherapeutic agent is a population of immune cells, such as leukocytes (nucleated leukocytes), comprising (e.g., expressing) a receptor that binds to an antigen of interest. The leukocytes of this disclosure can be, for example, neutrophils, eosinophils, basophils, lymphocytes, or monocytes. In some embodiments, the leukocytes are lymphocytes. Examples of lymphocytes include T cells, B cells, natural killer (NK) cells, or NKT cells. In some embodiments, the T cells are CD4+Th (T helper) cells, CD8+ cytotoxic T cells, γδ T cells, or regulatory (suppressive) T cells. In some embodiments, the immune cells are dendritic cells.

In some embodiments, the immune cells of this disclosure are genetically engineered to express antigen-binding receptors. A cell is considered “engineered” if it contains engineered (exogenous) nucleic acids. The engineered nucleic acids of this disclosure can be introduced into cells by any known (e.g., conventional) method. For example, engineered nucleic acids can be introduced into cells by: electroporation (see, for example, Heiser W.C. Transcription Factor Protocols: Methods in Molecular Biology. TM. 2000; 130:117-134), chemical methods (e.g., calcium phosphate or lipids), transfection (see, for example, Lewis W.H. et al., Somatic Cell Genet., May 1980; 6(3):333-47; Chen C. et al., Mol Cell Biol., Aug. 1987; 7(8):2745-2752), fusion with bacterial protoplasts containing recombinant plasmids (see, for example, Schaffner W. Proc Natl Acad Sci USA., Apr. 1980; 77(4):2163-7), direct microinjection of purified DNA into the cell nucleus (see, for example, Capecchi M.R. Cell., Nov. 1980; 22(2Pt 2):479-88), or retroviral transduction.

Some aspects of this disclosure provide an "adoptive cell" method involving isolating immune cells (e.g., T cells) from a subject with cancer, genetically engineering the immune cells (e.g., to express antigen-binding receptors, such as chimeric antigen receptors), expanding the cells in vitro, and then reintroducing the immune cells into the subject. This method generates a greater number of engineered immune cells in the subject than can be achieved through conventional gene delivery and vaccination methods. In some embodiments, immune cells are isolated from the subject, expanded in vitro without genetic modification, and then reintroduced into the subject.

As provided herein, the immune cells of this disclosure contain receptors that bind to antigens, such as antigens encoded by nucleic acids delivered exogenously. In some embodiments, leukocytes are modified (e.g., genetically modified) to express receptors that bind antigens. In some embodiments, the receptors may be naturally occurring antigen receptors (typically expressed on immune cells), recombinant antigen receptors (typically not expressed on immune cells), or chimeric antigen receptors (CARs). Naturally occurring and recombinant antigen receptors covered by this disclosure include T cell receptors, B cell receptors, NK cell receptors, NKT cell receptors, and dendritic cell receptors. A “chimeric antigen receptor” is an artificial immune cell receptor engineered to recognize and bind antigens expressed by tumor cells. Typically, CARs are designed for T cells and are a chimera of the signal transduction domain and the antigen recognition domain (e.g., a single-chain fragment of an antibody (scFv)) of the T cell receptor (TcR) complex (Enblad et al., Human Gene Therapy. 2015; 26(8):498-505), the entire contents of which are incorporated herein by reference.

In some implementations, the antigen-binding receptor is a chimeric antigen receptor (CAR). T cells expressing CAR are referred to as "CAR T cells". In some implementations, the CAR T cell receptor comprises a signal transduction domain and an antigen recognition domain (e.g., a single-chain fragment of an antibody (scFv)) of a T cell receptor (TcR) complex (Enblad et al., Human Gene Therapy. 2015; 26(8):498-505), the full text of which is incorporated herein by reference.

There are four generations of CARs, each containing different components. First-generation CARs connect the antibody-derived scFv to the intracellular signaling domain of the T cell receptor's CD3ζ (ζ or z) via a hinge and transmembrane domain. Second-generation CARs incorporate additional domains, such as CD28, 4-1BB (41BB), or ICOS, to provide co-stimulatory signaling. Third-generation CARs contain two co-stimulatory domains fused to the TCR CD3-ζ chain. These third-generation co-stimulatory domains can include combinations of, for example, CD3z, CD27, CD28, 4-1BB, ICOS, or OX40. In some implementations, the CAR contains an extracellular domain (e.g., CD3) typically derived from a single-stranded variable fragment (scFv), a hinge, a transmembrane domain, and an intracellular domain having one (first-generation), two (second-generation), or three (third-generation) signaling domains derived from CD3Z and/or co-stimulatory molecules (Maude et al., Blood. 2015; 125(26):4017-4023; Kakarla and Gottschalk, Cancer J. 2014; 20(2):151-155), the full text of which is incorporated herein by reference.

In some implementations, chimeric antigen receptors (CARs) are T cells retargeted for universal cytokine killing (TRUCK), also known as fourth-generation CARs. TRUCK cells are CAR-retargeted T cells that act as mediators for the production and release of transgenic cytokines that accumulate in the targeted tissue (e.g., the targeted tumor tissue). The transgenic cytokines are released when the CAR binds to the target. TRUCK cells can deposit a variety of therapeutic cytokines at the target. This can produce therapeutic concentrations at the target site and avoid systemic toxicity.

CARs typically differ in their functional properties. The CD3ζ signaling domain of the T cell receptor, when conjugated, activates and induces T cell proliferation, but can lead to non-responsiveness (a lack of response to the body's defense mechanisms, resulting in direct induction of peripheral lymphocyte tolerance). Lymphocytes are considered non-responsive when they do not respond to a specific antigen. Adding a co-stimulatory domain to second-generation CARs improves the replication capacity and persistence of modified T cells. Similar antitumor effects have been observed in vitro with CD28 or 4-1BB CARs, but preclinical in vivo studies have shown that the 4-1BB CAR produces superior proliferation and/or persistence. Clinical trials have shown that both second-generation CARs can induce substantial T cell proliferation in vivo, but the CAR containing the 4-1BB co-stimulatory domain appears to have a longer duration of action. Third-generation CARs incorporate multiple signaling domains (co-stimulatory domains) to increase potency. Fourth-generation CARs are further modified with constitutive or inducible expression cassettes of transgenic cytokines, which are released by CAR T cells to modulate T cell responses. See, for example, Enblad et al., Human Gene Therapy. 2015; 26(8):498-505; Chmielewski and Hinrich, Expert Opinion on Biological Therapy. 2015; 15(8):1145-1154, the full text of which is incorporated herein by reference.

In some embodiments, the exemplary immunotherapeutic agent is a first-generation chimeric antigen receptor (CAR). In some embodiments, the chimeric antigen receptor is a third-generation CAR. In some embodiments, the chimeric antigen receptor is a second-generation CAR. In some embodiments, the chimeric antigen receptor is a third-generation CAR. In some embodiments, the chimeric antigen receptor is a fourth-generation CAR or a T cell redirected for universal cytokine killing (TRUCK).

In some embodiments, the chimeric antigen receptor (CAR) includes an extracellular domain comprising an antigen-binding domain, a transmembrane domain, and a cytoplasmic domain. In some embodiments, the CAR is fully human. In some embodiments, the antigen-binding domain of the CAR is specific for one or more antigens. In some embodiments, a "spacer" domain or "hinge" domain is located between the extracellular domain (containing the antigen-binding domain) and the transmembrane domain of the CAR, or between the cytoplasmic domain and the transmembrane domain of the CAR. A "spacer" domain refers to any oligopeptide or polypeptide that serves to link the transmembrane domain to the extracellular domain and/or the cytoplasmic domain in a polypeptide chain. A "hinge" domain refers to any oligopeptide or polypeptide that serves to provide flexibility to the CAR or its domains, or to prevent steric hindrance to the CAR or its domains. In some embodiments, the spacer or hinge domain may contain up to 300 amino acids (e.g., 10 to 100 amino acids, or 5 to 20 amino acids). In some embodiments, one or more spacer domains may be included in other regions of the CAR.

In some embodiments, the CAR of this disclosure includes an antigen-binding domain, such as a single-stranded Fv (scFv) specific to a tumor antigen. The choice of the binding domain depends on the type and number of ligands defining the surface of the target cell. For example, the antigen-binding domain may be selected to recognize a ligand that acts as a cell surface marker on a target cell associated with a specific disease state, such as cancer or an autoimmune disease. Thus, examples of cell surface markers that can serve as ligands for the antigen-binding domain in the CAR of this disclosure include those associated with cancer cells and/or other forms of diseased cells. In some embodiments, the CAR is engineered to target tumor antigens of interest by engineering a desired antigen-binding domain on tumor cells that specifically binds to an antigen encoded by an engineered nucleic acid as provided herein.

The term "specific binding" refers to the antigen-binding domain (e.g., scFv) of a target or epitope, and methods for determining such specific binding are known in the art. A molecule is said to exhibit "specific binding" if it reacts or associates with a particular target antigen more frequently, rapidly, persistently, and/or with greater affinity compared to alternative targets. An antigen-binding domain (e.g., scFv) that specifically binds to a first target antigen may or may not specifically bind to a second target antigen. Thus, "specific binding" does not necessarily require (although it may include) exclusive binding.

In some implementations, CAR-expressing immune cells are genetically modified to recognize multiple targets or antigens, allowing for the recognition of unique target or antigen expression patterns on tumor cells. Examples of CARs that can bind to multiple targets include: “split signal CARs” that restrict the activation of fully immune cells against tumors expressing multiple antigens; “tandem CARs” (TanCARs) containing an extracellular domain with two scFvs; and “universal extracellular domain CARs” that incorporate avidin or fluorescein isothiocyanate (FITC)-specific scFvs to recognize tumor cells that have been incubated with labeled monoclonal antibodies (Mabs).

A CAR is considered "bispecific" if it recognizes two different antigens (having two different antigen recognition domains). In some embodiments, a bispecific CAR consists of two different antigen recognition domains tandemly present on a single transgenic receptor (referred to as a TanCAR; see, for example, Grada Z et al., Molecular Therapy Nucleic Acids 2013; 2:e105, the entire text of which is incorporated herein by reference). Thus, in some embodiments, these methods include delivering to a tumor a combination of a compound comprising formula I' and an immunotherapeutic agent, wherein the immunotherapeutic agent is an engineered nucleic acid encoding an antigen, or delivering to the tumor an engineered nucleic acid that induces the expression of an autoantigen, and delivering to the tumor immune cells expressing a bispecific CAR that binds to two antigens, one of which is encoded by an engineered nucleic acid.

In some embodiments, the CAR is an antigen-specific inhibitory CAR (iCAR), which can be used, for example, to avoid extratumor toxicity (Fedorov, V D et al., Sci. Transl. Med., published online December 11, 2013, the full text of which is incorporated herein by reference). The iCAR contains an antigen-specific inhibitory receptor, for example, to block nonspecific immunosuppression that may be caused by the expression of additional tumor targets. The iCAR may be based on, for example, the inhibitory molecule CTLA-4 or PD-1. In some embodiments, these iCARs block T-cell responses originating from their endogenous T-cell receptors or activated CAR-activated T cells. In some embodiments, this inhibitory effect is temporary.

In some implementations, CAR can be used for adoptive cell transfer, in which immune cells are removed from a subject and modified to express receptors specific to antigens, such as tumor-specific antigens. The modified immune cells, which can then recognize and kill cancer cells, are then reintroduced into the subject (Pule et al., Cytotherapy. 2003; 5(3):211-226; Maude et al., Blood. 2015; 125(26):4017-4023, each of which is incorporated herein by reference in its entirety).

According to other aspects of this disclosure, the tumor antigen component in the vaccine of the present invention is any natural or synthetic tumor-associated protein or peptide, or a combination of tumor-associated proteins and/or peptides or glycoproteins or glycopeptides. In other aspects, the antigen component may be patient-specific or common to many or most patients with a particular type of cancer. According to one aspect, the antigen component consists of cell lysates derived from tumor tissue taken from a patient to be treated. In another aspect, the lysates may be engineered or synthesized from exogenous sources derived from tumor tissue. In yet another aspect, the antigen component consists of cell lysates derived from tumor tissue extracted from one or more unrelated individuals or tumor cell lines.

In various embodiments, exemplary immunotherapeutic agents comprise one or more cancer vaccines for use in combination with compounds of formula I'. The tumor-associated antigen component of the vaccine can be manufactured using any of a variety of well-known techniques. For a single protein component, the antigen protein is isolated from tumor tissue or tumor cell lines by standard chromatographic methods such as high-performance liquid chromatography or affinity chromatography, or alternatively synthesized in a suitable expression system (such as *E. coli*, yeast, or plants) using standard recombinant DNA techniques. The tumor-associated antigen protein is then purified from the expression system by standard chromatographic methods. In the case of peptide antigen components, these are typically prepared by standard automated synthesis. Proteins and peptides can be modified by adding amino acids, lipids, and other agents to improve their incorporation into vaccine delivery systems (e.g., multilayer liposomes). For tumor-associated antigen components derived from a patient's own tumor or from tumors or cell lines from other individuals, tumor tissue or single-cell suspensions derived from tumor tissue are typically homogenized in a suitable buffer. Homogenization can also be performed, for example, by centrifugation to separate specific cellular components such as cell membranes or soluble substances. Tumor material can be used directly, or tumor-associated antigens can be extracted using a buffer solution containing low concentrations of suitable agents (such as detergents) for incorporation into vaccines. An example of a suitable detergent for extracting antigenic proteins from tumor tissue, tumor cells, and tumor cell membranes is diheptanoylphosphatidylcholine. Exogenous substances derived from tumor tissue or tumor cells, whether autologous or allogeneic to the patient, can be used as antigenic components for incorporation into vaccines or as starting materials for extracting tumor-associated antigens.

In some embodiments of this disclosure, a cancer vaccine is provided, comprising at least one tumor-associated antigen, at least one immunostimulant, and optionally at least one cell-based immunotherapeutic agent. In some embodiments, the immunostimulatory component of the cancer vaccine of this disclosure is any biological response modulator (BRM) capable of enhancing the effectiveness of the therapeutic cancer vaccine in inducing humoral and cellular immune responses against cancer cells in a patient. According to one aspect, the immunostimulant is a cytokine or a combination of cytokines. Examples of such cytokines include interferons (such as IFN-γ), interleukins (such as IL-2, IL-15, and IL-23), colony-stimulating factors (such as M-CSF and GM-CSF), and tumor necrosis factor. According to another aspect, the immunostimulatory component of the disclosed cancer vaccine comprises one or more adjuvanted immunostimulants, such as APC Toll-like receptor agonists or co-stimulatory/cell adhesion membrane proteins, with or without immunostimulatory cytokines. Examples of Toll-like receptor agonists include lipid A and CpG, and co-stimulatory/adhesion proteins such as CD80, CD86, and ICAM-1.

In some embodiments, the immunostimulant is selected from IFN-γ (IFN-γ), IL-2, IL-15, IL-23, M-CSF, GM-CSF, tumor necrosis factor, lipid A, CpG, CD80, CD86, and ICAM-1, or combinations thereof. According to other aspects, the cell-based immunotherapeutic agent is selected from dendritic cells, tumor-infiltrating T lymphocytes, chimeric antigen receptor-modified T effector cells targeting the patient's tumor type, B lymphocytes, natural killer cells, bone marrow cells, and any other cells of the patient's immune system, or combinations thereof. In one aspect, the cancer vaccine immunostimulant includes one or more cytokines (such as interleukin-2 (IL-2), GM-CSF, M-CSF, and interferon-γ (IFN-γ)), one or more Toll-like receptor agonists and/or adjuvants (such as monophospholipid A, lipid A, muramyl dipeptide (MDP) lipid conjugates, and double-stranded RNA), or one or more co-stimulatory membrane proteins and/or cell adhesion proteins (such as CD80, CD86, and ICAM-1), or any combination thereof. In one aspect, cancer vaccines include immunostimulants that are cytokines selected from interleukin-2 (IL-2), GM-CSF, M-CSF, and interferon-γ (IFN-γ). In another aspect, cancer vaccines include immunostimulants that are Toll-like receptor agonists and/or adjuvants selected from monophospholipid A, lipid A, and muramyl dipeptide (MDP) lipid conjugates and double-stranded RNA. In yet another aspect, cancer vaccines include immunostimulants that are co-stimulatory membrane proteins and/or cell adhesion proteins selected from CD80, CD86, and ICAM-1.

In various embodiments, the immunotherapeutic agent may include a cancer vaccine, wherein the cancer vaccine incorporates any tumor antigen that can potentially be used to construct the fusion protein according to the invention, particularly the following:

(a) Cancer-testis antigens, including NY-ESO-1, SSX2, SCP1, and RAGE, BAGE, GAGE, and MAGE family peptides, such as GAGE-1, GAGE-2, MAGE-1, MAGE-2, MAGE-3, MAGE-4, MAGE-5, MAGE-6, and MAGE-12, which can be used to treat, for example, melanoma, lung cancer, head and neck cancer, NSCLC, breast cancer, gastrointestinal cancer, and bladder tumors; (b) mutated antigens, including p53 associated with various solid tumors such as colorectal cancer, lung cancer, and head and neck cancer; and p2 associated with, for example, melanoma, pancreatic cancer, and colorectal cancer. 1/Ras; CDK4 associated with, for example, melanoma; MUM1 associated with, for example, melanoma; caspase-8 associated with, for example, head and neck cancer; CIA 0205 associated with, for example, bladder cancer; HLA-A2-R1701; β-catenin associated with, for example, melanoma; TCR associated with, for example, T-cell non-Hodgkin lymphoma; BCR-abl associated with, for example, chronic myeloid leukemia; triose phosphate isomerase; KIA0205; CDC-27 and LDLR-FUT; (c) overexpressed antigens, including galactolectin 4 associated with, for example, colorectal cancer; galactolectin 9 associated with, for example, Hodgkin's disease. ; proteinase 3 associated with, for example, chronic myeloid leukemia; WT 1 associated with, for example, various types of leukemia; carbonic anhydrase associated with, for example, renal cell carcinoma; aldolase A associated with, for example, lung cancer; PRAME associated with, for example, melanoma; HER-2/neu associated with, for example, breast cancer, colon cancer, lung cancer, and ovarian cancer; globin and alpha-fetoprotein associated with, for example, liver cancer; KSA associated with, for example, colorectal cancer; gastrin associated with, for example, pancreatic cancer and gastric cancer; telomerase catalytic protein and MUC-1 associated with, for example, breast cancer and ovarian cancer; G-250 associated with, for example, renal cell carcinoma; p53 associated with, for example, breast cancer and colon cancer; and (d) Carcinoembryonic antigens associated with, for example, breast cancer, lung cancer, and gastrointestinal cancers such as colorectal cancer; (e) Common antigens, including melanoma-melanocyte differentiation antigens such as MART-1/Melan A; gpl00; MC1R; melanocyte-stimulating hormone receptor; tyrosinase; tyrosinase-associated protein-1/TRP1 and tyrosinase-associated protein-2/TRP2 associated with, for example, melanoma; (f) Prostate-associated antigens, including PAP, PSA, PSMA, PSH-P1, PSM-P1, and PSM-P2 associated with, for example, prostate cancer; and (c) Immunoglobulin idiotypes associated with myeloma and B-cell lymphoma. In some implementations, one or more TAAs may be selected from pi 5, Hom/Mel-40, H-Ras, E2A-PRL, H4-RET, IGH-IGK, MYL-RAR, Epstein Barr virus antigen, EBNA, human papillomavirus (HPV) antigens including E6 and E7, hepatitis B and hepatitis C virus antigens, human T-cell lymphotropic virus antigen, TSP-180, pl85erbB2, pl80erbB-3, c-met, mn-23H1, TAG-72-4, CA 19-9, CA 72-4, CAM17.1, NuMa, K-ras, pi 6, TAGE, PS CA, CT7, 43-9F, 5T4, 791Tgp72, β-HCG, BCA225, BTAA, CA125, CA 15-3 (CA 27.29\BCAA), CA 195, CA 242, CA-50, CAM43, CD68\KP1, CO-029, FGF-5, Ga733 (EpCAM), HTgp-175, M344, MA-50, MG7-Ag, MOV18, NB/70K, NY-CO-1, RCAS1, SDCCAG16, TA-90 (Mac-2 binding protein/Cycophilic C-associated protein), TAAL6, TAG72, TLP, TPS, or any combination thereof.

In some embodiments, the cancer vaccine of this disclosure, used in combination with the compounds of Formula I', may include a tumor antigen comprising a specific immunogenic epitope of one of the following human proteins: TCTN1 ( SEQ ID NO.1; gene ID: ENSG00000204852), TCTN2 (SEQ ID NO.2; gene ID: ENSG00000168778), TCTN3 ( SEQ ID NO.3; gene ID: ENSG00000119977), HIGD2A ( SEQ ID NO.4; gene ID: ENSG00000146066), HIGD2B ( SEQ ID NO.5; gene ID: ENSG00000175202), C4ORF32 ( SEQ ID NO.6; gene ID: ENSG00000174749), FAM62A (E-SYT1, SEQ ID NO.1 ), and TCTN3B ( SEQ ID NO.2). NO.7; Gene ID: ENSG00000139641), COLEC11 ( SEQ ID NO.8; Gene ID: ENSG00000118004), FSTL5 ( SEQ ID NO.9; Gene ID: ENSG00000168843), FAM82A2 ( SEQ ID NO.10; Gene ID: ENSG00000137824), SCARA5 ( SEQ ID NO.11; Gene ID: ENSG00000168079), VSTM1 ( SEQ ID NO.12; Gene ID: ENSG00000189068), RNF5 ( SEQ ID NO.13; Gene ID: ENSG00000183574), UNQ6126 ( SEQ ID NO.14; Gene ID: gi|169216088), DPY19L3 ( SEQ ID NO.15; Gene ID: ENSG00000178904), SLC39A10 ( SEQ ID NO.16; Gene ID: ENSG00000196950), GPR107 ( SEQ ID NO.17; Gene ID: ENSG00000148358), COL20A1 ( SEQ ID NO.18; Gene ID: ENSG00000101203), GLT25D2 ( SEQ ID NO.19; Gene ID: ENSG00000198756), SYTL3 ( SEQ ID NO.20; Gene ID: ENSG00000164674), DENND1B ( SEQ ID NO.21; Gene ID: ENSG00000162701), C6orf98 ( SEQ ID NO.22; Gene ID: EG:387079), FAM69B ( SEQ ID NO. NO.23; Gene ID: ENSG00000165716), EMID1 ( SEQ ID NO.24; Gene ID: OTTHUMG00000030824), KLRG2 ( SEQ ID NO.25; Gene ID: ENSG00000188883), ERMP1 ( SEQ ID NO.26; Gene ID: ENSG00000099219), VMO1 ( SEQ ID NO.27; Gene ID: ENSG00000182853), C9orf46 ( SEQ ID NO.28; Gene ID: ENSG00000107020), F1137107 ( SEQ ID NO.29; Gene ID: ENSG00000177990), YIPF2 ( SEQ ID NO.30; Gene ID: ENSG00000130733), TRYX3 ( SEQ ID NO. NO.31; PRSS58, ENSG00000258223.2), C14orf135 ( SEQ ID NO.32; gene ID: ENSG00000126773), ANGPTL7 ( SEQ ID NO.33; gene ID: ENSG00000171819), TPCN2 ( SEQ ID NO.34; gene ID: ENSG00000162341), C18orf19 ( SEQ ID NO.35; gene ID: ENSG00000177150), OLFML1 ( SEQ ID NO.36; gene ID: ENSG00000183801), LYPD4 ( SEQ ID NO.37; gene ID: ENSG00000101203), MEGF8 ( SEQ ID NO.38; Gene ID: ENSG00000105429), F1142986 ( SEQ ID NO.39; Gene ID: ENSG00000196460), SLC46A1 ( SEQ ID NO.40; Gene ID: ENSG00000076351), FAM180A ( SEQ ID NO.41; Gene ID: ENSG00000189320), CRISP-3 ( SEQ ID NO.42; Gene ID: ENSG00000096006), or combinations thereof. These tumor antigens are disclosed in WO2010/086162, WO2010/086163, WO2011/051278, WO2011/051276, WO2011/051277, WO2011/051280, WO2011/051271, WO2011/135068, and WO2014/198919, the contents of which are incorporated herein by reference in their entirety.

In various embodiments, exemplary immunotherapeutic agents may include mRNAs operable to encode any one or more of the aforementioned cancer antigens that can be used to synthesize cancer vaccines. In some illustrative embodiments, the mRNA-based cancer vaccine may have one or more of the following characteristics: a) the mRNAs encoding each cancer antigen are dispersed at cleavage-sensitive sites; b) the mRNAs encoding each cancer antigen are directly linked to each other without linkers; c) the mRNAs encoding each cancer antigen are linked to each other via single nucleotide linkers; d) each cancer antigen contains 20-40 amino acids and includes a centrally located SNP mutation; e) at least 40% of the cancer antigens have the highest affinity for class I MHC molecules from the subject; f) to At least 40% of the cancer antigens have the highest affinity for class II MHC molecules from the subject; g) at least 40% of the cancer antigens have a predicted binding affinity for HLA-A, HLA-B, and/or DRB1 with an IC > 500 nM; h) the mRNA encodes 1 to 15 cancer antigens; i) 10%–60% of the cancer antigens have a binding affinity for class I MHCs and 10%–60% of the cancer antigens have a binding affinity for class II MHCs; and/or j) the mRNAs encoding cancer antigens are arranged such that the cancer antigens are sequenced to minimize pseudoepitopes.

In various embodiments, a combination of a compound comprising Formula I' and a cancer vaccine immunotherapy agent as disclosed herein can be used to elicit an immune response against a cancer antigen in a subject. The method involves administering to a subject an RNA vaccine comprising at least one RNA polynucleotide having an open reading frame encoding at least one antigenic polypeptide or an immunogenic fragment thereof, thereby inducing an immune response in the subject specific to that antigenic polypeptide or immunogenic fragment thereof, said administration being combined with the administration of a compound of Formula I' in the same or separate compositions, and administered simultaneously or sequentially in doses, wherein the anti-antigen polypeptide antibody titer in the vaccinated subject is increased relative to the anti-antigen polypeptide antibody titer in a subject vaccinated with a conventional anticancer vaccine of prophylactic efficacy. An "anti-antigen polypeptide antibody" is a serum antibody that specifically binds to an antigenic polypeptide.

The preventive effective dose is a clinically acceptable therapeutically effective dose for preventing cancer development. In some embodiments, the therapeutically effective dose is the dose listed in the vaccine's packaging insert. As used herein, a conventional vaccine refers to a vaccine other than the mRNA vaccine of this invention. For example, conventional vaccines include, but are not limited to, live microbial vaccines, inactivated microbial vaccines, subunit vaccines, protein antigen vaccines, DNA vaccines, etc. In exemplary embodiments, a conventional vaccine is a vaccine that has already received regulatory approval and/or is registered by a national drug regulatory agency (such as the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA)).

In some implementations, the anti-antigen peptide antibody titer in subjects increases by 1 to 10 log compared to the titer in subjects vaccinated with a conventional anti-cancer vaccine that is effective in prevention. In some implementations, the anti-antigen peptide antibody titer in subjects increases by 1 log compared to the titer in subjects vaccinated with a conventional anti-cancer vaccine that is effective in prevention. In some implementations, the anti-antigen peptide antibody titer in subjects increases by 2 log compared to the titer in subjects vaccinated with a conventional anti-cancer vaccine that is effective in prevention.

Aspects of the present invention provide nucleic acid vaccines comprising one or more RNA polynucleotides having an open reading frame encoding a first antigenic polypeptide, wherein the RNA polynucleotide is present in a formulation for in vivo administration to a host, and confers an antibody titer superior to the serological protection standard for the first antigen in an acceptable percentage of human subjects. In some embodiments, the antibody titer generated by the mRNA vaccine of the present invention is a neutralizing antibody titer. In some embodiments, the neutralizing antibody titer is greater than that of a protein vaccine. In other embodiments, the neutralizing antibody titer generated by the mRNA vaccine of the present invention is greater than that of an adjuvanted protein vaccine. In other embodiments, the neutralizing antibody titers generated by the mRNA vaccine of the present invention are 1,000-10,000, 1,200-10,000, 1,400-10,000, 1,500-10,000, 1,000-5,000, 1,000-4,000, 1,800-10,000, 2,000-10,000, 2,000-5,000, 2,000-3,000, 2,000-4,000, 3,000-5,000, 3,000-4,000, or 2,000-2,500. Neutralizing titers are generally expressed as the highest serum dilution required to achieve a 50% reduction in plaque count.

In a preferred aspect, the RNA vaccine immunotherapeutic agent (e.g., an mRNA vaccine) of this disclosure produces levels, concentrations, and/or titers of antigen-specific antibodies in the blood or serum of vaccinated subjects that are effective in prevention and/or treatment. As defined herein, the term antibody titer refers to the amount of antigen-specific antibodies produced in a subject (e.g., a human subject). In an exemplary embodiment, antibody titer is expressed as the reciprocal of the highest dilution (among successive dilutions) that still yields a positive result. In an exemplary embodiment, antibody titer is determined or measured by enzyme-linked immunosorbent assay (ELISA). In an exemplary embodiment, antibody titer is determined or measured by a neutralization assay (e.g., by a micro-neutralization assay). In some aspects, antibody titer measurements are expressed as ratios, such as 1:40, 1:100, etc.

In exemplary embodiments of the invention, an effective vaccine produces antibody titers greater than 1:40, 1:100, 1:400, 1:1000, 1:2000, 1:3000, 1:4000, 1:500, 1:6000, 1:7500, or 1:10000. In exemplary embodiments, this antibody titer is produced or reached 10 days, 20 days, 30 days, 40 days, or 50 days or more after vaccination. In exemplary embodiments, this titer is produced or reached after administration of a single dose of the vaccine to the subject. In other embodiments, this titer is produced or reached after multiple doses, such as after a first dose and a second dose (e.g., a booster dose). In exemplary aspects of the invention, antigen-specific antibodies are measured in g/ml, or in IU/L (International Units per Liter) or mIU/ml (milli-International Units per ml). In exemplary embodiments of the present invention, an effective vaccine produces >0.5 μg/mL, >0.1 μg/mL, >0.2 μg/mL, >0.35 μg/mL, >0.5 μg/mL, >1 μg/mL, >2 μg/mL, >5 μg/mL, or >10 μg/mL. In exemplary embodiments of the present invention, an effective vaccine produces >10 mIU/mL, >20 mIU/mL, >50 mIU/mL, >100 mIU/mL, >200 mIU/mL, >500 mIU/mL, or >1000 mIU/mL. In exemplary embodiments, this antibody level or concentration is produced or reached 10 days, 20 days, 30 days, 40 days, or 50 days or more after vaccination. In exemplary embodiments, this level or concentration is produced or reached after administration of a single dose of vaccine to the subject. In other embodiments, the level or concentration is generated or reached after multiple doses, such as after a first dose and a second dose (e.g., a booster dose). In exemplary embodiments, the antibody level or concentration is determined or measured by an enzyme-linked immunosorbent assay (ELISA). In exemplary embodiments, the antibody level or concentration is determined or measured by a neutralization assay (e.g., by a micro-neutralization assay). Nucleic acid vaccines comprising one or more RNA polynucleotides having an open reading frame encoding a first antigenic polypeptide or a tandem polypeptide are also provided, wherein the RNA polynucleotide is present in a formulation for in vivo administration to a host to induce a higher antibody titer that is more durable than that induced by an mRNA vaccine having a stabilizing element or formulated with an adjuvant and encoding the first antigenic polypeptide. In some embodiments, the RNA polynucleotide is formulated to generate neutralizing antibodies within one week of a single administration. In some embodiments, the adjuvant is selected from cationic peptides and immunostimulatory nucleic acids. In some embodiments, the cationic peptide is protamine.

An immunotherapeutic agent comprising a nucleic acid vaccine, said nucleic acid vaccine comprising one or more RNA polynucleotides having an open reading frame containing at least one chemical modification or optionally without nucleotide modification, said open reading frame encoding a first antigenic polypeptide or a tandem polypeptide, wherein said RNA polynucleotide is present in a formulation for in vivo administration to a host such that the antigen expression level in the host is significantly higher than the antigen expression level produced by an mRNA vaccine having a stabilizing element or formulated with an adjuvant and encoding the first antigenic polypeptide.

Other aspects provide nucleic acid vaccines comprising one or more RNA polynucleotides having an open reading frame containing at least one chemically modified or optionally unmodified nucleotide, the open reading frame encoding a first antigenic polypeptide or a tandem polypeptide, wherein the vaccine has at least 10 times fewer RNA polynucleotides than an unmodified mRNA vaccine required to produce the same antibody titer. In some embodiments, the RNA polynucleotide is present in a dose of 25-100 micrograms.

The invention also provides a unit of use for a vaccine comprising between 10 μg and 400 μg of one or more RNA polynucleotides and a pharmaceutically acceptable carrier or excipient, said RNA polynucleotide having an open reading frame containing at least one chemical modification or optionally no nucleotide modification, said open reading frame encoding a first antigenic polypeptide or tandem polypeptide, said vaccine being formulated for delivery to a human subject. In some embodiments, the vaccine further comprises cationic lipid nanoparticles.

Aspects of the present invention provide methods for generating, maintaining, or restoring antigenic memory of a tumor in an individual or population of individuals, comprising administering an antigen-memory-enhancing nucleic acid vaccine to said individual or population, said vaccine comprising (a) at least one RNA polynucleotide, said polynucleotide comprising at least one chemically modified or optionally unmodified open reading frame and two or more codon-optimized open reading frames encoding a set of reference antigen peptides, and (b) optionally a pharmaceutically acceptable carrier or excipient. In some embodiments, the vaccine is administered to the individual via a route selected from intramuscular, intradermal, and subcutaneous administration. In some embodiments, the administration step includes contacting the subject's muscle tissue with a device suitable for injecting the composition. In some embodiments, the administration step includes combining electroporation to contact the subject's muscle tissue with a device suitable for injecting the composition.

An aspect of the present invention provides a method of vaccinating a subject, comprising administering to the subject a single dose of a nucleic acid vaccine in an amount effective for vaccinating the subject, between 25 μg/kg and 400 μg/kg, the nucleic acid vaccine comprising one or more RNA polynucleotides having an open reading frame encoding a first antigen polypeptide or a tandem polypeptide.

Other aspects provide nucleic acid vaccines comprising one or more RNA polynucleotides having an open reading frame containing at least one chemical modification encoding a first antigenic polypeptide or a tandem polypeptide, wherein the vaccine contains at least 10 times fewer RNA polynucleotides than an unmodified mRNA vaccine required to produce the same antibody titer. In some embodiments, the RNA polynucleotides are present in a dose of 25-100 micrograms.

In some embodiments, exemplary immunotherapeutic agents may include one or more interfering RNAs, which may be administered in combination with compounds of Formula I'. As used herein, "RNA interfering agent" is defined as any agent that interferes with or inhibits the expression of a target biomarker gene by RNA interference (RNAi). Such RNA interfering agents include, but are not limited to, nucleic acid molecules (including RNA molecules homologous to the target biomarker gene of the present invention), or fragments thereof, short interfering RNA (siRNA), and small molecules that interfere with or inhibit the expression of a target biomarker nucleic acid by RNA interference (RNAi). Short interfering RNA (siRNA), also referred to herein as "small interfering RNA," is defined as an agent that, for example, inhibits the expression of a target biomarker nucleic acid by RNAi. siRNA may be chemically synthesized, produced by in vitro transcription, or produced within host cells. In one embodiment, the siRNA is a double-stranded RNA (dsRNA) molecule of about 15 to about 40 nucleotides in length, preferably about 15 to about 28 nucleotides, more preferably about 19 to about 25 nucleotides, and even more preferably about 19, 20, 21, or 22 nucleotides, and may contain 3' and/or 5' overhangs of about 0, 1, 2, 3, 4, or 5 nucleotides in length on each strand. The length of the overhangs is independent between the two strands, i.e., the length of the overhang on one strand does not depend on the length of the overhang on the second strand. Preferably, the siRNA is capable of promoting RNA interference through the degradation of target messenger RNA (mRNA) or specific posttranscriptional gene silencing (PTGS).

The length of antisense oligonucleotides can be, for example, about 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 or more nucleotides. Antisense nucleic acids can be constructed using chemical synthesis and enzymatic ligation reactions, employing procedures known in the art. For example, antisense nucleic acids (e.g., antisense oligonucleotides) can be chemically synthesized using naturally occurring nucleotides or various modified nucleotides designed to increase the biological stability of the molecule or the physical stability of the duplex formed between antisense and sense nucleic acids, such as phosphate thioester derivatives and acridine-substituted nucleotides. Examples of modified nucleotides that can be used to generate antisense nucleic acids include 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine, 5-(carboxyhydroxymethyl)uracil, 5-carboxymethylaminomethyl-2-thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosylqueosine, inosine, N6-isopentenyladenine, 1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine, 7-methylguanine, 5-methylaminomethyluracil, 5-methyl... 2,6-diaminopurine, beta-D-mannosylqueosine, 5'-methoxycarboxymethyluracil, 5-methoxyuracil, 2-methylthio-N6-isopentenyladenine, uracil-5-oxyacetic acid (v), wybutoxosine, pseudouracil, queosine, 2-mercaptocytosine, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, methyl uracil-5-oxyacetic acid, uracil-5-oxyacetic acid (v), 5-methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl)uracil, (acp3)w, and 2,6-diaminopurine. Alternatively, antisense nucleic acids can be produced using biological methods using an expression vector, wherein the nucleic acid has been subcloned into the expression vector with an antisense orientation (i.e., the RNA transcribed from the inserted nucleic acid will have an antisense orientation with the target nucleic acid of interest, which will be further described in the following subsections).

The antisense nucleic acid molecules of the present invention are typically administered to a subject or generated in situ, such that they hybridize or bind to cellular mRNA and/or genomic DNA encoding a polypeptide corresponding to a selected biomarker of the present invention, thereby inhibiting the expression of the biomarker, for example, by inhibiting transcription and/or translation. Hybridization can be performed by conventional nucleotide complementarity to form a stable duplex or, for example, by specific interactions in the major groove of the double helix in the case of antisense nucleic acid molecules bound to a DNA duplex. Examples of administration routes of the antisense nucleic acid molecules of the present invention include direct injection at a tissue site or infusion of the antisense nucleic acid into blood or bone marrow-related fluids. Alternatively, the antisense nucleic acid molecules can be modified to target selected cells and then administered systemically. For example, for systemic administration, the antisense molecules can be modified such that they specifically bind to a receptor or antigen expressed on the surface of a selected cell, for example, by linking the antisense nucleic acid molecules to a peptide or antibody that binds to a cell surface receptor or antigen. The antisense nucleic acid molecules can also be delivered to cells using the vectors described herein. To obtain sufficient intracellular concentrations of antisense molecules, it is preferable that the antisense nucleic acid molecules are placed under the control of a strong pol II or pol III promoter.

Antigens that can be targeted to synthesize corresponding antisense RNA molecules may include any antigens specific to one or more tumors, such as the antigens exemplified above in relation to cancer vaccines.

In some embodiments, the combination of an immunotherapeutic agent and a compound of formula I' may include a bispecific antibody immunotherapeutic agent. The bispecific antibody may include a protein construct having a first antigen-binding moiety and a second antigen-binding site that binds to cytotoxic immune cells. The first antigen-binding site may bind to a tumor antigen to be specifically treated by the combination of the present invention. For example, the first antigen-binding moiety may bind to non-limiting examples of tumor antigens selected from: EGFR, HGFR, Her2, Ep-CAM, CD20, CD30, CD33, CD47, CD52, CD133, CEA, gpA33, mucin, TAG-72, CIX, PSMA, folate-binding protein, GD2, GD3, GM2, VEGF, VEGFR, integrin αVβ3, integrin α5β1, MUC1, ERBB2, ERBB3, MET, IGF1R, EPHA3, TRAILR1, TRAILR2, RANKL, FAP, and tendinin, etc. In some embodiments, the first antigen-binding moiety is specific for proteins or peptides overexpressed on tumor cells compared to corresponding non-tumor cells. As used herein, "corresponding non-tumor cells" refers to non-tumor cells of the same cell type as the tumor cells. Note that such proteins are not necessarily different from tumor antigens. Non-limiting examples include carcinoembryonic antigen (CEA), which is overexpressed in most colon, rectal, breast, lung, pancreatic, and gastrointestinal cancers; hyalin receptors (HER-2, neu, or c-erbB-2), which are frequently overexpressed in breast, ovarian, colon, lung, prostate, and cervical cancers; epidermal growth factor receptor (EGFR), which is highly expressed in a range of solid tumors including breast, head and neck, non-small cell lung cancer, and prostate cancer; desialylate glycoprotein receptor; transferrin receptor; serine protease inhibitor enzyme complex receptor, which is expressed on hepatocytes; fibroblast growth factor receptor (FGFR), which is overexpressed on pancreatic duct adenocarcinoma cells; vascular endothelial growth factor receptor (VEGFR), used for anti-angiogenic gene therapy; folate receptor, which is selectively overexpressed in 90% of non-mucinous ovarian cancers; cell surface glycocalyx; carbohydrate receptors; and polymerase receptors.

The second antigen-binding moiety is any molecule that specifically binds to an antigen, protein, or polypeptide expressed on the surface of a cytotoxic immune cell (CIK cell). Exemplary non-restricted antigens suitable for use with this disclosure and expressed on the surface of cytotoxic immune cells may include CD2, CD3, CD4, CD5, CD8, CD11a, CD11b, CD14, CD16a, CD27, CD28, CD45, CD45RA, CD56, CD62L, Fc receptor, LFA, LFA-1, TCRαβ, CCR7, macrophage inflammatory protein 1a, perforin, PD-1, PD-L1, PD-L2 or CTLA-4, LAG-3, OX40, 41BB, LIGHT, CD40, GITR, TGF-β, TIM-3, SIRP-α, TIGIT, VSIG8, BTLA, SIGLEC7, SIGLEC9, ICOS, B7H3, B7H4, FAS, BTNL2, CD27, and Fas ligand. In some embodiments, the second antigen-binding portion binds to CD3 of cytotoxic immune cells (e.g., CIK cells). In some embodiments, the second antigen-binding portion binds to CD56 of cytotoxic immune cells. In some embodiments, the second antigen-binding portion binds to the Fc receptor of cytotoxic immune cells. In some embodiments, the Fc region of a bispecific antibody binds to the Fc receptor of cytotoxic immune cells. In some embodiments, the second antigen-binding portion is any molecule that specifically binds to an antigen expressed on the surface of cytotoxic immune cells (e.g., CIK cells). The second antigen-binding portion is specific to the antigen on the cytotoxic immune cells. Exemplary cytotoxic immune cells include, but are not limited to, CIK cells, T cells, CD8+ T cells, activated T cells, monocytes, natural killer (NK) cells, NK T cells, lymphokine-activated killer (LAK) cells, macrophages, and dendritic cells. The second antigen-binding portion specifically binds to an antigen expressed on the surface of the cytotoxic immune cells. Exemplary non-restricted antigens suitable for regulation on the surface of cytotoxic immune cells may include CD2, CD3, CD4, CD5, CD8, CD11a, CD11b, CD14, CD16a, CD27, CD28, CD45, CD45RA, CD56, CD62L, Fc receptor, LFA, LFA-1, TCRαβ, CCR7, macrophage inflammatory protein 1a, perforin, PD-1, PD-L1, PD-L2 or CTLA-4, LAG-3, OX40, 41BB, LIGHT, CD40, GITR, TGF-β, TIM-3, SIRP-α, TIGIT, VSIG8, BTLA, SIGLEC7, SIGLEC9, ICOS, B7H3, B7H4, FAS, BTNL2, CD27, and Fas ligand. In other embodiments, the bispecific antibody modulator is an activator of a co-stimulatory molecule (e.g., an OX40 agonist). In one embodiment, the OX40 agonist is a bispecific antibody molecule of OX40 and another tumor antigen or co-stimulatory antigen. The OX40 agonist may be administered alone or in combination with other immunomodulators, such as with inhibitors (e.g., antibody constructs) of PD-1, PD-L1, CTLA-4, CEACAM (e.g., CEACAM-1, -3, and/or -5), TIM-3, or LAG-3. In some embodiments, the anti-OX40 antibody molecule is a bispecific antibody that binds to GITR and PD-1, PD-L1, CTLA-4, CEACAM (e.g., CEACAM-1, -3, and/or -5), TIM-3, or LAG-3. In one exemplary embodiment, the OX40 antibody molecule is administered in combination with an anti-PD-1 antibody molecule (e.g., the anti-PD-1 molecule described herein). The OX40 antibody molecule and the anti-PD-1 antibody molecule can be in the form of separate antibody compositions or as bispecific antibody molecules. In other embodiments, the OX40 agonist can be administered in combination with other co-stimulatory molecules (e.g., agonists of GITR, CD2, CD27, CD28, CDS, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), 4-1BB (CD137), CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3, or CD83 ligands). In some embodiments, the second antigen-binding portion binds to Fc receptors on cytotoxic immune cells (e.g., CIK cells).

In some embodiments, the bispecific antibody immunotherapy agent is specific to both tumor antigens and CIK cells, which allows tumor cells expressing tumor antigens to approach CIK cells closely, resulting in the elimination of tumor cells through anti-tumor cytotoxicity of CIK cells. In some embodiments, the bispecific antibody is specific to tumor antigens but not to CIK cells; however, the Fc region of the bispecific antibody can bind to the Fc receptors of CIK cells, which in turn allows tumor cells to approach CIK cells closely, resulting in the elimination of tumor cells through anti-tumor cytotoxicity of CIK cells. In some embodiments, the bispecific antibody is specific to CIK cells but not to tumor cells; however, the Fc region of the bispecific antibody can bind to the Fc receptors of tumor cells, which in turn allows tumor cells to approach CIK cells closely, resulting in the elimination of tumor cells through anti-tumor cytotoxicity of CIK cells.

In some embodiments, the combination of an immunotherapeutic agent and a compound of formula I' may comprise an immune cell-conjugated multivalent antibody/fusion protein/construct immunotherapeutic agent. In various embodiments, exemplary immunotherapeutic agents may comprise immune cell-conjugated multivalent antibodies/fusion proteins/constructs, which may contain recombinant structures, such as engineered antibodies that do not mimic the original IgG structure. Different strategies for polymerizing antibody fragments are utilized here. For example, shortening the peptide linker between the V domains forces scFv to self-associate into a dimer (biantibody; 55 kDa). Bispecific biantibodies are formed by the non-covalent binding of two VHA-VLB and VHB-VLA fragments expressed in the same cell. This results in the formation of a heterodimer with two different binding sites. Single-chain biantibodies (sc-biantibodies) are bispecific molecules in which the VHA-VLB and VHB-VLA fragments are linked together by an additional third linker. Tandem biantibodies (Tandabs) are tetravalent bispecific antibodies generated from two sc-biantibodies.

Also included are bi-biantibodies known in the art. This 130-kDa molecule is formed by fusing a biantibody to the N-terminus of the CH3 domain of IgG, resulting in an IgG-like structure. Other biantibody derivatives are triantibodies and tetraantibodies, which fold into trimer and tetrameric fragments by shortening the linker to <5 or 0-2 residues. Also exemplified is the (scFv) ₂ construct known as the 'bispecific T-cell adaptor' (BITE). BITE is a bispecific single-chain antibody consisting of two scFv antibody fragments linked by a flexible linker targeting surface antigens on target cells and CD3 on T cells. Bivalent (Fab)2 and trivalent (Fab)3 antibody forms are also exemplified. Microbodies and trimers generated from scFv are also exemplified. Exemplary constructs that can be used to target tumor antigens may include one or more of the following: double-stranded antibodies, single-stranded (sc)-double-stranded antibodies (scFv)2, microantibodies, microbodies, Barnase-barstar, scFv-Fc, sc(Fab)2, trimer antibody constructs, triple-stranded antibody constructs, trimer antibody constructs, trisomic antibody constructs, collagen scaffold antibody constructs, (scFv-TNFa)3, and F(ab)3/DNL. In each of these exemplary constructs, at least one binding portion may bind to an antigen or protein or peptide expressed on the surface of a cytotoxic immune cell, and at least one binding portion will specifically bind to the antigen on the cytotoxic immune cell. Exemplary cytotoxic immune cells include, but are not limited to, CIK cells, T cells, CD8+ T cells, activated T cells, monocytes, natural killer (NK) cells, NK T cells, lymphokine-activated killer (LAK) cells, macrophages, and dendritic cells.

In some embodiments, the combination of the immunotherapeutic agent and the compound of formula I' may include a radioconjugated immunotherapeutic agent.

In various embodiments, a radioconjugate is a small or large molecule (referred to herein as a “cell target”) and peptide, antibody, or antibody fragment thereof coupled to or otherwise attached to a radionuclide or multiple radionuclides, such that the binding of the radioconjugate to its target (a protein or molecule on or in a cancer cell) will lead to the death or pathogenesis of said cancer cell. In various embodiments, the radioconjugate may be a cell target labeled with a radionuclide, or the cell target may be coupled to or otherwise attached to particles, microparticles, or nanoparticles containing multiple radionuclides, wherein these radionuclides may be the same or different. Methods for synthesizing radioconjugates are known in the art and may include a classification of immunoglobulins or their antigen-binding moieties conjugated to toxic radionuclides.

In some embodiments, the molecule that binds to cancer cells may be referred to as a “cell target.” As used herein, exemplary cell targets may allow drug-containing nanoparticles or radionuclides to target specific types of cells of interest. Examples of cell targets include, but are not limited to, small molecules (e.g., folic acid, adenosine, purines) and large molecules (e.g., peptides or antibodies) that bind to or target tumor-associated antigens. Examples of tumor-associated antigens include, but are not limited to, adenosine receptor, αvβ3, aminopeptidase P, alpha-fetoprotein, cancer antigen 125, carcinoembryonic antigen, c-cryptin-1, chemokine receptor, cluster protein, tumor-associated antigen, CD20, epithelial tumor antigen, melanoma-associated antigen, Ras, p53, Her2/Neu, ErbB2, ErbB3, ErbB4, folic acid receptor, prostate-specific membrane antigen, prostate-specific antigen, purine receptor, radiation-induced cell surface receptor, serine protease inhibitor B3, serine protease inhibitor B4, squamous cell carcinoma antigen, platelet-reactive protein, tumor antigen 4, tumor-associated glycoprotein 72, tyrosinase, and tyrosine kinase. In some embodiments, the cell target is folic acid or a folic acid derivative that specifically binds to the folic acid receptor (FR). In some embodiments, the cell target is an antibody, bispecific antibody, trispecific antibody, or antigen-binding construct thereof that specifically binds to a cancer antigen selected from: EGFR, HGFR, Her2, Ep-CAM, CD20, CD30, CD33, CD47, CD52, CD133, CEA, gpA33, mucin, TAG-72, CIX, PSMA, folic acid-binding protein, GD2, GD3, GM2, VEGF, VEGFR, integrin αVβ3, integrin α5β1, MUC1, ERBB2, ERBB3, MET, IGF1R, EPHA3, TRAILR1, TRAILR2, RANKL, FAP, and tendinin, etc.

The use of folic acid as a targeting agent in radioactive conjugates also allows for the targeted destruction of both tumor cells and regulatory T (Treg) cells. It is well known that a large number of Treg cells suppress tumor immunity. Specifically, Treg cells suppress (exogenous and autologous) reactive T cells without killing them through contact-dependent or cytokine secretion (e.g., IL-10, TGF-β, etc.). FR4 is selectively upregulated on Treg cells. It has been shown that antibody blocking of FR4 in tumor-bearing mice depletes Treg cells and stimulates tumor immunity. Therefore, folic acid-coated PBM nanoparticles carrying cytotoxic agents will take up FR-expressing cells for destruction, which will directly (i.e., BrCa cells) and indirectly (i.e., breast tumor-associated and peripheral Treg cells) inhibit tumor progression.

In another embodiment, the target is an antibody or peptide capable of binding to tumor-associated antigens, or an immune cell-conjugating multivalent antibody/fusion protein/construct, said antigens including but not limited to: adenosine receptor, αvβ3, aminopeptidase P, alpha-fetoprotein, cancer antigen 125, carcinoembryonic antigen, caveolin-1, chemokine receptor, cluster protein, tumor-associated antigen, CD20, human growth factor receptor (HGFR), epithelial tumor antigen, melanoma-associated antigen, MUC1, Ras, p53, Her2/Neu, ErbB2, ErbB3, ErbB4, folate receptor, prostate-specific membrane antigen, prostate-specific antigen, purine receptor, radiation-induced cell surface receptor, serine protease inhibitor B3, serine protease inhibitor B4, squamous cell carcinoma antigen, platelet-reactive protein, tumor antigen 4, tumor-associated glycoprotein 72, tyrosinase, tyrosine kinase, etc.

In one embodiment, the treatment method comprises co-administering a compound as disclosed herein or a pharmaceutically acceptable salt thereof and at least one cytotoxic agent. As used herein, the term "cytotoxic agent" refers to a substance that inhibits or prevents cell function and/or causes cell death or destruction. Cytotoxic agents include, but are not limited to: radioisotopes (e.g., radioisotopes of At ²¹¹ , I ¹³¹ , I ¹²⁵ , Y ⁹⁰ , Re ¹⁸⁶ , Re ¹⁸⁸ , Sm ¹⁵³ , Bi ²¹² , P ³² , Pb ²¹² , and Lu); chemotherapeutic agents; growth inhibitors; enzymes and fragments thereof, such as lysozymes; and toxins, such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant, or animal origin, including fragments and/or variants thereof.

Exemplary cytotoxic agents may be selected from anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotics, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormone analogs, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, pro-apoptotic agents, LDH-A inhibitors; fatty acid biosynthesis inhibitors; cell cycle signal transduction inhibitors; HDAC inhibitors, proteasome inhibitors; and cancer metabolism inhibitors.

Chemotherapy agents include chemical compounds used to treat cancer. Examples of chemotherapy agents include erlotinib (Genentech/OSIPharm), bortezomib (Millennium Pharm), disulfiram, epigallocatechin gallate, salinomycin A, carfilzomib, 17-AAG (gerdemycin), rhizobactam, lactate dehydrogenase A (LDH-A), fulvestrant (AstraZeneca), sunitinib (Pfizer/Sugen), letrozole (Novartis), imatinib mesylate (Novartis), and phenacetinib. (finasunate)(Novartis), oxaliplatin (Sanofi), 5-FU (5-fluorouracil), leucovorin, rapamycin (Sirolimus, Wyeth), lapatinib (GSK572016, Glaxo SmithKline), lonafazil (Lonafamib)(SCH 66336), sorafenib (Bayer Labs), gefitinib (AstraZeneca), AG1478; alkylating agents, such as thiotepa and cyclophosphamide; alkyl sulfonates, such as busulfan, inprofen, and piperazine; nitrogen Propidine, such as benzodopa, carboquinone, meturedopa, and uredopa; ethylene imine and methylmelamine, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylomelamine; Anthocyanins (especially bullatacin and bullatacinone); camptothecin (including topotecan and irinotecan); bryostatin; callystatin; CC-1065 (including its synthetic analogues adozelesin, carzelesin, and bizelesin); cryptophycins (especially cryptophycin 1 and cryptophycin 8); corticosteroids (including prednisone and prednisolone); acetic acid Cyproterone acetate; 5α-reductase (including finasteride and dutasteride); vorinostat, romidepsin, panobinostat, valproic acid, moxistatin, dolastatin; interleukin, talc duocarmycin (including synthetic analogs KW-2189 and CB1-TM1); eleutherobin; pancratistatin; sarcodictyin; spongistatin (spongistatin); nitrogen mustard, such as chlorambucil, naphthyl mustard, chlorphosphamide, estradiol, ifosfamide, nitrogen mustard, oxynitric acid mustard, melphalan, neonitric acid mustard, benzyl mustard cholesterol, pine monoxide benzyl mustard, tristyramine cyclophosphamide, uracil nitrogen mustard; nitrosourea, such as carmustine, chloramphenicol, formustine, lomustine, nimustine, and ranistine; antibiotics, such as enediyne antibiotics (e.g., galicarmycin, especially galicarmycin γ1I and galicarmycin ω1I (Angew Chem. Intl. Ed. Engl. 1994 33:183-186); dyinmycin, including This includes dysinic A; bisphosphonates, such as clophosphonate; esporamin; and neocarzinostatin chromophores and related chromoprotein endothymyl antibiotic chromophores, aclarubicin, actinomycin, autramycin, azoserine, bleomycin, cactinomycin C, carabicin, caminomycin, carzinophilin, chromomycin, and more. Doxorubicin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-leucine, (daunorubicin), morpholino-daunorubicin, cyanomorpholino-daunorubicin, 2-pyrrolino-daunorubicin and deoxydaunorubicin, epirubicin, isorubicin, idarubicin, marcellomycin, mitomycin such as mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, porfiromycin Cin, puromycin, quelamycin, rodorubicin, streptozocin, tuberculin, ubenimex, zinostatin, zorubicin; antimetabolites, such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs, such as folate, methotrexate, pteroxate, trimethoprim; purine analogs, such as fludarabine, 6-mercaptopurine, thioimidapurine, thioguanine; pyrimidine analogs, such as ancitabine and azacitidine. 6-azauridine, carmoflurane, cytarabine, dideoxyuridine, deoxyfluorouridine, enoxabin, fluorouridine; androgens, such as calotestosterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; antiadrenergics, such as aminoglutethimide, mitotane, trilostane; folic acid supplements, Such as leucovorin; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithi ne); elliptinium acetate; epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansine alkaloids, such as maytansine and anthraquinone; mitoxanthraquinone; mopidamnol; nitraerine; pentostatin ); Phenamet; Pirarubicin; Loxoanthraquinone; Podophyllinic acid; 2-Ethylhydrazide; Procarbazine; Polysaccharide complex (JHS Natural Products, Eugene, Ore.); Razoxane; Rhizoxin; Sizofuran; Spirogermanium; Tenuazonic acid; Triaziquone; 2,2’ ,2”-Trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A, and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactalol; piperobroman; g acytosine; cytarabine (“Ara-C”); cyclophosphamide; thiotepa; taxanes, such as TAXOL (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, N.J.), (cremophor-free), albumin-engineered nanoparticle formulations of paclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.), and (docetaxel, docetaxel; Sanofibrils) i-Aventis; chloranmbucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vincristine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; vinorelbine; mitoxantrone; teniposide; edaraxacin; donomycin; aminopterin; capecitabine ibandronate; CPT-11; topoisomerase inhibitor RFS2000; difluoromethylornithine (DMFO); visual pigments such as retinoic acid; and pharmaceutically acceptable salts, acids, and derivatives of any of the above.

Chemotherapy agents also include (i) anti-hormonal agents that act to regulate or inhibit the effects of hormones on tumors, such as anti-estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including tamoxifen citrate), raloxifene, droloxifen, iodoxyfene, 4-hydroxytamoxifen, trivoxifen, keoxifene, LY117018, onanasone, and toremifene citrate; (ii) aromatase inhibitors that inhibit aromatase production in the adrenal glands, such as 4(5)-imidazole, aminoglutethimide, megestrol acetate, exemestane, formestanie, fadrozole, vorozole, letrozole, and anastrozole; and (iii) anti-androgens, such as flutamide, nitroglycerin, etc. Mite, bicalutamide, leuprorelin and goserelin; buserelin, tripterelin, medroxyprogesterone acetate, diethylstilbestrol, premarin, fluoromethesterone, all-trans retinoids, fenivel-Aminide and trisatabine (1,3-dioxane-1,3-cytosine analog); (iv) protein kinase inhibitors; (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, particularly those that inhibit gene expression in signaling pathways involved in abnormal cell proliferation, such as PKC-α, Ralf and H-Ras; (vii) ribozymes, such as VEGF expression inhibitors (e.g.) and HER2 expression inhibitors; (viii) vaccines, such as gene therapy vaccines, such as rIL-2; topoisomerase 1 inhibitors, such as (ix) pharmaceutically acceptable salts, acids and derivatives of any of the above.

Chemotherapy agents also include antibodies as described above, including alemtuzumab (Campath), bevacizumab (Genentech); cetuximab (Imclone); panitumumab (Amgen), rituximab (Genentech/Biogen Idec), pertuzumab (2C4, Genentech), trastuzumab (Genentech), tosimoumab (Bexxar, Corixia), and the antibody conjugate gemtuzumab ozomicin (Wyeth). Other humanized monoclonal antibodies with therapeutic potential that can be combined with the compounds of the present invention as agents include: apolizumab, acelizumab, atlizumab, bapineuzumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumabpegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, and erlizumab. Monoclonal antibodies (erlizumab), felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motovizumab, natalizumab, nimotuzumab, nivolumab, nolovizumab, numavizumab, ocrel izumab), omalizumab, palivizumab, pascolizumab, pecfusituzumab, pectuzumab, pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab, resyvizumab, rovelizumab, ruplizumab, sibrotuzumab, siplizumab, sontuzumab, tacatuzumab tesetan The anti-interleukin-12 antibody includes raxetan, tadocizumab, talizumab, tefibazumab, tocilizumab, totalizumab, tucotuzumabcelmoleukin, tucusituzumab, umavizumab, urtoxazumab, ustekinumab, visilizumab, and a genetically modified recombinant exclusive human full-length IgG sub.1.λ antibody that recognizes the interleukin-12 p40 protein (ABT-8744695, Wyeth Research and Abbott Laboratories).

Chemotherapy agents also include "tyrosine kinase inhibitors," including EGFR inhibitors; small molecule HER2 tyrosine kinase inhibitors, such as mubritonib (TAK165, Takeda); CP-724.714 (Axon Medchem BV, an orally selective inhibitor of ErbB2 receptor tyrosine kinase); dual HER inhibitors, such as EKB-569 (purchased from Wyeth), which preferentially binds to EGFR but inhibits both HER2 and EGFR-overexpressing cells; lapatinib (GSK572016; purchased from Glaxo-SmithKline), an orally administered HER2 and EGFR tyrosine kinase inhibitor; PKI-166 (purchased from Novartis); pan-HER inhibitors, such as canenatinib (CI-1033; Ph armacia); Raf-1 inhibitors, such as the antisense agent ISIS-5132, which inhibits Raf-1 signaling, purchased from ISIS Pharmaceuticals; non-HER-targeted TK inhibitors, such as imatinib mesylate (purchased from Glaxo SmithKline); multi-targeted tyrosine kinase inhibitors, such as sunitinib (purchased from Pfizer); VEGF receptor tyrosine kinase inhibitors, such as vatalanib (PTK787/ZK222584, purchased from Novartis/Schering AG); MAPK extracellular regulated kinase 1 inhibitor CI-1040 (purchased from Pharmacia); quinazolines, such as PD 153035, 4-(3-chloroaniline)quinazoline; pyridopyrimidine; pyrimidine; pyrrolopyrimidine, such as C GP 59326, CGP 60261, and CGP 62706; pyrazolopyrimidine, 4-(phenylamino)-7H-pyrrolo[2,3-d]pyrimidine; curcumin (diferoylmethane, 4,5-bis(4-fluoroaniline)phthalimide); tyrosine phosphorylation containing a nitrothiophene moiety; antisense molecules (e.g., those that bind to nucleic acids encoding HER); quinoxaline (US Patent No. 5,804,396); tryphostins (US Patent No. 5,804,396); affinitac (ISIS 3521; Isis/Lilly); PKI166 (Novartis); semaxinib (Pfizer); INC-1C11 (Imclone); [unclear text - possibly a brand name or product] Paramycin (Sirolimus); or as described in any of the following patent disclosures: U.S. Patent No. 5,804,396; WO 1999/09016 (American Cyanamid); WO 1998/43960 (American Cyanamid); WO 1997/38983 (Warner Lambert); WO 1999/06378 (Warner Lambert); WO 1999/06396 (Warner Lambert); WO 1996/30347 (Pfizer, Inc.); WO 1996/33978 (Zeneca); WO 1996/3397 (Zeneca) and WO 1996/33980 (Zeneca). Tyrosine kinase inhibitors also include erlotinib, gefitinib, dasatinib, nilotinib, ruxotinib, vemurafenib, vande, tanipazol, panib, afatinib, alisertinib, amovatinib, axitinib, bosutinib, brivanib, canertinib, cabozantinib, cediranib, and crenolan. ib), dabrafenib, dacomitinib, danusertib, dovitinib, foretinib, ganesteb, ibrutinib, iniparib, lenvatinib, linifanib, linsitinib, masitinib, molotinib momelotinib, motesanib, neratinib, niraparib, oprozomib, olaparib, pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, saracatinib (ib), saridegib, tandutinib, tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, trametinib, veliparib, vismodegib, volasertib, cobimetinib, etc.

Chemotherapy agents also include dexamethasone, interferon, colchicine, metoprine, cyclosporine, amphotericin B, metronidazole, alemtuzumab, retinoic acid, allopurinol, amifostine, arsenic trioxide, asparaginase, BCG live vaccine, bevacizumab, bexarotine, cladribine, clofarabine, darbepoetine alpha, denileukin, dextromethorphan, and epioetin alpha. Alfa, erlotinib, filgrastim, histamine acetate, ibritumomab, interferon alpha-2a, interferon alpha-2b, lenalidomide, levamisole, mesna, methoxsalen, nandrolone, nelarabine, nofetumomab, op-leukin Relvekin), palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim, pemetrexed disodium, plicamycin, porfimer sodium, quinacrine, rasburicase, sargramostim, temozolomide, VM-26, 6-TG, toremifene, tretinoin, ATRA, valrubicin, zoledronate, and zoledronic acid, as well as their pharmaceutically acceptable salts.

Chemotherapy agents also include hydrocortisone, hydrocortisone acetate, tixocortol pivalate, triamcinolone, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinolone acetonide, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluclocolone, hydrocortisone-17-butyrate, hydrocortisone-17-valerate, aclometasone dipropionate, betamethasone valerate, and betamethasone dipropionate. dipropionate, prednicarbamate, clobetasol-17-butyrate, clobetasol-17-propionate, fluocortolone hexanoate, fluocortolone pivalate, and fluprednidene acetate; immunoselective anti-inflammatory peptides (ImSAIDs), such as phenylalanine-glutamine-glycine (FEG) and its D-isomer (feG) (IMULAN) BioTherapeutics, LLC; antirheumatic drugs, such as azathioprine, cyclosporine (cyclosporine A), D-penicillamine, gold salts, hydroxychloroquine, leflunomide, sulfasalazine, tumor necrosis factor α (TNFα) blockers (such as etanercept (Enbrel), infliximab (Remicade), adalimumab (1-Iumira), cetuzumab (Cimzia), golimumab (Simponi)), interleukin-1 (IL-1) blockers (such as anaerobicin (Kineret)), and T-cell co-stimulation blockers (such as abatacept). (abatacept)(Orencia)), interleukin-6 (IL-6) blockers such as tocilizumab; interleukin-13 (IL-13) blockers such as lebrikizumab; interferon-alpha (IFN) blockers such as rontalizumab; β7 integrin blockers such as rhuMAbβ7; IgE pathway blockers such as anti-M1 initiators; secretory homotrimer LTa3 and membrane-bound heterotrimer LTa1/132 blockers such as anti-lymphotoxin alpha (LTa); mixed investigation agents such as thioplatin, PS-341, phenyl butyrate, ET-18-OCH ₃ or farnesyltransferase inhibitors (L-739749, L-744832); polyphenols, such as quercetin, resveratrol, leucine, epigallocatechin gallate, theaflavins, flavanols, proanthocyanidins, betulinic acid and their derivatives; autophagy inhibitors, such as chloroquine; δ-9-tetrahydrocannabinol (drocannabinol); β-lapachone; laparol; colchicine; betulinic acid; acetylcamptothecin, scopolamine and 9-aminocamptothecin); podophyllotoxin; tegafur bexarotine bisphosphonates, such as clodronate (e.g., or), etidronate NE-58095, zoledronic acid/zoledronic acid alendronate pamidronate teludronate or risedronate and epidermal growth factor receptor (EGF-R); vaccines, etc. Examples of such treatments include vaccines; perifosine, COX-2 inhibitors (e.g., celecoxib or etoricoxib), protein body inhibitors (e.g., PS341); CCI-779; tipifarnib (R11577); orafenib (ABT510); Bcl-2 inhibitors, such as GENASENSE (pisenoside); farnesyltransferase inhibitors, such as lonafamib (SCH6636, SARASAR ^™ ); and pharmaceutically acceptable salts, acids, or derivatives of any of the above; and combinations of two or more of the above, such as CHOP, an abbreviation for combination therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone; and FOLFOX, an abbreviation for oxaliplatin (ELOXATIN ^™ ) combined with 5-FU and leucovorin.

Chemotherapy agents also include poly-ADP-ribose polymerase (PARP) inhibitors: olapaline, nirapaline, and talzoparib.

Effective combinations of compounds of Formula I' or any of the formulas described herein with other agents can be identified through preclinical and clinical testing of the combination and will depend on many factors, including disease type and stage of development, patient's overall health, agent toxicity and side effects, etc.

In some embodiments, compounds such as those disclosed herein may be used in combination therapy with any of the kinase inhibitors disclosed herein for the treatment of diseases such as cancer. Exemplary kinase inhibitors include imatinib, baricitinib, gefitinib, erlotinib, sorafenib, dasatinib, sunitinib, lapatinib, nilotinib, pirfenidone, pazopanib, crizotinib, vemurafenib, vandetanib, ruxotinib, axitinib, bosutinib, regorafenib, tofacitinib, cabozantinib, panatinib, trametinib, dabrafenib, afatinib, ibrutinib, ceritinib, idelalisib, nintedanib, palbociclib, lenvatinib, cobitinib, XL-147, XL-765, XL-499, and XL-880. In some embodiments, the compounds described herein may be used in combination with HSP90 inhibitors (e.g., XL888), hepatic X receptor (LXR) modulators, orphan receptor γ (RORy) modulators associated with visual pigments, CK1 inhibitors, CK1-α inhibitors, Wnt pathway inhibitors (e.g., SST-215), or mineralocorticoid receptor inhibitors (e.g., ethacetenone or XL-550) for the treatment of diseases disclosed herein, such as cancer.

In some implementations, for the treatment of cancer, the compounds disclosed herein may be used in combination with inhibitors of PD-1 or PD-L1, such as anti-PD-1 monoclonal antibodies or anti-PD-L1 monoclonal antibodies, such as nivolumab (Opdivo), pembrolizumab (Keytruda, MK-3475), atezolizumab, ovavamab, AMP-224, AMP-514, PDR001, and duruvalumab. ), pildizumab (CT-011), CK-301, BMS 936559 and MPDL3280A; CTLA-4 inhibitors, such as anti-CTLA-4 antibodies, such as ipilimumab (Yervoy) and tesilimumab; and phosphatidylserine inhibitors, such as bavitimab (PGN401); antibodies against cytokines (IL-10, TGF-β, etc.); and other anticancer agents, such as cimetizumab.

In some embodiments, the compounds described herein may be used in combination with vaccination regimens for the treatment of cancer. In some embodiments, the compounds described herein may be used in combination with vaccines to stimulate an immune response to pathogens, toxins, and self-antigens. Examples of pathogens for which this treatment may be particularly useful include pathogens for which there are currently no effective vaccines, or pathogens for which conventional vaccines are not entirely effective. These include, but are not limited to, HIV, hepatitis (A, B, and C), influenza, herpes, Giardia, malaria, Leishmania, Staphylococcus aureus, and Pseudomonas aeruginosa.

In some embodiments, compounds such as those disclosed herein can be used in combination with PARP inhibitors, such as olapapani, rucapinini, lapapani, and tazopani.

The amounts of the compounds disclosed herein, or salts thereof, and one or more additional therapeutic agents (in those compositions comprising additional therapeutic agents as described above) that can be combined with a carrier material to produce a single dosage form will vary depending on the host being treated and the specific administration method. In some embodiments, the compositions of the invention are formulated such that a dose of 0.01-100 mg/kg body weight/day can be administered.

The additional therapeutic agent and the compounds disclosed herein can act synergistically. Therefore, the amount of the additional therapeutic agent in such compositions may be less than that required in a monotherapy using only the therapeutic agent, or, with the use of lower doses, fewer side effects may occur for the patient. In some embodiments, in such compositions, an additional therapeutic agent may be administered at a dose of 0.01-10,000 μg/kg body weight/day.

Labeled compounds and assay methods

Another aspect of the invention relates to the labeled compounds (radiolabeled, fluorescently labeled, etc.) of the invention, which can be used not only in imaging techniques but also in vitro and in vivo assays for locating and quantifying TAM kinases in tissue samples (including humans) and for identifying TAM kinase ligands by inhibiting the binding of the labeled compounds. Therefore, the invention includes TAM kinase assays containing such labeled compounds.

This invention also includes isotopically labeled compounds of the invention. An "isotopic" or "radiolabeled" compound is a compound of the invention in which one or more atoms are replaced or substituted with atoms having an atomic mass or mass number different from those normally found in nature (i.e., naturally occurring). Suitable radionuclides that can be incorporated into the compounds of the invention include, but are not limited to, ^2H (also written as D for deuterium), ^3H (also written as T for tritium), ^11C , ^13C , ^14C , ^13N , ^15N , ^15O , ^17O , ^18O , ^18F , ^35S , ^36Cl , ^82Br , ^75Br , ^76Br , ^77Br , ^123I , ^124I , ^125I , and ^131I . The radionuclides incorporated into the radiolabeled compounds of the invention will depend on the specific application of the radiolabeled compound. For example, for in vitro metalloproteinase labeling and competitive assays, compounds doped with ^3H , ^14C , ^82Br , ^125I , ^131I , or ^35S will generally be most useful. For radio imaging applications, ^11C , ^18F , ^125I , ^123I , ^124I , ^131I , ^75Br , ^76Br , or ^77Br will generally be most useful.

It should be understood that "radiolabeled" or "labeled compound" is a compound that has been doped with at least one radionuclide. In some embodiments, the radionuclide is selected from ^3H , ^14C , ^125I , ^35S , and ^82Br .

The present invention may also include a method for synthesizing compounds incorporating radioactive isotopes. Methods for synthesizing organic compounds incorporating radioactive isotopes are well known in the art, and those skilled in the art will readily recognize the methods applicable to the compounds of the present invention.

The labeled compounds of this invention can be used in screening assays to identify/evaluate compounds. For example, the ability of a newly synthesized or identified labeled compound (i.e., the test compound) to bind to TAM can be assessed by tracking changes in its concentration when the label is in contact with TAM kinase. For example, the ability of the (labeled) test compound to reduce the binding of another compound (i.e., the standard compound) known to bind to TAM kinase can be assessed. Therefore, the ability of the test compound to compete with the standard compound for binding to TAM kinase is directly related to its binding affinity. Conversely, in some other screening assays, the standard compound is labeled, and the test compound is not labeled. Therefore, the concentration of the labeled standard compound is monitored to assess the competition between the standard compound and the test compound, thereby determining the relative binding affinity of the test compound.

synthesis

The compounds of the present invention can be prepared by the following synthetic procedure. The raw materials and reagents used to prepare these compounds are available from commercial suppliers such as Sigma Aldrich Chemical Co. (Milwaukee, Wis.) or Bachem (Torrance, Calif.), or can be prepared by methods known to those skilled in the art according to the procedures described in references such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carb On Compounds, Volumes 1–5 and Supplements (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1–40 (John Wiley and Sons, 1991); March’s Advanced Organic Chemistry (John Wiley and Sons, 4th edition); and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989). These schemes are merely examples of some methods for synthesizing the compounds of the present invention, and various modifications can be made to these schemes, which will be suggested to those skilled in the art upon reference to this disclosure. If desired, the starting materials and intermediates of the reaction can be separated and purified using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, etc. Conventional means can be used to characterize such substances, including physical constants and spectroscopic data.

Unless otherwise stated, the reactions described herein are carried out at atmospheric pressure and in a temperature range of about -78°C to about 150°C, more preferably about 0°C to about 125°C, and most preferably about room temperature (or ambient temperature) (e.g., about 20°C). Unless otherwise stated (e.g., in the case of hydrogenation), all reactions are carried out under a nitrogen atmosphere.

The compounds disclosed and claimed herein have asymmetric carbon atoms or quaternized nitrogen atoms in their structure and can be prepared by the synthesis described herein as single stereoisomers, racemates, or mixtures of enantiomers and diastereomers. The compounds may also exist as geometric isomers. All such single stereoisomers, racemates, and geometric isomers, and mixtures thereof, are within the scope of this invention.

Some compounds of the present invention can exist as tautomers. For example, in the presence of a ketone or aldehyde, the molecule can exist as an enol; in the presence of an amide, the molecule can exist as an imine; and in the presence of an enamine, the molecule can exist as an imine. All these tautomers are within the scope of the present invention.

Methods for preparing and/or separating and isolating single stereoisomers from racemic or non-racemic mixtures of stereoisomers are well known in the art. For example, optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. Enantiomers (R- and S-isomers) can be separated by methods known to those skilled in the art, such as by: forming diastereomer salts or complexes that can be separated, for example, by crystallization; by forming diastereomer derivatives that can be separated, for example, by crystallization; by a selective reaction of an enantiomer with an enantiomer-specific reagent, such as enzymatic oxidation or reduction, followed by separation of modified and unmodified enantiomers; or by gas-liquid or liquid chromatography in a chiral environment, such as on a chiral support (e.g., silica with bonded chiral ligands) or in the presence of a chiral solvent. It should be understood that in cases where a desired enantiomer is converted to another chemical entity by one of the above separation procedures, further steps may be required to release the desired enantiomer form. Alternatively, specific enantiomers can be synthesized via asymmetric synthesis using optically active reagents, substrates, catalysts, or solvents, or by converting one enantiomer into another via asymmetric transformation. For enantiomer mixtures rich in specific enantiomers, the major component enantiomer can be further enriched by recrystallization (with a loss of yield).

Furthermore, the compounds of the present invention can exist in both non-solventized and solvated forms with pharmaceutically acceptable solvents such as water and ethanol. Generally, for the purposes of this invention, the solvated form is considered equivalent to the non-solventized form.

The method of the present invention can be performed as a semi-continuous or continuous method, and more preferably as a continuous method.

Unless otherwise indicated, the present invention as described above can be carried out in the presence of a solvent or a mixture of two or more solvents. In particular, the solvent is an aqueous solvent or an organic solvent, such as an ether solvent (e.g., tetrahydrofuran, methyltetrahydrofuran, diisopropyl ether, tert-butyl methyl ether, or dibutyl ether), an aliphatic hydrocarbon solvent (e.g., hexane, heptane, or pentane), a saturated alicyclic hydrocarbon solvent (e.g., cyclohexane or cyclopentane), or an aromatic solvent (e.g., toluene, o-xylene, m-xylene, or p-xylene or tert-butylbenzene) or a mixture thereof.

Raw materials and reagents that do not have the synthetic routes explicitly disclosed herein are generally available from commercial sources or can be readily prepared using methods well known to those skilled in the art.

method

One aspect provides a method for preparing compounds of formula I:

Or a pharmaceutically acceptable salt thereof, the method comprising:

Compounds of formula II:

Z is selected from _NH₂ , SH, and OH;

Reaction with compounds of formula III:

Where X is a leaving group;

_R1 is selected _from -H, -CN, -CO- _NR5R6 , _-CO2R7 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted _{( C1} - _C6 )alkyl, optionally substituted ( _C3 - _C8 )cycloalkyl, optionally substituted ( _C3 - _C6 ) _{heterocycloalkyl} , _-SO2NR8R9 and -( _{SO2 )} -( _C1 - _C6 )alkyl;

Where _R1 is selected _{from -CN} , -CO- _NR5R6 , _-CO2R7 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted ( _C3 - _C8 )cycloalkyl, optionally substituted ( _C3 - _C6 ) heterocycloalkyl, _-SO2NR8R9 and -( _SO2 )-( _C1 - _C6 )alkyl, _{R2 is -H} , halogroup, _-NR5R6 or optionally substituted _{( C1} - _C6 )alkoxy;

Where _R1 is -H, an optionally substituted ( _C1 - _C6 ) alkyl, or _an optionally substituted ( _C1 - _C6 ) alkoxy, _R2 is -CO- _NR5R6 or _{-CO2R7 .}

Or _R1 and _R2 together with the atoms to which they are attached form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl;

_R3 is selected from -H, optionally substituted (C1 _{- C6} ) alkyl, -CN, and halogroup;

_R4 is -H or a halogenated group;

Optionally substituted with one, two, three or four independently selected groups from halogroups and ( _C1 - _C6 )alkyl groups, wherein the linkage point is indicated;

_R5 and _R6 are each independently -H, optionally substituted ( _C1 - _C6 ) alkyl, or optionally substituted ( _C1 - _C6 ) alkoxy;

_R7 is -H or an optionally substituted ( _C1 - _C6 ) alkyl group.

_R8 and _R9 are each independently -H or optionally substituted ( _C1 - _C6 ) alkyl; or

_R8 and _R9 can be connected to form an optionally substituted heterocyclic ring; and

Y is selected from O, S, SO, _SO₂ , NH and N-(( _C₁ - _C₆ )alkyl).

On the other hand, there is a method for preparing compounds of formula I:

Or a pharmaceutically acceptable salt thereof, the method comprising:

Compounds of formula IV:

Reaction with compounds of formula V:

_R1 is selected _from -H, -CN, -CO- _NR5R6 , _-CO2R7 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted _{( C1} - _C6 )alkyl, optionally substituted ( _C3 - _C8 )cycloalkyl, optionally substituted ( _C3 - _C6 ) _{heterocycloalkyl} , _-SO2NR8R9 , and ( _{SO2 )} -( _C1 - _C6 )alkyl;

Where _R1 is selected _{from -CN} , -CO- _NR5R6 , _-CO2R7 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted ( _C3 - _C8 )cycloalkyl, optionally substituted ( _C3 - _C6 ) heterocycloalkyl, _-SO2NR8R9 and -( _SO2 )-( _C1 - _C6 )alkyl, _{R2 is -H} , halogroup, _-NR5R6 or optionally substituted _{( C1} - _C6 )alkoxy;

Where _R1 is -H, an optionally substituted ( _C1 - _C6 ) alkyl or an optionally substituted ( _C1 - _C6 ) alkoxy, _R2 is -CO- _NR5R6 , an optionally substituted _heteroaryl or _{-CO2R7 .}

Or _R1 and _R2 together with the atoms to which they are attached form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl;

_R3 is selected from -H, optionally substituted (C1 _{- C6} ) alkyl, -CN, and halogroup;

_R4 is -H or a halogenated group;

Optionally substituted with one, two, three or four independently selected groups from halogenated and _C1 - _C6 alkyl groups, wherein the linkage point is indicated;

_R5 and _R6 are each independently -H, optionally substituted ( _C1 - _C6 ) alkyl, or optionally substituted ( _C1 - _C6 ) alkoxy;

_R7 is -H or an optionally substituted ( _C1 - _C6 ) alkyl group;

_R8 and _R9 are each independently -H or optionally substituted ( _C1 - _C6 ) alkyl; or

_R8 and _R9 can be connected to form an optionally substituted heterocyclic ring; and

Y is selected from O, S, SO, _SO₂ , NH and N-( _C₁ - _C₆ alkyl).

In one embodiment, the compound of formula V is prepared by a method comprising the following steps: making the compound of formula VI:

Reaction with compounds of formula VII:

Compounds of formula VIII:

Furthermore, the reducing compound of formula VIII is used to provide the compound of formula V.

in:

_R1 is selected from _-H , -CN, -CO- _NR5R6 , _-CO2R7 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted _{( C1} - _C6 )alkyl, optionally substituted ( _C3 - _C8 )cycloalkyl, optionally substituted ( _C3 - _C6 ) _{heterocycloalkyl} , _-SO2NR8R9 and -( _{SO2 )} -( _C1 - _C6 )alkyl;

Where _R1 is selected _{from -CN} , -CO- _NR5R6 , _-CO2R7 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted ( _C3 - _C8 )cycloalkyl, optionally substituted ( _C3 - _C6 ) heterocycloalkyl, _-SO2NR8R9 and -( _SO2 )-( _C1 - _C6 )alkyl, _{R2 is -H} , halogroup, _-NR5R6 or optionally substituted _{( C1} - _C6 )alkoxy;

Where _R1 is -H, an optionally substituted ( _C1 - _C6 ) alkyl, or _an optionally substituted ( _C1 - _C6 ) alkoxy, _R2 is -CO- _NR5R6 or _{-CO2R7 .}

Or _R1 and _R2 together with the atoms to which they are attached form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl;

_R3 is selected from -H, optionally substituted (C1 _{- C6} ) alkyl, -CN, and halogroup; and

W is a halogenated group.

The following embodiments are provided for illustrative purposes and are not intended to limit the scope of the claimed invention.

Example

Example 1: Methyl 4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-7-methoxyquinoline-6-carboxylic acid ester (5)

N-(4-Fluorophenyl)-N-(4-hydroxyphenyl)cyclopropane-1,1-dicarboxamide (3): 3-(ethyliminomethyleneamino)-N,N-dimethyl-propane-1-amine hydrochloride (EDCI) (10.31 g, 53.8 mmol, 1.2 equivalent) was added to a solution of compound 1 (10 g, 44.80 mmol, 1 equivalent) and compound 2 (5.87 g, 53.8 mmol, 1.2 equivalent) in dimethylacetamide (DMA) (60 mL). The mixture was stirred vigorously at 20 °C until the reaction was complete. The mixture was poured into a saturated aqueous solution of _NaHCO3 (aq) (400 mL) and extracted with EtOAc (4 x 100 mL). The combined organic phases were washed with a saturated aqueous solution of NaCl (100 mL), _dried over anhydrous _Na2SO4 , and concentrated. Compound 3 (21 g, crude) (50% purity) was given. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.16 (br s, 1H), 9.72 (br s, 1H), 7.61 (dd, 2H), 7.34 (d, 2H), 7.13 (t, 2H), 6.68 (d, 2H), 1.42 (s, 4H); MS (EI) was _{C₁₇H₁₅FN₂O₃ ,} measured value _{314.9 (} MH⁺).

Methyl 4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-7-methoxyquinoline-6-carboxylic acid (5): A mixture of compound 3 (5.99 g, 9.5 mmol, 1.2 equivalents), compound 4 (2 g, 8.0 mmol, 1.0 equivalents), Pd(OAc) ₂ (89 mg, 397.4 μmol, 0.05 equivalents), racemic-2-(di-tert-butylphosphino)-1,1'-binaphthyl (TrixiePhos, 316.71 mg, 794.7 _μmol , 0.1 equivalents), and _K3PO4 (2.53 g, 11.9 mmol, 1.5 equivalents) in anisole (50 mL) was stirred at 110 °C for 2 h under a nitrogen atmosphere. The mixture was filtered and the filtrate was concentrated. The residue was purified by rapid silica gel chromatography (1:1 petroleum ether:EtOAc to 20:1 EtOAc:MeOH). Compound 5 was given (2.6 g, 61.8% yield). ^¹H NMR (400MHz, _CDCl₃ ) δ 9.38 (s, ¹H), 8.80 (s, ¹H), 8.63 (d, 2H), 7.64 (d, 2H), 7.54–7.41 (m, 3H), 7.18 (d, 2H), 7.09–7.01 (m, 2H), 6.43 (d, ¹H), 4.05 (s, 3H), 3.97 (s, 3H), 1.78–1.72 (m, 2H), 1.69–1.63 (m, 2H); MS (EI ₎ was _{C₂ ₹ H₂₄FN₃O₆} , measured value 530.0 (MH⁺).

Example 2: 4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-7-methoxyquinoline-6-carboxylic acid (6)

4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-7-methoxyquinoline-6-carboxylic acid (6): 2M NaOH aqueous solution (7 mL, 4.1 equivalents) was added to a solution of compound 5 (1.8 g, 3.4 mmol, 1 equivalent) in tetrahydrofuran (THF) (15 mL) and MeOH (15 mL). The mixture was stirred at 6 °C–13 °C for 4 hours. The pH of the mixture was adjusted to approximately 8 with 1M HCl aqueous solution and concentrated to remove the solvent. Water (50 mL) was added, and the pH of the mixture was adjusted to approximately 6 with 1M HCl aqueous solution. The resulting precipitate was filtered, washed with water (2 x 10 mL), and dried under vacuum. Compound 6 (1.7 g, 97.0% yield) was given. ^1H NMR (400MHz, DMSO- _d₆ ) δ 10.22 (s, 1H), 10.08 (s, 1H), 8.65 (d, 1H), 8.48 (s, 1H), 7.77 (d, 2H), 7.64 (dd, 2H), 7.47 (s, 1H), 7.25 (d, 2H), 7.15 (t, 2H), 6.45 (d, 1H), 3.96 (s, 3H), 1.47 (s, 4H); _MS ( _{EI )} was _{C₂₈H₂₂FN₃O₆} , measured value 516.1 (MH⁺).

Example 3: 1-N-[4-(6-carbamoyl-7-methoxyquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (7)

1-N-[4-(6-carbamoyl-7-methoxyquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (7): A solution of compound 6 (350 mg, 679.0 μmol, 1 equivalent), 3-oxyhexafluorophosphate 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium (HATU) (388 mg, 1.0 mmol, 1.5 equivalent), and diisopropylethylamine (DIEA or DIPEA) (352 mg, 2.7 mmol, 474 μL, 4.0 equivalent) in dimethylformamide (DMF) (10 mL) was stirred at 6-10 °C for 1 h, then _NH4Cl (73 mg, 1.4 mmol, 2.0 equivalent) was added, and the mixture was stirred at 6-10 °C for another 17 h. The mixture was filtered, and the resulting filtrate was concentrated and purified by preparative HPLC (column: Waters Xbridge 150mm*25mm*5μm, gradient: 32%-62% acetonitrile in _{10mM NH4HCO3} aqueous solution, flow rate: 25mL/min). Compound 7 was given (90.1mg, 25.8% yield). ^1H NMR (400MHz, DMSO- _d₆ ) δ 10.20 (s, 1H), 10.06 (s, 1H), 8.68 (s, 1H), 8.66 (d, 1H), 7.86 (br s, 1H), 7.81-7.72 (m, 3H), 7.68-7.61 (m, 2H), 7.51 (s, 1H), 7.26 (d, 2H), 7.19-7.11 (m, 2H), 6.46 (d, 1H), 4.03 (s, _3H ), _1.47 (s, _4H ); MS (EI) was _{C₂₈H₂₃FN₄O₅} , measured value 515.1 (MH⁺).

Example 4: 1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (8)

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (8): A DMF (10 mL) solution of compound 6 (300 mg, 582.0 μmol, 1 equivalent), HATU (332 mg, 873.2 μmol, 1.5 equivalent), and DIEA (301 mg, 2.3 mmol, 406 μL, 4 equivalent) was stirred at 6-10 °C for 1 hour. Methylamine hydrochloride (79 mg, 1.2 mmol, 2.0 equivalent) was added, and the mixture was stirred at 6-10 °C for 17 hours. The mixture was filtered, and the resulting filtrate was purified by preparative HPLC (column: Waters Xbridge 150mm*25mm*5μm, gradient: 33%-63% acetonitrile in 10mM _{NH4HCO3 aqueous} solution, flow rate: 25mL/min). Compound 8 was given (105.4 mg, 34.3% yield). ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.20 (s, ¹H), 10.06 (s, ¹H), 8.65 (d, ¹H), 8.61 (s, ¹H), 8.42–8.33 (m, ¹H), 7.77 (d, 2H), 7.68–7.61 (m, 2H), 7.51 (s, ¹H), 7.25 (d, 2H), 7.19–7.11 (m, 2H), 6.46 (d, ¹H), 4.02 (s, 3H), 2.84 (d, 3H) _{, 1.47 (s, 4H); MS (EI) was C₂⁹H₂⁵FN₄O₅ ,} measured value _{529.1 (} MH⁺).

The following compounds were prepared using a method similar to that used for compound 8 in Example 4:

1-N-[4-[6-(ethylcarbamoyl)-7-methoxyquinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (9): ^¹H NMR (400MHz, DMSO- _d6 ) δ 10.20 (s, 1H), 10.06 (s, 1H), 8.65 (d, 1H), 8.56 (s, 1H), 8.40 (br t, 1H), 7.78 (br d,2H), 7.64(dd,2H), 7.51(s,1H), 7.25(d,2H), 7.15(t,2H), 6.46(d,1H), 4.02(s,3H), 3.37-3.29(m,2H), 1.48(s,4H), 1.15(t,3H).; MS ( _{EI )} is _C30H27FN4O5 , measured value _543.2 (MH+).

1-N-[4-[6-[2-(dimethylamino)ethylcarbamoyl]-7-methoxyquinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (10): ^1H NMR (400MHz, CDCl3 ₎ δ 9.38(s,1H), 9.23(s,1H), 9.16(s,1H), 8.61(d,1H), 8.50(s,1H), 7.68(d,2H), 7.49-7.46(m,3H), 7.12(d,2H), 7.03(t,2H), 6.43(d,1H), 4.11(s,3H), 3.66(q,2H), 2.68(t,2H), 2.41(s,6H), _{1.70 (} s,4H); MS(EI) was _{C32H32FN5O5 ,} measured value 586.2 (MH+).

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(2-piperidin-1-ylethylcarbamoyl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (11): ^1H NMR (400MHz, CDCl3 ₎ δ 9.79(s,1H), 9.63(s,1H), 9.13(s,1H), 8.68(s,1H), 8.58(d,1H), 7.74(d,2H), 7.49-7.41(m,3H), 7.06-6.96(m,4H), 6.38(d,1H), 4.13(s,3H), 3.65(q,2H), 2.60(t,2H), 2.49(s,4H), 1.70-1.65(m,8H), _{1.51(s,2H); MS(EI) is C35H36FN5O5 , measured} value _626.3 (MH+).

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(2-morpholin-4-ylethylcarbamoyl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (12): ^1H NMR (400MHz, CDCl3 ₎ δ 9.26(s,1H), 9.24(s,1H), 8.95(s,1H), 8.63(d,1H), 8.46(s,1H), 7.65(d,2H), 7.52(s,1H), 7.50-7.47(m,2H), 7.16(d,2H), 7.05(t,2H), 6.46(d,1H), 4.15(s,3H), 3.79(t,4H), 3.68-3.64(m,2H), 2.65(t,2H), 2.57(s,4H), 1.70(d, _4H ); MS ( _{EI) was C34H34FN5O6 , measured} value 628.3 (MH+).

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(oxetane-3-ylcarbamoyl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (13): ^1H NMR (400MHz, CDCl3 ₎ δ 9.34(s,1H), 9.22(s,1H), 8.92(s,1H), 8.64(d,1H), 8.47(d,1H), 7.65(d,2H), 7.55(s,1H), 7.50-7.46(m,2H), 7.14(d,2H), 7.05(t,2H), 6.47(d,1H), 5.36-5.27(m,1H), 5.06(t,2H), 4.68(t,2H), 4.17(s,3H), _{1.71(s,4H); MS(EI) was C31H27FN4O6 , measured value} 571.2 (MH+).

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-[(1-methylazacyclobutane-3-yl)carbamoyl]quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (14): ^1H NMR (400MHz, CDCl3 ₎ δ 9.60(s,2H), 9.11(s,1H), 8.58(d,1H), 8.34(d,1H), 7.67(d,2H), 7.53-7.37(m,3H), 7.06(d,2H), 6.98(t,2H), 6.40(d,1H), 4.82-4.66(m,1H), 4.12(s,3H), 3.73(t,2H), 3.10(t,2H), 2.38(s,3H), _{1.74-1.60(m,4H); MS(EI) was C32H30FN5O5 , measured} value _584.9 (MH+).

1-N-[4-[6-(azacyclobutane-1-carbonyl)-7-methoxyquinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (15): ^¹H NMR (400MHz, _CDCl₃ ) δ 9.40 (s, 1H), 9.22 (br s, 1H), 8.59 (d, 1H), 8.32 (s, 1H), 7.63 (d, 2H), 7.49 (td, 9.2Hz, 3H), 7.13 (d, 2H), 7.04 (t, 2H), 6.43 (d, 1H), 4.28 (t, 2H), 4.08–3.98 (m, 5H), 2.37–2.32 (m, 2H), 1.77–1.64 (m, 4H); MS (EI) was C ₃₁ H ₂₇ FN ₄ O ₅ , measured value 554.8 (MH+).

1-N'-(4-fluorophenyl)-1-N-[4-[6-(3-hydroxyazacyclobutane-1-carbonyl)-7-methoxyquinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (16): ^1H NMR (400MHz, CDCl3 ₎ )δ9.43(s,1H),9.18(s,1H),8.60(s,1H),8.31(s,1H),7.61(d,2H),7.5 0-7.46(m,3H),7.11(d,2H),7.06-7.00(m,2H),6.45(d,1H),4.75-4.70( m,1H),4.51-4.47(m,1H),4.19-4.13(m,1H),4.11-4.07(m,1H),4.01(s ,3H),3.95-3.91(m,1H),1.75-1.73(m,2H),1.72-1.69(m,2H); MS(EI) is C ₃₁ H ₂₇ FN ₄ O ₆ The measured value was 571.0 (MH+).

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(methoxycarbamoyl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (17): ^¹H NMR (400MHz, DMSO- _d6 ) δ 11.27 (br s, 1H), 10.20 (br s, 1H), 10.06 (br s, 1H), 8.65 (d, 1H), 8.44 (s, 1H), 7.76 (d, 2H), 7.63 (d, 2H), 7.49 (s, 1H), 7.25 (d, 2H), 6.46 (d, 2H), 6.93 (d, 1H), 3.98 (s, 3H), 3.74 (s, 3H), 1.47 (s _, 4H); MS (EI) _C29H25 FN ₄ O ₆ , measured value 545.1 (MH+).

(R)-2-((4-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylammono)phenoxy)-7-methoxyquinoline-6-carboxylammono)methyl)pyrrolidine-1- _{carboxylic acid tert-butyl ester (18): MS (EI) is C38H40FN5O7 , and the} measured value is 698.3 (MH+).

(S)-2-((4-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylammono)phenoxy)-7-methoxyquinoline-6-carboxylammono)methyl)pyrrolidine-1- _{carboxylic acid tert-butyl ester (19): MS (EI) is C38H40FN5O7 , measured} value _is 698.3 (MH+).

1-N'-(4-fluorophenyl)-1-N-[4-[6-(hydroxycarbamoyl)-7-methoxyquinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide hydrochloride (20): ^¹H NMR (400MHz, DMSO- _d₆ ) δ 11.08 (s, 1H), 10.32 (s, 1H), 10.04 (s, 1H), 8.97–8.88 (m, 1H), 8.54 (s, 1H), 7.84 (d, 2H), 7.72–7.58 (m, 3H), 7.35 (d, 2H), 7.15 (t, _2H ), 6.86–6.75 (m, 1H), 4.04 (s, 3H), 1.48 (d, 4H) _; MS (EI _{) C₂₈H₂₃FN₄O₆} The measured value was 531.0 (MH+).

Example 5: 1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-[[(2R)-pyrrolidone-2-yl]methylcarbamoyl]quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (21)

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-[[(2R)-pyrrolidone-2-yl]methylcarbamoyl]quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (21): Trifluoroacetic acid (TFA; 1 mL) was added in a single batch to a mixture of compound 18 (67 mg, 96.0 μmol, 1 equivalent) in dichloromethane (DCM) (3 mL) at 30 °C. The mixture was stirred at 30 °C for 0.5 h, and then the reaction mixture was concentrated under vacuum. The resulting residue was purified by preparative HPLC (column: Waters Xbridge 150*25*5μm; mobile phase: [water (0.05% ammonium hydroxide v/v)-acetonitrile (ACN)]; B%: 50%) to give compound 21 (24.4 mg, 42.5% yield). ^¹H NMR (400 MHz, DMSO- _d₆ ) δ 9.52–9.35 (m, 2H), 9.14 (s, 1H), 8.59 (d, 1H), 8.42 (br₆) t, 1H), 7.68(d, 2H), 7.51-7.44(m, 3H), 7.09(d, 2H), 7.06-6.97(m, 2H), 6.42(d, 1H), 4.13(s, 3H), 3.69(td, 1H), 3.55-3.47(m, 1H), 3.45-3.37(m, 1H), 3.01(t, 2H), 2.01-1.79(m, 8H), 1.58-1.45(m, 1H); MS(EI ₎ is _{C33H32FN5O5 ,} measured value _598.3 (MH+).

The following compounds were prepared from compound 19 in a manner similar to that used in Example 5 to convert compound 18 to compound 21:

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-[[(2S)-pyrrolidone-2-yl]methylcarbamoyl]quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (22): ^1H NMR (400MHz, CDCl3 ₎ )δ9.47(s,2H),9.15(s,1H),8.60(d,1H),8.40(t,1H),7.7-7.67(m,2H),7 .49-7.45(m,3H),7.10-7.04(m,2H),7.03-6.99(m,2H),6.41(d,1H),4.11( s,3H),3.71-3.65(m,1H),3.50-3.37(m,2H),3.02-2.96(m,2H),2.01-1.95 (m,2H),1.84-1.75(m,2H),1.71-1.66(m,4H),1.55-1.48(m,1H); MS(EI) is C ₃₃ H ₃₂ FN ₅ O ₅ , measured value 598.3 (MH+).

Example 6: 1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(oxacyclobutane-3-yloxycarbamoyl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (26)

2-(oxetane-3-yloxy)isoindoline-1,3-dione (24): PPh 3 (3.54 g, 13.5 mmol, 2 equivalents) and diisopropyl azodicarboxylate (DIAD) (2.81 g, 13.9 mmol, 2.7 mL, 2.1 equivalents) were added fractionally to a THF (30 mL) solution of compound ₂₃ (1.32 g, 8.1 mmol, 1.2 equivalents) and oxetane-3-ol (500 mg, 6.8 mmol, 1 equivalent). The resulting mixture was stirred at 20 °C for 15 h to give a brown solution. The mixture was concentrated with silica gel and purified by rapid silica gel chromatography (0% to approximately 70% EtOAc in a petroleum ether gradient). The residue was further purified by rapid silica gel chromatography using the same solvent system to give compound 24 (300 mg, 10.14% yield, 50% purity). MS( _{EI) is C11H9NO4 ,} measured value _219.8 (MH+).

O-(oxetane-3-yl)hydroxylamine (25): _{NH₂NH₂ - H₂O} (95.92 mg, 1.9 mmol, 93.13 μL, 1.5 equivalents) was added to a DCM (5 mL) solution of compound 24 (280 mg, 1.3 mmol, 1 equivalent) at 0 °C, and the mixture was stirred for 1 hour to obtain a white suspension. The mixture was filtered and washed with DCM (5 mL), and the filtrate was concentrated. Crude compound 25 (150 mg) was used in the next step without further purification.

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(oxetane-3-yloxycarbamoyl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (26): Propylphosphonic anhydride (T3P) (185.17 mg, 582.0 μmol, 1 equivalent) and DIEA (75.22 mg, 582.0 μmol, 101.37 μL, 3 equivalent) were added to a THF ( ₃ mL) solution of compound 6 (100 mg, 194.0 μmol, 1 equivalent) and compound 25 (20.74 mg, 232.8 μmol, 1.2 equivalent), and the resulting mixture was stirred at 20 °C for 10 hours. The mixture was concentrated, and the resulting residue was purified by preparative HPLC (column: YMC-Actus Triart C18150*30mm*5μm; mobile phase: [water (0.05% ammonium hydroxide v/v)-ACN]; B%: 25%-65%, 10 min) to give compound 26 (5.3 mg, 4.66% yield). ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.66(s,1H),10.21(br s,1H),10.06(br s,1H),8.67(d,1H),8.42(s,1H),7.78(d,2H),7.64-7.86(m,2H),7.51(s,1H),7.26(d,2H),7.13-7.18(m,2H ),6.47(d,1H),5.07-5.09(m,1H),4.73-4.76(m,2H),4.63-4.66(m,2H),3.99(s,3H),1.48(s,4H); MS(EI) is C ₃₁ H ₂₇ FN ₄ O ₇ The measured value was 587.1 (MH+).

The following compounds were prepared from compound 6 in a manner similar to that used in the last step of Example 6 to form compound 26 from compound 6:

1-N'-(4-fluorophenyl)-1-N-[4-[6-(2-hydroxyethoxycarbamoyl)-7-methoxyquinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (27): ^1H NMR (400MHz, DMSO- _d6) δ 11.47(s,1H), 10.22(s,1H), 10.07(s,1H), 8.67(d,1H), 8.46(s,1H), 7.78(d,2H), 7.61-7.67(m,2H), 7.51(s,1H), 7.26(d,2H), 7.12-7.18(m,2H), 6.47(d,1H), 4.82(t,1H), 4.00(s,3H), 3.97(t,2H), 3.65( _{q,2H), 1.48(s,4H); MS (EI) was C30H27FN4O7 , measured value} 575.1 (MH+).

N-(4-((6-(((2,2-dimethyl-1,3-dioxopentane-4-yl)methoxy)carbamoyl)-7-methoxyquinoline-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1- _{dicarboxamide (28). MS (EI) was C34H33FN4O8 , with a} measured value of 645.0 (MH+).

Example 7: 1-N-[4-[6-(2,3-dihydroxypropoxycarbamoyl)-7-methoxyquinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, enantiomers 1 (30) and 2 (31)

1-N-[4-[6-(2,3-dihydroxypropoxycarbamoyl)-7-methoxyquinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, racemic mixture (29): TFA (53.06 mg, 465.37 μmol, 34.46 μL, 1 equivalent) was added to a DCM (10 mL) solution of compound 28 (300 mg, 465.37 μmol, 1 equivalent), and the resulting mixture was stirred at 20 °C for 10 h. Two more equal portions of TFA, totaling 0.35 mL, were added, and stirring was continued at 20 °C for a further 5 h to obtain a brown solution. The reaction mixture was concentrated under vacuum, and the resulting residue was purified by preparative HPLC (column: Agela Dura Shell 150mm*25mm*5μm; mobile phase: [water (0.225% FA)-ACN]; B%: 11%-51%, 10 min) to give compound 29 (85 mg, 30.21%). ^¹H NMR (400 MHz, DMSO- _d⁶ ) δ 11.54 (br s, 1H), 10.22 (br s, 1H), 10.07 (br s, 1H), 8.67 (d, 1H), 8.49 (s, 1H), 7.77 (d, 2H), 7.64-7.67 (m, 2H), 7.52 (s, 1H), 7.26 (d, Hz, 2H), 7.14-7.16 (m, 2H), 6.47 (d, 1H), 5.00 (br s, 1H ... s, 1H), 4.67 (br s, 1H), 3.99-4.02 (m, 4H), 3.78-3.85 (m, 2H), 3.39-3.42 (m, 2H), 1.48 (s, 4H); MS (EI) is C ₃₁ H ₂₉ FN ₄ O ₈ , measured value 605.4 (MH+).

1-N-[4-[6-(2,3-dihydroxypropoxycarbamoyl)-7-methoxyquinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, enantiomers 1 (30) and 2 (31).

The enantiomers of racemic compound 29 were separated using an SFC (column: DAICL CHIRALPAK AD (250 mm * 30 mm, 10 μm); mobile phase: [0.1% NH3H2OIPA]; B%: 45%-45%, min) (85 mg, 140.59 μmol, 1 equivalent) to give compound 30 (53.0 mg, 62.35%) and compound 31 (21.3 mg, 25.06% yield). Compound 30: ^¹H NMR (400 MHz, DMSO- _d₆ ) δ 11.54 (br s, 1H), 10.22 (br s, 1H), 10.07 (br s, 1H), 8.67 (d, 1H), 8.49 (s, 1H), 7.77 (d, 2H), 7.64–7.67 (m, 2H), 7.52 (s, 1H), 7.26 (d, 2H), 7.14–7.16 (m, 2H), 6.47 (d, 1H), 5.00 (d, 1H), 4.67 (t, 1H), 3.99–4.03 (m, 4H), 3.78–3.93 (m, 2H), 3.39–3.47 (m, 2H), 1.48 (s _, 4H); MS (EI) _{C₃¹H₂₉FN 4} O ₈ , measured value 605.3 (MH+). Compound 31: ^¹H NMR (400MHz, DMSO- _d₆ ) δ 11.54 (br s, 1H), 10.23 (br s, 1H), 10.08 (br s, 1H), 8.67 (d, 1H), 8.49 (s, 1H), 7.79 (d, 2H), 7.64–7.67 (m, 2H), 7.51 (s, 1H), 7.26 (d, 2H), 7.14–7.18 (m, 2H), 6.47 (d, 1H), 5.03 (br s, 1H), 4.69 (br s, 1H), 4.00–4.04 (m, 4H), 3.76–3.86 (m, 2H), 3.52–3.56 (m, 2H), 1.48 (s, 4H); MS (EI) _{C₃¹H 29} FN ₄ O ₈ , measured value 605.0 (MH+).

Example 8: 1-N'-(4-fluorophenyl)-1-N-[4-[6-(hydrazylcarbonyl)-7-methoxyquinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (32)

1-N'-(4-fluorophenyl)-1-N-[4-[6-(hydrazylcarbonyl)-7-methoxyquinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (32): _{NH₂NH₂ - H₂O} (28.36 mg, 566.56 μmol, 27.54 μL, 3 equivalents) was added to a solution of compound 5 (100 mg, 188.85 μmol, 1 equivalent) in MeOH (5 mL). The resulting mixture was stirred at 50 °C for 2 h, and then concentrated under vacuum. The residue was ground with MeOH (3 mL), and the residue was filtered to give compound 32 (56.6 mg, 53.77% yield). ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.21 (s, ¹H), 10.06 (s, ¹H), 9.51 (br s, ¹H), 8.66 (d, ¹H), 8.53 (s, ¹H), 7.78 (d, 2H), 7.69–7.60 (m, 2H), 7.51 (s, ¹H), 7.26 (d, 2H), 7.16 (t, 2H), 6.48 (d, ¹H), 4.62 (br d, 2H), 4.01 (s, 3H) _{, 1.48 (s, 4H); MS (EI) was C₂₈H₂₄FN₅O₅ , measured value} 530.2 (MH⁺).

Example 9: 1-N-[4-(6-acetyl-7-methoxyquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (34)

N-(4-fluorophenyl)-N-(4-((7-methoxy-6-(methoxy(methyl)carbamoyl)quinoline-4-yl)oxy)phenyl)cyclopropane-1,1-dicarboxamide (33): HATU (442.57 mg, 1.16 mmol, 2 equivalents) and DIEA (225.65 mg, 1.75 mmol, 304.11 μL, 3 equivalents) were added to a DMF (3 mL) solution of compound 6 (300 mg, 581.97 μmol, 1 equivalent) and N,O-dimethylhydroxylamine hydrochloride (170.30 mg, 1.75 mmol, 3 equivalents). The resulting mixture was stirred at 20 °C for 3 hours to give a brown solution. The mixture was diluted with EtOAc (60 mL) and washed with water (2 x 20 mL) and saturated NaCl aqueous solution (20 mL). The organic phase was concentrated under vacuum, and the resulting residue was purified by rapid silica gel chromatography (5 g silica rapid column, eluent of 0% to approximately 20% MeOH/DCM gradient, flow rate of 10 mL/min) to give compound ₃₃ ( ₃₀₀ mg, 89.52% yield. _MS (EI) was _C30H27FN4O6 , measured value 559.2 (MH+).

1-N-[4-(6-acetyl-7-methoxyquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (34): MeMgBr (3M, 1.67mL, 10 equivalents) was added to a THF (5mL) solution of compound 33 (280mg, 501.29μmol, 1 equivalent) at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at 20°C for 15 hours to give a brown suspension. The reaction mixture was quenched with a saturated aqueous solution of _NH4Cl (20mL), extracted with EtOAc (3 x 15mL), and concentrated. The resulting residue was purified by rapid silica chromatography (4g silica rapid column, 0% to 4% MeOH/DCM gradient eluent, flow rate 10mL/min). The crude product was further purified (using a 4 g silica fast column with an eluent of 0% to approximately 60% EtOAc/petroleum ether gradient at 10 mL/min) to give compound 34 (190 mg, yield 73.81%). ^¹H NMR (400MHz, _CDCl₃ ) δ 9.40 (br s, 1H), 8.90 (br s, 1H), 8.68 (s, 1H), 7.51 (d, 1H), 7.63–7.66 (m, 2H), 7.45–7.50 (m, 3H), 7.14–7.16 (m, 2H), 7.02–7.07 (m, 2H), 6.43 (d, 1H), 4.05 (s, 3H), 2.71 (s, 3H), 1.16–1.72 (m, 4H); MS (EI ₎ was _{C₂ ₹ H₂₄FN₃O₅} , measured value 536.1 (MH+Na) ^⁺ .

Example 10: 1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-[(E)-N-methoxy-C-methylcarboiminoyl]quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (35) and 1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-[(Z)-N-methoxy-C-methylcarboiminoyl]quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (36)

Methoxyamine hydrochloride (45.54 mg, 545.26 μmol, 41.40 μL, 2 equivalents) was added to a solution of compound 34 (140 mg, 272.63 μmol, 1 equivalent) in water (2.5 mL) and EtOH (2.5 mL), and the resulting mixture was stirred at 50 °C for 2 h to obtain a brown solution. The reaction mixture was diluted with EtOAc (50 mL), washed with water (2 x 20 mL), and concentrated. The resulting residue was purified twice by rapid silica gel chromatography (4 g silica rapid column, eluent of 0% to approximately 80% EtOAc/petroleum ether gradient, flow rate of 10 mL/min). Compounds 35 and ₃₆ (110 mg, 69.7% yield) were recovered as a mixture of Z and E isomers (MS ( _EI ) _C30H27FN4O5 , _542.9 (MH+)). The Z and E isomers were separated by preparative HPLC (column: Agela DuraShell 150 mm * 25 mm * 5 μm; mobile phase: [water (0.05% ammonium hydroxide v/v) - ACN]; B%: 47%-87%, 10 min) to give compound 35 (54.7 mg, 52.10% yield) and compound 36 (6.4 mg, 6.10% yield). Compound 35: ^1H NMR (400 MHz, DMSO- _d6 ) δ 10.21 (br s, 1H), 10.07 (br s, 1H), 8.63(d, 1H), 8.09(s, 1H), 7.77(d, 2H), 7.65-7.68(m, 2H), 7.49(s, 1H), 7.77(d, 2H), 7.16(t, 2H), 6.44(d, 1H), 3.99(s, 3H), 3.91(s, 3H), 2.16(s, 3H), 1.48(s, 4H). Compound 36: ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.21(br s, 1H), 10.07(br s, 1H), 1.48(br s, 4H). s,1H),8.61(d,1H),7.97(s,1H),7.77(d,2H),7.63-7.66(m,2H),7.47(s,1H),7.25( d,2H),7.16(t,2H),6.43(d,1H),3.95(s,3H),3.70(s,3H),2.15(s,3H),1.48(s,4H).

Example 11: 1-N-[4-(6-cyano-7-methoxyquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (37)

1-N-[4-(6-cyano-7-methoxyquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (37): _POCl3 (7.78 g, 50.74 mmol, 4.72 mL, 134 equivalents) was added to a MeCN (10 mL) solution of compound 7 (200 mg, 379.12 μmol, 1 equivalent). The mixture was stirred at 80 °C for 3 h. The reaction mixture was filtered, and the filtrate was concentrated and dried under vacuum. The residue was diluted with water (5 mL), the pH was adjusted to 8-9 with an aqueous solution _{of Na2CO3} , and the residue was extracted with DCM (3 x 20 mL). The combined organic layers were concentrated and then dried under vacuum. The residue was purified by preparative HPLC to give compound 37 (80.3 mg, 42.37% yield). ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.23 (br s, 1H), 10.05 (br s, 1H), 8.79–8.72 (m, 2H), 7.79 (br d, 2H), 7.68–7.58 (m, 3H), 7.27 (d, 2H), 7.15 (t, 2H), 6.52 (d, 1H), 4.07 (s, 3H), 1.48 ( _{s, 4H); MS (EI) was C₂₈H₂₁FN₄O₄ ,} measured value _{497.1 (} MH⁺).

Example 12: N-(4-((6-bromo-7-methoxyquinoline-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (43)

5-(((4-bromo-3-methoxyphenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (40): A solution of compound 39 (4.10 g, 28.46 mmol, 1.15 equivalents) in trimethoxymethane (25 mL, 228.04 mmol, 9.22 equivalents) was refluxed at 105 °C for 1 h. Then compound 38 (5 g, 24.75 mmol, 1 equivalent) was added, and reflux was continued at 105 °C for another 1 h. The resulting suspension was filtered, washed with MeOH, and dried under vacuum to give compound 40 (7.7 g, 87.4% yield), which was used in the next step without further purification. ¹ HNMR (400MHz, CDCl ₃ ) δ11.24-11.20(d,1H),8.62-9.59(d,1H),7.57-7.54(d,1H),6.77-6.74(m,2H),3.94(s,3H),1.76(s,3H),1.74(s,3H).

6-Bromo-7-methoxyquinoline-4(1H)-one (41): Compound 40 (7.7 g, 21.62 mmol, 1 equivalent) was added to _Ph₂O (35 mL) at 230 °C, and the mixture was stirred for 1 hour. After cooling to room temperature, the reaction mixture was poured into hexane (20 mL), and the resulting precipitate was filtered and washed with hexane. The residue was dried under vacuum to give compound 41 (6.2 g, 75.8% yield, 67.2% purity). ^¹H NMR (400MHz, DMSO- _d₆ ) δ 11.78 (s, ¹H), 8.18 (s, ¹H), 7.88–7.86 (d, ¹H), 7.05 (s, ¹H), 6.03–6.01 ( _{d, ¹H), 3.92 (s, ³H); MS (EI) was C₁₀H₈BrNO₂ ,} measured value _254.2 (MH⁺).

6-Bromo-4-chloro-7-methoxyquinoline (42): A _POCl3 solution (15 mL, 161.41 mmol, 9.84 equivalents) of compound 41 (6.2 g, 16.40 mmol, 1 equivalent) was stirred at 110 °C for 1 h. After cooling, the reaction mixture was carefully poured into a mixture of saturated _{Na2CO3 aqueous} solution and ice with stirring. The resulting suspension was filtered, washed with water, and dried under vacuum to give compound 42 (7.78 g, 57.4% purity, 99.9% yield), which was used in subsequent steps without further purification. _{MS (EI) was C10H7BrClNO ,} measured at 272.2 (MH+).

N-(4-((6-bromo-7-methoxyquinoline-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (43): A mixture of compound 42 (5.72 g, 12.05 mmol, 1.26 equivalents), compound 3 (3.00 g, 9.54 mmol, 1 equivalent), and t-BuOK (3.21 g, 28.63 mmol, 3 equivalents) in DMSO (30 mL) was stirred at 150 °C for 2 h. A saturated aqueous solution of _NH4Cl (200 mL) was added, and the mixture was extracted with EtOAc (3 x 250 mL). The combined organic phases were dried over _{anhydrous Na2SO4} and concentrated under vacuum. The resulting residue was purified by rapid silica gel chromatography (40 g silica rapid column, eluent 0% to approximately 100% EtOAc/petroleum ether gradient, flow rate 40 mL/min). The resulting residue was ground with MeOH (50 mL) and filtered to give compound 43 (3.0 g, 57.11% yield). ^¹H NMR (400 MHz, _CDCl₃ ) δ 9.33 (s, 1H), 8.66 (br s, 1H), 8.60 (d, 1H), 8.58 (s, 1H), 7.64 (d, 2H), 7.48 (dd, 2H), 7.45 (s, 1H), 7.18 (d, 2H), 7.07 (t, 2H), 6.45 (d, 1H), 4.07 (s, 3H), 1.78–1.72 (m, 2H), 1.71–1.65 (m, 2H).

The following compounds were synthesized in a manner similar to that of compound 43 in the last step of Example 12, with 6-bromo-4-chloroquinoline replacing compound 42.

N-(4-((6-bromoquinoline-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1- _{dicarboxamide} (44). _{MS (EI) was C26H19BrFN3O3 , with} a measured value of 520.0 (MH+).

Example 13: 1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(1,3-oxazol-2-yl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (45)

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(1,3-oxazol-2-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (45): Compound 43 (200 mg, 363.39 μmol, 1 equivalent), tributyl(oxazol-2-yl)stanane (200.0 mg, 558.5 μmol, 1.5 equivalent), CuI (8 mg, 42.0 μmol, 0.12 equivalent) and Pd( _PPh3 ) ₄ (48.0 mg, 41.5 μmol, 0.11 equivalent) were mixed in 5 mL of 1,4-dioxane in a sealed tube and then heated at 100 °C for 30 minutes under microwave irradiation. The reaction mixture was concentrated under vacuum, and the resulting residue was first purified by rapid silica gel chromatography (0–100% EtOAc/petroleum ether) and then purified by preparative HPLC to give compound 45 (81.5 mg, 41.3% yield). ^¹H NMR (400MHz, _CDCl₃ ) δ 9.36 (s, 1H), 8.98 (s, 1H), 8.75 (br s, 1H), 8.63 (d, 1H), 7.82 (s, 1H), 7.65 (d, 2H), 7.57 (s, 1H), 7.48 (dd, 2H), 7.36 (s, 1H), 7.19 (d, 2H), 7.06 (t, 2H), 6.46 (d, 1H), 4.13 (s, 3H), 1.77–1.74 (m, 2H), 1.73–1.69 (m, 2H); MS ( _EI ) _{was C₃₀H₂₃FN₄O₅} , measured value _539.1 (MH⁺).

Example 14: 1-N'-(4-fluorophenyl)-1-N-[4-[7-(2-hydroxyethoxy)-6-(1,3-oxazol-2-yl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (50)

6-Bromo-4-chloroquinoline-7-ol (46): A mixture of compound 42 (5 g, 18.35 mmol, 1 equivalent) and BBr ₃ (13.00 g, 51.89 mmol, 5 mL, 2.83 equivalent) in a DCE (15 mL) was stirred at 90 °C for 2.5 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and poured into a saturated aqueous solution of NaHCO ₃ with vigorous stirring. The resulting residue was filtered, washed with water, dissolved in methyl tert-butyl ether, and dried. The solvent was removed under reduced pressure to give compound 46 (7 g), which could be used in subsequent reactions without further purification. ^¹H NMR (400MHz, DMSO- _d₆ ) δ 9.03 (d, ¹H), 8.49 (s, ¹H), 7.93 (d, ¹H), 7.69 (s, ¹H), 6.08 (s, ¹H); MS _{(EI) was C₉H₅BrClNO ,} measured value 260.2 (MH⁺).

6-Bromo-7-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-chloroquinoline (47): _K₂CO₃ (1.05 g, 7.60 mmol, 1 equivalent) and NaI (720 mg, 4.80 mmol, 1.24 equivalent) were added to a mixture of compound ₄₆ (1 g, 3.87 mmol, 1 equivalent) and 2-bromoethoxy-tert-butyl-dimethylsilane (1.15 g, 4.80 mmol, 1.24 equivalent) in DMF (10 mL), and the mixture was heated to 80 °C for 2 hours with stirring. The reaction mixture was partitioned between water (20 mL) and EtOAc (2 x 20 mL). The combined organic phases were washed with saturated aqueous NaCl solution (10 mL), _dried over anhydrous _Na₂SO₄ , and concentrated. The residue was purified by rapid silica gel chromatography (12 g silica gel column, eluent gradient of 0% to approximately 20% EtOAc/petroleum ether, flow rate of 30 mL/min) to give compound 47 (560 mg, 34.73% yield). ^¹H NMR (400 MHz, _CDCl₃ ) δ 8.71 (d, 1H), 8.45 (s, 1H), 7.47 (s, 1H), 7.37 (d, 1H), 4.29–4.26 (m, 2H), 4.13–4.11 (m, 2H), 0.93–0.92 (m, 9H _{), 0.16–0.14 (m, 6H); MS (EI) was C₁₇H₂₃BrClNO₂Si , measured} value 417.8 (MH⁺).

N-(4-((6-bromo-7-(2-((tert-butyldimethylsilyl)oxy)ethoxy)quinoline-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (48): Compound 48 was prepared in a similar manner to the preparation of compound 43 from compound 42 in Example 12. Compound 48 was recovered (400 mg, 48% yield). ^¹H NMR (400MHz, DMSO- _d₆ ) δ 10.20 (s, 1H), 10.01 (s, 1H), 8.63 (d, 1H), 8.47 (s, 1H), 7.77 (d, 2H), 7.65–7.62 (m, 2H), 7.55 (s, 1H), 7.25 (d, 2H), 7.17–7.13 (m, 2H), 6.46 (d, 1H), 4.32–4.30 (t, 2H), 4.05–4.03 (t, 2H), 1.47 (s, 4H), 0.88 (s, 9H), _{0.10 (s, 6H); MS (EI) was C₃₄H₃₇BrFN₃O₅Si , measured value} 696.1 (MH⁺).

N-(4-((7-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-(oxazol-2-yl)quinoline-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (49): Compound 49 was prepared in a manner similar to that used in the preparation of compound 45 from compound 43 in Example 13. Compound 49 was recovered (400 mg, crude). ^¹H NMR (400MHz, _CDCl₃ ) δ 10.20 (s, 1H), 10.06 (s, 1H), 8.74 (s, 1H), 8.67 (d, 1H), 8.25 (s, 1H), 7.78 (d, 2H), 7.62–7.59 (m, 3H), 7.43 (s, 1H), 7.28 (d, 2H), 7.19–7.09 (m, 2H), 6.48 (d, 1H), 4.41–4.25 (m, 2H), 4.04–4.02 (m, 2H), 1.47 (s, 4H), 0.83 (s, 9H), 0.02 (s, _6H ); MS (EI) was _{C₃₇H₃ ₹ FN₄O₆Si} , measured value 683.3 (MH⁺).

1-N'-(4-fluorophenyl)-1-N-[4-[7-(2-hydroxyethoxy)-6-(1,3-oxazol-2-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (50): Tetrabutylammonium fluoride (1M, 1.40mL, 2.73 equivalents) was added to a mixture of compound 49 (350mg, 512.6μmol, 1 equivalent) in THF (20mL), and the resulting reaction mixture was stirred at 0-20°C for 0.5h, and then poured into a saturated aqueous solution of _NaHCO3 under vigorous stirring. The resulting mixture was partitioned between water (20mL) and EtOAc (2 x 20mL). The combined organic phases were separated, washed with a saturated aqueous solution of NaCl (10mL), _dried over anhydrous _Na2SO4 , and concentrated. The residue was recrystallized with MeOH to give compound 50 (174.3 mg, 58.6% yield). ^1H NMR (400MHz, DMSO- _d₆ ) δ 10.20(s, 1H), 10.06(s, 1H), 8.77(s, 1H), 8.67(d, 1H), 8.30(s, 1H), 7.78(d, 2H), 7.66–7.63(m, 3H), 7.45(s, 1H), 7.28(d, 2H), 7.17–7.13(m, 2H), 6.47(d, 1H), 4.97–4.94(t, 1H), 4.32–4.30(t, 2H), 3.86–3.82(m, 2H), _{1.47(s, 4H); MS (EI) was C₃¹H₂₅FN₄O₆ , measured value} 569.2 (MH⁺).

Example 15: 1-N-[4-(6-dimethylphosphoryl-7-methoxyquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (51)

1-N-[4-(6-dimethylphosphoryl-7-methoxyquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (51): Methylphosphonomethane (21.27 mg, 272.5 μmol, 1.5 equivalent), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthocyanin (Xantphos) (21.03 mg, 36.3 μmol, 0.2 equivalent), tris(dibenzylideneacetone)dipalladium (0) (Pd ₂ (dba) ₃ ) (33.28 mg, 36.3 μmol, 0.2 equivalent) and Et ₃ were added to a dioxane (2 mL) solution of compound 43 (100 mg, 181.7 μmol, 1 equivalent). N (91.93 mg, 908.5 μmol, 126.5 μL, 5 equivalents). The resulting mixture was stirred at 110 °C for 1 h under a nitrogen atmosphere. The mixture was concentrated under vacuum and ground with EtOH (5 mL). The resulting residue was filtered, dried, and passed by preparative HPLC (YMC-Actus Triart C18 150*30 mm*5 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 20%-60%, 10 min) to give compound 51 (26.2 mg, 26.34% yield, 100% purity). ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.24 (s, ¹H), 10.10 (s, ¹H), 8.76 (d, ¹H), 8.69 (d, ¹H), 7.80 (d, 2H), 7.65 (dd, 2H), 7.52 (d, 1H), 7.28 (d, 2H), 7.16 (t, 2H), 6.48 (d, 1H), 4.04 (s, 3H), 1.75 (s, 3H), 1.72 (s, 3H), 1.48 ( _s , 4H); MS (EI) was _{C₂ ₹ H₂₇FN₃O₅P} , measured value 548.1 (MH⁺).

Example 16: Methyl 4-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylamino)phenoxy)quinoline-6-carboxylic acid ester (56)

4-(((2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-yl)methyl)amino)methyl benzoate (53): Compound 53 was synthesized from compounds 52 and 39 in a manner similar to that used in the preparation of compound 40 from compounds 38 and 39 in Example 12. Compound 53 was obtained (9 g, 89.1% yield). ^¹H NMR (400 MHz, _CDCl₃ ) δ 11.32 (br d, 1H), 8.70 (d, 1H), 8.13 (d, 2H), 7.31 (d, 2H), 3.94 (s, 3H), 1.77 (s, 6H).

4-O-1,4-Dihydroquinoline-6-carboxylic acid methyl ester (54): Compound 54 was synthesized from compound 53 in a manner similar to that used in the preparation of compound 41 from compound 40 in Example 12. Compound 54 (1.3 g, crude product) was obtained. ^¹H NMR (400 MHz, DMSO- _d⁶ ) δ 12.03 (s, ¹H), 8.74–8.64 (m, ¹H), 8.14 (dd, ¹H), 8.01–7.93 (m, ¹H), 7.64–7.58 (m, ¹H), 6.11 (d, ¹H), 3.88 (s, ³H).

4-Chloroquinoline-6-carboxylic acid methyl ester (55): Compound 55 was synthesized from compound 54 in a manner similar to that used in the preparation of compound 42 from compound 41 in Example 12. Compound 55 was obtained (0.5 g, 35.3% yield). ^¹H NMR (400 MHz, _CDCl₃ ) δ 9.00 (d, 1H), 8.89 (d, 1H), 8.38 (dd, 1H), 8.19 (d, 1H), 7.58 (d, 1H), 4.03 (s, _{3H); MS (EI) was C₁₁H₈ClNO₂ ,} measured _221.9 (MH⁺).

4-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylamino)phenoxy)quinoline-6-carboxylic acid methyl ester 56: Compound 56 was synthesized from compounds 55 and 3 in a manner similar to that used in the preparation of compound 43 from compounds 42 and 3 in Example 12. Compound 56 was obtained (0.9 g, 99.8% yield). _MS (EI) was _C28H22FN3O5 , _and the measured value _was 500.4 (MH+).

Example 17: 4-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylamino)phenoxy)quinoline-6-carboxylic acid (57)

4-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylamino)phenoxy)quinoline-6-carboxylic acid (57): Compound 57 was synthesized from compound 56 in a manner similar to that used in the preparation of compound 6 from compound 5 in Example 2. Compound 57 was obtained (0.5 g, 57.2% yield). _MS (EI) was _C27H20FN3O5 , _and the measured value _was 486.0 (MH+).

Example 18: 1-N-[4-(6-carbamoylquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (58)

N-(4-((6-carbamoylquinoline-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (58): Compound 58 was synthesized from compound 57 in a manner similar to that used in the preparation of compound 7 from compound 6 in Example 3. Compound 58 was obtained (26 mg, 26.0% yield). ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.22 (s, ¹H), 10.06 (s, ¹H), 8.90 (d, ¹H), 8.74 (d, ¹H), 8.34 (br s, ¹H), 8.26 (dd, ¹H), 8.06 (d, ¹H), 7.80 (d, 2H), 7.64 (dd, 2H), 7.56 (br s, ¹H), 7.29 (d, 2H), 7.15 (t, 2H), 6.61 (d, 1H) _{, 1.48 (s, 4H); MS (EI) was C₂₇H₂₁FN₄O₄ , measured value} 485.1 (MH⁺).

Example 19: 1-N'-(4-fluorophenyl)-1-N-[4-[6-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (59)

1-N'-(4-fluorophenyl)-1-N-[4-[6-(methylcarbamoyl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (59): Compound 59 was synthesized from compound 58 in a manner similar to that used in the preparation of compound 8 from compound 6 in Example 4. Compound 59 was obtained (31.1 mg, 30.3% yield). ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.22 (s, ¹H), 10.05 (s, ¹H), 8.86 (d, ¹H), 8.81 (br d, ¹H), 8.74 (d, ¹H), 8.23 (dd, ¹H), 8.07 (d, ¹H), 7.80 (d, 2H), 7.64 (dd, 2H), 7.29 (d, 2H), 7.15 (t, 2H), 6.61 (d, 1H), 2.85 (d, 3H) _, 1.48 (s, 4H); MS (EI) was _{C₂₈H₂₃FN₄O₄} , measured _{value 499.1} (MH⁺).

The following compounds were prepared using a method similar to that used in the preparation of compound 59 in Example 19:

1-N'-(4-fluorophenyl)-1-N-[4-[6-[(1-methylazacyclobutane-3-yl)carbamoyl]quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (60): ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.23 (s, 1H), 10.05 (s, 1H), 9.23–9.14 (m, 1H), 8.89 (s, 1H), 8.75 (d, 1H), 8.25 (d, 1H), 8.08 (d, 1H), 7.81 (br⁶) d,2H), 7.68-7.62(m,2H), 7.30(d,2H), 7.16(t,2H), 6.61(d,1H), 4.60-4.44(m,1H), 3.69-3.60(m,2H), 3.31(s,3H), 3.20-3.09(m,2H), 1.48(s,4H); MS( _{EI )} is _C31H28FN5O4 , measured value _554.1 (MH+).

Example 20: Methyl 7-fluoro-4-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylammono)phenoxy)quinoline-6-carboxylic acid ester (65)

4-(((2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-yl)methyl)amino)-2-fluorobenzoate (62): Compound 62 was synthesized from compounds 61 and 39 in a manner similar to that used in the preparation of compound 40 from compounds 38 and 39 in Example 12. Compound 62 was given (4.8 g, 50.2% yield). ^¹H NMR (400 MHz, DMSO- _d⁶ ) δ 11.28 (s, 1H), 8.65 (s, 1H), 7.91 (t, 1H), 7.72 (dd, 1H), 7.52 (dd, 1H), 3.84 (s, 3H), 1.68 (s, 6H).

7-Fluoro-4-oxo-1,4-dihydroquinoline-6-carboxylic acid methyl ester (63): Compound 63 was synthesized from compound 62 in a manner similar to that used in the preparation of compound 41 from compound 40 in Example 12. Compound 63 was obtained (0.8 g, 58.5% yield). _{MS (EI) was C11H8FNO3 , and} the measured value was 222.2 (MH+).

4-Chloro-7-fluoroquinoline-6-carboxylic acid methyl ester (64): Compound 64 was synthesized from compound 63 in a manner similar to that used in the preparation of compound 42 from compound 41 in Example 12. Compound 64 was obtained (110 mg, ₃₁ % yield). ^¹H NMR (400 MHz, _CDCl₃ ) δ 8.90 (d, 1H), 8.85 (d, 1H), 7.84 (d, 1H), 7.53 (d, 1H), 4.03 (s, 3H); MS (EI ₎ was _{C₁₁H₇ClFNO₂} , measured 240.0 (MH⁺).

4-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylamino)phenoxy)quinoline-6-carboxylic acid methyl ester (65): Compound 65 was synthesized from compounds 64 and 3 in a manner similar to that used in the preparation of compound 43 from compounds 42 and 3 in Example 12. Compound 65 was obtained (90 mg, 92.6% yield). _MS (EI) was _C28H21F2N3O5 , _and the measured value _was 518.3 ₍ MH+).

Example 21: 7-Fluoro-4-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylamino)phenoxy)quinoline-6-carboxylic acid (66)

7-Fluoro-4-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylamino)phenoxy)quinoline-6-carboxylic acid (66): Compound 66 was synthesized from compound 65 in a manner similar to that used in the preparation of compound 6 from compound 5 in Example 2. Compound 66 was obtained (50 _mg , 57.1% yield). _{MS (} EI) was _C27H19F2N3O5 , and the measured value _was 504.4 (MH+).

Example 22: 1-N-[4-(6-carbamoyl-7-fluoroquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (67)

1-N-[4-(6-carbamoyl-7-fluoroquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (67): Compound 67 was synthesized from compound 66 in a manner similar to that used in the preparation of compound 7 from compound 6 in Example 3. Compound 67 was obtained (7.6 mg, 15.2% yield). ^¹H NMR (400MHz, _CDCl₃ ) δ 9.47 (s, ¹H), 9.24 (d, ¹H), 8.84 (s, ¹H), 8.71 (d, ¹H), 7.79 (d, ¹H), 7.67 (d, 2H), 7.48 (dd, 2H), 7.15 (d, 2H), 7.04 ( _t , 2H), 6.86 (d, ¹H), 6.54 (d, 1H), 6.06 (s, ¹H), _{1.76 -1.68 (m, 4H); MS (EI) was C₂₇H₂₀F₂N₄O₄ , measured} value _503.1 (MH⁺).

By using a similar sequence to that used in the preparation of compound 67 from compound 61 in Examples 20 to 22, and replacing compound 61 with a suitable methyl 4-amino-2-halobenzoate, the following compounds were prepared:

1-N-[4-(6-carbamoyl-7-chloroquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (68): ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.23 (s, 1H), 10.05 (s, 1H), 8.75 (d, 1H), 8.35 (s, 1H), 8.14 (s, 2H), 7.88–7.73 (m, 3H), 7.64 (dd, 2H), 7.27 (d, 2H), 7.15 (t, 2H), 6.64 (d, _1H ), _1.47 (s, _4H ); MS (EI) was _{C₂₇H₂₀ClFN₄O₄} , measured value 519.4 (MH⁺).

1-N-[4-(7-bromo-6-carbamoylquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (69): ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.24 (br s, 1H), 10.07 (br s, 1H), 8.75 (d, 1H), 8.30 (d, 2H), 8.14 (br s, 1H), 7.80 (d, 2H), 7.64-7.67 (m, 2H), 7.27 (d, 2H), 7.18 ( _t , 3H), 6.65 (d, 1H), _{1.48 (s, 4H); MS (EI) was C₂₇H₂₀BrFN₄O₄ ,} measured value _563.3 (MH⁺).

Example 23: 1-N-[4-[6-carbamoyl-7-(2-methoxyethylamino)quinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (70)

1-N-[4-[6-carbamoyl-7-(2-methoxyethylamino)quinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (70): Di[(Z)-1-methyl- ₃ -oxo-but-1-enoxy]copper (70.62 mg, 269.80 μmol, 0.8 equivalent) was added to a mixture of compound 69 (200 mg, 337.25 μmol, 1 equivalent), 2-methoxyethane-1-amine (50.66 mg, 674.51 μmol, 2 equivalent) and _K₂CO₃ (93.22 mg, 674.51 μmol, 2 equivalent) in DMF (10 mL) under nitrogen atmosphere at 10 °C. The resulting mixture was stirred at 100 °C for 2 h under nitrogen atmosphere. Heating was stopped, and once the reaction mixture reached ambient temperature, it was quenched with saturated _NH₄OH aqueous solution (50 mL) and extracted with EtOAc (3 x 30 mL). The combined extracts were dried over _{anhydrous Na₂SO₄} , filtered, and concentrated. The residue was purified by preparative HPLC to give compound 70 (22.2 mg, 11.33% yield). ^¹H NMR (400MHz, _CD₃OD ) δ 8.62 (s, ¹H), 8.43 (d, ¹H), 7.72 (d, 2H), 7.56 (dd, 2H), 7.23 (d, 2H), 7.07 (t, 2H), 6.99 (s, ¹H), 6.32 (d, ¹H), 3.72 (t, 2H), 3.43 (s, 5H), 1.64 (s, 4H); MS (EI) was _{C₃₀H₂₈FN₅O₅ , measured value} 558.1 (MH⁺).

The following compounds were prepared using a method similar to that used for compound 70 in Example 23:

1-N-[4-[6-carbamoyl-7-(3-morpholin-4-ylpropylamino)quinolin-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (71): ^¹H NMR (400MHz, _CD₃OD ) δ 8.60 (s, 1H), 8.42 (d, 1H), 7.71 (d, 2H), 7.59–7.53 (m, 2H), 7.22 (d, 2H), 7.07 (t, 2H), 6.97 (s, 1H), 6.30 (d, 1H), 3.73 (t, 4H), 3.38–3.33 (m, 2H), 2.61–2.45 (m, 6H), 2.00–1.91 (m, 2H), 1.64 (s, 4H); MS (EI) was C₁₀. ₃₄ H ₃₅ FN ₆ O ₅ , measured value 627.2 (MH+).

1-N-[4-[7-(azacyclobutan-1-yl)-6-carbamoylquinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (72): ^¹H NMR (400MHz, _CD₃OD ) δ 8.46 (d, 1H), 8.32 (s, 1H), 7.71 (d, 2H), 7.59–7.53 (m, 2H), 7.21 (d, 2H), 7.11–7.04 (m, 2H), 6.86 (s, 1H), 6.37 (d, 1H), 4.11 (t, 4H), 2.42 (m, 2H), 1.64 (s, 4H); MS (EI) was _{C₃₀H₂₆FN₅O₄ ,} measured value _540.1 ( _MH⁺ ).

Example 24: Ethyl 7-bromo-4-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylamino)phenoxy)quinoline-6-carboxylic acid ester (79)

Ethyl 2-bromo-4-nitrobenzoate (74): _H₂SO₄ (7.81 g, 79.67 mmol, 1 equivalent) was added to a solution of compound ₇₃ (20.0 g, 79.67 mmol, 1 equivalent) in EtOH (78.80 g, 1.71 mol, 100.00 mL, 21.47 equivalent), and the reaction was stirred at 80 °C for 24 h. The reaction mixture was concentrated, and the residue was partitioned between water (200 mL) and DCM (100 mL). The phases were separated, and the aqueous phase was extracted with DCM (3 x 100 mL). The combined organic phases were dried over _{anhydrous Na₂SO₄} and concentrated under vacuum to give compound 74 (21.0 g, 91.37% yield). ^¹H NMR (400MHz, DMSO- _d₆ ) δ 8.52–8.47 (m, ¹H), 8.33–8.28 (m, ¹H), 7.97 (d, ¹H), 4.38 (q, 2H), 1.34 (t, 3H); MS _{(EI) was C₉H₈BrNO₄ , measured} value 274.0 (MH⁺).

Ethyl 4-amino-2-bromobenzoate (75): Iron (2.03 g, 36.4 mmol, 2.1 equivalents) and NH₄Cl (1.95 g, 36.4 mmol, 1.27 mL, 2.1 equivalents) were added to a solution of compound ₇₄ (2, 5.00 g, 17.3 mmol, 1 equivalent) in EtOH (22 mL), THF (22 mL), and water (11 mL) with stirring. The reaction mixture was heated to 80 °C for 3 hours. The reaction was repeated in exactly the same manner as using 16.0 g of compound 74. The two reactants were combined and filtered, and the filter cake was washed with EtOH (3 x 30 mL) and EtOAc (3 x 30 mL). The filtrate was concentrated and diluted with a saturated aqueous solution of _NaHCO₃ (200 mL) to ensure pH was about 8, and extracted with EtOAc (3 x 150 mL). The combined extracts were dried _over anhydrous _Na₂SO₄ and concentrated to give a crude product (19 g). The crude product was suspended in EtOAc (5 mL) and petroleum ether (25 mL) and stirred at room temperature for 20 min. The precipitate was collected by filtration and washed with petroleum ether (2 x 10 mL) to give compound 75 (16.0 g, 85.54% yield, 95% purity). ^¹H NMR (400 MHz, DMSO- _d₆ ) δ 7.62 (d, 1H), 6.84 (d, 1H), 6.54 (dd, 1H), 6.13 (s, 2H), 4.19 (q, _2H ), 1.27 (t, 3H); MS (EI) _{C₉H₁₀BrNO₂} , _243.9 (MH⁺).

2-Bromo-4-(((2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-ylidene)methyl)amino)ethyl benzoate (76): Compound 76 was synthesized from compounds 75 and 39 in a manner similar to that used in the preparation of compound 40 from compounds 38 and 39 in Example 12. Compound 76 was obtained (23 g, 88.1% yield). ^¹H NMR (400 MHz, _CDCl₃ ) δ 11.23 (d, 1H), 8.63 (d, 1H), 7.92 (d, 1H), 7.56 (d, 1H), 7.23 (dd, 1H), 4.40 (q, 2H), 1.76 (s, 6H), 1.41 (t, 3H).

7-Bromo-4-oxo-1,4-dihydroquinoline-6-carboxylic acid ethyl ester (77): Compound 77 was synthesized from compound 76 in a manner similar to that used in the preparation of compound 41 from compound 40 in Example 12. Compound 77 (20 g, 94.4% yield, 60% purity) was obtained and used in subsequent reactions without further purification. _{MS (EI) was C12H10BrNO3 ,} measured at _296.0 (MH+).

7-Bromo-4-chloroquinoline 6-carboxylic acid ethyl ester (78): Compound 78 was prepared from compound 77 as described in Example 12 for compound 42, except that pure _POCl3 was used instead. The reaction was carried out in MeCN with 4.21 equivalents of _POCl3 at 90 °C for 1.5 h (4.2 g, 33% yield). ^¹H NMR ( ₄₀₀ MHz, _CD₃OD ) δ 8.84 (d, 1H), 8.62 (s, 1H), 8.45 (s, 1H), 7.55 (d, 1H), 4.50 (q, 2H), 1.47 (t, 3H); MS (EI _{) C₁₂H₉BrClNO₂} , measured 313.8 (MH⁺).

7-Bromo-4-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylammono)phenoxy)quinoline-6-carboxylic acid ethyl ester (79): Compound 79 was prepared from compounds 78 and 3 as described in Example 12 for compound 43, except that cesium carbonate was used instead of potassium tert-butoxide and the reaction mixture was heated only to 50°C (6.7 g, 80.5% yield). ^¹H NMR (400MHz, _CD₃OD ) δ 9.55 (s, ¹H), 8.79 (s, ¹H), 8.70 (d, ¹H), 8.55 (s, ¹H), 8.40 (s, ¹H), 7.67 (d, 2H), 7.47 (dd, 2H), 7.18 (d, 2H), 7.06 (t, 2H), 6.56 (d, 1H), 4.48 (q, 2H), 1.79–1.73 ( _{m, 2H), 1.68–1.62 (m, 2H), 1.46 (t, 3H); MS (EI) was C₂₹H₂₃BrFN₃O₅ , measured} value _592.0 (MH⁺).

Example 25: 4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-7-(methylamino)quinoline-6-carboxylic acid (81)

Ethyl 4-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylamino)phenoxy)-7-(methylamino)quinoline-6-carboxylic acid (80): Pd₂(dba)₃ (440.54 mg, 481.08 μmol, 0.3 equivalent) was added to a mixture of compound 79 (1.00 g, 1.60 mmol, 1 equivalent), methylamine hydrogen chloride (216.55 _mg , 3.21 mmol, 2 equivalents), _Cs₂CO₃ (1.57 g, 4.81 mmol, 3 equivalents), and Xantphos (556.73 _mg , 962.17 μmol, 0.6 equivalents) in _1,4 -dioxane (25 mL) at 10 °C under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 3 h under a nitrogen atmosphere. The reaction mixture was cooled, then diluted with water (50 mL) and EtOAc (50 mL), neutralized with saturated _NH₄Cl aqueous solution to pH approximately 8, and filtered. The filter cake was washed with EtOAc. The phases of the filtrate were separated, and the aqueous phase was extracted with EtOAc (3 x 30 mL). The combined EtOAc phases were dried over _{anhydrous Na₂SO₄} and concentrated. The residue was purified by rapid silica gel chromatography (0–80% EtOAc: petroleum ether, then 0–15% EtOH in DCM solution), followed by further purification by preparative HPLC to give compound 80 (250 mg, 27.30% yield). ^¹H NMR (400MHz, _CDCl₃ ) δ 10.27 (s, 1H), 9.00 (s, 2H), 8.42 (s, 2H), 7.80 (d, 2H), 7.51 (dd, 2H), 7.39 (s, 1H), 7.17 (d, 2H), 7.03 (t, 2H), 6.38 (d, 1H), 4.44 (q, 2H), 3.11 (s, 3H), 1.85 (s, 2H), 1.73 (s, 2H), _{1.48–1.43 (m, 3H); MS (EI) was C₃₀H₂₇FN₄O₅ ,} measured value _543.1 ( _MH⁺ ).

4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-7-(methylamino)quinoline-6-carboxylic acid (81): A mixture of compound 80 (250 mg, 437.4 μmol, 1 equivalent) and lithium hydroxide:hydrate (183.69 mg, 4.38 mmol, 10 equivalent) in THF (10.0 mL) and water (10.0 mL) was stirred at 10 °C for 20 h. The reactants were diluted with water (40 mL), acidified to pH 6 with saturated _NH4Cl aqueous solution, and extracted with EtOAc (4 x 40 mL). The combined extracts were dried over _{anhydrous Na₂SO₄} and concentrated under reduced pressure to obtain a crude product, which was then purified by preparative HPLC (column: Ultimate C18 150*25mm*5μm; mobile phase: [water (0.05% HCl)-ACN]; B%: 16%-46%, 9.5 min) to give compound 81HCl salt (120 mg, 47.3% yield). ^¹H NMR (400MHz, _CD₃OD ) δ 9.13 (s, ¹H), 8.57 (d, ¹H), 7.81 (d, 2H), 7.56 (dd, 2H), 7.34 (d, 2H), 7.07 (t, 2H), 6.88 (s, ¹H), 6.61 (d, 1H), 3.07 (s, 3H), 1.66 (s _, 4H); MS (EI) was _{C₂₈H₂₃FN₄O₅ ,} measured value _515.1 (MH⁺).

Example 26: 1-N-[4-[6-carbamoyl-7-(methylamino)quinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (82)

1-N-[4-[6-carbamoyl-7-(methylamino)quinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (82): Compound 82 (29.9 mg, 24% yield) was synthesized from compound 81 in a manner similar to that used in the preparation of compound 7 from compound 6 in Example 3. ^¹H NMR (400MHz, _CD₃OD ) δ 8.61 (s, ¹H), 8.43 (d, ¹H), 7.72 (d, 2H), 7.59–7.54 (m, 2H), 7.23 (d, 2H), 7.07 (t, 2H), 6.94 (s, ¹H), 6.31 (d, ¹H), 2.97 (s, 3H), 1.64 ( _s , 4H); MS (EI) was _{C₂₈H₂₄FN₅O₄ ,} measured value _514.1 (MH⁺).

Example 27: 1-N'-(4-fluorophenyl)-1-N-[4-[7-(methylamino)-6-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (83)

1-N'-(4-fluorophenyl)-1-N-[4-[7-(methylamino)-6-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (83): Compound 83 (33.3 mg, 26% yield) was synthesized from compound 81 in a manner similar to that used in the preparation of compound 8 from compound 6 in Example 4. ^¹H NMR (400MHz, _CD₃OD ) δ 8.47 (s, ¹H), 8.42 (d, ¹H), 7.71 (d, 2H), 7.59–7.54 (m, 2H), 7.22 (d, 2H), 7.07 (t, 2H), 6.94 (s, ¹H), 6.32 (d, ¹H), 2.96 (s, 3H), 2.92 (s, 3H), 1.64 (s, 4H); MS (EI) was _{C₂ ₹ H₂₆FN₅O₄ ,} measured value 528.1 (MH⁺).

Example 28: Methyl 4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-7-(methylamino)quinoline-6-carboxylic acid ester (84)

4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-7-(methylamino)quinoline-6-carboxylic acid methyl ester (84): TMSCHN ₂ (2M, 276.97 μL, 10 equivalents) was added to a MeOH (5 mL) solution of compound 81 (30 mg, 55.39 μmol, 1 equivalent) at 10 °C, and the reaction was stirred at 10 °C for 6 h. The reaction was repeated in the same manner with an additional 45 mg of compound 81. The reaction solutions from the two batches were combined and concentrated under vacuum. The resulting residue was purified by preparative HPLC to give compound 84 (25.5 mg, 55.16% yield). ^¹H NMR (400MHz, _CD₃OD ) δ 8.99 (s, ¹H), 8.45 (d, ¹H), 7.72 (d, 2H), 7.57 (dd, 2H), 7.23 (d, 2H), 7.07 (t, 2H), 6.97 (s, ¹H), 6.29 (d, ¹H), 3.95 (s, 3H), 3.01 (s, 3H), 1.64 (s, 4H); MS (EI) was _{C₂ ₹ H₂₅FN₄O₅ ,} measured value 529.1 (MH⁺).

Example 29: 7-((tert-butoxycarbonyl)amino)-4-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylamino)phenoxy)quinoline-6-carboxylic acid (86)

7-((tert-butoxycarbonyl)amino)-4-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylamino)phenoxy)quinoline-6-carboxylic acid ethyl ester (85): A mixture of compound 79 (1.5 g, 2.53 mmol, 1 equivalent), _NH₂Boc (355.95 mg, 3.04 mmol, 1.2 equivalent), Xantphos (586.03 mg, 1.01 mmol, 0.4 equivalent), _Pd₂ (dba) _₃ (463.72 mg, 506.40 μmol, 0.2 equivalent) and _Cs₂CO₃ ( _2.47 g, 7.60 mmol, 3 equivalent) in dioxane (20 mL) was degassed and purged three times with nitrogen, and stirred at 90 °C for 16 hours under a nitrogen atmosphere. The mixture was filtered and concentrated, and the residue was purified by rapid silica gel chromatography (10% to 100% petroleum ether solution of EtOAc) to give compound 85 (1.3 g, 79.14% yield). ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.28 (s, 1H), 10.23 (s, 1H), 10.06 (s, 1H), 8.94 (s, 1H), 8.72 (d, 1H), 8.69 (s, 1H), 7.79 (d, 2H), 7.64 (dd, 2H), 7.30 (d, 2H), 7.16 (t, 2H), 6.46 (d, 1H), 4.42 (q, 2H), 1.53 (s, 9H), 1.48 (s, 4H), 1.38 (t, _{3H); MS (EI) was C₃₄H₃₃FN₄O₇ , measured value} 629.2 (MH⁺).

7-((tert-butoxycarbonyl)amino)-4-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylamino)phenoxy)quinoline-6-carboxylic acid (86): Compound 86 (0.7 g, 82.4% yield) was synthesized from compound 85 in a manner similar to that used in Example 2 to prepare compound 6 by hydrolysis of the methyl ester of compound 5. ^¹H NMR (400MHz, _CD₃OD ) δ 9.13 (s, ¹H), 8.57 (d, ¹H), 7.81 (d, 2H), 7.56 (dd, 2H), 7.34 (d, 2H), 7.07 (t, 2H), 6.88 (s, ¹H), 6.61 (d, 1H), 3.07 (s, 3H), 1.66 ( _s , 4H); MS (EI) was _{C₃₂H₂ ₹ FN₄O₇} , measured value 601.1 (MH⁺).

Example 30: 1-N-[4-(7-amino-6-carbamoylquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (87)

1-N-[4-(7-amino-6-carbamoylquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)-cyclopropane-1,1-dicarboxamide (87): Compound 87 was synthesized from compound 86 in two steps. The first step followed a similar manner to the preparation of compound 7 from compound 6 in Example 3. Step 2 involved TFA-mediated BOC-deprotection using a standard procedure (such as the standard procedure used in Example 5), which provided the final compound 87 (41.9 mg, 35% yield in 2 steps). ^¹H NMR (400MHz, _CD₃OD ) δ 8.63 (s, ¹H), 8.43 (d, ¹H), 7.73 (d, 2H), 7.66–7.52 (m, 2H), 7.32–7.22 (m, 2H), 7.15 (s, ¹H), 7.12–7.05 (m, 2H), 6.31 (d, ¹H), 1.66 (s, _{4H); MS (EI) was C₂₇H₂₂FN₅O₄ , measured} value _500.0 (MH⁺).

Example 31: 1-N-[4-[7-amino-6-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (88)

1-N-[4-[7-amino-6-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (88): Compound 88 was synthesized from compound 86 in two steps. The first step followed a similar manner to the preparation of compound 8 from compound 6 in Example 4. Step 2 involved TFA-mediated BOC-deprotection using a standard procedure (such as the standard procedure used in Example 5), which provided the final compound 88 (50.9 mg, 42% yield in 2 steps). ^¹H NMR (400MHz, DMSO- _d₆ ) δ 10.19 (s, 1H), 10.05 (s, 1H), 8.70 (br d, 1H), 8.52–8.38 (m, 2H), 7.77 (d, 2H), 7.69–7.59 (m, 2H), 7.30–7.06 (m, 5H), 6.55 (s, 2H), 6.17 (d, 1H), 2.79 (d, _3H ), 1.48 (s, 4H); MS ( _EI ) was _{C₂₈H₂₄FN₅O₄ ,} measured value 514.1 (MH⁺).

Example 32: 7-Amino-4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]quinoline-6-carboxylic acid (89)

7-Amino-4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]quinoline-6-carboxylic acid (89): Compound 89 was synthesized from compound 86 by TFA-mediated BOC-deprotection as described in Example 5. ^¹H NMR (400 MHz, DMSO- _d⁶ ) δ 10.19 (s, 1H), 10.07 (s, 1H), 8.80 (s, 1H), 8.48 (d, 1H), 7.76 (d, 2H), 7.69–7.58 (m, 2H), 7.24 (d, 2H), 7.19–7.10 (m, 3H), 6.16 ( _{d, 1H), 1.48 (s, 4H); MS (EI) was C₂₇H₂₁FN₄O₅ , measured 501.1} (MH⁺).

Example 33: Methyl 7-amino-4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]quinoline-6-carboxylic acid ester (90)

7-Amino-4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]quinoline-6-carboxylic acid methyl ester (90): A solution of compound 89 (100 mg, 199.81 μmol, 1 equivalent) in MeOH (3 mL) and _H₂SO₄ (0.1 _mL ) was stirred at 70 °C for 40 h. The reaction was concentrated under vacuum, and the resulting residue was purified by preparative HPLC to give compound 90 (28.5 mg, 26.88% yield). ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.20 (br s, 1H), 10.07 (br s, 1H), 8.81 (s, 1H), 8.50 (d, 1H), 7.77 (br d, 2H), 7.65 (br dd, 2H), 7.25 (br d, 2H), 7.21–7.06 (m, 3H), 6.83 (s, 2H), 6.15 (d, 1H), 3.90 (s, 3H), _1.48 (s, _{4H); MS (EI) was C₂₈H₂₃FN₄O₅ ,} measured value _515.2 (MH⁺).

Example 34: N-(4-((6-carbamoyl-7-hydroxyquinoline-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (91)

N-(4-((6-carbamoyl-7-hydroxyquinoline-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (91): A mixture of compound 7 (250 mg, 485.91 μmol, 1 equivalent) and BBr ₃ (1.04 g, 4.15 mmol, 0.4 mL, 8.54 equivalent) in 1,2-dichloroethane (2 mL) was stirred at 50 °C for 1 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and poured into a saturated aqueous solution of NaHCO ₃ with vigorous stirring. The resulting residue was filtered, washed with water, then washed with methyl tert-butyl ether, and dried. The crude compound was purified by preparative HPLC to give compound 91 (69.5 mg, 27.3% yield). ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 12.91 (s, 1H), 10.20 (s, 1H), 10.04 (s, 1H), 8.97 (s, 1H), 8.84 (s, 1H), 8.60–8.59 (d, 1H), 7.79 (s, 1H), 7.77–7.64 (d, 2H), 7.63–7.62 (d, 2H), 7.30–7.26 (m, 3H), 7.17–7.13 (m, 2H), 6.63–6.33 (d, 1H), _1.47 (s, _{4H )} ; MS (EI) was _{C₂₇H₂₁FN₄O₅} , measured value 501.1 (MH⁺).

Example 35: 1-N'-(4-fluorophenyl)-1-N-[4-[(2-methyl-4-oxo-2,3-dihydropyrido[3,2-g][1,3]benzoxazin-6-yl)oxy]phenyl]cyclopropane-1,1-dicarboxamide (92)

1-N'-(4-fluorophenyl)-1-N-[4-[(2-methyl-4-oxo-2,3-dihydropyridino[3,2-g][1,3]benzoxazin-6-yl)oxy]phenyl]cyclopropane-1,1-dicarboxamide (92): _T3P (535 mg, 1.68 mmol, 0.5 mL, 6.47 equivalents) and acetaldehyde (393 mg, 8.91 mmol, 0.5 mL, 34.30 equivalents) were added to a CHCl3 ₃ (5 mL) solution of compound 91 (130 mg, 259.75 μmol, 1 equivalent). The resulting mixture was stirred at 50 °C for 3 h and then concentrated under vacuum. The residue was purified by preparative HPLC to give compound 92 (30.7 mg, 22.45% yield). ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.22 (s, ¹H), 10.07 (s, ¹H), 9.05 (s, ¹H), 8.78 (s, ¹H), 8.70 (d, ¹H), 7.72 (d, 2H), 7.65 (d, 2H), 7.50 (s, ¹H), 7.28 (d, 2H), 7.17 (d, 2H), 6.50 (d, 1H), 5.62–5.58 (m, ¹H), 1.57 (d, 3H) _{, 1.48 (s, 4H); MS (EI) was C₂⁹H₂⁻³FN₄O₅ ,} measured value _{527.2 (} MH⁺).

Example 36: 1-N-[4-[(2-ethyl-4-oxo-2,3-dihydropyrido[3,2-g][1,3]benzoxazin-6-yl)oxy]phenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (96)

4-Chloro-7-methoxyquinoline-6-carboxamide (93): _NH₃ · _H₂O (10.58 g, 75.50 mmol, 1 equivalence) was added to a mixture of compound 4 (2.00 g, 7.55 mmol, 1 equivalence) in MeOH ( _{20 mL) at 10 °C. The mixture was stirred at 70 °C for 72 h. The precipitate was collected by filtration and dried under vacuum to give compound 93 (1.30 g, 69.1% yield); MS (EI) was C₁₁H₉ClN₂O₂ , measured 237.0} (MH⁺).

4-Chloro-7-hydroxyquinoline-6-carboxamide (94): BBr ₃ (6.54 g, 26.09 mmol, 2.51 mL, 5 equivalents) was added fractionally to a mixture of compound 93 (1.30 g, 5.22 mmol, 1 equivalent) in DCM (30 mL) at 0 °C. The mixture was stirred at 0 °C for 6 h. The reaction was quenched with saturated NaHCO ₃ aqueous solution (150 _mL ) and filtered. The resulting residue was dried under vacuum to give compound 94 ( _{1.00 g, 81.77% yield). MS (EI) was C10H7ClN2O2 , and} the result was 222.8 (MH+).

6-Chloro-2-ethyl-2,3-dihydro-4H-[1,3]oxazino[5,6-g]quinoline-4-one (95): Propanal (1.60 g, 27.48 mmol, 2 mL, 3.06 equivalents) and _T3P (10.42 g, 32.76 mmol, 9.74 mL, 3.65 equivalents) were added to a CHCl3 ₃ (15 mL) solution of compound 94 (2 g, 8.98 mmol, 1 equivalent). The resulting mixture was stirred at 50 °C for 15 h, and then propanal (1.60 g, 27.48 mmol, 2 mL, 3.06 equivalents) was added, and stirring was continued at 50 °C for another 15 h. The mixture was then concentrated to remove the solvent, giving crude compound 95 (2.2 g, 85.8% yield) as a yellow solid, which was used in the next step without further purification. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 9.16 (br s, 1H), 8.87 (d, 1H), 8.66 (s, 1H), 7.72 (d, 1H), 7.62 (s, 1H), 5.45–5.47 (m, 1H), 1.38–1.44 (m, 2H), 1.06 (t, 3H); MS _{( EI )} was _{C₁₃H₁₁ClN₂O₂} , measured value 262.9 (MH⁺).

1-N-[4-[(2-ethyl-4-oxo-2,3-dihydropyrido[3,2-g][1,3]benzoxazin-6-yl)oxy]phenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (96): A chlorobenzene (10 mL) solution of compound 95 (95 mg, 361.64 μmol, 1 equivalent) and compound 3 (284.17 mg, 904.10 μmol, 2.5 equivalent) was stirred at 140 °C for 15 h. The mixture was diluted with EtOAc (60 mL) and washed with 2N NaOH (3 x 20 mL). The combined aqueous phases were extracted with EtOAc (30 mL). The combined organic phases were concentrated, and the resulting residue was purified by preparative HPLC (column: YMC-Triart Prep C18150*40mm*7um; mobile phase: [water (0.05% ammonium hydroxide v/v)-ACN]; B%: 53%-73%, 10 min) to give compound 96 as a white solid (7.1 mg, 3.6% yield). ^¹H NMR (400MHz, DMSO- _d₆ ) δ 10.23 (s, ¹H), 10.07 (s, ¹H), 9.05 (s, ¹H), 8.78 (s, ¹H), 8.69 (s, ¹H), 7.78–7.86 (m, 2H), 7.64–7.67 (m, 2H), 7.51 (s, ¹H), 7.28–7.30 (m, 2H), 7.14–7.18 (m, 2H), 6.49–6.51 (m, 1H), 5.43 (s, 1H), 1.88–1.91 (m, 2H), 1.48 (s, 4H), 1.06 (t, 3H); MS ₍ EI ₎ was _{C₃₀H₂₅FN₄O₅ ,} measured value 541.1 (MH⁺).

Example 37: 1-N-[4-[6-carbamoyl-7-(3-morpholin-4-ylpropoxy)quinolin-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (98)

4-(3-Bromopropyl)morpholine (97): 3-morpholinopropan-1-ol (2.0 g, 13.77 mmol, 1 equivalent) and PPh ₃ (4.0 g, 15.25 mmol, 1.11 equivalent) were dissolved in THF (20 mL), and the reaction mixture was cooled in an ice-water bath under nitrogen. CBr ₄ (5.0 g, 15.08 mmol, 1.09 equivalent) was added in portions over 15 minutes. After stirring for 30 minutes, the mixture was heated to 30 °C and maintained for 18 hours. The reaction was quenched with water (10 mL) and EtOAc (30 mL). The layers were separated, and the organic layer was extracted with 1N HCl (2 x 15 mL). The pH of the combined aqueous extracts was adjusted to 10⁻¹¹ with 4N NaOH. The aqueous phase was extracted with EtOAc (3 x 30 mL). The combined EtOAc extracts were dried over anhydrous _Na₂SO₄ and concentrated to give compound ₉₇ (1.8 g, 63% yield), which was used in subsequent reactions without further purification. ^¹H NMR (400 MHz, _CDCl₃ ) δ 3.72–3.69 (m, 4H), 3.49–3.46 (t, 2H), 2.50–2.43 (m, 6H), 2.06–1.99 (m, 2H).

1-N-[4-[6-carbamoyl-7-(3-morpholin-4-ylpropoxy)quinolin-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (98): Cs₂CO₃ (81.18 _mg , 249.14 μmol, 2.90 equivalent) was added to a mixture of compound 91 (45 mg, 85.87 μmol, 1 equivalent) and compound ₉₇ (53.48 mg, 257.00 μmol, 2.99 equivalent) in DMF (2 mL) under nitrogen atmosphere. The mixture was stirred at 80 °C for 2 hours. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 20 mL). The combined organic phases were separated, washed with saturated NaCl aqueous solution, _dried over anhydrous _Na₂SO₄ , concentrated, and purified by preparative HPLC to give compound 98 (16.2 mg, 29.70% yield). ^¹H NMR (400 MHz, DMSO- _d₆ ) δ 9.36 (s, 1H), 9.29–9.27 (d, 1H), 9.00 (s, 1H), 8.64–8.63 (d, 1H), 7.99–7.98 (d, 1H), 7.69–67 (d, 2H), 7.54 (s, 1H), 7.51–7.47 (m, 2H), 7.17–7.14 (d, 2H), 7.07–7.01 (m,2H), 6.46-6.45(d,1H), 5.98-5.97(d,1H), 4.40-4.37(t,2H), 3.76-3.70(m,4H), 2.26-2.58(m,2H), 2.50(s,4H), 2.20-2.13(m,2H) _, 1.74-1.70(m,4H); MS(EI) is _{C34H34FN5O6 ,} measured value _628.5 (MH+).

Example 38: 1-N-[4-[6-carbamoyl-7-(2-methoxyethoxy)quinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (103)

6-Bromo-4-chloroquinoline-7-ol (99): A mixture of compound 42 (5 g, 18.35 mmol, 1 equivalent) and BBr ₃ (13.0 g, 51.89 mmol, 5 mL, 2.83 equivalent) in 1,2-dichloroethane (15 mL) was stirred at 90 °C for 2.5 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and poured into a saturated aqueous solution of NaHCO ₃ with vigorous stirring. The resulting residue was filtered, washed with water, then washed with methyl tert-butyl ether, and dried under vacuum to give compound 99 (7 g, crude), which could be used in subsequent steps without further purification. ^¹H NMR (400MHz, DMSO- _d₆ ) δ 9.04–9.03 (d, ¹H), 8.49 (s, ¹H), 7.93–7.92 (d, ¹H), 7.69 (s, ¹H), 6.08 (s, ¹H); MS _{(EI) was C₈H₅BrClNO ,} measured value 258.2 (MH⁺).

6-Bromo-4-chloro-7-(2-methoxyethoxy)quinoline (100): A mixture of compound 99 (500 mg, 1.93 mmol, 1 equivalent), 1-bromo-2-methoxy-ethane (1.08 g, 7.73 mmol, 726.35 _μL , 4 equivalents), and _Cs₂CO₃ (1.90 g, 5.83 mmol, 3.01 equivalents) in DMF (4 mL) was stirred at 80 °C for 2 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and water (2 mL) was added. The resulting residue was filtered, washed with water, and dried under vacuum to give compound 100 (590 mg, 96% yield), which could be used in subsequent reactions without further purification. ^¹H NMR (400MHz, DMSO- _d₆ ) δ 8.80–8.79 (d, ¹H), 8.37 (s, ¹H), 7.65–7.64 (d, ¹H), 7.62 (s, ¹H), 4.39–4.37 (t, 2H), 3.79–3.77 (t, 2H), 3.37 ( _{s, 3H); MS (EI) was C₁₂H₁₁BrClNO₂ ,} measured value 315.8 ( _MH⁺ ).

N-(4-((6-bromo-7-(2-methoxyethoxy)quinoline-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (101): Compound 101 (65 mg, 69.2% yield) was synthesized from compounds 100 and 3 in a manner similar to that used in Example 12 for the preparation of compound 43 from compounds _{42 and 3.} MS (EI) was _{C29H25BrFN3O5} , and the measured value was 594.1 (MH+).

N-(4-((6-cyano-7-(2-methoxyethoxy)quinoline-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (102): Compound 101 (65 mg, 109.35 μmol, 1 equivalent) and CuCN (15 mg, 167.48 μmol, 36.59 μL, 1.53 equivalent) were mixed in N-methyl-2-pyrrolidone (NMP) (2 mL) in a sealed tube and heated at 150 °C for 45 min under microwave irradiation. The reaction mixture was partitioned between water (10 mL), _NH4OH (5 mL), and EtOAc (20 mL), the phases were separated, and the aqueous phase was further extracted with EtOAc. The combined organic phases were washed with a saturated aqueous NaCl solution, dried over anhydrous _Na₂SO₄ , and concentrated to give compound 102 (40 mg, 68% yield), which was used in subsequent steps without further purification. _MS (EI) was _{C₃₀H₂₅FN₄O₅} , _with a measured value _{of 541.5} (MH⁺).

1-N-[4-[6-carbamoyl-7-(2-methoxyethoxy)quinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (103): Compound 102 (40 mg, 74.00 μmol, 1 equivalent) and NaOH (100 mg, 2.50 mmol, 33.79 equivalent) were dissolved in DMSO (1.5 mL) and water (0.5 mL). The resulting mixture was heated at 80 °C for 1 hour. The reaction mixture was partitioned between water (10 mL) and EtOAc (20 mL) to separate the phases, and the aqueous phase was further extracted with EtOAc. The combined organic phases were washed with a saturated aqueous solution of NaCl, dried over _{anhydrous Na₂SO₄} , and concentrated. The residue was purified by rapid silica gel chromatography (50–100% EtOAc/petroleum ether) to give compound 103 (18.6 mg, 44% yield). ¹ H NMR (400MHz, CDCl ₃ )δ9.30(s,1H),9.27(s,1H),9.02(s,1H),8.64-8.63(d,1H),8.15(s,1H),7.69-7.66(d,2H),7.51-7.48(m,3H),7.17-7.15(d,2H), 7.07-7.03(m,2H),6.47-6.45(d,1H),5.92(s,1H),4.44-4.42(t,2H),3.91-3.89(t,2H),3.50(s,3H),1.75-1.68(m,4H); MS(EI) is C ₃₀ H ₂₇ FN ₄ O ₆ The measured value was 559.4 (MH+).

Example 39: 1-N-[4-[6-carbamoyl-7-(2-hydroxyethoxy)quinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (106)

Ethyl 2-((6-carbamoyl-4-chloroquinoline-7-yl)oxy)ethyl acetate (104): Ethyl ₂ -bromoethyl acetate (285.05 mg, 1.71 mmol, 187.53 μL, 2.00 equivalent) was added to a mixture of compound 94 (200 mg, 853.44 μmol, 1 equivalent) and _K₂CO₃ (589.77 mg, 4.27 mmol, 5 equivalent) in DMF (10 mL) at 10 °C. The resulting mixture was stirred at 70 °C for 1 hour. After cooling, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 30 mL). The combined extracts were washed with saturated aqueous NaCl solution (3 x 100 mL), _dried over anhydrous _Na₂SO₄ , and concentrated under vacuum to give compound 104 (220 mg, 79.33% yield). MS(EI) is _C14H13ClN2O4 , measured _{value 309.0 (} MH+).

2-((6-carbamoyl-4-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylamino)phenoxy)quinoline-7-yl)oxy)ethyl acetate (105): Compound 104 (200 mg, 615.45 μmol) was converted to compound 105 by reaction with compound 3, using a method similar to that used in the preparation of compound 43 from compounds 42 and 3 in Example 12. The resulting reaction mixture was treated with water at 100 °C for 4 hours before undergoing the conventional post-reaction treatment as described in Example 12. The resulting product was a mixture of compounds 105 and 106. The mixture was separated by rapid silica gel chromatography to give compound 105 (100 mg, 24.93% yield), which was used in the next reaction, and compound 106 (100 mg, 25.36% yield, 85% purity), which was combined with the product of the next reaction for final purification. For compound 105: MS (EI) is _C31H27FN4O7 , _and the measured value _is 587.1 ₍ MH+).

1-N-[4-[6-carbamoyl-7-(2-hydroxyethoxy)quinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (106): LiOH·H₂O (64.39 mg, _1.53 mmol, 10 equivalents) was added to a solution of compound 105 (100 mg, 153.44 μmol, 1 equivalent) separated from the previous reaction in THF (5 mL) and water (1 mL). The resulting mixture was stirred at 70 °C for 1 hour. After the reaction mixture was cooled to room temperature, it was acidified to pH about 7 with a saturated aqueous _NH₄Cl solution, diluted with water (30 mL), and extracted with EtOAc (3 x 20 mL). The combined organic phases were dried over _{anhydrous Na₂SO₄} and concentrated under vacuum to give crude compound 106 (90 mg, 91.56% yield, 85% purity). The substance was combined with compound 106, which had been isolated from the previous step, and purified by rapid silica gel chromatography. The resulting product was suspended in a 1:1 mixture of DCM:MeCN and stirred for 10 minutes. The resulting solid was filtered, washed with MeCN, then washed with DCM, and dried under vacuum to give compound 106 (65.8 mg, 38.7% yield). ^¹H NMR (400MHz, DMSO- _d₆ ) δ 10.20 (s, ¹H), 10.06 (s, ¹H), 8.83 (s, ¹H), 8.66 (d, ¹H), 7.96 (s, ¹H), 7.84 (s, ¹H), 7.78 (d, 2H), 7.64 (dd, 2H), 7.56 (s, ¹H), 7.27 (d, 2H), 7.15 (t, 2H), 6.47 (d, ¹H), 5.14 (t, ¹H), 4.32 (t, 2H), 3.86 (dd, 2H), 1.47 (s, _{4H); MS (EI) was C₂₹H₂₅FN₄O₆ , measured value} 545.1 (MH⁺).

Example 40: 1-N'-(4-fluorophenyl)-1-N-[4-[7-(2-hydroxyethoxy)-6-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (110)

4-Chloro-7-methoxy-N-methylquinoline-6-carboxamide (107): A solution of methylamine (8 M, 50 mL, 10.07 equivalents) in EtOH was added to a solution of compound 4 (10 g, 39.74 mmol, 1 equivalent) in THF (150 mL) at 30 °C, and the mixture was stirred at this temperature for 25 h. The reaction mixture was concentrated under vacuum. The residue was slurried with warm water (100 _mL ), filtered, and dried under vacuum to give _compound 107 (9 g, 90.4% yield). _MS (EI) was _C12H11ClN2O2 , measured at 251.0 (MH+).

4-Chloro-7-hydroxy-N-methylquinoline-6-carboxamide (108): Compound 108 (730 mg, 62% yield) was synthesized from compound 107 in a manner similar to that used in the preparation of compound 94 from compound 93 in _{Example 36. MS (EI) was C11H9ClN2O2 , measured} at 237.0 (MH+).

2-((4-chloro-6-(methylcarbamoyl)quinolin-7-yl)oxy)ethyl acetate (109): Compound 109 was synthesized from compound 108 in a manner similar to _that used in Example 39 for the preparation of compound 104 (200 _mg , crude) from compound 94. _MS (EI) was _C15H15ClN2O4 , measured at 323.1 (MH+).

1-N'-(4-fluorophenyl)-1-N-[4-[7-(2-hydroxyethoxy)-6-(methylcarbamoyl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (110): t-BuOK (70 mg, 623.83 μmol, 2.01 equivalents) was added to a mixture of compound 3 (107 mg, 340.43 μmol, 1.10 equivalents) and compound 109 (100 mg, 309.84 μmol, 1 equivalent) in DMSO (10 mL). The resulting mixture was heated and stirred at 100 °C for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic phases were washed with saturated NaCl aqueous solution (2 x 100 mL), _dried over anhydrous _Na₂SO₄ , and concentrated under vacuum. The residue was purified by rapid silica gel chromatography (0-20% MeOH in EtOAc solution) to obtain the crude product, which was then purified by preparative TLC (20% MeOH in DCM solution, _Rf = 0.3) to obtain compound 110 (54.8 mg, 100% purity). ^¹H NMR (400MHz, DMSO- _d₆ ) δ 10.22 (s, 1H), 10.07 (s, 1H), 8.75 (s, 1H), 8.66 (d, 1H), 8.49 (q, 1H), 7.78 (d, 2H), 7.64 (dd, 2H), 7.57 (s, 1H), 7.27 (d, 2H), 7.15 (t, 2H), 6.46 (d, 1H), 5.19 (t, 1H), 4.32 (t, 2H), 3.86 (br d, 2H), 2.87 (d, 3H), _1.47 (s, _{4H )} ; MS (EI) was _{C₃₀H₂₇FN₄O₆} , measured value 559.1 (MH⁺).

Example 41: 1-N-[4-[6-carbamoyl-7-(2-hydroxypropoxy)quinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (115)

4-Chloro-7-(2-oxopropoxy)quinoline-6-carboxamide (111): 1-Chloropropan- _{2-one (1.45 g, 15.7 mmol, 11.97 μL, 18.4 equivalents) was added to a mixture of compound 94 (200 mg, 853.4 μmol, 1 equivalent) and K₂CO₃ (} 589.76 mg, 4.27 mmol, 5 equivalents) in DMF (10 mL) at 10 °C. The reaction mixture was then stirred at 65 °C for 1 hour. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 30 mL). The combined extracts were washed with saturated aqueous NaCl solution (3 x 100 mL), _dried over anhydrous _Na₂SO₄ , and concentrated. The resulting residue was purified by rapid silica gel chromatography (0–10% MeOH in DCM solution). The resulting yellow residue was further purified by preparative HPLC (column: Waters Xbridge 150mm*25mm*5μm; mobile phase: [water (0.05% ammonium hydroxide v/v)-ACN]; B%: 17%-47%, 7.8 min) to give compound 111 (55 _mg , _30.0 % yield). _{MS (EI) was C13H11ClN2O3 ,} measured value 279.0 (MH+).

4-Chloro-7-(2-hydroxypropoxy)quinoline-6-carboxamide (112): _NaBH4 (12.90 mg, 340.88 μmol, 2 equivalents) was added to a mixture of compound 111 (50 mg, 170.44 μmol, 1 equivalent) in MeOH (10 mL) at 10 °C. The reaction mixture was then stirred at 50 °C for 1 h. The reaction mixture was quenched with saturated _NH4Cl aqueous solution (30 mL) and extracted with EtOAc/i-PrOH (v/v = 3: ₁ , 5 x ₂₀ mL). The combined extracts were dried over anhydrous _Na2SO4 and concentrated under reduced pressure to give compound ₁₁₂ (50 _mg , 99.3% yield). MS (EI) was _C13H13ClN2O3 , and the measured value was 302.8 (MH+Na) ⁺ .

1-((6-carbamoyl-4-chloroquinoline-7-yl)oxy)propyl-2-yl acetate (113): _Ac₂O (65.46 mg, 641.24 μmol, 60.06 μL, 5 equivalents) and DMAP (15.67 mg, 128.25 μmol, 1 equivalent) were added to a mixture of compound 112 (45 mg, 128.25 μmol, 1 equivalent) in DCM (10 mL) at 10 °C. The mixture was then stirred at 10 °C for 16 h. The reaction mixture was diluted with water (30 mL) and extracted with DCM (5 x 20 _mL ). The combined extracts were dried over anhydrous _Na₂SO₄ and concentrated. The residue was purified by rapid silica gel chromatography (0-3% MeOH in EtOAc solution) to give compound 113 (45 mg, 86.98% yield, 80% purity). MS ( _{EI) is C15H15ClN2O4 ,} measured value _344.8 (MH ₊ Na) ⁺ .

1-((6-carbamoyl-4-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylamino)phenoxy)quinoline-7-yl)oxy)propyl-2-yl acetate (114): Compound 114 was synthesized from compounds 113 and 3 in a manner similar to that described for compound 43 in Example 12, except that cesium carbonate was used instead of potassium tert-butoxide, and the reaction mixture was heated to 100°C for 2 _hours ( ₄₀ mg, _72.9 % yield). MS (EI) was _C32H29FN4O7 , and the measured value was 601.1 (MH+).

1-N-[4-[6-carbamoyl-7-(2-hydroxypropoxy)quinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (115): LiOH· _H₂O (26.55 mg, 632.71 μmol, 10 equivalents) was added to a solution of compound 114 (40 mg, 63.27 μmol, 1 equivalent) in THF (5 mL) and water (1 mL). The mixture was stirred at 70 °C for 1 hour. After cooling to room temperature, the reactants were diluted with DCM (30 mL), dried _over anhydrous _Na₂SO₄ , and concentrated under reduced pressure. The product was suspended in MeCN (1 mL) and stirred at 10 °C for 5 minutes. The precipitate was collected by filtration and dried under vacuum to give compound 115 (16.7 mg, 46.78% yield). ^¹H NMR (400MHz, DMSO- _d₆ ) δ 10.20 (s, 1H), 10.06 (s, 1H), 8.81 (s, 1H), 8.66 (d, 1H), 8.02 (d, 1H), 7.84 (s, 1H), 7.78 (d, 2H), 7.64 (dd, 2H), 7.54 (s, 1H), 7.27 (d, 2H), 7.15 (t, 2H), 6.47 (d, 1H), 5.15 (d, 1H), 4.27–4.21 ( _m , 1H), 4.17–4.04 (m, 2H), 1.47 (s, 4H), _{1.22 (d, 3H); MS (EI) was C₃₀H₂₇FN₄O₆ ,} measured value _559.1 (MH⁺).

Using a similar sequence to that used in the preparation of compound 115 from compound 94 in Example 41, the following compounds were prepared by replacing compound 94 with compound 108:

1-N'-(4-fluorophenyl)-1-N-[4-[7-(2-hydroxypropoxy)-6-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (116). ^¹H NMR (400MHz, DMSO- _d₆ ) δ 10.27(s, ¹H), 10.13(s, ¹H), 8.80(s, ¹H), 8.73(d, ¹H), 8.62(d, ¹H), 7.85(d, 2H), 7.71(dd, 2H), 7.62(s, ¹H), 7.33(d, 2H), 7.22(t, 2H), 6.54(d, ¹H), 5.28(d, 1H), 4.31(dd, 1H), 4.23–4.10( _m , 2H), 2.94(d, 3H), 1.54(s, 4H), _{1.29(d, 3H); MS (EI) was C₃¹H₂₉FN₄O₆ ,} measured value _573.1 (MH⁺).

Example 42: 1-N'-(4-fluorophenyl)-1-N-[4-[7-(2-hydroxypropoxy)-6-(1,3-oxazol-2-yl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (125)

4-Chloro-7-methoxyquinoline-6-carboxylic acid (117): LiOH· _H₂O (1.33 g, 31.79 mmol, 2 equivalents) was added to a solution of compound 4 (4.0 g, 15.89 mmol, 1 equivalent) in THF (30 mL) and water (6 mL), and the resulting mixture was stirred at 20 °C for 10 h. The resulting solid was filtered to give crude compound 117 as a white solid (4.4 g), which could be used in the next step without further purification. _MS (EI) was _{C₁₁H₈ClNO₃} , _with a measured value of 238.0 (MH⁺).

4-Chloro-N-(2,2-Dimethoxyethyl)-7-methoxyquinoline-6-carboxamide (118): To a THF (40 mL) solution of compound 117 (4 g, 16.83 mmol, 1 equivalent) and 2,2-dimethoxyethylamine (7.08 g, 67.33 mmol, 7.34 mL, 4 equivalents), _T3P (16.07 g, 50.50 mmol, 15.02 mL, 3 equivalents) and DIPEA (8.70 g, 67.33 mmol, 11.73 mL, 4 equivalents) were added. The resulting reaction mixture was stirred at 20 °C for 15 h. An additional ₅ mL of T3P and 3 mL of 2,2-dimethoxyethylamine were added to the mixture, and stirring was continued at 20 °C for 25 h. The mixture was quenched with water (30 mL) and the pH was adjusted to 9–10 with 1 M NaOH aqueous solution. The resulting aqueous mixture was extracted with EtOAc (3 x 40 mL). The combined organic extracts were washed with saturated NaCl aqueous solution (15 mL) and concentrated to give crude compound 118 as a white solid (4.1 _g , _73.5 % yield), which was used in the next step without further purification. _{MS (EI) was C15H17ClN2O4 ,} measured at 325.1 (MH+).

2-(4-Chloro-7-methoxyquinoline-6-yl)oxazole (119): At 20 °C under nitrogen, 2.5 g (7.70 mmol, 1 equivalent) of compound 118 was added to Eaton's Reagent (7.7 wt% phosphorus pentoxide methanesulfonic acid solution, 23.09 mmol, 46.97 mL, 3 equivalents). The resulting mixture was heated at 145 °C for 7 hours. The mixture was quenched with water (100 mL) and the pH was adjusted to 8-9 with Et ₃ N. The resulting mixture was extracted with EtOAc (4 x 40 mL). The combined organic extracts were washed with saturated NaCl aqueous solution (40 mL) and concentrated. The residue was purified by rapid silica gel chromatography (20 g silica rapid column, eluent 0–80% ethyl acetate/petroleum ether gradient @ 32 mL/min) to give compound 119 as a white solid (1.38 g, 68.8% yield). ^¹H NMR (400MHz, _CDCl₃ ) δ 8.43 (s, ¹H), 8.76 (d, ¹H), 7.86 (s, ¹H), 7.62 (s _{, ¹H), 7.42 (d, ¹H), 7.40 (s, ¹H), 4.14 (s, ³H); MS (EI) was C₁₃H₉ClN₂O₂ ,} measured value _261.0 ( _MH⁺ ).

4-Chloro-6-(oxazol-2-yl)quinoline-7 _- ol (120): Compound 120 was synthesized from compound 119 in a manner similar to that used in Example 36 for the synthesis of compound 94 from compound 93. _MS (EI ₎ was _C12H7ClN2O2 , measured at 246.7 (MH+).

1-((4-chloro-6-(oxazol-2-yl)quinolin-7-yl)oxy)prop-2-one (121): Compound 121 was synthesized from compound 120 in a manner similar to _that used in Example 41 for the synthesis of compound 111 from compound 94. _MS (EI) was _C15H11ClN2O3 , measured at _302.7 (MH+).

1-((4-chloro-6-(oxazol-2-yl)quinolin-7-yl)oxy)prop-2-ol (122): Compound 122 was synthesized from compound 121 in a manner similar to that used in Example 41 for the synthesis of compound 112 from compound 111. _{MS (EI) was C15H13ClN2O3 , and} the measured value _was 326.9 [M+Na] ⁺ .

1-((4-chloro-6-(oxazol-2-yl)quinolin-7-yl)oxy)propyl-2-ylacetate (123): Compound 123 was synthesized from compound 122 in a manner similar to that used in Example 41 for the synthesis of compound 113 from compound 112. ^¹H NMR (400 MHz, _CDCl₃ ) δ 8.83 (s, 1H), 7.23 (d, 1H), 7.83 (s, 1H), 7.54 (s, 1H), 7.40 (d, 1H), 7.34 (s, 1H), 5.41–5.49 (m, 1H), 4.25 (d, 2H), 2.06 (s, 3H), _{1.43 (d, 3H); MS (EI) was C₁₇H₁₅ClN₂O₄ , measured 347.1} (MH⁺).

1-((4-(4-(1-(((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylammono)phenoxy)-6-(oxazol-2-yl)quinoline-7-yl)oxy)propane-2-yl acetate (124): Compound 124 was synthesized from compounds 123 and 3 using a variation of the method for synthesizing compound 43 from compounds 42 and 3 in Example 12. Cesium carbonate was used instead of potassium tert-butoxide, and the reaction mixture was heated to 100°C for 3 h. _{MS (EI) was C34H29FN4O7 , and} the measured value _was 625.0 (MH+).

1-N'-(4-fluorophenyl)-1-N-[4-[7-(2-hydroxypropoxy)-6-(1,3-oxazol-2-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (125): NaOH (51.23 mg, 1.28 mmol, 2 equivalents) was added to a solution of compound 124 (400 mg, 640.4 μmol, 1 equivalent) in water (5 mL) and MeOH (5 mL), and the mixture was stirred at 20 °C for 5 hours. The mixture was diluted with water (30 mL). The resulting precipitate was filtered and washed with water (2 x 5 mL) and MeOH (3 mL). The solid was then lyophilized to give compound 125 as a white solid (238.5 mg, 63.9% yield). ^¹H NMR (400MHz, DMSO- _d₆ ) δ 10.22 (s, ¹H), 10.07 (s, ¹H), 8.79 (s, ¹H), 8.68 (d, ¹H), 8.32 (s, ¹H), 7.79 (d, 2H), 7.65 (t, 2H), 7.60 (s, 1H), 7.47 (s, 1H), 7.29 (d, 2H), 7.18 (t, 2H), 6.49 (d, 1H), 5.02 (d, 1H), 4.15–4.10 (m, 3H), 1.48 (s, 4H), _1.26 (d, _{3H); MS (EI) was C₃₂H₂₇FN₄O₆ ,} measured value _583.3 (MH⁺).

Example 43: Methyl 4-[2-chloro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-7-methoxyquinoline-6-carboxylic acid ester (128)

N-(3-chloro-4-hydroxyphenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (127): Compound 127 (1.9 g, 73.5% yield) was synthesized from compounds 1 and 126 in a manner similar to that used in Example 1 for the preparation of compound 3 from compounds 1 and 2. ^¹H NMR (400 MHz, _CDCl₃ ) δ 9.03–8.85 (m, 2H), 7.68 (d, 1H), 7.50–7.40 (m, 2H), 7.18 (dd, 1H), 7.08–7.00 (m, 2H), 6.97 (d, 1H), 5.53 (s, 1H), _1.64 (s, _{4H); MS (EI) was C₁₇H₁₄ClFN₂O₃ ,} measured _349.0 (MH⁺).

4-[2-chloro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-7-methoxyquinoline-6-carboxylic acid methyl ester (128): Compound 128 (0.8 g, 32.1% yield) was synthesized from compounds 127 and 4 in a manner similar to that used in the preparation of compound 43 from compounds 42 and 3 in Example 12. ^¹H NMR (400MHz, _CDCl₃ ) δ 10.08 (s, ¹H), 8.83 (s, ¹H), 8.63 (d, ¹H), 8.20 (s, ¹H), 7.92 (d, ¹H), 7.55–7.48 (m, 2H), 7.48–7.41 (m, 2H), 7.21 (d, 1H), 7.10–7.02 (m, 2H), 6.30 (d, 1H), 4.04 (s, 3H), 3.97 (s, 3H), 1.85–1.78 (m, 2H), 1.66–1.58 (m, _{2H); MS (EI) was C₂₹H₂₃ClFN₃O₆ , measured value} 564.4 (MH⁺).

Using a sequence similar to that used in the synthesis of compound 128 in Example 43, the following compounds were prepared in two steps, replacing compound 126 with 4-amino-2-fluorophenol:

4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-7-methoxyquinoline-6-carboxylic acid methyl ester (129): ^1H NMR (400MHz, CDCl3 ₎ δ 10.05(s,1H), 8.83(s,1H), 8.65(d,1H), 8.09(s,1H), 7.78(dd,1H), 7.50(s,1H), 7.48-7.42(m,2H), 7.27-7.19(m,2H), 7.10-7.04(m,2H), 6.40(d,1H), 4.05(s,3H), 3.97(s,3H), 1.84-1.81(m,2H), 1.63-1.60(m,2H); MS (EI) was C ₂₉ H ₂₃ F ₂ N ₃ O ₆ , measured value 548.4 (MH+).

Example 44: 4-[2-chloro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-7-methoxyquinoline-6-carboxylic acid (130)

4-[2-chloro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-7-methoxyquinoline-6-carboxylic acid (130): Compound 130 (0.55 g, 76.6% yield) was synthesized from compound 128 in a manner similar to that used in the preparation of compound 6 from compound 5 in Example 2. ^¹H NMR (400MHz, DMSO- _d₆ ) δ 10.41 (s, 1H), 10.10 (s, 1H), 8.58 (d, 1H), 8.25 (s, 1H), 8.10 (d, 1H), 7.75–7.59 (m, 3H), 7.47–7.37 (m, 2H), 7.16 (t, 2H), 6.32 (d, 1H), 3.92 ( _s , 3H), 1.47 (s, 4H); MS (EI) was _{C₂₈H₂₁ClFN₃O₆} , _{measured value} 550.1 (MH⁺).

The following compounds were prepared from compound 129 using a similar preparation method to that used in Example 44 for the synthesis of compound 130 from compound 128:

4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-7-methoxyquinoline-6-carboxylic acid (131): ^¹H NMR (400 MHz, DMSO- _d⁶ ) δ 13.20 (s, 1H), 10.42 (s, 1H), 10.01 (s, 1H), 8.72 (d, 1H), 8.59 (s, 1H), 7.93 (d, 1H), 7.64 (dd, 2H), 7.56–7.51 (m, 2H), 7.50–7.44 (m, 1H), 7.15 (t, 2H), 6.54 (d, 1H), 3.99 (s, 3H), 1.47 (d, _{4H )} ; MS ( _{EI ) C₂₈H₂₁F₂N₃O₆} The measured value was 534.4 (MH+).

Example 45: 1-N'-[4-(6-carbamoyl-7-methoxyquinoline-4-yl)oxy-3-chlorophenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (132)

1-N'-[4-(6-carbamoyl-7-methoxyquinoline-4-yl)oxy-3-chlorophenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (132): Compound 132 (43.1 mg, 40.9% yield) was synthesized from compound 130 in a manner similar to that used in the preparation of compound 7 from compound 6 in Example 3. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.38 (s, ¹H), 10.04 (s, ¹H), 8.71 (s, ¹H), 8.67 (d, ¹H), 8.11 (d, ¹H), 7.89 (br s, ¹H), 7.78 (br s, ¹H), 7.73–7.61 (m, ³H), 7.54 (s, ¹H), 7.46 (d, ¹H), 7.16 (t, ²H), 6.37 (d, ¹H), 4.04 (s, ³H) _{, 1.47 (s, ⁴H); MS (EI) was C₂₈H₂₂ClFN₄O₅ , measured value} 549.4 (MH⁺).

The following compounds were prepared from compound 131 using a method similar to that used in Example 45 for the preparation of compound 132 from compound 130:

1-N'-[4-(6-carbamoyl-7-methoxyquinoline-4-yl)oxy-3-fluorophenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (133): ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.40 (s, 1H), 10.01 (s, 1H), 8.67 (m, 2H), 7.93–7.88 (m, 2H), 7.76 (s, 1H), 7.64 (dd, _2H ), 7.53–7.52 (m, 2H), 7.47–7.43 (m, 1H), 7.15 (t, 2H), 6.48 (d, 1H), 4.03 (s, 3H), _1.47 (s, _4H ); MS (EI _{) C₂₈H₂₂F₂N₄O₅} The measured value was 533.5 (MH+).

Example 46: 1-N'-[3-chloro-4-[7-methoxy-6-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (134)

1-N'-[3-chloro-4-[7-methoxy-6-(methylcarbamoyl)quinolin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (134): Compound 134 (49.7 mg, 48.6% yield) was synthesized from compound 130 in a manner similar to that used in the preparation of compound 8 from compound 6 in Example 4. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.38 (s, ¹H), 10.04 (s, ¹H), 8.66 (d, ¹H), 8.63 (s, ¹H), 8.40 (br d, ¹H), 8.11 (d, ¹H), 7.72–7.61 (m, ³H), 7.54 (s, ¹H), 7.46 (d, ¹H), 7.20–7.12 (m, ²H), 6.37 (d, ¹H), 4.03 (s, ³H), 2.85 (d, ³H) _{, 1.48 (s, ⁴H); MS (EI) was C₂⁹H₂⁴ClFN₄O₅ ,} measured _{value 563.1} (MH⁺).

The following compounds were prepared from compound 131 using a method similar to that used in Example 46 for the preparation of compound 134 from compound 130:

1-N'-[3-fluoro-4-[7-methoxy-6-(methylcarbamoyl)quinolin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (135): ^¹H NMR (400MHz, DMSO- _d6 ) δ 10.40 (s, 1H), 10.01 (s, 1H), 8.67 (d, 1H), 8.61 (s, 1H), 8.39 (d, 1H), 7.91 (d, 1H), 7.64 (dd, 2H), 7.53–7.52 (m, 2H), 7.47–7.42 (m, 1H), 7.15 (t, 2H), 6.48 (d, 1H), 4.02 (s, 3H), 2.84 (d, 3H), 1.47 (s, 4H); MS (EI) was C6. ₂₉ H ₂₄ F ₂ N ₄ O ₅ , measured value 547.5 (MH+).

Example 47: Methyl 4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-6-methylquinoline-7-carboxylic acid ester (140)

5-(((2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-yl)methyl)amino)-2-methylbenzoate (137): Compound 137 (4.74 g, 81.7% yield) was synthesized from compounds 136 and 39 in a manner similar to that used in the preparation of compound 40 from compounds 38 and 39 in Example 12. ^¹H NMR (400 MHz, DMSO- _d⁶ ) δ 11.28 (s, ¹H), 8.53 (s, ¹H), 8.01–7.88 (d, ¹H), 7.75–7.61 (dd, ¹H), 7.45–7.30 (d, ¹H), 3.85 (s, ³H), 2.49 (s, ³H), 1.67 (s, ⁶H).

6-Methyl-4-oxo-1,4-dihydroquinoline-7-carboxylic acid methyl ester (138): Compound 138 (625 mg, 25.9% yield) was synthesized from compound 137 in a manner similar to the preparation of compound 41 from compound 40 in _{Example 12.} MS (EI) was _C12H11NO3 , and the result was 218.1 (MH+).

4-Chloro-6-methylquinoline-7-carboxylic acid methyl ester (139): Compound 139 was synthesized from compound 138 in a similar manner to that described for compound 42 in Example 12, except that compound 138 was heated in a mixture of MeCN (10 mL) and POCl ₃ (3 mL) instead of in pure POCl ₃ (445 mg, 65.6% yield). _MS (EI) was _{C12H10ClNO 2} , measured at 236.3 (MH+).

4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-6-methylquinoline-7-carboxylic acid methyl ester (140): Compound 140 (320 mg, 36.7% yield) was synthesized from compounds 139 and 3 in a similar manner to the synthesis of compound 43 from compounds 42 and 3 in Example 12. ^¹H NMR (400MHz, _CD₃OD ) δ 8.66–8.61 (d, ¹H), 8.52 (s, ¹H), 8.28 (s, ¹H), 7.78–7.71 (d, 2H), 7.60–7.54 (m, 2H), 7.28–7.22 (d, 2H), 7.11–7.03 (m, 2H), 6.71–6.67 (d, ¹H), 3.98 (s, 3H), 2.76 (s, 3H), 1.64 (s, 4H); MS (EI) was _{C₂ ₹ H₂₄FN₃O₅ ,} measured value 514.1 (MH⁺).

Example 48: 4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-6-methylquinoline-7-carboxylic acid (141)

4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-6-methylquinoline-7-carboxylic acid (141): Compound 141 (100 mg, 93.5% yield) was synthesized from compound 140 in a manner similar to that used in Example 2 for the preparation of compound 6 from compound 5. ^¹H NMR (400MHz, _CD₃OD ) δ 8.66–8.61 (d, ¹H), 8.47 (s, ¹H), 8.27 (s, ¹H), 7.78–7.73 (d, 2H), 7.78–7.71 (dd, 2H), 7.28–7.24 (d, 2H), 7.11–7.03 (t, 2H), 6.73–6.69 (d, ¹H), 2.76 (s, 3H), _1.65 (s _{, 4H); MS (EI) was C₂₈H₂₂FN₃O₅ ,} measured value _500.5 (MH⁺).

Example 49: 1-N-[4-(7-carbamoyl-6-methylquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (142)

1-N-[4-(7-carbamoyl-6-methylquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (142): Compound 142 (17.4 mg, 34.9% yield) was synthesized from compound 141 in a manner similar to that used in the preparation of compound 7 in Example 3. ^¹H NMR (400MHz, _CD₃OD ) δ 8.65–8.57 (d, ¹H), 8.26 (s, ¹H), 8.05 (s, ¹H), 7.78–7.70 (d, 2H), 7.62–7.51 (m, 2H), 7.30–7.20 (m, 2H), 7.13–7.03 (m, 2H), 6.69–6.63 (d, ¹H), 2.65 (s, 3H), 1.64 ( _s , 4H); MS (EI) was _{C₂₈H₂₃FN₄O₄ ,} measured value _499.1 (MH⁺).

Example 50: 1-N'-(4-fluorophenyl)-1-N-[4-[6-methyl-7-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (143)

1-N'-(4-fluorophenyl)-1-N-[4-[6-methyl-7-(methylcarbamoyl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (143): Compound 143 (11.9 mg, 17.8% yield) was synthesized from compound 141 in a manner similar to that used in the preparation of compound 8 in Example 4. ^1H NMR (400MHz, CD ₃ OD) δ 8.64-8.55 (d, 1H), 8.25 (s, 1H), 7.97 (s, 1H), 7.78-7.68 (d, 2H), 7.61-7.50 (m, 2H), 7.28-7.18 (d, 2H), 7.11-7.02 (m, 2H), 6.70-6.61 (d, 1H), 2.98 (s, 3H), 2.60 (s, 3H), 1.64 (s, 4H); MS (EI) was C ₂₉ H ₂₅ FN ₄ O ₄ , measured value 513.1 (MH+).

Example 51: Methyl 4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-6-methoxyquinoline-7-carboxylic acid ester (150)

Methyl 5-amino-2-methoxybenzoate (145): 10% Pd/C (500 mg) was added to a solution of compound 144 (5.00 g, 23.68 mmol, 1 equivalent) in EtOH (50 mL), and the resulting mixture was degassed and purged under _H₂ . The reaction mixture was stirred at 25 °C for 12 h under _H₂ (15 psi). The reaction mixture was filtered, and the filtrate was concentrated to give compound 145 (4.5 g, 99.6% yield), which was used in subsequent steps without further purification. ^¹H NMR (400 MHz, _CDCl₃ ) δ 7.16 (t, 1H), 6.86–6.82 (m, 2H), 3.88 (s, 3H), 3.83 (s, 3H), 3.09 (br s, 2H).

Methyl 5-(((2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-ylidene)methyl)amino)-2-methoxybenzoate (147): Compound 145 (2 g, 10.49 mmol, 1 equivalent) was added in portions to a suspension of compound 146 (1.95 g, 10.49 mmol, 1 equivalent) in isopropanol (40 mL) at 20 °C. The reaction was heated at 80 °C for 30 min. The mixture was cooled to 20 °C, and the precipitate was collected, washed with tert-butyl methyl ether (50 mL), and dried to give compound 147 (3.3 g, 93.82% yield). ¹ H NMR (400MHz, CDCl ₃ ) δ 11.25 (d, 1H), 8.57 (d, 1H), 7.75 (d, 1H), 7.37 (dd, 1H), 7.05 (d, 1H), 3.95 (s, 3H), 3.93 (s, 3H), 1.76 (s, 6H).

Methyl 6-methoxy-4-oxo-1,4-dihydroquinoline-7-carboxylic acid (148): Compound 147 (1.0 g, 2.98 mmol, 1 equivalent) was added in portions to A (a eutectic mixture of 26.5% biphenyl and 73.5% diphenyl ether) (CAS Registry No. 8004-13-5) (10 mL) at 220 °C. The reaction was stirred at 220 °C for 10 min. The reaction was cooled to 20 °C–25 °C and then diluted with petroleum ether (50 mL). The resulting residue was collected, washed with petroleum ether (3 x 30 mL), and dried to give compound 148 (800 mg, 69.07% yield, 60% purity). ¹ H NMR (400MHz, DMSO-d ₆ ) δ12.22(d,1H),7.94(d,1H),7.92(s,1H),7.61(s,1H),6.06(d,1H),3.87(s,3H),3.84(s,3H).

4-Chloro-6-methoxyquinoline-7-carboxylic acid methyl ester (149): 5 drops of DMF were added to a mixture of compound 148 (700 mg, 1.80 mmol, ₁ equivalent) in _SOCl2 (10 mL). The resulting mixture was stirred at 80 °C for 1 h. The reaction mixture was concentrated under vacuum, and the resulting residue was diluted with saturated NaHCO3 aqueous solution (20 mL) and extracted with EtOAc (3 x 30 mL). The combined organic phases were washed with saturated NaCl aqueous solution (50 mL), _dried over anhydrous _Na2SO4 , and concentrated. The residue was purified by rapid silica gel chromatography (4 g silica rapid column, eluent 0–30% EtOAc/petroleum ether gradient, flow rate 25 mL/min) to give compound 149 (220 mg, 46.14% yield, 95% purity). ^¹H NMR (400MHz, _CDCl₃ ) δ 8.71 (d, ¹H), 8.49 (s, ¹H), 7.55–7.49 (m, 2H), 4.07 (s, 3H), 3.99 (s, 3H); MS ( _{EI )} was _{C₁₂H₁₀ClNO₃} , measured value 252.3 (MH⁺).

