Claims for Patent: 9,359,367

Summary for Patent: 9,359,367

Title:	Tetrahydroquinazolinone derivatives as PARP inhibitors
Abstract:	Disclosed are compounds of formula (I), their tautomeric forms, stereoisomers, and pharmaceutically acceptable salts thereof, wherein R.sup.1-R.sup.6, R.sup.7a-d, R.sup.8a-d, A, M, n, and p are as defined in the specification, pharmaceutical compositions including a compound, tautomer, stereoisomer, or salt thereof, and methods of treating or preventing diseases or disorders, for example, cancer, that are amenable to treatment or prevention by inhibiting the PARP enzyme of a subject. ##STR00001##
Inventor(s):	Jana; Gourhari (Pune, IN), Kurhade; Sanjay Pralhad (Pune, IN), Jagdale; Arun Rangnath (Pune, IN), Kukreja; Gagan (Pune, IN), Sinha; Neelima (Pune, IN), Palle; Venkata P. (Pune, IN), Kamboj; Rajender Kumar (Pune, IN)
Assignee:	Lupin Limited (Mumbai, IN)
Application Number:	14/411,968
Patent Claims:	1. A compound of the general formula (I), its tautomeric form, its stereoisomer, or its pharmaceutically acceptable salt, ##STR00111## wherein, M is selected from C, CH, and N; is a single bond when M is selected as N, and is either a single or a double bond when M is selected as CH or C respectively; R.sup.1 is selected from hydrogen, and substituted- or unsubstituted-alkyl; R.sup.2 and R.sup.3 groups are attached either to the same carbon atom or adjacent or non-adjacent carbon atoms of the carbocylic ring, and R.sup.2 and R.sup.3 together with the carbon atom(s) to which they are attached form a substituted- or unsubstituted carbocycle; R.sup.4 is selected independently at each occurrence from halogen, cyano, substituted- or unsubstituted-alkyl, --OR.sup.9, and --N(R.sup.10)R.sup.11; R.sup.5 and R.sup.6 are each independently selected from hydrogen, halogen, substituted- or unsubstituted-alkyl, perhaloalkyl, substituted- or unsubstituted-cycloalkyl, --OR.sup.9, and --N(R.sup.10)R.sup.11, or R.sup.5 and R.sup.6 together constitute oxo (.dbd.O), or both R.sup.5 and R.sup.6 attached to the same carbon atom or adjacent or non-adjacent carbon atoms together with the carbon atom(s) to which they are attached form a substituted- or unsubstituted-carbocycle, or when they are attached to adjacent carbon atoms, form a pi bond linking the said carbon atoms. R.sup.7a, R.sup.8a, R.sup.7b, R.sup.8b, R.sup.7c, R.sup.8c,R.sup.7d, and R.sup.8d are each independently selected from hydrogen, halogen, substituted- or unsubstituted-alkyl, --OR.sup.9, and --N(R.sup.10)R.sup.11; or any two groups out of R.sup.7a, R.sup.8a, R.sup.7b, R.sup.8b, R.sup.7c, R.sup.8c, R.sup.7d, and R.sup.8d form oxo (.dbd.O), or any two groups out of R.sup.7a, R.sup.8a, R.sup.7b, R.sup.8b, R.sup.7c, R.sup.8c,R.sup.7d, and R.sup.8d taken together with the carbon atom(s) to which they are attached form a substituted- or unsubstituted-carbocycle, or a substituted- or unsubstituted heterocycle, thereby making ring `A` either a spiro-bicycle or a fused-bicycle or a bridged-bicycle; Ar is selected from substituted- or unsubstituted-aryl and substituted- or unsubstituted heteroaryl; p is an integer selected from 0, 1, 2 and 3; n is an integer selected from 1, 2, 3, and 4; R.sup.9 is selected from hydrogen and substituted- or unsubstituted-alkyl; R.sup.10 and R.sup.11 are each independently selected from hydrogen and substituted- or unsubstituted-alkyl; when an alkyl group or alkenyl group is substituted, each of them is substituted with 1 to 4 substituents independently selected from oxo (.dbd.O), halogen, cyano, perhaloalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, --OR.sup.12a, --SO.sub.2(alkyl), --C(.dbd.O)O(alkyl), --C(.dbd.O)N(H)R.sup.12,--C(.dbd.O)N(alkyl).sub.2, --N(H)C(.dbd.O)(alkyl), --N(H)R.sup.12, and --N(alkyl)R.sup.12; when `cycloalkyl`, `cycloalkenyl` and `carbocycle` is substituted, the cycloalkyl, cycloalkenyl, or carbocycle group is substituted with 1 to 4 substituents independently selected from oxo (.dbd.O), halogen, cyano, alkyl, alkenyl, perhaloalkyl, --OR.sup.12, --SO.sub.2(alkyl), --C(.dbd.O)O(alkyl), --C(.dbd.O)N(H)R.sup.12, --C(.dbd.O)N(alkyl)R.sup.12, --N(H)C(.dbd.O)(alkyl), --N(H)R.sup.12, and --N(alkyl).sub.2; when the aryl group is substituted, it is substituted with 1 to 4 substituents independently selected from halogen, nitro, cyano, hydroxy, alkyl, alkenyl, perhaloalkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, --O-alkyl, --O-perhaloalkyl, --N(alkyl)alkyl, --N(H)alkyl, --NH.sub.2, 13 SO.sub.2-alkyl, --SO.sub.2-perhaloalkyl, --N(alkyl)C(.dbd.O)alkyl,--N(H)C(.dbd.O)alkyl, --C(.dbd.O)N(alkyl)alkyl, --C(.dbd.O)N(H)alkyl, --C(.dbd.O)N(H)cycloalkyl, --C(.dbd.O)NH.sub.2, --SO.sub.2N(alkyl)alkyl, --SO.sub.2N(H)alkyl, --SO.sub.2NH.sub.2, --C(.dbd.O)OH, --C(.dbd.O)O-alkyl, --O(C.dbd.O)N(alkyl)H, --O(C.dbd.O)N(alkyl).sub.2, --O(C.dbd.O)N(cycloalkyl)H, --N(H)C(.dbd.O)N(aryl)H, --N(H)C(.dbd.O)N(alkyl)H, and --N(H)C(.dbd.O)NH.sub.2; when the heteroaryl group is substituted, it is substituted with 1 to 4 substituents independently selected from halogen, nitro, cyano, hydroxy, alkyl, alkenyl, perhaloalkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, --O-alkyl, --O-perhaloalkyl, --N(alkyl)alkyl, --N(H)alkyl, --NH.sub.2, --SO.sub.2-alkyl, --SO.sub.2-perhaloalkyl, --N(alkyl)C(.dbd.O)alkyl, --N(H)C(.dbd.O)alkyl, --C(.dbd.O)N(alkyl)alkyl, --C(.dbd.O)N(H)alkyl, --C(.dbd.O)N(H)cycloalkyl, --C(.dbd.O)NH.sub.2, --SO.sub.2N(alkyl)alkyl, --SO.sub.2N(H)alkyl, --SO.sub.2NH.sub.2, --C(.dbd.O)OH, --C(.dbd.O)O-alkyl, --O(C.dbd.O)N(alkyl)H, --O(C.dbd.O)N(alkyl).sub.2, --O(C.dbd.O)N(cycloalkyl)H, --N(H)C(.dbd.O)N(aryl)H, --N(H)C(.dbd.O)N(alkyl)H, and --N(H)C(.dbd.O)NH.sub.2; when the heterocyclic group is substituted, it is substituted either on a ring carbon atom or on a ring hetero atom, and when it is substituted on a ring carbon atom, it is substituted with 1 to 4 substituents independently selected from oxo (.dbd.O), halogen, cyano, alkyl, alkenyl, perhaloalkyl, --OR.sup.12, --SO.sub.2(alkyl), --C(.dbd.O)O(alkyl), --C(.dbd.O)N(H)R.sup.12, --C(.dbd.O)N(alkyl)R.sup.12, --N(H)C(.dbd.O)(alkyl), --N(H)R.sup.12, and --N(alkyl).sub.2; and when the heterocyclic group is substituted on a ring nitrogen, it is substituted with substituents independently selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, --SO.sub.2(alkyl), --C(.dbd.O)(alkyl), C(.dbd.O)O(alkyl), --C(.dbd.O)N(H)R.sup.12, and --C(.dbd.O)N(alkyl)R.sup.12; R.sup.12 is selected from hydrogen and alkyl; and R.sup.12a is selected from hydrogen, alkyl, alkenyl, and perhaloalkyl. 2. The compound of formula (I), its tautomeric form, its stereoisomer, or its pharmaceutically acceptable salt, as claimed in claim 1, wherein n is 3. 3. The compound of formula (I), its tautomeric form, its stereoisomer, or its pharmaceutically acceptable salt, as claimed in claim 1, wherein R.sup.5 and R.sup.6 are each independently selected from hydrogen and methyl. 4. The compound of formula (I), its tautomeric form, its stereoisomer, or its pharmaceutically acceptable salt, as claimed in claim 1, wherein R.sup.5, R.sup.6 and the carbon atoms to which they are attached together form a substituted- or unsubstituted carbocycle, the said substituted- or unsubstituted carbocycle is selected from ##STR00112## 5. The compound of formula (I), its tautomeric form, its stereoisomer, or its pharmaceutically acceptable salt, as claimed in claim 1, wherein Ar is selected from substituted- or unsubstituted-phenyl, substituted- or unsubstituted-pyridinyl, substituted- or unsubstituted-thiazolyl, substituted- or unsubstituted-thiophenyl, and substituted- or unsubstituted-benzothiazolyl, wherein the substituted-phenyl, substituted-pyridinyl, substituted-thiazolyl, or substituted-benzothiazolyl group is substituted with 1-3 substituents independently selected from halo, cyano, thiophenyl, phenyl, methyl, ethyl, trifluoromethyl, methoxy, N-methylcarbamoyl, N,N-dimethylcarbamoyl, and N-cyclopropylcarbamoyl. 6. The compound of formula (I), its tautomeric form, its stereoisomer, or its pharmaceutically acceptable salt, as claimed in claim 1, wherein Ar is selected from ##STR00113## wherein, R.sup.A and R.sup.B are independently selected from halogen and methyl, R.sup.C is selected from halogen, methyl and methoxy, R.sup.D is selected from halogen, cyano, methyl, and N-methylcarbamoyl, R.sup.E is selected from hydrogen, halogen, methyl, N-cyclopropylcarbamoyl, N-methylcarbamoyl, N,N-dimethylcarbamoyl, and 3-thiophenyl, R.sup.F is selected from halogen, methyl, N-methylcarbamoyl, and trifluoromethyl, R.sup.G and R.sup.H are independently selected from hydrogen, halogen, methyl, and N-methylcarbamoyl, R.sup.J is selected from hydrogen and methyl, R.sup.K is selected from hydrogen, halogen, methyl and phenyl, R.sup.L is selected from hydrogen and ethyl, and R.sup.M is selected from hydrogen, methyl and N-methylcarbamoyl. 