5,6,7,8-tetrahydro-2,6-naphthyridine derivatives as cancer therapeutics

A compound of formula (A-I)

• —or a tautomer thereof, isotope thereof, prodrug thereof, N-oxide thereof, a pharmaceutically acceptable ester thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein
• A1 is absent or is independently selected from substituted or unsubstituted C1-4 alkyl, substituted or unsubstituted C2-4 alkenyl, substituted or unsubstituted C2-4 alkynyl, substituted or unsubstituted C3-10 cycloalkyl, substituted or unsubstituted C3-10 heterocycloalkyl, —(CRbRc)p—, —O—, —S—, —S(═O)p—, —C(═O)—, —NRx—, —CO—NRx— and —NRx—CO—;
• Cy1 is selected form a cyclic group selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl;
• Cy2 is selected from cyclic group selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl which is optionally substituted by G;
• G is a group capable of forming an interaction with Aspartic acid at 12 position of KRAS protein;
• R1 at each occurrence is independently selected from hydrogen, hydroxy, halogen, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, C(═O)ORb, —C(═O)Rb, —C(═S)R, —C(═O)NRbRc, —C(═O)ONRbRc, —NRbRc, —NRbC(═O)NRRc, —NR S(═O)Rc, —NR S(═O)2Rc, —NRb—ORc, ═N—NRbRc, —NRbC(═O)ORc, —NRbC(═O)Rc, —NRbC(═S)Rc, —NRbC(═S)NRbRc, —SONRbRc, —SO2NRbRc, —ORb, —ORbC(═O)NRbRc, —ORbC(═O)ORc, —OC(═O)Rb, —OC(═O)NRcRc, —RbNRcC(═O)Rb, —RbORc, —RbC(═O)ORc, —RcC(═O)NRcRc, —RbC(═O)Rc, —RbOC(═O)Rc, —SRb, —SORc, —SO2Rb, —CRbRcC(═O)Rb or —CRbRcC(═S)Rz;
• Ra at each occurrence is independently selected from hydrogen, hydroxy, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, —C(═O)ORb, —C(═O)Rb, —C(═S)Rb, —C(═O)NRbRc, —C(═O)ONRbRc, —NRbRc, —NRb—ORc, —NRbC(═O)NRbRc, —NRbS(═O)Rc, —NRbS(═O)2Rc, —NRb—ORc, ═N—NRbRc, —NRbC(═O)ORc, —NRbC(═O)Rc, —NRbC(═S)Rc, —NRbC(═S)NRbRc, —SONRbRc, —SO2NRbRc, —ORb, —ORbC(═O)NRbRc, —ORbC(═O)ORc, —OC(═O)Rb, —OC(═O)NRbRc, —RbNRcC(═O)Rb, —RbORc, —RbC(═O)ORc, —RbC(═O)NRbRc, —RbC(═O)Rc, —RbC(═O)Rc, —SRb, —SORc, —SO2Rb, —CRbRcC(═O)Rb or —CRbRcC(═S)Rz or any two Ra may be joined to a form a substituted or unsubstituted saturated or unsaturated 3-6 member ring, which may optionally include heteroatoms which maybe same or different and are selected from O, NRa or S or;
• any two Ra attached to the same carbon atom may be joined to a form a Oxo (C═O), Imino (═NRb), C═S(O)p, or substituted or unsubstituted saturated or unsaturated 3-6 member ring, which may optionally include heteroatoms which may be same or different and are selected from O, NRx or S;
• each occurrence of Rb and Rc is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic ring, substituted heterocyclylalkyl ring, or substituted or unsubstituted amino, or any two of Rb and Rb when bound to a common atom may be joined to form (i) a substituted or unsubstituted saturated or unsaturated 3-14 membered ring, which may optionally include one or more heteroatoms which may be the same or different and are selected from O, NRx or S, or (ii) an oxo (═O), thio(═S) or imino(═NRx) group;
• and
• each occurrence of p is independently 0, 1 or 2.