4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxyquinoline-7-carboxylic acid methyl ester (150): Pd(OAc)2 (8 mg, 35.63 μmol, 0.05 equivalent) was added to a mixture of compound 149 (190 mg, 679.47 μmol, 1 equivalent), compound ₃ (235 mg, 747.67 μmol, 1.1 equivalent), _K3PO4 (190 mg, 895.10 μmol, 1.32 equivalent) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos) (33 mg, 69.22 μmol, 0.1 equivalent) in toluene (3 mL) and ₁ -methyl-2-pyrrolidone (0.5 mL) under nitrogen atmosphere. The reaction was stirred at 100 °C for 3 hours. The mixture was diluted with EtOAc (30 mL) and any insoluble substances were filtered off. The filtrate was diluted with water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic phases were washed with a saturated aqueous NaCl solution (50 mL), _dried over anhydrous _Na₂SO₄ , and concentrated. The residue was purified by rapid silica gel chromatography (4 g silica rapid column, eluent of 0% to approximately 50% EtOAc/petroleum ether gradient, flow rate 25 mL/min) to give compound 150 (170 mg, 46.06% yield, 97.49% purity). ^¹H NMR (400MHz, _CDCl₃ ) δ 9.46 (s, ¹H), 8.59 (d, 2H), 8.47 (s, ¹H), 7.71–7.62 (m, 3H), 7.52–7.44 (m, 2H), 7.20 (d, 2H), 7.07 (t, 2H), 6.57 (d, 1H), 4.05 (s, 3H), 3.99 (s, 3H), 1.79–1.74 (m, 2H), 1.69–1.64 (m, 2H); MS (EI ₎ was _{C₂ ₹ H₂₄FN₃O₆} , measured value 530.2 (MH⁺).

Example 52: 4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]-amino]phenoxy]-6-methoxyquinoline-7-carboxylic acid (151)

4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]-amino]phenoxy]-6-methoxyquinoline-7-carboxylic acid (151): Compound 151 (110 mg, 75.2% yield) was synthesized from compound 150 in a manner similar to that used in the preparation of compound 81 from compound 80 in Example 25. ^1H NMR (400MHz, DMSO- _d₆ ) δ 10.21 (s, 1H), 10.05 (s, 1H), 8.60 (d, 1H), 8.18 (s, 1H), 7.79 (d, 2H), 7.69–7.59 (m, _3H ), 7.27 (d, 2H), 7.15 (t, 2H), 6.60 (d, 1H), 3.97 (s, 3H), 1.53–1.42 (m, 4H); MS (EI) was _{C₂₈H₂₂FN₃O₆} , _{measured value} 516.1 (MH⁺).

Example 53: 1-N-[4-(7-carbamoyl-6-methoxyquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (152)

1-N-[4-(7-carbamoyl-6-methoxyquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (152): Compound 152 (25.6 mg, 30.7% yield) was synthesized from compound 151 in a manner similar to that used in the preparation of compound 7 from compound 6 in Example 3. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.20 (s, 1H), 10.04 (s, 1H), 8.58 (d, 1H), 8.25 (s, 1H), 7.87 (br s, 1H), 7.78 (d, 2H), 7.72 (br s, 1H), 7.67–7.60 (m, 3H), 7.26 (d, 2H), 7.15 (t, 2H), 6.58 (d, 1H), 4.01 (s, 3H), _{1.52–1.46 (m, 4H); MS (EI) was C₂₈H₂₃FN₄O₅ , measured} value _515.1 (MH⁺).

Example 54: 1-N'-(4-fluorophenyl)-1-N-[4-[6-methoxy-7-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (153)

1-N'-(4-fluorophenyl)-1-N-[4-[6-methoxy-7-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (153): Compound 153 (25.2 mg, 53.1% yield) was synthesized from compound 151 in a manner similar to that used in the preparation of compound 8 from compound 6 in Example 4. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.23 (s, ¹H), 10.07 (s, ¹H), 8.58 (d, ¹H), 8.39 (q, ¹H), 8.20 (s, ¹H), 7.79 (d, 2H), 7.69–7.60 (m, 3H), 7.26 (d, 2H), 7.15 (t, 2H), 6.58 (d, ¹H), 4.00 (s, 3H), 2.84 (d, 3H), _{1.52–1.44 (m, 4H); MS (EI) was C₂⁹H₂⁵FN₄O₅ , measured} value _529.1 (MH⁺).

Example 56: Methyl 4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]quinoline-7-carboxylic acid ester (162)

4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]quinoline-7-carboxylic acid methyl ester (162): Compound 162 (20 mg, 16% yield) was synthesized from compounds 161 and 3 in a manner similar to that used in the preparation of compound 43 from compounds 42 and 3 in Example 12. ^¹H NMR (400MHz, _CDCl₃ ) δ 9.42 (s, ¹H), 8.81 (d, ¹H), 8.75 (d, ¹H), 8.60 (br s, ¹H), 8.43 (d, ¹H), 8.19 (dd, ¹H), 7.69–7.63 (m, 2H), 7.51–7.44 (m, 2H), 7.23–7.18 (m, 2H), 7.07 (t, 2H), 6.63 (d, ¹H), 4.03 (s, 3H), 1.79–1.74 (m, 2H), _{1.69–1.65 (m, 2H); MS (EI) was C₂₈H₂₂FN₃O₅ ,} measured value _500.1 ( _MH⁺ ).

Example 57: 4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]quinoline-7-carboxylic acid (163)

4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]quinoline-7-carboxylic acid (163): Compound 163 (70 mg, 68.4% yield) was synthesized from compound 162 in a manner similar to that used in Example 2 for the preparation of compound 6 from compound 5. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.22 (s, ¹H), 10.06 (s, ¹H), 8.79 (d, ¹H), 8.58 (s, ¹H), 8.43 (d, ¹H), 8.17–8.10 (m, ¹H), 7.79 (d, 2H), 7.65 (dd, 2H), 7.29 (d, 2H), 7.16 (t, 2H), 6.69 (d, 1H), 1.48 (s, 4H); MS _{(EI) was C₂₇H₂₀FN₃O₅ , measured value} 486.1 (MH⁺).

Example 58: 1-N-[4-(7-carbamoylquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (164)

1-N-[4-(7-carbamoylquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)-cyclopropane-1,1-dicarboxamide (164): Compound 164 (17.7 mg, 56.2% yield) was synthesized from compound 163 in a manner similar to that used in the preparation of compound 7 from compound 6 in Example 3. ^¹H NMR (400MHz, _CDCl₃ ) δ 9.47 (s, ¹H), 8.73 (d, ¹H), 8.60 (br s, ¹H), 8.50–8.43 (m, 2H), 8.08 (dd, ¹H), 7.66 (d, 2H), 7.51–7.43 (m, 2H), 7.19 (d, 2H), 7.06 (t, 2H), 6.62 (d, ¹H), 6.36 (br s, ¹H), 5.73 (br s, ¹H), 1.80–1.73 (m, 2H), _{1.70–1.65 (m, 2H); MS (EI) was C₂₇H₂₁FN₄O₄ , measured} value _485.1 (MH⁺).

Example 59: 1-N'-(4-fluorophenyl)-1-N-[4-[7-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (165)

1-N'-(4-fluorophenyl)-1-N-[4-[7-(methylcarbamoyl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (165): Compound 165 (16.5 mg, 33.9% yield) was synthesized from compound 163 in a manner similar to that used in the preparation of compound 8 from compound 6 in Example 4. ^¹H NMR (400MHz, _CDCl₃ ) δ 9.45 (br s, 1H), 8.71 (d, 1H), 8.63 (br s, 1H), 8.43 (d, 1H), 8.37 (d, 1H), 8.04 (d, 1H), 7.65 (d, 2H), 7.50–7.44 (m, 2H), 7.19 (d, 2H), 7.06 (t, 2H), 6.60 (d, 1H), 6.40 (br s, 1H), 3.11 (d, 3H), 1.79–1.74 (m, 2H), 1.69–1.64 (m, 2H) _; MS ₍ EI ₎ was _{C₂₈H₂₃FN₄O₄} , measured value 499.1 (MH⁺).

Example 60: 1-N'-(4-fluorophenyl)-1-N-[4-[7-(2-hydroxyethoxycarbamoyl)-quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (166)

1-N'-(4-fluorophenyl)-1-N-[4-[7-(2-hydroxyethoxycarbamoyl)-quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (166): Compound 166 (27 mg, 46.2% yield) was synthesized from compound 163 in a manner similar to that used in the preparation of compound 26 from compound 6 in Example 6. ^¹H NMR (400MHz, _CD₃OD ) δ 8.73(d, ¹H), 8.53(d, ¹H), 8.44(d, ¹H), 8.03(dd, ¹H), 7.77(d, 2H), 7.59(dd, 2H), 7.28(d, 2H), 7.10(t, 2H), 6.75(d, ¹H), 4.17–4.12(m, 2H), 3.88–3.83(m, 2H), 1.66(s, 4H); MS ( _{EI) was C₂₹H₂₅FN₄O₆ , measured value} 545.1 (MH⁺).

The following compounds were prepared using a method similar to that used for compound 166 in Example 60:

1-N'-(4-fluorophenyl)-1-N-[4-[7-(oxetane-3-yloxycarbamoyl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (167): ^1H NMR (400MHz, _CD3) OD)δ 8.72(d,1H), 8.50(d,1H), 8.43(d,1H), 8.02(dd,1H), 7.79-7.73(m,2H), 7.62-7.56(m,2H), 7.31-7.25(m,2H), 7.09(t,2H), 6.74(d,1H), 5.19(s,1H), 4.93(m,2H), 4.88-4.81(m,2H), 1.70-1.63(m,4H) _; MS( _{EI) is C30H25FN4O6 , measured} value 557.1(MH+).

N-(4-((7-(((2,2-dimethyl-1,3-dioxopentane-4-yl)methoxy)carbamoyl)quinoline-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (168): MS (EI) is _C29H25FN4O6 , _and the measured value _{is 615.3} (MH+).

Example 61: 1-N-[4-[7-[[(2R)-2,3-dihydroxypropoxy]carbamoyl]quinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (169) and 1-N-[4-[7-[[(2S)-2,3-dihydroxypropoxy]carbamoyl]quinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (170)

1-N-[4-[7-[[(2R)-2,3-dihydroxypropoxy]carbamoyl]quinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (169) and 1-N-[4-[7-[[(2S)-2,3-dihydroxypropoxy]carbamoyl]quinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (170): Compounds 169 and 170 were synthesized from compound 168 in a manner similar to that used in Example 7 for the preparation of compounds 30 and 31 from compound 28. Compound 169: ^¹H NMR (400MHz, _CD₃OD ) δ 8.73 (d, 1H), 8.52 (d, 1H), 8.44 (d, 1H), 8.02 (dd, 1H), 7.77 (d, 2H), 7.62–7.55 (m, 2H), 7.30–7.25 (m, 2H), 7.09 (t, 2H), 6.75 (d, 1H), 4.21–4.15 (m, 1H), 4.06 (s, 1H), 4.02–3.96 (m, 1H), 3.68 (m, 2H) _{, 1.66 (d, 4H); MS (EI) C₃₀H₂₇FN₄O₇ , measured} value 575.2 (MH⁺). Compound 170: ^¹H NMR (400MHz, _CD₃OD ) δ 8.73 (d, 1H), 8.52 (d, 1H), 8.43 (d, 1H), 8.02 (dd, 1H), 7.77 (d, 2H), 7.62–7.54 (m, 2H), 7.28 (d, 2H), 7.14–7.04 (m, 2H), 6.75 (d, 1H), 4.22–4.14 (m, 1H), 4.12–3.92 (m, 2H), 3.73–3.64 (m, 2H), _1.66 (s _{, 4H); MS (EI) C₃₀H₂₇FN₄O₇ ,} measured value 575.1 (MH⁺).

Example 62: 4-((6-bromo-7-methoxyquinoline-4-yl)oxy)aniline (171)

4-((6-bromo-7-methoxyquinoline-4-yl)oxy)aniline (171): Cs₂CO₃ ( _3.3 g, 10 mmol) was added to a DMA (15 mL) solution of a mixture of compound 42 (1.75 g, 6.38 mmol) and 4-aminophenol ₂ (1.1 g, 10 mmol) at room temperature. The mixture was stirred at ₁₀₀ °C for _{2 h} . The mixture was cooled to 20 °C, diluted with water, and filtered. The crude residue was purified by rapid silica gel chromatography to give compound 171 (900 mg, 40% yield). MS (EI) was _{C₁₆H₁₃BrN₂O₂} , measured value: 345 (MH⁺).

Example 63: 4-((7-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxocyclopentaborane-2-yl)quinoline-4-yl)oxy)aniline (172)

4-((7-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl)quinolin-4-yl)oxy)aniline (172): Pd(dppf)Cl₂ (42 mg, 0.06 mmol) was added to a mixture of compound 171 (200 mg, 0.58 mmol), bis(pinacol) _diboron (220 mg, 0.87 mmol), and potassium acetate (170 mg, 1.7 mmol) in 1,4-dioxane (3 mL). The resulting mixture was heated at _{100 °C for 2 hours. After cooling, the reaction mixture was diluted with EtOAc, washed successively with water and saturated NaCl aqueous solution, concentrated, and purified by rapid silica gel chromatography to give compound 172 (43% yield). MS (EI) was C₂₂H₂₅BN₂O₄ , measured value} : 393 (MH+).

Example 64: 1-N-[4-[6-(3-cyano-2-fluorophenyl)-7-methoxyquinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (175)

3-(4-(4-aminophenoxy)-7-methoxyquinoline-6-yl)-2-fluorobenzyl nitrile (174): Compound 172 (50 mg, 0.13 mmol), compound 173 (25 mg, 0.13 mmol), _Na₂CO₃ (41 mg, _0.39 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (9 mg, 0.013 mmol), 1,4-dioxane (2 mL), and water (0.4 mL) were mixed in a microwave-controlled reaction tube. The reaction mixture was stimulated in a microwave reactor at 150 °C for 5 min. After cooling, the mixture was extracted with EtOAc, washed with saturated aqueous NaCl solution, and concentrated. The crude product was purified by rapid column chromatography to give _compound 174. _MS (EI) was _{C₂₃H₁₆FN₃O₂} , measured value: ₃₈₆ (MH+).

1-N-[4-[6-(3-cyano-2-fluorophenyl)-7-methoxyquinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (175): HATU (38 mg, 0.1 mmol) was added to a mixture of compound 174, compound 1 (22 mg, 0.1 mmol), and DIEA (25 mg, 0.2 mmol) in a DCM (2 mL). The mixture was stirred at room temperature until the reaction was _complete , then diluted with EtOAc, washed with saturated _NaHCO3 aqueous solution, and concentrated. The crude product was purified by rapid _column chromatography to give _compound 175. _MS (EI) was _C34H24F2N4O4 , and the measured value was 591 (MH+).

The following compounds were prepared in a manner similar to that used in Example 64 for the two-step synthesis of compound 175 from compound 172:

1-N'-(4-fluorophenyl)-1-N-[4-(7-methoxy-6-pyridin-2-ylquinoline-4-yl)oxyphenyl]cyclopropane-1,1-dicarboxamide (176): 2- _{bromopyridine} was used instead of compound 173. MS (EI) was _C32H25FN4O4 , _and the measured value was ₅₄₉ (MH+).

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(1-methylimidazol-4-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (177). Compound 173 was replaced with 4-bromo- _{1-methyl-1H-imidazolium. MS (EI) was C31H26FN5O4 , and} the measured value was ₅₅₂ (MH+).

Example 65: 1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(5-methylfuran-2-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (180)

4-((7-methoxy-6-(5-methylfuran-2-yl)quinolin-4-yl)oxy)aniline (179): Compound 171 (100 mg, 0.29 mmol), compound 178 (82 mg, 0.43 mmol), _Na₂CO₃ (92 _mg , 0.9 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (20 mg, 0.029 mmol), 1,4-dioxane (2.5 mL), and water (0.5 mL) were mixed in a microwave-controlled reaction tube. The resulting mixture was irradiated in a microwave reactor at 150 °C for 5 min. After cooling, the mixture was extracted with EtOAc, washed with saturated NaCl aqueous solution, and concentrated. The crude product was purified by rapid _column chromatography to give _compound 179. _{MS (EI) was C₂₁H₁₈N₂O₃ ,} measured value: 347 (MH+).

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(5-methylfuran-2-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (180): Compound 180 was synthesized from compound 179 in a manner similar to that used in Example 64 for the synthesis of compound 175 from compound 174. MS ( _{EI )} was _C32H26FN3O5 , and the measured value _was 552 (MH+).

The following compounds were prepared in a manner similar to that used in Example 65 for the two-step synthesis of compound 180 from compound 171:

2-[4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]-amino]phenoxy]-7-methoxyquinoline-6-yl]pyrrole-1-carboxylic acid tert-butyl ester (181): Compound 178 was replaced with potassium salt of 2-(trifluoro-14-boronyl)-1H-pyrrole-1-carboxylic acid tert-butyl ester _{. MS} (EI) was _C36H33FN4O6 , and the measured value was ₆₃₇ (MH+).

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(1-methylpyrazol-4-yl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (182): Compound 178 was replaced with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxocyclopentaborane-2-yl) _-1H -pyrazole. MS (EI) was _{C31H26FN5O4 , and} the measured value was 552 (MH+).

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(1,2-oxazol-4-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (183): Compound 178 was replaced with _4- (4,4,5,5-tetramethyl-1,3,2-dioxocyclopentaborane-2-yl)isoxazole. _MS (EI) was _C30H23FN4O5 , _and the measured value was 539 (MH+).

1-N-[4-[6-(3,5-dimethyl-1,2-oxazol-4-yl)-7-methoxyquinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (184): Compound 178 was replaced with 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxocyclopentaborane-2-yl)isoxazole _{. MS (EI) was C32H27FN4O5 , and} the measured value _was 567 (MH+).

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(1H-pyrazol-5-yl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (185): Compound 178 was replaced with potassium 5-(trifluoro-14-boronyl)-1H-pyrazol. _{MS (EI) was C30H24FN5O4 , and} the measured value was ₅₃₈ (MH+).

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(1H-pyrazol-4-yl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (186): Compound 178 was replaced with potassium 4-(trifluoro-14-boronyl)-1H-pyrazol _{. MS (EI) was C30H24FN5O4 ;} measured value was ₅₃₈ (MH+).

1-N-[4-(6-cyclopropyl-7-methoxyquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (187): Compound 178 was replaced with potassium _{cyclopropyltrifluoro} -14-borane _. MS (EI) was _C30H26FN3O4 , _and the measured value was 512 (MH+).

Example 66: 1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(1H-pyrrolo-2-yl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (188)

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(1H-pyrrolo-2-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (188): Compound 181 and excess TFA were stirred in a DCM at room temperature until the reaction was complete. The mixture was concentrated and purified by preparative HPLC to give compound 188 (50% yield). _MS (EI) was _C31H25FN4O4 , _and the measured value was 537 ( _MH +).

Example 67: N-(4-fluorophenyl)-N-(4-((6-formyl-7-methoxyquinoline-4-yl)oxy)phenyl)cyclopropane-1,1-dicarboxamide (190)

4-Chloro-7-methoxyquinoline-6-carboxaldehyde (189): nBuLi (0.6 mL, 2.5 M THF solution, 1.5 mmol) was added to an 8 mL THF solution of a mixture of compound 42 (320 mg, 1.17 mmol) at -78 °C. The mixture was stirred at -78 °C for 45 min, then DMF (0.5 mL) was added. The mixture was heated to 0 °C and stirred for 1 h. The reaction was quenched with saturated _NH₄Cl and extracted with EtOAc. The organic phase was concentrated, and the crude residue was purified by rapid silica gel chromatography to give compound 189 (130 mg, 50% yield). _{MS (EI) was C₁₁H₈ClNO₂ , and} the result was 222 (MH+).

N-(4-fluorophenyl)-N-(4-((6-formyl-7-methoxyquinoline-4-yl)oxy)phenyl)cyclopropane-1,1-dicarboxamide (190): Compound 190 was synthesized from compound 189 using the improved method described in Example 12 for the synthesis of compound 43 from compound 42, with potassium tert-butoxide replaced by cesium carbonate and DMF used as a solvent.

Example 68: 1-N'-(4-fluorophenyl)-1-N-[4-[6-(1H-imidazol-2-yl)-7-methoxyquinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (191)

1-N'-(4-fluorophenyl)-1-N-[4-[6-(1H-imidazol-2-yl)-7-methoxyquinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (191): Compound 190 (60 mg, 0.12 mmol), glyoxal (60 mg, 40% aqueous solution), and ammonium hydroxide (130 mg, 30% aqueous solution) were mixed in iPrOH (1.5 mL). The resulting mixture was stirred at ambient temperature (room temperature) for 12 hours. The mixture was extracted with EtOAc and washed with saturated NaCl aqueous solution. The organic phase was concentrated and purified by preparative HPLC to give compound 191 (35 mg, 54% yield). _{MS (EI) was C30H24FN5O4 , and} the measured value _was 538.1 (MH+).

Example 69: 1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(1,3-oxazol-5-yl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (192)

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(1,3-oxazol-5-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (192): Compound 190 (30 mg, 0.06 mmol), TosMIC (15 mg, 0.08 mmol), and _K₂CO₃ (15 mg, 0.11 mmol) were mixed in iPrOH (1 mL). The resulting mixture was stirred at 80 ° _C for 30 min. The mixture was concentrated to dryness. The residue was extracted with EtOAc. The organic layer was washed with water and concentrated. The crude product was purified by preparative HPLC to give compound 192 (14 _mg , 43% yield). _MS (EI) was _{C₃₀H₂₃FN₄O₅} , _and the result was 539 (MH+).

Example 70: 1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-[(E)-methoxyiminomethyl]quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (193)

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-[(E)-methoxyiminomethyl]quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (193): O-methylhydroxylamine-HCl (41.74 mg, 500 μmol, 1.7 equivalent) was added to a mixture of compound 190 (150 mg, 300.31 μmol, 1 equivalent) in EtOH (3 mL) and water (0.6 mL). The mixture was stirred at 50 °C for 2 h. The resulting precipitate was filtered, slurried in 50 mL of water, and then filtered again. The filter cake was lyophilized to give compound 193 (125.0 mg, 73.2% yield). ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.32 (s, 1H), 10.05 (s, 1H), 8.87 (s, 1H), 8.68 (s, 1H), 8.51 (s, 1H), 7.85 (d, 2H), 7.72–7.58 (m, 3H), 7.37 (d, 2H), 7.16 (t, 2H), 6.72 (br d, 1H), 4.07 (s, 3H), 3.99 (s, 3H), _{1.49 (s, 4H); MS (EI) was C₂⁹H₂⁵FN₄O₅ , measured} value _529.2 (MH⁺).

Example 71: 3-[4-[4-[[1-([4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-7-methoxyquinoline-6-yl]-3-hydroxyazacyclobutane-1-carboxylic acid tert-butyl ester (195)

3-(4-chloro-7-methoxyquinoline-6-yl)-3-hydroxyazacyclobutane-1-carboxylic acid tert-butyl ester (194): A mixture of compound 42 (200 mg, 0.73 mmol) and THF (4 mL) was cooled to -78 °C. n-BuLi (0.4 mL, 1.0 mmol, 2.5 M THF solution) was slowly added. The resulting mixture was stirred at -78 °C for 40 min. A THF solution of N-Boc 3-oxazacyclobutane (125 mg, 0.73 mmol) (0.5 mL) was added. The reaction mixture was heated to 0 °C and stirred for 1 h. The reaction was quenched with water and extracted with EtOAc. The organic phase was washed with saturated NaCl aqueous solution, concentrated, and purified by rapid _{silica gel} chromatography to give compound 194 (38% yield). _MS (EI) was _C18H21ClN2O4 , measured value: 365 (MH+).

3-[4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-7-methoxyquinoline-6-yl]-3-hydroxyazacyclobutane-1-carboxylic acid tert-butyl ester (195): Compound 195 was synthesized from compound 194 in a manner similar to that used in Example 12 for the preparation of compound 43 from compound 42, except that cesium carbonate was used instead of tert-butanol, DMF was used as the solvent, the reaction temperature was 80°C, and the reaction time was 12 hours. Compound 195 was obtained in 68% yield _{. MS} (EI) was _C35H35FN4O7 , _and the measured value was 643 (MH+).

Similar to compound 195 in Example 71, the following compounds were prepared by replacing the Boc-protected aza-butane-3-one with an oxetane-3-one:

1-N'-(4-fluorophenyl)-1-N-[4-[6-(3-hydroxyoxetane-3-yl)-7-methoxyquinoline-4-yl]oxyphenyl]cyclopropane-1,1- _{dicarboxamide} (196). MS (EI) was _C30H26FN3O6 , _with a measured value of ₅₄₄ (MH+).

Example 72: 1-N'-(4-fluorophenyl)-1-N-[4-[6-(3-hydroxyazacyclobutane-3-yl)-7-methoxyquinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (197)

1-N'-(4-fluorophenyl)-1-N-[4-[6-(3-hydroxyazacyclobutane-3-yl)-7-methoxyquinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (197): Compound 197 was synthesized from compound 195 in a manner similar to that used in Example 66 for the preparation of compound 188 from compound 181 (55 _% yield). _MS (EI) was _C30H27FN4O5 , _and the measured value was 543 (MH+).

Example 73: 1-N-[4-[6-(azacyclobutane-1-yl)-7-methoxyquinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (198)

1-N-[4-[6-(azacyclobutan-1-yl)-7-methoxyquinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (198): Bis(tri-tert-butylphosphine)palladium (0) was added to a mixture of compound 43 (150 mg, 0.27 mmol), azacyclobutane ( ₃₀₀ mg, 5.25 mmol), and _K₃PO₄ (212 mg, 1.0 mmol) in DMA (2 mL). The resulting mixture was stirred at 100 °C for 12 hours. After cooling, water was added, and the mixture was extracted with EtOAc, washed with saturated NaCl aqueous solution, and concentrated. The crude product was purified by preparative HPLC to give compound 198. _MS (EI) was _{C₃₀H₂₇FN₄O₄ , and} the measured value was 527 (MH+).

The following compounds were prepared from compound 43 using a method similar to that used in Example 73 for the synthesis of compound 198 from compound 43:

1-N'-(4-fluorophenyl)-1-N-[4-[6-(3-hydroxyaziridine-1-yl)-7-methoxyquinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (199): Azacyclobutane-3-ol was used instead of aziridine. _{MS (EI) was C30H27FN4O5 , and} the measured value _was 543 (MH+).

1-N-[4-[6-(3,3-difluoroazacyclobutane-1-yl)-7-methoxyquinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (200): HCl salt of 3,3- _{difluoroazacyclobutane} was used instead of _{azacyclobutane} . _MS (EI) was _C30H25F3N4O4 , measured _value 563 (MH+).

Example 74: 1-N'-(4-fluorophenyl)-1-N-[4-(7-methoxy-6-pyridin-3-ylquinoline-4-yl)oxyphenyl]cyclopropane-1,1-dicarboxamide (201)

1-N'-(4-fluorophenyl)-1-N-[4-(7-methoxy-6-pyridin-3-ylquinoline-4-yl)oxyphenyl]cyclopropane-1,1-dicarboxamide (201): Compound 43 (50 mg, 0.09 mmol), 3-pyridylboronic acid (16 mg, 0.13 mmol), _Na₂CO₃ (28 mg, 0.27 mmol), bis ₍ di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (6 mg, 0.009 mmol), 1,4-dioxane (1.5 mL), and water (0.3 mL) were mixed in a microwave-controlled reaction tube. The reaction mixture was stimulated in a microwave reactor at 150 °C for 10 min. After cooling, the mixture was extracted with EtOAc, washed with a saturated aqueous NaCl solution, and concentrated. The crude product was purified by preparative HPLC to give compound 201. MS( _{EI) is C32H25FN4O4 , measured} value ₅₄₉ (MH+).

The following compounds were prepared from compound 43 in a manner similar to that used in Example 74 for preparing compound 201 from compound 43:

1-N'-(4-fluorophenyl)-1-N-[4-(7-methoxy-6-pyridin-4-ylquinoline-4-yl)oxyphenyl]cyclopropane-1,1-dicarboxamide (202): Pyridin-4-ylboronic acid was used instead of 3-pyridinylboronic acid. _{MS (EI) was C32H25FN4O4 , and} the measured value _was 549 (MH+).

The following compounds were prepared from compound 44 and the potassium salt of 5-(trifluoro-14-boryl)-1H-pyrazole in a manner similar to that used in the preparation of compound 201 from compound 43 and 3-pyridylboronic acid in Example 74:

1-N'-(4-fluorophenyl)-1-N-[4-[6-(1H-pyrazol-5-yl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1- _{dicarboxamide} (204): MS (EI ₎ is _{C29H22FN5O3 ,} measured value is 508 (MH+).

Example 75: 1-N'-(4-fluorophenyl)-1-N-[4-(7-methoxy-6-aminosulfonylquinoline-4-yl)oxyphenyl]cyclopropane-1,1-dicarboxamide (206)

S-(4-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylamino)phenoxy)-7-methoxyquinoline-6-yl)thioacetate (205): Pd₂(dba)₃ (16 mg, 0.017 mmol) and Xantphos (20 mg, 0.035 mmol) were added to a mixture of compound ₄₃ (200 mg, 0.36 mmol), potassium thioacetate (83 mg, 0.72 mmol), and DIEA (0.5 mL) in _1,4 -dioxane (4 mL). The resulting mixture was stirred at 120 °C for 15 min under microwave irradiation. After cooling, EtOAc and water were added. Any insoluble substances were filtered out. The filtrate was washed with saturated NaCl aqueous solution and concentrated. The crude product was purified by rapid silica gel chromatography to give compound 205 (37% yield plus 50% recovery of compound 43).

1-N'-(4-fluorophenyl)-1-N-[4-(7-methoxy-6-aminosulfonylquinoline-4-yl)oxyphenyl]cyclopropane-1,1-dicarboxamide (206): N-chlorosuccinimide (80 mg, 0.6 mmol) was added to a mixture of 2N HCl (0.5 mL) and MeCN (3 mL), and the resulting mixture was cooled to 0 °C. A solution of compound 205 (80 mg, 0.15 mmol) in MeCN (1.5 mL) was added. After stirring at 0 °C for 2 hours, the reaction mixture was extracted with EtOAc. The organic phase was washed with a saturated aqueous NaCl solution and concentrated. The resulting crude sulfonyl chloride was dissolved in i-PrOH (2 mL), and excess _NH4OH was added to it at room temperature. After the reaction was complete, the mixture was concentrated, and the crude product was purified by preparative HPLC to give compound 206 (60% yield). MS(EI) is C ₂₇ H ₂₃ FN ₄ O ₆ S, measured value 551 (MH+).

The following compounds were prepared from compound 205 in a manner similar to that used in the second step of Example 75 to prepare compound 206:

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(methylaminosulfonyl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (207): _NH4OH is replaced with methylamine. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.22 (s, ¹H), 10.06 (s, ¹H), 8.71 (d, ¹H), 8.69 (s, ¹H), 7.78 (d, 2H), 7.64–7.62 (m, 2H), 7.60 (s, ¹H), 7.30–7.28 (m, 3H), 7.17–7.12 (m, 2H), 6.50 (d, ¹H), 4.04 (s, 3H), 2.47 (s, 3H), _{1.47 (s, 4H); MS (EI) was C₂₈H₂₅FN₄O₆S , measured value} 565.1 (MH⁺).

1-N-[4-[6-(ethylaminosulfonyl)-7-methoxyquinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (208): _NH4OH was replaced with ethylamine. _MS (EI) was _C29H27FN4O6S , _with a measured value of ₅₇₉ (MH+).

The following compounds were prepared from compound 44 in a manner similar to that used in Example 75 for preparing compound 206 from compound 43:

1-N'-(4-fluorophenyl)-1-N-[4-(6-aminosulfonylquinoline-4-yl)oxyphenyl]cyclopropane-1,1- _{dicarboxamide} (209). _{MS (EI) was C26H21FN4O5S ,} with a measured value of ₅₂₁ (MH+).

Example 76: 1-N'-(4-fluorophenyl)-1-N-[4-(7-methoxy-6-methylsulfonylquinoline-4-yl)oxyphenyl]cyclopropane-1,1-dicarboxamide (210)

1-N'-(4-fluorophenyl)-1-N-[4-(7-methoxy-6-methylsulfonylquinoline-4-yl)oxyphenyl]cyclopropane-1,1-dicarboxamide (210): Compound 43 (100 mg, 0.18 mmol), sodium methanesulfonate (40 mg, 0.36 mmol), CuI (5 mg), proline (6 mg), and NaOH (3 mg) were mixed in DMSO (1 mL). The resulting mixture was stirred at 110 °C for 14 hours. After cooling to room temperature, water was added. The mixture was filtered and washed with EtOAc. The EtOAc filtrate was concentrated and purified by preparative _HPLC to give compound 210 (8% yield). _MS (EI) was _C28H24FN3O6S , _and the measured value was 550 (MH+).

Example 77: 1-N'-(4-fluorophenyl)-1-N-[4-[7-(methoxycarbamoyl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (213)

4-Chloro-N-methoxyquinoline-7-carboxamide (212): O-methylhydroxylamine hydrochloride (54.00 mg, 646.57 μmol, 49.09 μL, 2.24 equivalents) was added in a single batch to a mixture of compound 211 (60 mg, 289.00 μmol, 1 equivalent), HATU (180.00 mg, 473.40 μmol, 1.64 equivalents) in DMF (5 mL). The mixture was stirred at 20-30 °C for 0.5 h and then partitioned between water (10 mL) and EtOAc (2 x 10 mL). The organic extract was separated, washed with saturated NaCl aqueous solution (10 mL), _dried over anhydrous _Na₂SO₄ , and concentrated to give compound 212 (140 _mg , crude product), which could be used directly in the next step without further purification. _MS (EI) was _{C₁₁H₉ClN₂O₂} , _with a measured value of 236.9 (MH⁺).

1-N'-(4-fluorophenyl)-1-N-[4-[7-(methoxycarbamoyl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (213): t-BuOK (133 mg, 1.19 mmol, 2.00 equivalent) was added in a single batch to a mixture of compound 212 (140 mg, 591.58 μmol, 1 equivalent) and compound 3 (280.00 mg, 890.84 μmol, 1.51 equivalent) in DMSO (5 mL), and the resulting mixture was stirred at 100 °C for 1 hour. The reaction mixture was partitioned between water (10 mL) and EtOAc (2 x 10 mL). The combined organic extracts were washed with saturated aqueous NaCl solution (10 mL), _dried over anhydrous _Na₂SO₄ , and concentrated. The residue was purified by preparative HPLC (alkaline conditions; column: Waters Xbridge 150*25 5u; mobile phase: [water (0.05% ammonium hydroxide v/v)-ACN]; B%: 32%-57%, 6.5 min) to give compound 213 (7.9 mg, 2.54% yield). ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 12.11 (s, ¹H), 10.22 (s, ¹H), 10.06 (s, ¹H), 8.77 (d, ¹H), 8.44–8.37 (m, 2H), 7.99 (d, ¹H), 7.79 (d, 2H), 7.65 (dd, 2H), 7.28 (d, 2H), 7.16 (t, 2H), 6.66 (d, ¹H), 3.78 (s, 3H), _{1.48 (s, 4H); MS (EI) was C₂₈H₂₃FN₄O₅ , measured} value _515.1 (MH⁺).

The following compounds were prepared from compound 211 in a manner similar to that used in Example 77 for preparing compound 213 from compound 211:

1-N-[4-[7-(ethylcarbamoyl)quinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (214): In the first step, ethylamine hydrochloride is used instead of O-methylhydroxylamine hydrochloride. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.21 (s, ¹H), 10.06 (s, ¹H), 8.84 (t, ¹H), 8.75 (d, ¹H), 8.53 (d, ¹H), 8.38 (d, ¹H), 8.07 (dd, ¹H), 7.78 (d, 2H), 7.64 (dd, 2H), 7.28 (d, 2H), 7.15 (t, 2H), 6.63 (d, ¹H), 3.31 (brs, 2H), 1.47 (s, 4H), 1.18 (t, 3H); MS ₍ EI ₎ was _{C₂⁹H₂⁵FN₄O₄ ,} measured value 513.1 (MH⁺).

Example 78: 1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(1,3,4-oxadiazol-2-yl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (220)

7-Methoxy-4-(4-nitrophenoxy)quinoline-6-carboxylic acid methyl ester (215): Compound 4 (300 mg, 1.2 mmol), 4-nitrophenol (200 mg, 1.42 mmol), and DIEA (230 mg, 1.78 mmol) were mixed in toluene (1 mL). The resulting mixture was stirred at 110 °C for 12 hours. After cooling, water was added, and the mixture was extracted with EtOAc. The organic phase was washed with saturated NaCl aqueous solution, concentrated, and purified by rapid silica gel chromatography to give compound 215 (150 _mg , ₃₆ %). MS (EI) was _C18H14N2O6 , _and the measured value was 355 (MH+).

7-Methoxy-4-(4-nitrophenoxy)quinoline-6-carboxylic acid ( ₂₁₆ ): Compound 216 was synthesized in a manner similar to that used in the preparation of compound 81 in Example 25. _MS (EI) was _C17H12N2O6 , _and the measured value was 341 (MH+).

7-Methoxy-4-(4-nitrophenoxy)quinoline-6-carbazide (217): HATU (100 mg, 0.26 mmol) was added to a DMF (2 mL) solution of compound 216 (45 mg, 0.13 mmol) and DIEA (51 mg, 0.4 mmol). The resulting mixture was stirred at room temperature for 10 min, and then excess _NH₂ · _H₂O was added. After the reaction was complete, water was added. The precipitate was filtered and dried under vacuum to give crude compound ₂₁₇ , which could be _used in the next step without further purification. _MS (EI) was _{C₁₇H₁₄N₄O₅} , measured _value : 355 (MH⁺).

2-(7-Methoxy-4-(4-nitrophenoxy)quinolin-6-yl)-1,3,4-oxadiazole (218): Compound 217 (66 mg, 0.18 mmol) and p-TsOH· _H₂O (4 mg, 0.02 mmol) were mixed in triethyl orthoformate (1 mL). The resulting mixture was stirred at 120 °C for 5 hours. After cooling, the mixture was concentrated and a saturated _aqueous solution of _NaHCO₃ was added. The precipitate was filtered and washed with EtOAc to give crude compound 218, which could be _used in the next step without further purification. _{MS (EI) was C₁₈H₁₂N₄O₅ ,} measured value: 365 (MH+).

4-((7-methoxy-6-(1,3,4-oxadiazol-2-yl)quinoline-4-yl)oxy)aniline (219): Crude compound 218 was mixed with Fe powder (50 mg, 0.9 mmol) and _NH₄Cl (20 mg, 0.36 mmol) in EtOH (2 mL). The resulting mixture was stirred at 85 °C for 3 hours. After cooling, the mixture was filtered, washed with EtOAc, and the filtrate was concentrated. The residue was purified by rapid silica gel chromatography to give compound 219 (40 _mg , 66%, in two _steps ). _{MS (EI) was C₁₈H₁₄N₄O₃ ,} measured value: 335 (MH+).

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(1,3,4-oxadiazol-2-yl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide ( ₂₂₀ ): Compound 220 was synthesized in a manner similar to that used in the preparation of compound 175 in Example 64. _MS (EI) was _C29H22FN5O5 , _and the measured value was 540 (MH+).

The following compounds were prepared in a manner similar to that used in the synthesis of compound 220 in Example 78, using compound 55 instead of compound 4:

1-N'-(4-fluorophenyl)-1-N-[4-[6-(1,3,4-oxadiazol-2-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1- _{dicarboxamide} (221): MS (EI _{) was C28H20FN5O4} , and the measured value was 510 (MH+).

Example 81: N-(4-((7-bromoquinoline-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (232)

N-(4-((7-bromoquinoline-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (232): _Cs₂CO₃ (2.7 g, 8.26 mmol) was added to a mixture of compound 231 (1 g, 4.13 mmol) and compound ₃ (1.3 g, 4.13 mmol) in DMF (8 mL). The resulting mixture was stirred at 85 °C for ₁₂ h. The mixture was cooled to room temperature, diluted with water, and filtered. The residue was purified by rapid column chromatography to give compound 232 (1.5 g, 69% yield). _MS (EI) was _{C₂₆H₁₉BrFN₃O₃} , _with measured values of 520 and 522 (MH+).

Example 85: 1-N'-(4-fluorophenyl)-1-N-[4-(7-aminosulfonylquinoline-4-yl)oxyphenyl]cyclopropane-1,1-dicarboxamide (254)

S-(4-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylamino)phenoxy)quinoline-7-yl)thioacetate (253): Compound 253 (170 mg, crude) was synthesized from compound 232 in a manner similar to that used in the preparation of compound 205 from compound 43 in Example _{75. MS} ( _EI ) was _C28H22FN3O4S , measured value: 516.0 (MH+).

1-N'-(4-fluorophenyl)-1-N-[4-(7-aminosulfonylquinoline-4-yl)oxyphenyl]cyclopropane-1,1-dicarboxamide (254): Compound 254 (170 mg, crude) was synthesized from compound 253 in a manner similar to that used in the preparation of compound 206 from compound 205 in Example 75. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.28 (s, 1H), 10.05 (s, 1H), 8.95 (d, 1H), 8.62 (d, 1H), 8.52 (d, 1H), 8.11 (dd, Hz, 1H), 7.88–7.75 (m, 4H), 7.67–7.59 (m, 2H), 7.33 (d, 2H), 7.15 (t, 2H), 6.85 (d, 1H), _{1.48 (s, 4H); MS (EI) was C₂₆H₂₁FN₄O₅S , measured} value: 521.0 ( _MH⁺ ).

Example 86: 1-N'-(4-fluorophenyl)-1-N-[4-[7-[(E)-N-methoxy-C-methylcarboiminoyl]quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (256)

1-N-[4-(7-acetylquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (255): A solution of compound 232 (100 mg, 192.18 μmol, 1 equivalent), tributyl(1-ethoxyvinyl)stanane (138.81 mg, 384.36 μmol, 129.73 μL, 2 equivalents) and Pd( _PPh3 ) _2Cl2 (13.49 _mg , 19.22 μmol, 0.1 equivalents) in toluene (2 mL) was degassed with nitrogen for 10 min and heated at 110 °C for 12 h under nitrogen. After cooling, KF (2 mL, 2 M) was added, and the resulting mixture was stirred at room temperature for 30 min. A 6 M HCl aqueous solution (2 mL) was added to the residue, and the mixture was stirred at 25 °C for 30 min. The mixture was extracted with EtOAc. The organic layer was washed with water, saturated NaCl aqueous solution, _dried ( _Na₂SO₄ ), and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether/ethyl acetate = 1/1), then recrystallized from MeOH (2 mL) and lyophilized to give compound 255 (12.4 mg, 10.63% yield). ^¹H NMR (400MHz, _CDCl₃ ) δ 9.46 (s, ¹H), 8.75 (d, ¹H), 8.67 (s, ¹H), 8.57 (br s, ¹H), 8.43 (d, ¹H), 8.16 (dd, ¹H), 7.66 (d, 2H), 7.51–7.45 (m, 2H), 7.20 (d, 2H), 7.10–7.04 (m, 2H), 6.64 (d, ¹H), 2.78 (s, 3H), 1.76 (s, 2H), 1.67 (s, _2H ); MS (EI) was _{C₂₈H₂₂FN₃O₄} , measured value: _{484.2 (} MH⁺).

1-N'-(4-fluorophenyl)-1-N-[4-[7-[(E)-N-methoxy-C-methylcarboiminoyl]quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (256): O-methylhydroxylamine (43.18 mg, 517.07 μmol, 5 equivalents, HCl) was added to a mixture of compound 255 (50 mg, 103.41 μmol, 1 equivalent) in EtOH (2 mL) and _H₂O (0.3 mL). The mixture was stirred at 50 °C for 1 h. The mixture was concentrated under vacuum, and the resulting residue was purified by silica gel column chromatography (petroleum ether/EtOAc = 5/1 to 1/1), followed by recrystallization from MeOH (2 mL) to give compound 256 (27 mg, 48.90% yield). ^¹H NMR (400MHz, _CDCl₃ ) δ 10.24 (s, ¹H), 8.82 (s, ¹H), 8.72 (br d, ¹H), 8.48–8.40 (m, 2H), 8.22 (s, ¹H), 7.80 (d, 2H), 7.50–7.42 (m, 2H), 7.23 (br d, 2H), 7.07 (t, 2H), 6.83 (br d, ¹H), 4.11 (s, 3H), 2.40 (s, 3H), 1.89–1.81 (m, 2H), 1.68–1.64 (m, 2H); MS (EI) was _{C₂ ₹ H₂₅FN₄O₄} , _measured value: 513.1 (MH⁺).

Example 87: 4-(4-amino-2-fluorophenoxy)-7-methoxy-N-methylquinoline-6-carboxamide (258)

4-Chloro-7-methoxy-N-methylquinoline-6-carboxamide (257): A solution of methylamine (8 M, 50 mL, 10.07 equivalents) in EtOH was added to a solution of compound 4 (10 g, 39.74 mmol, 1 equivalent) in THF (150 mL) at 30 °C. The reaction mixture was stirred at 30 °C for 25 _h . The mixture was concentrated under vacuum. The residue was slurried with warm water (100 mL) and filtered. The filter cake was dried under vacuum to give compound 257 as a white solid (9 g, 90.35% yield). _{MS (EI) was C12H11ClN2O2 , and} the measured value was 251.0 (MH+).

4-(4-amino-2-fluorophenoxy)-7-methoxy-N-methylquinoline-6-carboxamide (258): Compound 258 was synthesized from compound 257 and 4-amino-2-fluorophenol in a manner similar to that used in Example 62 to synthesize compound 171 from compounds 42 and 2.

Example 88: 1-N-[3-fluoro-4-[7-methoxy-6-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)-1-N'-methylcyclopropane-1,1-dicarboxamide (262)

Methyl 1-((4-fluorophenyl)(methyl)carbamoyl)cyclopropane-1-carboxylic acid (260): A solution of compound 259 (215 mg, 1.5 mmol, 1.5 equivalents), HATU (568 mg, 149 μmol, 1.5 equivalents), and DIEA (0.52 mL, 3 equivalents) in DMF (5 mL, 0.2 M) was stirred at room temperature for 15 min. 4-fluoro-N-methylaniline (124 mg, 1.0 mmol, 1.0 equivalents) was added, and the mixture was stirred at room temperature for 17 h. Water was added, and the resulting mixture was extracted with EtOAc. The two phases were separated, and the organic layer was dried _{over Na₂SO₄} , concentrated under reduced pressure, absorbed onto silica gel, and purified by CombiFlash (60:40 hexane:EtOAc) to give compound 260 (221 mg, 88.7% yield). ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.38-7.35(m,2H),7.25(m,2H),3.40(s,3H),3.18(s,3H),1.37(d,2H),1.17(bs.2H).

1-((4-fluorophenyl)(methyl)carbamoyl)cyclopropane-1-carboxylic acid (261): Compound 260 (60 mg, 0.23 mmol, 1.0 equivalent) and NaOH (20 mg, 0.5 mmol) in MeOH and THF solutions (1 mL each) were stirred overnight at 50 °C. The reaction mixture was cooled and concentrated under reduced pressure. 1 N HCl was added to the residue, and the resulting mixture was extracted with DCM. The two phases were separated, _and the organic layer was dried over _Na₂SO₄ and concentrated under reduced pressure to give crude compound 261, which could be used in the next step without further purification (44.7 mg, 79% yield). ^¹H NMR (400 MHz, DMSO- _d₆ ) δ 7.39 (br s, 2H), 7.25 (m, 2H), 3.17 (s, 3H), 1.24 (br s, 2H), 0.99 (br s, 2H).

1-N-[3-fluoro-4-[7-methoxy-6-(methylcarbamoyl)quinolin-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)-1-N'-methylcyclopropane-1,1-dicarboxamide (262): A solution of compound 261 (23.7 mg, 0.1 mmol, 1.5 equivalent), HATU (38 mg, 0.1 mmol, 1.5 equivalent), and DIEA (34 μL, 3.0 equivalent) in DMF (0.4 mL) was stirred at room temperature for 15 min. Compound 258 (23.7 mg, 0.06 mmol, 1.0 equivalent) was added, and the mixture was stirred at room temperature for 17 h. Water was added to the mixture, and the resulting solid was extracted into EtOAc. The two phases were separated, and the organic layer was dried over _{Na₂SO₄ ,} concentrated under reduced pressure, absorbed onto silica gel, and purified by CombiFlash (5:95MeOH:DCM). The obtained product was further purified by preparative HPLC to give compound 262 (7 mg, 18.8% yield). ^¹H NMR (400 MHz, DMSO- _d₆ ) δ 9.94 (s, 1H), 8.79 (d, 1H), 8.59 (s, 1H), 8.38 (d, 1H), 7.50 (s, 1H), 7.37 (t, 2H), 7.22 (b m, 3H), 7.04 (t, 2H), 6.65 (d, 1H), 3.99 (s, 3H), 3.18 (s, 3H), 2.78 ( _d , 3H), 1.37 ( _{d, 2H), 1.17 (b s, 2H); MS (EI) was C₃₀H₂₆F₂N₄O₅ , measured} value _561.0 (MH⁺).

Compound 263 was prepared using a variant of the method used in Example 88 for synthesizing compound 262:

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]-1-N'-methylcyclopropane-1,1-dicarboxamide (263): In the last step of the 3-step sequence of Example 88, compound 258 was replaced with 4-(4-aminophenoxy)-7-methoxy-N-methylquinoline-6-carboxamide. 4-(4-aminophenoxy)-7-methoxy-N-methylquinoline-6-carboxamide was synthesized in the same manner as compound 258 in Example 87, but in the second step, 4-aminophenol was used instead of 4-amino-2-fluorophenol. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 9.69 (br s, 1H), 8.67 (d, 1H), 8.62 (s, 1H), 8.38 (d, 1H), 7.52 (s, 1H), 7.47 (s, 1H), 7.29 (m, 2H), 7.18 (d, 3H), 7.11 (t, 2H) 6.47 (d, 1H), 4.03 (s, 3H), 2.85 (d, 3H), 2.08 (s, 3H), 1.37 (d, 2H), 1.24 (br s, _{2H); MS (EI) was C₃₀H₂₇FN₄O₅ , measured value} 543.0 (MH⁺).

Following the same three-step procedure used in Example 88 for the synthesis of compound 262 from compounds 259 and 258, the following compounds were prepared from compounds 259 and 258:

1-N'-(2-chloro-4-fluorophenyl)-1-N-[3-fluoro-4-[7-methoxy-6-(methylcarbamoyl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (264): In the first step, 4-fluoro-N-methylaniline is replaced with 2-chloro-4-fluoroaniline. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.36 (s, ¹H), 10.25 (s, ¹H), 8.61 (d, ¹H), 8.54 (s, ¹H), 8.31 (m, ¹H), 7.84–7.79 (m, 2H), 7.47 (s, 2H), 7.40 (t, 2H), 7.18 (t, 1H), 6.42 (d, 1H), 3.96 (s, 3H), 2.77 (d, 3H), 1.56 (br s, 2H), 1.53 ( _br s _{, 2H); MS (EI) was C₂₉H₂₃ClF₂N₄O₅ , measured value} 581.0 (MH⁺).

1-N-[3-fluoro-4-[7-methoxy-6-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]-1-N'-(4-fluoro-2-methylphenyl)cyclopropane-1,1-dicarboxamide (265): In the first step, 4-fluoro-2-methylaniline is used instead of 4-fluoro-N-methylaniline. ^¹H NMR (400MHz, DMSO- _d₆ ) δ 10.58 (s, ¹H), 9.72 (s, ¹H), 8.68 (d, ¹H), 8.61 (s, ¹H), 8.39 (d, ¹H), 7.92 (d, ¹H), 7.54 (br s, 2H), 7.47 (t, 2H), 7.1 (d, 1H), 7.03 (t, 1H), 6.49 (d, 1H), 4.03 (s, 3H), 2.85 (d, 3H), 2.22 ( _{s, 3H), 1.54 (s, 4H); MS (EI) was C₃₀H₂₆F₂N₄O₅ , measured value 561.0} (MH⁺).

1-N'-(4-fluoro-2,6-dimethylphenyl)-1-N-[3-fluoro-4-[7-methoxy-6-(methylcarbamoyl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (267): In the first step, 4-fluoro-2,6-dimethylaniline is used instead of 4-fluoro-N-methylaniline. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.8 (s, ¹H), 9.19 (s, ¹H), 8.6 (d, ¹H), 8.54 (s, ¹H), 8.32 (d¹H), 7.87 (d¹H), 7.46–7.36 (m, ³H), 6.88 (d, 2H), 6.41 (d, ¹H), 3.96 (s, ³H), 2.77 (d, ³H), 2.09 (s, 6H), _1.47 ( _{s, 4H); MS (EI) was C₃¹H₂₈F₂N₄O₅ , measured} value _575.0 (MH⁺).

1-N-[3-fluoro-4-[7-methoxy-6-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]-1-N'-(4-fluoro-2-methoxyphenyl)cyclopropane-1,1-dicarboxamide (268): In the first step, 4-fluoro-2-methoxyaniline is used instead of 4-fluoro-N-methylaniline. ^¹H NMR (400MHz, DMSO- _d₆ ) δ 10.2 (s, ¹H), 10.17 (s, ¹H), 8.68 (d, ¹H), 8.62 (s, ¹H), 8.39 (d, ¹H), 7.98–7.96 (m, ¹H), 7.86 (d, ¹H), 7.54–7.47 (m, ³H), 7.01 (d, ¹H), 6.77 (t, ¹H), 6.51 (d, ¹H), 4.04 (s, ³H), 3.85 (s, ³H), 2.86 (d, ³H), 1.62 (s, ²H), _1.58 (s, _{²H); MS (EI) was C₃₀H₂₆F₂N₄O₆ , measured value} 577.0 (MH⁺).

1-N-[3-fluoro-4-[7-methoxy-6-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]-1-N'-(4-fluoro-2-propane-2-yloxyphenyl)cyclopropane-1,1-dicarboxamide (269): In the first step, 4-fluoro-2-isopropoxyaniline is used instead of 4-fluoro-N-methylaniline. ¹ H NMR (400MHz, DMSO-d ₆ )δ10.21(s,1H),10.06(s,1H),8.62(d,1H),8.55(s,1H),8.32(d,1H),8.05(t,1H),7.87(d,1H),7.52-7.41(m,3H),6.97(d,1H),6. 68(t,1H),6.41(d,1H),4.64-4.58(m,1H),3.96(s,3H),2.78(d,3H),1.51(s,2H),1.40(s.2H),1.17(s,3H),1.16(s,3H); MS(EI) is C ₃₂ H ₃₀ F ₂ N ₄ O ₆ The measured value was 605 (MH+).

1-N'-(2-Cyclopropyl-4-fluorophenyl)-1-N-[3-fluoro-4-[7-methoxy-6-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (270): In the first step, 4-fluoro-N-methylaniline is replaced with 2-cyclopropyl-4-fluoroaniline. ¹ H NMR (400MHz, DMSO-d ₆ ) δ10.53 (br s, 1H), 9.99 (br s,1H),8.68(d,1H),8.62(s,1H),8.39(d,1H),7.91(d,1H),7.61(s,1H),7.54(s,2H),7.49(br s,1H),7.01(t,1H)6.82(d,1H),6.49(d,1H),4.04(s,3H),2.85(d,3H),1.97(br s,1H),1.58(s,4H),0.94(d,2H),0.67(d,2H); MS(EI) is C ₃₂ H ₂₈ F ₂ N ₄ O ₅ The measured value was 587.4 (MH+).

The 2-cyclopropyl-4-fluoroaniline used in the synthesis of compound 270 was synthesized via the following procedure:

In a thick-walled reaction tube, tert-butyl (2-bromo-4-fluorophenyl)carbamate (289 mg, 1 mmol, 1.0 equivalent), cyclopropyl MIDA borate (236 mg, 1.2 mmol, 1.2 equivalent), and _K₃PO₄ ( ₆₃₆ mg, 3.0 equivalent) were added to toluene:water (4:1) and degassed under nitrogen for 5 minutes. Palladium acetate (9 mg, 4 mol%) and 2-(dicyclohexyl)phosphinobiphenyl (28 mg, 8 mol%) were added to the mixture and degassed under nitrogen for another 5 minutes. The tube was capped, and the mixture was heated overnight at 100 °C under nitrogen. After cooling to room temperature, the two phases were separated. The organic layer was dried with _{anhydrous Na₂SO₄} , concentrated under reduced pressure, absorbed into silica gel, and purified by CombiFlash using a 70:30 hexane:DCM gradient to give tert-butyl (2-cyclopropyl-4-fluorophenyl)carbamate as a colorless oil (90 mg, 36% yield).

A solution of tert-butyl (2-cyclopropyl-4-fluorophenyl)carbamate (86 mg, 0.3 mmol, 1.0 equivalent) and TFA (77 mg, 2.0 equivalent) in DCM (1 mL) was stirred overnight at 40 °C. The reaction solution was cooled and concentrated under reduced pressure. DCM (4 mL) was added to the residue, and the resulting solution was washed with a saturated aqueous solution of _NaHCO3 , dried over _{anhydrous Na2SO4} , and concentrated under reduced pressure to give crude 2-cyclopropyl-4-fluoroaniline as an almost colorless oil (43 mg, 81% yield), which could be used in subsequent reactions without further purification. ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.16-7.13(m,1H),7.01(t,1H),6.85(d,1H),1.91-1.85(m,1H),1.0(d,2H),0.73(d,2H).

Example 89: 1-((3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinoline-4-yl)oxy)phenyl)-carbamoyl)-cyclopropane-1-carboxylic acid (272)

Methyl 1-((3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-carbamoyl)cyclopropane-1-carboxylic acid (271): A solution of compound 259 (108 mg, 0.7 mmol, 1.5 equivalent), HATU (285 mg, 0.75 mmol, 1.5 equivalent), and DIEA (0.26 mL, 3 equivalent) in DMF (2.5 mL, 0.2 M) was stirred at room temperature for 15 min. Compound 258 (170 mg, 0.5 mmol, 1.0 equivalent) was added, and the mixture was stirred at room temperature for 17 h. Water was added, and the resulting mixture was extracted with EtOAc. The organic layer was separated and washed with a saturated aqueous solution of NaCl, _dried over anhydrous _Na₂SO₄ , and concentrated under reduced pressure. The resulting residue was aspirated onto silica gel and purified by CombiFlash using a gradient of 1:8 hexane:EtOAc followed by 1:6 hexane:DCM. The resulting product was sonicated with hexane. The resulting solid was filtered, dissolved in DCM, and washed with 10% LiCl aqueous solution. The organic layer was dried over _{anhydrous Na₂SO₄} and concentrated to give compound 271 (90 mg, 38% yield). ¹ HNMR(400MHz,DMSO-d ₆ )δ10.64(br s,1H),8.67(d,1H),8.61(s,1H),8.39(d,1H),7.88(m,1H),7.54(s,1H),7.51-7.44(m,2H) ,6.52(d,1H),4.03(s,3H),3.71(s,3H),2.85(d,3H),1.46-1.45(m,2H),1.43-1.42(m,2H).

1-((3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)carbamoyl)-cyclopropane-1-carboxylic acid (272): Compound 271 (70 mg, 0.2 mmol, 1.0 equivalent) and NaOH (12 mg, 0.5 mmol) in MeOH and THF solutions (1 mL each) were stirred overnight at 50 °C. The reaction solution was cooled and then concentrated under reduced pressure. 1 N HCl aqueous solution was added to the residue, and the resulting mixture was extracted with DCM. The organic phase was dried over _{anhydrous Na₂SO₄} and concentrated under reduced pressure to give crude compound 272 (60 mg, 89% yield), which could be used in subsequent reactions without further purification. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.85(br s,1H),8.87(d,1H),8.67(s,1H),8.46(d,1H),7.95(m,1H),7.62(s,1H) ,7.54-7.5(m,2H),6.83(d,1H),4.06(s,3H),2.85(d,3H),1.43(s,4H).

Example 90: 1-N'-[3-fluoro-4-[7-methoxy-6-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]-1-N-[4-(trifluoromethyl)phenyl]cyclopropane-1,1-dicarboxamide (273)

1-N'-[3-fluoro-4-[7-methoxy-6-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]-1-N-[4-(trifluoromethyl)phenyl]cyclopropane-1,1-dicarboxamide (273): Compound 273 was synthesized from compound 272 and 4-(trifluoromethyl)aniline using standard HATU amide bond forming techniques, such as those used in the first step of Examples 3, 4 and 89. ^¹H NMR (400MHz, _CD₃OD ) δ 8.90 (s, ¹H), 8.86 (d, ¹H), 7.89 (d, ¹H), 7.55 (s, ¹H), 7.51 (d, 2H), 7.43 (m, _2H ), 7.25 (d, 2H), 6.98 (d, ¹H), 4.13 (s, 3H), 2.94 (s, 3H), 1.64–1.54 (m, 4H). _{MS (EI) was C₃₀H₂₄F₄N₄O₅ ,} measured value _597.2 ( _MH⁺ ).

Following the same procedure used in Example 90 for the synthesis of compound 273 from compound 272, the following compounds were prepared from compound 272:

1-N-(4-chlorophenyl)-1-N'-[3-fluoro-4-[7-methoxy-6-(methylcarbamoyl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (274): 4-chloroaniline was used instead of 4-(trifluoromethyl)aniline. ^¹H NMR (400 MHz, _CD₃OD ) δ 8.99 (s, 1H), 8.95 (d, 1H), 7.98 (d, 1H), 7.83 (d, 2H), 7.65 (d, 3H), 7.54 (q, 2H), 7.06 (d, 1H), 4.22 (s, 3H), 3.03 (s, 3H), 1.84–1.64 (m, _4H ). _{MS (EI) was C₂₉H₂₄ClFN₄O₅ ,} measured _563.2 (MH⁺).

Example 91: 1-N'-(4-fluorophenyl)-1-N-[4-[7-[(E)-methoxyiminomethyl]quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (278)

(4-Chloroquinoline-7-yl)methanol (275): Compound 161 (400 mg, 1.80 mmol, 1 equivalent) in THF (2 mL) was added to a solution of _LiAlH4 (116.45 mg, 3.07 mmol, 1.7 equivalent) in THF (5 mL) at 0 °C. The mixture was stirred at 20 °C for 3 hours. _Na2SO4 · _10H2O ( ₅₀ mg) was added, the resulting mixture was filtered, and the filtrate was dried over _{anhydrous Na2SO4} and then concentrated under vacuum. The residue was purified by rapid silica gel chromatography (4 g silica rapid column, eluent 70%–100% ethyl acetate/petroleum ether gradient @ 25 mL/min) to give compound 275 as a pale yellow solid (150 mg, 36.5% yield). ¹ H NMR (400MHz, CDCl ₃ ) δ 8.74 (d, 1H), 8.19 (d, 1H), 8.12 (s, 1H), 7.64 (dd, 1H), 7.47 (d, 1H), 4.94 (s, 2H), 2.99 (br s, 1H).

N-(4-fluorophenyl)-N-(4-((7-(hydroxymethyl)quinoline-4-yl)oxy)phenyl)cyclopropane-1,1-dicarboxamide (276): Compound 276 was synthesized from compound 275 and compound 3 by lowering the reaction temperature to 85°C in a manner similar to that used in the last step of Example 12 for the synthesis of compound 43 from compound 42 and compound 3. ^¹H NMR (400MHz, _CD₃OD ) δ 8.63 (d, ¹H), 8.41 (d, ¹H), 8.03 (s, ¹H), 7.76 (d, 2H), 7.68 (dd, ¹H), 7.62–7.55 (m, 2H), 7.30–7.23 (m, 2H), 7.09 (t, 2H), 6.66 (d, ¹H), 4.88 (s, 2H), 1.66 (d, 4H); MS (EI) was _{C₂₇H₂₂FN₃O₄ , measured value} 472.1 (MH⁺).

N-(4-fluorophenyl)-N-(4-((7-formylquinoline-4-yl)oxy)phenyl)cyclopropane-1,1-dicarboxamide (277): _MnO₂ (239.72 mg, 2.76 mmol, 13 equivalents) was added to a DCM (5 mL) solution of compound 276 (100 mg, 212.1 μmol, 1 equivalent). The mixture was stirred at 20 °C for 1 _h . The mixture was filtered and concentrated under vacuum to give compound 277 as a yellow oil (50 mg, 40.2% yield). _{MS (EI) was C₂₇H₂₀FN₃O₄ , and} the measured value was 470.0 (MH⁺).

1-N'-(4-fluorophenyl)-1-N-[4-[7-[(E)-methoxyiminomethyl]quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (278): O-methylhydroxylamine (44.47 mg, 532.5 μol, 5 equivalents, HCl) was added to a mixture of compound 277 (50 mg, 106.5 μol, 1 equivalent) in EtOH (3 mL) and water (0.3 mL). The mixture was stirred at 50 °C for 2 h. The mixture was concentrated under vacuum, and EtOH (3 mL) was added to the residue. The obtained white solid was collected and then purified by preparative HPLC (YMC-Actus Triart C18 150*30mm*5um; mobile phase: [water (0.225% FA)-ACN]; B%: 37%-77%, 10 min) to give compound 278 as a white solid (14.5 mg, 26.2% yield). ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.22 (s, 1H), 10.07 (s, 1H), 8.72 (d, 1H), 8.51 (s, 1H), 8.34 (d, 1H), 8.18 (d, 1H), 7.97 (dd, 1H), 7.79 (d, 2H), 7.70–7.61 (m, 2H), 7.28 (d, 2H), 7.16 (t, 2H), 6.60 (d, 1H), 3.98 (s, 3H) _{, 1.48 (s, 4H); MS (EI) was C₂₈H₂₃FN₄O₄ , measured} value _499.2 (MH⁺).

Example 92: 1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(methylcarbamoylamino)-quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (279)

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(methylcarbamoylamino)-quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (279): 1-methylurea (48.46 mg, 654.10 μmol, 6 equivalents), _Pd₂ (dba) _₃ (14.97 mg, 16.35 μmol, 0.15 equivalents), Xantphos (18.92 mg, 32.70 μmol, 0.3 equivalents), and _Cs₂CO₃ (99.46 mg, 305.25 μmol, 2.8 equivalents) were added to a mixture of compound ₄₃ (60 mg, 109.02 μmol, 1 equivalent) in dioxane (3 mL) under a nitrogen atmosphere. The mixture was stirred at 100 °C for 1 h. The reaction mixture was concentrated, and water (20 mL) was added to the residue. The resulting mixture was extracted with EtOAc (3 x 25 mL). The combined organic extracts were dried over _{anhydrous Na₂SO₄} and concentrated under vacuum. The resulting residue was purified by preparative HPLC (column: DuraShell 150*25mm*5um; mobile phase: [water (0.05% ammonium hydroxide v/v)-ACN]; B%: 30%-70%, 10 min) to give compound 279 as a white solid (12.8 mg, 20.7% yield). ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.15 (s, ¹H), 10.07 (s, ¹H), 8.97 (s, ¹H), 8.44 (d, ¹H), 8.32 (s, ¹H), 7.76 (d, 2H), 7.65 (dd, 2H), 7.40 (s, 1H), 7.24–7.12 (m, 4H), 6.95 (br d, ¹H), 6.41 (d, 1H), 4.04 (s, 3H), 2.68 (s, 3H) _{, 1.48 (br d, 4H); MS (EI) was C₂⁹H₂⁶FN₅O₅ , measured value} 544.3 (MH⁺).

Example 93: Methyl N-[4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-7-methoxyquinoline-6-yl]carbamate (280)

N-[4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-7-methoxyquinoline-6-yl]carbamate (280): Compound 280 was synthesized from compound 43 by replacing 1-methylurea with methyl carbamate in a manner similar to that used in Example 92 for the synthesis of compound 279 from compound 43. ^¹H NMR (400MHz, DMSO- _d₆ ) δ 10.17 (s, ¹H), 10.06 (s, ¹H), 8.84 (s, ¹H), 8.67 (s, ¹H), 8.52 (d, ¹H), 7.77 (d, 2H), 7.70–7.62 (m, 2H), 7.45 (s, ¹H), 7.23 (d, 2H), 7.19–7.12 (m, 2H), 6.45 (d, ¹H), 4.00 ( _s , 3H), 3.72 (s, 3H), 1.48 (s, 4H); MS (EI) was _{C₂ ₹H₂₅FN₄O₆ ,} measured value 567.3 [M+Na] ^⁺

Example 94: 1-N'-(4-fluorophenyl)-1-N-[4-[7-(methylcarbamoylamino)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (281)

1-N'-(4-fluorophenyl)-1-N-[4-[7-(methylcarbamoylamino)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (281): A mixture of compound 232 (100 mg, 192.18 μmol, 1 equivalent), methylurea (42.71 mg, 576.54 μmol, 3 equivalent), Xantphos (22.24 mg, 38.44 μmol, 0.2 equivalent), t-BuONa (36.94 mg, 384.36 μmol, 2 equivalent) and _Pd₂ (dba)₃ (17.60 mg, 19.22 μmol, 0.1 equivalent) in dioxane (5 mL) was degassed and purged three times with nitrogen, then stirred at 100 °C for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: Ultimate C18 10μm 250mm*50mm; mobile phase: [water (0.05% ammonium hydroxide v/v)-ACN]; B%: 39%-69%, 9 min) to give compound 281 as a white solid (56.9 mg, 57.4% yield). ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.18 (s, ¹H), 10.06 (s, ¹H), 9.09 (s, ¹H), 8.55 (d, ¹H), 8.14 (d, 2H), 7.75 (d, 2H), 7.69–7.57 (m, 3H), 7.22 (d, 2H), 7.15 (t, 2H), 6.37 (d, ¹H), 6.26 (d, 1H), 2.69 (d, 3H), _1.48 (s, _{4H); MS (EI) was C₂₈H₂₄FN₅O₄ ,} measured value _514.3 (MH⁺).

Example 95: Methyl N-[4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]-amino]phenoxy]quinoline-7-yl]carbamate (282)

N-[4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]-amino]phenoxy]quinoline-7-yl]carbamate (282): Compound 282 was synthesized from compound 232 by replacing 1-methylurea with methyl carbamate in a manner similar to that used in Example 94 for the synthesis of compound 281 from compound 232. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.82–10.72 (m, 1H), 10.40–10.33 (m, 1H), 10.12–10.04 (m, 1H), 8.89 (d, 1H), 8.59 (d, 1H), 8.50 (d, 1H), 7.93–7.81 (m, 3H), 7.69–7.60 (m, 2H), 7.38 (d, 2H), 7.16 (t, 2H), 6.78 (d, 1H), 3.79 (s, 3H), _{1.50 (s, 4H); MS (EI) was C₂₈H₂₃FN₄O₅ , measured} value _515.3 (MH⁺).

Example 96: 1-N-[4-[6-(3-ethyl-1,2,4-oxadiazol-5-yl)-7-methoxyquinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide hydrochloride (283)

1-N-[4-[6-(3-ethyl-1,2,4-oxadiazol-5-yl)-7-methoxyquinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide hydrochloride (283): HATU (26.45 mg, 0.070 mmol) was added to a DMF (0.5 mL) solution of compound 6 (30 mg, 0.058 mmol), (Z)-N'-hydroxypropylimine amide (7.22 mg, 0.058 mmol), and DIEA (44 μL, 0.17 mmol), and the reaction mixture was stirred at room temperature until the starting material disappeared as determined by LC-MS. The reaction mixture was then heated to 60 °C and maintained for 2 hours. A saturated aqueous solution _{of NaHCO3} was added to the resulting mixture, which was then extracted with DCM (3x). The combined organic extracts were washed with a saturated aqueous solution of NaCl, _dried over _Na2SO4 , and concentrated. The crude residue was purified by HPLC (Gemini-NX, 10 μM, 250 x 30 mm, C18 column; eluent: 0.1%–100% acetonitrile aqueous solution, both eluents containing 0.1% trifluoroacetic acid, gradient elution for at least 15 minutes), followed by lyophilization. The resulting powder was placed in a 20% MeOH solution in DCM and passed through an Agilent PL-HCO3 ion exchange column (or placed in DCM and washed with saturated sodium bicarbonate), and concentrated under reduced pressure. HCl (4 M dioxane solution, 0.5 mL; or 1 M aqueous solution, 1 mL) was added to remove volatile solvents under reduced pressure, and the residue was dried under high vacuum to give the hydrochloride of compound 283 (4.1 mg, 11.7% yield). ^¹H NMR (400MHz, _CD₃OD ) δ 9.29 (s, ¹H), 8.94 (d, ¹H), 7.86 (q, 2H), 7.68 (s, ¹H), 7.61–7.54 (m, 2H), 7.41 (d, 2H), 7.10 (t, 2H), 7.02 (d, 1H), 4.26 (s, 3H), 2.91 (q, 2H), 1.68 (s, 4H), 1.42 (t, 3H). _{MS (EI) was C₃¹H₂₆FN₅O₅ ,} measured _{value 568.2} (MH⁺).

Example 97: 1-N'-[3-fluoro-4-[6-methyl-7-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (289)

4-Hydroxy-6-methylquinoline-7-carboxylic acid methyl ester (284): A mixture of compound 139 (290 mg, 1.11 mmol, 1 equivalent) and AcONa (454.26 mg, 5.54 mmol, 5 equivalent) in AcOH (6 mL) and water ( ₁₀ mL) was stirred at 90 °C for 48 h. After cooling to ambient temperature, the reaction mixture was neutralized with a saturated aqueous solution _{of NaHCO3} and extracted with EtOAc (3 x 30 mL). The combined extracts were dried over anhydrous _Na2SO4 and concentrated under reduced pressure to give compound 284 as a pale yellow solid (200 mg, 74.8% yield), which could be used directly in subsequent reactions without further purification. _{MS (EI) was C12H11NO3 , and} the result was 218.1 (MH+).

4-(2-fluoro-4-nitrophenoxy)-6-methylquinoline-7-carboxylic acid methyl ester (285): Cs₂CO₃ (809.97 mg, 2.49 mmol, 3 equivalents) was added to a mixture of compound 284 (200 mg, 828.65 μmol, ₁ equivalent) and 1,2-difluoro-4-nitrobenzene (197.75 mg, 1.24 mmol, 137.32 μL, 1.5 equivalents) in _ACN (15 mL) at 25 °C, and the mixture was stirred at 70 °C for 2 h. After cooling, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 30 mL). The combined organic extracts were washed with a saturated aqueous solution of NaCl (60 mL), _dried over anhydrous _Na₂SO₄ , and concentrated. The residue was purified by rapid silica gel chromatography, eluting with petroleum ether (0–60%) solution of EtOAc to give compound 285 as a pale yellow solid (120 mg, 38.6% yield). ^¹H NMR (400 MHz, _CDCl₃ ) δ 8.77 (d, 1H), 8.70 (s, 1H), 8.23–8.15 (m, 2H), 8.12 (s, 1H), 7.42–7.35 (m, 1H), 6.65 (d, 1H), 3.99 (s, 3H), 2.79 ( _{s, 3H); MS (EI) was C₁₈H₁₃FN₂O₅ ,} measured _357.0 ( _MH⁺ ).

4-(4-amino-2-fluorophenoxy)-6-methylquinoline-7-carboxylic acid methyl ester (286): Compound 286 was synthesized from compound 285 using a method similar to that used in Example 78 to convert compound 218 to compound 219. _MS ( _{EI )} was _C18H15FN2O3 , measured at 326.9 (MH+).

Methyl 4-(2-fluoro-4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylamino)phenoxy)-6-methylquinoline-7-carboxylic acid ester (287): A mixture of compound 1 (51.30 mg, 218.34 μmol, 1.5 equivalents) in _SOCl2 (8.20 g, 68.92 mmol, 5.00 mL, 473.51 equivalents) was stirred at 65 °C for 1 h. The mixture was concentrated, and the residue was dissolved in toluene and concentrated again. A solution of compound 286 (50 mg, 145.56 μmol, 1.0 equivalents) in THF (5 mL) was added to the resulting residue, followed by the addition of triethylamine (44.19 mg, 436.69 μmol, 60.78 μL, 3 equivalents). The resulting mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched with water (30 mL) and extracted with EtOAc (3 x 20 mL). The combined extracts were dried over _{anhydrous Na₂SO₄} and concentrated. The resulting residue was purified by silica gel chromatography, eluting with petroleum ether solution of EtOAc (0–70%), to give compound 287 as a grayish-white solid ( ₇₀ mg, _{85.95 %} yield). _MS (EI) was _{C₂₉H₂₃F₂N₃O₅} , and the result was 532.0 (MH⁺).

4-(2-Fluoro-4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylamino)phenoxy)-6-methylquinoline-7-carboxylic acid (288): A mixture of compound 287 (70.0 mg, 125.12 μmol, 1 equivalent) and LiOH· _H₂O (26.25 mg, 625.58 μmol, 5 equivalent) in THF (5 mL) and water (5 mL) was stirred at 25 °C for 4 H. The reaction mixture was acidified with 1 M HCl aqueous solution until a pH of ~5 was reached. The mixture was then diluted with water (30 mL) and extracted with EtOAc (3 x 20 _mL ). The combined organic extracts were dried over anhydrous _Na₂SO₄ and concentrated to give compound 288 as a white solid (70 mg, 86.49% yield), which could be used directly in subsequent reactions without further purification. _{MS(EI) is C28H21F2N3O5 , measured} value _{518.1 (} MH+).

1-1-N'-[3-fluoro-4-[6-methyl-7-(methylcarbamoyl)quinolin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (289): Compound 289 was synthesized from compound 288 in a manner similar to that used in the preparation of compound 8 in Example 4. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.39(s, ¹H), 9.99(s, ¹H), 8.67(d, ¹H), 8.48(d, ¹H), 8.16(s, ¹H), 7.95(s, ¹H), 7.91(d, ¹H), 7.63(dd, 2H), 7.56–7.49(m, ¹H), 7.47–7.41(m, ¹H), 7.15(t, 2H), 6.59(d, ¹H), 2.82(d, 3H), 2.54(s, 3H), 1.47(d, 4H); _MS ( _{EI )} was _{C₂⁹H₂⁴F₂N₄O₄ ,} measured value 531.1 (MH⁺).

The following compounds were prepared from compound 139 using the same 6-step method as used in Example 97 for the synthesis of compound 289:

1-N'-[2,5-difluoro-4-[6-methyl-7-(methylcarbamoyl)quinolin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (290): In step 2, 1,2-difluoro-4-nitrobenzene is replaced with 1,2,4-trifluoro-5-nitrobenzene. ^¹H NMR (400MHz, _CDCl₃ ) δ 10.09 (br s, ¹H), 8.59 (d, ¹H), 8.28 (dd, ¹H), 8.21 (s, ¹H), 8.09 (s, ¹H), 8.00 (s, ¹H), 7.36–7.43 (m, 2H), 6.96–7.06 (m, 3H), 6.47 (d, ¹H), 5.98 (d, 1H), 3.01 (d, 3H), 2.58 (s, 3H), 1.72–1.78 (m, 2H), 1.59–1.62 ( _m , 2H); MS (EI) was _{C₂ ₹ H₂₃F₃N₄O₄} , measured value _549.1 (MH⁺).

1-N'-[2-chloro-5-fluoro-4-[6-methyl-7-(methylcarbamoyl)quinolin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (291): In step 2, 1-chloro-4,5-difluoro-2-nitrobenzene is used instead of 1,2-difluoro-4-nitrobenzene. ^¹H NMR (400MHz, _CDCl₃ ) δ 10.08 (s, ¹H), 8.66 (d, ¹H), 8.61 (s, ¹H), 8.44 (d, ¹H), 8.15 (s, ¹H), 8.07 (s, ¹H), 7.52–7.45 (m, 2H), 7.36 (d, ¹H), 7.06 (t, 2H), 6.54 (d, ¹H), 6.15–6.07 (m, ¹H), 3.08 (d, 3H), 2.65 (s, 3H), 1.82–1.72 ( _m , 4H); MS (EI) was _{C₂ ₹ H₂₃ClF₂N₄O₄} , measured value _565.1 (MH⁺).

1-N-(4-fluorophenyl)-1-N'-[2,3,5-trifluoro-4-[6-methyl-7-(methylcarbamoyl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (292): In step 2, 1,2-difluoro-4-nitrobenzene is replaced with 1,2,3,4-tetrafluoro-5-nitrobenzene. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 11.33 (s, ¹H), 9.77 (s, ¹H), 8.71 (d, ¹H), 8.54–8.48 (m, ¹H), 8.18 (s, ¹H), 8.08–8.02 (m, ¹H), 7.98 (s, ¹H), 7.63–7.56 (m, 2H), 7.23–7.14 (m, 2H), 6.89 (d, ¹H), 2.83 (d, 3H), 2.55 (s, 3H), 1.72–1.65 (m, 2H), 1.62–1.57 (m, 2H); MS (EI) was _{C₂ ₹H₂₂F₄N₄O₄ , measured value} 567.1 (MH⁺).

Example 98: 1-N'-[4-(7-carbamoyl-6-methylquinoline-4-yl)oxy-3-fluorophenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (293)

1-N'-[4-(7-carbamoyl-6-methylquinoline-4-yl)oxy-3-fluorophenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (293): Compound 293 was synthesized from compound 288 in a manner similar to that used in the preparation of compound 7 in Example 3. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.40(s, ¹H), 10.00(s, ¹H), 8.67(d, ¹H), 8.16(s, ¹H), 8.03(s, ¹H), 7.99(s, ¹H), 7.91(d, ¹H), 7.64(dd, 2H), 7.58(s, ¹H), 7.56–7.51(m, ¹H), 7.47–7.41(m, ¹H), 7.15(t, 2H), 6.59(d, ¹H), 2.58(s, 3H), 1.47(d, 4H); _MS ( _{EI )} was _{C₂₈H₂₂F₂N₄O₄ ,} measured value 517.1 (MH⁺).

The following compounds were prepared using a method similar to that used in Example 98 for the synthesis of compound 293 from compound 288:

1-N'-[4-(7-carbamoyl-6-methylquinoline-4-yl)oxy-2,5-difluorophenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (294): 4-(2,5-difluoro-4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylamino)phenoxy)-6-methylquinoline-7-carboxylic acid was used instead of compound 288, prepared using the same multi-step procedure as that used in Example 97 for the synthesis of compound 288, except that in step 2, 1,2-difluoro-4-nitrobenzene was used instead of 1,2-difluoro-4-nitrobenzene. ^¹H NMR (400MHz, _CDCl₃ ) δ 10.19 (br s, 1H), 8.67 (d, 1H), 8.36 (dd, 1H), 8.26 (br s, 1H), 8.19 (s, 2H), 7.47 (dd, 2H), 7.03–7.12 (m, 3H), 6.55 (d, 1H), 6.04 (br s, 1H), 5.78 (br s, 1H), 2.70 (s, 3H), 1.75–1.90 ( _m , 2H), 1.67–1.69 (m, _{2H); MS (EI) was C₂₈H₂₁F₃N₄O₄ , measured} value _535.1 (MH⁺).

Example 99: 1-N'-[3-fluoro-4-[7-(2-hydroxyethoxycarbamoyl)quinoline-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (301)

4-Hydroxyquinoline-7-carboxylic acid methyl ester (296): Compound 295 (5 g, 22.32 mmol, 1 equivalence) and TEA (22.58 g, 223.16 mmol, 31.06 mL, 10 equivalence) in MeOH (60 mL) and DMSO (20 mL) solutions were added to a round-bottom flask. Then DPPP (1.84 g, 4.46 mmol, 0.2 eq) and Pd(OAc) _₂ (1.00 g, 4.46 mmol, 0.2 equivalence) were added. The flask was purged twice with carbon monoxide and placed under 30 psi of carbon monoxide while heating at 70 °C for 12 hours. MeOH (100 mL) was added, and the resulting suspension was filtered through a diatomaceous earth mat. The filter cake was washed with MeOH (3 x 50 mL). The combined filtrates were concentrated, and the resulting crude product was washed with water (50 mL), ground with MeOH (15 mL), and filtered to give compound 296 as a yellow solid (3.5 g, 77.19% yield). ^¹H NMR (400 MHz, _CDCl₃ ) δ 11.98 (br s, 1H), 8.23–8.15 (m, 2H), 8.01 (dd, 1H), 7.81 (br d, 1H), 6.11 (d, 1H), 3.90 (s, _{3H); MS (EI) was C₁₁H₉NO₃ , measured} 203.9 (MH⁺).

4-(2-fluoro-4-nitrophenoxy)quinoline-7-carboxylic acid methyl ester (297): Compound 297 was prepared from compound 296 in a similar manner to the preparation of compound 285 from compound 284 in Example 97. ^¹H NMR ( ₄₀₀ MHz, _CDCl₃ ) δ 8.88–8.83 (m, 2H), 8.37 (d, 1H), 8.25–8.16 (m, 3H), 7.43 (t, 1H), 6.70 (d, 1H), 4.04 (s, _{3H )} ; MS (EI) was _{C₁₇H₁₁FN₂O₅} , measured 343.2 (MH⁺).

4-(4-amino-2-fluorophenoxy)quinoline-7-carboxylic acid methyl ester (298): Compound 298 was synthesized from compound 297 using a method similar to that used in Example 78 to convert compound 218 to compound 219. MS (EI) _{was C17H13FN2O3} , _and the measured value _was 312.9 (MH+).

Methyl 4-(2-fluoro-4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylamino)phenoxy)quinoline-7-carboxylic acid (299): Compound 1 (428.83 mg, 1.92 mmol, 3 equivalents) was suspended in anhydrous DCM (10 mL) at 25 °C with stirring. DMF (4.68 mg, 64.04 μmol, 4.93 μL, 0.1 equivalents) was added under nitrogen atmosphere, followed by (COCl) _₂ (290.00 mg, 2.28 mmol, 0.2 mL, 3.57 equivalents). The mixture was stirred at 25 °C for 30 minutes. Toluene (5.0 mL) was added, and the solvent was removed under reduced pressure. The resulting acyl chloride product was dissolved in anhydrous THF (1.0 mL). Under nitrogen atmosphere, a THF solution of the acyl chloride prepared above was added to a DMA (6 mL) solution of compound 298 (200 mg, 640.42 μmol, 1 equivalent). The reaction mixture was stirred at 25 °C for 0.5 h. The reaction mixture was poured into a saturated _NaHCO3 aqueous solution (100 mL) and extracted with DCM (3 x 50 mL). The combined organic extracts were washed with a saturated _NaHCO3 aqueous solution (15 mL), then with a saturated NaCl aqueous solution (15 mL ₎ , dried over anhydrous _Na2SO4 , and concentrated under vacuum to give compound 299 as a yellow solid (270 mg, 81.47% yield), which _was used in subsequent reactions without further purification. _{MS (EI) was C28H21F2N3O5 , and} the measured value was 518.1 ₍ MH+).

4-(2-fluoro-4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylamino)-phenoxy)quinoline-7-carboxylic acid (300): Compound 300 was prepared from compound 299 in a manner similar to that used in Example 97 for the preparation of compound 288 from compound 287. _MS (EI) was _{C27H19F2N3O5 ,} and the measured value _was 504.1 ₍ MH+).

1-N'-[3-fluoro-4-[7-(2-hydroxyethoxycarbamoyl)quinolin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (301): HATU (72.50 mg, 190.68 μmol, 1.2 equivalent) and DIEA (61.61 mg, 476.71 μmol, 83.03 μL, 3 equivalent) were added to a DMF (3 mL) solution of compound 300 (80 mg, 158.90 μmol, 1 equivalent), and the resulting mixture was stirred at 25 °C for 30 min. 2-Aminooxyethanol (14.70 mg, 190.68 μmol, 1.2 equivalent) was added, and the reaction mixture was stirred at 25 °C for an additional 2 h. The reaction mixture was poured into a saturated _NH₄Cl aqueous solution (50 mL) and extracted with DCM (3 x 30 mL). The combined organic extracts were concentrated under vacuum, and the resulting residue was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um, gradient: 43%-63% acetonitrile aqueous solution (0.05% _NH3H2O ), flow rate: _25mL /min) to give compound 301 as a white solid (46.8mg, 52.36% yield). ¹ H NMR (400MHz, DMSO-d ₆ ) δ12.09(br s,1H),10.41(br s,1H),10.01(br s,1H),8.78(d,1H),8.45-8.40(m,2H),8.01(dd,1H),7.92(dd,1H),7.68-7.60(m, 2H),7.56-7.51(m,1H),7.50-7.44(m,1H),7.20-7.11(m,2H),6.68(d,1H),4.80(br s,1H),4.00(t,2H),3.66(t,2H),1.51-1.43(m,4H); MS(EI) is C ₂₉ H ₂₄ F ₂ N ₄ O ₆ The measured value was 563.1 (MH+).

The following compounds were prepared from compound 295 using the same 6-step method as used to synthesize compound 301 in Example 99:

1-N'-[2,5-difluoro-4-[7-(2-hydroxyethoxycarbamoyl)quinoline-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (302): In step 2, 1,2-difluoro-4-nitrobenzene is replaced with 1,2,4-trifluoro-5-nitrobenzene. ^¹H NMR (400MHz, DMSO- _d₆ ) δ 12.13 (br s, ¹H), 11.17 (br s, ¹H), 9.78 (br s, ¹H), 8.81 (d, ¹H), 8.46 (s, ¹H), 8.40 (m, ¹H), 8.19 (m, ¹H), 8.04 (d, ¹H), 7.73 (m, ¹H), 7.61 (dd, 2H), 7.19 (t, 2H), 6.83 (d, 1H), 4.81 (m, 1H), 4.00 (m, 2H), 3.68 (m, 2H), 1.69 (m, 2H), 1.61 (m, _2H ); MS (EI) was _{C₂ ₹ H₂₃F₃N₄O₆} , _measured value 581.1 (MH⁺).

Biological Examples

Example A: Kinase Assay

Kinase activity and compound inhibition were studied using a ^33P -phosphoryltransferrradiation assay performed using the KinaseProfiler ^™ service from Eurofins Pharma Discovery Services UK Limited. Dose-response experiments were conducted using nine compound concentrations in 96-well microtiter plates. For each assay, all compounds were prepared to a 50x final assay concentration (50 μM) in 100% DMSO and then serially diluted semi-logarithmically to a final maximum concentration of 1 μM. The working stock solution of the compound was added as the first component of the reaction to the assay wells, followed by the remaining components as detailed in the assay protocol below. The positive control wells (100% kinase activity) contained all components of the reaction, including 2% DMSO (a solvent effect control), but except for the compound of interest. The blank wells contained all components of the reaction, as well as the reference inhibitor astrocytin. This reference compound was used to eliminate kinase activity and produce a baseline of 0% kinase activity. The IC ₅₀ value was calculated using S-shaped dose-response (variable slope) curve fitting with XLFit version 5.3 (ID Business Solutions) via nonlinear regression analysis.

Example B: Human AXL kinase assay

Human Axl (H473-A894 with Q764R residues, 161 nM) was incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 250 μM KKSRGDYMTMQIG (SEQ ID NO.43) , 10 mM magnesium acetate, and 10 μM [γ- ^33P -ATP]. The reaction was initiated by adding the Mg/ATP mixture. After incubation at room temperature for 40 min, the reaction was terminated by adding phosphoric acid to a concentration of 0.5%. 10 μL aliquots of the reaction were then spotted onto a P30 filter pad, washed four times with 0.425% phosphoric acid for 4 min each time, followed by one wash in methanol, then dried and scintillation counted. The incorporated ^γ-33P was measured using a Wallac Microbeta scintillation counter (Perkin Elmer).

Example C: Human KDR kinase assay

Human KDR (residue K790-V1356, 55 nM) was incubated with 8 mM MOPS at pH 7.0, 0.2 mM EDTA, 0.33 mg/mL myelin basic protein, 10 mM magnesium acetate, and 10 μM [γ- ^33P -ATP]. The reaction was initiated by adding a Mg/ATP mixture. After incubation at room temperature for 40 minutes, the reaction was terminated by adding phosphate to a concentration of 0.5%. 10 μL aliquots of the reaction were then spotted onto a P30 filter pad and washed four times with 0.425% phosphate for 4 minutes each time, followed by one wash with methanol, then dried and scintillation counted. The incorporated ^γ-33P was measured using a Wallac Microbeta scintillation counter (Perkin Elmer).

Example D: Human Merkinase Assay

Human Mer (0.7 nM with R557-E882 residues of H628Q and R794A) was incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 30 mM NaCl, 250 μM GGMEDIYFEFMGGKKK (SEQ ID NO.44) , 10 mM magnesium acetate, and 10 μM [γ- ^33P -ATP]. The reaction was initiated by adding the Mg/ATP mixture. After incubation at room temperature for 40 min, the reaction was terminated by adding phosphoric acid to a concentration of 0.5%. 10 μL aliquots of the reaction were then spotted onto a P30 filter pad, washed four times with 0.425% phosphoric acid for 4 min each time, followed by one wash in methanol, then dried and scintillation counted. The incorporated ^γ-33P was measured using a Wallac Microbeta scintillation counter (Perkin Elmer).

Example E: Human Met Kinase Assay

Human Met (with R974-S1390 residues of A1209G and V1290L, 3.4 nM) was incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 250 μM KKKGQEEEYVFIE (SEQ ID NO.45) , 1 mM sodium orthovanadate, 5 mM sodium 6-glycerophosphate, 10 mM magnesium acetate, and 10 μM [γ- ^33P -ATP]. The reaction was initiated by adding the Mg/ATP mixture. After incubation at room temperature for 40 min, the reaction was terminated by adding phosphoric acid to a concentration of 0.5%. 10 μL aliquots of the reaction were then spotted onto a P30 filter pad, washed four times with 0.425% phosphoric acid for 4 min each time, followed by one wash in methanol, then dried and scintillation counted. The incorporated ^33P was measured using a Wallac Microbeta scintillation counter (Perkin Elmer).

Activity data of the compounds in the examples obtained by kinase assays in Examples A, B, D and E are provided in Table 2 (A: IC ₅₀ ≤ 10 nM; B: 10 nM < IC 50 ≤ 100 nM; C: 100 nM < IC ₅₀ ≤ 1000 nM; D: IC ₅₀ > 1000 nM).

Table 2: Activity data of the compounds selected in this invention

Example F: AXL autophosphorylation ELISA in A-172 cells

A-172 glioblastoma cells (ATCC#CRL-1620) were seeded at 2.5 x ^10⁵ cells/well in 24-well plates (Greiner#662165) in DMEM (Thermo Fisher#11995-040) containing 10% FBS (Thermo Fisher#26140-079), 1% MEM NEAA (Thermo Fisher#11140-050), 1% GlutaMax (Thermo Fisher#35050-061), and 1% penicillin-streptomycin (Thermo Fisher#15140-122). A-172 cells were incubated at 37°C and 5% _CO₂ for 24 hours, followed by starvation in serum-free medium for 24 hours. The test compound was serially diluted in fresh serum-free medium to a final concentration of 0.3% DMSO (the medium) to generate an 8-point dose curve, added to the cells, and incubated for 1 hour. Cells were then stimulated with 1 μg/mL recombinant human Gas6 (R&D Systems #885-GSB-500) for 15 min, washed with cold PBS, and immediately lysed with 150 μL of cold 1X lysis buffer [20 mM Tris, 137 mM sodium chloride, 2 mM EDTA, 10% glycerol, 1% NP-40 substitute, 1 mM activated sodium orthovanadate, 1 mM PefaBloc SC (Sigma-Aldrich #11429868001), protease/phosphatase inhibitor tablets (Thermo Fisher #A32959)]. Lysates were collected and added at 100 μL/well to a human phosphate-AXL DuoSet IC ELISA (R&D Systems #DYC2228-2). Assays were performed according to the manufacturer's instructions, and the phosphate-AXL concentration in the samples was extrapolated using a human phosphate-AXL control (R&D Systems #841645) as a standard. Positive control wells (100% activity) contained DMSO-treated cell lysates stimulated by Gas6. Negative control wells (0% activity) contained cell lysates treated with a reference inhibitor of Gas6. _IC50 values were calculated using a 4-parameter logistic curve fitted in ActivityBase XE (IDBS) via nonlinear regression analysis.

Example G: Met autophosphorylation ELISA in PC-3 cells

PC-3 prostate cancer cells (ATCC#CRL-1435) were seeded at 4 x ^10⁴ cells/well in 24-well plates (Greiner#662165) in DMEM (Thermo Fisher#11995-040) containing 10% FBS (Thermo Fisher#26140-079), 1% MEM NEAA (Thermo Fisher#11140-050), 1% GlutaMax (Thermo Fisher#35050-061), and 1% penicillin-streptomycin (Thermo Fisher#15140-122). PC-3 cells were incubated at 37°C and 5% _CO₂ for 24 hours, followed by starvation in serum-free medium for 3 hours. The test compound was serially diluted in fresh serum-free medium to a final concentration of 0.3% DMSO (the medium) to generate an 8-point dose curve, added to the cells, and incubated for 1 hour. Cells were then stimulated with 100 ng/mL recombinant human HGF (R&D Systems #294-HG-250) for 10 min, washed with cold PBS, and immediately lysed with 130 μL of cold 1X lysis buffer [20 mM Tris, 137 mM sodium chloride, 2 mM EDTA, 10% glycerol, 1% NP-40 substitute, 1 mM activated sodium orthovanadate, 1 mM PefaBloc SC (Sigma-Aldrich #11429868001), protease/phosphatase inhibitor tablet (Thermo Fisher #A32959)]. The lysate was clarified by centrifugation and added at 100 μL/well to a PathScan phosphate-Met (panTyr) sandwich ELISA (Cell Signaling Technology #7333). Assays were performed according to the manufacturer's instructions. Positive control wells (100% activity) contained HGF-stimulated DMSO-treated cell lysates. Negative control wells (0% activity) contained cell lysates treated with a reference inhibitor of HGF stimulation. _IC50 values were calculated using a 4-parameter logistic curve fitted in ActivityBase XE (IDBS) via nonlinear regression analysis.

Example H: KDR autophosphorylation ELISA in HUVEC cells

Human umbilical vein endothelial cells or HUVECs (Lonza#C2519A) were seeded at 2 x ^10⁴ cells/well in 96-well plates (Corning#3904) on EGM-2 growth medium (Lonza#CC-3162) containing 1% penicillin-streptomycin (Thermo Fisher#15140-122). HUVEC cells were incubated at 37°C and 5% _CO₂ for 24 hours, followed by starvation for 24 hours in serum-free EGM-2 basal medium (Lonza#CC-3156) containing 1% penicillin-streptomycin. The test compound was serially diluted in fresh serum-free medium to a final concentration of 0.3% DMSO (mediator) to generate an 8-point dose curve, added to the cells, and incubated for 1 hour. Cells were then stimulated with 100 ng/mL recombinant human VEGF165 (R&D Systems #293-VE-500) for 5 min, washed with cold PBS, and immediately lysed with 130 μL of cold 1X lysis buffer [20 mM Tris, 137 mM sodium chloride, 2 mM EDTA, 10% glycerol, 1% NP-40 substitute, 1 mM activated sodium orthovanadate, 1 mM PefaBloc SC (Sigma-Aldrich #11429868001), protease/phosphatase inhibitor tablet (Thermo Fisher #A32959)]. Lysates were collected and added at 100 μL/well to a human phosphate-KDR DuoSet IC ELISA (R&D Systems #DYC1766-2). Assays were performed according to the manufacturer's instructions, using a human phosphate-KDR control (R&D Systems #841421) as a standard to extrapolate the sample phosphate-KDR concentration. Positive control wells (100% viability) contained VEGF165-stimulated DMSO-treated cell lysates. Negative control wells (0% viability) contained unstimulated cell lysates. _IC50 values were calculated using a 4-parameter logistic curve fitted in ActivityBaseXE (IDBS) via nonlinear regression analysis.

Example 1: Mer autophosphorylation ELISA in transiently transfected 293A cells

293A cells (Thermo Fisher #R70507) were seeded at 1.5 x ^10⁶ cells/well in DMEM (Thermo Fisher #11995-040) containing 10% FBS (Thermo Fisher #26140-079), 1% MEM NEAA (Thermo Fisher #11140-050), 1% GlutaMax (Thermo Fisher #35050-061), and 1% penicillin-streptomycin (Thermo Fisher #15140-122) on 100 mm dishes (Greiner #664169). The 293A cells were incubated at 37°C and 5% _CO₂ for 24 hours, and then transfected with 6 μg of MERTKDNA (Genecopoeia #EX-Z8208-M02) using TransIT LT1 transfection reagent (Mirus-Bio #MIR2305). After 24 hours of incubation, transfected 293A cells were seeded at 1 x ^10⁵ cells/well in DMEM growth medium on 96-well plates (Corning #3904) and incubated overnight. The test compound was serially diluted in fresh serum-free medium to a final concentration of 0.3% DMSO (mediator) to generate an 8-point dose curve, and added to the cells and incubated for 1 hour. The cells were then immediately lysed with 150 μL of cold 1X lysis buffer [20 mM Tris, 137 mM sodium chloride, 2 mM EDTA, 10% glycerol, 1% NP-40 substitute, 1 mM activated sodium orthovanadate, 1 mM PefaBloc SC (Sigma-Aldrich #11429868001), protease/phosphatase inhibitor tablets (Thermo Fisher #A32959)]. The lysate was clarified by centrifugation and added at 50 μL/well to a human phosphate-Mer DuoSet IC ELISA (R&D Systems#DYC2579-2). Assays were performed according to the manufacturer's instructions, and the human phosphate-Mer control (R&D Systems#841793) was used as a standard to extrapolate the phosphate-Mer concentration in the samples. Positive control wells (100% activity) contained DMSO-treated cell lysates. Negative control wells (0% activity) contained cell lysates treated with a reference inhibitor. _IC50 values were calculated using a 4-parameter logistic curve fitted in ActivityBase XE (IDBS) via nonlinear regression analysis.

As illustrated herein, the compounds of this disclosure exhibit IC ₅₀ values in the following ranges: A: IC ₅₀ ≤ 10 nM; B: 10 nM < IC ₅₀ ≤ 100 nM; C: 100 nM < IC 50 ≤ 300 nM; D: IC ₅₀ > 300 nM. "NT" indicates not tested _.

Activity data of the compounds in the examples, obtained using cell-based kinase assays from Examples F, G, H, and I, are provided in Table 3.

Table 3: Cell activity data of the selected compounds of this invention

Example J: Pharmacokinetic Study

The pharmacokinetic properties of the selected compounds were evaluated in male Sprague-Dawley rats.

Non-GLP studies were designed to investigate the pharmacokinetics of the selected compounds in plasma after intravenous or oral administration to male Sprague-Dawley rats.

Two groups of male Sprague-Dawley rats (n=3 per group) received a target dose level of 3 mg/kg of the compound via intravenous or oral (force-feed) administration. Any clinically relevant abnormalities were observed in the animals during administration and at each sample collection period.

Animals in the PO group were fasted overnight before dose administration. They were reintroduced to food 4 hours after blood sampling. Water was not inhibited.

Record the weight of each animal immediately before administration. Calculate the dose based on pretreated body weight (kg) (rounded to the nearest 0.001 mL), with an intravenous dose volume of 2.5 mL/kg and an oral dose volume of 5 mL/kg. Intravenous formulations are administered via a jugular vein cannula. Immediately after administration, flush the cannula with saline and tie the line. Oral doses are administered via a bulb-tip feeding needle. The volume of the administration syringe used is validated by a second person before administration, and this volume is used in conjunction with the results of concentration validation analysis to calculate the actual dose. Weigh the administration syringe immediately before and after administration to each animal for gravimetric analysis.

Serial blood samples (approximately 200 μL/sample) were collected from each animal at 0.083 hours (IV administration only), 0.25, 0.5, 1, 2, 4, 6 hours (PO administration only), 8, 24, 32, 48, and 72 hours after administration. Blood samples were collected into tubes containing _K₂EDTA via a non-drug-treated jugular vein cannula (JVC), which was flushed with approximately an equal volume of saline after each collection.

Blood samples were stored on wet ice until they were processed into plasma by centrifugation (3500 rpm, 5°C for 10 minutes) within 1 hour of collection. Plasma samples were then transferred to matrix tubes and stored at -80°C.

Compounds of interest in plasma and dosage form samples were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Pharmacokinetic parameters were estimated from individual animal plasma concentration-time data using actual doses, based on the dosage form, nominal sampling time (all collections were within acceptable limits for the target), and non-compartmental methods. Concentration-time data were analyzed using WinNonlin Phoenix version 6.3 (Pharsight) software to fit intravenous bolus (IV) plasma analysis models (201) or extravascular (PO) plasma analysis models (200). The single-dose pharmacokinetic parameters assessed appropriately included: _Cmax (observed peak or maximum concentration); _Tmax (time to observed peak concentration); T1 _/2 (terminal half-life); _Vz (volume of distribution based on terminal phase); _Vss (volume of distribution at steady state); AUC _INF (area under the concentration-time curve calculated from time zero to infinity); AUC _last (area under the concentration-time curve calculated from time zero to the last quantifiable concentration); _C0 (back-extended concentration at time zero); CL (systemic clearance); Vz/F (volume of distribution based on extravascular administration at terminal phase); CL/F (systemic clearance after extravascular administration); F% (bioavailability); and MRT _last (mean residence time).

The area under the plasma concentration-time curve (AUC) was estimated using the linear logarithmic trapezoidal rule. The area under the last observable concentration (C _{_last} ) over time (T _{_last} ) was reported as AUC _{_last}. The AUC extrapolated to infinity (AUC _INF _f) was estimated by adding the ratios of AUC _{_last} and C _{_last} /λ_{_z}, where λ_{_z} is the terminal rate constant. The apparent terminal half-life (T _{_1/2}) was calculated as ln(2)/λ_{_z} and determined using the slope of the log-linear terminal phase of the concentration-time curve, which was defined by at least three plasma concentration-time points. The half-life was reported if the correlation of the regression line measured by r-squared after rounding was ≥0.9. After IV administration, the volume of distribution (V_z) was calculated as dose/λ_{_z *} AUC _{INF_obs} , the clearance (CL) was calculated as dose/AUC _{INF_obs}, and the steady-state volume of distribution (V _{_ss} ) was estimated as MRT _INF * CL. The mean residence time (MRT) from the time of administration to the time to the final measurable concentration is calculated as _{AUMC_final} / _{AUC_final} . For Model 200, bioavailability (i.e., the fraction of the total dose reaching the systemic circulation) cannot be calculated. Therefore, the volume and clearance for this model are Vz/F or CL/F, respectively; where F is defined as bioavailability (i.e., the fraction of the total dose reaching the systemic circulation; (mean _{AUC_final - po} / mean _{AUC_final - invoice} ) * [dose _{invoice invoice} / dose invoice _{invoice invoice} ] * 100).

Pharmacokinetic data of some compounds of the present invention generated by the above procedure are provided in Table 4 below.

Table 4: Rat pharmacokinetic data of the compounds selected in this invention

Other implementation plans

For purposes of clarity and understanding, the foregoing disclosure has been described in considerable detail by way of illustration and example. The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications are possible within the spirit and scope of the invention. It will be apparent to those skilled in the art that changes and modifications can be made within the scope of the appended claims. Therefore, it should be understood that the above description is intended to be illustrative rather than restrictive.

Therefore, the scope of the invention should not be determined by reference to the above description, but rather by reference to the full scope of the appended claims and their authorized equivalents.

The present invention also relates to embodiments of the following:

Item 1. A compound of formula A:

Or its pharmaceutically acceptable salt, wherein:

(i) _R1 is selected from the group consisting of: ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, ( _C6 - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-10 heteroaryl, 4-10 heterocycloalkyl, -CN, -NHOH, -C(O) ^Ra , -C( ^O ) ^NRaRa , -C(O) ^NHORa , ^-C (O) ^ORa , -C(O) ^NRaS (O) _2Ra , -OC(O) ^NRaRa , C(＝ ^NRa ) ^Ra , -C(＝NOH) ^Ra , ^-C (＝NOH) ^NRa , -C(＝NCN) ^NRaRa , -C(＝ ^NRa ) ^{NRaRa , -S} (O) ^NRaRa , -S ⁽ _O ) ^2NRaC (O) ^Ra , -P(O)R ^a R ^a , -P(O)(OR ^a )(OR ^a ), -B(OH) ₂ , -B(OR ^a ) ₂ and S(O) ₂ NR ^a R ^a ; and

_R2 is selected from -H, halogenated, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, (C1- _C6 )haloalkyl, (C1 _- C6)haloalkoxy, ( _{C6 - C10} )aryl-( _C1 - _C4 )alkylene-, (C3 _{-C10 )} cycloalkyl-( _C1 - _C4 )alkylene-, (5-14-membered heteroaryl)-( _{C1 - C4} )alkylene-, (4-14-membered heterocycloalkyl)-(C1 _{- C4} )alkylene-, -CN, _-NO2 , ^-ORa , ^-SRa , ^-NHORa , -C(O) ^{Ra ,} -C(O) ^NRaRa , -C(O) ^NHORa , -C(O) ^ORa , -C(O)NR ^a S(O) ₂ R ^a , -OC(O)R ^a , -OC(O)NR ^a R ^a , -NHR ^a , -NR ^a R ^a , -NR ^a C(O)R ^a , -NR ^a C(=NR ^a )R ^a , -NR ^a C(O)OR ^a , -NR ^a C(O)NR ^a R ^a , -C(=NR ^a )R ^a , -C(=NOH)R ^a , -C(=NOH)NR ^a , -C(=NCN)NR ^a R ^a , -NR ^a C(=NCN)NR ^a R ^a , -C(=NR ^a )NR ^a R ^a , -NR ^a C(=NR ^a )NR ^a R ^a , -NR ^a S(O)R ^a , -NR ^a S(O) ₂ R ^a , -NR ^a S(O) ₂ NR ^a R ^a ,-S(O)R ^a -S(O)NR ^aRa , ^-S (O) _2Ra , -S(O) _2NR ^aC (O) ^Ra , -P(O) ^RaRa , -P(O)(OR ^a )( ^{OR a )} , -B ⁽ OH) ₂ , -B(OR ^a ) ₂ and -S(O ^{)2NR aRa} _, ^wherein _R1 or _R2 is a (C1 _{- C6} )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, ( _C6 - _C10 )aryl-( _C1 - _C4 )alkylene-, ( _C3 - _C10 )cycloalkyl-( _C1 - _C4 )alkylene-, (5-14-membered heteroaryl)-(C1 _{- C4} )alkylene- and (4-14-membered heterocycloalkyl)-(C1 _- C ₄ ) Alkylenes – each optionally substituted by 1, 2, 3, 4, or 5 independently selected ^Rb substituents, provided that when _R1 is a 5-7-membered heteroaryl or 5-7-membered heterocyclic alkyl and _R2 is a _C1-6 alkoxy, the 5-7-membered heteroaryl or 5-7-membered heterocyclic alkyl is not connected to the fused benzene ring of the quinoline moiety via a cyclic nitrogen atom; or

(ii) _R1 is selected from -H, halogroup, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, (C2- _C6 )ynyl, ( _C1 - _C6 )haloalkyl, (C1 _{- C6} )haloalkoxy, ( _{C6 - C10} )aryl, ( _C3 - _C10 )cycloalkyl, 5-14-membered heteroaryl, 4-14-membered heterocycloalkyl, ( _C6 - _C10 )aryl-( _{C1- C4} )alkylene-, ( _C3 - _C10 )cycloalkyl-( _{C1- C4} )alkylene-, (5-14-membered heteroaryl)-( _{C1- C4} )alkylene-, (4-14-membered heterocycloalkyl)-( _{C1- C4} )alkylene-, -CN, _-NO2 , ^-ORa , -SR ^a , -NHOR ^a , -C(O)R ^a , -C(O)NR ^a R ^a , -C(O)NHOR ^a , -C(O)OR ^a , -C(O)NR ^a S(O) ₂ R ^a , -OC(O)R ^a , -OC(O)NR ^a R ^a , -NHR ^a , -NR ^a R ^a , -NR ^a C(O)R ^a , -NR ^a C(=NR ^a )R ^a , -NR ^a C(O)OR ^a , -NR ^a C(O)NR ^a R ^a , -C(=NR ^a )R ^a , -C(=NOH)R ^a , -C(=NOH)NR ^a , -C(=NCN)NR ^a R ^a , -NR ^a C(=NCN)NR ^a R ^a , -C(=NR ^a )NR ^a R ^a , -NR ^a C(=NR ^a )NR ^a R ^a , -NR ^a S(O) ^Ra , ^-NRaS (O) _2Ra , -NRaS ₍ O) ^2NRaRa , ^-S (O ₎ ^Ra , -S(O) ^NRaRa , -S(O) ^2Ra , ^-S (O) _2NRaC (O)Ra, ^-P (O) ^RaRa , -P ⁽ O) ^{( ORa} )( ^ORa ), ^-B (OH) ² , -B( ^ORa ) _{2 and} -S(O) _2NRaRa , wherein _R1 or ^R2 is a ( _C1 - _C6 )alkyl, ( _C2 - _C6 ) ^alkenyl , ( _C2 - _C6 )ynyl, (C6 _{-C10 )} aryl, ( _C3 - _C10 )cycloalkyl, 5-14 heteroaryl, 4-14 heterocycloalkyl, ( _C6 - _{C10 ) ...} The aryl-(C1 _{- C4} )alkylene-, (C3- _C10 )cycloalkyl-( _C1 -C4)alkylene-, (5-14-membered heteroaryl)-( _{C1- C4} )alkylene-, and (4-14-membered heterocycloalkyl)-( _{C1 - C4} )alkylene- are each optionally substituted by 1, 2, 3 _, 4, or 5 independently selected ^Rb substituents; and

R ₂ is selected from the group consisting of: (C ₂ -C ₆ )alkenyl, (C ₂ -C ₆ )alkynyl, -CN, -NHOH, -C(O)R ^a , -C(O)NR ^a R ^a , -C(O)NHOR ^a , -C(O)OR ^a , -C(O)NR ^a S(O) ₂ R ^a , -OC(O)NR ^a R ^a , C(=NR ^a )R ^a , -C(=NOH)R ^a , -C(=NOH)NR ^a , -C(=NCN)NR ^a R ^a , -NR ^a C(=NCN)NR ^a R ^a , -C(=NR ^a )NR ^a R ^a , -S(O)NR ^a R ^a , -S(O) ₂ NR ^a C(O)R ^a , -P(O)R ^a R ^a , -P(O)(OR ^a )(OR ^a ), -B(OH) ₂ -B(OR ^a ) ₂ and S(O) ₂ NR ^{a Ra} , provided that when R ₁ is a 5-7 membered heteroaryl or a 5-7 membered heterocyclic alkyl and R ₂ is a C _1-6 alkoxy, then the 5-7 membered heteroaryl or 5-7 membered heterocyclic alkyl of R ₁ is not connected to the fused benzene ring of the quinoline moiety through a cyclic nitrogen atom.

(iii) _R1 and _R2 together with the atoms to which they are attached form a fused (C3 _{- C7} ) cycloalkyl ring or a fused 4- to 10-membered heterocyclic alkyl ring, wherein the fused (C3 _{- C7} ) cycloalkyl ring and the fused 4- to 10-membered heterocyclic alkyl ring are each optionally substituted by one, two or three independently selected ^Rb substituents, provided that the compound is not 1-[2-(4-fluorophenyl)-acetyl]-cyclopropanecarboxylic acid [3-fluoro-4-(7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxa-1-aza-cyclododecane[b]naphthalene-4-yloxy)-phenyl]-amide;

_R10 and _R11 are each independently selected from the group consisting of: -H, halogroup, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )haloalkyl, (C1 _{- C6} )haloalkoxy, ( _C6 - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-14-membered heteroaryl, 4-14-membered heterocycloalkyl, ( _C6 - _C10 )aryl-( _{C1- C4} )alkylene-, ( _C3 - _C10 )cycloalkyl-( _C1 - _C4 )alkylene-, (5-14-membered heteroaryl)-( _{C1- C4} )alkylene-, (4-14-membered heterocycloalkyl)-(C1 _{- C4} )alkylene-, -CN, _-NO2 , ^-ORa , ^-SRa , ^-NHORa , -C(O)R ^a , -C(O)NR ^a R ^a , -C(O)OR ^a , -C(O)NR ^a S(O) ₂ R ^a , -OC(O)R ^a , -OC(O)NR ^a R ^a , -NHR ^a , -NR ^a R ^a , -NR ^a C(O)R ^a , -NR ^a C(=NR ^a )R ^a , -NR ^a C(O)OR ^a , -NR ^a C(O)NR ^a R ^a , -C(=NR ^a )R ^a , -C(=NOH)R ^a , -C(=NOH)NR ^a , -C(=NCN)NR ^a R ^a , -NR ^a C(=NCN)NR ^a R ^a , -C(=NR ^a )NR ^a R ^a , -NR ^a C(=NR ^a )NR ^a R ^a , -NR ^a S(O)R ^a , -NR ^a S(O) ₂ R ^a -NR ^a S(O) ₂ NR ^{a Ra} , -S(O) ^Ra , -S(O)NR ^{a Ra} , -S(O) ₂ ^Ra , -S(O) ₂ NR ^a C(O) ^Ra , -P(O) ^{Ra Ra} , -P(O)(OR ^a )(OR ^a ), -B(OH) ₂ , -B(OR ^a ) ₂ and S(O) ₂ NR ^{a Ra} , wherein R ₁ or R ₂ is a (C ₁ -C ₆ ) alkyl, (C ₆ -C ₁₀ ) aryl, (C ₃ -C ₁₀ ) cycloalkyl, 5-14-membered heteroaryl, 4-14-membered heterocycloalkyl, (C _{6 -} C ₁₀ ) aryl-(C ₁ -C ₄ ) alkylene-, (C _3- C _{10 )} cycloalkyl ... The alkylene-, (5-14-membered heteroaryl)-(C1 _{- C4} )alkylene- and (4-14-membered heterocyclic alkyl)-(C1 _{- C4} )alkylene- are each optionally substituted by 1, 2, 3, 4 or 5 independently selected ^Rb substituents;

Each _R3 is independently selected from the group consisting of: -H, halogroup, -OH, -CN, optionally substituted ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy, ( _C1 - _C6 )haloalkoxy, _-NH2 , -NH( _C1 - _C6 )alkyl, -N( _C1 - _C6 )alkyl) ₂ and ( _C3 - _C6 )cycloalkyl, wherein the ( _C1 - _C6 )alkoxy, -NH( _C1 - _C6 )alkyl, -N( _C1 - _C6 )alkyl) ₂ and ( _C3 - _C6 )cycloalkyl of _R3 are each optionally substituted by 1, 2 or 3 independently selected ^Rg substituents;

Each R ₁₄ is independently selected from halogen, -OH, -NH ₂ , -CN, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )haloalkyl, (C ₁ -C ₆ )haloalkoxy, -COOH, -NH(C ₁ -C ₆ )alkyl, -N(C ₁ -C _6alkyl ) ₂ , phenyl, phenyl-(C _1- C ₂ )alkylene, (C _3- C ₆ )cycloalkyl, (C _3- C ₆ )cycloalkyl-(C _1- C ₄ )alkylene-, 4 to 6-membered heterocycloalkyl, (4 to 6-membered heterocycloalkyl)-(C _1- C ₄ )alkylene-, 5 to 6-membered heteroaryl, (5 to 6-membered heteroaryl)-(C _1- C ₄ )alkylene- and -OR ^e , wherein R _The ( _C1 - _C6 )alkyl, phenyl, phenyl-(C1- _C2 )alkylene, ( _C3- C6)cycloalkyl, ( _{C3- C6} )cycloalkyl-(C1 _{- C4} )alkylene, 4- to ₆ -membered heterocycloalkyl, ( _4- to 6-membered heterocycloalkyl)-(C1 _{- C4} )alkylene, 5- to 6-membered heteroaryl and (5- to 6-membered heteroaryl)-(C1 _{- C4} )alkylene are each optionally substituted by one, two or three independently selected ^Rg substituents.

R ₁₅ is H or C _1-6 alkyl;

Each _R4 is independently selected from the group consisting of: -H, halogroup, -OH, -COOR ^e , -CONR ^{e Re} , -CN, -NH ₂ , -NH ((C1 _{- C6} )alkyl), -N (( _{C1- C6} )alkyl) ₂ , (C1 _{- C6} )alkyl, (C1 _{- C6} )alkoxy, ( _{C1- C6} )haloalkyl, (C1 _{- C6} )haloalkoxy, -CONR ^{a Ra} , -NR ^a COR ^a , -NR ^a CONR ^{a Ra} , -SO ₂ ^Ra , -NR ^a S(O) ₂ ^Ra , -NR ^a S(O) ₂ NR ^{a Ra} , (C3 _{- C6} )cycloalkyl, 4- to 6-membered heterocyclic alkyl, phenyl, 5- or 6-membered heteroaryl, (C3 _{- C6} )cycloalkyl-( _C1- C ₄ ) alkylene-, (4 to 6-membered heterocyclic alkyl)-(C1 _{- C4} )alkylene-, phenyl-( _{C1- C2} )alkylene- and (5 or 6-membered heteroaryl)-(C1 _{- C4} )alkylene-, wherein the (C1 _{- C6} )alkyl, ( _{C3- C6} )cycloalkyl, ₄ to 6-membered heterocyclic alkyl, phenyl, 5 or 6-membered heteroaryl, (C3 _{- C6} )cycloalkyl-( _{C1- C4} )alkylene-, (4 to 6-membered heterocyclic alkyl)-( _{C1- C4} )alkylene-, phenyl-(C1 _{- C2} )alkylene- and (5 or 6-membered heteroaryl)-( _{C1- C4} )alkylene- are each optionally substituted by 1, 2 or 3 independently selected ^Rf substituents;

Each Ra ^is independently selected from the group consisting of: -H, -CN, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )haloalkyl, ( _C2 - _C6 )alkenyl, (C2-C6)ynyl, ( _C6 - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-14-membered heteroaryl, 4-14-membered heterocycloalkyl, ( _C6 - _C10 )aryl-( _C1 - _C4 )alkylene-, (C3 _{- C10} )cycloalkyl-( _C1 - _C4 )alkylene-, (5-14-membered heteroaryl)-( _{C1- C4} )alkylene-, and (4-14-membered heterocycloalkyl)-(C1 _{- C4} )alkylene-, wherein the ( _{C1- C6} )alkyl, ( _C1 - _C6 )alkylene-, and ( _C2 - _C6) alkylene- of ^Ra are... ( _C2 - _C6 )alkenyl, (C2-C6)ynyl, ( _C6 - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-14-membered heteroaryl, 4-14-membered heterocycloalkyl, ( _C6 - _C10 )aryl-( _C1 - _C4 )alkylene-, ( _{C3- C10} )cycloalkyl-( _C1 - _C4 )alkylene-, (5-14-membered heteroaryl)-( _{C1 - C4} )alkylene- and (4-14-membered heterocycloalkyl)-( _{C1 - C4} )alkylene- are each optionally substituted by 1, 2, 3, 4 or 5 independently selected ^Rd substituents;

Each ^Rb is independently selected from halogen, oxo, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, (C1-C6)haloalkyl, ( _{C1 -C6 )} haloalkoxy, ( _C6 - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-10-membered heteroaryl, _4-10 -membered heterocycloalkyl, ( _C6 - _C10 )aryl-( _{C1- C4} )alkylene-, ( _{C3- C10} )cycloalkyl-(C1 _{- C4} )alkylene-, (5-10-membered heteroaryl)-(C1 _{- C4} )alkylene-, (4-10-membered heterocycloalkyl)-(C1 _{- C4} )alkylene-, -CN, -OH, _-NH2 , -NO _2. -NHOR ^c , -OR ^c , -SR ^c , -C(O)R ^c , -C(O)NR ^c R ^c , -C(O)OR ^c , -C(O)NR ^c S(O) ₂ R ^c , -OC(O)R ^c , -OC(O)NR ^c R ^c , -C(=NOH)R ^c , -C(=NOH)NR ^c , -C(=NCN)NR ^c R ^c , -NR ^c C(=NCN)NR ^c R ^c , -C(=NR ^c )NR ^c R ^c , -NR ^c C(=NR ^c )NR ^c R ^c , -NHR ^c , -NR ^c R ^c , -NR ^c C(O)R ^c , -NR ^c C(=NR ^c )R ^c , -NR ^c C(O)OR ^c , -NR ^c C(O)NR ^c R ^c , -NR ^c S(O)R ^c ,-NR ^c S(O) _2Rc ^{, -NRcS} (O) _2NRcRc , ^-S (O) ^Rc , -S(O) ^NRcRc , -S(O) ^2Rc , -S(O) ^2NRcC (O) ^Rc , -Si(Rc) ₃ , -P(O) ^RcRc , ^-P ( ^O ₎ ( ^ORc )(ORc), ^-B (OH) ₂ , ^-B ( ^ORc ) ₂ and -S(O) _2NRcRc , wherein ^Rb is a ⁽ C1-C6) ^alkyl , (C1- ^C6 ) _haloalkyl , ( _C1 - _C6 )haloalkoxy, (C2-C6)alkenyl, ( _C2 - _C6 )alkynyl, ( _C6 - _C10 )aryl, (C3-C10)alkyl, ( _C3 - _C10 )alkyl, ( _C4 - _C5 )alkyl, ( _C6 - _C10 )alkyl, ( _C3- C10)alkyl, (C4 _... ( _C6 - _C10 ) aryl-(C1-C4) alkylene-, (C3-C10) cycloalkyl-( _{C1- C4} ) alkylene-, ( _5-10 ) heteroaryl-( _{C1 - C4} ) alkylene-, and ( _4-10 ) heterocycloalkyl-(C1 _{- C4 )} alkylene- are each optionally further substituted by one, two, or three independently selected ^Rd substituents;

Each ^Rc is independently selected from the group consisting of: -H, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )haloalkyl, ( _C2 - _C6 )alkenyl, ( _C2 -C6)ynyl, ( _C6 - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-10 heteroaryl, 4-10 heterocycloalkyl, ( _C6 - _C10 )aryl-(C1- _C4 )alkylene-, (C3 _{- C10} )cycloalkyl-( _C1 - _C4 )alkylene-, (5-10 heteroaryl)-( _{C1- C4 ) alkylene-} , and (4-10 heterocycloalkyl)-(C1 _{- C4} )alkylene-, wherein ^the ( _C1 - _C6 )alkyl, ( _C2 - _C6)... Alkenyl, ( _C2 - _C6 ) ynyl, (C6- _C10 ) aryl, ( _C3 -C10) cycloalkyl, 5-10 heteroaryl, 4-10 heterocycloalkyl, ( _C6 - _C10 ) aryl-( _C1 - _C4 ) alkylene-, ( _C3 - _C10 ) cycloalkyl-( _C1 - _C4 ) alkylene-, (5-10 heteroaryl)-(C1 _{- C4} ) alkylene- and (4-10 heterocycloalkyl)-( _{C1- C4 )} alkylene- are each optionally substituted by 1, 2, 3 _, 4 or 5 independently selected ^Rf substituents;

Each R d is independently selected from (C <sub>1- C 6  )alkyl, (C <sub>1- C  6 )haloalkyl, haloyl, (C<sub>6-C10)aryl, 5-10 heteroaryl, (C <sub>3- C 10 )cycloalkyl, 4-10 heterocyclic alkyl, (C <sub>6- C 10 )aryl-(C <sub>1- C 4 )alkylene-, (C <sub>3- C 10 )cycloalkyl-(C <sub>1- C 4 )alkylene-, (5-10 heteroaryl)-(C <sub>1- C 4 )alkylene-, (4-10 heterocyclic alkyl)-(C <sub>1- C4 )alkylene-, -CN, -NH 2 , -NHOR e , -OR e , -SRe, -C(O)R  e , -C(O)NReRe , -C(O)OR e -OC(O)R e , -OC(O)NR eR e , -NHR e , -NR eR e , -NR e C(O)R e , -NR e C(O)NR eR e , -NR e C(O)OR e , -C(＝NR e )NR eR e , -NR e C(＝NR e )NR eR e , -NR e C(＝NOH)NR eR e, -NR e C(＝NCN)NR eR e , -S (O)R e , -S(O)NR eR e , -S(O) 2 Re, -NR e S (O) 2 Re , -NR e S(O) 2 NR e Re and -S (O) 2 NR e Re , wherein R d is a (C 1- C 6 ) alkyl , (C 1 - C 6 )haloalkyl, (C 6- C 10 )alkyl, (C 6- C 10 )alkyl, ... )aryl, 5-10 heteroaryl, ( C3- C10 )cycloalkyl, 4-10 heterocycloalkyl, (C6 - C10 )aryl-(C1-C4)alkylene-, (C3 - C10 )cycloalkyl-( C1- C4 )alkylene-, ( 5-10 heteroaryl)-(C1- C4 )alkylene- and (4-10 heterocycloalkyl)-( C1- C4 ) alkylene- are each optionally substituted by 1, 2 or 3 independently selected R f substituents;

Each ^Re is independently selected from the group consisting of: -H, (C1 _{- C6} )alkyl, ( _{C3- C6} )cycloalkyl-, (C3- _C6 )cycloalkyl-(C1 _- C4)alkylene-, (C6 _{- C10} )aryl, ( _{C6- C10} )aryl-(C1 _- C4)alkylene-, 5 or ₆ -membered heteroaryl, (5 or 6-membered heteroaryl)-(C1 _{- C4} )alkylene-, 4-7-membered heterocycloalkyl, ( _4-7 -membered heterocycloalkyl)-(C1-C4)alkylene-, ( _{C1- C6} )haloalkyl, (C1 _{- C6} )haloalkoxy, (C2-C4)alkenyl and (C2 _{- C4} )ynyl, wherein the (C1- _C4 )alkyl, (C1 _{- C6} )haloalkoxy, (C2 _- C4)alkenyl and (C2 _{- C4} )ynyl of ^Re are... _{3- C6} )cycloalkyl, ( _{C6- C10} )aryl, 5- or 6-membered heteroaryl, 4- or 7-membered heterocycloalkyl, ( _C6- or ₁₀ )aryl-(C1- or ₄ -membered heteroaryl)-( _{C1- or} 4-membered heterocycloalkyl)-(C1- or ₄ -membered heterocycloalkyl), ( _C2- or 4-membered heterocycloalkyl)-( _{C1- or 4-} membered heterocycloalkyl), (C2- _{or 4-} membered alkenyl) and ( _{C2- or 4-} membered ynyl are each optionally substituted by 1, 2 or 3 ^Rf substituents.

Or any two ^Ra substituents together with the nitrogen atom to which they are attached form a 4, 5, 6, 7, 8, 9 or 10-membered heterocyclic alkyl group, each heterocyclic alkyl group optionally being substituted by 1, 2 or 3 independently selected R ^f substituents;

Alternatively, any two ^Rc substituents together with the nitrogen atom to which they are attached can form a 4, 5, 6, 7, 8, 9, or 10-membered heterocyclic alkyl group, each heterocyclic alkyl group optionally being substituted by one, two, or three independently selected ^Rf substituents.

Or any two ^Re substituents together with the nitrogen atom to which they are attached form a 4, 5, 6, 7, 8, 9 or 10-membered heterocyclic alkyl group, each heterocyclic alkyl group optionally being substituted by 1, 2 or 3 independently selected R ^f substituents;

Each ^Rf is independently selected from halogen, -OH, -CN, -COOH, _-NH2 , -NH-(C1 _{- C6} )alkyl, -N((C1 _{- C6} )alkyl) ₂ , (C1 _{- C6} )alkyl, (C1- _C6 )alkoxy, ( _C1- C6)alkylthio, (C1 _{- C6} )haloalkyl, (C1 _{- C6} )haloalkoxy, phenyl, 5-6-membered heteroaryl, 4-6-membered heterocyclic alkyl, and ( _{C3 - C6} )cycloalkyl, wherein the (C1 _{- C6} )alkyl, phenyl, (C3 _{- C6} )cycloalkyl, 4-6-membered heterocyclic alkyl, and 5-6-membered heteroaryl of ^Rf are each optionally selected by 1, 2, or 3 from halogen, -OH, -CN, -COOH, _-NH2 , (C1 _- C6 ₎ alkyl, -NH- _{( ...} Substituents of alkyl, (C1 _{- C4} )alkoxy, (C1 _{- C4} )haloalkyl, ( _{C1- C4} )haloalkoxy, phenyl, (C3 _{- C10} )cycloalkyl, 5-6-membered heteroaryl and 4-6-membered heterocyclic alkyl groups;

Each R ^g is independently selected from halogenated, -OH, -CN, -COOH, -COO-( _{C1- C4} ) _alkyl , -NH2, -NH-(C1 _{- C6} )alkyl, -N((C1 _{- C6} )alkyl) ₂ , ( _{C1- C6} )alkyl, (C1 _{- C6} )alkoxy, (C1- _C6 )alkylthio, ( _{C1- C6 )} haloalkyl, (C1 _{- C6} )haloalkoxy, phenyl, 5-6-membered heteroaryl, 4-6-membered heterocyclic alkyl and (C3 _{- C6} )cycloalkyl;

Y is selected from -O-, -S-, -SO-, _-SO₂- , -NH-, and -N((C₁ _{- C₆} )alkyl)-;

The cyclic nitrogen atom on the quinoline moiety in Formula A may optionally be oxidized;

The subscript n is an integer of 1, 2, 3 or 4;

The subscript m is an integer of 1, 2, 3, 4, or 5; and

The subscript p is an integer of 0, 1, 2, 3 or 4.

Item 2. The compound as described in Item 1, having formula A-1:

Item 3. The compound as described in Item 1, having formula A-2:

Item 4. The compound as described in Item 1, having formula A-3:

^Ra1 is H or (C1 _{- C6} ) alkyl.

Item 5. The compound as described in Item 1, having formula A-4:

The ring A is a 5- to 14-membered heteroaryl group; and the subscript r is 1, 2, 3 or 4.

Item 6. The compound as described in Item 1, wherein:

_R1 is selected from the group consisting of: ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, ( _C6 - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, -CN, -NHOH, -C(O) ^Ra , -C(O)NRaRa, -C(O) ^NHORa , -C ⁽ O) ^ORa , -C(O ^{) NRaS} (O) _2Ra , -OC(O) ^NRaRa , C(＝ ^NRa ) ^Ra , ^-C (＝NOH) ^Ra , ^-C (＝NOH) ^NRa , -C(＝NCN) ^NRaRa , ^-NRaC (＝NCN) ^NRaRa , -C ⁽ ＝ ^NRa ) ^NRaRa , -S ⁽ O ^{) NRaRa} , ^-S (O) _2NR ^a C(O)R ^a , -P(O)R ^a R ^a , -P(O)(OR ^a )(OR ^a ), -B(OH) ₂ , -B(OR ^a ) ₂ and S(O) ₂ NR ^a R ^a ; and

_R2 is selected from -H, halogenated, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, (C1- _C6 )haloalkyl, (C1 _- C6)haloalkoxy, (C6 _{- C10} )aryl-( _C1 - _C4 )alkylene-, (C3 _{-C10 )} cycloalkyl-( _{C1 - C4} )alkylene-, (5-14-membered heteroaryl)-( _{C1 - C4} )alkylene-, (4-14-membered heterocycloalkyl)-(C1 _{- C4} )alkylene-, -CN, _-NO2 , ^-ORa , ^-SRa , ^-NHORa , -C(O) ^{Ra ,} -C(O) ^NRaRa , -C(O) ^NHORa , -C(O) ^ORa , -C(O)NR ^a S(O) ₂ R ^a , -OC(O)R ^a , -OC(O)NR ^a R ^a , -NHR ^a , -NR ^a R ^a , -NR ^a C(O)R ^a , -NR ^a C(=NR ^a )R ^a , -NR ^a C(O)OR ^a , -NR ^a C(O)NR ^a R ^a , -C(=NR ^a )R ^a , -C(=NOH)R ^a , -C(=NOH)NR ^a , -C(=NCN)NR ^a R ^a , -NR ^a C(=NCN)NR ^a R ^a , -C(=NR ^a )NR ^a R ^a , -NR ^a C(=NR ^a )NR ^a R ^a , -NR ^a S(O)R ^a , -NR ^a S(O) ₂ R ^a , -NR ^a S(O) ₂ NR ^a R ^a ,-S(O)R ^a -S(O)NR ^aRa , ^-S (O) _2Ra , -S(O) _2NR ^aC (O) ^Ra , -P(O) ^RaRa , -P(O)(OR ^a )( ^{OR a )} , -B ⁽ OH) ₂ , -B(OR ^a ) ₂ and -S(O ^{)2NR aRa} _, ^wherein _R1 or _R2 is a ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, ( _C6 - _C10 )aryl-( _C1 - _C4 )alkylene-, ( _C3 - _C10 )cycloalkyl-( _C1 - _C4 )alkylene-, (5-14-membered heteroaryl)-(C1 _{- C4} )alkylene- and (4-14-membered heterocycloalkyl)-(C1 _- C ₄ ) Alkylenes are each optionally substituted by 1, 2, 3, 4 or 5 independently selected ^Rb substituents, provided that when _R1 is a 5-7-membered heteroaryl or 5-7-membered heterocyclic alkyl and _R2 is a _C1-6 alkoxy, the 5-7-membered heteroaryl or 5-7-membered heterocyclic alkyl of _R1 is not connected to the fused benzene ring of the quinoline moiety through a cyclic nitrogen atom.

Item 7. The compound as described in Item 1, wherein:

_R1 is selected from -H, halogroup, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, (C1-C6)haloalkyl, (C1 _{- C6} )haloalkoxy, ( _{C6 - C10} )aryl, ( _C3 - _{C10 )} cycloalkyl, 5-14-membered heteroaryl, 4-14-membered heterocycloalkyl, ( _C6 - _C10 )aryl-( _{C1- C4} )alkylene-, ( _C3 - _C10 )cycloalkyl-(C1- _C4 )alkylene-, (5-14-membered heteroaryl)-( _{C1- C4 )} alkylene-, (4-14-membered heterocycloalkyl)-(C1 _{- C4} )alkylene-, -CN, _-NO2 , ^-ORa , -SR ^a , -NHOR ^a , -C(O)R ^a , -C(O)NR ^a R ^a , -C(O)NHOR ^a , -C(O)OR ^a , -C(O)NR ^a S(O) ₂ R ^a , -OC(O)R ^a , -OC(O)NR ^a R ^a , -NHR ^a , -NR ^a R ^a , -NR ^a C(O)R ^a , -NR ^a C(=NR ^a )R ^a , -NR ^a C(O)OR ^a , -NR ^a C(O)NR ^a R ^a , -C(=NR ^a )R ^a , -C(=NOH)R ^a , -C(=NOH)NR ^a , -C(=NCN)NR ^a R ^a , -NR ^a C(=NCN)NR ^a R ^a , -C(=NR ^a )NR ^a R ^a , -NR ^a C(=NR ^a )NR ^a R ^a ,-NR ^a S(O) ^Ra , ^-NRaS (O) _2Ra , -NRaS ₍ O) ^2NRaRa , ^-S (O ₎ ^Ra , -S(O) ^NRaRa , -S(O) ^2Ra , ^-S (O) _2NRaC (O)Ra, ^-P (O) ^RaRa , -P ⁽ O) ^{( ORa} )( ^ORa ), ^-B (OH) ² , -B( ^ORa ) _{2 and} -S(O) _2NRaRa , wherein _R1 or ^R2 is a ( _C1 - _C6 )alkyl, ( _C2 - _C6 ) ^alkenyl , ( _C2 - _C6 )ynyl, (C6 _{-C10 )} aryl, ( _C3 - _C10 )cycloalkyl, 5-14 heteroaryl, 4-14 heterocycloalkyl, ( _C6 - _{C10 ) ...} The aryl-(C1 _{- C4} )alkylene-, (C3- _C10 )cycloalkyl-( _C1 -C4)alkylene-, (5-14-membered heteroaryl)-( _{C1- C4} )alkylene-, and (4-14-membered heterocycloalkyl)-( _{C1 - C4} )alkylene- are each optionally substituted by 1, 2, 3 _, 4, or 5 independently selected ^Rb substituents; and

R ₂ is selected from the group consisting of: (C ₂ -C ₆ )alkenyl, (C ₂ -C ₆ )alkynyl, -CN, -NHOH, -C(O)R ^a , -C(O)NR ^a R ^a , -C(O)NHOR ^a , -C(O)OR ^a , -C(O)NR ^a S(O) ₂ R ^a , -OC(O)NR ^a R ^a , C(=NR ^a )R ^a , -C(=NOH)R ^a , -C(=NOH)NR ^a , -C(=NCN)NR ^a R ^a , -NR ^a C(=NCN)NR ^a R ^a , -C(=NR ^a )NR ^a R ^a , -S(O)NR ^a R ^a , -S(O) ₂ NR ^a C(O)R ^a , -P(O)R ^a R ^a , -P(O)(OR ^a )(OR ^a ), -B(OH) ₂ -B(OR ^a ) ₂ and S(O) ₂ NR ^{a Ra} , provided that when R ₁ is a 5-7 membered heteroaryl or a 5-7 membered heterocyclic alkyl and R ₂ is a C _1-6 alkoxy, the 5-7 membered heteroaryl or 5-7 membered heterocyclic alkyl of R ₁ is not connected to the fused benzene ring of the quinoline moiety through a cyclic nitrogen atom.

Item 8. The compound as described in Item 1, wherein:

_R1 and _R2, together with the atoms to which they are attached, form a fused (C3 _{- C7} ) cycloalkyl ring or a fused 4- to 10-membered heterocyclic alkyl ring, wherein the fused (C3 _{- C7} ) cycloalkyl ring and the fused 4- to 10-membered heterocyclic alkyl ring are each optionally substituted by one, two, or three independently selected ^Rb substituents, provided that the compound is not 1-[2-(4-fluorophenyl)-acetyl]-cyclopropanecarboxylic acid [3-fluoro-4-(7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxa-1-aza-cyclododecane[b]naphthalene-4-yloxy)-phenyl]-amide.

Item 9. The compound as described in Items 1, 6, 7 or 8, wherein:

R ₁₅ is H or CH ₃ .

Item 10. A compound as described in Item 1 or 9, wherein _R1 and _R2, together with the atoms to which they are attached, form a fused (C3 _{- C7} ) cycloalkyl ring or a fused 4- to 10-membered heterocyclic alkyl ring, wherein each of the fused (C3 _{- C7} ) cycloalkyl ring or the fused 4- to 10-membered heterocyclic alkyl ring is optionally substituted by one, two, or three independently selected ^Rb substituents, provided that the compound is not a compound having the following formula:

Wherein ring E is a fused 4- to 10-membered heterocyclic alkyl group.

Item 11. The compound as described in any one of items 2, 4, 7 and 9, wherein _R1 is -H.

Item 12. The compound as described in any one of items 1, 3, 5 and 6, wherein _R2 is -H.

Item 13. The compound of any one of items 1, 2, 4, 5 and 7-9, wherein _R1 is selected from the group consisting of: -H, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, -C(=NO-(C1 _{- C6} )alkyl) ^Ra , -CN, -C(O) ^{ORa ,} -C(O) ^NRaRa , -C(O) ^NHORa , -S(O ⁾ _2NRaRa , ^phenyl , 5- to 6-membered heteroaryl, (C3 _{- C6} )cycloalkyl and 4- to 6-membered heterocyclic alkyl.

Item 14. The compound as described in Item 13, wherein _R1 is -H, ^-RaNHC (O)-, ^RaOC (O)-, (C1 _{- C6} )alkyl, (C1 _{- C6} )alkoxy, or C(=NO- _CH3 ) ^Ra ; and

R ₂ is selected from 2-methoxyethylamino, methylamino, 3-morpholinopropoxy, 2-methoxyethoxy, 2-hydroxyethoxy, propoxy, 2-hydroxypropoxy, methoxycarbonyl, carboxyl, carbamoyl, methylcarbamoyl, (2-hydroxyethoxy)carbamoyl, (2,2-dihydroxyethoxy)carbamoyl, (oxetane-3-yloxy)carbamoyl, methoxycarbamoyl, 2-trimethylsilylethynyl, ethynyl, aminosulfonyl, acetyl, and -C(＝NOCH ₃ )CH ₃ .

Item 15. The compound of any one of items 1, 3, 5 and 6, wherein _R2 is selected from the group consisting of: -H, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, -C(=NO-(C1 _{- C6} )alkyl) ^Ra , -CN, -C(O) ^ORa , ^-C (O) ^NRaRa , -C(O) ^NHORa and -S( ^O ) _2NRaRa ^.

Item 16. The compound as described in Item 15, wherein _R1 is selected from 2-methoxyethylamino, aziridine-1-yl, methylamino, 3-morpholinopropoxy, 2-methoxyethoxy, 2-hydroxyethoxy, propoxy, 2-hydroxypropoxy, methoxycarbonyl, carboxyl, carbamoyl, methylcarbamoyl, 2-oxazolyl, pyrazol-3-yl, pyrazol-4-yl, 4-isooxazolyl, 3,5-dimethylisooxazol-4-yl, 1-methyl-pyrazol-4-yl, 2-methyl-pyrazol-3-yl, 2-ethyl-pyrazol-3-yl, 2-(2-hydroxyethyl)-pyrazol-3-yl, 2-(2,2,2-trifluoroethyl)-pyrazol-3-yl, 2-(2-fluoroethyl) -pyrazol-3-yl, 2-(2,2-difluoroethyl)-pyrazol-3-yl, 2-trifluoromethyl-pyrazol-3-yl, 2-difluoromethyl-pyrazol-3-yl, 1-methyl-imidazol-4-yl, 1-methyl-imidazol-2-yl, 1H-imidazol-2-yl, (2-hydroxyethoxy)carbamoyl, (2,2-dihydroxyethoxy)carbamoyl, (oxetane-3-yloxy)carbamoyl, methoxycarbamoyl, 2-trimethylsilylethynyl, ethynyl, 1,3,4-oxadiazol-3-yl, 1H-1,2,3-triazol-5-yl, aminosulfonyl, acetyl, and -C (＝NOCH) ₃ ) CH ₃ , and R ₂ is -H, ^-Ra NHC(O)-, ^-Ra OC(O)-, -(C _1- C ₆ )alkyl, (C _1- C ₆ )alkoxy or -C(＝NO-CH ₃ ) ^Ra .

Item 17. The compound as described in Item 5, wherein the subscript r is 1 or 2.

Item 18. The compound of any one of items 1-17, wherein R ₁₀ and R ₁₁ are each H.

Item 19. The compound as described in any one of items 1-18, wherein the subscript n is 1.

Item 20. The compound as described in any one of items 1-19, wherein the subscript m is 1.

Item 21. The compound as described in any one of items 1-20, wherein the subscript p is 1.

Item 22. The compound of any one of items 1-21, having formula B:

Or its pharmaceutically acceptable salt, wherein:

(i)R ₂ is:

-H or a group selected from the following groups:

( _C1 - _C6 )alkyl, halogroup, _-NO2 , _X1Ra ^, wherein _X1 is –O-, -S-, -SO-, -SO2-, -SO2NH-, -SO2NRa-, _{-NH- and} -N- _{( C1} - _C6 )alkyl-, wherein ( _C1 - _C6 )alkyl is optionally substituted; ^and

_R1 can be selected from the following groups:

( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, (C6- _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-10 heteroaryl, and 4-10 heterocycloalkyl, wherein the ( _{C2 - C6} )alkenyl, ( _C2 - _C6 )ynyl, ( _C6 - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-10 heteroaryl, and 4-10 heterocycloalkyl are each optionally substituted independently by the following:

-CN, -P(O)R ^a R ^a ,P(O)(OR ^a ) ₂ , B(OH) ₂ , B(OR ^a ) ₂ ,

X ₂ ^Ra , where X ₂ is -NHO-, -NH-S(O)-, -N-(C ₁ -C ₆ )alkyl-S(O)-, -NH-S(O) _2- , -N-(C ₁ -C ₆ )alkyl-S(O) ₂ ^Ra- , -NH-S(O)-NH-, -N-(C ₁ -C ₆ )alkyl-S(O)NH-, -NH-S(O) ₂ NH-, -N-(C ₁ -C ₆ )alkyl-S(O) ₂ NH-, -S(O) ₂ NHC(O)-; and

Where: represents the connection point, where:

_Y1 is absent, or is -NH-, -N-( _C1 - _C6 )alkyl-, or -O-;

_Y2 is absent, or is -O-, -NH-, -NHO-, -N-( _C1 - _C6 )alkyl-, _-N2H2- , -NH- _S (O)-, -NH-S(O) _2- ; or

_Y2 represents the optional substitution, where A is a 3-, 4-, 5-, 6-, or 7-membered ring; and

^Z1 is O, NH, N-( _C1 - _C6 )alkyl, NOH, NO-( _C1 - _C6 )alkyl, or NCN; or

(ii)

_R1 can be selected from the following groups:

( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, (C6- _C10 )aryl, ( _{C3 - C10} )cycloalkyl, 5-10 heteroaryl, and 4-10 heterocycloalkyl, wherein the ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, ( _C6 - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-14 heteroaryl, and 4-14 heterocycloalkyl are each optionally substituted independently by the following:

P(O)R ^a R ^a , P(O)(OR ^a )(OR ^a ) , B(OH) ₂ , B(OR ^a ) ₂ , CN,

X ₂ ^Ra , where X ₂ is -NHO-, -NH-S(O)-, -N-(C ₁ -C ₆ )alkyl-S(O)-, -NH-S(O) _2- , -N-(C ₁ -C ₆ )alkyl-S(O) ₂ ^Ra- , -NH-S(O)-NH-, -N-(C ₁ -C ₆ )alkyl-S(O)NH-, -NH-S(O) ₂ NH-, -N-(C ₁ -C ₆ )alkyl-S(O) ₂ NH-, -S(O)-, -S(O) _2- , -S(O) ₂ NHC(O); and

in:

_Y1 is absent, or is -NH-, -N-( _C1 - _C6 )alkyl-, or -O-;

_Y2 is absent, or is -O-, -NH-, -NHO-, -N-( _C1 - _C6 )alkyl-, _-N2H2- , -NH-S(O ₎ -, or -NH-S(O) ₂ ; or

_Y2 represents the optional substitution, where A is a 3-, 4-, 5-, 6-, or 7-membered ring; and

^Z1 is -O-, -NH-, -N-( _C1 - _C6 )alkyl-, -NOH-, -NO-( _C1 - _C6 )alkyl-, or –NCN-; or

_R2 can be selected from the following groups:

H, halogenated, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, (C2- _C6 )ynyl, ( _C1 - _C6 )haloalkyl, (C1 _- C6)haloalkoxy, ( _C6 - _C10 )aryl-(C1 _{- C4} )alkylene-, (C3 _{- C10} )cycloalkyl-( _{C1 - C4} )alkylene-, ( _5-14 -membered heteroaryl)-(C1 _{- C4} )alkylene-, and (4-14-membered heterocycloalkyl)-(C1 _{- C4} )alkylene-, wherein ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, ( _C1 - _C6 )haloalkyl, (C1 _{- C6} )haloalkoxy, ( _C6 - _C10) The aryl-(C1 _{- C4} )alkylene-, (C3- _C10 )cycloalkyl-( _C1 -C4)alkylene-, (5-14-membered heteroaryl)-( _{C1- C4} )alkylene-, and (4-14-membered heterocycloalkyl)-( _{C1- C4 ) alkylene-} are each independently and optionally substituted with the following:

CN, NO ₂ , P(O)R ^a R ^a , P(O)(OR ^a )(OR ^a ), B(OH) ₂ , B(OR ^a ) ₂ ,

_X1 ^Ra substitution, wherein _X1 is –O-, -S-, -NH- or -N-( _C1 - _C6 )-, -NHO-, -NH-S(O)-, -N-( _C1 - _C6 )alkyl-S(O)-, -NH-S(O) _2- , -N-( _C1 - _C6 )alkyl-S(O) _2- , -NH-S(O)-NH-, -N-( _C1 - _C6 )alkyl-S(O)NH-, -NH-S(O) _2NH- , -N-( _C1 - _C6 )alkyl-S(O) _2NH- , -S(O) _2NHC (O)-, -NH-S(O) ^Ra- , -N-( _C1 - _C6 )alkyl-S(O) ^Ra- , -NH-S(O) _2Ra- or -N-( ^C1 -C6)-. ₁ - _C6 )alkyl-S ^(O)2Ra- _;

in

_Y1 is absent or is -NH-, -N-( _C1 - _C6 )alkyl- or -O-;

_Y2 is absent or is -O-, -NH-, -NHO-, -N-( _C1 - _C6 )alkyl-, _-N2H2- , -NH-S(O)- or -NH-S(O) _2- ; _or

_Y2 is an optional substitution in which ring A is a 3-, 4-, 5-, 6-, or 7-membered ring, and where represents the connection point; and

^Z1 is O, NH, N-( _C1 - _C6 )alkyl, NOH, NO-( _C1 - _C6 )alkyl, or NCN; or

(iii)

_R1 and _R2, together with the atoms they are attached to, form a 4-10 membered heterocyclic alkyl ring optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of: halogroup, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )haloalkyl, ( _C1 - _C6 )haloalkoxy, -CN, -OH, _-NH2 , provided that the compound is not 1-[2-(4-fluoro-phenyl)-acetyl]-cyclopropanecarboxylic acid [3-fluoro-4-(7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxa-1-aza-cyclododecano[b]naphthalene-4-yloxy)-phenyl]-amide;

And _R10 , _R11 , _R3 , _R14 , _R4 , n, p, m and Y are defined as follows:

Each _R3 is independently selected from the group consisting of: -H, halogroup, -OH, -CN, optionally substituted ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy, ( _C1 - _C6 )haloalkoxy, _-NH2 , -NH( _C1 - _C6 )alkyl, -N( _C1 - _C6 )alkyl) ₂ and ( _C3 - _C6 )cycloalkyl, wherein ( _C1 - _C6 )alkoxy, -NH( _C1 - _C6 )alkyl, -N( _C1 - _C6 )alkyl) ₂ and ( _C3 - _C6 )cycloalkyl are each optionally substituted;

Each of _R10 and _R11 is independently selected from the group consisting of: -H, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy, and ( _C1 - _C6 )haloalkoxy.

Each R ₁₄ is independently selected from -halogroup, -OH, _-NH2 , -CN, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy, (C1- _C6 )haloalkyl, ( _C1 - _C6 )haloalkoxy, -COOH, -NH( _C1 - _C6 )alkyl, -N( _C1 - _C6alkyl ) ₂ , phenyl, phenyl-( _{C1 - C2} )alkylene, ( _{C3- C6} )cycloalkyl, (C3- _C6 )cycloalkyl-( _{C1- C4 )} alkylene-, 4- to 6-membered heterocycloalkyl, (4- to 6-membered heterocycloalkyl)-( _{C1- C4} )alkylene-, 5- to 6-membered heteroaryl, (5- to 6-membered heteroaryl)-(C1 _{- C4} )alkylene- and ^-ORe , wherein R _The ( _C1 - _C6 )alkyl, phenyl, phenyl-(C1 _{- C2} )alkylene, (C3- _C6 )cycloalkyl, (C3 _{- C6} )cycloalkyl-(C1 _{- C4} )alkylene, 4- to 6-membered heterocycloalkyl, ( _4- to 6-membered heterocycloalkyl)-(C1 _{- C4} )alkylene, 5- to 6-membered heteroaryl and (5- to 6-membered heteroaryl)-(C1 _{- C4} )alkylene are each optionally substituted;

Each _R4 is independently selected from -H, halogroup, -OH, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy, ( _C1 - _C6 )haloalkyl, and ( _C1 - _C6 )haloalkoxy, wherein the ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy, ( _C1 - _C6 )haloalkyl, and ( _C1 - _C6 )haloalkoxy are each optionally substituted independently;

Each ^Ra is independently selected from -H, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )haloalkyl, ( _C6 - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-14-membered heteroaryl, 4-14-membered heterocycloalkyl, ( _C6 - _C10 )aryl-( _C1 - _C4 )alkylene-, ( _C3 - _C10 )cycloalkyl-( _C1 - _C4 )alkylene-, (5-14-membered heteroaryl)-(C1 _{- C4} )alkylene-, and (4-14-membered heterocycloalkyl)-(C1 _{- C4} )alkylene-, wherein ( _C1 - _C6 )alkyl, ( _C1 - _C6 )haloalkyl, ( _C6 - _C10 )aryl, ( _C3 - _C10)... ( _C6 - _C10 ) aryl-(C1-C4) alkylene-, (C3-C10) cycloalkyl-( _C1 - _C4 ) alkylene-, (5-14) heteroaryl-( _C1 - _C4 ) alkylene-, and (4-14 ₎ heterocycloalkyl-( _{C1 - C4 )} alkylene- can each be substituted independently _;

n, p, and m are each an independent integer from 0 to 3; and

Y is selected from -O-, -S-, -SO-, _-SO2- , -NH- and -N((C1 _{- C6} )alkyl)-.

Item 23. The compound as described in Item 22, wherein:

_R1 can be -H, -CN, ( _C1 - _C6 )alkyl, ( _C3 - _C10 )cycloalkyl, ( _C6 - _C10 )aryl, 4-10 heterocyclic alkyl, 5-10 heteroaryl, -S(O ^)2NHRa _, -P(O) ^RaRa , ^{-ORa , or}

Where represents the connection point, and:

_Y1 is absent or is -NH-, -N-( _C1 - _C6 )alkyl- or -O-;

_Y2 is absent, or is -O-, -NH-, -NHO-, -N-( _C1 - _C6 )alkyl-, -NH-NH-, -NH-S(O)-, or NH-S(O) ₂ ; and

^Z1 is -O, -NH, -N-( _C1 - _C6 )alkyl, -N-OH or -NO( _C1 - _C6 )alkyl;

Item 24. The compound as described in Item 23, wherein:

_R2 can be -H, a halogroup, _-X1Ra , ( _C2 - _C6 ) ^alkenyl , ( _C2 - _C6 )ynyl, or...

Where: represents the connection point, where:

_Y1 is absent, or is NH, N-( _C1 - _C6 ) alkyl, or O;

_Y2 is absent, or is O, NH, NHO, N-( _{C1 - C6} )alkyl, _N2H2 , NH-S(O) or NH-S(O) ₂ ; and

^Z1 is -O, -NH, -N-( _C1 - _C6 )alkyl, -NOH-, or -NO( _C1 - _C6 )alkyl.

Item 25. The compound of any one of items 22-24, wherein _R3 is -H or a halogroup.

Item 26. The compound of any one of items 22-25, wherein _R4 is -H or a halogroup.

Item 27. The compound of any one of items 22-26, wherein R ₁₄ is -H or a halogroup.

Item 28. The compound of any one of items 22-27, wherein Y is -O-.

Item 29. A compound as described in any one of items 22-28, wherein the compound is a compound of formula B-1 or B-2:

Or its pharmaceutically acceptable salt.

Item 30. A compound of formula B-1 as described in Item 29, wherein:

^Ra1 is an optionally substituted ( _C1 - _C6 ) alkyl group;

_R1 is -H, -CN, optionally substituted 3-6 membered cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 membered heterocycloalkyl, optionally substituted 5-6 membered heteroaryl, _-SO2- ( _C1 - _C6 )alkyl, _-SO2NH2 , _-SO2 - _NH ( _C1 - _C6 )alkyl, or P(O)(( _C1 - _C6 )alkyl) ₂ ; or

Where represents the connection point, and:

_Y1 does not exist;

_Y2 is absent or is -O-, -NH-, -NHO-, -NH-NH-, -N-( _C1 - _C6 )alkyl-; or

_Y2 is an optional substitution where ring A is a 3-, 4-, 5-, 6-, or 7-membered ring, where represents the connection point.

^Z1 is O, NH, N-( _C1 - _C6 )alkyl, NHO, or NO-( _C1 - _C6 )alkyl; and

Ra ^can be -H, -( _C1 - _C6 )alkyl, 4-6 membered heterocyclic alkyl, 3-6 membered cycloalkyl, -( _C2 - _C6 )alkylene-OH, _-CH2CHOH- ( _C2 - _C6 )alkylene-OH, -( _C2 - _C6 )alkylene- _NH2 , -(C2- _C6 )alkylene-NH( _C1 - _C6 ), -( _C2 - _C6 )alkylene-N( _C1 - _C6 ) ₂ or -( _C2 - _C6 )alkylene-N-( _4-6 membered heterocyclic alkyl);

Item 31. A compound of formula B-1 as described in Item 30, wherein:

^Ra1 is a ( _C1 - _C6 ) alkyl group;

_R1 is -H, -CN, optionally substituted cyclopropyl, optionally substituted phenyl, optionally substituted 4-6 membered azacyclic butyl, optionally substituted pyrrolyl, optionally substituted piperidinyl, optionally substituted oxazolyl, optionally substituted pyridinyl, optionally substituted imidazolyl, optionally substituted pyrrolyl, optionally substituted furanyl, optionally substituted pyrazolyl, optionally substituted oxadiazolyl, _-SO₂- ( _C₁ - _C₆ )alkyl, _-SO₂NH₂ , _{-SO₂ -} NH( _C₁ - _C₆ )alkyl, or P(O)(( _C₁ - _C₆ )alkyl) _₂ ; or

_R1 is where:

_Y1 does not exist;

_Y2 is O, NH, NHO, NH-NH, or N-( _C1 - _C6 ) alkyl; or

_Y2 is an optionally substituted nitrogen-containing heterocyclic butyl group;

Z is O, NH, or N-( _C1 - _C6 ) alkyl; and

Ra ^can be H, ( _C1 - _C6 )alkyl, -( _C2 - _C6 )alkylene-OH, _-CH2CHOH- ( _C2 - _C6 )alkylene-OH, -( _C2 - _C6 )alkylene- _NH2 , -( _C2 - _C6 )alkylene-NH( _C1 - _C6 )alkyl, -( _C2 - _C6 )alkylene-N(( _C1 - _C6 )alkyl) ₂ , -( _C2 - _C6 )alkylene-heterocyclic alkyl) and 4-6 membered heterocyclic alkyl, wherein the heterocyclic alkyl is optionally substituted.

Item 32. A compound of formula B-2 as described in Item 30, wherein:

^Ra2 is an optionally substituted ( _C1 - _C6 ) alkyl group;

_R2 represents the connection point, where:

_Y1 does not exist;

_Y2 either does not exist or is -O- or -NH-; and

^Z1 is 0; and

^Ra is -H or -( _C1 - _C6 ) alkyl.

Item 33. A compound of formula B-2 as described in Item 32, wherein:

^Ra2 is a ( _C1 - _C6 ) alkyl group;

_R2 represents the connection point, where:

_Y1 does not exist;

_Y2 either does not exist or is -O- or -NH-; and

^Z1 is an O or NO-( _C1 - _C6 ) alkyl group; and

^Ra is -H or -( _C1 - _C6 ) alkyl.

Item 34. The compound of formula B-1 as described in any one of items 29-31, wherein ^Ra1 is methoxylated.

Item 35. The compound of formula B-2 as described in any one of items 29 and 32-33, wherein ^Ra2 is methoxylated.

Item 36. A compound as described in any one of items 22-28, wherein the compound is a compound of formula B-3 or B-4:

Or its pharmaceutically acceptable salt.

Item 37. The compound as described in Item 36, wherein the compound is a compound of formula B-3, wherein:

_R1 is -H or ( _C1 - _C6 ) alkyl; and

_Y1 does not exist;

_Y2 either does not exist or is -O-, -NHO-, or -NH-; and

^Z1 is an O or NO-( _C1 - _C6 ) alkyl group; and

^Ra is -H or -( _C1 - _C6 ) alkyl.

Item 38. The compound as described in Item 37, wherein the compound is a compound of formula B-3, wherein:

_R1 is –H or methyl;

_Y1 does not exist;

_Y2 either does not exist or is -O-, -NHO-, or -NH-; and

^Z1 is O or NO-Me; and

R ^a is –H or Me.

Item 39. The compound as described in Item 36, wherein the compound is a compound of formula B-3, wherein:

_R1 and ^Ra together with the atoms they are attached to form

4-6 membered heterocyclic alkyl rings optionally substituted with halogen groups, ( _C1 - _C6 )alkyl groups, and ( _C1 - _C6 )haloalkyl groups.

Item 40. The compound as described in Item 36, wherein the compound is a compound of formula B-4, wherein:

_Y1 does not exist;

_Y2 is O, NH, NHO, NH-NH, or N-( _C1 - _C6 ) alkyl; or

_Y2 is an optionally substituted nitrogen-containing heterocyclic butyl group;

^Z1 is O, NH, NO-( _C1 - _C6 )alkyl, or N-( _C1 - _C6 )alkyl; and

Ra ^can be -H, ( _C1 - _C6 )alkyl, -( _C2 - _C6 )alkylene-OH, _-CH2CHOH- ( _C2 - _C6 )alkylene-OH, -( _C2 - _C6 )alkylene- _NH2 , -( _C2 - _C6 )alkylene-NH( _C1 - _C6 )alkyl, -( _C2 - _C6 )alkylene-N(( _C1 - _C6 )alkyl) ₂ , -( _C2 - _C6 )alkylene-optionally substituted 4-6 membered heterocyclic alkyl) and optionally substituted 4-6 membered heterocyclic alkyl;

_R2 can be -H, F, Cl, Br, ( _C1 - _C6 )alkoxy, -O-( _C2 - _C6 )alkylene-OH, -O-( _C2 - _C6 )alkylene-O-( _C1 - _C6 alkyl), ( _C2 - _C6 )alkylene-O-( _C1 - _C6 )alkyl, _-NH2 , -NH-(C1- _C6 alkyl), -NH-( _C1 -C6)alkylene-(optionally substituted 4-6 membered heterocyclic alkyl), -NH-( _{C2 - C6 )} alkylene-O-( _C1 - _C6 alkyl).

Item 41. The compound as described in Item 40, wherein the compound is a compound of formula B-4, wherein:

_Y1 does not exist;

_Y2 is O, NH, NHO, NH-NH, or N-( _C1 - _C6 ) alkyl; or

_Y2 is an optionally substituted nitrogen-containing heterocyclic butyl group;

^Z1 is O, NH, NO-( _C1 - _C6 )alkyl, or N-( _C1 - _C6 )alkyl; and

Ra ^can be H, methyl, ethyl, -( _C2 - _C6 )alkylene-OH, _-CH2CHOH- ( _C2 - _C6 )alkylene-OH, -( _C2 - _C6 )alkylene- _NH2 , -( _C2 - _C6 )alkylene-NHMe, -( _C2 - _C6 )alkylene-N(Me) ₂ , -( _C1 - _C6 )alkylene-morpholinyl, -( _C1 - _C6 )alkylene-piperidinyl, ( _C1 - _C6 )alkylene-(optionally substituted pyrrolidinyl), optionally substituted azahexacyclic butyl or optionally substituted oxohexacyclic butyl;

_R2 is -H, H, F, Cl, Br, methoxy, -O-( _C2 - _C6 )alkylene-OH, -O-( _C2 - _C6 )alkylene-OMe, _-NH2 , -NH-( _C1 - _{C6 alkyl), -NH-(C2-C6 ) alkylene} -OMe, -NH-( _C2 - _C6 )alkylene-(optionally substituted morpholino) or -NH-( _C2 - _C6 )alkylene-O-( _C1 - _C6 alkyl).

Item 42. The compound as described in Item 36, wherein the compound is a compound of formula B-4, wherein:

_R2 and ^Ra, together with the atoms they are attached to, form 4-6 membered heterocyclic alkyl rings that are optionally substituted with halogen groups, ( _C1 - _C6 )alkyl groups, and ( _C1 - _C6 ) haloalkyl groups.

Item 43. The compound as described in items 22-28, wherein the compound is a compound of formula B-5:

Or a pharmaceutically acceptable salt thereof, wherein ring A in formula B-5 is an optionally substituted 5-10 membered heteroaryl or C _6-10 aryl.

Item 44. The compound as described in Item 43, wherein the compound is a compound of formula B-5, wherein:

Ring A is optionally substituted ( _C6 - _C10 ) aryl, optionally substituted ( _C3 - _C10 ) cycloalkyl, optionally substituted 5-10 heteroaryl, or optionally substituted 4-10 heterocycloalkyl; and

_R2 is H, or ( _C1 - _C6 )alkoxy.

Item 45. The compound as described in Item 44, wherein the compound is a compound of formula B-5, wherein:

Ring A is optionally substituted with phenyl, optionally substituted with cyclopropyl, optionally substituted with pyridyl, optionally substituted with imidazolyl, optionally substituted with pyrrole, optionally substituted with furanyl, optionally substituted with pyrazolyl, optionally substituted with oxazolyl, optionally substituted with aziridine or optionally substituted with oxacyclobutane; and

_R2 is H or methoxy.

Item 46. A compound as described in any one of items 22-28, wherein the compound is a compound of formula C:

Or its pharmaceutically acceptable salt, wherein:

_Y1 does not exist;

_Y2 is O, NH, NHO, NH-NH, or N-( _C1 - _C6 ) alkyl; or

_Y2 is an optionally substituted nitrogen-containing heterocyclic butyl group;

^Z1 is O, NH, NO-( _C1 - _C6 )alkyl or N-( _C1 - _C6 )alkyl;

Ra ^can be H, ( _C1 - _C6 )alkyl, -( _C2 - _C6 )alkylene-OH, _-CH2CHOH- ( _C2 - _C6 )alkylene-OH, -( _C2 - _C6 )alkylene- _NH2 , -( _C2 - _C6 )alkylene-NH( _C1 - _C6 )alkyl, -( _C2 - _C6 )alkylene-N(( _C1 - _C6 )alkyl) ₂ , -( _C2 - _C6 )alkylene-optionally substituted 4-6 membered heterocyclic alkyl) or optionally substituted 4-6 membered heterocyclic alkyl;

_R2 is -H, F, Cl, Br, ( _C1 - _C6 )alkoxy, -O-( _C2 - _C6 )alkylene-OH, -O-( _C2 - _C6 )alkylene-O-( _C1 - _C6 alkyl), ( _C2 - _C6 )alkylene-O-( _C1 - _C6 )alkyl, _-NH2 , -NH-( _{C1-C6 alkyl), -NH-(C1 - C6 )} alkylene-(optionally substituted 4-6 membered heterocyclic alkyl) or –NH-( _C2 - _C6 )alkylene-O-( _C1 - _C6 alkyl); and

n and m are each an independent integer from 0 to 3.

Item 47. The compound as described in Item 46, wherein:

_Y1 does not exist;

_Y2 is O, NH, NHO, NH-NH, or N-( _C1 - _C6 ) alkyl; or

_Y2 is an optionally substituted nitrogen-containing heterocyclic butyl group;

^Z1 is O, NH, NO-( _C1 - _C6 )alkyl or N-( _C1 - _C6 )alkyl;

Ra ^can be H, methyl, ethyl, -( _C2 - _C6 )alkylene-OH, _-CH2CHOH- ( _C2 - _C6 )alkylene-OH, -( _C2 - _C6 )alkylene- _NH2 , -( _C2 - _C6 )alkylene-NHMe, -( _C2 - _C6 )alkylene-N(Me) ₂ , -( _C1 - _C6 )alkylene-morpholinyl, -( _C1 - _C6 )alkylene-piperidinyl, ( _C1 - _C6 )alkylene-(optionally substituted pyrrolidinyl), optionally substituted azahexacyclic butyl or optionally substituted oxohexacyclic butyl;

_R2 is -H, H, F, Cl, Br, methoxy, -O-( _C2 - _C6 )alkylene-OH, -O-( _C2 - _C6 )alkylene-OMe, _-NH2 , -NH-( _C1 - _C6 alkyl), -NH-( _C2 - _C6 )alkylene-OMe, -NH-( _C2 - _C6 )alkylene-(optionally substituted morpholino) or -NH-( _C2 - _C6 )alkylene-O-( _C1 - _C6 alkyl); and

And n and m can each be 0 or 1.

Item 48. The compound of any one of items 46-47, wherein the compound is a compound of formula C-1.

Or its pharmaceutically acceptable salt, wherein:

_Y2 is O, NH, NHO, NH-NH, or N-( _C1 - _C6 ) alkyl; or

_Y2 is an optionally substituted nitrogen-containing heterocyclic butyl group.

^Z1 is O, NH, NO-( _C1 - _C6 )alkyl or N-( _C1 - _C6 )alkyl;

Ra ^can be H, methyl, ethyl, -( _C2 - _C6 )alkylene-OH, _-CH2CHOH- ( _C2 - _C6 )alkylene-OH, -( _C2 - _C6 )alkylene- _NH2 , -( _C2 - _C6 )alkylene-NHMe, -( _C2 - _C6 )alkylene-N(Me) ₂ , -( _C1 - _C6 )alkylene-morpholinyl, -( _C1 - _C6 )alkylene-piperidinyl, ( _C1 - _C6 )alkylene-(optionally substituted pyrrolidinyl), optionally substituted azahexacyclic butyl or optionally substituted oxohexacyclic butyl;

_R2 is -H, H, F, Cl, Br, methoxy, -O-( _C2 - _C6 )alkylene-OH, -O-( _C2 - _C6 )alkylene-OMe, _-NH2 , -NH-( _C1 - _C6 alkyl), -NH-( _C2 - _C6 )alkylene-OMe, -NH-( _C2 - _C6 )alkylene-(optionally substituted morpholino) or -NH-( _C2 - _C6 )alkylene-O-( _C1 - _C6 alkyl); and

Furthermore, n and m are each independently 0 or 1.

Item 49. A compound as described in any one of items 22-28, wherein the compound is a compound of formula D:

Item 50. The compound as described in any one of Item 49, wherein:

_R1 is -H or ( _C1 - _C6 ) alkyl; and

_Y1 does not exist;

_Y2 either does not exist or is -O-, -NHO-, or -NH-; and

^Z1 is an O or NO-( _C1 - _C6 ) alkyl group.

^Ra is -H or -( _C1 - _C6 ) alkyl; and

n and m are each an independent integer from 0 to 3.

Item 51. The compound as described in any one of Item 50, wherein:

_R1 is –H or methyl;

_Y1 does not exist;

_Y2 either does not exist or is -O-, -NHO-, or -NH-; and

^Z1 is O or NO-Me; and

R ^_a is either -H or Me.

n and m are each an independent integer between 0 and 1.

Item 52. The compound of any one of items 49-51, wherein the compound is a compound of formula D-1:

Item 53. A compound as described in any one of items 22-28, wherein the compound is a compound of formula E:

Or its pharmaceutically acceptable salt, wherein:

Ring A is optionally substituted ( _C6 - _C10 ) aryl, optionally substituted ( _C3 - _C10 ) cycloalkyl, optionally substituted 5-10 heteroaryl, or optionally substituted 4-10 heterocycloalkyl; and

_R2 is H or ( _C1 - _C6 ) alkoxy.

Item 54. The compound as described in Item 53, wherein:

Ring A is optionally substituted with phenyl, optionally substituted with cyclopropyl, optionally substituted with pyridyl, optionally substituted with imidazolyl, optionally substituted with pyrrole, optionally substituted with furanyl, optionally substituted with pyrazolyl, optionally substituted with oxazolyl, optionally substituted with aziridine or optionally substituted with oxacyclobutane; and

_R2 is H or methoxy.

Item 55. A compound as described in any one of items 22-28, wherein the compound is a compound of formula F:

Or its pharmaceutically acceptable salt, wherein

^Ra1 is an optionally substituted ( _C1 - _C6 ) alkyl group;

_R1 is -H, -CN, optionally substituted 3-6 membered cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 membered heterocycloalkyl, optionally substituted 5-6 membered heteroaryl, _-SO2- ( _C1 - _C6 )alkyl, _-SO2NH2 , _-SO2 - _NH ( _C1 - _C6 )alkyl, or P(O)(( _C1 - _C6 )alkyl) ₂ ; or

Where: represents the connection point; where:

_Y1 does not exist;

_Y2 is absent, or is -O-, -NH-, -NHO-, -NH-NH-, -N-( _C1 - _C6 )alkyl-; or

_Y2 is an optional substitution in which ring A is a 3, 4, 5, 6 or 7-membered ring, where represents the connection point;

^Z1 is O, NH, N-( _C1 - _C6 )alkyl, NHO, or NO-( _C1 - _C6 )alkyl; and

Ra ^can be -H, -( _C1 - _C6 )alkyl, 4-6 membered heterocyclic alkyl, 3-6 membered cycloalkyl, -( _C2 - _C6 )alkylene-OH, _-CH2CHOH- ( _C2 - _C6 )alkylene-OH, -( _C2 - _C6 )alkylene- _NH2 , -( _C2 - _C6 )alkylene-NH(C1- _C6 ), -( _C2 - _C6 )alkylene-N( _{C1 - C6} ) ₂ , -( _C2 - _C6 )alkylene-N-(4-6 membered heterocyclic alkyl);

Item 56. The compound as described in any one of Item 55, wherein:

^Ra1 is a methyl group;

_R1 is -H, -CN, optionally substituted cyclopropyl, optionally substituted phenyl, optionally substituted 4-6 membered azacyclic butyl, optionally substituted pyrrolyl, optionally substituted piperidinyl, optionally substituted oxazolyl, optionally substituted pyridinyl, optionally substituted imidazolyl, optionally substituted pyrrolyl, optionally substituted furanyl, optionally substituted pyrazolyl, optionally substituted oxadiazolyl, _-SO₂- ( _C₁ - _C₆ )alkyl, _-SO₂NH₂ , _{-SO₂ -} NH( _C₁ - _C₆ )alkyl, or P(O)(( _C₁ - _C₆ )alkyl) _₂ ; or

_R1 is where:

_Y1 does not exist;

_Y2 is O, NH, NHO, NH-NH, or N-( _C1 - _C6 ) alkyl; or

_Y2 is an optionally substituted nitrogen-containing heterocyclic butyl group;

^Z1 is an O, NH, or N-( _C1 - _C6 ) alkyl group; and

Ra ^can be H, ( _C1 - _C6 )alkyl, -( _C2 - _C6 )alkylene-OH, _-CH2CHOH- ( _C2 - _C6 )alkylene-OH, -( _C2 - _C6 )alkylene- _NH2 , -( _C2 - _C6 )alkylene-NH( _C1 - _C6 )alkyl, -( _C2 - _C6 )alkylene-N(( _C1 - _C6 )alkyl) ₂ , -( _C2 - _C6 )alkylene-heterocyclic alkyl) and 4-6 membered heterocyclic alkyl, wherein the heterocyclic alkyl is optionally substituted.

Item 57. A compound as described in any one of items 22-28, wherein the compound is a compound of formula G:

Or its pharmaceutically acceptable salt, wherein:

^Ra1 is an optionally substituted ( _C1 - _C6 ) alkyl group;

_R2 represents the connection point, where:

_Y1 does not exist;

_Y2 either does not exist or is -O- or -NH-; and

^Z1 is 0; and

^Ra is -H or -( _C1 - _C6 ) alkyl.

Item 58. The compound as described in Item 57, wherein:

^Ra2 is a methyl group;

_R2 represents the connection point, where:

_Y1 does not exist;

_Y2 either does not exist or is -O- or -NH-; and

^Z1 is an O or NO-( _C1 - _C6 ) alkyl group; and

^Ra is -H or -( _C1 - _C6 ) alkyl.

Item 59. The compound of any one of items 1-58, wherein the compound is a compound of formula H:

Or its pharmaceutically acceptable salt, wherein:

_R1 is selected from _the group consisting of: -H, _-CN , -CO- _NR5R6 , _-CO2R7 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted _C1 - _C6 alkyl, optionally substituted _C3 - _C8 cycloalkyl, optionally substituted _C3 - _C6 heterocycloalkyl, _-SO2NR8R9 and ( _{SO2 ) -C1 - C6} alkyl;

When _R1 is selected from _the group consisting of: -CN, -CO- _NR5R6 , _-CO2R7 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted _C3 - _{C8 cycloalkyl} , optionally substituted _C3 - _C6 heterocycloalkyl, _SO2NR8R9 and _{( SO2} ) _-C1 - _C6 alkyl, _R2 is H, halogroup, _NR5R6 or optionally substituted _{C1 - C6} alkoxy _.

Where _R1 is -H, _an optionally substituted _C1 - _C6 alkyl, or an optionally substituted _C1 - _C6 alkoxy, _R2 is -CO- _NR5R6 or _{-CO2R7 ;}

Or _R1 and _R2 together with the atoms to which they are attached form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl;

_R3 is selected from the group consisting of: -H, optionally substituted _C1-6 alkyl groups, -CN, and halogroups;

_R4 is -H or a halogenated group;

Optionally substituted with one, two, three or four groups independently selected from the group consisting of a halogroup and a _C1 - _C6 alkyl group, wherein the linkage point is indicated;

_R5 and _R6 are each independently -H, optionally substituted _C1 - _C6 alkyl, or optionally substituted _C1 - _C6 alkoxy;

_R7 is H or an optionally substituted _C1 - _C6 alkyl group;

_R8 and _R9 are each independently H and optionally substituted _C1 - _C6 alkyl groups or _R8 ; or

_R8 and _R9 can be connected to form an optionally substituted heterocyclic ring; and

Y is selected from the following groups: O, S, SO, _SO₂ , NH and N-( _C₁ - _C₆ alkyl).

Item 60. The compound as described in Item 59, wherein Y is O.

Item 61. The compound as described in Item 60, wherein _R3 is H.

Item 62. The compound as described in Item 61, wherein it is not substituted.

Item 63. The compound as described in Item 62, wherein _R4 is a halogroup.

Item 64. The compound as described in Item 63, wherein _R4 is p-fluorine.

Item 65. The compound of any one of items 59-64, wherein _R2 is -H, a halogroup or optionally substituted ( _C1 - _C6 )-alkoxy.

Item 66. The compound as described in Item 63, wherein _R1 is -CN.

Item 67. The compound as described in Item 63, wherein _R1 is _-CO₂H .

Item 68. The compound as described in Item 63, wherein _R1 is _-CO2 -Me.

Item 69. The compound as described in Item 63, wherein _R1 is -CO- _NHR6 .

Item 70. The compound as described in Item 69, wherein _R1 is -CO- _NH2 .

Item 71. The compound as described in Item 69, wherein _R1 is -CO- _NMeR6 .

Item 72. The compound as described in any one of items 1, 2, 4, 5, 7, 8, 9 and 63, wherein _R1 is selected from the group consisting of: -CN, -( _SO₂ ) _NH₂ , -OMe, -( _SO₂ ) _CH₃

Item 73. The compound as described in Item 72, wherein _R1 is selected from the group consisting of:

Item 74. The compound as described in Item 72, wherein _R1 is selected from the group consisting of:

Item 75. The compound as described in any one of items 1, 2, 3, 5, 6, 9 and 63-74, wherein _R2 is selected from the group consisting of: H, -CN, Br, F, Cl, -OMe, _CH3 , _-CH2NH2 , _NH2 , _NHMe ,

Item 76. The compound of any one of items 59-65, wherein _R1 is -H, methyl or methoxy.

Item 77. The compound as described in Item 76, wherein _R2 is _-CO2H .

Item 78. The compound of any one of items 59-65, wherein _R1 is _-CO2 -Me.

Item 79. The compound of any one of items 59-65, wherein _R1 is -CO- _NHR6 .

Item 80. The compound as described in Item 79, wherein _R1 is -CO- _NH2 .

Item 81. The compound of any one of items 59-65, wherein _R1 is -CO- _NMeR6 .

Item 82. The compound of any one of items 59-65, wherein _R1 is selected from the group consisting of:

Item 83. The compound as described in Item 64, wherein the compound is a compound of formula I-A:

Wherein _R6 is (C1 _{- C6} )alkyl, _R2 is (C1 _{- C6} )alkoxy, _R3 is -H or a halogroup, and _R4 is a halogroup.

Item 84. The compound of any one of items 1-83, wherein the compound is selected from the group consisting of:

Or its pharmaceutically acceptable salt.

Item 85. The compound of any one of items 1-83, wherein the compound is selected from the group consisting of:

Or its pharmaceutically acceptable salt.

Item 86. A method for preparing compounds of formula I:

Or a pharmaceutically acceptable salt thereof, the method comprising: making a compound of formula II:

          

Z is selected from _NH₂ , SH, and OH;

Reaction with compounds of formula III:

Where X is a leaving group;

_R1 is selected _from -H, -CN, -CO- _NR5R6 , _-CO2R7 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted _{( C1} - _C6 )alkyl, optionally substituted ( _C3 - _C8 )cycloalkyl, optionally substituted ( _C3 - _C6 ) _{heterocycloalkyl} , _-SO2NR8R9 and -( _{SO2 )} -( _C1 - _C6 )alkyl;

Where _R1 is selected _{from -CN} , -CO- _NR5R6 , _-CO2R7 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted ( _C3 - _C8 )cycloalkyl, optionally substituted ( _C3 - _C6 ) heterocycloalkyl, _-SO2NR8R9 and -( _SO2 )-( _C1 - _C6 )alkyl, _{R2 is -H} , halogroup, _-NR5R6 or optionally substituted _{( C1} - _C6 )alkoxy;

Where _R1 is -H, an optionally substituted ( _C1 - _C6 ) alkyl, or _an optionally substituted ( _C1 - _C6 ) alkoxy, _R2 is -CO- _NR5R6 or _{-CO2R7 ;}

Or _R1 and _R2 together with the atoms to which they are attached form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl;

_R3 is selected from -H, optionally substituted (C1 _{- C6} ) alkyl, -CN, and halogroup;

_R4 is -H or a halogenated group;

Optionally substituted with one, two, three or four independently selected groups from halogroups and ( _C1 - _C6 )alkyl groups, wherein the linkage point is indicated;

_R5 and _R6 are each independently -H, optionally substituted ( _C1 - _C6 ) alkyl, or optionally substituted ( _C1 - _C6 ) alkoxy;

_R7 is -H or an optionally substituted ( _C1 - _C6 ) alkyl group;

_R8 and _R9 are each independently -H and optionally substituted ( _C1 - _C6 ) alkyl; or

_R8 and _R9 can be connected to form an optionally substituted heterocyclic ring; and

Y is selected from O, S, SO, _SO₂ , NH and N-(( _C₁ - _C₆ )alkyl).

Item 87. A method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof:

The method includes:

Compounds of formula IV:

Reaction with compounds of formula V:

_R1 is selected from _{the group consisting of: -H, -CN, -CO-NR5R6, -CO2R7 , optionally substituted} aryl, optionally substituted heteroaryl, optionally substituted ( _C1 - _C6 )alkyl, optionally substituted ( _C3 - _C8 )cycloalkyl, optionally substituted ( _C3 - _{C6 ) heterocycloalkyl} , _-SO2NR8R9 and -( _SO2 )-( _C1 - _C6 )alkyl;

When _R1 is selected from _the group consisting of _: -CN, -CO- _NR5R6 , _-CO2R7 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted ( _C3 - _C8 )cycloalkyl, optionally substituted ( _C3 - _C6 ) heterocycloalkyl, _-SO2NR8R9 and -( _SO2 )- _{( C1} - _C6 )alkyl, _R2 is _-H , _halogroup , _-NR5R6 or optionally substituted ( _C1 - _C6 )alkoxy;

Where _R1 is -H, an optionally substituted ( _C1 - _C6 ) alkyl, or _an optionally substituted ( _C1 - _C6 ) alkoxy, _R2 is -CO- _NR5R6 or _{-CO2R7 ;}

Or _R1 and _R2 together with the atoms to which they are attached form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl;

_R3 is selected from the group consisting of: -H, optionally substituted (C1 _{- C6} ) alkyl, -CN, and halogroup;

_R4 is -H or a halogenated group;

Optionally substituted with one, two, three or four groups independently selected from the group consisting of a halogroup and a ( _C1 - _C6 ) alkyl group, wherein the linkage point is indicated;

_R5 and _R6 are each independently -H, optionally substituted ( _C1 - _C6 ) alkyl, or optionally substituted ( _C1 - _C6 ) alkoxy;

_R7 is -H or an optionally substituted ( _C1 - _C6 ) alkyl group;

_R8 and _R9 are each independently -H and optionally substituted ( _C1 - _C6 alkyl); or

_R8 and _R9 can be connected to form an optionally substituted heterocyclic ring; and

Y is selected from the group consisting of: O, S, SO, _SO₂ , NH and N-(( _C₁ - _C₆ )alkyl).

Item 88. The method of Item 87 further comprises making a compound of Formula VI:

Reaction with compounds of formula VII:

Compounds of formula VIII:

And reduce the compound of formula VIII to provide the compound of formula V.

in:

_R1 is selected from _{the group consisting of: -H, -CN, -CO-NR5R6, -CO2R7 , optionally substituted} aryl, optionally substituted heteroaryl, optionally substituted ( _C1 - _C6 )alkyl, optionally substituted ( _C3 - _C8 )cycloalkyl, optionally substituted ( _C3 - _{C6 ) heterocycloalkyl} , _-SO2NR8R9 and -( _SO2 )-( _C1 - _C6 )alkyl;

Where _R1 is selected _{from -CN} , -CO- _NR5R6 , _-CO2R7 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted ( _C3 - _C8 )cycloalkyl, optionally substituted ( _C3 - _C6 ) heterocycloalkyl, _-SO2NR8R9 and -( _SO2 )-( _C1 - _C6 )alkyl, _{R2 is -H} , halogroup, _-NR5R6 or optionally substituted _{( C1} - _C6 )alkoxy;

Where _R1 is -H, an optionally substituted ( _C1 - _C6 ) alkyl, or _an optionally substituted ( _C1 - _C6 ) alkoxy, _R2 is -CO- _NR5R6 or _{-CO2R7 .}

Or _R1 and _R2 together with the atoms to which they are attached form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl;

_R3 is selected from the group consisting of: -H, optionally substituted (C1 _{- C6} ) alkyl, -CN, and halogroup; and

W is a halogenated group.

Item 89. A pharmaceutical composition comprising a compound as described in any one of items 1-85 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

Item 90. A method of treating a disease, condition, or syndrome by at least partially modulating the in vivo activity of a protein kinase, the method comprising administering to a subject in need a compound as described in any one of items 1-85 or a pharmaceutical composition as described in item 89.

Item 91. The method of Item 90, wherein the disease, condition or syndrome mediated at least in part by regulating the in vivo activity of protein kinases is cancer.

Item 92. A method for inhibiting a protein kinase, the method comprising contacting the protein kinase with a compound as described in any one of items 1-85.

Item 93. The method of any one of items 90-92, wherein the protein kinase is Axl, Mer, c-Met, KDR or a combination thereof.

Compounds for treating kinase-dependent disorders

This application is a divisional application of the invention patent application filed on January 25, 2009, with application number 201980015066.9 (international application number PCT/US2019/015297) entitled "Compound for treating kinase-dependent diseases".

Technical Field

This invention relates to compounds that regulate cellular activities such as proliferation, differentiation, programmed cell death, migration, and chemical invasion by modulating protein kinase activity. More specifically, this invention relates to compounds that inhibit, regulate, and/or modulate Axl and Mer receptor tyrosine kinases, compositions containing these compounds, methods of using them to treat kinase-dependent diseases and disorders, the synthesis of said compounds, and methods of formulating compounds for pharmaceutical purposes.

Cross-references to related applications

This application claims priority to U.S. Provisional Application Serial No. 62/622,702, filed January 26, 2018 and U.S. Provisional Application Serial No. 62/758,321, filed November 9, 2018, the entire contents of which are incorporated herein by reference.

Background Technology

Human Axl belongs to the TAM subfamily of receptor tyrosine kinases, including Mer. TAM kinases are characterized by an extracellular ligand-binding domain consisting of two immunoglobulin-like domains and two fibronectin type III domains. Axl is overexpressed in many tumor cell types and was originally cloned from patients with chronic myeloid leukemia. When overexpressed, Axl exhibits transformative potential. Axl signaling is believed to induce tumor growth by activating proliferative and anti-apoptotic signaling pathways. Axl has been associated with cancers such as lung cancer, myeloid leukemia, uterine cancer, ovarian cancer, glioma, melanoma, thyroid cancer, renal cell carcinoma, osteosarcoma, gastric cancer, prostate cancer, and breast cancer. Overexpression of Axl leads to poor prognosis in patients with the indicated cancers.

Like Axl, Mer activation leads to downstream signaling pathways in tumor growth and activation. Mer binds to ligands such as the soluble protein Gas-6. Gas-6 binding to Mer induces autophosphorylation of Mer in its intracellular domain, resulting in downstream signal activation. Overexpression of Mer in cancer cells leads to increased metastasis, most likely through the generation of soluble Mer extracellular domain proteins as decoy receptors. Tumor cells secrete soluble forms of extracellular Mer receptors, which reduce the ability of soluble Gas-6 ligands to activate Mer on endothelial cells, thereby contributing to cancer progression.

Therefore, compounds that inhibit TAM receptor tyrosine kinases such as Axl and Mer are needed to treat selected cancers.

Summary of the Invention

In one aspect, the present invention provides compounds of formula I:

Or its pharmaceutically acceptable salt, wherein:

_R1 is selected _from -H, -CN, -CO- _NR5R6 , _-CO2R7 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted _{( C1} - _C6 )alkyl, optionally substituted ( _C3 - _C8 )cycloalkyl, optionally substituted ( _C3 - _C6 ) _{heterocycloalkyl} , _-SO2NR8R9 and -( _{SO2 )} -( _C1 - _C6 )alkyl;

Where _R1 is selected _{from -CN} , -CO- _NR5R6 , _-CO2R7 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted ( _C3 - _C8 )cycloalkyl, optionally substituted ( _C3 - _C6 ) heterocycloalkyl, _-SO2NR8R9 and -( _SO2 )-( _C1 - _C6 )alkyl, _{R2 is -H} , halogroup, _-NR5R6 or optionally substituted _{( C1} - _C6 )alkoxy;

Where _R1 is -H, an optionally substituted ( _C1 - _C6 ) alkyl, or _an optionally substituted ( _C1 - _C6 ) alkoxy, _R2 is -CO- _NR5R6 ; or _{-CO2R7 ;}

Or _R1 and _R2 together with the atoms to which they are attached form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl;

_R3 is selected from -H, optionally substituted (C1 _{- C6} ) alkyl, -CN, and halogroup;

_R4 is -H or a halogenated group;

Optionally substituted with one, two, three or four independently selected groups from halogroups and ( _C1 - _C6 )alkyl groups, wherein the linkage point is indicated;

_R5 and _R6 are each independently -H, optionally substituted ( _C1 - _C6 ) alkyl, or optionally substituted ( _C1 - _C6 ) alkoxy;

_R7 is -H or an optionally substituted ( _C1 - _C6 ) alkyl group.

_R8 and _R9 are each independently -H or optionally substituted ( _C1 - _C6 ) alkyl groups;

Alternatively, _R8 and _R9 can be connected to form an optionally substituted heterocyclic ring; and

Y is selected from O, S, SO, _SO₂ , NH and N-( _C₁ - _C₆ alkyl).

On the other hand, compounds of formula A are provided:

Or its pharmaceutically acceptable salt, wherein

(i) _R1 is selected from ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, ( _C6 - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-10 heteroaryl, 4-10 heterocycloalkyl, -CN, -NHOH, -C(O) ^Ra , -C(O) ^NRaRa , -C(O) ^NHORa , ^-C (O) ^ORa , -C(O)NRaS(O) _2Ra , ^-OC (O) ^NRaRa , ^C (＝ ^NRa ) ^{Ra ,} -C(＝NOH) ^Ra , -C(＝NOH) ^{NRa ,} -C(＝ ^NCN ) ^{NRaRa ,} -C(＝NRa) ^NRaRa , -S(O) ^{NRaRa ,} -S(O) _2NRaC ( ^O ) ^Ra , -P(O)R ^a R ^a , -P(O)(OR ^a )(OR ^a ), -B(OH) ₂ , -B(OR ^a ) ₂ and S(O) ₂ NR ^a R ^a ; and

_R2 is selected from -H, halogenated, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, (C1- _C6 )haloalkyl, (C1 _- C6)haloalkoxy, ( _{C6 - C10} )aryl-( _C1 - _C4 )alkylene-, (C3 _{-C10 )} cycloalkyl-( _C1 - _C4 )alkylene-, (5-14-membered heteroaryl)-( _{C1 - C4} )alkylene-, (4-14-membered heterocycloalkyl)-(C1 _{- C4} )alkylene-, -CN, _-NO2 , ^-ORa , ^-SRa , ^-NHORa , -C(O) ^{Ra ,} -C(O) ^NRaRa , -C(O) ^NHORa , -C(O) ^ORa , -C(O)NR ^a S(O) ₂ R ^a , -OC(O)R ^a , -OC(O)NR ^a R ^a , -NHR ^a , -NR ^a R ^a , -NR ^a C(O)R ^a , -NR ^a C(=NR ^a )R ^a , -NR ^a C(O)OR ^a , -NR ^a C(O)NR ^a R ^a , -C(=NR ^a )R ^a , -C(=NOH)R ^a , -C(=NOH)NR ^a , -C(=NCN)NR ^a R ^a , -NR ^a C(=NCN)NR ^a R ^a , -C(=NR ^a )NR ^a R ^a , -NR ^a C(=NR ^a )NR ^a R ^a , -NR ^a S(O)R ^a , -NR ^a S(O) ₂ R ^a , -NR ^a S(O) ₂ NR ^a R ^a ,-S(O)R ^a -S(O)NR ^aRa , ^-S (O) _2Ra , -S(O) _2NR ^aC (O) ^Ra , -P(O) ^RaRa , -P(O)(OR ^a )( ^{OR a )} , -B ⁽ OH) ₂ , -B(OR ^a ) ₂ and -S(O ^{)2NR aRa} _, ^wherein _R1 or _R2 is a (C1 _{- C6} )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, ( _C6 - _C10 )aryl-( _C1 - _C4 )alkylene-, ( _C3 - _C10 )cycloalkyl-( _C1 - _C4 )alkylene-, (5-14-membered heteroaryl)-(C1 _{- C4} )alkylene- and (4-14-membered heterocycloalkyl)-(C1 _- C ₄ ) Alkylenes – each optionally substituted by 1, 2, 3, 4, or 5 independently selected ^Rb substituents, provided that when _R1 is a 5-7-membered heteroaryl or 5-7-membered heterocyclic alkyl and _R2 is a _C1-6 alkoxy, the 5-7-membered heteroaryl or 5-7-membered heterocyclic alkyl is not connected to the fused benzene ring of the quinoline moiety via a cyclic nitrogen atom; or

(ii) _R1 is selected from -H, halogroup, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, (C2- _C6 )ynyl, ( _C1 - _C6 )haloalkyl, (C1 _{- C6} )haloalkoxy, ( _{C6 - C10} )aryl, ( _C3 - _C10 )cycloalkyl, 5-14-membered heteroaryl, 4-14-membered heterocycloalkyl, ( _C6 - _C10 )aryl-( _{C1- C4} )alkylene-, ( _C3 - _C10 )cycloalkyl-( _{C1- C4} )alkylene-, (5-14-membered heteroaryl)-( _{C1- C4} )alkylene-, (4-14-membered heterocycloalkyl)-( _{C1- C4} )alkylene-, -CN, _-NO2 , ^-ORa , -SR ^a , -NHOR ^a , -C(O)R ^a , -C(O)NR ^a R ^a , -C(O)NHOR ^a , -C(O)OR ^a , -C(O)NR ^a S(O) ₂ R ^a , -OC(O)R ^a , -OC(O)NR ^a R ^a , -NHR ^a , -NR ^a R ^a , -NR ^a C(O)R ^a , -NR ^a C(=NR ^a )R ^a , -NR ^a C(O)OR ^a , -NR ^a C(O)NR ^a R ^a , -C(=NR ^a )R ^a , -C(=NOH)R ^a , -C(=NOH)NR ^a , -C(=NCN)NR ^a R ^a , -NR ^a C(=NCN)NR ^a R ^a , -C(=NR ^a )NR ^a R ^a , -NR ^a C(=NR ^a )NR ^a R ^a , -NR ^a S(O) ^Ra , ^-NRaS (O) _2Ra , -NRaS ₍ O) ^2NRaRa , ^-S (O ₎ ^Ra , -S(O) ^NRaRa , -S(O) ^2Ra , ^-S (O) _2NRaC (O)Ra, ^-P (O) ^RaRa , -P ⁽ O)( ^ORa )( ^ORa ) ^{, -B} (OH) ² , -B( ^ORa ) _{2 and} -S(O) _2NRaRa , wherein _R1 or ^R2 is a ( _C1 - _C6 )alkyl, ( _C2 - _C6 ) ^alkenyl , ( _C2 - _C6 )ynyl, (C6 _{-C10 )} aryl, ( _C3 - _C10 )cycloalkyl, 5-14 heteroaryl, 4-14 heterocycloalkyl, ( _C6 - _{C10 ) ...} The aryl-(C1 _{- C4} )alkylene-, (C3- _C10 )cycloalkyl-( _C1 -C4)alkylene-, (5-14-membered heteroaryl)-( _{C1- C4} )alkylene-, and (4-14-membered heterocycloalkyl)-( _{C1 - C4} )alkylene- are each optionally substituted by 1, 2, 3 _, 4, or 5 independently selected ^Rb substituents; and

R ₂ is selected from (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, -CN, -NHOH, -C(O)R ^a , -C(O)NR ^a R ^a , -C(O)NHOR ^a , -C(O)OR ^a , -C(O)NR ^a S(O) ₂ R ^a , -OC(O)NR ^a R ^a , C(=NR ^a )R ^a , -C(=NOH)R ^a , -C(=NOH)NR ^a , -C(=NCN)NR ^a R ^a , -NR ^a C(=NCN)NR ^a R ^a , -C(=NR ^a )NR ^a R ^a , -S(O)NR ^a R ^a , -S(O) ₂ NR ^a C(O)R ^a , -P(O)R ^a R ^a , -P(O)(OR ^a )(OR ^a ), -B(OH) ₂ , -B(OR ^a ) ₂ and S(O) ₂ NR ^{a Ra} , provided that when R ₁ is a 5-7 membered heteroaryl or a 5-7 membered heterocyclic alkyl and R ₂ is a C _1-6 alkoxy, then the 5-7 membered heteroaryl or 5-7 membered heterocyclic alkyl of R ₁ is not connected to the fused benzene ring of the quinoline moiety through a cyclic nitrogen atom.

(iii) _R1 and _R2 together with the atoms to which they are attached form a fused (C3 _{- C7} ) cycloalkyl ring or a fused 4- to 10-membered heterocyclic alkyl ring, wherein the fused (C3 _{- C7} ) cycloalkyl ring and the fused 4- to 10-membered heterocyclic alkyl ring are each optionally substituted by one, two or three independently selected ^Rb substituents, provided that the compound is not 1-[2-(4-fluorophenyl)-acetyl]-cyclopropanecarboxylic acid [3-fluoro-4-(7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxa-1-aza-cyclododecane[b]naphthalene-4-yloxy)-phenyl]-amide;

_R10 and _R11 are each independently selected from -H, halogroup, ( _C1 - _C6 )alkyl, (C1- _C6 )haloalkyl, ( _{C1 - C6} )haloalkoxy, ( _C6 - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-14-membered heteroaryl, 4-14-membered heterocycloalkyl, ( _C6 - _C10 )aryl-( _C1 - _C4 )alkylene-, ( _C3 - _C10 )cycloalkyl-( _{C1- C4} )alkylene-, (5-14-membered heteroaryl)-( _{C1- C4} )alkylene-, (4-14-membered heterocycloalkyl)-( _{C1- C4} )alkylene-, -CN, _-NO2 ^{, -ORa} , -SRa, ^-NHORa , -C(O) ^Ra , -C(O)NR ^a R ^a , -C(O)OR ^a , -C(O)NR ^a S(O) ₂ R ^a , -OC(O)R ^a , -OC(O)NR ^a R ^a , -NHR ^a , -NR ^a R ^a , -NR ^a C(O)R ^a , -NR ^a C(=NR ^a )R ^a , -NR ^a C(O)OR ^a , -NR ^a C(O)NR ^a R ^a , -C(=NR ^a )R ^a , -C(=NOH)R ^a , -C(=NOH)NR ^a , -C(=NCN)NR ^a R ^a , -NR ^a C(=NCN)NR ^a R ^a , -C(=NR ^a )NR ^a R ^a , -NR ^a C(=NR ^a )NR ^a R ^a , -NR ^a S(O)R ^a , -NR ^a S(O) ₂ R ^a , -NR ^aS (O) ₂ NR ^{a Ra} , -S(O) ^Ra , -S(O)NR ^{a Ra} , -S(O) ₂ ^Ra , -S(O) ₂ NR ^a C(O) Ra, -P(O)Ra ^Ra , -P(O)( ^{OR a} )(OR ^a ), -B( ^OH ) ₂ , -B(OR ^a ) ₂ and S(O) ₂ NR ^{a Ra} , wherein _R1 or _R2 is a ( _{C1-C6)alkyl, (C6} - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-14-membered heteroaryl, 4-14-membered heterocycloalkyl, ( _C6 - _C10 )aryl-(C1-C4)alkylene-, (C3-C10)cycloalkyl-( _C1 - _C4 )alkylene-, (C3- _C10 )cycloalkyl-(C1 _- C4)alkylene-, ( _C3 - _C10 )cycloalkyl-(C1 _- C4 ₎ alkylene-. The alkylene-, (5-14-membered heteroaryl)-(C1 _{- C4} )alkylene- and (4-14-membered heterocyclic alkyl)-(C1 _{- C4} )alkylene- are each optionally substituted by 1, 2, 3, 4 or 5 independently selected ^Rb substituents;

Each _R3 is independently selected from -H, halogroup, -OH, -CN, optionally substituted ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy, ( _C1 - _C6 )haloalkoxy, _-NH2 , -NH( _C1 - _C6 )alkyl, -N( _C1 - _C6 )alkyl) ₂ and ( _C3 - _C6 )cycloalkyl, wherein the ( _C1 -C6)alkoxy, -NH( _C1 - _C6 )alkyl, -N( _C1 - _{C6 )} alkyl) _{2 and} ( _C3 - _C6 )cycloalkyl of R3 are each optionally substituted by 1, 2 or 3 independently selected ^Rg substituents;

Each R ₁₄ is independently selected from halogen, -OH, -NH ₂ , -CN, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )haloalkyl, (C ₁ -C ₆ )haloalkoxy, -COOH, -NH(C ₁ -C ₆ )alkyl, -N(C ₁ -C _6alkyl ) ₂ , phenyl, phenyl-(C _1- C ₂ )alkylene, (C _3- C ₆ )cycloalkyl, (C _3- C ₆ )cycloalkyl-(C _1- C ₄ )alkylene-, 4 to 6-membered heterocycloalkyl, (4 to 6-membered heterocycloalkyl)-(C _1- C ₄ )alkylene-, 5 to 6-membered heteroaryl, (5 to 6-membered heteroaryl)-(C _1- C ₄ )alkylene- and -OR ^e , wherein R _The ( _C1 - _C6 )alkyl, phenyl, phenyl-(C1- _C2 )alkylene, ( _C3- C6)cycloalkyl, ( _{C3- C6} )cycloalkyl-(C1 _{- C4} )alkylene, 4- to ₆ -membered heterocycloalkyl, ( _4- to 6-membered heterocycloalkyl)-(C1 _{- C4} )alkylene, 5- to 6-membered heteroaryl and (5- to 6-membered heteroaryl)-(C1 _{- C4} )alkylene are each optionally substituted by one, two or three independently selected ^Rg substituents.

