Substituted Bicyclic Heteroaryl Sulfonamide Derivatives for the Treatment of Cancer

Abstract

The invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof; wherein X.sup.1 is CR.sup.7 or N, X.sup.2 is CR.sup.8 or N, X.sup.3 is CR.sup.9 or N and wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8 and R.sup.9 are as defined in the claims, as well as methods of using the compounds for the treatment of neoplastic diseases such as cancer.

Claims

1. A compound of formula (I) ##STR00085## or a pharmaceutically acceptable salt thereof, wherein R.sup.1 is hydrogen, cyano, formyl, CONH.sub.2, CH.sub.2OH, CH.sub.2OC.sub.1-2 alkyl, C.sub.1-2 alkyl, C.sub.1-2 haloalkyl or ethynyl; R.sup.2 and R.sup.3 are independently C.sub.1-2 alkyl; or R.sup.2 and R.sup.3 together with the carbon atom to which they are attached form cyclopropyl or oxetanyl; X.sup.1 is CR.sup.7 or N; R.sup.7 is hydrogen or fluoro; X.sup.2 is CR.sup.8 or N; R.sup.8 is hydrogen or fluoro; X.sup.3 is CR.sup.9 or N; R.sup.9 is hydrogen, halogen, cyano, N(R.sup.m)R.sup.n, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkoxy, C.sub.2-4 alkynyl, C.sub.3-6 cycloalkyl, phenyl, heteroaryl, heterocyclyl, fused heterocyclyl, spiro heterocyclyl or bridged heterocyclyl, wherein the cycloalkyl, phenyl, heteroaryl, heterocyclyl, fused heterocyclyl, spiro heterocyclyl and bridged heterocyclyl are optionally substituted with R.sup.a, R.sup.b and/or R.sup.c; R.sup.a is hydrogen, N(R.sup.m)R.sup.n, C.sub.1-6 alkyl, hydroxy, C.sub.1-6 alkoxy, halogen, cyano, oxo, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, hydroxyC.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, heteroaryl, heterocyclyl, C(O)R.sup.d, C(O)OR.sup.e, C(O)N(R.sup.f)R.sup.g, S(O).sub.2N(R.sup.h)R.sup.n, or C.sub.1-6 alkyl-N(R.sup.j)R.sup.k; R.sup.b and R.sup.c are independently hydrogen, N(R.sup.m)R.sup.n, C.sub.1-6 alkyl, C.sub.1-4 alkyl-N(R.sup.m)R.sup.n, hydroxy, C.sub.1-6 alkoxy, halogen, cyano, C.sub.1-6 haloalkyl or C.sub.1-6 haloalkoxy; R.sup.d is hydrogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.3-6 cycloalkyl, phenyl, heteroaryl or heterocyclyl; R.sup.c is hydrogen or C.sub.1-6 alkyl; R.sup.f, R.sup.g, R.sup.h, R.sup.i, R.sup.j, R.sup.k, R.sup.m and R.sup.n are each independently hydrogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.3-6 cycloalkyl, aminoC.sub.1-6 alkyl or hydroxyC.sub.1-6 alkyl; or R.sup.f and R.sup.g, R.sup.h and R.sup.i, or R.sup.j and R.sup.k together with the nitrogen atom to which they are attached form heterocyclyl; wherein (i) the cycloalkyl, heteroaryl and heterocyclyl of R.sup.a; (ii) the alkyl, haloalkyl, cycloalkyl, phenyl, heteroaryl and heterocyclyl of R.sup.d; (iii) the heterocyclyl formed by R.sup.f and R.sup.g, R.sup.h and R.sup.i, or R.sup.j and R.sup.k combining with the nitrogen to which they are attached; are each ((i), (ii), (iii)) optionally substituted with 1, 2, 3 or 4 substituents independently selected from C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, C.sub.1-6 alkyl-NH.sub.2, C.sub.1-6 alkyl-NH(C.sub.1-4 alkyl), C.sub.1-6 alkyl-N(C.sub.1-4 alkyl).sub.2, hydroxy, oxo, C.sub.1-6 alkoxy, halogen, cyano, amino, NH(C.sub.1-4 alkyl), N(C.sub.1-4 alkyl).sub.2, C.sub.1-6 haloalkyl and C.sub.1-6 haloalkoxy; R.sup.4 is hydrogen or the group -L.sup.1A-L.sup.2A-L.sup.3A; L.sup.1A is absent or is C.sub.1-3 alkylene optionally substituted by C.sub.1-2 alkyl or oxo; L.sup.2A is absent or is O, S, S(O), S(O).sub.2, N(R.sup.a1), C(O), C(O)O, OC(O), C(O)N(R.sup.a1), N(R.sup.a1)C(O), N(R.sup.a1)C(O)N(R.sup.b1), S(O).sub.2N(R.sup.a1), or N(R.sup.a1)S(O).sub.2; R.sup.a1 and R.sup.b1 are each independently hydrogen or C.sub.1-2 alkyl; L.sup.3A is hydrogen, C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, phenyl, heterocyclyl or heteroaryl, wherein L.sup.3A is optionally substituted by one or more substituents independently selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, C.sub.1-4 alkyl, N(R.sup.c1)R.sup.d1, OR.sup.c1, C(O)R.sup.c1, C(O)OR.sup.c1, OC(O)R.sup.c1, C(O)N(R.sup.d1)R.sup.c1, N(R.sup.d1)C(O)R.sup.c1, S(O).sub.yR.sup.c1, S(O).sub.2N(R.sup.d1)R.sup.c1, N(R.sup.d1)S(O).sub.2R.sup.c1 and (CH.sub.2).sub.zN(R.sup.d1)R.sup.c1; R.sup.c1 and R.sup.d1 are each independently hydrogen or C.sub.1-4 alkyl; y is 0, 1 or 2; z is 1, 2 or 3; R.sup.5 is hydrogen or the group -L.sup.1B-L.sup.2B-L.sup.3B; L.sup.1B is absent or is C.sub.1-3 alkylene optionally substituted by C.sub.1-2 alkyl or oxo; L.sup.2B is absent or is O, S, S(O), S(O).sub.2, N(R.sup.a2), C(O), C(O)O, OC(O), C(O)N(R.sup.a2), N(R.sup.a2)C(O), N(R.sup.a2)C(O)N(R.sup.b2), S(O).sub.2N(R.sup.a2), or N(R.sup.a2)S(O).sub.2; R.sup.a2 and R.sup.b2 are each independently hydrogen or C.sub.1-2 alkyl; L.sup.3B is hydrogen, C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, phenyl, heterocyclyl or heteroaryl, wherein L.sup.3B is optionally substituted by one or more substituents independently selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, C.sub.1-4 alkyl, N(R.sup.c2)R.sup.d2, OR.sup.c2, C(O)R.sup.c2, C(O)OR.sup.c2, OC(O)R.sup.c2, C(O)N(R.sup.d2)R.sup.c2, N(R.sup.d2)C(O)R.sup.c2, S(O).sub.yR.sup.c2, S(O).sub.2N(R.sup.d2)R.sup.c2, N(R.sup.d2)S(O).sub.2R.sup.c2 and (CH.sub.2).sub.zN(R.sup.d2)R.sup.c2; R.sup.c2 and R.sup.d2 are each independently hydrogen or C.sub.1-4 alkyl; y is 0, 1 or 2; z is 1, 2 or 3; R.sup.6 is hydrogen or the group -L.sup.1C-L.sup.2C-L.sup.3C; L.sup.1C is absent or is C.sub.1-3 alkylene optionally substituted by C.sub.1-2 alkyl or oxo; L.sup.2C is absent or is O, S, S(O), S(O).sub.2, N(R.sup.a3), C(O), C(O)O, OC(O), C(O)N(R.sup.a3), N(R.sup.a3)C(O), N(R.sup.a3)C(O)N(R.sup.b3), S(O).sub.2N(R.sup.a3), or N(R.sup.a3)S(O).sub.2; R.sup.a3 and R.sup.b3 are each independently hydrogen or C.sub.1-2 alkyl; L.sup.3C is hydrogen, C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, phenyl, heterocyclyl or heteroaryl, wherein L.sup.3C is optionally substituted by one or more substituents independently selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, C.sub.1-4 alkyl, N(R.sup.c3)R.sup.d3, OR.sup.c3, C(O)R.sup.c3, C(O)OR.sup.c3, OC(O)R.sup.c3, C(O)N(R.sup.d3)R.sup.c3, N(R.sup.d3)C(O)R.sup.c3, S(O).sub.yR.sup.c3, S(O).sub.2N(R.sup.d3)R.sup.c3, N(R.sup.d3)S(O).sub.2R.sup.c3 and (CH.sub.2).sub.zN(R.sup.d3)R.sup.c3; R.sup.c3 and R.sup.d3 are each independently hydrogen or C.sub.1-4 alkyl; y is 0, 1 or 2; z is 1, 2 or 3; with the proviso that the groups -L.sup.1A-L.sup.2A-L.sup.3A-L.sup.1B-L.sup.2B-L.sup.3B, and -L.sup.1C-L.sup.2C-L.sup.3C do not contain an OO, SO, OS or SS unit as a linking unit within the group; the group -L.sup.1A-L.sup.2A-L.sup.3A does not place an ON or SN unit adjacent to the ring nitrogen atom connected to R.sup.4; the group -L.sup.1B-L.sup.2B-L.sup.3B does not place an N, O or S atom adjacent to the oxime oxygen atom connected to R.sup.5, and -L.sup.1C-L.sup.2C-L.sup.3C does not place an ON or SN unit adjacent to the ring nitrogen atom connected to R.sup.6.

2. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein X.sup.1 is CR.sup.7, X.sup.2 is CR.sup.8 and X.sup.3 is CR.sup.9.

3. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R.sup.1 is cyano, C.sub.1-2 alkyl or ethynyl.

4. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R.sup.2 and R.sup.3 together with the carbon atom to which they are attached form cyclopropyl or oxetanyl.

5. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R.sup.9 is hydrogen, halogen, cyano, C.sub.1-4 alkyl, C.sub.1-4haloalkyl, C.sub.1-4 alkoxy, C.sub.1-4haloalkoxy, C.sub.2-4 alkynyl, C.sub.3-6 cycloalkyl, phenyl, 5- to 6-membered heteroaryl containing 1, 2 or 3 heteroatoms as ring atoms independently selected from N, S and O, 5- to 7-membered monocyclic heterocyclyl containing 1, 2 or 3 heteroatoms as ring atoms independently selected from N, S and O, wherein the cycloalkyl, phenyl, heteroaryl and heterocyclyl are optionally substituted with R.sup.a, R.sup.b and/or R.sup.c; or R.sup.9 is spiro heterocyclyl, wherein the first ring connected to X.sup.3 is a 5- to 7-membered monocyclic heterocyclyl containing 1, 2 or 3 heteroatoms as ring atoms independently selected from N, S and O and the second ring is connected to the first ring with a common carbon atom and is a 3- to 6-membered monocyclic cycloalkyl or a 3- to 6-membered monocyclic heterocyclyl containing 1, 2 or 3 heteroatoms as ring atoms independently selected from N, S and O, wherein spiro heterocyclyl is optionally substituted by R.sup.a, R.sup.b and/or R.sup.c.

6. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 5, wherein R.sup.9 is hydrogen, halogen, cyano, phenyl, 5- to 6-membered heteroaryl containing 1 or 2 heteroatoms as ring atoms selected from N, wherein the phenyl and 6-membered heteroaryl are optionally substituted at the para position with respect to the connection to the rest of the molecule with R.sup.a and are additionally optionally substituted with R.sup.b, and the 5-membered heteroaryl is optionally substituted at the 3 position distal to the connection to the rest of the molecule with R.sup.a and is additionally optionally substituted with R.sup.b or is the moiety (R.sup.9a) or the moiety (R.sup.9b): ##STR00086## wherein Z.sup.1 is N or CH, Z.sup.2 is N(R.sup.a), O, S, CH(R.sup.a) or C(R.sup.x)(R.sup.y), wherein R.sup.x and R.sup.y together form a 4- to 6-membered monocyclic heterocyclyl containing one heteroatom selected from N, O and S.

7. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R.sup.a is hydrogen, N(R.sup.m)R.sup.n, C.sub.1-6 alkyl, oxo, C(O)R.sup.d, C(O)N(R.sup.f)R.sup.g or C.sub.1-6 alkyl-N(R.sup.j)R.sup.k; R.sup.b is hydrogen, amino, NH(C.sub.1-4 alkyl), N(C.sub.1-4 alkyl).sub.2, C.sub.1-4 alkyl, C.sub.1-4 alkyl-NH.sub.2, C.sub.1-4 alkyl-NH(C.sub.1-4 alkyl) or C.sub.1-4 alkyl-N(C.sub.1-4 alkyl).sub.2; R.sup.c is hydrogen or C.sub.1-4 alkyl; R.sup.d is hydrogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.3-6 cycloalkyl, phenyl, heteroaryl or heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl, phenyl, heteroaryl and heterocyclyl are optionally substituted with 1, 2, 3 or 4 substituents independently selected from C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, C.sub.1-6 alkyl-NH.sub.2, C.sub.1-6 alkyl-NH(C.sub.1-4 alkyl), C.sub.1-6 alkyl-N(C.sub.1-4 alkyl).sub.2, hydroxy, oxo, C.sub.1-6 alkoxy, halogen, cyano, amino, NH(C.sub.1-4 alkyl), N(C.sub.1-4 alkyl).sub.2, C.sub.1-6 haloalkyl and C.sub.1-6 haloalkoxy; R.sup.f is hydrogen or C.sub.1-4 alkyl; R.sup.g is hydrogen or C.sub.1-4 alkyl; R.sup.j is hydrogen or C.sub.1-4 alkyl; R.sup.k is hydrogen or C.sub.1-4 alkyl; R.sup.m is hydrogen or C.sub.1-4 alkyl; and R.sup.n is hydrogen or C.sub.1-4 alkyl.

8. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R.sup.4 is the group -L.sup.1A-L.sup.2A-L.sup.3A, L.sup.2A, L.sup.2B and L.sup.2C are absent; L.sup.3A is cycloalkyl, phenyl, heterocyclyl or heteroaryl, each optionally substituted; no more than two of L.sup.3A L.sup.3B, and L.sup.3C are cycloalkyl, phenyl, heterocyclyl or heteroaryl, each optionally substituted; and L.sup.3C is not cycloalkyl, phenyl, heterocyclyl or heteroaryl when R.sup.9 is cycloalkyl, phenyl, heteroaryl, heterocyclyl, fused heterocyclyl, spiro heterocyclyl or bridged heterocyclyl.

9. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R.sup.4 is the group -L.sup.1A-L.sup.2A-L.sup.3A, wherein L.sup.3A is cycloalkyl, phenyl, heterocyclyl or heteroaryl, each optionally substituted; R.sup.5 is hydrogen or the group -L.sup.1B-L.sup.2B-L.sup.3B, wherein L.sup.3B is cycloalkyl, phenyl, heterocyclyl or heteroaryl, each optionally substituted, or -L.sup.1B-L.sup.2B-L.sup.3B is C.sub.1-6 alkyl; and R.sup.6 is hydrogen or C.sub.1-6 alkyl.

10. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R.sup.4 is the group -L.sup.1A-L.sup.2A-L.sup.3A; L.sup.1A is C.sub.1-3 alkylene; L.sup.2A is absent; L.sup.3A is phenyl or a 5- to 6-membered heteroaryl containing 1, 2 or 3 heteroatoms as ring atoms independently selected from N, O and S, wherein L.sup.3A is optionally substituted by 1, 2 or 3 substituents independently selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, C.sub.1-4 alkyl, N(R.sup.c1)R.sup.d1, OR.sup.c1, C(O)R.sup.c1, C(O)OR.sup.c1, OC(O)R.sup.c1, C(O)N(R.sup.d1)R.sup.c1, N(R.sup.d1)C(O)R.sup.c1, S(O).sub.yR.sup.c1, S(O).sub.2N(R.sup.d1)R.sup.c1, N(R.sup.d1)S(O).sub.2R.sup.c1 and (CH.sub.2).sub.zN(R.sup.d1)R.sup.c1; R.sup.c1 is hydrogen or C.sub.1-4 alkyl; R.sup.d1 is hydrogen or C.sub.1-4 alkyl; y is 0, 1 or 2; z is 1, 2 or 3; R.sup.5 is hydrogen or the group -L.sup.1B-L.sup.2B-L.sup.3B; L.sup.1B is C.sub.1-3alkylene; L.sup.2B is absent; L.sup.3B is phenyl or a 5- to 6-membered heteroaryl containing 1, 2 or 3 heteroatoms as ring atoms independently selected from N, O and S, wherein L.sup.3B is optionally substituted by 1, 2 or 3 substituents independently selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, C.sub.1-4 alkyl, N(R.sup.c2)R.sup.d2, OR.sup.c2, C(O)R.sup.c2, C(O)OR.sup.c2, OC(O)R.sup.c2, C(O)N(R.sup.d2)R.sup.c2, N(R.sup.d2)C(O)R.sup.c2, S(O).sub.yR.sup.c2, S(O).sub.2N(R.sup.d2)R.sup.c2, N(R.sup.d2)S(O).sub.2R.sup.c2 and (CH.sub.2).sub.zN(R.sup.d2)R.sup.c2; R.sup.c2 is hydrogen or C.sub.1-4 alkyl; R.sup.d2 is hydrogen or C.sub.1-4 alkyl; y is 0, 1 or 2; z is 1, 2 or 3; or the group -L.sup.1B-L.sup.2B-L.sup.3B is C.sub.1-6 alkyl; and R.sup.6 is hydrogen or the group -L.sup.1C-L.sup.2C-L.sup.3C, wherein -L.sup.1C-L.sup.2C-L.sup.3C is C.sub.1-6 alkyl.

11. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R.sup.1 is cyano, C.sub.1-2 alkyl or ethynyl; R.sup.2 and R.sup.3 together with the carbon atom to which they are attached form cyclopropyl or oxetanyl; X.sup.1 is CR.sup.7; X.sup.2 is CR.sup.8; X.sup.3 is CR.sup.9; R.sup.7 and R.sup.8 are hydrogen; R.sup.9 is hydrogen, halogen, cyano, N(R.sup.m)R.sup.n, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkoxy, C.sub.2-4 alkynyl, C.sub.3-6 cycloalkyl, phenyl, 5- to 6-membered heteroaryl containing 1, 2 or 3 heteroatoms as ring atoms independently selected from N, S and O, 5- to 6-membered monocyclic heterocyclyl containing 1, 2 or 3 heteroatoms as ring atoms independently selected from N, S and O, wherein the cycloalkyl, phenyl, heteroaryl and heterocyclyl are optionally substituted with R.sup.a, R.sup.b and/or R.sup.c; or R.sup.9 is spiro heterocyclyl, wherein the first ring connected to X.sup.3 is a 5- to 7-membered monocyclic heterocyclyl containing 1, 2 or 3 heteroatoms as ring atoms independently selected from N, S and O and the second ring is connected to the first ring with a common carbon atom and is a 3- to 6-membered monocyclic cycloalkyl or a 3- to 6-membered monocyclic heterocyclyl containing 1, 2 or 3 heteroatoms as ring atoms independently selected from N, S and O, wherein spiro heterocyclyl is optionally substituted by R.sup.a, R.sup.b and/or R.sup.c; R.sup.a is hydrogen, N(R.sup.m)R.sup.n, C.sub.1-6 alkyl, oxo, C(O)R.sup.d, C(O)N(R.sup.f)R.sup.g or C.sub.1-6 alkyl-N(R.sup.j)R.sup.k; R.sup.b is hydrogen-amino, NH(C.sub.1-4 alkyl), N(C.sub.1-4 alkyl).sub.2, C.sub.1-4 alkyl, C.sub.1-4 alkyl-NH.sub.2, C.sub.1-4 alkyl-NH(C.sub.1-4 alkyl), C.sub.1-4 alkyl-N(C.sub.1-4 alkyl).sub.2; R.sup.c is hydrogen: R.sup.d is hydrogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.3-6 cycloalkyl, phenyl, heteroaryl or heterocyclyl, wherein the cycloalkyl, phenyl, heteroaryl and heterocyclyl are optionally substituted with 1, 2 or 3 substituents independently selected from C.sub.1-6 alkyl, C.sub.1-6 alkyl-NH.sub.2, C.sub.1-6 alkyl-NH(C.sub.1-4 alkyl), C.sub.1-6 alkyl-N(C.sub.1-4 alkyl).sub.2, hydroxy, C.sub.1-6 alkoxy, halogen, cyano, amino, NH(C.sub.1-4 alkyl), N(C.sub.1-4 alkyl).sub.2, C.sub.1-6 haloalkyl and C.sub.1-6 haloalkoxy; R.sup.f is hydrogen or C.sub.1-4 alkyl; R.sup.g is hydrogen or C.sub.1-4 alkyl; R.sup.j is hydrogen or C.sub.1-4 alkyl; R.sup.k is hydrogen or C.sub.1-4 alkyl; each R.sup.m is independently hydrogen or C.sub.1-4 alkyl; each R.sup.n is independently hydrogen or C.sub.1-4 alkyl; R.sup.4 is the group -L.sup.1A-L.sup.2A-L.sup.3A; L.sup.1A is C.sub.1-3alkylene; L.sup.1A is absent; L.sup.3A is phenyl or 5- to 6-membered heteroaryl containing 1, 2 or 3 heteroatoms as ring atoms independently selected from N, S and O, wherein L.sup.3A is optionally substituted by 1, 2 or 3 substituents independently selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, C.sub.1-4 alkyl, N(R.sup.c1)R.sup.d1, OR.sup.c1, C(O)R.sup.c1, C(O)OR.sup.c1, OC(O)R.sup.c1, C(O)N(R.sup.d1)R.sup.c1, N(R.sup.d1)C(O)R.sup.c1, S(O).sub.yR.sup.c1, S(O).sub.2N(R.sup.d1)R.sup.c1, N(R.sup.d1)S(O).sub.2R.sup.c1 and (CH.sub.2).sub.zN(R.sup.d1)R.sup.c1; or the group -L.sup.1A-L.sup.2A-L.sup.3A is C.sub.1-6 alkyl; R.sup.c1 is hydrogen or C.sub.1-4 alkyl; R.sup.d1 is hydrogen or C.sub.1-4 alkyl; y is 0, 1 or 2; z is 1, 2 or 3; R.sup.5 is hydrogen or the group -L.sup.1B-L.sup.2B-L.sup.3B; L.sup.1B is C.sub.1-3 alkylene; L.sup.2B is absent; L.sup.3B is phenyl or a 5- to 6-membered heteroaryl containing 1, 2 or 3 heteroatoms as ring atoms independently selected from N, O and S, wherein L.sup.3B is optionally substituted by 1, 2 or 3 substituents independently selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, C.sub.1-4 alkyl, N(R.sup.c2)R.sup.d2, OR.sup.c2, C(O)R.sup.c2, C(O)OR.sup.c2, OC(O)R.sup.c2, C(O)N(R.sup.d2)R.sup.c2, N(R.sup.d2)C(O)R.sup.c2, S(O).sub.yR.sup.c2, S(O).sub.2N(R.sup.d2)R.sup.c2, N(R.sup.d2)S(O).sub.2R.sup.c2 and (CH.sub.2).sub.zN(R.sup.d2)R.sup.c2; R.sup.c2 is hydrogen or C.sub.1-4 alkyl; R.sup.d2 is hydrogen or C.sub.1-4 alkyl; y is 0, 1 or 2; z is 1, 2 or 3; or the group -L.sup.1B-L.sup.2B-L.sup.3B is C.sub.1-6 alkyl; R.sup.6 is hydrogen or the group -L.sup.1C-L.sup.2C-L.sup.3C, wherein the group -L.sup.1C-L.sup.2C-L.sup.3C is C.sub.1-6 alkyl.

12. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is selected from 2-Methoxyimino-N-(1-methylcyclopropyl)-3-[(2-methylthiazol-5-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonamide; 2-methoxyimino-N-(3-methyloxetan-3-yl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonamide; 2-[(2,4-dimethylthiazol-5-yl)methoxyimino]-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonamide; 8-chloro-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonamide; 4-[2-methoxyimino-6-[(1-methylcyclopropyl)sulfamoyl]-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazolin-8-yl]-N,N-dimethyl-benzamide; 2-methoxyimino-N-(1-methylcyclopropyl)-4-oxo-3-[[1-(trifluoromethyl)pyrazol-4-yl]methyl]-1H-quinazoline-6-sulfonamide; 2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(3R)-3-methylpiperazin-1-yl]-1H-quinazoline-6-sulfonamide; 2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(3R)-3-methyl-4-(1-methylcyclopropanecarbonyl)piperazin-1-yl]-1H-quinazoline-6-sulfonamide; N-(1-cyanocyclopropyl)-2-methoxyimino-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonamide; 2-ethoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonamide; 2-isopropoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonamide; (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(3R)-4-acetyl-3-methyl-piperazin-1-yl]-1H-quinazoline-6-sulfonamide; (R,E)-2-(methoxyimino)-8-(6-methyl-1,2,3,6-tetrahydropyridin-4-yl)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide/(R,E)-2-(methoxyimino)-8-(2-methyl-1,2,3,6-tetrahydropyridin-4-yl)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; (E)-4-(2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-4-oxo-1,2,3,4-tetrahydroquinazolin-8-yl)-N,N,2-trimethylbenzamide; (E)-4-(2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-4-oxo-1,2,3,4-tetrahydroquinazolin-8-yl)benzamide; (E)-8-(4-acetylphenyl)-2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; (E)-8-(4-(aminomethyl)phenyl)-2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; (E)-5-(2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-4-oxo-1,2,3,4-tetrahydroquinazolin-8-yl)-N,N-dimethylpicolinamide; (E)-6-(2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-4-oxo-1,2,3,4-tetrahydroquinazolin-8-yl)-N,N-dimethylnicotinamide; (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(3R)-3,4-dimethylpiperazin-1-yl]-1H-quinazoline-6-sulfonamide; (E)-8-(4-(1-hydroxy-2-oxocyclobutyl)phenyl)-2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; (E)-5-(2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-4-oxo-1,2,3,4-tetrahydroquinazolin-8-yl)-N,N-dimethyl-1H-imidazole-2-carboxamide; (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(2R)-2-methyl-4-piperidyl]-1H-quinazoline-6-sulfonamide; (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(2R)-1,2-dimethyl-4-piperidyl]-1H-quinazoline-6-sulfonamide; (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(2R)-1-acetyl-2-methyl-4-piperidyl]-1H-quinazoline-6-sulfonamide; (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(2R)-2-methyl-1-(1-methylcyclopropanecarbonyl)-4-piperidyl]-1H-quinazoline-6-sulfonamide; (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(2R)-1,2-dimethyl-3,6-dihydro-2H-pyridin-4-yl]-1H-quinazoline-6-sulfonamide/(2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(6R)-1,6-dimethyl-3,6-dihydro-2H-pyridin-4-yl]-1H-quinazoline-6-sulfonamide; (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(2R)-1-acetyl-2-methyl-3,6-dihydro-2H-pyridin-4-yl]-1H-quinazoline-6-sulfonamide/(2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(6R)-1-acetyl-6-methyl-3,6-dihydro-2H-pyridin-4-yl]-1H-quinazoline-6-sulfonamide; (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(2R)-2-methyl-1-(1-methylcyclopropanecarbonyl)-3,6-dihydro-2H-pyridin-4-yl]-1H-quinazoline-6-sulfonamide/(2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(6R)-6-methyl-1-(1-methylcyclopropanecarbonyl)-3,6-dihydro-2H-pyridin-4-yl]-1H-quinazoline-6-sulfonamide; (R,E)-2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-8-(3-methyl-4-(3,3,3-trifluoropropanoyl)piperazin-1-yl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; (R,E)-2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-8-(3-methyl-4-(1-(trifluoromethyl)cyclopropane-1-carbonyl)piperazin-1-yl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; (R,E)-8-(4-(1-cyanocyclopropane-1-carbonyl)-3-methylpiperazin-1-yl)-2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; (R,E)-8-(4-(1-(dimethylamino)cyclopropane-1-carbonyl)-3-methylpiperazin-1-yl)-2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; (R,E)-8-(4-isobutyryl-3-methylpiperazin-1-yl)-2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; (R,E)-8-(4-(3,3-difluoropyrrolidine-1-carbonyl)-3-methylpiperazin-1-yl)-2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; (R,E)-4-(2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-4-oxo-1,2,3,4-tetrahydroquinazolin-8-yl)-N,2-dimethyl-N-(2,2,2-trifluoroethyl)piperazine-1-carboxamide; (R,E)-2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-8-(3-methyl-4-(1-methylcyclobutane-1-carbonyl)piperazin-1-yl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; (R,E)-8-(4-(cyclopentanecarbonyl)-3-methylpiperazin-1-yl)-2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; (R,E)-2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-8-(3-methyl-4-(pyrrolidine-1-carbonyl)piperazin-1-yl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; (R,E)-4-(2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-4-oxo-1,2,3,4-tetrahydroquinazolin-8-yl)-N,N,2-trimethylpiperazine-1-carboxamide; (R,E)-2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-8-(3-methyl-4-(2,2,2-trifluoroacetyl)piperazin-1-yl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; rel-(R,E)-8-(4-(2,2-difluoro-2-(1-hydroxycyclobutyl)acetyl)-3-methylpiperazin-1-yl)-2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; (E)-2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-8-(4-(1-methylcyclopropane-1-carbonyl)phenyl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; and rel-(R,E)-N-cyclopropyl-4-(2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-4-oxo-1,2,3,4-tetrahydroquinazolin-8-yl)-N,2-dimethylpiperazine-1-carboxamide.

13. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in claim 1 and optionally one or more pharmaceutically acceptable excipients.

14. A compound of formula (Int-I) ##STR00087## or a salt thereof, wherein R.sup.10 is hydrogen, halogen (e.g. chloro, bromo, iodo), B(OH).sub.2, B(OC(CH.sub.3).sub.2C(CH.sub.3).sub.2O), S(O).sub.2OH, S(O).sub.2C1 or SCH.sub.2-phenyl; and X.sup.1, X.sup.2, X.sup.3, R.sup.4, R.sup.5 and R.sup.6 are as defined for the compound of formula (I) in claim 1; and wherein the compound of (Int-I) is not 2-(Hydroxyamino)-6-iodo-3-phenyl-4(3H)-quinazolinone; 6-Iodo-2-(propoxyamino)-3-propyl-4(3H)-quinazolinone; 6-Bromo-2-(propoxyamino)-3-propyl-4(3H)-quinazolinone; 6-Iodo-2-[(2-methylpropoxy)amino]-3-propyl-4(3H)-quinazolinone; 6-Bromo-2-[(2-methylpropoxy)amino]-3-propyl-4(3H)-quinazolinone; 2-[[(3,4-Dihydro-6-iodo-4-oxo-3-phenyl-2-quinazolinyl)amino]oxy]acetic acid; (3,4-Dihydro-6-iodo-4-oxo-3-phenyl-2-quinazolinyl)azanyl acetate; 2,4(1H,3H)-Quinazolinedione, 6-iodo-3-phenyl-, 2-[O-(ethoxycarbonyl)oxime]; (3,4-Dihydro-6-iodo-4-oxo-3-phenyl-2-quinazolinyl)azanyl 2-chloroacetate; Ethyl 2-[[(3,4-dihydro-6-iodo-4-oxo-3-phenyl-2-quinazolinyl)amino]oxy]acetate; (3,4-Dihydro-6-iodo-4-oxo-3-phenyl-2-quinazolinyl)azanyl benzoate; (3,4-Dihydro-6-iodo-4-oxo-3-phenyl-2-quinazolinyl)azanyl benzeneacetate; 1-[(3,4-Dihydro-6-iodo-4-oxo-3-phenyl-2-quinazolinyl)azanyl]2-ethyl ethanedioate; 2-(Hydroxyamino)-3-phenyl-4(3H)-quinazoline; or a compound of formula (Int-II) ##STR00088## or a salt thereof, wherein R.sup.11 is hydrogen or C.sub.1-8 alkyl; and X.sup.1, X.sup.2, X.sup.3, R.sup.4, R.sup.5 and R.sup.6 are as defined for the compound of formula (I) in claim 1.

15. A method of treating neoplastic disease in a subject, comprising administering a compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, to said subject.

16. The method of claim 15, wherein the neoplastic disease is cancer.

17. The method of claim 15, wherein the subject is a mammal.

18. The method of claim 15, wherein the subject is a human.

Description

DESCRIPTION OF THE FIGURES

[0530] FIG. 1 shows the increase in cellular protein-bound PAR levels following PARG inhibitor treatment.

[0531] FIG. 1A: Kuramochi HGSOC cells were treated for 8 hours either with the compound vehicle DMSO, or with increasing concentrations of Examples 1, 5, 7 or 8, followed by cell extraction and detection of cellular PAR levels by Western blotting. -tubulin was blotted for as a loading control. FIG. 1B: NCI-H1650 NSCLC cells were treated for 8 hours either with the compound vehicle DMSO, or with increasing concentrations of Examples 1, 5, 7 or 8, followed by Western blotting as described above.

EXAMPLES

[0532] All reagents and solvents are generally used as received from the commercial supplier.

[0533] Reactions are routinely performed with anhydrous solvents in well-dried glassware under an argon or nitrogen atmosphere, unless otherwise specified.

[0534] Evaporations are carried out by rotary evaporation under reduced pressure and work-up procedures are carried out after removal of residual solids by filtration.

[0535] All temperatures are given in degree Celsius ( C.) and are approximate temperatures; unless otherwise noted, operations are carried out at room temperature (rt), that is typically in the range 18 C.-25 C.

[0536] Column chromatography (by the flash procedure) is used to purify compounds.

[0537] Classical flash chromatography is often replaced by automated systems. This does not change the separation process per se. A person skilled in the art will be able to replace a classical flash chromatography process by an automated one, and vice versa. Typical automated systems can be used, as they are provided by Buchi, Biotage or Isco (combiflash) for instance.

[0538] A reaction mixture can often be separated by preparative HPLC using e.g. water and acetonitrile as system of eluents, unless otherwise stated. A person skilled in the art will find suitable conditions for each separation; the compounds are isolated after purification as a parent compound or in a form of the corresponding trifluoroacetic acid (TFA) salt or the respective formic acid salt.

[0539] Reactions, which required higher temperature, are usually performed using classical heating instruments; but can also be performed using microwave apparatus (CEM Explorer) at a power of 250 W, unless otherwise noted.