A compound of formula (A-II)

• or a tautomer thereof, isotope thereof, prodrug thereof, N-oxide thereof, a pharmaceutically acceptable ester thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein
• A1 is absent or is independently selected from substituted or unsubstituted C1-4 alkyl, substituted or unsubstituted C2-4 alkenyl, substituted or unsubstituted C2-4 alkynyl, substituted or unsubstituted C3-10 cycloalkyl, substituted or unsubstituted C3-10 heterocycloalkyl, —(CRbRc)p—, —O—, —S—, —S(═O)p—, —C(═O)—, —NRx—, —CO—NRx— and —NRx—CO—;
• Cy1 is selected form a cyclic group selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl;
• Cy2 is substituted or unsubstituted heterocyclyl, which is optionally substituted by G;
• G is a group capable of forming an interaction with Aspartic acid at 12 position of KRAS protein;
• R1 at each occurrence is independently selected from hydrogen, hydroxy, halogen, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, C(═O)ORb, —C(═O)Rb, —C(═S)R, —C(═O)NRbRc, —C(═O)ONRbRc, —NbRc, —NbC(═O)NRbRc, —NRbS(═O)Rc, —NRbS(═O)2Rc, —NRb—ORc, ═N—NRbRc, —NbC(═O)ORc, —NRbC(═O)Rc, —NRbC(═S)Rc, —NRbC(═S)NbRc, —SONRbRc, —SO2NRbRc, —ORb, —ORbC(═O)NRbRc, —ORbC(═O)ORc, —OC(═O)Rb, —OC(═O)NRcRc, —RbNRcC(═O)Rb, —RbORc, —RbC(═O)ORc, —RcC(═O)NRcRc, —RbC(═O)Rc, —RbOC(═O)Rc, —SRb, —SORc, —SO2Rb, —CRbRcC(═O)Rb or —CRbRcC(═S)Rz;
• Ra at each occurrence is independently selected from hydrogen, hydroxy, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, —C(═O)ORb, —C(═O)Rb, —C(═S)Rb, —C(═O)NRbRc, —C(═O)ONRbRc, —NRbRc, —NRb—ORc, —NRbC(═O)NRbRc, —NRbS(═O)Rc, —NRbS(═O)2Rc, —NRb—ORc, ═N—NRbRc, —NRbC(═O)ORc, —NRbC(═O)Rc, —NRbC(═S)Rc, —NRbC(═S)NRbRc, —SONRbRc, —SO2NRbRc, —ORb, —ORbC(═O)NRbRc, —ORbC(═O)ORc, —OC(═O)Rb, —OC(═O)NRbRc, —RbNRcC(═O)Rb, —RbORc, —RbC(═O)ORc, —RbC(═O)NRbRc, —RbC(═O)Rc, —RbC(═O)Rc, —SRb, —SORc, —SO2Rb, —CRbRcC(═O)Rb or —CRbRcC(═S)Rz or any two Ra may be joined to a form a substituted or unsubstituted saturated or unsaturated 3-6 member ring, which may optionally include heteroatoms which maybe same or different and are selected from O, NRa or S or;
• any two Ra attached to the same carbon atom may be joined to a form a Oxo (C═O), Imino (═NRb), C═S(O)p, or substituted or unsubstituted saturated or unsaturated 3-6 member ring, which may optionally include heteroatoms which may be same or different and are selected from O, NRx or S;
• each occurrence of Rb and Rc is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic ring, substituted heterocyclylalkyl ring, or substituted or unsubstituted amino, or any two of Rb and Rc when bound to a common atom may be joined to form (i) a substituted or unsubstituted saturated or unsaturated 3-14 membered ring, which may optionally include one or more heteroatoms which may be the same or different and are selected from O, NRx or S, or (ii) an oxo (═O), thio(═S) or imino(═NRx) group;
• and
• each occurrence of p is independently 0, 1 or 2.