R ₁₅ is H or C _1-6 alkyl;

Each _R4 is independently selected from -H, halogroup, -OH, -COOR ^e , -CONR ^{e Re} , -CN, -NH ₂ , -NH ((C1 _{- C6} )alkyl), -N ((C1 _{- C6} )alkyl) ₂ , (C1 _{- C6} )alkyl, (C1 _{- C6} )alkoxy, (C1 _{- C6} )haloalkyl, (C1 _{- C6} )haloalkoxy, -CONR ^{a Ra} , -NR ^a COR ^a , -NR ^a CONR ^{a Ra} , -SO ₂ ^Ra , -NR ^a S(O) ₂ ^Ra , -NR ^a S(O) ₂ NR ^{a Ra} , (C3 _{- C6} )cycloalkyl, 4- to 6-membered heterocyclic alkyl, phenyl, 5- or 6-membered heteroaryl, (C3 _{- C6} )cycloalkyl-(C1 _- C4 ₎ R4 is optionally substituted with alkylene-, (4- to 6-membered heterocyclic alkyl)-(C1 _{- C4} )alkylene-, phenyl-(C1 _{- C2} )alkylene-, and (5 or 6-membered heteroaryl)-(C1 _{- C4} )alkylene-, wherein the ( _{C1- C6} )alkyl, ( _{C3- C6} )cycloalkyl, _4- to 6-membered heterocyclic alkyl, phenyl, 5 or 6-membered heteroaryl, ( _{C3- C6} )cycloalkyl-( _{C1- C4} )alkylene-, (4- to 6-membered heterocyclic alkyl)-(C1 _{- C4} )alkylene-, phenyl-(C1 _{- C2} )alkylene-, and (5 or 6-membered heteroaryl)-(C1 _{- C4} )alkylene-, respectively, by 1, 2 or 3 independently selected ^Rf substituents;

Each Ra ^is independently selected from -H, -CN, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )haloalkyl, ( _C2 - _C6 )alkenyl, (C2- _C6 )ynyl, ( _C6 -C10)aryl, ( _C3 - _C10 )cycloalkyl, 5-14-membered heteroaryl, 4-14-membered heterocycloalkyl, ( _{C6 - C10} )aryl-(C1- _C4 )alkylene-, (C3 _{- C10} )cycloalkyl-( _C1 - _C4 )alkylene-, (5-14-membered heteroaryl)-( _{C1- C4} )alkylene-, and (4-14-membered heterocycloalkyl)-( _{C1- C4 )} alkylene-, wherein the ( _C1 - _{C6)alkyl, (C1-C6 )} alkyl, ⁽ _C2 - _C6) alkylene- ... ( _C2 - _C6 )alkenyl, (C2-C6)ynyl, ( _C6 - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-14-membered heteroaryl, 4-14-membered heterocycloalkyl, ( _C6 - _C10 )aryl-( _C1 - _C4 )alkylene-, ( _{C3- C10} )cycloalkyl-( _C1 - _C4 )alkylene-, (5-14-membered heteroaryl)-( _{C1 - C4} )alkylene- and (4-14-membered heterocycloalkyl)-( _{C1 - C4} )alkylene- are each optionally substituted by 1, 2, 3, 4 or 5 independently selected ^Rd substituents;

Each ^Rb is independently selected from halogen, oxo, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, (C1-C6)haloalkyl, ( _{C1 -C6 )} haloalkoxy, ( _C6 - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-10-membered heteroaryl, _4-10 -membered heterocycloalkyl, ( _C6 - _C10 )aryl-( _{C1- C4} )alkylene-, ( _{C3- C10} )cycloalkyl-(C1 _{- C4} )alkylene-, (5-10-membered heteroaryl)-(C1 _{- C4} )alkylene-, (4-10-membered heterocycloalkyl)-(C1 _{- C4} )alkylene-, -CN, -OH, _-NH2 , -NO _2. -NHOR ^c , -OR ^c , -SR ^c , -C(O)R ^c , -C(O)NR ^c R ^c , -C(O)OR ^c , -C(O)NR ^c S(O) ₂ R ^c , -OC(O)R ^c , -OC(O)NR ^c R ^c , -C(=NOH)R ^c , -C(=NOH)NR ^c , -C(=NCN)NR ^c R ^c , -NR ^c C(=NCN)NR ^c R ^c , -C(=NR ^c )NR ^c R ^c , -NR ^c C(=NR ^c )NR ^c R ^c , -NHR ^c , -NR ^c R ^c , -NR ^c C(O)R ^c , -NR ^c C(=NR ^c )R ^c , -NR ^c C(O)OR ^c , -NR ^c C(O)NR ^c R ^c , -NR ^c S(O)R ^c ,-NR ^c S(O) _2Rc ^{, -NRcS} (O) _2NRcRc , ^-S (O) ^Rc , -S(O) ^NRcRc , -S(O) ^2Rc , -S(O) ^2NRcC (O) ^Rc , -Si(Rc) ₃ , -P(O) ^RcRc , ^-P ( ^O ₎ ( ^ORc )(ORc), ^-B (OH) ₂ , ^-B ( ^ORc ) ₂ and -S(O) _2NRcRc , wherein ^Rb is a ⁽ C1-C6) ^alkyl , (C1- ^C6 ) _haloalkyl , ( _C1 - _C6 )haloalkoxy, (C2-C6)alkenyl, ( _C2 - _C6 )alkynyl, ( _C6 - _C10 )aryl, (C3-C10)alkyl, ( _C3 - _C10 )alkyl, ( _C4 - _C5 )alkyl, ( _C6 - _C10 )alkyl, ( _C3- C10)alkyl, (C4 _... ( _C6 - _C10 ) aryl-(C1-C4) alkylene-, (C3-C10) cycloalkyl-( _{C1- C4} ) alkylene-, ( _5-10 ) heteroaryl-( _{C1 - C4} ) alkylene-, and ( _4-10 ) heterocycloalkyl-(C1 _{- C4 )} alkylene- are each optionally further substituted by one, two, or three independently selected ^Rd substituents;

Each ^Rc is independently selected from -H, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )haloalkyl, ( _C2 - _C6 )alkenyl, ( _C2 -C6)ynyl, (C6- _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-10 heteroaryl, 4-10 heterocycloalkyl, ( _C6 - _C10 )aryl-( _C1 - _C4 )alkylene-, (C3 _{- C10} )cycloalkyl-( _C1 - _C4 )alkylene-, (5-10 heteroaryl)-(C1 _{- C4} )alkylene-, and (4-10 heterocycloalkyl)-(C1 _{-C4)alkylene-, wherein the (C1- C6} )alkyl, ( _C2- C6)alkenyl, ( _C3 - _C10 ) alkylene-, ( ^C4 - _C10 ) alkylene-, ( _C6 - _C10 ) alkylene-, (C1 ... ₂ - _C6 ) ynyl, ( _C6 - _C10 ) aryl, ( _C3 - _C10 ) cycloalkyl, 5-10 heteroaryl, 4-10 heterocycloalkyl, (C6- _C10 ) aryl-( _C1 -C4) alkylene-, ( _C3 - _C10 ) cycloalkyl-(C1 _{- C4} ) alkylene-, (5-10 heteroaryl)-( _{C1 - C4} ) alkylene- and (4-10 heterocycloalkyl)-(C1 _{- C4} ) alkylene- are each optionally substituted by 1, 2, 3, ₄ or 5 independently selected R ^f substituents;

Each R d is independently selected from (C <sub>1- C 6  )alkyl, (C <sub>1- C  6 )haloalkyl, haloyl, (C<sub>6-C10)aryl, 5-10 heteroaryl, (C <sub>3- C 10 )cycloalkyl, 4-10 heterocyclic alkyl, (C <sub>6- C 10 )aryl-(C <sub>1- C 4 )alkylene-, (C <sub>3- C 10 )cycloalkyl-(C <sub>1- C 4 )alkylene-, (5-10 heteroaryl)-(C <sub>1- C 4 )alkylene-, (4-10 heterocyclic alkyl)-(C <sub>1- C4 )alkylene-, -CN, -NH 2 , -NHOR e , -OR e , -SRe, -C(O)R  e , -C(O)NReRe , -C(O)OR e -OC(O)R e , -OC(O)NR eR e , -NHR e , -NR eR e , -NR e C(O)R e , -NR e C(O)NR eR e , -NR e C(O)OR e , -C(＝NR e )NR eR e , -NR e C(＝NR e )NR eR e , -NR e C(＝NOH)NR eR e, -NR e C(＝NCN)NR eR e , -S (O)R e , -S(O)NR eR e , -S(O) 2 Re, -NR e S (O) 2 Re , -NR e S(O) 2 NR e Re and -S (O) 2 NR e Re , wherein R d is a (C 1- C 6 ) alkyl , (C 1 - C 6 )haloalkyl, (C 6- C 10 )alkyl, (C 6- C 10 )alkyl, ... )aryl, 5-10 heteroaryl, ( C3- C10 )cycloalkyl, 4-10 heterocycloalkyl, (C6 - C10 )aryl-(C1-C4)alkylene-, (C3 - C10 )cycloalkyl-( C1- C4 )alkylene-, ( 5-10 heteroaryl)-(C1- C4 )alkylene- and (4-10 heterocycloalkyl)-( C1- C4 ) alkylene- are each optionally substituted by 1, 2 or 3 independently selected R f substituents;

Each ^Re is independently selected from -H, (C1 _{- C6} )alkyl, (C3 _{- C6} )cycloalkyl-, (C3 _{- C6} )cycloalkyl-(C1 _{- C4} )alkylene-, (C6- _C10 )aryl, ( _{C6- C10} )aryl-( _{C1 - C4} )alkylene-, 5- or 6-membered heteroaryl, (5- or 6-membered heteroaryl)-(C1 _- C4)alkylene-, 4- or 7-membered heterocycloalkyl, (4- or 7-membered heterocycloalkyl)-(C1 _{- C4} )alkylene-, (C1- _C6 ) haloalkyl, ( _{C1 - C6} ) haloalkoxy, (C2 _{- C4} ) alkenyl, and (C2 _{- C4} ) ynyl, wherein ^the (C1 _{- C4} )alkyl, (C3 _{- C6)...} The cycloalkyl, ( _{C6- C10} ) aryl, 5- or 6-membered heteroaryl, 4- or 7-membered heterocycloalkyl, ( _{C6- or 10} ) aryl-( _{C1- or 4} ) alkylene-, (5- or 6-membered heteroaryl)-( _{C1- or 4} ) alkylene-, (4- or 7-membered heterocycloalkyl)-( _C1- or ₄ ) alkylene-, ( _{C2- or 4} ) alkenyl, and ( _C2- or ₄ ) ynyl groups are each optionally substituted with 1, 2, or 3 ^Rf substituents.

Or any two ^Ra substituents together with the nitrogen atom to which they are attached form a 4, 5, 6, 7, 8, 9 or 10-membered heterocyclic alkyl group, each heterocyclic alkyl group optionally being substituted by 1, 2 or 3 independently selected R ^f substituents;

Alternatively, any two ^Rc substituents together with the nitrogen atom to which they are attached can form a 4, 5, 6, 7, 8, 9, or 10-membered heterocyclic alkyl group, each heterocyclic alkyl group optionally being substituted by one, two, or three independently selected ^Rf substituents.

Or any two ^Re substituents together with the nitrogen atom to which they are attached form a 4, 5, 6, 7, 8, 9 or 10-membered heterocyclic alkyl group, each heterocyclic alkyl group optionally being substituted by 1, 2 or 3 independently selected R ^f substituents;

Each ^Rf is independently selected from halogen, -OH, -CN, -COOH, _-NH2 , -NH-(C1 _{- C6} )alkyl, -N((C1 _{- C6} )alkyl) ₂ , (C1 _{- C6} )alkyl, (C1- _C6 )alkoxy, ( _C1- C6)alkylthio, (C1 _{- C6} )haloalkyl, (C1 _{- C6} )haloalkoxy, phenyl, 5-6-membered heteroaryl, 4-6-membered heterocyclic alkyl, and ( _{C3 - C6} )cycloalkyl, wherein the (C1 _{- C6} )alkyl, phenyl, (C3 _{- C6} )cycloalkyl, 4-6-membered heterocyclic alkyl, and 5-6-membered heteroaryl of ^Rf are each optionally selected by 1, 2, or 3 from halogen, -OH, -CN, -COOH, _-NH2 , (C1 _- C6 ₎ alkyl, -NH- _{( ...} Substituents of alkyl, (C1 _{- C4} )alkoxy, (C1 _{- C4} )haloalkyl, ( _{C1- C4} )haloalkoxy, phenyl, (C3 _{- C10} )cycloalkyl, 5-6-membered heteroaryl and 4-6-membered heterocyclic alkyl groups;

Each R ^g is independently selected from halogenated, -OH, -CN, -COOH, -COO-( _{C1- C4} ) _alkyl , -NH2, -NH-( _{C1- C6} )alkyl, -N((C1 _{- C6} )alkyl) ₂ , ( _{C1- C6} )alkyl, (C1 _{- C6} )alkoxy, (C1- _C6 )alkylthio, ( _{C1- C6 )} haloalkyl, (C1 _{- C6} )haloalkoxy, phenyl, 5-6-membered heteroaryl, 4-6-membered heterocyclic alkyl and (C3 _{- C6} )cycloalkyl;

Y is selected from -O-, -S-, -SO-, _-SO₂- , -NH-, and -N((C₁ _{- C₆} )alkyl)-;

The cyclic nitrogen atom on the quinoline moiety in Formula A may optionally be oxidized;

The subscript n is an integer of 1, 2, 3 or 4;

The subscript m is an integer of 1, 2, 3, 4, or 5; and

The subscript p is an integer of 0, 1, 2, 3 or 4.

On the other hand, it provides a method for treating diseases, symptoms, or syndromes mediated at least in part by modulating the in vivo activity of protein kinases using compounds of Formula I or pharmaceutically acceptable salts thereof.

On the other hand, methods for preparing compounds of formula A and formula I are provided.

These and other aspects, as well as the implementation plan, are described below.

Detailed Implementation

Abbreviations and Definitions

The following abbreviations and terms have a consistent meaning throughout the text:

The symbol "-" represents a single bond, and "=" represents a double bond.

As used in this article, the singular forms “a,” “a,” and “the” include plural references unless the context clearly indicates otherwise.

When a variable is defined generally, it has many possible substituents, and each individual group can be defined as having or not having a bond. For example, if R ^_z can be hydrogen, this can be indicated as "-H" or "H" in the definition of R_^z.

When depicting or describing chemical structures, unless otherwise explicitly stated, it is assumed that all carbon atoms have tetravalent hydrogen substitutions. For example, in the structure on the left of the following diagram, nine hydrogen atoms are implied. Nine hydrogen atoms are depicted in the structure on the right. Sometimes, specific atoms in a structure are described in the textual formula as having one or more hydrogen atoms as substituents (explicitly defined as _hydrogen ), such as _-CH₂CH₂- . Those skilled in the art will understand that the above descriptive techniques are common in the field of chemistry to provide a concise and simple description of other complex structures.

If the group "R" is described as "floating" on the ring system, such as in the following formula:

Unless otherwise defined, the substituent “R” can be located on any atom of the ring system, assuming that a hydrogen atom described, implicit or explicitly defined is replaced from one of the ring atoms, as long as a stable structure is formed.

If the group "R" is described as floating on a fused ring system, such as in the following formula:

Unless otherwise defined, the substituent “R” can be located on any atom in a fused ring system, assuming substitution from one of the ring atoms for a hydrogen atom described (e.g., -NH- in the above formula), an implicit hydrogen atom (e.g., hydrogen not shown in the above formula but to be understood as present), or an explicitly defined hydrogen atom (e.g., “Z” equals =CH- in the above formula), as long as a stable structure is formed. In the example shown, the “R” group can be located on a 5-membered or 6-membered ring in the fused ring system. When the group “R” is described as being present on a ring system containing saturated carbon, for example in the following formula:

In this example, "y" can be more than one, assuming each substitutes for a currently depicted, implicit, or explicitly defined hydrogen atom on the ring; then, unless otherwise defined, two "R"s can be located on the same carbon atom, provided the resulting structure is stable. A simple example is that when R is a methyl group, a geminal dimethyl group can be present on the carbon atom of the ring shown (the "cyclic" carbon). In another example, two Rs (including the carbon atom) on the same carbon atom can form a ring, resulting in a spirocyclic ("spirocyclic" group) structure having a ring as shown, for example, in the following formula:

"Halogen" or "halogenated group" refers to fluorine, chlorine, bromine or iodine.

The term “C _nm ” or “C _n - _{C m} ” indicates a range including the endpoints, where n and m are integers and represent the number of carbons. Examples include C _1-4 , C ₁ -C ₄ , C _1-6 , C ₁ -C ₆ , etc.

"Alkyl" refers to a branched or straight-chain hydrocarbon chain having one to eight carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, and heptyl. ( _C1 - _C6 )alkyl is preferred. The terms "Cn _nm alkyl" or "( _Cn - _Cm )alkyl" refer to an alkyl group having n to m carbon atoms. When optionally substituted, one or more hydrogen atoms of the alkyl group (e.g., 1 to 4, 1 to 2, or 1) may be partially substituted as described in "Optional Substitution" below. In some aspects, the alkyl group is unsubstituted or not optionally substituted.

"alkylene" refers to a divalent saturated aliphatic group having 1 to 10 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 2 carbon atoms with optional substitution. When optionally substituted, one or more hydrogen atoms (e.g., 1 to 4, 1 to 2, or 1) of the alkylene group may be partially substituted as described in "Optional Substitution" below. In some aspects, the alkylene group is unsubstituted or not optionally substituted. The term "Cn-m alkylene" refers to an alkylene group having n to m carbon atoms. Examples of alkylene groups include, but are not limited to, methylene, ethane-1,2-diyl, propane-1,3-diyl, propane-1,2-diyl, butane-1,4-diyl, butane-1,3-diyl, butane-1,2-diyl, 2-methyl-propane-1,3-diyl, etc.

The term "alkenyl" refers to a straight-chain or branched hydrocarbon group corresponding to an alkyl group having one or more carbon-carbon double bonds. An alkenyl group formally corresponds to an alkene in which one of the CH bonds is replaced by the alkenyl group at the junction with the remainder of the compound. The terms "C_{_n}n-alkenyl" or "(C _{_n}-C _{_m} )alkenyl" refer to an alkenyl group having n to m carbon atoms. In some embodiments, the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Exemplary alkenyl groups include, but are not limited to, vinyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, etc.

The term "alkynyl" refers to a straight-chain or branched hydrocarbon group corresponding to an alkyl group having one or more carbon-carbon triple bonds. An alkynyl group formally corresponds to an alkyne in which one of the CH bonds is replaced by an alkyl group at the junction with the remainder of the compound. The terms "C _{_n}nm</sub>alkynyl" or "(C _{_n}-C _{_m} )alkynyl" refer to an alkynyl group having n to m carbon atoms. Exemplary alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl, etc. In some embodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

"Alkoxy" refers to the part of the formula -OR', where R' is a ( _C1 - _C6 ) alkyl moiety as defined herein. The terms "Cn _nm alkoxy" or "( _Cn - _Cm ) alkoxy" refer to an alkoxy group whose alkyl group has n to m carbons. Examples of alkoxy moiety include, but are not limited to, methoxy, ethoxy, isopropoxy, etc.

The alkoxy group may be unsubstituted or optionally substituted. When optionally substituted, one or more hydrogen atoms of the alkoxy group (e.g., 1 to 4, 1 to 2, or 1) may be partially substituted as described in “Optional Substitution” below, provided that the α-hydrogen atom of the ether oxygen is not substituted by a hydroxyl, amino, or thio group. In some aspects, the alkoxy group is unsubstituted or not optionally substituted.

"Alkoxycarbonyl" refers to the group -C(O)-R', where R' is a ( _C1 - _C6 ) alkoxy group as defined herein.

The term "amino" refers to a group with the formula -NH ₂ .

The term "carbamoyl" refers to a group with the formula -C(O)NH ₂ .

The term "carbonyl" used alone or in combination with other terms refers to the -C(=O)- group, which can also be written as C(O).

The term "cyano" or "nitrile" refers to a group with the formula -C≡N, which can also be written as -CN or CN.

The term "oxo" refers to an oxygen atom as a divalent substituent, which, when attached to carbon, forms a carbonyl group, or when attached to a heteroatom, forms a sulfoxide or sulfone group or an N-oxide group. In some embodiments, the heterocyclic group may optionally be substituted by one or two oxo (=O) substituents.

The term "sulfide" refers to a sulfur atom as a divalent substituent, which, when attached to carbon, forms a thiocarbonyl group (C=S).

The term “heteroatoms” as used in this article is intended to include boron, phosphorus, sulfur, oxygen, and nitrogen.

As used herein, the term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms have been replaced by halogen atoms. The term "C _{_n}nm haloalkyl" or (C _{_n}-C_{_m}) haloalkyl refers to a C _{_n} nm alkyl group having n to m carbon atoms and at least one to at most {2(nm)+1} halogen atoms that may be the same or different. In some embodiments, the halogen atom is a fluorine atom. In some embodiments, the haloalkyl group has 1 to 6 or 1 to 4 carbon atoms. Exemplary haloalkyl groups include CF _₃, C _₂F_₅ , CH _{_F2}, CCl _{₃, CHCl₂ ,} C _₂Cl _₅, etc. In some embodiments, the haloalkyl group is a fluoroalkyl group.

The term "haloalkoxy" used alone or in combination with other terms refers to a group of the formula -O-haloalkyl, wherein the haloalkyl group is as defined above. The term "C _{_n}nm</sub>haloalkoxy" or (C _{_n}-C_{_m} )haloalkoxy refers to a haloalkoxy group whose haloalkyl group has n to m carbons. Exemplary haloalkoxy groups include trifluoromethoxy, etc. In some embodiments, the haloalkoxy group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

"Aryl" refers to a monocyclic or dicyclic ring (e.g., having two fused rings) with a monovalent carbon group of six to fourteen members, wherein the monocyclic ring is aromatic and at least one ring in the dicyclic ring is aromatic. The terms "C _{_n}nm</sub>aryl" or "(C _{_n}-C_{_m})aryl" refer to an aryl group having n to m ring carbon atoms. In some embodiments, the aryl group has 6 to about 10 carbon atoms. In some embodiments, the aryl group has 6 carbon atoms. In some embodiments, the aryl group has 10 carbon atoms. Unless otherwise stated, the valence bond of the group may be located on any atom of any ring within the group, where permitted by the valence bond rules. Representative examples include phenyl, naphthyl, and indenyl.

The aryl group may be unsubstituted or optionally substituted. When optionally substituted, one or more hydrogen atoms of the aryl group (e.g., 1 to 5, 1 to 2, or 1) may be partially substituted as described in “Optional Substitution” below. In some aspects, the alkoxy group is unsubstituted or not optionally substituted.

"Arylene" refers to a divalent, six- to fourteen-membered single-carbon or double-carbon ring, wherein the single ring is aromatic and at least one ring in the double ring is aromatic. Representative examples include phenylene, naphthylene, and indenylene.

“Cycloalkyl” refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic, or polycyclic), including cyclic alkyl and alkenyl groups. The terms “C _{_n}nm cycloalkyl” or “(C _{_n}-C_{_m} )cycloalkyl” refer to a cycloalkyl group having n to m ring member carbon atoms. Cycloalkyl groups may include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) groups and spirocyclic groups. Cycloalkyl groups may have 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 cyclic carbons (C _{_3-14}). In some embodiments, the cycloalkyl group has 3 to 14 members, 3 to 10 members, 3 to 6 ring members, 3 to 5 ring members, or 3 to 4 ring members. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl group is a C _{_3-6} monocyclic cycloalkyl group. The cycloalkyl group may optionally be oxidized to form an oxo or thio group. The cycloalkyl group also includes a cycloalkylene group. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cyclohepttrienyl, norbornyl, norpinel, norcarelyl, bicyclo[1.1.1]pentenyl, bicyclo[2.1.1]hexenyl, etc. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, the cycloalkyl group comprises a single saturated carbon ring having three to eight carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The cycloalkyl group may optionally be substituted with one or more substituents (such as one, two, or three substituents). In some embodiments, the cycloalkyl substituent is selected from ( _C1 - _C6 )alkyl, hydroxyl, ( _C1 - _C6 )alkoxy, halo( _C1 - _C6 )alkyl, halo( _C1 - _C6 )alkoxy, halogroup, amino, mono- and di( _C1 - _C6 )alkylamino, hetero( _C1 - _C6 )alkyl, acyl, aryl, and heteroaryl.

The cycloalkyl group may be unsubstituted or optionally substituted. When optionally substituted, one or more hydrogen atoms (e.g., 1 to 4, 1 to 2, or 1) of the cycloalkyl group may be partially substituted as described in “Optional Substitution” below. In some aspects, the substituted cycloalkyl group may be incorporated into an external or internal cycloalkene (e.g., cyclohexyl-2-en-1-yl). In some aspects, the cycloalkyl group is unsubstituted or not optionally substituted.

"Cycloalkoxycarbonyl" means the group -C(O)-OR', where R' is a ( _C3 - _C6 ) cycloalkyl group as defined herein.

"Phenoxycarbonyl" refers to the group -C(O)-O phenyl.

"Heteroaryl" refers to a monocyclic, fused bicyclic, or fused tricyclic monocyclic group of 5 to 14 ring atoms, containing one or more (preferably one, two, three, or four) cyclic heteroatoms independently selected from -O-, -S(O) _n- (n is 0, 1, or 2), -N-, and -N(R')-, and the remaining ring atoms are carbon, wherein the ring containing the monocyclic group is aromatic, and at least one ring in the fused ring containing the bicyclic or tricyclic group is aromatic. One or both ring carbon atoms of any non-aromatic ring containing the bicyclic or tricyclic group may be replaced by a -C(O)-, -C(S)-, or -C(=NH)- group. R' is hydrogen, alkyl, hydroxyl, alkoxy, acyl, or alkylsulfonyl. Unless otherwise specified, the valence bond may be located on any atom of any ring of the heteroaryl group, where permitted by the valence bond rules. In particular, when the valence bond is located on nitrogen, there is no additional nitrogen substituent. More specifically, the term heteroaryl includes, but is not limited to, 1,2,4-triazolyl, 1,3,5-triazolyl, phthalimide, pyridyl, pyrroleyl, imidazolyl, thiophene, furanyl, indoleyl, 2,3-dihydro-1H-indoleyl (including, for example, 2,3-dihydro-1H-indole-2-yl or 2,3-dihydro-1H-indole-5-yl), isoindoleyl, dihydroindoleyl, isoindolelinyl, benzimidazolyl, benzo[a]dioxacyclopenten-4-yl, benzofuranyl, cyclolinyl, indazinyl, diazanaphthyl-3-yl, phthalazin-3-yl, phthalazin-4-yl, pteridinyl, and purineyl. Quinazolinyl, quinoxolinyl, tetrazolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, oxadiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl (including, for example, tetrahydroisoquinolin-4-yl or tetrahydroisoquinolin-6-yl), pyrrolo[3,2-c]pyridinyl (including, for example, pyrrolo[3,2-c]pyridin-2-yl or pyrrolo[3,2-c]pyridin-7-yl), benzopyranyl, thiazolyl, isothiazolyl, thiadiazolyl, benzothiazolyl, benzothiaphenyl, and their derivatives, as well as their N-oxides or protected derivatives.

A five-membered heteroaryl ring is a heteroaryl group having five ring atoms, wherein one or more (e.g., 1, 2, 3, or 4) ring atoms are independently selected from N, O, and S. Exemplary five-membered heteroaryl rings include thiophene, furanyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl.

A six-membered heteroaryl ring is a heteroaryl group having six ring atoms, wherein one or more (e.g., 1, 2, 3, or 4) ring atoms are independently selected from N, O, and S. Exemplary six-membered heteroaryl rings are pyridyl, pyrazinyl, pyrimidinyl, triazinyl, and pyridazinyl.

"Heteroarylene" refers to a divalent group of 5 to 14 ring atoms in a monocyclic, fused bicyclic, or fused tricyclic form, containing one or more (preferably one, two, three, or four) cyclic heteroatoms independently selected from -O-, -S(O) _n- (n is 0, 1, or 2), -N-, and -N(R ¹⁹ )-, and the remaining ring atoms are carbon, wherein the ring containing the monocyclic group is aromatic, and at least one ring in the fused ring containing the bicyclic or tricyclic group is aromatic. One or both ring carbon atoms of any non-aromatic ring containing the bicyclic or tricyclic group may be replaced by a -C(O)-, -C(S)-, or -C(=NH)- group. ^{R 19} is hydrogen, alkyl, or alkenyl. Unless otherwise specified, the valence bond may be located on any atom of any ring of the heteroarylene group, where permitted by the valence bond rules. In particular, when the valence bond is located on nitrogen, there is no additional nitrogen substituent. More specifically, the term heteroaryl includes, but is not limited to, thiophene-diyl, benzo[d]isoxazole-diyl, benzo[d]isothiazol-diyl, 1H-indazole-diyl (optionally substituted at the N1 position with R ¹⁹ ), benzo[d]oxazole-diyl, benzo[d]thiazol-diyl, 1H-benzo[d]imidazol-diyl (optionally substituted at the N1 position with R ¹⁹ ), 1H-benzo[d][1,2,3]triazole-diyl (optionally substituted at the N1 position with R ¹⁹ ), imidazo[1,2-a]pyridine-diyl, cycloline-diyl, quinoline-diyl, pyridine-diyl, 1-oxo-pyridine-diyl, [1,2,4]triazolo[4,3-a]pyridine-diyl and 2,3-dihydroimidazo[1,2-a]pyridine-diyl, etc.

As used herein, “heterocyclic alkyl” or “heterocyclic group” refers to a non-aromatic ring or ring system that optionally contains one or more alkenyl groups as part of a ring structure, has at least one heteroatom ring member independently selected from boron, nitrogen, sulfur, oxygen, and phosphorus, and has 4-14, 4-10, 4-7, or 4-6 ring members. The term “heterocyclic alkyl” includes monocyclic 4-, 5-, 6-, and 7-membered heterocyclic alkyl groups. Heterocyclic alkyl groups may include monocyclic, bicyclic, or polycyclic (e.g., having two or three fused or bridged rings) ring systems or spirocyclic rings. In some embodiments, the heterocyclic alkyl group is a monocyclic group having one, two, or three heteroatoms independently selected from nitrogen, sulfur, and oxygen. The cyclic carbon atom and heteroatom of the heterocyclic alkyl group may optionally be oxidized to form an oxo or thio group or other oxidized bond (e.g., C(O), S(O), C(S), S(O) _₂ , N-oxide, etc.), or the nitrogen atom may be quaternized. The heterocyclic alkyl group may be linked by a cyclic carbon atom or a cyclic heteroatom. In some embodiments, the heterocyclic alkyl group contains 0 to 3 double bonds. In some embodiments, the heterocyclic alkyl group contains 0 to 2 double bonds. The definition of heterocyclic alkyl also includes a portion having one or more aromatic rings fused with (i.e., sharing bonds with) the heterocyclic alkyl ring, such as benzo[a] or thiophene derivatives of piperidine, morpholine, aza, etc. Heterocyclic alkyl groups containing fused aromatic rings may be linked by any cyclic atom, including the cyclic atom of the fused aromatic ring. Examples of heterocyclic alkyl groups include azirrobutyl, azirroheptyl, dihydrobenzofuranyl, dihydropyranyl, morpholino, 3-oxa-9-azaspiro[5.5]undecyl, 1-oxa-8-azaspiro[4.5]decyl, piperidinyl, piperazinyl, oxoperazinyl, pyranyl, pyrrolidinyl, quininecycloyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,4-tetrahydroquinolinyl, scopolyl, 4,5,6,7-tetrahydrothiazo[5,4-c]pyridinyl, and thiomorpholino.

The term "heterocyclic alkyl" or "heterocyclic group" can be unsubstituted or optionally substituted. When optionally substituted, one or more hydrogen atoms of the group (e.g., 1 to 4, 1 to 2, or 1) can be partially substituted independently from fluorine, hydroxyl, alkoxy, amino, alkylamino, acylamino, thio, and alkylthio groups. In some aspects, the substituted heterocyclic group may be incorporated into an external or internal cyclic olefin (e.g., cyclohexyl-2-en-1-yl). In some aspects, the heterocyclic group is unsubstituted or not optionally substituted.

Optional replacement

Unless otherwise expressly stated, groups are optionally substituted herein. The term “optionally substituted” means substituted or unsubstituted. In some embodiments, alkyl, alkenyl, ynyl, carbocycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally substituted. “Optionally substituted” means a group that can be substituted or unsubstituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” ynyl, “substituted” or “unsubstituted” cycloalkyl, “substituted” or “unsubstituted” cycloalkyl, “substituted” or “unsubstituted” heterocycloalkyl, “substituted” or “unsubstituted” aryl, or “substituted” or “unsubstituted” heteroaryl). Generally, the term “substituted” means that at least one hydrogen present on the group is replaced by a permissible substituent, such as a substituent that, after substitution, yields a stable compound (e.g., a compound that does not spontaneously transform, such as through rearrangement, cyclization, elimination, or other reactions). Unless otherwise stated, a “substituted” group has a substituent at one or more substituted positions of the group, and the substituent is either the same or different at each position when more than one position is substituted in any given structure. The term “substituted” contemplates substitution by all permissible substituents of an organic compound, and includes any substituents described herein that result in the formation of a stable compound. The invention contemplates any and all such combinations to obtain a stable compound. For the purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituents described herein that satisfy the valence of the heteroatom and result in the formation of a stable moiety. The invention is not intended to be limited in any way to the exemplary substituents described herein.

Exemplary carbon atom substituents include, but are not limited to, halogens (halogenated groups), -CN, _-NO₂ , _-N₃ , _-SO₂H , _-SO₃H , -OH, -OR ^aa , -ON(R ^bb ) ₂ , -N(R ^bb ) ₂ , -N(R ^bb ) ₃ ⁺ X ^- , -N(OR ^cc )R ^bb , -SH, -SR ^aa , -SSR ^cc , -C(＝O)R ^aa , _-CO₂H , -CHO, -C(OR ^cc ) ₂ , _-CO₂R ^aa , -OC(＝O)R ^aa , _-OCO₂R ^aa , -C(＝O)N(R ^bb ) ₂ , -OC(＝O)N(R ^bb ) ₂ , -NR ^bb C(＝O)R ^aa , -NR ^bb _CO₂R ^aa , -NR ^bb C(=O)N(R ^bb ) ₂ , -C(=NR ^bb )R ^aa , -C(=NR ^bb )OR ^aa , -OC(=NR ^bb )R ^aa , -OC(=NR ^bb )OR ^aa , -C(=NR ^bb )N(R ^bb ) ₂ , -OC(=NR ^bb )N(R ^bb ) ₂ , -NR ^bb C(=NR ^bb )N(R ^bb ) ₂ , -C(=O)NR ^bb SO ₂ R ^aa , -NR ^bb SO ₂ R ^aa , -SO ₂ N(R ^bb ) ₂ , -SO ₂ R ^aa , -SO ₂ OR ^aa , -OSO ₂ R ^aa , -S(=O)R ^aa , -OS(=O)R ^aa , -Si(R ^aa ) ₃ , -OSi(R ^aa ) ₃ -C(=S)N(R ^bb ) ₂ , -C(=O)SR ^aa , -C(=S)SR ^aa , -SC(=S)SR ^aa , -SC(=O)SR ^aa , -OC(=O)SR ^aa , -SC(=O)OR ^aa , -SC(=O)R ^aa , -P(=O) ₂ R ^aa , -OP(=O) ₂ R ^aa , -P(＝O)(R ^aa ) ₂ , -OP(＝O)(R ^aa ) ₂ , -OP(＝O)(OR ^cc ) ₂ , -P(＝O) ₂ N(R ^bb ) ₂ , -OP(＝O) ₂ N(R ^bb ) ₂ , -P(＝O)(NR ^bb ) ₂ , -OP(＝O)(NR ^bb ) ₂ , ^-NRbb P(＝O)(OR ^cc ) ₂ 、 -NR ^bb P(＝O)(NR ^bb ) ₂ 、 -OP(R ^cc ) ₂ 、 -OP(R ^cc ) ₃ 、 -B(OR ^cc ) ₂ 、 -BR ^aa (OR ^cc ), C _1-10 alkyl, C _1-10 perhaloalkyl, C _2-10 alkenyl, C _2-10 ynyl, (C ₃ -C ₁₀ ) carbocycloalkyl, 3-14 membered heterocycloalkyl, (C ₆ -C ₁₄ ) aryl and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R ^dd groups;

Alternatively, the two hydrogen atoms on the carbon atom can be replaced by the groups =O, =S, =NN(R ^bb ) ₂ , =NNR ^bb C(=O)R ^aa , =NNR ^bb C(=O)OR ^aa , =NNR ^bb S(=O) ₂ R ^aa , =NR ^bb or =NOR ^cc ;

Each instance of ^Raa is independently selected from ( _C1 - _C10 ) alkyl, ( _C1 - _C10 ) perhaloalkyl, ( _C2 - _C10 ) alkenyl, ( _C2 - _C10 ) ynyl, ( _C3 - _C10 ) cycloalkyl, 3-14-membered heterocyclic alkyl, ( _C6 - _C14 ) aryl and 5-14-membered heteroaryl, or two ^Raa groups are joined to form a 3-14-membered heterocyclic alkyl or 5-14-membered heteroaryl ring, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic alkyl, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4 or 5 ^Rdd groups;

Each instance of R ^bb is independently selected from hydrogen, ( _C1 - _C10 ) perhaloalkyl, ( _C2 - _C10 ) alkenyl, ( _C2 - _C10 ) ynyl, ( _C3 - _C10 ) cycloalkyl, _C6-14 aryl and 5-14 heteroaryl, or two R ^bb groups are joined to form a 3-14 heterocyclic alkyl or 5-14 heteroaryl ring, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic alkyl, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4 or 5 R ^dd groups;

Each instance of R cc is independently selected from hydrogen, (C <sub>1 -C  10 )alkyl, (C <sub>1 -C 10 ) perhaloalkyl, (C <sub>2 -C 10 )alkenyl, (C <sub>2 -C10 )ynyl, (C<sub>3-C10)cycloalkyl, 3-14-membered heterocyclic alkyl, (C <sub>6 -C14 )aryl and 5-14-membered heteroaryl, or two R cc  groups are joined to form a 3-14-membered heterocyclic alkyl or 5-14-membered heteroaryl ring, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic alkyl, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4 or 5 R dd groups;

Each instance of R dd is independently selected from halogens, -CN, -NO2 , -SO 2 H, -SO 3 H, -OH, -OR ee , -ON(R ff )2, -N(Rff )  2  , -N(Rff) 3  + X- , -N(OR ee )R ff , -SH, -SR ee , -SSRee, -C ( =O)R ee , -CO 2 H, -CO 2 Ree, -OC(=O)R ee , -OCO 2 R ee , -C(=O)N(R ff ) 2 , -OC(=O)N(R ff ) 2 , -NR  ff C(=O)R ee , -NRffCO 2 R ee , -NRff C(=O)N(R ff ) 2 , -C(=NRff  )OR2 ee , -OC(=NR ff )R ee , -OC(=NR ff )OR ee , -C(=NR ff )N(R ff ) 2 , -OC(=NR ff )N(R ff ) 2 , -NR ff C(=NR ff )N(R ff ) 2 , -NR ff SO 2 R ee , -SO 2 N(R ff ) 2 , -SO 2 R ee , -SO 2 OR ee , -OSO 2 R ee , -S(=O)R ee , -Si(R ee ) 3 , -OSi(R ee ) 3 , -C(=S)N(R ff ) 2 , -C(=O)SR ee , -C(=S)SR ee , -SC(=S)SR ee , -P(=O) 2 R ee , -P(＝O)(R ee ) 2 , -OP(＝O)(R ee ) 2 , -OP(＝O)(OR ee ) 2 , (C 1 -C 10 )alkyl, (C 1 -C 10 )perhaloalkyl, (C 2 -C 10 )alkenyl, (C 2 -C 10 )ynyl, (C 3 -C 10 )cycloalkyl, 3-10-membered heterocyclic alkyl, (C 6 -C 10 )aryl, 5-10-membered heteroaryl, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic alkyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R gg groups, or two geminal R dd substituents may be joined to form =O or =S;

Each instance of ^Ree is independently selected from ( _C1 - _C6 )alkyl, ( _C1 - _C6 )perhaloalkyl, ( _C2 - _C6 )alkenyl, (C2-C6)ynyl, ( _C3 - _C10 )cycloalkyl, ( _{C6 - C10} )aryl, 3-10 heterocyclic alkyl, and 3-10 heteroaryl, wherein each alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, cycloalkyl, heterocyclic alkyl, aryl, and heteroaryl is independently substituted by 0, 1, 2, ₃ , 4, or 5 ^Rgg groups;

Each instance of R ff is independently selected from hydrogen, (C <sub>1 -C  6  )alkyl, (C<sub> 1- C6 )perhaloalkyl, (C <sub>2 -C 6 )alkenyl, (C <sub>2- C6 )ynyl, (C <sub>3 -C 10 )cycloalkyl, (C<sub>6-C10)aryl, and 5-10 heteroaryl, or two R ff  groups are joined to form a 3-10 heterocyclic alkyl or 5-10 heteroaryl ring, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic alkyl, aryl, and heteroaryl group is independently substituted by 0, 1, 2, 3, 4, or 5 R gg groups; and

Each instance of R gg  is independently a halogen, -CN, -NO2 , -SO 2 H, -SO 3 H, -OH, -OC 1-6 alkyl, -ON(C 1-6 alkyl) 2 , -N(C  1-6 alkyl) 2  + X - , -NH(C 1-6 alkyl) 2  + X - , -NH2 (C 1-6 alkyl) + X- , -NH 3  + X - , -N(OC 1-6 alkyl)(C  1-6 alkyl), -N(OH)(C1-6alkyl), -NH(OH), -SH, -SC 1-6 alkyl, -SS(C 1-6 alkyl), -C(＝O)(C 1-6 alkyl), -CO2 H, -CO 2 (C1-6alkyl), -OC(＝O)(C 1-6 alkyl), -OCO2 (C 1-6 alkyl), 1-6 alkyl), -C(=O)NH 2 , -C(=O)N(C 1-6 alkyl) 2 , -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -NHCO 2 (C 1-6 alkyl), -NHC(=O)N(C 1-6 alkyl) 2 , -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH 2 , -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1-6 alkyl), -OC(=NH)OC 1-6 alkyl, -C(=NH)N(C 1-6 alkyl) 2 , -C(=NH)NH(C 1-6 alkyl), -C(=NH)NH 2 , -OC(=NH)N(C 1-6 alkyl) 1-6 alkyl) 2 , -OC(NH)NH (C 1-6 alkyl), -OC(NH)NH 2 , -NHC(NH)N (C 1-6 alkyl) 2 , -NHC(＝NH)NH 2 , -NHSO 2 (C 1-6 alkyl), -SO 2N (C 1-6 alkyl) 2 , -SO 2NH (C 1-6 alkyl), -SO 2NH 2 , -SO 2 C 1-6 alkyl, -SO 2 OC 1-6 alkyl, -OSO 2 C 1-6 alkyl, -SOC 1-6 alkyl, -Si (C 1-6 alkyl) 3 , -OSi (C 1-6 alkyl) 3 , -C(＝S)N (C 1-6 alkyl) 2 , C(＝S)NH (C 1-6 alkyl), C(＝S)NH 2 , -C(＝O)S (C 1-6 alkyl) =1-6 alkyl), -C(=S)SC 1-6 alkyl, -SC(=S)SC 1-6 alkyl, -P(=O) 2 (C 1-6 alkyl), -P(=O)(C 1-6 alkyl) 2 , -OP(=O)(C 1-6 alkyl) 2 , -OP(=O)(OC 1-6 alkyl) 2 , (C 1 -C 6 ) alkyl, (C 1 -C 6 ) perhaloalkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) ynyl, (C 3 -C 10 ) cycloalkyl, (C 6 -C 10 ) aryl, 3-10 membered heterocyclic alkyl, 5-10 membered heteroaryl; or two homologous R gg substituents can be joined to form =O or =S; wherein X- is a counter ion.

As mentioned earlier, nitrogen atoms can be substituted or unsubstituted, where valence bonds allow, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, -OH, -OR ^aa , -N(R ^cc ) ₂ , -CN, -C(＝O)R ^aa , -C(＝O)N(R ^cc ) ₂ , -CO _2R ^aa , -SO _2R ^aa , -C(＝NR ^bb )R ^aa , -C(＝NR ^cc )OR ^aa , -C(＝NR ^cc )N(R ^cc ) ₂ , -SO _2N (R ^cc ) ₂ , -SO _2R ^cc , -SO _2OR ^cc , -SOR ^aa , -C(＝S)N(R ^cc ) ₂ , -C(＝O)SR ^cc , -C(＝S)SR ^cc , -P(＝O) _2R ^aa , -P(＝O)(R ^aa ) ₂ , -P(＝O) _2N (R ^cc ) ₂ , -P(＝O)(NR ^cc ) ₂ , (C ₁ -C ₁₀ ) alkyl, (C ₁ -C ₁₀ ) perhaloalkyl, (C ₂ -C ₁₀ ) alkenyl, (C ₂ -C ₁₀ ) ynyl, (C ₃ -C ₁₀ ) cycloalkyl, 3-14-membered heterocyclic alkyl, (C ₆ -C 1 ₄ ) aryl and 5-14-membered heteroaryl, or two R ^cc groups attached to the N atom are joined to form a 3-14-membered heterocyclic alkyl or 5-14-membered heteroaryl ring, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic alkyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R ^dd groups, and wherein ^Raaa , ^Rbb , ^Rcc and ^Rdd are as defined above.

In some embodiments, the substituents present on the nitrogen atom are nitrogen protecting groups (also referred to herein as "amino protecting groups"). Nitrogen-protecting groups include, but are not limited to, -OH, -OR ^aa , -N( ^Rcc ) ₂ , -C(=O)R ^aa , -C(=O)N( ^Rcc ) ₂ , _-CO2R ^aa , -SO2R _aa , -C(= ^NRcc ) ^{R aa ,} -C(= ^NRcc )OR ^aa , -C(=NRcc)N( ^Rcc ) ₂ , -SO2N( ^Rcc )2, _-SO2Rcc , -SO2ORcc, -SOR aa, _-C (= ^S )N( ^Rcc) ₂ , -C(=O ^)SRcc , ^-C (=S)SRcc, ( ^C1 -C10) _alkyl (e.g., aralkyl, heteroaralkyl ⁾ , (C2-C10) ^alkenyl , ( _C2 - _C10 )alkyl, ( _{C1-C10)alkyl, (C2 - C10} )alkyl, ( _C1 -C10)alkyl, _{... The} group may contain alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aralkyl _, aryl, and heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aralkyl, aryl, and heteroaryl group is independently substituted by 0, 1 _{, 2} , 3, 4, or 5 ^Rdd groups, wherein ^Raaa , ^Rbb , ^Rcc , and ^Rdd are as defined herein. Nitrogen protecting groups are well known in the art, including those described in detail in Protecting Groups in Organic Synthesis, TW Greene and PGMWuts, 3rd edition, John Wiley & Sons, 1999 (incorporated herein by reference).

For example, nitrogen-protecting groups such as amide groups (e.g., -C(=O) ^Raa ) include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropionamide, pyridine amide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetylacetamide, (N'-dithiobenzyloxyacetamide)acetamide, 3-(p-hydroxyphenyl)propionamide, 3-(o-nitrophenyl)propionamide, 2-methyl-2-(o-nitrophenoxy)propionamide, 2-methyl-2-(o-phenylazophenoxy)propionamide, 4-chlorobutyramide, 3-methyl-3-nitrobutyramide, o-nitrocinnamamide, N-acetylmethionine derivatives, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

Nitrogen protecting groups such as urethane groups (e.g., -C(=O)OR ^aa ) include, but are not limited to, methyl urethane, ethyl urethane, 9-fluorenyl methyl urethane (Fmoc), 9-(2-sulfonyl)fluorenyl methyl urethane, 9-(2,7-dibromo)fluorenyl methyl urethane, methyl 2,7-di-tert-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothiophene)]urethane (DBD-Tmoc), 4-methoxybenzoyl urethane (Phenoc), 2,2,2-trichloroethyl urethane (Troc), and 2-trimethylsilyl ethyl urethane. 1-(1-adamantyl)-1-methylethylcarbamate (Teoc), 2-phenylethylcarbamate (hZ), 1-(1-adamantyl)-1-methylethylcarbamate (Adpoc), 1,1-dimethyl-2-haloethylcarbamate, 1,1-dimethyl-2,2-dibromoethylcarbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethylcarbamate (TCBOC), ethyl 1-methyl-1-(4-biphenyl)carbamate (Bpoc), 1-(3,5-di-tert-butylphenyl)-1-methyl Ethyl carbamate (t-Bumeoc), ethyl 2-(2'- and 4'-pyridyl)carbamate (Pyoc), ethyl 2-(N,N-dicyclohexylcarboxylamino)carbamate, tert-butyl carbamate (BOC or Boc), 1-adamantane carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinoline carbamate Esters, N-hydroxypiperidinyl carbamates, alkyl dithiocarbamates, benzyl carbamates (Cbz), p-methoxybenzyl carbamates (Moz), p-nitrobenzyl carbamates, p-bromobenzyl carbamates, p-chlorobenzyl carbamates, 2,4-dichlorobenzyl carbamates, 4-methylsulfinylbenzyl carbamates (Msz), 9-anthraylmethyl carbamates, diphenylmethyl carbamates, 2-methylthioethyl carbamates, 2-methylsulfonylethyl carbamates, 2-(p-toluenesulfonyl)ethylcarbamates Esters, [2-(1,3-dithiaalkyl)]carbamate (Dmoc), 4-methylthiophenylcarbamate (Mtpc), 2,4-dimethylphenylthiocarbamate (Bmpc), 2-phosphonoethylcarbamate (Peoc), 2-triphenylphosphonoisopropylcarbamate (Ppoc), 1,1-dimethyl-2-cyanoethylcarbamate, m-chloro-p-acyloxybenzylcarbamate, p-(dihydroxyboryl)benzylcarbamate, 5-benzoxazolylmethylcarbamate, 2-(trifluoromethyl)-6- Tcroc, m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl (o-nitrophenyl)methyl carbamate, tert-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropyl methyl carbamate, p-decoxybenzyl carbamate, 2,2-dimethoxyylvinyl carbamate Ester, o-(N,N-dimethylcarbamoyl)benzylcarbamate, 1,1-dimethyl-3-(N,N-dimethylcarbamoyl)propylcarbamate, 1,1-dimethylpropynylcarbamate, di(2-pyridyl)methylcarbamate, 2-furanylmethylcarbamate, 2-iodoethylcarbamate, isobornylcarbamate, isobutylcarbamate, isonicocyanate, p-(p'-methoxyphenylazo)benzylcarbamate, 1-methylcyclobutylcarbamate, 1-methylcyclohexylcarbamate Ester, 1-methyl-1-cyclopropylmethylcarbamate, ethyl 1-methyl-1-(3,5-dimethoxyphenyl)carbamate, ethyl 1-methyl-1-(p-phenylazophenyl)carbamate, 1-methyl-1-phenylethylcarbamate, 1-methyl-1-(4-pyridyl)ethylcarbamate, phenyl carbamate, p-(benzoazo)benzylcarbamate, 2,4,6-tri-tert-butylphenylcarbamate, 4-(trimethylammonium)benzylcarbamate and 2,4,6-trimethylbenzylcarbamate of carbamate.

Nitrogen protecting groups such as sulfonamide groups (e.g., -S(=O) ₂ Raaa ⁾ This includes, but is not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylbenzodihydropyran-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilyl ethyl sulfonamide (SES), 9-anthracitesulfonamide, 4-(4',8'-dimethoxynaphthyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and benzoylmethanesulfonamide.

Other nitrogen-protecting groups include, but are not limited to, phenothiazinyl-(10)-acyl derivatives, N'-p-toluenesulfonylaminoacyl derivatives, N'-phenylaminothioyl derivatives, N-benzoylphenylpropionyl derivatives, N-acetylmethionine derivatives, 4,5-diphenyl-3-oxazoline-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldimethylsilylazacyclopentane adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexane-2-one, 5-substituted... 1,3-Dibenzyl-1,3,5-triazacyclohexane-2-one, 1-substituted 3,5-dinitro-4-pyridinone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyrrololin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferroceneylmethylamino (Fcm), N-2-pyridinemethylamino N'-oxide, N-1,1-dimethylthiomethyleneamine, N-benzylamine, N-p-methoxybenzylamine, N-diphenylmethyleneamine, N-[(2-pyridyl)trimethylmethyl]methyleneamine, N-(N',N'-dimethylaminomethylene)amine, N,N'-isopropylidenediamine, N-p-nitrobenzylamine, N-salicylamine, N-5-chlorosalicylamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexylamine, N-(5,5-dimethyl-3-oxo-1 -Cyclohexenyl)amine, N-borane derivatives, N-diphenylboronic acid derivatives, N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelate, N-zinc chelate, N-nitrosamine, N-nitrosamine, N-amine oxide, diphenylphosphamide (Dpp), dimethylthiophosphamide (Mpt), diphenylthiophosphamide (Ppt), dialkylaminophosphate, dibenzylaminophosphate, diphenylaminophosphate, benzenesulfinamide, o-nitrobenzenesulfinamide (Nps), 2,4-dinitrobenzenesulfinamide, pentachlorobenzenesulfinamide, 2-nitro-4-methoxybenzenesulfinamide, triphenylmethylsulfinamide, and 3-nitropyridinesulfinamide (Npys).

In some embodiments, the substituents present on the oxygen atom are oxygen protecting groups (also referred to herein as "hydroxy protecting groups"). Oxygen protecting groups include, but are not limited to, ^-Raa , -N( ^Rbb ) ₂ , -C(=O) ^SRaa , -C(=O) ^Raa _, ^-CO2Raa , -C(=O)N( ^Rbb ) ₂ , -C(= ^NRbb ) ^Raa , -C(= ^NRbb ) ^ORaa , -C(= ^NRbb )N( ^Rbb ) ₂ , -S(=O) ^Raa , -SO2Raa, -Si( ^Raa ) _{3 ,} ^-P ( ^Rcc ) ₂ , -P( ^Rcc ) ₃ , -P(=O) _2Raa , -P(=O)( ^Raa ) ₂ , -P(=O)( ^ORcc ) ₂ , -P(=O) _2N ( ^Rbb ) ₂ and -P(=O)(NRbb ^{) 2} ) ₂ , wherein ^Raaa , ^Rbb , and ^Rcc are as defined herein. Oxygen protecting groups are well known in the art, including those described in detail in Protecting Groups in Organic Synthesis, TW Greene and PGM Watts, 3rd edition, John Wiley & Sons, 1999 (incorporated herein by reference).

Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxymethyl (MOM), methylthiomethyl (MTM), tert-butylthiomethyl, (phenyl dimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacol methyl (GUM), tert-butoxymethyl, 4-pentenoxymethyl (POM), silyloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl ( THP), 3-bromotetrahydropyranyl, tetrahydrothiaranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiaranyl, 4-methoxytetrahydrothiaranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP), 1,4-dioxane-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methylenebenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-Methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenoyl)ethyl, tert-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-pyridinemethyl, 4-pyridinemethyl, 3-methyl-2-pyridinemethyl N-oxy, diphenylmethyl, p,p'-dinitrophenylmethyl, 5-dibenzocycloheptyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, Di(p-methoxyphenyl)phenylmethyl, Tri(p-methoxyphenyl)methyl, 4-(4'-bromobenzoyloxyphenyl)diphenylmethyl, 4,4',4”-tris(4,5-dichlorophthalimidephenyl)methyl, 4,4',4”-tris(acetylpropionyloxyphenyl)methyl, 4,4',4”-tris(benzoyloxyphenyl)methyl, 3-(imidazol-1-yl)bis(4',4”-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1'-pyrenemethyl, 9-anthrayl, 9-(9-phenyl)xanthrayl, 9-(9-phenyl-10-oxo)anthrayl, 1,3-benzodithiapentane-2-yl, benzisothiazolyl S,S - Dioxide, Trimethylsilyl (TMS), Triethylsilyl (TES), Triisopropylsilyl (TIPS), Dimethylisopropylsilyl (IPDMS), Diethylisopropylsilyl (DEIPS), Dimethylhexylsilyl, Tert-butyldimethylsilyl (TBDMS), Tert-butyldiphenylsilyl (TBDPS), Tribenzylsilyl, Tri-p-xylylsilyl, Triphenylsilyl, Diphenylmethylsilyl (DPMS), Tert-butylmethoxyphenylsilyl (TBMPS), Formate, Benzoylcarbamate, Acetate, Chloroacetic acid ester, Dichloroacetic acid ester, Trichloroacetic acid ester, Trifluoroacetic acid Esters, methoxyacetic acid esters, triphenylmethoxyacetic acid esters, phenoxyacetic acid esters, p-chlorophenoxyacetic acid esters, 3-phenylpropionate esters, 4-oxovalerate esters (acetylpropionate esters), 4,4-(ethylidene dithio)valerate esters (acetylpropionyl dithioacetal), neovalerate esters, adamantane esters, crotonate esters, 4-methoxycrotonate esters, benzoate esters, p-phenylbenzoate esters, 2,4,6-trimethylbenzoate esters (methanesulfonate esters), methyl carbonate, 9-fluorenyl methyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(benzenesulfonyl)ethyl carbonate (Psec) ), 2-(triphenylphosphino)ethyl carbonate (Peoc), isobutyl carbonate, ethylene carbonate, allyl carbonate, tert-butyl carbonate (BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p-methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzyl thiocarbonate, 4-ethoxy-1-naphthyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylvalerate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl) Benzoate esters, 2,6-dichloro-4-methylphenoxyacetic acid esters, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetic acid esters, 2,4-bis(1,1-dimethylpropyl)phenoxyacetic acid esters, dichlorophenylacetic acid esters, isobutyrate esters, monosuccinate esters, (E)-2-methyl-2-butenoate esters, o-(methoxyyl)benzoate esters, α-naphthyl esters, nitrate esters, N,N,N’,N’-tetramethyldiaminophosphate alkyl esters, N-phenylcarbamate alkyl esters, borate esters, dimethylthiophosphoryl, alkyl 2,4-dinitrobenzenesulfinic acid esters, sulfate esters, methanesulfonates (methanesulfonates), benzyl sulfonates, and toluenesulfonates (Ts).

In some implementations, the substituents present on the sulfur atom are sulfur protecting groups (also known as "thiol protecting groups"). Sulfur protecting groups include, but are not limited to, ^-Raa , -N( ^Rbb ) ₂ , -C(=O) ^SRaa , -C(=O) ^Raa _, ^-CO2Raa , -C(=O)N( ^Rbb ) ₂ , -C(= ^NRbb ) ^Raa , -C(= ^NRbb ) ^ORaa , -C(= ^NRbb )N( ^Rbb ) ₂ , -S(=O) ^Raa , -SO2Raa, -Si( ^Raa ) _{3 ,} ^-P ( ^Rcc ) ₂ , -P( ^Rcc ) ₃ , -P(=O) _2Raa , -P(=O)( ^Raa ) ₂ , -P(=O)( ^ORcc ) ₂ , -P(=O) _2N ( ^Rbb ) ₂ and -P(=O)(NRbb ^{) 2} ) ₂ , wherein ^Raaa , ^Rbb , and ^Rcc are as defined herein. Sulfur protecting groups are well known in the art, including those described in detail in Protecting Groups in Organic Synthesis, TWGreene and PGMWuts, 3rd edition, John Wiley & Sons, 1999 (incorporated herein by reference).

As used herein, “leaving group” (LG) is a term understood in the art as referring to a molecular fragment separated from a pair of electrons in bond heterolytic cleavage, wherein the molecular fragment is an anionic or neutral molecule. As used herein, the leaving group can be an atom or group that can be substituted by a nucleophile. See, for example, Smith, March Advanced Organic Chemistry, 6th edition (501-502). Exemplary leaving groups include, but are not limited to, halogens (e.g., chlorine, bromine, iodine), -OR ^aa (where ^Raaa is as defined herein when the O atom is attached to a carbonyl group), -O(C=O)R ^LG , or -O(SO) _2R ^LG (e.g., toluenesulfonyl, methanesulfonyl, benzenesulfonyl), wherein R ^LG is an optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, the leaving group is a halogen.

The terms defined above are illustrated with specific examples in the embodiments.

The “yield” for each reaction described in this article is expressed as a percentage of the theoretical yield.

For the purposes of this invention, "patient" includes humans and any other animals, particularly mammals and other organisms. Therefore, this method is suitable for human treatment and veterinary applications. In a preferred embodiment, the patient is a mammal, and in the most preferred embodiment, the patient is a human. Examples of preferred mammals include mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, and primates.

"Kinease-dependent diseases or disorders" refer to pathological conditions that depend on the activity of one or more kinases. Kinases directly or indirectly participate in signaling pathways for various cellular activities, including proliferation, adhesion, migration, differentiation, and invasion. Diseases associated with kinase activity include tumor growth, pathological angiogenesis that supports solid tumor growth, and other diseases involving excessive local angiogenesis, such as eye diseases (diabetic retinopathy, age-related macular degeneration, etc.) and inflammation (psoriasis, rheumatoid arthritis, etc.).

"Therapeutic effective amount" is the amount of the compound of the present invention that improves disease symptoms when administered to a patient. The amount of the compound of the present invention constituting the "therapeutic effective amount" will vary depending on the compound, the disease state and its severity, the age of the patient to be treated, etc. Therapeutic effective amount can be conventionally determined by those skilled in the art based on their own knowledge and the content of this disclosure.

"Cancer" refers to a proliferative cellular disease state, including but not limited to: Heart : sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma; Head and neck: squamous cell carcinoma of the head and neck, laryngeal and hypopharyngeal carcinoma, nasal cavity and paranasal sinus carcinoma, nasopharyngeal carcinoma, salivary gland carcinoma, oral cavity and pharyngeal carcinoma; Lung: bronchial carcinoma (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma, non-small cell lung cancer), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Colon: colorectal cancer, adenocarcinoma, gastrointestinal stromal tumor, lymphoma, carcinoid tumor, Turcot syndrome. Syndrome; Gastrointestinal tract : gastric cancer, adenocarcinoma of the esophagogastric junction, esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (cancer, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vasoactive intestinal peptide tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Breast: metastatic breast cancer, ductal carcinoma in situ, invasive ductal carcinoma, tubular carcinoma, medullary carcinoma, mucinous carcinoma, lobular carcinoma in situ, triple-negative breast cancer; Urogenital tract : kidney (adenocarcinoma, Wilms' tumor) Tumors: [Nephroblastoma], lymphoma, leukemia, renal cell carcinoma; bladder and urethra: squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma, urothelial carcinoma; prostate: adenocarcinoma, sarcoma, castration-resistant prostate cancer; testes: seminoma, teratoma, embryonal carcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoid tumor, lipoma; clear cell carcinoma, papillary carcinoma; liver: hepatocellular carcinoma, bile duct carcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; bone: osteoblastoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma. Sarcoma), malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell chordoma, osteochondroma (osteochondrogenic osteoma), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor; Thyroid: medullary thyroid carcinoma, differentiated thyroid carcinoma, papillary thyroid carcinoma, follicular thyroid carcinoma, Hurthle cell carcinoma. Cancer) and undifferentiated thyroid carcinoma; Nervous system : Skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), Meninges (meningioma, meningeal sarcoma, glioma), Brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor [pineal tumor], glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), Spinal cord neurofibroma, meningioma, glioma, sarcoma; Gynecology : Uterus (endometrial cancer), Cervix (cervical cancer, tumor-pre-cervical dysplasia), Ovary (ovarian cancer [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulosa cell-theca cell tumor, Sertoli-Leydig cell tumor) Tumors: dysgerminoma, malignant teratoma; vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma); vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma)); fallopian tube (cancer); hematology : blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma [malignant lymphoma]; skin : malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus dysplasia, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal glands : neuroblastoma. Therefore, the term "cancer cell" as used herein includes cells afflicted by any of the above-identified diseases.

"Pharmaceutically acceptable salts" include "pharmaceutically acceptable acid addition salts" and "pharmaceutical acceptable base addition salts." "Pharmaceutical acceptable acid addition salts" refer to those salts that, when formed with inorganic acids (such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.) and organic acids (such as acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc.), retain the biological validity of the free base and are not biologically or otherwise undesirable.

"Pharmaceutically acceptable base addition salts" include salts derived from inorganic bases, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Exemplary salts are ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, and salts of substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Exemplary organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. (See, for example, S.M. Berge et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977; 66: 1-19, which is incorporated herein by reference.)

As used herein, the term "compound" is intended to include all stereoisomers, geometric isomers, tautomers, and isotopes of the described structure. The term also means the compounds of the present invention, regardless of how they are prepared, such as synthetically, by biological processes (e.g., metabolism or enzymatic conversion), or combinations thereof.

The compounds of the present invention may also include all isotopes of the atoms present in the intermediates or the final compound. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

Any process step or sequence disclosed and/or claimed herein may be performed under an inert gas atmosphere, more particularly under argon or nitrogen. Furthermore, the method of the present invention may be performed as a semi-continuous or continuous method, more preferably as a continuous method.

Furthermore, many of the process steps and sequences described in this article are scalable.

Generally, the nomenclature used in this application is based on the nomenclature conventions adopted by the International Union of Pure and Applied Chemistry (IUPAC). The chemical structures shown herein are prepared using [method name missing]. Any open valence bonds appearing on carbon, oxygen, or nitrogen atoms in the structures herein indicate the presence of hydrogen atoms.

Embodiments of the present invention

On the one hand, compounds of formula A are provided:

Or a pharmaceutically acceptable salt thereof, wherein the variables and substituents in formula A are as defined in the invention summary.

In one embodiment of this aspect, the compound of formula A is a compound of formula A-1.

In another embodiment of this aspect, the compound of formula A is a compound of formula A-2.

In another embodiment of this aspect, the compound of formula A is a compound of formula A-3:

^Ra1 is -H or (C1 _{- C6} ) alkyl.

In another embodiment, _R1 in the compound of formula A-3 is -H.

In another embodiment of this aspect, the compound of formula A is a compound of formula A-4:

The ring A is a 5- to 14-membered heteroaryl group; and the subscript r is 1, 2, 3 or 4.

In this implementation, _R2 is -H.

In another implementation, r in formula A-4 is 1 or 2.

In another embodiment of formula A: _R1 is -H, optionally substituted ( _C1 - _C6 )alkyl, halogroup _, ^-ORa , -NO2, _-NH2 , _-NHRa , ^-NRaRa , ^-SRa , ^-SORa or -S(O) ^2Ra , and ^R2 is selected from ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, ( _C6 - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, ^-CN , -NHORa, -C ⁽ _O ) ^Ra , -C(O) ^{NRaRa ,} -C(O) ^NHORa , -C(O) ^ORa , -C(O) ^NRaS (O) ^2Ra , ^-OC (O) ^NRaRa , ^NRaC (O ₎ ^Ra , ^-NRaC (＝ ^NRa ) ^Ra , ^-NRa C(O)OR ^a , -NR ^a C(O)NR ^a R ^a , -C(=NR ^a )R ^a , -C(=NOH)R ^a , -C(=NOR ^a )R ^a , -C(=NOH)NR ^a , -C(=NCN)NR ^a R ^a , -NR ^a C(=NCN)NR ^a R ^a , -C(=NR ^a )NR ^a R ^a , -NR ^a C(=NR ^a )NR ^a R ^a , -NR ^a S(O)R ^a , -NR ^a S(O) ₂ R ^a , -NR ^a S(O) ₂ NR ^a R ^a , -S(O)R ^a , -S(O)NR ^a R ^a , -S(O) ₂ R ^a , -S(O) ₂ NR ^a C(O)R ^a , -P(O)R ^a R ^a , -P(O)(OR ^a )(OR ^a ), -B(OH) ₂ , -B(OR ^a ) ₂ and -S(O) ₂ NR ^a R ^a .

In one implementation of this scheme, _R1 is -H.

In another embodiment: _R1 is selected from ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, ( _C6 - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-10 heteroaryl, 4-10 heterocycloalkyl, -CN, -NHOR ^a , -C(O)Ra, -C(O) ^{NR aRa} , ^-C (O)NHOR ^a , -C(O)OR ^a , -C(O)NR ^aS (O) _2Ra ^, -OC(O)NR ^aRa , -NR ^aC (O) ^Ra , -NR ^aC (＝NR ^a ) ^{Ra ,} -NR ^aC (O)OR ^a , -NR ^aC (O) ^{NR aRa ,} -C(＝NR ^a ) ^Ra , -C(＝NOH)Ra, -C(＝NOH)NR ^{a ,} -C(＝NOR ^a) )R ^a , -C(=NCN)NR ^a R ^a , -NR ^a C(=NCN)NR ^a R ^a , -C(=NR ^a )NR ^a R ^a , -NR ^a C(=NR ^a )NR ^a R ^a , -NR ^a S(O)R ^a , -NR ^a S(O) ₂ R ^a , -NR ^a S(O) ₂ NR ^a R ^a , -S(O)R ^a , -S(O)NR ^{a and} _​ ^​ _​ ^{​ ​ ​ ​ ​ ​} _​ ^​ _{​ ​} ^{​ ​}

_R2 is -H, optionally substituted ( _C1 - _C6 ) ^alkyl , halogroup, ^-ORa , -NO2, _-NH2 , _-NHRa , ^{-NRaRa , -SRa} , ^-SORa or -S(O) _2Ra ^.

In one implementation of this scheme, _R2 is -H.

In another implementation scheme:

_R1 represents ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, ( _C6 - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-10 heteroaryl, 4-10 heterocycloalkyl, -CN, -NHOR ^a , -C(O)Ra, -C(O)NR ^aRa , -C(O) ^{NHOR a ,} -C(O)OR ^a , -C(O)NR ^aS (O) _2Ra , -OC(O)NR ^aRa , -NR ^aC (O) ^Ra , -NR ^aC (＝NR ^a ) ^{Ra ,} -NR ^aC (O)OR ^a , -NR ^aC (O)NR ^aRa , -C(＝NR ^a ) ^{Ra , -C} (＝NOH) ^Ra , -C(＝NOR ^a ) ^Ra , -C(＝NOH)NR ^a , -C(=NCN)NR ^a R ^a , -NR ^a C(=NCN)NR ^a R ^a , -C(=NR ^a )NR ^a R ^a , -NR ^a C(=NR ^a )NR ^a R ^a , -NR ^a S(O)R ^a , -NR ^a S(O) ₂ R ^a , -NR ^a S(O) ₂ NR ^a R ^a , -S(O)R ^a , -S(O)NR ^a R ^a , -S(O) ₂ R ^a , -S(O) ₂ NR ^a C(O)R ^a , -P(O)R ^a R ^a , -P(O)(OR ^a )(OR ^a ), -B(OH) ₂ , -B(OR ^a ) ₂ or -S(O) ₂ NR ^a R ^a ; and

_R2 is selected from -H, halogenated, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, (C1- _C6 )haloalkyl, (C1 _- C6)haloalkoxy, (C6 _{- C10} )aryl-( _C1 - _C4 )alkylene-, (C3 _{-C10 )} cycloalkyl-( _{C1 - C4} )alkylene-, (5-14-membered heteroaryl)-( _{C1 - C4} )alkylene-, (4-14-membered heterocycloalkyl)-(C1 _{- C4} )alkylene-, -CN, _-NO2 , ^-ORa , ^-SRa , ^-NHORa , -C(O) ^{Ra ,} -C(O) ^NRaRa , -C(O) ^NHORa , -C(O) ^ORa , -C(O)NR ^a S(O) ₂ R ^a , -OC(O)R ^a , -OC(O)NR ^a R ^a , -NHR ^a , -NR ^a R ^a , -NR ^a C(O)R ^a , -NR ^a C(=NR ^a )R ^a , -NR ^a C(O)OR ^a , -NR ^a C(O)NR ^a R ^a , -C(=NR ^a )R ^a , -C(=NOH)R ^a , -C(=NOH)NR ^a , -C(=NOR ^a )R ^a , -C(=NCN)NR ^a R ^a , -NR ^a C(=NCN)NR ^a R ^a , -C(=NR ^a )NR ^a R ^a , -NR ^a C(=NR ^a )NR ^a R ^a , -NR ^a S(O)R ^a , -NR ^a S(O) ₂ R ^a , -NR ^a S(O) ₂ NR ^a R ^a , -S(O)R ^a , -S(O)NR ^a R ^a , -S(O) ₂ R ^a , -S(O) ₂ NR ^a C(O)R ^a , -P(O)R ^a R ^a , -P(O)(OR ^a )(OR ^a ), -B(OH) ₂ , -B(OR ^a ) ₂ ; and -S(O) ₂ NR ^a R ^a .

In one implementation of this scheme, _R2 is -H.

In another implementation scheme:

_R1 is selected from -H, halogroup, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, (C1-C6)haloalkyl, (C1 _{- C6} )haloalkoxy, ( _{C6 - C10} )aryl, ( _C3 - _{C10 )} cycloalkyl, 5-14-membered heteroaryl, 4-14-membered heterocycloalkyl, ( _C6 - _C10 )aryl-( _C1 - _C4 )alkylene-, ( _C3 - _C10 )cycloalkyl-(C1- _C4 )alkylene-, (5-14-membered heteroaryl)-( _{C1- C4 )} alkylene-, (4-14-membered heterocycloalkyl)-(C1 _{- C4} )alkylene-, -CN, _-NO2 , ^-ORa , -SR ^a , -NHOR ^a , -C(O)R ^a , -C(O)NR ^a R ^a , -C(O)NHOR ^a , -C(O)OR ^a , -C(O)NR ^a S(O) ₂ R ^a , -OC(O)R ^a , -OC(O)NR ^a R ^a , -NHR ^a , -NR ^a R ^a , -NR ^a C(O)R ^a , -NR ^a C(=NR ^a )R ^a , -NR ^a C(O)OR ^a , -NR ^a C(O)NR ^a R ^a , -C(=NR ^a )R ^a , -C(=NOH)R ^a , -C(= ^NOH )R ^a , -C(=NOH)NR ^a , -C(=NCN)NR ^a R ^a , -NR ^a C(=NCN)NR ^a R ^a , -C(=NR ^a )NR ^a R ^a , -NR ^a C(=NR ^a )NR ^a R ^a , -NR ^a S(O)R ^a , -NR ^a S(O) ₂ R ^a , -NR ^a S(O) ₂ NR ^a R ^a , -S(O)R ^a , -S(O)NR ^a R ^a , -S(O) ₂ R ^a , -S(O) ₂ NR ^a C(O)R ^a , -P(O)R ^a R ^a , -P(O)(OR ^a )(OR ^a ), -B(OH) ₂ , -B(OR ^a ) ₂ and -S(O) ₂ NR ^a R ^a ; and

In one implementation of this scheme, _R1 is -H.

In another alternative implementation:

_R1 and _R2, together with the atoms to which they are attached, form a fused (C3 _{- C7} ) cycloalkyl ring or a fused 4- to 10-membered heterocyclic alkyl ring; wherein each of the fused (C3 _{- C7} ) cycloalkyl ring or the fused 4- to 10-membered heterocyclic alkyl ring is optionally substituted by one, two or three independently selected ^Rb substituents, provided that the compound is not 1-[2-(4-fluoro-phenyl)-acetyl]-cyclopropanecarboxylic acid [3-fluoro-4-(7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxa-1-aza-cyclododecane[b]naphthalene-4-yloxy)-phenyl]-amide.

In another embodiment: _R1 and _R2, together with the atoms to which they are attached, form a fused (C3 _{- C7} ) cycloalkyl ring or a fused 4- to 10-membered heterocyclic alkyl ring, wherein each of the fused ( _{C3- C7} ) cycloalkyl ring or the fused 4- to 10-membered heterocyclic alkyl ring is optionally substituted by one, two, or three independently selected ^Rb substituents, provided that the compound is not a compound having the following formula:

Wherein ring E is a fused 4- to 10-membered heterocyclic alkyl group.

In another embodiment, _R1 in the compounds of formula A, A-1, A-3, or A-4 is selected from -H, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, -C(=NO-(C1 _{- C6} )alkyl) ^Ra , ^-CN , -C(O)ORa, -C(O) ^NRaRa , ^-C (O) ^NHORa , -S(O ^{) 2NRaRa} , phenyl, _5- to 6-membered heteroaryl, (C3 _{- C6} )cycloalkyl, and 4- to 6-membered heterocyclic alkyl.

In another embodiment, _R1 is selected from -H, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, -C(=NO-(C1 _{- C6} )alkyl) ^Ra , -CN, -C(O) ^ORa , ^{-C(O)NRaRa, -C(O)NHORa, -S(O)2NRaRa , phenyl ,} _5- ^to 6-membered heteroaryl, (C3 _{- C6} )cycloalkyl, and 4- to 6-membered heterocycloalkyl; and

_R2 is H, an optional substituted ( _C1 - _C6 ) ^alkyl group, ^a halogroup, ^-ORa , -NO2, _-NH2 , _-NHRa , ^-NRaRa , ^-SRa , ^-SORa , or -S(O) _2Ra ^.

In another embodiment, _R1 is selected from -H, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, -C(=NO-(C1 _{- C6} )alkyl) ^Ra , -CN, -C(O) ^ORa , ^{-C(O)NRaRa, -C(O)NHORa, -S(O)2NRaRa , phenyl ,} _5- ^to 6-membered heteroaryl, (C3 _{- C6} )cycloalkyl, and 4- to 6-membered heterocycloalkyl; and

_R2 is selected from -H, halogroup, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, (C1- _C6 )haloalkyl, (C1 _- C6)haloalkoxy, ( _{C6 - C10} )aryl, ( _{C3-C10)cycloalkyl, (C6 - C10 )} aryl-( _C1 - _C4 )alkylene-, ( _C3 - _C10 )cycloalkyl-( _{C1 - C4} )alkylene-, (5-14-membered heteroaryl)-(C1 _{- C4} )alkylene-, (4-14-membered heterocycloalkyl)-( _{C1- C4} )alkylene-, -CN, _-NO2 , ^-ORa , ^-SRa , ^-NHORa , -C(O) ^Ra , -C(O)NR ^a R ^a , -C(O)NHOR ^a , -C(O)OR ^a , -C(O)NR ^a S(O) ₂ R ^a , -OC(O)R ^a , -OC(O)NR ^a R ^a , -NHR ^a , -NR ^a R ^a , -NR ^a C(O)R ^a , -NR ^a C(=NR ^a )R ^a , -NR ^a C(O)OR ^a , -NR ^a C(O)NR ^a R ^a , -C(=NR ^a )R ^a , -C(=NOH)R ^a , -C(=NOH)NR ^a , -C(=NOR ^a )R ^a , -C(=NCN)NR ^a R ^a , -NR ^a C(=NCN)NR ^a R ^a , -C(=NR ^a )NR ^a R ^a , -NR ^a C(=NR ^a )NR ^a R ^a , -NR ^a S(O)R ^a , -NR ^a S(O) ₂ R ^a , -NR ^a S(O) ₂ NR ^a R ^a , -S(O)R ^a , -S(O)NR ^a R ^a , -S(O) ₂ R ^a , -S(O) ₂ NR ^a C(O)R ^a , -P(O)R ^a R ^a , -P(O)(OR ^a )(OR ^a ), -B(OH) ₂ , -B(OR ^a ) ₂ ; and -S(O) ₂ NR ^a R ^a .

In another embodiment, _R1 is selected from -H, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, -C(=NO-(C1 _{- C6} )alkyl) ^Ra , -CN, -C(O) ^ORa , -C(O) ^NRaRa , -C( ^O ) ^NHORa , -S(O) _2NRaRa ^{, phenyl} , 5- to 6-membered heteroaryl, -( _{C3- C6} )cycloalkyl, and 4- to 6-membered heterocycloalkyl; and

R ₂ is (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, -CN, -NHOR ^a , -C(O)R ^a , -C(O)NR ^a R ^a , -C(O)NHOR ^a , -C(O)OR ^a , -C(O)NR ^a S(O) ₂ R ^a , -OC(O)NR ^a R ^a , -NR ^a C(O)R ^a , -NR ^a C(=NR ^a )R ^a , -NR ^a C(O)OR ^a , -NR ^a C(O)NR ^a R ^a , -C(=NR ^a )R ^a , -C(=NOH)R ^a , -C(=NOH)NR ^a , -C(=NOR ^a )R ^a , -C(=NCN)NR ^a R ^a , -NR ^a C(=NCN)NR ^a R ^a , -C(=NR ^a )NR ^a R ^a , -NR ^a C(＝NR ^a )NR ^a R ^a , -NR ^a S(O)R ^a , -NR ^a S(O) ₂ R ^a , -NR ^a S(O) ₂ NR ^a R ^a , -S(O)R ^a , -S(O)NR ^a R ^a , -S(O) ₂ R ^a , -S(O) ₂ NR ^a C(O)R ^a , -P(O)R ^a R ^a , -P(O)(OR ^a )(OR ^a ), -B(OH) ₂ , -B(OR ^a ) ₂ or -S(O) ₂ NR ^a R ^a .

In another embodiment, _R1 is -H, ^RaNHC (O)-, ^RaOC (O)-, (C1 _{- C6} )alkyl, (C1 _{- C6} )alkoxy, or -C(=NO- _CH3 ) ^Ra , and _R2 is selected from 2-methoxyethylamino, aziridine-1-yl, methylamino, 3-morpholinopropoxy, 2-methoxyethoxy, 2-hydroxyethoxy, propoxy, 2-hydroxypropoxy, methoxycarbonyl, carboxyl, carbamoyl, methylcarbamoyl, (2-hydroxyethoxy)carbamoyl, (2,2-dihydroxyethoxy)carbamoyl, (oxetane-3-yloxy)carbamoyl, methoxycarbamoyl, 2-trimethylsilylethynyl, aminosulfonyl, acetyl, and -C(= _NOCH3 ) _CH3 .

In another embodiment of formulas A and A-2, _R2 is selected from -H, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, -C(=NO-( _C1 - _C6 )alkyl) ^Ra , -CN, -C(O) ^ORa , -C( ^O ) ^NRaRa , -C(O) ^NHORa and ^-S (O) _2NRaRa ^.

In another embodiment, _R1 is -H, optionally substituted ( _C1 - _C6 ) alkyl, halogroup, ^-ORa , _-NO2 , _-NH2 , ^-NHRa , ^-NRaRa , ^-SRa , ^{-SORa ,} or S(O) _2Ra , ^and

_R2 is selected from -H, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, -C(=NO-(C1 _{- C6} )alkyl) ^Ra , -CN, -C(O) ^ORa , -C(O) ^NRaRa , -C(O) ^NHORa , -S( ^{O )} _2NRaRa , ^phenyl , and (C3 _{- C6} )cycloalkyl.

In another embodiment, _R1 is selected from -H, optionally substituted ( _C1 - _C6 ) alkyl, halogroup, ^-ORa , _-NO2 , _-NH2 , ^-NHRa , ^-NRaRa , ^-SRa , ^{-SORa and} -S(O) _2Ra , ^and

_R2 is selected from -H, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, -C(＝NO-(C1 _{- C6} )alkyl) ^Ra , -CN, -C(O) ^ORa , -C(O) ^{NRaRa ,} -C(O) ^NHORa , _-S (O ^{) 2NRaRa} .

In another embodiment, _R1 is selected from ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, ( _C6 - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-10 heteroaryl, 4-10 heterocycloalkyl, -CN, -NHOR ^a , -C(O)Ra, -C(O) ^{NR aRa} , ^-C (O)NHOR ^a , -C(O)OR ^a , -C(O)NR ^aS (O) _2Ra ^, -OC(O)NR ^aRa , -NR ^aC (O) ^Ra , -NR ^aC (＝NR ^a ) ^{Ra ,} -NR ^aC (O)OR ^a , -NR ^aC (O) ^{NR aRa ,} -C(＝NR ^a ) ^Ra , -C(＝NOH)Ra, -C(＝NOH)NR ^{a ,} -C(＝NOR ^a) )R ^a , -C(=NCN)NR ^a R ^a , -NR ^a C(=NCN)NR ^a R ^a , -C(=NR ^a )NR ^a R ^a , -NR ^a C(=NR ^a )NR ^a R ^a , -NR ^a S(O)R ^a , -NR ^a S(O) ₂ R ^a , -NR ^a S(O) ₂ NR ^a R ^a , -S(O)R ^a , -S(O)NR ^{a and} _​ ^​ _​ ^{​ ​ ​ ​ ​ ​} _​ ^​ _{​ ​} ^{​ ​}

_R2 is selected from -H, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, -C(＝NO-(C1 _{- C6} )alkyl) ^Ra , -CN, -C(O) ^ORa , -C(O) ^{NRaRa ,} -C(O) ^NHORa , _-S (O ^{) 2NRaRa} .

In another embodiment, _R1 is selected from -H, halogroup, ( _C1 - _C6 )alkyl, (C2- _C6 )alkenyl, ( _C2 - _C6 )ynyl, ( _C1 - _C6 )haloalkyl, ( _{C1 - C6} )haloalkoxy, ( _C6 - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-14-membered heteroaryl, 4-14-membered heterocycloalkyl, ( _C6 - _C10 )aryl-( _C1 - _C4 )alkylene-, ( _C3 - _C10 )cycloalkyl-(C1 _{- C4} )alkylene-, (5-14-membered heteroaryl)-( _C1 - _C4 )alkylene-, (4-14-membered heterocycloalkyl)-(C1 _{- C4} )alkylene-, -CN, _-NO2 , ^-ORa , -SR ^a , -NHOR ^a , -C(O)R ^a , -C(O)NR ^a R ^a , -C(O)NHOR ^a , -C(O)OR ^a , -C(O)NR ^a S(O) ₂ R ^a , -OC(O)R ^a , -OC(O)NR ^a R ^a , -NHR ^a , -NR ^a R ^a , -NR ^a C(O)R ^a , -NR ^a C(=NR ^a )R ^a , -NR ^a C(O)OR ^a , -NR ^a C(O)NR ^a R ^a , -C(=NR ^a )R ^a , -C(=NOH)R ^a , -C(=NOR ^a )R ^a , -C(=NOH)NR ^a , -C(=NCN)NR ^a R ^a , -NR ^a C(=NCN)NR ^a R ^a , -C(=NR ^a )NR ^a R ^a ,-NR ^a C(=NR ^a )NR ^a R ^a , -NR ^a S(O)R ^a , -NR ^a S(O) ₂ R ^a , -NR ^a S(O) ₂ NR ^a R ^a , -S(O)R ^a , -S(O)NR ^a R ^a , -S(O) ₂ R ^a , -S(O) ₂ NR ^a C(O)R ^a , -P(O)R ^a R ^a , -P(O)(OR ^a )(OR ^a ), -B(OH) ₂ , -B(OR ^a ) ₂ and -S(O) ₂ NR ^a R ^a ; and

_R2 is selected from -H, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, -C(＝NO-(C1 _{- C6} )alkyl) ^Ra , -CN, -C(O) ^ORa , -C(O) ^{NRaRa ,} -C(O) ^NHORa , _-S (O ^{) 2NRaRa} .

In another embodiment, _R1 is selected from 2-methoxyethylamino, aziridine-1-yl, methylamino, 3-morpholinopropoxy, 2-methoxyethoxy, 2-hydroxyethoxy, propoxy, 2-hydroxypropoxy, methoxycarbonyl, carboxyl, carbamoyl, methylcarbamoyl, 2-oxazolyl, pyrazol-3-yl, pyrazol-4-yl, 4-isooxazolyl, 3,5-dimethylisooxazol-4-yl, 1-methyl-pyrazol-4-yl, 2-methyl-pyrazol-3-yl, 2-ethyl-pyrazol-3-yl, 2-(2-hydroxyethyl)-pyrazol-3-yl, 2-(2,2,2-trifluoroethyl)-pyrazol-3-yl, 2-(2-fluoroethyl) -pyrazol-3-yl, 2-(2,2-difluoroethyl)-pyrazol-3-yl, 2-trifluoromethyl-pyrazol-3-yl, 2-difluoromethyl-pyrazol-3-yl, 1-methyl-imidazol-4-yl, 1-methyl-imidazol-2-yl, 1H-imidazol-2-yl, (2-hydroxyethoxy)carbamoyl, (2,2-dihydroxyethoxy)carbamoyl, (oxetane-3-yloxy)carbamoyl, methoxycarbamoyl, 2-trimethylsilylethynyl, ethynyl, 1,3,4-oxadiazol-3-yl, 1H-1,2,3-triazol-5-yl, aminosulfonyl, acetyl, and -C(＝ _NOCH3 ) _CH3 ; and

_R2 is -H, ^-RaNHC (O)-, ^-RaOC (O)-, (C1 _{- C6} )alkyl, (C1 _{- C6} )alkoxy, or -C(=NO- _CH3 ) ^Ra .

In another embodiment of formula A-4, the subscript r is 1 or 2.

In another embodiment of the above aspects and implementation scheme, R ₁₀ and R ₁₁ are each -H.

In another embodiment of the above aspects and implementation scheme, the subscript n is 1.

In another embodiment of the above aspects and implementation scheme, the subscript m is 1.

In another embodiment of the above aspects and implementation scheme, the subscript p is 1.

In another embodiment, compound A is a compound of formula B:

Or a pharmaceutically acceptable salt thereof, wherein _R1 and _R2 are as defined by (i), (ii) or (iii) of formula A; and _R3 , _R10 , _R11 , _R14 , _R4 , n, p, m and Y are defined as follows:

Each _R3 is independently selected from -H, halogroup, -OH, -CN, optionally substituted ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy, ( _C1 - _C6 )haloalkoxy, _-NH2 , -NH( _C1 - _C6 )alkyl, -N( _C1 - _C6 )alkyl) ₂ and ( _C3 - _C6 )cycloalkyl, wherein ( _C1 - _C6 )alkoxy, -NH( _C1 - _C6 )alkyl, -N( _C1 - _C6 )alkyl) ₂ and ( _C3 - _C6 )cycloalkyl are each optionally substituted;

Each of _R10 and _R11 is independently selected from -H, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy, and ( _C1 - _C6 )haloalkoxy.

Each R ₁₄ is independently selected from -halogroup, -OH, _-NH2 , -CN, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy, (C1- _C6 )haloalkyl, ( _C1 - _C6 )haloalkoxy, -COOH, -NH( _C1 - _C6 )alkyl, -N( _C1 - _C6alkyl ) ₂ , phenyl, phenyl-( _{C1 - C2} )alkylene, ( _{C3- C6} )cycloalkyl, (C3- _C6 )cycloalkyl-( _{C1- C4 )} alkylene-, 4- to 6-membered heterocycloalkyl, (4- to 6-membered heterocycloalkyl)-( _{C1- C4} )alkylene-, 5- to 6-membered heteroaryl, (5- to 6-membered heteroaryl)-(C1 _{- C4} )alkylene- and ^-ORe , wherein R _The ( _C1 - _C6 )alkyl, phenyl, phenyl-(C1 _{- C2} )alkylene, (C3- _C6 )cycloalkyl, (C3 _{- C6} )cycloalkyl-(C1 _{- C4} )alkylene, 4- to 6-membered heterocycloalkyl, ( _4- to 6-membered heterocycloalkyl)-(C1 _{- C4} )alkylene, 5- to 6-membered heteroaryl and (5- to 6-membered heteroaryl)-(C1 _{- C4} )alkylene are each optionally substituted;

Each _R4 is independently selected from -H, halogroup, -OH, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy, ( _C1 - _C6 )haloalkyl, and ( _C1 - _C6 )haloalkoxy, wherein the ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy, ( _C1 - _C6 )haloalkyl, and ( _C1 - _C6 )haloalkoxy are each optionally substituted independently;

Each ^Ra is independently selected from -H, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )haloalkyl, ( _C6 - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-14-membered heteroaryl, 4-14-membered heterocycloalkyl, ( _C6 - _C10 )aryl-( _C1 - _C4 )alkylene-, ( _C3 - _C10 )cycloalkyl-( _C1 - _C4 )alkylene-, (5-14-membered heteroaryl)-(C1 _{- C4} )alkylene-, and (4-14-membered heterocycloalkyl)-(C1 _{- C4} )alkylene-, wherein ( _C1 - _C6 )alkyl, ( _C1 - _C6 )haloalkyl, ( _C6 - _C10 )aryl, ( _C3 - _C10)... ( _C6 - _C10 ) aryl-(C1-C4) alkylene-, (C3-C10) cycloalkyl-( _C1 - _C4 ) alkylene-, (5-14) heteroaryl-( _C1 - _C4 ) alkylene-, and (4-14 ₎ heterocycloalkyl-( _{C1 - C4 )} alkylene- can each be substituted independently _;

n, p, and m are each an independent integer from 0 to 3; and

Y is selected from -O-, -S-, -SO-, _-SO2- , -NH- and -N((C1 _{- C6} )alkyl)-.

In one implementation of formulas A and B:

(i)R ₁ is selected from:

( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, (C6- _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-10 heteroaryl, and 4-10 heterocycloalkyl, wherein the ( _{C2 - C6} )alkenyl, ( _C2 - _C6 )ynyl, ( _C6 - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-10 heteroaryl, and 4-10 heterocycloalkyl are each optionally substituted independently by the following:

-CN, -P(O)R ^a R ^a ,P(O)(OR ^a ) ₂ , B(OH) ₂ , B(OR ^a ) ₂ ,

X ₂ ^Ra , where X ₂ is -NHO-, -NH-S(O)-, -N-( _C1 - _C6 )alkyl-S(O)-, -NH-S(O) _2- , -N-( _C1 - _C6 )alkyl-S(O) ₂ ^Ra- , -NH-S(O)-NH-, -N-( _C1 - _C6 )alkyl-S(O)NH-, -NH-S(O) ₂ NH-, -N-( _C1 - _C6 )alkyl-S(O) ₂ NH-, -S(O) ₂ NHC(O)-, and

Where represents the connection point, and:

_Y1 is absent, or is -NH-, -N-( _C1 - _C6 )alkyl-, or -O-.

_Y2 is absent, or is -O-, -NH-, -NHO-, -N-( _C1 - _C6 )alkyl-, _-N2H2- , -NH-S(O ₎ -, or -NH-S(O) _2- ; or

_Y2 represents the optional substitution, where A is a 3-, 4-, 5-, 6-, or 7-membered ring; and

^Z1 is O, NH, N-( _C1 - _C6 )alkyl, NOH, NO-( _C1 - _C6 )alkyl, or NCN; and

_R2 is:

-H or a group selected from the following:

( _C1 - _C6 )alkyl, halogroup ^, _-NO2 , and _X1Ra , wherein _X1 is –O-, -S-, -SO-, -SO2-, -SO2NH-, ^-SO2NRa- , _{-NH- and -N-} ( _C1 - _C6 )alkyl-, wherein ( _C1 - _C6 )alkyl is optionally substituted.

In another implementation of formulas A and B:

(ii)R ₁ is selected from:

( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, (C6- _C10 )aryl, ( _{C3 - C10} )cycloalkyl, 5-10 heteroaryl, and 4-10 heterocycloalkyl, wherein the ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, ( _C6 - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-14 heteroaryl, and 4-14 heterocycloalkyl are each optionally substituted independently by the following:

P(O)R ^a R ^a , P(O)(OR ^a )(OR ^a ) , B(OH) ₂ , B(OR ^a ) ₂ , CN,

X ₂ ^Ra , where X ₂ is -NHO-, -NH-S(O)-, -N-( _C1 - _C6 )alkyl-S(O)-, -NH-S(O) _2- , -N-( _C1 - _C6 )alkyl-S(O) ₂ ^Ra- , -NH-S(O)-NH-, -N-( _C1 - _C6 )alkyl-S(O)NH-, -NH-S(O) ₂ NH-, -N-( _C1 - _C6 )alkyl-S(O) ₂ NH-, -S(O)-, -S(O) _2- , -S(O) ₂ NHC(O), and

in:

_Y1 is absent, or is -NH-, -N-( _C1 - _C6 )alkyl-, or -O-.

_Y2 is absent, or is -O-, -NH-, -NHO-, -N-( _C1 - _C6 )alkyl-, _-N2H2- , _-NH -S(O)- or -NH-S(O) ₂ , or

_Y2 represents the connection point of any optional substitution, where ring A is a 3, 4, 5, 6 or 7-membered ring;

^Z1 is -O-, -NH-, -N-( _C1 - _C6 )alkyl-, -NOH-, -NO-( _C1 - _C6 )alkyl-, or –NCN-; and

_R2 is selected from

H, halogenated, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, (C2- _C6 )ynyl, ( _C1 - _C6 )haloalkyl, (C1 _- C6)haloalkoxy, ( _C6 - _C10 )aryl-(C1 _{- C4} )alkylene-, (C3 _{- C10} )cycloalkyl-( _{C1 - C4} )alkylene-, ( _5-14 -membered heteroaryl)-(C1 _{- C4} )alkylene-, and (4-14-membered heterocycloalkyl)-(C1 _{- C4} )alkylene-, wherein ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, ( _C1 - _C6 )haloalkyl, (C1 _{- C6} )haloalkoxy, ( _C6 - _C10) The aryl, ( _C3 - _C10 )cycloalkyl, (C6- _C10 )aryl-( _C1 -C4)alkylene-, ( _C3 - _C10 )cycloalkyl-( _C1 - _C4 )alkylene-, (5-14-membered heteroaryl)-( _{C1- C4 )} alkylene-, and (4-14-membered heterocycloalkyl)-(C1 _{- C4} )alkylene- are each independently _and optionally substituted with the following:

CN, NO ₂ , P(O)R ^a R ^a , P(O)(OR ^a )(OR ^a ), B(OH) ₂ , B(OR ^a ) ₂ ,

_X1 ^Ra substitution, wherein _X1 is –O-, -S-, -NH- or -N-( _C1 - _C6 )-, -NHO-, -NH-S(O)-, -N-(C1-C6)alkyl-S(O)-, -NH-S(O)2-, -N-( _C1 - _C6 )alkyl-S(O) _2- , -NH-S(O)-NH-, -N-( _C1 - _C6 )alkyl-S(O)NH-, -NH-S(O) _2NH- , -N-(C1- _C6 )alkyl-S(O)2NH-, -S(O) _2NHC (O)-, -NH-S(O)Ra-, -N-(C1-C6)alkyl-S(O) _Ra- , -NH-S(O)2Ra-, -N-( _C1 - _C6 )alkyl-S(O) _2NH- , -N-(C1-C6)alkyl-S(O) _2NH- , -N-(C1-C6)alkyl- ^S (O)2NH-, -N-( _C1 - _C6 )alkyl-S(O) ^2Ra- , -N-(C1-C6)alkyl-S(O)2Ra-, -N-(C1-C6) ^alkyl -S(O) _2NH ... ₁ - _C6 )alkyl-S(O) _2Ra- ^and

in:

_Y1 is absent or is -NH-, -N-( _C1 - _C6 )alkyl- or -O-;

_Y2 is absent, or is -O-, -NH-, -NHO-, -N-( _C1 - _C6 )alkyl-, _-N2H2- , _-NH -S(O)- or -NH-S(O) _2- , or

_Y2 is an optional substitution in which ring A is a 3, 4, 5, 6, or 7-membered ring, and where represents the connection point; and

^Z1 can be O, NH, N-( _C1 - _C6 )alkyl, NOH, NO-( _C1 - _C6 )alkyl, or NCN.

In another implementation of formulas A and B:

(iii) _R1 and _R2 together with the atoms to which they are attached form a 4-10 membered heterocyclic alkyl ring optionally substituted with 1, 2 or 3 independently selected from the following groups: halogroup, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )haloalkyl, ( _C1 - _C6 )haloalkoxy, -CN, -OH, _-NH2 , provided that the compound is not 1-[2-(4-fluoro-phenyl)-acetyl]-cyclopropanecarboxylic acid [3-fluoro-4-(7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxa-1-aza-cyclododecano[b]naphthalene-4-yloxy)-phenyl]-amide.

In another embodiment of the compounds of formulas A and B:

_R1 can be -H, -CN, ( _C1 - _C6 )alkyl, ( _C3 - _C10 )cycloalkyl, ( _C6 - _C10 )aryl, 4-10 heterocyclic alkyl, 5-10 heteroaryl, -S(O ^)2NHRa _, -P(O) ^RaRa , ^{-ORa , or}

Where represents the connection point, and:

_Y1 is absent or is -NH-, -N-( _C1 - _C6 )alkyl- or -O-;

_Y2 is absent, or is -O-, -NH-, -NHO-, -N-( _C1 - _C6 )alkyl-, -NH-NH-, -NH-S(O)-, or NH-S(O) ₂ ; and

^Z1 is -O, -NH, -N-( _C1 - _C6 )alkyl, -N-OH or -NO( _C1 - _C6 )alkyl.

In another implementation of formulas A and B:

_R2 is -H, a ^halogroup , _-X1Ra , ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, or

Where represents the connection point, and:

_Y1 is absent, or is NH, N-( _C1 - _C6 ) alkyl, or O;

_Y2 is absent, or is O, NH, NHO, N-( _{C1 - C6} )alkyl, _N2H2 , NH-S(O) or NH-S(O) ₂ ; and

^Z1 is -O, -NH, -N-( _C1 - _C6 )alkyl, -NOH-, or -NO( _C1 - _C6 )alkyl.

In another embodiment of formulas A and B, _R3 is -H or a halogenated group.

In another embodiment of formulas A and B, _R4 is -H or a halogenated group.

In another embodiment of formulas A and B, _R14 is -H or a halogenated group.

In another implementation of formulas A and B, Y is -O-.

In another embodiment, the compound of B is a compound of formula B-1 or B-2:

               

Or its pharmaceutically acceptable salt.

In one implementation of formula B-1:

^Ra1 is an optionally substituted ( _C1 - _C6 ) alkyl group;

_R1 is -H, -CN, optionally substituted 3-6 membered cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 membered heterocycloalkyl, optionally substituted 5-6 membered heteroaryl, _-SO2- ( _C1 - _C6 )alkyl, -SO2NH2, _{-SO2 -} NH( _C1 - _C6 )alkyl, P ₍ O)(( _C1 - _C6 )alkyl) ₂ , or

Where represents the connection point, and:

_Y1 does not exist;

_Y2 is absent, or is -O-, -NH-, -NHO-, -NH-NH-, -N-( _C1 - _C6 )alkyl-; or

_Y2 is an optional substitution in which ring A is a 3, 4, 5, 6 or 7-membered ring, where represents the connection point;

^Z1 is O, NH, N-( _C1 - _C6 )alkyl, NHO, or NO-( _C1 - _C6 )alkyl; and

Ra ^can be -H, -( _C1 - _C6 )alkyl, 4-6 membered heterocyclic alkyl, 3-6 membered cycloalkyl, -( _C2 - _C6 )alkylene-OH, _-CH2CHOH- ( _C2 - _C6 )alkylene-OH, -( _C2 - _C6 )alkylene- _NH2 , -( _C2 - _C6 )alkylene-NH(C1- _C6 ), -( _C2 - _C6 )alkylene-N( _C1 - _C6 ) ₂ or -( _C2 - _C6 )alkylene-N-( _4-6 membered heterocyclic alkyl);

In another embodiment of formula B-1:

^Ra1 is a ( _C1 - _C6 ) alkyl group;

_R1 is -H, -CN, optionally substituted cyclopropyl, optionally substituted phenyl, optionally substituted 4-6 membered azacyclic butyl, optionally substituted pyrrolyl, optionally substituted piperidinyl, optionally substituted oxazolyl, optionally substituted pyridinyl, optionally substituted imidazolyl, optionally substituted pyrrolyl, optionally substituted furanyl, optionally substituted pyrazolyl, optionally substituted oxadiazolyl, _-SO₂- ( _C₁ - _C₆ )alkyl, _-SO₂NH₂ , _{-SO₂ -} NH( _C₁ - _C₆ )alkyl, or P(O)(( _C₁ - _C₆ )alkyl) _₂ ; or

_R1 is where:

_Y1 does not exist;

_Y2 is O, NH, NHO, NH-NH, or N-( _C1 - _C6 ) alkyl; or

_Y2 is an optionally substituted nitrogen-containing heterocyclic butyl group;

^Z1 is an O, NH, or N-( _C1 - _C6 ) alkyl group; and

Ra ^can be H, ( _C1 - _C6 )alkyl, -( _C2 - _C6 )alkylene-OH, _-CH2CHOH- ( _C2 - _C6 )alkylene-OH, -( _C2 - _C6 )alkylene- _NH2 , -( _C2 - _C6 )alkylene-NH( _C1 - _C6 )alkyl, -( _C2 - _C6 )alkylene-N(( _C1 - _C6 )alkyl) ₂ , -( _C2 - _C6 )alkylene-heterocyclic alkyl) or 4-6 membered heterocyclic alkyl, wherein the heterocyclic alkyl is optionally substituted.

In one implementation of formula B-2:

^Ra2 is an optionally substituted ( _C1 - _C6 ) alkyl group;

_R2 represents the connection point, where:

_Y1 does not exist;

_Y2 either does not exist or is -O- or -NH-; and

^Z1 is 0; and

^Ra is -H or -( _C1 - _C6 ) alkyl.

In another implementation of formula B-2:

^Ra2 is a ( _C1 - _C6 ) alkyl group;

_R2 represents the connection point, where:

_Y1 does not exist;

_Y2 either does not exist or is -O- or -NH-; and

^Z1 is an O or NO-( _C1 - _C6 ) alkyl group; and

^Ra is -H or -( _C1 - _C6 ) alkyl.

In another embodiment of formula B-1, ^Ra1 is a methoxy group.

In another embodiment of formula B-2, ^Ra2 is a methoxy group.

In another embodiment, the compound of formula B is a compound of formula B-3 or formula B-4:

Or its pharmaceutically acceptable salt.

In one implementation of formula B-3:

_R1 is -H or ( _C1 - _C6 ) alkyl; and _Y1 is absent;

_Y2 is absent or is -O-, -NHO- or -NH-; and ^Z1 is O or NO-( _C1 - _C6 )alkyl; and ^Ra is -H or -( _C1 - _C6 )alkyl.

In another implementation of formula B-3:

_R1 is –H or methyl;

_Y1 does not exist;

_Y2 is nonexistent or is -O-, -NHO-, or -NH-; and ^Z1 is O or NO-Me; and ^Ra is -H or Me.

In another implementation of formula B-3:

_R1 and ^Ra together with the atoms they are attached to form

4-6 membered heterocyclic alkyl rings optionally substituted with a halogroup, ( _C1 - _C6 )alkyl or ( _C1 - _C6 )haloalkyl.

In one implementation of formula B-4:

_Y1 does not exist;

_Y2 is O, NH, NHO, NH-NH, or N-( _C1 - _C6 ) alkyl; or

_Y2 is an optionally substituted nitrogen-containing heterocyclic butyl group;

^Z1 is O, NH, NO-( _C1 - _C6 )alkyl or N-( _C1 - _C6 )alkyl; and

Ra ^can be H, ( _C1 - _C6 )alkyl, -( _C2 - _C6 )alkylene-OH, _-CH2CHOH- ( _C2 - _C6 )alkylene-OH, -( _C2 - _C6 )alkylene- _NH2 , -( _C2 - _C6 )alkylene-NH( _C1 - _C6 )alkyl, -( _C2 - _C6 )alkylene-N(( _C1 - _C6 )alkyl) ₂ , -( _C2 - _C6 )alkylene-optionally substituted 4-6 membered heterocyclic alkyl) or optionally substituted 4-6 membered heterocyclic alkyl;

_R2 can be -H, -F, -Cl, -Br, -( _C1 - _C6 )alkoxy, -O-( _C2 - _C6 )alkylene-OH, -O-( _C2 - _C6 )alkylene-O-( _C1 - _C6 alkyl), ( _C2 - _C6 )alkylene-O-( _C1 - _C6 )alkyl, _-NH2 , -NH-(C1- _C6 alkyl), -NH-( _C1 - _C6 )alkylene-(optionally substituted 4-6 membered heterocyclic alkyl) or –NH-( _{C2 - C6} )alkylene-O-( _C1 - _C6 alkyl).

In another implementation of formula B-4:

_Y1 does not exist;

_Y2 is O, NH, NHO, NH-NH, or N-( _C1 - _C6 ) alkyl; or

_Y2 is an optionally substituted nitrogen-containing heterocyclic butyl group;

^Z1 is O, NH, NO-( _C1 - _C6 )alkyl, or N-( _C1 - _C6 )alkyl; and

^Ra can be -H, methyl, ethyl, -( _C2 - _C6 )alkylene-OH, _-CH2CHOH- ( _C2 - _C6 )alkylene-OH, -( _C2 - _C6 )alkylene- _NH2 , -( _C2 - _C6 )alkylene-NHMe, -( _C2 - _C6 )alkylene-N(Me) ₂ , -( _C1 - _C6 )alkylene-morpholinyl), -( _C1 - _C6 )alkylene-piperidinyl), ( _C1 - _C6 )alkylene-(optionally substituted pyrrolidinyl), optionally substituted azahexacyclic butyl or optionally substituted oxohexacyclic butyl;

_R2 is -H, -F, -Cl, -Br, methoxy, -O-( _C2 - _C6 )alkylene-OH, -O-( _C2 - _C6 )alkylene-OMe, _-NH2 , -NH-( _C1 - _C6 alkyl), -NH-( _C2 - _C6 )alkylene-OMe, -NH-( _C2 - _C6 )alkylene-(optionally substituted morpholino) or -NH-( _C2 - _C6 )alkylene-O-( _C1 - _C6 alkyl).

In another implementation of formula B-4:

_R2 and ^Ra, together with the atoms they are attached to, form 4-6 membered heterocyclic alkyl rings that are optionally substituted with halogen groups, ( _C1 - _C6 )alkyl groups, or ( _C1 - _C6 )haloalkyl groups.

In another embodiment, the compound of formula B is a compound of formula B-5:

Or a pharmaceutically acceptable salt thereof, wherein ring A in formula B-5 is an optionally substituted 5-6 membered heteroaryl or aryl.

In one implementation of formula B-5:

Ring A is optionally substituted ( _C6 - _C10 ) aryl, optionally substituted ( _C3 - _C10 ) cycloalkyl, optionally substituted 5-10 heteroaryl, or optionally substituted 4-10 heterocycloalkyl; and

_R2 is H, or ( _C1 - _C6 )alkoxy.

In another implementation of formula B-5:

Ring A is optionally substituted with phenyl, optionally substituted with cyclopropyl, optionally substituted with pyridyl, optionally substituted with imidazolyl, optionally substituted with pyrrole, optionally substituted with furanyl, optionally substituted with pyrazolyl, optionally substituted with oxazolyl, optionally substituted with aziridine or optionally substituted with oxacyclobutane; and

_R2 is H or methoxy.

Another embodiment of the compounds of formulas A and B is the compound of formula C:

Or its pharmaceutically acceptable salt, wherein:

_Y1 does not exist;

_Y2 is O, NH, NHO, NH-NH, or N-( _C1 - _C6 ) alkyl; or

_Y2 is an optionally substituted nitrogen-containing heterocyclic butyl group;

Z can be O, NH, NO-( _C1 - _C6 )alkyl or N-( _C1 - _C6 )alkyl;

Ra ^can be -H, ( _C1 - _C6 )alkyl, -( _C2 - _C6 )alkylene-OH, _-CH2CHOH- ( _C2 - _C6 )alkylene-OH, -( _C2 - _C6 )alkylene- _NH2 , -( _C2 - _C6 )alkylene-NH( _C1 - _C6 )alkyl, -( _C2 - _C6 )alkylene-N(( _C1 - _C6 )alkyl) ₂ , -( _C2 - _C6 )alkylene-optionally substituted 4-6 membered heterocyclic alkyl) or optionally substituted 4-6 membered heterocyclic alkyl;

_R2 can be -H, -F, -Cl, -Br, -( _C1 - _C6 )alkoxy, -O-( _C2 - _C6 )alkylene-OH, -O-( _C2 - _C6 )alkylene-O-( _C1 - _C6 alkyl), ( _C2 - _C6 )alkylene-O-( _C1 - _C6 )alkyl, _-NH2 , -NH-(C1- _C6 alkyl), -NH-( _C1 - _C6 )alkylene-(optionally substituted 4-6 membered heterocyclic alkyl), -NH-( _{C2 - C6} )alkylene-O-( _C1 - _C6 alkyl); and

n and m are each an independent integer from 0 to 3.

In another implementation of formula C:

_Y1 does not exist;

_Y2 is O, NH, NHO, NH-NH, or N-( _C1 - _C6 ) alkyl; or

_Y2 is an optionally substituted nitrogen-containing heterocyclic butyl group;

^Z1 is O, NH, NO-( _C1 - _C6 )alkyl or N-( _C1 - _C6 )alkyl;

^Ra can be -H, methyl, ethyl, -( _C2 - _C6 )alkylene-OH, _-CH2CHOH- ( _C2 - _C6 )alkylene-OH, -( _C2 - _C6 )alkylene- _NH2 , -( _C2 - _C6 )alkylene-NHMe, -( _C2 - _C6 )alkylene-N(Me) ₂ , -( _C1 - _C6 )alkylene-morpholinyl), -( _C1 - _C6 )alkylene-piperidinyl), ( _C1 - _C6 )alkylene-(optionally substituted pyrrolidinyl), optionally substituted azahexacyclic butyl or optionally substituted oxohexacyclic butyl;

_R2 is -H, -F, -Cl, -Br, methoxy, -O-( _C2 - _C6 )alkylene-OH, -O-( _C2 - _C6 )alkylene-OMe, _-NH2 , -NH-( _C1 - _C6 alkyl), -NH-( _C2 - _C6 )alkylene-OMe, -NH-( _C2 - _C6 )alkylene-(optionally substituted morpholino) or -NH-( _C2 - _C6 )alkylene-O-( _C1 - _C6 alkyl); and

And n and m are each 0 or 1.

In another implementation of formula C:

_R2 and ^Ra, together with the atoms they are attached to, form 4-6 membered heterocyclic alkyl rings optionally substituted with halogroups, ( _C1 - _C6 )alkyl groups, and ( _C1 - _C6 ) haloalkyl groups; and

n and m are each an independent integer from 0 to 3.

Another embodiment of formula C is a compound of formula C-1.

Or its pharmaceutically acceptable salt, wherein:

_Y2 is O, NH, NHO, NH-NH, or N-( _C1 - _C6 ) alkyl; or

_Y2 is an optionally substituted nitrogen-containing heterocyclic butyl group;

^Z1 is O, NH, NO-( _C1 - _C6 )alkyl or N-( _C1 - _C6 )alkyl;

^Ra can be -H, methyl, ethyl, -( _C2 - _C6 )alkylene-OH, _-CH2CHOH- ( _C2 - _C6 )alkylene-OH, -( _C2 - _C6 )alkylene- _NH2 , -( _C2 - _C6 )alkylene-NHMe, -( _C2 - _C6 )alkylene-N(Me) ₂ , -( _C1 - _C6 )alkylene-morpholinyl), -( _C1 - _C6 )alkylene-piperidinyl), ( _C1 - _C6 )alkylene-(optionally substituted pyrrolidinyl), optionally substituted azahexacyclic butyl or optionally substituted oxohexacyclic butyl;

_R2 is -H, -F, -Cl, -Br, methoxy, -O-( _C2 - _C6 )alkylene-OH, -O-( _C2 - _C6 )alkylene-OMe, _-NH2 , -NH-( _C1 - _C6 alkyl), -NH-( _C2 - _C6 )alkylene-OMe, -NH-( _C2 - _C6 )alkylene-(optionally substituted morpholino) or -NH-( _C2 - _C6 )alkylene-O-( _C1 - _C6 alkyl); and

Furthermore, n and m are each independently 0 or 1.

Another embodiment of formulas A and B is a compound of formula D:

In one implementation of formula D:

_R1 is -H or ( _C1 - _C6 ) alkyl; and

_Y1 does not exist;

_Y2 either does not exist or is -O-, -NHO-, or -NH-; and

^Z1 is O or NO-( _C1 - _C6 ) alkyl;

^Ra is -H or -( _C1 - _C6 ) alkyl; and

n and m are each an independent integer from 0 to 3.

In another implementation of formula D:

_R1 is –H or methyl;

_Y1 does not exist;

_Y2 either does not exist or is -O-, -NHO-, or -NH-; and

^Z1 is O or NO-Me; and

R ^_a can be either -H or -Me.

n and m are each an independent integer between 0 and 1.

In another implementation of formula D:

_R1 and ^Ra together with the atoms they are attached to form

4-6 membered heterocyclic alkyl rings optionally substituted with a halogroup, ( _C1 - _C6 )alkyl, or ( _C1 - _C6 )haloalkyl; and

n and m are each an independent integer between 0 and 1.

Another embodiment of formula D is a compound of formula D-1.

Another embodiment of formulas A and B is a compound of formula E:

Or its pharmaceutically acceptable salt, wherein:

Ring A is optionally substituted ( _C6 - _C10 ) aryl, optionally substituted ( _C3 - _C10 ) cycloalkyl, optionally substituted 5-10 heteroaryl, or optionally substituted 4-10 heterocycloalkyl; and

_R2 is H or ( _C1 - _C6 ) alkoxy.

In another implementation of formula E:

Ring A is optionally substituted with phenyl, optionally substituted with cyclopropyl, optionally substituted with pyridyl, optionally substituted with imidazolyl, optionally substituted with pyrrole, optionally substituted with furanyl, optionally substituted with pyrazolyl, optionally substituted with oxazolyl, optionally substituted with aziridine or optionally substituted with oxacyclobutane; and

_R2 is H or methoxy.

Another embodiment of formulas A and B is a compound of formula F:

Or its pharmaceutically acceptable salt, wherein

^Ra1 is an optionally substituted ( _C1 - _C6 ) alkyl group;

_R1 is -H, -CN, optionally substituted 3-6 membered cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 membered heterocycloalkyl, optionally substituted 5-6 membered heteroaryl, _-SO2- ( _C1 - _C6 )alkyl, _-SO2NH2 , _-SO2 - _NH ( _C1 - _C6 )alkyl, or P(O)(( _C1 - _C6 )alkyl) ₂ , or

Where represents the connection point, and:

_Y1 does not exist;

_Y2 is absent, or is -O-, -NH-, -NHO-, -NH-NH-, -N-( _C1 - _C6 )alkyl-; or

_Y2 is an optional substitution in which ring A is a 3, 4, 5, 6 or 7-membered ring, where represents the connection point;

^Z1 is O, NH, N-( _C1 - _C6 )alkyl, NHO, or NO-( _C1 - _C6 )alkyl; and

Ra ^can be -H, -( _C1 - _C6 )alkyl, 4-6 membered heterocyclic alkyl, 3-6 membered cycloalkyl, -( _C2 - _C6 )alkylene-OH, _-CH2CHOH- ( _C2 - _C6 )alkylene-OH, -( _C2 - _C6 )alkylene- _NH2 , -( _C2 - _C6 )alkylene-NH(C1- _C6 ), -( _C2 - _C6 )alkylene-N( _{C1 - C6} ) ₂ , -( _C2 - _C6 )alkylene-N-(4-6 membered heterocyclic alkyl);

In another implementation of formula F:

^Ra1 is a methyl group;

_R1 is -H, -CN, optionally substituted cyclopropyl, optionally substituted phenyl, optionally substituted 4-6 membered azacyclic butyl, optionally substituted pyrrolyl, optionally substituted piperidinyl, optionally substituted oxazolyl, optionally substituted pyridinyl, optionally substituted imidazolyl, optionally substituted pyrrolyl, optionally substituted furanyl, optionally substituted pyrazolyl, optionally substituted oxadiazolyl, _-SO₂- ( _C₁ - _C₆ )alkyl, _-SO₂NH₂ , _{-SO₂ -} NH( _C₁ - _C₆ )alkyl, or P(O)(( _C₁ - _C₆ )alkyl) _₂ ; or

_R1 is where:

_Y1 does not exist;

_Y2 is O, NH, NHO, NH-NH, or N-( _C1 - _C6 ) alkyl; or

_Y2 is an optionally substituted nitrogen-containing heterocyclic butyl group;

^Z1 is an O, NH, or N-( _C1 - _C6 ) alkyl group; and

Ra ^can be H, ( _C1 - _C6 )alkyl, -( _C2 - _C6 )alkylene-OH, _-CH2CHOH- ( _C2 - _C6 )alkylene-OH, -( _C2 - _C6 )alkylene- _NH2 , -( _C2 - _C6 )alkylene-NH( _C1 - _C6 )alkyl, -( _C2 - _C6 )alkylene-N(( _C1 - _C6 )alkyl) ₂ , -( _C2 - _C6 )alkylene-heterocyclic alkyl) and 4-6 membered heterocyclic alkyl, wherein the heterocyclic alkyl is optionally substituted.

Another embodiment of formulas A and B is a compound of formula G:

Or its pharmaceutically acceptable salt, wherein:

^Ra1 is an optionally substituted ( _C1 - _C6 ) alkyl group;

_R2 represents the connection point, where:

_Y1 does not exist;

_Y2 either does not exist or is -O- or -NH-; and

^Z1 is 0; and

^Ra is -H or -( _C1 - _C6 ) alkyl.

In another implementation of formula G:

^Ra2 is a methyl group;

_R2 represents the connection point, where:

_Y1 does not exist;

_Y2 either does not exist or is -O- or -NH-; and

^Z1 is an O or NO-( _C1 - _C6 ) alkyl group; and

^Ra is –H or -( _C1 - _C6 )alkyl.

Another embodiment of formulas A and B is a compound for regulating kinase activity according to formula H:

Or its pharmaceutically acceptable salt, wherein:

_R1 is selected _from -H, -CN, -CO- _NR5R6 , _-CO2R7 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted _{( C1} - _C6 )alkyl, optionally substituted ( _C3 - _C8 )cycloalkyl, optionally substituted ( _C3 - _C6 ) _{heterocycloalkyl} , _-SO2NR8R9 or -( _{SO2 )} -( _C1 - _C6 )alkyl;

Where _R1 is selected _{from -CN} , -CO- _NR5R6 , _-CO2R7 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted ( _C3 - _C8 )cycloalkyl, optionally substituted ( _C3 - _C6 ) heterocycloalkyl, _-SO2NR8R9 and -( _SO2 )-( _C1 - _C6 )alkyl, _{R2 is} H, _halogroup , _-NR5R6 or optionally substituted _{( C1} - _C6 )alkoxy;

Where _R1 is -H, an optionally substituted ( _C1 - _C6 ) alkyl, or _an optionally substituted ( _C1 - _C6 ) alkoxy, _R2 is -CO- _NR5R6 or _{-CO2R7 ;}

Or _R1 and _R2 together with the atoms to which they are attached form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl;

_R3 is selected from -H, optionally substituted (C1 _{- C6} ) alkyl, -CN, and halogroup;

_R4 is -H or a halogenated group;

Optionally substituted with one, two, three or four independently selected groups from halogroups and ( _C1 - _C6 )alkyl groups, wherein the linkage point is indicated;

_R5 and _R6 are each independently -H, optionally substituted ( _C1 - _C6 ) alkyl or optionally substituted _C1 - _C6 alkoxy;

_R7 is -H or an optionally substituted ( _C1 - _C6 ) alkyl group;

_R8 and _R9 are each independently -H or optionally substituted ( _C1 - _C6 ) alkyl; or

_R8 and _R9 can be connected to form an optionally substituted heterocyclic ring; and

Y is selected from O, S, SO, _SO₂ , NH and N-(( _C₁ - _C₆ )alkyl).

In one embodiment of the compound of formula I, Y is O.

In another implementation, _R3 is -H.

In another implementation, it was not replaced.

In another implementation, _R4 is a halogenated group.

In another embodiment, _R4 is parafluorine.

In another embodiment, _R2 is -H, a halogroup, or an optionally substituted ( _C1 - _C6 )-alkoxy group.

In another implementation, _R1 is -CN.

In another implementation, _R1 is _-CO2H .

In another implementation, _R1 is _-CO2 -Me.

In another implementation, _R1 is -CO-NHR ₆ .

In another implementation, _R1 is -CO-NH2.

In another implementation, _R1 is -CO- _NMeR6 .

In another embodiment, _R3 is -H or a halogenated group.

In another embodiment, _R1 is selected from -CN, -( _SO2 ) _NH2 , -OMe, and -( _SO2 ) _CH3.

Where is the connection point.

In one implementation, _R1 is selected as a connection point.

In another implementation, _R1 is selected as the connection point.

In another implementation, _R2 is selected from -H, -CN, -Br, -F, -Cl, -OMe,

-CH ₂ NH ₂ 、NH ₂ 、NHMe, where is the connection point.

In another embodiment, _R1 is -H, methyl, or methoxy.

In another implementation, _R2 is _-CO2H .

In another implementation, _R1 is _-CO2 -Me.

In another implementation, _R1 is -CO-NHR ₆ .

In another implementation, _R1 is -CO- _NH2 .

In another implementation, _R1 is -CO- _NMeR6 .

In another implementation, _R1 is selected from

In another implementation, _R1 and _R2 together form

In another embodiment, the compound of formula I is the compound of formula I-1:

              

Wherein _R6 is (C1 _{- C6} )alkyl, _R2 is (C1 _{- C6} )alkoxy, _R3 is -H or a halogroup, and _R4 is a halogroup.

In another aspect, the present invention provides compounds of formula A or formula A-I provided in Table 1 below.

Table 1: Specific compounds of the present invention

Or its pharmaceutically acceptable salt.

General application

The application of the compounds of the present invention, either in their pure form or in suitable pharmaceutical compositions, or of their pharmaceutically acceptable salts, can be carried out by any acceptable mode of administration or agent for providing similar efficacy. Thus, administration can be, for example, in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms (such as tablets, suppositories, pills, soft and hard gelatin capsules, powders, solutions, suspensions, aerosols, etc.), preferably in unit dosage forms suitable for simple administration of precise dosage, orally, nasally, parenterally (intravenously, intramuscularly, or subcutaneously), topically, transdermally, intravaginally, intravesically, intracisionally, or rectally.

The composition will comprise a conventional pharmaceutical carrier or excipient and the compound of the present invention as an active agent, and may further include other pharmaceutical agents, pharmaceutical reagents, carriers, adjuvants, etc. The compositions of the present invention can be used in combination with anticancer agents or other agents commonly administered to cancer-treated patients. Adjuvants include preservatives, wetting agents, suspending agents, sweeteners, flavoring agents, aromatizers, emulsifiers, and dispersants. Prevention of microbial action can be ensured by various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, etc. Isotonic agents, such as sugars, sodium chloride, etc., may also be desired. Prolonged absorption of injectable drug forms can be achieved by using agents with delayed absorption, such as aluminum monostearate and gelatin.

If necessary, the pharmaceutical compositions of the present invention may also contain small amounts of excipients, such as wetting agents or emulsifiers, pH buffers, antioxidants, etc., for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylated hydroxytoluene, etc.

Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or mediators include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, etc.), suitable mixtures thereof, vegetable oils (e.g., olive oil), and injectable organic esters such as ethyl oleate. Appropriate flowability may be maintained, for example, by using coatings such as lecithin, by maintaining the desired particle size in the case of dispersions, and by using surfactants.

A preferred route of administration is oral, with a convenient daily dosage regimen that can be adjusted according to the severity of the disease state being treated.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with: at least one inert conventional excipient (or carrier), such as sodium citrate or dicalcium phosphate, or (a) a filler or extender, such as starch, lactose, sucrose, glucose, mannitol and silica, (b) a binder, such as cellulose derivatives, starch, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic, (c) a humectant, such as glycerin, (d) a disintegrant, such as agar, calcium carbonate, potato or cassava starch, alginate, croscarmellose sodium, complex silicates and sodium carbonate, (e) a solution retarder, such as paraffin, (f) an absorption enhancer, such as a quaternary ammonium compound, (g) a wetting agent, such as cetyl alcohol and glyceryl monostearate, magnesium stearate, etc., (h) an adsorbent, such as kaolin and bentonite, and (i) a lubricant, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate or mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also contain buffers.

Solid dosage forms as described above can be prepared using coatings and shells such as enteric coatings and other coatings well known in the art. They may contain soothing agents and may also have compositions in which they release one or more active compounds in a delayed manner at a portion of the intestine. Examples of usable embedding compositions are polymeric substances and waxes. If suitable, the active compounds may also be present in microencapsulated form together with one or more of the excipients described above.

Orally administered liquid dosage forms include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. Such dosage forms are prepared, for example, by dissolving, dispersing, etc., the compounds of the present invention or their pharmaceutically acceptable salts and optionally adjuvants in a carrier, such as water, saline solution, aqueous glucose solution, glycerol, ethanol, etc.; solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, and dimethylformamide; oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil; glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitol; or mixtures of these substances, thereby forming a solution or suspension.

In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar and tragacanth gum, or mixtures of these substances.

Compositions for rectal administration are, for example, suppositories, which can be prepared by mixing the compounds of the present invention with, for example, suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or suppository waxes, which are solid at room temperature but liquid at body temperature and thus melt and release the active component therein when in a suitable body cavity.

Dosage forms for topical application of the compounds of this invention include ointments, powders, sprays, and inhalers. The active ingredient is mixed under aseptic conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required. Ophthalmic preparations, ointments, powders, and solutions are also contemplated within the scope of this invention.

Typically, depending on the intended route of administration, a pharmaceutically acceptable composition will contain about 1% to about 99% by weight of the compound of the present invention or a pharmaceutically acceptable salt thereof, and 99% to 1% by weight of a suitable pharmaceutical excipient. In one example, the composition will contain between about 5% and about 75% by weight of the compound of the present invention or a pharmaceutically acceptable salt thereof, with the remainder being a suitable pharmaceutical excipient.

The actual methods for preparing such dosage forms are known or obvious to those skilled in the art; see, for example, Remington's Pharmaceutical Sciences, 18th edition (Mack Publishing Company, Easton, Pa., 1990). In any case, the composition to be administered will contain a therapeutically effective amount of the compound of the invention or a pharmaceutically acceptable salt thereof for treating the disease state taught according to the invention.

The compounds of the present invention, or pharmaceutically acceptable salts thereof, are administered in therapeutically effective amounts, which will vary depending on a variety of factors, including the activity of the specific compound used, the metabolic stability and duration of action of the compound, age, weight, general health condition, sex, diet, administration pattern and time, excretion rate, drug combination, severity of the specific disease state, and the host receiving treatment. The compounds of the present invention can be administered to patients at dose levels ranging from about 0.1 mg to about 1,000 mg per day. For a normal adult weighing about 70 kg, the dose range is, for example, from about 0.01 mg to about 100 mg per kg of body weight per day. However, the specific dose used can vary. For example, the dose can depend on many factors, including the patient's needs, the severity of the disease to be treated, and the pharmacological activity of the compound used. Determining the optimal dose for a particular patient is well known to those skilled in the art.

Combination therapy

The compounds disclosed herein may be administered as a monotherapy or in combination with one or more additional therapies (“co-administration”) for the treatment of diseases or conditions, such as those associated with excessive proliferation, such as cancer. Therapies that may be used in combination with the compounds disclosed herein include: (i) surgery; (ii) radiation therapy (e.g., gamma rays, neutron beam radiation therapy, electron beam radiation therapy, proton therapy, brachytherapy, and whole-body radioisotopes); (iii) endocrine therapy; (iv) adjuvant therapy, immunotherapy, CAR T-cell therapy; and (v) other chemotherapeutic agents.

The term "co-administration" ("co-administration") refers to the simultaneous or sequential administration of a compound of formula I' or a salt thereof and one or more other active pharmaceutical ingredients (including cytotoxic agents and radiotherapy). If the administration is not simultaneous, the compounds are administered at close intervals. Furthermore, it is irrelevant whether the compounds are administered in the same dosage form; for example, one compound may be administered topically and another may be administered orally.

Generally, any agent active in treating a disease or ailment may be administered together. Examples of such agents used for cancer treatment can be found, for example, at https://www.cancer.gov/about-cancer/treatment/drugs (last accessed January 22, 2019) and in publicly available sources such as Cancer Principles and Practice of Oncology, 11th edition (2018), by VTDevita and S. Hellman (eds.), Lippincott Williams & Wilkins. It will be useful for those skilled in the art to be able to identify which combination of agents is appropriate based on the specific properties of the drugs and the disease being treated.

In one implementation, the treatment method includes co-administration of a compound as disclosed herein or a pharmaceutically acceptable salt thereof, and at least one immunotherapy. Immunotherapy (also known as biological response modulator therapy, biologic therapy, biological agent therapy, immune therapy, or biological therapy) is a therapy that uses a part of the immune system to fight disease. Immunotherapy can help the immune system recognize cancer cells or enhance the response to cancer cells. Immunotherapy includes active and passive immunotherapy. Active immunotherapy stimulates the body's own immune system, while passive immunotherapy typically uses components of the immune system produced outside the body.

Examples of active immunotherapy include, but are not limited to, vaccines, including cancer vaccines, tumor cell vaccines (autologous or allogeneic), dendritic cell vaccines, antigen vaccines, anti-idiotypic vaccines, DNA vaccines, viral vaccines, or tumor-infiltrating lymphocyte (TIL) vaccines with interleukin-2 (IL-2) or lymphokine-activated killer (LAK) cell therapy.

Examples of passive immunotherapy include, but are not limited to, monoclonal antibodies and targeted therapies containing toxins. Monoclonal antibodies include naked antibodies and conjugated monoclonal antibodies (also known as labeled, tagged, or loaded antibodies). Naked monoclonal antibodies do not have a drug or radioactive substance attached to them, while conjugated monoclonal antibodies are attached to, for example, chemotherapeutic drugs (chemically labeled), radioactive particles (radiolabeled), or toxins (immunotoxins). Examples of these naked monoclonal antibody drugs include, but are not limited to: rituximab (Rituxan), an antibody against the CD20 antigen used to treat, for example, B-cell non-Hodgkin lymphoma; trastuzumab (Herceptin), an antibody against the HER2 protein used to treat, for example, advanced breast cancer; alemtuzumab (Campath), an antibody against the CD52 antigen used to treat, for example, B-cell chronic lymphocytic leukemia (B-CLL); cetuximab (Erbitux), an antibody against the EGFR protein used, for example, in combination with irinotecan, to treat, for example, advanced colorectal cancer and head and neck cancer; and bevacizumab (Avastin), an anti-angiogenic therapy that acts on the VEGF protein and is used, for example, in combination with chemotherapy to treat, for example, metastatic colorectal cancer. Examples of conjugated monoclonal antibodies include, but are not limited to: the radiolabeled antibody teimozumab (Zevalin), which delivers radioactivity directly to cancerous B lymphocytes and is used to treat, for example, B-cell non-Hodgkin lymphoma; the radiolabeled antibody tosimomumab (Bexxar), which is used to treat, for example, certain types of non-Hodgkin lymphoma; and the immunotoxin gemtuzumab ozomicin (Mylotarg), which contains calcineurin and is used to treat, for example, acute myeloid leukemia (AML). BL22 is a conjugated monoclonal antibody used to treat, for example, hairy cell leukemia; an immunotoxin used to treat, for example, leukemia, lymphoma, and brain tumors; and radiolabeled antibodies (such as OncoScint for colorectal and ovarian cancer and ProstaScint for prostate cancer).

Other examples of therapeutic antibodies that may be used include, but are not limited to: HERCEPTIN ^™ (trastuzumab) (Genentech, Calif.), a humanized anti-HER2 monoclonal antibody for the treatment of patients with metastatic breast cancer; REOPRO.RTM. (abciximab) (Centocor), an anti-glycoprotein IIb/IIIa receptor on platelets to prevent clot formation; ZENAPAX ^™ (dalizumab) (Roche Pharmaceuticals, Switzerland), an immunosuppressive humanized anti-CD25 monoclonal antibody for the prevention of acute renal allogeneic transplant rejection; PANOREX ^™ , a mouse anti-17-IA cell surface antigen IgG2a antibody (Glaxo Wellcome/Centocor); BEC2, a mouse anti-idiotype (GD3 epitope) IgG antibody (ImClone System); IMC-C225, a chimeric anti-EGFR IgG antibody (ImClone System); VITAXIN ^™ This product is a humanized anti-αVβ3 integrin antibody (Applied Molecular Evolution/Medlmmune); Camppath 1H/LDP-03 is a humanized anti-CD52 IgG1 antibody (Leukosite); Smart M195 is a humanized anti-CD33 IgG antibody (Protein Design Lab/Kanebo); RITUXAN ^™ is a chimeric anti-CD20 IgG1 antibody (IDEC Pharm/Genentech, Roche/Zettyaku); LYMPHOCIDE ^™ is a humanized anti-CD22 IgG antibody (Immunomedics); LYMPHOCIDE ^™ Y-90 (Immunomedics); Lymphoscan (Tc-99m labeling; radiographic imaging; Immunomedics); Nuvion (targeting CD3; Protein Design Labs); CM3 is a humanized anti-ICAM3 antibody (ICOS). IDEC-114 is a primate-derived anti-CD80 antibody (IDEC Pharm/Mitsubishi); ZEVALIN ^™ is a radiolabeled mouse anti-CD20 antibody (IDEC/Schering AG); IDEC-131 is a humanized anti-CD40L antibody (IDEC/Eisai); IDEC-151 is a primate-derived anti-CD4 antibody (IDEC); IDEC-152 is a primate-derived anti-CD23 antibody (IDEC/Seikagaku); SMART anti-CD3 is a humanized anti-CD3 IgG (Protein Design Lab); 5G1.1 is a humanized anti-complement factor 5 (C5) antibody (AlexionPharm); D2E7 is a humanized anti-TNF-α antibody (CAT/BASF); CDP870 is a humanized anti-TNF-α antibody. Fab fragment (Celltech); IDEC-151 is a primate-modified anti-CD4 IgG1 antibody (IDEC Pharm/SmithKline Beecham); MDX-CD4 is a human anti-CD4 IgG antibody (Medarex/Eisai/Genmab); CD20-streptomycin protein (+Biotin-Yttrium 90; NeoRx); CDP571 is a human-modified anti-TNF-α IgG4 antibody (Celltech); LDP-02 is a human-modified anti-α4β7 antibody (LeukoSite/Genentech); OrthoClone OKT4A is a human-modified anti-CD4 IgG antibody (Ortho Biotech); ANTOVA™ is a human-modified anti-CD40L IgG antibody (Biogen); ANTEGREN ^™ is a human-modified anti-VLA-4 IgG antibody (Elan); CAT-152 is a human anti-TGF- _β2 antibody (Cambridge Ab Tech). Others are provided in later paragraphs.

Immunotherapy that can be used in combination with the compounds disclosed herein includes adjuvant immunotherapy. Examples include cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte-macrophage colony-stimulating factor (G-CSF), macrophage inflammatory protein (MIP)-1-α, interleukins (including IL-1, IL-2, IL-4, IL-6, IL-7, IL-12, IL-15, IL-18, IL-21, and IL-27), tumor necrosis factor (including TNF-α), and interferons (including IFN-α, IFN-β, and IFN-γ); aluminum hydroxide (alum); BCG; keyhole hemocyanin (KLH); Freund's incomplete adjuvant (IFA); QS-21; DETOX; levamisole; and dinitrophenyl (DNP), as well as combinations thereof, such as interleukins (e.g., IL-2) combined with other cytokines (such as IFN-α).

In various implementations, immunotherapies or immunotherapeutic agents may include one or more of the following: adoptive cell transfer, angiogenesis inhibitors, BCG therapy, biochemotherapy, cancer vaccines, chimeric antigen receptor (CAR) T-cell therapy, cytokine therapy, gene therapy, immune checkpoint modulators, immune conjugates, radioconjugates, oncolytic virus therapy, or targeted drug therapy. The function or at least one of the functions of immunotherapies or immunotherapeutic agents is collectively referred to herein as "immunotherapeutic agents".

This disclosure provides a method for preventing, treating, reducing, inhibiting, or controlling tumor formation, tumors, or cancer in a subject of need, the method comprising administering a therapeutically effective amount of a combination of a compound containing formula I' and an immunotherapeutic agent. In one non-limiting embodiment, the method comprises administering a therapeutically effective amount of a combination of a compound containing formula I' and an immunotherapeutic agent. In various embodiments, when treated with the combination, the combination provides a synergistic, additive, or additive effect in reducing the number of cancer cells compared to each treatment alone. In some embodiments, administration of a therapeutically effective amount of a combination of a compound containing formula I' and an immunotherapeutic agent produces synergistic antitumor activity and/or more potent antitumor activity than the additive effect of administering the compound of formula I' or the immunotherapeutic agent alone.

Human cancers exhibit numerous genetic and epigenetic alterations, generating neoantigens that can be recognized by the immune system (Sjoblom et al. (2006) Science 314:268-74). The adaptive immune system, composed of T and B lymphocytes, possesses potent anti-cancer potential, exhibiting a broad capacity and fine specificity to respond to a variety of tumor antigens. Furthermore, the immune system displays considerable plasticity and a memory component. Successfully utilizing all these properties of the adaptive immune system will make immunotherapy unique among all cancer treatment modalities.

This disclosure provides combinations of compounds of formula I' and immunotherapeutic agents. These exemplary combinations can be used to treat subjects with cancer. In various embodiments, immunotherapeutic agents found to be usable in the compositions, formulations, and methods of the present invention may include one or more agents or therapies, including: adoptive cell transfer, angiogenesis inhibitors, BCG therapy, biochemotherapy, cancer vaccines, chimeric antigen receptor (CAR) T-cell therapy, cytokine therapy, gene therapy, immune checkpoint modulators such as immune checkpoint inhibitors, immune conjugates, radioconjugates, oncolytic virus therapy, or targeted drug therapy.

In some embodiments of this disclosure, the therapeutically effective combination comprises a compound of formula I' and an immunotherapeutic agent. In various related embodiments, the compound of formula I' enhances the activity of the immunotherapeutic agent.

In certain embodiments of each of the foregoing aspects, as well as in other aspects and embodiments described elsewhere herein, the immunotherapeutic agent enhances the activity of compound I'.

In certain embodiments of each of the foregoing aspects, and in other aspects and embodiments described elsewhere herein, the compounds of formula I' and the immunotherapeutic agents act synergistically. In the various embodiments described herein, exemplary immunotherapeutic agents are immune cell (e.g., T cells, dendritic cells, natural killer cells, etc.) modulators selected from co-stimulatory molecules that act as agonists or activators, wherein the modulator is a monoclonal antibody, a bispecific antibody comprising one or more immune checkpoint antigen-binding moieties, a trispecific antibody, or an immune cell-binding multivalent antibody/fusion protein/construct known in the art. In some embodiments, the immunotherapeutic agent may be an antibody that modulates co-stimulatory molecules, binding to antigens on the surface of immune cells or cancer cells. In each of these different implementations, the antibody modulator can be a monoclonal antibody, a polyclonal antibody, a bispecific antibody, a trispecific or multispecific antibody, a fusion protein or a fragment thereof, such as a double-stranded antibody, a single-stranded (sc)-double-stranded antibody (scFv)2, a microantibody, a microbody, Barnase-barstar, scFv-Fc, sc(Fab)2, a trimer antibody construct, a triabody antibody construct, a trimer antibody construct, a tribody antibody construct, a collagen scaffold antibody construct, or a (scFv-TNFa)3 or F(ab)3/DNL antibody construct.

In certain embodiments of each of the foregoing aspects, and in other aspects and embodiments described elsewhere herein, the immunotherapeutic agent is an agent that modulates the immune response, such as a checkpoint inhibitor or checkpoint agonist. In some embodiments, the immunotherapeutic agent is an agent that enhances the antitumor immune response. In some embodiments, the immunotherapeutic agent is an agent that increases cell-mediated immunity. In some embodiments, the immunotherapeutic agent is an agent that increases T cell activity. In some embodiments, the immunotherapeutic agent is an agent that increases cytolytic T cell (CTL) activity. In some embodiments, the immunotherapeutic agent is an antibody modulator that targets PD-1, PD-L1, PD-L2, CEACAM (e.g., CEACAM-1, -3, and/or -5), CTLA-4, TIM-3, LAG-3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, TGFβ, OX40, 41BB, LIGHT, CD40, GITR, TGF-β, TIM-3, SIRP-α, VSIG8, BTLA, SIGLEC7, SIGLEC9, ICOS, B7H3, B7H4, FAS, and/or BTNL2, as well as other antibodies known in the art. In some embodiments, the immunotherapeutic agent is an agent that increases the activity of natural killer (NK) cells. In some embodiments, the immunotherapeutic agent is an agent that inhibits the suppression of the immune response. In some embodiments, the immunotherapeutic agent is an agent that inhibits the activity of suppressor cells or suppressor cell activity. In some embodiments, the immunotherapeutic agent is an agent or therapy that inhibits Treg activity. In some embodiments, the immunotherapeutic agent is an agent that inhibits the activity of inhibitory immune checkpoint receptors. In some embodiments, the combinations of this disclosure comprise a compound of formula I' and an immunotherapeutic agent, wherein the immunotherapeutic agent comprises a T-cell modulator selected from agonists or activators of co-stimulatory molecules. In one embodiment, the agonist of the co-stimulatory molecule is selected from GITR, OX40, ICOS, SLAM (e.g., SLAMF7), HVEM, LIGHT, CD2, CD27, CD28, CDS, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), 4-1BB (CD137), CD30, CD40, BAFFR, CD7, NKG2C, NKp80, CD160, B7-H3, or CD83 ligands (e.g., agonist antibodies or their antigen-binding fragments, or soluble fusions). In other embodiments, the effector cell combination includes a bispecific T cell adaptor (e.g., a bispecific antibody molecule that binds to CD3 and tumor antigens (e.g., EGFR, PSCA, PSMA, EpCAM, HER2, etc.)).

In some implementations, the immunotherapeutic agent is a modulator of PD-1 activity, PD-L1 activity, PD-L2 activity, CTLA-4 activity, CD28 activity, CD80 activity, CD86 activity, 4-1BB activity, OX40 activity, KIR activity, Tim-3 activity, LAG3 activity, CD27 activity, CD40 activity, GITR activity, TIGIT activity, or CD20 activity. Modulators of various activities, including CD96, IDO1, SIRP-α, TIGIT, VSIG8, BTLA, SIGLEC7, SIGLEC9, ICOS, B7H3, B7H4, FAS, BTNL2, cytokines, chemokines, interferons, interleukins, lymphokines, tumor necrosis factor (TNF) family members, and immunostimulatory oligonucleotides. In some embodiments, the immunotherapeutic agent is an immune checkpoint modulator (e.g., an immune checkpoint inhibitor, such as an inhibitor of PD-1 activity, a modulator of PD-L1 activity, a modulator of PD-L2 activity, a modulator of CTLA-4, or a CD40 agonist (e.g., an anti-CD40 antibody molecule), (xi)OX40 agonist (e.g., an anti-OX40 antibody molecule), or (xii)CD27 agonist (e.g., an anti-CD27 antibody molecule). In one embodiment, the immunomodulator is PD-1, PD-L1 Inhibitors of PD-L2, CTLA-4, TIM-3, LAG-3, CEACAM (e.g., CEACAM-1, -3, and/or -5), VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, and/or TGFβ. In one embodiment, the inhibitors of immune checkpoint molecules inhibit PD-1, PD-L1, LAG-3, TIM-3, CEACAM (e.g., CEACAM-1, -3, and/or -5), CTLA-4, or any combination thereof.

Inhibition of inhibitory molecules can occur at the DNA, RNA, or protein level. In some embodiments, inhibitory nucleic acids (e.g., dsRNA, siRNA, or shRNA) can be used to inhibit the expression of inhibitory molecules. In other embodiments, the inhibitor of the inhibitory signal is a peptide, such as a soluble ligand (e.g., PD-1-Ig or CTLA-4Ig); or an antibody or an antigen-binding fragment thereof, such as a monoclonal antibody, a bispecific antibody containing one or more immune checkpoint antigen-binding moieties, a trispecific antibody; or an immune cell-conjugating multivalent antibody/fusion protein/construct known in the art that binds to an inhibitory molecule; for example, an antibody or fragment thereof (also referred to herein as an "antibody molecule") that binds to PD-1, PD-L1, PD-L2, CEACAM (e.g., CEACAM-1, -3, and/or -5), CTLA-4, TIM-3, LAG-3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, TGFβ, or combinations thereof.

In some embodiments, the combination comprises a compound of formula I' and an immunotherapeutic agent, wherein the immunotherapeutic agent is a monoclonal antibody or a bispecific antibody. For example, the monoclonal or bispecific antibody may specifically bind to a member of the c-Met pathway and/or an immune checkpoint modulator (e.g., a bispecific antibody that binds both the hepatocyte growth factor receptor (HGFR) and the immune checkpoint modulator described herein, such as antibodies that bind to PD-1, PD-L1, PD-L2, or CTLA-4, LAG-3, OX40, 41BB, LIGHT, CD40, GITR, TGF-β, TIM-3, SIRP-α, TIGIT, VSIG8, BTLA, SIGLEC7, SIGLEC9, ICOS, B7H3, B7H4, FAS, BTNL2, or CD27). In a specific embodiment, the bispecific antibody specifically binds to the human HGFR protein and one of PD-1, PD-L1, and CTLA-4.

In some embodiments, the immunotherapeutic agent is a cytokine, such as a chemokine, interferon, interleukin, lymphokine, or a member of the tumor necrosis factor family. In some embodiments, the cytokine is IL-2, IL-15, or interferon-γ.

In some embodiments of any of the foregoing aspects or those described elsewhere herein, the cancer is selected from lung cancer, pancreatic cancer, breast cancer, colon cancer, colorectal cancer, melanoma, gastrointestinal cancer, stomach cancer, kidney cancer, ovarian cancer, liver cancer, endometrial cancer, kidney cancer, prostate cancer, thyroid cancer, neuroblastoma, glioma, glioblastoma multiforme, cervical cancer, stomach cancer, bladder cancer, head and neck cancer, and liver cancer.

In some implementations of any of the foregoing aspects or those described elsewhere herein, the subject's cancer or tumor does not respond to immune checkpoint inhibition (e.g., to any immune checkpoint inhibitor described herein, such as a PD-1 antagonist or a PD-L1 antagonist), or the subject's cancer or tumor has progressed after an initial response to immune checkpoint inhibition (e.g., to any immune checkpoint inhibitor described herein, such as a PD-1 antagonist or a PD-L1 antagonist).

In some implementations of any of the foregoing aspects or those described elsewhere herein, the subject is a human being.

Checkpoint inhibitors can be any molecule, agent, treatment, and/or method that has the following effects: inhibiting immune checkpoints, and/or promoting immune checkpoint inhibitors, for example, by promoting intrinsic immune checkpoint inhibitors; inhibiting transcription factors involved in immune checkpoint expression; and/or by acting in synergy with some additional extrinsic factors. For example, checkpoint inhibitors may include treatments that inhibit transcription factors involved in the expression of immune checkpoint genes or promote the expression of transcription factors of tumor suppressor genes such as BACH2 (Luan et al., (2016). Transcription Factors and Checkpoint Inhibitor Expression with Age: Markers of Immunosenescence. Blood, 128(22), 5983). In addition, checkpoint inhibitors can inhibit: transcription of immune checkpoint genes; modification and/or processing of immune checkpoint mRNAs; translation of immune checkpoint proteins; and/or activation of molecules involved in the immune or immune checkpoint pathways, such as PD-1 transcription factors like HIF-1, STAT3, NF-κB, and AP-1, or common oncogenic pathways such as JAK/STAT, RAS/ERK, or PI3K/AKT/mTOR (Zerdes et al., Genetic, transcriptional and post-translational regulation of the programmed death protein ligand 1 in cancer: biology and clinical correlations, Oncogene, Vol. 37, pp. 4639-4661 (2018), the full text of which is incorporated herein by reference).

Checkpoint inhibitors can include therapies, molecules, agents, and/or methods that regulate immune checkpoints at the transcriptional level, such as using co-inhibition of RNA interference pathways and/or post-transcriptional gene silencing (PTGS) (e.g., microRNAs, miRNAs; silenced RNAs, small interfering RNAs, or short interfering RNAs (siRNAs)). Transcriptional regulation of checkpoint molecules has been shown to involve mir-16, which has been shown to target the 3'UTR of checkpoint mRNAs CD80, CD274 (PD-L1), and CD40 (Leibowitz et al., Post-transcriptional regulation of immune checkpoints). oint genes by mir-16 in melanoma, Annals of Oncology (2017) 28; v428-v448). Mir-33a has also been shown to be involved in regulating PD-1 expression in lung adenocarcinoma cases (Boldini et al., Role of microRNA-33a in regulating the expression of PD-1 in lung adenocarcinoma, Cancer Cell Int. 2017; 17:105, the full text of which is cited in this article).

T-cell specific aptamer-siRNA chimeras have been proposed as a highly specific method for inhibiting molecules in the immune checkpoint pathway (Hossain et al., The aptamer–siRNA conjugates: reprogramming T cells for cancer therapy, Ther. Deliv., January 2015; 6(1):1–4, the full text of which is cited in this paper).

Alternatively, treatments affecting related pathways (e.g., metabolism) can be used to suppress members of the immune checkpoint pathway. For example, CAD macrophages oversupply pyruvate, a glycolytic intermediate, in mitochondria, promoting PD-L1 expression via the induction of the bone morphogenetic protein 4/phosphorylated SMAD1/5/IFN regulator 1 (BMP4/p-SMAD1/5/IRF1) signaling pathway. Thus, implementing treatments that regulate metabolic pathways can lead to subsequent regulation of the immunosuppressive PD-1/PD-L1 checkpoint pathway (Watanabe et al., Pyruvate controls the checkpoint inhibitor PD-L1 and suppresses T cell immunity, J Clin Invest., 30 June 2017; 127(7):2725–2738).

Checkpoint immunity can be regulated by oncolytic viruses that selectively replicate within tumor cells and induce an acute immune response in the tumor microenvironment. This is achieved by acting as genetic vectors carrying agents specific to cancer cells (e.g., antibodies, miRNAs, siRNAs, etc.) and influencing their oncolytic activity, as well as the secretion of cytokines and chemokines, in synergistic effects with immune checkpoint inhibition (Shi et al., Cancer Immunotherapy: A Focus on the Regulation of Immune Checkpoints, Int J Mol Sci., May 2018; 19(5):1389). Currently, ongoing clinical trials utilize the following viruses as checkpoint inhibitors: poliovirus, measles virus, adenovirus, poxvirus, herpes simplex virus (HSV), Coxsackievirus, reovirus, Newcastle disease virus (NDV), T-VEC (herpesvirus encoded by GM-CSF (granulocyte-macrophage colony-stimulating factor)) and H101 (Shi et al., ibid.).

Checkpoint inhibitors can act at the translational level of checkpoint immunity. Translation from mRNA to protein represents a key event in gene expression regulation; therefore, inhibiting immune checkpoint translation is a method to suppress the immune checkpoint pathway.

Inhibition of the immune checkpoint pathway can occur at any stage of the immune checkpoint translation process. For example, drugs, molecules, agents, treatments, and/or methods can inhibit the initiation process (whereby the 40S ribosomal subunit is recruited to the 5' end of the mRNA and scans the 5'UTR of the mRNA toward its 3' end). Inhibition can occur by targeting the anticodon of the initiator methionyl transfer RNA (tRNA) (Met-tRNAi, which pairs with the start codon) or by recruiting the 60S subunit to begin elongation and sequentially adding amino acids in the translation of immune checkpoint-specific genes. Alternatively, checkpoint inhibitors can inhibit checkpoints at the translational level by preventing the formation of the ternary complex (TC), namely eukaryotic initiation factor (eIF)2 (or one or more of its α, β, and γ subunits), GTP, and Met-tRNAi.

Checkpoint inhibition can occur through the destabilizing effect of eIF2α, i.e., by preventing its phosphorylation via protein kinase R (PKR), PERK, GCN2, or HRI, or by preventing TC from binding to the 40S ribosome and/or other initiation factors, thereby preventing the formation of the pre-initiation complex (PIC); and by inhibiting the eIF4F complex and/or its cap-binding protein eIF4E, scaffold protein eIF4G, or eIF4A helicase. Methods for translational control in cancer are discussed in Truitt et al., New frontiers intranslational control of the cancer genome, Nat Rev Cancer., April 26, 2016; 16(5):288–304, the full text of which is incorporated herein by reference.

Checkpoint inhibitors may also include, for example, therapies, molecules, agents, and/or methods that modulate immune checkpoints at the cellular and/or protein level by inhibiting immune checkpoint receptors. Inhibition of checkpoints can occur through the use of antibodies, antibody fragments, antigen-binding fragments, small molecules, and/or other drugs, agents, therapies, and/or methods.

Immune checkpoints are inhibitory pathways within the immune system responsible for maintaining self-tolerance and modulating the immune response to minimize damage to peripheral tissues. However, tumor cells can also activate immune system checkpoints, reducing the effectiveness of the immune response against tumor tissue (“blocking” the immune response). Unlike most anticancer agents, checkpoint inhibitors do not directly target tumor cells but rather lymphocyte receptors or their ligands to enhance the endogenous antitumor activity of the immune system (Pardoll, 2012, Nature Reviews Cancer 12:252-264).

Until recently, cancer immunotherapy has largely focused on enhancing antitumor immune responses through adoptive transfer of activated effector cells, immunization against relevant antigens, or the delivery of nonspecific immunostimulants such as cytokines. However, in the past decade, significant efforts to develop specific immune checkpoint pathway inhibitors have begun to offer novel immunotherapies for cancer treatment, including the development of the antibody (Ab) ipilimumab (YERVOY.RTM.) which binds to and inhibits CTLA-4 for the treatment of patients with advanced melanoma (Hodi et al., (2010) N Engl J Med 363:711-23) and antibodies that specifically bind to the programmed death-1 (PD-1) receptor and block the inhibitory PD-1/PD-1 ligand pathway, such as nivolumab and pembrolizumab (formerly known as lambolizumab; USAN Council Statement (2013) Pembrolizumab: Statement on a nonproprietary name adopted). Developed by the USAN Council (ZZ-165), November 27, 2013 (Topalian et al. (2012a) N Engl J Med 366:2443-54; Topalian et al. (2012b) Curr Opin Immunol 24:207-12; Topalian et al. (2014) J Clin Oncol 32(10):1020-30; Hamid et al. (2013) N Engl J Med 369:134-144; Hamid and Carvajal (2013) Expert Opin Biol Ther 13(6):847-61; McDermott and Atkins (2013) Cancer Med 2(5):662-73).

PD-1 is a key immune checkpoint receptor expressed by activated T and B cells and mediates immunosuppression. Nivolumab (formerly known as 5C4, BMS-936558, MDX-1106, or ONO-4538) is a fully human IgG4 (S228P) PD-1 immune checkpoint inhibitor antibody that selectively prevents interaction with PD-1 ligands (PD-L1 and PD-L2), thereby blocking the downregulation of anti-tumor T cell function (US Patent No. 8,008,449; Wang et al. (2014) In vitro characterization of the anti-PD-1 antibody nivolumab, BMS-936558, and in vivo toxicology in non-human primates). Nivolumab has been approved for the treatment of patients with unresectable or metastatic melanoma who have progressed after ipilimumab treatment, and if BRAF V600 mutation is positive, BRAF inhibitors used to treat squamous non-small cell lung cancer are used.

Recent data suggest a secondary mechanism of anti-CTLA-4 antibodies that may occur within the tumor itself. CTLA-4 has been found to be expressed at higher levels on regulatory T cells (also referred to herein as "Treg cells") in tumors compared to effector T cells (also referred to herein as "Teff cells"), leading to the hypothesis that anti-CTLA-4 preferentially affects Treg cells. (See "Therapeutic use of anti-CTLA-4 antibodies," Christian U. Blank and Alexander Enk, International Immunology, Vol. 27, No. 1, pp. 3-10). Recent studies of the combination of PD-1 and CTLA-4 have shown that combined blocking of the CTLA-4 and PD-1 pathways also synergistically increases the ratio of Teff cells to regulatory T cells and MDSCs, thereby reducing suppression and promoting inflammation in the tumor microenvironment. "Combination of CTLA-4 and PD-1 blockade expands infiltrating T-cells and reduces regulatory T and myeloid cells within B16 melanoma tumors," Curran et al., PNAS | March 2, 2010; Vol. 107 (No. 9); pp. 4275-4280, the full text of which is incorporated herein by reference. Combinations of checkpoint inhibitors and other therapeutic agents can enhance or prolong the antitumor response of checkpoint inhibitors and/or the effects of therapeutic agents. In this regard, WO 2015/069770 discloses combination therapies based on activating adaptive immune responses for the treatment of cancer, particularly combinations of CTLA-4 and PD-1 inhibitors. The full text of the disclosure of WO 2015/069770 is incorporated herein by reference.

One mechanism by which checkpoint blocking anti-CTLA-4 antibodies mediate antitumor effects is through the reduction of regulatory T cells. Due to the unique mechanism of action of anti-CTLA-4 antibodies, they can be successfully combined with anti-PD1 checkpoint blocking antibodies to exert their effects by releasing inhibitory signaling conferred on effector T cells. The dual blocking combination of these antibodies has been shown to improve antitumor responses in preclinical (ProcNatl Acad Sci USA 2010, 107, 4275-4280) and clinical (N Engl J Med 2013, 369, 122-133; N Engl J Med 2015, 372, 2006-2017).

CTLA-4 attenuates early activation of naive and memory T cells through interactions with its ligands B7-1 (CD80) and B7-2 (CD86). PD-1 is a receptor expressed on the surface of activated mature T cells, activated NK cells, B cells, monocytes, and various normal tissues, and plays a key role in maintaining peripheral tolerance [20-21]. In contrast to CTLA-4, PD-1 functions through its interaction with its ligand PD-L1 (also known as B7-H1 or CD274) and is primarily involved in regulating T cell activity in peripheral tissues and providing key immune resistance mechanisms within the tumor microenvironment.

In some implementations, the immunotherapeutic agent is a modulator of PD-1 activity, a modulator of PD-L1 activity, a modulator of PD-L2 activity, a modulator of CTLA-4 activity, a modulator of CD28 activity, a modulator of CD80 activity, a modulator of CD86 activity, a modulator of 4-1BB activity, a modulator of OX40 activity, a modulator of KIR activity, a modulator of Tim-3 activity, a modulator of LAG3 activity, a modulator of CD27 activity, a modulator of CD40 activity, a modulator of GITR activity, a modulator of TIGIT activity, a modulator of CD20 activity, a modulator of CD96 activity, a modulator of IDO1 activity, a cytokine, a chemokine, an interferon, an interleukin, a lymphokine, a member of the tumor necrosis factor (TNF) family, or an immunostimulatory oligonucleotide. In some implementations, the immune checkpoint modulator is, for example, an inhibitor or antagonist, or an activator or agonist, such as a CD28 modulator, a 4-1BB modulator, an OX40 modulator, a CD27 modulator, a CD80 modulator, a CD86 modulator, a CD40 modulator, or a GITR modulator, a Lag-3 modulator, a 41BB modulator, a LIGHT modulator, a CD40 modulator, a GITR modulator, a TGF-β modulator, a TIM-3 modulator, a SIRP-α modulator, a TIGIT modulator, a VSIG8 modulator, a BTLA modulator, a SIGLEC7 modulator, a SIGLEC9 modulator, an ICOS modulator, a B7H3 modulator, a B7H4 modulator, a FAS modulator, and/or a BTNL2 modulator. In some embodiments, the immunotherapeutic agent is an immune checkpoint modulator as described above (e.g., an immune checkpoint modulator antibody, which may be a monoclonal antibody, a bispecific antibody containing one or more immune checkpoint antigen-binding moieties, a trispecific antibody, or in the form of an immune cell-conjugating multivalent antibody/fusion protein/construct known in the art).

Combination therapy with immune checkpoint inhibitor immunotherapies can include antibodies that specifically target immune system checkpoints such as CTLA4, PD1, and PD-L1, representing one of the most promising new avenues for immunotherapy in cancer and other diseases. Additional checkpoint targets such as TIM-3, LAG-3, various B-7 ligands, CHK1 and CHK2 kinases, BTLA, and A2aR are also under investigation. Currently, three checkpoint inhibitors have received fast-track approval from the U.S. Food and Drug Administration for cancer treatment: ipilimumab, a CTLA-4 inhibitor, and pembrolizumab and nivolumab, both PD-1 inhibitors. Several other checkpoint inhibitors are also in clinical trials.

Programmed cell death protein 1 (PD-1 or CD279), a 55-kD type I transmembrane protein, is a member of the CD28 family of T cell costimulatory receptors, which includes immunoglobulin superfamily members CD28, CTLA-4, inducible costimulatory factor (ICOS), and BTLA. PD-1 is highly expressed on activated T cells and B cells. PD-1 expression can also be detected on memory T cell subsets with variable expression levels. Two PD-1-specific ligands have been identified: programmed death ligand 1 (PD-L1, also known as B7-H1 or CD274) and PD-L2 (also known as B7-DC or CD273). In both mouse and human systems, PD-L1 and PD-L2 show downregulation of T cell activation upon binding to PD-1 (Okazaki et al., Int Immunol., 2007; 19:813-824). The interaction between PD-1 and its ligands PD-L1 and PD-L2 (expressed on antigen-presenting cells (APCs) and dendritic cells (DCs) transmits negative regulatory stimuli, downregulating the activated T cell immune response. Blocking PD-1 inhibits this negative signaling and amplifies the T cell response.

Numerous studies have shown that the cancer microenvironment manipulates the PD-L1-/PD-1 signaling pathway, and the induction of PD-L1 expression is associated with the suppression of the immune response against cancer, thereby enabling cancer progression and metastasis. The PD-L1/PD-1 signaling pathway is a major mechanism for cancer immune escape for several reasons. First, and most importantly, this pathway is involved in the negative regulation of the immune response of activated T effector cells found in the periphery. Second, PD-L1 is upregulated in the cancer microenvironment, while PD-1 is also upregulated on activated tumor-infiltrating T cells, potentially enhancing the vicious cycle of suppression. Third, this pathway is complexly involved in the regulation of both innate and adaptive immunity through bidirectional signaling. These factors make the PD-1/PD-L1 complex a central point through which cancer can manipulate the immune response and promote its own progression.

CTLA-4 (also known as cytotoxic T-lymphocyte-associated protein 4, CTLA4, CTLA-4, CD152, differentiation cluster 152; ALPS5, CD, CELIAC3, GRD4, GSE, and IDDM12) is a 24.6-kDa single-pass type I membrane protein that plays an inhibitory role in T cell function. CTLA-4 was initially identified by differential screening of a mouse cytotoxic T cell cDNA library; see Brunet et al., A new member of the immunoglobulin superfamily--CTLA-4, Nature., July 16-22, 1987; 328(6127):267-70. CTLA-4 has been shown to interact with b7 family ligands CD80 (also known as differentiation cluster 80 and B7-1) and CD86 (also known as differentiation cluster 86 or B7-2). See Linsley et al., CTLA-4 is a second receptor for the B cell activation antigen B7, J Exp Med., 1 Sep 1991; 174(3):561-9. Sequence comparison between the human CTLA-4 DNA coding region and the CD28 DNA coding region revealed significant homology between the two sequences, with the greatest similarity between the juxtamembranous and cytoplasmic regions; therefore, CTLA-4 is associated with the elimination/reduction of T cell activity and antagonism of CD28 activity. Mice lacking CTLA-4 have been shown to exhibit extensive lymphoproliferation. Chambers et al., Lymphoproliferation in CTLA-4-deficient mice is mediated by costimulation-dependent activation of CD4+ T cells, Immunity., Dec 1997; 7(6):885-95. It has been reported that CTLA-4 blockade enhances T cell responses, induces autoimmune diseases, and exacerbates antitumor immunity both in vitro and in vivo. (See Luhder, J. Exp. Med. 1998; 187:427-432; Walunas et al., Immunity. 1994; 1:405-413; Kearney, J. Immunol. 1995; 155:1032-1036; Leach, Science 1996; 271:1734-1736). CTLA-4 has also been reported to have alternative and/or additional effects on the initial characteristics of T-cell immune responses (Chambers, Curr. Opin. Immunol. 1997; 9:396-404; Bluestone, J. Immunol. 1997; 158:1989-1993; Thompson, Immunity 1997; 7:445-450).

The first immune checkpoint inhibitor to be tested in clinical trials is Yervoy (Bristol-Myers Squibb), a CTLA-4 mAb. CTLA-4 belongs to the receptor immunoglobulin superfamily, which also includes PD-1, BTLA, TIM-3, and T cell activation V-domain immunoglobulin inhibitor (VISTA). Anti-CTLA-4 mAbs are potent checkpoint inhibitors that remove “breakdowns” from naïve cells and antigen-treated cells. The therapy enhances the anti-tumor function of CD8+ T cells, increases the ratio of CD8+ T cells to Foxp3+ T regulatory cells, and inhibits the suppressive function of T regulatory cells. The main drawback of anti-CTLA-4 mAb therapy is autoimmune toxicity due to the on-target effects of an overactive immune system that has lost its self-regulation. It has been reported that up to 25% of patients treated with ipilimumab experienced serious grade 3-4 adverse events/autoimmune side effects, including dermatitis, enterocolitis, hepatitis, endocrine disorders (including hypophysitis, thyroiditis, and adrenalitis), arthritis, uveitis, nephritis, and aseptic meningitis. In contrast to the experience with anti-CTLA-4 therapy, anti-PD-1 therapy appears to be better tolerable and induces a relatively low rate of autoimmune side effects.

In some embodiments, the immunotherapy agent is an agent that inhibits PD-1 activity. In some embodiments, the immunotherapy agent is an agent that inhibits PD-L1 and/or PD-L2 activity. In some embodiments, the immunotherapy agent is an agent that inhibits CTLA-4 activity. In some embodiments, the immunotherapy agent is an agent that inhibits CD80 and/or CD86 activity. In some embodiments, the immunotherapy agent is an agent that inhibits TIGIT activity. In some embodiments, the immunotherapy agent is an agent that inhibits KIR activity. In some embodiments, the immunotherapy agent is an agent that enhances or stimulates the activity of activated immune checkpoint receptors.

In some embodiments of the methods described herein, the immunotherapeutic agent is a PD-1 antagonist, PD-L1 antagonist, PD-L2 antagonist, CTLA-4 antagonist, CD80 antagonist, CD86 antagonist, KIR antagonist, Tim-3 antagonist, LAG3 antagonist, TIGIT antagonist, CD20 antagonist, CD96 antagonist, or IDO1 antagonist.

In some implementations, the PD-1 antagonist is an antibody that specifically binds to PD-1. In some implementations, the PD-1-binding antibody is pembrolizumab (MK-3475; Merck), pidilizumab (CT-011; Curetech Ltd.), nivolumab (BMS-936558, MDX-1106; Bristol Myer Squibb), MEDI0680 (AMP-514; AstraZenenca/MedImmune), REGN2810 (Regeneron Pharmaceuticals), BGB-A317 (BeiGene Ltd.), PDR-001 (Novartis), or STI-A1110 (Sorrento Therapeutics). In some embodiments, antibodies binding to PD-1 are described in PCT Publication WO2014/179664, for example, antibodies identified as APE2058, APE1922, APE1923, APE1924, APE 1950, or APE1963 (Anaptysbio), or antibodies containing the CDR region of any of these antibodies. In other embodiments, the PD-1 antagonist is a fusion protein including the extracellular domain of PD-L1 or PD-L2, such as AMP-224 (AstraZeneca/MedImmune). In other embodiments, the PD-1 antagonist is a peptide inhibitor, such as AUNP-12 (Aurigene).

In some embodiments, the PD-L1 antagonist is an antibody that specifically binds to PD-L1. In some embodiments, the antibody binding to PD-L1 is atezolizumab (RG7446, MPDL3280A; Genentech), MEDI4736 (AstraZeneca/MedImmune), BMS-936559 (MDX-1105; Bristol Myers Squibb), avelumab (MSB0010718C; Merck KGaA), KD033 (Kadmon), an antibody fraction of KD033, or STI-A1014 (Sorrento Therapeutics). In some implementations, antibodies binding to PD-L1 are described in PCT Publication WO 2014/055897, such as Ab-14, Ab-16, Ab-30, Ab-31, Ab-42, Ab-50, Ab-52, Ab-55, or antibodies containing the CDR region of any of these antibodies, the entire contents of which are incorporated herein by reference.

In some embodiments, the CTLA-4 antagonist is an antibody that specifically binds to CTLA-4. In some embodiments, the antibody binding to CTLA-4 is ipilimumab (Bristol Myer Squibb) or tremelimumab (CP-675,206; Pfizer). In some embodiments, the CTLA-4 antagonist is a CTLA-4 fusion protein or a soluble CTLA-4 receptor, such as KARR-102 (Kahr Medical Ltd.).

In some embodiments, the LAG3 antagonist is an antibody that specifically binds to LAG3. In some embodiments, the LAG3-binding antibody is IMP701 (Prima BioMed), IMP731 (Prima BioMed/GlaxoSmithKline), BMS-986016 (Bristol Myer Squibb), LAG525 (Novartis), and GSK2831781 (GlaxoSmithKline). In some embodiments, the LAG3 antagonist comprises a soluble LAG3 receptor, such as IMP321 (Prima BioMed).

In some embodiments, the KIR antagonist is an antibody that specifically binds to a KIR. In some embodiments, the KIR-binding antibody is lirilumab (Bristol Myer Squibb/Innate Pharma).

In some embodiments, the immunotherapeutic agents used in the combinations disclosed herein (e.g., combinations with compounds of formula I') are activators or agonists of co-stimulatory molecules. In one embodiment, the agonist of the co-stimulatory molecule is selected from agonists of OX40, CD2, CD27, CD28, CDS, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3, or CD83 ligands (e.g., agonist antibodies or their antigen-binding fragments, or soluble fusions).

In some embodiments, the OX40 agonist comprises an OX40 ligand or its OX40-binding moiety. For example, the OX40 agonist may be MEDI6383 (AstraZeneca). In some embodiments, the OX40 agonist is an antibody that specifically binds to OX40. In some embodiments, the antibody binding to OX40 is MEDI6469 (AstraZeneca/MedImmune), MEDI0562 (AstraZeneca/MedImmune), or MOXR0916 (RG7888; Genentech). In some embodiments, the OX40 agonist is a vector capable of expressing the OX40 ligand (e.g., an expression vector or a virus, such as adenovirus). In some embodiments, the vector expressing OX40 is Delta-24-RGDOX (DNAtrix) or DNX2401 (DNAtrix).

In some embodiments, the 4-1BB (CD137) agonist is a binding molecule, such as an anticalin. In some embodiments, the anti-carrier protein is PRS-343 (Pieris AG). In some embodiments, the 4-1BB agonist is an antibody that specifically binds to 4-1BB. In some embodiments, the antibody that binds to 4-1BB is PF-2566 (PF-05082566; Pfizer) or urelumab (BMS-663513; Bristol Myer Squibb).

In some embodiments, the CD27 agonist is an antibody that specifically binds to CD27. In some embodiments, the antibody that binds to CD27 is varlilumab (CDX-1127; Celldex).

In some embodiments, the GITR agonist comprises a GITR ligand or its GITR-binding moiety. In some embodiments, the GITR agonist is an antibody that specifically binds to GITR. In some embodiments, the antibody that binds to GITR is TRX518 (GITR, Inc.), MK-4166 (Merck), or INBRX-110 (Five Prime Therapeutics/Inhibrx).

TIM-3 has been identified as another important inhibitory receptor expressed by exhausted CD8+ T cells. In mouse models of cancer, it has been shown that the most dysfunctional tumor-infiltrating CD8+ T cells actually co-express PD-1 and TIM-3.

LAG-3 is another recently identified inhibitory receptor that limits effector T cell function and increases the inhibitory activity of regulatory T cells. It has recently been revealed that PD-1 and LAG-3 are widely co-expressed by tumor-infiltrating T cells in mice, and that combined blockade of PD-1 and LAG-3 elicits a potent synergistic antitumor immune response in a mouse cancer model.

PD-1 pathway blockade can be combined with vaccines or other I’ antibody compounds to enhance therapeutic efficacy (Hirano, F. et al., Cancer Res., 65(3):1089-1096 (2005); Li, B. et al., Clin. Cancer Res., 15:1507-1509 (2009); and Curran, M.A. et al., Proc. Natl. Acad. Set, 107(9):4275-4280 (2010)).

In some embodiments, the immunotherapeutic agent used in the compositions and methods described herein may include a monoclonal antibody, a bispecific antibody comprising one or more immune checkpoint antigen-binding moieties, a trispecific antibody, or an immune cell-conjugating multivalent antibody/fusion protein/construct known in the art that specifically targets both PD-1 and its ligand PD-L1.

PD-1 (also known as programmed death 1, CD279, or PDCD1) is a cell surface receptor that plays a crucial role in regulating the balance between stimulatory and inhibitory signals in the immune system and maintaining peripheral tolerance (Ishida, Y et al., 1992 EMBO J.11 3887; Kier, Mary E et al., 2008 Annu Rev Immunol 26 677-704; Okazaki, Taku et al., 2007 International Immunology 19 813-824). PD-1 is an inhibitory member of the immunoglobulin superfamily, homologous to CD28. PD-1 is a monomeric type 1 transmembrane protein consisting of an immunoglobulin-variable extracellular domain and cytoplasmic domains containing an immunoreceptor tyrosine-based inhibitory motif (ITIM) and an immunoreceptor tyrosine-based switch motif (ITSM). PD-1 expression is inducible on T cells, B cells, natural killer (NK) cells, and monocytes, for example, after activation of lymphocytes via T cell receptor (TCR) or B cell receptor (BCR) signaling (Kier, Mary E et al., 2008 Annu Rev Immunol 26 677-704; Agata, Y et al., 1996 Int Immunol 8 765-72). PD-1 is the receptor for ligands CD80, CD86, PD-L1 (B7-H1, CD274), and PD-L2 (B7-DC, CD273), which are cell surface expression members of the B7 family (Freeman, Gordon et al., 2000 J Exp Med 1921027; Latchman, Y et al., 2001 Nat Immunol 2 261). Upon ligand binding, PD-1 recruits phosphatases such as SHP-1 and SHP-2 to their intracellular tyrosine motifs, subsequently dephosphorylating effector molecules activated by TCR or BCR signaling (Chemnitz, J et al., 2004 J Immunol 173 945-954; Riley, James L 2009 Immunological Reviews 229 114-125). Thus, PD-1 transduces inhibitory signals to T cells and B cells only when simultaneously bound to TCR or BCR.

PD-1 has been shown to downregulate effector T cell responses through both intrinsic and extracellular functional mechanisms. Inhibitory signaling by PD-1 induces a non-responsive state in T cells, resulting in clonal expansion or failure to produce optimal levels of effector cytokines. PD-1 can also induce T cell apoptosis through its ability to inhibit survival signals from co-stimuli, leading to decreased expression of key anti-apoptotic molecules such as Bcl-XL (Kier, Mary E et al., 2008 Annu Rev Immunol 26 677-704). In addition to these direct effects, recent publications have suggested that PD-1 participates in effector cell suppression by promoting the induction and maintenance of regulatory T cells (TREGs). For example, PD-L1 expressed on dendritic cells has been shown to synergize with TGF-β to promote the induction of CD4+FoxP3+ TREGs with enhanced inhibitory function (Francisco, Loise M et al., 2009 J Exp Med 206 3015-3029).

TIM-3 (also known as T cell immunoglobulin and mucin-containing domain-3, TIM-3, hepatitis A virus cell receptor 2, HAVCR2, HAVcr-2, KIM-3, TIMD-3, TIMD3, Tim-3 and CD366) is a 33.4-kDa single-pass type I membrane protein involved in the immune response (Sanchez-Fueyo et al., Tim-3 inhibits T helper type 1-mediated auto- and alloimmune responses and promotes immune tolerance, Nat. Immunol. 4:1093-1101 (2003)).

TIM-3 is selectively expressed on Th1 cells and phagocytes (e.g., macrophages and dendritic cells). Lowering human expression using siRNA or blocking antibodies leads to increased secretion of interferon-γ (IFN-γ) from CD4-positive T cells, suggesting an inhibitory role of TIM-3 in human T cells. Analysis of clinical samples from patients with autoimmune diseases showed no TIM-3 expression in CD4-positive cells. In particular, T-cell clones derived from the cerebrospinal fluid of multiple sclerosis patients showed lower levels of TIM-3 expression and higher levels of IFN-γ secretion compared to clones derived from healthy individuals (Koguchi K et al., JExp Med. 203:1413-8. (2006)).

TIM-3 is the receptor for galactoglobulin-9, a ligand of a member of the galactoglobulin family, which is a molecule universally expressed in multiple cell types and binds to the following molecules: β-galactoside; phosphatidylserine (PtdSer) (DeKryff et al., T cell/transmembrane, Ig, and mucin-3 allelelic variants differentially recognize phosphatidylserine and immediate phagocytosis of apoptotic cells, J Immunol., 15 Feb 2010; 184(4):1918-30); high-mobility group box 1 (also known as HMGB1, HMG1, HMG3, SBP-1, HMG-1 and high-mobility group box 1) (Chiba et al., Tumor-i Filtrating DCs suppresses nucleic acid-mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1, Nat Immunol., Sep 2012; 13(9):832-42); and carcinoembryonic antigen-associated cell adhesion molecule 1 (also known as CEACAM1, BGP, BGP1, BGPI, carcinoembryonic antigen-associated cell adhesion molecule 1) (Huang et al., CEACAM1 regulates TIM-3-mediated tolerance and exhaustion, Nature., Jan 15 2015; 517(7534):386-90).

BTLA (also known as B- and T-lymphocyte attenuators, BTLA1, CD272, and B- and T-lymphocyte-associated) is a 27.3-kDa single-pass type I membrane protein involved in lymphocyte suppression during the immune response. BTLA is constitutively expressed in both B cells and T cells. BTLA interacts with HVEM (herpesvirus entry mediator), a member of the tumor necrosis factor receptor (TNFR) family (Gonzalez et al., Proc. Natl. Acad. Sci. USA, 2005, 102:1116-21). The interaction between BTLA (belonging to the CD28 family of immunoglobulins) and HVEM (co-stimulatory tumor necrosis factor (TNF) receptor (TNFR)) is unique because it defines crosstalk between these two receptor families. BTLA contains an inhibitory motif (ITIM) based on the tyrosine residues of proximal immunoreceptors and a switch motif (ITSM) based on the tyrosine residues of distal immunoreceptors. Disruption of ITIM or ITSM abolishes BTLA's ability to recruit SHP1 or SHP2, indicating that BTLA recruits SHP1 and SHP2 in a different manner than PD-1 and requires two tyrosine motifs to block T cell activation. The BTLA cytoplasmic tail also contains a third conserved tyrosine motif within its cytoplasmic domain, with a sequence similar to the Grb-2 recruitment site (YXN). Furthermore, phosphorylated peptides containing this BTLA N-terminal tyrosine motif can interact with the p85 subunit of GRB2 and PI3K in vitro, although the functional effects of this interaction in vivo have not been explored (Gavrieli et al., Bioochem. Biophysi Res Commun, 2003, 312, 1236-43). BTLA is a receptor for ligands PTPN6/SHP-1, PTPN11/SHP-2, TNFRSF14/HVEM, and B7H4.

VISTA (also known as the V-domain Ig repressor of T-cell activation VSIR, B7-H5, B7H5, GI24, PP2135, SISP1, DD1α, VISTA, C10orf54, chromosome 10 open reading frame 54, PD-1H, and V-set immunomodulatory receptor) is a 33.9-kDa single-pass type I membrane protein involved in T-cell inhibitory responses, embryonic stem cell differentiation inhibited via BMP4 signaling, and MMP14-mediated MMP2 activation (Yoon et al., Control of signaling-mediated clearance of apoptotic cells by the tumor suppressor p53, Science., July 31, 2015; 349(6247):1261669). VISTA interacts with its ligand VSIG-3 (Wang et al., VSIG-3 as a ligand of VISTA inhibits human T-cell function, Immunology., January 2019; 156(1):74-85)

LAG-3 (also known as lymphocyte activation gene 3, LAG3, CD223, and lymphocyte activation 3) is a 57.4-kDa single-pass type I membrane protein involved in lymphocyte activation and binding to HLA class II antigens. LAG-3 is a member of the immunoglobulin superfamily and is expressed on activated T cells (Huard et al., 1994, Immunogenetics 39:213), NK cells (Triebel et al., 1990, J. Exp. Med. 171:1393-1405), regulatory T cells (Huang et al., 2004, Immunity 21:503-513; Camisaschi et al., 2010, J Immunol. 184:6545-6551; Gagliani et al., 2013, Nat Med 19:739-746), and plasmacytoid dendritic cells (DCs) (Workman et al., 2009, J Immunol 182:1885-1891). LAG-3 is a membrane protein encoded by a gene located on chromosome 12 and is structurally and genetically associated with CD4. Similar to CD4, LAG-3 can interact with MHC class II molecules on the cell surface (Baixeras et al., 1992, J. Exp. Med. 176:327-337; Huad et al., 1996, Eur. J. Immunol. 26:1180-1186). Direct binding of LAG-3 to MHC class II molecules has been shown to play a role in downregulating antigen-dependent stimulation of CD4+ T lymphocytes (Huard et al., 1994, Eur. J. Immunol. 24:3216-3221), and LAG-3 blockade has also been shown to restore CD8+ lymphocyte viability in tumor or autoantigen (Gross et al., 2007, J Clin Invest. 117:3383-3392) and viral models (Blackburn et al., 2009, Nat. Immunol. 10:29-37). Furthermore, the intracytoplasmic region of LAG-3 can interact with LAP (LAG-3-associated protein), a signal transduction molecule involved in the downregulation of the CD3/TCR activation pathway (Iouzalen et al., 2001, Eur. J. Immunol. 31:2885-2891). In addition, CD4+CD25+ regulatory T cells (Tregs) have been shown to express LAG-3 upon activation, which contributes to the inhibitory activity of Treg cells (Huang, C. et al., 2004, Immunity 21:503-513). LAG-3 can also negatively regulate T cell homeostasis through Tregs via T cell-dependent and T cell-independent mechanisms (Workman, C. J. and Vignali, D. A., 2005, J. Immunol. 174:688-695).

LAG-3 has been shown to interact with MHC class II molecules (Huard et al., CD4/majorhistocompatibility complex class II interaction analyzed with CD4-and lymphocyte activation gene-3 (LAG-3)-Ig fusion proteins, Eur J Immunol., Sep 1995; 25(9):2718-21).

In addition, several kinases are known to be checkpoint inhibitors. For example, CHEK-1, CHEK-2, and A2aR.

CHEK-1 (also known as CHK1 kinase, CHK1, and checkpoint kinase 1) is a serine/threonine protein kinase of approximately 54.4 kDa that is involved in checkpoint-mediated cell cycle arrest and in response to DNA damage and/or DNA repair of non-replicated DNA.

CHEK-2 (also known as CHK2 kinase, CDS1, CHK2, HuCds1, LFS2, PP1425, RAD53, hCds1, and checkpoint kinase 2) is a serine/threonine protein kinase of approximately 60.9 kDa involved in checkpoint-mediated cell cycle arrest, DNA repair activation, and double-strand break-mediated apoptosis.

A2aR (also known as adenosine A2A receptor, ADORA2A, adenosine A2a receptor, A2aR, ADORA2, and RDC8) is a 44.7-kDa multi-membrane receptor for adenosine and other ligands.

In various embodiments, immunotherapeutic agents may comprise antibodies or antigen-binding fragments thereof. Within this definition, immune checkpoint inhibitors include bispecific antibodies and immune cell-binding multivalent antibodies/fusion proteins/constructs known in the art. In some embodiments, immunotherapeutic agents comprising bispecific antibodies may include bivalent antibodies that bind to the same epitope of an immune checkpoint molecule, two different epitopes of the same immune checkpoint molecule, or different epitopes of two different immune checkpoints.

Those skilled in the art can realize several bispecific antibody forms known in the art to target CTLA4, PD1, PD-L1, TIM-3, LAG-3, various B-7 ligands, B7H3, B7H4, CHK1 and CHK2 kinases, BTLA, A2aR, OX40, 41BB, LIGHT, CD40, GITR, TGF-β, SIRP-α, TIGIT, VSIG8, SIGLEC7, SIGLEC9, ICOS, FAS, BTNL2, and one or more others used in the combinations described herein.

In various implementations, immunotherapeutic agents may include immune cell-conjugated multivalent antibodies/fusion proteins/constructs.

In one embodiment of this disclosure, a checkpoint inhibitor is combined with a compound of formula I' to reduce or inhibit the metastasis of a primary tumor or cancer to other sites, or the formation or establishment of a metastatic tumor or cancer at other sites distant from the primary tumor or cancer, thereby inhibiting or reducing the recurrence or progression of the tumor or cancer.

In another embodiment of this disclosure, a combination therapy for treating cancer is provided, comprising a compound of formula I' and a checkpoint inhibitor having the potential to elicit an effective and durable immune response and enhance therapeutic benefits and more controllable toxicity.

In another embodiment of this disclosure, a combination therapy for treating cancer is provided, the combination therapy comprising a compound of formula I' and an immune checkpoint inhibitor. In one embodiment of this disclosure, a method for treating cancer and/or preventing metastasis is provided by using a checkpoint inhibitor that synergizes with a compound of formula I'.

In another embodiment, the methods of this disclosure include one or more of the following: 1) reducing or inhibiting the growth, proliferation, migration, or invasion of tumors or cancer cells that may or have metastasized; 2) reducing or inhibiting the formation or establishment of metastases from the primary tumor or cancer to one or more other sites, locations, or regions different from the primary tumor or cancer; 3) reducing or inhibiting the growth or proliferation of metastases at one or more other sites, locations, or regions different from the primary tumor or cancer after metastasis has formed or been established; 4) reducing or inhibiting the formation or establishment of additional metastases after metastasis has formed or been established; 5) prolonging overall survival; 6) prolonging progression-free survival; or 7) stabilizing the disease.

In one embodiment of this disclosure, administration of an immunotherapeutic agent in combination with a compound of formula I' provides a detectable or measurable improvement in a given subject's condition, such as relief or improvement of one or more adverse (physical) symptoms or consequences associated with the presence of cell proliferation or cell hyperproliferation, tumor formation, tumor or cancer, or metastasis, i.e., therapeutic benefit or beneficial effect.

A therapeutic benefit or beneficial effect is any objective or subjective, temporary or long-term improvement in a disease or pathology, or a reduction in the onset, severity, duration, or frequency of adverse symptoms associated with or caused by cell proliferation or cell hyperproliferative disorders such as tumor formation, tumor or cancer, or metastasis. It can lead to improved survival. For example, a satisfactory clinical endpoint of the treatment method according to this disclosure is achieved when the severity, duration, or frequency of one or more associated pathologies, adverse symptoms, or complications gradually or partially decreases, or when one or more of the physiological, biochemical, or cellular manifestations or characteristics of cell proliferation or cell hyperproliferative disorders such as tumor formation, tumor or cancer, or metastasis are inhibited or reversed. Therefore, a therapeutic benefit or improvement can be, but is not limited to, the destruction of target proliferating cells (e.g., tumor formation, tumor or cancer, or metastasis) or the elimination of one, most, or all of the pathologies, adverse symptoms, or complications associated with or caused by cell proliferation or cell hyperproliferative disorders such as tumor formation, tumor or cancer, or metastasis. However, the benefits or improvements of treatment do not necessarily involve curing or completely destroying all target proliferating cells (e.g., tumor formation, tumor or cancer, or metastasis) or eliminating all pathologies, adverse symptoms, or complications associated with or caused by conditions of cell proliferation or excessive cell proliferation, such as tumor formation, tumor or cancer, or metastasis. For example, partially destroying a tumor or cancer mass by inhibiting its progression or worsening, or stabilizing the tumor or cancer mass, size, or cell number, can reduce mortality and prolong life, even if only for days, weeks, or months, although some or most of the tumor or cancer mass, size, or cells remain.

Specific, non-limiting examples of therapeutic benefits include a reduction in tumor formation, tumor or cancer, or metastatic volume (size or cell mass) or cell number; inhibition or prevention of tumor formation, tumor or cancer volume increase (e.g., stabilization); slowing or inhibiting tumor formation, tumor or cancer progression, worsening or metastasis; or inhibiting tumor formation, tumor or cancer proliferation, growth or metastasis.

In one embodiment of this disclosure, administration of an immunotherapeutic agent in combination with a compound of formula I' provides a detectable or measurable improvement or overall response based on irRC (e.g., derived from time-point response assessment and based on tumor burden), including one or more of the following: (i) irCR – complete disappearance of all lesions, whether or not measurable, and no new lesions (confirmed by repeated, continuous assessment for at least 4 weeks from the date of first recording), (ii) irPR – a reduction of .gtoreq. 50% in tumor burden relative to baseline (confirmed by continuous assessment for at least 4 weeks after the date of first recording).

Optionally, any of the methods described herein may not be immediately effective. For example, tumor formation, the number or quality of tumors or cancer cells may increase after treatment, but over time, the quality, size or number of tumor cells in a given subject may eventually stabilize or decrease.

Other adverse symptoms and complications associated with tumor formation, tumors, cancer, and metastasis that can be suppressed, reduced, decreased, delayed, or prevented include, for example, nausea, loss of appetite, somnolence, pain, and malaise. Therefore, a partial or complete reduction or decrease in the severity, duration, or frequency of adverse symptoms or complications associated with or caused by cell hyperproliferative disorders, and improvements in the subject's quality of life and/or well-being, such as increased energy, appetite, and psychological well-being, are specific, non-limiting examples of therapeutic benefits.

Therefore, treatment benefits or improvements may also include a subjective improvement in the quality of life of the treated subject. In another embodiment, a method prolongs or extends the lifespan (survival) of the subject. In yet another embodiment, a method improves the quality of life of the subject.

In one implementation, administration of an immunotherapeutic agent in combination with a compound of formula I' results in a clinically relevant improvement in one or more biomarkers of disease status and progression selected from one or more of the following: (i): overall survival, (ii): progression-free survival, (iii): overall response rate, (iv): reduction in metastatic disease, (v): circulating levels of tumor antigens such as carbohydrate antigen 19.9 (CA19.9) and carcinoembryonic antigen (CEA) or other tumor-dependent antigens, (vii) nutritional status (weight, appetite, serum albumin), (viii): pain control or analgesic use, and (ix): CRP/albumin ratio.

Combining compounds of formula I' with immunotherapeutic agents produces more complex immunity, including not only the development of innate and type 1 immunity, but also immune regulation that more effectively restores appropriate immune function.

In various exemplary methods, checkpoint inhibitor antibodies (monoclonal or polyclonal, bispecific, trispecific, or immune cell-conjugating multivalent antibodies/fusion proteins/constructs) targeting checkpoint molecules of interest (e.g., PD-1) can be sequenced, and the polynucleotide sequence can then be cloned into a vector for expression or propagation. The sequence encoding the antibody of interest or its antigen-binding fragment can be held in a vector within host cells, which can then be amplified and frozen for future use. Production of recombinant monoclonal antibodies in cell cultures can be performed by cloning antibody genes from B cells using methods known in the art. See, for example, Tiller et al., 2008, J. Immunol. Methods 329,112; U.S. Patent No. 7,314,622.

In some embodiments, the method for generating recombinant antibodies may include the step of culturing host cells containing isolated nucleic acids encoding antibodies of the present disclosure. The method for culturing host cells containing isolated nucleic acids encoding antibodies of the present disclosure may be carried out in various ways depending on the nature of the antibody. In some embodiments, where the antibody of the present disclosure is a full-length conventional antibody, for example, the heavy chain variable region and light chain variable region are included under conditions that allow for the generation and isolation of the antibody.

Typically, nucleic acids encoding antibodies or antigen-binding fragments thereof are provided. Such polynucleotides encode both variable and constant regions of each of the heavy and light chains, but other combinations are also contemplated in this disclosure. Oligonucleotide fragments derived from the disclosed polynucleotides and nucleic acid sequences complementary to these polynucleotides are also contemplated in this disclosure.

Polynucleotides can be in the form of RNA, DNA, cDNA, genomic DNA, nucleic acid analogs, and synthetic DNA. DNA can be double-stranded or single-stranded, and if single-stranded, it can be a coding (sense) strand or a non-coding (antisense) strand. The coding sequence of a polypeptide can be the same as or different from the coding sequence, even if the sequence encodes the same polypeptide due to redundancy or degeneracy of the genetic code.

In some embodiments, a nucleic acid encoding an antibody disclosed herein is bound to an expression vector, which may be extrachromosomal or designed to integrate into the genome of the host cell to which it is introduced. The expression vector may contain any number of suitable regulatory sequences (including, but not limited to, transcription and translation control sequences, promoters, ribosome binding sites, enhancers, origins of replication, etc.) or other components (selection genes, etc.), all of which are operatively linked as is well known in the art. In some cases, two nucleic acids are used and placed in separate expression vectors (e.g., the heavy chain in a first expression vector and the light chain in a second expression vector), or alternatively, they may be placed in the same expression vector. Those skilled in the art will understand that the design of the expression vector (including the selection of regulatory sequences) can depend on factors such as the choice of host cell and the desired protein expression level.

Typically, nucleic acids and/or expression can be introduced into suitable host cells to generate recombinant host cells using any method suitable for the selected host cells (e.g., transformation, transfection, electroporation, infection), such that the nucleic acid molecules are operatively linked to one or more expression control elements (e.g., in a vector, in a construct generated through a process within the cell, or integrated into the host cell genome). The resulting recombinant host cells can be maintained under conditions suitable for expression (e.g., in the presence of an inducer, in a suitable non-human animal, in a suitable culture medium supplemented with appropriate salts, growth factors, antibiotics, nutritional supplements, etc.), thereby producing the encoded polypeptide. In some cases, the heavy chain is produced in one cell while the light chain is produced in another cell.

Mammalian cell lines suitable as expression hosts are known in the art and include many immortalized cell lines purchased from American Type Culture Collection (ATCC), Manassas, VA, USA, including but not limited to Chinese hamster ovary (CHO) cells, HEK 293 cells, NSO cells, HeLa cells, baby hamster kidney (BHK) cells, monkey kidney cells (COS) cells, human hepatocellular carcinoma cells (e.g., Hep G2), and many other cell lines. Non-mammalian cells, including but not limited to bacteria, yeast, insects, and plants, can also be used to express recombinant antibodies. In some embodiments, the antibody may be produced in transgenic animals such as cattle or chickens.

Exemplary and illustrative recombinant methods for antibody molecular biology, expression, purification, and screening are described in, for example, Antibody Engineering, edited by Kontermann & Dubel, Springer, Heidelberg, 2001 and 2010, Hayhurst & Georgiou, 2001, Curr. Opin. Chem. Biol. 5:683-689; Maynard & Georgiou, 2000, Annu. Rev. Biomed. Eng. 2:339-76; and Morrison, S. (1985) Science 229:1202, the full text of which is incorporated herein by reference.

In various implementations, the polynucleotide sequences encoding the selected variable heavy and light chains can be genetically manipulated to humanize the antibody or improve its affinity or other characteristics. Antibodies can also be customized for use in, for example, dogs, cats, primates, horses, and cattle.

In some implementations, fully human antibodies can be obtained using commercially available mice engineered to express specific human immunoglobulins. Transgenic animals designed to produce a more desired (e.g., fully human antibody) or stronger immune response can also be used to generate humanized or human antibodies. Examples of such technologies are Xenomouse ^™ from Abgenix, Inc. (Fremont, Calif.) and HuMAb- and TC Mouse ^™ from Medarex, Inc. (Princeton, NJ).

The immune checkpoint modulator antibodies disclosed herein can be recombinantly prepared by first isolating antibodies and antibody-producing cells from a host animal, obtaining the gene sequence, and using the gene sequence to recombinantly express the antibody in host cells (e.g., CHO cells). Another approach is to express the antibody sequence in plant (e.g., tobacco) or yeast cells (e.g., Pichia pastoris or Saccharomyces cerevisiae). Methods for recombinantly expressing antibodies in plants or yeast have been disclosed. See, for example, Peeters et al., Vaccine 19:2756, 2001; Lonberg, N. and D. Huszar Int. Rev. Immunol 13:65, 1995; and Horwitz, A.H. et al., Proc. Natl. Acad. Sci. 85:8678-8682; the full text of these publications is incorporated herein by reference. Methods for preparing antibody derivatives (e.g., domains, single chains, etc.) are known in the art.

Immunoassays and flow cytometry sorting techniques, such as fluorescence activated cell sorting (FACS), can also be used to isolate antibodies specific to checkpoint molecules.

In some embodiments, the polynucleotide comprises a sequence encoding a heavy chain and/or light chain variable region encoding a checkpoint inhibitor antibody or an antigen-binding fragment thereof disclosed herein. The sequence encoding the antibody of interest or its antigen-binding fragment may be held in a vector within a host cell, which can then be amplified and frozen for future use. Vectors (including expression vectors) and host cells are further described herein.

This disclosure includes affinity-matured checkpoint regulator antibodies. For example, affinity-matured antibodies can be produced by procedures known in the art (Marks et al., 1992, Bio/Technology, 10:779-783; Barbas et al., 1994, Proc Nat. Acad. Sci. USA 91:3809-3813). A method for characterizing antibody CDRs and/or altering (such as improving) the binding affinity of peptides such as antibodies is called “library scanning mutagenesis”. An exemplary method for providing affinity-matured antibody and antigen-binding fragments may include replacing one or more amino acid positions in the CDR with two or more amino acids (such as 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) using methods recognized in the art. A clonal library is generated, each clone having the complexity of two or more members (if two or more amino acids are substituted at each position). Typically, the library also includes clones containing native (unsubstituted) amino acids. A small number of clones from each library (e.g., approximately 20-80 clones, depending on the complexity of the library) are screened for binding affinity to the target peptide (or other binding target) and candidates with increased, identical, decreased, or no binding are identified. Methods for determining binding affinity are well known in the art. Binding affinity can be determined using, for example, Biacore™ surface plasmon resonance analysis (which detects approximately 2-fold or greater differences in binding affinity), biosensors, scintillation affinity assays, ELISA, immunoassays, fluorescence quenching, fluorescence transfer, and/or yeast display. Binding affinity can also be screened using suitable bioassays. Biacore™ is particularly useful when the starting antibody has already bound with relatively high affinity (e.g., approximately 10 nM or lower KD). The clonal library can then be recombined into the selection construct using any methods known in the art for selection, including phage display, yeast display, and ribosome display.

Antibodies can also be modified, for example, in variable domains of the heavy and/or light chains, to alter the antibody's binding properties. Changes in the variable regions can alter binding affinity and/or specificity. In some embodiments, no more than one to five conserved amino acid substitutions are made within the CDR domain. In other embodiments, no more than one to three conserved amino acid substitutions are made within the CDR domain. For example, mutations can be made in one or more CDR regions to increase or decrease the KD of the antibody against the checkpoint molecule, increase or decrease the KON, or alter the antibody's binding specificity. Site-directed mutagenesis is well known in the art. See, for example, Sambrook et al. and Ausubel et al.

Pharmaceutical compositions containing compounds of formula I' according to this disclosure will comprise an effective amount of the compound of formula I', an immunotherapeutic agent, and/or both, typically dispersed in a pharmaceutically acceptable carrier. The phrase "pharmaceutically or pharmacologically acceptable" means a molecular entity and composition that does not produce adverse, allergic, or other adverse reactions when properly administered to animals, such as humans. The preparation of pharmaceutical compositions containing compounds of formula I' according to this disclosure is known to those skilled in the art, as exemplified in Remington's Pharmaceutical Sciences, 18th edition, Mack Printing Company, 1990. Furthermore, for animal (e.g., human) administration, it should be understood that the formulation should meet standards of sterility, pyrogenicity, general safety, and purity. Specific examples of pharmaceutically acceptable carriers for use in combination compositions containing compounds of formula I' mixed with immunotherapeutic agents as described herein are borate buffers or sterile saline solutions (0.9% NaCl).

Formulations of immunotherapeutic agents, such as immune checkpoint modulator antibodies used according to this disclosure, can be prepared by mixing an antibody of desired purity with an optional pharmaceutically acceptable carrier, excipient, or stabilizer as well described and illustrated in Remington's Pharmaceutical Sciences, 16th edition, Osol, A.Ed. [1980], for storage in the form of a lyophilized formulation or an aqueous solution and/or suspension. Acceptable carriers, excipients, buffers, or stabilizers are non-toxic to the recipient at the doses and concentrations employed and include suitable aqueous and/or non-aqueous excipients that can be used in the pharmaceutical compositions of this disclosure, such as water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate). For example, appropriate flowability can be maintained by using coating materials such as lecithin, by maintaining the desired particle size in the case of dispersions, and by using surfactants, buffers such as phosphates, citrates, and other organic acids. It may include antioxidants, such as (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, etc.; and (3) metal chelating agents, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.; preservatives (such as octadecane-dimethylbenzylammonium chloride; hexamethylammonium chloride; benzalkonium chloride; benzyl chloride; phenol, butanol or benzyl alcohol; alkyl esters of p-hydroxybenzoate such as methyl p-hydroxybenzoate or propyl p-hydroxybenzoate; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues). Other exemplary pharmaceutically acceptable excipients may include peptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers, such as polyvinylpyrrolidone; amino acids, such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrin; chelating agents, such as EDTA; sugars, such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions, such as sodium; metal complexes (e.g., Zn-protein complexes); and/or nonionic surfactants, such as TWEENTM, PLURONICS™, or polyethylene glycol (PEG).

In one illustrative embodiment, the pharmaceutical composition may optionally contain pharmaceutically acceptable excipients such as pH adjusters and buffers, and toxicity modifiers, such as sodium acetate, sodium chloride, potassium chloride, calcium chloride, and sodium lactate, to approximate physiological conditions. In some embodiments, the checkpoint inhibitor antibody or its antigen-binding fragment of the present disclosure is formulated and may be lyophilized for storage, and reconstituted in a suitable excipient according to lyophilization and reconstitution techniques known in the art prior to use. In an exemplary pharmaceutical composition containing one or more checkpoint inhibitor antibodies or their antigen-binding fragments, the composition is formulated as a sterile, preservative-free solution of one or more checkpoint inhibitor antibodies or their antigen-binding fragments for intravenous or subcutaneous administration. The formulation may be provided as a single-use pre-filled pen, a single-use glass syringe, for example, containing about 1 mL of pre-filled material, or a single-use institutional vial. Preferably, the pharmaceutical composition containing the checkpoint inhibitor antibody or its antigen-binding fragment is clear and colorless, with a pH of about 6.9-5.0, preferably 6.5-5.0, and even more preferably about 6.0 to about 5.0. In various embodiments, when reconstituted and administered to a subject, the formulation comprising the pharmaceutical composition may contain about 500 mg to about 10 mg, or about 400 mg to about 20 mg, or about 300 mg to about 30 mg, or about 200 mg to about 50 mg per mL of solution of a checkpoint inhibitor antibody or an antigen-binding fragment thereof. Exemplary injectable or infusion excipients may include mannitol, citrate monohydrate, disodium hydrogen phosphate dihydrate, disodium hydrogen phosphate monohydrate, polysorbate 80, sodium chloride, sodium citrate, and water for parenteral administration (e.g., intravenous, intramuscular, intraperitoneal, or subcutaneous).

In another exemplary embodiment, one or more immunotherapeutic agents or antigen-binding fragments thereof are formulated into a sterile aqueous solution for intravenous or subcutaneous administration, containing 1-75 mg/mL, or more preferably about 5-60 mg/mL, or even more preferably about 10-50 mg/mL, or even more preferably about 10-40 mg/mL, of an antibody, as well as sodium acetate, polysorbate 80, and sodium chloride, with a pH range of about 5-6. Preferably, the intravenous or subcutaneous formulation is a sterile aqueous solution containing 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 mg/mL of an immunotherapeutic agent (e.g., an immune checkpoint inhibitor antibody or its antigen-binding fragment), 20 mM sodium acetate, 0.2 mg/mL polysorbate 80, and 140 mM sodium chloride, with a pH of 5.5. In addition, solutions containing checkpoint inhibitor antibodies or their antigen-binding fragments may, among other compounds, contain histidine, mannitol, sucrose, trehalose, glycine, polyethylene glycol, EDTA, methionine, and any combination thereof, as well as many other compounds known in the relevant art.