7. The compound of formula (I), its tautomeric form, its stereoisomer, or its pharmaceutically acceptable salt, as claimed in claim 1, wherein ring A is selected from ##STR00114## 8. The compound of formula (I), its tautomeric form, its stereoisomer, or its pharmaceutically acceptable salt, as claimed in claim 1, wherein the compound is selected from: 2'-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-6',7'-dihydro-3'H-spiro[c- yclopropane-1,8'-quinazolin]-4'(5'H)-one (Compound 1); 2'-(3-(4-(4-chlorophenyl)piperazin-1-yl)propyl)-6',7'-dihydro-3'H-spiro[c- yclopropane-1,8'-quinazolin]-4'(5'H)-one (Compound 2); 2'-(3-(4-phenyl-5,6-dihydropyridin-1(2H)-yl)propyl)-6',7'-dihydro-3'H-spi- ro[cyclopropane-1,8'-quinazolin]-4'(5'H)-one (Compound 3); 2'-(3-(3-(4-fluorophenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)propyl)-4a',5- ',6',7'-tetrahydro-3'H-spiro[cyclopropane-1,8'-quinazolin]-4'(8a'H)-one (Compound 4); 2'-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-7',8'-dihydro-3'H-spiro[c- yclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 5); 2'-(3-(4-(4-chlorophenyl)piperazin-1-yl)propyl)-7',8'-dihydro-3'H-spiro[c- yclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 6); 2'-(3-(3-(4-fluorophenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)propyl)-7',8'- -dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 7); 2'-(3-(8-(4-fluorophenyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)propyl)-7',8'- -dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 8); 2'-(3-(4-(4-fluorophenyl)-5,6-dihydropyridin-1(2H)-yl)propyl)-7',8'-dihyd- ro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 9); 2'-(3-(4-(3,4-dichlorophenyl)piperazin-1-yl)propyl)-7',8'-dihydro-3'H-spi- ro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 10); 2'-(3-(5-(4-fluorophenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)propyl)-7',8- '-dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 11); 2'-(3-(3-(4-fluorophenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)propyl)-- 7',8'-dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 12); 2'-(3-(4-phenylpiperazin-1-yl)propyl)-7',8'-dihydro-3'H-spiro[cyclopropan- e-1,6'-quinazolin]-4'(5'H)-one (Compound 13); 2'-(3-(4-(2-chlorophenyl)piperazin-1-yl)propyl)-7',8'-dihydro-3'H-spiro[c- yclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 14); 2'-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-5',6'-dihydro-3'H-spiro[c- yclopropane-1,7'-quinazolin]-4'(8'H)-one (Compound 15); 2'-(3-(4-(4-fluorophenyl)-5,6-dihydropyridin-1(2H)-yl)propyl)-5',6'-dihyd- ro-3'H-spiro[cyclopropane-1,7'-quinazolin]-4'(8'H)-one (Compound 16); 2'-(3-(4-phenyl-5,6-dihydropyridin-1(2H)-yl)propyl)-5',6'-dihydro-3'H-spi- ro[cyclopropane-1,7'-quinazolin]-4'(8'H)-one (Compound 17); 2'-(3-(4-(3-chlorophenyl)piperazin-1-yl)propyl)-7',8'-dihydro-3'H-spiro[c- yclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 18); 2'-(3-(4-phenylpiperidin-1-yl)propyl)-7',8'-dihydro-3'H-spiro[cyclopropan- e-1,6'-quinazolin]-4'(5'H)-one (Compound 19); 2'-(3-(4-(pyridin-2-yl)piperazin-1-yl)propyl)-7',8'-dihydro-3'H-spiro[cyc- lopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 20); 2'-(3-(4-(4-fluorophenyl)piperazin-1-yl)butyl)-7',8'-dihydro-3'H-spiro[cy- clopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 21); 2'-(3-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)propyl)-7',8'-dihydro-- 3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 22); 2'-(3-(4-(m-tolyl)piperazin-1-yl)propyl)-7',8'-dihydro-3'H-spiro[cyclopro- pane-1,6'-quinazolin]-4'(5'H)-one (Compound 23); 2-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-5a,6,6a,7-tetrahydro-3H-cy- clopropa[g]quinazolin-4(5H)-one (Compound 24); 2-(3-(4-phenylpiperazin-1-yl)propyl)-5a,6,6a,7-tetrahydro-3H-cyclopropa[g- ]quinazolin-4(5H)-one (Compound 25); 2'-(3-(4-(4-fluorophenyl)-2,6-dimethylpiperazin-1-yl)propyl)-7',8'-dihydr- o-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 26); 2'-(3-(4-(4-fluorophenyl)-2-methylpiperazin-1-yl)propyl)-7',8'-dihydro-3'- H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 27); 2'-(3-(4-(2-fluorophenyl)piperazin-1-yl)propyl)-7',8'-dihydro-3'H-spiro[c- yclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 28); 2'-(3-(4-(pyridin-4-yl)piperazin-1-yl)propyl)-7',8'-dihydro-3'H-spiro[cyc- lopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 29); 2'-(3-(4-(4-fluorophenyl)piperazin-1-yl)-3-methylbutyl)-7',8'-dihydro-3'H- -spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 30); (E)-2'-(3-(4-(4-fluorophenyl)piperazin-1-yl)-3-methylbut-1-en-1-yl)-7',8'- -dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 31); 2'-(3-(4-(p-tolyl)piperazin-1-yl)propyl)-7',8'-dihydro-3'H-spiro[cyc- lopropane-1,6'quinazolin]-4'(5'H)-one (Compound 32); 2'-(3-(4-(4-fluorophenyl)-2-oxopiperazin-1-yl)propyl)-7',8'-dihydro-3'H-s- piro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 33); 2'-(3-(4-(2,4-dichlorophenyl)piperazin-1-yl)propyl)-7',8'-dihydro-3'H-spi- ro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 34); 2-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-5,6,7,8-tetrahydro-5,8-met- hanoquinazolin-4(3H)-one (Compound 35); 2-(3-(4-(4-chlorophenyl)piperazin-1-yl)propyl)-5,6,7,8-tetrahydro-5,8-met- hanoquinazolin-4(3H)-one (Compound 36); (R)-2'-(3-(4-(4-chlorophenyl)piperazin-1-yl)cyclopent-1-en-1-yl)-7',8'-di- hydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 37); (S)-2'-(3-(4-(4-chlorophenyl)piperazin-1-yl)cyclopent-1-en-1-yl)-7',8'-di- hydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 