A compound of formula (A-IIIA), (A-IIIB) or (A-IIIC)

• or a tautomer thereof, isotope thereof, prodrug thereof, N-oxide thereof, a pharmaceutically acceptable ester thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein
• A1 is absent or is independently selected from substituted or unsubstituted C1-4 alkyl, substituted or unsubstituted C2-4 alkenyl, substituted or unsubstituted C2-4 alkynyl, substituted or unsubstituted C3-10 cycloalkyl, substituted or unsubstituted C3-10 heterocycloalkyl, —(CRbRc)p—, —O—, —S—, —S(═O)p—, —C(═O)—, —NRx—, —CO—NRx— and —NRx—CO—;
• Cy1 is selected form a cyclic group selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl;
• X1 is C or N;
• X2 is selected from —N-G or CRyRy-G, O or S;
• G is a group capable of forming an interaction with Aspartic acid at 12 position of KRAS protein;
• R1 at each occurrence is independently selected from hydrogen, hydroxy, halogen, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, C(═O)ORb, —C(═O)Rb, —C(═S)Rb, —C(═O)NRbRc, —C(═O)ONRbRc, —NRbRc, —NbC(═O)NRbRc, —NRbS(═O)Rc, —NRbS(═O)2Rc, —NRb—ORc, ═N—NRbRc, —NRbC(═O)ORc, —NRbC(═O)Rc, —NRbC(═S)Rc, —NRbC(═S)NRbRc, —SONRbRc, —SO2NRbRc, —ORb, —ORbC(═O)NRbRc, —ORbC(═O)ORc, —OC(═O)Rb, —OC(═O)NRbRc, —RbNRcC(═O)Rb, —RbORc, —RbC(═O)ORc, —RbC(═O)NRbRc, —RbC(═O)Rc, —RbOC(═O)Rc, —SRb, —SORc, —SO2Rb, —CRbRcC(═O)Rb or —CRbRcC(═S)Rz;
• Ra at each occurrence is independently selected from hydrogen, hydroxy, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, —C(═O)ORb, —C(═O)Rb, —C(═S)Rb, —C(═O)NRbRc, —C(═O)ONRbRc, —NRbRc, —NRb—ORc, —NRbC(═O)NRbRc, —NRbS(═O)Rc, —NRbS(═O)2Rc, —NRb—ORc, ═N—NRbRc, —NRbC(═O)ORc, —NRbC(═O)Rc, —NRbC(═S)Rc, —NRbC(═S)NRbRc, —SONRbRc, —SO2NRbRc, —ORb, —ORbC(═O)NRbRc, —ORbC(═O)ORc, —OC(═O)Rb, —OC(═O)NRbRc, —RbNRcC(═O)Rb, —RbORc, —RbC(═O)ORc, —RbC(═O)NRbRc, —RbC(═O)Rc, —RbOC(═O)Rc, —SRb, —SORc, —SO2Rb, —CRbRcC(═O)Rb or —CRbRcC(═S)Rz or any two Ra may be joined to a form a substituted or unsubstituted saturated or unsaturated 3-6 member ring, which may optionally include heteroatoms which maybe same or different and are selected from O, NRa or S or;
• any two Ra attached to the same carbon atom may be joined to a form a Oxo (C═O), Imino (═NRb), C═S(O)p, or substituted or unsubstituted saturated or unsaturated 3-6 member ring, which may optionally include heteroatoms which may be same or different and are selected from O, NRx or S;
• each occurrence of Rb and Rc is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic ring, substituted heterocyclylalkyl ring, or substituted or unsubstituted amino, or any two of Rb and Rc when bound to a common atom may be joined to form (i) a substituted or unsubstituted saturated or unsaturated 3-14 membered ring, which may optionally include one or more heteroatoms which may be the same or different and are selected from O, NRx or S, or (ii) an oxo (═O), thio(═S) or imino(═NRx) group;
• each occurrence of Ry is independently selected from hydrogen, hydroxy, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, —C(═O)ORb, —C(═O)Rb, —C(═S)Rb, —C(═O)NRbRc, —C(═O)ONRbRc, —WR, —NRb—ORc, —NRbC(═O)NRbRc, —NRbS(═O)Rc, —NRWS(═O)2Rc, —NRb—ORc, —NRbC(═O)ORc, —NRbC(═O)Rc, —NRbC(═S)Rc, —NRbC(═S)NRbRc, —SONRbRc, —SO2NRbRc, —ORb, —ORbC(═O)NRbRc, —ORbC(═O)ORc, —OC(═O)Rb, —OC(═O)NRbRc, —RbNRcC(═O)Rb, —RbORc, —RbC(═O)ORc, —RbC(═O)NRbRc, —RbC(═O)Rc, —RbOC(═O)Rc, —SRb, —SORc, —SO2Rb, —CRbRcC(═O)Rb or —CRbRcC(═S)Rz or any two Ra may be joined to a form a substituted or unsubstituted saturated or unsaturated 3-6 member ring, which may optionally include heteroatoms which may be same or different and are selected from O, NRa or S or;
• any two Ra attached to the same carbon atom may be joined to a form a Oxo (C═O), Imino (═NRb), C═S(O)p, or substituted or unsubstituted saturated or unsaturated 3-6 member ring, which may optionally include heteroatoms which may be same or different and are selected from O, NRx or S;
• n is 0,1,2,3,4,5,6,7 or 8;
• and
• each occurrence of p is independently 0, 1 or 2.