[0540] Hydrogenation or hydrogenolysis reactions can be performed using hydrogen gas in balloon or using Parr-apparatus system or other suitable hydrogenation equipment.

[0541] Concentration of solutions and drying of solids are performed under reduced pressure unless otherwise stated.

[0542] In general, the course of reactions is followed by TLC, HPLC, or LC/MS and reaction times are given for illustration only; yields are given for illustration only and are not necessarily the maximum attainable.

[0543] The structure and purity of the final products of the invention are generally confirmed by NMR spectroscopy, HPLC and mass spectral techniques.

[0544] Proton NMR spectra are recorded on a Brucker 400 MHz spectrometer. Chemical shifts () are reported in ppm relative to Me.sub.4Si or the solvent peak as internal standard, and NMR coupling constants (J values) are in Hertz (Hz). Each peak is denoted as a broad singlet (br), singlet (s), doublet (d), triplet (t), quadruplet (q), doublet of doublets (dd), triplet of doublets (td) or multiplet (m).

[0545] HPLC of the final products are generated using (Method A) a Dionex Ultimate 3000 instrument coupled with Dionex MSQ ESI mode and the following conditions:

TABLE-US-00001 Mobile Phase A: Water with 0.1% Formic acid Mobile Phase B: Acetonitrile with 0.1% Formic acid Column: YMC triart C18 5 m 100 mm 4.6 mm Column Temperature: 25 C. Detection: UV 250 nm Injection: 2 L of 10 mM sample DMSO solution Flow: 1.6 mL/min Gradient Time (min) % Mobile Phase B 0 5 8 95 10 95 10.1 5 equilibration 13 5 equilibration
or using (Method B) a Waters Acquity Ultra Performance Liquid Chromatography (UPLC) equipped with a SQ 3100 Mass detector spectrometer.

TABLE-US-00002 Mobile Phase A: Water with 0.05% Formic acid Mobile Phase B: Acetonitrile with 0.05% Formic acid Column: Acquity BEH C18 1.7 m, 2.1 50 mm Flow: 0.6 mL/min Gradient Time (min) % Mobile Phase B 0 3 0.4 3 2.5 98 3.5 98 3.6 3 4 3

[0546] The gradient described could be altered in function of the physico-chemical properties of the compound analysed and is in no way restrictive.

[0547] Mass spectra are generated using a q-Tof Ultima (Waters AG or Thermo Scientific MSQ Plus) mass spectrometer in the positive or negative ESI mode. The system is equipped with the standard Lockspray interface.

[0548] Each intermediate is purified to the standard required for the subsequent stage and is characterized in sufficient detail to confirm that the assigned structure is correct.

[0549] Analytical and preparative HPLC on non-chiral phases are performed using RP-C18 based columns.

[0550] The following abbreviations may be used (reference can also be made to The Journal of Organic Chemistry Guidelines for Authors, for a comprehensive list of standard abbreviations and acronyms): [0551] AcOH Acetic acid [0552] ACN Acetonitrile [0553] Bn Benzyl [0554] BnSH Benzyl mercaptan [0555] CAS compound having Chemical Abstracts Services registry number [0556] Cbz N-Carboxybenzyl [0557] CDCl.sub.3 Deuterated chloroform [0558] DCDMH 1,3-Dichloro-5,5-dimethylhydantoin [0559] DCM Dichloromethane [0560] Diox 1,4-Dioxane [0561] DIPEA N,N-Diisopropylethylamine [0562] DMA N,N-Dimethylacetamide [0563] DME Dimethoxyethane [0564] DMF N,N-Dimethylformamide [0565] DMSO Dimethyl sulfoxide [0566] DMSO-d.sub.6 Deuterated dimethyl sulfoxide [0567] EA Ethyl acetate [0568] EDCI 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride [0569] ELSD Evaporative light scattering detection [0570] ESI Electrospray ionization [0571] EtOH Ethanol [0572] Ex. Example [0573] HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate [0574] HOBt N-Hydroxybenzotriazole [0575] HPLC High performance liquid chromatography [0576] LC/MS Liquid chromatography coupled to mass spectroscopy [0577] MeOH Methanol [0578] Me.sub.4Si Tetramethylsilane [0579] MS Mass spectrometry [0580] MW Microwave [0581] NCS N-Chlorosuccinimide [0582] NMR Nuclear magnetic resonance [0583] Pd/C Palladium on activated carbon [0584] Pd.sub.2(dba).sub.3 Tris(dibenzylideneacetone)dipalladium(0) [0585] Pd(dppf)Cl.sub.2 [1,1-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) [0586] Pd(PPh.sub.3).sub.4 Tetrakis(triphenlyphosphine)-palladium(0) [0587] PE Petroleum ether [0588] rt Room temperature [0589] TEA Triethylamine [0590] TFA Trifluoroacetic acid [0591] THF Tetrahydrofuran [0592] Xant-Phos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

[0593] The following Examples refer to the compounds of formula (I) as indicated in Table 1.

[0594] The Examples listed in the following table can be prepared using procedures described above, and detailed synthesis methodology is described in detail below. The Example numbers used in the leftmost column are used in the application text for identifying the respective compounds.