38); 2'-(3-(4-(pyridin-4-yl)piperazin-1-yl)cyclopent-1-en-1-yl)-7',8'-dihydro-- 3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 39); (S)-2'-(3-(4-(4-chlorophenyl)piperazin-1-yl)cyclopent-1-en-1-yl)-6',7'-di- hydro-3'H-spiro[cyclopropane-1,8'-quinazolin]-4'(5'H)-one (Compound 40); (R)-2'-(3-(4-(4-chlorophenyl)piperazin-1-yl)cyclopent-1-en-1-yl)-6',7'-di- hydro-3'H-spiro[cyclopropane-1,8'-quinazolin]-4'(5'H)-one (Compound 41); (R)-2'-(3-(4-(4-fluorophenyl)piperazin-1-yl)cyclopent-1-en-1-yl)-7',8'-di- hydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 42); (S)-2'-(3-(4-(4-fluorophenyl)piperazin-1-yl)cyclopent-1-en-1-yl)-7',8'-di- hydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 43); N-cyclopropyl-4-(4-(3-(4'-oxo-4',5',7',8'-tetrahydro-3'H-spiro[cyclopropa- ne-1,6'-quinazolin]-2'-yl)cyclopent-2-en-1-yl)piperazin-1-yl)benzamide (Compound 44); 2'-(3-(4-(4-fluorophenyl)-3-oxopiperazin-1-yl)cyclopent-1-en-1-yl)-7',8'-- dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 45); (R)-2'-(3-(4-(4-chlorophenyl)-5,6-dihydropyridin-1(2H)-yl)cyclopent-1-en-- 1-yl)-7',8'-dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H )-one (Compound 46); (S)-2'-(3-(4-(4-chlorophenyl)-5,6-dihydropyridin-1(2H)-yl)cyclopent-1-en-- 1-yl)-7',8'-dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H )-one (Compound 47); (R)-2'-(3-(4-(4-fluorophenyl)piperazin-1-yl)cyclopent-1-en-1-yl)-6',7'-di- hydro-3'H-spiro[cyclopropane-1,8'-quinazolin]-4'(5'H)-one (Compound 48); (S)-2'-(3-(4-(4-fluorophenyl)piperazin-1-yl)cyclopent-1-en-1-yl)-6',7'-di- hydro-3'H-spiro[cyclopropane-1,8'-quinazolin]-4'(5'H)-one (Compound 49); 2'-(3-(4-(4-bromophenyl)piperazin-1-yl)cyclopent-1-en-1-yl)-7',8'-dihydro- -3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H )-one (Compound 50); (S)-2'-(3-(4-(4-fluorophenyl)-5,6-dihydropyridin-1(2H)-yl)cyclopent-1-en-- 1-yl)-7',8'-dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H )-one (Compound 51); (R)-2'-(3-(4-(4-fluorophenyl)-5,6-dihydropyridin-1(2H)-yl)cyclopent-1-en-- 1-yl)-7',8'-dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H )-one (Compound 52); (S)-N-methyl-4-(4-(3-(4'-oxo-',5',7',8'-tetrahydro-3'H-spiro[cyclopropane- -1,6'-quinazolin]-2'-yl)cyclopent-2-en-1-yl)piperazin-1-yl)benzamide (Compound 53); (R)-N-methyl-4-(4-(3-(4'-oxo-4',5',7',8'-tetrahydro-3'H-spiro[cyclopropan- e-1,6'-quinazolin]-2'-yl)cyclopent-2-en-1-yl)piperazin-1-yl)benzamide (Compound 54); (S)-2'-(3-(4-(4-chlorophenyl)piperidin-1-yl)cyclopent-1-en-1-yl)-7',8'-di- hydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 55); (R)-2'-(3-(4-(4-chlorophenyl)piperidin-1-yl)cyclopent-1-en-1-yl)-7',8'-di- hydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 56); (R)-2'-(3-(4-(5-chloropyridin-2-yl)piperazin-1-yl)cyclopent-1-en-1-yl)-7'- ,8'-dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 57); (R)-2'-(3-(4-(5-fluoropyridin-2-yl)piperazin-1-yl)cyclopent-1-en-1-y- l)-7',8'-dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 58); (R)-2'-(3-(4-(3,4-dichlorophenyl)piperazin-1-yl)cyclopent-1-en-1-yl)-7',8- '-dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 59); (R)-2'-(3-(4-(3-chlorophenyl)piperazin-1-yl)cyclopent-1-en-1-yl)-7',- 8'-dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 60); (R)-2'-(3-(4-(2,4-difluorophenyl)piperazin-1-yl)cyclopent-1-en-1-yl)- -7',8'-dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 61); (R)-2'-(3-(4-(3,4-difluorophenyl)piperazin-1-yl)cyclopent-1-en-1-yl)-7',8- '-dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 62); (R)-2'-(3-(4-(4-chloro-2-fluorophenyl)piperazin-1-yl)cyclopent-1-en-- 1-yl)-7',8'-dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 63); (R)-2'-(3-(4-(3-chloro-4-fluorophenyl)piperazin-1-yl)cyclopent-1-en-1-yl)- -7',8'-dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 64); (R)-2'-(3-(4-(2,4-dichlorophenyl)piperazin-1-yl)cyclopent-1-en-1-yl)-7',8- '-dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 65); (R)-2'-(3-(4-(4-fluorophenyl)-2,2-dimethylpiperazin-1-yl)cyclopent-1- -en-1-yl)-7',8'-dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-on- e (Compound 66); (R)-2'-(3-(4-(4-fluorophenyl)-2,2-dimethylpiperazin-1-yl)cyclopent-1-en-1- -yl)-7',8'-dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 67); (R)-3-fluoro-N-methyl-4-(4-(3-(4'-oxo-4',5',7',8'-tetrahydro-3'H-spiro[cy- clopropane-1,6'-quinazolin]-2'-yl)cyclopent-2-en-1-yl)piperazin-1-yl)benza- mide (Compound 68); (R)-N,N-dimethyl-4-(4-(3-(4'-oxo-4',5',7',8'-tetrahydro-3'H-spiro[cyclopr- opane-1,6'-quinazolin]-2'-yl)cyclopent-2-en-1-yl)piperazin-1-yl)benzamide (Compound 69); (R)-2'-(3-(4-(4-fluorophenyl)piperazin-1-yl)-4,4-dimethylcyclopent-1-en-1- -yl)-7',8'-dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 