A compound selected from 1-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(3-hydroxynaphthalen-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride;

• 1 tert-butyl 4-(6-(8-chloronaphthalen-1-yl)-4-cyano-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-2-(cyanomethyl)piperazine-1-carboxylate;
• 6-(8-chloronaphthalen-1-yl)-1-(3-(cyanomethyl)piperazin-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride;
• 1 tert-butyl (1R,5S)-8-(4-cyano-6-(3-hydroxynaphthalen-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3, 8-diazabicyclo[3.2.1]octane-3-carboxylate;
• 1-((1R,5S)-3, 8-diazabicyclo[3.2.1]octan-8-yl)-6-(3-hydroxynaphthalen-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride;
• 1-((1R,5S)-3, 8-diazabicyclo[3.2.1]octan-8-yl)-6-(3-hydroxynaphthalen-1-yl)-3-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile compound with 2,2,2-trifluoroacetaldehyde (1:1);
• 1-((1R,5S)-3, 8-diazabicyclo[3.2.1]octan-8-yl)-6-(8-bromonaphthalen-1-yl)-3-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile compound with 2,2,2-trifluoroacetaldehyde (1:1);
• 1-((1R,5S)-3, 8-diazabicyclo[3.2.1]octan-8-yl)-6-(8-ethynylnaphthalen-1-yl)-3-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile compound with 2,2,2-trifluoroacetaldehyde (1:1);
• 1-((1R,5S,8r)-3-azabicyclo[3.2.1]octan-8-yl)-6-(8-bromo-3-hydroxynaphthalen-1-yl)-3-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile;
• 1-((1R,5S)-3, 8-diazabicyclo[3.2.1]octan-8-yl)-6-(8-bromonaphthalen-1-yl)-3-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile;
• 1-((1R,5S)-3, 8-diazabicyclo[3.2.1]octan-8-yl)-6-(8-ethynylnaphthalen-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile;
• 1-((1R,5S)-3, 8-diazabicyclo[3.2.1]octan-8-yl)-6-(8-ethynylnaphthalen-1-yl)-3-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile;
• 6-benzyl-1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-((1-(morpholinomethyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile;
• 1-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(8-ethynyl-3-hydroxynaphthalen-1-yl)-3-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile;
• 1-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(8-bromo-3-hydroxynaphthalen-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile;
• 1-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(8-chloronaphthalen-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile;
• 1-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(8-chloronaphthalen-1-yl)-3-(((2R)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile;
• 6-benzyl-1-(3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile;
• 6-benzyl-1-(3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2R)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile;
• 1 tert-butyl ((R)-1-(4-(6-benzyl-4-cyano-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate;
• 1-(4-(D-valyl)piperazin-1-yl)-6-benzyl-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile;
• 1 tert-butyl ((2S,3R)-1-(4-(6-benzyl-4-cyano-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazin-1-yl)-3-(benzyloxy)-1-oxobutan-2-yl)carbamate;
• 6-benzyl-1-(4-(O-benzyl-L-threonyl)piperazin-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile;
• 6-benzyl-1-(3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((1-(morpholinomethyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile;
• 1-(3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2R)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile;
• 3-(1,1-dioxidothiomorpholino)-6-(naphthalen-1-yl)-1-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile Hydrochloride;
• 6-(8-chloronaphthalen-1-yl)-3-morpholino-1-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile Hydrochloride;
• 3-(2-morpholinoethoxy)-6-(naphthalen-1-yl)-1-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile Hydrochloride;
• 6-(8-chloronaphthalen-1-yl)-3-(2-morpholinoethoxy)-1-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile Hydrochloride;
• 1-(2,6-dimethylmorpholino)-6-(naphthalen-1-yl)-3-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile Hydrochloride;
• 6-(8-chloronaphthalen-1-yl)-1-(2,6-dimethylmorpholino)-3-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile Hydrochloride;
• 3-(3-(cyanomethyl)piperazin-1-yl)-1-(2,6-dimethylmorpholino)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile Hydrochloride;
• (S)-6-(8-chloronaphthalen-1-yl)-3-((1-methylpyrrolidin-2-yl)methoxy)-1-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile Hydrochloride;
• (S)-6-(3-hydroxynaphthalen-1-yl)-3-((1-methylpyrrolidin-2-yl)methoxy)-1-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile Hydrochloride;
• (S)-3-((1-methylpyrrolidin-2-yl)methoxy)-1-(piperazin-1-yl)-6-(quinazolin-4-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile Hydrochloride;