In one embodiment, the pharmaceutical composition of this disclosure comprises the following components: 5-500 mg of the immunotherapeutic agent of this disclosure or its antigen-binding fragment, 10 mM histidine, 5% sucrose, and 0.01% polysorbate 80, at pH 5.8, with or without a compound of formula I'. The composition may be provided in lyophilized powder form. When the powder is reconstituted at its full volume, the composition retains the same formulation. Alternatively, the powder may be reconstituted at half volume, in which case the composition comprises 10-500 mg of the immunotherapeutic agent of this disclosure or its antigen-binding fragment, 20 mM histidine, 10% sucrose, and 0.02% polysorbate 80, at pH 5.8.

In one embodiment, a portion of the dose is administered via intravenous bolus injection, while the remainder is administered via infusion of the immunotherapeutic agent formulation. For example, an intravenously administered immunotherapeutic agent or its antigen-binding fragment may be given in bolus injection at doses of about 0.001 to about 200 mg/kg, such as about 0.001 mg/kg to about 100 mg/kg, or about 0.001 mg/kg to about 50 mg/kg, or about 0.001 mg/kg to about 10 mg/kg, and the remaining antibody dose may be administered via intravenous injection. The predetermined dose of the immunotherapeutic agent or its antigen-binding fragment may be administered, for example, over a period of one to two to five hours.

In another embodiment, a portion of the dose is administered via subcutaneous injection and/or infusion in the form of a bolus, with the remainder administered via infusion of the immunotherapy formulation. In some exemplary dosages, the immunotherapy formulation may be administered subcutaneously via intravenous injection of the immunotherapy agent or its antigen-binding fragment in the range of about 0.001 to about 200 mg/kg, for example, about 0.001 mg/kg to about 100 mg/kg, or about 0.001 mg/kg to about 50 mg/kg, or about 0.001 mg/kg to about 10 mg/kg. In some embodiments, the dose may be given as a bolus, and the remaining immunotherapy dose may be administered via subcutaneous or intravenous injection. The predetermined dose of the immunotherapy agent or its antigen-binding fragment may be administered, for example, over a period of one to two to five hours.

The formulation described herein may also contain one or more active compounds necessary for the specific indication to be treated, preferably those having complementary activities that do not adversely affect each other. For example, it may be desirable to provide one or more immunotherapeutic agents with other specificities. Alternatively or in addition, the composition may comprise anti-inflammatory agents, chemotherapeutic agents, cytotoxic agents, cytokines, growth inhibitors, and/or small molecule antagonists. Such molecules are suitably present in a combination of amounts effective for the intended purpose.

Preparations intended for internal administration should be sterile or near-sterile. This can be easily achieved through filtration using a sterile filter membrane.

In various embodiments, exemplary formulations of the pharmaceutical compositions described herein can be prepared using methods widely known in the field of pharmaceutical formulation. Typically, such preparation methods may include the steps of conjugating an active ingredient with a carrier or one or more other auxiliary ingredients, and then, if desired, packaging the product into desired single-dose or multi-dose units.

In some embodiments, compositions containing compounds of formula I' may also be delivered in vesicles, and immunotherapeutic agents may be delivered in the same liposomal formulation or in a separate formulation compatible with a liposomal formulation containing compounds of formula I'. In some illustrative examples, the liposomes contain liposomal surface portions, such as polyethylene glycol, antibodies, and antibody fragments thereof, that are selectively transported to specific cells or organs to target one or more desired tumor surface antigens, receptors, growth factors, glycoproteins, glycolipids, or neoantigens, thereby enhancing targeted drug delivery.

In another embodiment, the compound of formula I' can be delivered in vesicles, particularly in liposomes (see Langer, Science 249:1527-1533 (1990); Treat et al., Liposomes in the Therapy of Fifenaciodessesase and Cancer, Lopez-Berestein and Fidler (eds.), Liss, N.Y., pp. 353-365 (1989); Lopez-Berestein, ibid., pp. 317-327; see general sources ibid.).

In another embodiment, the compound of formula I', or a combination containing the composition, or a composition containing an immunotherapeutic agent, may be delivered in a controlled-release system. In one embodiment, a pump may be used (see Langer, ibid.; Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321:574 (1989)). In another embodiment, the controlled release of the compound of formula I' may include a polymeric material to provide sustained, intermediate, pulsed, or alternating release (see MEDICAL APPLICATIONS OF CONTROLLED RELEASE, Langer and Wise (eds.), CRC Pres., Boca Raton, Fla. (1974); CONTROLLED DRUG BIOAVAILABILITY, DRUG PRODUCT DESIGN AND PERFORM). ANCE, Smolen and Ball (eds.), Wiley, New York (1984); Ranger and Peppas, J. Macromol. Sci. Rev. Macromol. Chem. 23:61 (1983); see also Levy et al., Science 228:190 (1985); During et al., Ann. Neurol. 25:351 (1989); Howard et al., J. Neurosurg. 71:105 (1989)). Other controlled release systems discussed in Ranger's review (Science 249:1527-1533 (1990)) may be used.

The optimal concentration of the active ingredient in the selected medium can be determined empirically according to procedures well known to those skilled in the art, and will depend on the desired final pharmaceutical formulation and the intended use.

This disclosure also provides a pharmaceutical package or kit comprising one or more containers filled with one or more of the components of a pharmaceutical composition of this disclosure, the pharmaceutical composition comprising at least a compound of formula I' as described herein and one or more checkpoint inhibitor antibodies or antigen-binding fragments thereof. In other embodiments, the kit may contain one or more additional containers providing pharmaceutically acceptable excipients (e.g., diluents). In one embodiment, the kit may comprise at least one container wherein the container may include a compound of formula I' of this disclosure, a checkpoint inhibitor antibody, or an antigen-binding fragment thereof. The kit may also include a set of instructions for preparing and administering the final pharmaceutical composition to a subject in need of treating a checkpoint molecule-mediated disease or condition.

In some embodiments of this disclosure, the immunotherapeutic agent is a population of immune cells that can be administered in combination with a compound of formula I' to treat a subject with cancer. In some embodiments, the immunotherapeutic agent is a population of immune cells, such as leukocytes (nucleated leukocytes), comprising (e.g., expressing) a receptor that binds to an antigen of interest. The leukocytes of this disclosure can be, for example, neutrophils, eosinophils, basophils, lymphocytes, or monocytes. In some embodiments, the leukocytes are lymphocytes. Examples of lymphocytes include T cells, B cells, natural killer (NK) cells, or NKT cells. In some embodiments, the T cells are CD4+Th (T helper) cells, CD8+ cytotoxic T cells, γδ T cells, or regulatory (suppressive) T cells. In some embodiments, the immune cells are dendritic cells.

In some embodiments, the immune cells of this disclosure are genetically engineered to express antigen-binding receptors. A cell is considered “engineered” if it contains engineered (exogenous) nucleic acids. The engineered nucleic acids of this disclosure can be introduced into cells by any known (e.g., conventional) method. For example, engineered nucleic acids can be introduced into cells by: electroporation (see, for example, Heiser W.C. Transcription Factor Protocols: Methods in Molecular Biology. TM. 2000; 130:117-134), chemical methods (e.g., calcium phosphate or lipids), transfection (see, for example, Lewis W.H. et al., Somatic Cell Genet., May 1980; 6(3):333-47; Chen C. et al., Mol Cell Biol., Aug. 1987; 7(8):2745-2752), fusion with bacterial protoplasts containing recombinant plasmids (see, for example, Schaffner W. Proc Natl Acad Sci USA., Apr. 1980; 77(4):2163-7), direct microinjection of purified DNA into the cell nucleus (see, for example, Capecchi M.R. Cell., Nov. 1980; 22(2Pt 2):479-88), or retroviral transduction.

Some aspects of this disclosure provide an "adoptive cell" method involving isolating immune cells (e.g., T cells) from a subject with cancer, genetically engineering the immune cells (e.g., to express antigen-binding receptors, such as chimeric antigen receptors), expanding the cells in vitro, and then reintroducing the immune cells into the subject. This method generates a greater number of engineered immune cells in the subject than can be achieved through conventional gene delivery and vaccination methods. In some embodiments, immune cells are isolated from the subject, expanded in vitro without genetic modification, and then reintroduced into the subject.

As provided herein, the immune cells of this disclosure contain receptors that bind to antigens, such as antigens encoded by nucleic acids delivered exogenously. In some embodiments, leukocytes are modified (e.g., genetically modified) to express receptors that bind antigens. In some embodiments, the receptors may be naturally occurring antigen receptors (typically expressed on immune cells), recombinant antigen receptors (typically not expressed on immune cells), or chimeric antigen receptors (CARs). Naturally occurring and recombinant antigen receptors covered by this disclosure include T cell receptors, B cell receptors, NK cell receptors, NKT cell receptors, and dendritic cell receptors. A “chimeric antigen receptor” is an artificial immune cell receptor engineered to recognize and bind antigens expressed by tumor cells. Typically, CARs are designed for T cells and are a chimera of the signal transduction domain and the antigen recognition domain (e.g., a single-chain fragment of an antibody (scFv)) of the T cell receptor (TcR) complex (Enblad et al., Human Gene Therapy. 2015; 26(8):498-505), the entire contents of which are incorporated herein by reference.

In some implementations, the antigen-binding receptor is a chimeric antigen receptor (CAR). T cells expressing CAR are referred to as "CAR T cells". In some implementations, the CAR T cell receptor comprises a signal transduction domain and an antigen recognition domain (e.g., a single-chain fragment of an antibody (scFv)) of a T cell receptor (TcR) complex (Enblad et al., Human Gene Therapy. 2015; 26(8):498-505), the full text of which is incorporated herein by reference.

There are four generations of CARs, each containing different components. First-generation CARs connect the antibody-derived scFv to the intracellular signaling domain of the T cell receptor's CD3ζ (ζ or z) via a hinge and transmembrane domain. Second-generation CARs incorporate additional domains, such as CD28, 4-1BB (41BB), or ICOS, to provide co-stimulatory signaling. Third-generation CARs contain two co-stimulatory domains fused to the TCR CD3-ζ chain. These third-generation co-stimulatory domains can include combinations of, for example, CD3z, CD27, CD28, 4-1BB, ICOS, or OX40. In some implementations, the CAR contains an extracellular domain (e.g., CD3) typically derived from a single-stranded variable fragment (scFv), a hinge, a transmembrane domain, and an intracellular domain having one (first-generation), two (second-generation), or three (third-generation) signaling domains derived from CD3Z and/or co-stimulatory molecules (Maude et al., Blood. 2015; 125(26):4017-4023; Kakarla and Gottschalk, Cancer J. 2014; 20(2):151-155), the full text of which is incorporated herein by reference.

In some implementations, chimeric antigen receptors (CARs) are T cells retargeted for universal cytokine killing (TRUCK), also known as fourth-generation CARs. TRUCK cells are CAR-retargeted T cells that act as mediators for the production and release of transgenic cytokines that accumulate in the targeted tissue (e.g., the targeted tumor tissue). The transgenic cytokines are released when the CAR binds to the target. TRUCK cells can deposit a variety of therapeutic cytokines at the target. This can produce therapeutic concentrations at the target site and avoid systemic toxicity.

CARs typically differ in their functional properties. The CD3ζ signaling domain of the T cell receptor, when conjugated, activates and induces T cell proliferation, but can lead to non-responsiveness (a lack of response to the body's defense mechanisms, resulting in direct induction of peripheral lymphocyte tolerance). Lymphocytes are considered non-responsive when they do not respond to a specific antigen. Adding a co-stimulatory domain to second-generation CARs improves the replication capacity and persistence of modified T cells. Similar antitumor effects have been observed in vitro with CD28 or 4-1BB CARs, but preclinical in vivo studies have shown that the 4-1BB CAR produces superior proliferation and/or persistence. Clinical trials have shown that both second-generation CARs can induce substantial T cell proliferation in vivo, but the CAR containing the 4-1BB co-stimulatory domain appears to have a longer duration of action. Third-generation CARs incorporate multiple signaling domains (co-stimulatory domains) to increase potency. Fourth-generation CARs are further modified with constitutive or inducible expression cassettes of transgenic cytokines, which are released by CAR T cells to modulate T cell responses. See, for example, Enblad et al., Human Gene Therapy. 2015; 26(8):498-505; Chmielewski and Hinrich, Expert Opinion on Biological Therapy. 2015; 15(8):1145-1154, the full text of which is incorporated herein by reference.

In some embodiments, the exemplary immunotherapeutic agent is a first-generation chimeric antigen receptor (CAR). In some embodiments, the chimeric antigen receptor is a third-generation CAR. In some embodiments, the chimeric antigen receptor is a second-generation CAR. In some embodiments, the chimeric antigen receptor is a third-generation CAR. In some embodiments, the chimeric antigen receptor is a fourth-generation CAR or a T cell redirected for universal cytokine killing (TRUCK).

In some embodiments, the chimeric antigen receptor (CAR) includes an extracellular domain comprising an antigen-binding domain, a transmembrane domain, and a cytoplasmic domain. In some embodiments, the CAR is fully human. In some embodiments, the antigen-binding domain of the CAR is specific for one or more antigens. In some embodiments, a "spacer" domain or "hinge" domain is located between the extracellular domain (containing the antigen-binding domain) and the transmembrane domain of the CAR, or between the cytoplasmic domain and the transmembrane domain of the CAR. A "spacer" domain refers to any oligopeptide or polypeptide that serves to link the transmembrane domain to the extracellular domain and/or the cytoplasmic domain in a polypeptide chain. A "hinge" domain refers to any oligopeptide or polypeptide that serves to provide flexibility to the CAR or its domains, or to prevent steric hindrance to the CAR or its domains. In some embodiments, the spacer or hinge domain may contain up to 300 amino acids (e.g., 10 to 100 amino acids, or 5 to 20 amino acids). In some embodiments, one or more spacer domains may be included in other regions of the CAR.

In some embodiments, the CAR of this disclosure includes an antigen-binding domain, such as a single-stranded Fv (scFv) specific to a tumor antigen. The choice of the binding domain depends on the type and number of ligands defining the surface of the target cell. For example, the antigen-binding domain may be selected to recognize a ligand that acts as a cell surface marker on a target cell associated with a specific disease state, such as cancer or an autoimmune disease. Thus, examples of cell surface markers that can serve as ligands for the antigen-binding domain in the CAR of this disclosure include those associated with cancer cells and/or other forms of diseased cells. In some embodiments, the CAR is engineered to target tumor antigens of interest by engineering a desired antigen-binding domain on tumor cells that specifically binds to an antigen encoded by an engineered nucleic acid as provided herein.

The term "specific binding" refers to the antigen-binding domain (e.g., scFv) of a target or epitope, and methods for determining such specific binding are known in the art. A molecule is said to exhibit "specific binding" if it reacts or associates with a particular target antigen more frequently, rapidly, persistently, and/or with greater affinity compared to alternative targets. An antigen-binding domain (e.g., scFv) that specifically binds to a first target antigen may or may not specifically bind to a second target antigen. Thus, "specific binding" does not necessarily require (although it may include) exclusive binding.

In some implementations, CAR-expressing immune cells are genetically modified to recognize multiple targets or antigens, allowing for the recognition of unique target or antigen expression patterns on tumor cells. Examples of CARs that can bind to multiple targets include: “split signal CARs” that restrict the activation of fully immune cells against tumors expressing multiple antigens; “tandem CARs” (TanCARs) containing an extracellular domain with two scFvs; and “universal extracellular domain CARs” that incorporate avidin or fluorescein isothiocyanate (FITC)-specific scFvs to recognize tumor cells that have been incubated with labeled monoclonal antibodies (Mabs).

A CAR is considered "bispecific" if it recognizes two different antigens (having two different antigen recognition domains). In some embodiments, a bispecific CAR consists of two different antigen recognition domains tandemly present on a single transgenic receptor (referred to as a TanCAR; see, for example, Grada Z et al., Molecular Therapy Nucleic Acids 2013; 2:e105, the entire text of which is incorporated herein by reference). Thus, in some embodiments, these methods include delivering to a tumor a combination of a compound comprising formula I' and an immunotherapeutic agent, wherein the immunotherapeutic agent is an engineered nucleic acid encoding an antigen, or delivering to the tumor an engineered nucleic acid that induces the expression of an autoantigen, and delivering to the tumor immune cells expressing a bispecific CAR that binds to two antigens, one of which is encoded by an engineered nucleic acid.

In some embodiments, the CAR is an antigen-specific inhibitory CAR (iCAR), which can be used, for example, to avoid extratumor toxicity (Fedorov, V D et al., Sci. Transl. Med., published online December 11, 2013, the full text of which is incorporated herein by reference). The iCAR contains an antigen-specific inhibitory receptor, for example, to block nonspecific immunosuppression that may be caused by the expression of additional tumor targets. The iCAR may be based on, for example, the inhibitory molecule CTLA-4 or PD-1. In some embodiments, these iCARs block T-cell responses originating from their endogenous T-cell receptors or activated CAR-activated T cells. In some embodiments, this inhibitory effect is temporary.

In some implementations, CAR can be used for adoptive cell transfer, in which immune cells are removed from a subject and modified to express receptors specific to antigens, such as tumor-specific antigens. The modified immune cells, which can then recognize and kill cancer cells, are then reintroduced into the subject (Pule et al., Cytotherapy. 2003; 5(3):211-226; Maude et al., Blood. 2015; 125(26):4017-4023, each of which is incorporated herein by reference in its entirety).

According to other aspects of this disclosure, the tumor antigen component in the vaccine of the present invention is any natural or synthetic tumor-associated protein or peptide, or a combination of tumor-associated proteins and/or peptides or glycoproteins or glycopeptides. In other aspects, the antigen component may be patient-specific or common to many or most patients with a particular type of cancer. According to one aspect, the antigen component consists of cell lysates derived from tumor tissue taken from a patient to be treated. In another aspect, the lysates may be engineered or synthesized from exogenous sources derived from tumor tissue. In yet another aspect, the antigen component consists of cell lysates derived from tumor tissue extracted from one or more unrelated individuals or tumor cell lines.

In various embodiments, exemplary immunotherapeutic agents comprise one or more cancer vaccines for use in combination with compounds of formula I'. The tumor-associated antigen component of the vaccine can be manufactured using any of a variety of well-known techniques. For a single protein component, the antigen protein is isolated from tumor tissue or tumor cell lines by standard chromatographic methods such as high-performance liquid chromatography or affinity chromatography, or alternatively synthesized in a suitable expression system (such as *E. coli*, yeast, or plants) using standard recombinant DNA techniques. The tumor-associated antigen protein is then purified from the expression system by standard chromatographic methods. In the case of peptide antigen components, these are typically prepared by standard automated synthesis. Proteins and peptides can be modified by adding amino acids, lipids, and other agents to improve their incorporation into vaccine delivery systems (e.g., multilayer liposomes). For tumor-associated antigen components derived from a patient's own tumor or from tumors or cell lines from other individuals, tumor tissue or single-cell suspensions derived from tumor tissue are typically homogenized in a suitable buffer. Homogenization can also be performed, for example, by centrifugation to separate specific cellular components such as cell membranes or soluble substances. Tumor material can be used directly, or tumor-associated antigens can be extracted using a buffer solution containing low concentrations of suitable agents (such as detergents) for incorporation into vaccines. An example of a suitable detergent for extracting antigenic proteins from tumor tissue, tumor cells, and tumor cell membranes is diheptanoylphosphatidylcholine. Exogenous substances derived from tumor tissue or tumor cells, whether autologous or allogeneic to the patient, can be used as antigenic components for incorporation into vaccines or as starting materials for extracting tumor-associated antigens.

In some embodiments of this disclosure, a cancer vaccine is provided, comprising at least one tumor-associated antigen, at least one immunostimulant, and optionally at least one cell-based immunotherapeutic agent. In some embodiments, the immunostimulatory component of the cancer vaccine of this disclosure is any biological response modulator (BRM) capable of enhancing the effectiveness of the therapeutic cancer vaccine in inducing humoral and cellular immune responses against cancer cells in a patient. According to one aspect, the immunostimulant is a cytokine or a combination of cytokines. Examples of such cytokines include interferons (such as IFN-γ), interleukins (such as IL-2, IL-15, and IL-23), colony-stimulating factors (such as M-CSF and GM-CSF), and tumor necrosis factor. According to another aspect, the immunostimulatory component of the disclosed cancer vaccine comprises one or more adjuvanted immunostimulants, such as APC Toll-like receptor agonists or co-stimulatory/cell adhesion membrane proteins, with or without immunostimulatory cytokines. Examples of Toll-like receptor agonists include lipid A and CpG, and co-stimulatory/adhesion proteins such as CD80, CD86, and ICAM-1.

In some embodiments, the immunostimulant is selected from IFN-γ (IFN-γ), IL-2, IL-15, IL-23, M-CSF, GM-CSF, tumor necrosis factor, lipid A, CpG, CD80, CD86, and ICAM-1, or combinations thereof. According to other aspects, the cell-based immunotherapeutic agent is selected from dendritic cells, tumor-infiltrating T lymphocytes, chimeric antigen receptor-modified T effector cells targeting the patient's tumor type, B lymphocytes, natural killer cells, bone marrow cells, and any other cells of the patient's immune system, or combinations thereof. In one aspect, the cancer vaccine immunostimulant includes one or more cytokines (such as interleukin-2 (IL-2), GM-CSF, M-CSF, and interferon-γ (IFN-γ)), one or more Toll-like receptor agonists and/or adjuvants (such as monophospholipid A, lipid A, muramyl dipeptide (MDP) lipid conjugates, and double-stranded RNA), or one or more co-stimulatory membrane proteins and/or cell adhesion proteins (such as CD80, CD86, and ICAM-1), or any combination thereof. In one aspect, cancer vaccines include immunostimulants that are cytokines selected from interleukin-2 (IL-2), GM-CSF, M-CSF, and interferon-γ (IFN-γ). In another aspect, cancer vaccines include immunostimulants that are Toll-like receptor agonists and/or adjuvants selected from monophospholipid A, lipid A, and muramyl dipeptide (MDP) lipid conjugates and double-stranded RNA. In yet another aspect, cancer vaccines include immunostimulants that are co-stimulatory membrane proteins and/or cell adhesion proteins selected from CD80, CD86, and ICAM-1.

In various embodiments, the immunotherapeutic agent may include a cancer vaccine, wherein the cancer vaccine incorporates any tumor antigen that can potentially be used to construct the fusion protein according to the invention, particularly the following:

(a) Cancer-testis antigens, including NY-ESO-1, SSX2, SCP1, and RAGE, BAGE, GAGE, and MAGE family peptides, such as GAGE-1, GAGE-2, MAGE-1, MAGE-2, MAGE-3, MAGE-4, MAGE-5, MAGE-6, and MAGE-12, which can be used to treat, for example, melanoma, lung cancer, head and neck cancer, NSCLC, breast cancer, gastrointestinal cancer, and bladder tumors; (b) mutated antigens, including p53 associated with various solid tumors such as colorectal cancer, lung cancer, and head and neck cancer; and p2 associated with, for example, melanoma, pancreatic cancer, and colorectal cancer. 1/Ras; CDK4 associated with, for example, melanoma; MUM1 associated with, for example, melanoma; caspase-8 associated with, for example, head and neck cancer; CIA 0205 associated with, for example, bladder cancer; HLA-A2-R1701; β-catenin associated with, for example, melanoma; TCR associated with, for example, T-cell non-Hodgkin lymphoma; BCR-abl associated with, for example, chronic myeloid leukemia; triose phosphate isomerase; KIA0205; CDC-27 and LDLR-FUT; (c) overexpressed antigens, including galactolectin 4 associated with, for example, colorectal cancer; galactolectin 9 associated with, for example, Hodgkin's disease. ; proteinase 3 associated with, for example, chronic myeloid leukemia; WT 1 associated with, for example, various types of leukemia; carbonic anhydrase associated with, for example, renal cell carcinoma; aldolase A associated with, for example, lung cancer; PRAME associated with, for example, melanoma; HER-2/neu associated with, for example, breast cancer, colon cancer, lung cancer, and ovarian cancer; globin and alpha-fetoprotein associated with, for example, liver cancer; KSA associated with, for example, colorectal cancer; gastrin associated with, for example, pancreatic cancer and gastric cancer; telomerase catalytic protein and MUC-1 associated with, for example, breast cancer and ovarian cancer; G-250 associated with, for example, renal cell carcinoma; p53 associated with, for example, breast cancer and colon cancer; and (d) Carcinoembryonic antigens associated with, for example, breast cancer, lung cancer, and gastrointestinal cancers such as colorectal cancer; (e) Common antigens, including melanoma-melanocyte differentiation antigens such as MART-1/Melan A; gpl00; MC1R; melanocyte-stimulating hormone receptor; tyrosinase; tyrosinase-associated protein-1/TRP1 and tyrosinase-associated protein-2/TRP2 associated with, for example, melanoma; (f) Prostate-associated antigens, including PAP, PSA, PSMA, PSH-P1, PSM-P1, and PSM-P2 associated with, for example, prostate cancer; and (c) Immunoglobulin idiotypes associated with myeloma and B-cell lymphoma. In some implementations, one or more TAAs may be selected from pi 5, Hom/Mel-40, H-Ras, E2A-PRL, H4-RET, IGH-IGK, MYL-RAR, Epstein Barr virus antigen, EBNA, human papillomavirus (HPV) antigens including E6 and E7, hepatitis B and hepatitis C virus antigens, human T-cell lymphotropic virus antigen, TSP-180, pl85erbB2, pl80erbB-3, c-met, mn-23H1, TAG-72-4, CA 19-9, CA 72-4, CAM17.1, NuMa, K-ras, pi 6, TAGE, PS CA, CT7, 43-9F, 5T4, 791Tgp72, β-HCG, BCA225, BTAA, CA125, CA 15-3 (CA 27.29\BCAA), CA 195, CA 242, CA-50, CAM43, CD68\KP1, CO-029, FGF-5, Ga733 (EpCAM), HTgp-175, M344, MA-50, MG7-Ag, MOV18, NB/70K, NY-CO-1, RCAS1, SDCCAG16, TA-90 (Mac-2 binding protein/Cycophilic C-associated protein), TAAL6, TAG72, TLP, TPS, or any combination thereof.

In some embodiments, the cancer vaccine of this disclosure, used in combination with the compounds of Formula I', may include a tumor antigen comprising a specific immunogenic epitope of one of the following human proteins: TCTN1 ( SEQ ID NO.1; gene ID: ENSG00000204852), TCTN2 (SEQ ID NO.2; gene ID: ENSG00000168778), TCTN3 ( SEQ ID NO.3; gene ID: ENSG00000119977), HIGD2A ( SEQ ID NO.4; gene ID: ENSG00000146066), HIGD2B ( SEQ ID NO.5; gene ID: ENSG00000175202), C4ORF32 ( SEQ ID NO.6; gene ID: ENSG00000174749), FAM62A (E-SYT1, SEQ ID NO.1 ), and TCTN3B ( SEQ ID NO.2). NO.7; Gene ID: ENSG00000139641), COLEC11 ( SEQ ID NO.8; Gene ID: ENSG00000118004), FSTL5 ( SEQ ID NO.9; Gene ID: ENSG00000168843), FAM82A2 ( SEQ ID NO.10; Gene ID: ENSG00000137824), SCARA5 ( SEQ ID NO.11; Gene ID: ENSG00000168079), VSTM1 ( SEQ ID NO.12; Gene ID: ENSG00000189068), RNF5 ( SEQ ID NO.13; Gene ID: ENSG00000183574), UNQ6126 ( SEQ ID NO.14; Gene ID: gi|169216088), DPY19L3 ( SEQ ID NO.15; Gene ID: ENSG00000178904), SLC39A10 ( SEQ ID NO.16; Gene ID: ENSG00000196950), GPR107 ( SEQ ID NO.17; Gene ID: ENSG00000148358), COL20A1 ( SEQ ID NO.18; Gene ID: ENSG00000101203), GLT25D2 ( SEQ ID NO.19; Gene ID: ENSG00000198756), SYTL3 ( SEQ ID NO.20; Gene ID: ENSG00000164674), DENND1B ( SEQ ID NO.21; Gene ID: ENSG00000162701), C6orf98 ( SEQ ID NO.22; Gene ID: EG:387079), FAM69B ( SEQ ID NO. NO.23; Gene ID: ENSG00000165716), EMID1 ( SEQ ID NO.24; Gene ID: OTTHUMG00000030824), KLRG2 ( SEQ ID NO.25; Gene ID: ENSG00000188883), ERMP1 ( SEQ ID NO.26; Gene ID: ENSG00000099219), VMO1 ( SEQ ID NO.27; Gene ID: ENSG00000182853), C9orf46 ( SEQ ID NO.28; Gene ID: ENSG00000107020), F1137107 ( SEQ ID NO.29; Gene ID: ENSG00000177990), YIPF2 ( SEQ ID NO.30; Gene ID: ENSG00000130733), TRYX3 ( SEQ ID NO. NO.31; PRSS58, ENSG00000258223.2), C14orf135 ( SEQ ID NO.32; gene ID: ENSG00000126773), ANGPTL7 ( SEQ ID NO.33; gene ID: ENSG00000171819), TPCN2 ( SEQ ID NO.34; gene ID: ENSG00000162341), C18orf19 ( SEQ ID NO.35; gene ID: ENSG00000177150), OLFML1 ( SEQ ID NO.36; gene ID: ENSG00000183801), LYPD4 ( SEQ ID NO.37; gene ID: ENSG00000101203), MEGF8 ( SEQ ID NO.38; Gene ID: ENSG00000105429), F1142986 ( SEQ ID NO.39; Gene ID: ENSG00000196460), SLC46A1 ( SEQ ID NO.40; Gene ID: ENSG00000076351), FAM180A ( SEQ ID NO.41; Gene ID: ENSG00000189320), CRISP-3 ( SEQ ID NO.42; Gene ID: ENSG00000096006), or combinations thereof. These tumor antigens are disclosed in WO2010/086162, WO2010/086163, WO2011/051278, WO2011/051276, WO2011/051277, WO2011/051280, WO2011/051271, WO2011/135068, and WO2014/198919, the contents of which are incorporated herein by reference in their entirety.

In various embodiments, exemplary immunotherapeutic agents may include mRNAs operable to encode any one or more of the aforementioned cancer antigens that can be used to synthesize cancer vaccines. In some illustrative embodiments, the mRNA-based cancer vaccine may have one or more of the following characteristics: a) the mRNAs encoding each cancer antigen are dispersed at cleavage-sensitive sites; b) the mRNAs encoding each cancer antigen are directly linked to each other without linkers; c) the mRNAs encoding each cancer antigen are linked to each other via single nucleotide linkers; d) each cancer antigen contains 20-40 amino acids and includes a centrally located SNP mutation; e) at least 40% of the cancer antigens have the highest affinity for class I MHC molecules from the subject; f) to At least 40% of the cancer antigens have the highest affinity for class II MHC molecules from the subject; g) at least 40% of the cancer antigens have a predicted binding affinity for HLA-A, HLA-B, and/or DRB1 with an IC > 500 nM; h) the mRNA encodes 1 to 15 cancer antigens; i) 10%–60% of the cancer antigens have a binding affinity for class I MHCs and 10%–60% of the cancer antigens have a binding affinity for class II MHCs; and/or j) the mRNAs encoding cancer antigens are arranged such that the cancer antigens are sequenced to minimize pseudoepitopes.

In various embodiments, a combination of a compound comprising Formula I' and a cancer vaccine immunotherapy agent as disclosed herein can be used to elicit an immune response against a cancer antigen in a subject. The method involves administering to a subject an RNA vaccine comprising at least one RNA polynucleotide having an open reading frame encoding at least one antigenic polypeptide or an immunogenic fragment thereof, thereby inducing an immune response in the subject specific to that antigenic polypeptide or immunogenic fragment thereof, said administration being combined with the administration of a compound of Formula I' in the same or separate compositions, and administered simultaneously or sequentially in doses, wherein the anti-antigen polypeptide antibody titer in the vaccinated subject is increased relative to the anti-antigen polypeptide antibody titer in a subject vaccinated with a conventional anticancer vaccine of prophylactic efficacy. An "anti-antigen polypeptide antibody" is a serum antibody that specifically binds to an antigenic polypeptide.

The preventive effective dose is a clinically acceptable therapeutically effective dose for preventing cancer development. In some embodiments, the therapeutically effective dose is the dose listed in the vaccine's packaging insert. As used herein, a conventional vaccine refers to a vaccine other than the mRNA vaccine of this invention. For example, conventional vaccines include, but are not limited to, live microbial vaccines, inactivated microbial vaccines, subunit vaccines, protein antigen vaccines, DNA vaccines, etc. In exemplary embodiments, a conventional vaccine is a vaccine that has already received regulatory approval and/or is registered by a national drug regulatory agency (such as the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA)).

In some implementations, the anti-antigen peptide antibody titer in subjects increases by 1 to 10 log compared to the titer in subjects vaccinated with a conventional anti-cancer vaccine that is effective in prevention. In some implementations, the anti-antigen peptide antibody titer in subjects increases by 1 log compared to the titer in subjects vaccinated with a conventional anti-cancer vaccine that is effective in prevention. In some implementations, the anti-antigen peptide antibody titer in subjects increases by 2 log compared to the titer in subjects vaccinated with a conventional anti-cancer vaccine that is effective in prevention.

Aspects of the present invention provide nucleic acid vaccines comprising one or more RNA polynucleotides having an open reading frame encoding a first antigenic polypeptide, wherein the RNA polynucleotide is present in a formulation for in vivo administration to a host, and confers an antibody titer superior to the serological protection standard for the first antigen in an acceptable percentage of human subjects. In some embodiments, the antibody titer generated by the mRNA vaccine of the present invention is a neutralizing antibody titer. In some embodiments, the neutralizing antibody titer is greater than that of a protein vaccine. In other embodiments, the neutralizing antibody titer generated by the mRNA vaccine of the present invention is greater than that of an adjuvanted protein vaccine. In other embodiments, the neutralizing antibody titers generated by the mRNA vaccine of the present invention are 1,000-10,000, 1,200-10,000, 1,400-10,000, 1,500-10,000, 1,000-5,000, 1,000-4,000, 1,800-10,000, 2,000-10,000, 2,000-5,000, 2,000-3,000, 2,000-4,000, 3,000-5,000, 3,000-4,000, or 2,000-2,500. Neutralizing titers are generally expressed as the highest serum dilution required to achieve a 50% reduction in plaque count.

In a preferred aspect, the RNA vaccine immunotherapeutic agent (e.g., an mRNA vaccine) of this disclosure produces levels, concentrations, and/or titers of antigen-specific antibodies in the blood or serum of vaccinated subjects that are effective in prevention and/or treatment. As defined herein, the term antibody titer refers to the amount of antigen-specific antibodies produced in a subject (e.g., a human subject). In an exemplary embodiment, antibody titer is expressed as the reciprocal of the highest dilution (among successive dilutions) that still yields a positive result. In an exemplary embodiment, antibody titer is determined or measured by enzyme-linked immunosorbent assay (ELISA). In an exemplary embodiment, antibody titer is determined or measured by a neutralization assay (e.g., by a micro-neutralization assay). In some aspects, antibody titer measurements are expressed as ratios, such as 1:40, 1:100, etc.

In exemplary embodiments of the invention, an effective vaccine produces antibody titers greater than 1:40, 1:100, 1:400, 1:1000, 1:2000, 1:3000, 1:4000, 1:500, 1:6000, 1:7500, or 1:10000. In exemplary embodiments, this antibody titer is produced or reached 10 days, 20 days, 30 days, 40 days, or 50 days or more after vaccination. In exemplary embodiments, this titer is produced or reached after administration of a single dose of the vaccine to the subject. In other embodiments, this titer is produced or reached after multiple doses, such as after a first dose and a second dose (e.g., a booster dose). In exemplary aspects of the invention, antigen-specific antibodies are measured in g/ml, or in IU/L (International Units per Liter) or mIU/ml (milli-International Units per ml). In exemplary embodiments of the present invention, an effective vaccine produces >0.5 μg/mL, >0.1 μg/mL, >0.2 μg/mL, >0.35 μg/mL, >0.5 μg/mL, >1 μg/mL, >2 μg/mL, >5 μg/mL, or >10 μg/mL. In exemplary embodiments of the present invention, an effective vaccine produces >10 mIU/mL, >20 mIU/mL, >50 mIU/mL, >100 mIU/mL, >200 mIU/mL, >500 mIU/mL, or >1000 mIU/mL. In exemplary embodiments, this antibody level or concentration is produced or reached 10 days, 20 days, 30 days, 40 days, or 50 days or more after vaccination. In exemplary embodiments, this level or concentration is produced or reached after administration of a single dose of vaccine to the subject. In other embodiments, the level or concentration is generated or reached after multiple doses, such as after a first dose and a second dose (e.g., a booster dose). In exemplary embodiments, the antibody level or concentration is determined or measured by an enzyme-linked immunosorbent assay (ELISA). In exemplary embodiments, the antibody level or concentration is determined or measured by a neutralization assay (e.g., by a micro-neutralization assay). Nucleic acid vaccines comprising one or more RNA polynucleotides having an open reading frame encoding a first antigenic polypeptide or a tandem polypeptide are also provided, wherein the RNA polynucleotide is present in a formulation for in vivo administration to a host to induce a higher antibody titer that is more durable than that induced by an mRNA vaccine having a stabilizing element or formulated with an adjuvant and encoding the first antigenic polypeptide. In some embodiments, the RNA polynucleotide is formulated to generate neutralizing antibodies within one week of a single administration. In some embodiments, the adjuvant is selected from cationic peptides and immunostimulatory nucleic acids. In some embodiments, the cationic peptide is protamine.

An immunotherapeutic agent comprising a nucleic acid vaccine, said nucleic acid vaccine comprising one or more RNA polynucleotides having an open reading frame containing at least one chemical modification or optionally without nucleotide modification, said open reading frame encoding a first antigenic polypeptide or a tandem polypeptide, wherein said RNA polynucleotide is present in a formulation for in vivo administration to a host such that the antigen expression level in the host is significantly higher than the antigen expression level produced by an mRNA vaccine having a stabilizing element or formulated with an adjuvant and encoding the first antigenic polypeptide.

Other aspects provide nucleic acid vaccines comprising one or more RNA polynucleotides having an open reading frame containing at least one chemically modified or optionally unmodified nucleotide, the open reading frame encoding a first antigenic polypeptide or a tandem polypeptide, wherein the vaccine has at least 10 times fewer RNA polynucleotides than an unmodified mRNA vaccine required to produce the same antibody titer. In some embodiments, the RNA polynucleotide is present in a dose of 25-100 micrograms.

The invention also provides a unit of use for a vaccine comprising between 10 μg and 400 μg of one or more RNA polynucleotides and a pharmaceutically acceptable carrier or excipient, said RNA polynucleotide having an open reading frame containing at least one chemical modification or optionally no nucleotide modification, said open reading frame encoding a first antigenic polypeptide or tandem polypeptide, said vaccine being formulated for delivery to a human subject. In some embodiments, the vaccine further comprises cationic lipid nanoparticles.

Aspects of the present invention provide methods for generating, maintaining, or restoring antigenic memory of a tumor in an individual or population of individuals, comprising administering an antigen-memory-enhancing nucleic acid vaccine to said individual or population, said vaccine comprising (a) at least one RNA polynucleotide, said polynucleotide comprising at least one chemically modified or optionally unmodified open reading frame and two or more codon-optimized open reading frames encoding a set of reference antigen peptides, and (b) optionally a pharmaceutically acceptable carrier or excipient. In some embodiments, the vaccine is administered to the individual via a route selected from intramuscular, intradermal, and subcutaneous administration. In some embodiments, the administration step includes contacting the subject's muscle tissue with a device suitable for injecting the composition. In some embodiments, the administration step includes combining electroporation to contact the subject's muscle tissue with a device suitable for injecting the composition.

An aspect of the present invention provides a method of vaccinating a subject, comprising administering to the subject a single dose of a nucleic acid vaccine in an amount effective for vaccinating the subject, between 25 μg/kg and 400 μg/kg, the nucleic acid vaccine comprising one or more RNA polynucleotides having an open reading frame encoding a first antigen polypeptide or a tandem polypeptide.

Other aspects provide nucleic acid vaccines comprising one or more RNA polynucleotides having an open reading frame containing at least one chemical modification encoding a first antigenic polypeptide or a tandem polypeptide, wherein the vaccine contains at least 10 times fewer RNA polynucleotides than an unmodified mRNA vaccine required to produce the same antibody titer. In some embodiments, the RNA polynucleotides are present in a dose of 25-100 micrograms.

In some embodiments, exemplary immunotherapeutic agents may include one or more interfering RNAs, which may be administered in combination with compounds of Formula I'. As used herein, "RNA interfering agent" is defined as any agent that interferes with or inhibits the expression of a target biomarker gene by RNA interference (RNAi). Such RNA interfering agents include, but are not limited to, nucleic acid molecules (including RNA molecules homologous to the target biomarker gene of the present invention), or fragments thereof, short interfering RNA (siRNA), and small molecules that interfere with or inhibit the expression of a target biomarker nucleic acid by RNA interference (RNAi). Short interfering RNA (siRNA), also referred to herein as "small interfering RNA," is defined as an agent that, for example, inhibits the expression of a target biomarker nucleic acid by RNAi. siRNA may be chemically synthesized, produced by in vitro transcription, or produced within host cells. In one embodiment, the siRNA is a double-stranded RNA (dsRNA) molecule of about 15 to about 40 nucleotides in length, preferably about 15 to about 28 nucleotides, more preferably about 19 to about 25 nucleotides, and even more preferably about 19, 20, 21, or 22 nucleotides, and may contain 3' and/or 5' overhangs of about 0, 1, 2, 3, 4, or 5 nucleotides in length on each strand. The length of the overhangs is independent between the two strands, i.e., the length of the overhang on one strand does not depend on the length of the overhang on the second strand. Preferably, the siRNA is capable of promoting RNA interference through the degradation of target messenger RNA (mRNA) or specific posttranscriptional gene silencing (PTGS).

The length of antisense oligonucleotides can be, for example, about 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 or more nucleotides. Antisense nucleic acids can be constructed using chemical synthesis and enzymatic ligation reactions, employing procedures known in the art. For example, antisense nucleic acids (e.g., antisense oligonucleotides) can be chemically synthesized using naturally occurring nucleotides or various modified nucleotides designed to increase the biological stability of the molecule or the physical stability of the duplex formed between antisense and sense nucleic acids, such as phosphate thioester derivatives and acridine-substituted nucleotides. Examples of modified nucleotides that can be used to generate antisense nucleic acids include 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine, 5-(carboxyhydroxymethyl)uracil, 5-carboxymethylaminomethyl-2-thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosylqueosine, inosine, N6-isopentenyladenine, 1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine, 7-methylguanine, 5-methylaminomethyluracil, 5-methyl... 2,6-diaminopurine, beta-D-mannosylqueosine, 5'-methoxycarboxymethyluracil, 5-methoxyuracil, 2-methylthio-N6-isopentenyladenine, uracil-5-oxyacetic acid (v), wybutoxosine, pseudouracil, queosine, 2-mercaptocytosine, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, methyl uracil-5-oxyacetic acid, uracil-5-oxyacetic acid (v), 5-methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl)uracil, (acp3)w, and 2,6-diaminopurine. Alternatively, antisense nucleic acids can be produced using biological methods using an expression vector, wherein the nucleic acid has been subcloned into the expression vector with an antisense orientation (i.e., the RNA transcribed from the inserted nucleic acid will have an antisense orientation with the target nucleic acid of interest, which will be further described in the following subsections).

The antisense nucleic acid molecules of the present invention are typically administered to a subject or generated in situ, such that they hybridize or bind to cellular mRNA and/or genomic DNA encoding a polypeptide corresponding to a selected biomarker of the present invention, thereby inhibiting the expression of the biomarker, for example, by inhibiting transcription and/or translation. Hybridization can be performed by conventional nucleotide complementarity to form a stable duplex or, for example, by specific interactions in the major groove of the double helix in the case of antisense nucleic acid molecules bound to a DNA duplex. Examples of administration routes of the antisense nucleic acid molecules of the present invention include direct injection at a tissue site or infusion of the antisense nucleic acid into blood or bone marrow-related fluids. Alternatively, the antisense nucleic acid molecules can be modified to target selected cells and then administered systemically. For example, for systemic administration, the antisense molecules can be modified such that they specifically bind to a receptor or antigen expressed on the surface of a selected cell, for example, by linking the antisense nucleic acid molecules to a peptide or antibody that binds to a cell surface receptor or antigen. The antisense nucleic acid molecules can also be delivered to cells using the vectors described herein. To obtain sufficient intracellular concentrations of antisense molecules, it is preferable that the antisense nucleic acid molecules are placed under the control of a strong pol II or pol III promoter.

Antigens that can be targeted to synthesize corresponding antisense RNA molecules may include any antigens specific to one or more tumors, such as the antigens exemplified above in relation to cancer vaccines.

In some embodiments, the combination of an immunotherapeutic agent and a compound of formula I' may include a bispecific antibody immunotherapeutic agent. The bispecific antibody may include a protein construct having a first antigen-binding moiety and a second antigen-binding site that binds to cytotoxic immune cells. The first antigen-binding site may bind to a tumor antigen to be specifically treated by the combination of the present invention. For example, the first antigen-binding moiety may bind to non-limiting examples of tumor antigens selected from: EGFR, HGFR, Her2, Ep-CAM, CD20, CD30, CD33, CD47, CD52, CD133, CEA, gpA33, mucin, TAG-72, CIX, PSMA, folate-binding protein, GD2, GD3, GM2, VEGF, VEGFR, integrin αVβ3, integrin α5β1, MUC1, ERBB2, ERBB3, MET, IGF1R, EPHA3, TRAILR1, TRAILR2, RANKL, FAP, and tendinin, etc. In some embodiments, the first antigen-binding moiety is specific for proteins or peptides overexpressed on tumor cells compared to corresponding non-tumor cells. As used herein, "corresponding non-tumor cells" refers to non-tumor cells of the same cell type as the tumor cells. Note that such proteins are not necessarily different from tumor antigens. Non-limiting examples include carcinoembryonic antigen (CEA), which is overexpressed in most colon, rectal, breast, lung, pancreatic, and gastrointestinal cancers; hyalin receptors (HER-2, neu, or c-erbB-2), which are frequently overexpressed in breast, ovarian, colon, lung, prostate, and cervical cancers; epidermal growth factor receptor (EGFR), which is highly expressed in a range of solid tumors including breast, head and neck, non-small cell lung cancer, and prostate cancer; desialylate glycoprotein receptor; transferrin receptor; serine protease inhibitor enzyme complex receptor, which is expressed on hepatocytes; fibroblast growth factor receptor (FGFR), which is overexpressed on pancreatic duct adenocarcinoma cells; vascular endothelial growth factor receptor (VEGFR), used for anti-angiogenic gene therapy; folate receptor, which is selectively overexpressed in 90% of non-mucinous ovarian cancers; cell surface glycocalyx; carbohydrate receptors; and polymerase receptors.

The second antigen-binding moiety is any molecule that specifically binds to an antigen, protein, or polypeptide expressed on the surface of a cytotoxic immune cell (CIK cell). Exemplary non-restricted antigens suitable for use with this disclosure and expressed on the surface of cytotoxic immune cells may include CD2, CD3, CD4, CD5, CD8, CD11a, CD11b, CD14, CD16a, CD27, CD28, CD45, CD45RA, CD56, CD62L, Fc receptor, LFA, LFA-1, TCRαβ, CCR7, macrophage inflammatory protein 1a, perforin, PD-1, PD-L1, PD-L2 or CTLA-4, LAG-3, OX40, 41BB, LIGHT, CD40, GITR, TGF-β, TIM-3, SIRP-α, TIGIT, VSIG8, BTLA, SIGLEC7, SIGLEC9, ICOS, B7H3, B7H4, FAS, BTNL2, CD27, and Fas ligand. In some embodiments, the second antigen-binding portion binds to CD3 of cytotoxic immune cells (e.g., CIK cells). In some embodiments, the second antigen-binding portion binds to CD56 of cytotoxic immune cells. In some embodiments, the second antigen-binding portion binds to the Fc receptor of cytotoxic immune cells. In some embodiments, the Fc region of a bispecific antibody binds to the Fc receptor of cytotoxic immune cells. In some embodiments, the second antigen-binding portion is any molecule that specifically binds to an antigen expressed on the surface of cytotoxic immune cells (e.g., CIK cells). The second antigen-binding portion is specific to the antigen on the cytotoxic immune cells. Exemplary cytotoxic immune cells include, but are not limited to, CIK cells, T cells, CD8+ T cells, activated T cells, monocytes, natural killer (NK) cells, NK T cells, lymphokine-activated killer (LAK) cells, macrophages, and dendritic cells. The second antigen-binding portion specifically binds to an antigen expressed on the surface of the cytotoxic immune cells. Exemplary non-restricted antigens suitable for regulation on the surface of cytotoxic immune cells may include CD2, CD3, CD4, CD5, CD8, CD11a, CD11b, CD14, CD16a, CD27, CD28, CD45, CD45RA, CD56, CD62L, Fc receptor, LFA, LFA-1, TCRαβ, CCR7, macrophage inflammatory protein 1a, perforin, PD-1, PD-L1, PD-L2 or CTLA-4, LAG-3, OX40, 41BB, LIGHT, CD40, GITR, TGF-β, TIM-3, SIRP-α, TIGIT, VSIG8, BTLA, SIGLEC7, SIGLEC9, ICOS, B7H3, B7H4, FAS, BTNL2, CD27, and Fas ligand. In other embodiments, the bispecific antibody modulator is an activator of a co-stimulatory molecule (e.g., an OX40 agonist). In one embodiment, the OX40 agonist is a bispecific antibody molecule of OX40 and another tumor antigen or co-stimulatory antigen. The OX40 agonist may be administered alone or in combination with other immunomodulators, such as with inhibitors (e.g., antibody constructs) of PD-1, PD-L1, CTLA-4, CEACAM (e.g., CEACAM-1, -3, and/or -5), TIM-3, or LAG-3. In some embodiments, the anti-OX40 antibody molecule is a bispecific antibody that binds to GITR and PD-1, PD-L1, CTLA-4, CEACAM (e.g., CEACAM-1, -3, and/or -5), TIM-3, or LAG-3. In one exemplary embodiment, the OX40 antibody molecule is administered in combination with an anti-PD-1 antibody molecule (e.g., the anti-PD-1 molecule described herein). The OX40 antibody molecule and the anti-PD-1 antibody molecule can be in the form of separate antibody compositions or as bispecific antibody molecules. In other embodiments, the OX40 agonist can be administered in combination with other co-stimulatory molecules (e.g., agonists of GITR, CD2, CD27, CD28, CDS, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), 4-1BB (CD137), CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3, or CD83 ligands). In some embodiments, the second antigen-binding portion binds to Fc receptors on cytotoxic immune cells (e.g., CIK cells).

In some embodiments, the bispecific antibody immunotherapy agent is specific to both tumor antigens and CIK cells, which allows tumor cells expressing tumor antigens to approach CIK cells closely, resulting in the elimination of tumor cells through anti-tumor cytotoxicity of CIK cells. In some embodiments, the bispecific antibody is specific to tumor antigens but not to CIK cells; however, the Fc region of the bispecific antibody can bind to the Fc receptors of CIK cells, which in turn allows tumor cells to approach CIK cells closely, resulting in the elimination of tumor cells through anti-tumor cytotoxicity of CIK cells. In some embodiments, the bispecific antibody is specific to CIK cells but not to tumor cells; however, the Fc region of the bispecific antibody can bind to the Fc receptors of tumor cells, which in turn allows tumor cells to approach CIK cells closely, resulting in the elimination of tumor cells through anti-tumor cytotoxicity of CIK cells.

In some embodiments, the combination of an immunotherapeutic agent and a compound of formula I' may comprise an immune cell-conjugated multivalent antibody/fusion protein/construct immunotherapeutic agent. In various embodiments, exemplary immunotherapeutic agents may comprise immune cell-conjugated multivalent antibodies/fusion proteins/constructs, which may contain recombinant structures, such as engineered antibodies that do not mimic the original IgG structure. Different strategies for polymerizing antibody fragments are utilized here. For example, shortening the peptide linker between the V domains forces scFv to self-associate into a dimer (biantibody; 55 kDa). Bispecific biantibodies are formed by the non-covalent binding of two VHA-VLB and VHB-VLA fragments expressed in the same cell. This results in the formation of a heterodimer with two different binding sites. Single-chain biantibodies (sc-biantibodies) are bispecific molecules in which the VHA-VLB and VHB-VLA fragments are linked together by an additional third linker. Tandem biantibodies (Tandabs) are tetravalent bispecific antibodies generated from two sc-biantibodies.

Also included are bi-biantibodies known in the art. This 130-kDa molecule is formed by fusing a biantibody to the N-terminus of the CH3 domain of IgG, resulting in an IgG-like structure. Other biantibody derivatives are triantibodies and tetraantibodies, which fold into trimer and tetrameric fragments by shortening the linker to <5 or 0-2 residues. Also exemplified is the (scFv) ₂ construct known as the 'bispecific T-cell adaptor' (BITE). BITE is a bispecific single-chain antibody consisting of two scFv antibody fragments linked by a flexible linker targeting surface antigens on target cells and CD3 on T cells. Bivalent (Fab)2 and trivalent (Fab)3 antibody forms are also exemplified. Microbodies and trimers generated from scFv are also exemplified. Exemplary constructs that can be used to target tumor antigens may include one or more of the following: double-stranded antibodies, single-stranded (sc)-double-stranded antibodies (scFv)2, microantibodies, microbodies, Barnase-barstar, scFv-Fc, sc(Fab)2, trimer antibody constructs, triple-stranded antibody constructs, trimer antibody constructs, trisomic antibody constructs, collagen scaffold antibody constructs, (scFv-TNFa)3, and F(ab)3/DNL. In each of these exemplary constructs, at least one binding portion may bind to an antigen or protein or peptide expressed on the surface of a cytotoxic immune cell, and at least one binding portion will specifically bind to the antigen on the cytotoxic immune cell. Exemplary cytotoxic immune cells include, but are not limited to, CIK cells, T cells, CD8+ T cells, activated T cells, monocytes, natural killer (NK) cells, NK T cells, lymphokine-activated killer (LAK) cells, macrophages, and dendritic cells.

In some embodiments, the combination of the immunotherapeutic agent and the compound of formula I' may include a radioconjugated immunotherapeutic agent.

In various embodiments, a radioconjugate is a small or large molecule (referred to herein as a “cell target”) and peptide, antibody, or antibody fragment thereof coupled to or otherwise attached to a radionuclide or multiple radionuclides, such that the binding of the radioconjugate to its target (a protein or molecule on or in a cancer cell) will lead to the death or pathogenesis of said cancer cell. In various embodiments, the radioconjugate may be a cell target labeled with a radionuclide, or the cell target may be coupled to or otherwise attached to particles, microparticles, or nanoparticles containing multiple radionuclides, wherein these radionuclides may be the same or different. Methods for synthesizing radioconjugates are known in the art and may include a classification of immunoglobulins or their antigen-binding moieties conjugated to toxic radionuclides.

In some embodiments, the molecule that binds to cancer cells may be referred to as a “cell target.” As used herein, exemplary cell targets may allow drug-containing nanoparticles or radionuclides to target specific types of cells of interest. Examples of cell targets include, but are not limited to, small molecules (e.g., folic acid, adenosine, purines) and large molecules (e.g., peptides or antibodies) that bind to or target tumor-associated antigens. Examples of tumor-associated antigens include, but are not limited to, adenosine receptor, αvβ3, aminopeptidase P, alpha-fetoprotein, cancer antigen 125, carcinoembryonic antigen, c-cryptin-1, chemokine receptor, cluster protein, tumor-associated antigen, CD20, epithelial tumor antigen, melanoma-associated antigen, Ras, p53, Her2/Neu, ErbB2, ErbB3, ErbB4, folic acid receptor, prostate-specific membrane antigen, prostate-specific antigen, purine receptor, radiation-induced cell surface receptor, serine protease inhibitor B3, serine protease inhibitor B4, squamous cell carcinoma antigen, platelet-reactive protein, tumor antigen 4, tumor-associated glycoprotein 72, tyrosinase, and tyrosine kinase. In some embodiments, the cell target is folic acid or a folic acid derivative that specifically binds to the folic acid receptor (FR). In some embodiments, the cell target is an antibody, bispecific antibody, trispecific antibody, or antigen-binding construct thereof that specifically binds to a cancer antigen selected from: EGFR, HGFR, Her2, Ep-CAM, CD20, CD30, CD33, CD47, CD52, CD133, CEA, gpA33, mucin, TAG-72, CIX, PSMA, folic acid-binding protein, GD2, GD3, GM2, VEGF, VEGFR, integrin αVβ3, integrin α5β1, MUC1, ERBB2, ERBB3, MET, IGF1R, EPHA3, TRAILR1, TRAILR2, RANKL, FAP, and tendinin, etc.

The use of folic acid as a targeting agent in radioactive conjugates also allows for the targeted destruction of both tumor cells and regulatory T (Treg) cells. It is well known that a large number of Treg cells suppress tumor immunity. Specifically, Treg cells suppress (exogenous and autologous) reactive T cells without killing them through contact-dependent or cytokine secretion (e.g., IL-10, TGF-β, etc.). FR4 is selectively upregulated on Treg cells. It has been shown that antibody blocking of FR4 in tumor-bearing mice depletes Treg cells and stimulates tumor immunity. Therefore, folic acid-coated PBM nanoparticles carrying cytotoxic agents will take up FR-expressing cells for destruction, which will directly (i.e., BrCa cells) and indirectly (i.e., breast tumor-associated and peripheral Treg cells) inhibit tumor progression.

In another embodiment, the target is an antibody or peptide capable of binding to tumor-associated antigens, or an immune cell-conjugating multivalent antibody/fusion protein/construct, said antigens including but not limited to: adenosine receptor, αvβ3, aminopeptidase P, alpha-fetoprotein, cancer antigen 125, carcinoembryonic antigen, caveolin-1, chemokine receptor, cluster protein, tumor-associated antigen, CD20, human growth factor receptor (HGFR), epithelial tumor antigen, melanoma-associated antigen, MUC1, Ras, p53, Her2/Neu, ErbB2, ErbB3, ErbB4, folate receptor, prostate-specific membrane antigen, prostate-specific antigen, purine receptor, radiation-induced cell surface receptor, serine protease inhibitor B3, serine protease inhibitor B4, squamous cell carcinoma antigen, platelet-reactive protein, tumor antigen 4, tumor-associated glycoprotein 72, tyrosinase, tyrosine kinase, etc.

In one embodiment, the treatment method comprises co-administering a compound as disclosed herein or a pharmaceutically acceptable salt thereof and at least one cytotoxic agent. As used herein, the term "cytotoxic agent" refers to a substance that inhibits or prevents cell function and/or causes cell death or destruction. Cytotoxic agents include, but are not limited to: radioisotopes (e.g., radioisotopes of At ²¹¹ , I ¹³¹ , I ¹²⁵ , Y ⁹⁰ , Re ¹⁸⁶ , Re ¹⁸⁸ , Sm ¹⁵³ , Bi ²¹² , P ³² , Pb ²¹² , and Lu); chemotherapeutic agents; growth inhibitors; enzymes and fragments thereof, such as lysozymes; and toxins, such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant, or animal origin, including fragments and/or variants thereof.

Exemplary cytotoxic agents may be selected from anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotics, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormone analogs, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, pro-apoptotic agents, LDH-A inhibitors; fatty acid biosynthesis inhibitors; cell cycle signal transduction inhibitors; HDAC inhibitors, proteasome inhibitors; and cancer metabolism inhibitors.

Chemotherapy agents include chemical compounds used to treat cancer. Examples of chemotherapy agents include erlotinib (Genentech/OSIPharm), bortezomib (Millennium Pharm), disulfiram, epigallocatechin gallate, salinomycin A, carfilzomib, 17-AAG (gerdemycin), rhizobactam, lactate dehydrogenase A (LDH-A), fulvestrant (AstraZeneca), sunitinib (Pfizer/Sugen), letrozole (Novartis), imatinib mesylate (Novartis), and phenacetinib. (finasunate)(Novartis), oxaliplatin (Sanofi), 5-FU (5-fluorouracil), leucovorin, rapamycin (Sirolimus, Wyeth), lapatinib (GSK572016, Glaxo SmithKline), lonafazil (Lonafamib)(SCH 66336), sorafenib (Bayer Labs), gefitinib (AstraZeneca), AG1478; alkylating agents, such as thiotepa and cyclophosphamide; alkyl sulfonates, such as busulfan, inprofen, and piperazine; nitrogen Propidine, such as benzodopa, carboquinone, meturedopa, and uredopa; ethylene imine and methylmelamine, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylomelamine; Anthocyanins (especially bullatacin and bullatacinone); camptothecin (including topotecan and irinotecan); bryostatin; callystatin; CC-1065 (including its synthetic analogues adozelesin, carzelesin, and bizelesin); cryptophycins (especially cryptophycin 1 and cryptophycin 8); corticosteroids (including prednisone and prednisolone); acetic acid Cyproterone acetate; 5α-reductase (including finasteride and dutasteride); vorinostat, romidepsin, panobinostat, valproic acid, moxistatin, dolastatin; interleukin, talc duocarmycin (including synthetic analogs KW-2189 and CB1-TM1); eleutherobin; pancratistatin; sarcodictyin; spongistatin (spongistatin); nitrogen mustard, such as chlorambucil, naphthyl mustard, chlorphosphamide, estradiol, ifosfamide, nitrogen mustard, oxynitric acid mustard, melphalan, neonitric acid mustard, benzyl mustard cholesterol, pine monoxide benzyl mustard, tristyramine cyclophosphamide, uracil nitrogen mustard; nitrosourea, such as carmustine, chloramphenicol, formustine, lomustine, nimustine, and ranistine; antibiotics, such as enediyne antibiotics (e.g., galicarmycin, especially galicarmycin γ1I and galicarmycin ω1I (Angew Chem. Intl. Ed. Engl. 1994 33:183-186); dyinmycin, including This includes dysinic A; bisphosphonates, such as clophosphonate; esporamin; and neocarzinostatin chromophores and related chromoprotein endothymyl antibiotic chromophores, aclarubicin, actinomycin, autramycin, azoserine, bleomycin, cactinomycin C, carabicin, caminomycin, carzinophilin, chromomycin, and more. Doxorubicin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-leucine, (daunorubicin), morpholino-daunorubicin, cyanomorpholino-daunorubicin, 2-pyrrolino-daunorubicin and deoxydaunorubicin, epirubicin, isorubicin, idarubicin, marcellomycin, mitomycin such as mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, porfiromycin Cin, puromycin, quelamycin, rodorubicin, streptozocin, tuberculin, ubenimex, zinostatin, zorubicin; antimetabolites, such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs, such as folate, methotrexate, pteroxate, trimethoprim; purine analogs, such as fludarabine, 6-mercaptopurine, thioimidapurine, thioguanine; pyrimidine analogs, such as ancitabine and azacitidine. 6-azauridine, carmoflurane, cytarabine, dideoxyuridine, deoxyfluorouridine, enoxabin, fluorouridine; androgens, such as calotestosterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; antiadrenergics, such as aminoglutethimide, mitotane, trilostane; folic acid supplements, Such as leucovorin; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithi ne); elliptinium acetate; epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansine alkaloids, such as maytansine and anthraquinone; mitoxanthraquinone; mopidamnol; nitraerine; pentostatin ); Phenamet; Pirarubicin; Loxoanthraquinone; Podophyllinic acid; 2-Ethylhydrazide; Procarbazine; Polysaccharide complex (JHS Natural Products, Eugene, Ore.); Razoxane; Rhizoxin; Sizofuran; Spirogermanium; Tenuazonic acid; Triaziquone; 2,2’ ,2”-Trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A, and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactalol; piperobroman; g acytosine; cytarabine (“Ara-C”); cyclophosphamide; thiotepa; taxanes, such as TAXOL (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, N.J.), (cremophor-free), albumin-engineered nanoparticle formulations of paclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.), and (docetaxel, docetaxel; Sanofibrils) i-Aventis; chloranmbucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vincristine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; vinorelbine; mitoxantrone; teniposide; edaraxacin; donomycin; aminopterin; capecitabine ibandronate; CPT-11; topoisomerase inhibitor RFS2000; difluoromethylornithine (DMFO); visual pigments such as retinoic acid; and pharmaceutically acceptable salts, acids, and derivatives of any of the above.

Chemotherapy agents also include (i) anti-hormonal agents that act to regulate or inhibit the effects of hormones on tumors, such as anti-estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including tamoxifen citrate), raloxifene, droloxifen, iodoxyfene, 4-hydroxytamoxifen, trivoxifen, keoxifene, LY117018, onanasone, and toremifene citrate; (ii) aromatase inhibitors that inhibit aromatase production in the adrenal glands, such as 4(5)-imidazole, aminoglutethimide, megestrol acetate, exemestane, formestanie, fadrozole, vorozole, letrozole, and anastrozole; and (iii) anti-androgens, such as flutamide, nitroglycerin, etc. Mite, bicalutamide, leuprorelin and goserelin; buserelin, tripterelin, medroxyprogesterone acetate, diethylstilbestrol, premarin, fluoromethesterone, all-trans retinoids, fenivel-Aminide and trisatabine (1,3-dioxane-1,3-cytosine analog); (iv) protein kinase inhibitors; (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, particularly those that inhibit gene expression in signaling pathways involved in abnormal cell proliferation, such as PKC-α, Ralf and H-Ras; (vii) ribozymes, such as VEGF expression inhibitors (e.g.) and HER2 expression inhibitors; (viii) vaccines, such as gene therapy vaccines, such as rIL-2; topoisomerase 1 inhibitors, such as (ix) pharmaceutically acceptable salts, acids and derivatives of any of the above.

Chemotherapy agents also include antibodies as described above, including alemtuzumab (Campath), bevacizumab (Genentech); cetuximab (Imclone); panitumumab (Amgen), rituximab (Genentech/Biogen Idec), pertuzumab (2C4, Genentech), trastuzumab (Genentech), tosimoumab (Bexxar, Corixia), and the antibody conjugate gemtuzumab ozomicin (Wyeth). Other humanized monoclonal antibodies with therapeutic potential that can be combined with the compounds of the present invention as agents include: apolizumab, acelizumab, atlizumab, bapineuzumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumabpegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, and erlizumab. Monoclonal antibodies (erlizumab), felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motovizumab, natalizumab, nimotuzumab, nivolumab, nolovizumab, numavizumab, ocrel izumab), omalizumab, palivizumab, pascolizumab, pecfusituzumab, pectuzumab, pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab, resyvizumab, rovelizumab, ruplizumab, sibrotuzumab, siplizumab, sontuzumab, tacatuzumab tesetan The anti-interleukin-12 antibody includes raxetan, tadocizumab, talizumab, tefibazumab, tocilizumab, totalizumab, tucotuzumabcelmoleukin, tucusituzumab, umavizumab, urtoxazumab, ustekinumab, visilizumab, and a genetically modified recombinant exclusive human full-length IgG sub.1.λ antibody that recognizes the interleukin-12 p40 protein (ABT-8744695, Wyeth Research and Abbott Laboratories).

Chemotherapy agents also include "tyrosine kinase inhibitors," including EGFR inhibitors; small molecule HER2 tyrosine kinase inhibitors, such as mubritonib (TAK165, Takeda); CP-724.714 (Axon Medchem BV, an orally selective inhibitor of ErbB2 receptor tyrosine kinase); dual HER inhibitors, such as EKB-569 (purchased from Wyeth), which preferentially binds to EGFR but inhibits both HER2 and EGFR-overexpressing cells; lapatinib (GSK572016; purchased from Glaxo-SmithKline), an orally administered HER2 and EGFR tyrosine kinase inhibitor; PKI-166 (purchased from Novartis); pan-HER inhibitors, such as canenatinib (CI-1033; Ph armacia); Raf-1 inhibitors, such as the antisense agent ISIS-5132, which inhibits Raf-1 signaling, purchased from ISIS Pharmaceuticals; non-HER-targeted TK inhibitors, such as imatinib mesylate (purchased from Glaxo SmithKline); multi-targeted tyrosine kinase inhibitors, such as sunitinib (purchased from Pfizer); VEGF receptor tyrosine kinase inhibitors, such as vatalanib (PTK787/ZK222584, purchased from Novartis/Schering AG); MAPK extracellular regulated kinase 1 inhibitor CI-1040 (purchased from Pharmacia); quinazolines, such as PD 153035, 4-(3-chloroaniline)quinazoline; pyridopyrimidine; pyrimidine; pyrrolopyrimidine, such as C GP 59326, CGP 60261, and CGP 62706; pyrazolopyrimidine, 4-(phenylamino)-7H-pyrrolo[2,3-d]pyrimidine; curcumin (diferoylmethane, 4,5-bis(4-fluoroaniline)phthalimide); tyrosine phosphorylation containing a nitrothiophene moiety; antisense molecules (e.g., those that bind to nucleic acids encoding HER); quinoxaline (US Patent No. 5,804,396); tryphostins (US Patent No. 5,804,396); affinitac (ISIS 3521; Isis/Lilly); PKI166 (Novartis); semaxinib (Pfizer); INC-1C11 (Imclone); [unclear text - possibly a brand name or product] Paramycin (Sirolimus); or as described in any of the following patent disclosures: U.S. Patent No. 5,804,396; WO 1999/09016 (American Cyanamid); WO 1998/43960 (American Cyanamid); WO 1997/38983 (Warner Lambert); WO 1999/06378 (Warner Lambert); WO 1999/06396 (Warner Lambert); WO 1996/30347 (Pfizer, Inc.); WO 1996/33978 (Zeneca); WO 1996/3397 (Zeneca) and WO 1996/33980 (Zeneca). Tyrosine kinase inhibitors also include erlotinib, gefitinib, dasatinib, nilotinib, ruxotinib, vemurafenib, vande, tanipazol, panib, afatinib, alisertinib, amovatinib, axitinib, bosutinib, brivanib, canertinib, cabozantinib, cediranib, and crenolan. ib), dabrafenib, dacomitinib, danusertib, dovitinib, foretinib, ganesteb, ibrutinib, iniparib, lenvatinib, linifanib, linsitinib, masitinib, molotinib momelotinib, motesanib, neratinib, niraparib, oprozomib, olaparib, pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, saracatinib (ib), saridegib, tandutinib, tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, trametinib, veliparib, vismodegib, volasertib, cobimetinib, etc.

Chemotherapy agents also include dexamethasone, interferon, colchicine, metoprine, cyclosporine, amphotericin B, metronidazole, alemtuzumab, retinoic acid, allopurinol, amifostine, arsenic trioxide, asparaginase, BCG live vaccine, bevacizumab, bexarotine, cladribine, clofarabine, darbepoetine alpha, denileukin, dextromethorphan, and epioetin alpha. Alfa, erlotinib, filgrastim, histamine acetate, ibritumomab, interferon alpha-2a, interferon alpha-2b, lenalidomide, levamisole, mesna, methoxsalen, nandrolone, nelarabine, nofetumomab, op-leukin Relvekin), palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim, pemetrexed disodium, plicamycin, porfimer sodium, quinacrine, rasburicase, sargramostim, temozolomide, VM-26, 6-TG, toremifene, tretinoin, ATRA, valrubicin, zoledronate, and zoledronic acid, as well as their pharmaceutically acceptable salts.

Chemotherapy agents also include hydrocortisone, hydrocortisone acetate, tixocortol pivalate, triamcinolone, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinolone acetonide, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluclocolone, hydrocortisone-17-butyrate, hydrocortisone-17-valerate, aclometasone dipropionate, betamethasone valerate, and betamethasone dipropionate. dipropionate, prednicarbamate, clobetasol-17-butyrate, clobetasol-17-propionate, fluocortolone hexanoate, fluocortolone pivalate, and fluprednidene acetate; immunoselective anti-inflammatory peptides (ImSAIDs), such as phenylalanine-glutamine-glycine (FEG) and its D-isomer (feG) (IMULAN) BioTherapeutics, LLC; antirheumatic drugs, such as azathioprine, cyclosporine (cyclosporine A), D-penicillamine, gold salts, hydroxychloroquine, leflunomide, sulfasalazine, tumor necrosis factor α (TNFα) blockers (such as etanercept (Enbrel), infliximab (Remicade), adalimumab (1-Iumira), cetuzumab (Cimzia), golimumab (Simponi)), interleukin-1 (IL-1) blockers (such as anaerobicin (Kineret)), and T-cell co-stimulation blockers (such as abatacept). (abatacept)(Orencia)), interleukin-6 (IL-6) blockers such as tocilizumab; interleukin-13 (IL-13) blockers such as lebrikizumab; interferon-alpha (IFN) blockers such as rontalizumab; β7 integrin blockers such as rhuMAbβ7; IgE pathway blockers such as anti-M1 initiators; secretory homotrimer LTa3 and membrane-bound heterotrimer LTa1/132 blockers such as anti-lymphotoxin alpha (LTa); mixed investigation agents such as thioplatin, PS-341, phenyl butyrate, ET-18-OCH ₃ or farnesyltransferase inhibitors (L-739749, L-744832); polyphenols, such as quercetin, resveratrol, leucine, epigallocatechin gallate, theaflavins, flavanols, proanthocyanidins, betulinic acid and their derivatives; autophagy inhibitors, such as chloroquine; δ-9-tetrahydrocannabinol (drocannabinol); β-lapachone; laparol; colchicine; betulinic acid; acetylcamptothecin, scopolamine and 9-aminocamptothecin); podophyllotoxin; tegafur bexarotine bisphosphonates, such as clodronate (e.g., or), etidronate NE-58095, zoledronic acid/zoledronic acid alendronate pamidronate teludronate or risedronate and epidermal growth factor receptor (EGF-R); vaccines, etc. Examples of such treatments include vaccines; perifosine, COX-2 inhibitors (e.g., celecoxib or etoricoxib), protein body inhibitors (e.g., PS341); CCI-779; tipifarnib (R11577); orafenib (ABT510); Bcl-2 inhibitors, such as GENASENSE (pisenoside); farnesyltransferase inhibitors, such as lonafamib (SCH6636, SARASAR ^™ ); and pharmaceutically acceptable salts, acids, or derivatives of any of the above; and combinations of two or more of the above, such as CHOP, an abbreviation for combination therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone; and FOLFOX, an abbreviation for oxaliplatin (ELOXATIN ^™ ) combined with 5-FU and leucovorin.

Chemotherapy agents also include poly-ADP-ribose polymerase (PARP) inhibitors: olapaline, nirapaline, and talzoparib.

Effective combinations of compounds of Formula I' or any of the formulas described herein with other agents can be identified through preclinical and clinical testing of the combination and will depend on many factors, including disease type and stage of development, patient's overall health, agent toxicity and side effects, etc.

In some embodiments, compounds such as those disclosed herein may be used in combination therapy with any of the kinase inhibitors disclosed herein for the treatment of diseases such as cancer. Exemplary kinase inhibitors include imatinib, baricitinib, gefitinib, erlotinib, sorafenib, dasatinib, sunitinib, lapatinib, nilotinib, pirfenidone, pazopanib, crizotinib, vemurafenib, vandetanib, ruxotinib, axitinib, bosutinib, regorafenib, tofacitinib, cabozantinib, panatinib, trametinib, dabrafenib, afatinib, ibrutinib, ceritinib, idelalisib, nintedanib, palbociclib, lenvatinib, cobitinib, XL-147, XL-765, XL-499, and XL-880. In some embodiments, the compounds described herein may be used in combination with HSP90 inhibitors (e.g., XL888), hepatic X receptor (LXR) modulators, orphan receptor γ (RORy) modulators associated with visual pigments, CK1 inhibitors, CK1-α inhibitors, Wnt pathway inhibitors (e.g., SST-215), or mineralocorticoid receptor inhibitors (e.g., ethacetenone or XL-550) for the treatment of diseases disclosed herein, such as cancer.

In some implementations, for the treatment of cancer, the compounds disclosed herein may be used in combination with inhibitors of PD-1 or PD-L1, such as anti-PD-1 monoclonal antibodies or anti-PD-L1 monoclonal antibodies, such as nivolumab (Opdivo), pembrolizumab (Keytruda, MK-3475), atezolizumab, ovavamab, AMP-224, AMP-514, PDR001, and duruvalumab. ), pildizumab (CT-011), CK-301, BMS 936559 and MPDL3280A; CTLA-4 inhibitors, such as anti-CTLA-4 antibodies, such as ipilimumab (Yervoy) and tesilimumab; and phosphatidylserine inhibitors, such as bavitimab (PGN401); antibodies against cytokines (IL-10, TGF-β, etc.); and other anticancer agents, such as cimetizumab.

In some embodiments, the compounds described herein may be used in combination with vaccination regimens for the treatment of cancer. In some embodiments, the compounds described herein may be used in combination with vaccines to stimulate an immune response to pathogens, toxins, and self-antigens. Examples of pathogens for which this treatment may be particularly useful include pathogens for which there are currently no effective vaccines, or pathogens for which conventional vaccines are not entirely effective. These include, but are not limited to, HIV, hepatitis (A, B, and C), influenza, herpes, Giardia, malaria, Leishmania, Staphylococcus aureus, and Pseudomonas aeruginosa.

In some embodiments, compounds such as those disclosed herein can be used in combination with PARP inhibitors, such as olapapani, rucapinini, lapapani, and tazopani.

The amounts of the compounds disclosed herein, or salts thereof, and one or more additional therapeutic agents (in those compositions comprising additional therapeutic agents as described above) that can be combined with a carrier material to produce a single dosage form will vary depending on the host being treated and the specific administration method. In some embodiments, the compositions of the invention are formulated such that a dose of 0.01-100 mg/kg body weight/day can be administered.

The additional therapeutic agent and the compounds disclosed herein can act synergistically. Therefore, the amount of the additional therapeutic agent in such compositions may be less than that required in a monotherapy using only the therapeutic agent, or, with the use of lower doses, fewer side effects may occur for the patient. In some embodiments, in such compositions, an additional therapeutic agent may be administered at a dose of 0.01-10,000 μg/kg body weight/day.

Labeled compounds and assay methods

Another aspect of the invention relates to the labeled compounds (radiolabeled, fluorescently labeled, etc.) of the invention, which can be used not only in imaging techniques but also in vitro and in vivo assays for locating and quantifying TAM kinases in tissue samples (including humans) and for identifying TAM kinase ligands by inhibiting the binding of the labeled compounds. Therefore, the invention includes TAM kinase assays containing such labeled compounds.

This invention also includes isotopically labeled compounds of the invention. An "isotopic" or "radiolabeled" compound is a compound of the invention in which one or more atoms are replaced or substituted with atoms having an atomic mass or mass number different from those normally found in nature (i.e., naturally occurring). Suitable radionuclides that can be incorporated into the compounds of the invention include, but are not limited to, ^2H (also written as D for deuterium), ^3H (also written as T for tritium), ^11C , ^13C , ^14C , ^13N , ^15N , ^15O , ^17O , ^18O , ^18F , ^35S , ^36Cl , ^82Br , ^75Br , ^76Br , ^77Br , ^123I , ^124I , ^125I , and ^131I . The radionuclides incorporated into the radiolabeled compounds of the invention will depend on the specific application of the radiolabeled compound. For example, for in vitro metalloproteinase labeling and competitive assays, compounds doped with ^3H , ^14C , ^82Br , ^125I , ^131I , or ^35S will generally be most useful. For radio imaging applications, ^11C , ^18F , ^125I , ^123I , ^124I , ^131I , ^75Br , ^76Br , or ^77Br will generally be most useful.

It should be understood that "radiolabeled" or "labeled compound" is a compound that has been doped with at least one radionuclide. In some embodiments, the radionuclide is selected from ^3H , ^14C , ^125I , ^35S , and ^82Br .

The present invention may also include a method for synthesizing compounds incorporating radioactive isotopes. Methods for synthesizing organic compounds incorporating radioactive isotopes are well known in the art, and those skilled in the art will readily recognize the methods applicable to the compounds of the present invention.

The labeled compounds of this invention can be used in screening assays to identify/evaluate compounds. For example, the ability of a newly synthesized or identified labeled compound (i.e., the test compound) to bind to TAM can be assessed by tracking changes in its concentration when the label is in contact with TAM kinase. For example, the ability of the (labeled) test compound to reduce the binding of another compound (i.e., the standard compound) known to bind to TAM kinase can be assessed. Therefore, the ability of the test compound to compete with the standard compound for binding to TAM kinase is directly related to its binding affinity. Conversely, in some other screening assays, the standard compound is labeled, and the test compound is not labeled. Therefore, the concentration of the labeled standard compound is monitored to assess the competition between the standard compound and the test compound, thereby determining the relative binding affinity of the test compound.

synthesis

The compounds of the present invention can be prepared by the following synthetic procedure. The raw materials and reagents used to prepare these compounds are available from commercial suppliers such as Sigma Aldrich Chemical Co. (Milwaukee, Wis.) or Bachem (Torrance, Calif.), or can be prepared by methods known to those skilled in the art according to the procedures described in references such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carb On Compounds, Volumes 1–5 and Supplements (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1–40 (John Wiley and Sons, 1991); March’s Advanced Organic Chemistry (John Wiley and Sons, 4th edition); and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989). These schemes are merely examples of some methods for synthesizing the compounds of the present invention, and various modifications can be made to these schemes, which will be suggested to those skilled in the art upon reference to this disclosure. If desired, the starting materials and intermediates of the reaction can be separated and purified using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, etc. Conventional means can be used to characterize such substances, including physical constants and spectroscopic data.

Unless otherwise stated, the reactions described herein are carried out at atmospheric pressure and in a temperature range of about -78°C to about 150°C, more preferably about 0°C to about 125°C, and most preferably about room temperature (or ambient temperature) (e.g., about 20°C). Unless otherwise stated (e.g., in the case of hydrogenation), all reactions are carried out under a nitrogen atmosphere.

The compounds disclosed and claimed herein have asymmetric carbon atoms or quaternized nitrogen atoms in their structure and can be prepared by the synthesis described herein as single stereoisomers, racemates, or mixtures of enantiomers and diastereomers. The compounds may also exist as geometric isomers. All such single stereoisomers, racemates, and geometric isomers, and mixtures thereof, are within the scope of this invention.

Some compounds of the present invention can exist as tautomers. For example, in the presence of a ketone or aldehyde, the molecule can exist as an enol; in the presence of an amide, the molecule can exist as an imine; and in the presence of an enamine, the molecule can exist as an imine. All these tautomers are within the scope of the present invention.

Methods for preparing and/or separating and isolating single stereoisomers from racemic or non-racemic mixtures of stereoisomers are well known in the art. For example, optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. Enantiomers (R- and S-isomers) can be separated by methods known to those skilled in the art, such as by: forming diastereomer salts or complexes that can be separated, for example, by crystallization; by forming diastereomer derivatives that can be separated, for example, by crystallization; by a selective reaction of an enantiomer with an enantiomer-specific reagent, such as enzymatic oxidation or reduction, followed by separation of modified and unmodified enantiomers; or by gas-liquid or liquid chromatography in a chiral environment, such as on a chiral support (e.g., silica with bonded chiral ligands) or in the presence of a chiral solvent. It should be understood that in cases where a desired enantiomer is converted to another chemical entity by one of the above separation procedures, further steps may be required to release the desired enantiomer form. Alternatively, specific enantiomers can be synthesized via asymmetric synthesis using optically active reagents, substrates, catalysts, or solvents, or by converting one enantiomer into another via asymmetric transformation. For enantiomer mixtures rich in specific enantiomers, the major component enantiomer can be further enriched by recrystallization (with a loss of yield).

Furthermore, the compounds of the present invention can exist in both non-solventized and solvated forms with pharmaceutically acceptable solvents such as water and ethanol. Generally, for the purposes of this invention, the solvated form is considered equivalent to the non-solventized form.

The method of the present invention can be performed as a semi-continuous or continuous method, and more preferably as a continuous method.

Unless otherwise indicated, the present invention as described above can be carried out in the presence of a solvent or a mixture of two or more solvents. In particular, the solvent is an aqueous solvent or an organic solvent, such as an ether solvent (e.g., tetrahydrofuran, methyltetrahydrofuran, diisopropyl ether, tert-butyl methyl ether, or dibutyl ether), an aliphatic hydrocarbon solvent (e.g., hexane, heptane, or pentane), a saturated alicyclic hydrocarbon solvent (e.g., cyclohexane or cyclopentane), or an aromatic solvent (e.g., toluene, o-xylene, m-xylene, or p-xylene or tert-butylbenzene) or a mixture thereof.

Raw materials and reagents that do not have the synthetic routes explicitly disclosed herein are generally available from commercial sources or can be readily prepared using methods well known to those skilled in the art.

method

One aspect provides a method for preparing compounds of formula I:

Or a pharmaceutically acceptable salt thereof, the method comprising:

Compounds of formula II:

Z is selected from _NH₂ , SH, and OH;

Reaction with compounds of formula III:

Where X is a leaving group;

_R1 is selected _from -H, -CN, -CO- _NR5R6 , _-CO2R7 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted _{( C1} - _C6 )alkyl, optionally substituted ( _C3 - _C8 )cycloalkyl, optionally substituted ( _C3 - _C6 ) _{heterocycloalkyl} , _-SO2NR8R9 and -( _{SO2 )} -( _C1 - _C6 )alkyl;

Where _R1 is selected _{from -CN} , -CO- _NR5R6 , _-CO2R7 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted ( _C3 - _C8 )cycloalkyl, optionally substituted ( _C3 - _C6 ) heterocycloalkyl, _-SO2NR8R9 and -( _SO2 )-( _C1 - _C6 )alkyl, _{R2 is -H} , halogroup, _-NR5R6 or optionally substituted _{( C1} - _C6 )alkoxy;

Where _R1 is -H, an optionally substituted ( _C1 - _C6 ) alkyl, or _an optionally substituted ( _C1 - _C6 ) alkoxy, _R2 is -CO- _NR5R6 or _{-CO2R7 .}

Or _R1 and _R2 together with the atoms to which they are attached form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl;

_R3 is selected from -H, optionally substituted (C1 _{- C6} ) alkyl, -CN, and halogroup;

_R4 is -H or a halogenated group;

Optionally substituted with one, two, three or four independently selected groups from halogroups and ( _C1 - _C6 )alkyl groups, wherein the linkage point is indicated;

_R5 and _R6 are each independently -H, optionally substituted ( _C1 - _C6 ) alkyl, or optionally substituted ( _C1 - _C6 ) alkoxy;

_R7 is -H or an optionally substituted ( _C1 - _C6 ) alkyl group.

_R8 and _R9 are each independently -H or optionally substituted ( _C1 - _C6 ) alkyl; or

_R8 and _R9 can be connected to form an optionally substituted heterocyclic ring; and

Y is selected from O, S, SO, _SO₂ , NH and N-(( _C₁ - _C₆ )alkyl).

On the other hand, there is a method for preparing compounds of formula I:

Or a pharmaceutically acceptable salt thereof, the method comprising:

Compounds of formula IV:

Reaction with compounds of formula V:

_R1 is selected _from -H, -CN, -CO- _NR5R6 , _-CO2R7 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted _{( C1} - _C6 )alkyl, optionally substituted ( _C3 - _C8 )cycloalkyl, optionally substituted ( _C3 - _C6 ) _{heterocycloalkyl} , _-SO2NR8R9 , and ( _{SO2 )} -( _C1 - _C6 )alkyl;

Where _R1 is selected _{from -CN} , -CO- _NR5R6 , _-CO2R7 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted ( _C3 - _C8 )cycloalkyl, optionally substituted ( _C3 - _C6 ) heterocycloalkyl, _-SO2NR8R9 and -( _SO2 )-( _C1 - _C6 )alkyl, _{R2 is -H} , halogroup, _-NR5R6 or optionally substituted _{( C1} - _C6 )alkoxy;

Where _R1 is -H, an optionally substituted ( _C1 - _C6 ) alkyl or an optionally substituted ( _C1 - _C6 ) alkoxy, _R2 is -CO- _NR5R6 , an optionally substituted _heteroaryl or _{-CO2R7 .}

Or _R1 and _R2 together with the atoms to which they are attached form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl;

_R3 is selected from -H, optionally substituted (C1 _{- C6} ) alkyl, -CN, and halogroup;

_R4 is -H or a halogenated group;

Optionally substituted with one, two, three or four independently selected groups from halogenated and _C1 - _C6 alkyl groups, wherein the linkage point is indicated;

_R5 and _R6 are each independently -H, optionally substituted ( _C1 - _C6 ) alkyl, or optionally substituted ( _C1 - _C6 ) alkoxy;

_R7 is -H or an optionally substituted ( _C1 - _C6 ) alkyl group;

_R8 and _R9 are each independently -H or optionally substituted ( _C1 - _C6 ) alkyl; or

_R8 and _R9 can be connected to form an optionally substituted heterocyclic ring; and

Y is selected from O, S, SO, _SO₂ , NH and N-( _C₁ - _C₆ alkyl).

In one embodiment, the compound of formula V is prepared by a method comprising the following steps: making the compound of formula VI:

Reaction with compounds of formula VII:

Compounds of formula VIII:

Furthermore, the reducing compound of formula VIII is used to provide the compound of formula V.

in:

_R1 is selected from _-H , -CN, -CO- _NR5R6 , _-CO2R7 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted _{( C1} - _C6 )alkyl, optionally substituted ( _C3 - _C8 )cycloalkyl, optionally substituted ( _C3 - _C6 ) _{heterocycloalkyl} , _-SO2NR8R9 and -( _{SO2 )} -( _C1 - _C6 )alkyl;

Where _R1 is selected _{from -CN} , -CO- _NR5R6 , _-CO2R7 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted ( _C3 - _C8 )cycloalkyl, optionally substituted ( _C3 - _C6 ) heterocycloalkyl, _-SO2NR8R9 and -( _SO2 )-( _C1 - _C6 )alkyl, _{R2 is -H} , halogroup, _-NR5R6 or optionally substituted _{( C1} - _C6 )alkoxy;

Where _R1 is -H, an optionally substituted ( _C1 - _C6 ) alkyl, or _an optionally substituted ( _C1 - _C6 ) alkoxy, _R2 is -CO- _NR5R6 or _{-CO2R7 .}

Or _R1 and _R2 together with the atoms to which they are attached form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl;

_R3 is selected from -H, optionally substituted (C1 _{- C6} ) alkyl, -CN, and halogroup; and

W is a halogenated group.

The following embodiments are provided for illustrative purposes and are not intended to limit the scope of the claimed invention.

Example

Example 1: Methyl 4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-7-methoxyquinoline-6-carboxylic acid ester (5)

N-(4-Fluorophenyl)-N-(4-hydroxyphenyl)cyclopropane-1,1-dicarboxamide (3): 3-(ethyliminomethyleneamino)-N,N-dimethyl-propane-1-amine hydrochloride (EDCI) (10.31 g, 53.8 mmol, 1.2 equivalent) was added to a solution of compound 1 (10 g, 44.80 mmol, 1 equivalent) and compound 2 (5.87 g, 53.8 mmol, 1.2 equivalent) in dimethylacetamide (DMA) (60 mL). The mixture was stirred vigorously at 20 °C until the reaction was complete. The mixture was poured into a saturated aqueous solution of _NaHCO3 (aq) (400 mL) and extracted with EtOAc (4 x 100 mL). The combined organic phases were washed with a saturated aqueous solution of NaCl (100 mL), _dried over anhydrous _Na2SO4 , and concentrated. Compound 3 (21 g, crude) (50% purity) was given. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.16 (br s, 1H), 9.72 (br s, 1H), 7.61 (dd, 2H), 7.34 (d, 2H), 7.13 (t, 2H), 6.68 (d, 2H), 1.42 (s, 4H); MS (EI) was _{C₁₇H₁₅FN₂O₃ ,} measured value _{314.9 (} MH⁺).

Methyl 4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-7-methoxyquinoline-6-carboxylic acid (5): A mixture of compound 3 (5.99 g, 9.5 mmol, 1.2 equivalents), compound 4 (2 g, 8.0 mmol, 1.0 equivalents), Pd(OAc) ₂ (89 mg, 397.4 μmol, 0.05 equivalents), racemic-2-(di-tert-butylphosphino)-1,1'-binaphthyl (TrixiePhos, 316.71 mg, 794.7 _μmol , 0.1 equivalents), and _K3PO4 (2.53 g, 11.9 mmol, 1.5 equivalents) in anisole (50 mL) was stirred at 110 °C for 2 h under a nitrogen atmosphere. The mixture was filtered and the filtrate was concentrated. The residue was purified by rapid silica gel chromatography (1:1 petroleum ether:EtOAc to 20:1 EtOAc:MeOH). Compound 5 was given (2.6 g, 61.8% yield). ^¹H NMR (400MHz, _CDCl₃ ) δ 9.38 (s, ¹H), 8.80 (s, ¹H), 8.63 (d, 2H), 7.64 (d, 2H), 7.54–7.41 (m, 3H), 7.18 (d, 2H), 7.09–7.01 (m, 2H), 6.43 (d, ¹H), 4.05 (s, 3H), 3.97 (s, 3H), 1.78–1.72 (m, 2H), 1.69–1.63 (m, 2H); MS (EI ₎ was _{C₂ ₹ H₂₄FN₃O₆} , measured value 530.0 (MH⁺).

Example 2: 4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-7-methoxyquinoline-6-carboxylic acid (6)

4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-7-methoxyquinoline-6-carboxylic acid (6): 2M NaOH aqueous solution (7 mL, 4.1 equivalents) was added to a solution of compound 5 (1.8 g, 3.4 mmol, 1 equivalent) in tetrahydrofuran (THF) (15 mL) and MeOH (15 mL). The mixture was stirred at 6 °C–13 °C for 4 hours. The pH of the mixture was adjusted to approximately 8 with 1M HCl aqueous solution and concentrated to remove the solvent. Water (50 mL) was added, and the pH of the mixture was adjusted to approximately 6 with 1M HCl aqueous solution. The resulting precipitate was filtered, washed with water (2 x 10 mL), and dried under vacuum. Compound 6 (1.7 g, 97.0% yield) was given. ^1H NMR (400MHz, DMSO- _d₆ ) δ 10.22 (s, 1H), 10.08 (s, 1H), 8.65 (d, 1H), 8.48 (s, 1H), 7.77 (d, 2H), 7.64 (dd, 2H), 7.47 (s, 1H), 7.25 (d, 2H), 7.15 (t, 2H), 6.45 (d, 1H), 3.96 (s, 3H), 1.47 (s, 4H); _MS ( _{EI )} was _{C₂₈H₂₂FN₃O₆} , measured value 516.1 (MH⁺).

Example 3: 1-N-[4-(6-carbamoyl-7-methoxyquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (7)

1-N-[4-(6-carbamoyl-7-methoxyquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (7): A solution of compound 6 (350 mg, 679.0 μmol, 1 equivalent), 3-oxyhexafluorophosphate 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium (HATU) (388 mg, 1.0 mmol, 1.5 equivalent), and diisopropylethylamine (DIEA or DIPEA) (352 mg, 2.7 mmol, 474 μL, 4.0 equivalent) in dimethylformamide (DMF) (10 mL) was stirred at 6-10 °C for 1 h, then _NH4Cl (73 mg, 1.4 mmol, 2.0 equivalent) was added, and the mixture was stirred at 6-10 °C for another 17 h. The mixture was filtered, and the resulting filtrate was concentrated and purified by preparative HPLC (column: Waters Xbridge 150mm*25mm*5μm, gradient: 32%-62% acetonitrile in _{10mM NH4HCO3} aqueous solution, flow rate: 25mL/min). Compound 7 was given (90.1mg, 25.8% yield). ^1H NMR (400MHz, DMSO- _d₆ ) δ 10.20 (s, 1H), 10.06 (s, 1H), 8.68 (s, 1H), 8.66 (d, 1H), 7.86 (br s, 1H), 7.81-7.72 (m, 3H), 7.68-7.61 (m, 2H), 7.51 (s, 1H), 7.26 (d, 2H), 7.19-7.11 (m, 2H), 6.46 (d, 1H), 4.03 (s, _3H ), _1.47 (s, _4H ); MS (EI) was _{C₂₈H₂₃FN₄O₅} , measured value 515.1 (MH⁺).

Example 4: 1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (8)

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (8): A DMF (10 mL) solution of compound 6 (300 mg, 582.0 μmol, 1 equivalent), HATU (332 mg, 873.2 μmol, 1.5 equivalent), and DIEA (301 mg, 2.3 mmol, 406 μL, 4 equivalent) was stirred at 6-10 °C for 1 hour. Methylamine hydrochloride (79 mg, 1.2 mmol, 2.0 equivalent) was added, and the mixture was stirred at 6-10 °C for 17 hours. The mixture was filtered, and the resulting filtrate was purified by preparative HPLC (column: Waters Xbridge 150mm*25mm*5μm, gradient: 33%-63% acetonitrile in 10mM _{NH4HCO3 aqueous} solution, flow rate: 25mL/min). Compound 8 was given (105.4 mg, 34.3% yield). ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.20 (s, ¹H), 10.06 (s, ¹H), 8.65 (d, ¹H), 8.61 (s, ¹H), 8.42–8.33 (m, ¹H), 7.77 (d, 2H), 7.68–7.61 (m, 2H), 7.51 (s, ¹H), 7.25 (d, 2H), 7.19–7.11 (m, 2H), 6.46 (d, ¹H), 4.02 (s, 3H), 2.84 (d, 3H) _{, 1.47 (s, 4H); MS (EI) was C₂⁹H₂⁵FN₄O₅ ,} measured value _{529.1 (} MH⁺).

The following compounds were prepared using a method similar to that used for compound 8 in Example 4:

1-N-[4-[6-(ethylcarbamoyl)-7-methoxyquinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (9): ^¹H NMR (400MHz, DMSO- _d6 ) δ 10.20 (s, 1H), 10.06 (s, 1H), 8.65 (d, 1H), 8.56 (s, 1H), 8.40 (br t, 1H), 7.78 (br d,2H), 7.64(dd,2H), 7.51(s,1H), 7.25(d,2H), 7.15(t,2H), 6.46(d,1H), 4.02(s,3H), 3.37-3.29(m,2H), 1.48(s,4H), 1.15(t,3H).; MS ( _{EI )} is _C30H27FN4O5 , measured value _543.2 (MH+).

1-N-[4-[6-[2-(dimethylamino)ethylcarbamoyl]-7-methoxyquinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (10): ^1H NMR (400MHz, CDCl3 ₎ δ 9.38(s,1H), 9.23(s,1H), 9.16(s,1H), 8.61(d,1H), 8.50(s,1H), 7.68(d,2H), 7.49-7.46(m,3H), 7.12(d,2H), 7.03(t,2H), 6.43(d,1H), 4.11(s,3H), 3.66(q,2H), 2.68(t,2H), 2.41(s,6H), _{1.70 (} s,4H); MS(EI) was _{C32H32FN5O5 ,} measured value 586.2 (MH+).

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(2-piperidin-1-ylethylcarbamoyl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (11): ^1H NMR (400MHz, CDCl3 ₎ δ 9.79(s,1H), 9.63(s,1H), 9.13(s,1H), 8.68(s,1H), 8.58(d,1H), 7.74(d,2H), 7.49-7.41(m,3H), 7.06-6.96(m,4H), 6.38(d,1H), 4.13(s,3H), 3.65(q,2H), 2.60(t,2H), 2.49(s,4H), 1.70-1.65(m,8H), _{1.51(s,2H); MS(EI) is C35H36FN5O5 , measured} value _626.3 (MH+).

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(2-morpholin-4-ylethylcarbamoyl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (12): ^1H NMR (400MHz, CDCl3 ₎ δ 9.26(s,1H), 9.24(s,1H), 8.95(s,1H), 8.63(d,1H), 8.46(s,1H), 7.65(d,2H), 7.52(s,1H), 7.50-7.47(m,2H), 7.16(d,2H), 7.05(t,2H), 6.46(d,1H), 4.15(s,3H), 3.79(t,4H), 3.68-3.64(m,2H), 2.65(t,2H), 2.57(s,4H), 1.70(d, _4H ); MS ( _{EI) was C34H34FN5O6 , measured} value 628.3 (MH+).

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(oxetane-3-ylcarbamoyl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (13): ^1H NMR (400MHz, CDCl3 ₎ δ 9.34(s,1H), 9.22(s,1H), 8.92(s,1H), 8.64(d,1H), 8.47(d,1H), 7.65(d,2H), 7.55(s,1H), 7.50-7.46(m,2H), 7.14(d,2H), 7.05(t,2H), 6.47(d,1H), 5.36-5.27(m,1H), 5.06(t,2H), 4.68(t,2H), 4.17(s,3H), _{1.71(s,4H); MS(EI) was C31H27FN4O6 , measured value} 571.2 (MH+).

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-[(1-methylazacyclobutane-3-yl)carbamoyl]quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (14): ^1H NMR (400MHz, CDCl3 ₎ δ 9.60(s,2H), 9.11(s,1H), 8.58(d,1H), 8.34(d,1H), 7.67(d,2H), 7.53-7.37(m,3H), 7.06(d,2H), 6.98(t,2H), 6.40(d,1H), 4.82-4.66(m,1H), 4.12(s,3H), 3.73(t,2H), 3.10(t,2H), 2.38(s,3H), _{1.74-1.60(m,4H); MS(EI) was C32H30FN5O5 , measured} value _584.9 (MH+).

1-N-[4-[6-(azacyclobutane-1-carbonyl)-7-methoxyquinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (15): ^¹H NMR (400MHz, _CDCl₃ ) δ 9.40 (s, 1H), 9.22 (br s, 1H), 8.59 (d, 1H), 8.32 (s, 1H), 7.63 (d, 2H), 7.49 (td, 9.2Hz, 3H), 7.13 (d, 2H), 7.04 (t, 2H), 6.43 (d, 1H), 4.28 (t, 2H), 4.08–3.98 (m, 5H), 2.37–2.32 (m, 2H), 1.77–1.64 (m, 4H); MS (EI) was C ₃₁ H ₂₇ FN ₄ O ₅ , measured value 554.8 (MH+).

1-N'-(4-fluorophenyl)-1-N-[4-[6-(3-hydroxyazacyclobutane-1-carbonyl)-7-methoxyquinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (16): ^1H NMR (400MHz, CDCl3 ₎ )δ9.43(s,1H),9.18(s,1H),8.60(s,1H),8.31(s,1H),7.61(d,2H),7.5 0-7.46(m,3H),7.11(d,2H),7.06-7.00(m,2H),6.45(d,1H),4.75-4.70( m,1H),4.51-4.47(m,1H),4.19-4.13(m,1H),4.11-4.07(m,1H),4.01(s ,3H),3.95-3.91(m,1H),1.75-1.73(m,2H),1.72-1.69(m,2H); MS(EI) is C ₃₁ H ₂₇ FN ₄ O ₆ The measured value was 571.0 (MH+).

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(methoxycarbamoyl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (17): ^¹H NMR (400MHz, DMSO- _d6 ) δ 11.27 (br s, 1H), 10.20 (br s, 1H), 10.06 (br s, 1H), 8.65 (d, 1H), 8.44 (s, 1H), 7.76 (d, 2H), 7.63 (d, 2H), 7.49 (s, 1H), 7.25 (d, 2H), 6.46 (d, 2H), 6.93 (d, 1H), 3.98 (s, 3H), 3.74 (s, 3H), 1.47 (s _, 4H); MS (EI) _C29H25 FN ₄ O ₆ , measured value 545.1 (MH+).

(R)-2-((4-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylammono)phenoxy)-7-methoxyquinoline-6-carboxylammono)methyl)pyrrolidine-1- _{carboxylic acid tert-butyl ester (18): MS (EI) is C38H40FN5O7 , and the} measured value is 698.3 (MH+).

(S)-2-((4-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylammono)phenoxy)-7-methoxyquinoline-6-carboxylammono)methyl)pyrrolidine-1- _{carboxylic acid tert-butyl ester (19): MS (EI) is C38H40FN5O7 , measured} value _is 698.3 (MH+).

1-N'-(4-fluorophenyl)-1-N-[4-[6-(hydroxycarbamoyl)-7-methoxyquinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide hydrochloride (20): ^¹H NMR (400MHz, DMSO- _d₆ ) δ 11.08 (s, 1H), 10.32 (s, 1H), 10.04 (s, 1H), 8.97–8.88 (m, 1H), 8.54 (s, 1H), 7.84 (d, 2H), 7.72–7.58 (m, 3H), 7.35 (d, 2H), 7.15 (t, _2H ), 6.86–6.75 (m, 1H), 4.04 (s, 3H), 1.48 (d, 4H) _; MS (EI _{) C₂₈H₂₃FN₄O₆} The measured value was 531.0 (MH+).

Example 5: 1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-[[(2R)-pyrrolidone-2-yl]methylcarbamoyl]quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (21)

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-[[(2R)-pyrrolidone-2-yl]methylcarbamoyl]quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (21): Trifluoroacetic acid (TFA; 1 mL) was added in a single batch to a mixture of compound 18 (67 mg, 96.0 μmol, 1 equivalent) in dichloromethane (DCM) (3 mL) at 30 °C. The mixture was stirred at 30 °C for 0.5 h, and then the reaction mixture was concentrated under vacuum. The resulting residue was purified by preparative HPLC (column: Waters Xbridge 150*25*5μm; mobile phase: [water (0.05% ammonium hydroxide v/v)-acetonitrile (ACN)]; B%: 50%) to give compound 21 (24.4 mg, 42.5% yield). ^¹H NMR (400 MHz, DMSO- _d₆ ) δ 9.52–9.35 (m, 2H), 9.14 (s, 1H), 8.59 (d, 1H), 8.42 (br₆) t, 1H), 7.68(d, 2H), 7.51-7.44(m, 3H), 7.09(d, 2H), 7.06-6.97(m, 2H), 6.42(d, 1H), 4.13(s, 3H), 3.69(td, 1H), 3.55-3.47(m, 1H), 3.45-3.37(m, 1H), 3.01(t, 2H), 2.01-1.79(m, 8H), 1.58-1.45(m, 1H); MS(EI ₎ is _{C33H32FN5O5 ,} measured value _598.3 (MH+).

The following compounds were prepared from compound 19 in a manner similar to that used in Example 5 to convert compound 18 to compound 21:

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-[[(2S)-pyrrolidone-2-yl]methylcarbamoyl]quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (22): ^1H NMR (400MHz, CDCl3 ₎ )δ9.47(s,2H),9.15(s,1H),8.60(d,1H),8.40(t,1H),7.7-7.67(m,2H),7 .49-7.45(m,3H),7.10-7.04(m,2H),7.03-6.99(m,2H),6.41(d,1H),4.11( s,3H),3.71-3.65(m,1H),3.50-3.37(m,2H),3.02-2.96(m,2H),2.01-1.95 (m,2H),1.84-1.75(m,2H),1.71-1.66(m,4H),1.55-1.48(m,1H); MS(EI) is C ₃₃ H ₃₂ FN ₅ O ₅ , measured value 598.3 (MH+).

Example 6: 1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(oxacyclobutane-3-yloxycarbamoyl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (26)

2-(oxetane-3-yloxy)isoindoline-1,3-dione (24): PPh 3 (3.54 g, 13.5 mmol, 2 equivalents) and diisopropyl azodicarboxylate (DIAD) (2.81 g, 13.9 mmol, 2.7 mL, 2.1 equivalents) were added fractionally to a THF (30 mL) solution of compound ₂₃ (1.32 g, 8.1 mmol, 1.2 equivalents) and oxetane-3-ol (500 mg, 6.8 mmol, 1 equivalent). The resulting mixture was stirred at 20 °C for 15 h to give a brown solution. The mixture was concentrated with silica gel and purified by rapid silica gel chromatography (0% to approximately 70% EtOAc in a petroleum ether gradient). The residue was further purified by rapid silica gel chromatography using the same solvent system to give compound 24 (300 mg, 10.14% yield, 50% purity). MS( _{EI) is C11H9NO4 ,} measured value _219.8 (MH+).

O-(oxetane-3-yl)hydroxylamine (25): _{NH₂NH₂ - H₂O} (95.92 mg, 1.9 mmol, 93.13 μL, 1.5 equivalents) was added to a DCM (5 mL) solution of compound 24 (280 mg, 1.3 mmol, 1 equivalent) at 0 °C, and the mixture was stirred for 1 hour to obtain a white suspension. The mixture was filtered and washed with DCM (5 mL), and the filtrate was concentrated. Crude compound 25 (150 mg) was used in the next step without further purification.

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(oxetane-3-yloxycarbamoyl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (26): Propylphosphonic anhydride (T3P) (185.17 mg, 582.0 μmol, 1 equivalent) and DIEA (75.22 mg, 582.0 μmol, 101.37 μL, 3 equivalent) were added to a THF ( ₃ mL) solution of compound 6 (100 mg, 194.0 μmol, 1 equivalent) and compound 25 (20.74 mg, 232.8 μmol, 1.2 equivalent), and the resulting mixture was stirred at 20 °C for 10 hours. The mixture was concentrated, and the resulting residue was purified by preparative HPLC (column: YMC-Actus Triart C18150*30mm*5μm; mobile phase: [water (0.05% ammonium hydroxide v/v)-ACN]; B%: 25%-65%, 10 min) to give compound 26 (5.3 mg, 4.66% yield). ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.66(s,1H),10.21(br s,1H),10.06(br s,1H),8.67(d,1H),8.42(s,1H),7.78(d,2H),7.64-7.86(m,2H),7.51(s,1H),7.26(d,2H),7.13-7.18(m,2H ),6.47(d,1H),5.07-5.09(m,1H),4.73-4.76(m,2H),4.63-4.66(m,2H),3.99(s,3H),1.48(s,4H); MS(EI) is C ₃₁ H ₂₇ FN ₄ O ₇ The measured value was 587.1 (MH+).

The following compounds were prepared from compound 6 in a manner similar to that used in the last step of Example 6 to form compound 26 from compound 6:

1-N'-(4-fluorophenyl)-1-N-[4-[6-(2-hydroxyethoxycarbamoyl)-7-methoxyquinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (27): ^1H NMR (400MHz, DMSO- _d6) δ 11.47(s,1H), 10.22(s,1H), 10.07(s,1H), 8.67(d,1H), 8.46(s,1H), 7.78(d,2H), 7.61-7.67(m,2H), 7.51(s,1H), 7.26(d,2H), 7.12-7.18(m,2H), 6.47(d,1H), 4.82(t,1H), 4.00(s,3H), 3.97(t,2H), 3.65( _{q,2H), 1.48(s,4H); MS (EI) was C30H27FN4O7 , measured value} 575.1 (MH+).

N-(4-((6-(((2,2-dimethyl-1,3-dioxopentane-4-yl)methoxy)carbamoyl)-7-methoxyquinoline-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1- _{dicarboxamide (28). MS (EI) was C34H33FN4O8 , with a} measured value of 645.0 (MH+).

Example 7: 1-N-[4-[6-(2,3-dihydroxypropoxycarbamoyl)-7-methoxyquinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, enantiomers 1 (30) and 2 (31)

1-N-[4-[6-(2,3-dihydroxypropoxycarbamoyl)-7-methoxyquinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, racemic mixture (29): TFA (53.06 mg, 465.37 μmol, 34.46 μL, 1 equivalent) was added to a DCM (10 mL) solution of compound 28 (300 mg, 465.37 μmol, 1 equivalent), and the resulting mixture was stirred at 20 °C for 10 h. Two more equal portions of TFA, totaling 0.35 mL, were added, and stirring was continued at 20 °C for a further 5 h to obtain a brown solution. The reaction mixture was concentrated under vacuum, and the resulting residue was purified by preparative HPLC (column: Agela Dura Shell 150mm*25mm*5μm; mobile phase: [water (0.225% FA)-ACN]; B%: 11%-51%, 10 min) to give compound 29 (85 mg, 30.21%). ^¹H NMR (400 MHz, DMSO- _d⁶ ) δ 11.54 (br s, 1H), 10.22 (br s, 1H), 10.07 (br s, 1H), 8.67 (d, 1H), 8.49 (s, 1H), 7.77 (d, 2H), 7.64-7.67 (m, 2H), 7.52 (s, 1H), 7.26 (d, Hz, 2H), 7.14-7.16 (m, 2H), 6.47 (d, 1H), 5.00 (br s, 1H ... s, 1H), 4.67 (br s, 1H), 3.99-4.02 (m, 4H), 3.78-3.85 (m, 2H), 3.39-3.42 (m, 2H), 1.48 (s, 4H); MS (EI) is C ₃₁ H ₂₉ FN ₄ O ₈ , measured value 605.4 (MH+).

1-N-[4-[6-(2,3-dihydroxypropoxycarbamoyl)-7-methoxyquinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, enantiomers 1 (30) and 2 (31).

The enantiomers of racemic compound 29 were separated using an SFC (column: DAICL CHIRALPAK AD (250 mm * 30 mm, 10 μm); mobile phase: [0.1% NH3H2OIPA]; B%: 45%-45%, min) (85 mg, 140.59 μmol, 1 equivalent) to give compound 30 (53.0 mg, 62.35%) and compound 31 (21.3 mg, 25.06% yield). Compound 30: ^¹H NMR (400 MHz, DMSO- _d₆ ) δ 11.54 (br s, 1H), 10.22 (br s, 1H), 10.07 (br s, 1H), 8.67 (d, 1H), 8.49 (s, 1H), 7.77 (d, 2H), 7.64–7.67 (m, 2H), 7.52 (s, 1H), 7.26 (d, 2H), 7.14–7.16 (m, 2H), 6.47 (d, 1H), 5.00 (d, 1H), 4.67 (t, 1H), 3.99–4.03 (m, 4H), 3.78–3.93 (m, 2H), 3.39–3.47 (m, 2H), 1.48 (s _, 4H); MS (EI) _{C₃¹H₂₉FN 4} O ₈ , measured value 605.3 (MH+). Compound 31: ^¹H NMR (400MHz, DMSO- _d₆ ) δ 11.54 (br s, 1H), 10.23 (br s, 1H), 10.08 (br s, 1H), 8.67 (d, 1H), 8.49 (s, 1H), 7.79 (d, 2H), 7.64–7.67 (m, 2H), 7.51 (s, 1H), 7.26 (d, 2H), 7.14–7.18 (m, 2H), 6.47 (d, 1H), 5.03 (br s, 1H), 4.69 (br s, 1H), 4.00–4.04 (m, 4H), 3.76–3.86 (m, 2H), 3.52–3.56 (m, 2H), 1.48 (s, 4H); MS (EI) _{C₃¹H 29} FN ₄ O ₈ , measured value 605.0 (MH+).

Example 8: 1-N'-(4-fluorophenyl)-1-N-[4-[6-(hydrazylcarbonyl)-7-methoxyquinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (32)

1-N'-(4-fluorophenyl)-1-N-[4-[6-(hydrazylcarbonyl)-7-methoxyquinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (32): _{NH₂NH₂ - H₂O} (28.36 mg, 566.56 μmol, 27.54 μL, 3 equivalents) was added to a solution of compound 5 (100 mg, 188.85 μmol, 1 equivalent) in MeOH (5 mL). The resulting mixture was stirred at 50 °C for 2 h, and then concentrated under vacuum. The residue was ground with MeOH (3 mL), and the residue was filtered to give compound 32 (56.6 mg, 53.77% yield). ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.21 (s, ¹H), 10.06 (s, ¹H), 9.51 (br s, ¹H), 8.66 (d, ¹H), 8.53 (s, ¹H), 7.78 (d, 2H), 7.69–7.60 (m, 2H), 7.51 (s, ¹H), 7.26 (d, 2H), 7.16 (t, 2H), 6.48 (d, ¹H), 4.62 (br d, 2H), 4.01 (s, 3H) _{, 1.48 (s, 4H); MS (EI) was C₂₈H₂₄FN₅O₅ , measured value} 530.2 (MH⁺).

Example 9: 1-N-[4-(6-acetyl-7-methoxyquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (34)

N-(4-fluorophenyl)-N-(4-((7-methoxy-6-(methoxy(methyl)carbamoyl)quinoline-4-yl)oxy)phenyl)cyclopropane-1,1-dicarboxamide (33): HATU (442.57 mg, 1.16 mmol, 2 equivalents) and DIEA (225.65 mg, 1.75 mmol, 304.11 μL, 3 equivalents) were added to a DMF (3 mL) solution of compound 6 (300 mg, 581.97 μmol, 1 equivalent) and N,O-dimethylhydroxylamine hydrochloride (170.30 mg, 1.75 mmol, 3 equivalents). The resulting mixture was stirred at 20 °C for 3 hours to give a brown solution. The mixture was diluted with EtOAc (60 mL) and washed with water (2 x 20 mL) and saturated NaCl aqueous solution (20 mL). The organic phase was concentrated under vacuum, and the resulting residue was purified by rapid silica gel chromatography (5 g silica rapid column, eluent of 0% to approximately 20% MeOH/DCM gradient, flow rate of 10 mL/min) to give compound ₃₃ ( ₃₀₀ mg, 89.52% yield. _MS (EI) was _C30H27FN4O6 , measured value 559.2 (MH+).

1-N-[4-(6-acetyl-7-methoxyquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (34): MeMgBr (3M, 1.67mL, 10 equivalents) was added to a THF (5mL) solution of compound 33 (280mg, 501.29μmol, 1 equivalent) at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at 20°C for 15 hours to give a brown suspension. The reaction mixture was quenched with a saturated aqueous solution of _NH4Cl (20mL), extracted with EtOAc (3 x 15mL), and concentrated. The resulting residue was purified by rapid silica chromatography (4g silica rapid column, 0% to 4% MeOH/DCM gradient eluent, flow rate 10mL/min). The crude product was further purified (using a 4 g silica fast column with an eluent of 0% to approximately 60% EtOAc/petroleum ether gradient at 10 mL/min) to give compound 34 (190 mg, yield 73.81%). ^¹H NMR (400MHz, _CDCl₃ ) δ 9.40 (br s, 1H), 8.90 (br s, 1H), 8.68 (s, 1H), 7.51 (d, 1H), 7.63–7.66 (m, 2H), 7.45–7.50 (m, 3H), 7.14–7.16 (m, 2H), 7.02–7.07 (m, 2H), 6.43 (d, 1H), 4.05 (s, 3H), 2.71 (s, 3H), 1.16–1.72 (m, 4H); MS (EI ₎ was _{C₂ ₹ H₂₄FN₃O₅} , measured value 536.1 (MH+Na) ^⁺ .

Example 10: 1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-[(E)-N-methoxy-C-methylcarboiminoyl]quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (35) and 1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-[(Z)-N-methoxy-C-methylcarboiminoyl]quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (36)

Methoxyamine hydrochloride (45.54 mg, 545.26 μmol, 41.40 μL, 2 equivalents) was added to a solution of compound 34 (140 mg, 272.63 μmol, 1 equivalent) in water (2.5 mL) and EtOH (2.5 mL), and the resulting mixture was stirred at 50 °C for 2 h to obtain a brown solution. The reaction mixture was diluted with EtOAc (50 mL), washed with water (2 x 20 mL), and concentrated. The resulting residue was purified twice by rapid silica gel chromatography (4 g silica rapid column, eluent of 0% to approximately 80% EtOAc/petroleum ether gradient, flow rate of 10 mL/min). Compounds 35 and ₃₆ (110 mg, 69.7% yield) were recovered as a mixture of Z and E isomers (MS ( _EI ) _C30H27FN4O5 , _542.9 (MH+)). The Z and E isomers were separated by preparative HPLC (column: Agela DuraShell 150 mm * 25 mm * 5 μm; mobile phase: [water (0.05% ammonium hydroxide v/v) - ACN]; B%: 47%-87%, 10 min) to give compound 35 (54.7 mg, 52.10% yield) and compound 36 (6.4 mg, 6.10% yield). Compound 35: ^1H NMR (400 MHz, DMSO- _d6 ) δ 10.21 (br s, 1H), 10.07 (br s, 1H), 8.63(d, 1H), 8.09(s, 1H), 7.77(d, 2H), 7.65-7.68(m, 2H), 7.49(s, 1H), 7.77(d, 2H), 7.16(t, 2H), 6.44(d, 1H), 3.99(s, 3H), 3.91(s, 3H), 2.16(s, 3H), 1.48(s, 4H). Compound 36: ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.21(br s, 1H), 10.07(br s, 1H), 1.48(br s, 4H). s,1H),8.61(d,1H),7.97(s,1H),7.77(d,2H),7.63-7.66(m,2H),7.47(s,1H),7.25( d,2H),7.16(t,2H),6.43(d,1H),3.95(s,3H),3.70(s,3H),2.15(s,3H),1.48(s,4H).

Example 11: 1-N-[4-(6-cyano-7-methoxyquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (37)

1-N-[4-(6-cyano-7-methoxyquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (37): _POCl3 (7.78 g, 50.74 mmol, 4.72 mL, 134 equivalents) was added to a MeCN (10 mL) solution of compound 7 (200 mg, 379.12 μmol, 1 equivalent). The mixture was stirred at 80 °C for 3 h. The reaction mixture was filtered, and the filtrate was concentrated and dried under vacuum. The residue was diluted with water (5 mL), the pH was adjusted to 8-9 with an aqueous solution _{of Na2CO3} , and the residue was extracted with DCM (3 x 20 mL). The combined organic layers were concentrated and then dried under vacuum. The residue was purified by preparative HPLC to give compound 37 (80.3 mg, 42.37% yield). ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.23 (br s, 1H), 10.05 (br s, 1H), 8.79–8.72 (m, 2H), 7.79 (br d, 2H), 7.68–7.58 (m, 3H), 7.27 (d, 2H), 7.15 (t, 2H), 6.52 (d, 1H), 4.07 (s, 3H), 1.48 ( _{s, 4H); MS (EI) was C₂₈H₂₁FN₄O₄ ,} measured value _{497.1 (} MH⁺).

Example 12: N-(4-((6-bromo-7-methoxyquinoline-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (43)

5-(((4-bromo-3-methoxyphenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (40): A solution of compound 39 (4.10 g, 28.46 mmol, 1.15 equivalents) in trimethoxymethane (25 mL, 228.04 mmol, 9.22 equivalents) was refluxed at 105 °C for 1 h. Then compound 38 (5 g, 24.75 mmol, 1 equivalent) was added, and reflux was continued at 105 °C for another 1 h. The resulting suspension was filtered, washed with MeOH, and dried under vacuum to give compound 40 (7.7 g, 87.4% yield), which was used in the next step without further purification. ¹ HNMR (400MHz, CDCl ₃ ) δ11.24-11.20(d,1H),8.62-9.59(d,1H),7.57-7.54(d,1H),6.77-6.74(m,2H),3.94(s,3H),1.76(s,3H),1.74(s,3H).

6-Bromo-7-methoxyquinoline-4(1H)-one (41): Compound 40 (7.7 g, 21.62 mmol, 1 equivalent) was added to _Ph₂O (35 mL) at 230 °C, and the mixture was stirred for 1 hour. After cooling to room temperature, the reaction mixture was poured into hexane (20 mL), and the resulting precipitate was filtered and washed with hexane. The residue was dried under vacuum to give compound 41 (6.2 g, 75.8% yield, 67.2% purity). ^¹H NMR (400MHz, DMSO- _d₆ ) δ 11.78 (s, ¹H), 8.18 (s, ¹H), 7.88–7.86 (d, ¹H), 7.05 (s, ¹H), 6.03–6.01 ( _{d, ¹H), 3.92 (s, ³H); MS (EI) was C₁₀H₈BrNO₂ ,} measured value _254.2 (MH⁺).

6-Bromo-4-chloro-7-methoxyquinoline (42): A _POCl3 solution (15 mL, 161.41 mmol, 9.84 equivalents) of compound 41 (6.2 g, 16.40 mmol, 1 equivalent) was stirred at 110 °C for 1 h. After cooling, the reaction mixture was carefully poured into a mixture of saturated _{Na2CO3 aqueous} solution and ice with stirring. The resulting suspension was filtered, washed with water, and dried under vacuum to give compound 42 (7.78 g, 57.4% purity, 99.9% yield), which was used in subsequent steps without further purification. _{MS (EI) was C10H7BrClNO ,} measured at 272.2 (MH+).

N-(4-((6-bromo-7-methoxyquinoline-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (43): A mixture of compound 42 (5.72 g, 12.05 mmol, 1.26 equivalents), compound 3 (3.00 g, 9.54 mmol, 1 equivalent), and t-BuOK (3.21 g, 28.63 mmol, 3 equivalents) in DMSO (30 mL) was stirred at 150 °C for 2 h. A saturated aqueous solution of _NH4Cl (200 mL) was added, and the mixture was extracted with EtOAc (3 x 250 mL). The combined organic phases were dried over _{anhydrous Na2SO4} and concentrated under vacuum. The resulting residue was purified by rapid silica gel chromatography (40 g silica rapid column, eluent 0% to approximately 100% EtOAc/petroleum ether gradient, flow rate 40 mL/min). The resulting residue was ground with MeOH (50 mL) and filtered to give compound 43 (3.0 g, 57.11% yield). ^¹H NMR (400 MHz, _CDCl₃ ) δ 9.33 (s, 1H), 8.66 (br s, 1H), 8.60 (d, 1H), 8.58 (s, 1H), 7.64 (d, 2H), 7.48 (dd, 2H), 7.45 (s, 1H), 7.18 (d, 2H), 7.07 (t, 2H), 6.45 (d, 1H), 4.07 (s, 3H), 1.78–1.72 (m, 2H), 1.71–1.65 (m, 2H).

The following compounds were synthesized in a manner similar to that of compound 43 in the last step of Example 12, with 6-bromo-4-chloroquinoline replacing compound 42.

N-(4-((6-bromoquinoline-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1- _{dicarboxamide} (44). _{MS (EI) was C26H19BrFN3O3 , with} a measured value of 520.0 (MH+).

Example 13: 1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(1,3-oxazol-2-yl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (45)

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(1,3-oxazol-2-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (45): Compound 43 (200 mg, 363.39 μmol, 1 equivalent), tributyl(oxazol-2-yl)stanane (200.0 mg, 558.5 μmol, 1.5 equivalent), CuI (8 mg, 42.0 μmol, 0.12 equivalent) and Pd( _PPh3 ) ₄ (48.0 mg, 41.5 μmol, 0.11 equivalent) were mixed in 5 mL of 1,4-dioxane in a sealed tube and then heated at 100 °C for 30 minutes under microwave irradiation. The reaction mixture was concentrated under vacuum, and the resulting residue was first purified by rapid silica gel chromatography (0–100% EtOAc/petroleum ether) and then purified by preparative HPLC to give compound 45 (81.5 mg, 41.3% yield). ^¹H NMR (400MHz, _CDCl₃ ) δ 9.36 (s, 1H), 8.98 (s, 1H), 8.75 (br s, 1H), 8.63 (d, 1H), 7.82 (s, 1H), 7.65 (d, 2H), 7.57 (s, 1H), 7.48 (dd, 2H), 7.36 (s, 1H), 7.19 (d, 2H), 7.06 (t, 2H), 6.46 (d, 1H), 4.13 (s, 3H), 1.77–1.74 (m, 2H), 1.73–1.69 (m, 2H); MS ( _EI ) _{was C₃₀H₂₃FN₄O₅} , measured value _539.1 (MH⁺).

Example 14: 1-N'-(4-fluorophenyl)-1-N-[4-[7-(2-hydroxyethoxy)-6-(1,3-oxazol-2-yl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (50)

6-Bromo-4-chloroquinoline-7-ol (46): A mixture of compound 42 (5 g, 18.35 mmol, 1 equivalent) and BBr ₃ (13.00 g, 51.89 mmol, 5 mL, 2.83 equivalent) in a DCE (15 mL) was stirred at 90 °C for 2.5 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and poured into a saturated aqueous solution of NaHCO ₃ with vigorous stirring. The resulting residue was filtered, washed with water, dissolved in methyl tert-butyl ether, and dried. The solvent was removed under reduced pressure to give compound 46 (7 g), which could be used in subsequent reactions without further purification. ^¹H NMR (400MHz, DMSO- _d₆ ) δ 9.03 (d, ¹H), 8.49 (s, ¹H), 7.93 (d, ¹H), 7.69 (s, ¹H), 6.08 (s, ¹H); MS _{(EI) was C₉H₅BrClNO ,} measured value 260.2 (MH⁺).

6-Bromo-7-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-chloroquinoline (47): _K₂CO₃ (1.05 g, 7.60 mmol, 1 equivalent) and NaI (720 mg, 4.80 mmol, 1.24 equivalent) were added to a mixture of compound ₄₆ (1 g, 3.87 mmol, 1 equivalent) and 2-bromoethoxy-tert-butyl-dimethylsilane (1.15 g, 4.80 mmol, 1.24 equivalent) in DMF (10 mL), and the mixture was heated to 80 °C for 2 hours with stirring. The reaction mixture was partitioned between water (20 mL) and EtOAc (2 x 20 mL). The combined organic phases were washed with saturated aqueous NaCl solution (10 mL), _dried over anhydrous _Na₂SO₄ , and concentrated. The residue was purified by rapid silica gel chromatography (12 g silica gel column, eluent gradient of 0% to approximately 20% EtOAc/petroleum ether, flow rate of 30 mL/min) to give compound 47 (560 mg, 34.73% yield). ^¹H NMR (400 MHz, _CDCl₃ ) δ 8.71 (d, 1H), 8.45 (s, 1H), 7.47 (s, 1H), 7.37 (d, 1H), 4.29–4.26 (m, 2H), 4.13–4.11 (m, 2H), 0.93–0.92 (m, 9H _{), 0.16–0.14 (m, 6H); MS (EI) was C₁₇H₂₃BrClNO₂Si , measured} value 417.8 (MH⁺).

N-(4-((6-bromo-7-(2-((tert-butyldimethylsilyl)oxy)ethoxy)quinoline-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (48): Compound 48 was prepared in a similar manner to the preparation of compound 43 from compound 42 in Example 12. Compound 48 was recovered (400 mg, 48% yield). ^¹H NMR (400MHz, DMSO- _d₆ ) δ 10.20 (s, 1H), 10.01 (s, 1H), 8.63 (d, 1H), 8.47 (s, 1H), 7.77 (d, 2H), 7.65–7.62 (m, 2H), 7.55 (s, 1H), 7.25 (d, 2H), 7.17–7.13 (m, 2H), 6.46 (d, 1H), 4.32–4.30 (t, 2H), 4.05–4.03 (t, 2H), 1.47 (s, 4H), 0.88 (s, 9H), _{0.10 (s, 6H); MS (EI) was C₃₄H₃₇BrFN₃O₅Si , measured value} 696.1 (MH⁺).

N-(4-((7-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-(oxazol-2-yl)quinoline-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (49): Compound 49 was prepared in a manner similar to that used in the preparation of compound 45 from compound 43 in Example 13. Compound 49 was recovered (400 mg, crude). ^¹H NMR (400MHz, _CDCl₃ ) δ 10.20 (s, 1H), 10.06 (s, 1H), 8.74 (s, 1H), 8.67 (d, 1H), 8.25 (s, 1H), 7.78 (d, 2H), 7.62–7.59 (m, 3H), 7.43 (s, 1H), 7.28 (d, 2H), 7.19–7.09 (m, 2H), 6.48 (d, 1H), 4.41–4.25 (m, 2H), 4.04–4.02 (m, 2H), 1.47 (s, 4H), 0.83 (s, 9H), 0.02 (s, _6H ); MS (EI) was _{C₃₇H₃ ₹ FN₄O₆Si} , measured value 683.3 (MH⁺).

1-N'-(4-fluorophenyl)-1-N-[4-[7-(2-hydroxyethoxy)-6-(1,3-oxazol-2-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (50): Tetrabutylammonium fluoride (1M, 1.40mL, 2.73 equivalents) was added to a mixture of compound 49 (350mg, 512.6μmol, 1 equivalent) in THF (20mL), and the resulting reaction mixture was stirred at 0-20°C for 0.5h, and then poured into a saturated aqueous solution of _NaHCO3 under vigorous stirring. The resulting mixture was partitioned between water (20mL) and EtOAc (2 x 20mL). The combined organic phases were separated, washed with a saturated aqueous solution of NaCl (10mL), _dried over anhydrous _Na2SO4 , and concentrated. The residue was recrystallized with MeOH to give compound 50 (174.3 mg, 58.6% yield). ^1H NMR (400MHz, DMSO- _d₆ ) δ 10.20(s, 1H), 10.06(s, 1H), 8.77(s, 1H), 8.67(d, 1H), 8.30(s, 1H), 7.78(d, 2H), 7.66–7.63(m, 3H), 7.45(s, 1H), 7.28(d, 2H), 7.17–7.13(m, 2H), 6.47(d, 1H), 4.97–4.94(t, 1H), 4.32–4.30(t, 2H), 3.86–3.82(m, 2H), _{1.47(s, 4H); MS (EI) was C₃¹H₂₅FN₄O₆ , measured value} 569.2 (MH⁺).

Example 15: 1-N-[4-(6-dimethylphosphoryl-7-methoxyquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (51)

1-N-[4-(6-dimethylphosphoryl-7-methoxyquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (51): Methylphosphonomethane (21.27 mg, 272.5 μmol, 1.5 equivalent), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthocyanin (Xantphos) (21.03 mg, 36.3 μmol, 0.2 equivalent), tris(dibenzylideneacetone)dipalladium (0) (Pd ₂ (dba) ₃ ) (33.28 mg, 36.3 μmol, 0.2 equivalent) and Et ₃ were added to a dioxane (2 mL) solution of compound 43 (100 mg, 181.7 μmol, 1 equivalent). N (91.93 mg, 908.5 μmol, 126.5 μL, 5 equivalents). The resulting mixture was stirred at 110 °C for 1 h under a nitrogen atmosphere. The mixture was concentrated under vacuum and ground with EtOH (5 mL). The resulting residue was filtered, dried, and passed by preparative HPLC (YMC-Actus Triart C18 150*30 mm*5 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 20%-60%, 10 min) to give compound 51 (26.2 mg, 26.34% yield, 100% purity). ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.24 (s, ¹H), 10.10 (s, ¹H), 8.76 (d, ¹H), 8.69 (d, ¹H), 7.80 (d, 2H), 7.65 (dd, 2H), 7.52 (d, 1H), 7.28 (d, 2H), 7.16 (t, 2H), 6.48 (d, 1H), 4.04 (s, 3H), 1.75 (s, 3H), 1.72 (s, 3H), 1.48 ( _s , 4H); MS (EI) was _{C₂ ₹ H₂₇FN₃O₅P} , measured value 548.1 (MH⁺).

Example 16: Methyl 4-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylamino)phenoxy)quinoline-6-carboxylic acid ester (56)

4-(((2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-yl)methyl)amino)methyl benzoate (53): Compound 53 was synthesized from compounds 52 and 39 in a manner similar to that used in the preparation of compound 40 from compounds 38 and 39 in Example 12. Compound 53 was obtained (9 g, 89.1% yield). ^¹H NMR (400 MHz, _CDCl₃ ) δ 11.32 (br d, 1H), 8.70 (d, 1H), 8.13 (d, 2H), 7.31 (d, 2H), 3.94 (s, 3H), 1.77 (s, 6H).

4-O-1,4-Dihydroquinoline-6-carboxylic acid methyl ester (54): Compound 54 was synthesized from compound 53 in a manner similar to that used in the preparation of compound 41 from compound 40 in Example 12. Compound 54 (1.3 g, crude product) was obtained. ^¹H NMR (400 MHz, DMSO- _d⁶ ) δ 12.03 (s, ¹H), 8.74–8.64 (m, ¹H), 8.14 (dd, ¹H), 8.01–7.93 (m, ¹H), 7.64–7.58 (m, ¹H), 6.11 (d, ¹H), 3.88 (s, ³H).

4-Chloroquinoline-6-carboxylic acid methyl ester (55): Compound 55 was synthesized from compound 54 in a manner similar to that used in the preparation of compound 42 from compound 41 in Example 12. Compound 55 was obtained (0.5 g, 35.3% yield). ^¹H NMR (400 MHz, _CDCl₃ ) δ 9.00 (d, 1H), 8.89 (d, 1H), 8.38 (dd, 1H), 8.19 (d, 1H), 7.58 (d, 1H), 4.03 (s, _{3H); MS (EI) was C₁₁H₈ClNO₂ ,} measured _221.9 (MH⁺).

4-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylamino)phenoxy)quinoline-6-carboxylic acid methyl ester 56: Compound 56 was synthesized from compounds 55 and 3 in a manner similar to that used in the preparation of compound 43 from compounds 42 and 3 in Example 12. Compound 56 was obtained (0.9 g, 99.8% yield). _MS (EI) was _C28H22FN3O5 , _and the measured value _was 500.4 (MH+).

Example 17: 4-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylamino)phenoxy)quinoline-6-carboxylic acid (57)

4-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylamino)phenoxy)quinoline-6-carboxylic acid (57): Compound 57 was synthesized from compound 56 in a manner similar to that used in the preparation of compound 6 from compound 5 in Example 2. Compound 57 was obtained (0.5 g, 57.2% yield). _MS (EI) was _C27H20FN3O5 , _and the measured value _was 486.0 (MH+).

Example 18: 1-N-[4-(6-carbamoylquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (58)

N-(4-((6-carbamoylquinoline-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (58): Compound 58 was synthesized from compound 57 in a manner similar to that used in the preparation of compound 7 from compound 6 in Example 3. Compound 58 was obtained (26 mg, 26.0% yield). ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.22 (s, ¹H), 10.06 (s, ¹H), 8.90 (d, ¹H), 8.74 (d, ¹H), 8.34 (br s, ¹H), 8.26 (dd, ¹H), 8.06 (d, ¹H), 7.80 (d, 2H), 7.64 (dd, 2H), 7.56 (br s, ¹H), 7.29 (d, 2H), 7.15 (t, 2H), 6.61 (d, 1H) _{, 1.48 (s, 4H); MS (EI) was C₂₇H₂₁FN₄O₄ , measured value} 485.1 (MH⁺).

Example 19: 1-N'-(4-fluorophenyl)-1-N-[4-[6-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (59)

1-N'-(4-fluorophenyl)-1-N-[4-[6-(methylcarbamoyl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (59): Compound 59 was synthesized from compound 58 in a manner similar to that used in the preparation of compound 8 from compound 6 in Example 4. Compound 59 was obtained (31.1 mg, 30.3% yield). ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.22 (s, ¹H), 10.05 (s, ¹H), 8.86 (d, ¹H), 8.81 (br d, ¹H), 8.74 (d, ¹H), 8.23 (dd, ¹H), 8.07 (d, ¹H), 7.80 (d, 2H), 7.64 (dd, 2H), 7.29 (d, 2H), 7.15 (t, 2H), 6.61 (d, 1H), 2.85 (d, 3H) _, 1.48 (s, 4H); MS (EI) was _{C₂₈H₂₃FN₄O₄} , measured _{value 499.1} (MH⁺).

The following compounds were prepared using a method similar to that used in the preparation of compound 59 in Example 19:

1-N'-(4-fluorophenyl)-1-N-[4-[6-[(1-methylazacyclobutane-3-yl)carbamoyl]quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (60): ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.23 (s, 1H), 10.05 (s, 1H), 9.23–9.14 (m, 1H), 8.89 (s, 1H), 8.75 (d, 1H), 8.25 (d, 1H), 8.08 (d, 1H), 7.81 (br⁶) d,2H), 7.68-7.62(m,2H), 7.30(d,2H), 7.16(t,2H), 6.61(d,1H), 4.60-4.44(m,1H), 3.69-3.60(m,2H), 3.31(s,3H), 3.20-3.09(m,2H), 1.48(s,4H); MS( _{EI )} is _C31H28FN5O4 , measured value _554.1 (MH+).

Example 20: Methyl 7-fluoro-4-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylammono)phenoxy)quinoline-6-carboxylic acid ester (65)

4-(((2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-yl)methyl)amino)-2-fluorobenzoate (62): Compound 62 was synthesized from compounds 61 and 39 in a manner similar to that used in the preparation of compound 40 from compounds 38 and 39 in Example 12. Compound 62 was given (4.8 g, 50.2% yield). ^¹H NMR (400 MHz, DMSO- _d⁶ ) δ 11.28 (s, 1H), 8.65 (s, 1H), 7.91 (t, 1H), 7.72 (dd, 1H), 7.52 (dd, 1H), 3.84 (s, 3H), 1.68 (s, 6H).

7-Fluoro-4-oxo-1,4-dihydroquinoline-6-carboxylic acid methyl ester (63): Compound 63 was synthesized from compound 62 in a manner similar to that used in the preparation of compound 41 from compound 40 in Example 12. Compound 63 was obtained (0.8 g, 58.5% yield). _{MS (EI) was C11H8FNO3 , and} the measured value was 222.2 (MH+).

4-Chloro-7-fluoroquinoline-6-carboxylic acid methyl ester (64): Compound 64 was synthesized from compound 63 in a manner similar to that used in the preparation of compound 42 from compound 41 in Example 12. Compound 64 was obtained (110 mg, ₃₁ % yield). ^¹H NMR (400 MHz, _CDCl₃ ) δ 8.90 (d, 1H), 8.85 (d, 1H), 7.84 (d, 1H), 7.53 (d, 1H), 4.03 (s, 3H); MS (EI ₎ was _{C₁₁H₇ClFNO₂} , measured 240.0 (MH⁺).

4-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylamino)phenoxy)quinoline-6-carboxylic acid methyl ester (65): Compound 65 was synthesized from compounds 64 and 3 in a manner similar to that used in the preparation of compound 43 from compounds 42 and 3 in Example 12. Compound 65 was obtained (90 mg, 92.6% yield). _MS (EI) was _C28H21F2N3O5 , _and the measured value _was 518.3 ₍ MH+).

Example 21: 7-Fluoro-4-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylamino)phenoxy)quinoline-6-carboxylic acid (66)

7-Fluoro-4-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylamino)phenoxy)quinoline-6-carboxylic acid (66): Compound 66 was synthesized from compound 65 in a manner similar to that used in the preparation of compound 6 from compound 5 in Example 2. Compound 66 was obtained (50 _mg , 57.1% yield). _{MS (} EI) was _C27H19F2N3O5 , and the measured value _was 504.4 (MH+).

Example 22: 1-N-[4-(6-carbamoyl-7-fluoroquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (67)

1-N-[4-(6-carbamoyl-7-fluoroquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (67): Compound 67 was synthesized from compound 66 in a manner similar to that used in the preparation of compound 7 from compound 6 in Example 3. Compound 67 was obtained (7.6 mg, 15.2% yield). ^¹H NMR (400MHz, _CDCl₃ ) δ 9.47 (s, ¹H), 9.24 (d, ¹H), 8.84 (s, ¹H), 8.71 (d, ¹H), 7.79 (d, ¹H), 7.67 (d, 2H), 7.48 (dd, 2H), 7.15 (d, 2H), 7.04 ( _t , 2H), 6.86 (d, ¹H), 6.54 (d, 1H), 6.06 (s, ¹H), _{1.76 -1.68 (m, 4H); MS (EI) was C₂₇H₂₀F₂N₄O₄ , measured} value _503.1 (MH⁺).

By using a similar sequence to that used in the preparation of compound 67 from compound 61 in Examples 20 to 22, and replacing compound 61 with a suitable methyl 4-amino-2-halobenzoate, the following compounds were prepared:

1-N-[4-(6-carbamoyl-7-chloroquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (68): ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.23 (s, 1H), 10.05 (s, 1H), 8.75 (d, 1H), 8.35 (s, 1H), 8.14 (s, 2H), 7.88–7.73 (m, 3H), 7.64 (dd, 2H), 7.27 (d, 2H), 7.15 (t, 2H), 6.64 (d, _1H ), _1.47 (s, _4H ); MS (EI) was _{C₂₇H₂₀ClFN₄O₄} , measured value 519.4 (MH⁺).

1-N-[4-(7-bromo-6-carbamoylquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (69): ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.24 (br s, 1H), 10.07 (br s, 1H), 8.75 (d, 1H), 8.30 (d, 2H), 8.14 (br s, 1H), 7.80 (d, 2H), 7.64-7.67 (m, 2H), 7.27 (d, 2H), 7.18 ( _t , 3H), 6.65 (d, 1H), _{1.48 (s, 4H); MS (EI) was C₂₇H₂₀BrFN₄O₄ ,} measured value _563.3 (MH⁺).

Example 23: 1-N-[4-[6-carbamoyl-7-(2-methoxyethylamino)quinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (70)

1-N-[4-[6-carbamoyl-7-(2-methoxyethylamino)quinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (70): Di[(Z)-1-methyl- ₃ -oxo-but-1-enoxy]copper (70.62 mg, 269.80 μmol, 0.8 equivalent) was added to a mixture of compound 69 (200 mg, 337.25 μmol, 1 equivalent), 2-methoxyethane-1-amine (50.66 mg, 674.51 μmol, 2 equivalent) and _K₂CO₃ (93.22 mg, 674.51 μmol, 2 equivalent) in DMF (10 mL) under nitrogen atmosphere at 10 °C. The resulting mixture was stirred at 100 °C for 2 h under nitrogen atmosphere. Heating was stopped, and once the reaction mixture reached ambient temperature, it was quenched with saturated _NH₄OH aqueous solution (50 mL) and extracted with EtOAc (3 x 30 mL). The combined extracts were dried over _{anhydrous Na₂SO₄} , filtered, and concentrated. The residue was purified by preparative HPLC to give compound 70 (22.2 mg, 11.33% yield). ^¹H NMR (400MHz, _CD₃OD ) δ 8.62 (s, ¹H), 8.43 (d, ¹H), 7.72 (d, 2H), 7.56 (dd, 2H), 7.23 (d, 2H), 7.07 (t, 2H), 6.99 (s, ¹H), 6.32 (d, ¹H), 3.72 (t, 2H), 3.43 (s, 5H), 1.64 (s, 4H); MS (EI) was _{C₃₀H₂₈FN₅O₅ , measured value} 558.1 (MH⁺).

The following compounds were prepared using a method similar to that used for compound 70 in Example 23:

1-N-[4-[6-carbamoyl-7-(3-morpholin-4-ylpropylamino)quinolin-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (71): ^¹H NMR (400MHz, _CD₃OD ) δ 8.60 (s, 1H), 8.42 (d, 1H), 7.71 (d, 2H), 7.59–7.53 (m, 2H), 7.22 (d, 2H), 7.07 (t, 2H), 6.97 (s, 1H), 6.30 (d, 1H), 3.73 (t, 4H), 3.38–3.33 (m, 2H), 2.61–2.45 (m, 6H), 2.00–1.91 (m, 2H), 1.64 (s, 4H); MS (EI) was C₁₀. ₃₄ H ₃₅ FN ₆ O ₅ , measured value 627.2 (MH+).

1-N-[4-[7-(azacyclobutan-1-yl)-6-carbamoylquinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (72): ^¹H NMR (400MHz, _CD₃OD ) δ 8.46 (d, 1H), 8.32 (s, 1H), 7.71 (d, 2H), 7.59–7.53 (m, 2H), 7.21 (d, 2H), 7.11–7.04 (m, 2H), 6.86 (s, 1H), 6.37 (d, 1H), 4.11 (t, 4H), 2.42 (m, 2H), 1.64 (s, 4H); MS (EI) was _{C₃₀H₂₆FN₅O₄ ,} measured value _540.1 ( _MH⁺ ).

Example 24: Ethyl 7-bromo-4-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylamino)phenoxy)quinoline-6-carboxylic acid ester (79)

Ethyl 2-bromo-4-nitrobenzoate (74): _H₂SO₄ (7.81 g, 79.67 mmol, 1 equivalent) was added to a solution of compound ₇₃ (20.0 g, 79.67 mmol, 1 equivalent) in EtOH (78.80 g, 1.71 mol, 100.00 mL, 21.47 equivalent), and the reaction was stirred at 80 °C for 24 h. The reaction mixture was concentrated, and the residue was partitioned between water (200 mL) and DCM (100 mL). The phases were separated, and the aqueous phase was extracted with DCM (3 x 100 mL). The combined organic phases were dried over _{anhydrous Na₂SO₄} and concentrated under vacuum to give compound 74 (21.0 g, 91.37% yield). ^¹H NMR (400MHz, DMSO- _d₆ ) δ 8.52–8.47 (m, ¹H), 8.33–8.28 (m, ¹H), 7.97 (d, ¹H), 4.38 (q, 2H), 1.34 (t, 3H); MS _{(EI) was C₉H₈BrNO₄ , measured} value 274.0 (MH⁺).

Ethyl 4-amino-2-bromobenzoate (75): Iron (2.03 g, 36.4 mmol, 2.1 equivalents) and NH₄Cl (1.95 g, 36.4 mmol, 1.27 mL, 2.1 equivalents) were added to a solution of compound ₇₄ (2, 5.00 g, 17.3 mmol, 1 equivalent) in EtOH (22 mL), THF (22 mL), and water (11 mL) with stirring. The reaction mixture was heated to 80 °C for 3 hours. The reaction was repeated in exactly the same manner as using 16.0 g of compound 74. The two reactants were combined and filtered, and the filter cake was washed with EtOH (3 x 30 mL) and EtOAc (3 x 30 mL). The filtrate was concentrated and diluted with a saturated aqueous solution of _NaHCO₃ (200 mL) to ensure pH was about 8, and extracted with EtOAc (3 x 150 mL). The combined extracts were dried _over anhydrous _Na₂SO₄ and concentrated to give a crude product (19 g). The crude product was suspended in EtOAc (5 mL) and petroleum ether (25 mL) and stirred at room temperature for 20 min. The precipitate was collected by filtration and washed with petroleum ether (2 x 10 mL) to give compound 75 (16.0 g, 85.54% yield, 95% purity). ^¹H NMR (400 MHz, DMSO- _d₆ ) δ 7.62 (d, 1H), 6.84 (d, 1H), 6.54 (dd, 1H), 6.13 (s, 2H), 4.19 (q, _2H ), 1.27 (t, 3H); MS (EI) _{C₉H₁₀BrNO₂} , _243.9 (MH⁺).

2-Bromo-4-(((2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-ylidene)methyl)amino)ethyl benzoate (76): Compound 76 was synthesized from compounds 75 and 39 in a manner similar to that used in the preparation of compound 40 from compounds 38 and 39 in Example 12. Compound 76 was obtained (23 g, 88.1% yield). ^¹H NMR (400 MHz, _CDCl₃ ) δ 11.23 (d, 1H), 8.63 (d, 1H), 7.92 (d, 1H), 7.56 (d, 1H), 7.23 (dd, 1H), 4.40 (q, 2H), 1.76 (s, 6H), 1.41 (t, 3H).

7-Bromo-4-oxo-1,4-dihydroquinoline-6-carboxylic acid ethyl ester (77): Compound 77 was synthesized from compound 76 in a manner similar to that used in the preparation of compound 41 from compound 40 in Example 12. Compound 77 (20 g, 94.4% yield, 60% purity) was obtained and used in subsequent reactions without further purification. _{MS (EI) was C12H10BrNO3 ,} measured at _296.0 (MH+).

7-Bromo-4-chloroquinoline 6-carboxylic acid ethyl ester (78): Compound 78 was prepared from compound 77 as described in Example 12 for compound 42, except that pure _POCl3 was used instead. The reaction was carried out in MeCN with 4.21 equivalents of _POCl3 at 90 °C for 1.5 h (4.2 g, 33% yield). ^¹H NMR ( ₄₀₀ MHz, _CD₃OD ) δ 8.84 (d, 1H), 8.62 (s, 1H), 8.45 (s, 1H), 7.55 (d, 1H), 4.50 (q, 2H), 1.47 (t, 3H); MS (EI _{) C₁₂H₉BrClNO₂} , measured 313.8 (MH⁺).

7-Bromo-4-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylammono)phenoxy)quinoline-6-carboxylic acid ethyl ester (79): Compound 79 was prepared from compounds 78 and 3 as described in Example 12 for compound 43, except that cesium carbonate was used instead of potassium tert-butoxide and the reaction mixture was heated only to 50°C (6.7 g, 80.5% yield). ^¹H NMR (400MHz, _CD₃OD ) δ 9.55 (s, ¹H), 8.79 (s, ¹H), 8.70 (d, ¹H), 8.55 (s, ¹H), 8.40 (s, ¹H), 7.67 (d, 2H), 7.47 (dd, 2H), 7.18 (d, 2H), 7.06 (t, 2H), 6.56 (d, 1H), 4.48 (q, 2H), 1.79–1.73 ( _{m, 2H), 1.68–1.62 (m, 2H), 1.46 (t, 3H); MS (EI) was C₂₹H₂₃BrFN₃O₅ , measured} value _592.0 (MH⁺).

Example 25: 4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-7-(methylamino)quinoline-6-carboxylic acid (81)

Ethyl 4-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylamino)phenoxy)-7-(methylamino)quinoline-6-carboxylic acid (80): Pd₂(dba)₃ (440.54 mg, 481.08 μmol, 0.3 equivalent) was added to a mixture of compound 79 (1.00 g, 1.60 mmol, 1 equivalent), methylamine hydrogen chloride (216.55 _mg , 3.21 mmol, 2 equivalents), _Cs₂CO₃ (1.57 g, 4.81 mmol, 3 equivalents), and Xantphos (556.73 _mg , 962.17 μmol, 0.6 equivalents) in _1,4 -dioxane (25 mL) at 10 °C under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 3 h under a nitrogen atmosphere. The reaction mixture was cooled, then diluted with water (50 mL) and EtOAc (50 mL), neutralized with saturated _NH₄Cl aqueous solution to pH approximately 8, and filtered. The filter cake was washed with EtOAc. The phases of the filtrate were separated, and the aqueous phase was extracted with EtOAc (3 x 30 mL). The combined EtOAc phases were dried over _{anhydrous Na₂SO₄} and concentrated. The residue was purified by rapid silica gel chromatography (0–80% EtOAc: petroleum ether, then 0–15% EtOH in DCM solution), followed by further purification by preparative HPLC to give compound 80 (250 mg, 27.30% yield). ^¹H NMR (400MHz, _CDCl₃ ) δ 10.27 (s, 1H), 9.00 (s, 2H), 8.42 (s, 2H), 7.80 (d, 2H), 7.51 (dd, 2H), 7.39 (s, 1H), 7.17 (d, 2H), 7.03 (t, 2H), 6.38 (d, 1H), 4.44 (q, 2H), 3.11 (s, 3H), 1.85 (s, 2H), 1.73 (s, 2H), _{1.48–1.43 (m, 3H); MS (EI) was C₃₀H₂₇FN₄O₅ ,} measured value _543.1 ( _MH⁺ ).

4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-7-(methylamino)quinoline-6-carboxylic acid (81): A mixture of compound 80 (250 mg, 437.4 μmol, 1 equivalent) and lithium hydroxide:hydrate (183.69 mg, 4.38 mmol, 10 equivalent) in THF (10.0 mL) and water (10.0 mL) was stirred at 10 °C for 20 h. The reactants were diluted with water (40 mL), acidified to pH 6 with saturated _NH4Cl aqueous solution, and extracted with EtOAc (4 x 40 mL). The combined extracts were dried over _{anhydrous Na₂SO₄} and concentrated under reduced pressure to obtain a crude product, which was then purified by preparative HPLC (column: Ultimate C18 150*25mm*5μm; mobile phase: [water (0.05% HCl)-ACN]; B%: 16%-46%, 9.5 min) to give compound 81HCl salt (120 mg, 47.3% yield). ^¹H NMR (400MHz, _CD₃OD ) δ 9.13 (s, ¹H), 8.57 (d, ¹H), 7.81 (d, 2H), 7.56 (dd, 2H), 7.34 (d, 2H), 7.07 (t, 2H), 6.88 (s, ¹H), 6.61 (d, 1H), 3.07 (s, 3H), 1.66 (s _, 4H); MS (EI) was _{C₂₈H₂₃FN₄O₅ ,} measured value _515.1 (MH⁺).

Example 26: 1-N-[4-[6-carbamoyl-7-(methylamino)quinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (82)

1-N-[4-[6-carbamoyl-7-(methylamino)quinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (82): Compound 82 (29.9 mg, 24% yield) was synthesized from compound 81 in a manner similar to that used in the preparation of compound 7 from compound 6 in Example 3. ^¹H NMR (400MHz, _CD₃OD ) δ 8.61 (s, ¹H), 8.43 (d, ¹H), 7.72 (d, 2H), 7.59–7.54 (m, 2H), 7.23 (d, 2H), 7.07 (t, 2H), 6.94 (s, ¹H), 6.31 (d, ¹H), 2.97 (s, 3H), 1.64 ( _s , 4H); MS (EI) was _{C₂₈H₂₄FN₅O₄ ,} measured value _514.1 (MH⁺).

Example 27: 1-N'-(4-fluorophenyl)-1-N-[4-[7-(methylamino)-6-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (83)

1-N'-(4-fluorophenyl)-1-N-[4-[7-(methylamino)-6-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (83): Compound 83 (33.3 mg, 26% yield) was synthesized from compound 81 in a manner similar to that used in the preparation of compound 8 from compound 6 in Example 4. ^¹H NMR (400MHz, _CD₃OD ) δ 8.47 (s, ¹H), 8.42 (d, ¹H), 7.71 (d, 2H), 7.59–7.54 (m, 2H), 7.22 (d, 2H), 7.07 (t, 2H), 6.94 (s, ¹H), 6.32 (d, ¹H), 2.96 (s, 3H), 2.92 (s, 3H), 1.64 (s, 4H); MS (EI) was _{C₂ ₹ H₂₆FN₅O₄ ,} measured value 528.1 (MH⁺).

Example 28: Methyl 4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-7-(methylamino)quinoline-6-carboxylic acid ester (84)

4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-7-(methylamino)quinoline-6-carboxylic acid methyl ester (84): TMSCHN ₂ (2M, 276.97 μL, 10 equivalents) was added to a MeOH (5 mL) solution of compound 81 (30 mg, 55.39 μmol, 1 equivalent) at 10 °C, and the reaction was stirred at 10 °C for 6 h. The reaction was repeated in the same manner with an additional 45 mg of compound 81. The reaction solutions from the two batches were combined and concentrated under vacuum. The resulting residue was purified by preparative HPLC to give compound 84 (25.5 mg, 55.16% yield). ^¹H NMR (400MHz, _CD₃OD ) δ 8.99 (s, ¹H), 8.45 (d, ¹H), 7.72 (d, 2H), 7.57 (dd, 2H), 7.23 (d, 2H), 7.07 (t, 2H), 6.97 (s, ¹H), 6.29 (d, ¹H), 3.95 (s, 3H), 3.01 (s, 3H), 1.64 (s, 4H); MS (EI) was _{C₂ ₹ H₂₅FN₄O₅ ,} measured value 529.1 (MH⁺).

Example 29: 7-((tert-butoxycarbonyl)amino)-4-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylamino)phenoxy)quinoline-6-carboxylic acid (86)

7-((tert-butoxycarbonyl)amino)-4-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylamino)phenoxy)quinoline-6-carboxylic acid ethyl ester (85): A mixture of compound 79 (1.5 g, 2.53 mmol, 1 equivalent), _NH₂Boc (355.95 mg, 3.04 mmol, 1.2 equivalent), Xantphos (586.03 mg, 1.01 mmol, 0.4 equivalent), _Pd₂ (dba) _₃ (463.72 mg, 506.40 μmol, 0.2 equivalent) and _Cs₂CO₃ ( _2.47 g, 7.60 mmol, 3 equivalent) in dioxane (20 mL) was degassed and purged three times with nitrogen, and stirred at 90 °C for 16 hours under a nitrogen atmosphere. The mixture was filtered and concentrated, and the residue was purified by rapid silica gel chromatography (10% to 100% petroleum ether solution of EtOAc) to give compound 85 (1.3 g, 79.14% yield). ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.28 (s, 1H), 10.23 (s, 1H), 10.06 (s, 1H), 8.94 (s, 1H), 8.72 (d, 1H), 8.69 (s, 1H), 7.79 (d, 2H), 7.64 (dd, 2H), 7.30 (d, 2H), 7.16 (t, 2H), 6.46 (d, 1H), 4.42 (q, 2H), 1.53 (s, 9H), 1.48 (s, 4H), 1.38 (t, _{3H); MS (EI) was C₃₄H₃₃FN₄O₇ , measured value} 629.2 (MH⁺).

7-((tert-butoxycarbonyl)amino)-4-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylamino)phenoxy)quinoline-6-carboxylic acid (86): Compound 86 (0.7 g, 82.4% yield) was synthesized from compound 85 in a manner similar to that used in Example 2 to prepare compound 6 by hydrolysis of the methyl ester of compound 5. ^¹H NMR (400MHz, _CD₃OD ) δ 9.13 (s, ¹H), 8.57 (d, ¹H), 7.81 (d, 2H), 7.56 (dd, 2H), 7.34 (d, 2H), 7.07 (t, 2H), 6.88 (s, ¹H), 6.61 (d, 1H), 3.07 (s, 3H), 1.66 ( _s , 4H); MS (EI) was _{C₃₂H₂ ₹ FN₄O₇} , measured value 601.1 (MH⁺).

Example 30: 1-N-[4-(7-amino-6-carbamoylquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (87)

1-N-[4-(7-amino-6-carbamoylquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)-cyclopropane-1,1-dicarboxamide (87): Compound 87 was synthesized from compound 86 in two steps. The first step followed a similar manner to the preparation of compound 7 from compound 6 in Example 3. Step 2 involved TFA-mediated BOC-deprotection using a standard procedure (such as the standard procedure used in Example 5), which provided the final compound 87 (41.9 mg, 35% yield in 2 steps). ^¹H NMR (400MHz, _CD₃OD ) δ 8.63 (s, ¹H), 8.43 (d, ¹H), 7.73 (d, 2H), 7.66–7.52 (m, 2H), 7.32–7.22 (m, 2H), 7.15 (s, ¹H), 7.12–7.05 (m, 2H), 6.31 (d, ¹H), 1.66 (s, _{4H); MS (EI) was C₂₇H₂₂FN₅O₄ , measured} value _500.0 (MH⁺).

Example 31: 1-N-[4-[7-amino-6-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (88)

1-N-[4-[7-amino-6-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (88): Compound 88 was synthesized from compound 86 in two steps. The first step followed a similar manner to the preparation of compound 8 from compound 6 in Example 4. Step 2 involved TFA-mediated BOC-deprotection using a standard procedure (such as the standard procedure used in Example 5), which provided the final compound 88 (50.9 mg, 42% yield in 2 steps). ^¹H NMR (400MHz, DMSO- _d₆ ) δ 10.19 (s, 1H), 10.05 (s, 1H), 8.70 (br d, 1H), 8.52–8.38 (m, 2H), 7.77 (d, 2H), 7.69–7.59 (m, 2H), 7.30–7.06 (m, 5H), 6.55 (s, 2H), 6.17 (d, 1H), 2.79 (d, _3H ), 1.48 (s, 4H); MS ( _EI ) was _{C₂₈H₂₄FN₅O₄ ,} measured value 514.1 (MH⁺).

Example 32: 7-Amino-4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]quinoline-6-carboxylic acid (89)

7-Amino-4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]quinoline-6-carboxylic acid (89): Compound 89 was synthesized from compound 86 by TFA-mediated BOC-deprotection as described in Example 5. ^¹H NMR (400 MHz, DMSO- _d⁶ ) δ 10.19 (s, 1H), 10.07 (s, 1H), 8.80 (s, 1H), 8.48 (d, 1H), 7.76 (d, 2H), 7.69–7.58 (m, 2H), 7.24 (d, 2H), 7.19–7.10 (m, 3H), 6.16 ( _{d, 1H), 1.48 (s, 4H); MS (EI) was C₂₇H₂₁FN₄O₅ , measured 501.1} (MH⁺).

Example 33: Methyl 7-amino-4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]quinoline-6-carboxylic acid ester (90)

7-Amino-4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]quinoline-6-carboxylic acid methyl ester (90): A solution of compound 89 (100 mg, 199.81 μmol, 1 equivalent) in MeOH (3 mL) and _H₂SO₄ (0.1 _mL ) was stirred at 70 °C for 40 h. The reaction was concentrated under vacuum, and the resulting residue was purified by preparative HPLC to give compound 90 (28.5 mg, 26.88% yield). ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.20 (br s, 1H), 10.07 (br s, 1H), 8.81 (s, 1H), 8.50 (d, 1H), 7.77 (br d, 2H), 7.65 (br dd, 2H), 7.25 (br d, 2H), 7.21–7.06 (m, 3H), 6.83 (s, 2H), 6.15 (d, 1H), 3.90 (s, 3H), _1.48 (s, _{4H); MS (EI) was C₂₈H₂₃FN₄O₅ ,} measured value _515.2 (MH⁺).

Example 34: N-(4-((6-carbamoyl-7-hydroxyquinoline-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (91)

N-(4-((6-carbamoyl-7-hydroxyquinoline-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (91): A mixture of compound 7 (250 mg, 485.91 μmol, 1 equivalent) and BBr ₃ (1.04 g, 4.15 mmol, 0.4 mL, 8.54 equivalent) in 1,2-dichloroethane (2 mL) was stirred at 50 °C for 1 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and poured into a saturated aqueous solution of NaHCO ₃ with vigorous stirring. The resulting residue was filtered, washed with water, then washed with methyl tert-butyl ether, and dried. The crude compound was purified by preparative HPLC to give compound 91 (69.5 mg, 27.3% yield). ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 12.91 (s, 1H), 10.20 (s, 1H), 10.04 (s, 1H), 8.97 (s, 1H), 8.84 (s, 1H), 8.60–8.59 (d, 1H), 7.79 (s, 1H), 7.77–7.64 (d, 2H), 7.63–7.62 (d, 2H), 7.30–7.26 (m, 3H), 7.17–7.13 (m, 2H), 6.63–6.33 (d, 1H), _1.47 (s, _{4H )} ; MS (EI) was _{C₂₇H₂₁FN₄O₅} , measured value 501.1 (MH⁺).

Example 35: 1-N'-(4-fluorophenyl)-1-N-[4-[(2-methyl-4-oxo-2,3-dihydropyrido[3,2-g][1,3]benzoxazin-6-yl)oxy]phenyl]cyclopropane-1,1-dicarboxamide (92)

1-N'-(4-fluorophenyl)-1-N-[4-[(2-methyl-4-oxo-2,3-dihydropyridino[3,2-g][1,3]benzoxazin-6-yl)oxy]phenyl]cyclopropane-1,1-dicarboxamide (92): _T3P (535 mg, 1.68 mmol, 0.5 mL, 6.47 equivalents) and acetaldehyde (393 mg, 8.91 mmol, 0.5 mL, 34.30 equivalents) were added to a CHCl3 ₃ (5 mL) solution of compound 91 (130 mg, 259.75 μmol, 1 equivalent). The resulting mixture was stirred at 50 °C for 3 h and then concentrated under vacuum. The residue was purified by preparative HPLC to give compound 92 (30.7 mg, 22.45% yield). ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.22 (s, ¹H), 10.07 (s, ¹H), 9.05 (s, ¹H), 8.78 (s, ¹H), 8.70 (d, ¹H), 7.72 (d, 2H), 7.65 (d, 2H), 7.50 (s, ¹H), 7.28 (d, 2H), 7.17 (d, 2H), 6.50 (d, 1H), 5.62–5.58 (m, ¹H), 1.57 (d, 3H) _{, 1.48 (s, 4H); MS (EI) was C₂⁹H₂⁻³FN₄O₅ ,} measured value _{527.2 (} MH⁺).

Example 36: 1-N-[4-[(2-ethyl-4-oxo-2,3-dihydropyrido[3,2-g][1,3]benzoxazin-6-yl)oxy]phenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (96)

4-Chloro-7-methoxyquinoline-6-carboxamide (93): _NH₃ · _H₂O (10.58 g, 75.50 mmol, 1 equivalence) was added to a mixture of compound 4 (2.00 g, 7.55 mmol, 1 equivalence) in MeOH ( _{20 mL) at 10 °C. The mixture was stirred at 70 °C for 72 h. The precipitate was collected by filtration and dried under vacuum to give compound 93 (1.30 g, 69.1% yield); MS (EI) was C₁₁H₉ClN₂O₂ , measured 237.0} (MH⁺).

4-Chloro-7-hydroxyquinoline-6-carboxamide (94): BBr ₃ (6.54 g, 26.09 mmol, 2.51 mL, 5 equivalents) was added fractionally to a mixture of compound 93 (1.30 g, 5.22 mmol, 1 equivalent) in DCM (30 mL) at 0 °C. The mixture was stirred at 0 °C for 6 h. The reaction was quenched with saturated NaHCO ₃ aqueous solution (150 _mL ) and filtered. The resulting residue was dried under vacuum to give compound 94 ( _{1.00 g, 81.77% yield). MS (EI) was C10H7ClN2O2 , and} the result was 222.8 (MH+).

6-Chloro-2-ethyl-2,3-dihydro-4H-[1,3]oxazino[5,6-g]quinoline-4-one (95): Propanal (1.60 g, 27.48 mmol, 2 mL, 3.06 equivalents) and _T3P (10.42 g, 32.76 mmol, 9.74 mL, 3.65 equivalents) were added to a CHCl3 ₃ (15 mL) solution of compound 94 (2 g, 8.98 mmol, 1 equivalent). The resulting mixture was stirred at 50 °C for 15 h, and then propanal (1.60 g, 27.48 mmol, 2 mL, 3.06 equivalents) was added, and stirring was continued at 50 °C for another 15 h. The mixture was then concentrated to remove the solvent, giving crude compound 95 (2.2 g, 85.8% yield) as a yellow solid, which was used in the next step without further purification. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 9.16 (br s, 1H), 8.87 (d, 1H), 8.66 (s, 1H), 7.72 (d, 1H), 7.62 (s, 1H), 5.45–5.47 (m, 1H), 1.38–1.44 (m, 2H), 1.06 (t, 3H); MS _{( EI )} was _{C₁₃H₁₁ClN₂O₂} , measured value 262.9 (MH⁺).

1-N-[4-[(2-ethyl-4-oxo-2,3-dihydropyrido[3,2-g][1,3]benzoxazin-6-yl)oxy]phenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (96): A chlorobenzene (10 mL) solution of compound 95 (95 mg, 361.64 μmol, 1 equivalent) and compound 3 (284.17 mg, 904.10 μmol, 2.5 equivalent) was stirred at 140 °C for 15 h. The mixture was diluted with EtOAc (60 mL) and washed with 2N NaOH (3 x 20 mL). The combined aqueous phases were extracted with EtOAc (30 mL). The combined organic phases were concentrated, and the resulting residue was purified by preparative HPLC (column: YMC-Triart Prep C18150*40mm*7um; mobile phase: [water (0.05% ammonium hydroxide v/v)-ACN]; B%: 53%-73%, 10 min) to give compound 96 as a white solid (7.1 mg, 3.6% yield). ^¹H NMR (400MHz, DMSO- _d₆ ) δ 10.23 (s, ¹H), 10.07 (s, ¹H), 9.05 (s, ¹H), 8.78 (s, ¹H), 8.69 (s, ¹H), 7.78–7.86 (m, 2H), 7.64–7.67 (m, 2H), 7.51 (s, ¹H), 7.28–7.30 (m, 2H), 7.14–7.18 (m, 2H), 6.49–6.51 (m, 1H), 5.43 (s, 1H), 1.88–1.91 (m, 2H), 1.48 (s, 4H), 1.06 (t, 3H); MS ₍ EI ₎ was _{C₃₀H₂₅FN₄O₅ ,} measured value 541.1 (MH⁺).

Example 37: 1-N-[4-[6-carbamoyl-7-(3-morpholin-4-ylpropoxy)quinolin-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (98)

4-(3-Bromopropyl)morpholine (97): 3-morpholinopropan-1-ol (2.0 g, 13.77 mmol, 1 equivalent) and PPh ₃ (4.0 g, 15.25 mmol, 1.11 equivalent) were dissolved in THF (20 mL), and the reaction mixture was cooled in an ice-water bath under nitrogen. CBr ₄ (5.0 g, 15.08 mmol, 1.09 equivalent) was added in portions over 15 minutes. After stirring for 30 minutes, the mixture was heated to 30 °C and maintained for 18 hours. The reaction was quenched with water (10 mL) and EtOAc (30 mL). The layers were separated, and the organic layer was extracted with 1N HCl (2 x 15 mL). The pH of the combined aqueous extracts was adjusted to 10⁻¹¹ with 4N NaOH. The aqueous phase was extracted with EtOAc (3 x 30 mL). The combined EtOAc extracts were dried over anhydrous _Na₂SO₄ and concentrated to give compound ₉₇ (1.8 g, 63% yield), which was used in subsequent reactions without further purification. ^¹H NMR (400 MHz, _CDCl₃ ) δ 3.72–3.69 (m, 4H), 3.49–3.46 (t, 2H), 2.50–2.43 (m, 6H), 2.06–1.99 (m, 2H).

1-N-[4-[6-carbamoyl-7-(3-morpholin-4-ylpropoxy)quinolin-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (98): Cs₂CO₃ (81.18 _mg , 249.14 μmol, 2.90 equivalent) was added to a mixture of compound 91 (45 mg, 85.87 μmol, 1 equivalent) and compound ₉₇ (53.48 mg, 257.00 μmol, 2.99 equivalent) in DMF (2 mL) under nitrogen atmosphere. The mixture was stirred at 80 °C for 2 hours. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 20 mL). The combined organic phases were separated, washed with saturated NaCl aqueous solution, _dried over anhydrous _Na₂SO₄ , concentrated, and purified by preparative HPLC to give compound 98 (16.2 mg, 29.70% yield). ^¹H NMR (400 MHz, DMSO- _d₆ ) δ 9.36 (s, 1H), 9.29–9.27 (d, 1H), 9.00 (s, 1H), 8.64–8.63 (d, 1H), 7.99–7.98 (d, 1H), 7.69–67 (d, 2H), 7.54 (s, 1H), 7.51–7.47 (m, 2H), 7.17–7.14 (d, 2H), 7.07–7.01 (m,2H), 6.46-6.45(d,1H), 5.98-5.97(d,1H), 4.40-4.37(t,2H), 3.76-3.70(m,4H), 2.26-2.58(m,2H), 2.50(s,4H), 2.20-2.13(m,2H) _, 1.74-1.70(m,4H); MS(EI) is _{C34H34FN5O6 ,} measured value _628.5 (MH+).

Example 38: 1-N-[4-[6-carbamoyl-7-(2-methoxyethoxy)quinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (103)

6-Bromo-4-chloroquinoline-7-ol (99): A mixture of compound 42 (5 g, 18.35 mmol, 1 equivalent) and BBr ₃ (13.0 g, 51.89 mmol, 5 mL, 2.83 equivalent) in 1,2-dichloroethane (15 mL) was stirred at 90 °C for 2.5 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and poured into a saturated aqueous solution of NaHCO ₃ with vigorous stirring. The resulting residue was filtered, washed with water, then washed with methyl tert-butyl ether, and dried under vacuum to give compound 99 (7 g, crude), which could be used in subsequent steps without further purification. ^¹H NMR (400MHz, DMSO- _d₆ ) δ 9.04–9.03 (d, ¹H), 8.49 (s, ¹H), 7.93–7.92 (d, ¹H), 7.69 (s, ¹H), 6.08 (s, ¹H); MS _{(EI) was C₈H₅BrClNO ,} measured value 258.2 (MH⁺).

6-Bromo-4-chloro-7-(2-methoxyethoxy)quinoline (100): A mixture of compound 99 (500 mg, 1.93 mmol, 1 equivalent), 1-bromo-2-methoxy-ethane (1.08 g, 7.73 mmol, 726.35 _μL , 4 equivalents), and _Cs₂CO₃ (1.90 g, 5.83 mmol, 3.01 equivalents) in DMF (4 mL) was stirred at 80 °C for 2 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and water (2 mL) was added. The resulting residue was filtered, washed with water, and dried under vacuum to give compound 100 (590 mg, 96% yield), which could be used in subsequent reactions without further purification. ^¹H NMR (400MHz, DMSO- _d₆ ) δ 8.80–8.79 (d, ¹H), 8.37 (s, ¹H), 7.65–7.64 (d, ¹H), 7.62 (s, ¹H), 4.39–4.37 (t, 2H), 3.79–3.77 (t, 2H), 3.37 ( _{s, 3H); MS (EI) was C₁₂H₁₁BrClNO₂ ,} measured value 315.8 ( _MH⁺ ).

N-(4-((6-bromo-7-(2-methoxyethoxy)quinoline-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (101): Compound 101 (65 mg, 69.2% yield) was synthesized from compounds 100 and 3 in a manner similar to that used in Example 12 for the preparation of compound 43 from compounds _{42 and 3.} MS (EI) was _{C29H25BrFN3O5} , and the measured value was 594.1 (MH+).

N-(4-((6-cyano-7-(2-methoxyethoxy)quinoline-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (102): Compound 101 (65 mg, 109.35 μmol, 1 equivalent) and CuCN (15 mg, 167.48 μmol, 36.59 μL, 1.53 equivalent) were mixed in N-methyl-2-pyrrolidone (NMP) (2 mL) in a sealed tube and heated at 150 °C for 45 min under microwave irradiation. The reaction mixture was partitioned between water (10 mL), _NH4OH (5 mL), and EtOAc (20 mL), the phases were separated, and the aqueous phase was further extracted with EtOAc. The combined organic phases were washed with a saturated aqueous NaCl solution, dried over anhydrous _Na₂SO₄ , and concentrated to give compound 102 (40 mg, 68% yield), which was used in subsequent steps without further purification. _MS (EI) was _{C₃₀H₂₅FN₄O₅} , _with a measured value _{of 541.5} (MH⁺).

1-N-[4-[6-carbamoyl-7-(2-methoxyethoxy)quinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (103): Compound 102 (40 mg, 74.00 μmol, 1 equivalent) and NaOH (100 mg, 2.50 mmol, 33.79 equivalent) were dissolved in DMSO (1.5 mL) and water (0.5 mL). The resulting mixture was heated at 80 °C for 1 hour. The reaction mixture was partitioned between water (10 mL) and EtOAc (20 mL) to separate the phases, and the aqueous phase was further extracted with EtOAc. The combined organic phases were washed with a saturated aqueous solution of NaCl, dried over _{anhydrous Na₂SO₄} , and concentrated. The residue was purified by rapid silica gel chromatography (50–100% EtOAc/petroleum ether) to give compound 103 (18.6 mg, 44% yield). ¹ H NMR (400MHz, CDCl ₃ )δ9.30(s,1H),9.27(s,1H),9.02(s,1H),8.64-8.63(d,1H),8.15(s,1H),7.69-7.66(d,2H),7.51-7.48(m,3H),7.17-7.15(d,2H), 7.07-7.03(m,2H),6.47-6.45(d,1H),5.92(s,1H),4.44-4.42(t,2H),3.91-3.89(t,2H),3.50(s,3H),1.75-1.68(m,4H); MS(EI) is C ₃₀ H ₂₇ FN ₄ O ₆ The measured value was 559.4 (MH+).

Example 39: 1-N-[4-[6-carbamoyl-7-(2-hydroxyethoxy)quinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (106)

Ethyl 2-((6-carbamoyl-4-chloroquinoline-7-yl)oxy)ethyl acetate (104): Ethyl ₂ -bromoethyl acetate (285.05 mg, 1.71 mmol, 187.53 μL, 2.00 equivalent) was added to a mixture of compound 94 (200 mg, 853.44 μmol, 1 equivalent) and _K₂CO₃ (589.77 mg, 4.27 mmol, 5 equivalent) in DMF (10 mL) at 10 °C. The resulting mixture was stirred at 70 °C for 1 hour. After cooling, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 30 mL). The combined extracts were washed with saturated aqueous NaCl solution (3 x 100 mL), _dried over anhydrous _Na₂SO₄ , and concentrated under vacuum to give compound 104 (220 mg, 79.33% yield). MS(EI) is _C14H13ClN2O4 , measured _{value 309.0 (} MH+).

2-((6-carbamoyl-4-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylamino)phenoxy)quinoline-7-yl)oxy)ethyl acetate (105): Compound 104 (200 mg, 615.45 μmol) was converted to compound 105 by reaction with compound 3, using a method similar to that used in the preparation of compound 43 from compounds 42 and 3 in Example 12. The resulting reaction mixture was treated with water at 100 °C for 4 hours before undergoing the conventional post-reaction treatment as described in Example 12. The resulting product was a mixture of compounds 105 and 106. The mixture was separated by rapid silica gel chromatography to give compound 105 (100 mg, 24.93% yield), which was used in the next reaction, and compound 106 (100 mg, 25.36% yield, 85% purity), which was combined with the product of the next reaction for final purification. For compound 105: MS (EI) is _C31H27FN4O7 , _and the measured value _is 587.1 ₍ MH+).

1-N-[4-[6-carbamoyl-7-(2-hydroxyethoxy)quinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (106): LiOH·H₂O (64.39 mg, _1.53 mmol, 10 equivalents) was added to a solution of compound 105 (100 mg, 153.44 μmol, 1 equivalent) separated from the previous reaction in THF (5 mL) and water (1 mL). The resulting mixture was stirred at 70 °C for 1 hour. After the reaction mixture was cooled to room temperature, it was acidified to pH about 7 with a saturated aqueous _NH₄Cl solution, diluted with water (30 mL), and extracted with EtOAc (3 x 20 mL). The combined organic phases were dried over _{anhydrous Na₂SO₄} and concentrated under vacuum to give crude compound 106 (90 mg, 91.56% yield, 85% purity). The substance was combined with compound 106, which had been isolated from the previous step, and purified by rapid silica gel chromatography. The resulting product was suspended in a 1:1 mixture of DCM:MeCN and stirred for 10 minutes. The resulting solid was filtered, washed with MeCN, then washed with DCM, and dried under vacuum to give compound 106 (65.8 mg, 38.7% yield). ^¹H NMR (400MHz, DMSO- _d₆ ) δ 10.20 (s, ¹H), 10.06 (s, ¹H), 8.83 (s, ¹H), 8.66 (d, ¹H), 7.96 (s, ¹H), 7.84 (s, ¹H), 7.78 (d, 2H), 7.64 (dd, 2H), 7.56 (s, ¹H), 7.27 (d, 2H), 7.15 (t, 2H), 6.47 (d, ¹H), 5.14 (t, ¹H), 4.32 (t, 2H), 3.86 (dd, 2H), 1.47 (s, _{4H); MS (EI) was C₂₹H₂₅FN₄O₆ , measured value} 545.1 (MH⁺).

Example 40: 1-N'-(4-fluorophenyl)-1-N-[4-[7-(2-hydroxyethoxy)-6-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (110)

4-Chloro-7-methoxy-N-methylquinoline-6-carboxamide (107): A solution of methylamine (8 M, 50 mL, 10.07 equivalents) in EtOH was added to a solution of compound 4 (10 g, 39.74 mmol, 1 equivalent) in THF (150 mL) at 30 °C, and the mixture was stirred at this temperature for 25 h. The reaction mixture was concentrated under vacuum. The residue was slurried with warm water (100 _mL ), filtered, and dried under vacuum to give _compound 107 (9 g, 90.4% yield). _MS (EI) was _C12H11ClN2O2 , measured at 251.0 (MH+).

4-Chloro-7-hydroxy-N-methylquinoline-6-carboxamide (108): Compound 108 (730 mg, 62% yield) was synthesized from compound 107 in a manner similar to that used in the preparation of compound 94 from compound 93 in _{Example 36. MS (EI) was C11H9ClN2O2 , measured} at 237.0 (MH+).

2-((4-chloro-6-(methylcarbamoyl)quinolin-7-yl)oxy)ethyl acetate (109): Compound 109 was synthesized from compound 108 in a manner similar to _that used in Example 39 for the preparation of compound 104 (200 _mg , crude) from compound 94. _MS (EI) was _C15H15ClN2O4 , measured at 323.1 (MH+).

1-N'-(4-fluorophenyl)-1-N-[4-[7-(2-hydroxyethoxy)-6-(methylcarbamoyl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (110): t-BuOK (70 mg, 623.83 μmol, 2.01 equivalents) was added to a mixture of compound 3 (107 mg, 340.43 μmol, 1.10 equivalents) and compound 109 (100 mg, 309.84 μmol, 1 equivalent) in DMSO (10 mL). The resulting mixture was heated and stirred at 100 °C for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic phases were washed with saturated NaCl aqueous solution (2 x 100 mL), _dried over anhydrous _Na₂SO₄ , and concentrated under vacuum. The residue was purified by rapid silica gel chromatography (0-20% MeOH in EtOAc solution) to obtain the crude product, which was then purified by preparative TLC (20% MeOH in DCM solution, _Rf = 0.3) to obtain compound 110 (54.8 mg, 100% purity). ^¹H NMR (400MHz, DMSO- _d₆ ) δ 10.22 (s, 1H), 10.07 (s, 1H), 8.75 (s, 1H), 8.66 (d, 1H), 8.49 (q, 1H), 7.78 (d, 2H), 7.64 (dd, 2H), 7.57 (s, 1H), 7.27 (d, 2H), 7.15 (t, 2H), 6.46 (d, 1H), 5.19 (t, 1H), 4.32 (t, 2H), 3.86 (br d, 2H), 2.87 (d, 3H), _1.47 (s, _{4H )} ; MS (EI) was _{C₃₀H₂₇FN₄O₆} , measured value 559.1 (MH⁺).

Example 41: 1-N-[4-[6-carbamoyl-7-(2-hydroxypropoxy)quinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (115)

4-Chloro-7-(2-oxopropoxy)quinoline-6-carboxamide (111): 1-Chloropropan- _{2-one (1.45 g, 15.7 mmol, 11.97 μL, 18.4 equivalents) was added to a mixture of compound 94 (200 mg, 853.4 μmol, 1 equivalent) and K₂CO₃ (} 589.76 mg, 4.27 mmol, 5 equivalents) in DMF (10 mL) at 10 °C. The reaction mixture was then stirred at 65 °C for 1 hour. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 30 mL). The combined extracts were washed with saturated aqueous NaCl solution (3 x 100 mL), _dried over anhydrous _Na₂SO₄ , and concentrated. The resulting residue was purified by rapid silica gel chromatography (0–10% MeOH in DCM solution). The resulting yellow residue was further purified by preparative HPLC (column: Waters Xbridge 150mm*25mm*5μm; mobile phase: [water (0.05% ammonium hydroxide v/v)-ACN]; B%: 17%-47%, 7.8 min) to give compound 111 (55 _mg , _30.0 % yield). _{MS (EI) was C13H11ClN2O3 ,} measured value 279.0 (MH+).

4-Chloro-7-(2-hydroxypropoxy)quinoline-6-carboxamide (112): _NaBH4 (12.90 mg, 340.88 μmol, 2 equivalents) was added to a mixture of compound 111 (50 mg, 170.44 μmol, 1 equivalent) in MeOH (10 mL) at 10 °C. The reaction mixture was then stirred at 50 °C for 1 h. The reaction mixture was quenched with saturated _NH4Cl aqueous solution (30 mL) and extracted with EtOAc/i-PrOH (v/v = 3: ₁ , 5 x ₂₀ mL). The combined extracts were dried over anhydrous _Na2SO4 and concentrated under reduced pressure to give compound ₁₁₂ (50 _mg , 99.3% yield). MS (EI) was _C13H13ClN2O3 , and the measured value was 302.8 (MH+Na) ⁺ .

1-((6-carbamoyl-4-chloroquinoline-7-yl)oxy)propyl-2-yl acetate (113): _Ac₂O (65.46 mg, 641.24 μmol, 60.06 μL, 5 equivalents) and DMAP (15.67 mg, 128.25 μmol, 1 equivalent) were added to a mixture of compound 112 (45 mg, 128.25 μmol, 1 equivalent) in DCM (10 mL) at 10 °C. The mixture was then stirred at 10 °C for 16 h. The reaction mixture was diluted with water (30 mL) and extracted with DCM (5 x 20 _mL ). The combined extracts were dried over anhydrous _Na₂SO₄ and concentrated. The residue was purified by rapid silica gel chromatography (0-3% MeOH in EtOAc solution) to give compound 113 (45 mg, 86.98% yield, 80% purity). MS ( _{EI) is C15H15ClN2O4 ,} measured value _344.8 (MH ₊ Na) ⁺ .

1-((6-carbamoyl-4-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylamino)phenoxy)quinoline-7-yl)oxy)propyl-2-yl acetate (114): Compound 114 was synthesized from compounds 113 and 3 in a manner similar to that described for compound 43 in Example 12, except that cesium carbonate was used instead of potassium tert-butoxide, and the reaction mixture was heated to 100°C for 2 _hours ( ₄₀ mg, _72.9 % yield). MS (EI) was _C32H29FN4O7 , and the measured value was 601.1 (MH+).

1-N-[4-[6-carbamoyl-7-(2-hydroxypropoxy)quinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (115): LiOH· _H₂O (26.55 mg, 632.71 μmol, 10 equivalents) was added to a solution of compound 114 (40 mg, 63.27 μmol, 1 equivalent) in THF (5 mL) and water (1 mL). The mixture was stirred at 70 °C for 1 hour. After cooling to room temperature, the reactants were diluted with DCM (30 mL), dried _over anhydrous _Na₂SO₄ , and concentrated under reduced pressure. The product was suspended in MeCN (1 mL) and stirred at 10 °C for 5 minutes. The precipitate was collected by filtration and dried under vacuum to give compound 115 (16.7 mg, 46.78% yield). ^¹H NMR (400MHz, DMSO- _d₆ ) δ 10.20 (s, 1H), 10.06 (s, 1H), 8.81 (s, 1H), 8.66 (d, 1H), 8.02 (d, 1H), 7.84 (s, 1H), 7.78 (d, 2H), 7.64 (dd, 2H), 7.54 (s, 1H), 7.27 (d, 2H), 7.15 (t, 2H), 6.47 (d, 1H), 5.15 (d, 1H), 4.27–4.21 ( _m , 1H), 4.17–4.04 (m, 2H), 1.47 (s, 4H), _{1.22 (d, 3H); MS (EI) was C₃₀H₂₇FN₄O₆ ,} measured value _559.1 (MH⁺).

Using a similar sequence to that used in the preparation of compound 115 from compound 94 in Example 41, the following compounds were prepared by replacing compound 94 with compound 108:

1-N'-(4-fluorophenyl)-1-N-[4-[7-(2-hydroxypropoxy)-6-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (116). ^¹H NMR (400MHz, DMSO- _d₆ ) δ 10.27(s, ¹H), 10.13(s, ¹H), 8.80(s, ¹H), 8.73(d, ¹H), 8.62(d, ¹H), 7.85(d, 2H), 7.71(dd, 2H), 7.62(s, ¹H), 7.33(d, 2H), 7.22(t, 2H), 6.54(d, ¹H), 5.28(d, 1H), 4.31(dd, 1H), 4.23–4.10( _m , 2H), 2.94(d, 3H), 1.54(s, 4H), _{1.29(d, 3H); MS (EI) was C₃¹H₂₉FN₄O₆ ,} measured value _573.1 (MH⁺).

Example 42: 1-N'-(4-fluorophenyl)-1-N-[4-[7-(2-hydroxypropoxy)-6-(1,3-oxazol-2-yl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (125)

4-Chloro-7-methoxyquinoline-6-carboxylic acid (117): LiOH· _H₂O (1.33 g, 31.79 mmol, 2 equivalents) was added to a solution of compound 4 (4.0 g, 15.89 mmol, 1 equivalent) in THF (30 mL) and water (6 mL), and the resulting mixture was stirred at 20 °C for 10 h. The resulting solid was filtered to give crude compound 117 as a white solid (4.4 g), which could be used in the next step without further purification. _MS (EI) was _{C₁₁H₈ClNO₃} , _with a measured value of 238.0 (MH⁺).

4-Chloro-N-(2,2-Dimethoxyethyl)-7-methoxyquinoline-6-carboxamide (118): To a THF (40 mL) solution of compound 117 (4 g, 16.83 mmol, 1 equivalent) and 2,2-dimethoxyethylamine (7.08 g, 67.33 mmol, 7.34 mL, 4 equivalents), _T3P (16.07 g, 50.50 mmol, 15.02 mL, 3 equivalents) and DIPEA (8.70 g, 67.33 mmol, 11.73 mL, 4 equivalents) were added. The resulting reaction mixture was stirred at 20 °C for 15 h. An additional ₅ mL of T3P and 3 mL of 2,2-dimethoxyethylamine were added to the mixture, and stirring was continued at 20 °C for 25 h. The mixture was quenched with water (30 mL) and the pH was adjusted to 9–10 with 1 M NaOH aqueous solution. The resulting aqueous mixture was extracted with EtOAc (3 x 40 mL). The combined organic extracts were washed with saturated NaCl aqueous solution (15 mL) and concentrated to give crude compound 118 as a white solid (4.1 _g , _73.5 % yield), which was used in the next step without further purification. _{MS (EI) was C15H17ClN2O4 ,} measured at 325.1 (MH+).

2-(4-Chloro-7-methoxyquinoline-6-yl)oxazole (119): At 20 °C under nitrogen, 2.5 g (7.70 mmol, 1 equivalent) of compound 118 was added to Eaton's Reagent (7.7 wt% phosphorus pentoxide methanesulfonic acid solution, 23.09 mmol, 46.97 mL, 3 equivalents). The resulting mixture was heated at 145 °C for 7 hours. The mixture was quenched with water (100 mL) and the pH was adjusted to 8-9 with Et ₃ N. The resulting mixture was extracted with EtOAc (4 x 40 mL). The combined organic extracts were washed with saturated NaCl aqueous solution (40 mL) and concentrated. The residue was purified by rapid silica gel chromatography (20 g silica rapid column, eluent 0–80% ethyl acetate/petroleum ether gradient @ 32 mL/min) to give compound 119 as a white solid (1.38 g, 68.8% yield). ^¹H NMR (400MHz, _CDCl₃ ) δ 8.43 (s, ¹H), 8.76 (d, ¹H), 7.86 (s, ¹H), 7.62 (s _{, ¹H), 7.42 (d, ¹H), 7.40 (s, ¹H), 4.14 (s, ³H); MS (EI) was C₁₃H₉ClN₂O₂ ,} measured value _261.0 ( _MH⁺ ).

4-Chloro-6-(oxazol-2-yl)quinoline-7 _- ol (120): Compound 120 was synthesized from compound 119 in a manner similar to that used in Example 36 for the synthesis of compound 94 from compound 93. _MS (EI ₎ was _C12H7ClN2O2 , measured at 246.7 (MH+).

1-((4-chloro-6-(oxazol-2-yl)quinolin-7-yl)oxy)prop-2-one (121): Compound 121 was synthesized from compound 120 in a manner similar to _that used in Example 41 for the synthesis of compound 111 from compound 94. _MS (EI) was _C15H11ClN2O3 , measured at _302.7 (MH+).

1-((4-chloro-6-(oxazol-2-yl)quinolin-7-yl)oxy)prop-2-ol (122): Compound 122 was synthesized from compound 121 in a manner similar to that used in Example 41 for the synthesis of compound 112 from compound 111. _{MS (EI) was C15H13ClN2O3 , and} the measured value _was 326.9 [M+Na] ⁺ .

1-((4-chloro-6-(oxazol-2-yl)quinolin-7-yl)oxy)propyl-2-ylacetate (123): Compound 123 was synthesized from compound 122 in a manner similar to that used in Example 41 for the synthesis of compound 113 from compound 112. ^¹H NMR (400 MHz, _CDCl₃ ) δ 8.83 (s, 1H), 7.23 (d, 1H), 7.83 (s, 1H), 7.54 (s, 1H), 7.40 (d, 1H), 7.34 (s, 1H), 5.41–5.49 (m, 1H), 4.25 (d, 2H), 2.06 (s, 3H), _{1.43 (d, 3H); MS (EI) was C₁₇H₁₅ClN₂O₄ , measured 347.1} (MH⁺).

1-((4-(4-(1-(((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylammono)phenoxy)-6-(oxazol-2-yl)quinoline-7-yl)oxy)propane-2-yl acetate (124): Compound 124 was synthesized from compounds 123 and 3 using a variation of the method for synthesizing compound 43 from compounds 42 and 3 in Example 12. Cesium carbonate was used instead of potassium tert-butoxide, and the reaction mixture was heated to 100°C for 3 h. _{MS (EI) was C34H29FN4O7 , and} the measured value _was 625.0 (MH+).

1-N'-(4-fluorophenyl)-1-N-[4-[7-(2-hydroxypropoxy)-6-(1,3-oxazol-2-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (125): NaOH (51.23 mg, 1.28 mmol, 2 equivalents) was added to a solution of compound 124 (400 mg, 640.4 μmol, 1 equivalent) in water (5 mL) and MeOH (5 mL), and the mixture was stirred at 20 °C for 5 hours. The mixture was diluted with water (30 mL). The resulting precipitate was filtered and washed with water (2 x 5 mL) and MeOH (3 mL). The solid was then lyophilized to give compound 125 as a white solid (238.5 mg, 63.9% yield). ^¹H NMR (400MHz, DMSO- _d₆ ) δ 10.22 (s, ¹H), 10.07 (s, ¹H), 8.79 (s, ¹H), 8.68 (d, ¹H), 8.32 (s, ¹H), 7.79 (d, 2H), 7.65 (t, 2H), 7.60 (s, 1H), 7.47 (s, 1H), 7.29 (d, 2H), 7.18 (t, 2H), 6.49 (d, 1H), 5.02 (d, 1H), 4.15–4.10 (m, 3H), 1.48 (s, 4H), _1.26 (d, _{3H); MS (EI) was C₃₂H₂₇FN₄O₆ ,} measured value _583.3 (MH⁺).

Example 43: Methyl 4-[2-chloro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-7-methoxyquinoline-6-carboxylic acid ester (128)

N-(3-chloro-4-hydroxyphenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (127): Compound 127 (1.9 g, 73.5% yield) was synthesized from compounds 1 and 126 in a manner similar to that used in Example 1 for the preparation of compound 3 from compounds 1 and 2. ^¹H NMR (400 MHz, _CDCl₃ ) δ 9.03–8.85 (m, 2H), 7.68 (d, 1H), 7.50–7.40 (m, 2H), 7.18 (dd, 1H), 7.08–7.00 (m, 2H), 6.97 (d, 1H), 5.53 (s, 1H), _1.64 (s, _{4H); MS (EI) was C₁₇H₁₄ClFN₂O₃ ,} measured _349.0 (MH⁺).

4-[2-chloro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-7-methoxyquinoline-6-carboxylic acid methyl ester (128): Compound 128 (0.8 g, 32.1% yield) was synthesized from compounds 127 and 4 in a manner similar to that used in the preparation of compound 43 from compounds 42 and 3 in Example 12. ^¹H NMR (400MHz, _CDCl₃ ) δ 10.08 (s, ¹H), 8.83 (s, ¹H), 8.63 (d, ¹H), 8.20 (s, ¹H), 7.92 (d, ¹H), 7.55–7.48 (m, 2H), 7.48–7.41 (m, 2H), 7.21 (d, 1H), 7.10–7.02 (m, 2H), 6.30 (d, 1H), 4.04 (s, 3H), 3.97 (s, 3H), 1.85–1.78 (m, 2H), 1.66–1.58 (m, _{2H); MS (EI) was C₂₹H₂₃ClFN₃O₆ , measured value} 564.4 (MH⁺).

Using a sequence similar to that used in the synthesis of compound 128 in Example 43, the following compounds were prepared in two steps, replacing compound 126 with 4-amino-2-fluorophenol:

4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-7-methoxyquinoline-6-carboxylic acid methyl ester (129): ^1H NMR (400MHz, CDCl3 ₎ δ 10.05(s,1H), 8.83(s,1H), 8.65(d,1H), 8.09(s,1H), 7.78(dd,1H), 7.50(s,1H), 7.48-7.42(m,2H), 7.27-7.19(m,2H), 7.10-7.04(m,2H), 6.40(d,1H), 4.05(s,3H), 3.97(s,3H), 1.84-1.81(m,2H), 1.63-1.60(m,2H); MS (EI) was C ₂₉ H ₂₃ F ₂ N ₃ O ₆ , measured value 548.4 (MH+).

Example 44: 4-[2-chloro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-7-methoxyquinoline-6-carboxylic acid (130)

4-[2-chloro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-7-methoxyquinoline-6-carboxylic acid (130): Compound 130 (0.55 g, 76.6% yield) was synthesized from compound 128 in a manner similar to that used in the preparation of compound 6 from compound 5 in Example 2. ^¹H NMR (400MHz, DMSO- _d₆ ) δ 10.41 (s, 1H), 10.10 (s, 1H), 8.58 (d, 1H), 8.25 (s, 1H), 8.10 (d, 1H), 7.75–7.59 (m, 3H), 7.47–7.37 (m, 2H), 7.16 (t, 2H), 6.32 (d, 1H), 3.92 ( _s , 3H), 1.47 (s, 4H); MS (EI) was _{C₂₈H₂₁ClFN₃O₆} , _{measured value} 550.1 (MH⁺).

The following compounds were prepared from compound 129 using a similar preparation method to that used in Example 44 for the synthesis of compound 130 from compound 128:

4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-7-methoxyquinoline-6-carboxylic acid (131): ^¹H NMR (400 MHz, DMSO- _d⁶ ) δ 13.20 (s, 1H), 10.42 (s, 1H), 10.01 (s, 1H), 8.72 (d, 1H), 8.59 (s, 1H), 7.93 (d, 1H), 7.64 (dd, 2H), 7.56–7.51 (m, 2H), 7.50–7.44 (m, 1H), 7.15 (t, 2H), 6.54 (d, 1H), 3.99 (s, 3H), 1.47 (d, _{4H )} ; MS ( _{EI ) C₂₈H₂₁F₂N₃O₆} The measured value was 534.4 (MH+).

Example 45: 1-N'-[4-(6-carbamoyl-7-methoxyquinoline-4-yl)oxy-3-chlorophenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (132)

1-N'-[4-(6-carbamoyl-7-methoxyquinoline-4-yl)oxy-3-chlorophenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (132): Compound 132 (43.1 mg, 40.9% yield) was synthesized from compound 130 in a manner similar to that used in the preparation of compound 7 from compound 6 in Example 3. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.38 (s, ¹H), 10.04 (s, ¹H), 8.71 (s, ¹H), 8.67 (d, ¹H), 8.11 (d, ¹H), 7.89 (br s, ¹H), 7.78 (br s, ¹H), 7.73–7.61 (m, ³H), 7.54 (s, ¹H), 7.46 (d, ¹H), 7.16 (t, ²H), 6.37 (d, ¹H), 4.04 (s, ³H) _{, 1.47 (s, ⁴H); MS (EI) was C₂₈H₂₂ClFN₄O₅ , measured value} 549.4 (MH⁺).

The following compounds were prepared from compound 131 using a method similar to that used in Example 45 for the preparation of compound 132 from compound 130:

1-N'-[4-(6-carbamoyl-7-methoxyquinoline-4-yl)oxy-3-fluorophenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (133): ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.40 (s, 1H), 10.01 (s, 1H), 8.67 (m, 2H), 7.93–7.88 (m, 2H), 7.76 (s, 1H), 7.64 (dd, _2H ), 7.53–7.52 (m, 2H), 7.47–7.43 (m, 1H), 7.15 (t, 2H), 6.48 (d, 1H), 4.03 (s, 3H), _1.47 (s, _4H ); MS (EI _{) C₂₈H₂₂F₂N₄O₅} The measured value was 533.5 (MH+).

Example 46: 1-N'-[3-chloro-4-[7-methoxy-6-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (134)

1-N'-[3-chloro-4-[7-methoxy-6-(methylcarbamoyl)quinolin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (134): Compound 134 (49.7 mg, 48.6% yield) was synthesized from compound 130 in a manner similar to that used in the preparation of compound 8 from compound 6 in Example 4. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.38 (s, ¹H), 10.04 (s, ¹H), 8.66 (d, ¹H), 8.63 (s, ¹H), 8.40 (br d, ¹H), 8.11 (d, ¹H), 7.72–7.61 (m, ³H), 7.54 (s, ¹H), 7.46 (d, ¹H), 7.20–7.12 (m, ²H), 6.37 (d, ¹H), 4.03 (s, ³H), 2.85 (d, ³H) _{, 1.48 (s, ⁴H); MS (EI) was C₂⁹H₂⁴ClFN₄O₅ ,} measured _{value 563.1} (MH⁺).

The following compounds were prepared from compound 131 using a method similar to that used in Example 46 for the preparation of compound 134 from compound 130:

1-N'-[3-fluoro-4-[7-methoxy-6-(methylcarbamoyl)quinolin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (135): ^¹H NMR (400MHz, DMSO- _d6 ) δ 10.40 (s, 1H), 10.01 (s, 1H), 8.67 (d, 1H), 8.61 (s, 1H), 8.39 (d, 1H), 7.91 (d, 1H), 7.64 (dd, 2H), 7.53–7.52 (m, 2H), 7.47–7.42 (m, 1H), 7.15 (t, 2H), 6.48 (d, 1H), 4.02 (s, 3H), 2.84 (d, 3H), 1.47 (s, 4H); MS (EI) was C6. ₂₉ H ₂₄ F ₂ N ₄ O ₅ , measured value 547.5 (MH+).

Example 47: Methyl 4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-6-methylquinoline-7-carboxylic acid ester (140)

5-(((2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-yl)methyl)amino)-2-methylbenzoate (137): Compound 137 (4.74 g, 81.7% yield) was synthesized from compounds 136 and 39 in a manner similar to that used in the preparation of compound 40 from compounds 38 and 39 in Example 12. ^¹H NMR (400 MHz, DMSO- _d⁶ ) δ 11.28 (s, ¹H), 8.53 (s, ¹H), 8.01–7.88 (d, ¹H), 7.75–7.61 (dd, ¹H), 7.45–7.30 (d, ¹H), 3.85 (s, ³H), 2.49 (s, ³H), 1.67 (s, ⁶H).

6-Methyl-4-oxo-1,4-dihydroquinoline-7-carboxylic acid methyl ester (138): Compound 138 (625 mg, 25.9% yield) was synthesized from compound 137 in a manner similar to the preparation of compound 41 from compound 40 in _{Example 12.} MS (EI) was _C12H11NO3 , and the result was 218.1 (MH+).

4-Chloro-6-methylquinoline-7-carboxylic acid methyl ester (139): Compound 139 was synthesized from compound 138 in a similar manner to that described for compound 42 in Example 12, except that compound 138 was heated in a mixture of MeCN (10 mL) and POCl ₃ (3 mL) instead of in pure POCl ₃ (445 mg, 65.6% yield). _MS (EI) was _{C12H10ClNO 2} , measured at 236.3 (MH+).

4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-6-methylquinoline-7-carboxylic acid methyl ester (140): Compound 140 (320 mg, 36.7% yield) was synthesized from compounds 139 and 3 in a similar manner to the synthesis of compound 43 from compounds 42 and 3 in Example 12. ^¹H NMR (400MHz, _CD₃OD ) δ 8.66–8.61 (d, ¹H), 8.52 (s, ¹H), 8.28 (s, ¹H), 7.78–7.71 (d, 2H), 7.60–7.54 (m, 2H), 7.28–7.22 (d, 2H), 7.11–7.03 (m, 2H), 6.71–6.67 (d, ¹H), 3.98 (s, 3H), 2.76 (s, 3H), 1.64 (s, 4H); MS (EI) was _{C₂ ₹ H₂₄FN₃O₅ ,} measured value 514.1 (MH⁺).

Example 48: 4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-6-methylquinoline-7-carboxylic acid (141)

4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-6-methylquinoline-7-carboxylic acid (141): Compound 141 (100 mg, 93.5% yield) was synthesized from compound 140 in a manner similar to that used in Example 2 for the preparation of compound 6 from compound 5. ^¹H NMR (400MHz, _CD₃OD ) δ 8.66–8.61 (d, ¹H), 8.47 (s, ¹H), 8.27 (s, ¹H), 7.78–7.73 (d, 2H), 7.78–7.71 (dd, 2H), 7.28–7.24 (d, 2H), 7.11–7.03 (t, 2H), 6.73–6.69 (d, ¹H), 2.76 (s, 3H), _1.65 (s _{, 4H); MS (EI) was C₂₈H₂₂FN₃O₅ ,} measured value _500.5 (MH⁺).