70); (S)-2'-(3-(4-(4-fluorophenyl)piperazin-1-yl)-4,4-dimethylcyclopent-1-en-1- -yl)-7',8'-dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 71); (R)-N-methyl-4-(1-(3-(4'-oxo-4',5',7',8'-tetrahydro-3'H-spiro[cyclopropan- e-1,6'-quinazolin]-2'-yl)cyclopent-2-en-1-yl)-1,2,3,6-tetrahydropyridin-4-- yl)benzamide (Compound 72); (R)-2'-(3-(4-(p-tolyl)piperazin-1-yl)cyclopent-1-en-1-yl)-7',8'-dihydro-3- 'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 73); (R)-2'-(3-(4-(4-methoxyphenyl)piperazin-1-yl)cyclopent-1-en-1-yl)-7',8'-d- ihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 74); (R)-2'-(3-(4-(4-fluorophenyl)piperidin-1-yl)cyclopent-1-en-1-yl)-7',8'-di- hydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 75); (R)-N-methyl-6-(4-(3-(4'-oxo-4',5',7',8'-tetrahydro-3'H-spiro[cyclopropan- e-1,6'-quinazolin]-2'-yl)cyclopent-2-en-1-yl)piperazin-1-yl)nicotinamide (Compound 76); (R)-2'-(3-(4-(p-tolyl)piperidin-1-yl)cyclopent-1-en-1-yl)-7',8'-dihydro-3- 'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 77); (R)-2'-(3-(4-(3-fluorophenyl)piperazin-1-yl)cyclopent-1-en-1-yl)-7',8'-di- hydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 78); (R)-2'-(3-(4-(2-chloro-4-fluorophenyl)piperazin-1-yl)cyclopent-1-en-1-yl)- -7',8'-dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 79); (R)-2'-(3-(4-(4-fluoro-3-methylphenyl)piperazin-1-yl)cyclopent-1-en-1-yl)- -7',8'-dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 80); (R)-2'-(3-(4-(2-methylbenzo[d]thiazol-6-yl)piperazin-1-yl)cyclopent-1-en-- 1-yl)-7',8'-dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 81); (R)-2'-(3-(4-(3-chloro-4-methylphenyl)piperazin-1-yl)cyclopent-1-en-1-yl)- -7',8'-dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 82); (R)-2'-(3-(4-(4-fluoro-3-methylphenyl)piperazin-1-yl)cyclopent-1-en-1-yl)- -7',8'-dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 83); (R)-2'-(3-(4-(3-fluoro-4-methylphenyl)piperazin-1-yl)cyclopent-1-en-1-yl)- -7',8'-dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 84); (R)-2'-(3-(4-(m-tolyl)piperazin-1-yl)cyclopent-1-en-1-yl)-7',8'-dihydro-3- 'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 85); (R)-2'-(3-(4-(4-chloro-3-fluorophenyl)piperazin-1-yl)cyclopent-1-en-1-yl)- -7',8'-dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 86); (R)-N-methyl-3-(4-(3-(4'-oxo-4',5',7',8'-tetrahydro-3'H-spiro[cyclopropan- e-1,6'-quinazolin]-2'-yl)cyclopent-2-en-1-yl)piperazin-1-yl)benzamide (Compound 87); (R)-2'-(3-(4-(2-fluoro-4-methylphenyl)piperazin-1-yl)cyclopent-1-en-1-yl)- -7',8'-dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 88); (R)-2-fluoro-N-methyl-4-(4-(3-(4'-oxo-4',5',7',8'-tetrahydro-3'H-spiro[cy- clopropane-1,6'-quinazolin]-2'-y)cyclopent-2-en-1-yl)piperazin-1-yl)benzam- ide (Compound 89); (R)-2'-(3-(4-(o-tolyl)piperazin-1-yl)cyclopent-1-en-1-yl)-7',8'-dihydro-3- 'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 90); (R)-2'-(3-(4-(thiophen-3-yl)piperazin-1-yl)cyclopent-1-en-1-yl)-7',8'-dih- ydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 91); (R)-2'-(3-(4-(2-chloro-4-methylphenyl)piperazin-1-yl)cyclopent-1-en-1-yl)- -7',8'-dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 92); (R)-2'-(3-(4-(2-chloro-3-fluorophenyl)piperazin-1-yl)cyclopent-1-en-1-yl)- -7',8'-dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 93); (R)-2-chloro-N-methyl-4-(4-(3-(4'-oxo-4',5',7',8'-tetrahydro-3'H-spiro[cy- clopropane-1,6'-quinazolin]-2'-yl)cyclopent-2-en-1-yl)piperazin-1-yl)benza- mide (Compound 94); (R)-2'-(3-(4-(4-fluoro-2-methylphenyl)piperazin-1-yl)cyclopent-1-en-1-yl)- -7',8'-dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 95); (R)-2'-(3-(4-(4-chloro-2-methylphenyl)piperazin-1-yl)cyclopent-1-en-1-yl)- -7',8'-dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 96); (R)-N,3-dimethyl-4-(4-(3-(4'-oxo-4',5',7',8'-tetrahydro-3'H-spiro[cyclopr- opane-1,6'-quinazolin]-2'-yl)cyclopent-2-en-1-yl)piperazin-1-yl)benzamide (Compound 97); (R)-N,2-dimethyl-4-(4-(3-(4'-oxo-4',5',7',8'-tetrahydro-3'H-spiro[cyclopr- opane-1,6'-quinazolin]-2'-yl)cyclopent-2-en-1-yl)piperazin-1-yl)benzamide (Compound 98); (R)-2'-(3-(4-(3-chloro-2-fluorophenyl)piperazin-1-yl)cyclopent-1-en-1-yl)- -7',8'-dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 99); (R)-2'-(3-(4-(2,3-difluorophenyl)piperazin-1-yl)cyclopent-1-en-1-yl)-7',8- '-dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 100); (R)-2'-(3-(4-(thiazol-2-yl)piperazin-1-yl)cyclopent-1-en-1-yl)-7',8- '-dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 101); (R)-2'-(3-(4-(4-methylthiazol-2-yl)piperazin-1-yl)cyclopent-1-en-1-- yl)-7',8'-dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 102); (R)-5-chloro-N-methyl-6-(4-(3-(4'-oxo-4',5',7',8'-tetrahydro-3'H-spiro[cy- clopropane-1,6'-quinazolin]-2'-yl)cyclopent-2-en-1-yl)piperazin-1-yl)nicot- inamide (Compound 103); (R)-N-methyl-2-(4-(3-(4'-oxo-4',5',7',8'-tetrahydro-3'H-spiro[cyclopropan- e-1,6'-quinazolin]-2'-yl)cyclopent-2-en-1-yl)piperazin-1-yl)thiazole-5-car- boxamide (Compound 104); (R)-N-methyl-2-(4-(3-(4'-oxo-4',5',7',8'-tetrahydro-3'H-spiro[cyclopropan- e-1,6'-quinazolin]-2'-yl)cyclopent-2-en-1-yl)piperazin-1-yl)thiazole-4-car- boxamide (Compound 105); (R)-2'-(3-(4-(2,5-difluorophenyl)piperazin-1-yl)cyclopent-1-en-1-yl)-7',8- '-dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 106); (R)-2'-(3-(4-(3,5-dichloropyridin-2-yl)piperazin-1-yl)cyclopent-1-e- n-1-yl)-7',8'-dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 107); (R)-2'-(3-(4-(3-fluoro-2-methylphenyl)piperazin-1-yl)cyclopent-1-en-1-yl)- -7',8'-dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 108); (R)-2'-(3-(4-(3,5-difluorophenyl)piperazin-1-yl)cyclopent-1-en-1-yl)-7',8- '-dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 109); (R)-2'-(3-(4-(2,6-difluorophenyl)piperazin-1-yl)cyclopent-1-en-1-yl- )-7',8'-dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 110); (R)-3-fluoro-4-(4-(3-(4'-oxo-4',5',7',8'-tetrahydro-3'H-spiro[cyclopropan- e-1,6'-quinazolin]-2'-yl)cyclopent-2-en-1-yl)piperazin-1-yl)benzonitrile (Compound 111); (R)-5-fluoro-N-methyl-6-(4-(3-(4'-oxo-4',5',7',8'-tetrahydro-3'H-spiro[cy- clopropane-1,6'-quinazolin]-2'-yl)cyclopent-2-en-1-yl)piperazin-1-yl)nicot- inamide (Compound 112); (R)-2'-(3-(4-(5-methylthiazol-2-yl)piperazin-1-yl)cyclopent-1-en-1-yl)-7'- ,8'-dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 113); (R)-2'-(3-(4-(4-fluoro-3-methoxyphenyl)piperazin-1-yl)cyclopent-1-e- n-1-yl)-7',8'-dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 114); (R)-2'-(3-(4-(3-chloro-5-fluorophenyl)piperazin-1-yl)cyclopent-1-en-1-yl)- -7',8'-dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 115); (R)-2'-(3-(4-(2-fluorophenyl)piperazin-1-yl)cyclopent-1-en-1-yl)-7',8'-di- hydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 116); (R)-2'-(3-(4-phenylpiperazin-1-yl)cyclopent-1-en-1-yl)-7',8'-dihydro-3'H-- spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 117); 2'-((1R,3 S)-3-(4-(4-chlorophenyl)piperazin-1-yl)cyclopentyl)-7',8'-dihydro-3'H-spi- ro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 118); 2'-((1 S ,3S)-3-(4-(4-chlorophenyl)piperazin-1-yl)cyclopentyl)-7',8'-dihydro-3'H-s- piro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 119); 2'-((1S ,3R)-3-(4-(4-chlorophenyl)piperazin-1-yl)cyclopentyl)-7',8'-dihydro-3'H-s- piro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 120); 2'-((1R,3R)-3-(4-(4-chlorophenyl)piperazin-1-yl)cyclopentyl)-7',8'-dihydr- o-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 121); (R)-2'-(3-(4-(2-chlorophenyl)piperazin-1-yl)cyclopent-1-en-1-yl)-7',8'-di- hydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 122); (R)-2'-(3-(4-(5-fluoro-2-methylphenyl)piperazin-1-yl)cyclopent-1-en-1-yl)- -7',8'-dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 123); (R)-2'-(3-(4-(5-methylpyridin-2-yl)piperazin-1-yl)cyclopent-1-en-1-yl)-7'- ,8'-dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 124); (R)-2'-(3-(4-(4-methylpyridin-2-yl)piperazin-1-yl)cyclopent-1-en-1-- yl)-7',8'-dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 125); (R)-2'-(3-(4-(3-fluoro-5-methylphenyl)piperazin-1-yl)cyclopent-1-en-1-yl)- -7',8'-dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 126); (R)-2-fluoro-4-(4-(3-(4'-oxo-4',5',7',8'-tetrahydro-3'H-spiro[cyclopropan- e-1,6'-quinazolin]-2'-yl)cyclopent-2-en-1-yl)piperazin-1-yl)benzonitrile (Compound 127); (R)-2'-(3-(4-(pyrimidin-2-yl)piperazin-1yl)cyclopent-1-en-1-yl)-7',8'-dih- ydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 128); (R)-2'-(3-(4-(2-methylpyridin-3-yl)piperazin-1-yl)cyclopent-1-en-1-yl)-7'- ,8'-dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 129); (R)-N-methyl-2-(4-(3-(4'-oxo-4',5',7',8'-tetrahydro-3'H-spiro[cyclo- propane-1,6'-quinazolin]-2'-yl)cyclopent-2-en-1-yl)piperazin-1-yl)isonicot- inamide (Compound 130); (R)-N-methyl-2-(4-(3-(4'-oxo-4',5',7',8'-tetrahydro-3'H-spiro[cyclopropan- e-1,6'-quinazolin]-2'-yl)cyclopent-2-en-1-yl)piperazin-1-yl)nicotinamide (Compound 131); (R)-2'-(3-(4-(3-methylpyridin-2-yl)piperazin-1-yl)cyclopent-1-en-1-yl)-7'- ,8'-dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 132); (R)-2'-(3-(4-(4-fluoro-2-methoxyphenyl)piperazin-1-yl)cyclopent-1-e- n-1-yl)-7',8'-dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'1(5'H)-one (Compound 133); (R)-3-chloro-N-methyl-4-(4-(3-(4'-oxo-4',5',7',8'-tetrahydro-3'H-spiro[cy- clopropane-1,6'-quinazolin]-2'-yl)cyclopent-2-en-1-yl)piperazin-1-yl)benza- mide (Compound 134); (R)-2'-(3-(4-(5-ethylpyrimidin-2-yl)piperazin-1-yl)cyclopent-1-en-1-yl)-7- ',8'-dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 