TABLE-US-00003 TABLE 1 Exemplified compounds HPLC Reference Retention for .sup.1H-NMR Time/min MS m/z Ex. Formula Preparation (400 MHz) ppm (Method) (+ESI) 1 [00013] DMSO-d.sub.6 + D.sub.2O: 8.19 (d, J = 2.0 Hz, 1H), 7.86 (dd, J = 2.0, 8.8 Hz, 1H), 7.65 (s, 1H), 7.49 (d, J = 8.8 Hz, 1H), 5.11 (s, 2H), 3.83 (s, 3H), 2.57 (s, 3H), 1.03 (s, 3H), 0.57 (m, 2H), 0.35 (m, 2H) 5.42 (A) 436.2 [M + H].sup.+ 2 [00014] Example 1 using 735241-98-2, 593-56-6 and 874473-14-0 DMSO-d.sub.6 + D.sub.2O: 8.21 (d, J = 2.4 Hz, 1H), 7.87 (dd, J = 2.4, 8.8 Hz, 1H), 7.67 (s, 1H), 7.48 (d, J = 8.8 Hz, 1H), 7.42 (s, 1H), 4.81 (s, 2H), 4.49 (d, J = 6.0 Hz, 2H), 4.09 (d, J = 6.0 Hz, 2H), 3.81 (s, 3H), 3.75 (s, 3H), 1.38 (s, 3H) 4.31 (A) 435.3 [M + H].sup.+ 3 [00015] DMSO-d.sub.6 + D.sub.2O: 8.18 (d, J = 2.4 Hz, 1H), 7.84 (dd, J = 2.4, 8.8 Hz, 1H), 7.47 (m, 2H), 7.32 (s, 1H), 5.13 (s, 2H), 4.80 (s, 2H), 3.72 (s, 3H), 2.56 (s, 3H), 2.35 (s, 3H), 1.02 (s, 3H), 0.56 (m, 2H), 0.35 (m, 2H) 5.04 (A) 530.4 [M + H].sup.+ 4 [00016] Example 1 using 62484- 39-3, 735241-98-2, 593-56-6 and 88887-87-0 DMSO-d.sub.6: 8.45 (s, 1H), 8.20 (s, 1H), 8.18 (d, J = 1.6 Hz, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.70 (s, 1H), 7.44 (s, 1H), 4.83 (s, 2H), 3.87 (s, 3H), 3.77 (s, 3H), 1.08 (s, 3H), 0.60 (m, 2H), 0.41 (m, 2H) 6.17 (A) 453.2, 454.9 [M + H].sup.+ 5 [00017] DMSO-d.sub.6 + D.sub.2O: 8.28 (d, J = 2.0 Hz, 1H), 7.83 (d, J = 2.0 Hz, 1H), 7.69 (s, 1H), 7.62 (m, 4H), 7.43 (s, 1H), 4.82 (s, 2H), 3.75 (s, 3H), 3.69 (s, 3H), 3.01 (s, 3H), 2.94 (s, 3H), 1.08 (s, 3H), 0.62 (m, 2H), 0.40 (m, 2H) 5.46 (A) 566.4 [M + H].sup.+ 6 [00018] Example 1 using 2169440-61- 1, 593-56-6 and 88887- 87-0 DMSO-d.sub.6 + D.sub.2O: 8.38 (s, 1H), 8.20 (d, J = 1.6 Hz, 1H), 7.95 (s, 1H), 7.86 (dd, J = 2.0, 8.0 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 4.90 (s, 2H), 3.78 (s, 3H), 1.04 (s, 3H), 0.57 (m, 2H), 0.36 (m, 2H) 6.40 (A) 473.2 [M + H].sup.+ 7 [00019] DMSO-d.sub.6 + D.sub.2O: 8.01 (d, J = 2.0 Hz, 1H), 7.69 (d, J = 2.0 Hz, 1H), 7.67 (s, 1H), 7.42 (s, 1H), 4.81 (s, 2H), 3.83 (s, 3H), 3.74 (s, 3H), 3.19 (m, 2H), 3.01 (m, 3H), 2.81 (m, 1H), 2.62 (m, 1H), 1.16 (d, J = 6.4 Hz, 3H), 1.01 (s, 3H), 0.57 (m, 2H), 0.37 (m, 2H) 3.83 (A) 517.4 [M + H].sup.+ 8 [00020] DMSO-d.sub.6 + D.sub.2O: 8.03 (d, J = 2.0 Hz, 1H), 7.76 (d, J = 2.0 Hz, 1H), 7.69 (s, 1H), 7.43 (s, 1H), 4.82 (s, 2H), 4.61 (m, 1H), 4.26 (m, 1H), 3.82 (s, 3H), 3.76 (s, 3H), 2.96 (m, 3H), 2.67 (m, 2H), 1.41 (br, 3H), 1.25 (s, 3H), 1.01 (s, 3H), 0.83 (m, 2H), 0.57 (m, 4H), 0.37 (m, 2H) 5.96 (A) 519.5 [M + H].sup.+ 9 [00021] Example 1 using 735241-98-2, 593-56-6 and 127946-77-4 DMSO-d.sub.6: 10.82 (s, 1H), 9.08 (s, 1H), 8.26 (d, J = 2.0 Hz, 1H), 7.91 (dd, J = 2.4, 8.8 Hz, 1H), 7.69 (s, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.43 (s, 1H), 4.83 (s, 2H), 3.84 (s, 3H), 3.77 (s, 3H), 1.40 (m, 2H), 1.25 (m, 2H) 4.70 (A) 430.3 [M + H].sup.+ 10 [00022] Example 1 using 735241-98-2, 3332-29-4 and 88887- 87-0 DMSO-d.sub.6: 10.60 (s, 1H), 8.21 (d, J = 2.0 Hz, 1H), 8.01 (s, 1H), 7.85 (dd, J = 2.4, 8.8 Hz, 1H), 7.67 (s, 1H), 7.52 (d, J = 8.8 Hz, 1H), 7.42 (s, 1H), 4.84 (s, 2H), 4.07 (q, J = 6.8 Hz, 2H), 3.76 (s, 3H), 1.29 (t, J = 6.8 Hz, 3H), 1.05 (s, 3H), 0.58 (m, 2H), 0.36 (m, 2H) 5.51 (A) 433.3 [M + H].sup.+ 11 [00023] Example 3 using 735241-98-2, 4490-81-7 and 88887- 87-0 DMSO-d.sub.6: 10.37 (s, 1H), 8.21 (d, J = 2.0 Hz, 1H), 8.00 (s, 1H), 7.85 (dd, J = 2.4, 8.8 Hz, 1H), 7.65 (s, 1H), 7.55 (d, J = 8.8 Hz, 1H), 7.41 (s, 1H), 4.85 (s, 2H), 4.25 (m, 1H), 3.76 (s, 3H), 1.28 (d, J = 6.0 Hz, 6H), 1.05 (s, 3H), 0.58 (m, 2H), 0.36 (m, 2H) 5.95 (A) 447.3 [M + H].sup.+ 12 [00024] DMSO-d.sub.6 + D.sub.2O: 8.04 (d, J = 2.0 Hz, 1H), 7.71 (d, J = 2.0 Hz, 1H), 7.70 (s, 1H), 7.44 (s, 1H),4.83 (s, 2H), 4.68 and 4.20 (2m, 1H), 4.39 and 2.61 (2m, 1H), 3.82 (s, 3H), 3.77 (s, 3H), 3.46 (m, 1H), 2.96 (m, 3H), 2.77 (m, 1H), 2.06 and 2.04 (2s, 3H), 1.46 and 1.34 (2d, J = 6.8 Hz, 3H), 1.03 (s, 3H), 0.58 (m, 2H), 0.37 (m, 2H). 9.56 (A) 559.3 [M + H]+ 13 [00025] + [00026] DMSO-d.sub.6 + D.sub.2O: 8.26 (s, 0.8H, HCOOH), 8.18 (d, J = 2.0 Hz, 1H), 7.77 (d, J = 2.0 Hz, 0.64H), 7.73 (d, J = 2.0 Hz, 0.36H), 7.70 (s, 1H), 7.44 (s, 1H), 6.07 (m, 0.36H), 5.97 (m, 0.64H), 4.82 (s, 2H), 3.82 (s, 1.1H), 3.81 (s, 1.9H), 3.77 (s, 3H), 3.65 (m, 0.64H), 3.55 (m, 1H), 3.22 (m, 0.64H), 3.08 (m, 0.36H), 2.97 (m, 0.64H), 2.32 (m, 1H), 2.8 (m, 0.36H), 2.14 (m, 0.36H), 1.24 (d, J = 6.8 Hz, 1.9H), 1.19 (d, J = 6.8 Hz, 1.1H), 1.06 (s, 3H), 0.60 (m, 2H), 0.39 (m, 2H); mixture of two isomers (~36:64). 3.02 (A) 514.5 [M + H]+ 14 [00027] DMSO-d.sub.6 + D.sub.2O: 8.28 (d, J = 2.0 Hz, 1H), 7.84 (d, J = 2.0 Hz, 1H), 7.70 (s, 1H), 7.47 (s, 1H), 7.44 (s, 1H), 7.40 (m, 2H), 4.82 (s, 2H), 3.77 (s, 3H), 3.71 (s, 3H), 3.04 (s, 3H), 2.79 (s, 3H), 2.28 (s, 3H), 1.09 (s, 3H), 0.63 (m, 2H), 0.41 (m, 2H). 4.04 (A) 580.5 [M + H]+ 15 [00028] Example 14 using 123088-59-5 DMSO-d.sub.6 + D.sub.2O: 8.30 (d, J = 2.0 Hz, 1H), 8.08 (d, J = 8.4 Hz, 2H), 7.83 (d, J = 2.0 Hz, 1H), 7.70 (s, 1H), 7.65 (d, J = 8.4 Hz, 2H), 7.44 (s, 1H), 4.83 (s, 2H), 3.77 (s, 3H), 3.71 (s, 3H), 1.09 (s, 3H), 0.63 (m, 2H), 0.41 (m, 2H). 2.65 (A) 538.2 [M + H]+ 16 [00029] Example 14 using 149104-90-5 DMSO-d.sub.6 + D.sub.2O: 8.30 (d, J = 2.0 Hz, 1H), 8.17 (d, J = 8.4 Hz, 2H), 7.83 (d, J = 2.0 Hz, 1H), 7.72 (d, J = 8.4 Hz, 2H), 7.70 (s, 1H), 7.44 (s, 1H), 4.83 (s, 2H), 3.76 (s, 3H), 3.70 (s, 3H), 2.65 (s, 3H), 1.09 (s, 3H), 0.62 (m, 2H), 0.41 (m, 2H). 10.95 (A) 537.1 [M + H]+ 17 [00030] Example 14 using 75705- 21-4 DMSO-d.sub.6 + TFA + D.sub.2O: 8.30 (d, J = 2.0 Hz, 1H), 8.13 (s, 0.8H, HCOOH), 7.79 (d, J = 2.0 Hz, 1H), 7.67 (m, 5H), 7.45 (s, 1H), 4.83 (s, 2H), 4.16 (s, 2H), 3.77 (s, 3H), 3.71 (s, 3H), 1.09 (s, 3H), 0.62 (m, 2H), 0.40 (m, 2H). 3.00 (A) 524.3 [M + H]+ 18 [00031] Example 14 using Intermediate- III DMSO-d.sub.6 + D.sub.2O: 8.30 (d, J = 2.0 Hz, 1H), 7.94 (d, J = 8.0 Hz, 2H), 7.85 (d, J = 2.0 Hz, 1H), 7.69 (m, 3H), 7.44 (s, 1H), 4.82 (s, 2H), 3.76 (s, 3H), 3.70 (s, 3H), 1.41 (s, 3H), 1.20 (m, 2H), 1.09 (s, 3H), 0.90 (m, 2H), 0.62 (m, 2H), 0.41 (m, 2H). 4.66 (A) 577.4 [M + H]+ 19 [00032] Example 14 using 1006876-23- 8 DMSO-d.sub.6 + D.sub.2O: 8.73 (s, 1H), 8.32 (s, 1H), 8.12 (d, J = 8.0 Hz, 1H), 7.88 (s, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.70 (s, 1H), 7.44 (s, 1H), 4.84 (s, 2H), 3.77 (s, 3H), 3.71 (s, 3H), 3.05 (s, 3H), 2.99 (s, 3H), 1.09 (s, 3H), 0.63 (m, 2H), 0.41 (m, 2H). 3.70 (A) 567.5 [M + H]+ 20 [00033] DMSO-d.sub.6 + D.sub.2O): 8.79 (d, J = 2.0 Hz, 1H), 8.59 (d, J = 2.0 Hz, 1H), 8.34 (d, J = 2.0 Hz, 1H), 8.23 (d, J = 8.4 Hz, 1H), 8.15 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 7.71 (s, 1H), 7.45 (s, 1H), 4.86 (s, 2H), 3.90 (s, 3H), 3.76 (s, 3H), 3.04 (s, 3H), 2.99 (s, 3H), 1.06 (s, 3H), 0.64 (m, 2H), 0.40 (m, 2H). 3.95 (A) 567.4 [M + H]+ 21 [00034] DMSO-d.sub.6 + D.sub.2O: 8.01 (d, J = 2.0 Hz, 1H), 7.71 (m, 2H), 7.44 (s, 1H), 4.82 (s, 2H), 3.85 (s, 3H), 3.77 (s, 3H), 2.89 (m, 4H), 2.54 (m, 1H), 2.35 (m, 2H), 2.29 (s, 3H), 1.06 (d, J = 6.4 Hz, 3H), 1.02 (s, 3H), 0.58 (m, 2H), 0.37 (m, 2H). 7.08 (A) 531.4 [M + H]+ 22 [00035] DMSO-d.sub.6 + D.sub.2O: 8.27 (d, J = 2.0 Hz, 1H), 7.79 (d, J = 2.0 Hz, 1H), 7.68 (m, 3H), 7.57 (d, J = 8.4 Hz, 2H), 7.44 (s, 1H), 4.82 (s, 2H), 3.76 (s, 3H), 3.70 (s, 3H), 3.11 (m, 1H), 3.01 (m, 1H), 2.66 (m, 1H), 2.32 (m, 1H), 1.08 (s, 3H), 0.62 (m, 2H), 0.39 (m, 2H). 4.09 (A) 579.3 [M + H]+ 23 [00036] DMSO-d6 + D2O: 8.34 (d, J = 2.0 Hz, 1H), 8.17 (d, J = 2.0 Hz, 1H), 8.09 (s, 1H), 7.71 (s, 1H), 7.46 (s, 1H), 4.86 (s, 2H), 3.85 (s, 3H), 3.76 (s, 3H), 3.51 (s, 3H), 3.08 (s, 3H), 1.06 (s, 3H), 0.63 (m, 2H), 0.39 (m, 2H). 3.98 (A) 556.4 [M + H]+ 24 [00037] DMSO-d.sub.6 + D.sub.2O: 8.38 (s, 1H, HCOOH), 8.16 (d, J = 2.0 Hz, 1H), 7.78 and 7.74 (2d, J = 2.0 Hz, 1H, epimers), 7.69 (s, 1H), 7.44 (s, 1H), 4.84 (s, 2H), 3.84 and 3.83 (2s, 3H, epimers), 3.76 (s, 3H), 3.24 (m, 2H), 3.11 (m, 1H), 2.94 (m, 1H), 1.86 (m, 2H), 1.59 (m, 1H), 1.39 (m, 1H), 1.17 (d, J = 6.4 Hz, 3H), 1.02 (s, 3H), 0.57 (m, 2H), 0.36 (m, 2H). 2.92 (A) 516.4 [M + H]+ 25 [00038] DMSO-d.sub.6 + D.sub.2O: 8.22 (s, 1H, HCOOH), 8.15 (d, J = 2.0 Hz, 1H), 7.80 (d, J = 2.0 Hz, 1H), 7.69 (s, 1H), 7.43 (s, 1H), 4.83 (s, 2H), 3.84 and 3.83 (2s, 3H, epimers), 3.76 (s, 3H), 2.98 (m, 2H), 2.69 (m, 1H), 2.32 (m, 1H), 2.29 (s, 3H), 1.78 (m, 2H), 1.64 (m, 1H), 1.37 (m, 1H), 1.14 and 1.08 (2d, J = 6.8 Hz, 3H), 1.01 and 1.00 (2s, 3H, epimers), 0.57 (m, 2H), 0.36 (m, 2H). 