Example 49: 1-N-[4-(7-carbamoyl-6-methylquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (142)

1-N-[4-(7-carbamoyl-6-methylquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (142): Compound 142 (17.4 mg, 34.9% yield) was synthesized from compound 141 in a manner similar to that used in the preparation of compound 7 in Example 3. ^¹H NMR (400MHz, _CD₃OD ) δ 8.65–8.57 (d, ¹H), 8.26 (s, ¹H), 8.05 (s, ¹H), 7.78–7.70 (d, 2H), 7.62–7.51 (m, 2H), 7.30–7.20 (m, 2H), 7.13–7.03 (m, 2H), 6.69–6.63 (d, ¹H), 2.65 (s, 3H), 1.64 ( _s , 4H); MS (EI) was _{C₂₈H₂₃FN₄O₄ ,} measured value _499.1 (MH⁺).

Example 50: 1-N'-(4-fluorophenyl)-1-N-[4-[6-methyl-7-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (143)

1-N'-(4-fluorophenyl)-1-N-[4-[6-methyl-7-(methylcarbamoyl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (143): Compound 143 (11.9 mg, 17.8% yield) was synthesized from compound 141 in a manner similar to that used in the preparation of compound 8 in Example 4. ^1H NMR (400MHz, CD ₃ OD) δ 8.64-8.55 (d, 1H), 8.25 (s, 1H), 7.97 (s, 1H), 7.78-7.68 (d, 2H), 7.61-7.50 (m, 2H), 7.28-7.18 (d, 2H), 7.11-7.02 (m, 2H), 6.70-6.61 (d, 1H), 2.98 (s, 3H), 2.60 (s, 3H), 1.64 (s, 4H); MS (EI) was C ₂₉ H ₂₅ FN ₄ O ₄ , measured value 513.1 (MH+).

Example 51: Methyl 4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-6-methoxyquinoline-7-carboxylic acid ester (150)

Methyl 5-amino-2-methoxybenzoate (145): 10% Pd/C (500 mg) was added to a solution of compound 144 (5.00 g, 23.68 mmol, 1 equivalent) in EtOH (50 mL), and the resulting mixture was degassed and purged under _H₂ . The reaction mixture was stirred at 25 °C for 12 h under _H₂ (15 psi). The reaction mixture was filtered, and the filtrate was concentrated to give compound 145 (4.5 g, 99.6% yield), which was used in subsequent steps without further purification. ^¹H NMR (400 MHz, _CDCl₃ ) δ 7.16 (t, 1H), 6.86–6.82 (m, 2H), 3.88 (s, 3H), 3.83 (s, 3H), 3.09 (br s, 2H).

Methyl 5-(((2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-ylidene)methyl)amino)-2-methoxybenzoate (147): Compound 145 (2 g, 10.49 mmol, 1 equivalent) was added in portions to a suspension of compound 146 (1.95 g, 10.49 mmol, 1 equivalent) in isopropanol (40 mL) at 20 °C. The reaction was heated at 80 °C for 30 min. The mixture was cooled to 20 °C, and the precipitate was collected, washed with tert-butyl methyl ether (50 mL), and dried to give compound 147 (3.3 g, 93.82% yield). ¹ H NMR (400MHz, CDCl ₃ ) δ 11.25 (d, 1H), 8.57 (d, 1H), 7.75 (d, 1H), 7.37 (dd, 1H), 7.05 (d, 1H), 3.95 (s, 3H), 3.93 (s, 3H), 1.76 (s, 6H).

Methyl 6-methoxy-4-oxo-1,4-dihydroquinoline-7-carboxylic acid (148): Compound 147 (1.0 g, 2.98 mmol, 1 equivalent) was added in portions to A (a eutectic mixture of 26.5% biphenyl and 73.5% diphenyl ether) (CAS Registry No. 8004-13-5) (10 mL) at 220 °C. The reaction was stirred at 220 °C for 10 min. The reaction was cooled to 20 °C–25 °C and then diluted with petroleum ether (50 mL). The resulting residue was collected, washed with petroleum ether (3 x 30 mL), and dried to give compound 148 (800 mg, 69.07% yield, 60% purity). ¹ H NMR (400MHz, DMSO-d ₆ ) δ12.22(d,1H),7.94(d,1H),7.92(s,1H),7.61(s,1H),6.06(d,1H),3.87(s,3H),3.84(s,3H).

4-Chloro-6-methoxyquinoline-7-carboxylic acid methyl ester (149): 5 drops of DMF were added to a mixture of compound 148 (700 mg, 1.80 mmol, ₁ equivalent) in _SOCl2 (10 mL). The resulting mixture was stirred at 80 °C for 1 h. The reaction mixture was concentrated under vacuum, and the resulting residue was diluted with saturated NaHCO3 aqueous solution (20 mL) and extracted with EtOAc (3 x 30 mL). The combined organic phases were washed with saturated NaCl aqueous solution (50 mL), _dried over anhydrous _Na2SO4 , and concentrated. The residue was purified by rapid silica gel chromatography (4 g silica rapid column, eluent 0–30% EtOAc/petroleum ether gradient, flow rate 25 mL/min) to give compound 149 (220 mg, 46.14% yield, 95% purity). ^¹H NMR (400MHz, _CDCl₃ ) δ 8.71 (d, ¹H), 8.49 (s, ¹H), 7.55–7.49 (m, 2H), 4.07 (s, 3H), 3.99 (s, 3H); MS ( _{EI )} was _{C₁₂H₁₀ClNO₃} , measured value 252.3 (MH⁺).

4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxyquinoline-7-carboxylic acid methyl ester (150): Pd(OAc)2 (8 mg, 35.63 μmol, 0.05 equivalent) was added to a mixture of compound 149 (190 mg, 679.47 μmol, 1 equivalent), compound ₃ (235 mg, 747.67 μmol, 1.1 equivalent), _K3PO4 (190 mg, 895.10 μmol, 1.32 equivalent) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos) (33 mg, 69.22 μmol, 0.1 equivalent) in toluene (3 mL) and ₁ -methyl-2-pyrrolidone (0.5 mL) under nitrogen atmosphere. The reaction was stirred at 100 °C for 3 hours. The mixture was diluted with EtOAc (30 mL) and any insoluble substances were filtered off. The filtrate was diluted with water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic phases were washed with a saturated aqueous NaCl solution (50 mL), _dried over anhydrous _Na₂SO₄ , and concentrated. The residue was purified by rapid silica gel chromatography (4 g silica rapid column, eluent of 0% to approximately 50% EtOAc/petroleum ether gradient, flow rate 25 mL/min) to give compound 150 (170 mg, 46.06% yield, 97.49% purity). ^¹H NMR (400MHz, _CDCl₃ ) δ 9.46 (s, ¹H), 8.59 (d, 2H), 8.47 (s, ¹H), 7.71–7.62 (m, 3H), 7.52–7.44 (m, 2H), 7.20 (d, 2H), 7.07 (t, 2H), 6.57 (d, 1H), 4.05 (s, 3H), 3.99 (s, 3H), 1.79–1.74 (m, 2H), 1.69–1.64 (m, 2H); MS (EI ₎ was _{C₂ ₹ H₂₄FN₃O₆} , measured value 530.2 (MH⁺).

Example 52: 4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]-amino]phenoxy]-6-methoxyquinoline-7-carboxylic acid (151)

4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]-amino]phenoxy]-6-methoxyquinoline-7-carboxylic acid (151): Compound 151 (110 mg, 75.2% yield) was synthesized from compound 150 in a manner similar to that used in the preparation of compound 81 from compound 80 in Example 25. ^1H NMR (400MHz, DMSO- _d₆ ) δ 10.21 (s, 1H), 10.05 (s, 1H), 8.60 (d, 1H), 8.18 (s, 1H), 7.79 (d, 2H), 7.69–7.59 (m, _3H ), 7.27 (d, 2H), 7.15 (t, 2H), 6.60 (d, 1H), 3.97 (s, 3H), 1.53–1.42 (m, 4H); MS (EI) was _{C₂₈H₂₂FN₃O₆} , _{measured value} 516.1 (MH⁺).

Example 53: 1-N-[4-(7-carbamoyl-6-methoxyquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (152)

1-N-[4-(7-carbamoyl-6-methoxyquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (152): Compound 152 (25.6 mg, 30.7% yield) was synthesized from compound 151 in a manner similar to that used in the preparation of compound 7 from compound 6 in Example 3. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.20 (s, 1H), 10.04 (s, 1H), 8.58 (d, 1H), 8.25 (s, 1H), 7.87 (br s, 1H), 7.78 (d, 2H), 7.72 (br s, 1H), 7.67–7.60 (m, 3H), 7.26 (d, 2H), 7.15 (t, 2H), 6.58 (d, 1H), 4.01 (s, 3H), _{1.52–1.46 (m, 4H); MS (EI) was C₂₈H₂₃FN₄O₅ , measured} value _515.1 (MH⁺).

Example 54: 1-N'-(4-fluorophenyl)-1-N-[4-[6-methoxy-7-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (153)

1-N'-(4-fluorophenyl)-1-N-[4-[6-methoxy-7-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (153): Compound 153 (25.2 mg, 53.1% yield) was synthesized from compound 151 in a manner similar to that used in the preparation of compound 8 from compound 6 in Example 4. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.23 (s, ¹H), 10.07 (s, ¹H), 8.58 (d, ¹H), 8.39 (q, ¹H), 8.20 (s, ¹H), 7.79 (d, 2H), 7.69–7.60 (m, 3H), 7.26 (d, 2H), 7.15 (t, 2H), 6.58 (d, ¹H), 4.00 (s, 3H), 2.84 (d, 3H), _{1.52–1.44 (m, 4H); MS (EI) was C₂⁹H₂⁵FN₄O₅ , measured} value _529.1 (MH⁺).

Example 56: Methyl 4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]quinoline-7-carboxylic acid ester (162)

4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]quinoline-7-carboxylic acid methyl ester (162): Compound 162 (20 mg, 16% yield) was synthesized from compounds 161 and 3 in a manner similar to that used in the preparation of compound 43 from compounds 42 and 3 in Example 12. ^¹H NMR (400MHz, _CDCl₃ ) δ 9.42 (s, ¹H), 8.81 (d, ¹H), 8.75 (d, ¹H), 8.60 (br s, ¹H), 8.43 (d, ¹H), 8.19 (dd, ¹H), 7.69–7.63 (m, 2H), 7.51–7.44 (m, 2H), 7.23–7.18 (m, 2H), 7.07 (t, 2H), 6.63 (d, ¹H), 4.03 (s, 3H), 1.79–1.74 (m, 2H), _{1.69–1.65 (m, 2H); MS (EI) was C₂₈H₂₂FN₃O₅ ,} measured value _500.1 ( _MH⁺ ).

Example 57: 4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]quinoline-7-carboxylic acid (163)

4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]quinoline-7-carboxylic acid (163): Compound 163 (70 mg, 68.4% yield) was synthesized from compound 162 in a manner similar to that used in Example 2 for the preparation of compound 6 from compound 5. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.22 (s, ¹H), 10.06 (s, ¹H), 8.79 (d, ¹H), 8.58 (s, ¹H), 8.43 (d, ¹H), 8.17–8.10 (m, ¹H), 7.79 (d, 2H), 7.65 (dd, 2H), 7.29 (d, 2H), 7.16 (t, 2H), 6.69 (d, 1H), 1.48 (s, 4H); MS _{(EI) was C₂₇H₂₀FN₃O₅ , measured value} 486.1 (MH⁺).

Example 58: 1-N-[4-(7-carbamoylquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (164)

1-N-[4-(7-carbamoylquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)-cyclopropane-1,1-dicarboxamide (164): Compound 164 (17.7 mg, 56.2% yield) was synthesized from compound 163 in a manner similar to that used in the preparation of compound 7 from compound 6 in Example 3. ^¹H NMR (400MHz, _CDCl₃ ) δ 9.47 (s, ¹H), 8.73 (d, ¹H), 8.60 (br s, ¹H), 8.50–8.43 (m, 2H), 8.08 (dd, ¹H), 7.66 (d, 2H), 7.51–7.43 (m, 2H), 7.19 (d, 2H), 7.06 (t, 2H), 6.62 (d, ¹H), 6.36 (br s, ¹H), 5.73 (br s, ¹H), 1.80–1.73 (m, 2H), _{1.70–1.65 (m, 2H); MS (EI) was C₂₇H₂₁FN₄O₄ , measured} value _485.1 (MH⁺).

Example 59: 1-N'-(4-fluorophenyl)-1-N-[4-[7-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (165)

1-N'-(4-fluorophenyl)-1-N-[4-[7-(methylcarbamoyl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (165): Compound 165 (16.5 mg, 33.9% yield) was synthesized from compound 163 in a manner similar to that used in the preparation of compound 8 from compound 6 in Example 4. ^¹H NMR (400MHz, _CDCl₃ ) δ 9.45 (br s, 1H), 8.71 (d, 1H), 8.63 (br s, 1H), 8.43 (d, 1H), 8.37 (d, 1H), 8.04 (d, 1H), 7.65 (d, 2H), 7.50–7.44 (m, 2H), 7.19 (d, 2H), 7.06 (t, 2H), 6.60 (d, 1H), 6.40 (br s, 1H), 3.11 (d, 3H), 1.79–1.74 (m, 2H), 1.69–1.64 (m, 2H) _; MS ₍ EI ₎ was _{C₂₈H₂₃FN₄O₄} , measured value 499.1 (MH⁺).

Example 60: 1-N'-(4-fluorophenyl)-1-N-[4-[7-(2-hydroxyethoxycarbamoyl)-quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (166)

1-N'-(4-fluorophenyl)-1-N-[4-[7-(2-hydroxyethoxycarbamoyl)-quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (166): Compound 166 (27 mg, 46.2% yield) was synthesized from compound 163 in a manner similar to that used in the preparation of compound 26 from compound 6 in Example 6. ^¹H NMR (400MHz, _CD₃OD ) δ 8.73(d, ¹H), 8.53(d, ¹H), 8.44(d, ¹H), 8.03(dd, ¹H), 7.77(d, 2H), 7.59(dd, 2H), 7.28(d, 2H), 7.10(t, 2H), 6.75(d, ¹H), 4.17–4.12(m, 2H), 3.88–3.83(m, 2H), 1.66(s, 4H); MS ( _{EI) was C₂₹H₂₅FN₄O₆ , measured value} 545.1 (MH⁺).

The following compounds were prepared using a method similar to that used for compound 166 in Example 60:

1-N'-(4-fluorophenyl)-1-N-[4-[7-(oxetane-3-yloxycarbamoyl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (167): ^1H NMR (400MHz, _CD3) OD)δ 8.72(d,1H), 8.50(d,1H), 8.43(d,1H), 8.02(dd,1H), 7.79-7.73(m,2H), 7.62-7.56(m,2H), 7.31-7.25(m,2H), 7.09(t,2H), 6.74(d,1H), 5.19(s,1H), 4.93(m,2H), 4.88-4.81(m,2H), 1.70-1.63(m,4H) _; MS( _{EI) is C30H25FN4O6 , measured} value 557.1(MH+).

N-(4-((7-(((2,2-dimethyl-1,3-dioxopentane-4-yl)methoxy)carbamoyl)quinoline-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (168): MS (EI) is _C29H25FN4O6 , _and the measured value _{is 615.3} (MH+).

Example 61: 1-N-[4-[7-[[(2R)-2,3-dihydroxypropoxy]carbamoyl]quinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (169) and 1-N-[4-[7-[[(2S)-2,3-dihydroxypropoxy]carbamoyl]quinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (170)

1-N-[4-[7-[[(2R)-2,3-dihydroxypropoxy]carbamoyl]quinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (169) and 1-N-[4-[7-[[(2S)-2,3-dihydroxypropoxy]carbamoyl]quinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (170): Compounds 169 and 170 were synthesized from compound 168 in a manner similar to that used in Example 7 for the preparation of compounds 30 and 31 from compound 28. Compound 169: ^¹H NMR (400MHz, _CD₃OD ) δ 8.73 (d, 1H), 8.52 (d, 1H), 8.44 (d, 1H), 8.02 (dd, 1H), 7.77 (d, 2H), 7.62–7.55 (m, 2H), 7.30–7.25 (m, 2H), 7.09 (t, 2H), 6.75 (d, 1H), 4.21–4.15 (m, 1H), 4.06 (s, 1H), 4.02–3.96 (m, 1H), 3.68 (m, 2H) _{, 1.66 (d, 4H); MS (EI) C₃₀H₂₇FN₄O₇ , measured} value 575.2 (MH⁺). Compound 170: ^¹H NMR (400MHz, _CD₃OD ) δ 8.73 (d, 1H), 8.52 (d, 1H), 8.43 (d, 1H), 8.02 (dd, 1H), 7.77 (d, 2H), 7.62–7.54 (m, 2H), 7.28 (d, 2H), 7.14–7.04 (m, 2H), 6.75 (d, 1H), 4.22–4.14 (m, 1H), 4.12–3.92 (m, 2H), 3.73–3.64 (m, 2H), _1.66 (s _{, 4H); MS (EI) C₃₀H₂₇FN₄O₇ ,} measured value 575.1 (MH⁺).

Example 62: 4-((6-bromo-7-methoxyquinoline-4-yl)oxy)aniline (171)

4-((6-bromo-7-methoxyquinoline-4-yl)oxy)aniline (171): Cs₂CO₃ ( _3.3 g, 10 mmol) was added to a DMA (15 mL) solution of a mixture of compound 42 (1.75 g, 6.38 mmol) and 4-aminophenol ₂ (1.1 g, 10 mmol) at room temperature. The mixture was stirred at ₁₀₀ °C for _{2 h} . The mixture was cooled to 20 °C, diluted with water, and filtered. The crude residue was purified by rapid silica gel chromatography to give compound 171 (900 mg, 40% yield). MS (EI) was _{C₁₆H₁₃BrN₂O₂} , measured value: 345 (MH⁺).

Example 63: 4-((7-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxocyclopentaborane-2-yl)quinoline-4-yl)oxy)aniline (172)

4-((7-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl)quinolin-4-yl)oxy)aniline (172): Pd(dppf)Cl₂ (42 mg, 0.06 mmol) was added to a mixture of compound 171 (200 mg, 0.58 mmol), bis(pinacol) _diboron (220 mg, 0.87 mmol), and potassium acetate (170 mg, 1.7 mmol) in 1,4-dioxane (3 mL). The resulting mixture was heated at _{100 °C for 2 hours. After cooling, the reaction mixture was diluted with EtOAc, washed successively with water and saturated NaCl aqueous solution, concentrated, and purified by rapid silica gel chromatography to give compound 172 (43% yield). MS (EI) was C₂₂H₂₅BN₂O₄ , measured value} : 393 (MH+).

Example 64: 1-N-[4-[6-(3-cyano-2-fluorophenyl)-7-methoxyquinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (175)

3-(4-(4-aminophenoxy)-7-methoxyquinoline-6-yl)-2-fluorobenzyl nitrile (174): Compound 172 (50 mg, 0.13 mmol), compound 173 (25 mg, 0.13 mmol), _Na₂CO₃ (41 mg, _0.39 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (9 mg, 0.013 mmol), 1,4-dioxane (2 mL), and water (0.4 mL) were mixed in a microwave-controlled reaction tube. The reaction mixture was stimulated in a microwave reactor at 150 °C for 5 min. After cooling, the mixture was extracted with EtOAc, washed with saturated aqueous NaCl solution, and concentrated. The crude product was purified by rapid column chromatography to give _compound 174. _MS (EI) was _{C₂₃H₁₆FN₃O₂} , measured value: ₃₈₆ (MH+).

1-N-[4-[6-(3-cyano-2-fluorophenyl)-7-methoxyquinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (175): HATU (38 mg, 0.1 mmol) was added to a mixture of compound 174, compound 1 (22 mg, 0.1 mmol), and DIEA (25 mg, 0.2 mmol) in a DCM (2 mL). The mixture was stirred at room temperature until the reaction was _complete , then diluted with EtOAc, washed with saturated _NaHCO3 aqueous solution, and concentrated. The crude product was purified by rapid _column chromatography to give _compound 175. _MS (EI) was _C34H24F2N4O4 , and the measured value was 591 (MH+).

The following compounds were prepared in a manner similar to that used in Example 64 for the two-step synthesis of compound 175 from compound 172:

1-N'-(4-fluorophenyl)-1-N-[4-(7-methoxy-6-pyridin-2-ylquinoline-4-yl)oxyphenyl]cyclopropane-1,1-dicarboxamide (176): 2- _{bromopyridine} was used instead of compound 173. MS (EI) was _C32H25FN4O4 , _and the measured value was ₅₄₉ (MH+).

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(1-methylimidazol-4-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (177). Compound 173 was replaced with 4-bromo- _{1-methyl-1H-imidazolium. MS (EI) was C31H26FN5O4 , and} the measured value was ₅₅₂ (MH+).

Example 65: 1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(5-methylfuran-2-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (180)

4-((7-methoxy-6-(5-methylfuran-2-yl)quinolin-4-yl)oxy)aniline (179): Compound 171 (100 mg, 0.29 mmol), compound 178 (82 mg, 0.43 mmol), _Na₂CO₃ (92 _mg , 0.9 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (20 mg, 0.029 mmol), 1,4-dioxane (2.5 mL), and water (0.5 mL) were mixed in a microwave-controlled reaction tube. The resulting mixture was irradiated in a microwave reactor at 150 °C for 5 min. After cooling, the mixture was extracted with EtOAc, washed with saturated NaCl aqueous solution, and concentrated. The crude product was purified by rapid _column chromatography to give _compound 179. _{MS (EI) was C₂₁H₁₈N₂O₃ ,} measured value: 347 (MH+).

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(5-methylfuran-2-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (180): Compound 180 was synthesized from compound 179 in a manner similar to that used in Example 64 for the synthesis of compound 175 from compound 174. MS ( _{EI )} was _C32H26FN3O5 , and the measured value _was 552 (MH+).

The following compounds were prepared in a manner similar to that used in Example 65 for the two-step synthesis of compound 180 from compound 171:

2-[4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]-amino]phenoxy]-7-methoxyquinoline-6-yl]pyrrole-1-carboxylic acid tert-butyl ester (181): Compound 178 was replaced with potassium salt of 2-(trifluoro-14-boronyl)-1H-pyrrole-1-carboxylic acid tert-butyl ester _{. MS} (EI) was _C36H33FN4O6 , and the measured value was ₆₃₇ (MH+).

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(1-methylpyrazol-4-yl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (182): Compound 178 was replaced with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxocyclopentaborane-2-yl) _-1H -pyrazole. MS (EI) was _{C31H26FN5O4 , and} the measured value was 552 (MH+).

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(1,2-oxazol-4-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (183): Compound 178 was replaced with _4- (4,4,5,5-tetramethyl-1,3,2-dioxocyclopentaborane-2-yl)isoxazole. _MS (EI) was _C30H23FN4O5 , _and the measured value was 539 (MH+).

1-N-[4-[6-(3,5-dimethyl-1,2-oxazol-4-yl)-7-methoxyquinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (184): Compound 178 was replaced with 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxocyclopentaborane-2-yl)isoxazole _{. MS (EI) was C32H27FN4O5 , and} the measured value _was 567 (MH+).

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(1H-pyrazol-5-yl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (185): Compound 178 was replaced with potassium 5-(trifluoro-14-boronyl)-1H-pyrazol. _{MS (EI) was C30H24FN5O4 , and} the measured value was ₅₃₈ (MH+).

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(1H-pyrazol-4-yl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (186): Compound 178 was replaced with potassium 4-(trifluoro-14-boronyl)-1H-pyrazol _{. MS (EI) was C30H24FN5O4 ;} measured value was ₅₃₈ (MH+).

1-N-[4-(6-cyclopropyl-7-methoxyquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (187): Compound 178 was replaced with potassium _{cyclopropyltrifluoro} -14-borane _. MS (EI) was _C30H26FN3O4 , _and the measured value was 512 (MH+).

Example 66: 1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(1H-pyrrolo-2-yl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (188)

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(1H-pyrrolo-2-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (188): Compound 181 and excess TFA were stirred in a DCM at room temperature until the reaction was complete. The mixture was concentrated and purified by preparative HPLC to give compound 188 (50% yield). _MS (EI) was _C31H25FN4O4 , _and the measured value was 537 ( _MH +).

Example 67: N-(4-fluorophenyl)-N-(4-((6-formyl-7-methoxyquinoline-4-yl)oxy)phenyl)cyclopropane-1,1-dicarboxamide (190)

4-Chloro-7-methoxyquinoline-6-carboxaldehyde (189): nBuLi (0.6 mL, 2.5 M THF solution, 1.5 mmol) was added to an 8 mL THF solution of a mixture of compound 42 (320 mg, 1.17 mmol) at -78 °C. The mixture was stirred at -78 °C for 45 min, then DMF (0.5 mL) was added. The mixture was heated to 0 °C and stirred for 1 h. The reaction was quenched with saturated _NH₄Cl and extracted with EtOAc. The organic phase was concentrated, and the crude residue was purified by rapid silica gel chromatography to give compound 189 (130 mg, 50% yield). _{MS (EI) was C₁₁H₈ClNO₂ , and} the result was 222 (MH+).

N-(4-fluorophenyl)-N-(4-((6-formyl-7-methoxyquinoline-4-yl)oxy)phenyl)cyclopropane-1,1-dicarboxamide (190): Compound 190 was synthesized from compound 189 using the improved method described in Example 12 for the synthesis of compound 43 from compound 42, with potassium tert-butoxide replaced by cesium carbonate and DMF used as a solvent.

Example 68: 1-N'-(4-fluorophenyl)-1-N-[4-[6-(1H-imidazol-2-yl)-7-methoxyquinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (191)

1-N'-(4-fluorophenyl)-1-N-[4-[6-(1H-imidazol-2-yl)-7-methoxyquinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (191): Compound 190 (60 mg, 0.12 mmol), glyoxal (60 mg, 40% aqueous solution), and ammonium hydroxide (130 mg, 30% aqueous solution) were mixed in iPrOH (1.5 mL). The resulting mixture was stirred at ambient temperature (room temperature) for 12 hours. The mixture was extracted with EtOAc and washed with saturated NaCl aqueous solution. The organic phase was concentrated and purified by preparative HPLC to give compound 191 (35 mg, 54% yield). _{MS (EI) was C30H24FN5O4 , and} the measured value _was 538.1 (MH+).

Example 69: 1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(1,3-oxazol-5-yl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (192)

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(1,3-oxazol-5-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (192): Compound 190 (30 mg, 0.06 mmol), TosMIC (15 mg, 0.08 mmol), and _K₂CO₃ (15 mg, 0.11 mmol) were mixed in iPrOH (1 mL). The resulting mixture was stirred at 80 ° _C for 30 min. The mixture was concentrated to dryness. The residue was extracted with EtOAc. The organic layer was washed with water and concentrated. The crude product was purified by preparative HPLC to give compound 192 (14 _mg , 43% yield). _MS (EI) was _{C₃₀H₂₃FN₄O₅} , _and the result was 539 (MH+).

Example 70: 1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-[(E)-methoxyiminomethyl]quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (193)

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-[(E)-methoxyiminomethyl]quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (193): O-methylhydroxylamine-HCl (41.74 mg, 500 μmol, 1.7 equivalent) was added to a mixture of compound 190 (150 mg, 300.31 μmol, 1 equivalent) in EtOH (3 mL) and water (0.6 mL). The mixture was stirred at 50 °C for 2 h. The resulting precipitate was filtered, slurried in 50 mL of water, and then filtered again. The filter cake was lyophilized to give compound 193 (125.0 mg, 73.2% yield). ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.32 (s, 1H), 10.05 (s, 1H), 8.87 (s, 1H), 8.68 (s, 1H), 8.51 (s, 1H), 7.85 (d, 2H), 7.72–7.58 (m, 3H), 7.37 (d, 2H), 7.16 (t, 2H), 6.72 (br d, 1H), 4.07 (s, 3H), 3.99 (s, 3H), _{1.49 (s, 4H); MS (EI) was C₂⁹H₂⁵FN₄O₅ , measured} value _529.2 (MH⁺).

Example 71: 3-[4-[4-[[1-([4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-7-methoxyquinoline-6-yl]-3-hydroxyazacyclobutane-1-carboxylic acid tert-butyl ester (195)

3-(4-chloro-7-methoxyquinoline-6-yl)-3-hydroxyazacyclobutane-1-carboxylic acid tert-butyl ester (194): A mixture of compound 42 (200 mg, 0.73 mmol) and THF (4 mL) was cooled to -78 °C. n-BuLi (0.4 mL, 1.0 mmol, 2.5 M THF solution) was slowly added. The resulting mixture was stirred at -78 °C for 40 min. A THF solution of N-Boc 3-oxazacyclobutane (125 mg, 0.73 mmol) (0.5 mL) was added. The reaction mixture was heated to 0 °C and stirred for 1 h. The reaction was quenched with water and extracted with EtOAc. The organic phase was washed with saturated NaCl aqueous solution, concentrated, and purified by rapid _{silica gel} chromatography to give compound 194 (38% yield). _MS (EI) was _C18H21ClN2O4 , measured value: 365 (MH+).

3-[4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-7-methoxyquinoline-6-yl]-3-hydroxyazacyclobutane-1-carboxylic acid tert-butyl ester (195): Compound 195 was synthesized from compound 194 in a manner similar to that used in Example 12 for the preparation of compound 43 from compound 42, except that cesium carbonate was used instead of tert-butanol, DMF was used as the solvent, the reaction temperature was 80°C, and the reaction time was 12 hours. Compound 195 was obtained in 68% yield _{. MS} (EI) was _C35H35FN4O7 , _and the measured value was 643 (MH+).

Similar to compound 195 in Example 71, the following compounds were prepared by replacing the Boc-protected aza-butane-3-one with an oxetane-3-one:

1-N'-(4-fluorophenyl)-1-N-[4-[6-(3-hydroxyoxetane-3-yl)-7-methoxyquinoline-4-yl]oxyphenyl]cyclopropane-1,1- _{dicarboxamide} (196). MS (EI) was _C30H26FN3O6 , _with a measured value of ₅₄₄ (MH+).

Example 72: 1-N'-(4-fluorophenyl)-1-N-[4-[6-(3-hydroxyazacyclobutane-3-yl)-7-methoxyquinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (197)

1-N'-(4-fluorophenyl)-1-N-[4-[6-(3-hydroxyazacyclobutane-3-yl)-7-methoxyquinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (197): Compound 197 was synthesized from compound 195 in a manner similar to that used in Example 66 for the preparation of compound 188 from compound 181 (55 _% yield). _MS (EI) was _C30H27FN4O5 , _and the measured value was 543 (MH+).

Example 73: 1-N-[4-[6-(azacyclobutane-1-yl)-7-methoxyquinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (198)

1-N-[4-[6-(azacyclobutan-1-yl)-7-methoxyquinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (198): Bis(tri-tert-butylphosphine)palladium (0) was added to a mixture of compound 43 (150 mg, 0.27 mmol), azacyclobutane ( ₃₀₀ mg, 5.25 mmol), and _K₃PO₄ (212 mg, 1.0 mmol) in DMA (2 mL). The resulting mixture was stirred at 100 °C for 12 hours. After cooling, water was added, and the mixture was extracted with EtOAc, washed with saturated NaCl aqueous solution, and concentrated. The crude product was purified by preparative HPLC to give compound 198. _MS (EI) was _{C₃₀H₂₇FN₄O₄ , and} the measured value was 527 (MH+).

The following compounds were prepared from compound 43 using a method similar to that used in Example 73 for the synthesis of compound 198 from compound 43:

1-N'-(4-fluorophenyl)-1-N-[4-[6-(3-hydroxyaziridine-1-yl)-7-methoxyquinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (199): Azacyclobutane-3-ol was used instead of aziridine. _{MS (EI) was C30H27FN4O5 , and} the measured value _was 543 (MH+).

1-N-[4-[6-(3,3-difluoroazacyclobutane-1-yl)-7-methoxyquinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (200): HCl salt of 3,3- _{difluoroazacyclobutane} was used instead of _{azacyclobutane} . _MS (EI) was _C30H25F3N4O4 , measured _value 563 (MH+).

Example 74: 1-N'-(4-fluorophenyl)-1-N-[4-(7-methoxy-6-pyridin-3-ylquinoline-4-yl)oxyphenyl]cyclopropane-1,1-dicarboxamide (201)

1-N'-(4-fluorophenyl)-1-N-[4-(7-methoxy-6-pyridin-3-ylquinoline-4-yl)oxyphenyl]cyclopropane-1,1-dicarboxamide (201): Compound 43 (50 mg, 0.09 mmol), 3-pyridylboronic acid (16 mg, 0.13 mmol), _Na₂CO₃ (28 mg, 0.27 mmol), bis ₍ di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (6 mg, 0.009 mmol), 1,4-dioxane (1.5 mL), and water (0.3 mL) were mixed in a microwave-controlled reaction tube. The reaction mixture was stimulated in a microwave reactor at 150 °C for 10 min. After cooling, the mixture was extracted with EtOAc, washed with a saturated aqueous NaCl solution, and concentrated. The crude product was purified by preparative HPLC to give compound 201. MS( _{EI) is C32H25FN4O4 , measured} value ₅₄₉ (MH+).

The following compounds were prepared from compound 43 in a manner similar to that used in Example 74 for preparing compound 201 from compound 43:

1-N'-(4-fluorophenyl)-1-N-[4-(7-methoxy-6-pyridin-4-ylquinoline-4-yl)oxyphenyl]cyclopropane-1,1-dicarboxamide (202): Pyridin-4-ylboronic acid was used instead of 3-pyridinylboronic acid. _{MS (EI) was C32H25FN4O4 , and} the measured value _was 549 (MH+).

The following compounds were prepared from compound 44 and the potassium salt of 5-(trifluoro-14-boryl)-1H-pyrazole in a manner similar to that used in the preparation of compound 201 from compound 43 and 3-pyridylboronic acid in Example 74:

1-N'-(4-fluorophenyl)-1-N-[4-[6-(1H-pyrazol-5-yl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1- _{dicarboxamide} (204): MS (EI ₎ is _{C29H22FN5O3 ,} measured value is 508 (MH+).

Example 75: 1-N'-(4-fluorophenyl)-1-N-[4-(7-methoxy-6-aminosulfonylquinoline-4-yl)oxyphenyl]cyclopropane-1,1-dicarboxamide (206)

S-(4-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylamino)phenoxy)-7-methoxyquinoline-6-yl)thioacetate (205): Pd₂(dba)₃ (16 mg, 0.017 mmol) and Xantphos (20 mg, 0.035 mmol) were added to a mixture of compound ₄₃ (200 mg, 0.36 mmol), potassium thioacetate (83 mg, 0.72 mmol), and DIEA (0.5 mL) in _1,4 -dioxane (4 mL). The resulting mixture was stirred at 120 °C for 15 min under microwave irradiation. After cooling, EtOAc and water were added. Any insoluble substances were filtered out. The filtrate was washed with saturated NaCl aqueous solution and concentrated. The crude product was purified by rapid silica gel chromatography to give compound 205 (37% yield plus 50% recovery of compound 43).

1-N'-(4-fluorophenyl)-1-N-[4-(7-methoxy-6-aminosulfonylquinoline-4-yl)oxyphenyl]cyclopropane-1,1-dicarboxamide (206): N-chlorosuccinimide (80 mg, 0.6 mmol) was added to a mixture of 2N HCl (0.5 mL) and MeCN (3 mL), and the resulting mixture was cooled to 0 °C. A solution of compound 205 (80 mg, 0.15 mmol) in MeCN (1.5 mL) was added. After stirring at 0 °C for 2 hours, the reaction mixture was extracted with EtOAc. The organic phase was washed with a saturated aqueous NaCl solution and concentrated. The resulting crude sulfonyl chloride was dissolved in i-PrOH (2 mL), and excess _NH4OH was added to it at room temperature. After the reaction was complete, the mixture was concentrated, and the crude product was purified by preparative HPLC to give compound 206 (60% yield). MS(EI) is C ₂₇ H ₂₃ FN ₄ O ₆ S, measured value 551 (MH+).

The following compounds were prepared from compound 205 in a manner similar to that used in the second step of Example 75 to prepare compound 206:

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(methylaminosulfonyl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (207): _NH4OH is replaced with methylamine. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.22 (s, ¹H), 10.06 (s, ¹H), 8.71 (d, ¹H), 8.69 (s, ¹H), 7.78 (d, 2H), 7.64–7.62 (m, 2H), 7.60 (s, ¹H), 7.30–7.28 (m, 3H), 7.17–7.12 (m, 2H), 6.50 (d, ¹H), 4.04 (s, 3H), 2.47 (s, 3H), _{1.47 (s, 4H); MS (EI) was C₂₈H₂₅FN₄O₆S , measured value} 565.1 (MH⁺).

1-N-[4-[6-(ethylaminosulfonyl)-7-methoxyquinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (208): _NH4OH was replaced with ethylamine. _MS (EI) was _C29H27FN4O6S , _with a measured value of ₅₇₉ (MH+).

The following compounds were prepared from compound 44 in a manner similar to that used in Example 75 for preparing compound 206 from compound 43:

1-N'-(4-fluorophenyl)-1-N-[4-(6-aminosulfonylquinoline-4-yl)oxyphenyl]cyclopropane-1,1- _{dicarboxamide} (209). _{MS (EI) was C26H21FN4O5S ,} with a measured value of ₅₂₁ (MH+).

Example 76: 1-N'-(4-fluorophenyl)-1-N-[4-(7-methoxy-6-methylsulfonylquinoline-4-yl)oxyphenyl]cyclopropane-1,1-dicarboxamide (210)

1-N'-(4-fluorophenyl)-1-N-[4-(7-methoxy-6-methylsulfonylquinoline-4-yl)oxyphenyl]cyclopropane-1,1-dicarboxamide (210): Compound 43 (100 mg, 0.18 mmol), sodium methanesulfonate (40 mg, 0.36 mmol), CuI (5 mg), proline (6 mg), and NaOH (3 mg) were mixed in DMSO (1 mL). The resulting mixture was stirred at 110 °C for 14 hours. After cooling to room temperature, water was added. The mixture was filtered and washed with EtOAc. The EtOAc filtrate was concentrated and purified by preparative _HPLC to give compound 210 (8% yield). _MS (EI) was _C28H24FN3O6S , _and the measured value was 550 (MH+).

Example 77: 1-N'-(4-fluorophenyl)-1-N-[4-[7-(methoxycarbamoyl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (213)

4-Chloro-N-methoxyquinoline-7-carboxamide (212): O-methylhydroxylamine hydrochloride (54.00 mg, 646.57 μmol, 49.09 μL, 2.24 equivalents) was added in a single batch to a mixture of compound 211 (60 mg, 289.00 μmol, 1 equivalent), HATU (180.00 mg, 473.40 μmol, 1.64 equivalents) in DMF (5 mL). The mixture was stirred at 20-30 °C for 0.5 h and then partitioned between water (10 mL) and EtOAc (2 x 10 mL). The organic extract was separated, washed with saturated NaCl aqueous solution (10 mL), _dried over anhydrous _Na₂SO₄ , and concentrated to give compound 212 (140 _mg , crude product), which could be used directly in the next step without further purification. _MS (EI) was _{C₁₁H₉ClN₂O₂} , _with a measured value of 236.9 (MH⁺).

1-N'-(4-fluorophenyl)-1-N-[4-[7-(methoxycarbamoyl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (213): t-BuOK (133 mg, 1.19 mmol, 2.00 equivalent) was added in a single batch to a mixture of compound 212 (140 mg, 591.58 μmol, 1 equivalent) and compound 3 (280.00 mg, 890.84 μmol, 1.51 equivalent) in DMSO (5 mL), and the resulting mixture was stirred at 100 °C for 1 hour. The reaction mixture was partitioned between water (10 mL) and EtOAc (2 x 10 mL). The combined organic extracts were washed with saturated aqueous NaCl solution (10 mL), _dried over anhydrous _Na₂SO₄ , and concentrated. The residue was purified by preparative HPLC (alkaline conditions; column: Waters Xbridge 150*25 5u; mobile phase: [water (0.05% ammonium hydroxide v/v)-ACN]; B%: 32%-57%, 6.5 min) to give compound 213 (7.9 mg, 2.54% yield). ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 12.11 (s, ¹H), 10.22 (s, ¹H), 10.06 (s, ¹H), 8.77 (d, ¹H), 8.44–8.37 (m, 2H), 7.99 (d, ¹H), 7.79 (d, 2H), 7.65 (dd, 2H), 7.28 (d, 2H), 7.16 (t, 2H), 6.66 (d, ¹H), 3.78 (s, 3H), _{1.48 (s, 4H); MS (EI) was C₂₈H₂₃FN₄O₅ , measured} value _515.1 (MH⁺).

The following compounds were prepared from compound 211 in a manner similar to that used in Example 77 for preparing compound 213 from compound 211:

1-N-[4-[7-(ethylcarbamoyl)quinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (214): In the first step, ethylamine hydrochloride is used instead of O-methylhydroxylamine hydrochloride. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.21 (s, ¹H), 10.06 (s, ¹H), 8.84 (t, ¹H), 8.75 (d, ¹H), 8.53 (d, ¹H), 8.38 (d, ¹H), 8.07 (dd, ¹H), 7.78 (d, 2H), 7.64 (dd, 2H), 7.28 (d, 2H), 7.15 (t, 2H), 6.63 (d, ¹H), 3.31 (brs, 2H), 1.47 (s, 4H), 1.18 (t, 3H); MS ₍ EI ₎ was _{C₂⁹H₂⁵FN₄O₄ ,} measured value 513.1 (MH⁺).

Example 78: 1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(1,3,4-oxadiazol-2-yl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (220)

7-Methoxy-4-(4-nitrophenoxy)quinoline-6-carboxylic acid methyl ester (215): Compound 4 (300 mg, 1.2 mmol), 4-nitrophenol (200 mg, 1.42 mmol), and DIEA (230 mg, 1.78 mmol) were mixed in toluene (1 mL). The resulting mixture was stirred at 110 °C for 12 hours. After cooling, water was added, and the mixture was extracted with EtOAc. The organic phase was washed with saturated NaCl aqueous solution, concentrated, and purified by rapid silica gel chromatography to give compound 215 (150 _mg , ₃₆ %). MS (EI) was _C18H14N2O6 , _and the measured value was 355 (MH+).

7-Methoxy-4-(4-nitrophenoxy)quinoline-6-carboxylic acid ( ₂₁₆ ): Compound 216 was synthesized in a manner similar to that used in the preparation of compound 81 in Example 25. _MS (EI) was _C17H12N2O6 , _and the measured value was 341 (MH+).

7-Methoxy-4-(4-nitrophenoxy)quinoline-6-carbazide (217): HATU (100 mg, 0.26 mmol) was added to a DMF (2 mL) solution of compound 216 (45 mg, 0.13 mmol) and DIEA (51 mg, 0.4 mmol). The resulting mixture was stirred at room temperature for 10 min, and then excess _NH₂ · _H₂O was added. After the reaction was complete, water was added. The precipitate was filtered and dried under vacuum to give crude compound ₂₁₇ , which could be _used in the next step without further purification. _MS (EI) was _{C₁₇H₁₄N₄O₅} , measured _value : 355 (MH⁺).

2-(7-Methoxy-4-(4-nitrophenoxy)quinolin-6-yl)-1,3,4-oxadiazole (218): Compound 217 (66 mg, 0.18 mmol) and p-TsOH· _H₂O (4 mg, 0.02 mmol) were mixed in triethyl orthoformate (1 mL). The resulting mixture was stirred at 120 °C for 5 hours. After cooling, the mixture was concentrated and a saturated _aqueous solution of _NaHCO₃ was added. The precipitate was filtered and washed with EtOAc to give crude compound 218, which could be _used in the next step without further purification. _{MS (EI) was C₁₈H₁₂N₄O₅ ,} measured value: 365 (MH+).

4-((7-methoxy-6-(1,3,4-oxadiazol-2-yl)quinoline-4-yl)oxy)aniline (219): Crude compound 218 was mixed with Fe powder (50 mg, 0.9 mmol) and _NH₄Cl (20 mg, 0.36 mmol) in EtOH (2 mL). The resulting mixture was stirred at 85 °C for 3 hours. After cooling, the mixture was filtered, washed with EtOAc, and the filtrate was concentrated. The residue was purified by rapid silica gel chromatography to give compound 219 (40 _mg , 66%, in two _steps ). _{MS (EI) was C₁₈H₁₄N₄O₃ ,} measured value: 335 (MH+).

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(1,3,4-oxadiazol-2-yl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide ( ₂₂₀ ): Compound 220 was synthesized in a manner similar to that used in the preparation of compound 175 in Example 64. _MS (EI) was _C29H22FN5O5 , _and the measured value was 540 (MH+).

The following compounds were prepared in a manner similar to that used in the synthesis of compound 220 in Example 78, using compound 55 instead of compound 4:

1-N'-(4-fluorophenyl)-1-N-[4-[6-(1,3,4-oxadiazol-2-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1- _{dicarboxamide} (221): MS (EI _{) was C28H20FN5O4} , and the measured value was 510 (MH+).

Example 81: N-(4-((7-bromoquinoline-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (232)

N-(4-((7-bromoquinoline-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (232): _Cs₂CO₃ (2.7 g, 8.26 mmol) was added to a mixture of compound 231 (1 g, 4.13 mmol) and compound ₃ (1.3 g, 4.13 mmol) in DMF (8 mL). The resulting mixture was stirred at 85 °C for ₁₂ h. The mixture was cooled to room temperature, diluted with water, and filtered. The residue was purified by rapid column chromatography to give compound 232 (1.5 g, 69% yield). _MS (EI) was _{C₂₆H₁₉BrFN₃O₃} , _with measured values of 520 and 522 (MH+).

Example 85: 1-N'-(4-fluorophenyl)-1-N-[4-(7-aminosulfonylquinoline-4-yl)oxyphenyl]cyclopropane-1,1-dicarboxamide (254)

S-(4-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylamino)phenoxy)quinoline-7-yl)thioacetate (253): Compound 253 (170 mg, crude) was synthesized from compound 232 in a manner similar to that used in the preparation of compound 205 from compound 43 in Example _{75. MS} ( _EI ) was _C28H22FN3O4S , measured value: 516.0 (MH+).

1-N'-(4-fluorophenyl)-1-N-[4-(7-aminosulfonylquinoline-4-yl)oxyphenyl]cyclopropane-1,1-dicarboxamide (254): Compound 254 (170 mg, crude) was synthesized from compound 253 in a manner similar to that used in the preparation of compound 206 from compound 205 in Example 75. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.28 (s, 1H), 10.05 (s, 1H), 8.95 (d, 1H), 8.62 (d, 1H), 8.52 (d, 1H), 8.11 (dd, Hz, 1H), 7.88–7.75 (m, 4H), 7.67–7.59 (m, 2H), 7.33 (d, 2H), 7.15 (t, 2H), 6.85 (d, 1H), _{1.48 (s, 4H); MS (EI) was C₂₆H₂₁FN₄O₅S , measured} value: 521.0 ( _MH⁺ ).

Example 86: 1-N'-(4-fluorophenyl)-1-N-[4-[7-[(E)-N-methoxy-C-methylcarboiminoyl]quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (256)

1-N-[4-(7-acetylquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (255): A solution of compound 232 (100 mg, 192.18 μmol, 1 equivalent), tributyl(1-ethoxyvinyl)stanane (138.81 mg, 384.36 μmol, 129.73 μL, 2 equivalents) and Pd( _PPh3 ) _2Cl2 (13.49 _mg , 19.22 μmol, 0.1 equivalents) in toluene (2 mL) was degassed with nitrogen for 10 min and heated at 110 °C for 12 h under nitrogen. After cooling, KF (2 mL, 2 M) was added, and the resulting mixture was stirred at room temperature for 30 min. A 6 M HCl aqueous solution (2 mL) was added to the residue, and the mixture was stirred at 25 °C for 30 min. The mixture was extracted with EtOAc. The organic layer was washed with water, saturated NaCl aqueous solution, _dried ( _Na₂SO₄ ), and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether/ethyl acetate = 1/1), then recrystallized from MeOH (2 mL) and lyophilized to give compound 255 (12.4 mg, 10.63% yield). ^¹H NMR (400MHz, _CDCl₃ ) δ 9.46 (s, ¹H), 8.75 (d, ¹H), 8.67 (s, ¹H), 8.57 (br s, ¹H), 8.43 (d, ¹H), 8.16 (dd, ¹H), 7.66 (d, 2H), 7.51–7.45 (m, 2H), 7.20 (d, 2H), 7.10–7.04 (m, 2H), 6.64 (d, ¹H), 2.78 (s, 3H), 1.76 (s, 2H), 1.67 (s, _2H ); MS (EI) was _{C₂₈H₂₂FN₃O₄} , measured value: _{484.2 (} MH⁺).

1-N'-(4-fluorophenyl)-1-N-[4-[7-[(E)-N-methoxy-C-methylcarboiminoyl]quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (256): O-methylhydroxylamine (43.18 mg, 517.07 μmol, 5 equivalents, HCl) was added to a mixture of compound 255 (50 mg, 103.41 μmol, 1 equivalent) in EtOH (2 mL) and _H₂O (0.3 mL). The mixture was stirred at 50 °C for 1 h. The mixture was concentrated under vacuum, and the resulting residue was purified by silica gel column chromatography (petroleum ether/EtOAc = 5/1 to 1/1), followed by recrystallization from MeOH (2 mL) to give compound 256 (27 mg, 48.90% yield). ^¹H NMR (400MHz, _CDCl₃ ) δ 10.24 (s, ¹H), 8.82 (s, ¹H), 8.72 (br d, ¹H), 8.48–8.40 (m, 2H), 8.22 (s, ¹H), 7.80 (d, 2H), 7.50–7.42 (m, 2H), 7.23 (br d, 2H), 7.07 (t, 2H), 6.83 (br d, ¹H), 4.11 (s, 3H), 2.40 (s, 3H), 1.89–1.81 (m, 2H), 1.68–1.64 (m, 2H); MS (EI) was _{C₂ ₹ H₂₅FN₄O₄} , _measured value: 513.1 (MH⁺).

Example 87: 4-(4-amino-2-fluorophenoxy)-7-methoxy-N-methylquinoline-6-carboxamide (258)

4-Chloro-7-methoxy-N-methylquinoline-6-carboxamide (257): A solution of methylamine (8 M, 50 mL, 10.07 equivalents) in EtOH was added to a solution of compound 4 (10 g, 39.74 mmol, 1 equivalent) in THF (150 mL) at 30 °C. The reaction mixture was stirred at 30 °C for 25 _h . The mixture was concentrated under vacuum. The residue was slurried with warm water (100 mL) and filtered. The filter cake was dried under vacuum to give compound 257 as a white solid (9 g, 90.35% yield). _{MS (EI) was C12H11ClN2O2 , and} the measured value was 251.0 (MH+).

4-(4-amino-2-fluorophenoxy)-7-methoxy-N-methylquinoline-6-carboxamide (258): Compound 258 was synthesized from compound 257 and 4-amino-2-fluorophenol in a manner similar to that used in Example 62 to synthesize compound 171 from compounds 42 and 2.

Example 88: 1-N-[3-fluoro-4-[7-methoxy-6-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)-1-N'-methylcyclopropane-1,1-dicarboxamide (262)

Methyl 1-((4-fluorophenyl)(methyl)carbamoyl)cyclopropane-1-carboxylic acid (260): A solution of compound 259 (215 mg, 1.5 mmol, 1.5 equivalents), HATU (568 mg, 149 μmol, 1.5 equivalents), and DIEA (0.52 mL, 3 equivalents) in DMF (5 mL, 0.2 M) was stirred at room temperature for 15 min. 4-fluoro-N-methylaniline (124 mg, 1.0 mmol, 1.0 equivalents) was added, and the mixture was stirred at room temperature for 17 h. Water was added, and the resulting mixture was extracted with EtOAc. The two phases were separated, and the organic layer was dried _{over Na₂SO₄} , concentrated under reduced pressure, absorbed onto silica gel, and purified by CombiFlash (60:40 hexane:EtOAc) to give compound 260 (221 mg, 88.7% yield). ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.38-7.35(m,2H),7.25(m,2H),3.40(s,3H),3.18(s,3H),1.37(d,2H),1.17(bs.2H).

1-((4-fluorophenyl)(methyl)carbamoyl)cyclopropane-1-carboxylic acid (261): Compound 260 (60 mg, 0.23 mmol, 1.0 equivalent) and NaOH (20 mg, 0.5 mmol) in MeOH and THF solutions (1 mL each) were stirred overnight at 50 °C. The reaction mixture was cooled and concentrated under reduced pressure. 1 N HCl was added to the residue, and the resulting mixture was extracted with DCM. The two phases were separated, _and the organic layer was dried over _Na₂SO₄ and concentrated under reduced pressure to give crude compound 261, which could be used in the next step without further purification (44.7 mg, 79% yield). ^¹H NMR (400 MHz, DMSO- _d₆ ) δ 7.39 (br s, 2H), 7.25 (m, 2H), 3.17 (s, 3H), 1.24 (br s, 2H), 0.99 (br s, 2H).

1-N-[3-fluoro-4-[7-methoxy-6-(methylcarbamoyl)quinolin-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)-1-N'-methylcyclopropane-1,1-dicarboxamide (262): A solution of compound 261 (23.7 mg, 0.1 mmol, 1.5 equivalent), HATU (38 mg, 0.1 mmol, 1.5 equivalent), and DIEA (34 μL, 3.0 equivalent) in DMF (0.4 mL) was stirred at room temperature for 15 min. Compound 258 (23.7 mg, 0.06 mmol, 1.0 equivalent) was added, and the mixture was stirred at room temperature for 17 h. Water was added to the mixture, and the resulting solid was extracted into EtOAc. The two phases were separated, and the organic layer was dried over _{Na₂SO₄ ,} concentrated under reduced pressure, absorbed onto silica gel, and purified by CombiFlash (5:95MeOH:DCM). The obtained product was further purified by preparative HPLC to give compound 262 (7 mg, 18.8% yield). ^¹H NMR (400 MHz, DMSO- _d₆ ) δ 9.94 (s, 1H), 8.79 (d, 1H), 8.59 (s, 1H), 8.38 (d, 1H), 7.50 (s, 1H), 7.37 (t, 2H), 7.22 (b m, 3H), 7.04 (t, 2H), 6.65 (d, 1H), 3.99 (s, 3H), 3.18 (s, 3H), 2.78 ( _d , 3H), 1.37 ( _{d, 2H), 1.17 (b s, 2H); MS (EI) was C₃₀H₂₆F₂N₄O₅ , measured} value _561.0 (MH⁺).

Compound 263 was prepared using a variant of the method used in Example 88 for synthesizing compound 262:

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]-1-N'-methylcyclopropane-1,1-dicarboxamide (263): In the last step of the 3-step sequence of Example 88, compound 258 was replaced with 4-(4-aminophenoxy)-7-methoxy-N-methylquinoline-6-carboxamide. 4-(4-aminophenoxy)-7-methoxy-N-methylquinoline-6-carboxamide was synthesized in the same manner as compound 258 in Example 87, but in the second step, 4-aminophenol was used instead of 4-amino-2-fluorophenol. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 9.69 (br s, 1H), 8.67 (d, 1H), 8.62 (s, 1H), 8.38 (d, 1H), 7.52 (s, 1H), 7.47 (s, 1H), 7.29 (m, 2H), 7.18 (d, 3H), 7.11 (t, 2H) 6.47 (d, 1H), 4.03 (s, 3H), 2.85 (d, 3H), 2.08 (s, 3H), 1.37 (d, 2H), 1.24 (br s, _{2H); MS (EI) was C₃₀H₂₇FN₄O₅ , measured value} 543.0 (MH⁺).

Following the same three-step procedure used in Example 88 for the synthesis of compound 262 from compounds 259 and 258, the following compounds were prepared from compounds 259 and 258:

1-N'-(2-chloro-4-fluorophenyl)-1-N-[3-fluoro-4-[7-methoxy-6-(methylcarbamoyl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (264): In the first step, 4-fluoro-N-methylaniline is replaced with 2-chloro-4-fluoroaniline. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.36 (s, ¹H), 10.25 (s, ¹H), 8.61 (d, ¹H), 8.54 (s, ¹H), 8.31 (m, ¹H), 7.84–7.79 (m, 2H), 7.47 (s, 2H), 7.40 (t, 2H), 7.18 (t, 1H), 6.42 (d, 1H), 3.96 (s, 3H), 2.77 (d, 3H), 1.56 (br s, 2H), 1.53 ( _br s _{, 2H); MS (EI) was C₂₉H₂₃ClF₂N₄O₅ , measured value} 581.0 (MH⁺).

1-N-[3-fluoro-4-[7-methoxy-6-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]-1-N'-(4-fluoro-2-methylphenyl)cyclopropane-1,1-dicarboxamide (265): In the first step, 4-fluoro-2-methylaniline is used instead of 4-fluoro-N-methylaniline. ^¹H NMR (400MHz, DMSO- _d₆ ) δ 10.58 (s, ¹H), 9.72 (s, ¹H), 8.68 (d, ¹H), 8.61 (s, ¹H), 8.39 (d, ¹H), 7.92 (d, ¹H), 7.54 (br s, 2H), 7.47 (t, 2H), 7.1 (d, 1H), 7.03 (t, 1H), 6.49 (d, 1H), 4.03 (s, 3H), 2.85 (d, 3H), 2.22 ( _{s, 3H), 1.54 (s, 4H); MS (EI) was C₃₀H₂₆F₂N₄O₅ , measured value 561.0} (MH⁺).

1-N'-(4-fluoro-2,6-dimethylphenyl)-1-N-[3-fluoro-4-[7-methoxy-6-(methylcarbamoyl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (267): In the first step, 4-fluoro-2,6-dimethylaniline is used instead of 4-fluoro-N-methylaniline. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.8 (s, ¹H), 9.19 (s, ¹H), 8.6 (d, ¹H), 8.54 (s, ¹H), 8.32 (d¹H), 7.87 (d¹H), 7.46–7.36 (m, ³H), 6.88 (d, 2H), 6.41 (d, ¹H), 3.96 (s, ³H), 2.77 (d, ³H), 2.09 (s, 6H), _1.47 ( _{s, 4H); MS (EI) was C₃¹H₂₈F₂N₄O₅ , measured} value _575.0 (MH⁺).

1-N-[3-fluoro-4-[7-methoxy-6-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]-1-N'-(4-fluoro-2-methoxyphenyl)cyclopropane-1,1-dicarboxamide (268): In the first step, 4-fluoro-2-methoxyaniline is used instead of 4-fluoro-N-methylaniline. ^¹H NMR (400MHz, DMSO- _d₆ ) δ 10.2 (s, ¹H), 10.17 (s, ¹H), 8.68 (d, ¹H), 8.62 (s, ¹H), 8.39 (d, ¹H), 7.98–7.96 (m, ¹H), 7.86 (d, ¹H), 7.54–7.47 (m, ³H), 7.01 (d, ¹H), 6.77 (t, ¹H), 6.51 (d, ¹H), 4.04 (s, ³H), 3.85 (s, ³H), 2.86 (d, ³H), 1.62 (s, ²H), _1.58 (s, _{²H); MS (EI) was C₃₀H₂₆F₂N₄O₆ , measured value} 577.0 (MH⁺).

1-N-[3-fluoro-4-[7-methoxy-6-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]-1-N'-(4-fluoro-2-propane-2-yloxyphenyl)cyclopropane-1,1-dicarboxamide (269): In the first step, 4-fluoro-2-isopropoxyaniline is used instead of 4-fluoro-N-methylaniline. ¹ H NMR (400MHz, DMSO-d ₆ )δ10.21(s,1H),10.06(s,1H),8.62(d,1H),8.55(s,1H),8.32(d,1H),8.05(t,1H),7.87(d,1H),7.52-7.41(m,3H),6.97(d,1H),6. 68(t,1H),6.41(d,1H),4.64-4.58(m,1H),3.96(s,3H),2.78(d,3H),1.51(s,2H),1.40(s.2H),1.17(s,3H),1.16(s,3H); MS(EI) is C ₃₂ H ₃₀ F ₂ N ₄ O ₆ The measured value was 605 (MH+).

1-N'-(2-Cyclopropyl-4-fluorophenyl)-1-N-[3-fluoro-4-[7-methoxy-6-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (270): In the first step, 4-fluoro-N-methylaniline is replaced with 2-cyclopropyl-4-fluoroaniline. ¹ H NMR (400MHz, DMSO-d ₆ ) δ10.53 (br s, 1H), 9.99 (br s,1H),8.68(d,1H),8.62(s,1H),8.39(d,1H),7.91(d,1H),7.61(s,1H),7.54(s,2H),7.49(br s,1H),7.01(t,1H)6.82(d,1H),6.49(d,1H),4.04(s,3H),2.85(d,3H),1.97(br s,1H),1.58(s,4H),0.94(d,2H),0.67(d,2H); MS(EI) is C ₃₂ H ₂₈ F ₂ N ₄ O ₅ The measured value was 587.4 (MH+).

The 2-cyclopropyl-4-fluoroaniline used in the synthesis of compound 270 was synthesized via the following procedure:

In a thick-walled reaction tube, tert-butyl (2-bromo-4-fluorophenyl)carbamate (289 mg, 1 mmol, 1.0 equivalent), cyclopropyl MIDA borate (236 mg, 1.2 mmol, 1.2 equivalent), and _K₃PO₄ ( ₆₃₆ mg, 3.0 equivalent) were added to toluene:water (4:1) and degassed under nitrogen for 5 minutes. Palladium acetate (9 mg, 4 mol%) and 2-(dicyclohexyl)phosphinobiphenyl (28 mg, 8 mol%) were added to the mixture and degassed under nitrogen for another 5 minutes. The tube was capped, and the mixture was heated overnight at 100 °C under nitrogen. After cooling to room temperature, the two phases were separated. The organic layer was dried with _{anhydrous Na₂SO₄} , concentrated under reduced pressure, absorbed into silica gel, and purified by CombiFlash using a 70:30 hexane:DCM gradient to give tert-butyl (2-cyclopropyl-4-fluorophenyl)carbamate as a colorless oil (90 mg, 36% yield).

A solution of tert-butyl (2-cyclopropyl-4-fluorophenyl)carbamate (86 mg, 0.3 mmol, 1.0 equivalent) and TFA (77 mg, 2.0 equivalent) in DCM (1 mL) was stirred overnight at 40 °C. The reaction solution was cooled and concentrated under reduced pressure. DCM (4 mL) was added to the residue, and the resulting solution was washed with a saturated aqueous solution of _NaHCO3 , dried over _{anhydrous Na2SO4} , and concentrated under reduced pressure to give crude 2-cyclopropyl-4-fluoroaniline as an almost colorless oil (43 mg, 81% yield), which could be used in subsequent reactions without further purification. ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.16-7.13(m,1H),7.01(t,1H),6.85(d,1H),1.91-1.85(m,1H),1.0(d,2H),0.73(d,2H).

Example 89: 1-((3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinoline-4-yl)oxy)phenyl)-carbamoyl)-cyclopropane-1-carboxylic acid (272)

Methyl 1-((3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-carbamoyl)cyclopropane-1-carboxylic acid (271): A solution of compound 259 (108 mg, 0.7 mmol, 1.5 equivalent), HATU (285 mg, 0.75 mmol, 1.5 equivalent), and DIEA (0.26 mL, 3 equivalent) in DMF (2.5 mL, 0.2 M) was stirred at room temperature for 15 min. Compound 258 (170 mg, 0.5 mmol, 1.0 equivalent) was added, and the mixture was stirred at room temperature for 17 h. Water was added, and the resulting mixture was extracted with EtOAc. The organic layer was separated and washed with a saturated aqueous solution of NaCl, _dried over anhydrous _Na₂SO₄ , and concentrated under reduced pressure. The resulting residue was aspirated onto silica gel and purified by CombiFlash using a gradient of 1:8 hexane:EtOAc followed by 1:6 hexane:DCM. The resulting product was sonicated with hexane. The resulting solid was filtered, dissolved in DCM, and washed with 10% LiCl aqueous solution. The organic layer was dried over _{anhydrous Na₂SO₄} and concentrated to give compound 271 (90 mg, 38% yield). ¹ HNMR(400MHz,DMSO-d ₆ )δ10.64(br s,1H),8.67(d,1H),8.61(s,1H),8.39(d,1H),7.88(m,1H),7.54(s,1H),7.51-7.44(m,2H) ,6.52(d,1H),4.03(s,3H),3.71(s,3H),2.85(d,3H),1.46-1.45(m,2H),1.43-1.42(m,2H).

1-((3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)carbamoyl)-cyclopropane-1-carboxylic acid (272): Compound 271 (70 mg, 0.2 mmol, 1.0 equivalent) and NaOH (12 mg, 0.5 mmol) in MeOH and THF solutions (1 mL each) were stirred overnight at 50 °C. The reaction solution was cooled and then concentrated under reduced pressure. 1 N HCl aqueous solution was added to the residue, and the resulting mixture was extracted with DCM. The organic phase was dried over _{anhydrous Na₂SO₄} and concentrated under reduced pressure to give crude compound 272 (60 mg, 89% yield), which could be used in subsequent reactions without further purification. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.85(br s,1H),8.87(d,1H),8.67(s,1H),8.46(d,1H),7.95(m,1H),7.62(s,1H) ,7.54-7.5(m,2H),6.83(d,1H),4.06(s,3H),2.85(d,3H),1.43(s,4H).

Example 90: 1-N'-[3-fluoro-4-[7-methoxy-6-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]-1-N-[4-(trifluoromethyl)phenyl]cyclopropane-1,1-dicarboxamide (273)

1-N'-[3-fluoro-4-[7-methoxy-6-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]-1-N-[4-(trifluoromethyl)phenyl]cyclopropane-1,1-dicarboxamide (273): Compound 273 was synthesized from compound 272 and 4-(trifluoromethyl)aniline using standard HATU amide bond forming techniques, such as those used in the first step of Examples 3, 4 and 89. ^¹H NMR (400MHz, _CD₃OD ) δ 8.90 (s, ¹H), 8.86 (d, ¹H), 7.89 (d, ¹H), 7.55 (s, ¹H), 7.51 (d, 2H), 7.43 (m, _2H ), 7.25 (d, 2H), 6.98 (d, ¹H), 4.13 (s, 3H), 2.94 (s, 3H), 1.64–1.54 (m, 4H). _{MS (EI) was C₃₀H₂₄F₄N₄O₅ ,} measured value _597.2 ( _MH⁺ ).

Following the same procedure used in Example 90 for the synthesis of compound 273 from compound 272, the following compounds were prepared from compound 272:

1-N-(4-chlorophenyl)-1-N'-[3-fluoro-4-[7-methoxy-6-(methylcarbamoyl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (274): 4-chloroaniline was used instead of 4-(trifluoromethyl)aniline. ^¹H NMR (400 MHz, _CD₃OD ) δ 8.99 (s, 1H), 8.95 (d, 1H), 7.98 (d, 1H), 7.83 (d, 2H), 7.65 (d, 3H), 7.54 (q, 2H), 7.06 (d, 1H), 4.22 (s, 3H), 3.03 (s, 3H), 1.84–1.64 (m, _4H ). _{MS (EI) was C₂₉H₂₄ClFN₄O₅ ,} measured _563.2 (MH⁺).

Example 91: 1-N'-(4-fluorophenyl)-1-N-[4-[7-[(E)-methoxyiminomethyl]quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (278)

(4-Chloroquinoline-7-yl)methanol (275): Compound 161 (400 mg, 1.80 mmol, 1 equivalent) in THF (2 mL) was added to a solution of _LiAlH4 (116.45 mg, 3.07 mmol, 1.7 equivalent) in THF (5 mL) at 0 °C. The mixture was stirred at 20 °C for 3 hours. _Na2SO4 · _10H2O ( ₅₀ mg) was added, the resulting mixture was filtered, and the filtrate was dried over _{anhydrous Na2SO4} and then concentrated under vacuum. The residue was purified by rapid silica gel chromatography (4 g silica rapid column, eluent 70%–100% ethyl acetate/petroleum ether gradient @ 25 mL/min) to give compound 275 as a pale yellow solid (150 mg, 36.5% yield). ¹ H NMR (400MHz, CDCl ₃ ) δ 8.74 (d, 1H), 8.19 (d, 1H), 8.12 (s, 1H), 7.64 (dd, 1H), 7.47 (d, 1H), 4.94 (s, 2H), 2.99 (br s, 1H).

N-(4-fluorophenyl)-N-(4-((7-(hydroxymethyl)quinoline-4-yl)oxy)phenyl)cyclopropane-1,1-dicarboxamide (276): Compound 276 was synthesized from compound 275 and compound 3 by lowering the reaction temperature to 85°C in a manner similar to that used in the last step of Example 12 for the synthesis of compound 43 from compound 42 and compound 3. ^¹H NMR (400MHz, _CD₃OD ) δ 8.63 (d, ¹H), 8.41 (d, ¹H), 8.03 (s, ¹H), 7.76 (d, 2H), 7.68 (dd, ¹H), 7.62–7.55 (m, 2H), 7.30–7.23 (m, 2H), 7.09 (t, 2H), 6.66 (d, ¹H), 4.88 (s, 2H), 1.66 (d, 4H); MS (EI) was _{C₂₇H₂₂FN₃O₄ , measured value} 472.1 (MH⁺).

N-(4-fluorophenyl)-N-(4-((7-formylquinoline-4-yl)oxy)phenyl)cyclopropane-1,1-dicarboxamide (277): _MnO₂ (239.72 mg, 2.76 mmol, 13 equivalents) was added to a DCM (5 mL) solution of compound 276 (100 mg, 212.1 μmol, 1 equivalent). The mixture was stirred at 20 °C for 1 _h . The mixture was filtered and concentrated under vacuum to give compound 277 as a yellow oil (50 mg, 40.2% yield). _{MS (EI) was C₂₇H₂₀FN₃O₄ , and} the measured value was 470.0 (MH⁺).

1-N'-(4-fluorophenyl)-1-N-[4-[7-[(E)-methoxyiminomethyl]quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (278): O-methylhydroxylamine (44.47 mg, 532.5 μol, 5 equivalents, HCl) was added to a mixture of compound 277 (50 mg, 106.5 μol, 1 equivalent) in EtOH (3 mL) and water (0.3 mL). The mixture was stirred at 50 °C for 2 h. The mixture was concentrated under vacuum, and EtOH (3 mL) was added to the residue. The obtained white solid was collected and then purified by preparative HPLC (YMC-Actus Triart C18 150*30mm*5um; mobile phase: [water (0.225% FA)-ACN]; B%: 37%-77%, 10 min) to give compound 278 as a white solid (14.5 mg, 26.2% yield). ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.22 (s, 1H), 10.07 (s, 1H), 8.72 (d, 1H), 8.51 (s, 1H), 8.34 (d, 1H), 8.18 (d, 1H), 7.97 (dd, 1H), 7.79 (d, 2H), 7.70–7.61 (m, 2H), 7.28 (d, 2H), 7.16 (t, 2H), 6.60 (d, 1H), 3.98 (s, 3H) _{, 1.48 (s, 4H); MS (EI) was C₂₈H₂₃FN₄O₄ , measured} value _499.2 (MH⁺).

Example 92: 1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(methylcarbamoylamino)-quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (279)

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(methylcarbamoylamino)-quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (279): 1-methylurea (48.46 mg, 654.10 μmol, 6 equivalents), _Pd₂ (dba) _₃ (14.97 mg, 16.35 μmol, 0.15 equivalents), Xantphos (18.92 mg, 32.70 μmol, 0.3 equivalents), and _Cs₂CO₃ (99.46 mg, 305.25 μmol, 2.8 equivalents) were added to a mixture of compound ₄₃ (60 mg, 109.02 μmol, 1 equivalent) in dioxane (3 mL) under a nitrogen atmosphere. The mixture was stirred at 100 °C for 1 h. The reaction mixture was concentrated, and water (20 mL) was added to the residue. The resulting mixture was extracted with EtOAc (3 x 25 mL). The combined organic extracts were dried over _{anhydrous Na₂SO₄} and concentrated under vacuum. The resulting residue was purified by preparative HPLC (column: DuraShell 150*25mm*5um; mobile phase: [water (0.05% ammonium hydroxide v/v)-ACN]; B%: 30%-70%, 10 min) to give compound 279 as a white solid (12.8 mg, 20.7% yield). ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.15 (s, ¹H), 10.07 (s, ¹H), 8.97 (s, ¹H), 8.44 (d, ¹H), 8.32 (s, ¹H), 7.76 (d, 2H), 7.65 (dd, 2H), 7.40 (s, 1H), 7.24–7.12 (m, 4H), 6.95 (br d, ¹H), 6.41 (d, 1H), 4.04 (s, 3H), 2.68 (s, 3H) _{, 1.48 (br d, 4H); MS (EI) was C₂⁹H₂⁶FN₅O₅ , measured value} 544.3 (MH⁺).

Example 93: Methyl N-[4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-7-methoxyquinoline-6-yl]carbamate (280)

N-[4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-7-methoxyquinoline-6-yl]carbamate (280): Compound 280 was synthesized from compound 43 by replacing 1-methylurea with methyl carbamate in a manner similar to that used in Example 92 for the synthesis of compound 279 from compound 43. ^¹H NMR (400MHz, DMSO- _d₆ ) δ 10.17 (s, ¹H), 10.06 (s, ¹H), 8.84 (s, ¹H), 8.67 (s, ¹H), 8.52 (d, ¹H), 7.77 (d, 2H), 7.70–7.62 (m, 2H), 7.45 (s, ¹H), 7.23 (d, 2H), 7.19–7.12 (m, 2H), 6.45 (d, ¹H), 4.00 ( _s , 3H), 3.72 (s, 3H), 1.48 (s, 4H); MS (EI) was _{C₂ ₹H₂₅FN₄O₆ ,} measured value 567.3 [M+Na] ^⁺

Example 94: 1-N'-(4-fluorophenyl)-1-N-[4-[7-(methylcarbamoylamino)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (281)

1-N'-(4-fluorophenyl)-1-N-[4-[7-(methylcarbamoylamino)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (281): A mixture of compound 232 (100 mg, 192.18 μmol, 1 equivalent), methylurea (42.71 mg, 576.54 μmol, 3 equivalent), Xantphos (22.24 mg, 38.44 μmol, 0.2 equivalent), t-BuONa (36.94 mg, 384.36 μmol, 2 equivalent) and _Pd₂ (dba)₃ (17.60 mg, 19.22 μmol, 0.1 equivalent) in dioxane (5 mL) was degassed and purged three times with nitrogen, then stirred at 100 °C for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: Ultimate C18 10μm 250mm*50mm; mobile phase: [water (0.05% ammonium hydroxide v/v)-ACN]; B%: 39%-69%, 9 min) to give compound 281 as a white solid (56.9 mg, 57.4% yield). ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.18 (s, ¹H), 10.06 (s, ¹H), 9.09 (s, ¹H), 8.55 (d, ¹H), 8.14 (d, 2H), 7.75 (d, 2H), 7.69–7.57 (m, 3H), 7.22 (d, 2H), 7.15 (t, 2H), 6.37 (d, ¹H), 6.26 (d, 1H), 2.69 (d, 3H), _1.48 (s, _{4H); MS (EI) was C₂₈H₂₄FN₅O₄ ,} measured value _514.3 (MH⁺).

Example 95: Methyl N-[4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]-amino]phenoxy]quinoline-7-yl]carbamate (282)

N-[4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]-amino]phenoxy]quinoline-7-yl]carbamate (282): Compound 282 was synthesized from compound 232 by replacing 1-methylurea with methyl carbamate in a manner similar to that used in Example 94 for the synthesis of compound 281 from compound 232. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.82–10.72 (m, 1H), 10.40–10.33 (m, 1H), 10.12–10.04 (m, 1H), 8.89 (d, 1H), 8.59 (d, 1H), 8.50 (d, 1H), 7.93–7.81 (m, 3H), 7.69–7.60 (m, 2H), 7.38 (d, 2H), 7.16 (t, 2H), 6.78 (d, 1H), 3.79 (s, 3H), _{1.50 (s, 4H); MS (EI) was C₂₈H₂₃FN₄O₅ , measured} value _515.3 (MH⁺).

Example 96: 1-N-[4-[6-(3-ethyl-1,2,4-oxadiazol-5-yl)-7-methoxyquinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide hydrochloride (283)

1-N-[4-[6-(3-ethyl-1,2,4-oxadiazol-5-yl)-7-methoxyquinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide hydrochloride (283): HATU (26.45 mg, 0.070 mmol) was added to a DMF (0.5 mL) solution of compound 6 (30 mg, 0.058 mmol), (Z)-N'-hydroxypropylimine amide (7.22 mg, 0.058 mmol), and DIEA (44 μL, 0.17 mmol), and the reaction mixture was stirred at room temperature until the starting material disappeared as determined by LC-MS. The reaction mixture was then heated to 60 °C and maintained for 2 hours. A saturated aqueous solution _{of NaHCO3} was added to the resulting mixture, which was then extracted with DCM (3x). The combined organic extracts were washed with a saturated aqueous solution of NaCl, _dried over _Na2SO4 , and concentrated. The crude residue was purified by HPLC (Gemini-NX, 10 μM, 250 x 30 mm, C18 column; eluent: 0.1%–100% acetonitrile aqueous solution, both eluents containing 0.1% trifluoroacetic acid, gradient elution for at least 15 minutes), followed by lyophilization. The resulting powder was placed in a 20% MeOH solution in DCM and passed through an Agilent PL-HCO3 ion exchange column (or placed in DCM and washed with saturated sodium bicarbonate), and concentrated under reduced pressure. HCl (4 M dioxane solution, 0.5 mL; or 1 M aqueous solution, 1 mL) was added to remove volatile solvents under reduced pressure, and the residue was dried under high vacuum to give the hydrochloride of compound 283 (4.1 mg, 11.7% yield). ^¹H NMR (400MHz, _CD₃OD ) δ 9.29 (s, ¹H), 8.94 (d, ¹H), 7.86 (q, 2H), 7.68 (s, ¹H), 7.61–7.54 (m, 2H), 7.41 (d, 2H), 7.10 (t, 2H), 7.02 (d, 1H), 4.26 (s, 3H), 2.91 (q, 2H), 1.68 (s, 4H), 1.42 (t, 3H). _{MS (EI) was C₃¹H₂₆FN₅O₅ ,} measured _{value 568.2} (MH⁺).

Example 97: 1-N'-[3-fluoro-4-[6-methyl-7-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (289)

4-Hydroxy-6-methylquinoline-7-carboxylic acid methyl ester (284): A mixture of compound 139 (290 mg, 1.11 mmol, 1 equivalent) and AcONa (454.26 mg, 5.54 mmol, 5 equivalent) in AcOH (6 mL) and water ( ₁₀ mL) was stirred at 90 °C for 48 h. After cooling to ambient temperature, the reaction mixture was neutralized with a saturated aqueous solution _{of NaHCO3} and extracted with EtOAc (3 x 30 mL). The combined extracts were dried over anhydrous _Na2SO4 and concentrated under reduced pressure to give compound 284 as a pale yellow solid (200 mg, 74.8% yield), which could be used directly in subsequent reactions without further purification. _{MS (EI) was C12H11NO3 , and} the result was 218.1 (MH+).

4-(2-fluoro-4-nitrophenoxy)-6-methylquinoline-7-carboxylic acid methyl ester (285): Cs₂CO₃ (809.97 mg, 2.49 mmol, 3 equivalents) was added to a mixture of compound 284 (200 mg, 828.65 μmol, ₁ equivalent) and 1,2-difluoro-4-nitrobenzene (197.75 mg, 1.24 mmol, 137.32 μL, 1.5 equivalents) in _ACN (15 mL) at 25 °C, and the mixture was stirred at 70 °C for 2 h. After cooling, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 30 mL). The combined organic extracts were washed with a saturated aqueous solution of NaCl (60 mL), _dried over anhydrous _Na₂SO₄ , and concentrated. The residue was purified by rapid silica gel chromatography, eluting with petroleum ether (0–60%) solution of EtOAc to give compound 285 as a pale yellow solid (120 mg, 38.6% yield). ^¹H NMR (400 MHz, _CDCl₃ ) δ 8.77 (d, 1H), 8.70 (s, 1H), 8.23–8.15 (m, 2H), 8.12 (s, 1H), 7.42–7.35 (m, 1H), 6.65 (d, 1H), 3.99 (s, 3H), 2.79 ( _{s, 3H); MS (EI) was C₁₈H₁₃FN₂O₅ ,} measured _357.0 ( _MH⁺ ).

4-(4-amino-2-fluorophenoxy)-6-methylquinoline-7-carboxylic acid methyl ester (286): Compound 286 was synthesized from compound 285 using a method similar to that used in Example 78 to convert compound 218 to compound 219. _MS ( _{EI )} was _C18H15FN2O3 , measured at 326.9 (MH+).

Methyl 4-(2-fluoro-4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylamino)phenoxy)-6-methylquinoline-7-carboxylic acid ester (287): A mixture of compound 1 (51.30 mg, 218.34 μmol, 1.5 equivalents) in _SOCl2 (8.20 g, 68.92 mmol, 5.00 mL, 473.51 equivalents) was stirred at 65 °C for 1 h. The mixture was concentrated, and the residue was dissolved in toluene and concentrated again. A solution of compound 286 (50 mg, 145.56 μmol, 1.0 equivalents) in THF (5 mL) was added to the resulting residue, followed by the addition of triethylamine (44.19 mg, 436.69 μmol, 60.78 μL, 3 equivalents). The resulting mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched with water (30 mL) and extracted with EtOAc (3 x 20 mL). The combined extracts were dried over _{anhydrous Na₂SO₄} and concentrated. The resulting residue was purified by silica gel chromatography, eluting with petroleum ether solution of EtOAc (0–70%), to give compound 287 as a grayish-white solid ( ₇₀ mg, _{85.95 %} yield). _MS (EI) was _{C₂₉H₂₃F₂N₃O₅} , and the result was 532.0 (MH⁺).

4-(2-Fluoro-4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylamino)phenoxy)-6-methylquinoline-7-carboxylic acid (288): A mixture of compound 287 (70.0 mg, 125.12 μmol, 1 equivalent) and LiOH· _H₂O (26.25 mg, 625.58 μmol, 5 equivalent) in THF (5 mL) and water (5 mL) was stirred at 25 °C for 4 H. The reaction mixture was acidified with 1 M HCl aqueous solution until a pH of ~5 was reached. The mixture was then diluted with water (30 mL) and extracted with EtOAc (3 x 20 _mL ). The combined organic extracts were dried over anhydrous _Na₂SO₄ and concentrated to give compound 288 as a white solid (70 mg, 86.49% yield), which could be used directly in subsequent reactions without further purification. _{MS(EI) is C28H21F2N3O5 , measured} value _{518.1 (} MH+).

1-1-N'-[3-fluoro-4-[6-methyl-7-(methylcarbamoyl)quinolin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (289): Compound 289 was synthesized from compound 288 in a manner similar to that used in the preparation of compound 8 in Example 4. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.39(s, ¹H), 9.99(s, ¹H), 8.67(d, ¹H), 8.48(d, ¹H), 8.16(s, ¹H), 7.95(s, ¹H), 7.91(d, ¹H), 7.63(dd, 2H), 7.56–7.49(m, ¹H), 7.47–7.41(m, ¹H), 7.15(t, 2H), 6.59(d, ¹H), 2.82(d, 3H), 2.54(s, 3H), 1.47(d, 4H); _MS ( _{EI )} was _{C₂⁹H₂⁴F₂N₄O₄ ,} measured value 531.1 (MH⁺).

The following compounds were prepared from compound 139 using the same 6-step method as used in Example 97 for the synthesis of compound 289:

1-N'-[2,5-difluoro-4-[6-methyl-7-(methylcarbamoyl)quinolin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (290): In step 2, 1,2-difluoro-4-nitrobenzene is replaced with 1,2,4-trifluoro-5-nitrobenzene. ^¹H NMR (400MHz, _CDCl₃ ) δ 10.09 (br s, ¹H), 8.59 (d, ¹H), 8.28 (dd, ¹H), 8.21 (s, ¹H), 8.09 (s, ¹H), 8.00 (s, ¹H), 7.36–7.43 (m, 2H), 6.96–7.06 (m, 3H), 6.47 (d, ¹H), 5.98 (d, 1H), 3.01 (d, 3H), 2.58 (s, 3H), 1.72–1.78 (m, 2H), 1.59–1.62 ( _m , 2H); MS (EI) was _{C₂ ₹ H₂₃F₃N₄O₄} , measured value _549.1 (MH⁺).

1-N'-[2-chloro-5-fluoro-4-[6-methyl-7-(methylcarbamoyl)quinolin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (291): In step 2, 1-chloro-4,5-difluoro-2-nitrobenzene is used instead of 1,2-difluoro-4-nitrobenzene. ^¹H NMR (400MHz, _CDCl₃ ) δ 10.08 (s, ¹H), 8.66 (d, ¹H), 8.61 (s, ¹H), 8.44 (d, ¹H), 8.15 (s, ¹H), 8.07 (s, ¹H), 7.52–7.45 (m, 2H), 7.36 (d, ¹H), 7.06 (t, 2H), 6.54 (d, ¹H), 6.15–6.07 (m, ¹H), 3.08 (d, 3H), 2.65 (s, 3H), 1.82–1.72 ( _m , 4H); MS (EI) was _{C₂ ₹ H₂₃ClF₂N₄O₄} , measured value _565.1 (MH⁺).

1-N-(4-fluorophenyl)-1-N'-[2,3,5-trifluoro-4-[6-methyl-7-(methylcarbamoyl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (292): In step 2, 1,2-difluoro-4-nitrobenzene is replaced with 1,2,3,4-tetrafluoro-5-nitrobenzene. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 11.33 (s, ¹H), 9.77 (s, ¹H), 8.71 (d, ¹H), 8.54–8.48 (m, ¹H), 8.18 (s, ¹H), 8.08–8.02 (m, ¹H), 7.98 (s, ¹H), 7.63–7.56 (m, 2H), 7.23–7.14 (m, 2H), 6.89 (d, ¹H), 2.83 (d, 3H), 2.55 (s, 3H), 1.72–1.65 (m, 2H), 1.62–1.57 (m, 2H); MS (EI) was _{C₂ ₹H₂₂F₄N₄O₄ , measured value} 567.1 (MH⁺).

Example 98: 1-N'-[4-(7-carbamoyl-6-methylquinoline-4-yl)oxy-3-fluorophenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (293)

1-N'-[4-(7-carbamoyl-6-methylquinoline-4-yl)oxy-3-fluorophenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (293): Compound 293 was synthesized from compound 288 in a manner similar to that used in the preparation of compound 7 in Example 3. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.40(s, ¹H), 10.00(s, ¹H), 8.67(d, ¹H), 8.16(s, ¹H), 8.03(s, ¹H), 7.99(s, ¹H), 7.91(d, ¹H), 7.64(dd, 2H), 7.58(s, ¹H), 7.56–7.51(m, ¹H), 7.47–7.41(m, ¹H), 7.15(t, 2H), 6.59(d, ¹H), 2.58(s, 3H), 1.47(d, 4H); _MS ( _{EI )} was _{C₂₈H₂₂F₂N₄O₄ ,} measured value 517.1 (MH⁺).

The following compounds were prepared using a method similar to that used in Example 98 for the synthesis of compound 293 from compound 288:

1-N'-[4-(7-carbamoyl-6-methylquinoline-4-yl)oxy-2,5-difluorophenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (294): 4-(2,5-difluoro-4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylamino)phenoxy)-6-methylquinoline-7-carboxylic acid was used instead of compound 288, prepared using the same multi-step procedure as that used in Example 97 for the synthesis of compound 288, except that in step 2, 1,2-difluoro-4-nitrobenzene was used instead of 1,2-difluoro-4-nitrobenzene. ^¹H NMR (400MHz, _CDCl₃ ) δ 10.19 (br s, 1H), 8.67 (d, 1H), 8.36 (dd, 1H), 8.26 (br s, 1H), 8.19 (s, 2H), 7.47 (dd, 2H), 7.03–7.12 (m, 3H), 6.55 (d, 1H), 6.04 (br s, 1H), 5.78 (br s, 1H), 2.70 (s, 3H), 1.75–1.90 ( _m , 2H), 1.67–1.69 (m, _{2H); MS (EI) was C₂₈H₂₁F₃N₄O₄ , measured} value _535.1 (MH⁺).

Example 99: 1-N'-[3-fluoro-4-[7-(2-hydroxyethoxycarbamoyl)quinoline-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (301)

4-Hydroxyquinoline-7-carboxylic acid methyl ester (296): Compound 295 (5 g, 22.32 mmol, 1 equivalence) and TEA (22.58 g, 223.16 mmol, 31.06 mL, 10 equivalence) in MeOH (60 mL) and DMSO (20 mL) solutions were added to a round-bottom flask. Then DPPP (1.84 g, 4.46 mmol, 0.2 eq) and Pd(OAc) _₂ (1.00 g, 4.46 mmol, 0.2 equivalence) were added. The flask was purged twice with carbon monoxide and placed under 30 psi of carbon monoxide while heating at 70 °C for 12 hours. MeOH (100 mL) was added, and the resulting suspension was filtered through a diatomaceous earth mat. The filter cake was washed with MeOH (3 x 50 mL). The combined filtrates were concentrated, and the resulting crude product was washed with water (50 mL), ground with MeOH (15 mL), and filtered to give compound 296 as a yellow solid (3.5 g, 77.19% yield). ^¹H NMR (400 MHz, _CDCl₃ ) δ 11.98 (br s, 1H), 8.23–8.15 (m, 2H), 8.01 (dd, 1H), 7.81 (br d, 1H), 6.11 (d, 1H), 3.90 (s, _{3H); MS (EI) was C₁₁H₉NO₃ , measured} 203.9 (MH⁺).

4-(2-fluoro-4-nitrophenoxy)quinoline-7-carboxylic acid methyl ester (297): Compound 297 was prepared from compound 296 in a similar manner to the preparation of compound 285 from compound 284 in Example 97. ^¹H NMR ( ₄₀₀ MHz, _CDCl₃ ) δ 8.88–8.83 (m, 2H), 8.37 (d, 1H), 8.25–8.16 (m, 3H), 7.43 (t, 1H), 6.70 (d, 1H), 4.04 (s, _{3H )} ; MS (EI) was _{C₁₇H₁₁FN₂O₅} , measured 343.2 (MH⁺).

4-(4-amino-2-fluorophenoxy)quinoline-7-carboxylic acid methyl ester (298): Compound 298 was synthesized from compound 297 using a method similar to that used in Example 78 to convert compound 218 to compound 219. MS (EI) _{was C17H13FN2O3} , _and the measured value _was 312.9 (MH+).

Methyl 4-(2-fluoro-4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylamino)phenoxy)quinoline-7-carboxylic acid (299): Compound 1 (428.83 mg, 1.92 mmol, 3 equivalents) was suspended in anhydrous DCM (10 mL) at 25 °C with stirring. DMF (4.68 mg, 64.04 μmol, 4.93 μL, 0.1 equivalents) was added under nitrogen atmosphere, followed by (COCl) _₂ (290.00 mg, 2.28 mmol, 0.2 mL, 3.57 equivalents). The mixture was stirred at 25 °C for 30 minutes. Toluene (5.0 mL) was added, and the solvent was removed under reduced pressure. The resulting acyl chloride product was dissolved in anhydrous THF (1.0 mL). Under nitrogen atmosphere, a THF solution of the acyl chloride prepared above was added to a DMA (6 mL) solution of compound 298 (200 mg, 640.42 μmol, 1 equivalent). The reaction mixture was stirred at 25 °C for 0.5 h. The reaction mixture was poured into a saturated _NaHCO3 aqueous solution (100 mL) and extracted with DCM (3 x 50 mL). The combined organic extracts were washed with a saturated _NaHCO3 aqueous solution (15 mL), then with a saturated NaCl aqueous solution (15 mL ₎ , dried over anhydrous _Na2SO4 , and concentrated under vacuum to give compound 299 as a yellow solid (270 mg, 81.47% yield), which _was used in subsequent reactions without further purification. _{MS (EI) was C28H21F2N3O5 , and} the measured value was 518.1 ₍ MH+).

4-(2-fluoro-4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylamino)-phenoxy)quinoline-7-carboxylic acid (300): Compound 300 was prepared from compound 299 in a manner similar to that used in Example 97 for the preparation of compound 288 from compound 287. _MS (EI) was _{C27H19F2N3O5 ,} and the measured value _was 504.1 ₍ MH+).

1-N'-[3-fluoro-4-[7-(2-hydroxyethoxycarbamoyl)quinolin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (301): HATU (72.50 mg, 190.68 μmol, 1.2 equivalent) and DIEA (61.61 mg, 476.71 μmol, 83.03 μL, 3 equivalent) were added to a DMF (3 mL) solution of compound 300 (80 mg, 158.90 μmol, 1 equivalent), and the resulting mixture was stirred at 25 °C for 30 min. 2-Aminooxyethanol (14.70 mg, 190.68 μmol, 1.2 equivalent) was added, and the reaction mixture was stirred at 25 °C for an additional 2 h. The reaction mixture was poured into a saturated _NH₄Cl aqueous solution (50 mL) and extracted with DCM (3 x 30 mL). The combined organic extracts were concentrated under vacuum, and the resulting residue was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um, gradient: 43%-63% acetonitrile aqueous solution (0.05% _NH3H2O ), flow rate: _25mL /min) to give compound 301 as a white solid (46.8mg, 52.36% yield). ¹ H NMR (400MHz, DMSO-d ₆ ) δ12.09(br s,1H),10.41(br s,1H),10.01(br s,1H),8.78(d,1H),8.45-8.40(m,2H),8.01(dd,1H),7.92(dd,1H),7.68-7.60(m, 2H),7.56-7.51(m,1H),7.50-7.44(m,1H),7.20-7.11(m,2H),6.68(d,1H),4.80(br s,1H),4.00(t,2H),3.66(t,2H),1.51-1.43(m,4H); MS(EI) is C ₂₉ H ₂₄ F ₂ N ₄ O ₆ The measured value was 563.1 (MH+).

The following compounds were prepared from compound 295 using the same 6-step method as used to synthesize compound 301 in Example 99:

1-N'-[2,5-difluoro-4-[7-(2-hydroxyethoxycarbamoyl)quinoline-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (302): In step 2, 1,2-difluoro-4-nitrobenzene is replaced with 1,2,4-trifluoro-5-nitrobenzene. ^¹H NMR (400MHz, DMSO- _d₆ ) δ 12.13 (br s, ¹H), 11.17 (br s, ¹H), 9.78 (br s, ¹H), 8.81 (d, ¹H), 8.46 (s, ¹H), 8.40 (m, ¹H), 8.19 (m, ¹H), 8.04 (d, ¹H), 7.73 (m, ¹H), 7.61 (dd, 2H), 7.19 (t, 2H), 6.83 (d, 1H), 4.81 (m, 1H), 4.00 (m, 2H), 3.68 (m, 2H), 1.69 (m, 2H), 1.61 (m, _2H ); MS (EI) was _{C₂ ₹ H₂₃F₃N₄O₆} , _measured value 581.1 (MH⁺).

Biological Examples

Example A: Kinase Assay

Kinase activity and compound inhibition were studied using a ^33P -phosphoryltransferrradiation assay performed using the KinaseProfiler ^™ service from Eurofins Pharma Discovery Services UK Limited. Dose-response experiments were conducted using nine compound concentrations in 96-well microtiter plates. For each assay, all compounds were prepared to a 50x final assay concentration (50 μM) in 100% DMSO and then serially diluted semi-logarithmically to a final maximum concentration of 1 μM. The working stock solution of the compound was added as the first component of the reaction to the assay wells, followed by the remaining components as detailed in the assay protocol below. The positive control wells (100% kinase activity) contained all components of the reaction, including 2% DMSO (a solvent effect control), but except for the compound of interest. The blank wells contained all components of the reaction, as well as the reference inhibitor astrocytin. This reference compound was used to eliminate kinase activity and produce a baseline of 0% kinase activity. The IC ₅₀ value was calculated using S-shaped dose-response (variable slope) curve fitting with XLFit version 5.3 (ID Business Solutions) via nonlinear regression analysis.

Example B: Human AXL kinase assay

Human Axl (H473-A894 with Q764R residues, 161 nM) was incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 250 μM KKSRGDYMTMQIG (SEQ ID NO.43) , 10 mM magnesium acetate, and 10 μM [γ- ^33P -ATP]. The reaction was initiated by adding the Mg/ATP mixture. After incubation at room temperature for 40 min, the reaction was terminated by adding phosphoric acid to a concentration of 0.5%. 10 μL aliquots of the reaction were then spotted onto a P30 filter pad, washed four times with 0.425% phosphoric acid for 4 min each time, followed by one wash in methanol, then dried and scintillation counted. The incorporated ^γ-33P was measured using a Wallac Microbeta scintillation counter (Perkin Elmer).

Example C: Human KDR kinase assay

Human KDR (residue K790-V1356, 55 nM) was incubated with 8 mM MOPS at pH 7.0, 0.2 mM EDTA, 0.33 mg/mL myelin basic protein, 10 mM magnesium acetate, and 10 μM [γ- ^33P -ATP]. The reaction was initiated by adding a Mg/ATP mixture. After incubation at room temperature for 40 minutes, the reaction was terminated by adding phosphate to a concentration of 0.5%. 10 μL aliquots of the reaction were then spotted onto a P30 filter pad and washed four times with 0.425% phosphate for 4 minutes each time, followed by one wash with methanol, then dried and scintillation counted. The incorporated ^γ-33P was measured using a Wallac Microbeta scintillation counter (Perkin Elmer).

Example D: Human Merkinase Assay

Human Mer (0.7 nM with R557-E882 residues of H628Q and R794A) was incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 30 mM NaCl, 250 μM GGMEDIYFEFMGGKKK (SEQ ID NO.44) , 10 mM magnesium acetate, and 10 μM [γ- ^33P -ATP]. The reaction was initiated by adding the Mg/ATP mixture. After incubation at room temperature for 40 min, the reaction was terminated by adding phosphoric acid to a concentration of 0.5%. 10 μL aliquots of the reaction were then spotted onto a P30 filter pad, washed four times with 0.425% phosphoric acid for 4 min each time, followed by one wash in methanol, then dried and scintillation counted. The incorporated ^γ-33P was measured using a Wallac Microbeta scintillation counter (Perkin Elmer).

Example E: Human Met Kinase Assay

Human Met (with R974-S1390 residues of A1209G and V1290L, 3.4 nM) was incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 250 μM KKKGQEEEYVFIE (SEQ ID NO.45) , 1 mM sodium orthovanadate, 5 mM sodium 6-glycerophosphate, 10 mM magnesium acetate, and 10 μM [γ- ^33P -ATP]. The reaction was initiated by adding the Mg/ATP mixture. After incubation at room temperature for 40 min, the reaction was terminated by adding phosphoric acid to a concentration of 0.5%. 10 μL aliquots of the reaction were then spotted onto a P30 filter pad, washed four times with 0.425% phosphoric acid for 4 min each time, followed by one wash in methanol, then dried and scintillation counted. The incorporated ^33P was measured using a Wallac Microbeta scintillation counter (Perkin Elmer).

Activity data of the compounds in the examples obtained by kinase assays in Examples A, B, D and E are provided in Table 2 (A: IC ₅₀ ≤ 10 nM; B: 10 nM < IC 50 ≤ 100 nM; C: 100 nM < IC ₅₀ ≤ 1000 nM; D: IC ₅₀ > 1000 nM).

Table 2: Activity data of the compounds selected in this invention

Example F: AXL autophosphorylation ELISA in A-172 cells

A-172 glioblastoma cells (ATCC#CRL-1620) were seeded at 2.5 x ^10⁵ cells/well in 24-well plates (Greiner#662165) in DMEM (Thermo Fisher#11995-040) containing 10% FBS (Thermo Fisher#26140-079), 1% MEM NEAA (Thermo Fisher#11140-050), 1% GlutaMax (Thermo Fisher#35050-061), and 1% penicillin-streptomycin (Thermo Fisher#15140-122). A-172 cells were incubated at 37°C and 5% _CO₂ for 24 hours, followed by starvation in serum-free medium for 24 hours. The test compound was serially diluted in fresh serum-free medium to a final concentration of 0.3% DMSO (the medium) to generate an 8-point dose curve, added to the cells, and incubated for 1 hour. Cells were then stimulated with 1 μg/mL recombinant human Gas6 (R&D Systems #885-GSB-500) for 15 min, washed with cold PBS, and immediately lysed with 150 μL of cold 1X lysis buffer [20 mM Tris, 137 mM sodium chloride, 2 mM EDTA, 10% glycerol, 1% NP-40 substitute, 1 mM activated sodium orthovanadate, 1 mM PefaBloc SC (Sigma-Aldrich #11429868001), protease/phosphatase inhibitor tablets (Thermo Fisher #A32959)]. Lysates were collected and added at 100 μL/well to a human phosphate-AXL DuoSet IC ELISA (R&D Systems #DYC2228-2). Assays were performed according to the manufacturer's instructions, and the phosphate-AXL concentration in the samples was extrapolated using a human phosphate-AXL control (R&D Systems #841645) as a standard. Positive control wells (100% activity) contained DMSO-treated cell lysates stimulated by Gas6. Negative control wells (0% activity) contained cell lysates treated with a reference inhibitor of Gas6. _IC50 values were calculated using a 4-parameter logistic curve fitted in ActivityBase XE (IDBS) via nonlinear regression analysis.

Example G: Met autophosphorylation ELISA in PC-3 cells

PC-3 prostate cancer cells (ATCC#CRL-1435) were seeded at 4 x ^10⁴ cells/well in 24-well plates (Greiner#662165) in DMEM (Thermo Fisher#11995-040) containing 10% FBS (Thermo Fisher#26140-079), 1% MEM NEAA (Thermo Fisher#11140-050), 1% GlutaMax (Thermo Fisher#35050-061), and 1% penicillin-streptomycin (Thermo Fisher#15140-122). PC-3 cells were incubated at 37°C and 5% _CO₂ for 24 hours, followed by starvation in serum-free medium for 3 hours. The test compound was serially diluted in fresh serum-free medium to a final concentration of 0.3% DMSO (the medium) to generate an 8-point dose curve, added to the cells, and incubated for 1 hour. Cells were then stimulated with 100 ng/mL recombinant human HGF (R&D Systems #294-HG-250) for 10 min, washed with cold PBS, and immediately lysed with 130 μL of cold 1X lysis buffer [20 mM Tris, 137 mM sodium chloride, 2 mM EDTA, 10% glycerol, 1% NP-40 substitute, 1 mM activated sodium orthovanadate, 1 mM PefaBloc SC (Sigma-Aldrich #11429868001), protease/phosphatase inhibitor tablet (Thermo Fisher #A32959)]. The lysate was clarified by centrifugation and added at 100 μL/well to a PathScan phosphate-Met (panTyr) sandwich ELISA (Cell Signaling Technology #7333). Assays were performed according to the manufacturer's instructions. Positive control wells (100% activity) contained HGF-stimulated DMSO-treated cell lysates. Negative control wells (0% activity) contained cell lysates treated with a reference inhibitor of HGF stimulation. _IC50 values were calculated using a 4-parameter logistic curve fitted in ActivityBase XE (IDBS) via nonlinear regression analysis.

Example H: KDR autophosphorylation ELISA in HUVEC cells

Human umbilical vein endothelial cells or HUVECs (Lonza#C2519A) were seeded at 2 x ^10⁴ cells/well in 96-well plates (Corning#3904) on EGM-2 growth medium (Lonza#CC-3162) containing 1% penicillin-streptomycin (Thermo Fisher#15140-122). HUVEC cells were incubated at 37°C and 5% _CO₂ for 24 hours, followed by starvation for 24 hours in serum-free EGM-2 basal medium (Lonza#CC-3156) containing 1% penicillin-streptomycin. The test compound was serially diluted in fresh serum-free medium to a final concentration of 0.3% DMSO (mediator) to generate an 8-point dose curve, added to the cells, and incubated for 1 hour. Cells were then stimulated with 100 ng/mL recombinant human VEGF165 (R&D Systems #293-VE-500) for 5 min, washed with cold PBS, and immediately lysed with 130 μL of cold 1X lysis buffer [20 mM Tris, 137 mM sodium chloride, 2 mM EDTA, 10% glycerol, 1% NP-40 substitute, 1 mM activated sodium orthovanadate, 1 mM PefaBloc SC (Sigma-Aldrich #11429868001), protease/phosphatase inhibitor tablet (Thermo Fisher #A32959)]. Lysates were collected and added at 100 μL/well to a human phosphate-KDR DuoSet IC ELISA (R&D Systems #DYC1766-2). Assays were performed according to the manufacturer's instructions, using a human phosphate-KDR control (R&D Systems #841421) as a standard to extrapolate the sample phosphate-KDR concentration. Positive control wells (100% viability) contained VEGF165-stimulated DMSO-treated cell lysates. Negative control wells (0% viability) contained unstimulated cell lysates. _IC50 values were calculated using a 4-parameter logistic curve fitted in ActivityBaseXE (IDBS) via nonlinear regression analysis.

Example 1: Mer autophosphorylation ELISA in transiently transfected 293A cells

293A cells (Thermo Fisher #R70507) were seeded at 1.5 x ^10⁶ cells/well in DMEM (Thermo Fisher #11995-040) containing 10% FBS (Thermo Fisher #26140-079), 1% MEM NEAA (Thermo Fisher #11140-050), 1% GlutaMax (Thermo Fisher #35050-061), and 1% penicillin-streptomycin (Thermo Fisher #15140-122) on 100 mm dishes (Greiner #664169). The 293A cells were incubated at 37°C and 5% _CO₂ for 24 hours, and then transfected with 6 μg of MERTKDNA (Genecopoeia #EX-Z8208-M02) using TransIT LT1 transfection reagent (Mirus-Bio #MIR2305). After 24 hours of incubation, transfected 293A cells were seeded at 1 x ^10⁵ cells/well in DMEM growth medium on 96-well plates (Corning #3904) and incubated overnight. The test compound was serially diluted in fresh serum-free medium to a final concentration of 0.3% DMSO (mediator) to generate an 8-point dose curve, and added to the cells and incubated for 1 hour. The cells were then immediately lysed with 150 μL of cold 1X lysis buffer [20 mM Tris, 137 mM sodium chloride, 2 mM EDTA, 10% glycerol, 1% NP-40 substitute, 1 mM activated sodium orthovanadate, 1 mM PefaBloc SC (Sigma-Aldrich #11429868001), protease/phosphatase inhibitor tablets (Thermo Fisher #A32959)]. The lysate was clarified by centrifugation and added at 50 μL/well to a human phosphate-Mer DuoSet IC ELISA (R&D Systems#DYC2579-2). Assays were performed according to the manufacturer's instructions, and the human phosphate-Mer control (R&D Systems#841793) was used as a standard to extrapolate the phosphate-Mer concentration in the samples. Positive control wells (100% activity) contained DMSO-treated cell lysates. Negative control wells (0% activity) contained cell lysates treated with a reference inhibitor. _IC50 values were calculated using a 4-parameter logistic curve fitted in ActivityBase XE (IDBS) via nonlinear regression analysis.

As illustrated herein, the compounds of this disclosure exhibit IC ₅₀ values in the following ranges: A: IC ₅₀ ≤ 10 nM; B: 10 nM < IC ₅₀ ≤ 100 nM; C: 100 nM < IC 50 ≤ 300 nM; D: IC ₅₀ > 300 nM. "NT" indicates not tested _.

Activity data of the compounds in the examples, obtained using cell-based kinase assays from Examples F, G, H, and I, are provided in Table 3.

Table 3: Cell activity data of the selected compounds of this invention

Example J: Pharmacokinetic Study

The pharmacokinetic properties of the selected compounds were evaluated in male Sprague-Dawley rats.

Non-GLP studies were designed to investigate the pharmacokinetics of the selected compounds in plasma after intravenous or oral administration to male Sprague-Dawley rats.

Two groups of male Sprague-Dawley rats (n=3 per group) received a target dose level of 3 mg/kg of the compound via intravenous or oral (force-feed) administration. Any clinically relevant abnormalities were observed in the animals during administration and at each sample collection period.

Animals in the PO group were fasted overnight before dose administration. They were reintroduced to food 4 hours after blood sampling. Water was not inhibited.

Record the weight of each animal immediately before administration. Calculate the dose based on pretreated body weight (kg) (rounded to the nearest 0.001 mL), with an intravenous dose volume of 2.5 mL/kg and an oral dose volume of 5 mL/kg. Intravenous formulations are administered via a jugular vein cannula. Immediately after administration, flush the cannula with saline and tie the line. Oral doses are administered via a bulb-tip feeding needle. The volume of the administration syringe used is validated by a second person before administration, and this volume is used in conjunction with the results of concentration validation analysis to calculate the actual dose. Weigh the administration syringe immediately before and after administration to each animal for gravimetric analysis.

Serial blood samples (approximately 200 μL/sample) were collected from each animal at 0.083 hours (IV administration only), 0.25, 0.5, 1, 2, 4, 6 hours (PO administration only), 8, 24, 32, 48, and 72 hours after administration. Blood samples were collected into tubes containing _K₂EDTA via a non-drug-treated jugular vein cannula (JVC), which was flushed with approximately an equal volume of saline after each collection.

Blood samples were stored on wet ice until they were processed into plasma by centrifugation (3500 rpm, 5°C for 10 minutes) within 1 hour of collection. Plasma samples were then transferred to matrix tubes and stored at -80°C.

Compounds of interest in plasma and dosage form samples were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Pharmacokinetic parameters were estimated from individual animal plasma concentration-time data using actual doses, based on the dosage form, nominal sampling time (all collections were within acceptable limits for the target), and non-compartmental methods. Concentration-time data were analyzed using WinNonlin Phoenix version 6.3 (Pharsight) software to fit intravenous bolus (IV) plasma analysis models (201) or extravascular (PO) plasma analysis models (200). The single-dose pharmacokinetic parameters assessed appropriately included: _Cmax (observed peak or maximum concentration); _Tmax (time to observed peak concentration); T1 _/2 (terminal half-life); _Vz (volume of distribution based on terminal phase); _Vss (volume of distribution at steady state); AUC _INF (area under the concentration-time curve calculated from time zero to infinity); AUC _last (area under the concentration-time curve calculated from time zero to the last quantifiable concentration); _C0 (back-extended concentration at time zero); CL (systemic clearance); Vz/F (volume of distribution based on extravascular administration at terminal phase); CL/F (systemic clearance after extravascular administration); F% (bioavailability); and MRT _last (mean residence time).

The area under the plasma concentration-time curve (AUC) was estimated using the linear logarithmic trapezoidal rule. The area under the last observable concentration (C _{_last} ) over time (T _{_last} ) was reported as AUC _{_last}. The AUC extrapolated to infinity (AUC _INF _f) was estimated by adding the ratios of AUC _{_last} and C _{_last} /λ_{_z}, where λ_{_z} is the terminal rate constant. The apparent terminal half-life (T _{_1/2}) was calculated as ln(2)/λ_{_z} and determined using the slope of the log-linear terminal phase of the concentration-time curve, which was defined by at least three plasma concentration-time points. The half-life was reported if the correlation of the regression line measured by r-squared after rounding was ≥0.9. After IV administration, the volume of distribution (V_z) was calculated as dose/λ_{_z *} AUC _{INF_obs} , the clearance (CL) was calculated as dose/AUC _{INF_obs}, and the steady-state volume of distribution (V _{_ss} ) was estimated as MRT _INF * CL. The mean residence time (MRT) from the time of administration to the time to the final measurable concentration is calculated as _{AUMC_final} / _{AUC_final} . For Model 200, bioavailability (i.e., the fraction of the total dose reaching the systemic circulation) cannot be calculated. Therefore, the volume and clearance for this model are Vz/F or CL/F, respectively; where F is defined as bioavailability (i.e., the fraction of the total dose reaching the systemic circulation; (mean _{AUC_final - po} / mean _{AUC_final - invoice} ) * [dose _{invoice invoice} / dose invoice _{invoice invoice} ] * 100).

Pharmacokinetic data of some compounds of the present invention generated by the above procedure are provided in Table 4 below.

Table 4: Rat pharmacokinetic data of the compounds selected in this invention

Other implementation plans

For purposes of clarity and understanding, the foregoing disclosure has been described in considerable detail by way of illustration and example. The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications are possible within the spirit and scope of the invention. It will be apparent to those skilled in the art that changes and modifications can be made within the scope of the appended claims. Therefore, it should be understood that the above description is intended to be illustrative rather than restrictive.

Therefore, the scope of the invention should not be determined by reference to the above description, but rather by reference to the full scope of the appended claims and their authorized equivalents.

The present invention also relates to embodiments of the following:

Item 1. A compound of formula A:

Or its pharmaceutically acceptable salt, wherein:

(i) _R1 is selected from the group consisting of: ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, ( _C6 - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-10 heteroaryl, 4-10 heterocycloalkyl, -CN, -NHOH, -C(O) ^Ra , -C( ^O ) ^NRaRa , -C(O) ^NHORa , ^-C (O) ^ORa , -C(O) ^NRaS (O) _2Ra , -OC(O) ^NRaRa , C(＝ ^NRa ) ^Ra , -C(＝NOH) ^Ra , ^-C (＝NOH) ^NRa , -C(＝NCN) ^NRaRa , -C(＝ ^NRa ) ^{NRaRa , -S} (O) ^NRaRa , -S ⁽ _O ) ^2NRaC (O) ^Ra , -P(O)R ^a R ^a , -P(O)(OR ^a )(OR ^a ), -B(OH) ₂ , -B(OR ^a ) ₂ and S(O) ₂ NR ^a R ^a ; and

_R2 is selected from -H, halogenated, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, (C1- _C6 )haloalkyl, (C1 _- C6)haloalkoxy, ( _{C6 - C10} )aryl-( _C1 - _C4 )alkylene-, (C3 _{-C10 )} cycloalkyl-( _C1 - _C4 )alkylene-, (5-14-membered heteroaryl)-( _{C1 - C4} )alkylene-, (4-14-membered heterocycloalkyl)-(C1 _{- C4} )alkylene-, -CN, _-NO2 , ^-ORa , ^-SRa , ^-NHORa , -C(O) ^{Ra ,} -C(O) ^NRaRa , -C(O) ^NHORa , -C(O) ^ORa , -C(O)NR ^a S(O) ₂ R ^a , -OC(O)R ^a , -OC(O)NR ^a R ^a , -NHR ^a , -NR ^a R ^a , -NR ^a C(O)R ^a , -NR ^a C(=NR ^a )R ^a , -NR ^a C(O)OR ^a , -NR ^a C(O)NR ^a R ^a , -C(=NR ^a )R ^a , -C(=NOH)R ^a , -C(=NOH)NR ^a , -C(=NCN)NR ^a R ^a , -NR ^a C(=NCN)NR ^a R ^a , -C(=NR ^a )NR ^a R ^a , -NR ^a C(=NR ^a )NR ^a R ^a , -NR ^a S(O)R ^a , -NR ^a S(O) ₂ R ^a , -NR ^a S(O) ₂ NR ^a R ^a ,-S(O)R ^a -S(O)NR ^aRa , ^-S (O) _2Ra , -S(O) _2NR ^aC (O) ^Ra , -P(O) ^RaRa , -P(O)(OR ^a )( ^{OR a )} , -B ⁽ OH) ₂ , -B(OR ^a ) ₂ and -S(O ^{)2NR aRa} _, ^wherein _R1 or _R2 is a (C1 _{- C6} )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, ( _C6 - _C10 )aryl-( _C1 - _C4 )alkylene-, ( _C3 - _C10 )cycloalkyl-( _C1 - _C4 )alkylene-, (5-14-membered heteroaryl)-(C1 _{- C4} )alkylene- and (4-14-membered heterocycloalkyl)-(C1 _- C ₄ ) Alkylenes – each optionally substituted by 1, 2, 3, 4, or 5 independently selected ^Rb substituents, provided that when _R1 is a 5-7-membered heteroaryl or 5-7-membered heterocyclic alkyl and _R2 is a _C1-6 alkoxy, the 5-7-membered heteroaryl or 5-7-membered heterocyclic alkyl is not connected to the fused benzene ring of the quinoline moiety via a cyclic nitrogen atom; or

(ii) _R1 is selected from -H, halogroup, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, (C2- _C6 )ynyl, ( _C1 - _C6 )haloalkyl, (C1 _{- C6} )haloalkoxy, ( _{C6 - C10} )aryl, ( _C3 - _C10 )cycloalkyl, 5-14-membered heteroaryl, 4-14-membered heterocycloalkyl, ( _C6 - _C10 )aryl-( _{C1- C4} )alkylene-, ( _C3 - _C10 )cycloalkyl-( _{C1- C4} )alkylene-, (5-14-membered heteroaryl)-( _{C1- C4} )alkylene-, (4-14-membered heterocycloalkyl)-( _{C1- C4} )alkylene-, -CN, _-NO2 , ^-ORa , -SR ^a , -NHOR ^a , -C(O)R ^a , -C(O)NR ^a R ^a , -C(O)NHOR ^a , -C(O)OR ^a , -C(O)NR ^a S(O) ₂ R ^a , -OC(O)R ^a , -OC(O)NR ^a R ^a , -NHR ^a , -NR ^a R ^a , -NR ^a C(O)R ^a , -NR ^a C(=NR ^a )R ^a , -NR ^a C(O)OR ^a , -NR ^a C(O)NR ^a R ^a , -C(=NR ^a )R ^a , -C(=NOH)R ^a , -C(=NOH)NR ^a , -C(=NCN)NR ^a R ^a , -NR ^a C(=NCN)NR ^a R ^a , -C(=NR ^a )NR ^a R ^a , -NR ^a C(=NR ^a )NR ^a R ^a , -NR ^a S(O) ^Ra , ^-NRaS (O) _2Ra , -NRaS ₍ O) ^2NRaRa , ^-S (O ₎ ^Ra , -S(O) ^NRaRa , -S(O) ^2Ra , ^-S (O) _2NRaC (O)Ra, ^-P (O) ^RaRa , -P ⁽ O) ^{( ORa} )( ^ORa ), ^-B (OH) ² , -B( ^ORa ) _{2 and} -S(O) _2NRaRa , wherein _R1 or ^R2 is a ( _C1 - _C6 )alkyl, ( _C2 - _C6 ) ^alkenyl , ( _C2 - _C6 )ynyl, (C6 _{-C10 )} aryl, ( _C3 - _C10 )cycloalkyl, 5-14 heteroaryl, 4-14 heterocycloalkyl, ( _C6 - _{C10 ) ...} The aryl-(C1 _{- C4} )alkylene-, (C3- _C10 )cycloalkyl-( _C1 -C4)alkylene-, (5-14-membered heteroaryl)-( _{C1- C4} )alkylene-, and (4-14-membered heterocycloalkyl)-( _{C1 - C4} )alkylene- are each optionally substituted by 1, 2, 3 _, 4, or 5 independently selected ^Rb substituents; and

R ₂ is selected from the group consisting of: (C ₂ -C ₆ )alkenyl, (C ₂ -C ₆ )alkynyl, -CN, -NHOH, -C(O)R ^a , -C(O)NR ^a R ^a , -C(O)NHOR ^a , -C(O)OR ^a , -C(O)NR ^a S(O) ₂ R ^a , -OC(O)NR ^a R ^a , C(=NR ^a )R ^a , -C(=NOH)R ^a , -C(=NOH)NR ^a , -C(=NCN)NR ^a R ^a , -NR ^a C(=NCN)NR ^a R ^a , -C(=NR ^a )NR ^a R ^a , -S(O)NR ^a R ^a , -S(O) ₂ NR ^a C(O)R ^a , -P(O)R ^a R ^a , -P(O)(OR ^a )(OR ^a ), -B(OH) ₂ -B(OR ^a ) ₂ and S(O) ₂ NR ^{a Ra} , provided that when R ₁ is a 5-7 membered heteroaryl or a 5-7 membered heterocyclic alkyl and R ₂ is a C _1-6 alkoxy, then the 5-7 membered heteroaryl or 5-7 membered heterocyclic alkyl of R ₁ is not connected to the fused benzene ring of the quinoline moiety through a cyclic nitrogen atom.

(iii) _R1 and _R2 together with the atoms to which they are attached form a fused (C3 _{- C7} ) cycloalkyl ring or a fused 4- to 10-membered heterocyclic alkyl ring, wherein the fused (C3 _{- C7} ) cycloalkyl ring and the fused 4- to 10-membered heterocyclic alkyl ring are each optionally substituted by one, two or three independently selected ^Rb substituents, provided that the compound is not 1-[2-(4-fluorophenyl)-acetyl]-cyclopropanecarboxylic acid [3-fluoro-4-(7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxa-1-aza-cyclododecane[b]naphthalene-4-yloxy)-phenyl]-amide;

_R10 and _R11 are each independently selected from the group consisting of: -H, halogroup, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )haloalkyl, (C1 _{- C6} )haloalkoxy, ( _C6 - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-14-membered heteroaryl, 4-14-membered heterocycloalkyl, ( _C6 - _C10 )aryl-( _{C1- C4} )alkylene-, ( _C3 - _C10 )cycloalkyl-( _C1 - _C4 )alkylene-, (5-14-membered heteroaryl)-( _{C1- C4} )alkylene-, (4-14-membered heterocycloalkyl)-(C1 _{- C4} )alkylene-, -CN, _-NO2 , ^-ORa , ^-SRa , ^-NHORa , -C(O)R ^a , -C(O)NR ^a R ^a , -C(O)OR ^a , -C(O)NR ^a S(O) ₂ R ^a , -OC(O)R ^a , -OC(O)NR ^a R ^a , -NHR ^a , -NR ^a R ^a , -NR ^a C(O)R ^a , -NR ^a C(=NR ^a )R ^a , -NR ^a C(O)OR ^a , -NR ^a C(O)NR ^a R ^a , -C(=NR ^a )R ^a , -C(=NOH)R ^a , -C(=NOH)NR ^a , -C(=NCN)NR ^a R ^a , -NR ^a C(=NCN)NR ^a R ^a , -C(=NR ^a )NR ^a R ^a , -NR ^a C(=NR ^a )NR ^a R ^a , -NR ^a S(O)R ^a , -NR ^a S(O) ₂ R ^a -NR ^a S(O) ₂ NR ^{a Ra} , -S(O) ^Ra , -S(O)NR ^{a Ra} , -S(O) ₂ ^Ra , -S(O) ₂ NR ^a C(O) ^Ra , -P(O) ^{Ra Ra} , -P(O)(OR ^a )(OR ^a ), -B(OH) ₂ , -B(OR ^a ) ₂ and S(O) ₂ NR ^{a Ra} , wherein R ₁ or R ₂ is a (C ₁ -C ₆ ) alkyl, (C ₆ -C ₁₀ ) aryl, (C ₃ -C ₁₀ ) cycloalkyl, 5-14-membered heteroaryl, 4-14-membered heterocycloalkyl, (C _{6 -} C ₁₀ ) aryl-(C ₁ -C ₄ ) alkylene-, (C _3- C _{10 )} cycloalkyl ... The alkylene-, (5-14-membered heteroaryl)-(C1 _{- C4} )alkylene- and (4-14-membered heterocyclic alkyl)-(C1 _{- C4} )alkylene- are each optionally substituted by 1, 2, 3, 4 or 5 independently selected ^Rb substituents;

Each _R3 is independently selected from the group consisting of: -H, halogroup, -OH, -CN, optionally substituted ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy, ( _C1 - _C6 )haloalkoxy, _-NH2 , -NH( _C1 - _C6 )alkyl, -N( _C1 - _C6 )alkyl) ₂ and ( _C3 - _C6 )cycloalkyl, wherein the ( _C1 - _C6 )alkoxy, -NH( _C1 - _C6 )alkyl, -N( _C1 - _C6 )alkyl) ₂ and ( _C3 - _C6 )cycloalkyl of _R3 are each optionally substituted by 1, 2 or 3 independently selected ^Rg substituents;

Each R ₁₄ is independently selected from halogen, -OH, -NH ₂ , -CN, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )haloalkyl, (C ₁ -C ₆ )haloalkoxy, -COOH, -NH(C ₁ -C ₆ )alkyl, -N(C ₁ -C _6alkyl ) ₂ , phenyl, phenyl-(C _1- C ₂ )alkylene, (C _3- C ₆ )cycloalkyl, (C _3- C ₆ )cycloalkyl-(C _1- C ₄ )alkylene-, 4 to 6-membered heterocycloalkyl, (4 to 6-membered heterocycloalkyl)-(C _1- C ₄ )alkylene-, 5 to 6-membered heteroaryl, (5 to 6-membered heteroaryl)-(C _1- C ₄ )alkylene- and -OR ^e , wherein R _The ( _C1 - _C6 )alkyl, phenyl, phenyl-(C1- _C2 )alkylene, ( _C3- C6)cycloalkyl, ( _{C3- C6} )cycloalkyl-(C1 _{- C4} )alkylene, 4- to ₆ -membered heterocycloalkyl, ( _4- to 6-membered heterocycloalkyl)-(C1 _{- C4} )alkylene, 5- to 6-membered heteroaryl and (5- to 6-membered heteroaryl)-(C1 _{- C4} )alkylene are each optionally substituted by one, two or three independently selected ^Rg substituents.

R ₁₅ is H or C _1-6 alkyl;

Each _R4 is independently selected from the group consisting of: -H, halogroup, -OH, -COOR ^e , -CONR ^{e Re} , -CN, -NH ₂ , -NH ((C1 _{- C6} )alkyl), -N (( _{C1- C6} )alkyl) ₂ , (C1 _{- C6} )alkyl, (C1 _{- C6} )alkoxy, ( _{C1- C6} )haloalkyl, (C1 _{- C6} )haloalkoxy, -CONR ^{a Ra} , -NR ^a COR ^a , -NR ^a CONR ^{a Ra} , -SO ₂ ^Ra , -NR ^a S(O) ₂ ^Ra , -NR ^a S(O) ₂ NR ^{a Ra} , (C3 _{- C6} )cycloalkyl, 4- to 6-membered heterocyclic alkyl, phenyl, 5- or 6-membered heteroaryl, (C3 _{- C6} )cycloalkyl-( _C1- C ₄ ) alkylene-, (4 to 6-membered heterocyclic alkyl)-(C1 _{- C4} )alkylene-, phenyl-( _{C1- C2} )alkylene- and (5 or 6-membered heteroaryl)-(C1 _{- C4} )alkylene-, wherein the (C1 _{- C6} )alkyl, ( _{C3- C6} )cycloalkyl, ₄ to 6-membered heterocyclic alkyl, phenyl, 5 or 6-membered heteroaryl, (C3 _{- C6} )cycloalkyl-( _{C1- C4} )alkylene-, (4 to 6-membered heterocyclic alkyl)-( _{C1- C4} )alkylene-, phenyl-(C1 _{- C2} )alkylene- and (5 or 6-membered heteroaryl)-( _{C1- C4} )alkylene- are each optionally substituted by 1, 2 or 3 independently selected ^Rf substituents;

Each Ra ^is independently selected from the group consisting of: -H, -CN, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )haloalkyl, ( _C2 - _C6 )alkenyl, (C2-C6)ynyl, ( _C6 - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-14-membered heteroaryl, 4-14-membered heterocycloalkyl, ( _C6 - _C10 )aryl-( _C1 - _C4 )alkylene-, (C3 _{- C10} )cycloalkyl-( _C1 - _C4 )alkylene-, (5-14-membered heteroaryl)-( _{C1- C4} )alkylene-, and (4-14-membered heterocycloalkyl)-(C1 _{- C4} )alkylene-, wherein the ( _{C1- C6} )alkyl, ( _C1 - _C6 )alkylene-, and ( _C2 - _C6) alkylene- of ^Ra are... ( _C2 - _C6 )alkenyl, (C2-C6)ynyl, ( _C6 - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-14-membered heteroaryl, 4-14-membered heterocycloalkyl, ( _C6 - _C10 )aryl-( _C1 - _C4 )alkylene-, ( _{C3- C10} )cycloalkyl-( _C1 - _C4 )alkylene-, (5-14-membered heteroaryl)-( _{C1 - C4} )alkylene- and (4-14-membered heterocycloalkyl)-( _{C1 - C4} )alkylene- are each optionally substituted by 1, 2, 3, 4 or 5 independently selected ^Rd substituents;

Each ^Rb is independently selected from halogen, oxo, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, (C1-C6)haloalkyl, ( _{C1 -C6 )} haloalkoxy, ( _C6 - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-10-membered heteroaryl, _4-10 -membered heterocycloalkyl, ( _C6 - _C10 )aryl-( _{C1- C4} )alkylene-, ( _{C3- C10} )cycloalkyl-(C1 _{- C4} )alkylene-, (5-10-membered heteroaryl)-(C1 _{- C4} )alkylene-, (4-10-membered heterocycloalkyl)-(C1 _{- C4} )alkylene-, -CN, -OH, _-NH2 , -NO _2. -NHOR ^c , -OR ^c , -SR ^c , -C(O)R ^c , -C(O)NR ^c R ^c , -C(O)OR ^c , -C(O)NR ^c S(O) ₂ R ^c , -OC(O)R ^c , -OC(O)NR ^c R ^c , -C(=NOH)R ^c , -C(=NOH)NR ^c , -C(=NCN)NR ^c R ^c , -NR ^c C(=NCN)NR ^c R ^c , -C(=NR ^c )NR ^c R ^c , -NR ^c C(=NR ^c )NR ^c R ^c , -NHR ^c , -NR ^c R ^c , -NR ^c C(O)R ^c , -NR ^c C(=NR ^c )R ^c , -NR ^c C(O)OR ^c , -NR ^c C(O)NR ^c R ^c , -NR ^c S(O)R ^c ,-NR ^c S(O) _2Rc ^{, -NRcS} (O) _2NRcRc , ^-S (O) ^Rc , -S(O) ^NRcRc , -S(O) ^2Rc , -S(O) ^2NRcC (O) ^Rc , -Si(Rc) ₃ , -P(O) ^RcRc , ^-P ( ^O ₎ ( ^ORc )(ORc), ^-B (OH) ₂ , ^-B ( ^ORc ) ₂ and -S(O) _2NRcRc , wherein ^Rb is a ⁽ C1-C6) ^alkyl , (C1- ^C6 ) _haloalkyl , ( _C1 - _C6 )haloalkoxy, (C2-C6)alkenyl, ( _C2 - _C6 )alkynyl, ( _C6 - _C10 )aryl, (C3-C10)alkyl, ( _C3 - _C10 )alkyl, ( _C4 - _C5 )alkyl, ( _C6 - _C10 )alkyl, ( _C3- C10)alkyl, (C4 _... ( _C6 - _C10 ) aryl-(C1-C4) alkylene-, (C3-C10) cycloalkyl-( _{C1- C4} ) alkylene-, ( _5-10 ) heteroaryl-( _{C1 - C4} ) alkylene-, and ( _4-10 ) heterocycloalkyl-(C1 _{- C4 )} alkylene- are each optionally further substituted by one, two, or three independently selected ^Rd substituents;

Each ^Rc is independently selected from the group consisting of: -H, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )haloalkyl, ( _C2 - _C6 )alkenyl, ( _C2 -C6)ynyl, ( _C6 - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-10 heteroaryl, 4-10 heterocycloalkyl, ( _C6 - _C10 )aryl-(C1- _C4 )alkylene-, (C3 _{- C10} )cycloalkyl-( _C1 - _C4 )alkylene-, (5-10 heteroaryl)-( _{C1- C4 ) alkylene-} , and (4-10 heterocycloalkyl)-(C1 _{- C4} )alkylene-, wherein ^the ( _C1 - _C6 )alkyl, ( _C2 - _C6)... Alkenyl, ( _C2 - _C6 ) ynyl, (C6- _C10 ) aryl, ( _C3 -C10) cycloalkyl, 5-10 heteroaryl, 4-10 heterocycloalkyl, ( _C6 - _C10 ) aryl-( _C1 - _C4 ) alkylene-, ( _C3 - _C10 ) cycloalkyl-( _C1 - _C4 ) alkylene-, (5-10 heteroaryl)-(C1 _{- C4} ) alkylene- and (4-10 heterocycloalkyl)-( _{C1- C4 )} alkylene- are each optionally substituted by 1, 2, 3 _, 4 or 5 independently selected ^Rf substituents;

Each R d is independently selected from (C <sub>1- C 6  )alkyl, (C <sub>1- C  6 )haloalkyl, haloyl, (C<sub>6-C10)aryl, 5-10 heteroaryl, (C <sub>3- C 10 )cycloalkyl, 4-10 heterocyclic alkyl, (C <sub>6- C 10 )aryl-(C <sub>1- C 4 )alkylene-, (C <sub>3- C 10 )cycloalkyl-(C <sub>1- C 4 )alkylene-, (5-10 heteroaryl)-(C <sub>1- C 4 )alkylene-, (4-10 heterocyclic alkyl)-(C <sub>1- C4 )alkylene-, -CN, -NH 2 , -NHOR e , -OR e , -SRe, -C(O)R  e , -C(O)NReRe , -C(O)OR e -OC(O)R e , -OC(O)NR eR e , -NHR e , -NR eR e , -NR e C(O)R e , -NR e C(O)NR eR e , -NR e C(O)OR e , -C(＝NR e )NR eR e , -NR e C(＝NR e )NR eR e , -NR e C(＝NOH)NR eR e, -NR e C(＝NCN)NR eR e , -S (O)R e , -S(O)NR eR e , -S(O) 2 Re, -NR e S (O) 2 Re , -NR e S(O) 2 NR e Re and -S (O) 2 NR e Re , wherein R d is a (C 1- C 6 ) alkyl , (C 1 - C 6 )haloalkyl, (C 6- C 10 )alkyl, (C 6- C 10 )alkyl, ... )aryl, 5-10 heteroaryl, ( C3- C10 )cycloalkyl, 4-10 heterocycloalkyl, (C6 - C10 )aryl-(C1-C4)alkylene-, (C3 - C10 )cycloalkyl-( C1- C4 )alkylene-, ( 5-10 heteroaryl)-(C1- C4 )alkylene- and (4-10 heterocycloalkyl)-( C1- C4 ) alkylene- are each optionally substituted by 1, 2 or 3 independently selected R f substituents;

Each ^Re is independently selected from the group consisting of: -H, (C1 _{- C6} )alkyl, ( _{C3- C6} )cycloalkyl-, (C3- _C6 )cycloalkyl-(C1 _- C4)alkylene-, (C6 _{- C10} )aryl, ( _{C6- C10} )aryl-(C1 _- C4)alkylene-, 5 or ₆ -membered heteroaryl, (5 or 6-membered heteroaryl)-(C1 _{- C4} )alkylene-, 4-7-membered heterocycloalkyl, ( _4-7 -membered heterocycloalkyl)-(C1-C4)alkylene-, ( _{C1- C6} )haloalkyl, (C1 _{- C6} )haloalkoxy, (C2-C4)alkenyl and (C2 _{- C4} )ynyl, wherein the (C1- _C4 )alkyl, (C1 _{- C6} )haloalkoxy, (C2 _- C4)alkenyl and (C2 _{- C4} )ynyl of ^Re are... _{3- C6} )cycloalkyl, ( _{C6- C10} )aryl, 5- or 6-membered heteroaryl, 4- or 7-membered heterocycloalkyl, ( _C6- or ₁₀ )aryl-(C1- or ₄ -membered heteroaryl)-( _{C1- or} 4-membered heterocycloalkyl)-(C1- or ₄ -membered heterocycloalkyl), ( _C2- or 4-membered heterocycloalkyl)-( _{C1- or 4-} membered heterocycloalkyl), (C2- _{or 4-} membered alkenyl) and ( _{C2- or 4-} membered ynyl are each optionally substituted by 1, 2 or 3 ^Rf substituents.

Or any two ^Ra substituents together with the nitrogen atom to which they are attached form a 4, 5, 6, 7, 8, 9 or 10-membered heterocyclic alkyl group, each heterocyclic alkyl group optionally being substituted by 1, 2 or 3 independently selected R ^f substituents;

Alternatively, any two ^Rc substituents together with the nitrogen atom to which they are attached can form a 4, 5, 6, 7, 8, 9, or 10-membered heterocyclic alkyl group, each heterocyclic alkyl group optionally being substituted by one, two, or three independently selected ^Rf substituents.

Or any two ^Re substituents together with the nitrogen atom to which they are attached form a 4, 5, 6, 7, 8, 9 or 10-membered heterocyclic alkyl group, each heterocyclic alkyl group optionally being substituted by 1, 2 or 3 independently selected R ^f substituents;

Each ^Rf is independently selected from halogen, -OH, -CN, -COOH, _-NH2 , -NH-(C1 _{- C6} )alkyl, -N((C1 _{- C6} )alkyl) ₂ , (C1 _{- C6} )alkyl, (C1- _C6 )alkoxy, ( _C1- C6)alkylthio, (C1 _{- C6} )haloalkyl, (C1 _{- C6} )haloalkoxy, phenyl, 5-6-membered heteroaryl, 4-6-membered heterocyclic alkyl, and ( _{C3 - C6} )cycloalkyl, wherein the (C1 _{- C6} )alkyl, phenyl, (C3 _{- C6} )cycloalkyl, 4-6-membered heterocyclic alkyl, and 5-6-membered heteroaryl of ^Rf are each optionally selected by 1, 2, or 3 from halogen, -OH, -CN, -COOH, _-NH2 , (C1 _- C6 ₎ alkyl, -NH- _{( ...} Substituents of alkyl, (C1 _{- C4} )alkoxy, (C1 _{- C4} )haloalkyl, ( _{C1- C4} )haloalkoxy, phenyl, (C3 _{- C10} )cycloalkyl, 5-6-membered heteroaryl and 4-6-membered heterocyclic alkyl groups;

Each R ^g is independently selected from halogenated, -OH, -CN, -COOH, -COO-( _{C1- C4} ) _alkyl , -NH2, -NH-(C1 _{- C6} )alkyl, -N((C1 _{- C6} )alkyl) ₂ , ( _{C1- C6} )alkyl, (C1 _{- C6} )alkoxy, (C1- _C6 )alkylthio, ( _{C1- C6 )} haloalkyl, (C1 _{- C6} )haloalkoxy, phenyl, 5-6-membered heteroaryl, 4-6-membered heterocyclic alkyl and (C3 _{- C6} )cycloalkyl;

Y is selected from -O-, -S-, -SO-, _-SO₂- , -NH-, and -N((C₁ _{- C₆} )alkyl)-;

The cyclic nitrogen atom on the quinoline moiety in Formula A may optionally be oxidized;

The subscript n is an integer of 1, 2, 3 or 4;

The subscript m is an integer of 1, 2, 3, 4, or 5; and

The subscript p is an integer of 0, 1, 2, 3 or 4.

Item 2. The compound as described in Item 1, having formula A-1:

Item 3. The compound as described in Item 1, having formula A-2:

Item 4. The compound as described in Item 1, having formula A-3:

^Ra1 is H or (C1 _{- C6} ) alkyl.

Item 5. The compound as described in Item 1, having formula A-4:

The ring A is a 5- to 14-membered heteroaryl group; and the subscript r is 1, 2, 3 or 4.

Item 6. The compound as described in Item 1, wherein:

_R1 is selected from the group consisting of: ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, ( _C6 - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, -CN, -NHOH, -C(O) ^Ra , -C(O)NRaRa, -C(O) ^NHORa , -C ⁽ O) ^ORa , -C(O ^{) NRaS} (O) _2Ra , -OC(O) ^NRaRa , C(＝ ^NRa ) ^Ra , ^-C (＝NOH) ^Ra , ^-C (＝NOH) ^NRa , -C(＝NCN) ^NRaRa , ^-NRaC (＝NCN) ^NRaRa , -C ⁽ ＝ ^NRa ) ^NRaRa , -S ⁽ O ^{) NRaRa} , ^-S (O) _2NR ^a C(O)R ^a , -P(O)R ^a R ^a , -P(O)(OR ^a )(OR ^a ), -B(OH) ₂ , -B(OR ^a ) ₂ and S(O) ₂ NR ^a R ^a ; and

_R2 is selected from -H, halogenated, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, (C1- _C6 )haloalkyl, (C1 _- C6)haloalkoxy, (C6 _{- C10} )aryl-( _C1 - _C4 )alkylene-, (C3 _{-C10 )} cycloalkyl-( _{C1 - C4} )alkylene-, (5-14-membered heteroaryl)-( _{C1 - C4} )alkylene-, (4-14-membered heterocycloalkyl)-(C1 _{- C4} )alkylene-, -CN, _-NO2 , ^-ORa , ^-SRa , ^-NHORa , -C(O) ^{Ra ,} -C(O) ^NRaRa , -C(O) ^NHORa , -C(O) ^ORa , -C(O)NR ^a S(O) ₂ R ^a , -OC(O)R ^a , -OC(O)NR ^a R ^a , -NHR ^a , -NR ^a R ^a , -NR ^a C(O)R ^a , -NR ^a C(=NR ^a )R ^a , -NR ^a C(O)OR ^a , -NR ^a C(O)NR ^a R ^a , -C(=NR ^a )R ^a , -C(=NOH)R ^a , -C(=NOH)NR ^a , -C(=NCN)NR ^a R ^a , -NR ^a C(=NCN)NR ^a R ^a , -C(=NR ^a )NR ^a R ^a , -NR ^a C(=NR ^a )NR ^a R ^a , -NR ^a S(O)R ^a , -NR ^a S(O) ₂ R ^a , -NR ^a S(O) ₂ NR ^a R ^a ,-S(O)R ^a -S(O)NR ^aRa , ^-S (O) _2Ra , -S(O) _2NR ^aC (O) ^Ra , -P(O) ^RaRa , -P(O)(OR ^a )( ^{OR a )} , -B ⁽ OH) ₂ , -B(OR ^a ) ₂ and -S(O ^{)2NR aRa} _, ^wherein _R1 or _R2 is a ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, ( _C6 - _C10 )aryl-( _C1 - _C4 )alkylene-, ( _C3 - _C10 )cycloalkyl-( _C1 - _C4 )alkylene-, (5-14-membered heteroaryl)-(C1 _{- C4} )alkylene- and (4-14-membered heterocycloalkyl)-(C1 _- C ₄ ) Alkylenes are each optionally substituted by 1, 2, 3, 4 or 5 independently selected ^Rb substituents, provided that when _R1 is a 5-7-membered heteroaryl or 5-7-membered heterocyclic alkyl and _R2 is a _C1-6 alkoxy, the 5-7-membered heteroaryl or 5-7-membered heterocyclic alkyl of _R1 is not connected to the fused benzene ring of the quinoline moiety through a cyclic nitrogen atom.

Item 7. The compound as described in Item 1, wherein:

_R1 is selected from -H, halogroup, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, (C1-C6)haloalkyl, (C1 _{- C6} )haloalkoxy, ( _{C6 - C10} )aryl, ( _C3 - _{C10 )} cycloalkyl, 5-14-membered heteroaryl, 4-14-membered heterocycloalkyl, ( _C6 - _C10 )aryl-( _{C1- C4} )alkylene-, ( _C3 - _C10 )cycloalkyl-(C1- _C4 )alkylene-, (5-14-membered heteroaryl)-( _{C1- C4 )} alkylene-, (4-14-membered heterocycloalkyl)-(C1 _{- C4} )alkylene-, -CN, _-NO2 , ^-ORa , -SR ^a , -NHOR ^a , -C(O)R ^a , -C(O)NR ^a R ^a , -C(O)NHOR ^a , -C(O)OR ^a , -C(O)NR ^a S(O) ₂ R ^a , -OC(O)R ^a , -OC(O)NR ^a R ^a , -NHR ^a , -NR ^a R ^a , -NR ^a C(O)R ^a , -NR ^a C(=NR ^a )R ^a , -NR ^a C(O)OR ^a , -NR ^a C(O)NR ^a R ^a , -C(=NR ^a )R ^a , -C(=NOH)R ^a , -C(=NOH)NR ^a , -C(=NCN)NR ^a R ^a , -NR ^a C(=NCN)NR ^a R ^a , -C(=NR ^a )NR ^a R ^a , -NR ^a C(=NR ^a )NR ^a R ^a ,-NR ^a S(O) ^Ra , ^-NRaS (O) _2Ra , -NRaS ₍ O) ^2NRaRa , ^-S (O ₎ ^Ra , -S(O) ^NRaRa , -S(O) ^2Ra , ^-S (O) _2NRaC (O)Ra, ^-P (O) ^RaRa , -P ⁽ O) ^{( ORa} )( ^ORa ), ^-B (OH) ² , -B( ^ORa ) _{2 and} -S(O) _2NRaRa , wherein _R1 or ^R2 is a ( _C1 - _C6 )alkyl, ( _C2 - _C6 ) ^alkenyl , ( _C2 - _C6 )ynyl, (C6 _{-C10 )} aryl, ( _C3 - _C10 )cycloalkyl, 5-14 heteroaryl, 4-14 heterocycloalkyl, ( _C6 - _{C10 ) ...} The aryl-(C1 _{- C4} )alkylene-, (C3- _C10 )cycloalkyl-( _C1 -C4)alkylene-, (5-14-membered heteroaryl)-( _{C1- C4} )alkylene-, and (4-14-membered heterocycloalkyl)-( _{C1 - C4} )alkylene- are each optionally substituted by 1, 2, 3 _, 4, or 5 independently selected ^Rb substituents; and

R ₂ is selected from the group consisting of: (C ₂ -C ₆ )alkenyl, (C ₂ -C ₆ )alkynyl, -CN, -NHOH, -C(O)R ^a , -C(O)NR ^a R ^a , -C(O)NHOR ^a , -C(O)OR ^a , -C(O)NR ^a S(O) ₂ R ^a , -OC(O)NR ^a R ^a , C(=NR ^a )R ^a , -C(=NOH)R ^a , -C(=NOH)NR ^a , -C(=NCN)NR ^a R ^a , -NR ^a C(=NCN)NR ^a R ^a , -C(=NR ^a )NR ^a R ^a , -S(O)NR ^a R ^a , -S(O) ₂ NR ^a C(O)R ^a , -P(O)R ^a R ^a , -P(O)(OR ^a )(OR ^a ), -B(OH) ₂ -B(OR ^a ) ₂ and S(O) ₂ NR ^{a Ra} , provided that when R ₁ is a 5-7 membered heteroaryl or a 5-7 membered heterocyclic alkyl and R ₂ is a C _1-6 alkoxy, the 5-7 membered heteroaryl or 5-7 membered heterocyclic alkyl of R ₁ is not connected to the fused benzene ring of the quinoline moiety through a cyclic nitrogen atom.

Item 8. The compound as described in Item 1, wherein:

_R1 and _R2, together with the atoms to which they are attached, form a fused (C3 _{- C7} ) cycloalkyl ring or a fused 4- to 10-membered heterocyclic alkyl ring, wherein the fused (C3 _{- C7} ) cycloalkyl ring and the fused 4- to 10-membered heterocyclic alkyl ring are each optionally substituted by one, two, or three independently selected ^Rb substituents, provided that the compound is not 1-[2-(4-fluorophenyl)-acetyl]-cyclopropanecarboxylic acid [3-fluoro-4-(7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxa-1-aza-cyclododecane[b]naphthalene-4-yloxy)-phenyl]-amide.

Item 9. The compound as described in Items 1, 6, 7 or 8, wherein:

R ₁₅ is H or CH ₃ .

Item 10. A compound as described in Item 1 or 9, wherein _R1 and _R2, together with the atoms to which they are attached, form a fused (C3 _{- C7} ) cycloalkyl ring or a fused 4- to 10-membered heterocyclic alkyl ring, wherein each of the fused (C3 _{- C7} ) cycloalkyl ring or the fused 4- to 10-membered heterocyclic alkyl ring is optionally substituted by one, two, or three independently selected ^Rb substituents, provided that the compound is not a compound having the following formula:

Wherein ring E is a fused 4- to 10-membered heterocyclic alkyl group.

Item 11. The compound as described in any one of items 2, 4, 7 and 9, wherein _R1 is -H.

Item 12. The compound as described in any one of items 1, 3, 5 and 6, wherein _R2 is -H.

Item 13. The compound of any one of items 1, 2, 4, 5 and 7-9, wherein _R1 is selected from the group consisting of: -H, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, -C(=NO-(C1 _{- C6} )alkyl) ^Ra , -CN, -C(O) ^{ORa ,} -C(O) ^NRaRa , -C(O) ^NHORa , -S(O ⁾ _2NRaRa , ^phenyl , 5- to 6-membered heteroaryl, (C3 _{- C6} )cycloalkyl and 4- to 6-membered heterocyclic alkyl.

Item 14. The compound as described in Item 13, wherein _R1 is -H, ^-RaNHC (O)-, ^RaOC (O)-, (C1 _{- C6} )alkyl, (C1 _{- C6} )alkoxy, or C(=NO- _CH3 ) ^Ra ; and

R ₂ is selected from 2-methoxyethylamino, methylamino, 3-morpholinopropoxy, 2-methoxyethoxy, 2-hydroxyethoxy, propoxy, 2-hydroxypropoxy, methoxycarbonyl, carboxyl, carbamoyl, methylcarbamoyl, (2-hydroxyethoxy)carbamoyl, (2,2-dihydroxyethoxy)carbamoyl, (oxetane-3-yloxy)carbamoyl, methoxycarbamoyl, 2-trimethylsilylethynyl, ethynyl, aminosulfonyl, acetyl, and -C(＝NOCH ₃ )CH ₃ .

Item 15. The compound of any one of items 1, 3, 5 and 6, wherein _R2 is selected from the group consisting of: -H, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, -C(=NO-(C1 _{- C6} )alkyl) ^Ra , -CN, -C(O) ^ORa , ^-C (O) ^NRaRa , -C(O) ^NHORa and -S( ^O ) _2NRaRa ^.

Item 16. The compound as described in Item 15, wherein _R1 is selected from 2-methoxyethylamino, aziridine-1-yl, methylamino, 3-morpholinopropoxy, 2-methoxyethoxy, 2-hydroxyethoxy, propoxy, 2-hydroxypropoxy, methoxycarbonyl, carboxyl, carbamoyl, methylcarbamoyl, 2-oxazolyl, pyrazol-3-yl, pyrazol-4-yl, 4-isooxazolyl, 3,5-dimethylisooxazol-4-yl, 1-methyl-pyrazol-4-yl, 2-methyl-pyrazol-3-yl, 2-ethyl-pyrazol-3-yl, 2-(2-hydroxyethyl)-pyrazol-3-yl, 2-(2,2,2-trifluoroethyl)-pyrazol-3-yl, 2-(2-fluoroethyl) -pyrazol-3-yl, 2-(2,2-difluoroethyl)-pyrazol-3-yl, 2-trifluoromethyl-pyrazol-3-yl, 2-difluoromethyl-pyrazol-3-yl, 1-methyl-imidazol-4-yl, 1-methyl-imidazol-2-yl, 1H-imidazol-2-yl, (2-hydroxyethoxy)carbamoyl, (2,2-dihydroxyethoxy)carbamoyl, (oxetane-3-yloxy)carbamoyl, methoxycarbamoyl, 2-trimethylsilylethynyl, ethynyl, 1,3,4-oxadiazol-3-yl, 1H-1,2,3-triazol-5-yl, aminosulfonyl, acetyl, and -C (＝NOCH) ₃ ) CH ₃ , and R ₂ is -H, ^-Ra NHC(O)-, ^-Ra OC(O)-, -(C _1- C ₆ )alkyl, (C _1- C ₆ )alkoxy or -C(＝NO-CH ₃ ) ^Ra .

Item 17. The compound as described in Item 5, wherein the subscript r is 1 or 2.

Item 18. The compound of any one of items 1-17, wherein R ₁₀ and R ₁₁ are each H.

Item 19. The compound as described in any one of items 1-18, wherein the subscript n is 1.

Item 20. The compound as described in any one of items 1-19, wherein the subscript m is 1.

Item 21. The compound as described in any one of items 1-20, wherein the subscript p is 1.

Item 22. The compound of any one of items 1-21, having formula B:

Or its pharmaceutically acceptable salt, wherein:

(i)R ₂ is:

-H or a group selected from the following groups:

( _C1 - _C6 )alkyl, halogroup, _-NO2 , _X1Ra ^, wherein _X1 is –O-, -S-, -SO-, -SO2-, -SO2NH-, -SO2NRa-, _{-NH- and} -N- _{( C1} - _C6 )alkyl-, wherein ( _C1 - _C6 )alkyl is optionally substituted; ^and

_R1 can be selected from the following groups:

( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, (C6- _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-10 heteroaryl, and 4-10 heterocycloalkyl, wherein the ( _{C2 - C6} )alkenyl, ( _C2 - _C6 )ynyl, ( _C6 - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-10 heteroaryl, and 4-10 heterocycloalkyl are each optionally substituted independently by the following:

-CN, -P(O)R ^a R ^a ,P(O)(OR ^a ) ₂ , B(OH) ₂ , B(OR ^a ) ₂ ,

X ₂ ^Ra , where X ₂ is -NHO-, -NH-S(O)-, -N-(C ₁ -C ₆ )alkyl-S(O)-, -NH-S(O) _2- , -N-(C ₁ -C ₆ )alkyl-S(O) ₂ ^Ra- , -NH-S(O)-NH-, -N-(C ₁ -C ₆ )alkyl-S(O)NH-, -NH-S(O) ₂ NH-, -N-(C ₁ -C ₆ )alkyl-S(O) ₂ NH-, -S(O) ₂ NHC(O)-; and

Where: represents the connection point, where:

_Y1 is absent, or is -NH-, -N-( _C1 - _C6 )alkyl-, or -O-;

_Y2 is absent, or is -O-, -NH-, -NHO-, -N-( _C1 - _C6 )alkyl-, _-N2H2- , -NH- _S (O)-, -NH-S(O) _2- ; or

_Y2 represents the optional substitution, where A is a 3-, 4-, 5-, 6-, or 7-membered ring; and

^Z1 is O, NH, N-( _C1 - _C6 )alkyl, NOH, NO-( _C1 - _C6 )alkyl, or NCN; or

(ii)

_R1 can be selected from the following groups:

( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, (C6- _C10 )aryl, ( _{C3 - C10} )cycloalkyl, 5-10 heteroaryl, and 4-10 heterocycloalkyl, wherein the ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, ( _C6 - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-14 heteroaryl, and 4-14 heterocycloalkyl are each optionally substituted independently by the following:

P(O)R ^a R ^a , P(O)(OR ^a )(OR ^a ) , B(OH) ₂ , B(OR ^a ) ₂ , CN,

X ₂ ^Ra , where X ₂ is -NHO-, -NH-S(O)-, -N-(C ₁ -C ₆ )alkyl-S(O)-, -NH-S(O) _2- , -N-(C ₁ -C ₆ )alkyl-S(O) ₂ ^Ra- , -NH-S(O)-NH-, -N-(C ₁ -C ₆ )alkyl-S(O)NH-, -NH-S(O) ₂ NH-, -N-(C ₁ -C ₆ )alkyl-S(O) ₂ NH-, -S(O)-, -S(O) _2- , -S(O) ₂ NHC(O); and

in:

_Y1 is absent, or is -NH-, -N-( _C1 - _C6 )alkyl-, or -O-;

_Y2 is absent, or is -O-, -NH-, -NHO-, -N-( _C1 - _C6 )alkyl-, _-N2H2- , -NH-S(O ₎ -, or -NH-S(O) ₂ ; or

_Y2 represents the optional substitution, where A is a 3-, 4-, 5-, 6-, or 7-membered ring; and

^Z1 is -O-, -NH-, -N-( _C1 - _C6 )alkyl-, -NOH-, -NO-( _C1 - _C6 )alkyl-, or –NCN-; or

_R2 can be selected from the following groups:

H, halogenated, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, (C2- _C6 )ynyl, ( _C1 - _C6 )haloalkyl, (C1 _- C6)haloalkoxy, ( _C6 - _C10 )aryl-(C1 _{- C4} )alkylene-, (C3 _{- C10} )cycloalkyl-( _{C1 - C4} )alkylene-, ( _5-14 -membered heteroaryl)-(C1 _{- C4} )alkylene-, and (4-14-membered heterocycloalkyl)-(C1 _{- C4} )alkylene-, wherein ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, ( _C1 - _C6 )haloalkyl, (C1 _{- C6} )haloalkoxy, ( _C6 - _C10) The aryl-(C1 _{- C4} )alkylene-, (C3- _C10 )cycloalkyl-( _C1 -C4)alkylene-, (5-14-membered heteroaryl)-( _{C1- C4} )alkylene-, and (4-14-membered heterocycloalkyl)-( _{C1- C4 ) alkylene-} are each independently and optionally substituted with the following:

CN, NO ₂ , P(O)R ^a R ^a , P(O)(OR ^a )(OR ^a ), B(OH) ₂ , B(OR ^a ) ₂ ,

_X1 ^Ra substitution, wherein _X1 is –O-, -S-, -NH- or -N-( _C1 - _C6 )-, -NHO-, -NH-S(O)-, -N-( _C1 - _C6 )alkyl-S(O)-, -NH-S(O) _2- , -N-( _C1 - _C6 )alkyl-S(O) _2- , -NH-S(O)-NH-, -N-( _C1 - _C6 )alkyl-S(O)NH-, -NH-S(O) _2NH- , -N-( _C1 - _C6 )alkyl-S(O) _2NH- , -S(O) _2NHC (O)-, -NH-S(O) ^Ra- , -N-( _C1 - _C6 )alkyl-S(O) ^Ra- , -NH-S(O) _2Ra- or -N-( ^C1 -C6)-. ₁ - _C6 )alkyl-S ^(O)2Ra- _;

in

_Y1 is absent or is -NH-, -N-( _C1 - _C6 )alkyl- or -O-;

_Y2 is absent or is -O-, -NH-, -NHO-, -N-( _C1 - _C6 )alkyl-, _-N2H2- , -NH-S(O)- or -NH-S(O) _2- ; _or

_Y2 is an optional substitution in which ring A is a 3-, 4-, 5-, 6-, or 7-membered ring, and where represents the connection point; and

^Z1 is O, NH, N-( _C1 - _C6 )alkyl, NOH, NO-( _C1 - _C6 )alkyl, or NCN; or

(iii)

_R1 and _R2, together with the atoms they are attached to, form a 4-10 membered heterocyclic alkyl ring optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of: halogroup, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )haloalkyl, ( _C1 - _C6 )haloalkoxy, -CN, -OH, _-NH2 , provided that the compound is not 1-[2-(4-fluoro-phenyl)-acetyl]-cyclopropanecarboxylic acid [3-fluoro-4-(7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxa-1-aza-cyclododecano[b]naphthalene-4-yloxy)-phenyl]-amide;

And _R10 , _R11 , _R3 , _R14 , _R4 , n, p, m and Y are defined as follows:

Each _R3 is independently selected from the group consisting of: -H, halogroup, -OH, -CN, optionally substituted ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy, ( _C1 - _C6 )haloalkoxy, _-NH2 , -NH( _C1 - _C6 )alkyl, -N( _C1 - _C6 )alkyl) ₂ and ( _C3 - _C6 )cycloalkyl, wherein ( _C1 - _C6 )alkoxy, -NH( _C1 - _C6 )alkyl, -N( _C1 - _C6 )alkyl) ₂ and ( _C3 - _C6 )cycloalkyl are each optionally substituted;

Each of _R10 and _R11 is independently selected from the group consisting of: -H, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy, and ( _C1 - _C6 )haloalkoxy.

Each R ₁₄ is independently selected from -halogroup, -OH, _-NH2 , -CN, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy, (C1- _C6 )haloalkyl, ( _C1 - _C6 )haloalkoxy, -COOH, -NH( _C1 - _C6 )alkyl, -N( _C1 - _C6alkyl ) ₂ , phenyl, phenyl-( _{C1 - C2} )alkylene, ( _{C3- C6} )cycloalkyl, (C3- _C6 )cycloalkyl-( _{C1- C4 )} alkylene-, 4- to 6-membered heterocycloalkyl, (4- to 6-membered heterocycloalkyl)-( _{C1- C4} )alkylene-, 5- to 6-membered heteroaryl, (5- to 6-membered heteroaryl)-(C1 _{- C4} )alkylene- and ^-ORe , wherein R _The ( _C1 - _C6 )alkyl, phenyl, phenyl-(C1 _{- C2} )alkylene, (C3- _C6 )cycloalkyl, (C3 _{- C6} )cycloalkyl-(C1 _{- C4} )alkylene, 4- to 6-membered heterocycloalkyl, ( _4- to 6-membered heterocycloalkyl)-(C1 _{- C4} )alkylene, 5- to 6-membered heteroaryl and (5- to 6-membered heteroaryl)-(C1 _{- C4} )alkylene are each optionally substituted;

Each _R4 is independently selected from -H, halogroup, -OH, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy, ( _C1 - _C6 )haloalkyl, and ( _C1 - _C6 )haloalkoxy, wherein the ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy, ( _C1 - _C6 )haloalkyl, and ( _C1 - _C6 )haloalkoxy are each optionally substituted independently;

Each ^Ra is independently selected from -H, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )haloalkyl, ( _C6 - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-14-membered heteroaryl, 4-14-membered heterocycloalkyl, ( _C6 - _C10 )aryl-( _C1 - _C4 )alkylene-, ( _C3 - _C10 )cycloalkyl-( _C1 - _C4 )alkylene-, (5-14-membered heteroaryl)-(C1 _{- C4} )alkylene-, and (4-14-membered heterocycloalkyl)-(C1 _{- C4} )alkylene-, wherein ( _C1 - _C6 )alkyl, ( _C1 - _C6 )haloalkyl, ( _C6 - _C10 )aryl, ( _C3 - _C10)... ( _C6 - _C10 ) aryl-(C1-C4) alkylene-, (C3-C10) cycloalkyl-( _C1 - _C4 ) alkylene-, (5-14) heteroaryl-( _C1 - _C4 ) alkylene-, and (4-14 ₎ heterocycloalkyl-( _{C1 - C4 )} alkylene- can each be substituted independently _;

n, p, and m are each an independent integer from 0 to 3; and

Y is selected from -O-, -S-, -SO-, _-SO2- , -NH- and -N((C1 _{- C6} )alkyl)-.

Item 23. The compound as described in Item 22, wherein:

_R1 can be -H, -CN, ( _C1 - _C6 )alkyl, ( _C3 - _C10 )cycloalkyl, ( _C6 - _C10 )aryl, 4-10 heterocyclic alkyl, 5-10 heteroaryl, -S(O ^)2NHRa _, -P(O) ^RaRa , ^{-ORa , or}

Where represents the connection point, and:

_Y1 is absent or is -NH-, -N-( _C1 - _C6 )alkyl- or -O-;

_Y2 is absent, or is -O-, -NH-, -NHO-, -N-( _C1 - _C6 )alkyl-, -NH-NH-, -NH-S(O)-, or NH-S(O) ₂ ; and

^Z1 is -O, -NH, -N-( _C1 - _C6 )alkyl, -N-OH or -NO( _C1 - _C6 )alkyl;

Item 24. The compound as described in Item 23, wherein:

_R2 can be -H, a halogroup, _-X1Ra , ( _C2 - _C6 ) ^alkenyl , ( _C2 - _C6 )ynyl, or...

Where: represents the connection point, where:

_Y1 is absent, or is NH, N-( _C1 - _C6 ) alkyl, or O;

_Y2 is absent, or is O, NH, NHO, N-( _{C1 - C6} )alkyl, _N2H2 , NH-S(O) or NH-S(O) ₂ ; and

^Z1 is -O, -NH, -N-( _C1 - _C6 )alkyl, -NOH-, or -NO( _C1 - _C6 )alkyl.

Item 25. The compound of any one of items 22-24, wherein _R3 is -H or a halogroup.

Item 26. The compound of any one of items 22-25, wherein _R4 is -H or a halogroup.

Item 27. The compound of any one of items 22-26, wherein R ₁₄ is -H or a halogroup.

Item 28. The compound of any one of items 22-27, wherein Y is -O-.

Item 29. A compound as described in any one of items 22-28, wherein the compound is a compound of formula B-1 or B-2:

Or its pharmaceutically acceptable salt.

Item 30. A compound of formula B-1 as described in Item 29, wherein:

^Ra1 is an optionally substituted ( _C1 - _C6 ) alkyl group;

_R1 is -H, -CN, optionally substituted 3-6 membered cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 membered heterocycloalkyl, optionally substituted 5-6 membered heteroaryl, _-SO2- ( _C1 - _C6 )alkyl, _-SO2NH2 , _-SO2 - _NH ( _C1 - _C6 )alkyl, or P(O)(( _C1 - _C6 )alkyl) ₂ ; or

Where represents the connection point, and:

_Y1 does not exist;

_Y2 is absent or is -O-, -NH-, -NHO-, -NH-NH-, -N-( _C1 - _C6 )alkyl-; or

_Y2 is an optional substitution where ring A is a 3-, 4-, 5-, 6-, or 7-membered ring, where represents the connection point.

^Z1 is O, NH, N-( _C1 - _C6 )alkyl, NHO, or NO-( _C1 - _C6 )alkyl; and

Ra ^can be -H, -( _C1 - _C6 )alkyl, 4-6 membered heterocyclic alkyl, 3-6 membered cycloalkyl, -( _C2 - _C6 )alkylene-OH, _-CH2CHOH- ( _C2 - _C6 )alkylene-OH, -( _C2 - _C6 )alkylene- _NH2 , -(C2- _C6 )alkylene-NH( _C1 - _C6 ), -( _C2 - _C6 )alkylene-N( _C1 - _C6 ) ₂ or -( _C2 - _C6 )alkylene-N-( _4-6 membered heterocyclic alkyl);

Item 31. A compound of formula B-1 as described in Item 30, wherein:

^Ra1 is a ( _C1 - _C6 ) alkyl group;

_R1 is -H, -CN, optionally substituted cyclopropyl, optionally substituted phenyl, optionally substituted 4-6 membered azacyclic butyl, optionally substituted pyrrolyl, optionally substituted piperidinyl, optionally substituted oxazolyl, optionally substituted pyridinyl, optionally substituted imidazolyl, optionally substituted pyrrolyl, optionally substituted furanyl, optionally substituted pyrazolyl, optionally substituted oxadiazolyl, _-SO₂- ( _C₁ - _C₆ )alkyl, _-SO₂NH₂ , _{-SO₂ -} NH( _C₁ - _C₆ )alkyl, or P(O)(( _C₁ - _C₆ )alkyl) _₂ ; or

_R1 is where:

_Y1 does not exist;

_Y2 is O, NH, NHO, NH-NH, or N-( _C1 - _C6 ) alkyl; or

_Y2 is an optionally substituted nitrogen-containing heterocyclic butyl group;

Z is O, NH, or N-( _C1 - _C6 ) alkyl; and

Ra ^can be H, ( _C1 - _C6 )alkyl, -( _C2 - _C6 )alkylene-OH, _-CH2CHOH- ( _C2 - _C6 )alkylene-OH, -( _C2 - _C6 )alkylene- _NH2 , -( _C2 - _C6 )alkylene-NH( _C1 - _C6 )alkyl, -( _C2 - _C6 )alkylene-N(( _C1 - _C6 )alkyl) ₂ , -( _C2 - _C6 )alkylene-heterocyclic alkyl) and 4-6 membered heterocyclic alkyl, wherein the heterocyclic alkyl is optionally substituted.

Item 32. A compound of formula B-2 as described in Item 30, wherein:

^Ra2 is an optionally substituted ( _C1 - _C6 ) alkyl group;

_R2 represents the connection point, where:

_Y1 does not exist;

_Y2 either does not exist or is -O- or -NH-; and

^Z1 is 0; and

^Ra is -H or -( _C1 - _C6 ) alkyl.

Item 33. A compound of formula B-2 as described in Item 32, wherein:

^Ra2 is a ( _C1 - _C6 ) alkyl group;

_R2 represents the connection point, where:

_Y1 does not exist;

_Y2 either does not exist or is -O- or -NH-; and

^Z1 is an O or NO-( _C1 - _C6 ) alkyl group; and

^Ra is -H or -( _C1 - _C6 ) alkyl.

Item 34. The compound of formula B-1 as described in any one of items 29-31, wherein ^Ra1 is methoxylated.

Item 35. The compound of formula B-2 as described in any one of items 29 and 32-33, wherein ^Ra2 is methoxylated.

Item 36. A compound as described in any one of items 22-28, wherein the compound is a compound of formula B-3 or B-4:

Or its pharmaceutically acceptable salt.

Item 37. The compound as described in Item 36, wherein the compound is a compound of formula B-3, wherein:

_R1 is -H or ( _C1 - _C6 ) alkyl; and

_Y1 does not exist;

_Y2 either does not exist or is -O-, -NHO-, or -NH-; and

^Z1 is an O or NO-( _C1 - _C6 ) alkyl group; and

^Ra is -H or -( _C1 - _C6 ) alkyl.

Item 38. The compound as described in Item 37, wherein the compound is a compound of formula B-3, wherein:

_R1 is –H or methyl;

_Y1 does not exist;

_Y2 either does not exist or is -O-, -NHO-, or -NH-; and

^Z1 is O or NO-Me; and

R ^a is –H or Me.

Item 39. The compound as described in Item 36, wherein the compound is a compound of formula B-3, wherein:

_R1 and ^Ra together with the atoms they are attached to form

4-6 membered heterocyclic alkyl rings optionally substituted with halogen groups, ( _C1 - _C6 )alkyl groups, and ( _C1 - _C6 )haloalkyl groups.

Item 40. The compound as described in Item 36, wherein the compound is a compound of formula B-4, wherein:

_Y1 does not exist;

_Y2 is O, NH, NHO, NH-NH, or N-( _C1 - _C6 ) alkyl; or

_Y2 is an optionally substituted nitrogen-containing heterocyclic butyl group;

^Z1 is O, NH, NO-( _C1 - _C6 )alkyl, or N-( _C1 - _C6 )alkyl; and

Ra ^can be -H, ( _C1 - _C6 )alkyl, -( _C2 - _C6 )alkylene-OH, _-CH2CHOH- ( _C2 - _C6 )alkylene-OH, -( _C2 - _C6 )alkylene- _NH2 , -( _C2 - _C6 )alkylene-NH( _C1 - _C6 )alkyl, -( _C2 - _C6 )alkylene-N(( _C1 - _C6 )alkyl) ₂ , -( _C2 - _C6 )alkylene-optionally substituted 4-6 membered heterocyclic alkyl) and optionally substituted 4-6 membered heterocyclic alkyl;

_R2 can be -H, F, Cl, Br, ( _C1 - _C6 )alkoxy, -O-( _C2 - _C6 )alkylene-OH, -O-( _C2 - _C6 )alkylene-O-( _C1 - _C6 alkyl), ( _C2 - _C6 )alkylene-O-( _C1 - _C6 )alkyl, _-NH2 , -NH-(C1- _C6 alkyl), -NH-( _C1 -C6)alkylene-(optionally substituted 4-6 membered heterocyclic alkyl), -NH-( _{C2 - C6 )} alkylene-O-( _C1 - _C6 alkyl).

Item 41. The compound as described in Item 40, wherein the compound is a compound of formula B-4, wherein:

_Y1 does not exist;

_Y2 is O, NH, NHO, NH-NH, or N-( _C1 - _C6 ) alkyl; or

_Y2 is an optionally substituted nitrogen-containing heterocyclic butyl group;

^Z1 is O, NH, NO-( _C1 - _C6 )alkyl, or N-( _C1 - _C6 )alkyl; and

Ra ^can be H, methyl, ethyl, -( _C2 - _C6 )alkylene-OH, _-CH2CHOH- ( _C2 - _C6 )alkylene-OH, -( _C2 - _C6 )alkylene- _NH2 , -( _C2 - _C6 )alkylene-NHMe, -( _C2 - _C6 )alkylene-N(Me) ₂ , -( _C1 - _C6 )alkylene-morpholinyl, -( _C1 - _C6 )alkylene-piperidinyl, ( _C1 - _C6 )alkylene-(optionally substituted pyrrolidinyl), optionally substituted azahexacyclic butyl or optionally substituted oxohexacyclic butyl;

_R2 is -H, H, F, Cl, Br, methoxy, -O-( _C2 - _C6 )alkylene-OH, -O-( _C2 - _C6 )alkylene-OMe, _-NH2 , -NH-( _C1 - _{C6 alkyl), -NH-(C2-C6 ) alkylene} -OMe, -NH-( _C2 - _C6 )alkylene-(optionally substituted morpholino) or -NH-( _C2 - _C6 )alkylene-O-( _C1 - _C6 alkyl).

Item 42. The compound as described in Item 36, wherein the compound is a compound of formula B-4, wherein:

_R2 and ^Ra, together with the atoms they are attached to, form 4-6 membered heterocyclic alkyl rings that are optionally substituted with halogen groups, ( _C1 - _C6 )alkyl groups, and ( _C1 - _C6 ) haloalkyl groups.

Item 43. The compound as described in items 22-28, wherein the compound is a compound of formula B-5:

Or a pharmaceutically acceptable salt thereof, wherein ring A in formula B-5 is an optionally substituted 5-10 membered heteroaryl or C _6-10 aryl.

Item 44. The compound as described in Item 43, wherein the compound is a compound of formula B-5, wherein:

Ring A is optionally substituted ( _C6 - _C10 ) aryl, optionally substituted ( _C3 - _C10 ) cycloalkyl, optionally substituted 5-10 heteroaryl, or optionally substituted 4-10 heterocycloalkyl; and

_R2 is H, or ( _C1 - _C6 )alkoxy.

Item 45. The compound as described in Item 44, wherein the compound is a compound of formula B-5, wherein:

Ring A is optionally substituted with phenyl, optionally substituted with cyclopropyl, optionally substituted with pyridyl, optionally substituted with imidazolyl, optionally substituted with pyrrole, optionally substituted with furanyl, optionally substituted with pyrazolyl, optionally substituted with oxazolyl, optionally substituted with aziridine or optionally substituted with oxacyclobutane; and

_R2 is H or methoxy.

Item 46. A compound as described in any one of items 22-28, wherein the compound is a compound of formula C:

Or its pharmaceutically acceptable salt, wherein:

_Y1 does not exist;

_Y2 is O, NH, NHO, NH-NH, or N-( _C1 - _C6 ) alkyl; or

_Y2 is an optionally substituted nitrogen-containing heterocyclic butyl group;

^Z1 is O, NH, NO-( _C1 - _C6 )alkyl or N-( _C1 - _C6 )alkyl;

Ra ^can be H, ( _C1 - _C6 )alkyl, -( _C2 - _C6 )alkylene-OH, _-CH2CHOH- ( _C2 - _C6 )alkylene-OH, -( _C2 - _C6 )alkylene- _NH2 , -( _C2 - _C6 )alkylene-NH( _C1 - _C6 )alkyl, -( _C2 - _C6 )alkylene-N(( _C1 - _C6 )alkyl) ₂ , -( _C2 - _C6 )alkylene-optionally substituted 4-6 membered heterocyclic alkyl) or optionally substituted 4-6 membered heterocyclic alkyl;

_R2 is -H, F, Cl, Br, ( _C1 - _C6 )alkoxy, -O-( _C2 - _C6 )alkylene-OH, -O-( _C2 - _C6 )alkylene-O-( _C1 - _C6 alkyl), ( _C2 - _C6 )alkylene-O-( _C1 - _C6 )alkyl, _-NH2 , -NH-( _{C1-C6 alkyl), -NH-(C1 - C6 )} alkylene-(optionally substituted 4-6 membered heterocyclic alkyl) or –NH-( _C2 - _C6 )alkylene-O-( _C1 - _C6 alkyl); and

n and m are each an independent integer from 0 to 3.

Item 47. The compound as described in Item 46, wherein:

_Y1 does not exist;

_Y2 is O, NH, NHO, NH-NH, or N-( _C1 - _C6 ) alkyl; or

_Y2 is an optionally substituted nitrogen-containing heterocyclic butyl group;

^Z1 is O, NH, NO-( _C1 - _C6 )alkyl or N-( _C1 - _C6 )alkyl;

Ra ^can be H, methyl, ethyl, -( _C2 - _C6 )alkylene-OH, _-CH2CHOH- ( _C2 - _C6 )alkylene-OH, -( _C2 - _C6 )alkylene- _NH2 , -( _C2 - _C6 )alkylene-NHMe, -( _C2 - _C6 )alkylene-N(Me) ₂ , -( _C1 - _C6 )alkylene-morpholinyl, -( _C1 - _C6 )alkylene-piperidinyl, ( _C1 - _C6 )alkylene-(optionally substituted pyrrolidinyl), optionally substituted azahexacyclic butyl or optionally substituted oxohexacyclic butyl;

_R2 is -H, H, F, Cl, Br, methoxy, -O-( _C2 - _C6 )alkylene-OH, -O-( _C2 - _C6 )alkylene-OMe, _-NH2 , -NH-( _C1 - _C6 alkyl), -NH-( _C2 - _C6 )alkylene-OMe, -NH-( _C2 - _C6 )alkylene-(optionally substituted morpholino) or -NH-( _C2 - _C6 )alkylene-O-( _C1 - _C6 alkyl); and

And n and m can each be 0 or 1.

Item 48. The compound of any one of items 46-47, wherein the compound is a compound of formula C-1.

Or its pharmaceutically acceptable salt, wherein:

_Y2 is O, NH, NHO, NH-NH, or N-( _C1 - _C6 ) alkyl; or

_Y2 is an optionally substituted nitrogen-containing heterocyclic butyl group.

^Z1 is O, NH, NO-( _C1 - _C6 )alkyl or N-( _C1 - _C6 )alkyl;

Ra ^can be H, methyl, ethyl, -( _C2 - _C6 )alkylene-OH, _-CH2CHOH- ( _C2 - _C6 )alkylene-OH, -( _C2 - _C6 )alkylene- _NH2 , -( _C2 - _C6 )alkylene-NHMe, -( _C2 - _C6 )alkylene-N(Me) ₂ , -( _C1 - _C6 )alkylene-morpholinyl, -( _C1 - _C6 )alkylene-piperidinyl, ( _C1 - _C6 )alkylene-(optionally substituted pyrrolidinyl), optionally substituted azahexacyclic butyl or optionally substituted oxohexacyclic butyl;

_R2 is -H, H, F, Cl, Br, methoxy, -O-( _C2 - _C6 )alkylene-OH, -O-( _C2 - _C6 )alkylene-OMe, _-NH2 , -NH-( _C1 - _C6 alkyl), -NH-( _C2 - _C6 )alkylene-OMe, -NH-( _C2 - _C6 )alkylene-(optionally substituted morpholino) or -NH-( _C2 - _C6 )alkylene-O-( _C1 - _C6 alkyl); and

Furthermore, n and m are each independently 0 or 1.

Item 49. A compound as described in any one of items 22-28, wherein the compound is a compound of formula D:

Item 50. The compound as described in any one of Item 49, wherein:

_R1 is -H or ( _C1 - _C6 ) alkyl; and

_Y1 does not exist;

_Y2 either does not exist or is -O-, -NHO-, or -NH-; and

^Z1 is an O or NO-( _C1 - _C6 ) alkyl group.

^Ra is -H or -( _C1 - _C6 ) alkyl; and

n and m are each an independent integer from 0 to 3.

Item 51. The compound as described in any one of Item 50, wherein:

_R1 is –H or methyl;

_Y1 does not exist;

_Y2 either does not exist or is -O-, -NHO-, or -NH-; and

^Z1 is O or NO-Me; and

R ^_a is either -H or Me.

n and m are each an independent integer between 0 and 1.

Item 52. The compound of any one of items 49-51, wherein the compound is a compound of formula D-1:

Item 53. A compound as described in any one of items 22-28, wherein the compound is a compound of formula E:

Or its pharmaceutically acceptable salt, wherein:

Ring A is optionally substituted ( _C6 - _C10 ) aryl, optionally substituted ( _C3 - _C10 ) cycloalkyl, optionally substituted 5-10 heteroaryl, or optionally substituted 4-10 heterocycloalkyl; and

_R2 is H or ( _C1 - _C6 ) alkoxy.

Item 54. The compound as described in Item 53, wherein:

Ring A is optionally substituted with phenyl, optionally substituted with cyclopropyl, optionally substituted with pyridyl, optionally substituted with imidazolyl, optionally substituted with pyrrole, optionally substituted with furanyl, optionally substituted with pyrazolyl, optionally substituted with oxazolyl, optionally substituted with aziridine or optionally substituted with oxacyclobutane; and

_R2 is H or methoxy.

Item 55. A compound as described in any one of items 22-28, wherein the compound is a compound of formula F:

Or its pharmaceutically acceptable salt, wherein

^Ra1 is an optionally substituted ( _C1 - _C6 ) alkyl group;

_R1 is -H, -CN, optionally substituted 3-6 membered cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 membered heterocycloalkyl, optionally substituted 5-6 membered heteroaryl, _-SO2- ( _C1 - _C6 )alkyl, _-SO2NH2 , _-SO2 - _NH ( _C1 - _C6 )alkyl, or P(O)(( _C1 - _C6 )alkyl) ₂ ; or

Where: represents the connection point; where:

_Y1 does not exist;

_Y2 is absent, or is -O-, -NH-, -NHO-, -NH-NH-, -N-( _C1 - _C6 )alkyl-; or

_Y2 is an optional substitution in which ring A is a 3, 4, 5, 6 or 7-membered ring, where represents the connection point;

^Z1 is O, NH, N-( _C1 - _C6 )alkyl, NHO, or NO-( _C1 - _C6 )alkyl; and

Ra ^can be -H, -( _C1 - _C6 )alkyl, 4-6 membered heterocyclic alkyl, 3-6 membered cycloalkyl, -( _C2 - _C6 )alkylene-OH, _-CH2CHOH- ( _C2 - _C6 )alkylene-OH, -( _C2 - _C6 )alkylene- _NH2 , -( _C2 - _C6 )alkylene-NH(C1- _C6 ), -( _C2 - _C6 )alkylene-N( _{C1 - C6} ) ₂ , -( _C2 - _C6 )alkylene-N-(4-6 membered heterocyclic alkyl);

Item 56. The compound as described in any one of Item 55, wherein:

^Ra1 is a methyl group;

_R1 is -H, -CN, optionally substituted cyclopropyl, optionally substituted phenyl, optionally substituted 4-6 membered azacyclic butyl, optionally substituted pyrrolyl, optionally substituted piperidinyl, optionally substituted oxazolyl, optionally substituted pyridinyl, optionally substituted imidazolyl, optionally substituted pyrrolyl, optionally substituted furanyl, optionally substituted pyrazolyl, optionally substituted oxadiazolyl, _-SO₂- ( _C₁ - _C₆ )alkyl, _-SO₂NH₂ , _{-SO₂ -} NH( _C₁ - _C₆ )alkyl, or P(O)(( _C₁ - _C₆ )alkyl) _₂ ; or

_R1 is where:

_Y1 does not exist;

_Y2 is O, NH, NHO, NH-NH, or N-( _C1 - _C6 ) alkyl; or

_Y2 is an optionally substituted nitrogen-containing heterocyclic butyl group;

^Z1 is an O, NH, or N-( _C1 - _C6 ) alkyl group; and

Ra ^can be H, ( _C1 - _C6 )alkyl, -( _C2 - _C6 )alkylene-OH, _-CH2CHOH- ( _C2 - _C6 )alkylene-OH, -( _C2 - _C6 )alkylene- _NH2 , -( _C2 - _C6 )alkylene-NH( _C1 - _C6 )alkyl, -( _C2 - _C6 )alkylene-N(( _C1 - _C6 )alkyl) ₂ , -( _C2 - _C6 )alkylene-heterocyclic alkyl) and 4-6 membered heterocyclic alkyl, wherein the heterocyclic alkyl is optionally substituted.

Item 57. A compound as described in any one of items 22-28, wherein the compound is a compound of formula G:

Or its pharmaceutically acceptable salt, wherein:

^Ra1 is an optionally substituted ( _C1 - _C6 ) alkyl group;

_R2 represents the connection point, where:

_Y1 does not exist;

_Y2 either does not exist or is -O- or -NH-; and

^Z1 is 0; and

^Ra is -H or -( _C1 - _C6 ) alkyl.

Item 58. The compound as described in Item 57, wherein:

^Ra2 is a methyl group;

_R2 represents the connection point, where:

_Y1 does not exist;

_Y2 either does not exist or is -O- or -NH-; and

^Z1 is an O or NO-( _C1 - _C6 ) alkyl group; and

^Ra is -H or -( _C1 - _C6 ) alkyl.

Item 59. The compound of any one of items 1-58, wherein the compound is a compound of formula H:

Or its pharmaceutically acceptable salt, wherein:

_R1 is selected from _the group consisting of: -H, _-CN , -CO- _NR5R6 , _-CO2R7 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted _C1 - _C6 alkyl, optionally substituted _C3 - _C8 cycloalkyl, optionally substituted _C3 - _C6 heterocycloalkyl, _-SO2NR8R9 and ( _{SO2 ) -C1 - C6} alkyl;

When _R1 is selected from _the group consisting of: -CN, -CO- _NR5R6 , _-CO2R7 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted _C3 - _{C8 cycloalkyl} , optionally substituted _C3 - _C6 heterocycloalkyl, _SO2NR8R9 and _{( SO2} ) _-C1 - _C6 alkyl, _R2 is H, halogroup, _NR5R6 or optionally substituted _{C1 - C6} alkoxy _.

Where _R1 is -H, _an optionally substituted _C1 - _C6 alkyl, or an optionally substituted _C1 - _C6 alkoxy, _R2 is -CO- _NR5R6 or _{-CO2R7 ;}

Or _R1 and _R2 together with the atoms to which they are attached form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl;

_R3 is selected from the group consisting of: -H, optionally substituted _C1-6 alkyl groups, -CN, and halogroups;

_R4 is -H or a halogenated group;

Optionally substituted with one, two, three or four groups independently selected from the group consisting of a halogroup and a _C1 - _C6 alkyl group, wherein the linkage point is indicated;

_R5 and _R6 are each independently -H, optionally substituted _C1 - _C6 alkyl, or optionally substituted _C1 - _C6 alkoxy;

_R7 is H or an optionally substituted _C1 - _C6 alkyl group;

_R8 and _R9 are each independently H and optionally substituted _C1 - _C6 alkyl groups or _R8 ; or

_R8 and _R9 can be connected to form an optionally substituted heterocyclic ring; and

Y is selected from the following groups: O, S, SO, _SO₂ , NH and N-( _C₁ - _C₆ alkyl).

Item 60. The compound as described in Item 59, wherein Y is O.

Item 61. The compound as described in Item 60, wherein _R3 is H.

Item 62. The compound as described in Item 61, wherein it is not substituted.

Item 63. The compound as described in Item 62, wherein _R4 is a halogroup.

Item 64. The compound as described in Item 63, wherein _R4 is p-fluorine.

Item 65. The compound of any one of items 59-64, wherein _R2 is -H, a halogroup or optionally substituted ( _C1 - _C6 )-alkoxy.

Item 66. The compound as described in Item 63, wherein _R1 is -CN.

Item 67. The compound as described in Item 63, wherein _R1 is _-CO₂H .

Item 68. The compound as described in Item 63, wherein _R1 is _-CO2 -Me.

Item 69. The compound as described in Item 63, wherein _R1 is -CO- _NHR6 .

Item 70. The compound as described in Item 69, wherein _R1 is -CO- _NH2 .

Item 71. The compound as described in Item 69, wherein _R1 is -CO- _NMeR6 .

Item 72. The compound as described in any one of items 1, 2, 4, 5, 7, 8, 9 and 63, wherein _R1 is selected from the group consisting of: -CN, -( _SO₂ ) _NH₂ , -OMe, -( _SO₂ ) _CH₃

Item 73. The compound as described in Item 72, wherein _R1 is selected from the group consisting of:

Item 74. The compound as described in Item 72, wherein _R1 is selected from the group consisting of:

Item 75. The compound as described in any one of items 1, 2, 3, 5, 6, 9 and 63-74, wherein _R2 is selected from the group consisting of: H, -CN, Br, F, Cl, -OMe, _CH3 , _-CH2NH2 , _NH2 , _NHMe ,

Item 76. The compound of any one of items 59-65, wherein _R1 is -H, methyl or methoxy.

Item 77. The compound as described in Item 76, wherein _R2 is _-CO2H .

Item 78. The compound of any one of items 59-65, wherein _R1 is _-CO2 -Me.

Item 79. The compound of any one of items 59-65, wherein _R1 is -CO- _NHR6 .

Item 80. The compound as described in Item 79, wherein _R1 is -CO- _NH2 .

Item 81. The compound of any one of items 59-65, wherein _R1 is -CO- _NMeR6 .

Item 82. The compound of any one of items 59-65, wherein _R1 is selected from the group consisting of:

Item 83. The compound as described in Item 64, wherein the compound is a compound of formula I-A:

Wherein _R6 is (C1 _{- C6} )alkyl, _R2 is (C1 _{- C6} )alkoxy, _R3 is -H or a halogroup, and _R4 is a halogroup.

Item 84. The compound of any one of items 1-83, wherein the compound is selected from the group consisting of:

Or its pharmaceutically acceptable salt.

Item 85. The compound of any one of items 1-83, wherein the compound is selected from the group consisting of:

Or its pharmaceutically acceptable salt.

Item 86. A method for preparing compounds of formula I:

Or a pharmaceutically acceptable salt thereof, the method comprising: making a compound of formula II:

          

Z is selected from _NH₂ , SH, and OH;

Reaction with compounds of formula III:

Where X is a leaving group;

_R1 is selected _from -H, -CN, -CO- _NR5R6 , _-CO2R7 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted _{( C1} - _C6 )alkyl, optionally substituted ( _C3 - _C8 )cycloalkyl, optionally substituted ( _C3 - _C6 ) _{heterocycloalkyl} , _-SO2NR8R9 and -( _{SO2 )} -( _C1 - _C6 )alkyl;

Where _R1 is selected _{from -CN} , -CO- _NR5R6 , _-CO2R7 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted ( _C3 - _C8 )cycloalkyl, optionally substituted ( _C3 - _C6 ) heterocycloalkyl, _-SO2NR8R9 and -( _SO2 )-( _C1 - _C6 )alkyl, _{R2 is -H} , halogroup, _-NR5R6 or optionally substituted _{( C1} - _C6 )alkoxy;

Where _R1 is -H, an optionally substituted ( _C1 - _C6 ) alkyl, or _an optionally substituted ( _C1 - _C6 ) alkoxy, _R2 is -CO- _NR5R6 or _{-CO2R7 ;}

Or _R1 and _R2 together with the atoms to which they are attached form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl;

_R3 is selected from -H, optionally substituted (C1 _{- C6} ) alkyl, -CN, and halogroup;

_R4 is -H or a halogenated group;

Optionally substituted with one, two, three or four independently selected groups from halogroups and ( _C1 - _C6 )alkyl groups, wherein the linkage point is indicated;

_R5 and _R6 are each independently -H, optionally substituted ( _C1 - _C6 ) alkyl, or optionally substituted ( _C1 - _C6 ) alkoxy;

_R7 is -H or an optionally substituted ( _C1 - _C6 ) alkyl group;

_R8 and _R9 are each independently -H and optionally substituted ( _C1 - _C6 ) alkyl; or

_R8 and _R9 can be connected to form an optionally substituted heterocyclic ring; and

Y is selected from O, S, SO, _SO₂ , NH and N-(( _C₁ - _C₆ )alkyl).

Item 87. A method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof:

The method includes:

Compounds of formula IV:

Reaction with compounds of formula V:

_R1 is selected from _{the group consisting of: -H, -CN, -CO-NR5R6, -CO2R7 , optionally substituted} aryl, optionally substituted heteroaryl, optionally substituted ( _C1 - _C6 )alkyl, optionally substituted ( _C3 - _C8 )cycloalkyl, optionally substituted ( _C3 - _{C6 ) heterocycloalkyl} , _-SO2NR8R9 and -( _SO2 )-( _C1 - _C6 )alkyl;

When _R1 is selected from _the group consisting of _: -CN, -CO- _NR5R6 , _-CO2R7 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted ( _C3 - _C8 )cycloalkyl, optionally substituted ( _C3 - _C6 ) heterocycloalkyl, _-SO2NR8R9 and -( _SO2 )- _{( C1} - _C6 )alkyl, _R2 is _-H , _halogroup , _-NR5R6 or optionally substituted ( _C1 - _C6 )alkoxy;

Where _R1 is -H, an optionally substituted ( _C1 - _C6 ) alkyl, or _an optionally substituted ( _C1 - _C6 ) alkoxy, _R2 is -CO- _NR5R6 or _{-CO2R7 ;}

Or _R1 and _R2 together with the atoms to which they are attached form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl;

_R3 is selected from the group consisting of: -H, optionally substituted (C1 _{- C6} ) alkyl, -CN, and halogroup;

_R4 is -H or a halogenated group;

Optionally substituted with one, two, three or four groups independently selected from the group consisting of a halogroup and a ( _C1 - _C6 ) alkyl group, wherein the linkage point is indicated;

_R5 and _R6 are each independently -H, optionally substituted ( _C1 - _C6 ) alkyl, or optionally substituted ( _C1 - _C6 ) alkoxy;

_R7 is -H or an optionally substituted ( _C1 - _C6 ) alkyl group;

_R8 and _R9 are each independently -H and optionally substituted ( _C1 - _C6 alkyl); or

_R8 and _R9 can be connected to form an optionally substituted heterocyclic ring; and

Y is selected from the group consisting of: O, S, SO, _SO₂ , NH and N-(( _C₁ - _C₆ )alkyl).

Item 88. The method of Item 87 further comprises making a compound of Formula VI:

Reaction with compounds of formula VII:

Compounds of formula VIII:

And reduce the compound of formula VIII to provide the compound of formula V.

in:

_R1 is selected from _{the group consisting of: -H, -CN, -CO-NR5R6, -CO2R7 , optionally substituted} aryl, optionally substituted heteroaryl, optionally substituted ( _C1 - _C6 )alkyl, optionally substituted ( _C3 - _C8 )cycloalkyl, optionally substituted ( _C3 - _{C6 ) heterocycloalkyl} , _-SO2NR8R9 and -( _SO2 )-( _C1 - _C6 )alkyl;

Where _R1 is selected _{from -CN} , -CO- _NR5R6 , _-CO2R7 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted ( _C3 - _C8 )cycloalkyl, optionally substituted ( _C3 - _C6 ) heterocycloalkyl, _-SO2NR8R9 and -( _SO2 )-( _C1 - _C6 )alkyl, _{R2 is -H} , halogroup, _-NR5R6 or optionally substituted _{( C1} - _C6 )alkoxy;

Where _R1 is -H, an optionally substituted ( _C1 - _C6 ) alkyl, or _an optionally substituted ( _C1 - _C6 ) alkoxy, _R2 is -CO- _NR5R6 or _{-CO2R7 .}

Or _R1 and _R2 together with the atoms to which they are attached form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl;

_R3 is selected from the group consisting of: -H, optionally substituted (C1 _{- C6} ) alkyl, -CN, and halogroup; and

W is a halogenated group.

Item 89. A pharmaceutical composition comprising a compound as described in any one of items 1-85 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

Item 90. A method of treating a disease, condition, or syndrome by at least partially modulating the in vivo activity of a protein kinase, the method comprising administering to a subject in need a compound as described in any one of items 1-85 or a pharmaceutical composition as described in item 89.

Item 91. The method of Item 90, wherein the disease, condition or syndrome mediated at least in part by regulating the in vivo activity of protein kinases is cancer.

Item 92. A method for inhibiting a protein kinase, the method comprising contacting the protein kinase with a compound as described in any one of items 1-85.

Item 93. The method of any one of items 90-92, wherein the protein kinase is Axl, Mer, c-Met, KDR or a combination thereof.

This application is a divisional application of the invention patent application filed on January 25, 2009, with application number 201980015066.9 (international application number PCT/US2019/015297) entitled "Compound for treating kinase-dependent diseases".

Technical Field

This invention relates to compounds that regulate cellular activities such as proliferation, differentiation, programmed cell death, migration, and chemical invasion by modulating protein kinase activity. More specifically, this invention relates to compounds that inhibit, regulate, and/or modulate Axl and Mer receptor tyrosine kinases, compositions containing these compounds, methods of using them to treat kinase-dependent diseases and disorders, the synthesis of said compounds, and methods of formulating compounds for pharmaceutical purposes.

Cross-references to related applications

This application claims priority to U.S. Provisional Application Serial No. 62/622,702, filed January 26, 2018 and U.S. Provisional Application Serial No. 62/758,321, filed November 9, 2018, the entire contents of which are incorporated herein by reference.

Background Technology

Human Axl belongs to the TAM subfamily of receptor tyrosine kinases, including Mer. TAM kinases are characterized by an extracellular ligand-binding domain consisting of two immunoglobulin-like domains and two fibronectin type III domains. Axl is overexpressed in many tumor cell types and was originally cloned from patients with chronic myeloid leukemia. When overexpressed, Axl exhibits transformative potential. Axl signaling is believed to induce tumor growth by activating proliferative and anti-apoptotic signaling pathways. Axl has been associated with cancers such as lung cancer, myeloid leukemia, uterine cancer, ovarian cancer, glioma, melanoma, thyroid cancer, renal cell carcinoma, osteosarcoma, gastric cancer, prostate cancer, and breast cancer. Overexpression of Axl leads to poor prognosis in patients with the indicated cancers.

Like Axl, Mer activation leads to downstream signaling pathways in tumor growth and activation. Mer binds to ligands such as the soluble protein Gas-6. Gas-6 binding to Mer induces autophosphorylation of Mer in its intracellular domain, resulting in downstream signal activation. Overexpression of Mer in cancer cells leads to increased metastasis, most likely through the generation of soluble Mer extracellular domain proteins as decoy receptors. Tumor cells secrete soluble forms of extracellular Mer receptors, which reduce the ability of soluble Gas-6 ligands to activate Mer on endothelial cells, thereby contributing to cancer progression.

Therefore, compounds that inhibit TAM receptor tyrosine kinases such as Axl and Mer are needed to treat selected cancers.

Summary of the Invention

In one aspect, the present invention provides compounds of formula I:

Or its pharmaceutically acceptable salt, wherein:

_R1 is selected _from -H, -CN, -CO- _NR5R6 , _-CO2R7 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted _{( C1} - _C6 )alkyl, optionally substituted ( _C3 - _C8 )cycloalkyl, optionally substituted ( _C3 - _C6 ) _{heterocycloalkyl} , _-SO2NR8R9 and -( _{SO2 )} -( _C1 - _C6 )alkyl;

Where _R1 is selected _{from -CN} , -CO- _NR5R6 , _-CO2R7 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted ( _C3 - _C8 )cycloalkyl, optionally substituted ( _C3 - _C6 ) heterocycloalkyl, _-SO2NR8R9 and -( _SO2 )-( _C1 - _C6 )alkyl, _{R2 is -H} , halogroup, _-NR5R6 or optionally substituted _{( C1} - _C6 )alkoxy;

Where _R1 is -H, an optionally substituted ( _C1 - _C6 ) alkyl, or _an optionally substituted ( _C1 - _C6 ) alkoxy, _R2 is -CO- _NR5R6 ; or _{-CO2R7 ;}

Or _R1 and _R2 together with the atoms to which they are attached form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl;

_R3 is selected from -H, optionally substituted (C1 _{- C6} ) alkyl, -CN, and halogroup;

_R4 is -H or a halogenated group;

Optionally substituted with one, two, three or four independently selected groups from halogroups and ( _C1 - _C6 )alkyl groups, wherein the linkage point is indicated;

_R5 and _R6 are each independently -H, optionally substituted ( _C1 - _C6 ) alkyl, or optionally substituted ( _C1 - _C6 ) alkoxy;

_R7 is -H or an optionally substituted ( _C1 - _C6 ) alkyl group.

_R8 and _R9 are each independently -H or optionally substituted ( _C1 - _C6 ) alkyl groups;

Alternatively, _R8 and _R9 can be connected to form an optionally substituted heterocyclic ring; and

Y is selected from O, S, SO, _SO₂ , NH and N-( _C₁ - _C₆ alkyl).

On the other hand, compounds of formula A are provided:

Or its pharmaceutically acceptable salt, wherein

(i) _R1 is selected from ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, ( _C6 - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-10 heteroaryl, 4-10 heterocycloalkyl, -CN, -NHOH, -C(O) ^Ra , -C(O) ^NRaRa , -C(O) ^NHORa , ^-C (O) ^ORa , -C(O)NRaS(O) _2Ra , ^-OC (O) ^NRaRa , ^C (＝ ^NRa ) ^{Ra ,} -C(＝NOH) ^Ra , -C(＝NOH) ^{NRa ,} -C(＝ ^NCN ) ^{NRaRa ,} -C(＝NRa) ^NRaRa , -S(O) ^{NRaRa ,} -S(O) _2NRaC ( ^O ) ^Ra , -P(O)R ^a R ^a , -P(O)(OR ^a )(OR ^a ), -B(OH) ₂ , -B(OR ^a ) ₂ and S(O) ₂ NR ^a R ^a ; and

_R2 is selected from -H, halogenated, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, (C1- _C6 )haloalkyl, (C1 _- C6)haloalkoxy, ( _{C6 - C10} )aryl-( _C1 - _C4 )alkylene-, (C3 _{-C10 )} cycloalkyl-( _C1 - _C4 )alkylene-, (5-14-membered heteroaryl)-( _{C1 - C4} )alkylene-, (4-14-membered heterocycloalkyl)-(C1 _{- C4} )alkylene-, -CN, _-NO2 , ^-ORa , ^-SRa , ^-NHORa , -C(O) ^{Ra ,} -C(O) ^NRaRa , -C(O) ^NHORa , -C(O) ^ORa , -C(O)NR ^a S(O) ₂ R ^a , -OC(O)R ^a , -OC(O)NR ^a R ^a , -NHR ^a , -NR ^a R ^a , -NR ^a C(O)R ^a , -NR ^a C(=NR ^a )R ^a , -NR ^a C(O)OR ^a , -NR ^a C(O)NR ^a R ^a , -C(=NR ^a )R ^a , -C(=NOH)R ^a , -C(=NOH)NR ^a , -C(=NCN)NR ^a R ^a , -NR ^a C(=NCN)NR ^a R ^a , -C(=NR ^a )NR ^a R ^a , -NR ^a C(=NR ^a )NR ^a R ^a , -NR ^a S(O)R ^a , -NR ^a S(O) ₂ R ^a , -NR ^a S(O) ₂ NR ^a R ^a ,-S(O)R ^a -S(O)NR ^aRa , ^-S (O) _2Ra , -S(O) _2NR ^aC (O) ^Ra , -P(O) ^RaRa , -P(O)(OR ^a )( ^{OR a )} , -B ⁽ OH) ₂ , -B(OR ^a ) ₂ and -S(O ^{)2NR aRa} _, ^wherein _R1 or _R2 is a (C1 _{- C6} )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, ( _C6 - _C10 )aryl-( _C1 - _C4 )alkylene-, ( _C3 - _C10 )cycloalkyl-( _C1 - _C4 )alkylene-, (5-14-membered heteroaryl)-(C1 _{- C4} )alkylene- and (4-14-membered heterocycloalkyl)-(C1 _- C ₄ ) Alkylenes – each optionally substituted by 1, 2, 3, 4, or 5 independently selected ^Rb substituents, provided that when _R1 is a 5-7-membered heteroaryl or 5-7-membered heterocyclic alkyl and _R2 is a _C1-6 alkoxy, the 5-7-membered heteroaryl or 5-7-membered heterocyclic alkyl is not connected to the fused benzene ring of the quinoline moiety via a cyclic nitrogen atom; or

(ii) _R1 is selected from -H, halogroup, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, (C2- _C6 )ynyl, ( _C1 - _C6 )haloalkyl, (C1 _{- C6} )haloalkoxy, ( _{C6 - C10} )aryl, ( _C3 - _C10 )cycloalkyl, 5-14-membered heteroaryl, 4-14-membered heterocycloalkyl, ( _C6 - _C10 )aryl-( _{C1- C4} )alkylene-, ( _C3 - _C10 )cycloalkyl-( _{C1- C4} )alkylene-, (5-14-membered heteroaryl)-( _{C1- C4} )alkylene-, (4-14-membered heterocycloalkyl)-( _{C1- C4} )alkylene-, -CN, _-NO2 , ^-ORa , -SR ^a , -NHOR ^a , -C(O)R ^a , -C(O)NR ^a R ^a , -C(O)NHOR ^a , -C(O)OR ^a , -C(O)NR ^a S(O) ₂ R ^a , -OC(O)R ^a , -OC(O)NR ^a R ^a , -NHR ^a , -NR ^a R ^a , -NR ^a C(O)R ^a , -NR ^a C(=NR ^a )R ^a , -NR ^a C(O)OR ^a , -NR ^a C(O)NR ^a R ^a , -C(=NR ^a )R ^a , -C(=NOH)R ^a , -C(=NOH)NR ^a , -C(=NCN)NR ^a R ^a , -NR ^a C(=NCN)NR ^a R ^a , -C(=NR ^a )NR ^a R ^a , -NR ^a C(=NR ^a )NR ^a R ^a , -NR ^a S(O) ^Ra , ^-NRaS (O) _2Ra , -NRaS ₍ O) ^2NRaRa , ^-S (O ₎ ^Ra , -S(O) ^NRaRa , -S(O) ^2Ra , ^-S (O) _2NRaC (O)Ra, ^-P (O) ^RaRa , -P ⁽ O)( ^ORa )( ^ORa ) ^{, -B} (OH) ² , -B( ^ORa ) _{2 and} -S(O) _2NRaRa , wherein _R1 or ^R2 is a ( _C1 - _C6 )alkyl, ( _C2 - _C6 ) ^alkenyl , ( _C2 - _C6 )ynyl, (C6 _{-C10 )} aryl, ( _C3 - _C10 )cycloalkyl, 5-14 heteroaryl, 4-14 heterocycloalkyl, ( _C6 - _{C10 ) ...} The aryl-(C1 _{- C4} )alkylene-, (C3- _C10 )cycloalkyl-( _C1 -C4)alkylene-, (5-14-membered heteroaryl)-( _{C1- C4} )alkylene-, and (4-14-membered heterocycloalkyl)-( _{C1 - C4} )alkylene- are each optionally substituted by 1, 2, 3 _, 4, or 5 independently selected ^Rb substituents; and

R ₂ is selected from (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, -CN, -NHOH, -C(O)R ^a , -C(O)NR ^a R ^a , -C(O)NHOR ^a , -C(O)OR ^a , -C(O)NR ^a S(O) ₂ R ^a , -OC(O)NR ^a R ^a , C(=NR ^a )R ^a , -C(=NOH)R ^a , -C(=NOH)NR ^a , -C(=NCN)NR ^a R ^a , -NR ^a C(=NCN)NR ^a R ^a , -C(=NR ^a )NR ^a R ^a , -S(O)NR ^a R ^a , -S(O) ₂ NR ^a C(O)R ^a , -P(O)R ^a R ^a , -P(O)(OR ^a )(OR ^a ), -B(OH) ₂ , -B(OR ^a ) ₂ and S(O) ₂ NR ^{a Ra} , provided that when R ₁ is a 5-7 membered heteroaryl or a 5-7 membered heterocyclic alkyl and R ₂ is a C _1-6 alkoxy, then the 5-7 membered heteroaryl or 5-7 membered heterocyclic alkyl of R ₁ is not connected to the fused benzene ring of the quinoline moiety through a cyclic nitrogen atom.