135); (R)-2'-(3-(4-(3,4-dimethylphenyl)piperazin-1-yl)cyclopent-1-en-1-yl- )-7',8'-dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 136); (R)-2'-(3-(4-(5-fluoro-4-methylpyridin-2-yl)piperazin-1-yl)cyclopent-1-en- -1-yl)-7',8'-dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 137); (R)-2'-(3-(4-(5-chloro-2-fluorophenyl)piperazin-1-yl)cyclopent-1-en-1-yl)- -7',8'-dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 138); (R)-2'-(3-(4-(2-chloro-6-fluorophenyl)piperazin-1-yl)cyclopent-1-en-1-yl)- -7',8'-dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 139); (R)-2'-(3-(4-(2,3-dimethylphenyl)piperazin-1-yl)cyclopent-1-en-1-yl)-7',8- '-dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 140); (R)-2'-(3-(4-(5-chloro-4-methylpyridin-2-yl)piperazin-1-yl)cyclopen- t-1-en-1-yl)-7',8'-dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)- -one (Compound 141); (R)-2'-(3-(4-(5-fluoropyridin-3-yl)piperazin-1-yl)cyclopent-1-en-1-yl)-7'- ,8'-dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 142); (R)-2'-(3-(4-(3-chloro-2-methylphenyl)piperazin-1-yl)cyclopent-1-en- -1-yl)-7',8'-dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 143); (R)-2'-(3-(4-(2,5-dimethylphenyl)piperazin-1-yl)cyclopent-1-en-1-yl)-7',8- '-dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 144); (R)-2'-(3-(4-(6-methylpyridin-2-yl)piperazin-1-yl)cyclopent-1-en-1-- yl)-7',8'-dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 145); (R)-2'-(3-(4-(5-chloro-3-fluoropyridin-2-yl)piperazin-1-yl)cyclopent-1-en- -1-yl)-7',8'-dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 146); (R)-2'-(3-(4-(2-methylpyridin-4-yl)piperazin-1-yl)cyclopent-1-en-1-yl)-7'- ,8'-dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 147); (R)-2'-(3-(4-(4-(thiophen-3-yl)phenyl)piperazin-1-yl)cyclopent-1-en- -1-yl)-7',8'-dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 148); 2'-((1S,3S)-3-(4-(4-fluorophenyl)piperazin-1-yl)cyclopentyl)-7',8'-dihydr- o-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 149); 2'-((1R,3S)-3-(4-(4-fluorophenyl)piperazin-1-yl)cyclopentyl)-7',8'-dihydr- o-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 150); 2'-((1S,3R)-3-(4-(4-fluorophenyl)piperazin-1-yl)cyclopentyl)-7',8'-dihydr- o-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 151); 2'-((1R,3R)-3-(4-(4-fluorophenyl)piperazin-1-yl)cyclopentyl)-7',8'-dihydr- o-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 152); 2'-((1R,3S)-3-(4-(3-fluorophenyl)piperazin-1-yl)cyclopentyl)-7',8'-dihydr- o-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 153); 2'-((1S,3S)-3-(4-(3-fluorophenyl)piperazin-1-yl)cyclopentyl)-7',8'-dihydr- o-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 154); 2'-((1S,3R)-3-(4-(3-fluorophenyl)piperazin-1-yl)cyclopentyl)-7',8'-dihydr- o-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 155); 2'-((1R,3R)-3-(4-(3-fluorophenyl)piperazin-1-yl)cyclopentyl)-7',8'-dihydr- o-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 156); (R)-2'-(3-(4-(6-phenylpyridin-3-yl)piperazin-1-yl)cyclopent-1-en-1-yl)-7'- ,8'-dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 157); (R)-2'-(3-(4-([1,1'-biphenyl]-4-yl)piperazin-1-yl)cyclopent-1-en-1-- yl)-7',8'-dihydro-3'H-spiro[cyclopropane-1,6'-quinazolin]-4'(5'H)-one (Compound 158); and 2'-(3-(3-(4-chlorophenyl)-3,8-diazabicyclo [3.2.1]octan-8-yl)cyclopent-1-en-1-yl)-7',8'-dihydro-3'H-spiro[cyclopropa- ne-1,6'-quinazolin]-4'(5'H)-one (Compound 159). 9. A pharmaceutical composition comprising the compound of claim 1, its tautomeric form, its stereoisomer, or its pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier. 10. The pharmaceutical composition of claim 9, further comprising at least one known anticancer agent, or a pharmaceutically acceptable salt of said agent. 11. The pharmaceutical composition of claim 9, further comprising at least one compound selected from busulfan, melphalan, chlorambucil, cyclophosphamide, ifosfamide, temozolomide, bendamustine, cisplatin, mitomycin C, bleomycin, carboplatin, camptothecin, irinotecan, topotecan, doxorubicin, epirubicin, aclarubicin, mitoxantrone, elliptinium, etoposide, 5-azacytidine, gemcitabine, 5-fluorouracil, methotrexate, 5-fluoro-2'-deoxy-uridine, fludarabine, nelarabine, ara-C, alanosine, pralatrexate, pemetrexed, hydroxyurea, thioguanine, colchicine, vinblastine, vincristine, vinorelbine, paclitaxel, ixabepilone, cabazitaxel, docetaxel, campath, imatinib, gefitinib, erlotinib, lapatinib, sorafenib, sunitinib, nilotinib, dasatinib, pazopanib, temsirolimus, everolimus, vorinostat, romidepsin, tamoxifen, letrozole, fulvestrant, mitoguazone, octreotide, retinoic acid, arsenic trioxide, zoledronic acid, bortezomib, thalidomide and lenalidomide. 