3.92 (A) 530.5 [M + H]+ 26 [00039] DMSO-d.sub.6 + D.sub.2O: 8.15 (d, J = 2.0 Hz, 1H), 7.83 (d, J = 2.0 Hz, 1H), 7.69 (s, 1H), 7.43 (s, 1H), 4.83 (s, 2H), 4.17 (m, 1H), 3.84 (s, 3H), 3.76 (s, 3H), 3.28 (m, 1H), 3.12 (m, 2H), 2.22 (m, 1H), 2.04 (s, 3H), 1.87 (m, 1H), 1.73 (m, 1H), 1.44 (m, 1H), 1.14 (d, J = 6.4 Hz, 3H), 1.01 (s, 3H), 0.58 (m, 2H), 0.37 (m, 2H). 3.86 (A) 558.5 [M + H]+ 27 [00040] DMSO-d.sub.6 + D.sub.2O: 8.14 (d, J = 2.0 Hz, 1H), 7.78 (d, J = 2.0 Hz, 1H), 7.69 and 7.68 (2s, 1H, epimers), 7.44 and 7.43 (2s, 1H, epimers), 4.83 and 4.82 (2s, 2H, epimers), 4.74 and 4.32 (m, 1H, epimers), 4.21 (m, 1H), 4.05 (m, 1H), 3.84 and 3.81 (2s, 3H, epimers), 3.76 and 3.75 (2s, 3H, epimers), 3.10 (m, 1H), 2.32 (m, 1H), 1.91 (m, 1H), 1.76 (m, 1H), 1.38 (m, 1H), 1.27 and 1.23 (2s, 3H, epimers), 1.12 (d, J = 6.4 Hz, 3H), 1.01 and 0.98 (2s, 3H, epimers), 0.88 (m, 1H), 0.75 (m, 1H), 0.57 (m, 4H), 0.36 (m, 2H). 4.25 (A) 598.6 [M + H]+ 28 [00041] + [00042] DMSO-d.sub.6 + D.sub.2O: 8.18 (m, 1H), 8.16 (s, 0.7H, HCOOH), 7.78 (d, J = 2.0 Hz, 0.57H), 7.73 (d, J = 2.0 Hz, 0.43H), 7.70 (s, 1H), 7.44 (s, 1H), 6.00 (m, 0.43H), 5.90 (m, 0.57H), 4.82 (s, 2H), 3.82 (s, 1.3H), 2.81 (s, 1.7H), 3.77 (s, 3H), 3.36 (m, 0.6H), 3.15 (m, 0.4H), 2.99 (m, 1H), 2.82 (m, 0.4H), 2.58 (m, 0.6H), 2.47-2.30 (m, 1.6H), 2.16 (m, 0.4H), 1.22 (d, J = 6.8 Hz, 1.7H), 1.12 (d, J = 6.8 Hz, 1.3H), 1.06 (s, 3H), 0.60 (m, 2H), 0.39 (m, 2H); mixture of two isomers (~40:60). 7.06 (A) 528.3 [M + H]+ 29 [00043] + [00044] DMSO-d.sub.6 + D.sub.2O: 8.18 (d, J = 2.0 Hz, 0.4H, isomer 1), 8.16 (d, J = 2.0 Hz, 0.6H, isomer 2), 7.74 (m, 0.6H, isomer 2), 7.69 (m, 1.4H), 7.43 (s, 1H), 6.06 (m, 0.6H, isomer 2), 6.03 (m, 0.4H, isomer 1), 4.91 (m, 0.4H, isomer 1), 4.82 (s, 2H), 4.57 (m, 0.6H, isomer 2), 4.33 (m, 0.4H, isomer 1), 3.92 (m, 0.6H, isomer 2), 3.80 (m, 3H), 3.76 (s, 3H), 3.55-3.30 (m, 1H, overlapped with H.sub.2O peak), 2.83 (m, 0.4H), 2.67 (m, 0.6H), 2.07 (m, 4H), 1.35-1.15 (4d, J = 6.8 Hz, 3H, isomers), 1.05 (s, 3H), 0.59 (m, 2H), 0.38 (m, 2H); mixture of two isomers (~40:60). 9.52 (A) 556.3 [M + H]+ 30 [00045] + [00046] DMSO-d.sub.6 + D.sub.2O: 8.19 (d, J = 2.0 Hz, 0.42H, isomer 1), 8.18 (d, J = 2.0 Hz, 0.58H, isomer 2), 7.80 (d, J = 2.0 Hz, 0.58H, isomer 2), 7.73 (d, J = 2.0 Hz, 0.42H, isomer 1), 7.70 (s, 1H), 7.44 (s, 1H), 6.09 (m, 0.58H, isomer 2), 6.05 (m, 0.42H, isomer 1), 4.86 (m, 1H), 4.82 (s, 2H), 4.63 (m, 0.42H, isomer 1), 4.36 (m, 0.58H, isomer 2), 3.81 (s, 1.7H, isomer 2), 3.80 (s, 1.3H, isomer 1), 3.77 (s, 3H), 3.38 (m, 1.42H, overlapped with H.sub.2O peak), 2.75 (m, 0.58H, isomer 2), 2.10 (m, 1H), 1.28 (m, 6H), 1.06 (s, 3H), 0.93 (m, 1H), 0.78 (m, 1H), 0.60 (m, 4H), 0.39 (m, 2H); mixture of two isomers (~40:60). 4.23 (A) 596.4 [M + H]+ 31 [00047] Example 32 using 2516- 99-6 DMSO-d6: 8.61 (s, 1H), 8.04-8.01 (m, 2H), 7.72- 7.71 (m, 1H), 7.70 (s, 1H) 7.44 (s, 1H), 4.87-4.79 (m, 2H), 4.70-4.25 (m, 2H), 3.83 (s, 3H), 3.77 (s, 3H), 3.65-3.53 (m, 3H), 3.16-2.93 (m, 3H), 2.85- 2.75 (m, 1H), 1.49-1.35 (m, 3H), 1.03 (s, 3H), 0.60-0.57 (m, 2H), 0.38- 0.35 (m, 2H). 1.89 (B) 627.3 [M + H]+ 32 [00048] DMSO-d6: 8.63 (s, 1H), 8.04 (d, J = 1.6 Hz, 1H), 8.01 (s, 1H), 7.77 (d, J = 1.6 Hz, 1H), 7.70 (s, 1H), 7.44 (s, 1H), 4.87-4.79 (m, 2H), 4.64 (bs, 1H), 4.30-4.23 (m, 1H), 3.83 (s, 3H), 3.77 (s, 3H), 3.52-3.50 (m, 1H), 2.99- 2.96 (m, 3H), 2.67-2.66 (m, 1H), 1.42-1.23 (m, 7H), 1.03 (s, 3H), 0.60- 0.57 (m, 2H), 0.38-0.36 (m, 2H). 1.99 (B) 651.3 [M + H]+ 33 [00049] Example 32 using 6914- 79-0 DMSO-d6: 8.65 (s, 1H), 8.05 (d, J = 1.6 Hz, 1H), 8.03 (s, 1H), 7.78-7.77 (m, 1H), 7.70 (s, 1H), 7.44 (s, 1H), 4.87-4.79 (m, 2H), 4.66-4.64 (m, 1H), 4.29-4.26 (m, 1H), 3.84 (s, 3H), 3.77 (s, 3H), 3.02- 2.66 (m, 5H), 1.63-1.46 (m, 7H), 1.03 (s, 3H), 0.60-0.58 (m, 2H), 0.38- 0.30 (m, 2H). 5.18 (B) 610.4 [M + H]+ 34 [00050] Example 32 using 119111-65-8 DMSO-d6: 8.62 (s, 1H), 8.03 (d, J = 1.6 Hz, 1H), 8.01 (s, 1H), 7.75 (d, J = 1.6 Hz, 1H), 7.70 (s, 1H), 7.44 (s, 1H), 4.87-4.79 (m, 2H), 4.67-4.66 (m, 1H), 4.36-4.33 (m, 1H), 3.83 (s, 3H), 3.77 (s, 3H), 2.98-2.95 (m, 4H), 2.67- 2.66 (m, 1H), 2.32-2.18 (m, 6H), 1.42 (brs, 3H), 1.02 (s, 3H), 0.88-0.73 (m, 4H), 0.60-0.58 (m, 2H), 0.37-0.36 (m, 2H). 1.51 (B) 628.4 [M + H]+ 35 [00051] Example 32 using 79-31- 2 DMSO-d6: 8.62 (s, 1H), 8.04 (d, J = 2.0 Hz, 1H), 8.00 (s, 1H), 7.75 (d, J = 2.0 Hz, 1H), 7.70 (s, 1H), 7.44 (s, 1H), 4.87-4.79 (m, 2H), 4.71-3.96 (m, 2H), 3.82 (s, 3H), 3.77 (s, 3H), 3.50-3.32 (m, 1H), 3.00-2.91 (m, 2H), 2.89- 2.66 (m, 3H), 1.48-1.33 (m, 3H), 1.09-0.99 (m, 9H), 0.60-0.57 (m, 2H), 0.38-0.37 (m, 2H). 10.02 (B) 587.4 [M + H]+ 36 [00052] DMSO-d6: 8.60 (s, 1H), 8.03 (d, J = 1.6 Hz, 1H), 8.00 (s, 1H), 7.75 (d, J = 2.0 Hz, 1H), 7.70 (s, 1H), 7.44 (s, 1H), 4.82 (s, 2H), 4.02-4.01 (m, 1H), 3.83 (s, 3H), 3.77-3.70 (m, 5H), 3.60-3.57 (m, 3H), 3.36-3.26 (m, 1H), 2.99- 2.88 (m, 3H), 2.76-2.72 (m, 1H), 2.45-2.32 (m, 2H), 1.44-1.42 (m, 3H), 1.03 (s, 3H), 0.60-0.58 (m, 2H), 0.38-0.36 (m, 2H). 10.31 (B) 650.5 [M + H]+ 37 [00053] Example 36 using 2730- 67-8 DMSO-d6: 8.61 (s, 1H), 8.04 (d, J = 8.4 Hz, 1H), 8.01 (s, 1H), 7.76 (d, J = 1.6 Hz, 1H), 7.70 (s, 1H), 7.44 (s, 1H), 4.82 (s, 2H), 4.24-4.18 (m, 1H), 4.02- 3.96 (m, 2H), 3.85 (s, 3H), 3.77 (s, 3H), 3.47-3.27 (m, 2H), 3.01 (s, 3H), 2.98-2.90 (m, 3H), 2.78- 2.74 (m, 1H), 1.42-1.40 (m, 3H), 1.02 (s, 3H), 0.60-0.58 (m, 2H), 0.38- 0.35 (m, 2H). 5.49 (B) 656.3 [M + H]+ 38 [00054] Example 32 using 32936- 76-8 DMSO-d6: 8.61 (s, 1H), 8.03 (d, J = 1.6 Hz, 1H), 8.00 (s, 1H), 7.77-7.76 (m, 1H), 7.70 (s, 1H), 7.43 (s, 1H), 4.83-4.82 (m, 2H), 4.64-4.27 (m, 1H), 3.82 (s, 3H), 3.77 (s, 3H), 3.53-3.31 (m, 1H), 3.03- 2.89 (m, 3H), 2.78-2.60 (m, 1H), 1.98-1.90 (m, 1H), 1.84-1.79 (m, 2H), 1.65-1.59 (m, 1H), 1.51- 1.50 (m, 1H), 1.41-1.26 (m, 7H), 1.23-1.02 (m, 1H), 1.02 (s, 3H), 0.60- 0.57 (m, 2H), 0.38-0.35 (m, 2H). 1.96 (B) 613.4 [M + H]+ 39 [00055] Example 32 using 3400- 45-1 DMSO-d6: 8.62 (s, 1H), 8.04 (d, J = 2.0 Hz, 1H), 8.01 (s, 1H), 7.74 (d, J = 1.6 Hz, 1H), 7.70 (s, 1H), 7.44 (s, 1H), 4.83-4.82 (m, 2H), 4.71-3.98 (m, 2H), 3.82 (s, 3H), 3.77 (s, 3H), 3.46-3.31 (m, 1H), 3.01-2.92 (m, 4H), 2.78- 2.60 (m, 1H), 1.75-1.23 (m, 11H), 1.03 (s, 3H), 0.60-0.57 (m, 2H), 0.38- 0.35 (m, 2H). 2.01 (B) 613.4 [M + H]+ 40 [00056] Example 36 using 123- 75-1 DMSO-d6: 8.60 (s, 1H), 8.02 (d, J = 2.0 Hz, 1H), 8.00 (s, 1H), 7.75 (d, J = 2.0 Hz, 1H), 7.70 (s, 1H), 7.44 (s, 1H), 4.88-4.78 (m, 2H), 4.02-4.01 (m, 1H), 3.83 (s, 3H), 3.77 (s, 3H), 3.59-3.57 (m, 1H), 3.31-3.21 (m, 5H), 2.97- 2.87 (m, 3H), 2.74-2.66 (m, 1H), 1.78-1.75 (m, 4H), 1.43-1.41 (m, 3H), 1.02 (s, 3H), 0.60-0.58 (m, 2H), 0.38-0.37 (m, 2H). 1.88 (B) 614.4 [M + H]+ 41 [00057] Example 36 using 124- 40-3 DMSO-d6: 8.60 (s, 1H), 8.03 (d, J = 2.0 Hz, 1H), 8.00 (s, 1H), 7.75 (d, J = 1.6 Hz, 1H), 7.70 (s, 1H), 7.43 (s, 1H), 4.86-4.78 (m, 2H), 3.89-3.85 (m, 1H), 3.83 (s, 3H), 3.77 (s, 3H), 3.44-3.31 (m, 1H), 3.27-3.24 (m, 1H), 2.98- 2.85 (m, 3H), 2.77-2.66 (m, 7H), 1.40-1.38 (m, 3H), 1.02 (s, 3H), 0.60- 0.58 (m, 2H), 0.38-0.35 (m, 2H). 1.80 (B) 588.4 [M + H]+ 42 [00058] DMSO-d6: 8.60 (brs, 1H), 8.04-8.00 (m, 2H), 7.78 (brs, 1H), 7.69 (s, 1H), 7.43 (s, 1H), 4.86-4.78 (m, 2H), 4.65-4.26 (m, 2H), 3.82-3.68 (m, 7H), 3.06-2.81 (m, 4H), 1.60- 1.48 (m, 3H), 1.03(s, 3H), 0.60-0.59 (m, 2H), 0.36- 0.35 (m, 2H). 2.02 (B) 613.3 [M + H]+ 43 [00059] Example 32 using 681240-09-5 DMSO-d6, VT at 90 C.): 8.76-7.55 (m, 5H), 7.41 (s, 1H), 5.71 (s, 1H), 4.84 (s, 2H), 4.67-4.66 (m, 1H), 4.34-4.31 (m, 1H), 3.77-3.75 (m, 6H), 3.40- 3.11 (m, 3H), 2.93-2.87 (m, 1H), 2.75-2.71 (m, 1H), 2.53-2.50 (m, 2H), 2.04-1.99 (m, 2H), 1.90- 1.86 (m, 1H), 1.70-1.65 (m, 1H), 1.48-1.47 (m, 3H), 1.09 (s, 3H), 0.65- 0.62 (m, 2H), 0.37-0.34 (m, 2H). 2.03 (B) 665.4 [M + H]+ 44 [00060] Example 36 using 5163- 20-2 CDCl.sub.3: 8.63 (s, 1H), 8.30 (d, J = 1.6 Hz, 1H), 7.71 (d, J = 2.0 Hz, 1H), 7.65 (s, 1H), 7.55 (s, 1H), 4.96 (s, 2H), 4.83 (s, 1H), 4.25- 4.23 (m, 1H), 3.90 (s, 3H), 3.84 (s, 3H), 3.75-3.69 (m, 1H), 3.45-3.38 (m, 1H), 3.01-2.98 (m, 2H), 2.96-2.85 (m, 5H), 2.65- 2.60 (m, 1H), 1.49-1.47 (m, 3H), 1.21 (s, 3H), 0.77-0.62 (m, 6H), 0.49- 0.47 (m, 2H). 1.88 (B) 614.4 [M + H]+ A hyphen in the third column indicates that the synthesis procedure is described below.