• 6-(8-chloronaphthalen-1-yl)-1-(3-methylpiperazin-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile Hydrochloride;
• 1-(3-(cyanomethyl)piperazin-1-yl)-3-(2,6-dimethylmorpholino)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile Hydrochloride;
• 1-((S)-3-(cyanomethyl)piperazin-1-yl)-3-(2,6-dimethylmorpholino)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile Hydrochloride;
• 1-((R)-3-(cyanomethyl)piperazin-1-yl)-3-(2,6-dimethylmorpholino)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile Hydrochloride;
• 1-(3-(cyanomethyl)piperazin-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile Hydrochloride;
• 1-((S)-3-(cyanomethyl)piperazin-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile Hydrochloride;
• 1-((R)-3-(cyanomethyl)piperazin-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile Hydrochloride;
• 1-(3-(cyanomethyl)piperazin-1-yl)-6-(3-hydroxynaphthalen-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile Hydrochloride;
• (S)-6-(isoquinolin-4-yl)-3-((1-methylpyrrolidin-2-yl)methoxy)-1-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile Hydrochloride;
• (S)-3-((1-methylpyrrolidin-2-yl)methoxy)-1-(piperazin-1-yl)-6-(quinolin-8-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile Hydrochloride;
• 6-(8-chloronaphthalen-1-yl)-1-(3-(cyanomethyl)piperazin-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile Hydrochloride;
• 6-(8-chloronaphthalen-1-yl)-1-((S)-3-(cyanomethyl)piperazin-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile Hydrochloride;
• 6-(8-chloronaphthalen-1-yl)-1-((S)-3-(cyanomethyl)piperazin-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile Hydrochloride;
• 6-benzyl-3-chloro-1-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile Hydrochloride;
• 1-(4-aminopiperidin-1-yl)-6-benzyl-3-chloro-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile Hydrochloride;
• 1-(4-aminopiperidin-1-yl)-6-benzyl-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile Hydrochloride;
• 6-benzyl-1,3-di(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile Hydrochloride;
• 6-benzyl-3-hydroxy-1-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile Hydrochloride;
• 6-benzyl-3-morpholino-1-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile Hydrochloride;
• 6-benzyl-3-(4-methylpiperazin-1-yl)-1-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile Hydrochloride;
• 6-benzyl-1-(3-(cyanomethyl)piperazin-1-yl)-3-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile Hydrochloride;
• 6-(1-naphthoyl)-1-(3-(cyanomethyl)piperazin-1-yl)-3-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile Hydrochloride;
• (S)-6-benzyl-1-(2-methylpiperazin-1-yl)-3-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile Hydrochloride;
• (R)-6-benzyl-1-(2-methylpiperazin-1-yl)-3-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile Hydrochloride;
• 3-(4-methylpiperazin-1-yl)-6-(naphthalen-1-yl)-1-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile Hydrochloride;
• 6-benzyl-1-(piperazin-1-yl)-3-(piperidin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile Hydrochloride;
• 6-benzyl-3-(2-fluoropyridin-4-yl)-1-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile;
• 6-(naphthalen-1-yl)-1-(piperazin-1-yl)-3-(piperidin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile Hydrochloride;
• 6-benzyl-3-((1-methylpyrrolidin-2-yl)methoxy)-1-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile Hydrochloride;
• 6-(naphthalen-1-yl)-1,3-di(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile Hydrochloride;
• 6-(benzo[b]thiophen-4-yl)-1,3-di(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile dihydrochloride;
• 3-morpholino-6-(naphthalen-1-yl)-1-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile Hydrochloride;
• 3-(4-acetylpiperazin-1-yl)-6-(naphthalen-1-yl)-1-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile Hydrochloride;
• 3-(2,6-dimethylmorpholino)-6-(naphthalen-1-yl)-1-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile Hydrochloride;
• 3-(4-(methylsulfonyl)piperazin-1-yl)-6-(naphthalen-1-yl)-1-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile Hydrochloride;
• 3-(4-ethylpiperazin-1-yl)-6-(naphthalen-1-yl)-1-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile Hydrochloride;
• (S)-3-((1-methylpyrrolidin-2-yl)methoxy)-6-(naphthalen-1-yl)-1-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile Hydrochloride;
• 6-(naphthalen-1-yl)-1-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile Hydrochloride;
• 6-(naphthalen-1-yl)-1-(piperazin-1-yl)-3-(4-propionylpiperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile Hydrochloride;
• and
• 6-benzyl-1-((S)-2-methylpiperazin-1-yl)-3-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile and pharmaceutically acceptable salts thereof.