(iii) _R1 and _R2 together with the atoms to which they are attached form a fused (C3 _{- C7} ) cycloalkyl ring or a fused 4- to 10-membered heterocyclic alkyl ring, wherein the fused (C3 _{- C7} ) cycloalkyl ring and the fused 4- to 10-membered heterocyclic alkyl ring are each optionally substituted by one, two or three independently selected ^Rb substituents, provided that the compound is not 1-[2-(4-fluorophenyl)-acetyl]-cyclopropanecarboxylic acid [3-fluoro-4-(7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxa-1-aza-cyclododecane[b]naphthalene-4-yloxy)-phenyl]-amide;

_R10 and _R11 are each independently selected from -H, halogroup, ( _C1 - _C6 )alkyl, (C1- _C6 )haloalkyl, ( _{C1 - C6} )haloalkoxy, ( _C6 - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-14-membered heteroaryl, 4-14-membered heterocycloalkyl, ( _C6 - _C10 )aryl-( _C1 - _C4 )alkylene-, ( _C3 - _C10 )cycloalkyl-( _{C1- C4} )alkylene-, (5-14-membered heteroaryl)-( _{C1- C4} )alkylene-, (4-14-membered heterocycloalkyl)-( _{C1- C4} )alkylene-, -CN, _-NO2 ^{, -ORa} , -SRa, ^-NHORa , -C(O) ^Ra , -C(O)NR ^a R ^a , -C(O)OR ^a , -C(O)NR ^a S(O) ₂ R ^a , -OC(O)R ^a , -OC(O)NR ^a R ^a , -NHR ^a , -NR ^a R ^a , -NR ^a C(O)R ^a , -NR ^a C(=NR ^a )R ^a , -NR ^a C(O)OR ^a , -NR ^a C(O)NR ^a R ^a , -C(=NR ^a )R ^a , -C(=NOH)R ^a , -C(=NOH)NR ^a , -C(=NCN)NR ^a R ^a , -NR ^a C(=NCN)NR ^a R ^a , -C(=NR ^a )NR ^a R ^a , -NR ^a C(=NR ^a )NR ^a R ^a , -NR ^a S(O)R ^a , -NR ^a S(O) ₂ R ^a , -NR ^aS (O) ₂ NR ^{a Ra} , -S(O) ^Ra , -S(O)NR ^{a Ra} , -S(O) ₂ ^Ra , -S(O) ₂ NR ^a C(O) Ra, -P(O)Ra ^Ra , -P(O)( ^{OR a} )(OR ^a ), -B( ^OH ) ₂ , -B(OR ^a ) ₂ and S(O) ₂ NR ^{a Ra} , wherein _R1 or _R2 is a ( _{C1-C6)alkyl, (C6} - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-14-membered heteroaryl, 4-14-membered heterocycloalkyl, ( _C6 - _C10 )aryl-(C1-C4)alkylene-, (C3-C10)cycloalkyl-( _C1 - _C4 )alkylene-, (C3- _C10 )cycloalkyl-(C1 _- C4)alkylene-, ( _C3 - _C10 )cycloalkyl-(C1 _- C4 ₎ alkylene-. The alkylene-, (5-14-membered heteroaryl)-(C1 _{- C4} )alkylene- and (4-14-membered heterocyclic alkyl)-(C1 _{- C4} )alkylene- are each optionally substituted by 1, 2, 3, 4 or 5 independently selected ^Rb substituents;

Each _R3 is independently selected from -H, halogroup, -OH, -CN, optionally substituted ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy, ( _C1 - _C6 )haloalkoxy, _-NH2 , -NH( _C1 - _C6 )alkyl, -N( _C1 - _C6 )alkyl) ₂ and ( _C3 - _C6 )cycloalkyl, wherein the ( _C1 -C6)alkoxy, -NH( _C1 - _C6 )alkyl, -N( _C1 - _{C6 )} alkyl) _{2 and} ( _C3 - _C6 )cycloalkyl of R3 are each optionally substituted by 1, 2 or 3 independently selected ^Rg substituents;

Each R ₁₄ is independently selected from halogen, -OH, -NH ₂ , -CN, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )haloalkyl, (C ₁ -C ₆ )haloalkoxy, -COOH, -NH(C ₁ -C ₆ )alkyl, -N(C ₁ -C _6alkyl ) ₂ , phenyl, phenyl-(C _1- C ₂ )alkylene, (C _3- C ₆ )cycloalkyl, (C _3- C ₆ )cycloalkyl-(C _1- C ₄ )alkylene-, 4 to 6-membered heterocycloalkyl, (4 to 6-membered heterocycloalkyl)-(C _1- C ₄ )alkylene-, 5 to 6-membered heteroaryl, (5 to 6-membered heteroaryl)-(C _1- C ₄ )alkylene- and -OR ^e , wherein R _The ( _C1 - _C6 )alkyl, phenyl, phenyl-(C1- _C2 )alkylene, ( _C3- C6)cycloalkyl, ( _{C3- C6} )cycloalkyl-(C1 _{- C4} )alkylene, 4- to ₆ -membered heterocycloalkyl, ( _4- to 6-membered heterocycloalkyl)-(C1 _{- C4} )alkylene, 5- to 6-membered heteroaryl and (5- to 6-membered heteroaryl)-(C1 _{- C4} )alkylene are each optionally substituted by one, two or three independently selected ^Rg substituents.

R ₁₅ is H or C _1-6 alkyl;

Each _R4 is independently selected from -H, halogroup, -OH, -COOR ^e , -CONR ^{e Re} , -CN, -NH ₂ , -NH ((C1 _{- C6} )alkyl), -N ((C1 _{- C6} )alkyl) ₂ , (C1 _{- C6} )alkyl, (C1 _{- C6} )alkoxy, (C1 _{- C6} )haloalkyl, (C1 _{- C6} )haloalkoxy, -CONR ^{a Ra} , -NR ^a COR ^a , -NR ^a CONR ^{a Ra} , -SO ₂ ^Ra , -NR ^a S(O) ₂ ^Ra , -NR ^a S(O) ₂ NR ^{a Ra} , (C3 _{- C6} )cycloalkyl, 4- to 6-membered heterocyclic alkyl, phenyl, 5- or 6-membered heteroaryl, (C3 _{- C6} )cycloalkyl-(C1 _- C4 ₎ R4 is optionally substituted with alkylene-, (4- to 6-membered heterocyclic alkyl)-(C1 _{- C4} )alkylene-, phenyl-(C1 _{- C2} )alkylene-, and (5 or 6-membered heteroaryl)-(C1 _{- C4} )alkylene-, wherein the ( _{C1- C6} )alkyl, ( _{C3- C6} )cycloalkyl, _4- to 6-membered heterocyclic alkyl, phenyl, 5 or 6-membered heteroaryl, ( _{C3- C6} )cycloalkyl-( _{C1- C4} )alkylene-, (4- to 6-membered heterocyclic alkyl)-(C1 _{- C4} )alkylene-, phenyl-(C1 _{- C2} )alkylene-, and (5 or 6-membered heteroaryl)-(C1 _{- C4} )alkylene-, respectively, by 1, 2 or 3 independently selected ^Rf substituents;

Each Ra ^is independently selected from -H, -CN, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )haloalkyl, ( _C2 - _C6 )alkenyl, (C2- _C6 )ynyl, ( _C6 -C10)aryl, ( _C3 - _C10 )cycloalkyl, 5-14-membered heteroaryl, 4-14-membered heterocycloalkyl, ( _{C6 - C10} )aryl-(C1- _C4 )alkylene-, (C3 _{- C10} )cycloalkyl-( _C1 - _C4 )alkylene-, (5-14-membered heteroaryl)-( _{C1- C4} )alkylene-, and (4-14-membered heterocycloalkyl)-( _{C1- C4 )} alkylene-, wherein the ( _C1 - _{C6)alkyl, (C1-C6 )} alkyl, ⁽ _C2 - _C6) alkylene- ... ( _C2 - _C6 )alkenyl, (C2-C6)ynyl, ( _C6 - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-14-membered heteroaryl, 4-14-membered heterocycloalkyl, ( _C6 - _C10 )aryl-( _C1 - _C4 )alkylene-, ( _{C3- C10} )cycloalkyl-( _C1 - _C4 )alkylene-, (5-14-membered heteroaryl)-( _{C1 - C4} )alkylene- and (4-14-membered heterocycloalkyl)-( _{C1 - C4} )alkylene- are each optionally substituted by 1, 2, 3, 4 or 5 independently selected ^Rd substituents;

Each ^Rb is independently selected from halogen, oxo, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, (C1-C6)haloalkyl, ( _{C1 -C6 )} haloalkoxy, ( _C6 - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-10-membered heteroaryl, _4-10 -membered heterocycloalkyl, ( _C6 - _C10 )aryl-( _{C1- C4} )alkylene-, ( _{C3- C10} )cycloalkyl-(C1 _{- C4} )alkylene-, (5-10-membered heteroaryl)-(C1 _{- C4} )alkylene-, (4-10-membered heterocycloalkyl)-(C1 _{- C4} )alkylene-, -CN, -OH, _-NH2 , -NO _2. -NHOR ^c , -OR ^c , -SR ^c , -C(O)R ^c , -C(O)NR ^c R ^c , -C(O)OR ^c , -C(O)NR ^c S(O) ₂ R ^c , -OC(O)R ^c , -OC(O)NR ^c R ^c , -C(=NOH)R ^c , -C(=NOH)NR ^c , -C(=NCN)NR ^c R ^c , -NR ^c C(=NCN)NR ^c R ^c , -C(=NR ^c )NR ^c R ^c , -NR ^c C(=NR ^c )NR ^c R ^c , -NHR ^c , -NR ^c R ^c , -NR ^c C(O)R ^c , -NR ^c C(=NR ^c )R ^c , -NR ^c C(O)OR ^c , -NR ^c C(O)NR ^c R ^c , -NR ^c S(O)R ^c ,-NR ^c S(O) _2Rc ^{, -NRcS} (O) _2NRcRc , ^-S (O) ^Rc , -S(O) ^NRcRc , -S(O) ^2Rc , -S(O) ^2NRcC (O) ^Rc , -Si(Rc) ₃ , -P(O) ^RcRc , ^-P ( ^O ₎ ( ^ORc )(ORc), ^-B (OH) ₂ , ^-B ( ^ORc ) ₂ and -S(O) _2NRcRc , wherein ^Rb is a ⁽ C1-C6) ^alkyl , (C1- ^C6 ) _haloalkyl , ( _C1 - _C6 )haloalkoxy, (C2-C6)alkenyl, ( _C2 - _C6 )alkynyl, ( _C6 - _C10 )aryl, (C3-C10)alkyl, ( _C3 - _C10 )alkyl, ( _C4 - _C5 )alkyl, ( _C6 - _C10 )alkyl, ( _C3- C10)alkyl, (C4 _... ( _C6 - _C10 ) aryl-(C1-C4) alkylene-, (C3-C10) cycloalkyl-( _{C1- C4} ) alkylene-, ( _5-10 ) heteroaryl-( _{C1 - C4} ) alkylene-, and ( _4-10 ) heterocycloalkyl-(C1 _{- C4 )} alkylene- are each optionally further substituted by one, two, or three independently selected ^Rd substituents;

Each ^Rc is independently selected from -H, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )haloalkyl, ( _C2 - _C6 )alkenyl, ( _C2 -C6)ynyl, (C6- _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-10 heteroaryl, 4-10 heterocycloalkyl, ( _C6 - _C10 )aryl-( _C1 - _C4 )alkylene-, (C3 _{- C10} )cycloalkyl-( _C1 - _C4 )alkylene-, (5-10 heteroaryl)-(C1 _{- C4} )alkylene-, and (4-10 heterocycloalkyl)-(C1 _{-C4)alkylene-, wherein the (C1- C6} )alkyl, ( _C2- C6)alkenyl, ( _C3 - _C10 ) alkylene-, ( ^C4 - _C10 ) alkylene-, ( _C6 - _C10 ) alkylene-, (C1 ... ₂ - _C6 ) ynyl, ( _C6 - _C10 ) aryl, ( _C3 - _C10 ) cycloalkyl, 5-10 heteroaryl, 4-10 heterocycloalkyl, (C6- _C10 ) aryl-( _C1 -C4) alkylene-, ( _C3 - _C10 ) cycloalkyl-(C1 _{- C4} ) alkylene-, (5-10 heteroaryl)-( _{C1 - C4} ) alkylene- and (4-10 heterocycloalkyl)-(C1 _{- C4} ) alkylene- are each optionally substituted by 1, 2, 3, ₄ or 5 independently selected R ^f substituents;

Each R d is independently selected from (C <sub>1- C 6  )alkyl, (C <sub>1- C  6 )haloalkyl, haloyl, (C<sub>6-C10)aryl, 5-10 heteroaryl, (C <sub>3- C 10 )cycloalkyl, 4-10 heterocyclic alkyl, (C <sub>6- C 10 )aryl-(C <sub>1- C 4 )alkylene-, (C <sub>3- C 10 )cycloalkyl-(C <sub>1- C 4 )alkylene-, (5-10 heteroaryl)-(C <sub>1- C 4 )alkylene-, (4-10 heterocyclic alkyl)-(C <sub>1- C4 )alkylene-, -CN, -NH 2 , -NHOR e , -OR e , -SRe, -C(O)R  e , -C(O)NReRe , -C(O)OR e -OC(O)R e , -OC(O)NR eR e , -NHR e , -NR eR e , -NR e C(O)R e , -NR e C(O)NR eR e , -NR e C(O)OR e , -C(＝NR e )NR eR e , -NR e C(＝NR e )NR eR e , -NR e C(＝NOH)NR eR e, -NR e C(＝NCN)NR eR e , -S (O)R e , -S(O)NR eR e , -S(O) 2 Re, -NR e S (O) 2 Re , -NR e S(O) 2 NR e Re and -S (O) 2 NR e Re , wherein R d is a (C 1- C 6 ) alkyl , (C 1 - C 6 )haloalkyl, (C 6- C 10 )alkyl, (C 6- C 10 )alkyl, ... )aryl, 5-10 heteroaryl, ( C3- C10 )cycloalkyl, 4-10 heterocycloalkyl, (C6 - C10 )aryl-(C1-C4)alkylene-, (C3 - C10 )cycloalkyl-( C1- C4 )alkylene-, ( 5-10 heteroaryl)-(C1- C4 )alkylene- and (4-10 heterocycloalkyl)-( C1- C4 ) alkylene- are each optionally substituted by 1, 2 or 3 independently selected R f substituents;

Each ^Re is independently selected from -H, (C1 _{- C6} )alkyl, (C3 _{- C6} )cycloalkyl-, (C3 _{- C6} )cycloalkyl-(C1 _{- C4} )alkylene-, (C6- _C10 )aryl, ( _{C6- C10} )aryl-( _{C1 - C4} )alkylene-, 5- or 6-membered heteroaryl, (5- or 6-membered heteroaryl)-(C1 _- C4)alkylene-, 4- or 7-membered heterocycloalkyl, (4- or 7-membered heterocycloalkyl)-(C1 _{- C4} )alkylene-, (C1- _C6 ) haloalkyl, ( _{C1 - C6} ) haloalkoxy, (C2 _{- C4} ) alkenyl, and (C2 _{- C4} ) ynyl, wherein ^the (C1 _{- C4} )alkyl, (C3 _{- C6)...} The cycloalkyl, ( _{C6- C10} ) aryl, 5- or 6-membered heteroaryl, 4- or 7-membered heterocycloalkyl, ( _{C6- or 10} ) aryl-( _{C1- or 4} ) alkylene-, (5- or 6-membered heteroaryl)-( _{C1- or 4} ) alkylene-, (4- or 7-membered heterocycloalkyl)-( _C1- or ₄ ) alkylene-, ( _{C2- or 4} ) alkenyl, and ( _C2- or ₄ ) ynyl groups are each optionally substituted with 1, 2, or 3 ^Rf substituents.

Or any two ^Ra substituents together with the nitrogen atom to which they are attached form a 4, 5, 6, 7, 8, 9 or 10-membered heterocyclic alkyl group, each heterocyclic alkyl group optionally being substituted by 1, 2 or 3 independently selected R ^f substituents;

Alternatively, any two ^Rc substituents together with the nitrogen atom to which they are attached can form a 4, 5, 6, 7, 8, 9, or 10-membered heterocyclic alkyl group, each heterocyclic alkyl group optionally being substituted by one, two, or three independently selected ^Rf substituents.

Or any two ^Re substituents together with the nitrogen atom to which they are attached form a 4, 5, 6, 7, 8, 9 or 10-membered heterocyclic alkyl group, each heterocyclic alkyl group optionally being substituted by 1, 2 or 3 independently selected R ^f substituents;

Each ^Rf is independently selected from halogen, -OH, -CN, -COOH, _-NH2 , -NH-(C1 _{- C6} )alkyl, -N((C1 _{- C6} )alkyl) ₂ , (C1 _{- C6} )alkyl, (C1- _C6 )alkoxy, ( _C1- C6)alkylthio, (C1 _{- C6} )haloalkyl, (C1 _{- C6} )haloalkoxy, phenyl, 5-6-membered heteroaryl, 4-6-membered heterocyclic alkyl, and ( _{C3 - C6} )cycloalkyl, wherein the (C1 _{- C6} )alkyl, phenyl, (C3 _{- C6} )cycloalkyl, 4-6-membered heterocyclic alkyl, and 5-6-membered heteroaryl of ^Rf are each optionally selected by 1, 2, or 3 from halogen, -OH, -CN, -COOH, _-NH2 , (C1 _- C6 ₎ alkyl, -NH- _{( ...} Substituents of alkyl, (C1 _{- C4} )alkoxy, (C1 _{- C4} )haloalkyl, ( _{C1- C4} )haloalkoxy, phenyl, (C3 _{- C10} )cycloalkyl, 5-6-membered heteroaryl and 4-6-membered heterocyclic alkyl groups;

Each R ^g is independently selected from halogenated, -OH, -CN, -COOH, -COO-( _{C1- C4} ) _alkyl , -NH2, -NH-( _{C1- C6} )alkyl, -N((C1 _{- C6} )alkyl) ₂ , ( _{C1- C6} )alkyl, (C1 _{- C6} )alkoxy, (C1- _C6 )alkylthio, ( _{C1- C6 )} haloalkyl, (C1 _{- C6} )haloalkoxy, phenyl, 5-6-membered heteroaryl, 4-6-membered heterocyclic alkyl and (C3 _{- C6} )cycloalkyl;

Y is selected from -O-, -S-, -SO-, _-SO₂- , -NH-, and -N((C₁ _{- C₆} )alkyl)-;

The cyclic nitrogen atom on the quinoline moiety in Formula A may optionally be oxidized;

The subscript n is an integer of 1, 2, 3 or 4;

The subscript m is an integer of 1, 2, 3, 4, or 5; and

The subscript p is an integer of 0, 1, 2, 3 or 4.

On the other hand, it provides a method for treating diseases, symptoms, or syndromes mediated at least in part by modulating the in vivo activity of protein kinases using compounds of Formula I or pharmaceutically acceptable salts thereof.

On the other hand, methods for preparing compounds of formula A and formula I are provided.

These and other aspects, as well as the implementation plan, are described below.

Detailed Implementation

Abbreviations and Definitions

The following abbreviations and terms have a consistent meaning throughout the text:

The symbol "-" represents a single bond, and "=" represents a double bond.

As used in this article, the singular forms “a,” “a,” and “the” include plural references unless the context clearly indicates otherwise.

When a variable is defined generally, it has many possible substituents, and each individual group can be defined as having or not having a bond. For example, if R ^_z can be hydrogen, this can be indicated as "-H" or "H" in the definition of R_^z.

When depicting or describing chemical structures, unless otherwise explicitly stated, it is assumed that all carbon atoms have tetravalent hydrogen substitutions. For example, in the structure on the left of the following diagram, nine hydrogen atoms are implied. Nine hydrogen atoms are depicted in the structure on the right. Sometimes, specific atoms in a structure are described in the textual formula as having one or more hydrogen atoms as substituents (explicitly defined as _hydrogen ), such as _-CH₂CH₂- . Those skilled in the art will understand that the above descriptive techniques are common in the field of chemistry to provide a concise and simple description of other complex structures.

If the group "R" is described as "floating" on the ring system, such as in the following formula:

Unless otherwise defined, the substituent “R” can be located on any atom of the ring system, assuming that a hydrogen atom described, implicit or explicitly defined is replaced from one of the ring atoms, as long as a stable structure is formed.

If the group "R" is described as floating on a fused ring system, such as in the following formula:

Unless otherwise defined, the substituent “R” can be located on any atom in a fused ring system, assuming substitution from one of the ring atoms for a hydrogen atom described (e.g., -NH- in the above formula), an implicit hydrogen atom (e.g., hydrogen not shown in the above formula but to be understood as present), or an explicitly defined hydrogen atom (e.g., “Z” equals =CH- in the above formula), as long as a stable structure is formed. In the example shown, the “R” group can be located on a 5-membered or 6-membered ring in the fused ring system. When the group “R” is described as being present on a ring system containing saturated carbon, for example in the following formula:

In this example, "y" can be more than one, assuming each substitutes for a currently depicted, implicit, or explicitly defined hydrogen atom on the ring; then, unless otherwise defined, two "R"s can be located on the same carbon atom, provided the resulting structure is stable. A simple example is that when R is a methyl group, a geminal dimethyl group can be present on the carbon atom of the ring shown (the "cyclic" carbon). In another example, two Rs (including the carbon atom) on the same carbon atom can form a ring, resulting in a spirocyclic ("spirocyclic" group) structure having a ring as shown, for example, in the following formula:

"Halogen" or "halogenated group" refers to fluorine, chlorine, bromine or iodine.

The term “C _nm ” or “C _n - _{C m} ” indicates a range including the endpoints, where n and m are integers and represent the number of carbons. Examples include C _1-4 , C ₁ -C ₄ , C _1-6 , C ₁ -C ₆ , etc.

"Alkyl" refers to a branched or straight-chain hydrocarbon chain having one to eight carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, and heptyl. ( _C1 - _C6 )alkyl is preferred. The terms "Cn _nm alkyl" or "( _Cn - _Cm )alkyl" refer to an alkyl group having n to m carbon atoms. When optionally substituted, one or more hydrogen atoms of the alkyl group (e.g., 1 to 4, 1 to 2, or 1) may be partially substituted as described in "Optional Substitution" below. In some aspects, the alkyl group is unsubstituted or not optionally substituted.

"alkylene" refers to a divalent saturated aliphatic group having 1 to 10 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 2 carbon atoms with optional substitution. When optionally substituted, one or more hydrogen atoms (e.g., 1 to 4, 1 to 2, or 1) of the alkylene group may be partially substituted as described in "Optional Substitution" below. In some aspects, the alkylene group is unsubstituted or not optionally substituted. The term "Cn-m alkylene" refers to an alkylene group having n to m carbon atoms. Examples of alkylene groups include, but are not limited to, methylene, ethane-1,2-diyl, propane-1,3-diyl, propane-1,2-diyl, butane-1,4-diyl, butane-1,3-diyl, butane-1,2-diyl, 2-methyl-propane-1,3-diyl, etc.

The term "alkenyl" refers to a straight-chain or branched hydrocarbon group corresponding to an alkyl group having one or more carbon-carbon double bonds. An alkenyl group formally corresponds to an alkene in which one of the CH bonds is replaced by the alkenyl group at the junction with the remainder of the compound. The terms "C_{_n}n-alkenyl" or "(C _{_n}-C _{_m} )alkenyl" refer to an alkenyl group having n to m carbon atoms. In some embodiments, the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Exemplary alkenyl groups include, but are not limited to, vinyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, etc.

The term "alkynyl" refers to a straight-chain or branched hydrocarbon group corresponding to an alkyl group having one or more carbon-carbon triple bonds. An alkynyl group formally corresponds to an alkyne in which one of the CH bonds is replaced by an alkyl group at the junction with the remainder of the compound. The terms "C _{_n}nm</sub>alkynyl" or "(C _{_n}-C _{_m} )alkynyl" refer to an alkynyl group having n to m carbon atoms. Exemplary alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl, etc. In some embodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

"Alkoxy" refers to the part of the formula -OR', where R' is a ( _C1 - _C6 ) alkyl moiety as defined herein. The terms "Cn _nm alkoxy" or "( _Cn - _Cm ) alkoxy" refer to an alkoxy group whose alkyl group has n to m carbons. Examples of alkoxy moiety include, but are not limited to, methoxy, ethoxy, isopropoxy, etc.

The alkoxy group may be unsubstituted or optionally substituted. When optionally substituted, one or more hydrogen atoms of the alkoxy group (e.g., 1 to 4, 1 to 2, or 1) may be partially substituted as described in “Optional Substitution” below, provided that the α-hydrogen atom of the ether oxygen is not substituted by a hydroxyl, amino, or thio group. In some aspects, the alkoxy group is unsubstituted or not optionally substituted.

"Alkoxycarbonyl" refers to the group -C(O)-R', where R' is a ( _C1 - _C6 ) alkoxy group as defined herein.

The term "amino" refers to a group with the formula -NH ₂ .

The term "carbamoyl" refers to a group with the formula -C(O)NH ₂ .

The term "carbonyl" used alone or in combination with other terms refers to the -C(=O)- group, which can also be written as C(O).

The term "cyano" or "nitrile" refers to a group with the formula -C≡N, which can also be written as -CN or CN.

The term "oxo" refers to an oxygen atom as a divalent substituent, which, when attached to carbon, forms a carbonyl group, or when attached to a heteroatom, forms a sulfoxide or sulfone group or an N-oxide group. In some embodiments, the heterocyclic group may optionally be substituted by one or two oxo (=O) substituents.

The term "sulfide" refers to a sulfur atom as a divalent substituent, which, when attached to carbon, forms a thiocarbonyl group (C=S).

The term “heteroatoms” as used in this article is intended to include boron, phosphorus, sulfur, oxygen, and nitrogen.

As used herein, the term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms have been replaced by halogen atoms. The term "C _{_n}nm haloalkyl" or (C _{_n}-C_{_m}) haloalkyl refers to a C _{_n} nm alkyl group having n to m carbon atoms and at least one to at most {2(nm)+1} halogen atoms that may be the same or different. In some embodiments, the halogen atom is a fluorine atom. In some embodiments, the haloalkyl group has 1 to 6 or 1 to 4 carbon atoms. Exemplary haloalkyl groups include CF _₃, C _₂F_₅ , CH _{_F2}, CCl _{₃, CHCl₂ ,} C _₂Cl _₅, etc. In some embodiments, the haloalkyl group is a fluoroalkyl group.

The term "haloalkoxy" used alone or in combination with other terms refers to a group of the formula -O-haloalkyl, wherein the haloalkyl group is as defined above. The term "C _{_n}nm</sub>haloalkoxy" or (C _{_n}-C_{_m} )haloalkoxy refers to a haloalkoxy group whose haloalkyl group has n to m carbons. Exemplary haloalkoxy groups include trifluoromethoxy, etc. In some embodiments, the haloalkoxy group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

"Aryl" refers to a monocyclic or dicyclic ring (e.g., having two fused rings) with a monovalent carbon group of six to fourteen members, wherein the monocyclic ring is aromatic and at least one ring in the dicyclic ring is aromatic. The terms "C _{_n}nm</sub>aryl" or "(C _{_n}-C_{_m})aryl" refer to an aryl group having n to m ring carbon atoms. In some embodiments, the aryl group has 6 to about 10 carbon atoms. In some embodiments, the aryl group has 6 carbon atoms. In some embodiments, the aryl group has 10 carbon atoms. Unless otherwise stated, the valence bond of the group may be located on any atom of any ring within the group, where permitted by the valence bond rules. Representative examples include phenyl, naphthyl, and indenyl.

The aryl group may be unsubstituted or optionally substituted. When optionally substituted, one or more hydrogen atoms of the aryl group (e.g., 1 to 5, 1 to 2, or 1) may be partially substituted as described in “Optional Substitution” below. In some aspects, the alkoxy group is unsubstituted or not optionally substituted.

"Arylene" refers to a divalent, six- to fourteen-membered single-carbon or double-carbon ring, wherein the single ring is aromatic and at least one ring in the double ring is aromatic. Representative examples include phenylene, naphthylene, and indenylene.

“Cycloalkyl” refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic, or polycyclic), including cyclic alkyl and alkenyl groups. The terms “C _{_n}nm cycloalkyl” or “(C _{_n}-C_{_m} )cycloalkyl” refer to a cycloalkyl group having n to m ring member carbon atoms. Cycloalkyl groups may include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) groups and spirocyclic groups. Cycloalkyl groups may have 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 cyclic carbons (C _{_3-14}). In some embodiments, the cycloalkyl group has 3 to 14 members, 3 to 10 members, 3 to 6 ring members, 3 to 5 ring members, or 3 to 4 ring members. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl group is a C _{_3-6} monocyclic cycloalkyl group. The cycloalkyl group may optionally be oxidized to form an oxo or thio group. The cycloalkyl group also includes a cycloalkylene group. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cyclohepttrienyl, norbornyl, norpinel, norcarelyl, bicyclo[1.1.1]pentenyl, bicyclo[2.1.1]hexenyl, etc. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, the cycloalkyl group comprises a single saturated carbon ring having three to eight carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The cycloalkyl group may optionally be substituted with one or more substituents (such as one, two, or three substituents). In some embodiments, the cycloalkyl substituent is selected from ( _C1 - _C6 )alkyl, hydroxyl, ( _C1 - _C6 )alkoxy, halo( _C1 - _C6 )alkyl, halo( _C1 - _C6 )alkoxy, halogroup, amino, mono- and di( _C1 - _C6 )alkylamino, hetero( _C1 - _C6 )alkyl, acyl, aryl, and heteroaryl.

The cycloalkyl group may be unsubstituted or optionally substituted. When optionally substituted, one or more hydrogen atoms (e.g., 1 to 4, 1 to 2, or 1) of the cycloalkyl group may be partially substituted as described in “Optional Substitution” below. In some aspects, the substituted cycloalkyl group may be incorporated into an external or internal cycloalkene (e.g., cyclohexyl-2-en-1-yl). In some aspects, the cycloalkyl group is unsubstituted or not optionally substituted.

"Cycloalkoxycarbonyl" means the group -C(O)-OR', where R' is a ( _C3 - _C6 ) cycloalkyl group as defined herein.

"Phenoxycarbonyl" refers to the group -C(O)-O phenyl.

"Heteroaryl" refers to a monocyclic, fused bicyclic, or fused tricyclic monocyclic group of 5 to 14 ring atoms, containing one or more (preferably one, two, three, or four) cyclic heteroatoms independently selected from -O-, -S(O) _n- (n is 0, 1, or 2), -N-, and -N(R')-, and the remaining ring atoms are carbon, wherein the ring containing the monocyclic group is aromatic, and at least one ring in the fused ring containing the bicyclic or tricyclic group is aromatic. One or both ring carbon atoms of any non-aromatic ring containing the bicyclic or tricyclic group may be replaced by a -C(O)-, -C(S)-, or -C(=NH)- group. R' is hydrogen, alkyl, hydroxyl, alkoxy, acyl, or alkylsulfonyl. Unless otherwise specified, the valence bond may be located on any atom of any ring of the heteroaryl group, where permitted by the valence bond rules. In particular, when the valence bond is located on nitrogen, there is no additional nitrogen substituent. More specifically, the term heteroaryl includes, but is not limited to, 1,2,4-triazolyl, 1,3,5-triazolyl, phthalimide, pyridyl, pyrroleyl, imidazolyl, thiophene, furanyl, indoleyl, 2,3-dihydro-1H-indoleyl (including, for example, 2,3-dihydro-1H-indole-2-yl or 2,3-dihydro-1H-indole-5-yl), isoindoleyl, dihydroindoleyl, isoindolelinyl, benzimidazolyl, benzo[a]dioxacyclopenten-4-yl, benzofuranyl, cyclolinyl, indazinyl, diazanaphthyl-3-yl, phthalazin-3-yl, phthalazin-4-yl, pteridinyl, and purineyl. Quinazolinyl, quinoxolinyl, tetrazolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, oxadiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl (including, for example, tetrahydroisoquinolin-4-yl or tetrahydroisoquinolin-6-yl), pyrrolo[3,2-c]pyridinyl (including, for example, pyrrolo[3,2-c]pyridin-2-yl or pyrrolo[3,2-c]pyridin-7-yl), benzopyranyl, thiazolyl, isothiazolyl, thiadiazolyl, benzothiazolyl, benzothiaphenyl, and their derivatives, as well as their N-oxides or protected derivatives.

A five-membered heteroaryl ring is a heteroaryl group having five ring atoms, wherein one or more (e.g., 1, 2, 3, or 4) ring atoms are independently selected from N, O, and S. Exemplary five-membered heteroaryl rings include thiophene, furanyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl.

A six-membered heteroaryl ring is a heteroaryl group having six ring atoms, wherein one or more (e.g., 1, 2, 3, or 4) ring atoms are independently selected from N, O, and S. Exemplary six-membered heteroaryl rings are pyridyl, pyrazinyl, pyrimidinyl, triazinyl, and pyridazinyl.

"Heteroarylene" refers to a divalent group of 5 to 14 ring atoms in a monocyclic, fused bicyclic, or fused tricyclic form, containing one or more (preferably one, two, three, or four) cyclic heteroatoms independently selected from -O-, -S(O) _n- (n is 0, 1, or 2), -N-, and -N(R ¹⁹ )-, and the remaining ring atoms are carbon, wherein the ring containing the monocyclic group is aromatic, and at least one ring in the fused ring containing the bicyclic or tricyclic group is aromatic. One or both ring carbon atoms of any non-aromatic ring containing the bicyclic or tricyclic group may be replaced by a -C(O)-, -C(S)-, or -C(=NH)- group. ^{R 19} is hydrogen, alkyl, or alkenyl. Unless otherwise specified, the valence bond may be located on any atom of any ring of the heteroarylene group, where permitted by the valence bond rules. In particular, when the valence bond is located on nitrogen, there is no additional nitrogen substituent. More specifically, the term heteroaryl includes, but is not limited to, thiophene-diyl, benzo[d]isoxazole-diyl, benzo[d]isothiazol-diyl, 1H-indazole-diyl (optionally substituted at the N1 position with R ¹⁹ ), benzo[d]oxazole-diyl, benzo[d]thiazol-diyl, 1H-benzo[d]imidazol-diyl (optionally substituted at the N1 position with R ¹⁹ ), 1H-benzo[d][1,2,3]triazole-diyl (optionally substituted at the N1 position with R ¹⁹ ), imidazo[1,2-a]pyridine-diyl, cycloline-diyl, quinoline-diyl, pyridine-diyl, 1-oxo-pyridine-diyl, [1,2,4]triazolo[4,3-a]pyridine-diyl and 2,3-dihydroimidazo[1,2-a]pyridine-diyl, etc.

As used herein, “heterocyclic alkyl” or “heterocyclic group” refers to a non-aromatic ring or ring system that optionally contains one or more alkenyl groups as part of a ring structure, has at least one heteroatom ring member independently selected from boron, nitrogen, sulfur, oxygen, and phosphorus, and has 4-14, 4-10, 4-7, or 4-6 ring members. The term “heterocyclic alkyl” includes monocyclic 4-, 5-, 6-, and 7-membered heterocyclic alkyl groups. Heterocyclic alkyl groups may include monocyclic, bicyclic, or polycyclic (e.g., having two or three fused or bridged rings) ring systems or spirocyclic rings. In some embodiments, the heterocyclic alkyl group is a monocyclic group having one, two, or three heteroatoms independently selected from nitrogen, sulfur, and oxygen. The cyclic carbon atom and heteroatom of the heterocyclic alkyl group may optionally be oxidized to form an oxo or thio group or other oxidized bond (e.g., C(O), S(O), C(S), S(O) _₂ , N-oxide, etc.), or the nitrogen atom may be quaternized. The heterocyclic alkyl group may be linked by a cyclic carbon atom or a cyclic heteroatom. In some embodiments, the heterocyclic alkyl group contains 0 to 3 double bonds. In some embodiments, the heterocyclic alkyl group contains 0 to 2 double bonds. The definition of heterocyclic alkyl also includes a portion having one or more aromatic rings fused with (i.e., sharing bonds with) the heterocyclic alkyl ring, such as benzo[a] or thiophene derivatives of piperidine, morpholine, aza, etc. Heterocyclic alkyl groups containing fused aromatic rings may be linked by any cyclic atom, including the cyclic atom of the fused aromatic ring. Examples of heterocyclic alkyl groups include azirrobutyl, azirroheptyl, dihydrobenzofuranyl, dihydropyranyl, morpholino, 3-oxa-9-azaspiro[5.5]undecyl, 1-oxa-8-azaspiro[4.5]decyl, piperidinyl, piperazinyl, oxoperazinyl, pyranyl, pyrrolidinyl, quininecycloyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,4-tetrahydroquinolinyl, scopolyl, 4,5,6,7-tetrahydrothiazo[5,4-c]pyridinyl, and thiomorpholino.

The term "heterocyclic alkyl" or "heterocyclic group" can be unsubstituted or optionally substituted. When optionally substituted, one or more hydrogen atoms of the group (e.g., 1 to 4, 1 to 2, or 1) can be partially substituted independently from fluorine, hydroxyl, alkoxy, amino, alkylamino, acylamino, thio, and alkylthio groups. In some aspects, the substituted heterocyclic group may be incorporated into an external or internal cyclic olefin (e.g., cyclohexyl-2-en-1-yl). In some aspects, the heterocyclic group is unsubstituted or not optionally substituted.

Optional replacement

Unless otherwise expressly stated, groups are optionally substituted herein. The term “optionally substituted” means substituted or unsubstituted. In some embodiments, alkyl, alkenyl, ynyl, carbocycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally substituted. “Optionally substituted” means a group that can be substituted or unsubstituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” ynyl, “substituted” or “unsubstituted” cycloalkyl, “substituted” or “unsubstituted” cycloalkyl, “substituted” or “unsubstituted” heterocycloalkyl, “substituted” or “unsubstituted” aryl, or “substituted” or “unsubstituted” heteroaryl). Generally, the term “substituted” means that at least one hydrogen present on the group is replaced by a permissible substituent, such as a substituent that, after substitution, yields a stable compound (e.g., a compound that does not spontaneously transform, such as through rearrangement, cyclization, elimination, or other reactions). Unless otherwise stated, a “substituted” group has a substituent at one or more substituted positions of the group, and the substituent is either the same or different at each position when more than one position is substituted in any given structure. The term “substituted” contemplates substitution by all permissible substituents of an organic compound, and includes any substituents described herein that result in the formation of a stable compound. The invention contemplates any and all such combinations to obtain a stable compound. For the purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituents described herein that satisfy the valence of the heteroatom and result in the formation of a stable moiety. The invention is not intended to be limited in any way to the exemplary substituents described herein.

Exemplary carbon atom substituents include, but are not limited to, halogens (halogenated groups), -CN, _-NO₂ , _-N₃ , _-SO₂H , _-SO₃H , -OH, -OR ^aa , -ON(R ^bb ) ₂ , -N(R ^bb ) ₂ , -N(R ^bb ) ₃ ⁺ X ^- , -N(OR ^cc )R ^bb , -SH, -SR ^aa , -SSR ^cc , -C(＝O)R ^aa , _-CO₂H , -CHO, -C(OR ^cc ) ₂ , _-CO₂R ^aa , -OC(＝O)R ^aa , _-OCO₂R ^aa , -C(＝O)N(R ^bb ) ₂ , -OC(＝O)N(R ^bb ) ₂ , -NR ^bb C(＝O)R ^aa , -NR ^bb _CO₂R ^aa , -NR ^bb C(=O)N(R ^bb ) ₂ , -C(=NR ^bb )R ^aa , -C(=NR ^bb )OR ^aa , -OC(=NR ^bb )R ^aa , -OC(=NR ^bb )OR ^aa , -C(=NR ^bb )N(R ^bb ) ₂ , -OC(=NR ^bb )N(R ^bb ) ₂ , -NR ^bb C(=NR ^bb )N(R ^bb ) ₂ , -C(=O)NR ^bb SO ₂ R ^aa , -NR ^bb SO ₂ R ^aa , -SO ₂ N(R ^bb ) ₂ , -SO ₂ R ^aa , -SO ₂ OR ^aa , -OSO ₂ R ^aa , -S(=O)R ^aa , -OS(=O)R ^aa , -Si(R ^aa ) ₃ , -OSi(R ^aa ) ₃ -C(=S)N(R ^bb ) ₂ , -C(=O)SR ^aa , -C(=S)SR ^aa , -SC(=S)SR ^aa , -SC(=O)SR ^aa , -OC(=O)SR ^aa , -SC(=O)OR ^aa , -SC(=O)R ^aa , -P(=O) ₂ R ^aa , -OP(=O) ₂ R ^aa , -P(＝O)(R ^aa ) ₂ , -OP(＝O)(R ^aa ) ₂ , -OP(＝O)(OR ^cc ) ₂ , -P(＝O) ₂ N(R ^bb ) ₂ , -OP(＝O) ₂ N(R ^bb ) ₂ , -P(＝O)(NR ^bb ) ₂ , -OP(＝O)(NR ^bb ) ₂ , ^-NRbb P(＝O)(OR ^cc ) ₂ 、 -NR ^bb P(＝O)(NR ^bb ) ₂ 、 -OP(R ^cc ) ₂ 、 -OP(R ^cc ) ₃ 、 -B(OR ^cc ) ₂ 、 -BR ^aa (OR ^cc ), C _1-10 alkyl, C _1-10 perhaloalkyl, C _2-10 alkenyl, C _2-10 ynyl, (C ₃ -C ₁₀ ) carbocycloalkyl, 3-14 membered heterocycloalkyl, (C ₆ -C ₁₄ ) aryl and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R ^dd groups;

Alternatively, the two hydrogen atoms on the carbon atom can be replaced by the groups =O, =S, =NN(R ^bb ) ₂ , =NNR ^bb C(=O)R ^aa , =NNR ^bb C(=O)OR ^aa , =NNR ^bb S(=O) ₂ R ^aa , =NR ^bb or =NOR ^cc ;

Each instance of ^Raa is independently selected from ( _C1 - _C10 ) alkyl, ( _C1 - _C10 ) perhaloalkyl, ( _C2 - _C10 ) alkenyl, ( _C2 - _C10 ) ynyl, ( _C3 - _C10 ) cycloalkyl, 3-14-membered heterocyclic alkyl, ( _C6 - _C14 ) aryl and 5-14-membered heteroaryl, or two ^Raa groups are joined to form a 3-14-membered heterocyclic alkyl or 5-14-membered heteroaryl ring, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic alkyl, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4 or 5 ^Rdd groups;

Each instance of R ^bb is independently selected from hydrogen, ( _C1 - _C10 ) perhaloalkyl, ( _C2 - _C10 ) alkenyl, ( _C2 - _C10 ) ynyl, ( _C3 - _C10 ) cycloalkyl, _C6-14 aryl and 5-14 heteroaryl, or two R ^bb groups are joined to form a 3-14 heterocyclic alkyl or 5-14 heteroaryl ring, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic alkyl, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4 or 5 R ^dd groups;

Each instance of R cc is independently selected from hydrogen, (C <sub>1 -C  10 )alkyl, (C <sub>1 -C 10 ) perhaloalkyl, (C <sub>2 -C 10 )alkenyl, (C <sub>2 -C10 )ynyl, (C<sub>3-C10)cycloalkyl, 3-14-membered heterocyclic alkyl, (C <sub>6 -C14 )aryl and 5-14-membered heteroaryl, or two R cc  groups are joined to form a 3-14-membered heterocyclic alkyl or 5-14-membered heteroaryl ring, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic alkyl, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4 or 5 R dd groups;

Each instance of R dd is independently selected from halogens, -CN, -NO2 , -SO 2 H, -SO 3 H, -OH, -OR ee , -ON(R ff )2, -N(Rff )  2  , -N(Rff) 3  + X- , -N(OR ee )R ff , -SH, -SR ee , -SSRee, -C ( =O)R ee , -CO 2 H, -CO 2 Ree, -OC(=O)R ee , -OCO 2 R ee , -C(=O)N(R ff ) 2 , -OC(=O)N(R ff ) 2 , -NR  ff C(=O)R ee , -NRffCO 2 R ee , -NRff C(=O)N(R ff ) 2 , -C(=NRff  )OR2 ee , -OC(=NR ff )R ee , -OC(=NR ff )OR ee , -C(=NR ff )N(R ff ) 2 , -OC(=NR ff )N(R ff ) 2 , -NR ff C(=NR ff )N(R ff ) 2 , -NR ff SO 2 R ee , -SO 2 N(R ff ) 2 , -SO 2 R ee , -SO 2 OR ee , -OSO 2 R ee , -S(=O)R ee , -Si(R ee ) 3 , -OSi(R ee ) 3 , -C(=S)N(R ff ) 2 , -C(=O)SR ee , -C(=S)SR ee , -SC(=S)SR ee , -P(=O) 2 R ee , -P(＝O)(R ee ) 2 , -OP(＝O)(R ee ) 2 , -OP(＝O)(OR ee ) 2 , (C 1 -C 10 )alkyl, (C 1 -C 10 )perhaloalkyl, (C 2 -C 10 )alkenyl, (C 2 -C 10 )ynyl, (C 3 -C 10 )cycloalkyl, 3-10-membered heterocyclic alkyl, (C 6 -C 10 )aryl, 5-10-membered heteroaryl, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic alkyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R gg groups, or two geminal R dd substituents may be joined to form =O or =S;

Each instance of ^Ree is independently selected from ( _C1 - _C6 )alkyl, ( _C1 - _C6 )perhaloalkyl, ( _C2 - _C6 )alkenyl, (C2-C6)ynyl, ( _C3 - _C10 )cycloalkyl, ( _{C6 - C10} )aryl, 3-10 heterocyclic alkyl, and 3-10 heteroaryl, wherein each alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, cycloalkyl, heterocyclic alkyl, aryl, and heteroaryl is independently substituted by 0, 1, 2, ₃ , 4, or 5 ^Rgg groups;

Each instance of R ff is independently selected from hydrogen, (C <sub>1 -C  6  )alkyl, (C<sub> 1- C6 )perhaloalkyl, (C <sub>2 -C 6 )alkenyl, (C <sub>2- C6 )ynyl, (C <sub>3 -C 10 )cycloalkyl, (C<sub>6-C10)aryl, and 5-10 heteroaryl, or two R ff  groups are joined to form a 3-10 heterocyclic alkyl or 5-10 heteroaryl ring, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic alkyl, aryl, and heteroaryl group is independently substituted by 0, 1, 2, 3, 4, or 5 R gg groups; and

Each instance of R gg  is independently a halogen, -CN, -NO2 , -SO 2 H, -SO 3 H, -OH, -OC 1-6 alkyl, -ON(C 1-6 alkyl) 2 , -N(C  1-6 alkyl) 2  + X - , -NH(C 1-6 alkyl) 2  + X - , -NH2 (C 1-6 alkyl) + X- , -NH 3  + X - , -N(OC 1-6 alkyl)(C  1-6 alkyl), -N(OH)(C1-6alkyl), -NH(OH), -SH, -SC 1-6 alkyl, -SS(C 1-6 alkyl), -C(＝O)(C 1-6 alkyl), -CO2 H, -CO 2 (C1-6alkyl), -OC(＝O)(C 1-6 alkyl), -OCO2 (C 1-6 alkyl), 1-6 alkyl), -C(=O)NH 2 , -C(=O)N(C 1-6 alkyl) 2 , -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -NHCO 2 (C 1-6 alkyl), -NHC(=O)N(C 1-6 alkyl) 2 , -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH 2 , -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1-6 alkyl), -OC(=NH)OC 1-6 alkyl, -C(=NH)N(C 1-6 alkyl) 2 , -C(=NH)NH(C 1-6 alkyl), -C(=NH)NH 2 , -OC(=NH)N(C 1-6 alkyl) 1-6 alkyl) 2 , -OC(NH)NH (C 1-6 alkyl), -OC(NH)NH 2 , -NHC(NH)N (C 1-6 alkyl) 2 , -NHC(＝NH)NH 2 , -NHSO 2 (C 1-6 alkyl), -SO 2N (C 1-6 alkyl) 2 , -SO 2NH (C 1-6 alkyl), -SO 2NH 2 , -SO 2 C 1-6 alkyl, -SO 2 OC 1-6 alkyl, -OSO 2 C 1-6 alkyl, -SOC 1-6 alkyl, -Si (C 1-6 alkyl) 3 , -OSi (C 1-6 alkyl) 3 , -C(＝S)N (C 1-6 alkyl) 2 , C(＝S)NH (C 1-6 alkyl), C(＝S)NH 2 , -C(＝O)S (C 1-6 alkyl) =1-6 alkyl), -C(=S)SC 1-6 alkyl, -SC(=S)SC 1-6 alkyl, -P(=O) 2 (C 1-6 alkyl), -P(=O)(C 1-6 alkyl) 2 , -OP(=O)(C 1-6 alkyl) 2 , -OP(=O)(OC 1-6 alkyl) 2 , (C 1 -C 6 ) alkyl, (C 1 -C 6 ) perhaloalkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) ynyl, (C 3 -C 10 ) cycloalkyl, (C 6 -C 10 ) aryl, 3-10 membered heterocyclic alkyl, 5-10 membered heteroaryl; or two homologous R gg substituents can be joined to form =O or =S; wherein X- is a counter ion.

As mentioned earlier, nitrogen atoms can be substituted or unsubstituted, where valence bonds allow, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, -OH, -OR ^aa , -N(R ^cc ) ₂ , -CN, -C(＝O)R ^aa , -C(＝O)N(R ^cc ) ₂ , -CO _2R ^aa , -SO _2R ^aa , -C(＝NR ^bb )R ^aa , -C(＝NR ^cc )OR ^aa , -C(＝NR ^cc )N(R ^cc ) ₂ , -SO _2N (R ^cc ) ₂ , -SO _2R ^cc , -SO _2OR ^cc , -SOR ^aa , -C(＝S)N(R ^cc ) ₂ , -C(＝O)SR ^cc , -C(＝S)SR ^cc , -P(＝O) _2R ^aa , -P(＝O)(R ^aa ) ₂ , -P(＝O) _2N (R ^cc ) ₂ , -P(＝O)(NR ^cc ) ₂ , (C ₁ -C ₁₀ ) alkyl, (C ₁ -C ₁₀ ) perhaloalkyl, (C ₂ -C ₁₀ ) alkenyl, (C ₂ -C ₁₀ ) ynyl, (C ₃ -C ₁₀ ) cycloalkyl, 3-14-membered heterocyclic alkyl, (C ₆ -C 1 ₄ ) aryl and 5-14-membered heteroaryl, or two R ^cc groups attached to the N atom are joined to form a 3-14-membered heterocyclic alkyl or 5-14-membered heteroaryl ring, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic alkyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R ^dd groups, and wherein ^Raaa , ^Rbb , ^Rcc and ^Rdd are as defined above.

In some embodiments, the substituents present on the nitrogen atom are nitrogen protecting groups (also referred to herein as "amino protecting groups"). Nitrogen-protecting groups include, but are not limited to, -OH, -OR ^aa , -N( ^Rcc ) ₂ , -C(=O)R ^aa , -C(=O)N( ^Rcc ) ₂ , _-CO2R ^aa , -SO2R _aa , -C(= ^NRcc ) ^{R aa ,} -C(= ^NRcc )OR ^aa , -C(=NRcc)N( ^Rcc ) ₂ , -SO2N( ^Rcc )2, _-SO2Rcc , -SO2ORcc, -SOR aa, _-C (= ^S )N( ^Rcc) ₂ , -C(=O ^)SRcc , ^-C (=S)SRcc, ( ^C1 -C10) _alkyl (e.g., aralkyl, heteroaralkyl ⁾ , (C2-C10) ^alkenyl , ( _C2 - _C10 )alkyl, ( _{C1-C10)alkyl, (C2 - C10} )alkyl, ( _C1 -C10)alkyl, _{... The} group may contain alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aralkyl _, aryl, and heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aralkyl, aryl, and heteroaryl group is independently substituted by 0, 1 _{, 2} , 3, 4, or 5 ^Rdd groups, wherein ^Raaa , ^Rbb , ^Rcc , and ^Rdd are as defined herein. Nitrogen protecting groups are well known in the art, including those described in detail in Protecting Groups in Organic Synthesis, TW Greene and PGMWuts, 3rd edition, John Wiley & Sons, 1999 (incorporated herein by reference).

For example, nitrogen-protecting groups such as amide groups (e.g., -C(=O) ^Raa ) include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropionamide, pyridine amide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetylacetamide, (N'-dithiobenzyloxyacetamide)acetamide, 3-(p-hydroxyphenyl)propionamide, 3-(o-nitrophenyl)propionamide, 2-methyl-2-(o-nitrophenoxy)propionamide, 2-methyl-2-(o-phenylazophenoxy)propionamide, 4-chlorobutyramide, 3-methyl-3-nitrobutyramide, o-nitrocinnamamide, N-acetylmethionine derivatives, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

Nitrogen protecting groups such as urethane groups (e.g., -C(=O)OR ^aa ) include, but are not limited to, methyl urethane, ethyl urethane, 9-fluorenyl methyl urethane (Fmoc), 9-(2-sulfonyl)fluorenyl methyl urethane, 9-(2,7-dibromo)fluorenyl methyl urethane, methyl 2,7-di-tert-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothiophene)]urethane (DBD-Tmoc), 4-methoxybenzoyl urethane (Phenoc), 2,2,2-trichloroethyl urethane (Troc), and 2-trimethylsilyl ethyl urethane. 1-(1-adamantyl)-1-methylethylcarbamate (Teoc), 2-phenylethylcarbamate (hZ), 1-(1-adamantyl)-1-methylethylcarbamate (Adpoc), 1,1-dimethyl-2-haloethylcarbamate, 1,1-dimethyl-2,2-dibromoethylcarbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethylcarbamate (TCBOC), ethyl 1-methyl-1-(4-biphenyl)carbamate (Bpoc), 1-(3,5-di-tert-butylphenyl)-1-methyl Ethyl carbamate (t-Bumeoc), ethyl 2-(2'- and 4'-pyridyl)carbamate (Pyoc), ethyl 2-(N,N-dicyclohexylcarboxylamino)carbamate, tert-butyl carbamate (BOC or Boc), 1-adamantane carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinoline carbamate Esters, N-hydroxypiperidinyl carbamates, alkyl dithiocarbamates, benzyl carbamates (Cbz), p-methoxybenzyl carbamates (Moz), p-nitrobenzyl carbamates, p-bromobenzyl carbamates, p-chlorobenzyl carbamates, 2,4-dichlorobenzyl carbamates, 4-methylsulfinylbenzyl carbamates (Msz), 9-anthraylmethyl carbamates, diphenylmethyl carbamates, 2-methylthioethyl carbamates, 2-methylsulfonylethyl carbamates, 2-(p-toluenesulfonyl)ethylcarbamates Esters, [2-(1,3-dithiaalkyl)]carbamate (Dmoc), 4-methylthiophenylcarbamate (Mtpc), 2,4-dimethylphenylthiocarbamate (Bmpc), 2-phosphonoethylcarbamate (Peoc), 2-triphenylphosphonoisopropylcarbamate (Ppoc), 1,1-dimethyl-2-cyanoethylcarbamate, m-chloro-p-acyloxybenzylcarbamate, p-(dihydroxyboryl)benzylcarbamate, 5-benzoxazolylmethylcarbamate, 2-(trifluoromethyl)-6- Tcroc, m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl (o-nitrophenyl)methyl carbamate, tert-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropyl methyl carbamate, p-decoxybenzyl carbamate, 2,2-dimethoxyylvinyl carbamate Ester, o-(N,N-dimethylcarbamoyl)benzylcarbamate, 1,1-dimethyl-3-(N,N-dimethylcarbamoyl)propylcarbamate, 1,1-dimethylpropynylcarbamate, di(2-pyridyl)methylcarbamate, 2-furanylmethylcarbamate, 2-iodoethylcarbamate, isobornylcarbamate, isobutylcarbamate, isonicocyanate, p-(p'-methoxyphenylazo)benzylcarbamate, 1-methylcyclobutylcarbamate, 1-methylcyclohexylcarbamate Ester, 1-methyl-1-cyclopropylmethylcarbamate, ethyl 1-methyl-1-(3,5-dimethoxyphenyl)carbamate, ethyl 1-methyl-1-(p-phenylazophenyl)carbamate, 1-methyl-1-phenylethylcarbamate, 1-methyl-1-(4-pyridyl)ethylcarbamate, phenyl carbamate, p-(benzoazo)benzylcarbamate, 2,4,6-tri-tert-butylphenylcarbamate, 4-(trimethylammonium)benzylcarbamate and 2,4,6-trimethylbenzylcarbamate of carbamate.

Nitrogen protecting groups such as sulfonamide groups (e.g., -S(=O) ₂ Raaa ⁾ This includes, but is not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylbenzodihydropyran-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilyl ethyl sulfonamide (SES), 9-anthracitesulfonamide, 4-(4',8'-dimethoxynaphthyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and benzoylmethanesulfonamide.

Other nitrogen-protecting groups include, but are not limited to, phenothiazinyl-(10)-acyl derivatives, N'-p-toluenesulfonylaminoacyl derivatives, N'-phenylaminothioyl derivatives, N-benzoylphenylpropionyl derivatives, N-acetylmethionine derivatives, 4,5-diphenyl-3-oxazoline-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldimethylsilylazacyclopentane adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexane-2-one, 5-substituted... 1,3-Dibenzyl-1,3,5-triazacyclohexane-2-one, 1-substituted 3,5-dinitro-4-pyridinone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyrrololin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferroceneylmethylamino (Fcm), N-2-pyridinemethylamino N'-oxide, N-1,1-dimethylthiomethyleneamine, N-benzylamine, N-p-methoxybenzylamine, N-diphenylmethyleneamine, N-[(2-pyridyl)trimethylmethyl]methyleneamine, N-(N',N'-dimethylaminomethylene)amine, N,N'-isopropylidenediamine, N-p-nitrobenzylamine, N-salicylamine, N-5-chlorosalicylamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexylamine, N-(5,5-dimethyl-3-oxo-1 -Cyclohexenyl)amine, N-borane derivatives, N-diphenylboronic acid derivatives, N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelate, N-zinc chelate, N-nitrosamine, N-nitrosamine, N-amine oxide, diphenylphosphamide (Dpp), dimethylthiophosphamide (Mpt), diphenylthiophosphamide (Ppt), dialkylaminophosphate, dibenzylaminophosphate, diphenylaminophosphate, benzenesulfinamide, o-nitrobenzenesulfinamide (Nps), 2,4-dinitrobenzenesulfinamide, pentachlorobenzenesulfinamide, 2-nitro-4-methoxybenzenesulfinamide, triphenylmethylsulfinamide, and 3-nitropyridinesulfinamide (Npys).

In some embodiments, the substituents present on the oxygen atom are oxygen protecting groups (also referred to herein as "hydroxy protecting groups"). Oxygen protecting groups include, but are not limited to, ^-Raa , -N( ^Rbb ) ₂ , -C(=O) ^SRaa , -C(=O) ^Raa _, ^-CO2Raa , -C(=O)N( ^Rbb ) ₂ , -C(= ^NRbb ) ^Raa , -C(= ^NRbb ) ^ORaa , -C(= ^NRbb )N( ^Rbb ) ₂ , -S(=O) ^Raa , -SO2Raa, -Si( ^Raa ) _{3 ,} ^-P ( ^Rcc ) ₂ , -P( ^Rcc ) ₃ , -P(=O) _2Raa , -P(=O)( ^Raa ) ₂ , -P(=O)( ^ORcc ) ₂ , -P(=O) _2N ( ^Rbb ) ₂ and -P(=O)(NRbb ^{) 2} ) ₂ , wherein ^Raaa , ^Rbb , and ^Rcc are as defined herein. Oxygen protecting groups are well known in the art, including those described in detail in Protecting Groups in Organic Synthesis, TW Greene and PGM Watts, 3rd edition, John Wiley & Sons, 1999 (incorporated herein by reference).

Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxymethyl (MOM), methylthiomethyl (MTM), tert-butylthiomethyl, (phenyl dimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacol methyl (GUM), tert-butoxymethyl, 4-pentenoxymethyl (POM), silyloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl ( THP), 3-bromotetrahydropyranyl, tetrahydrothiaranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiaranyl, 4-methoxytetrahydrothiaranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP), 1,4-dioxane-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methylenebenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-Methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenoyl)ethyl, tert-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-pyridinemethyl, 4-pyridinemethyl, 3-methyl-2-pyridinemethyl N-oxy, diphenylmethyl, p,p'-dinitrophenylmethyl, 5-dibenzocycloheptyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, Di(p-methoxyphenyl)phenylmethyl, Tri(p-methoxyphenyl)methyl, 4-(4'-bromobenzoyloxyphenyl)diphenylmethyl, 4,4',4”-tris(4,5-dichlorophthalimidephenyl)methyl, 4,4',4”-tris(acetylpropionyloxyphenyl)methyl, 4,4',4”-tris(benzoyloxyphenyl)methyl, 3-(imidazol-1-yl)bis(4',4”-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1'-pyrenemethyl, 9-anthrayl, 9-(9-phenyl)xanthrayl, 9-(9-phenyl-10-oxo)anthrayl, 1,3-benzodithiapentane-2-yl, benzisothiazolyl S,S - Dioxide, Trimethylsilyl (TMS), Triethylsilyl (TES), Triisopropylsilyl (TIPS), Dimethylisopropylsilyl (IPDMS), Diethylisopropylsilyl (DEIPS), Dimethylhexylsilyl, Tert-butyldimethylsilyl (TBDMS), Tert-butyldiphenylsilyl (TBDPS), Tribenzylsilyl, Tri-p-xylylsilyl, Triphenylsilyl, Diphenylmethylsilyl (DPMS), Tert-butylmethoxyphenylsilyl (TBMPS), Formate, Benzoylcarbamate, Acetate, Chloroacetic acid ester, Dichloroacetic acid ester, Trichloroacetic acid ester, Trifluoroacetic acid Esters, methoxyacetic acid esters, triphenylmethoxyacetic acid esters, phenoxyacetic acid esters, p-chlorophenoxyacetic acid esters, 3-phenylpropionate esters, 4-oxovalerate esters (acetylpropionate esters), 4,4-(ethylidene dithio)valerate esters (acetylpropionyl dithioacetal), neovalerate esters, adamantane esters, crotonate esters, 4-methoxycrotonate esters, benzoate esters, p-phenylbenzoate esters, 2,4,6-trimethylbenzoate esters (methanesulfonate esters), methyl carbonate, 9-fluorenyl methyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(benzenesulfonyl)ethyl carbonate (Psec) ), 2-(triphenylphosphino)ethyl carbonate (Peoc), isobutyl carbonate, ethylene carbonate, allyl carbonate, tert-butyl carbonate (BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p-methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzyl thiocarbonate, 4-ethoxy-1-naphthyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylvalerate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl) Benzoate esters, 2,6-dichloro-4-methylphenoxyacetic acid esters, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetic acid esters, 2,4-bis(1,1-dimethylpropyl)phenoxyacetic acid esters, dichlorophenylacetic acid esters, isobutyrate esters, monosuccinate esters, (E)-2-methyl-2-butenoate esters, o-(methoxyyl)benzoate esters, α-naphthyl esters, nitrate esters, N,N,N’,N’-tetramethyldiaminophosphate alkyl esters, N-phenylcarbamate alkyl esters, borate esters, dimethylthiophosphoryl, alkyl 2,4-dinitrobenzenesulfinic acid esters, sulfate esters, methanesulfonates (methanesulfonates), benzyl sulfonates, and toluenesulfonates (Ts).

In some implementations, the substituents present on the sulfur atom are sulfur protecting groups (also known as "thiol protecting groups"). Sulfur protecting groups include, but are not limited to, ^-Raa , -N( ^Rbb ) ₂ , -C(=O) ^SRaa , -C(=O) ^Raa _, ^-CO2Raa , -C(=O)N( ^Rbb ) ₂ , -C(= ^NRbb ) ^Raa , -C(= ^NRbb ) ^ORaa , -C(= ^NRbb )N( ^Rbb ) ₂ , -S(=O) ^Raa , -SO2Raa, -Si( ^Raa ) _{3 ,} ^-P ( ^Rcc ) ₂ , -P( ^Rcc ) ₃ , -P(=O) _2Raa , -P(=O)( ^Raa ) ₂ , -P(=O)( ^ORcc ) ₂ , -P(=O) _2N ( ^Rbb ) ₂ and -P(=O)(NRbb ^{) 2} ) ₂ , wherein ^Raaa , ^Rbb , and ^Rcc are as defined herein. Sulfur protecting groups are well known in the art, including those described in detail in Protecting Groups in Organic Synthesis, TWGreene and PGMWuts, 3rd edition, John Wiley & Sons, 1999 (incorporated herein by reference).

As used herein, “leaving group” (LG) is a term understood in the art as referring to a molecular fragment separated from a pair of electrons in bond heterolytic cleavage, wherein the molecular fragment is an anionic or neutral molecule. As used herein, the leaving group can be an atom or group that can be substituted by a nucleophile. See, for example, Smith, March Advanced Organic Chemistry, 6th edition (501-502). Exemplary leaving groups include, but are not limited to, halogens (e.g., chlorine, bromine, iodine), -OR ^aa (where ^Raaa is as defined herein when the O atom is attached to a carbonyl group), -O(C=O)R ^LG , or -O(SO) _2R ^LG (e.g., toluenesulfonyl, methanesulfonyl, benzenesulfonyl), wherein R ^LG is an optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, the leaving group is a halogen.

The terms defined above are illustrated with specific examples in the embodiments.

The “yield” for each reaction described in this article is expressed as a percentage of the theoretical yield.

For the purposes of this invention, "patient" includes humans and any other animals, particularly mammals and other organisms. Therefore, this method is suitable for human treatment and veterinary applications. In a preferred embodiment, the patient is a mammal, and in the most preferred embodiment, the patient is a human. Examples of preferred mammals include mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, and primates.

"Kinease-dependent diseases or disorders" refer to pathological conditions that depend on the activity of one or more kinases. Kinases directly or indirectly participate in signaling pathways for various cellular activities, including proliferation, adhesion, migration, differentiation, and invasion. Diseases associated with kinase activity include tumor growth, pathological angiogenesis that supports solid tumor growth, and other diseases involving excessive local angiogenesis, such as eye diseases (diabetic retinopathy, age-related macular degeneration, etc.) and inflammation (psoriasis, rheumatoid arthritis, etc.).

"Therapeutic effective amount" is the amount of the compound of the present invention that improves disease symptoms when administered to a patient. The amount of the compound of the present invention constituting the "therapeutic effective amount" will vary depending on the compound, the disease state and its severity, the age of the patient to be treated, etc. Therapeutic effective amount can be conventionally determined by those skilled in the art based on their own knowledge and the content of this disclosure.

"Cancer" refers to a proliferative cellular disease state, including but not limited to: Heart : sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma; Head and neck: squamous cell carcinoma of the head and neck, laryngeal and hypopharyngeal carcinoma, nasal cavity and paranasal sinus carcinoma, nasopharyngeal carcinoma, salivary gland carcinoma, oral cavity and pharyngeal carcinoma; Lung: bronchial carcinoma (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma, non-small cell lung cancer), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Colon: colorectal cancer, adenocarcinoma, gastrointestinal stromal tumor, lymphoma, carcinoid tumor, Turcot syndrome. Syndrome; Gastrointestinal tract : gastric cancer, adenocarcinoma of the esophagogastric junction, esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (cancer, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vasoactive intestinal peptide tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Breast: metastatic breast cancer, ductal carcinoma in situ, invasive ductal carcinoma, tubular carcinoma, medullary carcinoma, mucinous carcinoma, lobular carcinoma in situ, triple-negative breast cancer; Urogenital tract : kidney (adenocarcinoma, Wilms' tumor) Tumors: [Nephroblastoma], lymphoma, leukemia, renal cell carcinoma; bladder and urethra: squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma, urothelial carcinoma; prostate: adenocarcinoma, sarcoma, castration-resistant prostate cancer; testes: seminoma, teratoma, embryonal carcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoid tumor, lipoma; clear cell carcinoma, papillary carcinoma; liver: hepatocellular carcinoma, bile duct carcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; bone: osteoblastoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma. Sarcoma), malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell chordoma, osteochondroma (osteochondrogenic osteoma), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor; Thyroid: medullary thyroid carcinoma, differentiated thyroid carcinoma, papillary thyroid carcinoma, follicular thyroid carcinoma, Hurthle cell carcinoma. Cancer) and undifferentiated thyroid carcinoma; Nervous system : Skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), Meninges (meningioma, meningeal sarcoma, glioma), Brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor [pineal tumor], glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), Spinal cord neurofibroma, meningioma, glioma, sarcoma; Gynecology : Uterus (endometrial cancer), Cervix (cervical cancer, tumor-pre-cervical dysplasia), Ovary (ovarian cancer [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulosa cell-theca cell tumor, Sertoli-Leydig cell tumor) Tumors: dysgerminoma, malignant teratoma; vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma); vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma)); fallopian tube (cancer); hematology : blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma [malignant lymphoma]; skin : malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus dysplasia, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal glands : neuroblastoma. Therefore, the term "cancer cell" as used herein includes cells afflicted by any of the above-identified diseases.

"Pharmaceutically acceptable salts" include "pharmaceutically acceptable acid addition salts" and "pharmaceutical acceptable base addition salts." "Pharmaceutical acceptable acid addition salts" refer to those salts that, when formed with inorganic acids (such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.) and organic acids (such as acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc.), retain the biological validity of the free base and are not biologically or otherwise undesirable.

"Pharmaceutically acceptable base addition salts" include salts derived from inorganic bases, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Exemplary salts are ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, and salts of substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Exemplary organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. (See, for example, S.M. Berge et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977; 66: 1-19, which is incorporated herein by reference.)

As used herein, the term "compound" is intended to include all stereoisomers, geometric isomers, tautomers, and isotopes of the described structure. The term also means the compounds of the present invention, regardless of how they are prepared, such as synthetically, by biological processes (e.g., metabolism or enzymatic conversion), or combinations thereof.

The compounds of the present invention may also include all isotopes of the atoms present in the intermediates or the final compound. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

Any process step or sequence disclosed and/or claimed herein may be performed under an inert gas atmosphere, more particularly under argon or nitrogen. Furthermore, the method of the present invention may be performed as a semi-continuous or continuous method, more preferably as a continuous method.

Furthermore, many of the process steps and sequences described in this article are scalable.

Generally, the nomenclature used in this application is based on the nomenclature conventions adopted by the International Union of Pure and Applied Chemistry (IUPAC). The chemical structures shown herein are prepared using [method name missing]. Any open valence bonds appearing on carbon, oxygen, or nitrogen atoms in the structures herein indicate the presence of hydrogen atoms.

Embodiments of the present invention

On the one hand, compounds of formula A are provided:

Or a pharmaceutically acceptable salt thereof, wherein the variables and substituents in formula A are as defined in the invention summary.

In one embodiment of this aspect, the compound of formula A is a compound of formula A-1.

In another embodiment of this aspect, the compound of formula A is a compound of formula A-2.

In another embodiment of this aspect, the compound of formula A is a compound of formula A-3:

^Ra1 is -H or (C1 _{- C6} ) alkyl.

In another embodiment, _R1 in the compound of formula A-3 is -H.

In another embodiment of this aspect, the compound of formula A is a compound of formula A-4:

The ring A is a 5- to 14-membered heteroaryl group; and the subscript r is 1, 2, 3 or 4.

In this implementation, _R2 is -H.

In another implementation, r in formula A-4 is 1 or 2.

In another embodiment of formula A: _R1 is -H, optionally substituted ( _C1 - _C6 )alkyl, halogroup _, ^-ORa , -NO2, _-NH2 , _-NHRa , ^-NRaRa , ^-SRa , ^-SORa or -S(O) ^2Ra , and ^R2 is selected from ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, ( _C6 - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, ^-CN , -NHORa, -C ⁽ _O ) ^Ra , -C(O) ^{NRaRa ,} -C(O) ^NHORa , -C(O) ^ORa , -C(O) ^NRaS (O) ^2Ra , ^-OC (O) ^NRaRa , ^NRaC (O ₎ ^Ra , ^-NRaC (＝ ^NRa ) ^Ra , ^-NRa C(O)OR ^a , -NR ^a C(O)NR ^a R ^a , -C(=NR ^a )R ^a , -C(=NOH)R ^a , -C(=NOR ^a )R ^a , -C(=NOH)NR ^a , -C(=NCN)NR ^a R ^a , -NR ^a C(=NCN)NR ^a R ^a , -C(=NR ^a )NR ^a R ^a , -NR ^a C(=NR ^a )NR ^a R ^a , -NR ^a S(O)R ^a , -NR ^a S(O) ₂ R ^a , -NR ^a S(O) ₂ NR ^a R ^a , -S(O)R ^a , -S(O)NR ^a R ^a , -S(O) ₂ R ^a , -S(O) ₂ NR ^a C(O)R ^a , -P(O)R ^a R ^a , -P(O)(OR ^a )(OR ^a ), -B(OH) ₂ , -B(OR ^a ) ₂ and -S(O) ₂ NR ^a R ^a .

In one implementation of this scheme, _R1 is -H.

In another embodiment: _R1 is selected from ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, ( _C6 - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-10 heteroaryl, 4-10 heterocycloalkyl, -CN, -NHOR ^a , -C(O)Ra, -C(O) ^{NR aRa} , ^-C (O)NHOR ^a , -C(O)OR ^a , -C(O)NR ^aS (O) _2Ra ^, -OC(O)NR ^aRa , -NR ^aC (O) ^Ra , -NR ^aC (＝NR ^a ) ^{Ra ,} -NR ^aC (O)OR ^a , -NR ^aC (O) ^{NR aRa ,} -C(＝NR ^a ) ^Ra , -C(＝NOH)Ra, -C(＝NOH)NR ^{a ,} -C(＝NOR ^a) )R ^a , -C(=NCN)NR ^a R ^a , -NR ^a C(=NCN)NR ^a R ^a , -C(=NR ^a )NR ^a R ^a , -NR ^a C(=NR ^a )NR ^a R ^a , -NR ^a S(O)R ^a , -NR ^a S(O) ₂ R ^a , -NR ^a S(O) ₂ NR ^a R ^a , -S(O)R ^a , -S(O)NR ^{a and} _​ ^​ _​ ^{​ ​ ​ ​ ​ ​} _​ ^​ _{​ ​} ^{​ ​}

_R2 is -H, optionally substituted ( _C1 - _C6 ) ^alkyl , halogroup, ^-ORa , -NO2, _-NH2 , _-NHRa , ^{-NRaRa , -SRa} , ^-SORa or -S(O) _2Ra ^.

In one implementation of this scheme, _R2 is -H.

In another implementation scheme:

_R1 represents ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, ( _C6 - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-10 heteroaryl, 4-10 heterocycloalkyl, -CN, -NHOR ^a , -C(O)Ra, -C(O)NR ^aRa , -C(O) ^{NHOR a ,} -C(O)OR ^a , -C(O)NR ^aS (O) _2Ra , -OC(O)NR ^aRa , -NR ^aC (O) ^Ra , -NR ^aC (＝NR ^a ) ^{Ra ,} -NR ^aC (O)OR ^a , -NR ^aC (O)NR ^aRa , -C(＝NR ^a ) ^{Ra , -C} (＝NOH) ^Ra , -C(＝NOR ^a ) ^Ra , -C(＝NOH)NR ^a , -C(=NCN)NR ^a R ^a , -NR ^a C(=NCN)NR ^a R ^a , -C(=NR ^a )NR ^a R ^a , -NR ^a C(=NR ^a )NR ^a R ^a , -NR ^a S(O)R ^a , -NR ^a S(O) ₂ R ^a , -NR ^a S(O) ₂ NR ^a R ^a , -S(O)R ^a , -S(O)NR ^a R ^a , -S(O) ₂ R ^a , -S(O) ₂ NR ^a C(O)R ^a , -P(O)R ^a R ^a , -P(O)(OR ^a )(OR ^a ), -B(OH) ₂ , -B(OR ^a ) ₂ or -S(O) ₂ NR ^a R ^a ; and

_R2 is selected from -H, halogenated, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, (C1- _C6 )haloalkyl, (C1 _- C6)haloalkoxy, (C6 _{- C10} )aryl-( _C1 - _C4 )alkylene-, (C3 _{-C10 )} cycloalkyl-( _{C1 - C4} )alkylene-, (5-14-membered heteroaryl)-( _{C1 - C4} )alkylene-, (4-14-membered heterocycloalkyl)-(C1 _{- C4} )alkylene-, -CN, _-NO2 , ^-ORa , ^-SRa , ^-NHORa , -C(O) ^{Ra ,} -C(O) ^NRaRa , -C(O) ^NHORa , -C(O) ^ORa , -C(O)NR ^a S(O) ₂ R ^a , -OC(O)R ^a , -OC(O)NR ^a R ^a , -NHR ^a , -NR ^a R ^a , -NR ^a C(O)R ^a , -NR ^a C(=NR ^a )R ^a , -NR ^a C(O)OR ^a , -NR ^a C(O)NR ^a R ^a , -C(=NR ^a )R ^a , -C(=NOH)R ^a , -C(=NOH)NR ^a , -C(=NOR ^a )R ^a , -C(=NCN)NR ^a R ^a , -NR ^a C(=NCN)NR ^a R ^a , -C(=NR ^a )NR ^a R ^a , -NR ^a C(=NR ^a )NR ^a R ^a , -NR ^a S(O)R ^a , -NR ^a S(O) ₂ R ^a , -NR ^a S(O) ₂ NR ^a R ^a , -S(O)R ^a , -S(O)NR ^a R ^a , -S(O) ₂ R ^a , -S(O) ₂ NR ^a C(O)R ^a , -P(O)R ^a R ^a , -P(O)(OR ^a )(OR ^a ), -B(OH) ₂ , -B(OR ^a ) ₂ ; and -S(O) ₂ NR ^a R ^a .

In one implementation of this scheme, _R2 is -H.

In another implementation scheme:

_R1 is selected from -H, halogroup, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, (C1-C6)haloalkyl, (C1 _{- C6} )haloalkoxy, ( _{C6 - C10} )aryl, ( _C3 - _{C10 )} cycloalkyl, 5-14-membered heteroaryl, 4-14-membered heterocycloalkyl, ( _C6 - _C10 )aryl-( _C1 - _C4 )alkylene-, ( _C3 - _C10 )cycloalkyl-(C1- _C4 )alkylene-, (5-14-membered heteroaryl)-( _{C1- C4 )} alkylene-, (4-14-membered heterocycloalkyl)-(C1 _{- C4} )alkylene-, -CN, _-NO2 , ^-ORa , -SR ^a , -NHOR ^a , -C(O)R ^a , -C(O)NR ^a R ^a , -C(O)NHOR ^a , -C(O)OR ^a , -C(O)NR ^a S(O) ₂ R ^a , -OC(O)R ^a , -OC(O)NR ^a R ^a , -NHR ^a , -NR ^a R ^a , -NR ^a C(O)R ^a , -NR ^a C(=NR ^a )R ^a , -NR ^a C(O)OR ^a , -NR ^a C(O)NR ^a R ^a , -C(=NR ^a )R ^a , -C(=NOH)R ^a , -C(= ^NOH )R ^a , -C(=NOH)NR ^a , -C(=NCN)NR ^a R ^a , -NR ^a C(=NCN)NR ^a R ^a , -C(=NR ^a )NR ^a R ^a , -NR ^a C(=NR ^a )NR ^a R ^a , -NR ^a S(O)R ^a , -NR ^a S(O) ₂ R ^a , -NR ^a S(O) ₂ NR ^a R ^a , -S(O)R ^a , -S(O)NR ^a R ^a , -S(O) ₂ R ^a , -S(O) ₂ NR ^a C(O)R ^a , -P(O)R ^a R ^a , -P(O)(OR ^a )(OR ^a ), -B(OH) ₂ , -B(OR ^a ) ₂ and -S(O) ₂ NR ^a R ^a ; and

In one implementation of this scheme, _R1 is -H.

In another alternative implementation:

_R1 and _R2, together with the atoms to which they are attached, form a fused (C3 _{- C7} ) cycloalkyl ring or a fused 4- to 10-membered heterocyclic alkyl ring; wherein each of the fused (C3 _{- C7} ) cycloalkyl ring or the fused 4- to 10-membered heterocyclic alkyl ring is optionally substituted by one, two or three independently selected ^Rb substituents, provided that the compound is not 1-[2-(4-fluoro-phenyl)-acetyl]-cyclopropanecarboxylic acid [3-fluoro-4-(7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxa-1-aza-cyclododecane[b]naphthalene-4-yloxy)-phenyl]-amide.

In another embodiment: _R1 and _R2, together with the atoms to which they are attached, form a fused (C3 _{- C7} ) cycloalkyl ring or a fused 4- to 10-membered heterocyclic alkyl ring, wherein each of the fused ( _{C3- C7} ) cycloalkyl ring or the fused 4- to 10-membered heterocyclic alkyl ring is optionally substituted by one, two, or three independently selected ^Rb substituents, provided that the compound is not a compound having the following formula:

Wherein ring E is a fused 4- to 10-membered heterocyclic alkyl group.

In another embodiment, _R1 in the compounds of formula A, A-1, A-3, or A-4 is selected from -H, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, -C(=NO-(C1 _{- C6} )alkyl) ^Ra , ^-CN , -C(O)ORa, -C(O) ^NRaRa , ^-C (O) ^NHORa , -S(O ^{) 2NRaRa} , phenyl, _5- to 6-membered heteroaryl, (C3 _{- C6} )cycloalkyl, and 4- to 6-membered heterocyclic alkyl.

In another embodiment, _R1 is selected from -H, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, -C(=NO-(C1 _{- C6} )alkyl) ^Ra , -CN, -C(O) ^ORa , ^{-C(O)NRaRa, -C(O)NHORa, -S(O)2NRaRa , phenyl ,} _5- ^to 6-membered heteroaryl, (C3 _{- C6} )cycloalkyl, and 4- to 6-membered heterocycloalkyl; and

_R2 is H, an optional substituted ( _C1 - _C6 ) ^alkyl group, ^a halogroup, ^-ORa , -NO2, _-NH2 , _-NHRa , ^-NRaRa , ^-SRa , ^-SORa , or -S(O) _2Ra ^.

In another embodiment, _R1 is selected from -H, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, -C(=NO-(C1 _{- C6} )alkyl) ^Ra , -CN, -C(O) ^ORa , ^{-C(O)NRaRa, -C(O)NHORa, -S(O)2NRaRa , phenyl ,} _5- ^to 6-membered heteroaryl, (C3 _{- C6} )cycloalkyl, and 4- to 6-membered heterocycloalkyl; and

_R2 is selected from -H, halogroup, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, (C1- _C6 )haloalkyl, (C1 _- C6)haloalkoxy, ( _{C6 - C10} )aryl, ( _{C3-C10)cycloalkyl, (C6 - C10 )} aryl-( _C1 - _C4 )alkylene-, ( _C3 - _C10 )cycloalkyl-( _{C1 - C4} )alkylene-, (5-14-membered heteroaryl)-(C1 _{- C4} )alkylene-, (4-14-membered heterocycloalkyl)-( _{C1- C4} )alkylene-, -CN, _-NO2 , ^-ORa , ^-SRa , ^-NHORa , -C(O) ^Ra , -C(O)NR ^a R ^a , -C(O)NHOR ^a , -C(O)OR ^a , -C(O)NR ^a S(O) ₂ R ^a , -OC(O)R ^a , -OC(O)NR ^a R ^a , -NHR ^a , -NR ^a R ^a , -NR ^a C(O)R ^a , -NR ^a C(=NR ^a )R ^a , -NR ^a C(O)OR ^a , -NR ^a C(O)NR ^a R ^a , -C(=NR ^a )R ^a , -C(=NOH)R ^a , -C(=NOH)NR ^a , -C(=NOR ^a )R ^a , -C(=NCN)NR ^a R ^a , -NR ^a C(=NCN)NR ^a R ^a , -C(=NR ^a )NR ^a R ^a , -NR ^a C(=NR ^a )NR ^a R ^a , -NR ^a S(O)R ^a , -NR ^a S(O) ₂ R ^a , -NR ^a S(O) ₂ NR ^a R ^a , -S(O)R ^a , -S(O)NR ^a R ^a , -S(O) ₂ R ^a , -S(O) ₂ NR ^a C(O)R ^a , -P(O)R ^a R ^a , -P(O)(OR ^a )(OR ^a ), -B(OH) ₂ , -B(OR ^a ) ₂ ; and -S(O) ₂ NR ^a R ^a .

In another embodiment, _R1 is selected from -H, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, -C(=NO-(C1 _{- C6} )alkyl) ^Ra , -CN, -C(O) ^ORa , -C(O) ^NRaRa , -C( ^O ) ^NHORa , -S(O) _2NRaRa ^{, phenyl} , 5- to 6-membered heteroaryl, -( _{C3- C6} )cycloalkyl, and 4- to 6-membered heterocycloalkyl; and

R ₂ is (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, -CN, -NHOR ^a , -C(O)R ^a , -C(O)NR ^a R ^a , -C(O)NHOR ^a , -C(O)OR ^a , -C(O)NR ^a S(O) ₂ R ^a , -OC(O)NR ^a R ^a , -NR ^a C(O)R ^a , -NR ^a C(=NR ^a )R ^a , -NR ^a C(O)OR ^a , -NR ^a C(O)NR ^a R ^a , -C(=NR ^a )R ^a , -C(=NOH)R ^a , -C(=NOH)NR ^a , -C(=NOR ^a )R ^a , -C(=NCN)NR ^a R ^a , -NR ^a C(=NCN)NR ^a R ^a , -C(=NR ^a )NR ^a R ^a , -NR ^a C(＝NR ^a )NR ^a R ^a , -NR ^a S(O)R ^a , -NR ^a S(O) ₂ R ^a , -NR ^a S(O) ₂ NR ^a R ^a , -S(O)R ^a , -S(O)NR ^a R ^a , -S(O) ₂ R ^a , -S(O) ₂ NR ^a C(O)R ^a , -P(O)R ^a R ^a , -P(O)(OR ^a )(OR ^a ), -B(OH) ₂ , -B(OR ^a ) ₂ or -S(O) ₂ NR ^a R ^a .

In another embodiment, _R1 is -H, ^RaNHC (O)-, ^RaOC (O)-, (C1 _{- C6} )alkyl, (C1 _{- C6} )alkoxy, or -C(=NO- _CH3 ) ^Ra , and _R2 is selected from 2-methoxyethylamino, aziridine-1-yl, methylamino, 3-morpholinopropoxy, 2-methoxyethoxy, 2-hydroxyethoxy, propoxy, 2-hydroxypropoxy, methoxycarbonyl, carboxyl, carbamoyl, methylcarbamoyl, (2-hydroxyethoxy)carbamoyl, (2,2-dihydroxyethoxy)carbamoyl, (oxetane-3-yloxy)carbamoyl, methoxycarbamoyl, 2-trimethylsilylethynyl, aminosulfonyl, acetyl, and -C(= _NOCH3 ) _CH3 .

In another embodiment of formulas A and A-2, _R2 is selected from -H, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, -C(=NO-( _C1 - _C6 )alkyl) ^Ra , -CN, -C(O) ^ORa , -C( ^O ) ^NRaRa , -C(O) ^NHORa and ^-S (O) _2NRaRa ^.

In another embodiment, _R1 is -H, optionally substituted ( _C1 - _C6 ) alkyl, halogroup, ^-ORa , _-NO2 , _-NH2 , ^-NHRa , ^-NRaRa , ^-SRa , ^{-SORa ,} or S(O) _2Ra , ^and

_R2 is selected from -H, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, -C(=NO-(C1 _{- C6} )alkyl) ^Ra , -CN, -C(O) ^ORa , -C(O) ^NRaRa , -C(O) ^NHORa , -S( ^{O )} _2NRaRa , ^phenyl , and (C3 _{- C6} )cycloalkyl.

In another embodiment, _R1 is selected from -H, optionally substituted ( _C1 - _C6 ) alkyl, halogroup, ^-ORa , _-NO2 , _-NH2 , ^-NHRa , ^-NRaRa , ^-SRa , ^{-SORa and} -S(O) _2Ra , ^and

_R2 is selected from -H, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, -C(＝NO-(C1 _{- C6} )alkyl) ^Ra , -CN, -C(O) ^ORa , -C(O) ^{NRaRa ,} -C(O) ^NHORa , _-S (O ^{) 2NRaRa} .

In another embodiment, _R1 is selected from ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, ( _C6 - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-10 heteroaryl, 4-10 heterocycloalkyl, -CN, -NHOR ^a , -C(O)Ra, -C(O) ^{NR aRa} , ^-C (O)NHOR ^a , -C(O)OR ^a , -C(O)NR ^aS (O) _2Ra ^, -OC(O)NR ^aRa , -NR ^aC (O) ^Ra , -NR ^aC (＝NR ^a ) ^{Ra ,} -NR ^aC (O)OR ^a , -NR ^aC (O) ^{NR aRa ,} -C(＝NR ^a ) ^Ra , -C(＝NOH)Ra, -C(＝NOH)NR ^{a ,} -C(＝NOR ^a) )R ^a , -C(=NCN)NR ^a R ^a , -NR ^a C(=NCN)NR ^a R ^a , -C(=NR ^a )NR ^a R ^a , -NR ^a C(=NR ^a )NR ^a R ^a , -NR ^a S(O)R ^a , -NR ^a S(O) ₂ R ^a , -NR ^a S(O) ₂ NR ^a R ^a , -S(O)R ^a , -S(O)NR ^{a and} _​ ^​ _​ ^{​ ​ ​ ​ ​ ​} _​ ^​ _{​ ​} ^{​ ​}

_R2 is selected from -H, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, -C(＝NO-(C1 _{- C6} )alkyl) ^Ra , -CN, -C(O) ^ORa , -C(O) ^{NRaRa ,} -C(O) ^NHORa , _-S (O ^{) 2NRaRa} .

In another embodiment, _R1 is selected from -H, halogroup, ( _C1 - _C6 )alkyl, (C2- _C6 )alkenyl, ( _C2 - _C6 )ynyl, ( _C1 - _C6 )haloalkyl, ( _{C1 - C6} )haloalkoxy, ( _C6 - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-14-membered heteroaryl, 4-14-membered heterocycloalkyl, ( _C6 - _C10 )aryl-( _C1 - _C4 )alkylene-, ( _C3 - _C10 )cycloalkyl-(C1 _{- C4} )alkylene-, (5-14-membered heteroaryl)-( _C1 - _C4 )alkylene-, (4-14-membered heterocycloalkyl)-(C1 _{- C4} )alkylene-, -CN, _-NO2 , ^-ORa , -SR ^a , -NHOR ^a , -C(O)R ^a , -C(O)NR ^a R ^a , -C(O)NHOR ^a , -C(O)OR ^a , -C(O)NR ^a S(O) ₂ R ^a , -OC(O)R ^a , -OC(O)NR ^a R ^a , -NHR ^a , -NR ^a R ^a , -NR ^a C(O)R ^a , -NR ^a C(=NR ^a )R ^a , -NR ^a C(O)OR ^a , -NR ^a C(O)NR ^a R ^a , -C(=NR ^a )R ^a , -C(=NOH)R ^a , -C(=NOR ^a )R ^a , -C(=NOH)NR ^a , -C(=NCN)NR ^a R ^a , -NR ^a C(=NCN)NR ^a R ^a , -C(=NR ^a )NR ^a R ^a ,-NR ^a C(=NR ^a )NR ^a R ^a , -NR ^a S(O)R ^a , -NR ^a S(O) ₂ R ^a , -NR ^a S(O) ₂ NR ^a R ^a , -S(O)R ^a , -S(O)NR ^a R ^a , -S(O) ₂ R ^a , -S(O) ₂ NR ^a C(O)R ^a , -P(O)R ^a R ^a , -P(O)(OR ^a )(OR ^a ), -B(OH) ₂ , -B(OR ^a ) ₂ and -S(O) ₂ NR ^a R ^a ; and

_R2 is selected from -H, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, -C(＝NO-(C1 _{- C6} )alkyl) ^Ra , -CN, -C(O) ^ORa , -C(O) ^{NRaRa ,} -C(O) ^NHORa , _-S (O ^{) 2NRaRa} .

In another embodiment, _R1 is selected from 2-methoxyethylamino, aziridine-1-yl, methylamino, 3-morpholinopropoxy, 2-methoxyethoxy, 2-hydroxyethoxy, propoxy, 2-hydroxypropoxy, methoxycarbonyl, carboxyl, carbamoyl, methylcarbamoyl, 2-oxazolyl, pyrazol-3-yl, pyrazol-4-yl, 4-isooxazolyl, 3,5-dimethylisooxazol-4-yl, 1-methyl-pyrazol-4-yl, 2-methyl-pyrazol-3-yl, 2-ethyl-pyrazol-3-yl, 2-(2-hydroxyethyl)-pyrazol-3-yl, 2-(2,2,2-trifluoroethyl)-pyrazol-3-yl, 2-(2-fluoroethyl) -pyrazol-3-yl, 2-(2,2-difluoroethyl)-pyrazol-3-yl, 2-trifluoromethyl-pyrazol-3-yl, 2-difluoromethyl-pyrazol-3-yl, 1-methyl-imidazol-4-yl, 1-methyl-imidazol-2-yl, 1H-imidazol-2-yl, (2-hydroxyethoxy)carbamoyl, (2,2-dihydroxyethoxy)carbamoyl, (oxetane-3-yloxy)carbamoyl, methoxycarbamoyl, 2-trimethylsilylethynyl, ethynyl, 1,3,4-oxadiazol-3-yl, 1H-1,2,3-triazol-5-yl, aminosulfonyl, acetyl, and -C(＝ _NOCH3 ) _CH3 ; and

_R2 is -H, ^-RaNHC (O)-, ^-RaOC (O)-, (C1 _{- C6} )alkyl, (C1 _{- C6} )alkoxy, or -C(=NO- _CH3 ) ^Ra .

In another embodiment of formula A-4, the subscript r is 1 or 2.

In another embodiment of the above aspects and implementation scheme, R ₁₀ and R ₁₁ are each -H.

In another embodiment of the above aspects and implementation scheme, the subscript n is 1.

In another embodiment of the above aspects and implementation scheme, the subscript m is 1.

In another embodiment of the above aspects and implementation scheme, the subscript p is 1.

In another embodiment, compound A is a compound of formula B:

Or a pharmaceutically acceptable salt thereof, wherein _R1 and _R2 are as defined by (i), (ii) or (iii) of formula A; and _R3 , _R10 , _R11 , _R14 , _R4 , n, p, m and Y are defined as follows:

Each _R3 is independently selected from -H, halogroup, -OH, -CN, optionally substituted ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy, ( _C1 - _C6 )haloalkoxy, _-NH2 , -NH( _C1 - _C6 )alkyl, -N( _C1 - _C6 )alkyl) ₂ and ( _C3 - _C6 )cycloalkyl, wherein ( _C1 - _C6 )alkoxy, -NH( _C1 - _C6 )alkyl, -N( _C1 - _C6 )alkyl) ₂ and ( _C3 - _C6 )cycloalkyl are each optionally substituted;

Each of _R10 and _R11 is independently selected from -H, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy, and ( _C1 - _C6 )haloalkoxy.

Each R ₁₄ is independently selected from -halogroup, -OH, _-NH2 , -CN, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy, (C1- _C6 )haloalkyl, ( _C1 - _C6 )haloalkoxy, -COOH, -NH( _C1 - _C6 )alkyl, -N( _C1 - _C6alkyl ) ₂ , phenyl, phenyl-( _{C1 - C2} )alkylene, ( _{C3- C6} )cycloalkyl, (C3- _C6 )cycloalkyl-( _{C1- C4 )} alkylene-, 4- to 6-membered heterocycloalkyl, (4- to 6-membered heterocycloalkyl)-( _{C1- C4} )alkylene-, 5- to 6-membered heteroaryl, (5- to 6-membered heteroaryl)-(C1 _{- C4} )alkylene- and ^-ORe , wherein R _The ( _C1 - _C6 )alkyl, phenyl, phenyl-(C1 _{- C2} )alkylene, (C3- _C6 )cycloalkyl, (C3 _{- C6} )cycloalkyl-(C1 _{- C4} )alkylene, 4- to 6-membered heterocycloalkyl, ( _4- to 6-membered heterocycloalkyl)-(C1 _{- C4} )alkylene, 5- to 6-membered heteroaryl and (5- to 6-membered heteroaryl)-(C1 _{- C4} )alkylene are each optionally substituted;

Each _R4 is independently selected from -H, halogroup, -OH, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy, ( _C1 - _C6 )haloalkyl, and ( _C1 - _C6 )haloalkoxy, wherein the ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy, ( _C1 - _C6 )haloalkyl, and ( _C1 - _C6 )haloalkoxy are each optionally substituted independently;

Each ^Ra is independently selected from -H, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )haloalkyl, ( _C6 - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-14-membered heteroaryl, 4-14-membered heterocycloalkyl, ( _C6 - _C10 )aryl-( _C1 - _C4 )alkylene-, ( _C3 - _C10 )cycloalkyl-( _C1 - _C4 )alkylene-, (5-14-membered heteroaryl)-(C1 _{- C4} )alkylene-, and (4-14-membered heterocycloalkyl)-(C1 _{- C4} )alkylene-, wherein ( _C1 - _C6 )alkyl, ( _C1 - _C6 )haloalkyl, ( _C6 - _C10 )aryl, ( _C3 - _C10)... ( _C6 - _C10 ) aryl-(C1-C4) alkylene-, (C3-C10) cycloalkyl-( _C1 - _C4 ) alkylene-, (5-14) heteroaryl-( _C1 - _C4 ) alkylene-, and (4-14 ₎ heterocycloalkyl-( _{C1 - C4 )} alkylene- can each be substituted independently _;

n, p, and m are each an independent integer from 0 to 3; and

Y is selected from -O-, -S-, -SO-, _-SO2- , -NH- and -N((C1 _{- C6} )alkyl)-.

In one implementation of formulas A and B:

(i)R ₁ is selected from:

( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, (C6- _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-10 heteroaryl, and 4-10 heterocycloalkyl, wherein the ( _{C2 - C6} )alkenyl, ( _C2 - _C6 )ynyl, ( _C6 - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-10 heteroaryl, and 4-10 heterocycloalkyl are each optionally substituted independently by the following:

-CN, -P(O)R ^a R ^a ,P(O)(OR ^a ) ₂ , B(OH) ₂ , B(OR ^a ) ₂ ,

X ₂ ^Ra , where X ₂ is -NHO-, -NH-S(O)-, -N-( _C1 - _C6 )alkyl-S(O)-, -NH-S(O) _2- , -N-( _C1 - _C6 )alkyl-S(O) ₂ ^Ra- , -NH-S(O)-NH-, -N-( _C1 - _C6 )alkyl-S(O)NH-, -NH-S(O) ₂ NH-, -N-( _C1 - _C6 )alkyl-S(O) ₂ NH-, -S(O) ₂ NHC(O)-, and

Where represents the connection point, and:

_Y1 is absent, or is -NH-, -N-( _C1 - _C6 )alkyl-, or -O-.

_Y2 is absent, or is -O-, -NH-, -NHO-, -N-( _C1 - _C6 )alkyl-, _-N2H2- , -NH-S(O ₎ -, or -NH-S(O) _2- ; or

_Y2 represents the optional substitution, where A is a 3-, 4-, 5-, 6-, or 7-membered ring; and

^Z1 is O, NH, N-( _C1 - _C6 )alkyl, NOH, NO-( _C1 - _C6 )alkyl, or NCN; and

_R2 is:

-H or a group selected from the following:

( _C1 - _C6 )alkyl, halogroup ^, _-NO2 , and _X1Ra , wherein _X1 is –O-, -S-, -SO-, -SO2-, -SO2NH-, ^-SO2NRa- , _{-NH- and -N-} ( _C1 - _C6 )alkyl-, wherein ( _C1 - _C6 )alkyl is optionally substituted.

In another implementation of formulas A and B:

(ii)R ₁ is selected from:

( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, (C6- _C10 )aryl, ( _{C3 - C10} )cycloalkyl, 5-10 heteroaryl, and 4-10 heterocycloalkyl, wherein the ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, ( _C6 - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-14 heteroaryl, and 4-14 heterocycloalkyl are each optionally substituted independently by the following:

P(O)R ^a R ^a , P(O)(OR ^a )(OR ^a ) , B(OH) ₂ , B(OR ^a ) ₂ , CN,

X ₂ ^Ra , where X ₂ is -NHO-, -NH-S(O)-, -N-( _C1 - _C6 )alkyl-S(O)-, -NH-S(O) _2- , -N-( _C1 - _C6 )alkyl-S(O) ₂ ^Ra- , -NH-S(O)-NH-, -N-( _C1 - _C6 )alkyl-S(O)NH-, -NH-S(O) ₂ NH-, -N-( _C1 - _C6 )alkyl-S(O) ₂ NH-, -S(O)-, -S(O) _2- , -S(O) ₂ NHC(O), and

in:

_Y1 is absent, or is -NH-, -N-( _C1 - _C6 )alkyl-, or -O-.

_Y2 is absent, or is -O-, -NH-, -NHO-, -N-( _C1 - _C6 )alkyl-, _-N2H2- , _-NH -S(O)- or -NH-S(O) ₂ , or

_Y2 represents the connection point of any optional substitution, where ring A is a 3, 4, 5, 6 or 7-membered ring;

^Z1 is -O-, -NH-, -N-( _C1 - _C6 )alkyl-, -NOH-, -NO-( _C1 - _C6 )alkyl-, or –NCN-; and

_R2 is selected from

H, halogenated, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, (C2- _C6 )ynyl, ( _C1 - _C6 )haloalkyl, (C1 _- C6)haloalkoxy, ( _C6 - _C10 )aryl-(C1 _{- C4} )alkylene-, (C3 _{- C10} )cycloalkyl-( _{C1 - C4} )alkylene-, ( _5-14 -membered heteroaryl)-(C1 _{- C4} )alkylene-, and (4-14-membered heterocycloalkyl)-(C1 _{- C4} )alkylene-, wherein ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, ( _C1 - _C6 )haloalkyl, (C1 _{- C6} )haloalkoxy, ( _C6 - _C10) The aryl, ( _C3 - _C10 )cycloalkyl, (C6- _C10 )aryl-( _C1 -C4)alkylene-, ( _C3 - _C10 )cycloalkyl-( _C1 - _C4 )alkylene-, (5-14-membered heteroaryl)-( _{C1- C4 )} alkylene-, and (4-14-membered heterocycloalkyl)-(C1 _{- C4} )alkylene- are each independently _and optionally substituted with the following:

CN, NO ₂ , P(O)R ^a R ^a , P(O)(OR ^a )(OR ^a ), B(OH) ₂ , B(OR ^a ) ₂ ,

_X1 ^Ra substitution, wherein _X1 is –O-, -S-, -NH- or -N-( _C1 - _C6 )-, -NHO-, -NH-S(O)-, -N-(C1-C6)alkyl-S(O)-, -NH-S(O)2-, -N-( _C1 - _C6 )alkyl-S(O) _2- , -NH-S(O)-NH-, -N-( _C1 - _C6 )alkyl-S(O)NH-, -NH-S(O) _2NH- , -N-(C1- _C6 )alkyl-S(O)2NH-, -S(O) _2NHC (O)-, -NH-S(O)Ra-, -N-(C1-C6)alkyl-S(O) _Ra- , -NH-S(O)2Ra-, -N-( _C1 - _C6 )alkyl-S(O) _2NH- , -N-(C1-C6)alkyl-S(O) _2NH- , -N-(C1-C6)alkyl- ^S (O)2NH-, -N-( _C1 - _C6 )alkyl-S(O) ^2Ra- , -N-(C1-C6)alkyl-S(O)2Ra-, -N-(C1-C6) ^alkyl -S(O) _2NH ... ₁ - _C6 )alkyl-S(O) _2Ra- ^and

in:

_Y1 is absent or is -NH-, -N-( _C1 - _C6 )alkyl- or -O-;

_Y2 is absent, or is -O-, -NH-, -NHO-, -N-( _C1 - _C6 )alkyl-, _-N2H2- , _-NH -S(O)- or -NH-S(O) _2- , or

_Y2 is an optional substitution in which ring A is a 3, 4, 5, 6, or 7-membered ring, and where represents the connection point; and

^Z1 can be O, NH, N-( _C1 - _C6 )alkyl, NOH, NO-( _C1 - _C6 )alkyl, or NCN.

In another implementation of formulas A and B:

(iii) _R1 and _R2 together with the atoms to which they are attached form a 4-10 membered heterocyclic alkyl ring optionally substituted with 1, 2 or 3 independently selected from the following groups: halogroup, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )haloalkyl, ( _C1 - _C6 )haloalkoxy, -CN, -OH, _-NH2 , provided that the compound is not 1-[2-(4-fluoro-phenyl)-acetyl]-cyclopropanecarboxylic acid [3-fluoro-4-(7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxa-1-aza-cyclododecano[b]naphthalene-4-yloxy)-phenyl]-amide.

In another embodiment of the compounds of formulas A and B:

_R1 can be -H, -CN, ( _C1 - _C6 )alkyl, ( _C3 - _C10 )cycloalkyl, ( _C6 - _C10 )aryl, 4-10 heterocyclic alkyl, 5-10 heteroaryl, -S(O ^)2NHRa _, -P(O) ^RaRa , ^{-ORa , or}

Where represents the connection point, and:

_Y1 is absent or is -NH-, -N-( _C1 - _C6 )alkyl- or -O-;

_Y2 is absent, or is -O-, -NH-, -NHO-, -N-( _C1 - _C6 )alkyl-, -NH-NH-, -NH-S(O)-, or NH-S(O) ₂ ; and

^Z1 is -O, -NH, -N-( _C1 - _C6 )alkyl, -N-OH or -NO( _C1 - _C6 )alkyl.

In another implementation of formulas A and B:

_R2 is -H, a ^halogroup , _-X1Ra , ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, or

Where represents the connection point, and:

_Y1 is absent, or is NH, N-( _C1 - _C6 ) alkyl, or O;

_Y2 is absent, or is O, NH, NHO, N-( _{C1 - C6} )alkyl, _N2H2 , NH-S(O) or NH-S(O) ₂ ; and

^Z1 is -O, -NH, -N-( _C1 - _C6 )alkyl, -NOH-, or -NO( _C1 - _C6 )alkyl.

In another embodiment of formulas A and B, _R3 is -H or a halogenated group.

In another embodiment of formulas A and B, _R4 is -H or a halogenated group.

In another embodiment of formulas A and B, _R14 is -H or a halogenated group.

In another implementation of formulas A and B, Y is -O-.

In another embodiment, the compound of B is a compound of formula B-1 or B-2:

               

Or its pharmaceutically acceptable salt.

In one implementation of formula B-1:

^Ra1 is an optionally substituted ( _C1 - _C6 ) alkyl group;

_R1 is -H, -CN, optionally substituted 3-6 membered cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 membered heterocycloalkyl, optionally substituted 5-6 membered heteroaryl, _-SO2- ( _C1 - _C6 )alkyl, -SO2NH2, _{-SO2 -} NH( _C1 - _C6 )alkyl, P ₍ O)(( _C1 - _C6 )alkyl) ₂ , or

Where represents the connection point, and:

_Y1 does not exist;

_Y2 is absent, or is -O-, -NH-, -NHO-, -NH-NH-, -N-( _C1 - _C6 )alkyl-; or

_Y2 is an optional substitution in which ring A is a 3, 4, 5, 6 or 7-membered ring, where represents the connection point;

^Z1 is O, NH, N-( _C1 - _C6 )alkyl, NHO, or NO-( _C1 - _C6 )alkyl; and

Ra ^can be -H, -( _C1 - _C6 )alkyl, 4-6 membered heterocyclic alkyl, 3-6 membered cycloalkyl, -( _C2 - _C6 )alkylene-OH, _-CH2CHOH- ( _C2 - _C6 )alkylene-OH, -( _C2 - _C6 )alkylene- _NH2 , -( _C2 - _C6 )alkylene-NH(C1- _C6 ), -( _C2 - _C6 )alkylene-N( _C1 - _C6 ) ₂ or -( _C2 - _C6 )alkylene-N-( _4-6 membered heterocyclic alkyl);

In another embodiment of formula B-1:

^Ra1 is a ( _C1 - _C6 ) alkyl group;

_R1 is -H, -CN, optionally substituted cyclopropyl, optionally substituted phenyl, optionally substituted 4-6 membered azacyclic butyl, optionally substituted pyrrolyl, optionally substituted piperidinyl, optionally substituted oxazolyl, optionally substituted pyridinyl, optionally substituted imidazolyl, optionally substituted pyrrolyl, optionally substituted furanyl, optionally substituted pyrazolyl, optionally substituted oxadiazolyl, _-SO₂- ( _C₁ - _C₆ )alkyl, _-SO₂NH₂ , _{-SO₂ -} NH( _C₁ - _C₆ )alkyl, or P(O)(( _C₁ - _C₆ )alkyl) _₂ ; or

_R1 is where:

_Y1 does not exist;

_Y2 is O, NH, NHO, NH-NH, or N-( _C1 - _C6 ) alkyl; or

_Y2 is an optionally substituted nitrogen-containing heterocyclic butyl group;

^Z1 is an O, NH, or N-( _C1 - _C6 ) alkyl group; and

Ra ^can be H, ( _C1 - _C6 )alkyl, -( _C2 - _C6 )alkylene-OH, _-CH2CHOH- ( _C2 - _C6 )alkylene-OH, -( _C2 - _C6 )alkylene- _NH2 , -( _C2 - _C6 )alkylene-NH( _C1 - _C6 )alkyl, -( _C2 - _C6 )alkylene-N(( _C1 - _C6 )alkyl) ₂ , -( _C2 - _C6 )alkylene-heterocyclic alkyl) or 4-6 membered heterocyclic alkyl, wherein the heterocyclic alkyl is optionally substituted.

In one implementation of formula B-2:

^Ra2 is an optionally substituted ( _C1 - _C6 ) alkyl group;

_R2 represents the connection point, where:

_Y1 does not exist;

_Y2 either does not exist or is -O- or -NH-; and

^Z1 is 0; and

^Ra is -H or -( _C1 - _C6 ) alkyl.

In another implementation of formula B-2:

^Ra2 is a ( _C1 - _C6 ) alkyl group;

_R2 represents the connection point, where:

_Y1 does not exist;

_Y2 either does not exist or is -O- or -NH-; and

^Z1 is an O or NO-( _C1 - _C6 ) alkyl group; and

^Ra is -H or -( _C1 - _C6 ) alkyl.

In another embodiment of formula B-1, ^Ra1 is a methoxy group.

In another embodiment of formula B-2, ^Ra2 is a methoxy group.

In another embodiment, the compound of formula B is a compound of formula B-3 or formula B-4:

Or its pharmaceutically acceptable salt.

In one implementation of formula B-3:

_R1 is -H or ( _C1 - _C6 ) alkyl; and _Y1 is absent;

_Y2 is absent or is -O-, -NHO- or -NH-; and ^Z1 is O or NO-( _C1 - _C6 )alkyl; and ^Ra is -H or -( _C1 - _C6 )alkyl.

In another implementation of formula B-3:

_R1 is –H or methyl;

_Y1 does not exist;

_Y2 is nonexistent or is -O-, -NHO-, or -NH-; and ^Z1 is O or NO-Me; and ^Ra is -H or Me.

In another implementation of formula B-3:

_R1 and ^Ra together with the atoms they are attached to form

4-6 membered heterocyclic alkyl rings optionally substituted with a halogroup, ( _C1 - _C6 )alkyl or ( _C1 - _C6 )haloalkyl.

In one implementation of formula B-4:

_Y1 does not exist;

_Y2 is O, NH, NHO, NH-NH, or N-( _C1 - _C6 ) alkyl; or

_Y2 is an optionally substituted nitrogen-containing heterocyclic butyl group;

^Z1 is O, NH, NO-( _C1 - _C6 )alkyl or N-( _C1 - _C6 )alkyl; and

Ra ^can be H, ( _C1 - _C6 )alkyl, -( _C2 - _C6 )alkylene-OH, _-CH2CHOH- ( _C2 - _C6 )alkylene-OH, -( _C2 - _C6 )alkylene- _NH2 , -( _C2 - _C6 )alkylene-NH( _C1 - _C6 )alkyl, -( _C2 - _C6 )alkylene-N(( _C1 - _C6 )alkyl) ₂ , -( _C2 - _C6 )alkylene-optionally substituted 4-6 membered heterocyclic alkyl) or optionally substituted 4-6 membered heterocyclic alkyl;

_R2 can be -H, -F, -Cl, -Br, -( _C1 - _C6 )alkoxy, -O-( _C2 - _C6 )alkylene-OH, -O-( _C2 - _C6 )alkylene-O-( _C1 - _C6 alkyl), ( _C2 - _C6 )alkylene-O-( _C1 - _C6 )alkyl, _-NH2 , -NH-(C1- _C6 alkyl), -NH-( _C1 - _C6 )alkylene-(optionally substituted 4-6 membered heterocyclic alkyl) or –NH-( _{C2 - C6} )alkylene-O-( _C1 - _C6 alkyl).

In another implementation of formula B-4:

_Y1 does not exist;

_Y2 is O, NH, NHO, NH-NH, or N-( _C1 - _C6 ) alkyl; or

_Y2 is an optionally substituted nitrogen-containing heterocyclic butyl group;

^Z1 is O, NH, NO-( _C1 - _C6 )alkyl, or N-( _C1 - _C6 )alkyl; and

^Ra can be -H, methyl, ethyl, -( _C2 - _C6 )alkylene-OH, _-CH2CHOH- ( _C2 - _C6 )alkylene-OH, -( _C2 - _C6 )alkylene- _NH2 , -( _C2 - _C6 )alkylene-NHMe, -( _C2 - _C6 )alkylene-N(Me) ₂ , -( _C1 - _C6 )alkylene-morpholinyl), -( _C1 - _C6 )alkylene-piperidinyl), ( _C1 - _C6 )alkylene-(optionally substituted pyrrolidinyl), optionally substituted azahexacyclic butyl or optionally substituted oxohexacyclic butyl;

_R2 is -H, -F, -Cl, -Br, methoxy, -O-( _C2 - _C6 )alkylene-OH, -O-( _C2 - _C6 )alkylene-OMe, _-NH2 , -NH-( _C1 - _C6 alkyl), -NH-( _C2 - _C6 )alkylene-OMe, -NH-( _C2 - _C6 )alkylene-(optionally substituted morpholino) or -NH-( _C2 - _C6 )alkylene-O-( _C1 - _C6 alkyl).

In another implementation of formula B-4:

_R2 and ^Ra, together with the atoms they are attached to, form 4-6 membered heterocyclic alkyl rings that are optionally substituted with halogen groups, ( _C1 - _C6 )alkyl groups, or ( _C1 - _C6 )haloalkyl groups.

In another embodiment, the compound of formula B is a compound of formula B-5:

Or a pharmaceutically acceptable salt thereof, wherein ring A in formula B-5 is an optionally substituted 5-6 membered heteroaryl or aryl.

In one implementation of formula B-5:

Ring A is optionally substituted ( _C6 - _C10 ) aryl, optionally substituted ( _C3 - _C10 ) cycloalkyl, optionally substituted 5-10 heteroaryl, or optionally substituted 4-10 heterocycloalkyl; and

_R2 is H, or ( _C1 - _C6 )alkoxy.

In another implementation of formula B-5:

Ring A is optionally substituted with phenyl, optionally substituted with cyclopropyl, optionally substituted with pyridyl, optionally substituted with imidazolyl, optionally substituted with pyrrole, optionally substituted with furanyl, optionally substituted with pyrazolyl, optionally substituted with oxazolyl, optionally substituted with aziridine or optionally substituted with oxacyclobutane; and

_R2 is H or methoxy.

Another embodiment of the compounds of formulas A and B is the compound of formula C:

Or its pharmaceutically acceptable salt, wherein:

_Y1 does not exist;

_Y2 is O, NH, NHO, NH-NH, or N-( _C1 - _C6 ) alkyl; or

_Y2 is an optionally substituted nitrogen-containing heterocyclic butyl group;

Z can be O, NH, NO-( _C1 - _C6 )alkyl or N-( _C1 - _C6 )alkyl;

Ra ^can be -H, ( _C1 - _C6 )alkyl, -( _C2 - _C6 )alkylene-OH, _-CH2CHOH- ( _C2 - _C6 )alkylene-OH, -( _C2 - _C6 )alkylene- _NH2 , -( _C2 - _C6 )alkylene-NH( _C1 - _C6 )alkyl, -( _C2 - _C6 )alkylene-N(( _C1 - _C6 )alkyl) ₂ , -( _C2 - _C6 )alkylene-optionally substituted 4-6 membered heterocyclic alkyl) or optionally substituted 4-6 membered heterocyclic alkyl;

_R2 can be -H, -F, -Cl, -Br, -( _C1 - _C6 )alkoxy, -O-( _C2 - _C6 )alkylene-OH, -O-( _C2 - _C6 )alkylene-O-( _C1 - _C6 alkyl), ( _C2 - _C6 )alkylene-O-( _C1 - _C6 )alkyl, _-NH2 , -NH-(C1- _C6 alkyl), -NH-( _C1 - _C6 )alkylene-(optionally substituted 4-6 membered heterocyclic alkyl), -NH-( _{C2 - C6} )alkylene-O-( _C1 - _C6 alkyl); and

n and m are each an independent integer from 0 to 3.

In another implementation of formula C:

_Y1 does not exist;

_Y2 is O, NH, NHO, NH-NH, or N-( _C1 - _C6 ) alkyl; or

_Y2 is an optionally substituted nitrogen-containing heterocyclic butyl group;

^Z1 is O, NH, NO-( _C1 - _C6 )alkyl or N-( _C1 - _C6 )alkyl;

^Ra can be -H, methyl, ethyl, -( _C2 - _C6 )alkylene-OH, _-CH2CHOH- ( _C2 - _C6 )alkylene-OH, -( _C2 - _C6 )alkylene- _NH2 , -( _C2 - _C6 )alkylene-NHMe, -( _C2 - _C6 )alkylene-N(Me) ₂ , -( _C1 - _C6 )alkylene-morpholinyl), -( _C1 - _C6 )alkylene-piperidinyl), ( _C1 - _C6 )alkylene-(optionally substituted pyrrolidinyl), optionally substituted azahexacyclic butyl or optionally substituted oxohexacyclic butyl;

_R2 is -H, -F, -Cl, -Br, methoxy, -O-( _C2 - _C6 )alkylene-OH, -O-( _C2 - _C6 )alkylene-OMe, _-NH2 , -NH-( _C1 - _C6 alkyl), -NH-( _C2 - _C6 )alkylene-OMe, -NH-( _C2 - _C6 )alkylene-(optionally substituted morpholino) or -NH-( _C2 - _C6 )alkylene-O-( _C1 - _C6 alkyl); and

And n and m are each 0 or 1.

In another implementation of formula C:

_R2 and ^Ra, together with the atoms they are attached to, form 4-6 membered heterocyclic alkyl rings optionally substituted with halogroups, ( _C1 - _C6 )alkyl groups, and ( _C1 - _C6 ) haloalkyl groups; and

n and m are each an independent integer from 0 to 3.

Another embodiment of formula C is a compound of formula C-1.

Or its pharmaceutically acceptable salt, wherein:

_Y2 is O, NH, NHO, NH-NH, or N-( _C1 - _C6 ) alkyl; or

_Y2 is an optionally substituted nitrogen-containing heterocyclic butyl group;

^Z1 is O, NH, NO-( _C1 - _C6 )alkyl or N-( _C1 - _C6 )alkyl;

^Ra can be -H, methyl, ethyl, -( _C2 - _C6 )alkylene-OH, _-CH2CHOH- ( _C2 - _C6 )alkylene-OH, -( _C2 - _C6 )alkylene- _NH2 , -( _C2 - _C6 )alkylene-NHMe, -( _C2 - _C6 )alkylene-N(Me) ₂ , -( _C1 - _C6 )alkylene-morpholinyl), -( _C1 - _C6 )alkylene-piperidinyl), ( _C1 - _C6 )alkylene-(optionally substituted pyrrolidinyl), optionally substituted azahexacyclic butyl or optionally substituted oxohexacyclic butyl;

_R2 is -H, -F, -Cl, -Br, methoxy, -O-( _C2 - _C6 )alkylene-OH, -O-( _C2 - _C6 )alkylene-OMe, _-NH2 , -NH-( _C1 - _C6 alkyl), -NH-( _C2 - _C6 )alkylene-OMe, -NH-( _C2 - _C6 )alkylene-(optionally substituted morpholino) or -NH-( _C2 - _C6 )alkylene-O-( _C1 - _C6 alkyl); and

Furthermore, n and m are each independently 0 or 1.

Another embodiment of formulas A and B is a compound of formula D:

In one implementation of formula D:

_R1 is -H or ( _C1 - _C6 ) alkyl; and

_Y1 does not exist;

_Y2 either does not exist or is -O-, -NHO-, or -NH-; and

^Z1 is O or NO-( _C1 - _C6 ) alkyl;

^Ra is -H or -( _C1 - _C6 ) alkyl; and

n and m are each an independent integer from 0 to 3.

In another implementation of formula D:

_R1 is –H or methyl;

_Y1 does not exist;

_Y2 either does not exist or is -O-, -NHO-, or -NH-; and

^Z1 is O or NO-Me; and

R ^_a can be either -H or -Me.

n and m are each an independent integer between 0 and 1.

In another implementation of formula D:

_R1 and ^Ra together with the atoms they are attached to form

4-6 membered heterocyclic alkyl rings optionally substituted with a halogroup, ( _C1 - _C6 )alkyl, or ( _C1 - _C6 )haloalkyl; and

n and m are each an independent integer between 0 and 1.

Another embodiment of formula D is a compound of formula D-1.

Another embodiment of formulas A and B is a compound of formula E:

Or its pharmaceutically acceptable salt, wherein:

Ring A is optionally substituted ( _C6 - _C10 ) aryl, optionally substituted ( _C3 - _C10 ) cycloalkyl, optionally substituted 5-10 heteroaryl, or optionally substituted 4-10 heterocycloalkyl; and

_R2 is H or ( _C1 - _C6 ) alkoxy.

In another implementation of formula E:

Ring A is optionally substituted with phenyl, optionally substituted with cyclopropyl, optionally substituted with pyridyl, optionally substituted with imidazolyl, optionally substituted with pyrrole, optionally substituted with furanyl, optionally substituted with pyrazolyl, optionally substituted with oxazolyl, optionally substituted with aziridine or optionally substituted with oxacyclobutane; and

_R2 is H or methoxy.

Another embodiment of formulas A and B is a compound of formula F:

Or its pharmaceutically acceptable salt, wherein

^Ra1 is an optionally substituted ( _C1 - _C6 ) alkyl group;

_R1 is -H, -CN, optionally substituted 3-6 membered cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 membered heterocycloalkyl, optionally substituted 5-6 membered heteroaryl, _-SO2- ( _C1 - _C6 )alkyl, _-SO2NH2 , _-SO2 - _NH ( _C1 - _C6 )alkyl, or P(O)(( _C1 - _C6 )alkyl) ₂ , or

Where represents the connection point, and:

_Y1 does not exist;

_Y2 is absent, or is -O-, -NH-, -NHO-, -NH-NH-, -N-( _C1 - _C6 )alkyl-; or

_Y2 is an optional substitution in which ring A is a 3, 4, 5, 6 or 7-membered ring, where represents the connection point;

^Z1 is O, NH, N-( _C1 - _C6 )alkyl, NHO, or NO-( _C1 - _C6 )alkyl; and

Ra ^can be -H, -( _C1 - _C6 )alkyl, 4-6 membered heterocyclic alkyl, 3-6 membered cycloalkyl, -( _C2 - _C6 )alkylene-OH, _-CH2CHOH- ( _C2 - _C6 )alkylene-OH, -( _C2 - _C6 )alkylene- _NH2 , -( _C2 - _C6 )alkylene-NH(C1- _C6 ), -( _C2 - _C6 )alkylene-N( _{C1 - C6} ) ₂ , -( _C2 - _C6 )alkylene-N-(4-6 membered heterocyclic alkyl);

In another implementation of formula F:

^Ra1 is a methyl group;

_R1 is -H, -CN, optionally substituted cyclopropyl, optionally substituted phenyl, optionally substituted 4-6 membered azacyclic butyl, optionally substituted pyrrolyl, optionally substituted piperidinyl, optionally substituted oxazolyl, optionally substituted pyridinyl, optionally substituted imidazolyl, optionally substituted pyrrolyl, optionally substituted furanyl, optionally substituted pyrazolyl, optionally substituted oxadiazolyl, _-SO₂- ( _C₁ - _C₆ )alkyl, _-SO₂NH₂ , _{-SO₂ -} NH( _C₁ - _C₆ )alkyl, or P(O)(( _C₁ - _C₆ )alkyl) _₂ ; or

_R1 is where:

_Y1 does not exist;

_Y2 is O, NH, NHO, NH-NH, or N-( _C1 - _C6 ) alkyl; or

_Y2 is an optionally substituted nitrogen-containing heterocyclic butyl group;

^Z1 is an O, NH, or N-( _C1 - _C6 ) alkyl group; and

Ra ^can be H, ( _C1 - _C6 )alkyl, -( _C2 - _C6 )alkylene-OH, _-CH2CHOH- ( _C2 - _C6 )alkylene-OH, -( _C2 - _C6 )alkylene- _NH2 , -( _C2 - _C6 )alkylene-NH( _C1 - _C6 )alkyl, -( _C2 - _C6 )alkylene-N(( _C1 - _C6 )alkyl) ₂ , -( _C2 - _C6 )alkylene-heterocyclic alkyl) and 4-6 membered heterocyclic alkyl, wherein the heterocyclic alkyl is optionally substituted.

Another embodiment of formulas A and B is a compound of formula G:

Or its pharmaceutically acceptable salt, wherein:

^Ra1 is an optionally substituted ( _C1 - _C6 ) alkyl group;

_R2 represents the connection point, where:

_Y1 does not exist;

_Y2 either does not exist or is -O- or -NH-; and

^Z1 is 0; and

^Ra is -H or -( _C1 - _C6 ) alkyl.

In another implementation of formula G:

^Ra2 is a methyl group;

_R2 represents the connection point, where:

_Y1 does not exist;

_Y2 either does not exist or is -O- or -NH-; and

^Z1 is an O or NO-( _C1 - _C6 ) alkyl group; and

^Ra is –H or -( _C1 - _C6 )alkyl.

Another embodiment of formulas A and B is a compound for regulating kinase activity according to formula H:

Or its pharmaceutically acceptable salt, wherein:

_R1 is selected _from -H, -CN, -CO- _NR5R6 , _-CO2R7 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted _{( C1} - _C6 )alkyl, optionally substituted ( _C3 - _C8 )cycloalkyl, optionally substituted ( _C3 - _C6 ) _{heterocycloalkyl} , _-SO2NR8R9 or -( _{SO2 )} -( _C1 - _C6 )alkyl;

Where _R1 is selected _{from -CN} , -CO- _NR5R6 , _-CO2R7 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted ( _C3 - _C8 )cycloalkyl, optionally substituted ( _C3 - _C6 ) heterocycloalkyl, _-SO2NR8R9 and -( _SO2 )-( _C1 - _C6 )alkyl, _{R2 is} H, _halogroup , _-NR5R6 or optionally substituted _{( C1} - _C6 )alkoxy;

Where _R1 is -H, an optionally substituted ( _C1 - _C6 ) alkyl, or _an optionally substituted ( _C1 - _C6 ) alkoxy, _R2 is -CO- _NR5R6 or _{-CO2R7 ;}

Or _R1 and _R2 together with the atoms to which they are attached form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl;

_R3 is selected from -H, optionally substituted (C1 _{- C6} ) alkyl, -CN, and halogroup;

_R4 is -H or a halogenated group;

Optionally substituted with one, two, three or four independently selected groups from halogroups and ( _C1 - _C6 )alkyl groups, wherein the linkage point is indicated;

_R5 and _R6 are each independently -H, optionally substituted ( _C1 - _C6 ) alkyl or optionally substituted _C1 - _C6 alkoxy;

_R7 is -H or an optionally substituted ( _C1 - _C6 ) alkyl group;

_R8 and _R9 are each independently -H or optionally substituted ( _C1 - _C6 ) alkyl; or

_R8 and _R9 can be connected to form an optionally substituted heterocyclic ring; and

Y is selected from O, S, SO, _SO₂ , NH and N-(( _C₁ - _C₆ )alkyl).

In one embodiment of the compound of formula I, Y is O.

In another implementation, _R3 is -H.

In another implementation, it was not replaced.

In another implementation, _R4 is a halogenated group.

In another embodiment, _R4 is parafluorine.

In another embodiment, _R2 is -H, a halogroup, or an optionally substituted ( _C1 - _C6 )-alkoxy group.

In another implementation, _R1 is -CN.

In another implementation, _R1 is _-CO2H .

In another implementation, _R1 is _-CO2 -Me.

In another implementation, _R1 is -CO-NHR ₆ .

In another implementation, _R1 is -CO-NH2.

In another implementation, _R1 is -CO- _NMeR6 .

In another embodiment, _R3 is -H or a halogenated group.

In another embodiment, _R1 is selected from -CN, -( _SO2 ) _NH2 , -OMe, and -( _SO2 ) _CH3.

Where is the connection point.

In one implementation, _R1 is selected as a connection point.

In another implementation, _R1 is selected as the connection point.

In another implementation, _R2 is selected from -H, -CN, -Br, -F, -Cl, -OMe,

-CH ₂ NH ₂ 、NH ₂ 、NHMe, where is the connection point.

In another embodiment, _R1 is -H, methyl, or methoxy.

In another implementation, _R2 is _-CO2H .

In another implementation, _R1 is _-CO2 -Me.

In another implementation, _R1 is -CO-NHR ₆ .

In another implementation, _R1 is -CO- _NH2 .

In another implementation, _R1 is -CO- _NMeR6 .

In another implementation, _R1 is selected from

In another implementation, _R1 and _R2 together form

In another embodiment, the compound of formula I is the compound of formula I-1:

              

Wherein _R6 is (C1 _{- C6} )alkyl, _R2 is (C1 _{- C6} )alkoxy, _R3 is -H or a halogroup, and _R4 is a halogroup.

In another aspect, the present invention provides compounds of formula A or formula A-I provided in Table 1 below.

Table 1: Specific compounds of the present invention

Or its pharmaceutically acceptable salt.

General application

The application of the compounds of the present invention, either in their pure form or in suitable pharmaceutical compositions, or of their pharmaceutically acceptable salts, can be carried out by any acceptable mode of administration or agent for providing similar efficacy. Thus, administration can be, for example, in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms (such as tablets, suppositories, pills, soft and hard gelatin capsules, powders, solutions, suspensions, aerosols, etc.), preferably in unit dosage forms suitable for simple administration of precise dosage, orally, nasally, parenterally (intravenously, intramuscularly, or subcutaneously), topically, transdermally, intravaginally, intravesically, intracisionally, or rectally.

The composition will comprise a conventional pharmaceutical carrier or excipient and the compound of the present invention as an active agent, and may further include other pharmaceutical agents, pharmaceutical reagents, carriers, adjuvants, etc. The compositions of the present invention can be used in combination with anticancer agents or other agents commonly administered to cancer-treated patients. Adjuvants include preservatives, wetting agents, suspending agents, sweeteners, flavoring agents, aromatizers, emulsifiers, and dispersants. Prevention of microbial action can be ensured by various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, etc. Isotonic agents, such as sugars, sodium chloride, etc., may also be desired. Prolonged absorption of injectable drug forms can be achieved by using agents with delayed absorption, such as aluminum monostearate and gelatin.

If necessary, the pharmaceutical compositions of the present invention may also contain small amounts of excipients, such as wetting agents or emulsifiers, pH buffers, antioxidants, etc., for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylated hydroxytoluene, etc.

Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or mediators include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, etc.), suitable mixtures thereof, vegetable oils (e.g., olive oil), and injectable organic esters such as ethyl oleate. Appropriate flowability may be maintained, for example, by using coatings such as lecithin, by maintaining the desired particle size in the case of dispersions, and by using surfactants.

A preferred route of administration is oral, with a convenient daily dosage regimen that can be adjusted according to the severity of the disease state being treated.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with: at least one inert conventional excipient (or carrier), such as sodium citrate or dicalcium phosphate, or (a) a filler or extender, such as starch, lactose, sucrose, glucose, mannitol and silica, (b) a binder, such as cellulose derivatives, starch, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic, (c) a humectant, such as glycerin, (d) a disintegrant, such as agar, calcium carbonate, potato or cassava starch, alginate, croscarmellose sodium, complex silicates and sodium carbonate, (e) a solution retarder, such as paraffin, (f) an absorption enhancer, such as a quaternary ammonium compound, (g) a wetting agent, such as cetyl alcohol and glyceryl monostearate, magnesium stearate, etc., (h) an adsorbent, such as kaolin and bentonite, and (i) a lubricant, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate or mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also contain buffers.

Solid dosage forms as described above can be prepared using coatings and shells such as enteric coatings and other coatings well known in the art. They may contain soothing agents and may also have compositions in which they release one or more active compounds in a delayed manner at a portion of the intestine. Examples of usable embedding compositions are polymeric substances and waxes. If suitable, the active compounds may also be present in microencapsulated form together with one or more of the excipients described above.

Orally administered liquid dosage forms include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. Such dosage forms are prepared, for example, by dissolving, dispersing, etc., the compounds of the present invention or their pharmaceutically acceptable salts and optionally adjuvants in a carrier, such as water, saline solution, aqueous glucose solution, glycerol, ethanol, etc.; solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, and dimethylformamide; oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil; glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitol; or mixtures of these substances, thereby forming a solution or suspension.

In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar and tragacanth gum, or mixtures of these substances.

Compositions for rectal administration are, for example, suppositories, which can be prepared by mixing the compounds of the present invention with, for example, suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or suppository waxes, which are solid at room temperature but liquid at body temperature and thus melt and release the active component therein when in a suitable body cavity.

Dosage forms for topical application of the compounds of this invention include ointments, powders, sprays, and inhalers. The active ingredient is mixed under aseptic conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required. Ophthalmic preparations, ointments, powders, and solutions are also contemplated within the scope of this invention.

Typically, depending on the intended route of administration, a pharmaceutically acceptable composition will contain about 1% to about 99% by weight of the compound of the present invention or a pharmaceutically acceptable salt thereof, and 99% to 1% by weight of a suitable pharmaceutical excipient. In one example, the composition will contain between about 5% and about 75% by weight of the compound of the present invention or a pharmaceutically acceptable salt thereof, with the remainder being a suitable pharmaceutical excipient.

The actual methods for preparing such dosage forms are known or obvious to those skilled in the art; see, for example, Remington's Pharmaceutical Sciences, 18th edition (Mack Publishing Company, Easton, Pa., 1990). In any case, the composition to be administered will contain a therapeutically effective amount of the compound of the invention or a pharmaceutically acceptable salt thereof for treating the disease state taught according to the invention.

The compounds of the present invention, or pharmaceutically acceptable salts thereof, are administered in therapeutically effective amounts, which will vary depending on a variety of factors, including the activity of the specific compound used, the metabolic stability and duration of action of the compound, age, weight, general health condition, sex, diet, administration pattern and time, excretion rate, drug combination, severity of the specific disease state, and the host receiving treatment. The compounds of the present invention can be administered to patients at dose levels ranging from about 0.1 mg to about 1,000 mg per day. For a normal adult weighing about 70 kg, the dose range is, for example, from about 0.01 mg to about 100 mg per kg of body weight per day. However, the specific dose used can vary. For example, the dose can depend on many factors, including the patient's needs, the severity of the disease to be treated, and the pharmacological activity of the compound used. Determining the optimal dose for a particular patient is well known to those skilled in the art.

Combination therapy

The compounds disclosed herein may be administered as a monotherapy or in combination with one or more additional therapies (“co-administration”) for the treatment of diseases or conditions, such as those associated with excessive proliferation, such as cancer. Therapies that may be used in combination with the compounds disclosed herein include: (i) surgery; (ii) radiation therapy (e.g., gamma rays, neutron beam radiation therapy, electron beam radiation therapy, proton therapy, brachytherapy, and whole-body radioisotopes); (iii) endocrine therapy; (iv) adjuvant therapy, immunotherapy, CAR T-cell therapy; and (v) other chemotherapeutic agents.

The term "co-administration" ("co-administration") refers to the simultaneous or sequential administration of a compound of formula I' or a salt thereof and one or more other active pharmaceutical ingredients (including cytotoxic agents and radiotherapy). If the administration is not simultaneous, the compounds are administered at close intervals. Furthermore, it is irrelevant whether the compounds are administered in the same dosage form; for example, one compound may be administered topically and another may be administered orally.

Generally, any agent active in treating a disease or ailment may be administered together. Examples of such agents used for cancer treatment can be found, for example, at https://www.cancer.gov/about-cancer/treatment/drugs (last accessed January 22, 2019) and in publicly available sources such as Cancer Principles and Practice of Oncology, 11th edition (2018), by VTDevita and S. Hellman (eds.), Lippincott Williams & Wilkins. It will be useful for those skilled in the art to be able to identify which combination of agents is appropriate based on the specific properties of the drugs and the disease being treated.

In one implementation, the treatment method includes co-administration of a compound as disclosed herein or a pharmaceutically acceptable salt thereof, and at least one immunotherapy. Immunotherapy (also known as biological response modulator therapy, biologic therapy, biological agent therapy, immune therapy, or biological therapy) is a therapy that uses a part of the immune system to fight disease. Immunotherapy can help the immune system recognize cancer cells or enhance the response to cancer cells. Immunotherapy includes active and passive immunotherapy. Active immunotherapy stimulates the body's own immune system, while passive immunotherapy typically uses components of the immune system produced outside the body.

Examples of active immunotherapy include, but are not limited to, vaccines, including cancer vaccines, tumor cell vaccines (autologous or allogeneic), dendritic cell vaccines, antigen vaccines, anti-idiotypic vaccines, DNA vaccines, viral vaccines, or tumor-infiltrating lymphocyte (TIL) vaccines with interleukin-2 (IL-2) or lymphokine-activated killer (LAK) cell therapy.

Examples of passive immunotherapy include, but are not limited to, monoclonal antibodies and targeted therapies containing toxins. Monoclonal antibodies include naked antibodies and conjugated monoclonal antibodies (also known as labeled, tagged, or loaded antibodies). Naked monoclonal antibodies do not have a drug or radioactive substance attached to them, while conjugated monoclonal antibodies are attached to, for example, chemotherapeutic drugs (chemically labeled), radioactive particles (radiolabeled), or toxins (immunotoxins). Examples of these naked monoclonal antibody drugs include, but are not limited to: rituximab (Rituxan), an antibody against the CD20 antigen used to treat, for example, B-cell non-Hodgkin lymphoma; trastuzumab (Herceptin), an antibody against the HER2 protein used to treat, for example, advanced breast cancer; alemtuzumab (Campath), an antibody against the CD52 antigen used to treat, for example, B-cell chronic lymphocytic leukemia (B-CLL); cetuximab (Erbitux), an antibody against the EGFR protein used, for example, in combination with irinotecan, to treat, for example, advanced colorectal cancer and head and neck cancer; and bevacizumab (Avastin), an anti-angiogenic therapy that acts on the VEGF protein and is used, for example, in combination with chemotherapy to treat, for example, metastatic colorectal cancer. Examples of conjugated monoclonal antibodies include, but are not limited to: the radiolabeled antibody teimozumab (Zevalin), which delivers radioactivity directly to cancerous B lymphocytes and is used to treat, for example, B-cell non-Hodgkin lymphoma; the radiolabeled antibody tosimomumab (Bexxar), which is used to treat, for example, certain types of non-Hodgkin lymphoma; and the immunotoxin gemtuzumab ozomicin (Mylotarg), which contains calcineurin and is used to treat, for example, acute myeloid leukemia (AML). BL22 is a conjugated monoclonal antibody used to treat, for example, hairy cell leukemia; an immunotoxin used to treat, for example, leukemia, lymphoma, and brain tumors; and radiolabeled antibodies (such as OncoScint for colorectal and ovarian cancer and ProstaScint for prostate cancer).

Other examples of therapeutic antibodies that may be used include, but are not limited to: HERCEPTIN ^™ (trastuzumab) (Genentech, Calif.), a humanized anti-HER2 monoclonal antibody for the treatment of patients with metastatic breast cancer; REOPRO.RTM. (abciximab) (Centocor), an anti-glycoprotein IIb/IIIa receptor on platelets to prevent clot formation; ZENAPAX ^™ (dalizumab) (Roche Pharmaceuticals, Switzerland), an immunosuppressive humanized anti-CD25 monoclonal antibody for the prevention of acute renal allogeneic transplant rejection; PANOREX ^™ , a mouse anti-17-IA cell surface antigen IgG2a antibody (Glaxo Wellcome/Centocor); BEC2, a mouse anti-idiotype (GD3 epitope) IgG antibody (ImClone System); IMC-C225, a chimeric anti-EGFR IgG antibody (ImClone System); VITAXIN ^™ This product is a humanized anti-αVβ3 integrin antibody (Applied Molecular Evolution/Medlmmune); Camppath 1H/LDP-03 is a humanized anti-CD52 IgG1 antibody (Leukosite); Smart M195 is a humanized anti-CD33 IgG antibody (Protein Design Lab/Kanebo); RITUXAN ^™ is a chimeric anti-CD20 IgG1 antibody (IDEC Pharm/Genentech, Roche/Zettyaku); LYMPHOCIDE ^™ is a humanized anti-CD22 IgG antibody (Immunomedics); LYMPHOCIDE ^™ Y-90 (Immunomedics); Lymphoscan (Tc-99m labeling; radiographic imaging; Immunomedics); Nuvion (targeting CD3; Protein Design Labs); CM3 is a humanized anti-ICAM3 antibody (ICOS). IDEC-114 is a primate-derived anti-CD80 antibody (IDEC Pharm/Mitsubishi); ZEVALIN ^™ is a radiolabeled mouse anti-CD20 antibody (IDEC/Schering AG); IDEC-131 is a humanized anti-CD40L antibody (IDEC/Eisai); IDEC-151 is a primate-derived anti-CD4 antibody (IDEC); IDEC-152 is a primate-derived anti-CD23 antibody (IDEC/Seikagaku); SMART anti-CD3 is a humanized anti-CD3 IgG (Protein Design Lab); 5G1.1 is a humanized anti-complement factor 5 (C5) antibody (AlexionPharm); D2E7 is a humanized anti-TNF-α antibody (CAT/BASF); CDP870 is a humanized anti-TNF-α antibody. Fab fragment (Celltech); IDEC-151 is a primate-modified anti-CD4 IgG1 antibody (IDEC Pharm/SmithKline Beecham); MDX-CD4 is a human anti-CD4 IgG antibody (Medarex/Eisai/Genmab); CD20-streptomycin protein (+Biotin-Yttrium 90; NeoRx); CDP571 is a human-modified anti-TNF-α IgG4 antibody (Celltech); LDP-02 is a human-modified anti-α4β7 antibody (LeukoSite/Genentech); OrthoClone OKT4A is a human-modified anti-CD4 IgG antibody (Ortho Biotech); ANTOVA™ is a human-modified anti-CD40L IgG antibody (Biogen); ANTEGREN ^™ is a human-modified anti-VLA-4 IgG antibody (Elan); CAT-152 is a human anti-TGF- _β2 antibody (Cambridge Ab Tech). Others are provided in later paragraphs.

Immunotherapy that can be used in combination with the compounds disclosed herein includes adjuvant immunotherapy. Examples include cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte-macrophage colony-stimulating factor (G-CSF), macrophage inflammatory protein (MIP)-1-α, interleukins (including IL-1, IL-2, IL-4, IL-6, IL-7, IL-12, IL-15, IL-18, IL-21, and IL-27), tumor necrosis factor (including TNF-α), and interferons (including IFN-α, IFN-β, and IFN-γ); aluminum hydroxide (alum); BCG; keyhole hemocyanin (KLH); Freund's incomplete adjuvant (IFA); QS-21; DETOX; levamisole; and dinitrophenyl (DNP), as well as combinations thereof, such as interleukins (e.g., IL-2) combined with other cytokines (such as IFN-α).

In various implementations, immunotherapies or immunotherapeutic agents may include one or more of the following: adoptive cell transfer, angiogenesis inhibitors, BCG therapy, biochemotherapy, cancer vaccines, chimeric antigen receptor (CAR) T-cell therapy, cytokine therapy, gene therapy, immune checkpoint modulators, immune conjugates, radioconjugates, oncolytic virus therapy, or targeted drug therapy. The function or at least one of the functions of immunotherapies or immunotherapeutic agents is collectively referred to herein as "immunotherapeutic agents".

This disclosure provides a method for preventing, treating, reducing, inhibiting, or controlling tumor formation, tumors, or cancer in a subject of need, the method comprising administering a therapeutically effective amount of a combination of a compound containing formula I' and an immunotherapeutic agent. In one non-limiting embodiment, the method comprises administering a therapeutically effective amount of a combination of a compound containing formula I' and an immunotherapeutic agent. In various embodiments, when treated with the combination, the combination provides a synergistic, additive, or additive effect in reducing the number of cancer cells compared to each treatment alone. In some embodiments, administration of a therapeutically effective amount of a combination of a compound containing formula I' and an immunotherapeutic agent produces synergistic antitumor activity and/or more potent antitumor activity than the additive effect of administering the compound of formula I' or the immunotherapeutic agent alone.

Human cancers exhibit numerous genetic and epigenetic alterations, generating neoantigens that can be recognized by the immune system (Sjoblom et al. (2006) Science 314:268-74). The adaptive immune system, composed of T and B lymphocytes, possesses potent anti-cancer potential, exhibiting a broad capacity and fine specificity to respond to a variety of tumor antigens. Furthermore, the immune system displays considerable plasticity and a memory component. Successfully utilizing all these properties of the adaptive immune system will make immunotherapy unique among all cancer treatment modalities.

This disclosure provides combinations of compounds of formula I' and immunotherapeutic agents. These exemplary combinations can be used to treat subjects with cancer. In various embodiments, immunotherapeutic agents found to be usable in the compositions, formulations, and methods of the present invention may include one or more agents or therapies, including: adoptive cell transfer, angiogenesis inhibitors, BCG therapy, biochemotherapy, cancer vaccines, chimeric antigen receptor (CAR) T-cell therapy, cytokine therapy, gene therapy, immune checkpoint modulators such as immune checkpoint inhibitors, immune conjugates, radioconjugates, oncolytic virus therapy, or targeted drug therapy.

In some embodiments of this disclosure, the therapeutically effective combination comprises a compound of formula I' and an immunotherapeutic agent. In various related embodiments, the compound of formula I' enhances the activity of the immunotherapeutic agent.

In certain embodiments of each of the foregoing aspects, as well as in other aspects and embodiments described elsewhere herein, the immunotherapeutic agent enhances the activity of compound I'.

In certain embodiments of each of the foregoing aspects, and in other aspects and embodiments described elsewhere herein, the compounds of formula I' and the immunotherapeutic agents act synergistically. In the various embodiments described herein, exemplary immunotherapeutic agents are immune cell (e.g., T cells, dendritic cells, natural killer cells, etc.) modulators selected from co-stimulatory molecules that act as agonists or activators, wherein the modulator is a monoclonal antibody, a bispecific antibody comprising one or more immune checkpoint antigen-binding moieties, a trispecific antibody, or an immune cell-binding multivalent antibody/fusion protein/construct known in the art. In some embodiments, the immunotherapeutic agent may be an antibody that modulates co-stimulatory molecules, binding to antigens on the surface of immune cells or cancer cells. In each of these different implementations, the antibody modulator can be a monoclonal antibody, a polyclonal antibody, a bispecific antibody, a trispecific or multispecific antibody, a fusion protein or a fragment thereof, such as a double-stranded antibody, a single-stranded (sc)-double-stranded antibody (scFv)2, a microantibody, a microbody, Barnase-barstar, scFv-Fc, sc(Fab)2, a trimer antibody construct, a triabody antibody construct, a trimer antibody construct, a tribody antibody construct, a collagen scaffold antibody construct, or a (scFv-TNFa)3 or F(ab)3/DNL antibody construct.

In certain embodiments of each of the foregoing aspects, and in other aspects and embodiments described elsewhere herein, the immunotherapeutic agent is an agent that modulates the immune response, such as a checkpoint inhibitor or checkpoint agonist. In some embodiments, the immunotherapeutic agent is an agent that enhances the antitumor immune response. In some embodiments, the immunotherapeutic agent is an agent that increases cell-mediated immunity. In some embodiments, the immunotherapeutic agent is an agent that increases T cell activity. In some embodiments, the immunotherapeutic agent is an agent that increases cytolytic T cell (CTL) activity. In some embodiments, the immunotherapeutic agent is an antibody modulator that targets PD-1, PD-L1, PD-L2, CEACAM (e.g., CEACAM-1, -3, and/or -5), CTLA-4, TIM-3, LAG-3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, TGFβ, OX40, 41BB, LIGHT, CD40, GITR, TGF-β, TIM-3, SIRP-α, VSIG8, BTLA, SIGLEC7, SIGLEC9, ICOS, B7H3, B7H4, FAS, and/or BTNL2, as well as other antibodies known in the art. In some embodiments, the immunotherapeutic agent is an agent that increases the activity of natural killer (NK) cells. In some embodiments, the immunotherapeutic agent is an agent that inhibits the suppression of the immune response. In some embodiments, the immunotherapeutic agent is an agent that inhibits the activity of suppressor cells or suppressor cell activity. In some embodiments, the immunotherapeutic agent is an agent or therapy that inhibits Treg activity. In some embodiments, the immunotherapeutic agent is an agent that inhibits the activity of inhibitory immune checkpoint receptors. In some embodiments, the combinations of this disclosure comprise a compound of formula I' and an immunotherapeutic agent, wherein the immunotherapeutic agent comprises a T-cell modulator selected from agonists or activators of co-stimulatory molecules. In one embodiment, the agonist of the co-stimulatory molecule is selected from GITR, OX40, ICOS, SLAM (e.g., SLAMF7), HVEM, LIGHT, CD2, CD27, CD28, CDS, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), 4-1BB (CD137), CD30, CD40, BAFFR, CD7, NKG2C, NKp80, CD160, B7-H3, or CD83 ligands (e.g., agonist antibodies or their antigen-binding fragments, or soluble fusions). In other embodiments, the effector cell combination includes a bispecific T cell adaptor (e.g., a bispecific antibody molecule that binds to CD3 and tumor antigens (e.g., EGFR, PSCA, PSMA, EpCAM, HER2, etc.)).

In some implementations, the immunotherapeutic agent is a modulator of PD-1 activity, PD-L1 activity, PD-L2 activity, CTLA-4 activity, CD28 activity, CD80 activity, CD86 activity, 4-1BB activity, OX40 activity, KIR activity, Tim-3 activity, LAG3 activity, CD27 activity, CD40 activity, GITR activity, TIGIT activity, or CD20 activity. Modulators of various activities, including CD96, IDO1, SIRP-α, TIGIT, VSIG8, BTLA, SIGLEC7, SIGLEC9, ICOS, B7H3, B7H4, FAS, BTNL2, cytokines, chemokines, interferons, interleukins, lymphokines, tumor necrosis factor (TNF) family members, and immunostimulatory oligonucleotides. In some embodiments, the immunotherapeutic agent is an immune checkpoint modulator (e.g., an immune checkpoint inhibitor, such as an inhibitor of PD-1 activity, a modulator of PD-L1 activity, a modulator of PD-L2 activity, a modulator of CTLA-4, or a CD40 agonist (e.g., an anti-CD40 antibody molecule), (xi)OX40 agonist (e.g., an anti-OX40 antibody molecule), or (xii)CD27 agonist (e.g., an anti-CD27 antibody molecule). In one embodiment, the immunomodulator is PD-1, PD-L1 Inhibitors of PD-L2, CTLA-4, TIM-3, LAG-3, CEACAM (e.g., CEACAM-1, -3, and/or -5), VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, and/or TGFβ. In one embodiment, the inhibitors of immune checkpoint molecules inhibit PD-1, PD-L1, LAG-3, TIM-3, CEACAM (e.g., CEACAM-1, -3, and/or -5), CTLA-4, or any combination thereof.

Inhibition of inhibitory molecules can occur at the DNA, RNA, or protein level. In some embodiments, inhibitory nucleic acids (e.g., dsRNA, siRNA, or shRNA) can be used to inhibit the expression of inhibitory molecules. In other embodiments, the inhibitor of the inhibitory signal is a peptide, such as a soluble ligand (e.g., PD-1-Ig or CTLA-4Ig); or an antibody or an antigen-binding fragment thereof, such as a monoclonal antibody, a bispecific antibody containing one or more immune checkpoint antigen-binding moieties, a trispecific antibody; or an immune cell-conjugating multivalent antibody/fusion protein/construct known in the art that binds to an inhibitory molecule; for example, an antibody or fragment thereof (also referred to herein as an "antibody molecule") that binds to PD-1, PD-L1, PD-L2, CEACAM (e.g., CEACAM-1, -3, and/or -5), CTLA-4, TIM-3, LAG-3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, TGFβ, or combinations thereof.

In some embodiments, the combination comprises a compound of formula I' and an immunotherapeutic agent, wherein the immunotherapeutic agent is a monoclonal antibody or a bispecific antibody. For example, the monoclonal or bispecific antibody may specifically bind to a member of the c-Met pathway and/or an immune checkpoint modulator (e.g., a bispecific antibody that binds both the hepatocyte growth factor receptor (HGFR) and the immune checkpoint modulator described herein, such as antibodies that bind to PD-1, PD-L1, PD-L2, or CTLA-4, LAG-3, OX40, 41BB, LIGHT, CD40, GITR, TGF-β, TIM-3, SIRP-α, TIGIT, VSIG8, BTLA, SIGLEC7, SIGLEC9, ICOS, B7H3, B7H4, FAS, BTNL2, or CD27). In a specific embodiment, the bispecific antibody specifically binds to the human HGFR protein and one of PD-1, PD-L1, and CTLA-4.

In some embodiments, the immunotherapeutic agent is a cytokine, such as a chemokine, interferon, interleukin, lymphokine, or a member of the tumor necrosis factor family. In some embodiments, the cytokine is IL-2, IL-15, or interferon-γ.

In some embodiments of any of the foregoing aspects or those described elsewhere herein, the cancer is selected from lung cancer, pancreatic cancer, breast cancer, colon cancer, colorectal cancer, melanoma, gastrointestinal cancer, stomach cancer, kidney cancer, ovarian cancer, liver cancer, endometrial cancer, kidney cancer, prostate cancer, thyroid cancer, neuroblastoma, glioma, glioblastoma multiforme, cervical cancer, stomach cancer, bladder cancer, head and neck cancer, and liver cancer.

In some implementations of any of the foregoing aspects or those described elsewhere herein, the subject's cancer or tumor does not respond to immune checkpoint inhibition (e.g., to any immune checkpoint inhibitor described herein, such as a PD-1 antagonist or a PD-L1 antagonist), or the subject's cancer or tumor has progressed after an initial response to immune checkpoint inhibition (e.g., to any immune checkpoint inhibitor described herein, such as a PD-1 antagonist or a PD-L1 antagonist).

In some implementations of any of the foregoing aspects or those described elsewhere herein, the subject is a human being.

Checkpoint inhibitors can be any molecule, agent, treatment, and/or method that has the following effects: inhibiting immune checkpoints, and/or promoting immune checkpoint inhibitors, for example, by promoting intrinsic immune checkpoint inhibitors; inhibiting transcription factors involved in immune checkpoint expression; and/or by acting in synergy with some additional extrinsic factors. For example, checkpoint inhibitors may include treatments that inhibit transcription factors involved in the expression of immune checkpoint genes or promote the expression of transcription factors of tumor suppressor genes such as BACH2 (Luan et al., (2016). Transcription Factors and Checkpoint Inhibitor Expression with Age: Markers of Immunosenescence. Blood, 128(22), 5983). In addition, checkpoint inhibitors can inhibit: transcription of immune checkpoint genes; modification and/or processing of immune checkpoint mRNAs; translation of immune checkpoint proteins; and/or activation of molecules involved in the immune or immune checkpoint pathways, such as PD-1 transcription factors like HIF-1, STAT3, NF-κB, and AP-1, or common oncogenic pathways such as JAK/STAT, RAS/ERK, or PI3K/AKT/mTOR (Zerdes et al., Genetic, transcriptional and post-translational regulation of the programmed death protein ligand 1 in cancer: biology and clinical correlations, Oncogene, Vol. 37, pp. 4639-4661 (2018), the full text of which is incorporated herein by reference).

Checkpoint inhibitors can include therapies, molecules, agents, and/or methods that regulate immune checkpoints at the transcriptional level, such as using co-inhibition of RNA interference pathways and/or post-transcriptional gene silencing (PTGS) (e.g., microRNAs, miRNAs; silenced RNAs, small interfering RNAs, or short interfering RNAs (siRNAs)). Transcriptional regulation of checkpoint molecules has been shown to involve mir-16, which has been shown to target the 3'UTR of checkpoint mRNAs CD80, CD274 (PD-L1), and CD40 (Leibowitz et al., Post-transcriptional regulation of immune checkpoints). oint genes by mir-16 in melanoma, Annals of Oncology (2017) 28; v428-v448). Mir-33a has also been shown to be involved in regulating PD-1 expression in lung adenocarcinoma cases (Boldini et al., Role of microRNA-33a in regulating the expression of PD-1 in lung adenocarcinoma, Cancer Cell Int. 2017; 17:105, the full text of which is cited in this article).

T-cell specific aptamer-siRNA chimeras have been proposed as a highly specific method for inhibiting molecules in the immune checkpoint pathway (Hossain et al., The aptamer–siRNA conjugates: reprogramming T cells for cancer therapy, Ther. Deliv., January 2015; 6(1):1–4, the full text of which is cited in this paper).

Alternatively, treatments affecting related pathways (e.g., metabolism) can be used to suppress members of the immune checkpoint pathway. For example, CAD macrophages oversupply pyruvate, a glycolytic intermediate, in mitochondria, promoting PD-L1 expression via the induction of the bone morphogenetic protein 4/phosphorylated SMAD1/5/IFN regulator 1 (BMP4/p-SMAD1/5/IRF1) signaling pathway. Thus, implementing treatments that regulate metabolic pathways can lead to subsequent regulation of the immunosuppressive PD-1/PD-L1 checkpoint pathway (Watanabe et al., Pyruvate controls the checkpoint inhibitor PD-L1 and suppresses T cell immunity, J Clin Invest., 30 June 2017; 127(7):2725–2738).

Checkpoint immunity can be regulated by oncolytic viruses that selectively replicate within tumor cells and induce an acute immune response in the tumor microenvironment. This is achieved by acting as genetic vectors carrying agents specific to cancer cells (e.g., antibodies, miRNAs, siRNAs, etc.) and influencing their oncolytic activity, as well as the secretion of cytokines and chemokines, in synergistic effects with immune checkpoint inhibition (Shi et al., Cancer Immunotherapy: A Focus on the Regulation of Immune Checkpoints, Int J Mol Sci., May 2018; 19(5):1389). Currently, ongoing clinical trials utilize the following viruses as checkpoint inhibitors: poliovirus, measles virus, adenovirus, poxvirus, herpes simplex virus (HSV), Coxsackievirus, reovirus, Newcastle disease virus (NDV), T-VEC (herpesvirus encoded by GM-CSF (granulocyte-macrophage colony-stimulating factor)) and H101 (Shi et al., ibid.).

Checkpoint inhibitors can act at the translational level of checkpoint immunity. Translation from mRNA to protein represents a key event in gene expression regulation; therefore, inhibiting immune checkpoint translation is a method to suppress the immune checkpoint pathway.

Inhibition of the immune checkpoint pathway can occur at any stage of the immune checkpoint translation process. For example, drugs, molecules, agents, treatments, and/or methods can inhibit the initiation process (whereby the 40S ribosomal subunit is recruited to the 5' end of the mRNA and scans the 5'UTR of the mRNA toward its 3' end). Inhibition can occur by targeting the anticodon of the initiator methionyl transfer RNA (tRNA) (Met-tRNAi, which pairs with the start codon) or by recruiting the 60S subunit to begin elongation and sequentially adding amino acids in the translation of immune checkpoint-specific genes. Alternatively, checkpoint inhibitors can inhibit checkpoints at the translational level by preventing the formation of the ternary complex (TC), namely eukaryotic initiation factor (eIF)2 (or one or more of its α, β, and γ subunits), GTP, and Met-tRNAi.

Checkpoint inhibition can occur through the destabilizing effect of eIF2α, i.e., by preventing its phosphorylation via protein kinase R (PKR), PERK, GCN2, or HRI, or by preventing TC from binding to the 40S ribosome and/or other initiation factors, thereby preventing the formation of the pre-initiation complex (PIC); and by inhibiting the eIF4F complex and/or its cap-binding protein eIF4E, scaffold protein eIF4G, or eIF4A helicase. Methods for translational control in cancer are discussed in Truitt et al., New frontiers intranslational control of the cancer genome, Nat Rev Cancer., April 26, 2016; 16(5):288–304, the full text of which is incorporated herein by reference.

Checkpoint inhibitors may also include, for example, therapies, molecules, agents, and/or methods that modulate immune checkpoints at the cellular and/or protein level by inhibiting immune checkpoint receptors. Inhibition of checkpoints can occur through the use of antibodies, antibody fragments, antigen-binding fragments, small molecules, and/or other drugs, agents, therapies, and/or methods.

Immune checkpoints are inhibitory pathways within the immune system responsible for maintaining self-tolerance and modulating the immune response to minimize damage to peripheral tissues. However, tumor cells can also activate immune system checkpoints, reducing the effectiveness of the immune response against tumor tissue (“blocking” the immune response). Unlike most anticancer agents, checkpoint inhibitors do not directly target tumor cells but rather lymphocyte receptors or their ligands to enhance the endogenous antitumor activity of the immune system (Pardoll, 2012, Nature Reviews Cancer 12:252-264).

Until recently, cancer immunotherapy has largely focused on enhancing antitumor immune responses through adoptive transfer of activated effector cells, immunization against relevant antigens, or the delivery of nonspecific immunostimulants such as cytokines. However, in the past decade, significant efforts to develop specific immune checkpoint pathway inhibitors have begun to offer novel immunotherapies for cancer treatment, including the development of the antibody (Ab) ipilimumab (YERVOY.RTM.) which binds to and inhibits CTLA-4 for the treatment of patients with advanced melanoma (Hodi et al., (2010) N Engl J Med 363:711-23) and antibodies that specifically bind to the programmed death-1 (PD-1) receptor and block the inhibitory PD-1/PD-1 ligand pathway, such as nivolumab and pembrolizumab (formerly known as lambolizumab; USAN Council Statement (2013) Pembrolizumab: Statement on a nonproprietary name adopted). Developed by the USAN Council (ZZ-165), November 27, 2013 (Topalian et al. (2012a) N Engl J Med 366:2443-54; Topalian et al. (2012b) Curr Opin Immunol 24:207-12; Topalian et al. (2014) J Clin Oncol 32(10):1020-30; Hamid et al. (2013) N Engl J Med 369:134-144; Hamid and Carvajal (2013) Expert Opin Biol Ther 13(6):847-61; McDermott and Atkins (2013) Cancer Med 2(5):662-73).

PD-1 is a key immune checkpoint receptor expressed by activated T and B cells and mediates immunosuppression. Nivolumab (formerly known as 5C4, BMS-936558, MDX-1106, or ONO-4538) is a fully human IgG4 (S228P) PD-1 immune checkpoint inhibitor antibody that selectively prevents interaction with PD-1 ligands (PD-L1 and PD-L2), thereby blocking the downregulation of anti-tumor T cell function (US Patent No. 8,008,449; Wang et al. (2014) In vitro characterization of the anti-PD-1 antibody nivolumab, BMS-936558, and in vivo toxicology in non-human primates). Nivolumab has been approved for the treatment of patients with unresectable or metastatic melanoma who have progressed after ipilimumab treatment, and if BRAF V600 mutation is positive, BRAF inhibitors used to treat squamous non-small cell lung cancer are used.

Recent data suggest a secondary mechanism of anti-CTLA-4 antibodies that may occur within the tumor itself. CTLA-4 has been found to be expressed at higher levels on regulatory T cells (also referred to herein as "Treg cells") in tumors compared to effector T cells (also referred to herein as "Teff cells"), leading to the hypothesis that anti-CTLA-4 preferentially affects Treg cells. (See "Therapeutic use of anti-CTLA-4 antibodies," Christian U. Blank and Alexander Enk, International Immunology, Vol. 27, No. 1, pp. 3-10). Recent studies of the combination of PD-1 and CTLA-4 have shown that combined blocking of the CTLA-4 and PD-1 pathways also synergistically increases the ratio of Teff cells to regulatory T cells and MDSCs, thereby reducing suppression and promoting inflammation in the tumor microenvironment. "Combination of CTLA-4 and PD-1 blockade expands infiltrating T-cells and reduces regulatory T and myeloid cells within B16 melanoma tumors," Curran et al., PNAS | March 2, 2010; Vol. 107 (No. 9); pp. 4275-4280, the full text of which is incorporated herein by reference. Combinations of checkpoint inhibitors and other therapeutic agents can enhance or prolong the antitumor response of checkpoint inhibitors and/or the effects of therapeutic agents. In this regard, WO 2015/069770 discloses combination therapies based on activating adaptive immune responses for the treatment of cancer, particularly combinations of CTLA-4 and PD-1 inhibitors. The full text of the disclosure of WO 2015/069770 is incorporated herein by reference.

One mechanism by which checkpoint blocking anti-CTLA-4 antibodies mediate antitumor effects is through the reduction of regulatory T cells. Due to the unique mechanism of action of anti-CTLA-4 antibodies, they can be successfully combined with anti-PD1 checkpoint blocking antibodies to exert their effects by releasing inhibitory signaling conferred on effector T cells. The dual blocking combination of these antibodies has been shown to improve antitumor responses in preclinical (ProcNatl Acad Sci USA 2010, 107, 4275-4280) and clinical (N Engl J Med 2013, 369, 122-133; N Engl J Med 2015, 372, 2006-2017).

CTLA-4 attenuates early activation of naive and memory T cells through interactions with its ligands B7-1 (CD80) and B7-2 (CD86). PD-1 is a receptor expressed on the surface of activated mature T cells, activated NK cells, B cells, monocytes, and various normal tissues, and plays a key role in maintaining peripheral tolerance [20-21]. In contrast to CTLA-4, PD-1 functions through its interaction with its ligand PD-L1 (also known as B7-H1 or CD274) and is primarily involved in regulating T cell activity in peripheral tissues and providing key immune resistance mechanisms within the tumor microenvironment.

In some implementations, the immunotherapeutic agent is a modulator of PD-1 activity, a modulator of PD-L1 activity, a modulator of PD-L2 activity, a modulator of CTLA-4 activity, a modulator of CD28 activity, a modulator of CD80 activity, a modulator of CD86 activity, a modulator of 4-1BB activity, a modulator of OX40 activity, a modulator of KIR activity, a modulator of Tim-3 activity, a modulator of LAG3 activity, a modulator of CD27 activity, a modulator of CD40 activity, a modulator of GITR activity, a modulator of TIGIT activity, a modulator of CD20 activity, a modulator of CD96 activity, a modulator of IDO1 activity, a cytokine, a chemokine, an interferon, an interleukin, a lymphokine, a member of the tumor necrosis factor (TNF) family, or an immunostimulatory oligonucleotide. In some implementations, the immune checkpoint modulator is, for example, an inhibitor or antagonist, or an activator or agonist, such as a CD28 modulator, a 4-1BB modulator, an OX40 modulator, a CD27 modulator, a CD80 modulator, a CD86 modulator, a CD40 modulator, or a GITR modulator, a Lag-3 modulator, a 41BB modulator, a LIGHT modulator, a CD40 modulator, a GITR modulator, a TGF-β modulator, a TIM-3 modulator, a SIRP-α modulator, a TIGIT modulator, a VSIG8 modulator, a BTLA modulator, a SIGLEC7 modulator, a SIGLEC9 modulator, an ICOS modulator, a B7H3 modulator, a B7H4 modulator, a FAS modulator, and/or a BTNL2 modulator. In some embodiments, the immunotherapeutic agent is an immune checkpoint modulator as described above (e.g., an immune checkpoint modulator antibody, which may be a monoclonal antibody, a bispecific antibody containing one or more immune checkpoint antigen-binding moieties, a trispecific antibody, or in the form of an immune cell-conjugating multivalent antibody/fusion protein/construct known in the art).

Combination therapy with immune checkpoint inhibitor immunotherapies can include antibodies that specifically target immune system checkpoints such as CTLA4, PD1, and PD-L1, representing one of the most promising new avenues for immunotherapy in cancer and other diseases. Additional checkpoint targets such as TIM-3, LAG-3, various B-7 ligands, CHK1 and CHK2 kinases, BTLA, and A2aR are also under investigation. Currently, three checkpoint inhibitors have received fast-track approval from the U.S. Food and Drug Administration for cancer treatment: ipilimumab, a CTLA-4 inhibitor, and pembrolizumab and nivolumab, both PD-1 inhibitors. Several other checkpoint inhibitors are also in clinical trials.

Programmed cell death protein 1 (PD-1 or CD279), a 55-kD type I transmembrane protein, is a member of the CD28 family of T cell costimulatory receptors, which includes immunoglobulin superfamily members CD28, CTLA-4, inducible costimulatory factor (ICOS), and BTLA. PD-1 is highly expressed on activated T cells and B cells. PD-1 expression can also be detected on memory T cell subsets with variable expression levels. Two PD-1-specific ligands have been identified: programmed death ligand 1 (PD-L1, also known as B7-H1 or CD274) and PD-L2 (also known as B7-DC or CD273). In both mouse and human systems, PD-L1 and PD-L2 show downregulation of T cell activation upon binding to PD-1 (Okazaki et al., Int Immunol., 2007; 19:813-824). The interaction between PD-1 and its ligands PD-L1 and PD-L2 (expressed on antigen-presenting cells (APCs) and dendritic cells (DCs) transmits negative regulatory stimuli, downregulating the activated T cell immune response. Blocking PD-1 inhibits this negative signaling and amplifies the T cell response.

Numerous studies have shown that the cancer microenvironment manipulates the PD-L1-/PD-1 signaling pathway, and the induction of PD-L1 expression is associated with the suppression of the immune response against cancer, thereby enabling cancer progression and metastasis. The PD-L1/PD-1 signaling pathway is a major mechanism for cancer immune escape for several reasons. First, and most importantly, this pathway is involved in the negative regulation of the immune response of activated T effector cells found in the periphery. Second, PD-L1 is upregulated in the cancer microenvironment, while PD-1 is also upregulated on activated tumor-infiltrating T cells, potentially enhancing the vicious cycle of suppression. Third, this pathway is complexly involved in the regulation of both innate and adaptive immunity through bidirectional signaling. These factors make the PD-1/PD-L1 complex a central point through which cancer can manipulate the immune response and promote its own progression.

CTLA-4 (also known as cytotoxic T-lymphocyte-associated protein 4, CTLA4, CTLA-4, CD152, differentiation cluster 152; ALPS5, CD, CELIAC3, GRD4, GSE, and IDDM12) is a 24.6-kDa single-pass type I membrane protein that plays an inhibitory role in T cell function. CTLA-4 was initially identified by differential screening of a mouse cytotoxic T cell cDNA library; see Brunet et al., A new member of the immunoglobulin superfamily--CTLA-4, Nature., July 16-22, 1987; 328(6127):267-70. CTLA-4 has been shown to interact with b7 family ligands CD80 (also known as differentiation cluster 80 and B7-1) and CD86 (also known as differentiation cluster 86 or B7-2). See Linsley et al., CTLA-4 is a second receptor for the B cell activation antigen B7, J Exp Med., 1 Sep 1991; 174(3):561-9. Sequence comparison between the human CTLA-4 DNA coding region and the CD28 DNA coding region revealed significant homology between the two sequences, with the greatest similarity between the juxtamembranous and cytoplasmic regions; therefore, CTLA-4 is associated with the elimination/reduction of T cell activity and antagonism of CD28 activity. Mice lacking CTLA-4 have been shown to exhibit extensive lymphoproliferation. Chambers et al., Lymphoproliferation in CTLA-4-deficient mice is mediated by costimulation-dependent activation of CD4+ T cells, Immunity., Dec 1997; 7(6):885-95. It has been reported that CTLA-4 blockade enhances T cell responses, induces autoimmune diseases, and exacerbates antitumor immunity both in vitro and in vivo. (See Luhder, J. Exp. Med. 1998; 187:427-432; Walunas et al., Immunity. 1994; 1:405-413; Kearney, J. Immunol. 1995; 155:1032-1036; Leach, Science 1996; 271:1734-1736). CTLA-4 has also been reported to have alternative and/or additional effects on the initial characteristics of T-cell immune responses (Chambers, Curr. Opin. Immunol. 1997; 9:396-404; Bluestone, J. Immunol. 1997; 158:1989-1993; Thompson, Immunity 1997; 7:445-450).

The first immune checkpoint inhibitor to be tested in clinical trials is Yervoy (Bristol-Myers Squibb), a CTLA-4 mAb. CTLA-4 belongs to the receptor immunoglobulin superfamily, which also includes PD-1, BTLA, TIM-3, and T cell activation V-domain immunoglobulin inhibitor (VISTA). Anti-CTLA-4 mAbs are potent checkpoint inhibitors that remove “breakdowns” from naïve cells and antigen-treated cells. The therapy enhances the anti-tumor function of CD8+ T cells, increases the ratio of CD8+ T cells to Foxp3+ T regulatory cells, and inhibits the suppressive function of T regulatory cells. The main drawback of anti-CTLA-4 mAb therapy is autoimmune toxicity due to the on-target effects of an overactive immune system that has lost its self-regulation. It has been reported that up to 25% of patients treated with ipilimumab experienced serious grade 3-4 adverse events/autoimmune side effects, including dermatitis, enterocolitis, hepatitis, endocrine disorders (including hypophysitis, thyroiditis, and adrenalitis), arthritis, uveitis, nephritis, and aseptic meningitis. In contrast to the experience with anti-CTLA-4 therapy, anti-PD-1 therapy appears to be better tolerable and induces a relatively low rate of autoimmune side effects.

In some embodiments, the immunotherapy agent is an agent that inhibits PD-1 activity. In some embodiments, the immunotherapy agent is an agent that inhibits PD-L1 and/or PD-L2 activity. In some embodiments, the immunotherapy agent is an agent that inhibits CTLA-4 activity. In some embodiments, the immunotherapy agent is an agent that inhibits CD80 and/or CD86 activity. In some embodiments, the immunotherapy agent is an agent that inhibits TIGIT activity. In some embodiments, the immunotherapy agent is an agent that inhibits KIR activity. In some embodiments, the immunotherapy agent is an agent that enhances or stimulates the activity of activated immune checkpoint receptors.

In some embodiments of the methods described herein, the immunotherapeutic agent is a PD-1 antagonist, PD-L1 antagonist, PD-L2 antagonist, CTLA-4 antagonist, CD80 antagonist, CD86 antagonist, KIR antagonist, Tim-3 antagonist, LAG3 antagonist, TIGIT antagonist, CD20 antagonist, CD96 antagonist, or IDO1 antagonist.

In some implementations, the PD-1 antagonist is an antibody that specifically binds to PD-1. In some implementations, the PD-1-binding antibody is pembrolizumab (MK-3475; Merck), pidilizumab (CT-011; Curetech Ltd.), nivolumab (BMS-936558, MDX-1106; Bristol Myer Squibb), MEDI0680 (AMP-514; AstraZenenca/MedImmune), REGN2810 (Regeneron Pharmaceuticals), BGB-A317 (BeiGene Ltd.), PDR-001 (Novartis), or STI-A1110 (Sorrento Therapeutics). In some embodiments, antibodies binding to PD-1 are described in PCT Publication WO2014/179664, for example, antibodies identified as APE2058, APE1922, APE1923, APE1924, APE 1950, or APE1963 (Anaptysbio), or antibodies containing the CDR region of any of these antibodies. In other embodiments, the PD-1 antagonist is a fusion protein including the extracellular domain of PD-L1 or PD-L2, such as AMP-224 (AstraZeneca/MedImmune). In other embodiments, the PD-1 antagonist is a peptide inhibitor, such as AUNP-12 (Aurigene).

In some embodiments, the PD-L1 antagonist is an antibody that specifically binds to PD-L1. In some embodiments, the antibody binding to PD-L1 is atezolizumab (RG7446, MPDL3280A; Genentech), MEDI4736 (AstraZeneca/MedImmune), BMS-936559 (MDX-1105; Bristol Myers Squibb), avelumab (MSB0010718C; Merck KGaA), KD033 (Kadmon), an antibody fraction of KD033, or STI-A1014 (Sorrento Therapeutics). In some implementations, antibodies binding to PD-L1 are described in PCT Publication WO 2014/055897, such as Ab-14, Ab-16, Ab-30, Ab-31, Ab-42, Ab-50, Ab-52, Ab-55, or antibodies containing the CDR region of any of these antibodies, the entire contents of which are incorporated herein by reference.

In some embodiments, the CTLA-4 antagonist is an antibody that specifically binds to CTLA-4. In some embodiments, the antibody binding to CTLA-4 is ipilimumab (Bristol Myer Squibb) or tremelimumab (CP-675,206; Pfizer). In some embodiments, the CTLA-4 antagonist is a CTLA-4 fusion protein or a soluble CTLA-4 receptor, such as KARR-102 (Kahr Medical Ltd.).

In some embodiments, the LAG3 antagonist is an antibody that specifically binds to LAG3. In some embodiments, the LAG3-binding antibody is IMP701 (Prima BioMed), IMP731 (Prima BioMed/GlaxoSmithKline), BMS-986016 (Bristol Myer Squibb), LAG525 (Novartis), and GSK2831781 (GlaxoSmithKline). In some embodiments, the LAG3 antagonist comprises a soluble LAG3 receptor, such as IMP321 (Prima BioMed).

In some embodiments, the KIR antagonist is an antibody that specifically binds to a KIR. In some embodiments, the KIR-binding antibody is lirilumab (Bristol Myer Squibb/Innate Pharma).

In some embodiments, the immunotherapeutic agents used in the combinations disclosed herein (e.g., combinations with compounds of formula I') are activators or agonists of co-stimulatory molecules. In one embodiment, the agonist of the co-stimulatory molecule is selected from agonists of OX40, CD2, CD27, CD28, CDS, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3, or CD83 ligands (e.g., agonist antibodies or their antigen-binding fragments, or soluble fusions).

In some embodiments, the OX40 agonist comprises an OX40 ligand or its OX40-binding moiety. For example, the OX40 agonist may be MEDI6383 (AstraZeneca). In some embodiments, the OX40 agonist is an antibody that specifically binds to OX40. In some embodiments, the antibody binding to OX40 is MEDI6469 (AstraZeneca/MedImmune), MEDI0562 (AstraZeneca/MedImmune), or MOXR0916 (RG7888; Genentech). In some embodiments, the OX40 agonist is a vector capable of expressing the OX40 ligand (e.g., an expression vector or a virus, such as adenovirus). In some embodiments, the vector expressing OX40 is Delta-24-RGDOX (DNAtrix) or DNX2401 (DNAtrix).

In some embodiments, the 4-1BB (CD137) agonist is a binding molecule, such as an anticalin. In some embodiments, the anti-carrier protein is PRS-343 (Pieris AG). In some embodiments, the 4-1BB agonist is an antibody that specifically binds to 4-1BB. In some embodiments, the antibody that binds to 4-1BB is PF-2566 (PF-05082566; Pfizer) or urelumab (BMS-663513; Bristol Myer Squibb).

In some embodiments, the CD27 agonist is an antibody that specifically binds to CD27. In some embodiments, the antibody that binds to CD27 is varlilumab (CDX-1127; Celldex).

In some embodiments, the GITR agonist comprises a GITR ligand or its GITR-binding moiety. In some embodiments, the GITR agonist is an antibody that specifically binds to GITR. In some embodiments, the antibody that binds to GITR is TRX518 (GITR, Inc.), MK-4166 (Merck), or INBRX-110 (Five Prime Therapeutics/Inhibrx).

TIM-3 has been identified as another important inhibitory receptor expressed by exhausted CD8+ T cells. In mouse models of cancer, it has been shown that the most dysfunctional tumor-infiltrating CD8+ T cells actually co-express PD-1 and TIM-3.

LAG-3 is another recently identified inhibitory receptor that limits effector T cell function and increases the inhibitory activity of regulatory T cells. It has recently been revealed that PD-1 and LAG-3 are widely co-expressed by tumor-infiltrating T cells in mice, and that combined blockade of PD-1 and LAG-3 elicits a potent synergistic antitumor immune response in a mouse cancer model.

PD-1 pathway blockade can be combined with vaccines or other I’ antibody compounds to enhance therapeutic efficacy (Hirano, F. et al., Cancer Res., 65(3):1089-1096 (2005); Li, B. et al., Clin. Cancer Res., 15:1507-1509 (2009); and Curran, M.A. et al., Proc. Natl. Acad. Set, 107(9):4275-4280 (2010)).

In some embodiments, the immunotherapeutic agent used in the compositions and methods described herein may include a monoclonal antibody, a bispecific antibody comprising one or more immune checkpoint antigen-binding moieties, a trispecific antibody, or an immune cell-conjugating multivalent antibody/fusion protein/construct known in the art that specifically targets both PD-1 and its ligand PD-L1.

PD-1 (also known as programmed death 1, CD279, or PDCD1) is a cell surface receptor that plays a crucial role in regulating the balance between stimulatory and inhibitory signals in the immune system and maintaining peripheral tolerance (Ishida, Y et al., 1992 EMBO J.11 3887; Kier, Mary E et al., 2008 Annu Rev Immunol 26 677-704; Okazaki, Taku et al., 2007 International Immunology 19 813-824). PD-1 is an inhibitory member of the immunoglobulin superfamily, homologous to CD28. PD-1 is a monomeric type 1 transmembrane protein consisting of an immunoglobulin-variable extracellular domain and cytoplasmic domains containing an immunoreceptor tyrosine-based inhibitory motif (ITIM) and an immunoreceptor tyrosine-based switch motif (ITSM). PD-1 expression is inducible on T cells, B cells, natural killer (NK) cells, and monocytes, for example, after activation of lymphocytes via T cell receptor (TCR) or B cell receptor (BCR) signaling (Kier, Mary E et al., 2008 Annu Rev Immunol 26 677-704; Agata, Y et al., 1996 Int Immunol 8 765-72). PD-1 is the receptor for ligands CD80, CD86, PD-L1 (B7-H1, CD274), and PD-L2 (B7-DC, CD273), which are cell surface expression members of the B7 family (Freeman, Gordon et al., 2000 J Exp Med 1921027; Latchman, Y et al., 2001 Nat Immunol 2 261). Upon ligand binding, PD-1 recruits phosphatases such as SHP-1 and SHP-2 to their intracellular tyrosine motifs, subsequently dephosphorylating effector molecules activated by TCR or BCR signaling (Chemnitz, J et al., 2004 J Immunol 173 945-954; Riley, James L 2009 Immunological Reviews 229 114-125). Thus, PD-1 transduces inhibitory signals to T cells and B cells only when simultaneously bound to TCR or BCR.

PD-1 has been shown to downregulate effector T cell responses through both intrinsic and extracellular functional mechanisms. Inhibitory signaling by PD-1 induces a non-responsive state in T cells, resulting in clonal expansion or failure to produce optimal levels of effector cytokines. PD-1 can also induce T cell apoptosis through its ability to inhibit survival signals from co-stimuli, leading to decreased expression of key anti-apoptotic molecules such as Bcl-XL (Kier, Mary E et al., 2008 Annu Rev Immunol 26 677-704). In addition to these direct effects, recent publications have suggested that PD-1 participates in effector cell suppression by promoting the induction and maintenance of regulatory T cells (TREGs). For example, PD-L1 expressed on dendritic cells has been shown to synergize with TGF-β to promote the induction of CD4+FoxP3+ TREGs with enhanced inhibitory function (Francisco, Loise M et al., 2009 J Exp Med 206 3015-3029).

TIM-3 (also known as T cell immunoglobulin and mucin-containing domain-3, TIM-3, hepatitis A virus cell receptor 2, HAVCR2, HAVcr-2, KIM-3, TIMD-3, TIMD3, Tim-3 and CD366) is a 33.4-kDa single-pass type I membrane protein involved in the immune response (Sanchez-Fueyo et al., Tim-3 inhibits T helper type 1-mediated auto- and alloimmune responses and promotes immune tolerance, Nat. Immunol. 4:1093-1101 (2003)).

TIM-3 is selectively expressed on Th1 cells and phagocytes (e.g., macrophages and dendritic cells). Lowering human expression using siRNA or blocking antibodies leads to increased secretion of interferon-γ (IFN-γ) from CD4-positive T cells, suggesting an inhibitory role of TIM-3 in human T cells. Analysis of clinical samples from patients with autoimmune diseases showed no TIM-3 expression in CD4-positive cells. In particular, T-cell clones derived from the cerebrospinal fluid of multiple sclerosis patients showed lower levels of TIM-3 expression and higher levels of IFN-γ secretion compared to clones derived from healthy individuals (Koguchi K et al., JExp Med. 203:1413-8. (2006)).

TIM-3 is the receptor for galactoglobulin-9, a ligand of a member of the galactoglobulin family, which is a molecule universally expressed in multiple cell types and binds to the following molecules: β-galactoside; phosphatidylserine (PtdSer) (DeKryff et al., T cell/transmembrane, Ig, and mucin-3 allelelic variants differentially recognize phosphatidylserine and immediate phagocytosis of apoptotic cells, J Immunol., 15 Feb 2010; 184(4):1918-30); high-mobility group box 1 (also known as HMGB1, HMG1, HMG3, SBP-1, HMG-1 and high-mobility group box 1) (Chiba et al., Tumor-i Filtrating DCs suppresses nucleic acid-mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1, Nat Immunol., Sep 2012; 13(9):832-42); and carcinoembryonic antigen-associated cell adhesion molecule 1 (also known as CEACAM1, BGP, BGP1, BGPI, carcinoembryonic antigen-associated cell adhesion molecule 1) (Huang et al., CEACAM1 regulates TIM-3-mediated tolerance and exhaustion, Nature., Jan 15 2015; 517(7534):386-90).

BTLA (also known as B- and T-lymphocyte attenuators, BTLA1, CD272, and B- and T-lymphocyte-associated) is a 27.3-kDa single-pass type I membrane protein involved in lymphocyte suppression during the immune response. BTLA is constitutively expressed in both B cells and T cells. BTLA interacts with HVEM (herpesvirus entry mediator), a member of the tumor necrosis factor receptor (TNFR) family (Gonzalez et al., Proc. Natl. Acad. Sci. USA, 2005, 102:1116-21). The interaction between BTLA (belonging to the CD28 family of immunoglobulins) and HVEM (co-stimulatory tumor necrosis factor (TNF) receptor (TNFR)) is unique because it defines crosstalk between these two receptor families. BTLA contains an inhibitory motif (ITIM) based on the tyrosine residues of proximal immunoreceptors and a switch motif (ITSM) based on the tyrosine residues of distal immunoreceptors. Disruption of ITIM or ITSM abolishes BTLA's ability to recruit SHP1 or SHP2, indicating that BTLA recruits SHP1 and SHP2 in a different manner than PD-1 and requires two tyrosine motifs to block T cell activation. The BTLA cytoplasmic tail also contains a third conserved tyrosine motif within its cytoplasmic domain, with a sequence similar to the Grb-2 recruitment site (YXN). Furthermore, phosphorylated peptides containing this BTLA N-terminal tyrosine motif can interact with the p85 subunit of GRB2 and PI3K in vitro, although the functional effects of this interaction in vivo have not been explored (Gavrieli et al., Bioochem. Biophysi Res Commun, 2003, 312, 1236-43). BTLA is a receptor for ligands PTPN6/SHP-1, PTPN11/SHP-2, TNFRSF14/HVEM, and B7H4.

VISTA (also known as the V-domain Ig repressor of T-cell activation VSIR, B7-H5, B7H5, GI24, PP2135, SISP1, DD1α, VISTA, C10orf54, chromosome 10 open reading frame 54, PD-1H, and V-set immunomodulatory receptor) is a 33.9-kDa single-pass type I membrane protein involved in T-cell inhibitory responses, embryonic stem cell differentiation inhibited via BMP4 signaling, and MMP14-mediated MMP2 activation (Yoon et al., Control of signaling-mediated clearance of apoptotic cells by the tumor suppressor p53, Science., July 31, 2015; 349(6247):1261669). VISTA interacts with its ligand VSIG-3 (Wang et al., VSIG-3 as a ligand of VISTA inhibits human T-cell function, Immunology., January 2019; 156(1):74-85)

LAG-3 (also known as lymphocyte activation gene 3, LAG3, CD223, and lymphocyte activation 3) is a 57.4-kDa single-pass type I membrane protein involved in lymphocyte activation and binding to HLA class II antigens. LAG-3 is a member of the immunoglobulin superfamily and is expressed on activated T cells (Huard et al., 1994, Immunogenetics 39:213), NK cells (Triebel et al., 1990, J. Exp. Med. 171:1393-1405), regulatory T cells (Huang et al., 2004, Immunity 21:503-513; Camisaschi et al., 2010, J Immunol. 184:6545-6551; Gagliani et al., 2013, Nat Med 19:739-746), and plasmacytoid dendritic cells (DCs) (Workman et al., 2009, J Immunol 182:1885-1891). LAG-3 is a membrane protein encoded by a gene located on chromosome 12 and is structurally and genetically associated with CD4. Similar to CD4, LAG-3 can interact with MHC class II molecules on the cell surface (Baixeras et al., 1992, J. Exp. Med. 176:327-337; Huad et al., 1996, Eur. J. Immunol. 26:1180-1186). Direct binding of LAG-3 to MHC class II molecules has been shown to play a role in downregulating antigen-dependent stimulation of CD4+ T lymphocytes (Huard et al., 1994, Eur. J. Immunol. 24:3216-3221), and LAG-3 blockade has also been shown to restore CD8+ lymphocyte viability in tumor or autoantigen (Gross et al., 2007, J Clin Invest. 117:3383-3392) and viral models (Blackburn et al., 2009, Nat. Immunol. 10:29-37). Furthermore, the intracytoplasmic region of LAG-3 can interact with LAP (LAG-3-associated protein), a signal transduction molecule involved in the downregulation of the CD3/TCR activation pathway (Iouzalen et al., 2001, Eur. J. Immunol. 31:2885-2891). In addition, CD4+CD25+ regulatory T cells (Tregs) have been shown to express LAG-3 upon activation, which contributes to the inhibitory activity of Treg cells (Huang, C. et al., 2004, Immunity 21:503-513). LAG-3 can also negatively regulate T cell homeostasis through Tregs via T cell-dependent and T cell-independent mechanisms (Workman, C. J. and Vignali, D. A., 2005, J. Immunol. 174:688-695).

LAG-3 has been shown to interact with MHC class II molecules (Huard et al., CD4/majorhistocompatibility complex class II interaction analyzed with CD4-and lymphocyte activation gene-3 (LAG-3)-Ig fusion proteins, Eur J Immunol., Sep 1995; 25(9):2718-21).

In addition, several kinases are known to be checkpoint inhibitors. For example, CHEK-1, CHEK-2, and A2aR.

CHEK-1 (also known as CHK1 kinase, CHK1, and checkpoint kinase 1) is a serine/threonine protein kinase of approximately 54.4 kDa that is involved in checkpoint-mediated cell cycle arrest and in response to DNA damage and/or DNA repair of non-replicated DNA.

CHEK-2 (also known as CHK2 kinase, CDS1, CHK2, HuCds1, LFS2, PP1425, RAD53, hCds1, and checkpoint kinase 2) is a serine/threonine protein kinase of approximately 60.9 kDa involved in checkpoint-mediated cell cycle arrest, DNA repair activation, and double-strand break-mediated apoptosis.

A2aR (also known as adenosine A2A receptor, ADORA2A, adenosine A2a receptor, A2aR, ADORA2, and RDC8) is a 44.7-kDa multi-membrane receptor for adenosine and other ligands.

In various embodiments, immunotherapeutic agents may comprise antibodies or antigen-binding fragments thereof. Within this definition, immune checkpoint inhibitors include bispecific antibodies and immune cell-binding multivalent antibodies/fusion proteins/constructs known in the art. In some embodiments, immunotherapeutic agents comprising bispecific antibodies may include bivalent antibodies that bind to the same epitope of an immune checkpoint molecule, two different epitopes of the same immune checkpoint molecule, or different epitopes of two different immune checkpoints.

Those skilled in the art can realize several bispecific antibody forms known in the art to target CTLA4, PD1, PD-L1, TIM-3, LAG-3, various B-7 ligands, B7H3, B7H4, CHK1 and CHK2 kinases, BTLA, A2aR, OX40, 41BB, LIGHT, CD40, GITR, TGF-β, SIRP-α, TIGIT, VSIG8, SIGLEC7, SIGLEC9, ICOS, FAS, BTNL2, and one or more others used in the combinations described herein.

In various implementations, immunotherapeutic agents may include immune cell-conjugated multivalent antibodies/fusion proteins/constructs.

In one embodiment of this disclosure, a checkpoint inhibitor is combined with a compound of formula I' to reduce or inhibit the metastasis of a primary tumor or cancer to other sites, or the formation or establishment of a metastatic tumor or cancer at other sites distant from the primary tumor or cancer, thereby inhibiting or reducing the recurrence or progression of the tumor or cancer.

In another embodiment of this disclosure, a combination therapy for treating cancer is provided, comprising a compound of formula I' and a checkpoint inhibitor having the potential to elicit an effective and durable immune response and enhance therapeutic benefits and more controllable toxicity.

In another embodiment of this disclosure, a combination therapy for treating cancer is provided, the combination therapy comprising a compound of formula I' and an immune checkpoint inhibitor. In one embodiment of this disclosure, a method for treating cancer and/or preventing metastasis is provided by using a checkpoint inhibitor that synergizes with a compound of formula I'.

In another embodiment, the methods of this disclosure include one or more of the following: 1) reducing or inhibiting the growth, proliferation, migration, or invasion of tumors or cancer cells that may or have metastasized; 2) reducing or inhibiting the formation or establishment of metastases from the primary tumor or cancer to one or more other sites, locations, or regions different from the primary tumor or cancer; 3) reducing or inhibiting the growth or proliferation of metastases at one or more other sites, locations, or regions different from the primary tumor or cancer after metastasis has formed or been established; 4) reducing or inhibiting the formation or establishment of additional metastases after metastasis has formed or been established; 5) prolonging overall survival; 6) prolonging progression-free survival; or 7) stabilizing the disease.

In one embodiment of this disclosure, administration of an immunotherapeutic agent in combination with a compound of formula I' provides a detectable or measurable improvement in a given subject's condition, such as relief or improvement of one or more adverse (physical) symptoms or consequences associated with the presence of cell proliferation or cell hyperproliferation, tumor formation, tumor or cancer, or metastasis, i.e., therapeutic benefit or beneficial effect.

A therapeutic benefit or beneficial effect is any objective or subjective, temporary or long-term improvement in a disease or pathology, or a reduction in the onset, severity, duration, or frequency of adverse symptoms associated with or caused by cell proliferation or cell hyperproliferative disorders such as tumor formation, tumor or cancer, or metastasis. It can lead to improved survival. For example, a satisfactory clinical endpoint of the treatment method according to this disclosure is achieved when the severity, duration, or frequency of one or more associated pathologies, adverse symptoms, or complications gradually or partially decreases, or when one or more of the physiological, biochemical, or cellular manifestations or characteristics of cell proliferation or cell hyperproliferative disorders such as tumor formation, tumor or cancer, or metastasis are inhibited or reversed. Therefore, a therapeutic benefit or improvement can be, but is not limited to, the destruction of target proliferating cells (e.g., tumor formation, tumor or cancer, or metastasis) or the elimination of one, most, or all of the pathologies, adverse symptoms, or complications associated with or caused by cell proliferation or cell hyperproliferative disorders such as tumor formation, tumor or cancer, or metastasis. However, the benefits or improvements of treatment do not necessarily involve curing or completely destroying all target proliferating cells (e.g., tumor formation, tumor or cancer, or metastasis) or eliminating all pathologies, adverse symptoms, or complications associated with or caused by conditions of cell proliferation or excessive cell proliferation, such as tumor formation, tumor or cancer, or metastasis. For example, partially destroying a tumor or cancer mass by inhibiting its progression or worsening, or stabilizing the tumor or cancer mass, size, or cell number, can reduce mortality and prolong life, even if only for days, weeks, or months, although some or most of the tumor or cancer mass, size, or cells remain.

Specific, non-limiting examples of therapeutic benefits include a reduction in tumor formation, tumor or cancer, or metastatic volume (size or cell mass) or cell number; inhibition or prevention of tumor formation, tumor or cancer volume increase (e.g., stabilization); slowing or inhibiting tumor formation, tumor or cancer progression, worsening or metastasis; or inhibiting tumor formation, tumor or cancer proliferation, growth or metastasis.

In one embodiment of this disclosure, administration of an immunotherapeutic agent in combination with a compound of formula I' provides a detectable or measurable improvement or overall response based on irRC (e.g., derived from time-point response assessment and based on tumor burden), including one or more of the following: (i) irCR – complete disappearance of all lesions, whether or not measurable, and no new lesions (confirmed by repeated, continuous assessment for at least 4 weeks from the date of first recording), (ii) irPR – a reduction of .gtoreq. 50% in tumor burden relative to baseline (confirmed by continuous assessment for at least 4 weeks after the date of first recording).

Optionally, any of the methods described herein may not be immediately effective. For example, tumor formation, the number or quality of tumors or cancer cells may increase after treatment, but over time, the quality, size or number of tumor cells in a given subject may eventually stabilize or decrease.

Other adverse symptoms and complications associated with tumor formation, tumors, cancer, and metastasis that can be suppressed, reduced, decreased, delayed, or prevented include, for example, nausea, loss of appetite, somnolence, pain, and malaise. Therefore, a partial or complete reduction or decrease in the severity, duration, or frequency of adverse symptoms or complications associated with or caused by cell hyperproliferative disorders, and improvements in the subject's quality of life and/or well-being, such as increased energy, appetite, and psychological well-being, are specific, non-limiting examples of therapeutic benefits.

Therefore, treatment benefits or improvements may also include a subjective improvement in the quality of life of the treated subject. In another embodiment, a method prolongs or extends the lifespan (survival) of the subject. In yet another embodiment, a method improves the quality of life of the subject.

In one implementation, administration of an immunotherapeutic agent in combination with a compound of formula I' results in a clinically relevant improvement in one or more biomarkers of disease status and progression selected from one or more of the following: (i): overall survival, (ii): progression-free survival, (iii): overall response rate, (iv): reduction in metastatic disease, (v): circulating levels of tumor antigens such as carbohydrate antigen 19.9 (CA19.9) and carcinoembryonic antigen (CEA) or other tumor-dependent antigens, (vii) nutritional status (weight, appetite, serum albumin), (viii): pain control or analgesic use, and (ix): CRP/albumin ratio.

Combining compounds of formula I' with immunotherapeutic agents produces more complex immunity, including not only the development of innate and type 1 immunity, but also immune regulation that more effectively restores appropriate immune function.

In various exemplary methods, checkpoint inhibitor antibodies (monoclonal or polyclonal, bispecific, trispecific, or immune cell-conjugating multivalent antibodies/fusion proteins/constructs) targeting checkpoint molecules of interest (e.g., PD-1) can be sequenced, and the polynucleotide sequence can then be cloned into a vector for expression or propagation. The sequence encoding the antibody of interest or its antigen-binding fragment can be held in a vector within host cells, which can then be amplified and frozen for future use. Production of recombinant monoclonal antibodies in cell cultures can be performed by cloning antibody genes from B cells using methods known in the art. See, for example, Tiller et al., 2008, J. Immunol. Methods 329,112; U.S. Patent No. 7,314,622.

In some embodiments, the method for generating recombinant antibodies may include the step of culturing host cells containing isolated nucleic acids encoding antibodies of the present disclosure. The method for culturing host cells containing isolated nucleic acids encoding antibodies of the present disclosure may be carried out in various ways depending on the nature of the antibody. In some embodiments, where the antibody of the present disclosure is a full-length conventional antibody, for example, the heavy chain variable region and light chain variable region are included under conditions that allow for the generation and isolation of the antibody.

Typically, nucleic acids encoding antibodies or antigen-binding fragments thereof are provided. Such polynucleotides encode both variable and constant regions of each of the heavy and light chains, but other combinations are also contemplated in this disclosure. Oligonucleotide fragments derived from the disclosed polynucleotides and nucleic acid sequences complementary to these polynucleotides are also contemplated in this disclosure.

Polynucleotides can be in the form of RNA, DNA, cDNA, genomic DNA, nucleic acid analogs, and synthetic DNA. DNA can be double-stranded or single-stranded, and if single-stranded, it can be a coding (sense) strand or a non-coding (antisense) strand. The coding sequence of a polypeptide can be the same as or different from the coding sequence, even if the sequence encodes the same polypeptide due to redundancy or degeneracy of the genetic code.

In some embodiments, a nucleic acid encoding an antibody disclosed herein is bound to an expression vector, which may be extrachromosomal or designed to integrate into the genome of the host cell to which it is introduced. The expression vector may contain any number of suitable regulatory sequences (including, but not limited to, transcription and translation control sequences, promoters, ribosome binding sites, enhancers, origins of replication, etc.) or other components (selection genes, etc.), all of which are operatively linked as is well known in the art. In some cases, two nucleic acids are used and placed in separate expression vectors (e.g., the heavy chain in a first expression vector and the light chain in a second expression vector), or alternatively, they may be placed in the same expression vector. Those skilled in the art will understand that the design of the expression vector (including the selection of regulatory sequences) can depend on factors such as the choice of host cell and the desired protein expression level.

Typically, nucleic acids and/or expression can be introduced into suitable host cells to generate recombinant host cells using any method suitable for the selected host cells (e.g., transformation, transfection, electroporation, infection), such that the nucleic acid molecules are operatively linked to one or more expression control elements (e.g., in a vector, in a construct generated through a process within the cell, or integrated into the host cell genome). The resulting recombinant host cells can be maintained under conditions suitable for expression (e.g., in the presence of an inducer, in a suitable non-human animal, in a suitable culture medium supplemented with appropriate salts, growth factors, antibiotics, nutritional supplements, etc.), thereby producing the encoded polypeptide. In some cases, the heavy chain is produced in one cell while the light chain is produced in another cell.

Mammalian cell lines suitable as expression hosts are known in the art and include many immortalized cell lines purchased from American Type Culture Collection (ATCC), Manassas, VA, USA, including but not limited to Chinese hamster ovary (CHO) cells, HEK 293 cells, NSO cells, HeLa cells, baby hamster kidney (BHK) cells, monkey kidney cells (COS) cells, human hepatocellular carcinoma cells (e.g., Hep G2), and many other cell lines. Non-mammalian cells, including but not limited to bacteria, yeast, insects, and plants, can also be used to express recombinant antibodies. In some embodiments, the antibody may be produced in transgenic animals such as cattle or chickens.

Exemplary and illustrative recombinant methods for antibody molecular biology, expression, purification, and screening are described in, for example, Antibody Engineering, edited by Kontermann & Dubel, Springer, Heidelberg, 2001 and 2010, Hayhurst & Georgiou, 2001, Curr. Opin. Chem. Biol. 5:683-689; Maynard & Georgiou, 2000, Annu. Rev. Biomed. Eng. 2:339-76; and Morrison, S. (1985) Science 229:1202, the full text of which is incorporated herein by reference.

In various implementations, the polynucleotide sequences encoding the selected variable heavy and light chains can be genetically manipulated to humanize the antibody or improve its affinity or other characteristics. Antibodies can also be customized for use in, for example, dogs, cats, primates, horses, and cattle.

In some implementations, fully human antibodies can be obtained using commercially available mice engineered to express specific human immunoglobulins. Transgenic animals designed to produce a more desired (e.g., fully human antibody) or stronger immune response can also be used to generate humanized or human antibodies. Examples of such technologies are Xenomouse ^™ from Abgenix, Inc. (Fremont, Calif.) and HuMAb- and TC Mouse ^™ from Medarex, Inc. (Princeton, NJ).

The immune checkpoint modulator antibodies disclosed herein can be recombinantly prepared by first isolating antibodies and antibody-producing cells from a host animal, obtaining the gene sequence, and using the gene sequence to recombinantly express the antibody in host cells (e.g., CHO cells). Another approach is to express the antibody sequence in plant (e.g., tobacco) or yeast cells (e.g., Pichia pastoris or Saccharomyces cerevisiae). Methods for recombinantly expressing antibodies in plants or yeast have been disclosed. See, for example, Peeters et al., Vaccine 19:2756, 2001; Lonberg, N. and D. Huszar Int. Rev. Immunol 13:65, 1995; and Horwitz, A.H. et al., Proc. Natl. Acad. Sci. 85:8678-8682; the full text of these publications is incorporated herein by reference. Methods for preparing antibody derivatives (e.g., domains, single chains, etc.) are known in the art.

Immunoassays and flow cytometry sorting techniques, such as fluorescence activated cell sorting (FACS), can also be used to isolate antibodies specific to checkpoint molecules.

In some embodiments, the polynucleotide comprises a sequence encoding a heavy chain and/or light chain variable region encoding a checkpoint inhibitor antibody or an antigen-binding fragment thereof disclosed herein. The sequence encoding the antibody of interest or its antigen-binding fragment may be held in a vector within a host cell, which can then be amplified and frozen for future use. Vectors (including expression vectors) and host cells are further described herein.

This disclosure includes affinity-matured checkpoint regulator antibodies. For example, affinity-matured antibodies can be produced by procedures known in the art (Marks et al., 1992, Bio/Technology, 10:779-783; Barbas et al., 1994, Proc Nat. Acad. Sci. USA 91:3809-3813). A method for characterizing antibody CDRs and/or altering (such as improving) the binding affinity of peptides such as antibodies is called “library scanning mutagenesis”. An exemplary method for providing affinity-matured antibody and antigen-binding fragments may include replacing one or more amino acid positions in the CDR with two or more amino acids (such as 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) using methods recognized in the art. A clonal library is generated, each clone having the complexity of two or more members (if two or more amino acids are substituted at each position). Typically, the library also includes clones containing native (unsubstituted) amino acids. A small number of clones from each library (e.g., approximately 20-80 clones, depending on the complexity of the library) are screened for binding affinity to the target peptide (or other binding target) and candidates with increased, identical, decreased, or no binding are identified. Methods for determining binding affinity are well known in the art. Binding affinity can be determined using, for example, Biacore™ surface plasmon resonance analysis (which detects approximately 2-fold or greater differences in binding affinity), biosensors, scintillation affinity assays, ELISA, immunoassays, fluorescence quenching, fluorescence transfer, and/or yeast display. Binding affinity can also be screened using suitable bioassays. Biacore™ is particularly useful when the starting antibody has already bound with relatively high affinity (e.g., approximately 10 nM or lower KD). The clonal library can then be recombined into the selection construct using any methods known in the art for selection, including phage display, yeast display, and ribosome display.

Antibodies can also be modified, for example, in variable domains of the heavy and/or light chains, to alter the antibody's binding properties. Changes in the variable regions can alter binding affinity and/or specificity. In some embodiments, no more than one to five conserved amino acid substitutions are made within the CDR domain. In other embodiments, no more than one to three conserved amino acid substitutions are made within the CDR domain. For example, mutations can be made in one or more CDR regions to increase or decrease the KD of the antibody against the checkpoint molecule, increase or decrease the KON, or alter the antibody's binding specificity. Site-directed mutagenesis is well known in the art. See, for example, Sambrook et al. and Ausubel et al.