Preparation of Example 1: 2-methoxyimino-N-(1-methylcyclopropyl)-3-[(2-methylthiazol-5-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonamide

##STR00061##

Step 1: Preparation of 2-chloro-3-[(2-methylthiazol-5-1)methyl]quinazolin-4-one

[0595] NaH (0.76 g, 19.1 mmol, 60% dispersion in mineral oil) was added at 0 C. to a stirred solution of 5-(chloromethyl)-2-methyl-thiazole (2.70 g, 17.4 mmol) in DME (50 mL) and DMF (10 mL), followed by LiBr (3.05 g, 34.7 mmol) and 2-chloro-3H-quinazolin-4-one (3.3 g, 17.4 mmol). After 16 h stirring at 60 C., the reaction mixture was extracted with EA and H.sub.2O. The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, concentrated and purified by column chromatography (silica gel; PE:EA; 7:3; v:v) to afford 2-chloro-3-[(2-methylthiazol-5-yl)methyl]quinazolin-4-one as an off-white solid (3.8 g, 71% yield).

[0596] MS m/z (+ESI): 292.1, 294.1 [M+H].sup.+.

Step 2: Preparation of 2-methoxyimino-3-[(2-methylthiazol-5-yl)methyl]-1H-quinazolin-4-one

[0597] Methoxyamine hydrochloride (0.7 g, 8.14 mmol) was added to a stirred solution of 2-chloro-3-[(2-methylthiazol-5-yl)methyl]quinazolin-4-one (0.5 g, 1.63 mmol) in DMF (5 mL), followed by TEA (1.0 g, 9.77 mmol). After 2 h stirring at 100 C., the reaction mixture was poured into H.sub.2O (50 mL) and the resulting precipitate was collected by filtration to afford 2-methoxyimino-3-[(2-methylthiazol-5-yl)methyl]-1H-quinazolin-4-one as a white solid (0.4 g, 77% yield).

[0598] MS m/z (+ESI): 303.1 [M+H].sup.+.

Step 3: Preparation of 2-methoxyimino-3-[(2-methylthiazol-5-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonic acid

[0599] A solution of 2-methoxyimino-3-[(2-methylthiazol-5-yl)methyl]-1H-quinazolin-4-one (0.35 g, 1.10 mmol) in chlorosulfonic acid (1 mL) was stirred at 60 C. for 1 h. The reaction mixture was then poured into ice and purified by Biotage combiflash to afford 2-methoxyimino-3-[(2-methylthiazol-5-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonic acid as a light yellow solid (0.42 g, 90% yield).

[0600] MS m/z (+ESI): 333.1 [M+H].sup.+.

Step 4: Preparation of 2-methoxyimino-3-[(2-methylthiazol-5-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonyl chloride

[0601] A solution of 2-methoxyimino-3-[(2-methylthiazol-5-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonic acid (0.42 g, 0.99 mmol) in SOCl.sub.2 (4 mL) was stirred at 75 C. for 2 h. The reaction mixture was then concentrated and purified by preparative HPLC to afford 2-methoxyimino-3-[(2-methylthiazol-5-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonyl chloride as a light yellow solid (0.21 g, 48% yield).

[0602] MS m/z (+ESI): 401.0, 403.0 [M+H].sup.+.

Step 5: Preparation of 2-methoxyimino-N-(1-methylcyclopropyl)-3-[(2-methylthiazol-5-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonamide

[0603] 1-Methylcycloproanamine hydrochloride (0.5 g, 4.49 mmol) was added to a stirred solution of 2-methoxyimino-3-[(2-methylthiazol-5-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonyl chloride (0.2 g, 0.45 mmol) in DCM (10 mL), followed by TEA (1.92 mL, 13.5 mmol). After 1 h stirring, the reaction mixture was concentrated and purified by preparative HPLC to afford 2-methoxyimino-N-(1-methylcyclopropyl)-3-[(2-methylthiazol-5-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonamide as a white solid (35 mg, 17% yield).

[0604] .sup.1H NMR (400 MHz, DMSO-d.sub.6+D.sub.2O) ppm: 8.19 (d, J=2.0 Hz, 1H), 7.86 (dd, J=2.0, 8.8 Hz, 1H), 7.65 (s, 1H), 7.49 (d, J=8.8 Hz, 1H), 5.11 (s, 2H), 3.83 (s, 3H), 2.57 (s, 3H), 1.03 (s, 3H), 0.57 (m, 2H), 0.35 (m, 2H).

[0605] MS m/z (+ESI): 436.5 [M+H].sup.+.

Preparation of Example 3: 2-[(2,4-dimethylthiazol-5-yl)methoxyimino]-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonamide

##STR00062##

Step 1: Preparation of 2-[(2,4-dimethylthiazol-5-yl)methoxylisoindoline-1,3-dione

[0606] N-Hydroxyphthalimide (93 mg, 0.56 mmol) was added to a stirred solution of 5-(chloromethyl)-2,4-dimethyl-thiazole (100 mg, 0.56 mmol) in ACN (5 mL), followed by DIPEA (202 L, 1.11 mmol). After 16 h stirring, the reaction mixture was concentrated and purified by column chromatography (silica gel; PE:EA; 2:1; v:v) to afford 2-[(2,4-dimethylthiazol-5-yl)methoxy]isoindoline-1,3-dione as a white solid (140 mg, 83% yield).

[0607] MS m/z (+ESI): 289.1 [M+H].sup.+.

Step 2: Preparation of O-[(2,4-dimethylthiazol-5-yl)methyl]hydroxylamine

[0608] Hydrazine hydrate (0.93 g, 18.3 mmol) was added to a stirred solution of 2-[(2,4-dimethylthiazol-5-yl)methoxy]isoindoline-1,3-dione (3.7 g, 12.2 mmol) in DCM (100 mL). After 4 h stirring, the reaction mixture was filtered and the filtrate was concentrated to afford O-[(2,4-dimethylthiazol-5-yl)methyl]hydroxylamine as a yellow oil (1.9 g, 89% yield) which was used in the next step without further purification.

[0609] MS m/z (+ESI): 159.1 [M+H].sup.+.

Step 3: Preparation of 6-bromo-2-chloro-3-[(1-methylpyrazol-4-yl)methyl]quinazolin-4-one

[0610] 4-(Chloromethyl)-1-methyl-pyrazole (3.42 g, 23.6 mmol) was added to a stirred solution of 6-bromo-2-chloro-3H-quinazolin-4-one (4.3 g, 12.4 mmol) in DMF (40 mL), followed by K.sub.2CO.sub.3 (5.25 g, 37.3 mmol).

[0611] After 16 h stirring, the reaction mixture was diluted with H.sub.2O (150 mL) and the resulting suspension was filtered. The cake was washed with H.sub.2O and dried under high vacuum to give a yellow solid that was suspended in PE:EA (60 mL, 2:1, v:v). The resulting suspension was sonicated for 30 minutes and filtered. The cake was dried under high vacuum to afford 6-bromo-2-chloro-3-[(1-methylpyrazol-4-yl)methyl]quinazolin-4-one as a yellow solid (2.5 g, 51% yield).

[0612] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm: 8.21 (d, J=2.4 Hz, 1H), 8.01 (dd, J=2.4, 8.4 Hz, 1H), 7.76 (s, 1H), 7.58 (d, J=8.4 Hz, 1H), 7.48 (s, 1H), 5.21 (s, 2H), 3.77 (s, 3H).

[0613] MS m/z (+ESI): 353.0, 355.0 [M+H].sup.+.

Step 4: Preparation of 6-bromo-2-[(2,4-dimethylthiazol-5-yl)methoxyimino]-3-[(1-methylpyrazol-4-yl)methyl]-1H-quinazolin-4-one

[0614] O-[(2,4-dimethylthiazol-5-yl)methyl]hydroxylamine (180 mg, 1.02 mmol) was added to a stirred solution of 6-bromo-2-chloro-3-[(1-methylpyrazol-4-yl)methyl]quinazolin-4-one (200 mg, 0.51 mmol) in DMA (5 mL), followed by TEA (290 L, 2.04 mmol). After 3 h stirring at 100 C., the reaction mixture was diluted with H.sub.2O (50 mL) and the resulting suspension was filtered. The cake was washed with H.sub.2O and dried under high vacuum to afford 6-bromo-2-[(2,4-dimethylthiazol-5-yl)methoxyimino]-3-[(1-methylpyrazol-4-yl)methyl]-1H-quinazolin-4-one as a yellow solid (220 mg, 82% yield) which was used in the next step without further purification.

[0615] MS m/z (+ESI): 475.0, 477.0 [M+H].sup.+.