12. A pharmaceutical composition comprising the compound of claim 2, its tautomeric form, its stereoisomer, or its pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier. 13. A pharmaceutical composition comprising the compound of claim 8, its tautomeric form, its stereoisomer, or its pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier. 14. A method of treating a cancer comprising administering to the mammal in need of such treatment a therapeutically effective amount of a compound, its tautomeric form, its stereoisomer, or its pharmaceutically acceptable sat, of claim 1 wherein the cancer is selected from liver cancer, melanoma, Hodgkin's disease, non-Hodgkin's lymphomas, acute or chronic lymphocytic leukaemia, multiple myeloma, neuroblastoma, breast carcinoma, ovarian carcinoma, lung carcinoma, Wilms' tumor, cervical carcinoma, testicular carcinoma, soft-tissue sarcoma, primary macroglobulinemia, bladder carcinoma, chronic granulocytic leukaemia, primary brain carcinoma, small-cell king carcinoma, stomach carcinoma, colon carcinoma, malignant pancreatic insulinoma, malignant carcinoid carcinoma, malignant melanoma, chorio carcinoma, mycosis fungoide, head or neck carcinoma, osteogenic sarcoma, pancreatic carcinoma, acute granulocytic leukaemia, hairy cell leukemia, neuroblastoma, rhabdomyosarcoma, Kaposi's sarcoma, genitourinary carcinoma, thyroid carcinoma, esophageal carcinoma, malignant hypercalcemia, cervca hyperplasia, renal cell carcinoma, endometrial carcinoma, polycythemia vera, essential thrombocytosis, adrenal cortex carcinoma, skin cancer, or prostatic carcinoma. 15. A method of potentiating the efficacy of chemotherapeutic regimen for a patient undergoing chemotherapeutic treatment comprising co-administering to the patient an effective amount of a compound, tautomer, stereoisomer, or salt of claim 1. 16. The method of claim 15, wherein the compound, tautomer, stereoisomer, or salt is co-administered simultaneously, sequentially, or cyclically with the anticancer agent. 17. The method of claim 16, wherein the anticancer agent is selected from busulfan, melphalan, chlorambucil, cyclophosphamide, ifosfamide, temozolomide, bendamustine, cisplatin, mitomycin C, bleomycin, carboplatin, camptothecin, irinotecan, topotecan, doxorubicin, epirubicin, aclarubicin, mitoxantrone, elliptinium, etoposide, 5-azacytidine, gemcitabine, 5-fluorouracil, methotrexate, 5-fluoro-2'-deoxy-uridine, fludarabine, nelarabine, ara-C, alanosine, pralatrexate, pemetrexed, hydroxyurea, thioguanine, colchicine, vinblastine, vincristine, vinorelbine, paclitaxel, ixabepilone, cabazitaxel, docetaxel, campath, panitumumab, ofatumumab, bevacizumab, trastuzumab, adalimumab, imatinib, gefitinib, erlotinib, lapatinib, sorafenib, sunitinib, nilotinib, dasatinib, pazopanib, temsirolimus, everolimus, vorinostat, romidepsin, tamoxifen, letrozole, fulvestrant, mitoguazone, octreotide, retinoic acid, arsenic trioxide, zoledronic acid, bortezomib, thalidomide and lenalidomide. 18. A method for sensitizing a patient who has developed or is likely to develop resistance for chemotherapic agents comprising administering an effective amount of a compound, its tautomeric form, its stereoisomer, or its pharmaceutically acceptable salt, of claim 1. 19. A method of treating a cancer comprising administering to the mammal in need of such treatment a therapeutically effective amount of a compound, its tautomeric form, its stereoisorner, or its pharmaceutically acceptable salt, of claim 8 wherein the cancer is selected from liver cancer, melanoma, Hodgkin's disease, non-Hodgkin's lymphomas, acute or chronic lymphocytic leukaemia, multiple myeloma, neuroblastorna, breast carcinoma, ovarian carcinoma, lung carcinoma, Wilms' tumor, cervical carcinoma, testicular carcinoma, soft-tissue sarcoma, primary macroalobulinemia, bladder carcinoma, chronic granulocytic leukaemia, primary brain carcinoma, small-cell king carcinoma, stomach carcinoma, colon carcinoma, malignant pancreatic insulinoma, malignant carcinoid carcinoma, malignant melanoma, chorio carcinoma, mycosis fungoide, head or neck carcinoma, osteogenic sarcoma, pancreatic carcinoma, acute granulocytic leukaemia, hairy cell leukemia, neuroblastoma, rhabdomyosarcoma. Kaposi's sarcoma, genitourinary carcinoma, thyroid carcinoma, esophageal carcinoma, malignant hypercalcemia, cervca hyperplasia, renal cell carcinoma, endometrial carcinoma, polycythemia vera, essential thrombocytosis, adrenal cortex carcinoma, skin cancer, or prostatic carcinoma.

Details for Patent 9,359,367

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	09/25/1998		2032-07-09
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	02/10/2017		2032-07-09
Genzyme Corporation	CAMPATH	alemtuzumab	Injection	103948	05/07/2001		2032-07-09
Genzyme Corporation	LEMTRADA	alemtuzumab	Injection	103948	11/14/2014		2032-07-09