Pharmaceutical compositions containing compounds of formula I' according to this disclosure will comprise an effective amount of the compound of formula I', an immunotherapeutic agent, and/or both, typically dispersed in a pharmaceutically acceptable carrier. The phrase "pharmaceutically or pharmacologically acceptable" means a molecular entity and composition that does not produce adverse, allergic, or other adverse reactions when properly administered to animals, such as humans. The preparation of pharmaceutical compositions containing compounds of formula I' according to this disclosure is known to those skilled in the art, as exemplified in Remington's Pharmaceutical Sciences, 18th edition, Mack Printing Company, 1990. Furthermore, for animal (e.g., human) administration, it should be understood that the formulation should meet standards of sterility, pyrogenicity, general safety, and purity. Specific examples of pharmaceutically acceptable carriers for use in combination compositions containing compounds of formula I' mixed with immunotherapeutic agents as described herein are borate buffers or sterile saline solutions (0.9% NaCl).

Formulations of immunotherapeutic agents, such as immune checkpoint modulator antibodies used according to this disclosure, can be prepared by mixing an antibody of desired purity with an optional pharmaceutically acceptable carrier, excipient, or stabilizer as well described and illustrated in Remington's Pharmaceutical Sciences, 16th edition, Osol, A.Ed. [1980], for storage in the form of a lyophilized formulation or an aqueous solution and/or suspension. Acceptable carriers, excipients, buffers, or stabilizers are non-toxic to the recipient at the doses and concentrations employed and include suitable aqueous and/or non-aqueous excipients that can be used in the pharmaceutical compositions of this disclosure, such as water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate). For example, appropriate flowability can be maintained by using coating materials such as lecithin, by maintaining the desired particle size in the case of dispersions, and by using surfactants, buffers such as phosphates, citrates, and other organic acids. It may include antioxidants, such as (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, etc.; and (3) metal chelating agents, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.; preservatives (such as octadecane-dimethylbenzylammonium chloride; hexamethylammonium chloride; benzalkonium chloride; benzyl chloride; phenol, butanol or benzyl alcohol; alkyl esters of p-hydroxybenzoate such as methyl p-hydroxybenzoate or propyl p-hydroxybenzoate; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues). Other exemplary pharmaceutically acceptable excipients may include peptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers, such as polyvinylpyrrolidone; amino acids, such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrin; chelating agents, such as EDTA; sugars, such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions, such as sodium; metal complexes (e.g., Zn-protein complexes); and/or nonionic surfactants, such as TWEENTM, PLURONICS™, or polyethylene glycol (PEG).

In one illustrative embodiment, the pharmaceutical composition may optionally contain pharmaceutically acceptable excipients such as pH adjusters and buffers, and toxicity modifiers, such as sodium acetate, sodium chloride, potassium chloride, calcium chloride, and sodium lactate, to approximate physiological conditions. In some embodiments, the checkpoint inhibitor antibody or its antigen-binding fragment of the present disclosure is formulated and may be lyophilized for storage, and reconstituted in a suitable excipient according to lyophilization and reconstitution techniques known in the art prior to use. In an exemplary pharmaceutical composition containing one or more checkpoint inhibitor antibodies or their antigen-binding fragments, the composition is formulated as a sterile, preservative-free solution of one or more checkpoint inhibitor antibodies or their antigen-binding fragments for intravenous or subcutaneous administration. The formulation may be provided as a single-use pre-filled pen, a single-use glass syringe, for example, containing about 1 mL of pre-filled material, or a single-use institutional vial. Preferably, the pharmaceutical composition containing the checkpoint inhibitor antibody or its antigen-binding fragment is clear and colorless, with a pH of about 6.9-5.0, preferably 6.5-5.0, and even more preferably about 6.0 to about 5.0. In various embodiments, when reconstituted and administered to a subject, the formulation comprising the pharmaceutical composition may contain about 500 mg to about 10 mg, or about 400 mg to about 20 mg, or about 300 mg to about 30 mg, or about 200 mg to about 50 mg per mL of solution of a checkpoint inhibitor antibody or an antigen-binding fragment thereof. Exemplary injectable or infusion excipients may include mannitol, citrate monohydrate, disodium hydrogen phosphate dihydrate, disodium hydrogen phosphate monohydrate, polysorbate 80, sodium chloride, sodium citrate, and water for parenteral administration (e.g., intravenous, intramuscular, intraperitoneal, or subcutaneous).

In another exemplary embodiment, one or more immunotherapeutic agents or antigen-binding fragments thereof are formulated into a sterile aqueous solution for intravenous or subcutaneous administration, containing 1-75 mg/mL, or more preferably about 5-60 mg/mL, or even more preferably about 10-50 mg/mL, or even more preferably about 10-40 mg/mL, of an antibody, as well as sodium acetate, polysorbate 80, and sodium chloride, with a pH range of about 5-6. Preferably, the intravenous or subcutaneous formulation is a sterile aqueous solution containing 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 mg/mL of an immunotherapeutic agent (e.g., an immune checkpoint inhibitor antibody or its antigen-binding fragment), 20 mM sodium acetate, 0.2 mg/mL polysorbate 80, and 140 mM sodium chloride, with a pH of 5.5. In addition, solutions containing checkpoint inhibitor antibodies or their antigen-binding fragments may, among other compounds, contain histidine, mannitol, sucrose, trehalose, glycine, polyethylene glycol, EDTA, methionine, and any combination thereof, as well as many other compounds known in the relevant art.

In one embodiment, the pharmaceutical composition of this disclosure comprises the following components: 5-500 mg of the immunotherapeutic agent of this disclosure or its antigen-binding fragment, 10 mM histidine, 5% sucrose, and 0.01% polysorbate 80, at pH 5.8, with or without a compound of formula I'. The composition may be provided in lyophilized powder form. When the powder is reconstituted at its full volume, the composition retains the same formulation. Alternatively, the powder may be reconstituted at half volume, in which case the composition comprises 10-500 mg of the immunotherapeutic agent of this disclosure or its antigen-binding fragment, 20 mM histidine, 10% sucrose, and 0.02% polysorbate 80, at pH 5.8.

In one embodiment, a portion of the dose is administered via intravenous bolus injection, while the remainder is administered via infusion of the immunotherapeutic agent formulation. For example, an intravenously administered immunotherapeutic agent or its antigen-binding fragment may be given in bolus injection at doses of about 0.001 to about 200 mg/kg, such as about 0.001 mg/kg to about 100 mg/kg, or about 0.001 mg/kg to about 50 mg/kg, or about 0.001 mg/kg to about 10 mg/kg, and the remaining antibody dose may be administered via intravenous injection. The predetermined dose of the immunotherapeutic agent or its antigen-binding fragment may be administered, for example, over a period of one to two to five hours.

In another embodiment, a portion of the dose is administered via subcutaneous injection and/or infusion in the form of a bolus, with the remainder administered via infusion of the immunotherapy formulation. In some exemplary dosages, the immunotherapy formulation may be administered subcutaneously via intravenous injection of the immunotherapy agent or its antigen-binding fragment in the range of about 0.001 to about 200 mg/kg, for example, about 0.001 mg/kg to about 100 mg/kg, or about 0.001 mg/kg to about 50 mg/kg, or about 0.001 mg/kg to about 10 mg/kg. In some embodiments, the dose may be given as a bolus, and the remaining immunotherapy dose may be administered via subcutaneous or intravenous injection. The predetermined dose of the immunotherapy agent or its antigen-binding fragment may be administered, for example, over a period of one to two to five hours.

The formulation described herein may also contain one or more active compounds necessary for the specific indication to be treated, preferably those having complementary activities that do not adversely affect each other. For example, it may be desirable to provide one or more immunotherapeutic agents with other specificities. Alternatively or in addition, the composition may comprise anti-inflammatory agents, chemotherapeutic agents, cytotoxic agents, cytokines, growth inhibitors, and/or small molecule antagonists. Such molecules are suitably present in a combination of amounts effective for the intended purpose.

Preparations intended for internal administration should be sterile or near-sterile. This can be easily achieved through filtration using a sterile filter membrane.

In various embodiments, exemplary formulations of the pharmaceutical compositions described herein can be prepared using methods widely known in the field of pharmaceutical formulation. Typically, such preparation methods may include the steps of conjugating an active ingredient with a carrier or one or more other auxiliary ingredients, and then, if desired, packaging the product into desired single-dose or multi-dose units.

In some embodiments, compositions containing compounds of formula I' may also be delivered in vesicles, and immunotherapeutic agents may be delivered in the same liposomal formulation or in a separate formulation compatible with a liposomal formulation containing compounds of formula I'. In some illustrative examples, the liposomes contain liposomal surface portions, such as polyethylene glycol, antibodies, and antibody fragments thereof, that are selectively transported to specific cells or organs to target one or more desired tumor surface antigens, receptors, growth factors, glycoproteins, glycolipids, or neoantigens, thereby enhancing targeted drug delivery.

In another embodiment, the compound of formula I' can be delivered in vesicles, particularly in liposomes (see Langer, Science 249:1527-1533 (1990); Treat et al., Liposomes in the Therapy of Fifenaciodessesase and Cancer, Lopez-Berestein and Fidler (eds.), Liss, N.Y., pp. 353-365 (1989); Lopez-Berestein, ibid., pp. 317-327; see general sources ibid.).

In another embodiment, the compound of formula I', or a combination containing the composition, or a composition containing an immunotherapeutic agent, may be delivered in a controlled-release system. In one embodiment, a pump may be used (see Langer, ibid.; Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321:574 (1989)). In another embodiment, the controlled release of the compound of formula I' may include a polymeric material to provide sustained, intermediate, pulsed, or alternating release (see MEDICAL APPLICATIONS OF CONTROLLED RELEASE, Langer and Wise (eds.), CRC Pres., Boca Raton, Fla. (1974); CONTROLLED DRUG BIOAVAILABILITY, DRUG PRODUCT DESIGN AND PERFORM). ANCE, Smolen and Ball (eds.), Wiley, New York (1984); Ranger and Peppas, J. Macromol. Sci. Rev. Macromol. Chem. 23:61 (1983); see also Levy et al., Science 228:190 (1985); During et al., Ann. Neurol. 25:351 (1989); Howard et al., J. Neurosurg. 71:105 (1989)). Other controlled release systems discussed in Ranger's review (Science 249:1527-1533 (1990)) may be used.

The optimal concentration of the active ingredient in the selected medium can be determined empirically according to procedures well known to those skilled in the art, and will depend on the desired final pharmaceutical formulation and the intended use.

This disclosure also provides a pharmaceutical package or kit comprising one or more containers filled with one or more of the components of a pharmaceutical composition of this disclosure, the pharmaceutical composition comprising at least a compound of formula I' as described herein and one or more checkpoint inhibitor antibodies or antigen-binding fragments thereof. In other embodiments, the kit may contain one or more additional containers providing pharmaceutically acceptable excipients (e.g., diluents). In one embodiment, the kit may comprise at least one container wherein the container may include a compound of formula I' of this disclosure, a checkpoint inhibitor antibody, or an antigen-binding fragment thereof. The kit may also include a set of instructions for preparing and administering the final pharmaceutical composition to a subject in need of treating a checkpoint molecule-mediated disease or condition.

In some embodiments of this disclosure, the immunotherapeutic agent is a population of immune cells that can be administered in combination with a compound of formula I' to treat a subject with cancer. In some embodiments, the immunotherapeutic agent is a population of immune cells, such as leukocytes (nucleated leukocytes), comprising (e.g., expressing) a receptor that binds to an antigen of interest. The leukocytes of this disclosure can be, for example, neutrophils, eosinophils, basophils, lymphocytes, or monocytes. In some embodiments, the leukocytes are lymphocytes. Examples of lymphocytes include T cells, B cells, natural killer (NK) cells, or NKT cells. In some embodiments, the T cells are CD4+Th (T helper) cells, CD8+ cytotoxic T cells, γδ T cells, or regulatory (suppressive) T cells. In some embodiments, the immune cells are dendritic cells.

In some embodiments, the immune cells of this disclosure are genetically engineered to express antigen-binding receptors. A cell is considered “engineered” if it contains engineered (exogenous) nucleic acids. The engineered nucleic acids of this disclosure can be introduced into cells by any known (e.g., conventional) method. For example, engineered nucleic acids can be introduced into cells by: electroporation (see, for example, Heiser W.C. Transcription Factor Protocols: Methods in Molecular Biology. TM. 2000; 130:117-134), chemical methods (e.g., calcium phosphate or lipids), transfection (see, for example, Lewis W.H. et al., Somatic Cell Genet., May 1980; 6(3):333-47; Chen C. et al., Mol Cell Biol., Aug. 1987; 7(8):2745-2752), fusion with bacterial protoplasts containing recombinant plasmids (see, for example, Schaffner W. Proc Natl Acad Sci USA., Apr. 1980; 77(4):2163-7), direct microinjection of purified DNA into the cell nucleus (see, for example, Capecchi M.R. Cell., Nov. 1980; 22(2Pt 2):479-88), or retroviral transduction.

Some aspects of this disclosure provide an "adoptive cell" method involving isolating immune cells (e.g., T cells) from a subject with cancer, genetically engineering the immune cells (e.g., to express antigen-binding receptors, such as chimeric antigen receptors), expanding the cells in vitro, and then reintroducing the immune cells into the subject. This method generates a greater number of engineered immune cells in the subject than can be achieved through conventional gene delivery and vaccination methods. In some embodiments, immune cells are isolated from the subject, expanded in vitro without genetic modification, and then reintroduced into the subject.

As provided herein, the immune cells of this disclosure contain receptors that bind to antigens, such as antigens encoded by nucleic acids delivered exogenously. In some embodiments, leukocytes are modified (e.g., genetically modified) to express receptors that bind antigens. In some embodiments, the receptors may be naturally occurring antigen receptors (typically expressed on immune cells), recombinant antigen receptors (typically not expressed on immune cells), or chimeric antigen receptors (CARs). Naturally occurring and recombinant antigen receptors covered by this disclosure include T cell receptors, B cell receptors, NK cell receptors, NKT cell receptors, and dendritic cell receptors. A “chimeric antigen receptor” is an artificial immune cell receptor engineered to recognize and bind antigens expressed by tumor cells. Typically, CARs are designed for T cells and are a chimera of the signal transduction domain and the antigen recognition domain (e.g., a single-chain fragment of an antibody (scFv)) of the T cell receptor (TcR) complex (Enblad et al., Human Gene Therapy. 2015; 26(8):498-505), the entire contents of which are incorporated herein by reference.

In some implementations, the antigen-binding receptor is a chimeric antigen receptor (CAR). T cells expressing CAR are referred to as "CAR T cells". In some implementations, the CAR T cell receptor comprises a signal transduction domain and an antigen recognition domain (e.g., a single-chain fragment of an antibody (scFv)) of a T cell receptor (TcR) complex (Enblad et al., Human Gene Therapy. 2015; 26(8):498-505), the full text of which is incorporated herein by reference.

There are four generations of CARs, each containing different components. First-generation CARs connect the antibody-derived scFv to the intracellular signaling domain of the T cell receptor's CD3ζ (ζ or z) via a hinge and transmembrane domain. Second-generation CARs incorporate additional domains, such as CD28, 4-1BB (41BB), or ICOS, to provide co-stimulatory signaling. Third-generation CARs contain two co-stimulatory domains fused to the TCR CD3-ζ chain. These third-generation co-stimulatory domains can include combinations of, for example, CD3z, CD27, CD28, 4-1BB, ICOS, or OX40. In some implementations, the CAR contains an extracellular domain (e.g., CD3) typically derived from a single-stranded variable fragment (scFv), a hinge, a transmembrane domain, and an intracellular domain having one (first-generation), two (second-generation), or three (third-generation) signaling domains derived from CD3Z and/or co-stimulatory molecules (Maude et al., Blood. 2015; 125(26):4017-4023; Kakarla and Gottschalk, Cancer J. 2014; 20(2):151-155), the full text of which is incorporated herein by reference.

In some implementations, chimeric antigen receptors (CARs) are T cells retargeted for universal cytokine killing (TRUCK), also known as fourth-generation CARs. TRUCK cells are CAR-retargeted T cells that act as mediators for the production and release of transgenic cytokines that accumulate in the targeted tissue (e.g., the targeted tumor tissue). The transgenic cytokines are released when the CAR binds to the target. TRUCK cells can deposit a variety of therapeutic cytokines at the target. This can produce therapeutic concentrations at the target site and avoid systemic toxicity.

CARs typically differ in their functional properties. The CD3ζ signaling domain of the T cell receptor, when conjugated, activates and induces T cell proliferation, but can lead to non-responsiveness (a lack of response to the body's defense mechanisms, resulting in direct induction of peripheral lymphocyte tolerance). Lymphocytes are considered non-responsive when they do not respond to a specific antigen. Adding a co-stimulatory domain to second-generation CARs improves the replication capacity and persistence of modified T cells. Similar antitumor effects have been observed in vitro with CD28 or 4-1BB CARs, but preclinical in vivo studies have shown that the 4-1BB CAR produces superior proliferation and/or persistence. Clinical trials have shown that both second-generation CARs can induce substantial T cell proliferation in vivo, but the CAR containing the 4-1BB co-stimulatory domain appears to have a longer duration of action. Third-generation CARs incorporate multiple signaling domains (co-stimulatory domains) to increase potency. Fourth-generation CARs are further modified with constitutive or inducible expression cassettes of transgenic cytokines, which are released by CAR T cells to modulate T cell responses. See, for example, Enblad et al., Human Gene Therapy. 2015; 26(8):498-505; Chmielewski and Hinrich, Expert Opinion on Biological Therapy. 2015; 15(8):1145-1154, the full text of which is incorporated herein by reference.

In some embodiments, the exemplary immunotherapeutic agent is a first-generation chimeric antigen receptor (CAR). In some embodiments, the chimeric antigen receptor is a third-generation CAR. In some embodiments, the chimeric antigen receptor is a second-generation CAR. In some embodiments, the chimeric antigen receptor is a third-generation CAR. In some embodiments, the chimeric antigen receptor is a fourth-generation CAR or a T cell redirected for universal cytokine killing (TRUCK).

In some embodiments, the chimeric antigen receptor (CAR) includes an extracellular domain comprising an antigen-binding domain, a transmembrane domain, and a cytoplasmic domain. In some embodiments, the CAR is fully human. In some embodiments, the antigen-binding domain of the CAR is specific for one or more antigens. In some embodiments, a "spacer" domain or "hinge" domain is located between the extracellular domain (containing the antigen-binding domain) and the transmembrane domain of the CAR, or between the cytoplasmic domain and the transmembrane domain of the CAR. A "spacer" domain refers to any oligopeptide or polypeptide that serves to link the transmembrane domain to the extracellular domain and/or the cytoplasmic domain in a polypeptide chain. A "hinge" domain refers to any oligopeptide or polypeptide that serves to provide flexibility to the CAR or its domains, or to prevent steric hindrance to the CAR or its domains. In some embodiments, the spacer or hinge domain may contain up to 300 amino acids (e.g., 10 to 100 amino acids, or 5 to 20 amino acids). In some embodiments, one or more spacer domains may be included in other regions of the CAR.

In some embodiments, the CAR of this disclosure includes an antigen-binding domain, such as a single-stranded Fv (scFv) specific to a tumor antigen. The choice of the binding domain depends on the type and number of ligands defining the surface of the target cell. For example, the antigen-binding domain may be selected to recognize a ligand that acts as a cell surface marker on a target cell associated with a specific disease state, such as cancer or an autoimmune disease. Thus, examples of cell surface markers that can serve as ligands for the antigen-binding domain in the CAR of this disclosure include those associated with cancer cells and/or other forms of diseased cells. In some embodiments, the CAR is engineered to target tumor antigens of interest by engineering a desired antigen-binding domain on tumor cells that specifically binds to an antigen encoded by an engineered nucleic acid as provided herein.

The term "specific binding" refers to the antigen-binding domain (e.g., scFv) of a target or epitope, and methods for determining such specific binding are known in the art. A molecule is said to exhibit "specific binding" if it reacts or associates with a particular target antigen more frequently, rapidly, persistently, and/or with greater affinity compared to alternative targets. An antigen-binding domain (e.g., scFv) that specifically binds to a first target antigen may or may not specifically bind to a second target antigen. Thus, "specific binding" does not necessarily require (although it may include) exclusive binding.

In some implementations, CAR-expressing immune cells are genetically modified to recognize multiple targets or antigens, allowing for the recognition of unique target or antigen expression patterns on tumor cells. Examples of CARs that can bind to multiple targets include: “split signal CARs” that restrict the activation of fully immune cells against tumors expressing multiple antigens; “tandem CARs” (TanCARs) containing an extracellular domain with two scFvs; and “universal extracellular domain CARs” that incorporate avidin or fluorescein isothiocyanate (FITC)-specific scFvs to recognize tumor cells that have been incubated with labeled monoclonal antibodies (Mabs).

A CAR is considered "bispecific" if it recognizes two different antigens (having two different antigen recognition domains). In some embodiments, a bispecific CAR consists of two different antigen recognition domains tandemly present on a single transgenic receptor (referred to as a TanCAR; see, for example, Grada Z et al., Molecular Therapy Nucleic Acids 2013; 2:e105, the entire text of which is incorporated herein by reference). Thus, in some embodiments, these methods include delivering to a tumor a combination of a compound comprising formula I' and an immunotherapeutic agent, wherein the immunotherapeutic agent is an engineered nucleic acid encoding an antigen, or delivering to the tumor an engineered nucleic acid that induces the expression of an autoantigen, and delivering to the tumor immune cells expressing a bispecific CAR that binds to two antigens, one of which is encoded by an engineered nucleic acid.

In some embodiments, the CAR is an antigen-specific inhibitory CAR (iCAR), which can be used, for example, to avoid extratumor toxicity (Fedorov, V D et al., Sci. Transl. Med., published online December 11, 2013, the full text of which is incorporated herein by reference). The iCAR contains an antigen-specific inhibitory receptor, for example, to block nonspecific immunosuppression that may be caused by the expression of additional tumor targets. The iCAR may be based on, for example, the inhibitory molecule CTLA-4 or PD-1. In some embodiments, these iCARs block T-cell responses originating from their endogenous T-cell receptors or activated CAR-activated T cells. In some embodiments, this inhibitory effect is temporary.

In some implementations, CAR can be used for adoptive cell transfer, in which immune cells are removed from a subject and modified to express receptors specific to antigens, such as tumor-specific antigens. The modified immune cells, which can then recognize and kill cancer cells, are then reintroduced into the subject (Pule et al., Cytotherapy. 2003; 5(3):211-226; Maude et al., Blood. 2015; 125(26):4017-4023, each of which is incorporated herein by reference in its entirety).

According to other aspects of this disclosure, the tumor antigen component in the vaccine of the present invention is any natural or synthetic tumor-associated protein or peptide, or a combination of tumor-associated proteins and/or peptides or glycoproteins or glycopeptides. In other aspects, the antigen component may be patient-specific or common to many or most patients with a particular type of cancer. According to one aspect, the antigen component consists of cell lysates derived from tumor tissue taken from a patient to be treated. In another aspect, the lysates may be engineered or synthesized from exogenous sources derived from tumor tissue. In yet another aspect, the antigen component consists of cell lysates derived from tumor tissue extracted from one or more unrelated individuals or tumor cell lines.

In various embodiments, exemplary immunotherapeutic agents comprise one or more cancer vaccines for use in combination with compounds of formula I'. The tumor-associated antigen component of the vaccine can be manufactured using any of a variety of well-known techniques. For a single protein component, the antigen protein is isolated from tumor tissue or tumor cell lines by standard chromatographic methods such as high-performance liquid chromatography or affinity chromatography, or alternatively synthesized in a suitable expression system (such as *E. coli*, yeast, or plants) using standard recombinant DNA techniques. The tumor-associated antigen protein is then purified from the expression system by standard chromatographic methods. In the case of peptide antigen components, these are typically prepared by standard automated synthesis. Proteins and peptides can be modified by adding amino acids, lipids, and other agents to improve their incorporation into vaccine delivery systems (e.g., multilayer liposomes). For tumor-associated antigen components derived from a patient's own tumor or from tumors or cell lines from other individuals, tumor tissue or single-cell suspensions derived from tumor tissue are typically homogenized in a suitable buffer. Homogenization can also be performed, for example, by centrifugation to separate specific cellular components such as cell membranes or soluble substances. Tumor material can be used directly, or tumor-associated antigens can be extracted using a buffer solution containing low concentrations of suitable agents (such as detergents) for incorporation into vaccines. An example of a suitable detergent for extracting antigenic proteins from tumor tissue, tumor cells, and tumor cell membranes is diheptanoylphosphatidylcholine. Exogenous substances derived from tumor tissue or tumor cells, whether autologous or allogeneic to the patient, can be used as antigenic components for incorporation into vaccines or as starting materials for extracting tumor-associated antigens.

In some embodiments of this disclosure, a cancer vaccine is provided, comprising at least one tumor-associated antigen, at least one immunostimulant, and optionally at least one cell-based immunotherapeutic agent. In some embodiments, the immunostimulatory component of the cancer vaccine of this disclosure is any biological response modulator (BRM) capable of enhancing the effectiveness of the therapeutic cancer vaccine in inducing humoral and cellular immune responses against cancer cells in a patient. According to one aspect, the immunostimulant is a cytokine or a combination of cytokines. Examples of such cytokines include interferons (such as IFN-γ), interleukins (such as IL-2, IL-15, and IL-23), colony-stimulating factors (such as M-CSF and GM-CSF), and tumor necrosis factor. According to another aspect, the immunostimulatory component of the disclosed cancer vaccine comprises one or more adjuvanted immunostimulants, such as APC Toll-like receptor agonists or co-stimulatory/cell adhesion membrane proteins, with or without immunostimulatory cytokines. Examples of Toll-like receptor agonists include lipid A and CpG, and co-stimulatory/adhesion proteins such as CD80, CD86, and ICAM-1.

In some embodiments, the immunostimulant is selected from IFN-γ (IFN-γ), IL-2, IL-15, IL-23, M-CSF, GM-CSF, tumor necrosis factor, lipid A, CpG, CD80, CD86, and ICAM-1, or combinations thereof. According to other aspects, the cell-based immunotherapeutic agent is selected from dendritic cells, tumor-infiltrating T lymphocytes, chimeric antigen receptor-modified T effector cells targeting the patient's tumor type, B lymphocytes, natural killer cells, bone marrow cells, and any other cells of the patient's immune system, or combinations thereof. In one aspect, the cancer vaccine immunostimulant includes one or more cytokines (such as interleukin-2 (IL-2), GM-CSF, M-CSF, and interferon-γ (IFN-γ)), one or more Toll-like receptor agonists and/or adjuvants (such as monophospholipid A, lipid A, muramyl dipeptide (MDP) lipid conjugates, and double-stranded RNA), or one or more co-stimulatory membrane proteins and/or cell adhesion proteins (such as CD80, CD86, and ICAM-1), or any combination thereof. In one aspect, cancer vaccines include immunostimulants that are cytokines selected from interleukin-2 (IL-2), GM-CSF, M-CSF, and interferon-γ (IFN-γ). In another aspect, cancer vaccines include immunostimulants that are Toll-like receptor agonists and/or adjuvants selected from monophospholipid A, lipid A, and muramyl dipeptide (MDP) lipid conjugates and double-stranded RNA. In yet another aspect, cancer vaccines include immunostimulants that are co-stimulatory membrane proteins and/or cell adhesion proteins selected from CD80, CD86, and ICAM-1.

In various embodiments, the immunotherapeutic agent may include a cancer vaccine, wherein the cancer vaccine incorporates any tumor antigen that can potentially be used to construct the fusion protein according to the invention, particularly the following:

(a) Cancer-testis antigens, including NY-ESO-1, SSX2, SCP1, and RAGE, BAGE, GAGE, and MAGE family peptides, such as GAGE-1, GAGE-2, MAGE-1, MAGE-2, MAGE-3, MAGE-4, MAGE-5, MAGE-6, and MAGE-12, which can be used to treat, for example, melanoma, lung cancer, head and neck cancer, NSCLC, breast cancer, gastrointestinal cancer, and bladder tumors; (b) mutated antigens, including p53 associated with various solid tumors such as colorectal cancer, lung cancer, and head and neck cancer; and p2 associated with, for example, melanoma, pancreatic cancer, and colorectal cancer. 1/Ras; CDK4 associated with, for example, melanoma; MUM1 associated with, for example, melanoma; caspase-8 associated with, for example, head and neck cancer; CIA 0205 associated with, for example, bladder cancer; HLA-A2-R1701; β-catenin associated with, for example, melanoma; TCR associated with, for example, T-cell non-Hodgkin lymphoma; BCR-abl associated with, for example, chronic myeloid leukemia; triose phosphate isomerase; KIA0205; CDC-27 and LDLR-FUT; (c) overexpressed antigens, including galactolectin 4 associated with, for example, colorectal cancer; galactolectin 9 associated with, for example, Hodgkin's disease. ; proteinase 3 associated with, for example, chronic myeloid leukemia; WT 1 associated with, for example, various types of leukemia; carbonic anhydrase associated with, for example, renal cell carcinoma; aldolase A associated with, for example, lung cancer; PRAME associated with, for example, melanoma; HER-2/neu associated with, for example, breast cancer, colon cancer, lung cancer, and ovarian cancer; globin and alpha-fetoprotein associated with, for example, liver cancer; KSA associated with, for example, colorectal cancer; gastrin associated with, for example, pancreatic cancer and gastric cancer; telomerase catalytic protein and MUC-1 associated with, for example, breast cancer and ovarian cancer; G-250 associated with, for example, renal cell carcinoma; p53 associated with, for example, breast cancer and colon cancer; and (d) Carcinoembryonic antigens associated with, for example, breast cancer, lung cancer, and gastrointestinal cancers such as colorectal cancer; (e) Common antigens, including melanoma-melanocyte differentiation antigens such as MART-1/Melan A; gpl00; MC1R; melanocyte-stimulating hormone receptor; tyrosinase; tyrosinase-associated protein-1/TRP1 and tyrosinase-associated protein-2/TRP2 associated with, for example, melanoma; (f) Prostate-associated antigens, including PAP, PSA, PSMA, PSH-P1, PSM-P1, and PSM-P2 associated with, for example, prostate cancer; and (c) Immunoglobulin idiotypes associated with myeloma and B-cell lymphoma. In some implementations, one or more TAAs may be selected from pi 5, Hom/Mel-40, H-Ras, E2A-PRL, H4-RET, IGH-IGK, MYL-RAR, Epstein Barr virus antigen, EBNA, human papillomavirus (HPV) antigens including E6 and E7, hepatitis B and hepatitis C virus antigens, human T-cell lymphotropic virus antigen, TSP-180, pl85erbB2, pl80erbB-3, c-met, mn-23H1, TAG-72-4, CA 19-9, CA 72-4, CAM17.1, NuMa, K-ras, pi 6, TAGE, PS CA, CT7, 43-9F, 5T4, 791Tgp72, β-HCG, BCA225, BTAA, CA125, CA 15-3 (CA 27.29\BCAA), CA 195, CA 242, CA-50, CAM43, CD68\KP1, CO-029, FGF-5, Ga733 (EpCAM), HTgp-175, M344, MA-50, MG7-Ag, MOV18, NB/70K, NY-CO-1, RCAS1, SDCCAG16, TA-90 (Mac-2 binding protein/Cycophilic C-associated protein), TAAL6, TAG72, TLP, TPS, or any combination thereof.

In some embodiments, the cancer vaccine of this disclosure, used in combination with the compounds of Formula I', may include a tumor antigen comprising a specific immunogenic epitope of one of the following human proteins: TCTN1 ( SEQ ID NO.1; gene ID: ENSG00000204852), TCTN2 (SEQ ID NO.2; gene ID: ENSG00000168778), TCTN3 ( SEQ ID NO.3; gene ID: ENSG00000119977), HIGD2A ( SEQ ID NO.4; gene ID: ENSG00000146066), HIGD2B ( SEQ ID NO.5; gene ID: ENSG00000175202), C4ORF32 ( SEQ ID NO.6; gene ID: ENSG00000174749), FAM62A (E-SYT1, SEQ ID NO.1 ), and TCTN3B ( SEQ ID NO.2). NO.7; Gene ID: ENSG00000139641), COLEC11 ( SEQ ID NO.8; Gene ID: ENSG00000118004), FSTL5 ( SEQ ID NO.9; Gene ID: ENSG00000168843), FAM82A2 ( SEQ ID NO.10; Gene ID: ENSG00000137824), SCARA5 ( SEQ ID NO.11; Gene ID: ENSG00000168079), VSTM1 ( SEQ ID NO.12; Gene ID: ENSG00000189068), RNF5 ( SEQ ID NO.13; Gene ID: ENSG00000183574), UNQ6126 ( SEQ ID NO.14; Gene ID: gi|169216088), DPY19L3 ( SEQ ID NO.15; Gene ID: ENSG00000178904), SLC39A10 ( SEQ ID NO.16; Gene ID: ENSG00000196950), GPR107 ( SEQ ID NO.17; Gene ID: ENSG00000148358), COL20A1 ( SEQ ID NO.18; Gene ID: ENSG00000101203), GLT25D2 ( SEQ ID NO.19; Gene ID: ENSG00000198756), SYTL3 ( SEQ ID NO.20; Gene ID: ENSG00000164674), DENND1B ( SEQ ID NO.21; Gene ID: ENSG00000162701), C6orf98 ( SEQ ID NO.22; Gene ID: EG:387079), FAM69B ( SEQ ID NO. NO.23; Gene ID: ENSG00000165716), EMID1 ( SEQ ID NO.24; Gene ID: OTTHUMG00000030824), KLRG2 ( SEQ ID NO.25; Gene ID: ENSG00000188883), ERMP1 ( SEQ ID NO.26; Gene ID: ENSG00000099219), VMO1 ( SEQ ID NO.27; Gene ID: ENSG00000182853), C9orf46 ( SEQ ID NO.28; Gene ID: ENSG00000107020), F1137107 ( SEQ ID NO.29; Gene ID: ENSG00000177990), YIPF2 ( SEQ ID NO.30; Gene ID: ENSG00000130733), TRYX3 ( SEQ ID NO. NO.31; PRSS58, ENSG00000258223.2), C14orf135 ( SEQ ID NO.32; gene ID: ENSG00000126773), ANGPTL7 ( SEQ ID NO.33; gene ID: ENSG00000171819), TPCN2 ( SEQ ID NO.34; gene ID: ENSG00000162341), C18orf19 ( SEQ ID NO.35; gene ID: ENSG00000177150), OLFML1 ( SEQ ID NO.36; gene ID: ENSG00000183801), LYPD4 ( SEQ ID NO.37; gene ID: ENSG00000101203), MEGF8 ( SEQ ID NO.38; Gene ID: ENSG00000105429), F1142986 ( SEQ ID NO.39; Gene ID: ENSG00000196460), SLC46A1 ( SEQ ID NO.40; Gene ID: ENSG00000076351), FAM180A ( SEQ ID NO.41; Gene ID: ENSG00000189320), CRISP-3 ( SEQ ID NO.42; Gene ID: ENSG00000096006), or combinations thereof. These tumor antigens are disclosed in WO2010/086162, WO2010/086163, WO2011/051278, WO2011/051276, WO2011/051277, WO2011/051280, WO2011/051271, WO2011/135068, and WO2014/198919, the contents of which are incorporated herein by reference in their entirety.

In various embodiments, exemplary immunotherapeutic agents may include mRNAs operable to encode any one or more of the aforementioned cancer antigens that can be used to synthesize cancer vaccines. In some illustrative embodiments, the mRNA-based cancer vaccine may have one or more of the following characteristics: a) the mRNAs encoding each cancer antigen are dispersed at cleavage-sensitive sites; b) the mRNAs encoding each cancer antigen are directly linked to each other without linkers; c) the mRNAs encoding each cancer antigen are linked to each other via single nucleotide linkers; d) each cancer antigen contains 20-40 amino acids and includes a centrally located SNP mutation; e) at least 40% of the cancer antigens have the highest affinity for class I MHC molecules from the subject; f) to At least 40% of the cancer antigens have the highest affinity for class II MHC molecules from the subject; g) at least 40% of the cancer antigens have a predicted binding affinity for HLA-A, HLA-B, and/or DRB1 with an IC > 500 nM; h) the mRNA encodes 1 to 15 cancer antigens; i) 10%–60% of the cancer antigens have a binding affinity for class I MHCs and 10%–60% of the cancer antigens have a binding affinity for class II MHCs; and/or j) the mRNAs encoding cancer antigens are arranged such that the cancer antigens are sequenced to minimize pseudoepitopes.

In various embodiments, a combination of a compound comprising Formula I' and a cancer vaccine immunotherapy agent as disclosed herein can be used to elicit an immune response against a cancer antigen in a subject. The method involves administering to a subject an RNA vaccine comprising at least one RNA polynucleotide having an open reading frame encoding at least one antigenic polypeptide or an immunogenic fragment thereof, thereby inducing an immune response in the subject specific to that antigenic polypeptide or immunogenic fragment thereof, said administration being combined with the administration of a compound of Formula I' in the same or separate compositions, and administered simultaneously or sequentially in doses, wherein the anti-antigen polypeptide antibody titer in the vaccinated subject is increased relative to the anti-antigen polypeptide antibody titer in a subject vaccinated with a conventional anticancer vaccine of prophylactic efficacy. An "anti-antigen polypeptide antibody" is a serum antibody that specifically binds to an antigenic polypeptide.

The preventive effective dose is a clinically acceptable therapeutically effective dose for preventing cancer development. In some embodiments, the therapeutically effective dose is the dose listed in the vaccine's packaging insert. As used herein, a conventional vaccine refers to a vaccine other than the mRNA vaccine of this invention. For example, conventional vaccines include, but are not limited to, live microbial vaccines, inactivated microbial vaccines, subunit vaccines, protein antigen vaccines, DNA vaccines, etc. In exemplary embodiments, a conventional vaccine is a vaccine that has already received regulatory approval and/or is registered by a national drug regulatory agency (such as the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA)).

In some implementations, the anti-antigen peptide antibody titer in subjects increases by 1 to 10 log compared to the titer in subjects vaccinated with a conventional anti-cancer vaccine that is effective in prevention. In some implementations, the anti-antigen peptide antibody titer in subjects increases by 1 log compared to the titer in subjects vaccinated with a conventional anti-cancer vaccine that is effective in prevention. In some implementations, the anti-antigen peptide antibody titer in subjects increases by 2 log compared to the titer in subjects vaccinated with a conventional anti-cancer vaccine that is effective in prevention.

Aspects of the present invention provide nucleic acid vaccines comprising one or more RNA polynucleotides having an open reading frame encoding a first antigenic polypeptide, wherein the RNA polynucleotide is present in a formulation for in vivo administration to a host, and confers an antibody titer superior to the serological protection standard for the first antigen in an acceptable percentage of human subjects. In some embodiments, the antibody titer generated by the mRNA vaccine of the present invention is a neutralizing antibody titer. In some embodiments, the neutralizing antibody titer is greater than that of a protein vaccine. In other embodiments, the neutralizing antibody titer generated by the mRNA vaccine of the present invention is greater than that of an adjuvanted protein vaccine. In other embodiments, the neutralizing antibody titers generated by the mRNA vaccine of the present invention are 1,000-10,000, 1,200-10,000, 1,400-10,000, 1,500-10,000, 1,000-5,000, 1,000-4,000, 1,800-10,000, 2,000-10,000, 2,000-5,000, 2,000-3,000, 2,000-4,000, 3,000-5,000, 3,000-4,000, or 2,000-2,500. Neutralizing titers are generally expressed as the highest serum dilution required to achieve a 50% reduction in plaque count.

In a preferred aspect, the RNA vaccine immunotherapeutic agent (e.g., an mRNA vaccine) of this disclosure produces levels, concentrations, and/or titers of antigen-specific antibodies in the blood or serum of vaccinated subjects that are effective in prevention and/or treatment. As defined herein, the term antibody titer refers to the amount of antigen-specific antibodies produced in a subject (e.g., a human subject). In an exemplary embodiment, antibody titer is expressed as the reciprocal of the highest dilution (among successive dilutions) that still yields a positive result. In an exemplary embodiment, antibody titer is determined or measured by enzyme-linked immunosorbent assay (ELISA). In an exemplary embodiment, antibody titer is determined or measured by a neutralization assay (e.g., by a micro-neutralization assay). In some aspects, antibody titer measurements are expressed as ratios, such as 1:40, 1:100, etc.

In exemplary embodiments of the invention, an effective vaccine produces antibody titers greater than 1:40, 1:100, 1:400, 1:1000, 1:2000, 1:3000, 1:4000, 1:500, 1:6000, 1:7500, or 1:10000. In exemplary embodiments, this antibody titer is produced or reached 10 days, 20 days, 30 days, 40 days, or 50 days or more after vaccination. In exemplary embodiments, this titer is produced or reached after administration of a single dose of the vaccine to the subject. In other embodiments, this titer is produced or reached after multiple doses, such as after a first dose and a second dose (e.g., a booster dose). In exemplary aspects of the invention, antigen-specific antibodies are measured in g/ml, or in IU/L (International Units per Liter) or mIU/ml (milli-International Units per ml). In exemplary embodiments of the present invention, an effective vaccine produces >0.5 μg/mL, >0.1 μg/mL, >0.2 μg/mL, >0.35 μg/mL, >0.5 μg/mL, >1 μg/mL, >2 μg/mL, >5 μg/mL, or >10 μg/mL. In exemplary embodiments of the present invention, an effective vaccine produces >10 mIU/mL, >20 mIU/mL, >50 mIU/mL, >100 mIU/mL, >200 mIU/mL, >500 mIU/mL, or >1000 mIU/mL. In exemplary embodiments, this antibody level or concentration is produced or reached 10 days, 20 days, 30 days, 40 days, or 50 days or more after vaccination. In exemplary embodiments, this level or concentration is produced or reached after administration of a single dose of vaccine to the subject. In other embodiments, the level or concentration is generated or reached after multiple doses, such as after a first dose and a second dose (e.g., a booster dose). In exemplary embodiments, the antibody level or concentration is determined or measured by an enzyme-linked immunosorbent assay (ELISA). In exemplary embodiments, the antibody level or concentration is determined or measured by a neutralization assay (e.g., by a micro-neutralization assay). Nucleic acid vaccines comprising one or more RNA polynucleotides having an open reading frame encoding a first antigenic polypeptide or a tandem polypeptide are also provided, wherein the RNA polynucleotide is present in a formulation for in vivo administration to a host to induce a higher antibody titer that is more durable than that induced by an mRNA vaccine having a stabilizing element or formulated with an adjuvant and encoding the first antigenic polypeptide. In some embodiments, the RNA polynucleotide is formulated to generate neutralizing antibodies within one week of a single administration. In some embodiments, the adjuvant is selected from cationic peptides and immunostimulatory nucleic acids. In some embodiments, the cationic peptide is protamine.

An immunotherapeutic agent comprising a nucleic acid vaccine, said nucleic acid vaccine comprising one or more RNA polynucleotides having an open reading frame containing at least one chemical modification or optionally without nucleotide modification, said open reading frame encoding a first antigenic polypeptide or a tandem polypeptide, wherein said RNA polynucleotide is present in a formulation for in vivo administration to a host such that the antigen expression level in the host is significantly higher than the antigen expression level produced by an mRNA vaccine having a stabilizing element or formulated with an adjuvant and encoding the first antigenic polypeptide.

Other aspects provide nucleic acid vaccines comprising one or more RNA polynucleotides having an open reading frame containing at least one chemically modified or optionally unmodified nucleotide, the open reading frame encoding a first antigenic polypeptide or a tandem polypeptide, wherein the vaccine has at least 10 times fewer RNA polynucleotides than an unmodified mRNA vaccine required to produce the same antibody titer. In some embodiments, the RNA polynucleotide is present in a dose of 25-100 micrograms.

The invention also provides a unit of use for a vaccine comprising between 10 μg and 400 μg of one or more RNA polynucleotides and a pharmaceutically acceptable carrier or excipient, said RNA polynucleotide having an open reading frame containing at least one chemical modification or optionally no nucleotide modification, said open reading frame encoding a first antigenic polypeptide or tandem polypeptide, said vaccine being formulated for delivery to a human subject. In some embodiments, the vaccine further comprises cationic lipid nanoparticles.

Aspects of the present invention provide methods for generating, maintaining, or restoring antigenic memory of a tumor in an individual or population of individuals, comprising administering an antigen-memory-enhancing nucleic acid vaccine to said individual or population, said vaccine comprising (a) at least one RNA polynucleotide, said polynucleotide comprising at least one chemically modified or optionally unmodified open reading frame and two or more codon-optimized open reading frames encoding a set of reference antigen peptides, and (b) optionally a pharmaceutically acceptable carrier or excipient. In some embodiments, the vaccine is administered to the individual via a route selected from intramuscular, intradermal, and subcutaneous administration. In some embodiments, the administration step includes contacting the subject's muscle tissue with a device suitable for injecting the composition. In some embodiments, the administration step includes combining electroporation to contact the subject's muscle tissue with a device suitable for injecting the composition.

An aspect of the present invention provides a method of vaccinating a subject, comprising administering to the subject a single dose of a nucleic acid vaccine in an amount effective for vaccinating the subject, between 25 μg/kg and 400 μg/kg, the nucleic acid vaccine comprising one or more RNA polynucleotides having an open reading frame encoding a first antigen polypeptide or a tandem polypeptide.

Other aspects provide nucleic acid vaccines comprising one or more RNA polynucleotides having an open reading frame containing at least one chemical modification encoding a first antigenic polypeptide or a tandem polypeptide, wherein the vaccine contains at least 10 times fewer RNA polynucleotides than an unmodified mRNA vaccine required to produce the same antibody titer. In some embodiments, the RNA polynucleotides are present in a dose of 25-100 micrograms.

In some embodiments, exemplary immunotherapeutic agents may include one or more interfering RNAs, which may be administered in combination with compounds of Formula I'. As used herein, "RNA interfering agent" is defined as any agent that interferes with or inhibits the expression of a target biomarker gene by RNA interference (RNAi). Such RNA interfering agents include, but are not limited to, nucleic acid molecules (including RNA molecules homologous to the target biomarker gene of the present invention), or fragments thereof, short interfering RNA (siRNA), and small molecules that interfere with or inhibit the expression of a target biomarker nucleic acid by RNA interference (RNAi). Short interfering RNA (siRNA), also referred to herein as "small interfering RNA," is defined as an agent that, for example, inhibits the expression of a target biomarker nucleic acid by RNAi. siRNA may be chemically synthesized, produced by in vitro transcription, or produced within host cells. In one embodiment, the siRNA is a double-stranded RNA (dsRNA) molecule of about 15 to about 40 nucleotides in length, preferably about 15 to about 28 nucleotides, more preferably about 19 to about 25 nucleotides, and even more preferably about 19, 20, 21, or 22 nucleotides, and may contain 3' and/or 5' overhangs of about 0, 1, 2, 3, 4, or 5 nucleotides in length on each strand. The length of the overhangs is independent between the two strands, i.e., the length of the overhang on one strand does not depend on the length of the overhang on the second strand. Preferably, the siRNA is capable of promoting RNA interference through the degradation of target messenger RNA (mRNA) or specific posttranscriptional gene silencing (PTGS).

The length of antisense oligonucleotides can be, for example, about 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 or more nucleotides. Antisense nucleic acids can be constructed using chemical synthesis and enzymatic ligation reactions, employing procedures known in the art. For example, antisense nucleic acids (e.g., antisense oligonucleotides) can be chemically synthesized using naturally occurring nucleotides or various modified nucleotides designed to increase the biological stability of the molecule or the physical stability of the duplex formed between antisense and sense nucleic acids, such as phosphate thioester derivatives and acridine-substituted nucleotides. Examples of modified nucleotides that can be used to generate antisense nucleic acids include 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine, 5-(carboxyhydroxymethyl)uracil, 5-carboxymethylaminomethyl-2-thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosylqueosine, inosine, N6-isopentenyladenine, 1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine, 7-methylguanine, 5-methylaminomethyluracil, 5-methyl... 2,6-diaminopurine, beta-D-mannosylqueosine, 5'-methoxycarboxymethyluracil, 5-methoxyuracil, 2-methylthio-N6-isopentenyladenine, uracil-5-oxyacetic acid (v), wybutoxosine, pseudouracil, queosine, 2-mercaptocytosine, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, methyl uracil-5-oxyacetic acid, uracil-5-oxyacetic acid (v), 5-methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl)uracil, (acp3)w, and 2,6-diaminopurine. Alternatively, antisense nucleic acids can be produced using biological methods using an expression vector, wherein the nucleic acid has been subcloned into the expression vector with an antisense orientation (i.e., the RNA transcribed from the inserted nucleic acid will have an antisense orientation with the target nucleic acid of interest, which will be further described in the following subsections).

The antisense nucleic acid molecules of the present invention are typically administered to a subject or generated in situ, such that they hybridize or bind to cellular mRNA and/or genomic DNA encoding a polypeptide corresponding to a selected biomarker of the present invention, thereby inhibiting the expression of the biomarker, for example, by inhibiting transcription and/or translation. Hybridization can be performed by conventional nucleotide complementarity to form a stable duplex or, for example, by specific interactions in the major groove of the double helix in the case of antisense nucleic acid molecules bound to a DNA duplex. Examples of administration routes of the antisense nucleic acid molecules of the present invention include direct injection at a tissue site or infusion of the antisense nucleic acid into blood or bone marrow-related fluids. Alternatively, the antisense nucleic acid molecules can be modified to target selected cells and then administered systemically. For example, for systemic administration, the antisense molecules can be modified such that they specifically bind to a receptor or antigen expressed on the surface of a selected cell, for example, by linking the antisense nucleic acid molecules to a peptide or antibody that binds to a cell surface receptor or antigen. The antisense nucleic acid molecules can also be delivered to cells using the vectors described herein. To obtain sufficient intracellular concentrations of antisense molecules, it is preferable that the antisense nucleic acid molecules are placed under the control of a strong pol II or pol III promoter.

Antigens that can be targeted to synthesize corresponding antisense RNA molecules may include any antigens specific to one or more tumors, such as the antigens exemplified above in relation to cancer vaccines.

In some embodiments, the combination of an immunotherapeutic agent and a compound of formula I' may include a bispecific antibody immunotherapeutic agent. The bispecific antibody may include a protein construct having a first antigen-binding moiety and a second antigen-binding site that binds to cytotoxic immune cells. The first antigen-binding site may bind to a tumor antigen to be specifically treated by the combination of the present invention. For example, the first antigen-binding moiety may bind to non-limiting examples of tumor antigens selected from: EGFR, HGFR, Her2, Ep-CAM, CD20, CD30, CD33, CD47, CD52, CD133, CEA, gpA33, mucin, TAG-72, CIX, PSMA, folate-binding protein, GD2, GD3, GM2, VEGF, VEGFR, integrin αVβ3, integrin α5β1, MUC1, ERBB2, ERBB3, MET, IGF1R, EPHA3, TRAILR1, TRAILR2, RANKL, FAP, and tendinin, etc. In some embodiments, the first antigen-binding moiety is specific for proteins or peptides overexpressed on tumor cells compared to corresponding non-tumor cells. As used herein, "corresponding non-tumor cells" refers to non-tumor cells of the same cell type as the tumor cells. Note that such proteins are not necessarily different from tumor antigens. Non-limiting examples include carcinoembryonic antigen (CEA), which is overexpressed in most colon, rectal, breast, lung, pancreatic, and gastrointestinal cancers; hyalin receptors (HER-2, neu, or c-erbB-2), which are frequently overexpressed in breast, ovarian, colon, lung, prostate, and cervical cancers; epidermal growth factor receptor (EGFR), which is highly expressed in a range of solid tumors including breast, head and neck, non-small cell lung cancer, and prostate cancer; desialylate glycoprotein receptor; transferrin receptor; serine protease inhibitor enzyme complex receptor, which is expressed on hepatocytes; fibroblast growth factor receptor (FGFR), which is overexpressed on pancreatic duct adenocarcinoma cells; vascular endothelial growth factor receptor (VEGFR), used for anti-angiogenic gene therapy; folate receptor, which is selectively overexpressed in 90% of non-mucinous ovarian cancers; cell surface glycocalyx; carbohydrate receptors; and polymerase receptors.

The second antigen-binding moiety is any molecule that specifically binds to an antigen, protein, or polypeptide expressed on the surface of a cytotoxic immune cell (CIK cell). Exemplary non-restricted antigens suitable for use with this disclosure and expressed on the surface of cytotoxic immune cells may include CD2, CD3, CD4, CD5, CD8, CD11a, CD11b, CD14, CD16a, CD27, CD28, CD45, CD45RA, CD56, CD62L, Fc receptor, LFA, LFA-1, TCRαβ, CCR7, macrophage inflammatory protein 1a, perforin, PD-1, PD-L1, PD-L2 or CTLA-4, LAG-3, OX40, 41BB, LIGHT, CD40, GITR, TGF-β, TIM-3, SIRP-α, TIGIT, VSIG8, BTLA, SIGLEC7, SIGLEC9, ICOS, B7H3, B7H4, FAS, BTNL2, CD27, and Fas ligand. In some embodiments, the second antigen-binding portion binds to CD3 of cytotoxic immune cells (e.g., CIK cells). In some embodiments, the second antigen-binding portion binds to CD56 of cytotoxic immune cells. In some embodiments, the second antigen-binding portion binds to the Fc receptor of cytotoxic immune cells. In some embodiments, the Fc region of a bispecific antibody binds to the Fc receptor of cytotoxic immune cells. In some embodiments, the second antigen-binding portion is any molecule that specifically binds to an antigen expressed on the surface of cytotoxic immune cells (e.g., CIK cells). The second antigen-binding portion is specific to the antigen on the cytotoxic immune cells. Exemplary cytotoxic immune cells include, but are not limited to, CIK cells, T cells, CD8+ T cells, activated T cells, monocytes, natural killer (NK) cells, NK T cells, lymphokine-activated killer (LAK) cells, macrophages, and dendritic cells. The second antigen-binding portion specifically binds to an antigen expressed on the surface of the cytotoxic immune cells. Exemplary non-restricted antigens suitable for regulation on the surface of cytotoxic immune cells may include CD2, CD3, CD4, CD5, CD8, CD11a, CD11b, CD14, CD16a, CD27, CD28, CD45, CD45RA, CD56, CD62L, Fc receptor, LFA, LFA-1, TCRαβ, CCR7, macrophage inflammatory protein 1a, perforin, PD-1, PD-L1, PD-L2 or CTLA-4, LAG-3, OX40, 41BB, LIGHT, CD40, GITR, TGF-β, TIM-3, SIRP-α, TIGIT, VSIG8, BTLA, SIGLEC7, SIGLEC9, ICOS, B7H3, B7H4, FAS, BTNL2, CD27, and Fas ligand. In other embodiments, the bispecific antibody modulator is an activator of a co-stimulatory molecule (e.g., an OX40 agonist). In one embodiment, the OX40 agonist is a bispecific antibody molecule of OX40 and another tumor antigen or co-stimulatory antigen. The OX40 agonist may be administered alone or in combination with other immunomodulators, such as with inhibitors (e.g., antibody constructs) of PD-1, PD-L1, CTLA-4, CEACAM (e.g., CEACAM-1, -3, and/or -5), TIM-3, or LAG-3. In some embodiments, the anti-OX40 antibody molecule is a bispecific antibody that binds to GITR and PD-1, PD-L1, CTLA-4, CEACAM (e.g., CEACAM-1, -3, and/or -5), TIM-3, or LAG-3. In one exemplary embodiment, the OX40 antibody molecule is administered in combination with an anti-PD-1 antibody molecule (e.g., the anti-PD-1 molecule described herein). The OX40 antibody molecule and the anti-PD-1 antibody molecule can be in the form of separate antibody compositions or as bispecific antibody molecules. In other embodiments, the OX40 agonist can be administered in combination with other co-stimulatory molecules (e.g., agonists of GITR, CD2, CD27, CD28, CDS, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), 4-1BB (CD137), CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3, or CD83 ligands). In some embodiments, the second antigen-binding portion binds to Fc receptors on cytotoxic immune cells (e.g., CIK cells).

In some embodiments, the bispecific antibody immunotherapy agent is specific to both tumor antigens and CIK cells, which allows tumor cells expressing tumor antigens to approach CIK cells closely, resulting in the elimination of tumor cells through anti-tumor cytotoxicity of CIK cells. In some embodiments, the bispecific antibody is specific to tumor antigens but not to CIK cells; however, the Fc region of the bispecific antibody can bind to the Fc receptors of CIK cells, which in turn allows tumor cells to approach CIK cells closely, resulting in the elimination of tumor cells through anti-tumor cytotoxicity of CIK cells. In some embodiments, the bispecific antibody is specific to CIK cells but not to tumor cells; however, the Fc region of the bispecific antibody can bind to the Fc receptors of tumor cells, which in turn allows tumor cells to approach CIK cells closely, resulting in the elimination of tumor cells through anti-tumor cytotoxicity of CIK cells.

In some embodiments, the combination of an immunotherapeutic agent and a compound of formula I' may comprise an immune cell-conjugated multivalent antibody/fusion protein/construct immunotherapeutic agent. In various embodiments, exemplary immunotherapeutic agents may comprise immune cell-conjugated multivalent antibodies/fusion proteins/constructs, which may contain recombinant structures, such as engineered antibodies that do not mimic the original IgG structure. Different strategies for polymerizing antibody fragments are utilized here. For example, shortening the peptide linker between the V domains forces scFv to self-associate into a dimer (biantibody; 55 kDa). Bispecific biantibodies are formed by the non-covalent binding of two VHA-VLB and VHB-VLA fragments expressed in the same cell. This results in the formation of a heterodimer with two different binding sites. Single-chain biantibodies (sc-biantibodies) are bispecific molecules in which the VHA-VLB and VHB-VLA fragments are linked together by an additional third linker. Tandem biantibodies (Tandabs) are tetravalent bispecific antibodies generated from two sc-biantibodies.

Also included are bi-biantibodies known in the art. This 130-kDa molecule is formed by fusing a biantibody to the N-terminus of the CH3 domain of IgG, resulting in an IgG-like structure. Other biantibody derivatives are triantibodies and tetraantibodies, which fold into trimer and tetrameric fragments by shortening the linker to <5 or 0-2 residues. Also exemplified is the (scFv) ₂ construct known as the 'bispecific T-cell adaptor' (BITE). BITE is a bispecific single-chain antibody consisting of two scFv antibody fragments linked by a flexible linker targeting surface antigens on target cells and CD3 on T cells. Bivalent (Fab)2 and trivalent (Fab)3 antibody forms are also exemplified. Microbodies and trimers generated from scFv are also exemplified. Exemplary constructs that can be used to target tumor antigens may include one or more of the following: double-stranded antibodies, single-stranded (sc)-double-stranded antibodies (scFv)2, microantibodies, microbodies, Barnase-barstar, scFv-Fc, sc(Fab)2, trimer antibody constructs, triple-stranded antibody constructs, trimer antibody constructs, trisomic antibody constructs, collagen scaffold antibody constructs, (scFv-TNFa)3, and F(ab)3/DNL. In each of these exemplary constructs, at least one binding portion may bind to an antigen or protein or peptide expressed on the surface of a cytotoxic immune cell, and at least one binding portion will specifically bind to the antigen on the cytotoxic immune cell. Exemplary cytotoxic immune cells include, but are not limited to, CIK cells, T cells, CD8+ T cells, activated T cells, monocytes, natural killer (NK) cells, NK T cells, lymphokine-activated killer (LAK) cells, macrophages, and dendritic cells.

In some embodiments, the combination of the immunotherapeutic agent and the compound of formula I' may include a radioconjugated immunotherapeutic agent.

In various embodiments, a radioconjugate is a small or large molecule (referred to herein as a “cell target”) and peptide, antibody, or antibody fragment thereof coupled to or otherwise attached to a radionuclide or multiple radionuclides, such that the binding of the radioconjugate to its target (a protein or molecule on or in a cancer cell) will lead to the death or pathogenesis of said cancer cell. In various embodiments, the radioconjugate may be a cell target labeled with a radionuclide, or the cell target may be coupled to or otherwise attached to particles, microparticles, or nanoparticles containing multiple radionuclides, wherein these radionuclides may be the same or different. Methods for synthesizing radioconjugates are known in the art and may include a classification of immunoglobulins or their antigen-binding moieties conjugated to toxic radionuclides.

In some embodiments, the molecule that binds to cancer cells may be referred to as a “cell target.” As used herein, exemplary cell targets may allow drug-containing nanoparticles or radionuclides to target specific types of cells of interest. Examples of cell targets include, but are not limited to, small molecules (e.g., folic acid, adenosine, purines) and large molecules (e.g., peptides or antibodies) that bind to or target tumor-associated antigens. Examples of tumor-associated antigens include, but are not limited to, adenosine receptor, αvβ3, aminopeptidase P, alpha-fetoprotein, cancer antigen 125, carcinoembryonic antigen, c-cryptin-1, chemokine receptor, cluster protein, tumor-associated antigen, CD20, epithelial tumor antigen, melanoma-associated antigen, Ras, p53, Her2/Neu, ErbB2, ErbB3, ErbB4, folic acid receptor, prostate-specific membrane antigen, prostate-specific antigen, purine receptor, radiation-induced cell surface receptor, serine protease inhibitor B3, serine protease inhibitor B4, squamous cell carcinoma antigen, platelet-reactive protein, tumor antigen 4, tumor-associated glycoprotein 72, tyrosinase, and tyrosine kinase. In some embodiments, the cell target is folic acid or a folic acid derivative that specifically binds to the folic acid receptor (FR). In some embodiments, the cell target is an antibody, bispecific antibody, trispecific antibody, or antigen-binding construct thereof that specifically binds to a cancer antigen selected from: EGFR, HGFR, Her2, Ep-CAM, CD20, CD30, CD33, CD47, CD52, CD133, CEA, gpA33, mucin, TAG-72, CIX, PSMA, folic acid-binding protein, GD2, GD3, GM2, VEGF, VEGFR, integrin αVβ3, integrin α5β1, MUC1, ERBB2, ERBB3, MET, IGF1R, EPHA3, TRAILR1, TRAILR2, RANKL, FAP, and tendinin, etc.

The use of folic acid as a targeting agent in radioactive conjugates also allows for the targeted destruction of both tumor cells and regulatory T (Treg) cells. It is well known that a large number of Treg cells suppress tumor immunity. Specifically, Treg cells suppress (exogenous and autologous) reactive T cells without killing them through contact-dependent or cytokine secretion (e.g., IL-10, TGF-β, etc.). FR4 is selectively upregulated on Treg cells. It has been shown that antibody blocking of FR4 in tumor-bearing mice depletes Treg cells and stimulates tumor immunity. Therefore, folic acid-coated PBM nanoparticles carrying cytotoxic agents will take up FR-expressing cells for destruction, which will directly (i.e., BrCa cells) and indirectly (i.e., breast tumor-associated and peripheral Treg cells) inhibit tumor progression.

In another embodiment, the target is an antibody or peptide capable of binding to tumor-associated antigens, or an immune cell-conjugating multivalent antibody/fusion protein/construct, said antigens including but not limited to: adenosine receptor, αvβ3, aminopeptidase P, alpha-fetoprotein, cancer antigen 125, carcinoembryonic antigen, caveolin-1, chemokine receptor, cluster protein, tumor-associated antigen, CD20, human growth factor receptor (HGFR), epithelial tumor antigen, melanoma-associated antigen, MUC1, Ras, p53, Her2/Neu, ErbB2, ErbB3, ErbB4, folate receptor, prostate-specific membrane antigen, prostate-specific antigen, purine receptor, radiation-induced cell surface receptor, serine protease inhibitor B3, serine protease inhibitor B4, squamous cell carcinoma antigen, platelet-reactive protein, tumor antigen 4, tumor-associated glycoprotein 72, tyrosinase, tyrosine kinase, etc.

In one embodiment, the treatment method comprises co-administering a compound as disclosed herein or a pharmaceutically acceptable salt thereof and at least one cytotoxic agent. As used herein, the term "cytotoxic agent" refers to a substance that inhibits or prevents cell function and/or causes cell death or destruction. Cytotoxic agents include, but are not limited to: radioisotopes (e.g., radioisotopes of At ²¹¹ , I ¹³¹ , I ¹²⁵ , Y ⁹⁰ , Re ¹⁸⁶ , Re ¹⁸⁸ , Sm ¹⁵³ , Bi ²¹² , P ³² , Pb ²¹² , and Lu); chemotherapeutic agents; growth inhibitors; enzymes and fragments thereof, such as lysozymes; and toxins, such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant, or animal origin, including fragments and/or variants thereof.

Exemplary cytotoxic agents may be selected from anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotics, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormone analogs, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, pro-apoptotic agents, LDH-A inhibitors; fatty acid biosynthesis inhibitors; cell cycle signal transduction inhibitors; HDAC inhibitors, proteasome inhibitors; and cancer metabolism inhibitors.

Chemotherapy agents include chemical compounds used to treat cancer. Examples of chemotherapy agents include erlotinib (Genentech/OSIPharm), bortezomib (Millennium Pharm), disulfiram, epigallocatechin gallate, salinomycin A, carfilzomib, 17-AAG (gerdemycin), rhizobactam, lactate dehydrogenase A (LDH-A), fulvestrant (AstraZeneca), sunitinib (Pfizer/Sugen), letrozole (Novartis), imatinib mesylate (Novartis), and phenacetinib. (finasunate)(Novartis), oxaliplatin (Sanofi), 5-FU (5-fluorouracil), leucovorin, rapamycin (Sirolimus, Wyeth), lapatinib (GSK572016, Glaxo SmithKline), lonafazil (Lonafamib)(SCH 66336), sorafenib (Bayer Labs), gefitinib (AstraZeneca), AG1478; alkylating agents, such as thiotepa and cyclophosphamide; alkyl sulfonates, such as busulfan, inprofen, and piperazine; nitrogen Propidine, such as benzodopa, carboquinone, meturedopa, and uredopa; ethylene imine and methylmelamine, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylomelamine; Anthocyanins (especially bullatacin and bullatacinone); camptothecin (including topotecan and irinotecan); bryostatin; callystatin; CC-1065 (including its synthetic analogues adozelesin, carzelesin, and bizelesin); cryptophycins (especially cryptophycin 1 and cryptophycin 8); corticosteroids (including prednisone and prednisolone); acetic acid Cyproterone acetate; 5α-reductase (including finasteride and dutasteride); vorinostat, romidepsin, panobinostat, valproic acid, moxistatin, dolastatin; interleukin, talc duocarmycin (including synthetic analogs KW-2189 and CB1-TM1); eleutherobin; pancratistatin; sarcodictyin; spongistatin (spongistatin); nitrogen mustard, such as chlorambucil, naphthyl mustard, chlorphosphamide, estradiol, ifosfamide, nitrogen mustard, oxynitric acid mustard, melphalan, neonitric acid mustard, benzyl mustard cholesterol, pine monoxide benzyl mustard, tristyramine cyclophosphamide, uracil nitrogen mustard; nitrosourea, such as carmustine, chloramphenicol, formustine, lomustine, nimustine, and ranistine; antibiotics, such as enediyne antibiotics (e.g., galicarmycin, especially galicarmycin γ1I and galicarmycin ω1I (Angew Chem. Intl. Ed. Engl. 1994 33:183-186); dyinmycin, including This includes dysinic A; bisphosphonates, such as clophosphonate; esporamin; and neocarzinostatin chromophores and related chromoprotein endothymyl antibiotic chromophores, aclarubicin, actinomycin, autramycin, azoserine, bleomycin, cactinomycin C, carabicin, caminomycin, carzinophilin, chromomycin, and more. Doxorubicin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-leucine, (daunorubicin), morpholino-daunorubicin, cyanomorpholino-daunorubicin, 2-pyrrolino-daunorubicin and deoxydaunorubicin, epirubicin, isorubicin, idarubicin, marcellomycin, mitomycin such as mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, porfiromycin Cin, puromycin, quelamycin, rodorubicin, streptozocin, tuberculin, ubenimex, zinostatin, zorubicin; antimetabolites, such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs, such as folate, methotrexate, pteroxate, trimethoprim; purine analogs, such as fludarabine, 6-mercaptopurine, thioimidapurine, thioguanine; pyrimidine analogs, such as ancitabine and azacitidine. 6-azauridine, carmoflurane, cytarabine, dideoxyuridine, deoxyfluorouridine, enoxabin, fluorouridine; androgens, such as calotestosterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; antiadrenergics, such as aminoglutethimide, mitotane, trilostane; folic acid supplements, Such as leucovorin; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithi ne); elliptinium acetate; epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansine alkaloids, such as maytansine and anthraquinone; mitoxanthraquinone; mopidamnol; nitraerine; pentostatin ); Phenamet; Pirarubicin; Loxoanthraquinone; Podophyllinic acid; 2-Ethylhydrazide; Procarbazine; Polysaccharide complex (JHS Natural Products, Eugene, Ore.); Razoxane; Rhizoxin; Sizofuran; Spirogermanium; Tenuazonic acid; Triaziquone; 2,2’ ,2”-Trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A, and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactalol; piperobroman; g acytosine; cytarabine (“Ara-C”); cyclophosphamide; thiotepa; taxanes, such as TAXOL (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, N.J.), (cremophor-free), albumin-engineered nanoparticle formulations of paclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.), and (docetaxel, docetaxel; Sanofibrils) i-Aventis; chloranmbucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vincristine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; vinorelbine; mitoxantrone; teniposide; edaraxacin; donomycin; aminopterin; capecitabine ibandronate; CPT-11; topoisomerase inhibitor RFS2000; difluoromethylornithine (DMFO); visual pigments such as retinoic acid; and pharmaceutically acceptable salts, acids, and derivatives of any of the above.

Chemotherapy agents also include (i) anti-hormonal agents that act to regulate or inhibit the effects of hormones on tumors, such as anti-estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including tamoxifen citrate), raloxifene, droloxifen, iodoxyfene, 4-hydroxytamoxifen, trivoxifen, keoxifene, LY117018, onanasone, and toremifene citrate; (ii) aromatase inhibitors that inhibit aromatase production in the adrenal glands, such as 4(5)-imidazole, aminoglutethimide, megestrol acetate, exemestane, formestanie, fadrozole, vorozole, letrozole, and anastrozole; and (iii) anti-androgens, such as flutamide, nitroglycerin, etc. Mite, bicalutamide, leuprorelin and goserelin; buserelin, tripterelin, medroxyprogesterone acetate, diethylstilbestrol, premarin, fluoromethesterone, all-trans retinoids, fenivel-Aminide and trisatabine (1,3-dioxane-1,3-cytosine analog); (iv) protein kinase inhibitors; (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, particularly those that inhibit gene expression in signaling pathways involved in abnormal cell proliferation, such as PKC-α, Ralf and H-Ras; (vii) ribozymes, such as VEGF expression inhibitors (e.g.) and HER2 expression inhibitors; (viii) vaccines, such as gene therapy vaccines, such as rIL-2; topoisomerase 1 inhibitors, such as (ix) pharmaceutically acceptable salts, acids and derivatives of any of the above.

Chemotherapy agents also include antibodies as described above, including alemtuzumab (Campath), bevacizumab (Genentech); cetuximab (Imclone); panitumumab (Amgen), rituximab (Genentech/Biogen Idec), pertuzumab (2C4, Genentech), trastuzumab (Genentech), tosimoumab (Bexxar, Corixia), and the antibody conjugate gemtuzumab ozomicin (Wyeth). Other humanized monoclonal antibodies with therapeutic potential that can be combined with the compounds of the present invention as agents include: apolizumab, acelizumab, atlizumab, bapineuzumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumabpegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, and erlizumab. Monoclonal antibodies (erlizumab), felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motovizumab, natalizumab, nimotuzumab, nivolumab, nolovizumab, numavizumab, ocrel izumab), omalizumab, palivizumab, pascolizumab, pecfusituzumab, pectuzumab, pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab, resyvizumab, rovelizumab, ruplizumab, sibrotuzumab, siplizumab, sontuzumab, tacatuzumab tesetan The anti-interleukin-12 antibody includes raxetan, tadocizumab, talizumab, tefibazumab, tocilizumab, totalizumab, tucotuzumabcelmoleukin, tucusituzumab, umavizumab, urtoxazumab, ustekinumab, visilizumab, and a genetically modified recombinant exclusive human full-length IgG sub.1.λ antibody that recognizes the interleukin-12 p40 protein (ABT-8744695, Wyeth Research and Abbott Laboratories).

Chemotherapy agents also include "tyrosine kinase inhibitors," including EGFR inhibitors; small molecule HER2 tyrosine kinase inhibitors, such as mubritonib (TAK165, Takeda); CP-724.714 (Axon Medchem BV, an orally selective inhibitor of ErbB2 receptor tyrosine kinase); dual HER inhibitors, such as EKB-569 (purchased from Wyeth), which preferentially binds to EGFR but inhibits both HER2 and EGFR-overexpressing cells; lapatinib (GSK572016; purchased from Glaxo-SmithKline), an orally administered HER2 and EGFR tyrosine kinase inhibitor; PKI-166 (purchased from Novartis); pan-HER inhibitors, such as canenatinib (CI-1033; Ph armacia); Raf-1 inhibitors, such as the antisense agent ISIS-5132, which inhibits Raf-1 signaling, purchased from ISIS Pharmaceuticals; non-HER-targeted TK inhibitors, such as imatinib mesylate (purchased from Glaxo SmithKline); multi-targeted tyrosine kinase inhibitors, such as sunitinib (purchased from Pfizer); VEGF receptor tyrosine kinase inhibitors, such as vatalanib (PTK787/ZK222584, purchased from Novartis/Schering AG); MAPK extracellular regulated kinase 1 inhibitor CI-1040 (purchased from Pharmacia); quinazolines, such as PD 153035, 4-(3-chloroaniline)quinazoline; pyridopyrimidine; pyrimidine; pyrrolopyrimidine, such as C GP 59326, CGP 60261, and CGP 62706; pyrazolopyrimidine, 4-(phenylamino)-7H-pyrrolo[2,3-d]pyrimidine; curcumin (diferoylmethane, 4,5-bis(4-fluoroaniline)phthalimide); tyrosine phosphorylation containing a nitrothiophene moiety; antisense molecules (e.g., those that bind to nucleic acids encoding HER); quinoxaline (US Patent No. 5,804,396); tryphostins (US Patent No. 5,804,396); affinitac (ISIS 3521; Isis/Lilly); PKI166 (Novartis); semaxinib (Pfizer); INC-1C11 (Imclone); [unclear text - possibly a brand name or product] Paramycin (Sirolimus); or as described in any of the following patent disclosures: U.S. Patent No. 5,804,396; WO 1999/09016 (American Cyanamid); WO 1998/43960 (American Cyanamid); WO 1997/38983 (Warner Lambert); WO 1999/06378 (Warner Lambert); WO 1999/06396 (Warner Lambert); WO 1996/30347 (Pfizer, Inc.); WO 1996/33978 (Zeneca); WO 1996/3397 (Zeneca) and WO 1996/33980 (Zeneca). Tyrosine kinase inhibitors also include erlotinib, gefitinib, dasatinib, nilotinib, ruxotinib, vemurafenib, vande, tanipazol, panib, afatinib, alisertinib, amovatinib, axitinib, bosutinib, brivanib, canertinib, cabozantinib, cediranib, and crenolan. ib), dabrafenib, dacomitinib, danusertib, dovitinib, foretinib, ganesteb, ibrutinib, iniparib, lenvatinib, linifanib, linsitinib, masitinib, molotinib momelotinib, motesanib, neratinib, niraparib, oprozomib, olaparib, pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, saracatinib (ib), saridegib, tandutinib, tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, trametinib, veliparib, vismodegib, volasertib, cobimetinib, etc.

Chemotherapy agents also include dexamethasone, interferon, colchicine, metoprine, cyclosporine, amphotericin B, metronidazole, alemtuzumab, retinoic acid, allopurinol, amifostine, arsenic trioxide, asparaginase, BCG live vaccine, bevacizumab, bexarotine, cladribine, clofarabine, darbepoetine alpha, denileukin, dextromethorphan, and epioetin alpha. Alfa, erlotinib, filgrastim, histamine acetate, ibritumomab, interferon alpha-2a, interferon alpha-2b, lenalidomide, levamisole, mesna, methoxsalen, nandrolone, nelarabine, nofetumomab, op-leukin Relvekin), palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim, pemetrexed disodium, plicamycin, porfimer sodium, quinacrine, rasburicase, sargramostim, temozolomide, VM-26, 6-TG, toremifene, tretinoin, ATRA, valrubicin, zoledronate, and zoledronic acid, as well as their pharmaceutically acceptable salts.

Chemotherapy agents also include hydrocortisone, hydrocortisone acetate, tixocortol pivalate, triamcinolone, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinolone acetonide, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluclocolone, hydrocortisone-17-butyrate, hydrocortisone-17-valerate, aclometasone dipropionate, betamethasone valerate, and betamethasone dipropionate. dipropionate, prednicarbamate, clobetasol-17-butyrate, clobetasol-17-propionate, fluocortolone hexanoate, fluocortolone pivalate, and fluprednidene acetate; immunoselective anti-inflammatory peptides (ImSAIDs), such as phenylalanine-glutamine-glycine (FEG) and its D-isomer (feG) (IMULAN) BioTherapeutics, LLC; antirheumatic drugs, such as azathioprine, cyclosporine (cyclosporine A), D-penicillamine, gold salts, hydroxychloroquine, leflunomide, sulfasalazine, tumor necrosis factor α (TNFα) blockers (such as etanercept (Enbrel), infliximab (Remicade), adalimumab (1-Iumira), cetuzumab (Cimzia), golimumab (Simponi)), interleukin-1 (IL-1) blockers (such as anaerobicin (Kineret)), and T-cell co-stimulation blockers (such as abatacept). (abatacept)(Orencia)), interleukin-6 (IL-6) blockers such as tocilizumab; interleukin-13 (IL-13) blockers such as lebrikizumab; interferon-alpha (IFN) blockers such as rontalizumab; β7 integrin blockers such as rhuMAbβ7; IgE pathway blockers such as anti-M1 initiators; secretory homotrimer LTa3 and membrane-bound heterotrimer LTa1/132 blockers such as anti-lymphotoxin alpha (LTa); mixed investigation agents such as thioplatin, PS-341, phenyl butyrate, ET-18-OCH ₃ or farnesyltransferase inhibitors (L-739749, L-744832); polyphenols, such as quercetin, resveratrol, leucine, epigallocatechin gallate, theaflavins, flavanols, proanthocyanidins, betulinic acid and their derivatives; autophagy inhibitors, such as chloroquine; δ-9-tetrahydrocannabinol (drocannabinol); β-lapachone; laparol; colchicine; betulinic acid; acetylcamptothecin, scopolamine and 9-aminocamptothecin); podophyllotoxin; tegafur bexarotine bisphosphonates, such as clodronate (e.g., or), etidronate NE-58095, zoledronic acid/zoledronic acid alendronate pamidronate teludronate or risedronate and epidermal growth factor receptor (EGF-R); vaccines, etc. Examples of such treatments include vaccines; perifosine, COX-2 inhibitors (e.g., celecoxib or etoricoxib), protein body inhibitors (e.g., PS341); CCI-779; tipifarnib (R11577); orafenib (ABT510); Bcl-2 inhibitors, such as GENASENSE (pisenoside); farnesyltransferase inhibitors, such as lonafamib (SCH6636, SARASAR ^™ ); and pharmaceutically acceptable salts, acids, or derivatives of any of the above; and combinations of two or more of the above, such as CHOP, an abbreviation for combination therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone; and FOLFOX, an abbreviation for oxaliplatin (ELOXATIN ^™ ) combined with 5-FU and leucovorin.

Chemotherapy agents also include poly-ADP-ribose polymerase (PARP) inhibitors: olapaline, nirapaline, and talzoparib.

Effective combinations of compounds of Formula I' or any of the formulas described herein with other agents can be identified through preclinical and clinical testing of the combination and will depend on many factors, including disease type and stage of development, patient's overall health, agent toxicity and side effects, etc.

In some embodiments, compounds such as those disclosed herein may be used in combination therapy with any of the kinase inhibitors disclosed herein for the treatment of diseases such as cancer. Exemplary kinase inhibitors include imatinib, baricitinib, gefitinib, erlotinib, sorafenib, dasatinib, sunitinib, lapatinib, nilotinib, pirfenidone, pazopanib, crizotinib, vemurafenib, vandetanib, ruxotinib, axitinib, bosutinib, regorafenib, tofacitinib, cabozantinib, panatinib, trametinib, dabrafenib, afatinib, ibrutinib, ceritinib, idelalisib, nintedanib, palbociclib, lenvatinib, cobitinib, XL-147, XL-765, XL-499, and XL-880. In some embodiments, the compounds described herein may be used in combination with HSP90 inhibitors (e.g., XL888), hepatic X receptor (LXR) modulators, orphan receptor γ (RORy) modulators associated with visual pigments, CK1 inhibitors, CK1-α inhibitors, Wnt pathway inhibitors (e.g., SST-215), or mineralocorticoid receptor inhibitors (e.g., ethacetenone or XL-550) for the treatment of diseases disclosed herein, such as cancer.

In some implementations, for the treatment of cancer, the compounds disclosed herein may be used in combination with inhibitors of PD-1 or PD-L1, such as anti-PD-1 monoclonal antibodies or anti-PD-L1 monoclonal antibodies, such as nivolumab (Opdivo), pembrolizumab (Keytruda, MK-3475), atezolizumab, ovavamab, AMP-224, AMP-514, PDR001, and duruvalumab. ), pildizumab (CT-011), CK-301, BMS 936559 and MPDL3280A; CTLA-4 inhibitors, such as anti-CTLA-4 antibodies, such as ipilimumab (Yervoy) and tesilimumab; and phosphatidylserine inhibitors, such as bavitimab (PGN401); antibodies against cytokines (IL-10, TGF-β, etc.); and other anticancer agents, such as cimetizumab.

In some embodiments, the compounds described herein may be used in combination with vaccination regimens for the treatment of cancer. In some embodiments, the compounds described herein may be used in combination with vaccines to stimulate an immune response to pathogens, toxins, and self-antigens. Examples of pathogens for which this treatment may be particularly useful include pathogens for which there are currently no effective vaccines, or pathogens for which conventional vaccines are not entirely effective. These include, but are not limited to, HIV, hepatitis (A, B, and C), influenza, herpes, Giardia, malaria, Leishmania, Staphylococcus aureus, and Pseudomonas aeruginosa.

In some embodiments, compounds such as those disclosed herein can be used in combination with PARP inhibitors, such as olapapani, rucapinini, lapapani, and tazopani.

The amounts of the compounds disclosed herein, or salts thereof, and one or more additional therapeutic agents (in those compositions comprising additional therapeutic agents as described above) that can be combined with a carrier material to produce a single dosage form will vary depending on the host being treated and the specific administration method. In some embodiments, the compositions of the invention are formulated such that a dose of 0.01-100 mg/kg body weight/day can be administered.

The additional therapeutic agent and the compounds disclosed herein can act synergistically. Therefore, the amount of the additional therapeutic agent in such compositions may be less than that required in a monotherapy using only the therapeutic agent, or, with the use of lower doses, fewer side effects may occur for the patient. In some embodiments, in such compositions, an additional therapeutic agent may be administered at a dose of 0.01-10,000 μg/kg body weight/day.

Labeled compounds and assay methods

Another aspect of the invention relates to the labeled compounds (radiolabeled, fluorescently labeled, etc.) of the invention, which can be used not only in imaging techniques but also in vitro and in vivo assays for locating and quantifying TAM kinases in tissue samples (including humans) and for identifying TAM kinase ligands by inhibiting the binding of the labeled compounds. Therefore, the invention includes TAM kinase assays containing such labeled compounds.

This invention also includes isotopically labeled compounds of the invention. An "isotopic" or "radiolabeled" compound is a compound of the invention in which one or more atoms are replaced or substituted with atoms having an atomic mass or mass number different from those normally found in nature (i.e., naturally occurring). Suitable radionuclides that can be incorporated into the compounds of the invention include, but are not limited to, ^2H (also written as D for deuterium), ^3H (also written as T for tritium), ^11C , ^13C , ^14C , ^13N , ^15N , ^15O , ^17O , ^18O , ^18F , ^35S , ^36Cl , ^82Br , ^75Br , ^76Br , ^77Br , ^123I , ^124I , ^125I , and ^131I . The radionuclides incorporated into the radiolabeled compounds of the invention will depend on the specific application of the radiolabeled compound. For example, for in vitro metalloproteinase labeling and competitive assays, compounds doped with ^3H , ^14C , ^82Br , ^125I , ^131I , or ^35S will generally be most useful. For radio imaging applications, ^11C , ^18F , ^125I , ^123I , ^124I , ^131I , ^75Br , ^76Br , or ^77Br will generally be most useful.

It should be understood that "radiolabeled" or "labeled compound" is a compound that has been doped with at least one radionuclide. In some embodiments, the radionuclide is selected from ^3H , ^14C , ^125I , ^35S , and ^82Br .

The present invention may also include a method for synthesizing compounds incorporating radioactive isotopes. Methods for synthesizing organic compounds incorporating radioactive isotopes are well known in the art, and those skilled in the art will readily recognize the methods applicable to the compounds of the present invention.

The labeled compounds of this invention can be used in screening assays to identify/evaluate compounds. For example, the ability of a newly synthesized or identified labeled compound (i.e., the test compound) to bind to TAM can be assessed by tracking changes in its concentration when the label is in contact with TAM kinase. For example, the ability of the (labeled) test compound to reduce the binding of another compound (i.e., the standard compound) known to bind to TAM kinase can be assessed. Therefore, the ability of the test compound to compete with the standard compound for binding to TAM kinase is directly related to its binding affinity. Conversely, in some other screening assays, the standard compound is labeled, and the test compound is not labeled. Therefore, the concentration of the labeled standard compound is monitored to assess the competition between the standard compound and the test compound, thereby determining the relative binding affinity of the test compound.

synthesis

The compounds of the present invention can be prepared by the following synthetic procedure. The raw materials and reagents used to prepare these compounds are available from commercial suppliers such as Sigma Aldrich Chemical Co. (Milwaukee, Wis.) or Bachem (Torrance, Calif.), or can be prepared by methods known to those skilled in the art according to the procedures described in references such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carb On Compounds, Volumes 1–5 and Supplements (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1–40 (John Wiley and Sons, 1991); March’s Advanced Organic Chemistry (John Wiley and Sons, 4th edition); and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989). These schemes are merely examples of some methods for synthesizing the compounds of the present invention, and various modifications can be made to these schemes, which will be suggested to those skilled in the art upon reference to this disclosure. If desired, the starting materials and intermediates of the reaction can be separated and purified using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, etc. Conventional means can be used to characterize such substances, including physical constants and spectroscopic data.

Unless otherwise stated, the reactions described herein are carried out at atmospheric pressure and in a temperature range of about -78°C to about 150°C, more preferably about 0°C to about 125°C, and most preferably about room temperature (or ambient temperature) (e.g., about 20°C). Unless otherwise stated (e.g., in the case of hydrogenation), all reactions are carried out under a nitrogen atmosphere.

The compounds disclosed and claimed herein have asymmetric carbon atoms or quaternized nitrogen atoms in their structure and can be prepared by the synthesis described herein as single stereoisomers, racemates, or mixtures of enantiomers and diastereomers. The compounds may also exist as geometric isomers. All such single stereoisomers, racemates, and geometric isomers, and mixtures thereof, are within the scope of this invention.

Some compounds of the present invention can exist as tautomers. For example, in the presence of a ketone or aldehyde, the molecule can exist as an enol; in the presence of an amide, the molecule can exist as an imine; and in the presence of an enamine, the molecule can exist as an imine. All these tautomers are within the scope of the present invention.

Methods for preparing and/or separating and isolating single stereoisomers from racemic or non-racemic mixtures of stereoisomers are well known in the art. For example, optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. Enantiomers (R- and S-isomers) can be separated by methods known to those skilled in the art, such as by: forming diastereomer salts or complexes that can be separated, for example, by crystallization; by forming diastereomer derivatives that can be separated, for example, by crystallization; by a selective reaction of an enantiomer with an enantiomer-specific reagent, such as enzymatic oxidation or reduction, followed by separation of modified and unmodified enantiomers; or by gas-liquid or liquid chromatography in a chiral environment, such as on a chiral support (e.g., silica with bonded chiral ligands) or in the presence of a chiral solvent. It should be understood that in cases where a desired enantiomer is converted to another chemical entity by one of the above separation procedures, further steps may be required to release the desired enantiomer form. Alternatively, specific enantiomers can be synthesized via asymmetric synthesis using optically active reagents, substrates, catalysts, or solvents, or by converting one enantiomer into another via asymmetric transformation. For enantiomer mixtures rich in specific enantiomers, the major component enantiomer can be further enriched by recrystallization (with a loss of yield).

Furthermore, the compounds of the present invention can exist in both non-solventized and solvated forms with pharmaceutically acceptable solvents such as water and ethanol. Generally, for the purposes of this invention, the solvated form is considered equivalent to the non-solventized form.

The method of the present invention can be performed as a semi-continuous or continuous method, and more preferably as a continuous method.

Unless otherwise indicated, the present invention as described above can be carried out in the presence of a solvent or a mixture of two or more solvents. In particular, the solvent is an aqueous solvent or an organic solvent, such as an ether solvent (e.g., tetrahydrofuran, methyltetrahydrofuran, diisopropyl ether, tert-butyl methyl ether, or dibutyl ether), an aliphatic hydrocarbon solvent (e.g., hexane, heptane, or pentane), a saturated alicyclic hydrocarbon solvent (e.g., cyclohexane or cyclopentane), or an aromatic solvent (e.g., toluene, o-xylene, m-xylene, or p-xylene or tert-butylbenzene) or a mixture thereof.

Raw materials and reagents that do not have the synthetic routes explicitly disclosed herein are generally available from commercial sources or can be readily prepared using methods well known to those skilled in the art.

method

One aspect provides a method for preparing compounds of formula I:

Or a pharmaceutically acceptable salt thereof, the method comprising:

Compounds of formula II:

Z is selected from _NH₂ , SH, and OH;

Reaction with compounds of formula III:

Where X is a leaving group;

_R1 is selected _from -H, -CN, -CO- _NR5R6 , _-CO2R7 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted _{( C1} - _C6 )alkyl, optionally substituted ( _C3 - _C8 )cycloalkyl, optionally substituted ( _C3 - _C6 ) _{heterocycloalkyl} , _-SO2NR8R9 and -( _{SO2 )} -( _C1 - _C6 )alkyl;

Where _R1 is selected _{from -CN} , -CO- _NR5R6 , _-CO2R7 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted ( _C3 - _C8 )cycloalkyl, optionally substituted ( _C3 - _C6 ) heterocycloalkyl, _-SO2NR8R9 and -( _SO2 )-( _C1 - _C6 )alkyl, _{R2 is -H} , halogroup, _-NR5R6 or optionally substituted _{( C1} - _C6 )alkoxy;

Where _R1 is -H, an optionally substituted ( _C1 - _C6 ) alkyl, or _an optionally substituted ( _C1 - _C6 ) alkoxy, _R2 is -CO- _NR5R6 or _{-CO2R7 .}

Or _R1 and _R2 together with the atoms to which they are attached form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl;

_R3 is selected from -H, optionally substituted (C1 _{- C6} ) alkyl, -CN, and halogroup;

_R4 is -H or a halogenated group;

Optionally substituted with one, two, three or four independently selected groups from halogroups and ( _C1 - _C6 )alkyl groups, wherein the linkage point is indicated;

_R5 and _R6 are each independently -H, optionally substituted ( _C1 - _C6 ) alkyl, or optionally substituted ( _C1 - _C6 ) alkoxy;

_R7 is -H or an optionally substituted ( _C1 - _C6 ) alkyl group.

_R8 and _R9 are each independently -H or optionally substituted ( _C1 - _C6 ) alkyl; or

_R8 and _R9 can be connected to form an optionally substituted heterocyclic ring; and

Y is selected from O, S, SO, _SO₂ , NH and N-(( _C₁ - _C₆ )alkyl).

On the other hand, there is a method for preparing compounds of formula I:

Or a pharmaceutically acceptable salt thereof, the method comprising:

Compounds of formula IV:

Reaction with compounds of formula V:

_R1 is selected _from -H, -CN, -CO- _NR5R6 , _-CO2R7 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted _{( C1} - _C6 )alkyl, optionally substituted ( _C3 - _C8 )cycloalkyl, optionally substituted ( _C3 - _C6 ) _{heterocycloalkyl} , _-SO2NR8R9 , and ( _{SO2 )} -( _C1 - _C6 )alkyl;

Where _R1 is selected _{from -CN} , -CO- _NR5R6 , _-CO2R7 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted ( _C3 - _C8 )cycloalkyl, optionally substituted ( _C3 - _C6 ) heterocycloalkyl, _-SO2NR8R9 and -( _SO2 )-( _C1 - _C6 )alkyl, _{R2 is -H} , halogroup, _-NR5R6 or optionally substituted _{( C1} - _C6 )alkoxy;

Where _R1 is -H, an optionally substituted ( _C1 - _C6 ) alkyl or an optionally substituted ( _C1 - _C6 ) alkoxy, _R2 is -CO- _NR5R6 , an optionally substituted _heteroaryl or _{-CO2R7 .}

Or _R1 and _R2 together with the atoms to which they are attached form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl;

_R3 is selected from -H, optionally substituted (C1 _{- C6} ) alkyl, -CN, and halogroup;

_R4 is -H or a halogenated group;

Optionally substituted with one, two, three or four independently selected groups from halogenated and _C1 - _C6 alkyl groups, wherein the linkage point is indicated;

_R5 and _R6 are each independently -H, optionally substituted ( _C1 - _C6 ) alkyl, or optionally substituted ( _C1 - _C6 ) alkoxy;

_R7 is -H or an optionally substituted ( _C1 - _C6 ) alkyl group;

_R8 and _R9 are each independently -H or optionally substituted ( _C1 - _C6 ) alkyl; or

_R8 and _R9 can be connected to form an optionally substituted heterocyclic ring; and

Y is selected from O, S, SO, _SO₂ , NH and N-( _C₁ - _C₆ alkyl).

In one embodiment, the compound of formula V is prepared by a method comprising the following steps: making the compound of formula VI:

Reaction with compounds of formula VII:

Compounds of formula VIII:

Furthermore, the reducing compound of formula VIII is used to provide the compound of formula V.

in:

_R1 is selected from _-H , -CN, -CO- _NR5R6 , _-CO2R7 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted _{( C1} - _C6 )alkyl, optionally substituted ( _C3 - _C8 )cycloalkyl, optionally substituted ( _C3 - _C6 ) _{heterocycloalkyl} , _-SO2NR8R9 and -( _{SO2 )} -( _C1 - _C6 )alkyl;

Where _R1 is selected _{from -CN} , -CO- _NR5R6 , _-CO2R7 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted ( _C3 - _C8 )cycloalkyl, optionally substituted ( _C3 - _C6 ) heterocycloalkyl, _-SO2NR8R9 and -( _SO2 )-( _C1 - _C6 )alkyl, _{R2 is -H} , halogroup, _-NR5R6 or optionally substituted _{( C1} - _C6 )alkoxy;

Where _R1 is -H, an optionally substituted ( _C1 - _C6 ) alkyl, or _an optionally substituted ( _C1 - _C6 ) alkoxy, _R2 is -CO- _NR5R6 or _{-CO2R7 .}

Or _R1 and _R2 together with the atoms to which they are attached form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl;

_R3 is selected from -H, optionally substituted (C1 _{- C6} ) alkyl, -CN, and halogroup; and

W is a halogenated group.

The following embodiments are provided for illustrative purposes and are not intended to limit the scope of the claimed invention.

Example

Example 1: Methyl 4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-7-methoxyquinoline-6-carboxylic acid ester (5)

N-(4-Fluorophenyl)-N-(4-hydroxyphenyl)cyclopropane-1,1-dicarboxamide (3): 3-(ethyliminomethyleneamino)-N,N-dimethyl-propane-1-amine hydrochloride (EDCI) (10.31 g, 53.8 mmol, 1.2 equivalent) was added to a solution of compound 1 (10 g, 44.80 mmol, 1 equivalent) and compound 2 (5.87 g, 53.8 mmol, 1.2 equivalent) in dimethylacetamide (DMA) (60 mL). The mixture was stirred vigorously at 20 °C until the reaction was complete. The mixture was poured into a saturated aqueous solution of _NaHCO3 (aq) (400 mL) and extracted with EtOAc (4 x 100 mL). The combined organic phases were washed with a saturated aqueous solution of NaCl (100 mL), _dried over anhydrous _Na2SO4 , and concentrated. Compound 3 (21 g, crude) (50% purity) was given. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.16 (br s, 1H), 9.72 (br s, 1H), 7.61 (dd, 2H), 7.34 (d, 2H), 7.13 (t, 2H), 6.68 (d, 2H), 1.42 (s, 4H); MS (EI) was _{C₁₇H₁₅FN₂O₃ ,} measured value _{314.9 (} MH⁺).

Methyl 4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-7-methoxyquinoline-6-carboxylic acid (5): A mixture of compound 3 (5.99 g, 9.5 mmol, 1.2 equivalents), compound 4 (2 g, 8.0 mmol, 1.0 equivalents), Pd(OAc) ₂ (89 mg, 397.4 μmol, 0.05 equivalents), racemic-2-(di-tert-butylphosphino)-1,1'-binaphthyl (TrixiePhos, 316.71 mg, 794.7 _μmol , 0.1 equivalents), and _K3PO4 (2.53 g, 11.9 mmol, 1.5 equivalents) in anisole (50 mL) was stirred at 110 °C for 2 h under a nitrogen atmosphere. The mixture was filtered and the filtrate was concentrated. The residue was purified by rapid silica gel chromatography (1:1 petroleum ether:EtOAc to 20:1 EtOAc:MeOH). Compound 5 was given (2.6 g, 61.8% yield). ^¹H NMR (400MHz, _CDCl₃ ) δ 9.38 (s, ¹H), 8.80 (s, ¹H), 8.63 (d, 2H), 7.64 (d, 2H), 7.54–7.41 (m, 3H), 7.18 (d, 2H), 7.09–7.01 (m, 2H), 6.43 (d, ¹H), 4.05 (s, 3H), 3.97 (s, 3H), 1.78–1.72 (m, 2H), 1.69–1.63 (m, 2H); MS (EI ₎ was _{C₂ ₹ H₂₄FN₃O₆} , measured value 530.0 (MH⁺).

Example 2: 4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-7-methoxyquinoline-6-carboxylic acid (6)

4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-7-methoxyquinoline-6-carboxylic acid (6): 2M NaOH aqueous solution (7 mL, 4.1 equivalents) was added to a solution of compound 5 (1.8 g, 3.4 mmol, 1 equivalent) in tetrahydrofuran (THF) (15 mL) and MeOH (15 mL). The mixture was stirred at 6 °C–13 °C for 4 hours. The pH of the mixture was adjusted to approximately 8 with 1M HCl aqueous solution and concentrated to remove the solvent. Water (50 mL) was added, and the pH of the mixture was adjusted to approximately 6 with 1M HCl aqueous solution. The resulting precipitate was filtered, washed with water (2 x 10 mL), and dried under vacuum. Compound 6 (1.7 g, 97.0% yield) was given. ^1H NMR (400MHz, DMSO- _d₆ ) δ 10.22 (s, 1H), 10.08 (s, 1H), 8.65 (d, 1H), 8.48 (s, 1H), 7.77 (d, 2H), 7.64 (dd, 2H), 7.47 (s, 1H), 7.25 (d, 2H), 7.15 (t, 2H), 6.45 (d, 1H), 3.96 (s, 3H), 1.47 (s, 4H); _MS ( _{EI )} was _{C₂₈H₂₂FN₃O₆} , measured value 516.1 (MH⁺).

Example 3: 1-N-[4-(6-carbamoyl-7-methoxyquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (7)

1-N-[4-(6-carbamoyl-7-methoxyquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (7): A solution of compound 6 (350 mg, 679.0 μmol, 1 equivalent), 3-oxyhexafluorophosphate 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium (HATU) (388 mg, 1.0 mmol, 1.5 equivalent), and diisopropylethylamine (DIEA or DIPEA) (352 mg, 2.7 mmol, 474 μL, 4.0 equivalent) in dimethylformamide (DMF) (10 mL) was stirred at 6-10 °C for 1 h, then _NH4Cl (73 mg, 1.4 mmol, 2.0 equivalent) was added, and the mixture was stirred at 6-10 °C for another 17 h. The mixture was filtered, and the resulting filtrate was concentrated and purified by preparative HPLC (column: Waters Xbridge 150mm*25mm*5μm, gradient: 32%-62% acetonitrile in _{10mM NH4HCO3} aqueous solution, flow rate: 25mL/min). Compound 7 was given (90.1mg, 25.8% yield). ^1H NMR (400MHz, DMSO- _d₆ ) δ 10.20 (s, 1H), 10.06 (s, 1H), 8.68 (s, 1H), 8.66 (d, 1H), 7.86 (br s, 1H), 7.81-7.72 (m, 3H), 7.68-7.61 (m, 2H), 7.51 (s, 1H), 7.26 (d, 2H), 7.19-7.11 (m, 2H), 6.46 (d, 1H), 4.03 (s, _3H ), _1.47 (s, _4H ); MS (EI) was _{C₂₈H₂₃FN₄O₅} , measured value 515.1 (MH⁺).

Example 4: 1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (8)

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (8): A DMF (10 mL) solution of compound 6 (300 mg, 582.0 μmol, 1 equivalent), HATU (332 mg, 873.2 μmol, 1.5 equivalent), and DIEA (301 mg, 2.3 mmol, 406 μL, 4 equivalent) was stirred at 6-10 °C for 1 hour. Methylamine hydrochloride (79 mg, 1.2 mmol, 2.0 equivalent) was added, and the mixture was stirred at 6-10 °C for 17 hours. The mixture was filtered, and the resulting filtrate was purified by preparative HPLC (column: Waters Xbridge 150mm*25mm*5μm, gradient: 33%-63% acetonitrile in 10mM _{NH4HCO3 aqueous} solution, flow rate: 25mL/min). Compound 8 was given (105.4 mg, 34.3% yield). ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.20 (s, ¹H), 10.06 (s, ¹H), 8.65 (d, ¹H), 8.61 (s, ¹H), 8.42–8.33 (m, ¹H), 7.77 (d, 2H), 7.68–7.61 (m, 2H), 7.51 (s, ¹H), 7.25 (d, 2H), 7.19–7.11 (m, 2H), 6.46 (d, ¹H), 4.02 (s, 3H), 2.84 (d, 3H) _{, 1.47 (s, 4H); MS (EI) was C₂⁹H₂⁵FN₄O₅ ,} measured value _{529.1 (} MH⁺).

The following compounds were prepared using a method similar to that used for compound 8 in Example 4:

1-N-[4-[6-(ethylcarbamoyl)-7-methoxyquinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (9): ^¹H NMR (400MHz, DMSO- _d6 ) δ 10.20 (s, 1H), 10.06 (s, 1H), 8.65 (d, 1H), 8.56 (s, 1H), 8.40 (br t, 1H), 7.78 (br d,2H), 7.64(dd,2H), 7.51(s,1H), 7.25(d,2H), 7.15(t,2H), 6.46(d,1H), 4.02(s,3H), 3.37-3.29(m,2H), 1.48(s,4H), 1.15(t,3H).; MS ( _{EI )} is _C30H27FN4O5 , measured value _543.2 (MH+).

1-N-[4-[6-[2-(dimethylamino)ethylcarbamoyl]-7-methoxyquinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (10): ^1H NMR (400MHz, CDCl3 ₎ δ 9.38(s,1H), 9.23(s,1H), 9.16(s,1H), 8.61(d,1H), 8.50(s,1H), 7.68(d,2H), 7.49-7.46(m,3H), 7.12(d,2H), 7.03(t,2H), 6.43(d,1H), 4.11(s,3H), 3.66(q,2H), 2.68(t,2H), 2.41(s,6H), _{1.70 (} s,4H); MS(EI) was _{C32H32FN5O5 ,} measured value 586.2 (MH+).

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(2-piperidin-1-ylethylcarbamoyl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (11): ^1H NMR (400MHz, CDCl3 ₎ δ 9.79(s,1H), 9.63(s,1H), 9.13(s,1H), 8.68(s,1H), 8.58(d,1H), 7.74(d,2H), 7.49-7.41(m,3H), 7.06-6.96(m,4H), 6.38(d,1H), 4.13(s,3H), 3.65(q,2H), 2.60(t,2H), 2.49(s,4H), 1.70-1.65(m,8H), _{1.51(s,2H); MS(EI) is C35H36FN5O5 , measured} value _626.3 (MH+).

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(2-morpholin-4-ylethylcarbamoyl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (12): ^1H NMR (400MHz, CDCl3 ₎ δ 9.26(s,1H), 9.24(s,1H), 8.95(s,1H), 8.63(d,1H), 8.46(s,1H), 7.65(d,2H), 7.52(s,1H), 7.50-7.47(m,2H), 7.16(d,2H), 7.05(t,2H), 6.46(d,1H), 4.15(s,3H), 3.79(t,4H), 3.68-3.64(m,2H), 2.65(t,2H), 2.57(s,4H), 1.70(d, _4H ); MS ( _{EI) was C34H34FN5O6 , measured} value 628.3 (MH+).

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(oxetane-3-ylcarbamoyl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (13): ^1H NMR (400MHz, CDCl3 ₎ δ 9.34(s,1H), 9.22(s,1H), 8.92(s,1H), 8.64(d,1H), 8.47(d,1H), 7.65(d,2H), 7.55(s,1H), 7.50-7.46(m,2H), 7.14(d,2H), 7.05(t,2H), 6.47(d,1H), 5.36-5.27(m,1H), 5.06(t,2H), 4.68(t,2H), 4.17(s,3H), _{1.71(s,4H); MS(EI) was C31H27FN4O6 , measured value} 571.2 (MH+).

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-[(1-methylazacyclobutane-3-yl)carbamoyl]quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (14): ^1H NMR (400MHz, CDCl3 ₎ δ 9.60(s,2H), 9.11(s,1H), 8.58(d,1H), 8.34(d,1H), 7.67(d,2H), 7.53-7.37(m,3H), 7.06(d,2H), 6.98(t,2H), 6.40(d,1H), 4.82-4.66(m,1H), 4.12(s,3H), 3.73(t,2H), 3.10(t,2H), 2.38(s,3H), _{1.74-1.60(m,4H); MS(EI) was C32H30FN5O5 , measured} value _584.9 (MH+).

1-N-[4-[6-(azacyclobutane-1-carbonyl)-7-methoxyquinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (15): ^¹H NMR (400MHz, _CDCl₃ ) δ 9.40 (s, 1H), 9.22 (br s, 1H), 8.59 (d, 1H), 8.32 (s, 1H), 7.63 (d, 2H), 7.49 (td, 9.2Hz, 3H), 7.13 (d, 2H), 7.04 (t, 2H), 6.43 (d, 1H), 4.28 (t, 2H), 4.08–3.98 (m, 5H), 2.37–2.32 (m, 2H), 1.77–1.64 (m, 4H); MS (EI) was C ₃₁ H ₂₇ FN ₄ O ₅ , measured value 554.8 (MH+).

1-N'-(4-fluorophenyl)-1-N-[4-[6-(3-hydroxyazacyclobutane-1-carbonyl)-7-methoxyquinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (16): ^1H NMR (400MHz, CDCl3 ₎ )δ9.43(s,1H),9.18(s,1H),8.60(s,1H),8.31(s,1H),7.61(d,2H),7.5 0-7.46(m,3H),7.11(d,2H),7.06-7.00(m,2H),6.45(d,1H),4.75-4.70( m,1H),4.51-4.47(m,1H),4.19-4.13(m,1H),4.11-4.07(m,1H),4.01(s ,3H),3.95-3.91(m,1H),1.75-1.73(m,2H),1.72-1.69(m,2H); MS(EI) is C ₃₁ H ₂₇ FN ₄ O ₆ The measured value was 571.0 (MH+).

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(methoxycarbamoyl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (17): ^¹H NMR (400MHz, DMSO- _d6 ) δ 11.27 (br s, 1H), 10.20 (br s, 1H), 10.06 (br s, 1H), 8.65 (d, 1H), 8.44 (s, 1H), 7.76 (d, 2H), 7.63 (d, 2H), 7.49 (s, 1H), 7.25 (d, 2H), 6.46 (d, 2H), 6.93 (d, 1H), 3.98 (s, 3H), 3.74 (s, 3H), 1.47 (s _, 4H); MS (EI) _C29H25 FN ₄ O ₆ , measured value 545.1 (MH+).

(R)-2-((4-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylammono)phenoxy)-7-methoxyquinoline-6-carboxylammono)methyl)pyrrolidine-1- _{carboxylic acid tert-butyl ester (18): MS (EI) is C38H40FN5O7 , and the} measured value is 698.3 (MH+).

(S)-2-((4-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylammono)phenoxy)-7-methoxyquinoline-6-carboxylammono)methyl)pyrrolidine-1- _{carboxylic acid tert-butyl ester (19): MS (EI) is C38H40FN5O7 , measured} value _is 698.3 (MH+).

1-N'-(4-fluorophenyl)-1-N-[4-[6-(hydroxycarbamoyl)-7-methoxyquinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide hydrochloride (20): ^¹H NMR (400MHz, DMSO- _d₆ ) δ 11.08 (s, 1H), 10.32 (s, 1H), 10.04 (s, 1H), 8.97–8.88 (m, 1H), 8.54 (s, 1H), 7.84 (d, 2H), 7.72–7.58 (m, 3H), 7.35 (d, 2H), 7.15 (t, _2H ), 6.86–6.75 (m, 1H), 4.04 (s, 3H), 1.48 (d, 4H) _; MS (EI _{) C₂₈H₂₃FN₄O₆} The measured value was 531.0 (MH+).

Example 5: 1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-[[(2R)-pyrrolidone-2-yl]methylcarbamoyl]quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (21)

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-[[(2R)-pyrrolidone-2-yl]methylcarbamoyl]quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (21): Trifluoroacetic acid (TFA; 1 mL) was added in a single batch to a mixture of compound 18 (67 mg, 96.0 μmol, 1 equivalent) in dichloromethane (DCM) (3 mL) at 30 °C. The mixture was stirred at 30 °C for 0.5 h, and then the reaction mixture was concentrated under vacuum. The resulting residue was purified by preparative HPLC (column: Waters Xbridge 150*25*5μm; mobile phase: [water (0.05% ammonium hydroxide v/v)-acetonitrile (ACN)]; B%: 50%) to give compound 21 (24.4 mg, 42.5% yield). ^¹H NMR (400 MHz, DMSO- _d₆ ) δ 9.52–9.35 (m, 2H), 9.14 (s, 1H), 8.59 (d, 1H), 8.42 (br₆) t, 1H), 7.68(d, 2H), 7.51-7.44(m, 3H), 7.09(d, 2H), 7.06-6.97(m, 2H), 6.42(d, 1H), 4.13(s, 3H), 3.69(td, 1H), 3.55-3.47(m, 1H), 3.45-3.37(m, 1H), 3.01(t, 2H), 2.01-1.79(m, 8H), 1.58-1.45(m, 1H); MS(EI ₎ is _{C33H32FN5O5 ,} measured value _598.3 (MH+).

The following compounds were prepared from compound 19 in a manner similar to that used in Example 5 to convert compound 18 to compound 21:

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-[[(2S)-pyrrolidone-2-yl]methylcarbamoyl]quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (22): ^1H NMR (400MHz, CDCl3 ₎ )δ9.47(s,2H),9.15(s,1H),8.60(d,1H),8.40(t,1H),7.7-7.67(m,2H),7 .49-7.45(m,3H),7.10-7.04(m,2H),7.03-6.99(m,2H),6.41(d,1H),4.11( s,3H),3.71-3.65(m,1H),3.50-3.37(m,2H),3.02-2.96(m,2H),2.01-1.95 (m,2H),1.84-1.75(m,2H),1.71-1.66(m,4H),1.55-1.48(m,1H); MS(EI) is C ₃₃ H ₃₂ FN ₅ O ₅ , measured value 598.3 (MH+).

Example 6: 1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(oxacyclobutane-3-yloxycarbamoyl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (26)

2-(oxetane-3-yloxy)isoindoline-1,3-dione (24): PPh 3 (3.54 g, 13.5 mmol, 2 equivalents) and diisopropyl azodicarboxylate (DIAD) (2.81 g, 13.9 mmol, 2.7 mL, 2.1 equivalents) were added fractionally to a THF (30 mL) solution of compound ₂₃ (1.32 g, 8.1 mmol, 1.2 equivalents) and oxetane-3-ol (500 mg, 6.8 mmol, 1 equivalent). The resulting mixture was stirred at 20 °C for 15 h to give a brown solution. The mixture was concentrated with silica gel and purified by rapid silica gel chromatography (0% to approximately 70% EtOAc in a petroleum ether gradient). The residue was further purified by rapid silica gel chromatography using the same solvent system to give compound 24 (300 mg, 10.14% yield, 50% purity). MS( _{EI) is C11H9NO4 ,} measured value _219.8 (MH+).

O-(oxetane-3-yl)hydroxylamine (25): _{NH₂NH₂ - H₂O} (95.92 mg, 1.9 mmol, 93.13 μL, 1.5 equivalents) was added to a DCM (5 mL) solution of compound 24 (280 mg, 1.3 mmol, 1 equivalent) at 0 °C, and the mixture was stirred for 1 hour to obtain a white suspension. The mixture was filtered and washed with DCM (5 mL), and the filtrate was concentrated. Crude compound 25 (150 mg) was used in the next step without further purification.

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(oxetane-3-yloxycarbamoyl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (26): Propylphosphonic anhydride (T3P) (185.17 mg, 582.0 μmol, 1 equivalent) and DIEA (75.22 mg, 582.0 μmol, 101.37 μL, 3 equivalent) were added to a THF ( ₃ mL) solution of compound 6 (100 mg, 194.0 μmol, 1 equivalent) and compound 25 (20.74 mg, 232.8 μmol, 1.2 equivalent), and the resulting mixture was stirred at 20 °C for 10 hours. The mixture was concentrated, and the resulting residue was purified by preparative HPLC (column: YMC-Actus Triart C18150*30mm*5μm; mobile phase: [water (0.05% ammonium hydroxide v/v)-ACN]; B%: 25%-65%, 10 min) to give compound 26 (5.3 mg, 4.66% yield). ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.66(s,1H),10.21(br s,1H),10.06(br s,1H),8.67(d,1H),8.42(s,1H),7.78(d,2H),7.64-7.86(m,2H),7.51(s,1H),7.26(d,2H),7.13-7.18(m,2H ),6.47(d,1H),5.07-5.09(m,1H),4.73-4.76(m,2H),4.63-4.66(m,2H),3.99(s,3H),1.48(s,4H); MS(EI) is C ₃₁ H ₂₇ FN ₄ O ₇ The measured value was 587.1 (MH+).

The following compounds were prepared from compound 6 in a manner similar to that used in the last step of Example 6 to form compound 26 from compound 6:

1-N'-(4-fluorophenyl)-1-N-[4-[6-(2-hydroxyethoxycarbamoyl)-7-methoxyquinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (27): ^1H NMR (400MHz, DMSO- _d6) δ 11.47(s,1H), 10.22(s,1H), 10.07(s,1H), 8.67(d,1H), 8.46(s,1H), 7.78(d,2H), 7.61-7.67(m,2H), 7.51(s,1H), 7.26(d,2H), 7.12-7.18(m,2H), 6.47(d,1H), 4.82(t,1H), 4.00(s,3H), 3.97(t,2H), 3.65( _{q,2H), 1.48(s,4H); MS (EI) was C30H27FN4O7 , measured value} 575.1 (MH+).

N-(4-((6-(((2,2-dimethyl-1,3-dioxopentane-4-yl)methoxy)carbamoyl)-7-methoxyquinoline-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1- _{dicarboxamide (28). MS (EI) was C34H33FN4O8 , with a} measured value of 645.0 (MH+).

Example 7: 1-N-[4-[6-(2,3-dihydroxypropoxycarbamoyl)-7-methoxyquinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, enantiomers 1 (30) and 2 (31)

1-N-[4-[6-(2,3-dihydroxypropoxycarbamoyl)-7-methoxyquinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, racemic mixture (29): TFA (53.06 mg, 465.37 μmol, 34.46 μL, 1 equivalent) was added to a DCM (10 mL) solution of compound 28 (300 mg, 465.37 μmol, 1 equivalent), and the resulting mixture was stirred at 20 °C for 10 h. Two more equal portions of TFA, totaling 0.35 mL, were added, and stirring was continued at 20 °C for a further 5 h to obtain a brown solution. The reaction mixture was concentrated under vacuum, and the resulting residue was purified by preparative HPLC (column: Agela Dura Shell 150mm*25mm*5μm; mobile phase: [water (0.225% FA)-ACN]; B%: 11%-51%, 10 min) to give compound 29 (85 mg, 30.21%). ^¹H NMR (400 MHz, DMSO- _d⁶ ) δ 11.54 (br s, 1H), 10.22 (br s, 1H), 10.07 (br s, 1H), 8.67 (d, 1H), 8.49 (s, 1H), 7.77 (d, 2H), 7.64-7.67 (m, 2H), 7.52 (s, 1H), 7.26 (d, Hz, 2H), 7.14-7.16 (m, 2H), 6.47 (d, 1H), 5.00 (br s, 1H ... s, 1H), 4.67 (br s, 1H), 3.99-4.02 (m, 4H), 3.78-3.85 (m, 2H), 3.39-3.42 (m, 2H), 1.48 (s, 4H); MS (EI) is C ₃₁ H ₂₉ FN ₄ O ₈ , measured value 605.4 (MH+).

1-N-[4-[6-(2,3-dihydroxypropoxycarbamoyl)-7-methoxyquinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, enantiomers 1 (30) and 2 (31).

The enantiomers of racemic compound 29 were separated using an SFC (column: DAICL CHIRALPAK AD (250 mm * 30 mm, 10 μm); mobile phase: [0.1% NH3H2OIPA]; B%: 45%-45%, min) (85 mg, 140.59 μmol, 1 equivalent) to give compound 30 (53.0 mg, 62.35%) and compound 31 (21.3 mg, 25.06% yield). Compound 30: ^¹H NMR (400 MHz, DMSO- _d₆ ) δ 11.54 (br s, 1H), 10.22 (br s, 1H), 10.07 (br s, 1H), 8.67 (d, 1H), 8.49 (s, 1H), 7.77 (d, 2H), 7.64–7.67 (m, 2H), 7.52 (s, 1H), 7.26 (d, 2H), 7.14–7.16 (m, 2H), 6.47 (d, 1H), 5.00 (d, 1H), 4.67 (t, 1H), 3.99–4.03 (m, 4H), 3.78–3.93 (m, 2H), 3.39–3.47 (m, 2H), 1.48 (s _, 4H); MS (EI) _{C₃¹H₂₉FN 4} O ₈ , measured value 605.3 (MH+). Compound 31: ^¹H NMR (400MHz, DMSO- _d₆ ) δ 11.54 (br s, 1H), 10.23 (br s, 1H), 10.08 (br s, 1H), 8.67 (d, 1H), 8.49 (s, 1H), 7.79 (d, 2H), 7.64–7.67 (m, 2H), 7.51 (s, 1H), 7.26 (d, 2H), 7.14–7.18 (m, 2H), 6.47 (d, 1H), 5.03 (br s, 1H), 4.69 (br s, 1H), 4.00–4.04 (m, 4H), 3.76–3.86 (m, 2H), 3.52–3.56 (m, 2H), 1.48 (s, 4H); MS (EI) _{C₃¹H 29} FN ₄ O ₈ , measured value 605.0 (MH+).

Example 8: 1-N'-(4-fluorophenyl)-1-N-[4-[6-(hydrazylcarbonyl)-7-methoxyquinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (32)

1-N'-(4-fluorophenyl)-1-N-[4-[6-(hydrazylcarbonyl)-7-methoxyquinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (32): _{NH₂NH₂ - H₂O} (28.36 mg, 566.56 μmol, 27.54 μL, 3 equivalents) was added to a solution of compound 5 (100 mg, 188.85 μmol, 1 equivalent) in MeOH (5 mL). The resulting mixture was stirred at 50 °C for 2 h, and then concentrated under vacuum. The residue was ground with MeOH (3 mL), and the residue was filtered to give compound 32 (56.6 mg, 53.77% yield). ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.21 (s, ¹H), 10.06 (s, ¹H), 9.51 (br s, ¹H), 8.66 (d, ¹H), 8.53 (s, ¹H), 7.78 (d, 2H), 7.69–7.60 (m, 2H), 7.51 (s, ¹H), 7.26 (d, 2H), 7.16 (t, 2H), 6.48 (d, ¹H), 4.62 (br d, 2H), 4.01 (s, 3H) _{, 1.48 (s, 4H); MS (EI) was C₂₈H₂₄FN₅O₅ , measured value} 530.2 (MH⁺).

Example 9: 1-N-[4-(6-acetyl-7-methoxyquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (34)

N-(4-fluorophenyl)-N-(4-((7-methoxy-6-(methoxy(methyl)carbamoyl)quinoline-4-yl)oxy)phenyl)cyclopropane-1,1-dicarboxamide (33): HATU (442.57 mg, 1.16 mmol, 2 equivalents) and DIEA (225.65 mg, 1.75 mmol, 304.11 μL, 3 equivalents) were added to a DMF (3 mL) solution of compound 6 (300 mg, 581.97 μmol, 1 equivalent) and N,O-dimethylhydroxylamine hydrochloride (170.30 mg, 1.75 mmol, 3 equivalents). The resulting mixture was stirred at 20 °C for 3 hours to give a brown solution. The mixture was diluted with EtOAc (60 mL) and washed with water (2 x 20 mL) and saturated NaCl aqueous solution (20 mL). The organic phase was concentrated under vacuum, and the resulting residue was purified by rapid silica gel chromatography (5 g silica rapid column, eluent of 0% to approximately 20% MeOH/DCM gradient, flow rate of 10 mL/min) to give compound ₃₃ ( ₃₀₀ mg, 89.52% yield. _MS (EI) was _C30H27FN4O6 , measured value 559.2 (MH+).

1-N-[4-(6-acetyl-7-methoxyquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (34): MeMgBr (3M, 1.67mL, 10 equivalents) was added to a THF (5mL) solution of compound 33 (280mg, 501.29μmol, 1 equivalent) at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at 20°C for 15 hours to give a brown suspension. The reaction mixture was quenched with a saturated aqueous solution of _NH4Cl (20mL), extracted with EtOAc (3 x 15mL), and concentrated. The resulting residue was purified by rapid silica chromatography (4g silica rapid column, 0% to 4% MeOH/DCM gradient eluent, flow rate 10mL/min). The crude product was further purified (using a 4 g silica fast column with an eluent of 0% to approximately 60% EtOAc/petroleum ether gradient at 10 mL/min) to give compound 34 (190 mg, yield 73.81%). ^¹H NMR (400MHz, _CDCl₃ ) δ 9.40 (br s, 1H), 8.90 (br s, 1H), 8.68 (s, 1H), 7.51 (d, 1H), 7.63–7.66 (m, 2H), 7.45–7.50 (m, 3H), 7.14–7.16 (m, 2H), 7.02–7.07 (m, 2H), 6.43 (d, 1H), 4.05 (s, 3H), 2.71 (s, 3H), 1.16–1.72 (m, 4H); MS (EI ₎ was _{C₂ ₹ H₂₄FN₃O₅} , measured value 536.1 (MH+Na) ^⁺ .

Example 10: 1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-[(E)-N-methoxy-C-methylcarboiminoyl]quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (35) and 1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-[(Z)-N-methoxy-C-methylcarboiminoyl]quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (36)

Methoxyamine hydrochloride (45.54 mg, 545.26 μmol, 41.40 μL, 2 equivalents) was added to a solution of compound 34 (140 mg, 272.63 μmol, 1 equivalent) in water (2.5 mL) and EtOH (2.5 mL), and the resulting mixture was stirred at 50 °C for 2 h to obtain a brown solution. The reaction mixture was diluted with EtOAc (50 mL), washed with water (2 x 20 mL), and concentrated. The resulting residue was purified twice by rapid silica gel chromatography (4 g silica rapid column, eluent of 0% to approximately 80% EtOAc/petroleum ether gradient, flow rate of 10 mL/min). Compounds 35 and ₃₆ (110 mg, 69.7% yield) were recovered as a mixture of Z and E isomers (MS ( _EI ) _C30H27FN4O5 , _542.9 (MH+)). The Z and E isomers were separated by preparative HPLC (column: Agela DuraShell 150 mm * 25 mm * 5 μm; mobile phase: [water (0.05% ammonium hydroxide v/v) - ACN]; B%: 47%-87%, 10 min) to give compound 35 (54.7 mg, 52.10% yield) and compound 36 (6.4 mg, 6.10% yield). Compound 35: ^1H NMR (400 MHz, DMSO- _d6 ) δ 10.21 (br s, 1H), 10.07 (br s, 1H), 8.63(d, 1H), 8.09(s, 1H), 7.77(d, 2H), 7.65-7.68(m, 2H), 7.49(s, 1H), 7.77(d, 2H), 7.16(t, 2H), 6.44(d, 1H), 3.99(s, 3H), 3.91(s, 3H), 2.16(s, 3H), 1.48(s, 4H). Compound 36: ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.21(br s, 1H), 10.07(br s, 1H), 1.48(br s, 4H). s,1H),8.61(d,1H),7.97(s,1H),7.77(d,2H),7.63-7.66(m,2H),7.47(s,1H),7.25( d,2H),7.16(t,2H),6.43(d,1H),3.95(s,3H),3.70(s,3H),2.15(s,3H),1.48(s,4H).

Example 11: 1-N-[4-(6-cyano-7-methoxyquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (37)

1-N-[4-(6-cyano-7-methoxyquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (37): _POCl3 (7.78 g, 50.74 mmol, 4.72 mL, 134 equivalents) was added to a MeCN (10 mL) solution of compound 7 (200 mg, 379.12 μmol, 1 equivalent). The mixture was stirred at 80 °C for 3 h. The reaction mixture was filtered, and the filtrate was concentrated and dried under vacuum. The residue was diluted with water (5 mL), the pH was adjusted to 8-9 with an aqueous solution _{of Na2CO3} , and the residue was extracted with DCM (3 x 20 mL). The combined organic layers were concentrated and then dried under vacuum. The residue was purified by preparative HPLC to give compound 37 (80.3 mg, 42.37% yield). ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.23 (br s, 1H), 10.05 (br s, 1H), 8.79–8.72 (m, 2H), 7.79 (br d, 2H), 7.68–7.58 (m, 3H), 7.27 (d, 2H), 7.15 (t, 2H), 6.52 (d, 1H), 4.07 (s, 3H), 1.48 ( _{s, 4H); MS (EI) was C₂₈H₂₁FN₄O₄ ,} measured value _{497.1 (} MH⁺).

Example 12: N-(4-((6-bromo-7-methoxyquinoline-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (43)

5-(((4-bromo-3-methoxyphenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (40): A solution of compound 39 (4.10 g, 28.46 mmol, 1.15 equivalents) in trimethoxymethane (25 mL, 228.04 mmol, 9.22 equivalents) was refluxed at 105 °C for 1 h. Then compound 38 (5 g, 24.75 mmol, 1 equivalent) was added, and reflux was continued at 105 °C for another 1 h. The resulting suspension was filtered, washed with MeOH, and dried under vacuum to give compound 40 (7.7 g, 87.4% yield), which was used in the next step without further purification. ¹ HNMR (400MHz, CDCl ₃ ) δ11.24-11.20(d,1H),8.62-9.59(d,1H),7.57-7.54(d,1H),6.77-6.74(m,2H),3.94(s,3H),1.76(s,3H),1.74(s,3H).

6-Bromo-7-methoxyquinoline-4(1H)-one (41): Compound 40 (7.7 g, 21.62 mmol, 1 equivalent) was added to _Ph₂O (35 mL) at 230 °C, and the mixture was stirred for 1 hour. After cooling to room temperature, the reaction mixture was poured into hexane (20 mL), and the resulting precipitate was filtered and washed with hexane. The residue was dried under vacuum to give compound 41 (6.2 g, 75.8% yield, 67.2% purity). ^¹H NMR (400MHz, DMSO- _d₆ ) δ 11.78 (s, ¹H), 8.18 (s, ¹H), 7.88–7.86 (d, ¹H), 7.05 (s, ¹H), 6.03–6.01 ( _{d, ¹H), 3.92 (s, ³H); MS (EI) was C₁₀H₈BrNO₂ ,} measured value _254.2 (MH⁺).

6-Bromo-4-chloro-7-methoxyquinoline (42): A _POCl3 solution (15 mL, 161.41 mmol, 9.84 equivalents) of compound 41 (6.2 g, 16.40 mmol, 1 equivalent) was stirred at 110 °C for 1 h. After cooling, the reaction mixture was carefully poured into a mixture of saturated _{Na2CO3 aqueous} solution and ice with stirring. The resulting suspension was filtered, washed with water, and dried under vacuum to give compound 42 (7.78 g, 57.4% purity, 99.9% yield), which was used in subsequent steps without further purification. _{MS (EI) was C10H7BrClNO ,} measured at 272.2 (MH+).

N-(4-((6-bromo-7-methoxyquinoline-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (43): A mixture of compound 42 (5.72 g, 12.05 mmol, 1.26 equivalents), compound 3 (3.00 g, 9.54 mmol, 1 equivalent), and t-BuOK (3.21 g, 28.63 mmol, 3 equivalents) in DMSO (30 mL) was stirred at 150 °C for 2 h. A saturated aqueous solution of _NH4Cl (200 mL) was added, and the mixture was extracted with EtOAc (3 x 250 mL). The combined organic phases were dried over _{anhydrous Na2SO4} and concentrated under vacuum. The resulting residue was purified by rapid silica gel chromatography (40 g silica rapid column, eluent 0% to approximately 100% EtOAc/petroleum ether gradient, flow rate 40 mL/min). The resulting residue was ground with MeOH (50 mL) and filtered to give compound 43 (3.0 g, 57.11% yield). ^¹H NMR (400 MHz, _CDCl₃ ) δ 9.33 (s, 1H), 8.66 (br s, 1H), 8.60 (d, 1H), 8.58 (s, 1H), 7.64 (d, 2H), 7.48 (dd, 2H), 7.45 (s, 1H), 7.18 (d, 2H), 7.07 (t, 2H), 6.45 (d, 1H), 4.07 (s, 3H), 1.78–1.72 (m, 2H), 1.71–1.65 (m, 2H).

The following compounds were synthesized in a manner similar to that of compound 43 in the last step of Example 12, with 6-bromo-4-chloroquinoline replacing compound 42.

N-(4-((6-bromoquinoline-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1- _{dicarboxamide} (44). _{MS (EI) was C26H19BrFN3O3 , with} a measured value of 520.0 (MH+).

Example 13: 1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(1,3-oxazol-2-yl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (45)

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(1,3-oxazol-2-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (45): Compound 43 (200 mg, 363.39 μmol, 1 equivalent), tributyl(oxazol-2-yl)stanane (200.0 mg, 558.5 μmol, 1.5 equivalent), CuI (8 mg, 42.0 μmol, 0.12 equivalent) and Pd( _PPh3 ) ₄ (48.0 mg, 41.5 μmol, 0.11 equivalent) were mixed in 5 mL of 1,4-dioxane in a sealed tube and then heated at 100 °C for 30 minutes under microwave irradiation. The reaction mixture was concentrated under vacuum, and the resulting residue was first purified by rapid silica gel chromatography (0–100% EtOAc/petroleum ether) and then purified by preparative HPLC to give compound 45 (81.5 mg, 41.3% yield). ^¹H NMR (400MHz, _CDCl₃ ) δ 9.36 (s, 1H), 8.98 (s, 1H), 8.75 (br s, 1H), 8.63 (d, 1H), 7.82 (s, 1H), 7.65 (d, 2H), 7.57 (s, 1H), 7.48 (dd, 2H), 7.36 (s, 1H), 7.19 (d, 2H), 7.06 (t, 2H), 6.46 (d, 1H), 4.13 (s, 3H), 1.77–1.74 (m, 2H), 1.73–1.69 (m, 2H); MS ( _EI ) _{was C₃₀H₂₃FN₄O₅} , measured value _539.1 (MH⁺).

Example 14: 1-N'-(4-fluorophenyl)-1-N-[4-[7-(2-hydroxyethoxy)-6-(1,3-oxazol-2-yl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (50)

6-Bromo-4-chloroquinoline-7-ol (46): A mixture of compound 42 (5 g, 18.35 mmol, 1 equivalent) and BBr ₃ (13.00 g, 51.89 mmol, 5 mL, 2.83 equivalent) in a DCE (15 mL) was stirred at 90 °C for 2.5 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and poured into a saturated aqueous solution of NaHCO ₃ with vigorous stirring. The resulting residue was filtered, washed with water, dissolved in methyl tert-butyl ether, and dried. The solvent was removed under reduced pressure to give compound 46 (7 g), which could be used in subsequent reactions without further purification. ^¹H NMR (400MHz, DMSO- _d₆ ) δ 9.03 (d, ¹H), 8.49 (s, ¹H), 7.93 (d, ¹H), 7.69 (s, ¹H), 6.08 (s, ¹H); MS _{(EI) was C₉H₅BrClNO ,} measured value 260.2 (MH⁺).

6-Bromo-7-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-chloroquinoline (47): _K₂CO₃ (1.05 g, 7.60 mmol, 1 equivalent) and NaI (720 mg, 4.80 mmol, 1.24 equivalent) were added to a mixture of compound ₄₆ (1 g, 3.87 mmol, 1 equivalent) and 2-bromoethoxy-tert-butyl-dimethylsilane (1.15 g, 4.80 mmol, 1.24 equivalent) in DMF (10 mL), and the mixture was heated to 80 °C for 2 hours with stirring. The reaction mixture was partitioned between water (20 mL) and EtOAc (2 x 20 mL). The combined organic phases were washed with saturated aqueous NaCl solution (10 mL), _dried over anhydrous _Na₂SO₄ , and concentrated. The residue was purified by rapid silica gel chromatography (12 g silica gel column, eluent gradient of 0% to approximately 20% EtOAc/petroleum ether, flow rate of 30 mL/min) to give compound 47 (560 mg, 34.73% yield). ^¹H NMR (400 MHz, _CDCl₃ ) δ 8.71 (d, 1H), 8.45 (s, 1H), 7.47 (s, 1H), 7.37 (d, 1H), 4.29–4.26 (m, 2H), 4.13–4.11 (m, 2H), 0.93–0.92 (m, 9H _{), 0.16–0.14 (m, 6H); MS (EI) was C₁₇H₂₃BrClNO₂Si , measured} value 417.8 (MH⁺).

N-(4-((6-bromo-7-(2-((tert-butyldimethylsilyl)oxy)ethoxy)quinoline-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (48): Compound 48 was prepared in a similar manner to the preparation of compound 43 from compound 42 in Example 12. Compound 48 was recovered (400 mg, 48% yield). ^¹H NMR (400MHz, DMSO- _d₆ ) δ 10.20 (s, 1H), 10.01 (s, 1H), 8.63 (d, 1H), 8.47 (s, 1H), 7.77 (d, 2H), 7.65–7.62 (m, 2H), 7.55 (s, 1H), 7.25 (d, 2H), 7.17–7.13 (m, 2H), 6.46 (d, 1H), 4.32–4.30 (t, 2H), 4.05–4.03 (t, 2H), 1.47 (s, 4H), 0.88 (s, 9H), _{0.10 (s, 6H); MS (EI) was C₃₄H₃₇BrFN₃O₅Si , measured value} 696.1 (MH⁺).

N-(4-((7-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-(oxazol-2-yl)quinoline-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (49): Compound 49 was prepared in a manner similar to that used in the preparation of compound 45 from compound 43 in Example 13. Compound 49 was recovered (400 mg, crude). ^¹H NMR (400MHz, _CDCl₃ ) δ 10.20 (s, 1H), 10.06 (s, 1H), 8.74 (s, 1H), 8.67 (d, 1H), 8.25 (s, 1H), 7.78 (d, 2H), 7.62–7.59 (m, 3H), 7.43 (s, 1H), 7.28 (d, 2H), 7.19–7.09 (m, 2H), 6.48 (d, 1H), 4.41–4.25 (m, 2H), 4.04–4.02 (m, 2H), 1.47 (s, 4H), 0.83 (s, 9H), 0.02 (s, _6H ); MS (EI) was _{C₃₇H₃ ₹ FN₄O₆Si} , measured value 683.3 (MH⁺).

1-N'-(4-fluorophenyl)-1-N-[4-[7-(2-hydroxyethoxy)-6-(1,3-oxazol-2-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (50): Tetrabutylammonium fluoride (1M, 1.40mL, 2.73 equivalents) was added to a mixture of compound 49 (350mg, 512.6μmol, 1 equivalent) in THF (20mL), and the resulting reaction mixture was stirred at 0-20°C for 0.5h, and then poured into a saturated aqueous solution of _NaHCO3 under vigorous stirring. The resulting mixture was partitioned between water (20mL) and EtOAc (2 x 20mL). The combined organic phases were separated, washed with a saturated aqueous solution of NaCl (10mL), _dried over anhydrous _Na2SO4 , and concentrated. The residue was recrystallized with MeOH to give compound 50 (174.3 mg, 58.6% yield). ^1H NMR (400MHz, DMSO- _d₆ ) δ 10.20(s, 1H), 10.06(s, 1H), 8.77(s, 1H), 8.67(d, 1H), 8.30(s, 1H), 7.78(d, 2H), 7.66–7.63(m, 3H), 7.45(s, 1H), 7.28(d, 2H), 7.17–7.13(m, 2H), 6.47(d, 1H), 4.97–4.94(t, 1H), 4.32–4.30(t, 2H), 3.86–3.82(m, 2H), _{1.47(s, 4H); MS (EI) was C₃¹H₂₅FN₄O₆ , measured value} 569.2 (MH⁺).

Example 15: 1-N-[4-(6-dimethylphosphoryl-7-methoxyquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (51)

1-N-[4-(6-dimethylphosphoryl-7-methoxyquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (51): Methylphosphonomethane (21.27 mg, 272.5 μmol, 1.5 equivalent), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthocyanin (Xantphos) (21.03 mg, 36.3 μmol, 0.2 equivalent), tris(dibenzylideneacetone)dipalladium (0) (Pd ₂ (dba) ₃ ) (33.28 mg, 36.3 μmol, 0.2 equivalent) and Et ₃ were added to a dioxane (2 mL) solution of compound 43 (100 mg, 181.7 μmol, 1 equivalent). N (91.93 mg, 908.5 μmol, 126.5 μL, 5 equivalents). The resulting mixture was stirred at 110 °C for 1 h under a nitrogen atmosphere. The mixture was concentrated under vacuum and ground with EtOH (5 mL). The resulting residue was filtered, dried, and passed by preparative HPLC (YMC-Actus Triart C18 150*30 mm*5 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 20%-60%, 10 min) to give compound 51 (26.2 mg, 26.34% yield, 100% purity). ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.24 (s, ¹H), 10.10 (s, ¹H), 8.76 (d, ¹H), 8.69 (d, ¹H), 7.80 (d, 2H), 7.65 (dd, 2H), 7.52 (d, 1H), 7.28 (d, 2H), 7.16 (t, 2H), 6.48 (d, 1H), 4.04 (s, 3H), 1.75 (s, 3H), 1.72 (s, 3H), 1.48 ( _s , 4H); MS (EI) was _{C₂ ₹ H₂₇FN₃O₅P} , measured value 548.1 (MH⁺).

Example 16: Methyl 4-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylamino)phenoxy)quinoline-6-carboxylic acid ester (56)

4-(((2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-yl)methyl)amino)methyl benzoate (53): Compound 53 was synthesized from compounds 52 and 39 in a manner similar to that used in the preparation of compound 40 from compounds 38 and 39 in Example 12. Compound 53 was obtained (9 g, 89.1% yield). ^¹H NMR (400 MHz, _CDCl₃ ) δ 11.32 (br d, 1H), 8.70 (d, 1H), 8.13 (d, 2H), 7.31 (d, 2H), 3.94 (s, 3H), 1.77 (s, 6H).

4-O-1,4-Dihydroquinoline-6-carboxylic acid methyl ester (54): Compound 54 was synthesized from compound 53 in a manner similar to that used in the preparation of compound 41 from compound 40 in Example 12. Compound 54 (1.3 g, crude product) was obtained. ^¹H NMR (400 MHz, DMSO- _d⁶ ) δ 12.03 (s, ¹H), 8.74–8.64 (m, ¹H), 8.14 (dd, ¹H), 8.01–7.93 (m, ¹H), 7.64–7.58 (m, ¹H), 6.11 (d, ¹H), 3.88 (s, ³H).

4-Chloroquinoline-6-carboxylic acid methyl ester (55): Compound 55 was synthesized from compound 54 in a manner similar to that used in the preparation of compound 42 from compound 41 in Example 12. Compound 55 was obtained (0.5 g, 35.3% yield). ^¹H NMR (400 MHz, _CDCl₃ ) δ 9.00 (d, 1H), 8.89 (d, 1H), 8.38 (dd, 1H), 8.19 (d, 1H), 7.58 (d, 1H), 4.03 (s, _{3H); MS (EI) was C₁₁H₈ClNO₂ ,} measured _221.9 (MH⁺).

4-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylamino)phenoxy)quinoline-6-carboxylic acid methyl ester 56: Compound 56 was synthesized from compounds 55 and 3 in a manner similar to that used in the preparation of compound 43 from compounds 42 and 3 in Example 12. Compound 56 was obtained (0.9 g, 99.8% yield). _MS (EI) was _C28H22FN3O5 , _and the measured value _was 500.4 (MH+).

Example 17: 4-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylamino)phenoxy)quinoline-6-carboxylic acid (57)

4-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylamino)phenoxy)quinoline-6-carboxylic acid (57): Compound 57 was synthesized from compound 56 in a manner similar to that used in the preparation of compound 6 from compound 5 in Example 2. Compound 57 was obtained (0.5 g, 57.2% yield). _MS (EI) was _C27H20FN3O5 , _and the measured value _was 486.0 (MH+).

Example 18: 1-N-[4-(6-carbamoylquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (58)

N-(4-((6-carbamoylquinoline-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (58): Compound 58 was synthesized from compound 57 in a manner similar to that used in the preparation of compound 7 from compound 6 in Example 3. Compound 58 was obtained (26 mg, 26.0% yield). ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.22 (s, ¹H), 10.06 (s, ¹H), 8.90 (d, ¹H), 8.74 (d, ¹H), 8.34 (br s, ¹H), 8.26 (dd, ¹H), 8.06 (d, ¹H), 7.80 (d, 2H), 7.64 (dd, 2H), 7.56 (br s, ¹H), 7.29 (d, 2H), 7.15 (t, 2H), 6.61 (d, 1H) _{, 1.48 (s, 4H); MS (EI) was C₂₇H₂₁FN₄O₄ , measured value} 485.1 (MH⁺).

Example 19: 1-N'-(4-fluorophenyl)-1-N-[4-[6-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (59)

1-N'-(4-fluorophenyl)-1-N-[4-[6-(methylcarbamoyl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (59): Compound 59 was synthesized from compound 58 in a manner similar to that used in the preparation of compound 8 from compound 6 in Example 4. Compound 59 was obtained (31.1 mg, 30.3% yield). ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.22 (s, ¹H), 10.05 (s, ¹H), 8.86 (d, ¹H), 8.81 (br d, ¹H), 8.74 (d, ¹H), 8.23 (dd, ¹H), 8.07 (d, ¹H), 7.80 (d, 2H), 7.64 (dd, 2H), 7.29 (d, 2H), 7.15 (t, 2H), 6.61 (d, 1H), 2.85 (d, 3H) _, 1.48 (s, 4H); MS (EI) was _{C₂₈H₂₃FN₄O₄} , measured _{value 499.1} (MH⁺).

The following compounds were prepared using a method similar to that used in the preparation of compound 59 in Example 19:

1-N'-(4-fluorophenyl)-1-N-[4-[6-[(1-methylazacyclobutane-3-yl)carbamoyl]quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (60): ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.23 (s, 1H), 10.05 (s, 1H), 9.23–9.14 (m, 1H), 8.89 (s, 1H), 8.75 (d, 1H), 8.25 (d, 1H), 8.08 (d, 1H), 7.81 (br⁶) d,2H), 7.68-7.62(m,2H), 7.30(d,2H), 7.16(t,2H), 6.61(d,1H), 4.60-4.44(m,1H), 3.69-3.60(m,2H), 3.31(s,3H), 3.20-3.09(m,2H), 1.48(s,4H); MS( _{EI )} is _C31H28FN5O4 , measured value _554.1 (MH+).

Example 20: Methyl 7-fluoro-4-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylammono)phenoxy)quinoline-6-carboxylic acid ester (65)

4-(((2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-yl)methyl)amino)-2-fluorobenzoate (62): Compound 62 was synthesized from compounds 61 and 39 in a manner similar to that used in the preparation of compound 40 from compounds 38 and 39 in Example 12. Compound 62 was given (4.8 g, 50.2% yield). ^¹H NMR (400 MHz, DMSO- _d⁶ ) δ 11.28 (s, 1H), 8.65 (s, 1H), 7.91 (t, 1H), 7.72 (dd, 1H), 7.52 (dd, 1H), 3.84 (s, 3H), 1.68 (s, 6H).

7-Fluoro-4-oxo-1,4-dihydroquinoline-6-carboxylic acid methyl ester (63): Compound 63 was synthesized from compound 62 in a manner similar to that used in the preparation of compound 41 from compound 40 in Example 12. Compound 63 was obtained (0.8 g, 58.5% yield). _{MS (EI) was C11H8FNO3 , and} the measured value was 222.2 (MH+).

4-Chloro-7-fluoroquinoline-6-carboxylic acid methyl ester (64): Compound 64 was synthesized from compound 63 in a manner similar to that used in the preparation of compound 42 from compound 41 in Example 12. Compound 64 was obtained (110 mg, ₃₁ % yield). ^¹H NMR (400 MHz, _CDCl₃ ) δ 8.90 (d, 1H), 8.85 (d, 1H), 7.84 (d, 1H), 7.53 (d, 1H), 4.03 (s, 3H); MS (EI ₎ was _{C₁₁H₇ClFNO₂} , measured 240.0 (MH⁺).

4-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylamino)phenoxy)quinoline-6-carboxylic acid methyl ester (65): Compound 65 was synthesized from compounds 64 and 3 in a manner similar to that used in the preparation of compound 43 from compounds 42 and 3 in Example 12. Compound 65 was obtained (90 mg, 92.6% yield). _MS (EI) was _C28H21F2N3O5 , _and the measured value _was 518.3 ₍ MH+).

Example 21: 7-Fluoro-4-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylamino)phenoxy)quinoline-6-carboxylic acid (66)

7-Fluoro-4-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylamino)phenoxy)quinoline-6-carboxylic acid (66): Compound 66 was synthesized from compound 65 in a manner similar to that used in the preparation of compound 6 from compound 5 in Example 2. Compound 66 was obtained (50 _mg , 57.1% yield). _{MS (} EI) was _C27H19F2N3O5 , and the measured value _was 504.4 (MH+).

Example 22: 1-N-[4-(6-carbamoyl-7-fluoroquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (67)

1-N-[4-(6-carbamoyl-7-fluoroquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (67): Compound 67 was synthesized from compound 66 in a manner similar to that used in the preparation of compound 7 from compound 6 in Example 3. Compound 67 was obtained (7.6 mg, 15.2% yield). ^¹H NMR (400MHz, _CDCl₃ ) δ 9.47 (s, ¹H), 9.24 (d, ¹H), 8.84 (s, ¹H), 8.71 (d, ¹H), 7.79 (d, ¹H), 7.67 (d, 2H), 7.48 (dd, 2H), 7.15 (d, 2H), 7.04 ( _t , 2H), 6.86 (d, ¹H), 6.54 (d, 1H), 6.06 (s, ¹H), _{1.76 -1.68 (m, 4H); MS (EI) was C₂₇H₂₀F₂N₄O₄ , measured} value _503.1 (MH⁺).

By using a similar sequence to that used in the preparation of compound 67 from compound 61 in Examples 20 to 22, and replacing compound 61 with a suitable methyl 4-amino-2-halobenzoate, the following compounds were prepared:

1-N-[4-(6-carbamoyl-7-chloroquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (68): ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.23 (s, 1H), 10.05 (s, 1H), 8.75 (d, 1H), 8.35 (s, 1H), 8.14 (s, 2H), 7.88–7.73 (m, 3H), 7.64 (dd, 2H), 7.27 (d, 2H), 7.15 (t, 2H), 6.64 (d, _1H ), _1.47 (s, _4H ); MS (EI) was _{C₂₇H₂₀ClFN₄O₄} , measured value 519.4 (MH⁺).

1-N-[4-(7-bromo-6-carbamoylquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (69): ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.24 (br s, 1H), 10.07 (br s, 1H), 8.75 (d, 1H), 8.30 (d, 2H), 8.14 (br s, 1H), 7.80 (d, 2H), 7.64-7.67 (m, 2H), 7.27 (d, 2H), 7.18 ( _t , 3H), 6.65 (d, 1H), _{1.48 (s, 4H); MS (EI) was C₂₇H₂₀BrFN₄O₄ ,} measured value _563.3 (MH⁺).

Example 23: 1-N-[4-[6-carbamoyl-7-(2-methoxyethylamino)quinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (70)

1-N-[4-[6-carbamoyl-7-(2-methoxyethylamino)quinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (70): Di[(Z)-1-methyl- ₃ -oxo-but-1-enoxy]copper (70.62 mg, 269.80 μmol, 0.8 equivalent) was added to a mixture of compound 69 (200 mg, 337.25 μmol, 1 equivalent), 2-methoxyethane-1-amine (50.66 mg, 674.51 μmol, 2 equivalent) and _K₂CO₃ (93.22 mg, 674.51 μmol, 2 equivalent) in DMF (10 mL) under nitrogen atmosphere at 10 °C. The resulting mixture was stirred at 100 °C for 2 h under nitrogen atmosphere. Heating was stopped, and once the reaction mixture reached ambient temperature, it was quenched with saturated _NH₄OH aqueous solution (50 mL) and extracted with EtOAc (3 x 30 mL). The combined extracts were dried over _{anhydrous Na₂SO₄} , filtered, and concentrated. The residue was purified by preparative HPLC to give compound 70 (22.2 mg, 11.33% yield). ^¹H NMR (400MHz, _CD₃OD ) δ 8.62 (s, ¹H), 8.43 (d, ¹H), 7.72 (d, 2H), 7.56 (dd, 2H), 7.23 (d, 2H), 7.07 (t, 2H), 6.99 (s, ¹H), 6.32 (d, ¹H), 3.72 (t, 2H), 3.43 (s, 5H), 1.64 (s, 4H); MS (EI) was _{C₃₀H₂₈FN₅O₅ , measured value} 558.1 (MH⁺).

The following compounds were prepared using a method similar to that used for compound 70 in Example 23:

1-N-[4-[6-carbamoyl-7-(3-morpholin-4-ylpropylamino)quinolin-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (71): ^¹H NMR (400MHz, _CD₃OD ) δ 8.60 (s, 1H), 8.42 (d, 1H), 7.71 (d, 2H), 7.59–7.53 (m, 2H), 7.22 (d, 2H), 7.07 (t, 2H), 6.97 (s, 1H), 6.30 (d, 1H), 3.73 (t, 4H), 3.38–3.33 (m, 2H), 2.61–2.45 (m, 6H), 2.00–1.91 (m, 2H), 1.64 (s, 4H); MS (EI) was C₁₀. ₃₄ H ₃₅ FN ₆ O ₅ , measured value 627.2 (MH+).

1-N-[4-[7-(azacyclobutan-1-yl)-6-carbamoylquinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (72): ^¹H NMR (400MHz, _CD₃OD ) δ 8.46 (d, 1H), 8.32 (s, 1H), 7.71 (d, 2H), 7.59–7.53 (m, 2H), 7.21 (d, 2H), 7.11–7.04 (m, 2H), 6.86 (s, 1H), 6.37 (d, 1H), 4.11 (t, 4H), 2.42 (m, 2H), 1.64 (s, 4H); MS (EI) was _{C₃₀H₂₆FN₅O₄ ,} measured value _540.1 ( _MH⁺ ).

Example 24: Ethyl 7-bromo-4-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylamino)phenoxy)quinoline-6-carboxylic acid ester (79)

Ethyl 2-bromo-4-nitrobenzoate (74): _H₂SO₄ (7.81 g, 79.67 mmol, 1 equivalent) was added to a solution of compound ₇₃ (20.0 g, 79.67 mmol, 1 equivalent) in EtOH (78.80 g, 1.71 mol, 100.00 mL, 21.47 equivalent), and the reaction was stirred at 80 °C for 24 h. The reaction mixture was concentrated, and the residue was partitioned between water (200 mL) and DCM (100 mL). The phases were separated, and the aqueous phase was extracted with DCM (3 x 100 mL). The combined organic phases were dried over _{anhydrous Na₂SO₄} and concentrated under vacuum to give compound 74 (21.0 g, 91.37% yield). ^¹H NMR (400MHz, DMSO- _d₆ ) δ 8.52–8.47 (m, ¹H), 8.33–8.28 (m, ¹H), 7.97 (d, ¹H), 4.38 (q, 2H), 1.34 (t, 3H); MS _{(EI) was C₉H₈BrNO₄ , measured} value 274.0 (MH⁺).

Ethyl 4-amino-2-bromobenzoate (75): Iron (2.03 g, 36.4 mmol, 2.1 equivalents) and NH₄Cl (1.95 g, 36.4 mmol, 1.27 mL, 2.1 equivalents) were added to a solution of compound ₇₄ (2, 5.00 g, 17.3 mmol, 1 equivalent) in EtOH (22 mL), THF (22 mL), and water (11 mL) with stirring. The reaction mixture was heated to 80 °C for 3 hours. The reaction was repeated in exactly the same manner as using 16.0 g of compound 74. The two reactants were combined and filtered, and the filter cake was washed with EtOH (3 x 30 mL) and EtOAc (3 x 30 mL). The filtrate was concentrated and diluted with a saturated aqueous solution of _NaHCO₃ (200 mL) to ensure pH was about 8, and extracted with EtOAc (3 x 150 mL). The combined extracts were dried _over anhydrous _Na₂SO₄ and concentrated to give a crude product (19 g). The crude product was suspended in EtOAc (5 mL) and petroleum ether (25 mL) and stirred at room temperature for 20 min. The precipitate was collected by filtration and washed with petroleum ether (2 x 10 mL) to give compound 75 (16.0 g, 85.54% yield, 95% purity). ^¹H NMR (400 MHz, DMSO- _d₆ ) δ 7.62 (d, 1H), 6.84 (d, 1H), 6.54 (dd, 1H), 6.13 (s, 2H), 4.19 (q, _2H ), 1.27 (t, 3H); MS (EI) _{C₉H₁₀BrNO₂} , _243.9 (MH⁺).

2-Bromo-4-(((2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-ylidene)methyl)amino)ethyl benzoate (76): Compound 76 was synthesized from compounds 75 and 39 in a manner similar to that used in the preparation of compound 40 from compounds 38 and 39 in Example 12. Compound 76 was obtained (23 g, 88.1% yield). ^¹H NMR (400 MHz, _CDCl₃ ) δ 11.23 (d, 1H), 8.63 (d, 1H), 7.92 (d, 1H), 7.56 (d, 1H), 7.23 (dd, 1H), 4.40 (q, 2H), 1.76 (s, 6H), 1.41 (t, 3H).

7-Bromo-4-oxo-1,4-dihydroquinoline-6-carboxylic acid ethyl ester (77): Compound 77 was synthesized from compound 76 in a manner similar to that used in the preparation of compound 41 from compound 40 in Example 12. Compound 77 (20 g, 94.4% yield, 60% purity) was obtained and used in subsequent reactions without further purification. _{MS (EI) was C12H10BrNO3 ,} measured at _296.0 (MH+).

7-Bromo-4-chloroquinoline 6-carboxylic acid ethyl ester (78): Compound 78 was prepared from compound 77 as described in Example 12 for compound 42, except that pure _POCl3 was used instead. The reaction was carried out in MeCN with 4.21 equivalents of _POCl3 at 90 °C for 1.5 h (4.2 g, 33% yield). ^¹H NMR ( ₄₀₀ MHz, _CD₃OD ) δ 8.84 (d, 1H), 8.62 (s, 1H), 8.45 (s, 1H), 7.55 (d, 1H), 4.50 (q, 2H), 1.47 (t, 3H); MS (EI _{) C₁₂H₉BrClNO₂} , measured 313.8 (MH⁺).

7-Bromo-4-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylammono)phenoxy)quinoline-6-carboxylic acid ethyl ester (79): Compound 79 was prepared from compounds 78 and 3 as described in Example 12 for compound 43, except that cesium carbonate was used instead of potassium tert-butoxide and the reaction mixture was heated only to 50°C (6.7 g, 80.5% yield). ^¹H NMR (400MHz, _CD₃OD ) δ 9.55 (s, ¹H), 8.79 (s, ¹H), 8.70 (d, ¹H), 8.55 (s, ¹H), 8.40 (s, ¹H), 7.67 (d, 2H), 7.47 (dd, 2H), 7.18 (d, 2H), 7.06 (t, 2H), 6.56 (d, 1H), 4.48 (q, 2H), 1.79–1.73 ( _{m, 2H), 1.68–1.62 (m, 2H), 1.46 (t, 3H); MS (EI) was C₂₹H₂₃BrFN₃O₅ , measured} value _592.0 (MH⁺).

Example 25: 4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-7-(methylamino)quinoline-6-carboxylic acid (81)

Ethyl 4-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylamino)phenoxy)-7-(methylamino)quinoline-6-carboxylic acid (80): Pd₂(dba)₃ (440.54 mg, 481.08 μmol, 0.3 equivalent) was added to a mixture of compound 79 (1.00 g, 1.60 mmol, 1 equivalent), methylamine hydrogen chloride (216.55 _mg , 3.21 mmol, 2 equivalents), _Cs₂CO₃ (1.57 g, 4.81 mmol, 3 equivalents), and Xantphos (556.73 _mg , 962.17 μmol, 0.6 equivalents) in _1,4 -dioxane (25 mL) at 10 °C under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 3 h under a nitrogen atmosphere. The reaction mixture was cooled, then diluted with water (50 mL) and EtOAc (50 mL), neutralized with saturated _NH₄Cl aqueous solution to pH approximately 8, and filtered. The filter cake was washed with EtOAc. The phases of the filtrate were separated, and the aqueous phase was extracted with EtOAc (3 x 30 mL). The combined EtOAc phases were dried over _{anhydrous Na₂SO₄} and concentrated. The residue was purified by rapid silica gel chromatography (0–80% EtOAc: petroleum ether, then 0–15% EtOH in DCM solution), followed by further purification by preparative HPLC to give compound 80 (250 mg, 27.30% yield). ^¹H NMR (400MHz, _CDCl₃ ) δ 10.27 (s, 1H), 9.00 (s, 2H), 8.42 (s, 2H), 7.80 (d, 2H), 7.51 (dd, 2H), 7.39 (s, 1H), 7.17 (d, 2H), 7.03 (t, 2H), 6.38 (d, 1H), 4.44 (q, 2H), 3.11 (s, 3H), 1.85 (s, 2H), 1.73 (s, 2H), _{1.48–1.43 (m, 3H); MS (EI) was C₃₀H₂₇FN₄O₅ ,} measured value _543.1 ( _MH⁺ ).

4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-7-(methylamino)quinoline-6-carboxylic acid (81): A mixture of compound 80 (250 mg, 437.4 μmol, 1 equivalent) and lithium hydroxide:hydrate (183.69 mg, 4.38 mmol, 10 equivalent) in THF (10.0 mL) and water (10.0 mL) was stirred at 10 °C for 20 h. The reactants were diluted with water (40 mL), acidified to pH 6 with saturated _NH4Cl aqueous solution, and extracted with EtOAc (4 x 40 mL). The combined extracts were dried over _{anhydrous Na₂SO₄} and concentrated under reduced pressure to obtain a crude product, which was then purified by preparative HPLC (column: Ultimate C18 150*25mm*5μm; mobile phase: [water (0.05% HCl)-ACN]; B%: 16%-46%, 9.5 min) to give compound 81HCl salt (120 mg, 47.3% yield). ^¹H NMR (400MHz, _CD₃OD ) δ 9.13 (s, ¹H), 8.57 (d, ¹H), 7.81 (d, 2H), 7.56 (dd, 2H), 7.34 (d, 2H), 7.07 (t, 2H), 6.88 (s, ¹H), 6.61 (d, 1H), 3.07 (s, 3H), 1.66 (s _, 4H); MS (EI) was _{C₂₈H₂₃FN₄O₅ ,} measured value _515.1 (MH⁺).

Example 26: 1-N-[4-[6-carbamoyl-7-(methylamino)quinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (82)

1-N-[4-[6-carbamoyl-7-(methylamino)quinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (82): Compound 82 (29.9 mg, 24% yield) was synthesized from compound 81 in a manner similar to that used in the preparation of compound 7 from compound 6 in Example 3. ^¹H NMR (400MHz, _CD₃OD ) δ 8.61 (s, ¹H), 8.43 (d, ¹H), 7.72 (d, 2H), 7.59–7.54 (m, 2H), 7.23 (d, 2H), 7.07 (t, 2H), 6.94 (s, ¹H), 6.31 (d, ¹H), 2.97 (s, 3H), 1.64 ( _s , 4H); MS (EI) was _{C₂₈H₂₄FN₅O₄ ,} measured value _514.1 (MH⁺).

Example 27: 1-N'-(4-fluorophenyl)-1-N-[4-[7-(methylamino)-6-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (83)

1-N'-(4-fluorophenyl)-1-N-[4-[7-(methylamino)-6-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (83): Compound 83 (33.3 mg, 26% yield) was synthesized from compound 81 in a manner similar to that used in the preparation of compound 8 from compound 6 in Example 4. ^¹H NMR (400MHz, _CD₃OD ) δ 8.47 (s, ¹H), 8.42 (d, ¹H), 7.71 (d, 2H), 7.59–7.54 (m, 2H), 7.22 (d, 2H), 7.07 (t, 2H), 6.94 (s, ¹H), 6.32 (d, ¹H), 2.96 (s, 3H), 2.92 (s, 3H), 1.64 (s, 4H); MS (EI) was _{C₂ ₹ H₂₆FN₅O₄ ,} measured value 528.1 (MH⁺).

Example 28: Methyl 4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-7-(methylamino)quinoline-6-carboxylic acid ester (84)

4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-7-(methylamino)quinoline-6-carboxylic acid methyl ester (84): TMSCHN ₂ (2M, 276.97 μL, 10 equivalents) was added to a MeOH (5 mL) solution of compound 81 (30 mg, 55.39 μmol, 1 equivalent) at 10 °C, and the reaction was stirred at 10 °C for 6 h. The reaction was repeated in the same manner with an additional 45 mg of compound 81. The reaction solutions from the two batches were combined and concentrated under vacuum. The resulting residue was purified by preparative HPLC to give compound 84 (25.5 mg, 55.16% yield). ^¹H NMR (400MHz, _CD₃OD ) δ 8.99 (s, ¹H), 8.45 (d, ¹H), 7.72 (d, 2H), 7.57 (dd, 2H), 7.23 (d, 2H), 7.07 (t, 2H), 6.97 (s, ¹H), 6.29 (d, ¹H), 3.95 (s, 3H), 3.01 (s, 3H), 1.64 (s, 4H); MS (EI) was _{C₂ ₹ H₂₅FN₄O₅ ,} measured value 529.1 (MH⁺).

Example 29: 7-((tert-butoxycarbonyl)amino)-4-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylamino)phenoxy)quinoline-6-carboxylic acid (86)

7-((tert-butoxycarbonyl)amino)-4-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylamino)phenoxy)quinoline-6-carboxylic acid ethyl ester (85): A mixture of compound 79 (1.5 g, 2.53 mmol, 1 equivalent), _NH₂Boc (355.95 mg, 3.04 mmol, 1.2 equivalent), Xantphos (586.03 mg, 1.01 mmol, 0.4 equivalent), _Pd₂ (dba) _₃ (463.72 mg, 506.40 μmol, 0.2 equivalent) and _Cs₂CO₃ ( _2.47 g, 7.60 mmol, 3 equivalent) in dioxane (20 mL) was degassed and purged three times with nitrogen, and stirred at 90 °C for 16 hours under a nitrogen atmosphere. The mixture was filtered and concentrated, and the residue was purified by rapid silica gel chromatography (10% to 100% petroleum ether solution of EtOAc) to give compound 85 (1.3 g, 79.14% yield). ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.28 (s, 1H), 10.23 (s, 1H), 10.06 (s, 1H), 8.94 (s, 1H), 8.72 (d, 1H), 8.69 (s, 1H), 7.79 (d, 2H), 7.64 (dd, 2H), 7.30 (d, 2H), 7.16 (t, 2H), 6.46 (d, 1H), 4.42 (q, 2H), 1.53 (s, 9H), 1.48 (s, 4H), 1.38 (t, _{3H); MS (EI) was C₃₄H₃₃FN₄O₇ , measured value} 629.2 (MH⁺).

7-((tert-butoxycarbonyl)amino)-4-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylamino)phenoxy)quinoline-6-carboxylic acid (86): Compound 86 (0.7 g, 82.4% yield) was synthesized from compound 85 in a manner similar to that used in Example 2 to prepare compound 6 by hydrolysis of the methyl ester of compound 5. ^¹H NMR (400MHz, _CD₃OD ) δ 9.13 (s, ¹H), 8.57 (d, ¹H), 7.81 (d, 2H), 7.56 (dd, 2H), 7.34 (d, 2H), 7.07 (t, 2H), 6.88 (s, ¹H), 6.61 (d, 1H), 3.07 (s, 3H), 1.66 ( _s , 4H); MS (EI) was _{C₃₂H₂ ₹ FN₄O₇} , measured value 601.1 (MH⁺).

Example 30: 1-N-[4-(7-amino-6-carbamoylquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (87)

1-N-[4-(7-amino-6-carbamoylquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)-cyclopropane-1,1-dicarboxamide (87): Compound 87 was synthesized from compound 86 in two steps. The first step followed a similar manner to the preparation of compound 7 from compound 6 in Example 3. Step 2 involved TFA-mediated BOC-deprotection using a standard procedure (such as the standard procedure used in Example 5), which provided the final compound 87 (41.9 mg, 35% yield in 2 steps). ^¹H NMR (400MHz, _CD₃OD ) δ 8.63 (s, ¹H), 8.43 (d, ¹H), 7.73 (d, 2H), 7.66–7.52 (m, 2H), 7.32–7.22 (m, 2H), 7.15 (s, ¹H), 7.12–7.05 (m, 2H), 6.31 (d, ¹H), 1.66 (s, _{4H); MS (EI) was C₂₇H₂₂FN₅O₄ , measured} value _500.0 (MH⁺).

Example 31: 1-N-[4-[7-amino-6-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (88)

1-N-[4-[7-amino-6-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (88): Compound 88 was synthesized from compound 86 in two steps. The first step followed a similar manner to the preparation of compound 8 from compound 6 in Example 4. Step 2 involved TFA-mediated BOC-deprotection using a standard procedure (such as the standard procedure used in Example 5), which provided the final compound 88 (50.9 mg, 42% yield in 2 steps). ^¹H NMR (400MHz, DMSO- _d₆ ) δ 10.19 (s, 1H), 10.05 (s, 1H), 8.70 (br d, 1H), 8.52–8.38 (m, 2H), 7.77 (d, 2H), 7.69–7.59 (m, 2H), 7.30–7.06 (m, 5H), 6.55 (s, 2H), 6.17 (d, 1H), 2.79 (d, _3H ), 1.48 (s, 4H); MS ( _EI ) was _{C₂₈H₂₄FN₅O₄ ,} measured value 514.1 (MH⁺).

Example 32: 7-Amino-4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]quinoline-6-carboxylic acid (89)

7-Amino-4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]quinoline-6-carboxylic acid (89): Compound 89 was synthesized from compound 86 by TFA-mediated BOC-deprotection as described in Example 5. ^¹H NMR (400 MHz, DMSO- _d⁶ ) δ 10.19 (s, 1H), 10.07 (s, 1H), 8.80 (s, 1H), 8.48 (d, 1H), 7.76 (d, 2H), 7.69–7.58 (m, 2H), 7.24 (d, 2H), 7.19–7.10 (m, 3H), 6.16 ( _{d, 1H), 1.48 (s, 4H); MS (EI) was C₂₇H₂₁FN₄O₅ , measured 501.1} (MH⁺).

Example 33: Methyl 7-amino-4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]quinoline-6-carboxylic acid ester (90)

7-Amino-4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]quinoline-6-carboxylic acid methyl ester (90): A solution of compound 89 (100 mg, 199.81 μmol, 1 equivalent) in MeOH (3 mL) and _H₂SO₄ (0.1 _mL ) was stirred at 70 °C for 40 h. The reaction was concentrated under vacuum, and the resulting residue was purified by preparative HPLC to give compound 90 (28.5 mg, 26.88% yield). ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.20 (br s, 1H), 10.07 (br s, 1H), 8.81 (s, 1H), 8.50 (d, 1H), 7.77 (br d, 2H), 7.65 (br dd, 2H), 7.25 (br d, 2H), 7.21–7.06 (m, 3H), 6.83 (s, 2H), 6.15 (d, 1H), 3.90 (s, 3H), _1.48 (s, _{4H); MS (EI) was C₂₈H₂₃FN₄O₅ ,} measured value _515.2 (MH⁺).

Example 34: N-(4-((6-carbamoyl-7-hydroxyquinoline-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (91)

N-(4-((6-carbamoyl-7-hydroxyquinoline-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (91): A mixture of compound 7 (250 mg, 485.91 μmol, 1 equivalent) and BBr ₃ (1.04 g, 4.15 mmol, 0.4 mL, 8.54 equivalent) in 1,2-dichloroethane (2 mL) was stirred at 50 °C for 1 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and poured into a saturated aqueous solution of NaHCO ₃ with vigorous stirring. The resulting residue was filtered, washed with water, then washed with methyl tert-butyl ether, and dried. The crude compound was purified by preparative HPLC to give compound 91 (69.5 mg, 27.3% yield). ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 12.91 (s, 1H), 10.20 (s, 1H), 10.04 (s, 1H), 8.97 (s, 1H), 8.84 (s, 1H), 8.60–8.59 (d, 1H), 7.79 (s, 1H), 7.77–7.64 (d, 2H), 7.63–7.62 (d, 2H), 7.30–7.26 (m, 3H), 7.17–7.13 (m, 2H), 6.63–6.33 (d, 1H), _1.47 (s, _{4H )} ; MS (EI) was _{C₂₇H₂₁FN₄O₅} , measured value 501.1 (MH⁺).

Example 35: 1-N'-(4-fluorophenyl)-1-N-[4-[(2-methyl-4-oxo-2,3-dihydropyrido[3,2-g][1,3]benzoxazin-6-yl)oxy]phenyl]cyclopropane-1,1-dicarboxamide (92)

1-N'-(4-fluorophenyl)-1-N-[4-[(2-methyl-4-oxo-2,3-dihydropyridino[3,2-g][1,3]benzoxazin-6-yl)oxy]phenyl]cyclopropane-1,1-dicarboxamide (92): _T3P (535 mg, 1.68 mmol, 0.5 mL, 6.47 equivalents) and acetaldehyde (393 mg, 8.91 mmol, 0.5 mL, 34.30 equivalents) were added to a CHCl3 ₃ (5 mL) solution of compound 91 (130 mg, 259.75 μmol, 1 equivalent). The resulting mixture was stirred at 50 °C for 3 h and then concentrated under vacuum. The residue was purified by preparative HPLC to give compound 92 (30.7 mg, 22.45% yield). ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.22 (s, ¹H), 10.07 (s, ¹H), 9.05 (s, ¹H), 8.78 (s, ¹H), 8.70 (d, ¹H), 7.72 (d, 2H), 7.65 (d, 2H), 7.50 (s, ¹H), 7.28 (d, 2H), 7.17 (d, 2H), 6.50 (d, 1H), 5.62–5.58 (m, ¹H), 1.57 (d, 3H) _{, 1.48 (s, 4H); MS (EI) was C₂⁹H₂⁻³FN₄O₅ ,} measured value _{527.2 (} MH⁺).

Example 36: 1-N-[4-[(2-ethyl-4-oxo-2,3-dihydropyrido[3,2-g][1,3]benzoxazin-6-yl)oxy]phenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (96)

4-Chloro-7-methoxyquinoline-6-carboxamide (93): _NH₃ · _H₂O (10.58 g, 75.50 mmol, 1 equivalence) was added to a mixture of compound 4 (2.00 g, 7.55 mmol, 1 equivalence) in MeOH ( _{20 mL) at 10 °C. The mixture was stirred at 70 °C for 72 h. The precipitate was collected by filtration and dried under vacuum to give compound 93 (1.30 g, 69.1% yield); MS (EI) was C₁₁H₉ClN₂O₂ , measured 237.0} (MH⁺).

4-Chloro-7-hydroxyquinoline-6-carboxamide (94): BBr ₃ (6.54 g, 26.09 mmol, 2.51 mL, 5 equivalents) was added fractionally to a mixture of compound 93 (1.30 g, 5.22 mmol, 1 equivalent) in DCM (30 mL) at 0 °C. The mixture was stirred at 0 °C for 6 h. The reaction was quenched with saturated NaHCO ₃ aqueous solution (150 _mL ) and filtered. The resulting residue was dried under vacuum to give compound 94 ( _{1.00 g, 81.77% yield). MS (EI) was C10H7ClN2O2 , and} the result was 222.8 (MH+).

6-Chloro-2-ethyl-2,3-dihydro-4H-[1,3]oxazino[5,6-g]quinoline-4-one (95): Propanal (1.60 g, 27.48 mmol, 2 mL, 3.06 equivalents) and _T3P (10.42 g, 32.76 mmol, 9.74 mL, 3.65 equivalents) were added to a CHCl3 ₃ (15 mL) solution of compound 94 (2 g, 8.98 mmol, 1 equivalent). The resulting mixture was stirred at 50 °C for 15 h, and then propanal (1.60 g, 27.48 mmol, 2 mL, 3.06 equivalents) was added, and stirring was continued at 50 °C for another 15 h. The mixture was then concentrated to remove the solvent, giving crude compound 95 (2.2 g, 85.8% yield) as a yellow solid, which was used in the next step without further purification. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 9.16 (br s, 1H), 8.87 (d, 1H), 8.66 (s, 1H), 7.72 (d, 1H), 7.62 (s, 1H), 5.45–5.47 (m, 1H), 1.38–1.44 (m, 2H), 1.06 (t, 3H); MS _{( EI )} was _{C₁₃H₁₁ClN₂O₂} , measured value 262.9 (MH⁺).

1-N-[4-[(2-ethyl-4-oxo-2,3-dihydropyrido[3,2-g][1,3]benzoxazin-6-yl)oxy]phenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (96): A chlorobenzene (10 mL) solution of compound 95 (95 mg, 361.64 μmol, 1 equivalent) and compound 3 (284.17 mg, 904.10 μmol, 2.5 equivalent) was stirred at 140 °C for 15 h. The mixture was diluted with EtOAc (60 mL) and washed with 2N NaOH (3 x 20 mL). The combined aqueous phases were extracted with EtOAc (30 mL). The combined organic phases were concentrated, and the resulting residue was purified by preparative HPLC (column: YMC-Triart Prep C18150*40mm*7um; mobile phase: [water (0.05% ammonium hydroxide v/v)-ACN]; B%: 53%-73%, 10 min) to give compound 96 as a white solid (7.1 mg, 3.6% yield). ^¹H NMR (400MHz, DMSO- _d₆ ) δ 10.23 (s, ¹H), 10.07 (s, ¹H), 9.05 (s, ¹H), 8.78 (s, ¹H), 8.69 (s, ¹H), 7.78–7.86 (m, 2H), 7.64–7.67 (m, 2H), 7.51 (s, ¹H), 7.28–7.30 (m, 2H), 7.14–7.18 (m, 2H), 6.49–6.51 (m, 1H), 5.43 (s, 1H), 1.88–1.91 (m, 2H), 1.48 (s, 4H), 1.06 (t, 3H); MS ₍ EI ₎ was _{C₃₀H₂₅FN₄O₅ ,} measured value 541.1 (MH⁺).

Example 37: 1-N-[4-[6-carbamoyl-7-(3-morpholin-4-ylpropoxy)quinolin-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (98)

4-(3-Bromopropyl)morpholine (97): 3-morpholinopropan-1-ol (2.0 g, 13.77 mmol, 1 equivalent) and PPh ₃ (4.0 g, 15.25 mmol, 1.11 equivalent) were dissolved in THF (20 mL), and the reaction mixture was cooled in an ice-water bath under nitrogen. CBr ₄ (5.0 g, 15.08 mmol, 1.09 equivalent) was added in portions over 15 minutes. After stirring for 30 minutes, the mixture was heated to 30 °C and maintained for 18 hours. The reaction was quenched with water (10 mL) and EtOAc (30 mL). The layers were separated, and the organic layer was extracted with 1N HCl (2 x 15 mL). The pH of the combined aqueous extracts was adjusted to 10⁻¹¹ with 4N NaOH. The aqueous phase was extracted with EtOAc (3 x 30 mL). The combined EtOAc extracts were dried over anhydrous _Na₂SO₄ and concentrated to give compound ₉₇ (1.8 g, 63% yield), which was used in subsequent reactions without further purification. ^¹H NMR (400 MHz, _CDCl₃ ) δ 3.72–3.69 (m, 4H), 3.49–3.46 (t, 2H), 2.50–2.43 (m, 6H), 2.06–1.99 (m, 2H).

1-N-[4-[6-carbamoyl-7-(3-morpholin-4-ylpropoxy)quinolin-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (98): Cs₂CO₃ (81.18 _mg , 249.14 μmol, 2.90 equivalent) was added to a mixture of compound 91 (45 mg, 85.87 μmol, 1 equivalent) and compound ₉₇ (53.48 mg, 257.00 μmol, 2.99 equivalent) in DMF (2 mL) under nitrogen atmosphere. The mixture was stirred at 80 °C for 2 hours. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 20 mL). The combined organic phases were separated, washed with saturated NaCl aqueous solution, _dried over anhydrous _Na₂SO₄ , concentrated, and purified by preparative HPLC to give compound 98 (16.2 mg, 29.70% yield). ^¹H NMR (400 MHz, DMSO- _d₆ ) δ 9.36 (s, 1H), 9.29–9.27 (d, 1H), 9.00 (s, 1H), 8.64–8.63 (d, 1H), 7.99–7.98 (d, 1H), 7.69–67 (d, 2H), 7.54 (s, 1H), 7.51–7.47 (m, 2H), 7.17–7.14 (d, 2H), 7.07–7.01 (m,2H), 6.46-6.45(d,1H), 5.98-5.97(d,1H), 4.40-4.37(t,2H), 3.76-3.70(m,4H), 2.26-2.58(m,2H), 2.50(s,4H), 2.20-2.13(m,2H) _, 1.74-1.70(m,4H); MS(EI) is _{C34H34FN5O6 ,} measured value _628.5 (MH+).

Example 38: 1-N-[4-[6-carbamoyl-7-(2-methoxyethoxy)quinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (103)

6-Bromo-4-chloroquinoline-7-ol (99): A mixture of compound 42 (5 g, 18.35 mmol, 1 equivalent) and BBr ₃ (13.0 g, 51.89 mmol, 5 mL, 2.83 equivalent) in 1,2-dichloroethane (15 mL) was stirred at 90 °C for 2.5 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and poured into a saturated aqueous solution of NaHCO ₃ with vigorous stirring. The resulting residue was filtered, washed with water, then washed with methyl tert-butyl ether, and dried under vacuum to give compound 99 (7 g, crude), which could be used in subsequent steps without further purification. ^¹H NMR (400MHz, DMSO- _d₆ ) δ 9.04–9.03 (d, ¹H), 8.49 (s, ¹H), 7.93–7.92 (d, ¹H), 7.69 (s, ¹H), 6.08 (s, ¹H); MS _{(EI) was C₈H₅BrClNO ,} measured value 258.2 (MH⁺).

6-Bromo-4-chloro-7-(2-methoxyethoxy)quinoline (100): A mixture of compound 99 (500 mg, 1.93 mmol, 1 equivalent), 1-bromo-2-methoxy-ethane (1.08 g, 7.73 mmol, 726.35 _μL , 4 equivalents), and _Cs₂CO₃ (1.90 g, 5.83 mmol, 3.01 equivalents) in DMF (4 mL) was stirred at 80 °C for 2 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and water (2 mL) was added. The resulting residue was filtered, washed with water, and dried under vacuum to give compound 100 (590 mg, 96% yield), which could be used in subsequent reactions without further purification. ^¹H NMR (400MHz, DMSO- _d₆ ) δ 8.80–8.79 (d, ¹H), 8.37 (s, ¹H), 7.65–7.64 (d, ¹H), 7.62 (s, ¹H), 4.39–4.37 (t, 2H), 3.79–3.77 (t, 2H), 3.37 ( _{s, 3H); MS (EI) was C₁₂H₁₁BrClNO₂ ,} measured value 315.8 ( _MH⁺ ).

N-(4-((6-bromo-7-(2-methoxyethoxy)quinoline-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (101): Compound 101 (65 mg, 69.2% yield) was synthesized from compounds 100 and 3 in a manner similar to that used in Example 12 for the preparation of compound 43 from compounds _{42 and 3.} MS (EI) was _{C29H25BrFN3O5} , and the measured value was 594.1 (MH+).

N-(4-((6-cyano-7-(2-methoxyethoxy)quinoline-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (102): Compound 101 (65 mg, 109.35 μmol, 1 equivalent) and CuCN (15 mg, 167.48 μmol, 36.59 μL, 1.53 equivalent) were mixed in N-methyl-2-pyrrolidone (NMP) (2 mL) in a sealed tube and heated at 150 °C for 45 min under microwave irradiation. The reaction mixture was partitioned between water (10 mL), _NH4OH (5 mL), and EtOAc (20 mL), the phases were separated, and the aqueous phase was further extracted with EtOAc. The combined organic phases were washed with a saturated aqueous NaCl solution, dried over anhydrous _Na₂SO₄ , and concentrated to give compound 102 (40 mg, 68% yield), which was used in subsequent steps without further purification. _MS (EI) was _{C₃₀H₂₅FN₄O₅} , _with a measured value _{of 541.5} (MH⁺).

1-N-[4-[6-carbamoyl-7-(2-methoxyethoxy)quinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (103): Compound 102 (40 mg, 74.00 μmol, 1 equivalent) and NaOH (100 mg, 2.50 mmol, 33.79 equivalent) were dissolved in DMSO (1.5 mL) and water (0.5 mL). The resulting mixture was heated at 80 °C for 1 hour. The reaction mixture was partitioned between water (10 mL) and EtOAc (20 mL) to separate the phases, and the aqueous phase was further extracted with EtOAc. The combined organic phases were washed with a saturated aqueous solution of NaCl, dried over _{anhydrous Na₂SO₄} , and concentrated. The residue was purified by rapid silica gel chromatography (50–100% EtOAc/petroleum ether) to give compound 103 (18.6 mg, 44% yield). ¹ H NMR (400MHz, CDCl ₃ )δ9.30(s,1H),9.27(s,1H),9.02(s,1H),8.64-8.63(d,1H),8.15(s,1H),7.69-7.66(d,2H),7.51-7.48(m,3H),7.17-7.15(d,2H), 7.07-7.03(m,2H),6.47-6.45(d,1H),5.92(s,1H),4.44-4.42(t,2H),3.91-3.89(t,2H),3.50(s,3H),1.75-1.68(m,4H); MS(EI) is C ₃₀ H ₂₇ FN ₄ O ₆ The measured value was 559.4 (MH+).

Example 39: 1-N-[4-[6-carbamoyl-7-(2-hydroxyethoxy)quinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (106)

Ethyl 2-((6-carbamoyl-4-chloroquinoline-7-yl)oxy)ethyl acetate (104): Ethyl ₂ -bromoethyl acetate (285.05 mg, 1.71 mmol, 187.53 μL, 2.00 equivalent) was added to a mixture of compound 94 (200 mg, 853.44 μmol, 1 equivalent) and _K₂CO₃ (589.77 mg, 4.27 mmol, 5 equivalent) in DMF (10 mL) at 10 °C. The resulting mixture was stirred at 70 °C for 1 hour. After cooling, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 30 mL). The combined extracts were washed with saturated aqueous NaCl solution (3 x 100 mL), _dried over anhydrous _Na₂SO₄ , and concentrated under vacuum to give compound 104 (220 mg, 79.33% yield). MS(EI) is _C14H13ClN2O4 , measured _{value 309.0 (} MH+).

2-((6-carbamoyl-4-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylamino)phenoxy)quinoline-7-yl)oxy)ethyl acetate (105): Compound 104 (200 mg, 615.45 μmol) was converted to compound 105 by reaction with compound 3, using a method similar to that used in the preparation of compound 43 from compounds 42 and 3 in Example 12. The resulting reaction mixture was treated with water at 100 °C for 4 hours before undergoing the conventional post-reaction treatment as described in Example 12. The resulting product was a mixture of compounds 105 and 106. The mixture was separated by rapid silica gel chromatography to give compound 105 (100 mg, 24.93% yield), which was used in the next reaction, and compound 106 (100 mg, 25.36% yield, 85% purity), which was combined with the product of the next reaction for final purification. For compound 105: MS (EI) is _C31H27FN4O7 , _and the measured value _is 587.1 ₍ MH+).

1-N-[4-[6-carbamoyl-7-(2-hydroxyethoxy)quinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (106): LiOH·H₂O (64.39 mg, _1.53 mmol, 10 equivalents) was added to a solution of compound 105 (100 mg, 153.44 μmol, 1 equivalent) separated from the previous reaction in THF (5 mL) and water (1 mL). The resulting mixture was stirred at 70 °C for 1 hour. After the reaction mixture was cooled to room temperature, it was acidified to pH about 7 with a saturated aqueous _NH₄Cl solution, diluted with water (30 mL), and extracted with EtOAc (3 x 20 mL). The combined organic phases were dried over _{anhydrous Na₂SO₄} and concentrated under vacuum to give crude compound 106 (90 mg, 91.56% yield, 85% purity). The substance was combined with compound 106, which had been isolated from the previous step, and purified by rapid silica gel chromatography. The resulting product was suspended in a 1:1 mixture of DCM:MeCN and stirred for 10 minutes. The resulting solid was filtered, washed with MeCN, then washed with DCM, and dried under vacuum to give compound 106 (65.8 mg, 38.7% yield). ^¹H NMR (400MHz, DMSO- _d₆ ) δ 10.20 (s, ¹H), 10.06 (s, ¹H), 8.83 (s, ¹H), 8.66 (d, ¹H), 7.96 (s, ¹H), 7.84 (s, ¹H), 7.78 (d, 2H), 7.64 (dd, 2H), 7.56 (s, ¹H), 7.27 (d, 2H), 7.15 (t, 2H), 6.47 (d, ¹H), 5.14 (t, ¹H), 4.32 (t, 2H), 3.86 (dd, 2H), 1.47 (s, _{4H); MS (EI) was C₂₹H₂₅FN₄O₆ , measured value} 545.1 (MH⁺).

Example 40: 1-N'-(4-fluorophenyl)-1-N-[4-[7-(2-hydroxyethoxy)-6-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (110)

4-Chloro-7-methoxy-N-methylquinoline-6-carboxamide (107): A solution of methylamine (8 M, 50 mL, 10.07 equivalents) in EtOH was added to a solution of compound 4 (10 g, 39.74 mmol, 1 equivalent) in THF (150 mL) at 30 °C, and the mixture was stirred at this temperature for 25 h. The reaction mixture was concentrated under vacuum. The residue was slurried with warm water (100 _mL ), filtered, and dried under vacuum to give _compound 107 (9 g, 90.4% yield). _MS (EI) was _C12H11ClN2O2 , measured at 251.0 (MH+).

4-Chloro-7-hydroxy-N-methylquinoline-6-carboxamide (108): Compound 108 (730 mg, 62% yield) was synthesized from compound 107 in a manner similar to that used in the preparation of compound 94 from compound 93 in _{Example 36. MS (EI) was C11H9ClN2O2 , measured} at 237.0 (MH+).

2-((4-chloro-6-(methylcarbamoyl)quinolin-7-yl)oxy)ethyl acetate (109): Compound 109 was synthesized from compound 108 in a manner similar to _that used in Example 39 for the preparation of compound 104 (200 _mg , crude) from compound 94. _MS (EI) was _C15H15ClN2O4 , measured at 323.1 (MH+).

1-N'-(4-fluorophenyl)-1-N-[4-[7-(2-hydroxyethoxy)-6-(methylcarbamoyl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (110): t-BuOK (70 mg, 623.83 μmol, 2.01 equivalents) was added to a mixture of compound 3 (107 mg, 340.43 μmol, 1.10 equivalents) and compound 109 (100 mg, 309.84 μmol, 1 equivalent) in DMSO (10 mL). The resulting mixture was heated and stirred at 100 °C for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic phases were washed with saturated NaCl aqueous solution (2 x 100 mL), _dried over anhydrous _Na₂SO₄ , and concentrated under vacuum. The residue was purified by rapid silica gel chromatography (0-20% MeOH in EtOAc solution) to obtain the crude product, which was then purified by preparative TLC (20% MeOH in DCM solution, _Rf = 0.3) to obtain compound 110 (54.8 mg, 100% purity). ^¹H NMR (400MHz, DMSO- _d₆ ) δ 10.22 (s, 1H), 10.07 (s, 1H), 8.75 (s, 1H), 8.66 (d, 1H), 8.49 (q, 1H), 7.78 (d, 2H), 7.64 (dd, 2H), 7.57 (s, 1H), 7.27 (d, 2H), 7.15 (t, 2H), 6.46 (d, 1H), 5.19 (t, 1H), 4.32 (t, 2H), 3.86 (br d, 2H), 2.87 (d, 3H), _1.47 (s, _{4H )} ; MS (EI) was _{C₃₀H₂₇FN₄O₆} , measured value 559.1 (MH⁺).

Example 41: 1-N-[4-[6-carbamoyl-7-(2-hydroxypropoxy)quinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (115)

4-Chloro-7-(2-oxopropoxy)quinoline-6-carboxamide (111): 1-Chloropropan- _{2-one (1.45 g, 15.7 mmol, 11.97 μL, 18.4 equivalents) was added to a mixture of compound 94 (200 mg, 853.4 μmol, 1 equivalent) and K₂CO₃ (} 589.76 mg, 4.27 mmol, 5 equivalents) in DMF (10 mL) at 10 °C. The reaction mixture was then stirred at 65 °C for 1 hour. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 30 mL). The combined extracts were washed with saturated aqueous NaCl solution (3 x 100 mL), _dried over anhydrous _Na₂SO₄ , and concentrated. The resulting residue was purified by rapid silica gel chromatography (0–10% MeOH in DCM solution). The resulting yellow residue was further purified by preparative HPLC (column: Waters Xbridge 150mm*25mm*5μm; mobile phase: [water (0.05% ammonium hydroxide v/v)-ACN]; B%: 17%-47%, 7.8 min) to give compound 111 (55 _mg , _30.0 % yield). _{MS (EI) was C13H11ClN2O3 ,} measured value 279.0 (MH+).

4-Chloro-7-(2-hydroxypropoxy)quinoline-6-carboxamide (112): _NaBH4 (12.90 mg, 340.88 μmol, 2 equivalents) was added to a mixture of compound 111 (50 mg, 170.44 μmol, 1 equivalent) in MeOH (10 mL) at 10 °C. The reaction mixture was then stirred at 50 °C for 1 h. The reaction mixture was quenched with saturated _NH4Cl aqueous solution (30 mL) and extracted with EtOAc/i-PrOH (v/v = 3: ₁ , 5 x ₂₀ mL). The combined extracts were dried over anhydrous _Na2SO4 and concentrated under reduced pressure to give compound ₁₁₂ (50 _mg , 99.3% yield). MS (EI) was _C13H13ClN2O3 , and the measured value was 302.8 (MH+Na) ⁺ .

1-((6-carbamoyl-4-chloroquinoline-7-yl)oxy)propyl-2-yl acetate (113): _Ac₂O (65.46 mg, 641.24 μmol, 60.06 μL, 5 equivalents) and DMAP (15.67 mg, 128.25 μmol, 1 equivalent) were added to a mixture of compound 112 (45 mg, 128.25 μmol, 1 equivalent) in DCM (10 mL) at 10 °C. The mixture was then stirred at 10 °C for 16 h. The reaction mixture was diluted with water (30 mL) and extracted with DCM (5 x 20 _mL ). The combined extracts were dried over anhydrous _Na₂SO₄ and concentrated. The residue was purified by rapid silica gel chromatography (0-3% MeOH in EtOAc solution) to give compound 113 (45 mg, 86.98% yield, 80% purity). MS ( _{EI) is C15H15ClN2O4 ,} measured value _344.8 (MH ₊ Na) ⁺ .

1-((6-carbamoyl-4-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylamino)phenoxy)quinoline-7-yl)oxy)propyl-2-yl acetate (114): Compound 114 was synthesized from compounds 113 and 3 in a manner similar to that described for compound 43 in Example 12, except that cesium carbonate was used instead of potassium tert-butoxide, and the reaction mixture was heated to 100°C for 2 _hours ( ₄₀ mg, _72.9 % yield). MS (EI) was _C32H29FN4O7 , and the measured value was 601.1 (MH+).

1-N-[4-[6-carbamoyl-7-(2-hydroxypropoxy)quinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (115): LiOH· _H₂O (26.55 mg, 632.71 μmol, 10 equivalents) was added to a solution of compound 114 (40 mg, 63.27 μmol, 1 equivalent) in THF (5 mL) and water (1 mL). The mixture was stirred at 70 °C for 1 hour. After cooling to room temperature, the reactants were diluted with DCM (30 mL), dried _over anhydrous _Na₂SO₄ , and concentrated under reduced pressure. The product was suspended in MeCN (1 mL) and stirred at 10 °C for 5 minutes. The precipitate was collected by filtration and dried under vacuum to give compound 115 (16.7 mg, 46.78% yield). ^¹H NMR (400MHz, DMSO- _d₆ ) δ 10.20 (s, 1H), 10.06 (s, 1H), 8.81 (s, 1H), 8.66 (d, 1H), 8.02 (d, 1H), 7.84 (s, 1H), 7.78 (d, 2H), 7.64 (dd, 2H), 7.54 (s, 1H), 7.27 (d, 2H), 7.15 (t, 2H), 6.47 (d, 1H), 5.15 (d, 1H), 4.27–4.21 ( _m , 1H), 4.17–4.04 (m, 2H), 1.47 (s, 4H), _{1.22 (d, 3H); MS (EI) was C₃₀H₂₇FN₄O₆ ,} measured value _559.1 (MH⁺).

Using a similar sequence to that used in the preparation of compound 115 from compound 94 in Example 41, the following compounds were prepared by replacing compound 94 with compound 108:

1-N'-(4-fluorophenyl)-1-N-[4-[7-(2-hydroxypropoxy)-6-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (116). ^¹H NMR (400MHz, DMSO- _d₆ ) δ 10.27(s, ¹H), 10.13(s, ¹H), 8.80(s, ¹H), 8.73(d, ¹H), 8.62(d, ¹H), 7.85(d, 2H), 7.71(dd, 2H), 7.62(s, ¹H), 7.33(d, 2H), 7.22(t, 2H), 6.54(d, ¹H), 5.28(d, 1H), 4.31(dd, 1H), 4.23–4.10( _m , 2H), 2.94(d, 3H), 1.54(s, 4H), _{1.29(d, 3H); MS (EI) was C₃¹H₂₉FN₄O₆ ,} measured value _573.1 (MH⁺).

Example 42: 1-N'-(4-fluorophenyl)-1-N-[4-[7-(2-hydroxypropoxy)-6-(1,3-oxazol-2-yl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (125)

4-Chloro-7-methoxyquinoline-6-carboxylic acid (117): LiOH· _H₂O (1.33 g, 31.79 mmol, 2 equivalents) was added to a solution of compound 4 (4.0 g, 15.89 mmol, 1 equivalent) in THF (30 mL) and water (6 mL), and the resulting mixture was stirred at 20 °C for 10 h. The resulting solid was filtered to give crude compound 117 as a white solid (4.4 g), which could be used in the next step without further purification. _MS (EI) was _{C₁₁H₈ClNO₃} , _with a measured value of 238.0 (MH⁺).

4-Chloro-N-(2,2-Dimethoxyethyl)-7-methoxyquinoline-6-carboxamide (118): To a THF (40 mL) solution of compound 117 (4 g, 16.83 mmol, 1 equivalent) and 2,2-dimethoxyethylamine (7.08 g, 67.33 mmol, 7.34 mL, 4 equivalents), _T3P (16.07 g, 50.50 mmol, 15.02 mL, 3 equivalents) and DIPEA (8.70 g, 67.33 mmol, 11.73 mL, 4 equivalents) were added. The resulting reaction mixture was stirred at 20 °C for 15 h. An additional ₅ mL of T3P and 3 mL of 2,2-dimethoxyethylamine were added to the mixture, and stirring was continued at 20 °C for 25 h. The mixture was quenched with water (30 mL) and the pH was adjusted to 9–10 with 1 M NaOH aqueous solution. The resulting aqueous mixture was extracted with EtOAc (3 x 40 mL). The combined organic extracts were washed with saturated NaCl aqueous solution (15 mL) and concentrated to give crude compound 118 as a white solid (4.1 _g , _73.5 % yield), which was used in the next step without further purification. _{MS (EI) was C15H17ClN2O4 ,} measured at 325.1 (MH+).

2-(4-Chloro-7-methoxyquinoline-6-yl)oxazole (119): At 20 °C under nitrogen, 2.5 g (7.70 mmol, 1 equivalent) of compound 118 was added to Eaton's Reagent (7.7 wt% phosphorus pentoxide methanesulfonic acid solution, 23.09 mmol, 46.97 mL, 3 equivalents). The resulting mixture was heated at 145 °C for 7 hours. The mixture was quenched with water (100 mL) and the pH was adjusted to 8-9 with Et ₃ N. The resulting mixture was extracted with EtOAc (4 x 40 mL). The combined organic extracts were washed with saturated NaCl aqueous solution (40 mL) and concentrated. The residue was purified by rapid silica gel chromatography (20 g silica rapid column, eluent 0–80% ethyl acetate/petroleum ether gradient @ 32 mL/min) to give compound 119 as a white solid (1.38 g, 68.8% yield). ^¹H NMR (400MHz, _CDCl₃ ) δ 8.43 (s, ¹H), 8.76 (d, ¹H), 7.86 (s, ¹H), 7.62 (s _{, ¹H), 7.42 (d, ¹H), 7.40 (s, ¹H), 4.14 (s, ³H); MS (EI) was C₁₃H₉ClN₂O₂ ,} measured value _261.0 ( _MH⁺ ).

4-Chloro-6-(oxazol-2-yl)quinoline-7 _- ol (120): Compound 120 was synthesized from compound 119 in a manner similar to that used in Example 36 for the synthesis of compound 94 from compound 93. _MS (EI ₎ was _C12H7ClN2O2 , measured at 246.7 (MH+).

1-((4-chloro-6-(oxazol-2-yl)quinolin-7-yl)oxy)prop-2-one (121): Compound 121 was synthesized from compound 120 in a manner similar to _that used in Example 41 for the synthesis of compound 111 from compound 94. _MS (EI) was _C15H11ClN2O3 , measured at _302.7 (MH+).

1-((4-chloro-6-(oxazol-2-yl)quinolin-7-yl)oxy)prop-2-ol (122): Compound 122 was synthesized from compound 121 in a manner similar to that used in Example 41 for the synthesis of compound 112 from compound 111. _{MS (EI) was C15H13ClN2O3 , and} the measured value _was 326.9 [M+Na] ⁺ .

1-((4-chloro-6-(oxazol-2-yl)quinolin-7-yl)oxy)propyl-2-ylacetate (123): Compound 123 was synthesized from compound 122 in a manner similar to that used in Example 41 for the synthesis of compound 113 from compound 112. ^¹H NMR (400 MHz, _CDCl₃ ) δ 8.83 (s, 1H), 7.23 (d, 1H), 7.83 (s, 1H), 7.54 (s, 1H), 7.40 (d, 1H), 7.34 (s, 1H), 5.41–5.49 (m, 1H), 4.25 (d, 2H), 2.06 (s, 3H), _{1.43 (d, 3H); MS (EI) was C₁₇H₁₅ClN₂O₄ , measured 347.1} (MH⁺).

1-((4-(4-(1-(((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylammono)phenoxy)-6-(oxazol-2-yl)quinoline-7-yl)oxy)propane-2-yl acetate (124): Compound 124 was synthesized from compounds 123 and 3 using a variation of the method for synthesizing compound 43 from compounds 42 and 3 in Example 12. Cesium carbonate was used instead of potassium tert-butoxide, and the reaction mixture was heated to 100°C for 3 h. _{MS (EI) was C34H29FN4O7 , and} the measured value _was 625.0 (MH+).

1-N'-(4-fluorophenyl)-1-N-[4-[7-(2-hydroxypropoxy)-6-(1,3-oxazol-2-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (125): NaOH (51.23 mg, 1.28 mmol, 2 equivalents) was added to a solution of compound 124 (400 mg, 640.4 μmol, 1 equivalent) in water (5 mL) and MeOH (5 mL), and the mixture was stirred at 20 °C for 5 hours. The mixture was diluted with water (30 mL). The resulting precipitate was filtered and washed with water (2 x 5 mL) and MeOH (3 mL). The solid was then lyophilized to give compound 125 as a white solid (238.5 mg, 63.9% yield). ^¹H NMR (400MHz, DMSO- _d₆ ) δ 10.22 (s, ¹H), 10.07 (s, ¹H), 8.79 (s, ¹H), 8.68 (d, ¹H), 8.32 (s, ¹H), 7.79 (d, 2H), 7.65 (t, 2H), 7.60 (s, 1H), 7.47 (s, 1H), 7.29 (d, 2H), 7.18 (t, 2H), 6.49 (d, 1H), 5.02 (d, 1H), 4.15–4.10 (m, 3H), 1.48 (s, 4H), _1.26 (d, _{3H); MS (EI) was C₃₂H₂₇FN₄O₆ ,} measured value _583.3 (MH⁺).

Example 43: Methyl 4-[2-chloro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-7-methoxyquinoline-6-carboxylic acid ester (128)

N-(3-chloro-4-hydroxyphenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (127): Compound 127 (1.9 g, 73.5% yield) was synthesized from compounds 1 and 126 in a manner similar to that used in Example 1 for the preparation of compound 3 from compounds 1 and 2. ^¹H NMR (400 MHz, _CDCl₃ ) δ 9.03–8.85 (m, 2H), 7.68 (d, 1H), 7.50–7.40 (m, 2H), 7.18 (dd, 1H), 7.08–7.00 (m, 2H), 6.97 (d, 1H), 5.53 (s, 1H), _1.64 (s, _{4H); MS (EI) was C₁₇H₁₄ClFN₂O₃ ,} measured _349.0 (MH⁺).

4-[2-chloro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-7-methoxyquinoline-6-carboxylic acid methyl ester (128): Compound 128 (0.8 g, 32.1% yield) was synthesized from compounds 127 and 4 in a manner similar to that used in the preparation of compound 43 from compounds 42 and 3 in Example 12. ^¹H NMR (400MHz, _CDCl₃ ) δ 10.08 (s, ¹H), 8.83 (s, ¹H), 8.63 (d, ¹H), 8.20 (s, ¹H), 7.92 (d, ¹H), 7.55–7.48 (m, 2H), 7.48–7.41 (m, 2H), 7.21 (d, 1H), 7.10–7.02 (m, 2H), 6.30 (d, 1H), 4.04 (s, 3H), 3.97 (s, 3H), 1.85–1.78 (m, 2H), 1.66–1.58 (m, _{2H); MS (EI) was C₂₹H₂₃ClFN₃O₆ , measured value} 564.4 (MH⁺).

Using a sequence similar to that used in the synthesis of compound 128 in Example 43, the following compounds were prepared in two steps, replacing compound 126 with 4-amino-2-fluorophenol:

4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-7-methoxyquinoline-6-carboxylic acid methyl ester (129): ^1H NMR (400MHz, CDCl3 ₎ δ 10.05(s,1H), 8.83(s,1H), 8.65(d,1H), 8.09(s,1H), 7.78(dd,1H), 7.50(s,1H), 7.48-7.42(m,2H), 7.27-7.19(m,2H), 7.10-7.04(m,2H), 6.40(d,1H), 4.05(s,3H), 3.97(s,3H), 1.84-1.81(m,2H), 1.63-1.60(m,2H); MS (EI) was C ₂₉ H ₂₃ F ₂ N ₃ O ₆ , measured value 548.4 (MH+).

Example 44: 4-[2-chloro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-7-methoxyquinoline-6-carboxylic acid (130)

4-[2-chloro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-7-methoxyquinoline-6-carboxylic acid (130): Compound 130 (0.55 g, 76.6% yield) was synthesized from compound 128 in a manner similar to that used in the preparation of compound 6 from compound 5 in Example 2. ^¹H NMR (400MHz, DMSO- _d₆ ) δ 10.41 (s, 1H), 10.10 (s, 1H), 8.58 (d, 1H), 8.25 (s, 1H), 8.10 (d, 1H), 7.75–7.59 (m, 3H), 7.47–7.37 (m, 2H), 7.16 (t, 2H), 6.32 (d, 1H), 3.92 ( _s , 3H), 1.47 (s, 4H); MS (EI) was _{C₂₈H₂₁ClFN₃O₆} , _{measured value} 550.1 (MH⁺).

The following compounds were prepared from compound 129 using a similar preparation method to that used in Example 44 for the synthesis of compound 130 from compound 128:

4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-7-methoxyquinoline-6-carboxylic acid (131): ^¹H NMR (400 MHz, DMSO- _d⁶ ) δ 13.20 (s, 1H), 10.42 (s, 1H), 10.01 (s, 1H), 8.72 (d, 1H), 8.59 (s, 1H), 7.93 (d, 1H), 7.64 (dd, 2H), 7.56–7.51 (m, 2H), 7.50–7.44 (m, 1H), 7.15 (t, 2H), 6.54 (d, 1H), 3.99 (s, 3H), 1.47 (d, _{4H )} ; MS ( _{EI ) C₂₈H₂₁F₂N₃O₆} The measured value was 534.4 (MH+).

Example 45: 1-N'-[4-(6-carbamoyl-7-methoxyquinoline-4-yl)oxy-3-chlorophenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (132)

1-N'-[4-(6-carbamoyl-7-methoxyquinoline-4-yl)oxy-3-chlorophenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (132): Compound 132 (43.1 mg, 40.9% yield) was synthesized from compound 130 in a manner similar to that used in the preparation of compound 7 from compound 6 in Example 3. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.38 (s, ¹H), 10.04 (s, ¹H), 8.71 (s, ¹H), 8.67 (d, ¹H), 8.11 (d, ¹H), 7.89 (br s, ¹H), 7.78 (br s, ¹H), 7.73–7.61 (m, ³H), 7.54 (s, ¹H), 7.46 (d, ¹H), 7.16 (t, ²H), 6.37 (d, ¹H), 4.04 (s, ³H) _{, 1.47 (s, ⁴H); MS (EI) was C₂₈H₂₂ClFN₄O₅ , measured value} 549.4 (MH⁺).

The following compounds were prepared from compound 131 using a method similar to that used in Example 45 for the preparation of compound 132 from compound 130:

1-N'-[4-(6-carbamoyl-7-methoxyquinoline-4-yl)oxy-3-fluorophenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (133): ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.40 (s, 1H), 10.01 (s, 1H), 8.67 (m, 2H), 7.93–7.88 (m, 2H), 7.76 (s, 1H), 7.64 (dd, _2H ), 7.53–7.52 (m, 2H), 7.47–7.43 (m, 1H), 7.15 (t, 2H), 6.48 (d, 1H), 4.03 (s, 3H), _1.47 (s, _4H ); MS (EI _{) C₂₈H₂₂F₂N₄O₅} The measured value was 533.5 (MH+).

Example 46: 1-N'-[3-chloro-4-[7-methoxy-6-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (134)

1-N'-[3-chloro-4-[7-methoxy-6-(methylcarbamoyl)quinolin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (134): Compound 134 (49.7 mg, 48.6% yield) was synthesized from compound 130 in a manner similar to that used in the preparation of compound 8 from compound 6 in Example 4. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.38 (s, ¹H), 10.04 (s, ¹H), 8.66 (d, ¹H), 8.63 (s, ¹H), 8.40 (br d, ¹H), 8.11 (d, ¹H), 7.72–7.61 (m, ³H), 7.54 (s, ¹H), 7.46 (d, ¹H), 7.20–7.12 (m, ²H), 6.37 (d, ¹H), 4.03 (s, ³H), 2.85 (d, ³H) _{, 1.48 (s, ⁴H); MS (EI) was C₂⁹H₂⁴ClFN₄O₅ ,} measured _{value 563.1} (MH⁺).

The following compounds were prepared from compound 131 using a method similar to that used in Example 46 for the preparation of compound 134 from compound 130:

1-N'-[3-fluoro-4-[7-methoxy-6-(methylcarbamoyl)quinolin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (135): ^¹H NMR (400MHz, DMSO- _d6 ) δ 10.40 (s, 1H), 10.01 (s, 1H), 8.67 (d, 1H), 8.61 (s, 1H), 8.39 (d, 1H), 7.91 (d, 1H), 7.64 (dd, 2H), 7.53–7.52 (m, 2H), 7.47–7.42 (m, 1H), 7.15 (t, 2H), 6.48 (d, 1H), 4.02 (s, 3H), 2.84 (d, 3H), 1.47 (s, 4H); MS (EI) was C6. ₂₉ H ₂₄ F ₂ N ₄ O ₅ , measured value 547.5 (MH+).

Example 47: Methyl 4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-6-methylquinoline-7-carboxylic acid ester (140)

5-(((2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-yl)methyl)amino)-2-methylbenzoate (137): Compound 137 (4.74 g, 81.7% yield) was synthesized from compounds 136 and 39 in a manner similar to that used in the preparation of compound 40 from compounds 38 and 39 in Example 12. ^¹H NMR (400 MHz, DMSO- _d⁶ ) δ 11.28 (s, ¹H), 8.53 (s, ¹H), 8.01–7.88 (d, ¹H), 7.75–7.61 (dd, ¹H), 7.45–7.30 (d, ¹H), 3.85 (s, ³H), 2.49 (s, ³H), 1.67 (s, ⁶H).

6-Methyl-4-oxo-1,4-dihydroquinoline-7-carboxylic acid methyl ester (138): Compound 138 (625 mg, 25.9% yield) was synthesized from compound 137 in a manner similar to the preparation of compound 41 from compound 40 in _{Example 12.} MS (EI) was _C12H11NO3 , and the result was 218.1 (MH+).

4-Chloro-6-methylquinoline-7-carboxylic acid methyl ester (139): Compound 139 was synthesized from compound 138 in a similar manner to that described for compound 42 in Example 12, except that compound 138 was heated in a mixture of MeCN (10 mL) and POCl ₃ (3 mL) instead of in pure POCl ₃ (445 mg, 65.6% yield). _MS (EI) was _{C12H10ClNO 2} , measured at 236.3 (MH+).

4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-6-methylquinoline-7-carboxylic acid methyl ester (140): Compound 140 (320 mg, 36.7% yield) was synthesized from compounds 139 and 3 in a similar manner to the synthesis of compound 43 from compounds 42 and 3 in Example 12. ^¹H NMR (400MHz, _CD₃OD ) δ 8.66–8.61 (d, ¹H), 8.52 (s, ¹H), 8.28 (s, ¹H), 7.78–7.71 (d, 2H), 7.60–7.54 (m, 2H), 7.28–7.22 (d, 2H), 7.11–7.03 (m, 2H), 6.71–6.67 (d, ¹H), 3.98 (s, 3H), 2.76 (s, 3H), 1.64 (s, 4H); MS (EI) was _{C₂ ₹ H₂₄FN₃O₅ ,} measured value 514.1 (MH⁺).

Example 48: 4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-6-methylquinoline-7-carboxylic acid (141)

4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-6-methylquinoline-7-carboxylic acid (141): Compound 141 (100 mg, 93.5% yield) was synthesized from compound 140 in a manner similar to that used in Example 2 for the preparation of compound 6 from compound 5. ^¹H NMR (400MHz, _CD₃OD ) δ 8.66–8.61 (d, ¹H), 8.47 (s, ¹H), 8.27 (s, ¹H), 7.78–7.73 (d, 2H), 7.78–7.71 (dd, 2H), 7.28–7.24 (d, 2H), 7.11–7.03 (t, 2H), 6.73–6.69 (d, ¹H), 2.76 (s, 3H), _1.65 (s _{, 4H); MS (EI) was C₂₈H₂₂FN₃O₅ ,} measured value _500.5 (MH⁺).

Example 49: 1-N-[4-(7-carbamoyl-6-methylquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (142)

1-N-[4-(7-carbamoyl-6-methylquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (142): Compound 142 (17.4 mg, 34.9% yield) was synthesized from compound 141 in a manner similar to that used in the preparation of compound 7 in Example 3. ^¹H NMR (400MHz, _CD₃OD ) δ 8.65–8.57 (d, ¹H), 8.26 (s, ¹H), 8.05 (s, ¹H), 7.78–7.70 (d, 2H), 7.62–7.51 (m, 2H), 7.30–7.20 (m, 2H), 7.13–7.03 (m, 2H), 6.69–6.63 (d, ¹H), 2.65 (s, 3H), 1.64 ( _s , 4H); MS (EI) was _{C₂₈H₂₃FN₄O₄ ,} measured value _499.1 (MH⁺).

Example 50: 1-N'-(4-fluorophenyl)-1-N-[4-[6-methyl-7-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (143)

1-N'-(4-fluorophenyl)-1-N-[4-[6-methyl-7-(methylcarbamoyl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (143): Compound 143 (11.9 mg, 17.8% yield) was synthesized from compound 141 in a manner similar to that used in the preparation of compound 8 in Example 4. ^1H NMR (400MHz, CD ₃ OD) δ 8.64-8.55 (d, 1H), 8.25 (s, 1H), 7.97 (s, 1H), 7.78-7.68 (d, 2H), 7.61-7.50 (m, 2H), 7.28-7.18 (d, 2H), 7.11-7.02 (m, 2H), 6.70-6.61 (d, 1H), 2.98 (s, 3H), 2.60 (s, 3H), 1.64 (s, 4H); MS (EI) was C ₂₉ H ₂₅ FN ₄ O ₄ , measured value 513.1 (MH+).

Example 51: Methyl 4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-6-methoxyquinoline-7-carboxylic acid ester (150)

Methyl 5-amino-2-methoxybenzoate (145): 10% Pd/C (500 mg) was added to a solution of compound 144 (5.00 g, 23.68 mmol, 1 equivalent) in EtOH (50 mL), and the resulting mixture was degassed and purged under _H₂ . The reaction mixture was stirred at 25 °C for 12 h under _H₂ (15 psi). The reaction mixture was filtered, and the filtrate was concentrated to give compound 145 (4.5 g, 99.6% yield), which was used in subsequent steps without further purification. ^¹H NMR (400 MHz, _CDCl₃ ) δ 7.16 (t, 1H), 6.86–6.82 (m, 2H), 3.88 (s, 3H), 3.83 (s, 3H), 3.09 (br s, 2H).

Methyl 5-(((2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-ylidene)methyl)amino)-2-methoxybenzoate (147): Compound 145 (2 g, 10.49 mmol, 1 equivalent) was added in portions to a suspension of compound 146 (1.95 g, 10.49 mmol, 1 equivalent) in isopropanol (40 mL) at 20 °C. The reaction was heated at 80 °C for 30 min. The mixture was cooled to 20 °C, and the precipitate was collected, washed with tert-butyl methyl ether (50 mL), and dried to give compound 147 (3.3 g, 93.82% yield). ¹ H NMR (400MHz, CDCl ₃ ) δ 11.25 (d, 1H), 8.57 (d, 1H), 7.75 (d, 1H), 7.37 (dd, 1H), 7.05 (d, 1H), 3.95 (s, 3H), 3.93 (s, 3H), 1.76 (s, 6H).

Methyl 6-methoxy-4-oxo-1,4-dihydroquinoline-7-carboxylic acid (148): Compound 147 (1.0 g, 2.98 mmol, 1 equivalent) was added in portions to A (a eutectic mixture of 26.5% biphenyl and 73.5% diphenyl ether) (CAS Registry No. 8004-13-5) (10 mL) at 220 °C. The reaction was stirred at 220 °C for 10 min. The reaction was cooled to 20 °C–25 °C and then diluted with petroleum ether (50 mL). The resulting residue was collected, washed with petroleum ether (3 x 30 mL), and dried to give compound 148 (800 mg, 69.07% yield, 60% purity). ¹ H NMR (400MHz, DMSO-d ₆ ) δ12.22(d,1H),7.94(d,1H),7.92(s,1H),7.61(s,1H),6.06(d,1H),3.87(s,3H),3.84(s,3H).

4-Chloro-6-methoxyquinoline-7-carboxylic acid methyl ester (149): 5 drops of DMF were added to a mixture of compound 148 (700 mg, 1.80 mmol, ₁ equivalent) in _SOCl2 (10 mL). The resulting mixture was stirred at 80 °C for 1 h. The reaction mixture was concentrated under vacuum, and the resulting residue was diluted with saturated NaHCO3 aqueous solution (20 mL) and extracted with EtOAc (3 x 30 mL). The combined organic phases were washed with saturated NaCl aqueous solution (50 mL), _dried over anhydrous _Na2SO4 , and concentrated. The residue was purified by rapid silica gel chromatography (4 g silica rapid column, eluent 0–30% EtOAc/petroleum ether gradient, flow rate 25 mL/min) to give compound 149 (220 mg, 46.14% yield, 95% purity). ^¹H NMR (400MHz, _CDCl₃ ) δ 8.71 (d, ¹H), 8.49 (s, ¹H), 7.55–7.49 (m, 2H), 4.07 (s, 3H), 3.99 (s, 3H); MS ( _{EI )} was _{C₁₂H₁₀ClNO₃} , measured value 252.3 (MH⁺).

4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxyquinoline-7-carboxylic acid methyl ester (150): Pd(OAc)2 (8 mg, 35.63 μmol, 0.05 equivalent) was added to a mixture of compound 149 (190 mg, 679.47 μmol, 1 equivalent), compound ₃ (235 mg, 747.67 μmol, 1.1 equivalent), _K3PO4 (190 mg, 895.10 μmol, 1.32 equivalent) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos) (33 mg, 69.22 μmol, 0.1 equivalent) in toluene (3 mL) and ₁ -methyl-2-pyrrolidone (0.5 mL) under nitrogen atmosphere. The reaction was stirred at 100 °C for 3 hours. The mixture was diluted with EtOAc (30 mL) and any insoluble substances were filtered off. The filtrate was diluted with water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic phases were washed with a saturated aqueous NaCl solution (50 mL), _dried over anhydrous _Na₂SO₄ , and concentrated. The residue was purified by rapid silica gel chromatography (4 g silica rapid column, eluent of 0% to approximately 50% EtOAc/petroleum ether gradient, flow rate 25 mL/min) to give compound 150 (170 mg, 46.06% yield, 97.49% purity). ^¹H NMR (400MHz, _CDCl₃ ) δ 9.46 (s, ¹H), 8.59 (d, 2H), 8.47 (s, ¹H), 7.71–7.62 (m, 3H), 7.52–7.44 (m, 2H), 7.20 (d, 2H), 7.07 (t, 2H), 6.57 (d, 1H), 4.05 (s, 3H), 3.99 (s, 3H), 1.79–1.74 (m, 2H), 1.69–1.64 (m, 2H); MS (EI ₎ was _{C₂ ₹ H₂₄FN₃O₆} , measured value 530.2 (MH⁺).

Example 52: 4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]-amino]phenoxy]-6-methoxyquinoline-7-carboxylic acid (151)

4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]-amino]phenoxy]-6-methoxyquinoline-7-carboxylic acid (151): Compound 151 (110 mg, 75.2% yield) was synthesized from compound 150 in a manner similar to that used in the preparation of compound 81 from compound 80 in Example 25. ^1H NMR (400MHz, DMSO- _d₆ ) δ 10.21 (s, 1H), 10.05 (s, 1H), 8.60 (d, 1H), 8.18 (s, 1H), 7.79 (d, 2H), 7.69–7.59 (m, _3H ), 7.27 (d, 2H), 7.15 (t, 2H), 6.60 (d, 1H), 3.97 (s, 3H), 1.53–1.42 (m, 4H); MS (EI) was _{C₂₈H₂₂FN₃O₆} , _{measured value} 516.1 (MH⁺).

Example 53: 1-N-[4-(7-carbamoyl-6-methoxyquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (152)

1-N-[4-(7-carbamoyl-6-methoxyquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (152): Compound 152 (25.6 mg, 30.7% yield) was synthesized from compound 151 in a manner similar to that used in the preparation of compound 7 from compound 6 in Example 3. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.20 (s, 1H), 10.04 (s, 1H), 8.58 (d, 1H), 8.25 (s, 1H), 7.87 (br s, 1H), 7.78 (d, 2H), 7.72 (br s, 1H), 7.67–7.60 (m, 3H), 7.26 (d, 2H), 7.15 (t, 2H), 6.58 (d, 1H), 4.01 (s, 3H), _{1.52–1.46 (m, 4H); MS (EI) was C₂₈H₂₃FN₄O₅ , measured} value _515.1 (MH⁺).

Example 54: 1-N'-(4-fluorophenyl)-1-N-[4-[6-methoxy-7-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (153)

1-N'-(4-fluorophenyl)-1-N-[4-[6-methoxy-7-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (153): Compound 153 (25.2 mg, 53.1% yield) was synthesized from compound 151 in a manner similar to that used in the preparation of compound 8 from compound 6 in Example 4. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.23 (s, ¹H), 10.07 (s, ¹H), 8.58 (d, ¹H), 8.39 (q, ¹H), 8.20 (s, ¹H), 7.79 (d, 2H), 7.69–7.60 (m, 3H), 7.26 (d, 2H), 7.15 (t, 2H), 6.58 (d, ¹H), 4.00 (s, 3H), 2.84 (d, 3H), _{1.52–1.44 (m, 4H); MS (EI) was C₂⁹H₂⁵FN₄O₅ , measured} value _529.1 (MH⁺).

Example 56: Methyl 4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]quinoline-7-carboxylic acid ester (162)

4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]quinoline-7-carboxylic acid methyl ester (162): Compound 162 (20 mg, 16% yield) was synthesized from compounds 161 and 3 in a manner similar to that used in the preparation of compound 43 from compounds 42 and 3 in Example 12. ^¹H NMR (400MHz, _CDCl₃ ) δ 9.42 (s, ¹H), 8.81 (d, ¹H), 8.75 (d, ¹H), 8.60 (br s, ¹H), 8.43 (d, ¹H), 8.19 (dd, ¹H), 7.69–7.63 (m, 2H), 7.51–7.44 (m, 2H), 7.23–7.18 (m, 2H), 7.07 (t, 2H), 6.63 (d, ¹H), 4.03 (s, 3H), 1.79–1.74 (m, 2H), _{1.69–1.65 (m, 2H); MS (EI) was C₂₈H₂₂FN₃O₅ ,} measured value _500.1 ( _MH⁺ ).

Example 57: 4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]quinoline-7-carboxylic acid (163)

4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]quinoline-7-carboxylic acid (163): Compound 163 (70 mg, 68.4% yield) was synthesized from compound 162 in a manner similar to that used in Example 2 for the preparation of compound 6 from compound 5. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.22 (s, ¹H), 10.06 (s, ¹H), 8.79 (d, ¹H), 8.58 (s, ¹H), 8.43 (d, ¹H), 8.17–8.10 (m, ¹H), 7.79 (d, 2H), 7.65 (dd, 2H), 7.29 (d, 2H), 7.16 (t, 2H), 6.69 (d, 1H), 1.48 (s, 4H); MS _{(EI) was C₂₇H₂₀FN₃O₅ , measured value} 486.1 (MH⁺).

Example 58: 1-N-[4-(7-carbamoylquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (164)

1-N-[4-(7-carbamoylquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)-cyclopropane-1,1-dicarboxamide (164): Compound 164 (17.7 mg, 56.2% yield) was synthesized from compound 163 in a manner similar to that used in the preparation of compound 7 from compound 6 in Example 3. ^¹H NMR (400MHz, _CDCl₃ ) δ 9.47 (s, ¹H), 8.73 (d, ¹H), 8.60 (br s, ¹H), 8.50–8.43 (m, 2H), 8.08 (dd, ¹H), 7.66 (d, 2H), 7.51–7.43 (m, 2H), 7.19 (d, 2H), 7.06 (t, 2H), 6.62 (d, ¹H), 6.36 (br s, ¹H), 5.73 (br s, ¹H), 1.80–1.73 (m, 2H), _{1.70–1.65 (m, 2H); MS (EI) was C₂₇H₂₁FN₄O₄ , measured} value _485.1 (MH⁺).

Example 59: 1-N'-(4-fluorophenyl)-1-N-[4-[7-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (165)

1-N'-(4-fluorophenyl)-1-N-[4-[7-(methylcarbamoyl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (165): Compound 165 (16.5 mg, 33.9% yield) was synthesized from compound 163 in a manner similar to that used in the preparation of compound 8 from compound 6 in Example 4. ^¹H NMR (400MHz, _CDCl₃ ) δ 9.45 (br s, 1H), 8.71 (d, 1H), 8.63 (br s, 1H), 8.43 (d, 1H), 8.37 (d, 1H), 8.04 (d, 1H), 7.65 (d, 2H), 7.50–7.44 (m, 2H), 7.19 (d, 2H), 7.06 (t, 2H), 6.60 (d, 1H), 6.40 (br s, 1H), 3.11 (d, 3H), 1.79–1.74 (m, 2H), 1.69–1.64 (m, 2H) _; MS ₍ EI ₎ was _{C₂₈H₂₃FN₄O₄} , measured value 499.1 (MH⁺).

Example 60: 1-N'-(4-fluorophenyl)-1-N-[4-[7-(2-hydroxyethoxycarbamoyl)-quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (166)

1-N'-(4-fluorophenyl)-1-N-[4-[7-(2-hydroxyethoxycarbamoyl)-quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (166): Compound 166 (27 mg, 46.2% yield) was synthesized from compound 163 in a manner similar to that used in the preparation of compound 26 from compound 6 in Example 6. ^¹H NMR (400MHz, _CD₃OD ) δ 8.73(d, ¹H), 8.53(d, ¹H), 8.44(d, ¹H), 8.03(dd, ¹H), 7.77(d, 2H), 7.59(dd, 2H), 7.28(d, 2H), 7.10(t, 2H), 6.75(d, ¹H), 4.17–4.12(m, 2H), 3.88–3.83(m, 2H), 1.66(s, 4H); MS ( _{EI) was C₂₹H₂₅FN₄O₆ , measured value} 545.1 (MH⁺).

The following compounds were prepared using a method similar to that used for compound 166 in Example 60:

1-N'-(4-fluorophenyl)-1-N-[4-[7-(oxetane-3-yloxycarbamoyl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (167): ^1H NMR (400MHz, _CD3) OD)δ 8.72(d,1H), 8.50(d,1H), 8.43(d,1H), 8.02(dd,1H), 7.79-7.73(m,2H), 7.62-7.56(m,2H), 7.31-7.25(m,2H), 7.09(t,2H), 6.74(d,1H), 5.19(s,1H), 4.93(m,2H), 4.88-4.81(m,2H), 1.70-1.63(m,4H) _; MS( _{EI) is C30H25FN4O6 , measured} value 557.1(MH+).

N-(4-((7-(((2,2-dimethyl-1,3-dioxopentane-4-yl)methoxy)carbamoyl)quinoline-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (168): MS (EI) is _C29H25FN4O6 , _and the measured value _{is 615.3} (MH+).

Example 61: 1-N-[4-[7-[[(2R)-2,3-dihydroxypropoxy]carbamoyl]quinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (169) and 1-N-[4-[7-[[(2S)-2,3-dihydroxypropoxy]carbamoyl]quinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (170)

1-N-[4-[7-[[(2R)-2,3-dihydroxypropoxy]carbamoyl]quinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (169) and 1-N-[4-[7-[[(2S)-2,3-dihydroxypropoxy]carbamoyl]quinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (170): Compounds 169 and 170 were synthesized from compound 168 in a manner similar to that used in Example 7 for the preparation of compounds 30 and 31 from compound 28. Compound 169: ^¹H NMR (400MHz, _CD₃OD ) δ 8.73 (d, 1H), 8.52 (d, 1H), 8.44 (d, 1H), 8.02 (dd, 1H), 7.77 (d, 2H), 7.62–7.55 (m, 2H), 7.30–7.25 (m, 2H), 7.09 (t, 2H), 6.75 (d, 1H), 4.21–4.15 (m, 1H), 4.06 (s, 1H), 4.02–3.96 (m, 1H), 3.68 (m, 2H) _{, 1.66 (d, 4H); MS (EI) C₃₀H₂₇FN₄O₇ , measured} value 575.2 (MH⁺). Compound 170: ^¹H NMR (400MHz, _CD₃OD ) δ 8.73 (d, 1H), 8.52 (d, 1H), 8.43 (d, 1H), 8.02 (dd, 1H), 7.77 (d, 2H), 7.62–7.54 (m, 2H), 7.28 (d, 2H), 7.14–7.04 (m, 2H), 6.75 (d, 1H), 4.22–4.14 (m, 1H), 4.12–3.92 (m, 2H), 3.73–3.64 (m, 2H), _1.66 (s _{, 4H); MS (EI) C₃₀H₂₇FN₄O₇ ,} measured value 575.1 (MH⁺).

Example 62: 4-((6-bromo-7-methoxyquinoline-4-yl)oxy)aniline (171)

4-((6-bromo-7-methoxyquinoline-4-yl)oxy)aniline (171): Cs₂CO₃ ( _3.3 g, 10 mmol) was added to a DMA (15 mL) solution of a mixture of compound 42 (1.75 g, 6.38 mmol) and 4-aminophenol ₂ (1.1 g, 10 mmol) at room temperature. The mixture was stirred at ₁₀₀ °C for _{2 h} . The mixture was cooled to 20 °C, diluted with water, and filtered. The crude residue was purified by rapid silica gel chromatography to give compound 171 (900 mg, 40% yield). MS (EI) was _{C₁₆H₁₃BrN₂O₂} , measured value: 345 (MH⁺).

Example 63: 4-((7-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxocyclopentaborane-2-yl)quinoline-4-yl)oxy)aniline (172)

4-((7-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl)quinolin-4-yl)oxy)aniline (172): Pd(dppf)Cl₂ (42 mg, 0.06 mmol) was added to a mixture of compound 171 (200 mg, 0.58 mmol), bis(pinacol) _diboron (220 mg, 0.87 mmol), and potassium acetate (170 mg, 1.7 mmol) in 1,4-dioxane (3 mL). The resulting mixture was heated at _{100 °C for 2 hours. After cooling, the reaction mixture was diluted with EtOAc, washed successively with water and saturated NaCl aqueous solution, concentrated, and purified by rapid silica gel chromatography to give compound 172 (43% yield). MS (EI) was C₂₂H₂₅BN₂O₄ , measured value} : 393 (MH+).

Example 64: 1-N-[4-[6-(3-cyano-2-fluorophenyl)-7-methoxyquinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (175)

3-(4-(4-aminophenoxy)-7-methoxyquinoline-6-yl)-2-fluorobenzyl nitrile (174): Compound 172 (50 mg, 0.13 mmol), compound 173 (25 mg, 0.13 mmol), _Na₂CO₃ (41 mg, _0.39 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (9 mg, 0.013 mmol), 1,4-dioxane (2 mL), and water (0.4 mL) were mixed in a microwave-controlled reaction tube. The reaction mixture was stimulated in a microwave reactor at 150 °C for 5 min. After cooling, the mixture was extracted with EtOAc, washed with saturated aqueous NaCl solution, and concentrated. The crude product was purified by rapid column chromatography to give _compound 174. _MS (EI) was _{C₂₃H₁₆FN₃O₂} , measured value: ₃₈₆ (MH+).

1-N-[4-[6-(3-cyano-2-fluorophenyl)-7-methoxyquinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (175): HATU (38 mg, 0.1 mmol) was added to a mixture of compound 174, compound 1 (22 mg, 0.1 mmol), and DIEA (25 mg, 0.2 mmol) in a DCM (2 mL). The mixture was stirred at room temperature until the reaction was _complete , then diluted with EtOAc, washed with saturated _NaHCO3 aqueous solution, and concentrated. The crude product was purified by rapid _column chromatography to give _compound 175. _MS (EI) was _C34H24F2N4O4 , and the measured value was 591 (MH+).

The following compounds were prepared in a manner similar to that used in Example 64 for the two-step synthesis of compound 175 from compound 172:

1-N'-(4-fluorophenyl)-1-N-[4-(7-methoxy-6-pyridin-2-ylquinoline-4-yl)oxyphenyl]cyclopropane-1,1-dicarboxamide (176): 2- _{bromopyridine} was used instead of compound 173. MS (EI) was _C32H25FN4O4 , _and the measured value was ₅₄₉ (MH+).

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(1-methylimidazol-4-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (177). Compound 173 was replaced with 4-bromo- _{1-methyl-1H-imidazolium. MS (EI) was C31H26FN5O4 , and} the measured value was ₅₅₂ (MH+).

Example 65: 1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(5-methylfuran-2-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (180)

4-((7-methoxy-6-(5-methylfuran-2-yl)quinolin-4-yl)oxy)aniline (179): Compound 171 (100 mg, 0.29 mmol), compound 178 (82 mg, 0.43 mmol), _Na₂CO₃ (92 _mg , 0.9 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (20 mg, 0.029 mmol), 1,4-dioxane (2.5 mL), and water (0.5 mL) were mixed in a microwave-controlled reaction tube. The resulting mixture was irradiated in a microwave reactor at 150 °C for 5 min. After cooling, the mixture was extracted with EtOAc, washed with saturated NaCl aqueous solution, and concentrated. The crude product was purified by rapid _column chromatography to give _compound 179. _{MS (EI) was C₂₁H₁₈N₂O₃ ,} measured value: 347 (MH+).

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(5-methylfuran-2-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (180): Compound 180 was synthesized from compound 179 in a manner similar to that used in Example 64 for the synthesis of compound 175 from compound 174. MS ( _{EI )} was _C32H26FN3O5 , and the measured value _was 552 (MH+).

The following compounds were prepared in a manner similar to that used in Example 65 for the two-step synthesis of compound 180 from compound 171:

2-[4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]-amino]phenoxy]-7-methoxyquinoline-6-yl]pyrrole-1-carboxylic acid tert-butyl ester (181): Compound 178 was replaced with potassium salt of 2-(trifluoro-14-boronyl)-1H-pyrrole-1-carboxylic acid tert-butyl ester _{. MS} (EI) was _C36H33FN4O6 , and the measured value was ₆₃₇ (MH+).

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(1-methylpyrazol-4-yl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (182): Compound 178 was replaced with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxocyclopentaborane-2-yl) _-1H -pyrazole. MS (EI) was _{C31H26FN5O4 , and} the measured value was 552 (MH+).

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(1,2-oxazol-4-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (183): Compound 178 was replaced with _4- (4,4,5,5-tetramethyl-1,3,2-dioxocyclopentaborane-2-yl)isoxazole. _MS (EI) was _C30H23FN4O5 , _and the measured value was 539 (MH+).

1-N-[4-[6-(3,5-dimethyl-1,2-oxazol-4-yl)-7-methoxyquinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (184): Compound 178 was replaced with 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxocyclopentaborane-2-yl)isoxazole _{. MS (EI) was C32H27FN4O5 , and} the measured value _was 567 (MH+).

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(1H-pyrazol-5-yl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (185): Compound 178 was replaced with potassium 5-(trifluoro-14-boronyl)-1H-pyrazol. _{MS (EI) was C30H24FN5O4 , and} the measured value was ₅₃₈ (MH+).

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(1H-pyrazol-4-yl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (186): Compound 178 was replaced with potassium 4-(trifluoro-14-boronyl)-1H-pyrazol _{. MS (EI) was C30H24FN5O4 ;} measured value was ₅₃₈ (MH+).

1-N-[4-(6-cyclopropyl-7-methoxyquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (187): Compound 178 was replaced with potassium _{cyclopropyltrifluoro} -14-borane _. MS (EI) was _C30H26FN3O4 , _and the measured value was 512 (MH+).

Example 66: 1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(1H-pyrrolo-2-yl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (188)

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(1H-pyrrolo-2-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (188): Compound 181 and excess TFA were stirred in a DCM at room temperature until the reaction was complete. The mixture was concentrated and purified by preparative HPLC to give compound 188 (50% yield). _MS (EI) was _C31H25FN4O4 , _and the measured value was 537 ( _MH +).

Example 67: N-(4-fluorophenyl)-N-(4-((6-formyl-7-methoxyquinoline-4-yl)oxy)phenyl)cyclopropane-1,1-dicarboxamide (190)

4-Chloro-7-methoxyquinoline-6-carboxaldehyde (189): nBuLi (0.6 mL, 2.5 M THF solution, 1.5 mmol) was added to an 8 mL THF solution of a mixture of compound 42 (320 mg, 1.17 mmol) at -78 °C. The mixture was stirred at -78 °C for 45 min, then DMF (0.5 mL) was added. The mixture was heated to 0 °C and stirred for 1 h. The reaction was quenched with saturated _NH₄Cl and extracted with EtOAc. The organic phase was concentrated, and the crude residue was purified by rapid silica gel chromatography to give compound 189 (130 mg, 50% yield). _{MS (EI) was C₁₁H₈ClNO₂ , and} the result was 222 (MH+).

N-(4-fluorophenyl)-N-(4-((6-formyl-7-methoxyquinoline-4-yl)oxy)phenyl)cyclopropane-1,1-dicarboxamide (190): Compound 190 was synthesized from compound 189 using the improved method described in Example 12 for the synthesis of compound 43 from compound 42, with potassium tert-butoxide replaced by cesium carbonate and DMF used as a solvent.

Example 68: 1-N'-(4-fluorophenyl)-1-N-[4-[6-(1H-imidazol-2-yl)-7-methoxyquinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (191)

1-N'-(4-fluorophenyl)-1-N-[4-[6-(1H-imidazol-2-yl)-7-methoxyquinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (191): Compound 190 (60 mg, 0.12 mmol), glyoxal (60 mg, 40% aqueous solution), and ammonium hydroxide (130 mg, 30% aqueous solution) were mixed in iPrOH (1.5 mL). The resulting mixture was stirred at ambient temperature (room temperature) for 12 hours. The mixture was extracted with EtOAc and washed with saturated NaCl aqueous solution. The organic phase was concentrated and purified by preparative HPLC to give compound 191 (35 mg, 54% yield). _{MS (EI) was C30H24FN5O4 , and} the measured value _was 538.1 (MH+).

Example 69: 1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(1,3-oxazol-5-yl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (192)

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(1,3-oxazol-5-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (192): Compound 190 (30 mg, 0.06 mmol), TosMIC (15 mg, 0.08 mmol), and _K₂CO₃ (15 mg, 0.11 mmol) were mixed in iPrOH (1 mL). The resulting mixture was stirred at 80 ° _C for 30 min. The mixture was concentrated to dryness. The residue was extracted with EtOAc. The organic layer was washed with water and concentrated. The crude product was purified by preparative HPLC to give compound 192 (14 _mg , 43% yield). _MS (EI) was _{C₃₀H₂₃FN₄O₅} , _and the result was 539 (MH+).

Example 70: 1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-[(E)-methoxyiminomethyl]quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (193)

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-[(E)-methoxyiminomethyl]quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (193): O-methylhydroxylamine-HCl (41.74 mg, 500 μmol, 1.7 equivalent) was added to a mixture of compound 190 (150 mg, 300.31 μmol, 1 equivalent) in EtOH (3 mL) and water (0.6 mL). The mixture was stirred at 50 °C for 2 h. The resulting precipitate was filtered, slurried in 50 mL of water, and then filtered again. The filter cake was lyophilized to give compound 193 (125.0 mg, 73.2% yield). ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.32 (s, 1H), 10.05 (s, 1H), 8.87 (s, 1H), 8.68 (s, 1H), 8.51 (s, 1H), 7.85 (d, 2H), 7.72–7.58 (m, 3H), 7.37 (d, 2H), 7.16 (t, 2H), 6.72 (br d, 1H), 4.07 (s, 3H), 3.99 (s, 3H), _{1.49 (s, 4H); MS (EI) was C₂⁹H₂⁵FN₄O₅ , measured} value _529.2 (MH⁺).

Example 71: 3-[4-[4-[[1-([4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-7-methoxyquinoline-6-yl]-3-hydroxyazacyclobutane-1-carboxylic acid tert-butyl ester (195)

3-(4-chloro-7-methoxyquinoline-6-yl)-3-hydroxyazacyclobutane-1-carboxylic acid tert-butyl ester (194): A mixture of compound 42 (200 mg, 0.73 mmol) and THF (4 mL) was cooled to -78 °C. n-BuLi (0.4 mL, 1.0 mmol, 2.5 M THF solution) was slowly added. The resulting mixture was stirred at -78 °C for 40 min. A THF solution of N-Boc 3-oxazacyclobutane (125 mg, 0.73 mmol) (0.5 mL) was added. The reaction mixture was heated to 0 °C and stirred for 1 h. The reaction was quenched with water and extracted with EtOAc. The organic phase was washed with saturated NaCl aqueous solution, concentrated, and purified by rapid _{silica gel} chromatography to give compound 194 (38% yield). _MS (EI) was _C18H21ClN2O4 , measured value: 365 (MH+).

3-[4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-7-methoxyquinoline-6-yl]-3-hydroxyazacyclobutane-1-carboxylic acid tert-butyl ester (195): Compound 195 was synthesized from compound 194 in a manner similar to that used in Example 12 for the preparation of compound 43 from compound 42, except that cesium carbonate was used instead of tert-butanol, DMF was used as the solvent, the reaction temperature was 80°C, and the reaction time was 12 hours. Compound 195 was obtained in 68% yield _{. MS} (EI) was _C35H35FN4O7 , _and the measured value was 643 (MH+).

Similar to compound 195 in Example 71, the following compounds were prepared by replacing the Boc-protected aza-butane-3-one with an oxetane-3-one:

1-N'-(4-fluorophenyl)-1-N-[4-[6-(3-hydroxyoxetane-3-yl)-7-methoxyquinoline-4-yl]oxyphenyl]cyclopropane-1,1- _{dicarboxamide} (196). MS (EI) was _C30H26FN3O6 , _with a measured value of ₅₄₄ (MH+).

Example 72: 1-N'-(4-fluorophenyl)-1-N-[4-[6-(3-hydroxyazacyclobutane-3-yl)-7-methoxyquinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (197)

1-N'-(4-fluorophenyl)-1-N-[4-[6-(3-hydroxyazacyclobutane-3-yl)-7-methoxyquinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (197): Compound 197 was synthesized from compound 195 in a manner similar to that used in Example 66 for the preparation of compound 188 from compound 181 (55 _% yield). _MS (EI) was _C30H27FN4O5 , _and the measured value was 543 (MH+).

Example 73: 1-N-[4-[6-(azacyclobutane-1-yl)-7-methoxyquinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (198)

1-N-[4-[6-(azacyclobutan-1-yl)-7-methoxyquinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (198): Bis(tri-tert-butylphosphine)palladium (0) was added to a mixture of compound 43 (150 mg, 0.27 mmol), azacyclobutane ( ₃₀₀ mg, 5.25 mmol), and _K₃PO₄ (212 mg, 1.0 mmol) in DMA (2 mL). The resulting mixture was stirred at 100 °C for 12 hours. After cooling, water was added, and the mixture was extracted with EtOAc, washed with saturated NaCl aqueous solution, and concentrated. The crude product was purified by preparative HPLC to give compound 198. _MS (EI) was _{C₃₀H₂₇FN₄O₄ , and} the measured value was 527 (MH+).

The following compounds were prepared from compound 43 using a method similar to that used in Example 73 for the synthesis of compound 198 from compound 43:

1-N'-(4-fluorophenyl)-1-N-[4-[6-(3-hydroxyaziridine-1-yl)-7-methoxyquinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (199): Azacyclobutane-3-ol was used instead of aziridine. _{MS (EI) was C30H27FN4O5 , and} the measured value _was 543 (MH+).

1-N-[4-[6-(3,3-difluoroazacyclobutane-1-yl)-7-methoxyquinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (200): HCl salt of 3,3- _{difluoroazacyclobutane} was used instead of _{azacyclobutane} . _MS (EI) was _C30H25F3N4O4 , measured _value 563 (MH+).

Example 74: 1-N'-(4-fluorophenyl)-1-N-[4-(7-methoxy-6-pyridin-3-ylquinoline-4-yl)oxyphenyl]cyclopropane-1,1-dicarboxamide (201)

1-N'-(4-fluorophenyl)-1-N-[4-(7-methoxy-6-pyridin-3-ylquinoline-4-yl)oxyphenyl]cyclopropane-1,1-dicarboxamide (201): Compound 43 (50 mg, 0.09 mmol), 3-pyridylboronic acid (16 mg, 0.13 mmol), _Na₂CO₃ (28 mg, 0.27 mmol), bis ₍ di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (6 mg, 0.009 mmol), 1,4-dioxane (1.5 mL), and water (0.3 mL) were mixed in a microwave-controlled reaction tube. The reaction mixture was stimulated in a microwave reactor at 150 °C for 10 min. After cooling, the mixture was extracted with EtOAc, washed with a saturated aqueous NaCl solution, and concentrated. The crude product was purified by preparative HPLC to give compound 201. MS( _{EI) is C32H25FN4O4 , measured} value ₅₄₉ (MH+).

The following compounds were prepared from compound 43 in a manner similar to that used in Example 74 for preparing compound 201 from compound 43:

1-N'-(4-fluorophenyl)-1-N-[4-(7-methoxy-6-pyridin-4-ylquinoline-4-yl)oxyphenyl]cyclopropane-1,1-dicarboxamide (202): Pyridin-4-ylboronic acid was used instead of 3-pyridinylboronic acid. _{MS (EI) was C32H25FN4O4 , and} the measured value _was 549 (MH+).

The following compounds were prepared from compound 44 and the potassium salt of 5-(trifluoro-14-boryl)-1H-pyrazole in a manner similar to that used in the preparation of compound 201 from compound 43 and 3-pyridylboronic acid in Example 74:

1-N'-(4-fluorophenyl)-1-N-[4-[6-(1H-pyrazol-5-yl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1- _{dicarboxamide} (204): MS (EI ₎ is _{C29H22FN5O3 ,} measured value is 508 (MH+).

Example 75: 1-N'-(4-fluorophenyl)-1-N-[4-(7-methoxy-6-aminosulfonylquinoline-4-yl)oxyphenyl]cyclopropane-1,1-dicarboxamide (206)

S-(4-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylamino)phenoxy)-7-methoxyquinoline-6-yl)thioacetate (205): Pd₂(dba)₃ (16 mg, 0.017 mmol) and Xantphos (20 mg, 0.035 mmol) were added to a mixture of compound ₄₃ (200 mg, 0.36 mmol), potassium thioacetate (83 mg, 0.72 mmol), and DIEA (0.5 mL) in _1,4 -dioxane (4 mL). The resulting mixture was stirred at 120 °C for 15 min under microwave irradiation. After cooling, EtOAc and water were added. Any insoluble substances were filtered out. The filtrate was washed with saturated NaCl aqueous solution and concentrated. The crude product was purified by rapid silica gel chromatography to give compound 205 (37% yield plus 50% recovery of compound 43).

1-N'-(4-fluorophenyl)-1-N-[4-(7-methoxy-6-aminosulfonylquinoline-4-yl)oxyphenyl]cyclopropane-1,1-dicarboxamide (206): N-chlorosuccinimide (80 mg, 0.6 mmol) was added to a mixture of 2N HCl (0.5 mL) and MeCN (3 mL), and the resulting mixture was cooled to 0 °C. A solution of compound 205 (80 mg, 0.15 mmol) in MeCN (1.5 mL) was added. After stirring at 0 °C for 2 hours, the reaction mixture was extracted with EtOAc. The organic phase was washed with a saturated aqueous NaCl solution and concentrated. The resulting crude sulfonyl chloride was dissolved in i-PrOH (2 mL), and excess _NH4OH was added to it at room temperature. After the reaction was complete, the mixture was concentrated, and the crude product was purified by preparative HPLC to give compound 206 (60% yield). MS(EI) is C ₂₇ H ₂₃ FN ₄ O ₆ S, measured value 551 (MH+).

The following compounds were prepared from compound 205 in a manner similar to that used in the second step of Example 75 to prepare compound 206:

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(methylaminosulfonyl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (207): _NH4OH is replaced with methylamine. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.22 (s, ¹H), 10.06 (s, ¹H), 8.71 (d, ¹H), 8.69 (s, ¹H), 7.78 (d, 2H), 7.64–7.62 (m, 2H), 7.60 (s, ¹H), 7.30–7.28 (m, 3H), 7.17–7.12 (m, 2H), 6.50 (d, ¹H), 4.04 (s, 3H), 2.47 (s, 3H), _{1.47 (s, 4H); MS (EI) was C₂₈H₂₅FN₄O₆S , measured value} 565.1 (MH⁺).

1-N-[4-[6-(ethylaminosulfonyl)-7-methoxyquinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (208): _NH4OH was replaced with ethylamine. _MS (EI) was _C29H27FN4O6S , _with a measured value of ₅₇₉ (MH+).

The following compounds were prepared from compound 44 in a manner similar to that used in Example 75 for preparing compound 206 from compound 43:

1-N'-(4-fluorophenyl)-1-N-[4-(6-aminosulfonylquinoline-4-yl)oxyphenyl]cyclopropane-1,1- _{dicarboxamide} (209). _{MS (EI) was C26H21FN4O5S ,} with a measured value of ₅₂₁ (MH+).

Example 76: 1-N'-(4-fluorophenyl)-1-N-[4-(7-methoxy-6-methylsulfonylquinoline-4-yl)oxyphenyl]cyclopropane-1,1-dicarboxamide (210)

1-N'-(4-fluorophenyl)-1-N-[4-(7-methoxy-6-methylsulfonylquinoline-4-yl)oxyphenyl]cyclopropane-1,1-dicarboxamide (210): Compound 43 (100 mg, 0.18 mmol), sodium methanesulfonate (40 mg, 0.36 mmol), CuI (5 mg), proline (6 mg), and NaOH (3 mg) were mixed in DMSO (1 mL). The resulting mixture was stirred at 110 °C for 14 hours. After cooling to room temperature, water was added. The mixture was filtered and washed with EtOAc. The EtOAc filtrate was concentrated and purified by preparative _HPLC to give compound 210 (8% yield). _MS (EI) was _C28H24FN3O6S , _and the measured value was 550 (MH+).

Example 77: 1-N'-(4-fluorophenyl)-1-N-[4-[7-(methoxycarbamoyl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (213)

4-Chloro-N-methoxyquinoline-7-carboxamide (212): O-methylhydroxylamine hydrochloride (54.00 mg, 646.57 μmol, 49.09 μL, 2.24 equivalents) was added in a single batch to a mixture of compound 211 (60 mg, 289.00 μmol, 1 equivalent), HATU (180.00 mg, 473.40 μmol, 1.64 equivalents) in DMF (5 mL). The mixture was stirred at 20-30 °C for 0.5 h and then partitioned between water (10 mL) and EtOAc (2 x 10 mL). The organic extract was separated, washed with saturated NaCl aqueous solution (10 mL), _dried over anhydrous _Na₂SO₄ , and concentrated to give compound 212 (140 _mg , crude product), which could be used directly in the next step without further purification. _MS (EI) was _{C₁₁H₉ClN₂O₂} , _with a measured value of 236.9 (MH⁺).

1-N'-(4-fluorophenyl)-1-N-[4-[7-(methoxycarbamoyl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (213): t-BuOK (133 mg, 1.19 mmol, 2.00 equivalent) was added in a single batch to a mixture of compound 212 (140 mg, 591.58 μmol, 1 equivalent) and compound 3 (280.00 mg, 890.84 μmol, 1.51 equivalent) in DMSO (5 mL), and the resulting mixture was stirred at 100 °C for 1 hour. The reaction mixture was partitioned between water (10 mL) and EtOAc (2 x 10 mL). The combined organic extracts were washed with saturated aqueous NaCl solution (10 mL), _dried over anhydrous _Na₂SO₄ , and concentrated. The residue was purified by preparative HPLC (alkaline conditions; column: Waters Xbridge 150*25 5u; mobile phase: [water (0.05% ammonium hydroxide v/v)-ACN]; B%: 32%-57%, 6.5 min) to give compound 213 (7.9 mg, 2.54% yield). ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 12.11 (s, ¹H), 10.22 (s, ¹H), 10.06 (s, ¹H), 8.77 (d, ¹H), 8.44–8.37 (m, 2H), 7.99 (d, ¹H), 7.79 (d, 2H), 7.65 (dd, 2H), 7.28 (d, 2H), 7.16 (t, 2H), 6.66 (d, ¹H), 3.78 (s, 3H), _{1.48 (s, 4H); MS (EI) was C₂₈H₂₃FN₄O₅ , measured} value _515.1 (MH⁺).

The following compounds were prepared from compound 211 in a manner similar to that used in Example 77 for preparing compound 213 from compound 211:

1-N-[4-[7-(ethylcarbamoyl)quinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (214): In the first step, ethylamine hydrochloride is used instead of O-methylhydroxylamine hydrochloride. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.21 (s, ¹H), 10.06 (s, ¹H), 8.84 (t, ¹H), 8.75 (d, ¹H), 8.53 (d, ¹H), 8.38 (d, ¹H), 8.07 (dd, ¹H), 7.78 (d, 2H), 7.64 (dd, 2H), 7.28 (d, 2H), 7.15 (t, 2H), 6.63 (d, ¹H), 3.31 (brs, 2H), 1.47 (s, 4H), 1.18 (t, 3H); MS ₍ EI ₎ was _{C₂⁹H₂⁵FN₄O₄ ,} measured value 513.1 (MH⁺).

Example 78: 1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(1,3,4-oxadiazol-2-yl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (220)

7-Methoxy-4-(4-nitrophenoxy)quinoline-6-carboxylic acid methyl ester (215): Compound 4 (300 mg, 1.2 mmol), 4-nitrophenol (200 mg, 1.42 mmol), and DIEA (230 mg, 1.78 mmol) were mixed in toluene (1 mL). The resulting mixture was stirred at 110 °C for 12 hours. After cooling, water was added, and the mixture was extracted with EtOAc. The organic phase was washed with saturated NaCl aqueous solution, concentrated, and purified by rapid silica gel chromatography to give compound 215 (150 _mg , ₃₆ %). MS (EI) was _C18H14N2O6 , _and the measured value was 355 (MH+).

7-Methoxy-4-(4-nitrophenoxy)quinoline-6-carboxylic acid ( ₂₁₆ ): Compound 216 was synthesized in a manner similar to that used in the preparation of compound 81 in Example 25. _MS (EI) was _C17H12N2O6 , _and the measured value was 341 (MH+).

7-Methoxy-4-(4-nitrophenoxy)quinoline-6-carbazide (217): HATU (100 mg, 0.26 mmol) was added to a DMF (2 mL) solution of compound 216 (45 mg, 0.13 mmol) and DIEA (51 mg, 0.4 mmol). The resulting mixture was stirred at room temperature for 10 min, and then excess _NH₂ · _H₂O was added. After the reaction was complete, water was added. The precipitate was filtered and dried under vacuum to give crude compound ₂₁₇ , which could be _used in the next step without further purification. _MS (EI) was _{C₁₇H₁₄N₄O₅} , measured _value : 355 (MH⁺).

2-(7-Methoxy-4-(4-nitrophenoxy)quinolin-6-yl)-1,3,4-oxadiazole (218): Compound 217 (66 mg, 0.18 mmol) and p-TsOH· _H₂O (4 mg, 0.02 mmol) were mixed in triethyl orthoformate (1 mL). The resulting mixture was stirred at 120 °C for 5 hours. After cooling, the mixture was concentrated and a saturated _aqueous solution of _NaHCO₃ was added. The precipitate was filtered and washed with EtOAc to give crude compound 218, which could be _used in the next step without further purification. _{MS (EI) was C₁₈H₁₂N₄O₅ ,} measured value: 365 (MH+).

4-((7-methoxy-6-(1,3,4-oxadiazol-2-yl)quinoline-4-yl)oxy)aniline (219): Crude compound 218 was mixed with Fe powder (50 mg, 0.9 mmol) and _NH₄Cl (20 mg, 0.36 mmol) in EtOH (2 mL). The resulting mixture was stirred at 85 °C for 3 hours. After cooling, the mixture was filtered, washed with EtOAc, and the filtrate was concentrated. The residue was purified by rapid silica gel chromatography to give compound 219 (40 _mg , 66%, in two _steps ). _{MS (EI) was C₁₈H₁₄N₄O₃ ,} measured value: 335 (MH+).

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(1,3,4-oxadiazol-2-yl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide ( ₂₂₀ ): Compound 220 was synthesized in a manner similar to that used in the preparation of compound 175 in Example 64. _MS (EI) was _C29H22FN5O5 , _and the measured value was 540 (MH+).

The following compounds were prepared in a manner similar to that used in the synthesis of compound 220 in Example 78, using compound 55 instead of compound 4:

1-N'-(4-fluorophenyl)-1-N-[4-[6-(1,3,4-oxadiazol-2-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1- _{dicarboxamide} (221): MS (EI _{) was C28H20FN5O4} , and the measured value was 510 (MH+).

Example 81: N-(4-((7-bromoquinoline-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (232)

N-(4-((7-bromoquinoline-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (232): _Cs₂CO₃ (2.7 g, 8.26 mmol) was added to a mixture of compound 231 (1 g, 4.13 mmol) and compound ₃ (1.3 g, 4.13 mmol) in DMF (8 mL). The resulting mixture was stirred at 85 °C for ₁₂ h. The mixture was cooled to room temperature, diluted with water, and filtered. The residue was purified by rapid column chromatography to give compound 232 (1.5 g, 69% yield). _MS (EI) was _{C₂₆H₁₉BrFN₃O₃} , _with measured values of 520 and 522 (MH+).

Example 85: 1-N'-(4-fluorophenyl)-1-N-[4-(7-aminosulfonylquinoline-4-yl)oxyphenyl]cyclopropane-1,1-dicarboxamide (254)

S-(4-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylamino)phenoxy)quinoline-7-yl)thioacetate (253): Compound 253 (170 mg, crude) was synthesized from compound 232 in a manner similar to that used in the preparation of compound 205 from compound 43 in Example _{75. MS} ( _EI ) was _C28H22FN3O4S , measured value: 516.0 (MH+).

1-N'-(4-fluorophenyl)-1-N-[4-(7-aminosulfonylquinoline-4-yl)oxyphenyl]cyclopropane-1,1-dicarboxamide (254): Compound 254 (170 mg, crude) was synthesized from compound 253 in a manner similar to that used in the preparation of compound 206 from compound 205 in Example 75. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.28 (s, 1H), 10.05 (s, 1H), 8.95 (d, 1H), 8.62 (d, 1H), 8.52 (d, 1H), 8.11 (dd, Hz, 1H), 7.88–7.75 (m, 4H), 7.67–7.59 (m, 2H), 7.33 (d, 2H), 7.15 (t, 2H), 6.85 (d, 1H), _{1.48 (s, 4H); MS (EI) was C₂₆H₂₁FN₄O₅S , measured} value: 521.0 ( _MH⁺ ).

Example 86: 1-N'-(4-fluorophenyl)-1-N-[4-[7-[(E)-N-methoxy-C-methylcarboiminoyl]quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (256)

1-N-[4-(7-acetylquinoline-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (255): A solution of compound 232 (100 mg, 192.18 μmol, 1 equivalent), tributyl(1-ethoxyvinyl)stanane (138.81 mg, 384.36 μmol, 129.73 μL, 2 equivalents) and Pd( _PPh3 ) _2Cl2 (13.49 _mg , 19.22 μmol, 0.1 equivalents) in toluene (2 mL) was degassed with nitrogen for 10 min and heated at 110 °C for 12 h under nitrogen. After cooling, KF (2 mL, 2 M) was added, and the resulting mixture was stirred at room temperature for 30 min. A 6 M HCl aqueous solution (2 mL) was added to the residue, and the mixture was stirred at 25 °C for 30 min. The mixture was extracted with EtOAc. The organic layer was washed with water, saturated NaCl aqueous solution, _dried ( _Na₂SO₄ ), and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether/ethyl acetate = 1/1), then recrystallized from MeOH (2 mL) and lyophilized to give compound 255 (12.4 mg, 10.63% yield). ^¹H NMR (400MHz, _CDCl₃ ) δ 9.46 (s, ¹H), 8.75 (d, ¹H), 8.67 (s, ¹H), 8.57 (br s, ¹H), 8.43 (d, ¹H), 8.16 (dd, ¹H), 7.66 (d, 2H), 7.51–7.45 (m, 2H), 7.20 (d, 2H), 7.10–7.04 (m, 2H), 6.64 (d, ¹H), 2.78 (s, 3H), 1.76 (s, 2H), 1.67 (s, _2H ); MS (EI) was _{C₂₈H₂₂FN₃O₄} , measured value: _{484.2 (} MH⁺).

1-N'-(4-fluorophenyl)-1-N-[4-[7-[(E)-N-methoxy-C-methylcarboiminoyl]quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (256): O-methylhydroxylamine (43.18 mg, 517.07 μmol, 5 equivalents, HCl) was added to a mixture of compound 255 (50 mg, 103.41 μmol, 1 equivalent) in EtOH (2 mL) and _H₂O (0.3 mL). The mixture was stirred at 50 °C for 1 h. The mixture was concentrated under vacuum, and the resulting residue was purified by silica gel column chromatography (petroleum ether/EtOAc = 5/1 to 1/1), followed by recrystallization from MeOH (2 mL) to give compound 256 (27 mg, 48.90% yield). ^¹H NMR (400MHz, _CDCl₃ ) δ 10.24 (s, ¹H), 8.82 (s, ¹H), 8.72 (br d, ¹H), 8.48–8.40 (m, 2H), 8.22 (s, ¹H), 7.80 (d, 2H), 7.50–7.42 (m, 2H), 7.23 (br d, 2H), 7.07 (t, 2H), 6.83 (br d, ¹H), 4.11 (s, 3H), 2.40 (s, 3H), 1.89–1.81 (m, 2H), 1.68–1.64 (m, 2H); MS (EI) was _{C₂ ₹ H₂₅FN₄O₄} , _measured value: 513.1 (MH⁺).

Example 87: 4-(4-amino-2-fluorophenoxy)-7-methoxy-N-methylquinoline-6-carboxamide (258)

4-Chloro-7-methoxy-N-methylquinoline-6-carboxamide (257): A solution of methylamine (8 M, 50 mL, 10.07 equivalents) in EtOH was added to a solution of compound 4 (10 g, 39.74 mmol, 1 equivalent) in THF (150 mL) at 30 °C. The reaction mixture was stirred at 30 °C for 25 _h . The mixture was concentrated under vacuum. The residue was slurried with warm water (100 mL) and filtered. The filter cake was dried under vacuum to give compound 257 as a white solid (9 g, 90.35% yield). _{MS (EI) was C12H11ClN2O2 , and} the measured value was 251.0 (MH+).

4-(4-amino-2-fluorophenoxy)-7-methoxy-N-methylquinoline-6-carboxamide (258): Compound 258 was synthesized from compound 257 and 4-amino-2-fluorophenol in a manner similar to that used in Example 62 to synthesize compound 171 from compounds 42 and 2.

Example 88: 1-N-[3-fluoro-4-[7-methoxy-6-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)-1-N'-methylcyclopropane-1,1-dicarboxamide (262)

Methyl 1-((4-fluorophenyl)(methyl)carbamoyl)cyclopropane-1-carboxylic acid (260): A solution of compound 259 (215 mg, 1.5 mmol, 1.5 equivalents), HATU (568 mg, 149 μmol, 1.5 equivalents), and DIEA (0.52 mL, 3 equivalents) in DMF (5 mL, 0.2 M) was stirred at room temperature for 15 min. 4-fluoro-N-methylaniline (124 mg, 1.0 mmol, 1.0 equivalents) was added, and the mixture was stirred at room temperature for 17 h. Water was added, and the resulting mixture was extracted with EtOAc. The two phases were separated, and the organic layer was dried _{over Na₂SO₄} , concentrated under reduced pressure, absorbed onto silica gel, and purified by CombiFlash (60:40 hexane:EtOAc) to give compound 260 (221 mg, 88.7% yield). ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.38-7.35(m,2H),7.25(m,2H),3.40(s,3H),3.18(s,3H),1.37(d,2H),1.17(bs.2H).

1-((4-fluorophenyl)(methyl)carbamoyl)cyclopropane-1-carboxylic acid (261): Compound 260 (60 mg, 0.23 mmol, 1.0 equivalent) and NaOH (20 mg, 0.5 mmol) in MeOH and THF solutions (1 mL each) were stirred overnight at 50 °C. The reaction mixture was cooled and concentrated under reduced pressure. 1 N HCl was added to the residue, and the resulting mixture was extracted with DCM. The two phases were separated, _and the organic layer was dried over _Na₂SO₄ and concentrated under reduced pressure to give crude compound 261, which could be used in the next step without further purification (44.7 mg, 79% yield). ^¹H NMR (400 MHz, DMSO- _d₆ ) δ 7.39 (br s, 2H), 7.25 (m, 2H), 3.17 (s, 3H), 1.24 (br s, 2H), 0.99 (br s, 2H).

1-N-[3-fluoro-4-[7-methoxy-6-(methylcarbamoyl)quinolin-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)-1-N'-methylcyclopropane-1,1-dicarboxamide (262): A solution of compound 261 (23.7 mg, 0.1 mmol, 1.5 equivalent), HATU (38 mg, 0.1 mmol, 1.5 equivalent), and DIEA (34 μL, 3.0 equivalent) in DMF (0.4 mL) was stirred at room temperature for 15 min. Compound 258 (23.7 mg, 0.06 mmol, 1.0 equivalent) was added, and the mixture was stirred at room temperature for 17 h. Water was added to the mixture, and the resulting solid was extracted into EtOAc. The two phases were separated, and the organic layer was dried over _{Na₂SO₄ ,} concentrated under reduced pressure, absorbed onto silica gel, and purified by CombiFlash (5:95MeOH:DCM). The obtained product was further purified by preparative HPLC to give compound 262 (7 mg, 18.8% yield). ^¹H NMR (400 MHz, DMSO- _d₆ ) δ 9.94 (s, 1H), 8.79 (d, 1H), 8.59 (s, 1H), 8.38 (d, 1H), 7.50 (s, 1H), 7.37 (t, 2H), 7.22 (b m, 3H), 7.04 (t, 2H), 6.65 (d, 1H), 3.99 (s, 3H), 3.18 (s, 3H), 2.78 ( _d , 3H), 1.37 ( _{d, 2H), 1.17 (b s, 2H); MS (EI) was C₃₀H₂₆F₂N₄O₅ , measured} value _561.0 (MH⁺).

Compound 263 was prepared using a variant of the method used in Example 88 for synthesizing compound 262:

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]-1-N'-methylcyclopropane-1,1-dicarboxamide (263): In the last step of the 3-step sequence of Example 88, compound 258 was replaced with 4-(4-aminophenoxy)-7-methoxy-N-methylquinoline-6-carboxamide. 4-(4-aminophenoxy)-7-methoxy-N-methylquinoline-6-carboxamide was synthesized in the same manner as compound 258 in Example 87, but in the second step, 4-aminophenol was used instead of 4-amino-2-fluorophenol. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 9.69 (br s, 1H), 8.67 (d, 1H), 8.62 (s, 1H), 8.38 (d, 1H), 7.52 (s, 1H), 7.47 (s, 1H), 7.29 (m, 2H), 7.18 (d, 3H), 7.11 (t, 2H) 6.47 (d, 1H), 4.03 (s, 3H), 2.85 (d, 3H), 2.08 (s, 3H), 1.37 (d, 2H), 1.24 (br s, _{2H); MS (EI) was C₃₀H₂₇FN₄O₅ , measured value} 543.0 (MH⁺).

Following the same three-step procedure used in Example 88 for the synthesis of compound 262 from compounds 259 and 258, the following compounds were prepared from compounds 259 and 258:

1-N'-(2-chloro-4-fluorophenyl)-1-N-[3-fluoro-4-[7-methoxy-6-(methylcarbamoyl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (264): In the first step, 4-fluoro-N-methylaniline is replaced with 2-chloro-4-fluoroaniline. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.36 (s, ¹H), 10.25 (s, ¹H), 8.61 (d, ¹H), 8.54 (s, ¹H), 8.31 (m, ¹H), 7.84–7.79 (m, 2H), 7.47 (s, 2H), 7.40 (t, 2H), 7.18 (t, 1H), 6.42 (d, 1H), 3.96 (s, 3H), 2.77 (d, 3H), 1.56 (br s, 2H), 1.53 ( _br s _{, 2H); MS (EI) was C₂₉H₂₃ClF₂N₄O₅ , measured value} 581.0 (MH⁺).

1-N-[3-fluoro-4-[7-methoxy-6-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]-1-N'-(4-fluoro-2-methylphenyl)cyclopropane-1,1-dicarboxamide (265): In the first step, 4-fluoro-2-methylaniline is used instead of 4-fluoro-N-methylaniline. ^¹H NMR (400MHz, DMSO- _d₆ ) δ 10.58 (s, ¹H), 9.72 (s, ¹H), 8.68 (d, ¹H), 8.61 (s, ¹H), 8.39 (d, ¹H), 7.92 (d, ¹H), 7.54 (br s, 2H), 7.47 (t, 2H), 7.1 (d, 1H), 7.03 (t, 1H), 6.49 (d, 1H), 4.03 (s, 3H), 2.85 (d, 3H), 2.22 ( _{s, 3H), 1.54 (s, 4H); MS (EI) was C₃₀H₂₆F₂N₄O₅ , measured value 561.0} (MH⁺).

1-N'-(4-fluoro-2,6-dimethylphenyl)-1-N-[3-fluoro-4-[7-methoxy-6-(methylcarbamoyl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (267): In the first step, 4-fluoro-2,6-dimethylaniline is used instead of 4-fluoro-N-methylaniline. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.8 (s, ¹H), 9.19 (s, ¹H), 8.6 (d, ¹H), 8.54 (s, ¹H), 8.32 (d¹H), 7.87 (d¹H), 7.46–7.36 (m, ³H), 6.88 (d, 2H), 6.41 (d, ¹H), 3.96 (s, ³H), 2.77 (d, ³H), 2.09 (s, 6H), _1.47 ( _{s, 4H); MS (EI) was C₃¹H₂₈F₂N₄O₅ , measured} value _575.0 (MH⁺).

1-N-[3-fluoro-4-[7-methoxy-6-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]-1-N'-(4-fluoro-2-methoxyphenyl)cyclopropane-1,1-dicarboxamide (268): In the first step, 4-fluoro-2-methoxyaniline is used instead of 4-fluoro-N-methylaniline. ^¹H NMR (400MHz, DMSO- _d₆ ) δ 10.2 (s, ¹H), 10.17 (s, ¹H), 8.68 (d, ¹H), 8.62 (s, ¹H), 8.39 (d, ¹H), 7.98–7.96 (m, ¹H), 7.86 (d, ¹H), 7.54–7.47 (m, ³H), 7.01 (d, ¹H), 6.77 (t, ¹H), 6.51 (d, ¹H), 4.04 (s, ³H), 3.85 (s, ³H), 2.86 (d, ³H), 1.62 (s, ²H), _1.58 (s, _{²H); MS (EI) was C₃₀H₂₆F₂N₄O₆ , measured value} 577.0 (MH⁺).

1-N-[3-fluoro-4-[7-methoxy-6-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]-1-N'-(4-fluoro-2-propane-2-yloxyphenyl)cyclopropane-1,1-dicarboxamide (269): In the first step, 4-fluoro-2-isopropoxyaniline is used instead of 4-fluoro-N-methylaniline. ¹ H NMR (400MHz, DMSO-d ₆ )δ10.21(s,1H),10.06(s,1H),8.62(d,1H),8.55(s,1H),8.32(d,1H),8.05(t,1H),7.87(d,1H),7.52-7.41(m,3H),6.97(d,1H),6. 68(t,1H),6.41(d,1H),4.64-4.58(m,1H),3.96(s,3H),2.78(d,3H),1.51(s,2H),1.40(s.2H),1.17(s,3H),1.16(s,3H); MS(EI) is C ₃₂ H ₃₀ F ₂ N ₄ O ₆ The measured value was 605 (MH+).

1-N'-(2-Cyclopropyl-4-fluorophenyl)-1-N-[3-fluoro-4-[7-methoxy-6-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (270): In the first step, 4-fluoro-N-methylaniline is replaced with 2-cyclopropyl-4-fluoroaniline. ¹ H NMR (400MHz, DMSO-d ₆ ) δ10.53 (br s, 1H), 9.99 (br s,1H),8.68(d,1H),8.62(s,1H),8.39(d,1H),7.91(d,1H),7.61(s,1H),7.54(s,2H),7.49(br s,1H),7.01(t,1H)6.82(d,1H),6.49(d,1H),4.04(s,3H),2.85(d,3H),1.97(br s,1H),1.58(s,4H),0.94(d,2H),0.67(d,2H); MS(EI) is C ₃₂ H ₂₈ F ₂ N ₄ O ₅ The measured value was 587.4 (MH+).

The 2-cyclopropyl-4-fluoroaniline used in the synthesis of compound 270 was synthesized via the following procedure:

In a thick-walled reaction tube, tert-butyl (2-bromo-4-fluorophenyl)carbamate (289 mg, 1 mmol, 1.0 equivalent), cyclopropyl MIDA borate (236 mg, 1.2 mmol, 1.2 equivalent), and _K₃PO₄ ( ₆₃₆ mg, 3.0 equivalent) were added to toluene:water (4:1) and degassed under nitrogen for 5 minutes. Palladium acetate (9 mg, 4 mol%) and 2-(dicyclohexyl)phosphinobiphenyl (28 mg, 8 mol%) were added to the mixture and degassed under nitrogen for another 5 minutes. The tube was capped, and the mixture was heated overnight at 100 °C under nitrogen. After cooling to room temperature, the two phases were separated. The organic layer was dried with _{anhydrous Na₂SO₄} , concentrated under reduced pressure, absorbed into silica gel, and purified by CombiFlash using a 70:30 hexane:DCM gradient to give tert-butyl (2-cyclopropyl-4-fluorophenyl)carbamate as a colorless oil (90 mg, 36% yield).

A solution of tert-butyl (2-cyclopropyl-4-fluorophenyl)carbamate (86 mg, 0.3 mmol, 1.0 equivalent) and TFA (77 mg, 2.0 equivalent) in DCM (1 mL) was stirred overnight at 40 °C. The reaction solution was cooled and concentrated under reduced pressure. DCM (4 mL) was added to the residue, and the resulting solution was washed with a saturated aqueous solution of _NaHCO3 , dried over _{anhydrous Na2SO4} , and concentrated under reduced pressure to give crude 2-cyclopropyl-4-fluoroaniline as an almost colorless oil (43 mg, 81% yield), which could be used in subsequent reactions without further purification. ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.16-7.13(m,1H),7.01(t,1H),6.85(d,1H),1.91-1.85(m,1H),1.0(d,2H),0.73(d,2H).

Example 89: 1-((3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinoline-4-yl)oxy)phenyl)-carbamoyl)-cyclopropane-1-carboxylic acid (272)

Methyl 1-((3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)-carbamoyl)cyclopropane-1-carboxylic acid (271): A solution of compound 259 (108 mg, 0.7 mmol, 1.5 equivalent), HATU (285 mg, 0.75 mmol, 1.5 equivalent), and DIEA (0.26 mL, 3 equivalent) in DMF (2.5 mL, 0.2 M) was stirred at room temperature for 15 min. Compound 258 (170 mg, 0.5 mmol, 1.0 equivalent) was added, and the mixture was stirred at room temperature for 17 h. Water was added, and the resulting mixture was extracted with EtOAc. The organic layer was separated and washed with a saturated aqueous solution of NaCl, _dried over anhydrous _Na₂SO₄ , and concentrated under reduced pressure. The resulting residue was aspirated onto silica gel and purified by CombiFlash using a gradient of 1:8 hexane:EtOAc followed by 1:6 hexane:DCM. The resulting product was sonicated with hexane. The resulting solid was filtered, dissolved in DCM, and washed with 10% LiCl aqueous solution. The organic layer was dried over _{anhydrous Na₂SO₄} and concentrated to give compound 271 (90 mg, 38% yield). ¹ HNMR(400MHz,DMSO-d ₆ )δ10.64(br s,1H),8.67(d,1H),8.61(s,1H),8.39(d,1H),7.88(m,1H),7.54(s,1H),7.51-7.44(m,2H) ,6.52(d,1H),4.03(s,3H),3.71(s,3H),2.85(d,3H),1.46-1.45(m,2H),1.43-1.42(m,2H).

1-((3-fluoro-4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)carbamoyl)-cyclopropane-1-carboxylic acid (272): Compound 271 (70 mg, 0.2 mmol, 1.0 equivalent) and NaOH (12 mg, 0.5 mmol) in MeOH and THF solutions (1 mL each) were stirred overnight at 50 °C. The reaction solution was cooled and then concentrated under reduced pressure. 1 N HCl aqueous solution was added to the residue, and the resulting mixture was extracted with DCM. The organic phase was dried over _{anhydrous Na₂SO₄} and concentrated under reduced pressure to give crude compound 272 (60 mg, 89% yield), which could be used in subsequent reactions without further purification. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.85(br s,1H),8.87(d,1H),8.67(s,1H),8.46(d,1H),7.95(m,1H),7.62(s,1H) ,7.54-7.5(m,2H),6.83(d,1H),4.06(s,3H),2.85(d,3H),1.43(s,4H).

Example 90: 1-N'-[3-fluoro-4-[7-methoxy-6-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]-1-N-[4-(trifluoromethyl)phenyl]cyclopropane-1,1-dicarboxamide (273)

1-N'-[3-fluoro-4-[7-methoxy-6-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]-1-N-[4-(trifluoromethyl)phenyl]cyclopropane-1,1-dicarboxamide (273): Compound 273 was synthesized from compound 272 and 4-(trifluoromethyl)aniline using standard HATU amide bond forming techniques, such as those used in the first step of Examples 3, 4 and 89. ^¹H NMR (400MHz, _CD₃OD ) δ 8.90 (s, ¹H), 8.86 (d, ¹H), 7.89 (d, ¹H), 7.55 (s, ¹H), 7.51 (d, 2H), 7.43 (m, _2H ), 7.25 (d, 2H), 6.98 (d, ¹H), 4.13 (s, 3H), 2.94 (s, 3H), 1.64–1.54 (m, 4H). _{MS (EI) was C₃₀H₂₄F₄N₄O₅ ,} measured value _597.2 ( _MH⁺ ).

Following the same procedure used in Example 90 for the synthesis of compound 273 from compound 272, the following compounds were prepared from compound 272:

1-N-(4-chlorophenyl)-1-N'-[3-fluoro-4-[7-methoxy-6-(methylcarbamoyl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (274): 4-chloroaniline was used instead of 4-(trifluoromethyl)aniline. ^¹H NMR (400 MHz, _CD₃OD ) δ 8.99 (s, 1H), 8.95 (d, 1H), 7.98 (d, 1H), 7.83 (d, 2H), 7.65 (d, 3H), 7.54 (q, 2H), 7.06 (d, 1H), 4.22 (s, 3H), 3.03 (s, 3H), 1.84–1.64 (m, _4H ). _{MS (EI) was C₂₉H₂₄ClFN₄O₅ ,} measured _563.2 (MH⁺).

Example 91: 1-N'-(4-fluorophenyl)-1-N-[4-[7-[(E)-methoxyiminomethyl]quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (278)

(4-Chloroquinoline-7-yl)methanol (275): Compound 161 (400 mg, 1.80 mmol, 1 equivalent) in THF (2 mL) was added to a solution of _LiAlH4 (116.45 mg, 3.07 mmol, 1.7 equivalent) in THF (5 mL) at 0 °C. The mixture was stirred at 20 °C for 3 hours. _Na2SO4 · _10H2O ( ₅₀ mg) was added, the resulting mixture was filtered, and the filtrate was dried over _{anhydrous Na2SO4} and then concentrated under vacuum. The residue was purified by rapid silica gel chromatography (4 g silica rapid column, eluent 70%–100% ethyl acetate/petroleum ether gradient @ 25 mL/min) to give compound 275 as a pale yellow solid (150 mg, 36.5% yield). ¹ H NMR (400MHz, CDCl ₃ ) δ 8.74 (d, 1H), 8.19 (d, 1H), 8.12 (s, 1H), 7.64 (dd, 1H), 7.47 (d, 1H), 4.94 (s, 2H), 2.99 (br s, 1H).

N-(4-fluorophenyl)-N-(4-((7-(hydroxymethyl)quinoline-4-yl)oxy)phenyl)cyclopropane-1,1-dicarboxamide (276): Compound 276 was synthesized from compound 275 and compound 3 by lowering the reaction temperature to 85°C in a manner similar to that used in the last step of Example 12 for the synthesis of compound 43 from compound 42 and compound 3. ^¹H NMR (400MHz, _CD₃OD ) δ 8.63 (d, ¹H), 8.41 (d, ¹H), 8.03 (s, ¹H), 7.76 (d, 2H), 7.68 (dd, ¹H), 7.62–7.55 (m, 2H), 7.30–7.23 (m, 2H), 7.09 (t, 2H), 6.66 (d, ¹H), 4.88 (s, 2H), 1.66 (d, 4H); MS (EI) was _{C₂₇H₂₂FN₃O₄ , measured value} 472.1 (MH⁺).

N-(4-fluorophenyl)-N-(4-((7-formylquinoline-4-yl)oxy)phenyl)cyclopropane-1,1-dicarboxamide (277): _MnO₂ (239.72 mg, 2.76 mmol, 13 equivalents) was added to a DCM (5 mL) solution of compound 276 (100 mg, 212.1 μmol, 1 equivalent). The mixture was stirred at 20 °C for 1 _h . The mixture was filtered and concentrated under vacuum to give compound 277 as a yellow oil (50 mg, 40.2% yield). _{MS (EI) was C₂₇H₂₀FN₃O₄ , and} the measured value was 470.0 (MH⁺).

1-N'-(4-fluorophenyl)-1-N-[4-[7-[(E)-methoxyiminomethyl]quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (278): O-methylhydroxylamine (44.47 mg, 532.5 μol, 5 equivalents, HCl) was added to a mixture of compound 277 (50 mg, 106.5 μol, 1 equivalent) in EtOH (3 mL) and water (0.3 mL). The mixture was stirred at 50 °C for 2 h. The mixture was concentrated under vacuum, and EtOH (3 mL) was added to the residue. The obtained white solid was collected and then purified by preparative HPLC (YMC-Actus Triart C18 150*30mm*5um; mobile phase: [water (0.225% FA)-ACN]; B%: 37%-77%, 10 min) to give compound 278 as a white solid (14.5 mg, 26.2% yield). ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.22 (s, 1H), 10.07 (s, 1H), 8.72 (d, 1H), 8.51 (s, 1H), 8.34 (d, 1H), 8.18 (d, 1H), 7.97 (dd, 1H), 7.79 (d, 2H), 7.70–7.61 (m, 2H), 7.28 (d, 2H), 7.16 (t, 2H), 6.60 (d, 1H), 3.98 (s, 3H) _{, 1.48 (s, 4H); MS (EI) was C₂₈H₂₃FN₄O₄ , measured} value _499.2 (MH⁺).

Example 92: 1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(methylcarbamoylamino)-quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (279)

1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(methylcarbamoylamino)-quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (279): 1-methylurea (48.46 mg, 654.10 μmol, 6 equivalents), _Pd₂ (dba) _₃ (14.97 mg, 16.35 μmol, 0.15 equivalents), Xantphos (18.92 mg, 32.70 μmol, 0.3 equivalents), and _Cs₂CO₃ (99.46 mg, 305.25 μmol, 2.8 equivalents) were added to a mixture of compound ₄₃ (60 mg, 109.02 μmol, 1 equivalent) in dioxane (3 mL) under a nitrogen atmosphere. The mixture was stirred at 100 °C for 1 h. The reaction mixture was concentrated, and water (20 mL) was added to the residue. The resulting mixture was extracted with EtOAc (3 x 25 mL). The combined organic extracts were dried over _{anhydrous Na₂SO₄} and concentrated under vacuum. The resulting residue was purified by preparative HPLC (column: DuraShell 150*25mm*5um; mobile phase: [water (0.05% ammonium hydroxide v/v)-ACN]; B%: 30%-70%, 10 min) to give compound 279 as a white solid (12.8 mg, 20.7% yield). ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.15 (s, ¹H), 10.07 (s, ¹H), 8.97 (s, ¹H), 8.44 (d, ¹H), 8.32 (s, ¹H), 7.76 (d, 2H), 7.65 (dd, 2H), 7.40 (s, 1H), 7.24–7.12 (m, 4H), 6.95 (br d, ¹H), 6.41 (d, 1H), 4.04 (s, 3H), 2.68 (s, 3H) _{, 1.48 (br d, 4H); MS (EI) was C₂⁹H₂⁶FN₅O₅ , measured value} 544.3 (MH⁺).

Example 93: Methyl N-[4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-7-methoxyquinoline-6-yl]carbamate (280)

N-[4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-7-methoxyquinoline-6-yl]carbamate (280): Compound 280 was synthesized from compound 43 by replacing 1-methylurea with methyl carbamate in a manner similar to that used in Example 92 for the synthesis of compound 279 from compound 43. ^¹H NMR (400MHz, DMSO- _d₆ ) δ 10.17 (s, ¹H), 10.06 (s, ¹H), 8.84 (s, ¹H), 8.67 (s, ¹H), 8.52 (d, ¹H), 7.77 (d, 2H), 7.70–7.62 (m, 2H), 7.45 (s, ¹H), 7.23 (d, 2H), 7.19–7.12 (m, 2H), 6.45 (d, ¹H), 4.00 ( _s , 3H), 3.72 (s, 3H), 1.48 (s, 4H); MS (EI) was _{C₂ ₹H₂₅FN₄O₆ ,} measured value 567.3 [M+Na] ^⁺

Example 94: 1-N'-(4-fluorophenyl)-1-N-[4-[7-(methylcarbamoylamino)quinoline-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (281)

1-N'-(4-fluorophenyl)-1-N-[4-[7-(methylcarbamoylamino)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (281): A mixture of compound 232 (100 mg, 192.18 μmol, 1 equivalent), methylurea (42.71 mg, 576.54 μmol, 3 equivalent), Xantphos (22.24 mg, 38.44 μmol, 0.2 equivalent), t-BuONa (36.94 mg, 384.36 μmol, 2 equivalent) and _Pd₂ (dba)₃ (17.60 mg, 19.22 μmol, 0.1 equivalent) in dioxane (5 mL) was degassed and purged three times with nitrogen, then stirred at 100 °C for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: Ultimate C18 10μm 250mm*50mm; mobile phase: [water (0.05% ammonium hydroxide v/v)-ACN]; B%: 39%-69%, 9 min) to give compound 281 as a white solid (56.9 mg, 57.4% yield). ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.18 (s, ¹H), 10.06 (s, ¹H), 9.09 (s, ¹H), 8.55 (d, ¹H), 8.14 (d, 2H), 7.75 (d, 2H), 7.69–7.57 (m, 3H), 7.22 (d, 2H), 7.15 (t, 2H), 6.37 (d, ¹H), 6.26 (d, 1H), 2.69 (d, 3H), _1.48 (s, _{4H); MS (EI) was C₂₈H₂₄FN₅O₄ ,} measured value _514.3 (MH⁺).

Example 95: Methyl N-[4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]-amino]phenoxy]quinoline-7-yl]carbamate (282)

N-[4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]-amino]phenoxy]quinoline-7-yl]carbamate (282): Compound 282 was synthesized from compound 232 by replacing 1-methylurea with methyl carbamate in a manner similar to that used in Example 94 for the synthesis of compound 281 from compound 232. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.82–10.72 (m, 1H), 10.40–10.33 (m, 1H), 10.12–10.04 (m, 1H), 8.89 (d, 1H), 8.59 (d, 1H), 8.50 (d, 1H), 7.93–7.81 (m, 3H), 7.69–7.60 (m, 2H), 7.38 (d, 2H), 7.16 (t, 2H), 6.78 (d, 1H), 3.79 (s, 3H), _{1.50 (s, 4H); MS (EI) was C₂₈H₂₃FN₄O₅ , measured} value _515.3 (MH⁺).

Example 96: 1-N-[4-[6-(3-ethyl-1,2,4-oxadiazol-5-yl)-7-methoxyquinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide hydrochloride (283)

1-N-[4-[6-(3-ethyl-1,2,4-oxadiazol-5-yl)-7-methoxyquinoline-4-yl]oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide hydrochloride (283): HATU (26.45 mg, 0.070 mmol) was added to a DMF (0.5 mL) solution of compound 6 (30 mg, 0.058 mmol), (Z)-N'-hydroxypropylimine amide (7.22 mg, 0.058 mmol), and DIEA (44 μL, 0.17 mmol), and the reaction mixture was stirred at room temperature until the starting material disappeared as determined by LC-MS. The reaction mixture was then heated to 60 °C and maintained for 2 hours. A saturated aqueous solution _{of NaHCO3} was added to the resulting mixture, which was then extracted with DCM (3x). The combined organic extracts were washed with a saturated aqueous solution of NaCl, _dried over _Na2SO4 , and concentrated. The crude residue was purified by HPLC (Gemini-NX, 10 μM, 250 x 30 mm, C18 column; eluent: 0.1%–100% acetonitrile aqueous solution, both eluents containing 0.1% trifluoroacetic acid, gradient elution for at least 15 minutes), followed by lyophilization. The resulting powder was placed in a 20% MeOH solution in DCM and passed through an Agilent PL-HCO3 ion exchange column (or placed in DCM and washed with saturated sodium bicarbonate), and concentrated under reduced pressure. HCl (4 M dioxane solution, 0.5 mL; or 1 M aqueous solution, 1 mL) was added to remove volatile solvents under reduced pressure, and the residue was dried under high vacuum to give the hydrochloride of compound 283 (4.1 mg, 11.7% yield). ^¹H NMR (400MHz, _CD₃OD ) δ 9.29 (s, ¹H), 8.94 (d, ¹H), 7.86 (q, 2H), 7.68 (s, ¹H), 7.61–7.54 (m, 2H), 7.41 (d, 2H), 7.10 (t, 2H), 7.02 (d, 1H), 4.26 (s, 3H), 2.91 (q, 2H), 1.68 (s, 4H), 1.42 (t, 3H). _{MS (EI) was C₃¹H₂₆FN₅O₅ ,} measured _{value 568.2} (MH⁺).

Example 97: 1-N'-[3-fluoro-4-[6-methyl-7-(methylcarbamoyl)quinoline-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (289)

4-Hydroxy-6-methylquinoline-7-carboxylic acid methyl ester (284): A mixture of compound 139 (290 mg, 1.11 mmol, 1 equivalent) and AcONa (454.26 mg, 5.54 mmol, 5 equivalent) in AcOH (6 mL) and water ( ₁₀ mL) was stirred at 90 °C for 48 h. After cooling to ambient temperature, the reaction mixture was neutralized with a saturated aqueous solution _{of NaHCO3} and extracted with EtOAc (3 x 30 mL). The combined extracts were dried over anhydrous _Na2SO4 and concentrated under reduced pressure to give compound 284 as a pale yellow solid (200 mg, 74.8% yield), which could be used directly in subsequent reactions without further purification. _{MS (EI) was C12H11NO3 , and} the result was 218.1 (MH+).

4-(2-fluoro-4-nitrophenoxy)-6-methylquinoline-7-carboxylic acid methyl ester (285): Cs₂CO₃ (809.97 mg, 2.49 mmol, 3 equivalents) was added to a mixture of compound 284 (200 mg, 828.65 μmol, ₁ equivalent) and 1,2-difluoro-4-nitrobenzene (197.75 mg, 1.24 mmol, 137.32 μL, 1.5 equivalents) in _ACN (15 mL) at 25 °C, and the mixture was stirred at 70 °C for 2 h. After cooling, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 30 mL). The combined organic extracts were washed with a saturated aqueous solution of NaCl (60 mL), _dried over anhydrous _Na₂SO₄ , and concentrated. The residue was purified by rapid silica gel chromatography, eluting with petroleum ether (0–60%) solution of EtOAc to give compound 285 as a pale yellow solid (120 mg, 38.6% yield). ^¹H NMR (400 MHz, _CDCl₃ ) δ 8.77 (d, 1H), 8.70 (s, 1H), 8.23–8.15 (m, 2H), 8.12 (s, 1H), 7.42–7.35 (m, 1H), 6.65 (d, 1H), 3.99 (s, 3H), 2.79 ( _{s, 3H); MS (EI) was C₁₈H₁₃FN₂O₅ ,} measured _357.0 ( _MH⁺ ).

4-(4-amino-2-fluorophenoxy)-6-methylquinoline-7-carboxylic acid methyl ester (286): Compound 286 was synthesized from compound 285 using a method similar to that used in Example 78 to convert compound 218 to compound 219. _MS ( _{EI )} was _C18H15FN2O3 , measured at 326.9 (MH+).

Methyl 4-(2-fluoro-4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylamino)phenoxy)-6-methylquinoline-7-carboxylic acid ester (287): A mixture of compound 1 (51.30 mg, 218.34 μmol, 1.5 equivalents) in _SOCl2 (8.20 g, 68.92 mmol, 5.00 mL, 473.51 equivalents) was stirred at 65 °C for 1 h. The mixture was concentrated, and the residue was dissolved in toluene and concentrated again. A solution of compound 286 (50 mg, 145.56 μmol, 1.0 equivalents) in THF (5 mL) was added to the resulting residue, followed by the addition of triethylamine (44.19 mg, 436.69 μmol, 60.78 μL, 3 equivalents). The resulting mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched with water (30 mL) and extracted with EtOAc (3 x 20 mL). The combined extracts were dried over _{anhydrous Na₂SO₄} and concentrated. The resulting residue was purified by silica gel chromatography, eluting with petroleum ether solution of EtOAc (0–70%), to give compound 287 as a grayish-white solid ( ₇₀ mg, _{85.95 %} yield). _MS (EI) was _{C₂₉H₂₃F₂N₃O₅} , and the result was 532.0 (MH⁺).

4-(2-Fluoro-4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylamino)phenoxy)-6-methylquinoline-7-carboxylic acid (288): A mixture of compound 287 (70.0 mg, 125.12 μmol, 1 equivalent) and LiOH· _H₂O (26.25 mg, 625.58 μmol, 5 equivalent) in THF (5 mL) and water (5 mL) was stirred at 25 °C for 4 H. The reaction mixture was acidified with 1 M HCl aqueous solution until a pH of ~5 was reached. The mixture was then diluted with water (30 mL) and extracted with EtOAc (3 x 20 _mL ). The combined organic extracts were dried over anhydrous _Na₂SO₄ and concentrated to give compound 288 as a white solid (70 mg, 86.49% yield), which could be used directly in subsequent reactions without further purification. _{MS(EI) is C28H21F2N3O5 , measured} value _{518.1 (} MH+).

1-1-N'-[3-fluoro-4-[6-methyl-7-(methylcarbamoyl)quinolin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (289): Compound 289 was synthesized from compound 288 in a manner similar to that used in the preparation of compound 8 in Example 4. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.39(s, ¹H), 9.99(s, ¹H), 8.67(d, ¹H), 8.48(d, ¹H), 8.16(s, ¹H), 7.95(s, ¹H), 7.91(d, ¹H), 7.63(dd, 2H), 7.56–7.49(m, ¹H), 7.47–7.41(m, ¹H), 7.15(t, 2H), 6.59(d, ¹H), 2.82(d, 3H), 2.54(s, 3H), 1.47(d, 4H); _MS ( _{EI )} was _{C₂⁹H₂⁴F₂N₄O₄ ,} measured value 531.1 (MH⁺).

The following compounds were prepared from compound 139 using the same 6-step method as used in Example 97 for the synthesis of compound 289:

1-N'-[2,5-difluoro-4-[6-methyl-7-(methylcarbamoyl)quinolin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (290): In step 2, 1,2-difluoro-4-nitrobenzene is replaced with 1,2,4-trifluoro-5-nitrobenzene. ^¹H NMR (400MHz, _CDCl₃ ) δ 10.09 (br s, ¹H), 8.59 (d, ¹H), 8.28 (dd, ¹H), 8.21 (s, ¹H), 8.09 (s, ¹H), 8.00 (s, ¹H), 7.36–7.43 (m, 2H), 6.96–7.06 (m, 3H), 6.47 (d, ¹H), 5.98 (d, 1H), 3.01 (d, 3H), 2.58 (s, 3H), 1.72–1.78 (m, 2H), 1.59–1.62 ( _m , 2H); MS (EI) was _{C₂ ₹ H₂₃F₃N₄O₄} , measured value _549.1 (MH⁺).

1-N'-[2-chloro-5-fluoro-4-[6-methyl-7-(methylcarbamoyl)quinolin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (291): In step 2, 1-chloro-4,5-difluoro-2-nitrobenzene is used instead of 1,2-difluoro-4-nitrobenzene. ^¹H NMR (400MHz, _CDCl₃ ) δ 10.08 (s, ¹H), 8.66 (d, ¹H), 8.61 (s, ¹H), 8.44 (d, ¹H), 8.15 (s, ¹H), 8.07 (s, ¹H), 7.52–7.45 (m, 2H), 7.36 (d, ¹H), 7.06 (t, 2H), 6.54 (d, ¹H), 6.15–6.07 (m, ¹H), 3.08 (d, 3H), 2.65 (s, 3H), 1.82–1.72 ( _m , 4H); MS (EI) was _{C₂ ₹ H₂₃ClF₂N₄O₄} , measured value _565.1 (MH⁺).

1-N-(4-fluorophenyl)-1-N'-[2,3,5-trifluoro-4-[6-methyl-7-(methylcarbamoyl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (292): In step 2, 1,2-difluoro-4-nitrobenzene is replaced with 1,2,3,4-tetrafluoro-5-nitrobenzene. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 11.33 (s, ¹H), 9.77 (s, ¹H), 8.71 (d, ¹H), 8.54–8.48 (m, ¹H), 8.18 (s, ¹H), 8.08–8.02 (m, ¹H), 7.98 (s, ¹H), 7.63–7.56 (m, 2H), 7.23–7.14 (m, 2H), 6.89 (d, ¹H), 2.83 (d, 3H), 2.55 (s, 3H), 1.72–1.65 (m, 2H), 1.62–1.57 (m, 2H); MS (EI) was _{C₂ ₹H₂₂F₄N₄O₄ , measured value} 567.1 (MH⁺).

Example 98: 1-N'-[4-(7-carbamoyl-6-methylquinoline-4-yl)oxy-3-fluorophenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (293)

1-N'-[4-(7-carbamoyl-6-methylquinoline-4-yl)oxy-3-fluorophenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (293): Compound 293 was synthesized from compound 288 in a manner similar to that used in the preparation of compound 7 in Example 3. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 10.40(s, ¹H), 10.00(s, ¹H), 8.67(d, ¹H), 8.16(s, ¹H), 8.03(s, ¹H), 7.99(s, ¹H), 7.91(d, ¹H), 7.64(dd, 2H), 7.58(s, ¹H), 7.56–7.51(m, ¹H), 7.47–7.41(m, ¹H), 7.15(t, 2H), 6.59(d, ¹H), 2.58(s, 3H), 1.47(d, 4H); _MS ( _{EI )} was _{C₂₈H₂₂F₂N₄O₄ ,} measured value 517.1 (MH⁺).

The following compounds were prepared using a method similar to that used in Example 98 for the synthesis of compound 293 from compound 288:

1-N'-[4-(7-carbamoyl-6-methylquinoline-4-yl)oxy-2,5-difluorophenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (294): 4-(2,5-difluoro-4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylamino)phenoxy)-6-methylquinoline-7-carboxylic acid was used instead of compound 288, prepared using the same multi-step procedure as that used in Example 97 for the synthesis of compound 288, except that in step 2, 1,2-difluoro-4-nitrobenzene was used instead of 1,2-difluoro-4-nitrobenzene. ^¹H NMR (400MHz, _CDCl₃ ) δ 10.19 (br s, 1H), 8.67 (d, 1H), 8.36 (dd, 1H), 8.26 (br s, 1H), 8.19 (s, 2H), 7.47 (dd, 2H), 7.03–7.12 (m, 3H), 6.55 (d, 1H), 6.04 (br s, 1H), 5.78 (br s, 1H), 2.70 (s, 3H), 1.75–1.90 ( _m , 2H), 1.67–1.69 (m, _{2H); MS (EI) was C₂₈H₂₁F₃N₄O₄ , measured} value _535.1 (MH⁺).

Example 99: 1-N'-[3-fluoro-4-[7-(2-hydroxyethoxycarbamoyl)quinoline-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (301)

4-Hydroxyquinoline-7-carboxylic acid methyl ester (296): Compound 295 (5 g, 22.32 mmol, 1 equivalence) and TEA (22.58 g, 223.16 mmol, 31.06 mL, 10 equivalence) in MeOH (60 mL) and DMSO (20 mL) solutions were added to a round-bottom flask. Then DPPP (1.84 g, 4.46 mmol, 0.2 eq) and Pd(OAc) _₂ (1.00 g, 4.46 mmol, 0.2 equivalence) were added. The flask was purged twice with carbon monoxide and placed under 30 psi of carbon monoxide while heating at 70 °C for 12 hours. MeOH (100 mL) was added, and the resulting suspension was filtered through a diatomaceous earth mat. The filter cake was washed with MeOH (3 x 50 mL). The combined filtrates were concentrated, and the resulting crude product was washed with water (50 mL), ground with MeOH (15 mL), and filtered to give compound 296 as a yellow solid (3.5 g, 77.19% yield). ^¹H NMR (400 MHz, _CDCl₃ ) δ 11.98 (br s, 1H), 8.23–8.15 (m, 2H), 8.01 (dd, 1H), 7.81 (br d, 1H), 6.11 (d, 1H), 3.90 (s, _{3H); MS (EI) was C₁₁H₉NO₃ , measured} 203.9 (MH⁺).

4-(2-fluoro-4-nitrophenoxy)quinoline-7-carboxylic acid methyl ester (297): Compound 297 was prepared from compound 296 in a similar manner to the preparation of compound 285 from compound 284 in Example 97. ^¹H NMR ( ₄₀₀ MHz, _CDCl₃ ) δ 8.88–8.83 (m, 2H), 8.37 (d, 1H), 8.25–8.16 (m, 3H), 7.43 (t, 1H), 6.70 (d, 1H), 4.04 (s, _{3H )} ; MS (EI) was _{C₁₇H₁₁FN₂O₅} , measured 343.2 (MH⁺).

4-(4-amino-2-fluorophenoxy)quinoline-7-carboxylic acid methyl ester (298): Compound 298 was synthesized from compound 297 using a method similar to that used in Example 78 to convert compound 218 to compound 219. MS (EI) _{was C17H13FN2O3} , _and the measured value _was 312.9 (MH+).

Methyl 4-(2-fluoro-4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylamino)phenoxy)quinoline-7-carboxylic acid (299): Compound 1 (428.83 mg, 1.92 mmol, 3 equivalents) was suspended in anhydrous DCM (10 mL) at 25 °C with stirring. DMF (4.68 mg, 64.04 μmol, 4.93 μL, 0.1 equivalents) was added under nitrogen atmosphere, followed by (COCl) _₂ (290.00 mg, 2.28 mmol, 0.2 mL, 3.57 equivalents). The mixture was stirred at 25 °C for 30 minutes. Toluene (5.0 mL) was added, and the solvent was removed under reduced pressure. The resulting acyl chloride product was dissolved in anhydrous THF (1.0 mL). Under nitrogen atmosphere, a THF solution of the acyl chloride prepared above was added to a DMA (6 mL) solution of compound 298 (200 mg, 640.42 μmol, 1 equivalent). The reaction mixture was stirred at 25 °C for 0.5 h. The reaction mixture was poured into a saturated _NaHCO3 aqueous solution (100 mL) and extracted with DCM (3 x 50 mL). The combined organic extracts were washed with a saturated _NaHCO3 aqueous solution (15 mL), then with a saturated NaCl aqueous solution (15 mL ₎ , dried over anhydrous _Na2SO4 , and concentrated under vacuum to give compound 299 as a yellow solid (270 mg, 81.47% yield), which _was used in subsequent reactions without further purification. _{MS (EI) was C28H21F2N3O5 , and} the measured value was 518.1 ₍ MH+).

4-(2-fluoro-4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylamino)-phenoxy)quinoline-7-carboxylic acid (300): Compound 300 was prepared from compound 299 in a manner similar to that used in Example 97 for the preparation of compound 288 from compound 287. _MS (EI) was _{C27H19F2N3O5 ,} and the measured value _was 504.1 ₍ MH+).

1-N'-[3-fluoro-4-[7-(2-hydroxyethoxycarbamoyl)quinolin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (301): HATU (72.50 mg, 190.68 μmol, 1.2 equivalent) and DIEA (61.61 mg, 476.71 μmol, 83.03 μL, 3 equivalent) were added to a DMF (3 mL) solution of compound 300 (80 mg, 158.90 μmol, 1 equivalent), and the resulting mixture was stirred at 25 °C for 30 min. 2-Aminooxyethanol (14.70 mg, 190.68 μmol, 1.2 equivalent) was added, and the reaction mixture was stirred at 25 °C for an additional 2 h. The reaction mixture was poured into a saturated _NH₄Cl aqueous solution (50 mL) and extracted with DCM (3 x 30 mL). The combined organic extracts were concentrated under vacuum, and the resulting residue was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um, gradient: 43%-63% acetonitrile aqueous solution (0.05% _NH3H2O ), flow rate: _25mL /min) to give compound 301 as a white solid (46.8mg, 52.36% yield). ¹ H NMR (400MHz, DMSO-d ₆ ) δ12.09(br s,1H),10.41(br s,1H),10.01(br s,1H),8.78(d,1H),8.45-8.40(m,2H),8.01(dd,1H),7.92(dd,1H),7.68-7.60(m, 2H),7.56-7.51(m,1H),7.50-7.44(m,1H),7.20-7.11(m,2H),6.68(d,1H),4.80(br s,1H),4.00(t,2H),3.66(t,2H),1.51-1.43(m,4H); MS(EI) is C ₂₉ H ₂₄ F ₂ N ₄ O ₆ The measured value was 563.1 (MH+).

The following compounds were prepared from compound 295 using the same 6-step method as used to synthesize compound 301 in Example 99:

1-N'-[2,5-difluoro-4-[7-(2-hydroxyethoxycarbamoyl)quinoline-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (302): In step 2, 1,2-difluoro-4-nitrobenzene is replaced with 1,2,4-trifluoro-5-nitrobenzene. ^¹H NMR (400MHz, DMSO- _d₆ ) δ 12.13 (br s, ¹H), 11.17 (br s, ¹H), 9.78 (br s, ¹H), 8.81 (d, ¹H), 8.46 (s, ¹H), 8.40 (m, ¹H), 8.19 (m, ¹H), 8.04 (d, ¹H), 7.73 (m, ¹H), 7.61 (dd, 2H), 7.19 (t, 2H), 6.83 (d, 1H), 4.81 (m, 1H), 4.00 (m, 2H), 3.68 (m, 2H), 1.69 (m, 2H), 1.61 (m, _2H ); MS (EI) was _{C₂ ₹ H₂₃F₃N₄O₆} , _measured value 581.1 (MH⁺).

Biological Examples

Example A: Kinase Assay

Kinase activity and compound inhibition were studied using a ^33P -phosphoryltransferrradiation assay performed using the KinaseProfiler ^™ service from Eurofins Pharma Discovery Services UK Limited. Dose-response experiments were conducted using nine compound concentrations in 96-well microtiter plates. For each assay, all compounds were prepared to a 50x final assay concentration (50 μM) in 100% DMSO and then serially diluted semi-logarithmically to a final maximum concentration of 1 μM. The working stock solution of the compound was added as the first component of the reaction to the assay wells, followed by the remaining components as detailed in the assay protocol below. The positive control wells (100% kinase activity) contained all components of the reaction, including 2% DMSO (a solvent effect control), but except for the compound of interest. The blank wells contained all components of the reaction, as well as the reference inhibitor astrocytin. This reference compound was used to eliminate kinase activity and produce a baseline of 0% kinase activity. The IC ₅₀ value was calculated using S-shaped dose-response (variable slope) curve fitting with XLFit version 5.3 (ID Business Solutions) via nonlinear regression analysis.

Example B: Human AXL kinase assay

Human Axl (H473-A894 with Q764R residues, 161 nM) was incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 250 μM KKSRGDYMTMQIG (SEQ ID NO.43) , 10 mM magnesium acetate, and 10 μM [γ- ^33P -ATP]. The reaction was initiated by adding the Mg/ATP mixture. After incubation at room temperature for 40 min, the reaction was terminated by adding phosphoric acid to a concentration of 0.5%. 10 μL aliquots of the reaction were then spotted onto a P30 filter pad, washed four times with 0.425% phosphoric acid for 4 min each time, followed by one wash in methanol, then dried and scintillation counted. The incorporated ^γ-33P was measured using a Wallac Microbeta scintillation counter (Perkin Elmer).

Example C: Human KDR kinase assay

Human KDR (residue K790-V1356, 55 nM) was incubated with 8 mM MOPS at pH 7.0, 0.2 mM EDTA, 0.33 mg/mL myelin basic protein, 10 mM magnesium acetate, and 10 μM [γ- ^33P -ATP]. The reaction was initiated by adding a Mg/ATP mixture. After incubation at room temperature for 40 minutes, the reaction was terminated by adding phosphate to a concentration of 0.5%. 10 μL aliquots of the reaction were then spotted onto a P30 filter pad and washed four times with 0.425% phosphate for 4 minutes each time, followed by one wash with methanol, then dried and scintillation counted. The incorporated ^γ-33P was measured using a Wallac Microbeta scintillation counter (Perkin Elmer).

Example D: Human Merkinase Assay

Human Mer (0.7 nM with R557-E882 residues of H628Q and R794A) was incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 30 mM NaCl, 250 μM GGMEDIYFEFMGGKKK (SEQ ID NO.44) , 10 mM magnesium acetate, and 10 μM [γ- ^33P -ATP]. The reaction was initiated by adding the Mg/ATP mixture. After incubation at room temperature for 40 min, the reaction was terminated by adding phosphoric acid to a concentration of 0.5%. 10 μL aliquots of the reaction were then spotted onto a P30 filter pad, washed four times with 0.425% phosphoric acid for 4 min each time, followed by one wash in methanol, then dried and scintillation counted. The incorporated ^γ-33P was measured using a Wallac Microbeta scintillation counter (Perkin Elmer).

Example E: Human Met Kinase Assay

Human Met (with R974-S1390 residues of A1209G and V1290L, 3.4 nM) was incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 250 μM KKKGQEEEYVFIE (SEQ ID NO.45) , 1 mM sodium orthovanadate, 5 mM sodium 6-glycerophosphate, 10 mM magnesium acetate, and 10 μM [γ- ^33P -ATP]. The reaction was initiated by adding the Mg/ATP mixture. After incubation at room temperature for 40 min, the reaction was terminated by adding phosphoric acid to a concentration of 0.5%. 10 μL aliquots of the reaction were then spotted onto a P30 filter pad, washed four times with 0.425% phosphoric acid for 4 min each time, followed by one wash in methanol, then dried and scintillation counted. The incorporated ^33P was measured using a Wallac Microbeta scintillation counter (Perkin Elmer).

Activity data of the compounds in the examples obtained by kinase assays in Examples A, B, D and E are provided in Table 2 (A: IC ₅₀ ≤ 10 nM; B: 10 nM < IC 50 ≤ 100 nM; C: 100 nM < IC ₅₀ ≤ 1000 nM; D: IC ₅₀ > 1000 nM).

Table 2: Activity data of the compounds selected in this invention

Example F: AXL autophosphorylation ELISA in A-172 cells

A-172 glioblastoma cells (ATCC#CRL-1620) were seeded at 2.5 x ^10⁵ cells/well in 24-well plates (Greiner#662165) in DMEM (Thermo Fisher#11995-040) containing 10% FBS (Thermo Fisher#26140-079), 1% MEM NEAA (Thermo Fisher#11140-050), 1% GlutaMax (Thermo Fisher#35050-061), and 1% penicillin-streptomycin (Thermo Fisher#15140-122). A-172 cells were incubated at 37°C and 5% _CO₂ for 24 hours, followed by starvation in serum-free medium for 24 hours. The test compound was serially diluted in fresh serum-free medium to a final concentration of 0.3% DMSO (the medium) to generate an 8-point dose curve, added to the cells, and incubated for 1 hour. Cells were then stimulated with 1 μg/mL recombinant human Gas6 (R&D Systems #885-GSB-500) for 15 min, washed with cold PBS, and immediately lysed with 150 μL of cold 1X lysis buffer [20 mM Tris, 137 mM sodium chloride, 2 mM EDTA, 10% glycerol, 1% NP-40 substitute, 1 mM activated sodium orthovanadate, 1 mM PefaBloc SC (Sigma-Aldrich #11429868001), protease/phosphatase inhibitor tablets (Thermo Fisher #A32959)]. Lysates were collected and added at 100 μL/well to a human phosphate-AXL DuoSet IC ELISA (R&D Systems #DYC2228-2). Assays were performed according to the manufacturer's instructions, and the phosphate-AXL concentration in the samples was extrapolated using a human phosphate-AXL control (R&D Systems #841645) as a standard. Positive control wells (100% activity) contained DMSO-treated cell lysates stimulated by Gas6. Negative control wells (0% activity) contained cell lysates treated with a reference inhibitor of Gas6. _IC50 values were calculated using a 4-parameter logistic curve fitted in ActivityBase XE (IDBS) via nonlinear regression analysis.

Example G: Met autophosphorylation ELISA in PC-3 cells

PC-3 prostate cancer cells (ATCC#CRL-1435) were seeded at 4 x ^10⁴ cells/well in 24-well plates (Greiner#662165) in DMEM (Thermo Fisher#11995-040) containing 10% FBS (Thermo Fisher#26140-079), 1% MEM NEAA (Thermo Fisher#11140-050), 1% GlutaMax (Thermo Fisher#35050-061), and 1% penicillin-streptomycin (Thermo Fisher#15140-122). PC-3 cells were incubated at 37°C and 5% _CO₂ for 24 hours, followed by starvation in serum-free medium for 3 hours. The test compound was serially diluted in fresh serum-free medium to a final concentration of 0.3% DMSO (the medium) to generate an 8-point dose curve, added to the cells, and incubated for 1 hour. Cells were then stimulated with 100 ng/mL recombinant human HGF (R&D Systems #294-HG-250) for 10 min, washed with cold PBS, and immediately lysed with 130 μL of cold 1X lysis buffer [20 mM Tris, 137 mM sodium chloride, 2 mM EDTA, 10% glycerol, 1% NP-40 substitute, 1 mM activated sodium orthovanadate, 1 mM PefaBloc SC (Sigma-Aldrich #11429868001), protease/phosphatase inhibitor tablet (Thermo Fisher #A32959)]. The lysate was clarified by centrifugation and added at 100 μL/well to a PathScan phosphate-Met (panTyr) sandwich ELISA (Cell Signaling Technology #7333). Assays were performed according to the manufacturer's instructions. Positive control wells (100% activity) contained HGF-stimulated DMSO-treated cell lysates. Negative control wells (0% activity) contained cell lysates treated with a reference inhibitor of HGF stimulation. _IC50 values were calculated using a 4-parameter logistic curve fitted in ActivityBase XE (IDBS) via nonlinear regression analysis.

Example H: KDR autophosphorylation ELISA in HUVEC cells

Human umbilical vein endothelial cells or HUVECs (Lonza#C2519A) were seeded at 2 x ^10⁴ cells/well in 96-well plates (Corning#3904) on EGM-2 growth medium (Lonza#CC-3162) containing 1% penicillin-streptomycin (Thermo Fisher#15140-122). HUVEC cells were incubated at 37°C and 5% _CO₂ for 24 hours, followed by starvation for 24 hours in serum-free EGM-2 basal medium (Lonza#CC-3156) containing 1% penicillin-streptomycin. The test compound was serially diluted in fresh serum-free medium to a final concentration of 0.3% DMSO (mediator) to generate an 8-point dose curve, added to the cells, and incubated for 1 hour. Cells were then stimulated with 100 ng/mL recombinant human VEGF165 (R&D Systems #293-VE-500) for 5 min, washed with cold PBS, and immediately lysed with 130 μL of cold 1X lysis buffer [20 mM Tris, 137 mM sodium chloride, 2 mM EDTA, 10% glycerol, 1% NP-40 substitute, 1 mM activated sodium orthovanadate, 1 mM PefaBloc SC (Sigma-Aldrich #11429868001), protease/phosphatase inhibitor tablet (Thermo Fisher #A32959)]. Lysates were collected and added at 100 μL/well to a human phosphate-KDR DuoSet IC ELISA (R&D Systems #DYC1766-2). Assays were performed according to the manufacturer's instructions, using a human phosphate-KDR control (R&D Systems #841421) as a standard to extrapolate the sample phosphate-KDR concentration. Positive control wells (100% viability) contained VEGF165-stimulated DMSO-treated cell lysates. Negative control wells (0% viability) contained unstimulated cell lysates. _IC50 values were calculated using a 4-parameter logistic curve fitted in ActivityBaseXE (IDBS) via nonlinear regression analysis.

Example 1: Mer autophosphorylation ELISA in transiently transfected 293A cells

293A cells (Thermo Fisher #R70507) were seeded at 1.5 x ^10⁶ cells/well in DMEM (Thermo Fisher #11995-040) containing 10% FBS (Thermo Fisher #26140-079), 1% MEM NEAA (Thermo Fisher #11140-050), 1% GlutaMax (Thermo Fisher #35050-061), and 1% penicillin-streptomycin (Thermo Fisher #15140-122) on 100 mm dishes (Greiner #664169). The 293A cells were incubated at 37°C and 5% _CO₂ for 24 hours, and then transfected with 6 μg of MERTKDNA (Genecopoeia #EX-Z8208-M02) using TransIT LT1 transfection reagent (Mirus-Bio #MIR2305). After 24 hours of incubation, transfected 293A cells were seeded at 1 x ^10⁵ cells/well in DMEM growth medium on 96-well plates (Corning #3904) and incubated overnight. The test compound was serially diluted in fresh serum-free medium to a final concentration of 0.3% DMSO (mediator) to generate an 8-point dose curve, and added to the cells and incubated for 1 hour. The cells were then immediately lysed with 150 μL of cold 1X lysis buffer [20 mM Tris, 137 mM sodium chloride, 2 mM EDTA, 10% glycerol, 1% NP-40 substitute, 1 mM activated sodium orthovanadate, 1 mM PefaBloc SC (Sigma-Aldrich #11429868001), protease/phosphatase inhibitor tablets (Thermo Fisher #A32959)]. The lysate was clarified by centrifugation and added at 50 μL/well to a human phosphate-Mer DuoSet IC ELISA (R&D Systems#DYC2579-2). Assays were performed according to the manufacturer's instructions, and the human phosphate-Mer control (R&D Systems#841793) was used as a standard to extrapolate the phosphate-Mer concentration in the samples. Positive control wells (100% activity) contained DMSO-treated cell lysates. Negative control wells (0% activity) contained cell lysates treated with a reference inhibitor. _IC50 values were calculated using a 4-parameter logistic curve fitted in ActivityBase XE (IDBS) via nonlinear regression analysis.

As illustrated herein, the compounds of this disclosure exhibit IC ₅₀ values in the following ranges: A: IC ₅₀ ≤ 10 nM; B: 10 nM < IC ₅₀ ≤ 100 nM; C: 100 nM < IC 50 ≤ 300 nM; D: IC ₅₀ > 300 nM. "NT" indicates not tested _.

Activity data of the compounds in the examples, obtained using cell-based kinase assays from Examples F, G, H, and I, are provided in Table 3.

Table 3: Cell activity data of the selected compounds of this invention

Example J: Pharmacokinetic Study

The pharmacokinetic properties of the selected compounds were evaluated in male Sprague-Dawley rats.

Non-GLP studies were designed to investigate the pharmacokinetics of the selected compounds in plasma after intravenous or oral administration to male Sprague-Dawley rats.

Two groups of male Sprague-Dawley rats (n=3 per group) received a target dose level of 3 mg/kg of the compound via intravenous or oral (force-feed) administration. Any clinically relevant abnormalities were observed in the animals during administration and at each sample collection period.

Animals in the PO group were fasted overnight before dose administration. They were reintroduced to food 4 hours after blood sampling. Water was not inhibited.

Record the weight of each animal immediately before administration. Calculate the dose based on pretreated body weight (kg) (rounded to the nearest 0.001 mL), with an intravenous dose volume of 2.5 mL/kg and an oral dose volume of 5 mL/kg. Intravenous formulations are administered via a jugular vein cannula. Immediately after administration, flush the cannula with saline and tie the line. Oral doses are administered via a bulb-tip feeding needle. The volume of the administration syringe used is validated by a second person before administration, and this volume is used in conjunction with the results of concentration validation analysis to calculate the actual dose. Weigh the administration syringe immediately before and after administration to each animal for gravimetric analysis.

Serial blood samples (approximately 200 μL/sample) were collected from each animal at 0.083 hours (IV administration only), 0.25, 0.5, 1, 2, 4, 6 hours (PO administration only), 8, 24, 32, 48, and 72 hours after administration. Blood samples were collected into tubes containing _K₂EDTA via a non-drug-treated jugular vein cannula (JVC), which was flushed with approximately an equal volume of saline after each collection.

Blood samples were stored on wet ice until they were processed into plasma by centrifugation (3500 rpm, 5°C for 10 minutes) within 1 hour of collection. Plasma samples were then transferred to matrix tubes and stored at -80°C.

Compounds of interest in plasma and dosage form samples were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Pharmacokinetic parameters were estimated from individual animal plasma concentration-time data using actual doses, based on the dosage form, nominal sampling time (all collections were within acceptable limits for the target), and non-compartmental methods. Concentration-time data were analyzed using WinNonlin Phoenix version 6.3 (Pharsight) software to fit intravenous bolus (IV) plasma analysis models (201) or extravascular (PO) plasma analysis models (200). The single-dose pharmacokinetic parameters assessed appropriately included: _Cmax (observed peak or maximum concentration); _Tmax (time to observed peak concentration); T1 _/2 (terminal half-life); _Vz (volume of distribution based on terminal phase); _Vss (volume of distribution at steady state); AUC _INF (area under the concentration-time curve calculated from time zero to infinity); AUC _last (area under the concentration-time curve calculated from time zero to the last quantifiable concentration); _C0 (back-extended concentration at time zero); CL (systemic clearance); Vz/F (volume of distribution based on extravascular administration at terminal phase); CL/F (systemic clearance after extravascular administration); F% (bioavailability); and MRT _last (mean residence time).

The area under the plasma concentration-time curve (AUC) was estimated using the linear logarithmic trapezoidal rule. The area under the last observable concentration (C _{_last} ) over time (T _{_last} ) was reported as AUC _{_last}. The AUC extrapolated to infinity (AUC _INF _f) was estimated by adding the ratios of AUC _{_last} and C _{_last} /λ_{_z}, where λ_{_z} is the terminal rate constant. The apparent terminal half-life (T _{_1/2}) was calculated as ln(2)/λ_{_z} and determined using the slope of the log-linear terminal phase of the concentration-time curve, which was defined by at least three plasma concentration-time points. The half-life was reported if the correlation of the regression line measured by r-squared after rounding was ≥0.9. After IV administration, the volume of distribution (V_z) was calculated as dose/λ_{_z *} AUC _{INF_obs} , the clearance (CL) was calculated as dose/AUC _{INF_obs}, and the steady-state volume of distribution (V _{_ss} ) was estimated as MRT _INF * CL. The mean residence time (MRT) from the time of administration to the time to the final measurable concentration is calculated as _{AUMC_final} / _{AUC_final} . For Model 200, bioavailability (i.e., the fraction of the total dose reaching the systemic circulation) cannot be calculated. Therefore, the volume and clearance for this model are Vz/F or CL/F, respectively; where F is defined as bioavailability (i.e., the fraction of the total dose reaching the systemic circulation; (mean _{AUC_final - po} / mean _{AUC_final - invoice} ) * [dose _{invoice invoice} / dose invoice _{invoice invoice} ] * 100).

Pharmacokinetic data of some compounds of the present invention generated by the above procedure are provided in Table 4 below.

Table 4: Rat pharmacokinetic data of the compounds selected in this invention

Other implementation plans

For purposes of clarity and understanding, the foregoing disclosure has been described in considerable detail by way of illustration and example. The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications are possible within the spirit and scope of the invention. It will be apparent to those skilled in the art that changes and modifications can be made within the scope of the appended claims. Therefore, it should be understood that the above description is intended to be illustrative rather than restrictive.

Therefore, the scope of the invention should not be determined by reference to the above description, but rather by reference to the full scope of the appended claims and their authorized equivalents.

The present invention also relates to embodiments of the following:

Item 1. A compound of formula A:

Or its pharmaceutically acceptable salt, wherein:

(i) _R1 is selected from the group consisting of: ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, ( _C6 - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-10 heteroaryl, 4-10 heterocycloalkyl, -CN, -NHOH, -C(O) ^Ra , -C( ^O ) ^NRaRa , -C(O) ^NHORa , ^-C (O) ^ORa , -C(O) ^NRaS (O) _2Ra , -OC(O) ^NRaRa , C(＝ ^NRa ) ^Ra , -C(＝NOH) ^Ra , ^-C (＝NOH) ^NRa , -C(＝NCN) ^NRaRa , -C(＝ ^NRa ) ^{NRaRa , -S} (O) ^NRaRa , -S ⁽ _O ) ^2NRaC (O) ^Ra , -P(O)R ^a R ^a , -P(O)(OR ^a )(OR ^a ), -B(OH) ₂ , -B(OR ^a ) ₂ and S(O) ₂ NR ^a R ^a ; and

_R2 is selected from -H, halogenated, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, (C1- _C6 )haloalkyl, (C1 _- C6)haloalkoxy, ( _{C6 - C10} )aryl-( _C1 - _C4 )alkylene-, (C3 _{-C10 )} cycloalkyl-( _C1 - _C4 )alkylene-, (5-14-membered heteroaryl)-( _{C1 - C4} )alkylene-, (4-14-membered heterocycloalkyl)-(C1 _{- C4} )alkylene-, -CN, _-NO2 , ^-ORa , ^-SRa , ^-NHORa , -C(O) ^{Ra ,} -C(O) ^NRaRa , -C(O) ^NHORa , -C(O) ^ORa , -C(O)NR ^a S(O) ₂ R ^a , -OC(O)R ^a , -OC(O)NR ^a R ^a , -NHR ^a , -NR ^a R ^a , -NR ^a C(O)R ^a , -NR ^a C(=NR ^a )R ^a , -NR ^a C(O)OR ^a , -NR ^a C(O)NR ^a R ^a , -C(=NR ^a )R ^a , -C(=NOH)R ^a , -C(=NOH)NR ^a , -C(=NCN)NR ^a R ^a , -NR ^a C(=NCN)NR ^a R ^a , -C(=NR ^a )NR ^a R ^a , -NR ^a C(=NR ^a )NR ^a R ^a , -NR ^a S(O)R ^a , -NR ^a S(O) ₂ R ^a , -NR ^a S(O) ₂ NR ^a R ^a ,-S(O)R ^a -S(O)NR ^aRa , ^-S (O) _2Ra , -S(O) _2NR ^aC (O) ^Ra , -P(O) ^RaRa , -P(O)(OR ^a )( ^{OR a )} , -B ⁽ OH) ₂ , -B(OR ^a ) ₂ and -S(O ^{)2NR aRa} _, ^wherein _R1 or _R2 is a (C1 _{- C6} )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, ( _C6 - _C10 )aryl-( _C1 - _C4 )alkylene-, ( _C3 - _C10 )cycloalkyl-( _C1 - _C4 )alkylene-, (5-14-membered heteroaryl)-(C1 _{- C4} )alkylene- and (4-14-membered heterocycloalkyl)-(C1 _- C ₄ ) Alkylenes – each optionally substituted by 1, 2, 3, 4, or 5 independently selected ^Rb substituents, provided that when _R1 is a 5-7-membered heteroaryl or 5-7-membered heterocyclic alkyl and _R2 is a _C1-6 alkoxy, the 5-7-membered heteroaryl or 5-7-membered heterocyclic alkyl is not connected to the fused benzene ring of the quinoline moiety via a cyclic nitrogen atom; or

(ii) _R1 is selected from -H, halogroup, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, (C2- _C6 )ynyl, ( _C1 - _C6 )haloalkyl, (C1 _{- C6} )haloalkoxy, ( _{C6 - C10} )aryl, ( _C3 - _C10 )cycloalkyl, 5-14-membered heteroaryl, 4-14-membered heterocycloalkyl, ( _C6 - _C10 )aryl-( _{C1- C4} )alkylene-, ( _C3 - _C10 )cycloalkyl-( _{C1- C4} )alkylene-, (5-14-membered heteroaryl)-( _{C1- C4} )alkylene-, (4-14-membered heterocycloalkyl)-( _{C1- C4} )alkylene-, -CN, _-NO2 , ^-ORa , -SR ^a , -NHOR ^a , -C(O)R ^a , -C(O)NR ^a R ^a , -C(O)NHOR ^a , -C(O)OR ^a , -C(O)NR ^a S(O) ₂ R ^a , -OC(O)R ^a , -OC(O)NR ^a R ^a , -NHR ^a , -NR ^a R ^a , -NR ^a C(O)R ^a , -NR ^a C(=NR ^a )R ^a , -NR ^a C(O)OR ^a , -NR ^a C(O)NR ^a R ^a , -C(=NR ^a )R ^a , -C(=NOH)R ^a , -C(=NOH)NR ^a , -C(=NCN)NR ^a R ^a , -NR ^a C(=NCN)NR ^a R ^a , -C(=NR ^a )NR ^a R ^a , -NR ^a C(=NR ^a )NR ^a R ^a , -NR ^a S(O) ^Ra , ^-NRaS (O) _2Ra , -NRaS ₍ O) ^2NRaRa , ^-S (O ₎ ^Ra , -S(O) ^NRaRa , -S(O) ^2Ra , ^-S (O) _2NRaC (O)Ra, ^-P (O) ^RaRa , -P ⁽ O) ^{( ORa} )( ^ORa ), ^-B (OH) ² , -B( ^ORa ) _{2 and} -S(O) _2NRaRa , wherein _R1 or ^R2 is a ( _C1 - _C6 )alkyl, ( _C2 - _C6 ) ^alkenyl , ( _C2 - _C6 )ynyl, (C6 _{-C10 )} aryl, ( _C3 - _C10 )cycloalkyl, 5-14 heteroaryl, 4-14 heterocycloalkyl, ( _C6 - _{C10 ) ...} The aryl-(C1 _{- C4} )alkylene-, (C3- _C10 )cycloalkyl-( _C1 -C4)alkylene-, (5-14-membered heteroaryl)-( _{C1- C4} )alkylene-, and (4-14-membered heterocycloalkyl)-( _{C1 - C4} )alkylene- are each optionally substituted by 1, 2, 3 _, 4, or 5 independently selected ^Rb substituents; and

R ₂ is selected from the group consisting of: (C ₂ -C ₆ )alkenyl, (C ₂ -C ₆ )alkynyl, -CN, -NHOH, -C(O)R ^a , -C(O)NR ^a R ^a , -C(O)NHOR ^a , -C(O)OR ^a , -C(O)NR ^a S(O) ₂ R ^a , -OC(O)NR ^a R ^a , C(=NR ^a )R ^a , -C(=NOH)R ^a , -C(=NOH)NR ^a , -C(=NCN)NR ^a R ^a , -NR ^a C(=NCN)NR ^a R ^a , -C(=NR ^a )NR ^a R ^a , -S(O)NR ^a R ^a , -S(O) ₂ NR ^a C(O)R ^a , -P(O)R ^a R ^a , -P(O)(OR ^a )(OR ^a ), -B(OH) ₂ -B(OR ^a ) ₂ and S(O) ₂ NR ^{a Ra} , provided that when R ₁ is a 5-7 membered heteroaryl or a 5-7 membered heterocyclic alkyl and R ₂ is a C _1-6 alkoxy, then the 5-7 membered heteroaryl or 5-7 membered heterocyclic alkyl of R ₁ is not connected to the fused benzene ring of the quinoline moiety through a cyclic nitrogen atom.

(iii) _R1 and _R2 together with the atoms to which they are attached form a fused (C3 _{- C7} ) cycloalkyl ring or a fused 4- to 10-membered heterocyclic alkyl ring, wherein the fused (C3 _{- C7} ) cycloalkyl ring and the fused 4- to 10-membered heterocyclic alkyl ring are each optionally substituted by one, two or three independently selected ^Rb substituents, provided that the compound is not 1-[2-(4-fluorophenyl)-acetyl]-cyclopropanecarboxylic acid [3-fluoro-4-(7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxa-1-aza-cyclododecane[b]naphthalene-4-yloxy)-phenyl]-amide;

_R10 and _R11 are each independently selected from the group consisting of: -H, halogroup, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )haloalkyl, (C1 _{- C6} )haloalkoxy, ( _C6 - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-14-membered heteroaryl, 4-14-membered heterocycloalkyl, ( _C6 - _C10 )aryl-( _{C1- C4} )alkylene-, ( _C3 - _C10 )cycloalkyl-( _C1 - _C4 )alkylene-, (5-14-membered heteroaryl)-( _{C1- C4} )alkylene-, (4-14-membered heterocycloalkyl)-(C1 _{- C4} )alkylene-, -CN, _-NO2 , ^-ORa , ^-SRa , ^-NHORa , -C(O)R ^a , -C(O)NR ^a R ^a , -C(O)OR ^a , -C(O)NR ^a S(O) ₂ R ^a , -OC(O)R ^a , -OC(O)NR ^a R ^a , -NHR ^a , -NR ^a R ^a , -NR ^a C(O)R ^a , -NR ^a C(=NR ^a )R ^a , -NR ^a C(O)OR ^a , -NR ^a C(O)NR ^a R ^a , -C(=NR ^a )R ^a , -C(=NOH)R ^a , -C(=NOH)NR ^a , -C(=NCN)NR ^a R ^a , -NR ^a C(=NCN)NR ^a R ^a , -C(=NR ^a )NR ^a R ^a , -NR ^a C(=NR ^a )NR ^a R ^a , -NR ^a S(O)R ^a , -NR ^a S(O) ₂ R ^a -NR ^a S(O) ₂ NR ^{a Ra} , -S(O) ^Ra , -S(O)NR ^{a Ra} , -S(O) ₂ ^Ra , -S(O) ₂ NR ^a C(O) ^Ra , -P(O) ^{Ra Ra} , -P(O)(OR ^a )(OR ^a ), -B(OH) ₂ , -B(OR ^a ) ₂ and S(O) ₂ NR ^{a Ra} , wherein R ₁ or R ₂ is a (C ₁ -C ₆ ) alkyl, (C ₆ -C ₁₀ ) aryl, (C ₃ -C ₁₀ ) cycloalkyl, 5-14-membered heteroaryl, 4-14-membered heterocycloalkyl, (C _{6 -} C ₁₀ ) aryl-(C ₁ -C ₄ ) alkylene-, (C _3- C _{10 )} cycloalkyl ... The alkylene-, (5-14-membered heteroaryl)-(C1 _{- C4} )alkylene- and (4-14-membered heterocyclic alkyl)-(C1 _{- C4} )alkylene- are each optionally substituted by 1, 2, 3, 4 or 5 independently selected ^Rb substituents;

Each _R3 is independently selected from the group consisting of: -H, halogroup, -OH, -CN, optionally substituted ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy, ( _C1 - _C6 )haloalkoxy, _-NH2 , -NH( _C1 - _C6 )alkyl, -N( _C1 - _C6 )alkyl) ₂ and ( _C3 - _C6 )cycloalkyl, wherein the ( _C1 - _C6 )alkoxy, -NH( _C1 - _C6 )alkyl, -N( _C1 - _C6 )alkyl) ₂ and ( _C3 - _C6 )cycloalkyl of _R3 are each optionally substituted by 1, 2 or 3 independently selected ^Rg substituents;

Each R ₁₄ is independently selected from halogen, -OH, -NH ₂ , -CN, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )haloalkyl, (C ₁ -C ₆ )haloalkoxy, -COOH, -NH(C ₁ -C ₆ )alkyl, -N(C ₁ -C _6alkyl ) ₂ , phenyl, phenyl-(C _1- C ₂ )alkylene, (C _3- C ₆ )cycloalkyl, (C _3- C ₆ )cycloalkyl-(C _1- C ₄ )alkylene-, 4 to 6-membered heterocycloalkyl, (4 to 6-membered heterocycloalkyl)-(C _1- C ₄ )alkylene-, 5 to 6-membered heteroaryl, (5 to 6-membered heteroaryl)-(C _1- C ₄ )alkylene- and -OR ^e , wherein R _The ( _C1 - _C6 )alkyl, phenyl, phenyl-(C1- _C2 )alkylene, ( _C3- C6)cycloalkyl, ( _{C3- C6} )cycloalkyl-(C1 _{- C4} )alkylene, 4- to ₆ -membered heterocycloalkyl, ( _4- to 6-membered heterocycloalkyl)-(C1 _{- C4} )alkylene, 5- to 6-membered heteroaryl and (5- to 6-membered heteroaryl)-(C1 _{- C4} )alkylene are each optionally substituted by one, two or three independently selected ^Rg substituents.

R ₁₅ is H or C _1-6 alkyl;

Each _R4 is independently selected from the group consisting of: -H, halogroup, -OH, -COOR ^e , -CONR ^{e Re} , -CN, -NH ₂ , -NH ((C1 _{- C6} )alkyl), -N (( _{C1- C6} )alkyl) ₂ , (C1 _{- C6} )alkyl, (C1 _{- C6} )alkoxy, ( _{C1- C6} )haloalkyl, (C1 _{- C6} )haloalkoxy, -CONR ^{a Ra} , -NR ^a COR ^a , -NR ^a CONR ^{a Ra} , -SO ₂ ^Ra , -NR ^a S(O) ₂ ^Ra , -NR ^a S(O) ₂ NR ^{a Ra} , (C3 _{- C6} )cycloalkyl, 4- to 6-membered heterocyclic alkyl, phenyl, 5- or 6-membered heteroaryl, (C3 _{- C6} )cycloalkyl-( _C1- C ₄ ) alkylene-, (4 to 6-membered heterocyclic alkyl)-(C1 _{- C4} )alkylene-, phenyl-( _{C1- C2} )alkylene- and (5 or 6-membered heteroaryl)-(C1 _{- C4} )alkylene-, wherein the (C1 _{- C6} )alkyl, ( _{C3- C6} )cycloalkyl, ₄ to 6-membered heterocyclic alkyl, phenyl, 5 or 6-membered heteroaryl, (C3 _{- C6} )cycloalkyl-( _{C1- C4} )alkylene-, (4 to 6-membered heterocyclic alkyl)-( _{C1- C4} )alkylene-, phenyl-(C1 _{- C2} )alkylene- and (5 or 6-membered heteroaryl)-( _{C1- C4} )alkylene- are each optionally substituted by 1, 2 or 3 independently selected ^Rf substituents;

Each Ra ^is independently selected from the group consisting of: -H, -CN, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )haloalkyl, ( _C2 - _C6 )alkenyl, (C2-C6)ynyl, ( _C6 - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-14-membered heteroaryl, 4-14-membered heterocycloalkyl, ( _C6 - _C10 )aryl-( _C1 - _C4 )alkylene-, (C3 _{- C10} )cycloalkyl-( _C1 - _C4 )alkylene-, (5-14-membered heteroaryl)-( _{C1- C4} )alkylene-, and (4-14-membered heterocycloalkyl)-(C1 _{- C4} )alkylene-, wherein the ( _{C1- C6} )alkyl, ( _C1 - _C6 )alkylene-, and ( _C2 - _C6) alkylene- of ^Ra are... ( _C2 - _C6 )alkenyl, (C2-C6)ynyl, ( _C6 - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-14-membered heteroaryl, 4-14-membered heterocycloalkyl, ( _C6 - _C10 )aryl-( _C1 - _C4 )alkylene-, ( _{C3- C10} )cycloalkyl-( _C1 - _C4 )alkylene-, (5-14-membered heteroaryl)-( _{C1 - C4} )alkylene- and (4-14-membered heterocycloalkyl)-( _{C1 - C4} )alkylene- are each optionally substituted by 1, 2, 3, 4 or 5 independently selected ^Rd substituents;

Each ^Rb is independently selected from halogen, oxo, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, (C1-C6)haloalkyl, ( _{C1 -C6 )} haloalkoxy, ( _C6 - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-10-membered heteroaryl, _4-10 -membered heterocycloalkyl, ( _C6 - _C10 )aryl-( _{C1- C4} )alkylene-, ( _{C3- C10} )cycloalkyl-(C1 _{- C4} )alkylene-, (5-10-membered heteroaryl)-(C1 _{- C4} )alkylene-, (4-10-membered heterocycloalkyl)-(C1 _{- C4} )alkylene-, -CN, -OH, _-NH2 , -NO _2. -NHOR ^c , -OR ^c , -SR ^c , -C(O)R ^c , -C(O)NR ^c R ^c , -C(O)OR ^c , -C(O)NR ^c S(O) ₂ R ^c , -OC(O)R ^c , -OC(O)NR ^c R ^c , -C(=NOH)R ^c , -C(=NOH)NR ^c , -C(=NCN)NR ^c R ^c , -NR ^c C(=NCN)NR ^c R ^c , -C(=NR ^c )NR ^c R ^c , -NR ^c C(=NR ^c )NR ^c R ^c , -NHR ^c , -NR ^c R ^c , -NR ^c C(O)R ^c , -NR ^c C(=NR ^c )R ^c , -NR ^c C(O)OR ^c , -NR ^c C(O)NR ^c R ^c , -NR ^c S(O)R ^c ,-NR ^c S(O) _2Rc ^{, -NRcS} (O) _2NRcRc , ^-S (O) ^Rc , -S(O) ^NRcRc , -S(O) ^2Rc , -S(O) ^2NRcC (O) ^Rc , -Si(Rc) ₃ , -P(O) ^RcRc , ^-P ( ^O ₎ ( ^ORc )(ORc), ^-B (OH) ₂ , ^-B ( ^ORc ) ₂ and -S(O) _2NRcRc , wherein ^Rb is a ⁽ C1-C6) ^alkyl , (C1- ^C6 ) _haloalkyl , ( _C1 - _C6 )haloalkoxy, (C2-C6)alkenyl, ( _C2 - _C6 )alkynyl, ( _C6 - _C10 )aryl, (C3-C10)alkyl, ( _C3 - _C10 )alkyl, ( _C4 - _C5 )alkyl, ( _C6 - _C10 )alkyl, ( _C3- C10)alkyl, (C4 _... ( _C6 - _C10 ) aryl-(C1-C4) alkylene-, (C3-C10) cycloalkyl-( _{C1- C4} ) alkylene-, ( _5-10 ) heteroaryl-( _{C1 - C4} ) alkylene-, and ( _4-10 ) heterocycloalkyl-(C1 _{- C4 )} alkylene- are each optionally further substituted by one, two, or three independently selected ^Rd substituents;

Each ^Rc is independently selected from the group consisting of: -H, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )haloalkyl, ( _C2 - _C6 )alkenyl, ( _C2 -C6)ynyl, ( _C6 - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-10 heteroaryl, 4-10 heterocycloalkyl, ( _C6 - _C10 )aryl-(C1- _C4 )alkylene-, (C3 _{- C10} )cycloalkyl-( _C1 - _C4 )alkylene-, (5-10 heteroaryl)-( _{C1- C4 ) alkylene-} , and (4-10 heterocycloalkyl)-(C1 _{- C4} )alkylene-, wherein ^the ( _C1 - _C6 )alkyl, ( _C2 - _C6)... Alkenyl, ( _C2 - _C6 ) ynyl, (C6- _C10 ) aryl, ( _C3 -C10) cycloalkyl, 5-10 heteroaryl, 4-10 heterocycloalkyl, ( _C6 - _C10 ) aryl-( _C1 - _C4 ) alkylene-, ( _C3 - _C10 ) cycloalkyl-( _C1 - _C4 ) alkylene-, (5-10 heteroaryl)-(C1 _{- C4} ) alkylene- and (4-10 heterocycloalkyl)-( _{C1- C4 )} alkylene- are each optionally substituted by 1, 2, 3 _, 4 or 5 independently selected ^Rf substituents;

Each R d is independently selected from (C <sub>1- C 6  )alkyl, (C <sub>1- C  6 )haloalkyl, haloyl, (C<sub>6-C10)aryl, 5-10 heteroaryl, (C <sub>3- C 10 )cycloalkyl, 4-10 heterocyclic alkyl, (C <sub>6- C 10 )aryl-(C <sub>1- C 4 )alkylene-, (C <sub>3- C 10 )cycloalkyl-(C <sub>1- C 4 )alkylene-, (5-10 heteroaryl)-(C <sub>1- C 4 )alkylene-, (4-10 heterocyclic alkyl)-(C <sub>1- C4 )alkylene-, -CN, -NH 2 , -NHOR e , -OR e , -SRe, -C(O)R  e , -C(O)NReRe , -C(O)OR e -OC(O)R e , -OC(O)NR eR e , -NHR e , -NR eR e , -NR e C(O)R e , -NR e C(O)NR eR e , -NR e C(O)OR e , -C(＝NR e )NR eR e , -NR e C(＝NR e )NR eR e , -NR e C(＝NOH)NR eR e, -NR e C(＝NCN)NR eR e , -S (O)R e , -S(O)NR eR e , -S(O) 2 Re, -NR e S (O) 2 Re , -NR e S(O) 2 NR e Re and -S (O) 2 NR e Re , wherein R d is a (C 1- C 6 ) alkyl , (C 1 - C 6 )haloalkyl, (C 6- C 10 )alkyl, (C 6- C 10 )alkyl, ... )aryl, 5-10 heteroaryl, ( C3- C10 )cycloalkyl, 4-10 heterocycloalkyl, (C6 - C10 )aryl-(C1-C4)alkylene-, (C3 - C10 )cycloalkyl-( C1- C4 )alkylene-, ( 5-10 heteroaryl)-(C1- C4 )alkylene- and (4-10 heterocycloalkyl)-( C1- C4 ) alkylene- are each optionally substituted by 1, 2 or 3 independently selected R f substituents;

Each ^Re is independently selected from the group consisting of: -H, (C1 _{- C6} )alkyl, ( _{C3- C6} )cycloalkyl-, (C3- _C6 )cycloalkyl-(C1 _- C4)alkylene-, (C6 _{- C10} )aryl, ( _{C6- C10} )aryl-(C1 _- C4)alkylene-, 5 or ₆ -membered heteroaryl, (5 or 6-membered heteroaryl)-(C1 _{- C4} )alkylene-, 4-7-membered heterocycloalkyl, ( _4-7 -membered heterocycloalkyl)-(C1-C4)alkylene-, ( _{C1- C6} )haloalkyl, (C1 _{- C6} )haloalkoxy, (C2-C4)alkenyl and (C2 _{- C4} )ynyl, wherein the (C1- _C4 )alkyl, (C1 _{- C6} )haloalkoxy, (C2 _- C4)alkenyl and (C2 _{- C4} )ynyl of ^Re are... _{3- C6} )cycloalkyl, ( _{C6- C10} )aryl, 5- or 6-membered heteroaryl, 4- or 7-membered heterocycloalkyl, ( _C6- or ₁₀ )aryl-(C1- or ₄ -membered heteroaryl)-( _{C1- or} 4-membered heterocycloalkyl)-(C1- or ₄ -membered heterocycloalkyl), ( _C2- or 4-membered heterocycloalkyl)-( _{C1- or 4-} membered heterocycloalkyl), (C2- _{or 4-} membered alkenyl) and ( _{C2- or 4-} membered ynyl are each optionally substituted by 1, 2 or 3 ^Rf substituents.

Or any two ^Ra substituents together with the nitrogen atom to which they are attached form a 4, 5, 6, 7, 8, 9 or 10-membered heterocyclic alkyl group, each heterocyclic alkyl group optionally being substituted by 1, 2 or 3 independently selected R ^f substituents;

Alternatively, any two ^Rc substituents together with the nitrogen atom to which they are attached can form a 4, 5, 6, 7, 8, 9, or 10-membered heterocyclic alkyl group, each heterocyclic alkyl group optionally being substituted by one, two, or three independently selected ^Rf substituents.

Or any two ^Re substituents together with the nitrogen atom to which they are attached form a 4, 5, 6, 7, 8, 9 or 10-membered heterocyclic alkyl group, each heterocyclic alkyl group optionally being substituted by 1, 2 or 3 independently selected R ^f substituents;

Each ^Rf is independently selected from halogen, -OH, -CN, -COOH, _-NH2 , -NH-(C1 _{- C6} )alkyl, -N((C1 _{- C6} )alkyl) ₂ , (C1 _{- C6} )alkyl, (C1- _C6 )alkoxy, ( _C1- C6)alkylthio, (C1 _{- C6} )haloalkyl, (C1 _{- C6} )haloalkoxy, phenyl, 5-6-membered heteroaryl, 4-6-membered heterocyclic alkyl, and ( _{C3 - C6} )cycloalkyl, wherein the (C1 _{- C6} )alkyl, phenyl, (C3 _{- C6} )cycloalkyl, 4-6-membered heterocyclic alkyl, and 5-6-membered heteroaryl of ^Rf are each optionally selected by 1, 2, or 3 from halogen, -OH, -CN, -COOH, _-NH2 , (C1 _- C6 ₎ alkyl, -NH- _{( ...} Substituents of alkyl, (C1 _{- C4} )alkoxy, (C1 _{- C4} )haloalkyl, ( _{C1- C4} )haloalkoxy, phenyl, (C3 _{- C10} )cycloalkyl, 5-6-membered heteroaryl and 4-6-membered heterocyclic alkyl groups;

Each R ^g is independently selected from halogenated, -OH, -CN, -COOH, -COO-( _{C1- C4} ) _alkyl , -NH2, -NH-(C1 _{- C6} )alkyl, -N((C1 _{- C6} )alkyl) ₂ , ( _{C1- C6} )alkyl, (C1 _{- C6} )alkoxy, (C1- _C6 )alkylthio, ( _{C1- C6 )} haloalkyl, (C1 _{- C6} )haloalkoxy, phenyl, 5-6-membered heteroaryl, 4-6-membered heterocyclic alkyl and (C3 _{- C6} )cycloalkyl;

Y is selected from -O-, -S-, -SO-, _-SO₂- , -NH-, and -N((C₁ _{- C₆} )alkyl)-;

The cyclic nitrogen atom on the quinoline moiety in Formula A may optionally be oxidized;

The subscript n is an integer of 1, 2, 3 or 4;

The subscript m is an integer of 1, 2, 3, 4, or 5; and

The subscript p is an integer of 0, 1, 2, 3 or 4.

Item 2. The compound as described in Item 1, having formula A-1:

Item 3. The compound as described in Item 1, having formula A-2:

Item 4. The compound as described in Item 1, having formula A-3:

^Ra1 is H or (C1 _{- C6} ) alkyl.

Item 5. The compound as described in Item 1, having formula A-4:

The ring A is a 5- to 14-membered heteroaryl group; and the subscript r is 1, 2, 3 or 4.

Item 6. The compound as described in Item 1, wherein:

_R1 is selected from the group consisting of: ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, ( _C6 - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, -CN, -NHOH, -C(O) ^Ra , -C(O)NRaRa, -C(O) ^NHORa , -C ⁽ O) ^ORa , -C(O ^{) NRaS} (O) _2Ra , -OC(O) ^NRaRa , C(＝ ^NRa ) ^Ra , ^-C (＝NOH) ^Ra , ^-C (＝NOH) ^NRa , -C(＝NCN) ^NRaRa , ^-NRaC (＝NCN) ^NRaRa , -C ⁽ ＝ ^NRa ) ^NRaRa , -S ⁽ O ^{) NRaRa} , ^-S (O) _2NR ^a C(O)R ^a , -P(O)R ^a R ^a , -P(O)(OR ^a )(OR ^a ), -B(OH) ₂ , -B(OR ^a ) ₂ and S(O) ₂ NR ^a R ^a ; and

_R2 is selected from -H, halogenated, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, (C1- _C6 )haloalkyl, (C1 _- C6)haloalkoxy, (C6 _{- C10} )aryl-( _C1 - _C4 )alkylene-, (C3 _{-C10 )} cycloalkyl-( _{C1 - C4} )alkylene-, (5-14-membered heteroaryl)-( _{C1 - C4} )alkylene-, (4-14-membered heterocycloalkyl)-(C1 _{- C4} )alkylene-, -CN, _-NO2 , ^-ORa , ^-SRa , ^-NHORa , -C(O) ^{Ra ,} -C(O) ^NRaRa , -C(O) ^NHORa , -C(O) ^ORa , -C(O)NR ^a S(O) ₂ R ^a , -OC(O)R ^a , -OC(O)NR ^a R ^a , -NHR ^a , -NR ^a R ^a , -NR ^a C(O)R ^a , -NR ^a C(=NR ^a )R ^a , -NR ^a C(O)OR ^a , -NR ^a C(O)NR ^a R ^a , -C(=NR ^a )R ^a , -C(=NOH)R ^a , -C(=NOH)NR ^a , -C(=NCN)NR ^a R ^a , -NR ^a C(=NCN)NR ^a R ^a , -C(=NR ^a )NR ^a R ^a , -NR ^a C(=NR ^a )NR ^a R ^a , -NR ^a S(O)R ^a , -NR ^a S(O) ₂ R ^a , -NR ^a S(O) ₂ NR ^a R ^a ,-S(O)R ^a -S(O)NR ^aRa , ^-S (O) _2Ra , -S(O) _2NR ^aC (O) ^Ra , -P(O) ^RaRa , -P(O)(OR ^a )( ^{OR a )} , -B ⁽ OH) ₂ , -B(OR ^a ) ₂ and -S(O ^{)2NR aRa} _, ^wherein _R1 or _R2 is a ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, ( _C6 - _C10 )aryl-( _C1 - _C4 )alkylene-, ( _C3 - _C10 )cycloalkyl-( _C1 - _C4 )alkylene-, (5-14-membered heteroaryl)-(C1 _{- C4} )alkylene- and (4-14-membered heterocycloalkyl)-(C1 _- C ₄ ) Alkylenes are each optionally substituted by 1, 2, 3, 4 or 5 independently selected ^Rb substituents, provided that when _R1 is a 5-7-membered heteroaryl or 5-7-membered heterocyclic alkyl and _R2 is a _C1-6 alkoxy, the 5-7-membered heteroaryl or 5-7-membered heterocyclic alkyl of _R1 is not connected to the fused benzene ring of the quinoline moiety through a cyclic nitrogen atom.

Item 7. The compound as described in Item 1, wherein:

_R1 is selected from -H, halogroup, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, (C1-C6)haloalkyl, (C1 _{- C6} )haloalkoxy, ( _{C6 - C10} )aryl, ( _C3 - _{C10 )} cycloalkyl, 5-14-membered heteroaryl, 4-14-membered heterocycloalkyl, ( _C6 - _C10 )aryl-( _{C1- C4} )alkylene-, ( _C3 - _C10 )cycloalkyl-(C1- _C4 )alkylene-, (5-14-membered heteroaryl)-( _{C1- C4 )} alkylene-, (4-14-membered heterocycloalkyl)-(C1 _{- C4} )alkylene-, -CN, _-NO2 , ^-ORa , -SR ^a , -NHOR ^a , -C(O)R ^a , -C(O)NR ^a R ^a , -C(O)NHOR ^a , -C(O)OR ^a , -C(O)NR ^a S(O) ₂ R ^a , -OC(O)R ^a , -OC(O)NR ^a R ^a , -NHR ^a , -NR ^a R ^a , -NR ^a C(O)R ^a , -NR ^a C(=NR ^a )R ^a , -NR ^a C(O)OR ^a , -NR ^a C(O)NR ^a R ^a , -C(=NR ^a )R ^a , -C(=NOH)R ^a , -C(=NOH)NR ^a , -C(=NCN)NR ^a R ^a , -NR ^a C(=NCN)NR ^a R ^a , -C(=NR ^a )NR ^a R ^a , -NR ^a C(=NR ^a )NR ^a R ^a ,-NR ^a S(O) ^Ra , ^-NRaS (O) _2Ra , -NRaS ₍ O) ^2NRaRa , ^-S (O ₎ ^Ra , -S(O) ^NRaRa , -S(O) ^2Ra , ^-S (O) _2NRaC (O)Ra, ^-P (O) ^RaRa , -P ⁽ O) ^{( ORa} )( ^ORa ), ^-B (OH) ² , -B( ^ORa ) _{2 and} -S(O) _2NRaRa , wherein _R1 or ^R2 is a ( _C1 - _C6 )alkyl, ( _C2 - _C6 ) ^alkenyl , ( _C2 - _C6 )ynyl, (C6 _{-C10 )} aryl, ( _C3 - _C10 )cycloalkyl, 5-14 heteroaryl, 4-14 heterocycloalkyl, ( _C6 - _{C10 ) ...} The aryl-(C1 _{- C4} )alkylene-, (C3- _C10 )cycloalkyl-( _C1 -C4)alkylene-, (5-14-membered heteroaryl)-( _{C1- C4} )alkylene-, and (4-14-membered heterocycloalkyl)-( _{C1 - C4} )alkylene- are each optionally substituted by 1, 2, 3 _, 4, or 5 independently selected ^Rb substituents; and

R ₂ is selected from the group consisting of: (C ₂ -C ₆ )alkenyl, (C ₂ -C ₆ )alkynyl, -CN, -NHOH, -C(O)R ^a , -C(O)NR ^a R ^a , -C(O)NHOR ^a , -C(O)OR ^a , -C(O)NR ^a S(O) ₂ R ^a , -OC(O)NR ^a R ^a , C(=NR ^a )R ^a , -C(=NOH)R ^a , -C(=NOH)NR ^a , -C(=NCN)NR ^a R ^a , -NR ^a C(=NCN)NR ^a R ^a , -C(=NR ^a )NR ^a R ^a , -S(O)NR ^a R ^a , -S(O) ₂ NR ^a C(O)R ^a , -P(O)R ^a R ^a , -P(O)(OR ^a )(OR ^a ), -B(OH) ₂ -B(OR ^a ) ₂ and S(O) ₂ NR ^{a Ra} , provided that when R ₁ is a 5-7 membered heteroaryl or a 5-7 membered heterocyclic alkyl and R ₂ is a C _1-6 alkoxy, the 5-7 membered heteroaryl or 5-7 membered heterocyclic alkyl of R ₁ is not connected to the fused benzene ring of the quinoline moiety through a cyclic nitrogen atom.

Item 8. The compound as described in Item 1, wherein:

_R1 and _R2, together with the atoms to which they are attached, form a fused (C3 _{- C7} ) cycloalkyl ring or a fused 4- to 10-membered heterocyclic alkyl ring, wherein the fused (C3 _{- C7} ) cycloalkyl ring and the fused 4- to 10-membered heterocyclic alkyl ring are each optionally substituted by one, two, or three independently selected ^Rb substituents, provided that the compound is not 1-[2-(4-fluorophenyl)-acetyl]-cyclopropanecarboxylic acid [3-fluoro-4-(7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxa-1-aza-cyclododecane[b]naphthalene-4-yloxy)-phenyl]-amide.

Item 9. The compound as described in Items 1, 6, 7 or 8, wherein:

R ₁₅ is H or CH ₃ .

Item 10. A compound as described in Item 1 or 9, wherein _R1 and _R2, together with the atoms to which they are attached, form a fused (C3 _{- C7} ) cycloalkyl ring or a fused 4- to 10-membered heterocyclic alkyl ring, wherein each of the fused (C3 _{- C7} ) cycloalkyl ring or the fused 4- to 10-membered heterocyclic alkyl ring is optionally substituted by one, two, or three independently selected ^Rb substituents, provided that the compound is not a compound having the following formula:

Wherein ring E is a fused 4- to 10-membered heterocyclic alkyl group.

Item 11. The compound as described in any one of items 2, 4, 7 and 9, wherein _R1 is -H.

Item 12. The compound as described in any one of items 1, 3, 5 and 6, wherein _R2 is -H.

Item 13. The compound of any one of items 1, 2, 4, 5 and 7-9, wherein _R1 is selected from the group consisting of: -H, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, -C(=NO-(C1 _{- C6} )alkyl) ^Ra , -CN, -C(O) ^{ORa ,} -C(O) ^NRaRa , -C(O) ^NHORa , -S(O ⁾ _2NRaRa , ^phenyl , 5- to 6-membered heteroaryl, (C3 _{- C6} )cycloalkyl and 4- to 6-membered heterocyclic alkyl.

Item 14. The compound as described in Item 13, wherein _R1 is -H, ^-RaNHC (O)-, ^RaOC (O)-, (C1 _{- C6} )alkyl, (C1 _{- C6} )alkoxy, or C(=NO- _CH3 ) ^Ra ; and

R ₂ is selected from 2-methoxyethylamino, methylamino, 3-morpholinopropoxy, 2-methoxyethoxy, 2-hydroxyethoxy, propoxy, 2-hydroxypropoxy, methoxycarbonyl, carboxyl, carbamoyl, methylcarbamoyl, (2-hydroxyethoxy)carbamoyl, (2,2-dihydroxyethoxy)carbamoyl, (oxetane-3-yloxy)carbamoyl, methoxycarbamoyl, 2-trimethylsilylethynyl, ethynyl, aminosulfonyl, acetyl, and -C(＝NOCH ₃ )CH ₃ .

Item 15. The compound of any one of items 1, 3, 5 and 6, wherein _R2 is selected from the group consisting of: -H, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, -C(=NO-(C1 _{- C6} )alkyl) ^Ra , -CN, -C(O) ^ORa , ^-C (O) ^NRaRa , -C(O) ^NHORa and -S( ^O ) _2NRaRa ^.

Item 16. The compound as described in Item 15, wherein _R1 is selected from 2-methoxyethylamino, aziridine-1-yl, methylamino, 3-morpholinopropoxy, 2-methoxyethoxy, 2-hydroxyethoxy, propoxy, 2-hydroxypropoxy, methoxycarbonyl, carboxyl, carbamoyl, methylcarbamoyl, 2-oxazolyl, pyrazol-3-yl, pyrazol-4-yl, 4-isooxazolyl, 3,5-dimethylisooxazol-4-yl, 1-methyl-pyrazol-4-yl, 2-methyl-pyrazol-3-yl, 2-ethyl-pyrazol-3-yl, 2-(2-hydroxyethyl)-pyrazol-3-yl, 2-(2,2,2-trifluoroethyl)-pyrazol-3-yl, 2-(2-fluoroethyl) -pyrazol-3-yl, 2-(2,2-difluoroethyl)-pyrazol-3-yl, 2-trifluoromethyl-pyrazol-3-yl, 2-difluoromethyl-pyrazol-3-yl, 1-methyl-imidazol-4-yl, 1-methyl-imidazol-2-yl, 1H-imidazol-2-yl, (2-hydroxyethoxy)carbamoyl, (2,2-dihydroxyethoxy)carbamoyl, (oxetane-3-yloxy)carbamoyl, methoxycarbamoyl, 2-trimethylsilylethynyl, ethynyl, 1,3,4-oxadiazol-3-yl, 1H-1,2,3-triazol-5-yl, aminosulfonyl, acetyl, and -C (＝NOCH) ₃ ) CH ₃ , and R ₂ is -H, ^-Ra NHC(O)-, ^-Ra OC(O)-, -(C _1- C ₆ )alkyl, (C _1- C ₆ )alkoxy or -C(＝NO-CH ₃ ) ^Ra .

Item 17. The compound as described in Item 5, wherein the subscript r is 1 or 2.

Item 18. The compound of any one of items 1-17, wherein R ₁₀ and R ₁₁ are each H.

Item 19. The compound as described in any one of items 1-18, wherein the subscript n is 1.

Item 20. The compound as described in any one of items 1-19, wherein the subscript m is 1.

Item 21. The compound as described in any one of items 1-20, wherein the subscript p is 1.

Item 22. The compound of any one of items 1-21, having formula B:

Or its pharmaceutically acceptable salt, wherein:

(i)R ₂ is:

-H or a group selected from the following groups:

( _C1 - _C6 )alkyl, halogroup, _-NO2 , _X1Ra ^, wherein _X1 is –O-, -S-, -SO-, -SO2-, -SO2NH-, -SO2NRa-, _{-NH- and} -N- _{( C1} - _C6 )alkyl-, wherein ( _C1 - _C6 )alkyl is optionally substituted; ^and

_R1 can be selected from the following groups:

( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, (C6- _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-10 heteroaryl, and 4-10 heterocycloalkyl, wherein the ( _{C2 - C6} )alkenyl, ( _C2 - _C6 )ynyl, ( _C6 - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-10 heteroaryl, and 4-10 heterocycloalkyl are each optionally substituted independently by the following:

-CN, -P(O)R ^a R ^a ,P(O)(OR ^a ) ₂ , B(OH) ₂ , B(OR ^a ) ₂ ,

X ₂ ^Ra , where X ₂ is -NHO-, -NH-S(O)-, -N-(C ₁ -C ₆ )alkyl-S(O)-, -NH-S(O) _2- , -N-(C ₁ -C ₆ )alkyl-S(O) ₂ ^Ra- , -NH-S(O)-NH-, -N-(C ₁ -C ₆ )alkyl-S(O)NH-, -NH-S(O) ₂ NH-, -N-(C ₁ -C ₆ )alkyl-S(O) ₂ NH-, -S(O) ₂ NHC(O)-; and

Where: represents the connection point, where:

_Y1 is absent, or is -NH-, -N-( _C1 - _C6 )alkyl-, or -O-;

_Y2 is absent, or is -O-, -NH-, -NHO-, -N-( _C1 - _C6 )alkyl-, _-N2H2- , -NH- _S (O)-, -NH-S(O) _2- ; or

_Y2 represents the optional substitution, where A is a 3-, 4-, 5-, 6-, or 7-membered ring; and

^Z1 is O, NH, N-( _C1 - _C6 )alkyl, NOH, NO-( _C1 - _C6 )alkyl, or NCN; or

(ii)

_R1 can be selected from the following groups:

( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, (C6- _C10 )aryl, ( _{C3 - C10} )cycloalkyl, 5-10 heteroaryl, and 4-10 heterocycloalkyl, wherein the ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, ( _C6 - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-14 heteroaryl, and 4-14 heterocycloalkyl are each optionally substituted independently by the following:

P(O)R ^a R ^a , P(O)(OR ^a )(OR ^a ) , B(OH) ₂ , B(OR ^a ) ₂ , CN,

X ₂ ^Ra , where X ₂ is -NHO-, -NH-S(O)-, -N-(C ₁ -C ₆ )alkyl-S(O)-, -NH-S(O) _2- , -N-(C ₁ -C ₆ )alkyl-S(O) ₂ ^Ra- , -NH-S(O)-NH-, -N-(C ₁ -C ₆ )alkyl-S(O)NH-, -NH-S(O) ₂ NH-, -N-(C ₁ -C ₆ )alkyl-S(O) ₂ NH-, -S(O)-, -S(O) _2- , -S(O) ₂ NHC(O); and

in:

_Y1 is absent, or is -NH-, -N-( _C1 - _C6 )alkyl-, or -O-;

_Y2 is absent, or is -O-, -NH-, -NHO-, -N-( _C1 - _C6 )alkyl-, _-N2H2- , -NH-S(O ₎ -, or -NH-S(O) ₂ ; or

_Y2 represents the optional substitution, where A is a 3-, 4-, 5-, 6-, or 7-membered ring; and

^Z1 is -O-, -NH-, -N-( _C1 - _C6 )alkyl-, -NOH-, -NO-( _C1 - _C6 )alkyl-, or –NCN-; or

_R2 can be selected from the following groups:

H, halogenated, ( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkenyl, (C2- _C6 )ynyl, ( _C1 - _C6 )haloalkyl, (C1 _- C6)haloalkoxy, ( _C6 - _C10 )aryl-(C1 _{- C4} )alkylene-, (C3 _{- C10} )cycloalkyl-( _{C1 - C4} )alkylene-, ( _5-14 -membered heteroaryl)-(C1 _{- C4} )alkylene-, and (4-14-membered heterocycloalkyl)-(C1 _{- C4} )alkylene-, wherein ( _C2 - _C6 )alkenyl, ( _C2 - _C6 )ynyl, ( _C1 - _C6 )haloalkyl, (C1 _{- C6} )haloalkoxy, ( _C6 - _C10) The aryl-(C1 _{- C4} )alkylene-, (C3- _C10 )cycloalkyl-( _C1 -C4)alkylene-, (5-14-membered heteroaryl)-( _{C1- C4} )alkylene-, and (4-14-membered heterocycloalkyl)-( _{C1- C4 ) alkylene-} are each independently and optionally substituted with the following:

CN, NO ₂ , P(O)R ^a R ^a , P(O)(OR ^a )(OR ^a ), B(OH) ₂ , B(OR ^a ) ₂ ,

_X1 ^Ra substitution, wherein _X1 is –O-, -S-, -NH- or -N-( _C1 - _C6 )-, -NHO-, -NH-S(O)-, -N-( _C1 - _C6 )alkyl-S(O)-, -NH-S(O) _2- , -N-( _C1 - _C6 )alkyl-S(O) _2- , -NH-S(O)-NH-, -N-( _C1 - _C6 )alkyl-S(O)NH-, -NH-S(O) _2NH- , -N-( _C1 - _C6 )alkyl-S(O) _2NH- , -S(O) _2NHC (O)-, -NH-S(O) ^Ra- , -N-( _C1 - _C6 )alkyl-S(O) ^Ra- , -NH-S(O) _2Ra- or -N-( ^C1 -C6)-. ₁ - _C6 )alkyl-S ^(O)2Ra- _;

in

_Y1 is absent or is -NH-, -N-( _C1 - _C6 )alkyl- or -O-;

_Y2 is absent or is -O-, -NH-, -NHO-, -N-( _C1 - _C6 )alkyl-, _-N2H2- , -NH-S(O)- or -NH-S(O) _2- ; _or

_Y2 is an optional substitution in which ring A is a 3-, 4-, 5-, 6-, or 7-membered ring, and where represents the connection point; and

^Z1 is O, NH, N-( _C1 - _C6 )alkyl, NOH, NO-( _C1 - _C6 )alkyl, or NCN; or

(iii)

_R1 and _R2, together with the atoms they are attached to, form a 4-10 membered heterocyclic alkyl ring optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of: halogroup, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )haloalkyl, ( _C1 - _C6 )haloalkoxy, -CN, -OH, _-NH2 , provided that the compound is not 1-[2-(4-fluoro-phenyl)-acetyl]-cyclopropanecarboxylic acid [3-fluoro-4-(7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxa-1-aza-cyclododecano[b]naphthalene-4-yloxy)-phenyl]-amide;

And _R10 , _R11 , _R3 , _R14 , _R4 , n, p, m and Y are defined as follows:

Each _R3 is independently selected from the group consisting of: -H, halogroup, -OH, -CN, optionally substituted ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy, ( _C1 - _C6 )haloalkoxy, _-NH2 , -NH( _C1 - _C6 )alkyl, -N( _C1 - _C6 )alkyl) ₂ and ( _C3 - _C6 )cycloalkyl, wherein ( _C1 - _C6 )alkoxy, -NH( _C1 - _C6 )alkyl, -N( _C1 - _C6 )alkyl) ₂ and ( _C3 - _C6 )cycloalkyl are each optionally substituted;

Each of _R10 and _R11 is independently selected from the group consisting of: -H, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy, and ( _C1 - _C6 )haloalkoxy.

Each R ₁₄ is independently selected from -halogroup, -OH, _-NH2 , -CN, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy, (C1- _C6 )haloalkyl, ( _C1 - _C6 )haloalkoxy, -COOH, -NH( _C1 - _C6 )alkyl, -N( _C1 - _C6alkyl ) ₂ , phenyl, phenyl-( _{C1 - C2} )alkylene, ( _{C3- C6} )cycloalkyl, (C3- _C6 )cycloalkyl-( _{C1- C4 )} alkylene-, 4- to 6-membered heterocycloalkyl, (4- to 6-membered heterocycloalkyl)-( _{C1- C4} )alkylene-, 5- to 6-membered heteroaryl, (5- to 6-membered heteroaryl)-(C1 _{- C4} )alkylene- and ^-ORe , wherein R _The ( _C1 - _C6 )alkyl, phenyl, phenyl-(C1 _{- C2} )alkylene, (C3- _C6 )cycloalkyl, (C3 _{- C6} )cycloalkyl-(C1 _{- C4} )alkylene, 4- to 6-membered heterocycloalkyl, ( _4- to 6-membered heterocycloalkyl)-(C1 _{- C4} )alkylene, 5- to 6-membered heteroaryl and (5- to 6-membered heteroaryl)-(C1 _{- C4} )alkylene are each optionally substituted;

Each _R4 is independently selected from -H, halogroup, -OH, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy, ( _C1 - _C6 )haloalkyl, and ( _C1 - _C6 )haloalkoxy, wherein the ( _C1 - _C6 )alkyl, ( _C1 - _C6 )alkoxy, ( _C1 - _C6 )haloalkyl, and ( _C1 - _C6 )haloalkoxy are each optionally substituted independently;

Each ^Ra is independently selected from -H, ( _C1 - _C6 )alkyl, ( _C1 - _C6 )haloalkyl, ( _C6 - _C10 )aryl, ( _C3 - _C10 )cycloalkyl, 5-14-membered heteroaryl, 4-14-membered heterocycloalkyl, ( _C6 - _C10 )aryl-( _C1 - _C4 )alkylene-, ( _C3 - _C10 )cycloalkyl-( _C1 - _C4 )alkylene-, (5-14-membered heteroaryl)-(C1 _{- C4} )alkylene-, and (4-14-membered heterocycloalkyl)-(C1 _{- C4} )alkylene-, wherein ( _C1 - _C6 )alkyl, ( _C1 - _C6 )haloalkyl, ( _C6 - _C10 )aryl, ( _C3 - _C10)... ( _C6 - _C10 ) aryl-(C1-C4) alkylene-, (C3-C10) cycloalkyl-( _C1 - _C4 ) alkylene-, (5-14) heteroaryl-( _C1 - _C4 ) alkylene-, and (4-14 ₎ heterocycloalkyl-( _{C1 - C4 )} alkylene- can each be substituted independently _;

n, p, and m are each an independent integer from 0 to 3; and

Y is selected from -O-, -S-, -SO-, _-SO2- , -NH- and -N((C1 _{- C6} )alkyl)-.

Item 23. The compound as described in Item 22, wherein:

_R1 can be -H, -CN, ( _C1 - _C6 )alkyl, ( _C3 - _C10 )cycloalkyl, ( _C6 - _C10 )aryl, 4-10 heterocyclic alkyl, 5-10 heteroaryl, -S(O ^)2NHRa _, -P(O) ^RaRa , ^{-ORa , or}

Where represents the connection point, and:

_Y1 is absent or is -NH-, -N-( _C1 - _C6 )alkyl- or -O-;

_Y2 is absent, or is -O-, -NH-, -NHO-, -N-( _C1 - _C6 )alkyl-, -NH-NH-, -NH-S(O)-, or NH-S(O) ₂ ; and

^Z1 is -O, -NH, -N-( _C1 - _C6 )alkyl, -N-OH or -NO( _C1 - _C6 )alkyl;

Item 24. The compound as described in Item 23, wherein:

_R2 can be -H, a halogroup, _-X1Ra , ( _C2 - _C6 ) ^alkenyl , ( _C2 - _C6 )ynyl, or...

Where: represents the connection point, where:

_Y1 is absent, or is NH, N-( _C1 - _C6 ) alkyl, or O;

_Y2 is absent, or is O, NH, NHO, N-( _{C1 - C6} )alkyl, _N2H2 , NH-S(O) or NH-S(O) ₂ ; and

^Z1 is -O, -NH, -N-( _C1 - _C6 )alkyl, -NOH-, or -NO( _C1 - _C6 )alkyl.

Item 25. The compound of any one of items 22-24, wherein _R3 is -H or a halogroup.

Item 26. The compound of any one of items 22-25, wherein _R4 is -H or a halogroup.

Item 27. The compound of any one of items 22-26, wherein R ₁₄ is -H or a halogroup.

Item 28. The compound of any one of items 22-27, wherein Y is -O-.

Item 29. A compound as described in any one of items 22-28, wherein the compound is a compound of formula B-1 or B-2:

Or its pharmaceutically acceptable salt.

Item 30. A compound of formula B-1 as described in Item 29, wherein:

^Ra1 is an optionally substituted ( _C1 - _C6 ) alkyl group;

_R1 is -H, -CN, optionally substituted 3-6 membered cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 membered heterocycloalkyl, optionally substituted 5-6 membered heteroaryl, _-SO2- ( _C1 - _C6 )alkyl, _-SO2NH2 , _-SO2 - _NH ( _C1 - _C6 )alkyl, or P(O)(( _C1 - _C6 )alkyl) ₂ ; or

Where represents the connection point, and:

_Y1 does not exist;

_Y2 is absent or is -O-, -NH-, -NHO-, -NH-NH-, -N-( _C1 - _C6 )alkyl-; or

_Y2 is an optional substitution where ring A is a 3-, 4-, 5-, 6-, or 7-membered ring, where represents the connection point.

^Z1 is O, NH, N-( _C1 - _C6 )alkyl, NHO, or NO-( _C1 - _C6 )alkyl; and

Ra ^can be -H, -( _C1 - _C6 )alkyl, 4-6 membered heterocyclic alkyl, 3-6 membered cycloalkyl, -( _C2 - _C6 )alkylene-OH, _-CH2CHOH- ( _C2 - _C6 )alkylene-OH, -( _C2 - _C6 )alkylene- _NH2 , -(C2- _C6 )alkylene-NH( _C1 - _C6 ), -( _C2 - _C6 )alkylene-N( _C1 - _C6 ) ₂ or -( _C2 - _C6 )alkylene-N-( _4-6 membered heterocyclic alkyl);

Item 31. A compound of formula B-1 as described in Item 30, wherein:

^Ra1 is a ( _C1 - _C6 ) alkyl group;

_R1 is -H, -CN, optionally substituted cyclopropyl, optionally substituted phenyl, optionally substituted 4-6 membered azacyclic butyl, optionally substituted pyrrolyl, optionally substituted piperidinyl, optionally substituted oxazolyl, optionally substituted pyridinyl, optionally substituted imidazolyl, optionally substituted pyrrolyl, optionally substituted furanyl, optionally substituted pyrazolyl, optionally substituted oxadiazolyl, _-SO₂- ( _C₁ - _C₆ )alkyl, _-SO₂NH₂ , _{-SO₂ -} NH( _C₁ - _C₆ )alkyl, or P(O)(( _C₁ - _C₆ )alkyl) _₂ ; or

_R1 is where:

_Y1 does not exist;

_Y2 is O, NH, NHO, NH-NH, or N-( _C1 - _C6 ) alkyl; or

_Y2 is an optionally substituted nitrogen-containing heterocyclic butyl group;

Z is O, NH, or N-( _C1 - _C6 ) alkyl; and

Ra ^can be H, ( _C1 - _C6 )alkyl, -( _C2 - _C6 )alkylene-OH, _-CH2CHOH- ( _C2 - _C6 )alkylene-OH, -( _C2 - _C6 )alkylene- _NH2 , -( _C2 - _C6 )alkylene-NH( _C1 - _C6 )alkyl, -( _C2 - _C6 )alkylene-N(( _C1 - _C6 )alkyl) ₂ , -( _C2 - _C6 )alkylene-heterocyclic alkyl) and 4-6 membered heterocyclic alkyl, wherein the heterocyclic alkyl is optionally substituted.

Item 32. A compound of formula B-2 as described in Item 30, wherein:

^Ra2 is an optionally substituted ( _C1 - _C6 ) alkyl group;

_R2 represents the connection point, where:

_Y1 does not exist;

_Y2 either does not exist or is -O- or -NH-; and

^Z1 is 0; and

^Ra is -H or -( _C1 - _C6 ) alkyl.

Item 33. A compound of formula B-2 as described in Item 32, wherein:

^Ra2 is a ( _C1 - _C6 ) alkyl group;

_R2 represents the connection point, where:

_Y1 does not exist;

_Y2 either does not exist or is -O- or -NH-; and

^Z1 is an O or NO-( _C1 - _C6 ) alkyl group; and

^Ra is -H or -( _C1 - _C6 ) alkyl.

Item 34. The compound of formula B-1 as described in any one of items 29-31, wherein ^Ra1 is methoxylated.

Item 35. The compound of formula B-2 as described in any one of items 29 and 32-33, wherein ^Ra2 is methoxylated.

Item 36. A compound as described in any one of items 22-28, wherein the compound is a compound of formula B-3 or B-4:

Or its pharmaceutically acceptable salt.

Item 37. The compound as described in Item 36, wherein the compound is a compound of formula B-3, wherein:

_R1 is -H or ( _C1 - _C6 ) alkyl; and

_Y1 does not exist;

_Y2 either does not exist or is -O-, -NHO-, or -NH-; and

^Z1 is an O or NO-( _C1 - _C6 ) alkyl group; and

^Ra is -H or -( _C1 - _C6 ) alkyl.

Item 38. The compound as described in Item 37, wherein the compound is a compound of formula B-3, wherein:

_R1 is –H or methyl;

_Y1 does not exist;

_Y2 either does not exist or is -O-, -NHO-, or -NH-; and

^Z1 is O or NO-Me; and

R ^a is –H or Me.

Item 39. The compound as described in Item 36, wherein the compound is a compound of formula B-3, wherein:

_R1 and ^Ra together with the atoms they are attached to form

4-6 membered heterocyclic alkyl rings optionally substituted with halogen groups, ( _C1 - _C6 )alkyl groups, and ( _C1 - _C6 )haloalkyl groups.

Item 40. The compound as described in Item 36, wherein the compound is a compound of formula B-4, wherein:

_Y1 does not exist;

_Y2 is O, NH, NHO, NH-NH, or N-( _C1 - _C6 ) alkyl; or

_Y2 is an optionally substituted nitrogen-containing heterocyclic butyl group;

^Z1 is O, NH, NO-( _C1 - _C6 )alkyl, or N-( _C1 - _C6 )alkyl; and

Ra ^can be -H, ( _C1 - _C6 )alkyl, -( _C2 - _C6 )alkylene-OH, _-CH2CHOH- ( _C2 - _C6 )alkylene-OH, -( _C2 - _C6 )alkylene- _NH2 , -( _C2 - _C6 )alkylene-NH( _C1 - _C6 )alkyl, -( _C2 - _C6 )alkylene-N(( _C1 - _C6 )alkyl) ₂ , -( _C2 - _C6 )alkylene-optionally substituted 4-6 membered heterocyclic alkyl) and optionally substituted 4-6 membered heterocyclic alkyl;

_R2 can be -H, F, Cl, Br, ( _C1 - _C6 )alkoxy, -O-( _C2 - _C6 )alkylene-OH, -O-( _C2 - _C6 )alkylene-O-( _C1 - _C6 alkyl), ( _C2 - _C6 )alkylene-O-( _C1 - _C6 )alkyl, _-NH2 , -NH-(C1- _C6 alkyl), -NH-( _C1 -C6)alkylene-(optionally substituted 4-6 membered heterocyclic alkyl), -NH-( _{C2 - C6 )} alkylene-O-( _C1 - _C6 alkyl).

Item 41. The compound as described in Item 40, wherein the compound is a compound of formula B-4, wherein:

_Y1 does not exist;

_Y2 is O, NH, NHO, NH-NH, or N-( _C1 - _C6 ) alkyl; or

_Y2 is an optionally substituted nitrogen-containing heterocyclic butyl group;

^Z1 is O, NH, NO-( _C1 - _C6 )alkyl, or N-( _C1 - _C6 )alkyl; and

Ra ^can be H, methyl, ethyl, -( _C2 - _C6 )alkylene-OH, _-CH2CHOH- ( _C2 - _C6 )alkylene-OH, -( _C2 - _C6 )alkylene- _NH2 , -( _C2 - _C6 )alkylene-NHMe, -( _C2 - _C6 )alkylene-N(Me) ₂ , -( _C1 - _C6 )alkylene-morpholinyl, -( _C1 - _C6 )alkylene-piperidinyl, ( _C1 - _C6 )alkylene-(optionally substituted pyrrolidinyl), optionally substituted azahexacyclic butyl or optionally substituted oxohexacyclic butyl;

_R2 is -H, H, F, Cl, Br, methoxy, -O-( _C2 - _C6 )alkylene-OH, -O-( _C2 - _C6 )alkylene-OMe, _-NH2 , -NH-( _C1 - _{C6 alkyl), -NH-(C2-C6 ) alkylene} -OMe, -NH-( _C2 - _C6 )alkylene-(optionally substituted morpholino) or -NH-( _C2 - _C6 )alkylene-O-( _C1 - _C6 alkyl).

Item 42. The compound as described in Item 36, wherein the compound is a compound of formula B-4, wherein:

_R2 and ^Ra, together with the atoms they are attached to, form 4-6 membered heterocyclic alkyl rings that are optionally substituted with halogen groups, ( _C1 - _C6 )alkyl groups, and ( _C1 - _C6 ) haloalkyl groups.

Item 43. The compound as described in items 22-28, wherein the compound is a compound of formula B-5:

Or a pharmaceutically acceptable salt thereof, wherein ring A in formula B-5 is an optionally substituted 5-10 membered heteroaryl or C _6-10 aryl.

Item 44. The compound as described in Item 43, wherein the compound is a compound of formula B-5, wherein:

Ring A is optionally substituted ( _C6 - _C10 ) aryl, optionally substituted ( _C3 - _C10 ) cycloalkyl, optionally substituted 5-10 heteroaryl, or optionally substituted 4-10 heterocycloalkyl; and

_R2 is H, or ( _C1 - _C6 )alkoxy.

Item 45. The compound as described in Item 44, wherein the compound is a compound of formula B-5, wherein:

Ring A is optionally substituted with phenyl, optionally substituted with cyclopropyl, optionally substituted with pyridyl, optionally substituted with imidazolyl, optionally substituted with pyrrole, optionally substituted with furanyl, optionally substituted with pyrazolyl, optionally substituted with oxazolyl, optionally substituted with aziridine or optionally substituted with oxacyclobutane; and

_R2 is H or methoxy.

Item 46. A compound as described in any one of items 22-28, wherein the compound is a compound of formula C:

Or its pharmaceutically acceptable salt, wherein:

_Y1 does not exist;

_Y2 is O, NH, NHO, NH-NH, or N-( _C1 - _C6 ) alkyl; or

_Y2 is an optionally substituted nitrogen-containing heterocyclic butyl group;

^Z1 is O, NH, NO-( _C1 - _C6 )alkyl or N-( _C1 - _C6 )alkyl;

Ra ^can be H, ( _C1 - _C6 )alkyl, -( _C2 - _C6 )alkylene-OH, _-CH2CHOH- ( _C2 - _C6 )alkylene-OH, -( _C2 - _C6 )alkylene- _NH2 , -( _C2 - _C6 )alkylene-NH( _C1 - _C6 )alkyl, -( _C2 - _C6 )alkylene-N(( _C1 - _C6 )alkyl) ₂ , -( _C2 - _C6 )alkylene-optionally substituted 4-6 membered heterocyclic alkyl) or optionally substituted 4-6 membered heterocyclic alkyl;

_R2 is -H, F, Cl, Br, ( _C1 - _C6 )alkoxy, -O-( _C2 - _C6 )alkylene-OH, -O-( _C2 - _C6 )alkylene-O-( _C1 - _C6 alkyl), ( _C2 - _C6 )alkylene-O-( _C1 - _C6 )alkyl, _-NH2 , -NH-( _{C1-C6 alkyl), -NH-(C1 - C6 )} alkylene-(optionally substituted 4-6 membered heterocyclic alkyl) or –NH-( _C2 - _C6 )alkylene-O-( _C1 - _C6 alkyl); and

n and m are each an independent integer from 0 to 3.

Item 47. The compound as described in Item 46, wherein:

_Y1 does not exist;

_Y2 is O, NH, NHO, NH-NH, or N-( _C1 - _C6 ) alkyl; or

_Y2 is an optionally substituted nitrogen-containing heterocyclic butyl group;

^Z1 is O, NH, NO-( _C1 - _C6 )alkyl or N-( _C1 - _C6 )alkyl;

Ra ^can be H, methyl, ethyl, -( _C2 - _C6 )alkylene-OH, _-CH2CHOH- ( _C2 - _C6 )alkylene-OH, -( _C2 - _C6 )alkylene- _NH2 , -( _C2 - _C6 )alkylene-NHMe, -( _C2 - _C6 )alkylene-N(Me) ₂ , -( _C1 - _C6 )alkylene-morpholinyl, -( _C1 - _C6 )alkylene-piperidinyl, ( _C1 - _C6 )alkylene-(optionally substituted pyrrolidinyl), optionally substituted azahexacyclic butyl or optionally substituted oxohexacyclic butyl;

_R2 is -H, H, F, Cl, Br, methoxy, -O-( _C2 - _C6 )alkylene-OH, -O-( _C2 - _C6 )alkylene-OMe, _-NH2 , -NH-( _C1 - _C6 alkyl), -NH-( _C2 - _C6 )alkylene-OMe, -NH-( _C2 - _C6 )alkylene-(optionally substituted morpholino) or -NH-( _C2 - _C6 )alkylene-O-( _C1 - _C6 alkyl); and

And n and m can each be 0 or 1.

Item 48. The compound of any one of items 46-47, wherein the compound is a compound of formula C-1.

Or its pharmaceutically acceptable salt, wherein:

_Y2 is O, NH, NHO, NH-NH, or N-( _C1 - _C6 ) alkyl; or

_Y2 is an optionally substituted nitrogen-containing heterocyclic butyl group.

^Z1 is O, NH, NO-( _C1 - _C6 )alkyl or N-( _C1 - _C6 )alkyl;

Ra ^can be H, methyl, ethyl, -( _C2 - _C6 )alkylene-OH, _-CH2CHOH- ( _C2 - _C6 )alkylene-OH, -( _C2 - _C6 )alkylene- _NH2 , -( _C2 - _C6 )alkylene-NHMe, -( _C2 - _C6 )alkylene-N(Me) ₂ , -( _C1 - _C6 )alkylene-morpholinyl, -( _C1 - _C6 )alkylene-piperidinyl, ( _C1 - _C6 )alkylene-(optionally substituted pyrrolidinyl), optionally substituted azahexacyclic butyl or optionally substituted oxohexacyclic butyl;

_R2 is -H, H, F, Cl, Br, methoxy, -O-( _C2 - _C6 )alkylene-OH, -O-( _C2 - _C6 )alkylene-OMe, _-NH2 , -NH-( _C1 - _C6 alkyl), -NH-( _C2 - _C6 )alkylene-OMe, -NH-( _C2 - _C6 )alkylene-(optionally substituted morpholino) or -NH-( _C2 - _C6 )alkylene-O-( _C1 - _C6 alkyl); and

Furthermore, n and m are each independently 0 or 1.

Item 49. A compound as described in any one of items 22-28, wherein the compound is a compound of formula D:

Item 50. The compound as described in any one of Item 49, wherein:

_R1 is -H or ( _C1 - _C6 ) alkyl; and

_Y1 does not exist;

_Y2 either does not exist or is -O-, -NHO-, or -NH-; and

^Z1 is an O or NO-( _C1 - _C6 ) alkyl group.

^Ra is -H or -( _C1 - _C6 ) alkyl; and

n and m are each an independent integer from 0 to 3.

Item 51. The compound as described in any one of Item 50, wherein:

_R1 is –H or methyl;

_Y1 does not exist;

_Y2 either does not exist or is -O-, -NHO-, or -NH-; and

^Z1 is O or NO-Me; and

R ^_a is either -H or Me.

n and m are each an independent integer between 0 and 1.

Item 52. The compound of any one of items 49-51, wherein the compound is a compound of formula D-1:

Item 53. A compound as described in any one of items 22-28, wherein the compound is a compound of formula E:

Or its pharmaceutically acceptable salt, wherein:

Ring A is optionally substituted ( _C6 - _C10 ) aryl, optionally substituted ( _C3 - _C10 ) cycloalkyl, optionally substituted 5-10 heteroaryl, or optionally substituted 4-10 heterocycloalkyl; and

_R2 is H or ( _C1 - _C6 ) alkoxy.

Item 54. The compound as described in Item 53, wherein:

Ring A is optionally substituted with phenyl, optionally substituted with cyclopropyl, optionally substituted with pyridyl, optionally substituted with imidazolyl, optionally substituted with pyrrole, optionally substituted with furanyl, optionally substituted with pyrazolyl, optionally substituted with oxazolyl, optionally substituted with aziridine or optionally substituted with oxacyclobutane; and

_R2 is H or methoxy.

Item 55. A compound as described in any one of items 22-28, wherein the compound is a compound of formula F:

Or its pharmaceutically acceptable salt, wherein

^Ra1 is an optionally substituted ( _C1 - _C6 ) alkyl group;

_R1 is -H, -CN, optionally substituted 3-6 membered cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 membered heterocycloalkyl, optionally substituted 5-6 membered heteroaryl, _-SO2- ( _C1 - _C6 )alkyl, _-SO2NH2 , _-SO2 - _NH ( _C1 - _C6 )alkyl, or P(O)(( _C1 - _C6 )alkyl) ₂ ; or

Where: represents the connection point; where:

_Y1 does not exist;

_Y2 is absent, or is -O-, -NH-, -NHO-, -NH-NH-, -N-( _C1 - _C6 )alkyl-; or

_Y2 is an optional substitution in which ring A is a 3, 4, 5, 6 or 7-membered ring, where represents the connection point;

^Z1 is O, NH, N-( _C1 - _C6 )alkyl, NHO, or NO-( _C1 - _C6 )alkyl; and

Ra ^can be -H, -( _C1 - _C6 )alkyl, 4-6 membered heterocyclic alkyl, 3-6 membered cycloalkyl, -( _C2 - _C6 )alkylene-OH, _-CH2CHOH- ( _C2 - _C6 )alkylene-OH, -( _C2 - _C6 )alkylene- _NH2 , -( _C2 - _C6 )alkylene-NH(C1- _C6 ), -( _C2 - _C6 )alkylene-N( _{C1 - C6} ) ₂ , -( _C2 - _C6 )alkylene-N-(4-6 membered heterocyclic alkyl);

Item 56. The compound as described in any one of Item 55, wherein:

^Ra1 is a methyl group;

_R1 is -H, -CN, optionally substituted cyclopropyl, optionally substituted phenyl, optionally substituted 4-6 membered azacyclic butyl, optionally substituted pyrrolyl, optionally substituted piperidinyl, optionally substituted oxazolyl, optionally substituted pyridinyl, optionally substituted imidazolyl, optionally substituted pyrrolyl, optionally substituted furanyl, optionally substituted pyrazolyl, optionally substituted oxadiazolyl, _-SO₂- ( _C₁ - _C₆ )alkyl, _-SO₂NH₂ , _{-SO₂ -} NH( _C₁ - _C₆ )alkyl, or P(O)(( _C₁ - _C₆ )alkyl) _₂ ; or

_R1 is where:

_Y1 does not exist;

_Y2 is O, NH, NHO, NH-NH, or N-( _C1 - _C6 ) alkyl; or

_Y2 is an optionally substituted nitrogen-containing heterocyclic butyl group;

^Z1 is an O, NH, or N-( _C1 - _C6 ) alkyl group; and

Ra ^can be H, ( _C1 - _C6 )alkyl, -( _C2 - _C6 )alkylene-OH, _-CH2CHOH- ( _C2 - _C6 )alkylene-OH, -( _C2 - _C6 )alkylene- _NH2 , -( _C2 - _C6 )alkylene-NH( _C1 - _C6 )alkyl, -( _C2 - _C6 )alkylene-N(( _C1 - _C6 )alkyl) ₂ , -( _C2 - _C6 )alkylene-heterocyclic alkyl) and 4-6 membered heterocyclic alkyl, wherein the heterocyclic alkyl is optionally substituted.

Item 57. A compound as described in any one of items 22-28, wherein the compound is a compound of formula G:

Or its pharmaceutically acceptable salt, wherein:

^Ra1 is an optionally substituted ( _C1 - _C6 ) alkyl group;

_R2 represents the connection point, where:

_Y1 does not exist;

_Y2 either does not exist or is -O- or -NH-; and

^Z1 is 0; and

^Ra is -H or -( _C1 - _C6 ) alkyl.

Item 58. The compound as described in Item 57, wherein:

^Ra2 is a methyl group;

_R2 represents the connection point, where:

_Y1 does not exist;

_Y2 either does not exist or is -O- or -NH-; and

^Z1 is an O or NO-( _C1 - _C6 ) alkyl group; and

^Ra is -H or -( _C1 - _C6 ) alkyl.

Item 59. The compound of any one of items 1-58, wherein the compound is a compound of formula H:

Or its pharmaceutically acceptable salt, wherein:

_R1 is selected from _the group consisting of: -H, _-CN , -CO- _NR5R6 , _-CO2R7 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted _C1 - _C6 alkyl, optionally substituted _C3 - _C8 cycloalkyl, optionally substituted _C3 - _C6 heterocycloalkyl, _-SO2NR8R9 and ( _{SO2 ) -C1 - C6} alkyl;

When _R1 is selected from _the group consisting of: -CN, -CO- _NR5R6 , _-CO2R7 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted _C3 - _{C8 cycloalkyl} , optionally substituted _C3 - _C6 heterocycloalkyl, _SO2NR8R9 and _{( SO2} ) _-C1 - _C6 alkyl, _R2 is H, halogroup, _NR5R6 or optionally substituted _{C1 - C6} alkoxy _.

Where _R1 is -H, _an optionally substituted _C1 - _C6 alkyl, or an optionally substituted _C1 - _C6 alkoxy, _R2 is -CO- _NR5R6 or _{-CO2R7 ;}

Or _R1 and _R2 together with the atoms to which they are attached form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl;

_R3 is selected from the group consisting of: -H, optionally substituted _C1-6 alkyl groups, -CN, and halogroups;

_R4 is -H or a halogenated group;

Optionally substituted with one, two, three or four groups independently selected from the group consisting of a halogroup and a _C1 - _C6 alkyl group, wherein the linkage point is indicated;

_R5 and _R6 are each independently -H, optionally substituted _C1 - _C6 alkyl, or optionally substituted _C1 - _C6 alkoxy;

_R7 is H or an optionally substituted _C1 - _C6 alkyl group;

_R8 and _R9 are each independently H and optionally substituted _C1 - _C6 alkyl groups or _R8 ; or

_R8 and _R9 can be connected to form an optionally substituted heterocyclic ring; and

Y is selected from the following groups: O, S, SO, _SO₂ , NH and N-( _C₁ - _C₆ alkyl).

Item 60. The compound as described in Item 59, wherein Y is O.

Item 61. The compound as described in Item 60, wherein _R3 is H.

Item 62. The compound as described in Item 61, wherein it is not substituted.

Item 63. The compound as described in Item 62, wherein _R4 is a halogroup.

Item 64. The compound as described in Item 63, wherein _R4 is p-fluorine.

Item 65. The compound of any one of items 59-64, wherein _R2 is -H, a halogroup or optionally substituted ( _C1 - _C6 )-alkoxy.

Item 66. The compound as described in Item 63, wherein _R1 is -CN.

Item 67. The compound as described in Item 63, wherein _R1 is _-CO₂H .

Item 68. The compound as described in Item 63, wherein _R1 is _-CO2 -Me.

Item 69. The compound as described in Item 63, wherein _R1 is -CO- _NHR6 .

Item 70. The compound as described in Item 69, wherein _R1 is -CO- _NH2 .

Item 71. The compound as described in Item 69, wherein _R1 is -CO- _NMeR6 .

Item 72. The compound as described in any one of items 1, 2, 4, 5, 7, 8, 9 and 63, wherein _R1 is selected from the group consisting of: -CN, -( _SO₂ ) _NH₂ , -OMe, -( _SO₂ ) _CH₃

Item 73. The compound as described in Item 72, wherein _R1 is selected from the group consisting of:

Item 74. The compound as described in Item 72, wherein _R1 is selected from the group consisting of:

Item 75. The compound as described in any one of items 1, 2, 3, 5, 6, 9 and 63-74, wherein _R2 is selected from the group consisting of: H, -CN, Br, F, Cl, -OMe, _CH3 , _-CH2NH2 , _NH2 , _NHMe ,

Item 76. The compound of any one of items 59-65, wherein _R1 is -H, methyl or methoxy.

Item 77. The compound as described in Item 76, wherein _R2 is _-CO2H .

Item 78. The compound of any one of items 59-65, wherein _R1 is _-CO2 -Me.

Item 79. The compound of any one of items 59-65, wherein _R1 is -CO- _NHR6 .

Item 80. The compound as described in Item 79, wherein _R1 is -CO- _NH2 .

Item 81. The compound of any one of items 59-65, wherein _R1 is -CO- _NMeR6 .

Item 82. The compound of any one of items 59-65, wherein _R1 is selected from the group consisting of:

Item 83. The compound as described in Item 64, wherein the compound is a compound of formula I-A:

Wherein _R6 is (C1 _{- C6} )alkyl, _R2 is (C1 _{- C6} )alkoxy, _R3 is -H or a halogroup, and _R4 is a halogroup.

Item 84. The compound of any one of items 1-83, wherein the compound is selected from the group consisting of:

Or its pharmaceutically acceptable salt.

Item 85. The compound of any one of items 1-83, wherein the compound is selected from the group consisting of:

Or its pharmaceutically acceptable salt.

Item 86. A method for preparing compounds of formula I:

Or a pharmaceutically acceptable salt thereof, the method comprising: making a compound of formula II:

          

Z is selected from _NH₂ , SH, and OH;

Reaction with compounds of formula III:

Where X is a leaving group;

_R1 is selected _from -H, -CN, -CO- _NR5R6 , _-CO2R7 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted _{( C1} - _C6 )alkyl, optionally substituted ( _C3 - _C8 )cycloalkyl, optionally substituted ( _C3 - _C6 ) _{heterocycloalkyl} , _-SO2NR8R9 and -( _{SO2 )} -( _C1 - _C6 )alkyl;

Where _R1 is selected _{from -CN} , -CO- _NR5R6 , _-CO2R7 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted ( _C3 - _C8 )cycloalkyl, optionally substituted ( _C3 - _C6 ) heterocycloalkyl, _-SO2NR8R9 and -( _SO2 )-( _C1 - _C6 )alkyl, _{R2 is -H} , halogroup, _-NR5R6 or optionally substituted _{( C1} - _C6 )alkoxy;

Where _R1 is -H, an optionally substituted ( _C1 - _C6 ) alkyl, or _an optionally substituted ( _C1 - _C6 ) alkoxy, _R2 is -CO- _NR5R6 or _{-CO2R7 ;}

Or _R1 and _R2 together with the atoms to which they are attached form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl;

_R3 is selected from -H, optionally substituted (C1 _{- C6} ) alkyl, -CN, and halogroup;

_R4 is -H or a halogenated group;

Optionally substituted with one, two, three or four independently selected groups from halogroups and ( _C1 - _C6 )alkyl groups, wherein the linkage point is indicated;

_R5 and _R6 are each independently -H, optionally substituted ( _C1 - _C6 ) alkyl, or optionally substituted ( _C1 - _C6 ) alkoxy;

_R7 is -H or an optionally substituted ( _C1 - _C6 ) alkyl group;

_R8 and _R9 are each independently -H and optionally substituted ( _C1 - _C6 ) alkyl; or

_R8 and _R9 can be connected to form an optionally substituted heterocyclic ring; and

Y is selected from O, S, SO, _SO₂ , NH and N-(( _C₁ - _C₆ )alkyl).

Item 87. A method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof:

The method includes:

Compounds of formula IV:

Reaction with compounds of formula V:

_R1 is selected from _{the group consisting of: -H, -CN, -CO-NR5R6, -CO2R7 , optionally substituted} aryl, optionally substituted heteroaryl, optionally substituted ( _C1 - _C6 )alkyl, optionally substituted ( _C3 - _C8 )cycloalkyl, optionally substituted ( _C3 - _{C6 ) heterocycloalkyl} , _-SO2NR8R9 and -( _SO2 )-( _C1 - _C6 )alkyl;

When _R1 is selected from _the group consisting of _: -CN, -CO- _NR5R6 , _-CO2R7 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted ( _C3 - _C8 )cycloalkyl, optionally substituted ( _C3 - _C6 ) heterocycloalkyl, _-SO2NR8R9 and -( _SO2 )- _{( C1} - _C6 )alkyl, _R2 is _-H , _halogroup , _-NR5R6 or optionally substituted ( _C1 - _C6 )alkoxy;

Where _R1 is -H, an optionally substituted ( _C1 - _C6 ) alkyl, or _an optionally substituted ( _C1 - _C6 ) alkoxy, _R2 is -CO- _NR5R6 or _{-CO2R7 ;}

Or _R1 and _R2 together with the atoms to which they are attached form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl;

_R3 is selected from the group consisting of: -H, optionally substituted (C1 _{- C6} ) alkyl, -CN, and halogroup;

_R4 is -H or a halogenated group;

Optionally substituted with one, two, three or four groups independently selected from the group consisting of a halogroup and a ( _C1 - _C6 ) alkyl group, wherein the linkage point is indicated;

_R5 and _R6 are each independently -H, optionally substituted ( _C1 - _C6 ) alkyl, or optionally substituted ( _C1 - _C6 ) alkoxy;

_R7 is -H or an optionally substituted ( _C1 - _C6 ) alkyl group;

_R8 and _R9 are each independently -H and optionally substituted ( _C1 - _C6 alkyl); or

_R8 and _R9 can be connected to form an optionally substituted heterocyclic ring; and

Y is selected from the group consisting of: O, S, SO, _SO₂ , NH and N-(( _C₁ - _C₆ )alkyl).

Item 88. The method of Item 87 further comprises making a compound of Formula VI:

Reaction with compounds of formula VII:

Compounds of formula VIII:

And reduce the compound of formula VIII to provide the compound of formula V.

in:

_R1 is selected from _{the group consisting of: -H, -CN, -CO-NR5R6, -CO2R7 , optionally substituted} aryl, optionally substituted heteroaryl, optionally substituted ( _C1 - _C6 )alkyl, optionally substituted ( _C3 - _C8 )cycloalkyl, optionally substituted ( _C3 - _{C6 ) heterocycloalkyl} , _-SO2NR8R9 and -( _SO2 )-( _C1 - _C6 )alkyl;

Where _R1 is selected _{from -CN} , -CO- _NR5R6 , _-CO2R7 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted ( _C3 - _C8 )cycloalkyl, optionally substituted ( _C3 - _C6 ) heterocycloalkyl, _-SO2NR8R9 and -( _SO2 )-( _C1 - _C6 )alkyl, _{R2 is -H} , halogroup, _-NR5R6 or optionally substituted _{( C1} - _C6 )alkoxy;

Where _R1 is -H, an optionally substituted ( _C1 - _C6 ) alkyl, or _an optionally substituted ( _C1 - _C6 ) alkoxy, _R2 is -CO- _NR5R6 or _{-CO2R7 .}

Or _R1 and _R2 together with the atoms to which they are attached form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl;

_R3 is selected from the group consisting of: -H, optionally substituted (C1 _{- C6} ) alkyl, -CN, and halogroup; and

W is a halogenated group.

Item 89. A pharmaceutical composition comprising a compound as described in any one of items 1-85 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

Item 90. A method of treating a disease, condition, or syndrome by at least partially modulating the in vivo activity of a protein kinase, the method comprising administering to a subject in need a compound as described in any one of items 1-85 or a pharmaceutical composition as described in item 89.

Item 91. The method of Item 90, wherein the disease, condition or syndrome mediated at least in part by regulating the in vivo activity of protein kinases is cancer.

Item 92. A method for inhibiting a protein kinase, the method comprising contacting the protein kinase with a compound as described in any one of items 1-85.

Item 93. The method of any one of items 90-92, wherein the protein kinase is Axl, Mer, c-Met, KDR or a combination thereof.

Claims (3)

1. A method for preparing compounds of formula I:

Or a pharmaceutically acceptable salt thereof, the method comprising:

Compounds of formula II:

Z is selected from _NH₂ , SH, and OH;

Reaction with compounds of formula III:

Where X is a leaving group;

_R1 is selected _from -H, -CN, -CO- _NR5R6 , _-CO2R7 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted _{( C1} - _C6 )alkyl, optionally substituted ( _C3 - _C8 )cycloalkyl, optionally substituted ( _C3 - _C6 ) _{heterocycloalkyl} , _-SO2NR8R9 and -( _{SO2 )} -( _C1 - _C6 )alkyl;

Where _R1 is selected _{from -CN} , -CO- _NR5R6 , _-CO2R7 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted ( _C3 - _C8 )cycloalkyl, optionally substituted ( _C3 - _C6 ) heterocycloalkyl, _-SO2NR8R9 and -( _SO2 )-( _C1 - _C6 )alkyl, _{R2 is -H} , halogroup, _-NR5R6 or optionally substituted _{( C1} - _C6 )alkoxy;

Where _R1 is -H, an optionally substituted ( _C1 - _C6 ) alkyl, or _an optionally substituted ( _C1 - _C6 ) alkoxy, _R2 is -CO- _NR5R6 or _{-CO2R7 ;}

Or _R1 and _R2 together with the atoms to which they are attached form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl;

_R3 is selected from -H, optionally substituted (C1 _{- C6} ) alkyl, -CN, and halogroup;

_R4 is -H or a halogenated group;

Optionally substituted with one, two, three or four independently selected groups from halogroups and ( _C1 - _C6 )alkyl groups, wherein the linkage point is indicated;

_R5 and _R6 are each independently -H, optionally substituted ( _C1 - _C6 ) alkyl, or optionally substituted ( _C1 - _C6 ) alkoxy;

_R7 is -H or an optionally substituted ( _C1 - _C6 ) alkyl group;

_R8 and _R9 are each independently -H and optionally substituted ( _C1 - _C6 ) alkyl; or

_R8 and _R9 can be connected to form an optionally substituted heterocyclic ring; and

Y is selected from O, S, SO, _SO₂ , NH and N-(( _C₁ - _C₆ )alkyl).

2. A method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof:

The method includes:

Compounds of formula IV:

Reaction with compounds of formula V:

_R1 is selected from _{the group consisting of: -H, -CN, -CO-NR5R6, -CO2R7 , optionally substituted} aryl, optionally substituted heteroaryl, optionally substituted ( _C1 - _C6 )alkyl, optionally substituted ( _C3 - _C8 )cycloalkyl, optionally substituted ( _C3 - _{C6 ) heterocycloalkyl} , _-SO2NR8R9 and -( _SO2 )-( _C1 - _C6 )alkyl;

When _R1 is selected from _the group consisting of _: -CN, -CO- _NR5R6 , _-CO2R7 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted ( _C3 - _C8 )cycloalkyl, optionally substituted ( _C3 - _C6 ) heterocycloalkyl, _-SO2NR8R9 and -( _SO2 )-( _C1 - _C6 )alkyl, _R2 is _-H , _halogroup , _-NR5R6 or optionally substituted _{( C1} - _C6 )alkoxy.

Where _R1 is -H, an optionally substituted ( _C1 - _C6 ) alkyl, or _an optionally substituted ( _C1 - _C6 ) alkoxy, _R2 is -CO- _NR5R6 or _{-CO2R7 ;}

Or _R1 and _R2 together with the atoms to which they are attached form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl;

_R3 is selected from the group consisting of: -H, optionally substituted (C1 _{- C6} ) alkyl, -CN, and halogroup;

_R4 is -H or a halogenated group;

Optionally substituted with one, two, three or four groups independently selected from the group consisting of a halogroup and a ( _C1 - _C6 ) alkyl group, wherein the linkage point is indicated;

_R5 and _R6 are each independently -H, optionally substituted ( _C1 - _C6 ) alkyl, or optionally substituted ( _C1 - _C6 ) alkoxy;

_R7 is -H or an optionally substituted ( _C1 - _C6 ) alkyl group;

_R8 and _R9 are each independently -H and optionally substituted ( _C1 - _C6 alkyl); or

_R8 and _R9 can be connected to form an optionally substituted heterocyclic ring; and

Y is selected from the group consisting of: O, S, SO, _SO₂ , NH and N-(( _C₁ - _C₆ )alkyl).

3. The method of claim 2, further comprising a compound of formula VI:

    

Reaction with compounds of formula VII:

Compounds of formula VIII:

And reduce the compound of formula VIII to provide the compound of formula V.

in:

_R1 is selected from _{the group consisting of: -H, -CN, -CO-NR5R6, -CO2R7 , optionally substituted} aryl, optionally substituted heteroaryl, optionally substituted ( _C1 - _C6 )alkyl, optionally substituted ( _C3 - _C8 )cycloalkyl, optionally substituted ( _C3 - _{C6 ) heterocycloalkyl} , _-SO2NR8R9 and -( _SO2 )-( _C1 - _C6 )alkyl;

Where _R1 is selected _{from -CN} , -CO- _NR5R6 , _-CO2R7 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted ( _C3 - _C8 )cycloalkyl, optionally substituted ( _C3 - _C6 ) heterocycloalkyl, _-SO2NR8R9 and -( _SO2 )-( _C1 - _C6 )alkyl, _{R2 is -H} , halogroup, _-NR5R6 or optionally substituted _{( C1} - _C6 )alkoxy;

Where _R1 is -H, an optionally substituted ( _C1 - _C6 ) alkyl, or _an optionally substituted ( _C1 - _C6 ) alkoxy, _R2 is -CO- _NR5R6 or _{-CO2R7 .}

Or _R1 and _R2 together with the atoms to which they are attached form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl;

_R3 is selected from the group consisting of: -H, optionally substituted (C1 _{- C6} ) alkyl, -CN, and halogroup; and

W is a halogenated group.