Step 5: Preparation of 6-benzylsulfanyl-2-[(2,4-dimethylthiazol-5-yl)methoxyimino]-3-[(1-methylpyrazol-4-yl)methyl]-1H-quinazolin-4-one

[0616] Benzyl mercaptan (221 L, 1.84 mmol) was added to a stirred suspension of 6-bromo-2-[(2,4-dimethylthiazol-5-yl)methoxyimino]-3-[(1-methylpyrazol-4-yl)methyl]-1H-quinazolin-4-one (650 mg, 1.23 mmol) in Diox (30 mL), followed by Xant-Phos (145 mg, 0.24 mmol), Pd.sub.2(dba).sub.3 (115 mg, 0.12 mmol) and DIPEA (415 L, 2.46 mmol). After 2 h stirring at 100 C., the reaction mixture was concentrated and purified by column chromatography (silica gel; PE:EA; 1:1; v:v) to afford 6-benzylsulfanyl-2-[(2,4-dimethylthiazol-5-yl)methoxyimino]-3-[(1-methylpyrazol-4-yl)methyl]-1H-quinazolin-4-one as a yellow solid (530 mg, 75% yield).

[0617] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm: 10.35 (s, 1H), 7.70 (d, J=2.0 Hz, 1H), 7.48 (dd, J=2.0, 8.4 Hz, 1H), 7.45 (s, 1H), 7.30 (m, 2H), 7.25 (m, 4H), 7.21 (m, 1H), 5.11 (s, 2H), 4.78 (s, 2H), 4.15 (s, 2H), 3.72 (s, 3H), 2.56 (s, 3H), 2.35 (s, 3H).

[0618] MS m/z (+ESI): 519.2 [M+H].sup.+.

Step 6: Preparation of -2-[(2,4-dimethylthiazol-5-yl)methoxyimino]-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonyl chloride

[0619] NCS (293 mg, 2.08 mmol) was added to a stirred solution of 6-benzylsulfanyl-2-[(2,4-dimethylthiazol-5-yl)methoxyimino]-3-[(1-methylpyrazol-4-yl)methyl]-1H-quinazolin-4-one (300 mg, 0.52 mmol) in AcOH (3 mL) and H.sub.2O (1 mL). After 2 h stirring, the reaction mixture was diluted with EA (20 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to afford -2-[(2,4-dimethylthiazol-5-yl)methoxyimino]-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonyl chloride as a yellow oil (260 mg, 40% yield) which was used in the next step without further purification.

[0620] MS m/z (+ESI): 495.1, 497.1 [M+H].sup.+.

Step 7: Preparation of 2-[(2,4-dimethylthiazol-5-yl)methoxyimino]-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonamide

[0621] The title compound was prepared as a white solid (17 mg, 14% yield) following Scheme 1 and in analogy to Example 1 (step 5) using 2-[(2,4-dimethylthiazol-5-yl)methoxyimino]-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonyl chloride (260 mg, 0.21 mmol) as starting material.

[0622] .sup.1H NMR (400 MHz, DMSO-d.sub.6+D.sub.2O) ppm: 8.18 (d, J=2.4 Hz, 1H), 7.84 (dd, J=2.4, 8.8 Hz, 1H), 7.47 (m, 2H), 7.32 (s, 1H), 5.13 (s, 2H), 4.80 (s, 2H), 3.72 (s, 3H), 2.56 (s, 3H), 2.35 (s, 3H), 1.02 (s, 3H), 0.56 (m, 2H), 0.35 (m, 2H).

[0623] MS m/z (+ESI): 530.4 [M+H].sup.+.

Preparation of Example 5: 4-[2-methoxyimino-6-[(1-methylcyclopropyl)sulfamoyl]-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazolin-8-yl]-N,N-dimethyl-benzamide

##STR00063##

[0624] [4-(Dimethylcarbamoyl)phenyl]boronic acid (60 mg, 0.30 mmol) was added to a stirred solution of 8-chloro-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonamide (120 mg, 0.25 mmol) in Diox (1.5 mL) and H.sub.2O (0.3 mL), followed by K.sub.3PO.sub.4 (163 mg, 0.76 mmol), Pd(PPh.sub.3).sub.4 (45 mg, 0.04 mmol) and PdCl.sub.2(dppf).sub.2 (28 mg, 0.04 mmol). After 4 h stirring at 95 C., the reaction mixture was filtered. The filtrate was concentrated and purified by preparative HPLC to afford 4-[2-methoxyimino-6-[(1-methylcyclopropyl)sulfamoyl]-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazolin-8-yl]-N,N-dimethyl-benzamide as a white solid (38 mg, 26% yield).

[0625] .sup.1H NMR (400 MHz, DMSO-d.sub.6+D.sub.2O) ppm: 8.28 (d, J=2.0 Hz, 1H), 7.83 (d, J=2.0 Hz, 1H), 7.69 (s, 1H), 7.62 (m, 4H), 7.43 (s, 1H), 4.82 (s, 2H), 3.75 (s, 3H), 3.69 (s, 3H), 3.01 (s, 3H), 2.94 (s, 3H), 1.08 (s, 3H), 0.62 (m, 2H), 0.40 (m, 2H).

[0626] MS m/z (+ESI): 566.4 [M+H].sup.+.

Preparation of Examples 7 and 8: 2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(3R)-3-methylpiperazin-1-yl]-1H-quinazoline-6-sulfonamide and 2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(3R)-3-methyl-4-(1-methylcyclopropanecarbonyl)piperazin-1-yl]-1H-quinazoline-6-sulfonamide

##STR00064##

Step 1: Preparation of 5-bromo-3-fluoro-2-nitro-benzoic acid

[0627] 30% aqueous H.sub.2O.sub.2 (5.9 mL, 58.0 mmol) was added to a stirred solution of 2-amino-5-bromo-3-fluoro-benzoic acid in TFA (10 mL). After 2 h stirring at 60 C., the reaction mixture was quenched by addition at 0 C. of aqueous NaHSO.sub.3, concentrated and purified by Biotage combiflash to afford 5-bromo-3-fluoro-2-nitro-benzoic acid as a yellow solid (1.52 g, 63% yield).

[0628] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm: 8.31 (dd, J=9.2 Hz, 2.0 Hz, 1H), 7.98 (t, J=1.6 Hz, 1H).

[0629] MS m/z (+ESI): 263.9, 265.9 [M+H].sup.+.

Step 2: Preparation of 3-[(3R)-4-benzyloxycarbonyl-3-methyl-piperazin-1-yl]-5-bromo-2-nitro-benzoic acid

[0630] Benzyl (2R)-2-methylpiperazine-1-carboxylate (416 mg, 1.70 mmol) was added to a stirred solution of 5-bromo-3-fluoro-2-nitro-benzoic acid (100 mg, 0.34 mmol) in EtOH (1 mL). After 2 h stirring at 115 C., the reaction mixture was concentrated and purified by Biotage combiflash to afford 3-[(3R)-4-benzyloxycarbonyl-3-methyl-piperazin-1-yl]-5-bromo-2-nitro-benzoic acid as a yellow solid (160 mg, 88% yield).

[0631] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm: 14.28 (br, 1H), 7.98 (d, J=2.0 Hz, 1H), 7.87 (d, J=2.0 Hz, 1H), 7.36 (m, 5H), 5.10 (m, 2H), 4.25 (m, 1H), 3.86 (m, 1H), 3.08 (m, 1H), 2.93 (m, 4H), 1.14 (d, J=6.8 Hz, 3H).

[0632] MS m/z (+ESI): 476.4, 478.4 [M+H].sup.+.

Step 3: Preparation of 2-amino-3-[(3R)-4-benzyloxycarbonyl-3-methyl-piperazin-1-yl]-5-bromo-benzoic acid

[0633] Zn (186 mg, 2.82 mmol) was added to a stirred solution of 3-[(3R)-4-benzyloxycarbonyl-3-methyl-piperazin-1-yl]-5-bromo-2-nitro-benzoic acid (150 mg, 0.28 mmol) in THF (2 mL) and AcOH (1 mL). After 16 h stirring, the reaction mixture was diluted with THF and filtered. The filtrate was concentrated and purified by Biotage combiflash to afford 2-amino-3-[(3R)-4-benzyloxycarbonyl-3-methyl-piperazin-1-yl]-5-bromo-benzoic acid as a yellow solid (110 mg, 78% yield).

[0634] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm: 7.61 (d, J=2.0 Hz, 1H), 7.38 (m, 4H), 7.33 (m, 1H), 7.17 (d, J=2.0 Hz, 1H), 5.11 (m, 2H), 4.30 (m, 1H), 3.85 (m, 1H), 3.38 (m, 1H), 2.83 (m, 1H), 2.83 (m, 2H), 2.46 (m, 1H), 1.32 (d, J=6.8 Hz, 3H).

[0635] MS m/z (+ESI): 448.2, 450.2 [M+H].sup.+.

Step 4: Preparation of benzyl (2R)-4-[2-amino-5-bromo-3-[(1-methylpyrazol-4-yl)methylcarbamoyl]phenyl]-2-methyl-piperazine-1-carboxylate

[0636] (1-Methylpyrazol-4-yl)methanamine (563 mg, 5.02 mmol) was added to a stirred solution of 2-amino-3-[(3R)-4-benzyloxycarbonyl-3-methyl-piperazin-1-yl]-5-bromo-benzoic acid (1.25 g, 2.51 mmol) in DMF (8 mL), followed by HATU (1.28 g, 3.26 mmol) and DIPEA (1.3 mL, 7.53 mmol). After 4 h stirring, the reaction mixture was concentrated and purified by Biotage combiflash to afford benzyl (2R)-4-[2-amino-5-bromo-3-[(1-methylpyrazol-4-yl)methylcarbamoyl]phenyl]-2-methyl-piperazine-1-carboxylate as a white solid (1.18 g, 78% yield).

[0637] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm: 8.72 (t, J=5.6 Hz, 1H), 7.58 (s, 1H), 7.48 (d, J=2.0 Hz, 1H), 7.35 (m, 6H), 7.09 (d, J=2.0 Hz, 1H), 6.28 (s, 2H), 5.10 (m, 2H), 4.29 (m, 1H), 4.21 (d, J=5.6 Hz, 2H), 3.85 (m, 1H), 3.77 (s, 3H), 3.37 (m, 1H), 2.99 (m, 1H), 2.80 (m, 2H), 2.46 (m, 1H), 1.31 (d, J=6.8 Hz, 3H).

[0638] MS m/z (+ESI): 541.2, 543.2 [M+H].sup.+.

Step 5: Preparation of benzyl (2R)-4-[6-bromo-2-chloro-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-quinazolin-8-yl]-2-methyl-piperazine-1-carboxylate

[0639] Thiophosgene (81 mg, 0.70 mmol) was added to a stirred solution of benzyl (2R)-4-[2-amino-5-bromo-3-[(1-methylpyrazol-4-yl)methylcarbamoyl]phenyl]-2-methyl-piperazine-1-carboxylate (105 mg, 0.17 mmol) in Diox (4 mL). After 1 h stirring at rt and 1 h at 105 C., the reaction mixture was concentrated and purified by Biotage combiflash to afford benzyl (2R)-4-[6-bromo-2-chloro-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-quinazolin-8-yl]-2-methyl-piperazine-1-carboxylate as a yellow solid (87 mg, 76% yield).

[0640] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm: 7.75 (m, 2H), 7.47 (s, 1H), 7.35 (m, 6H), 5.19 (s, 2H), 5.11 (m, 2H), 4.29 (m, 1H), 3.92 (m, 1H), 3.78 (m, 1H), 3.77 (s, 3H), 3.48 (m, 1H), 3.27 (m, 1H), 2.82 (m, 2H), 1.37 (d, J=6.8 Hz, 3H).

[0641] MS m/z (+ESI): 584.9, 586.8 [M+H].sup.+.

Steps 6-9: Preparation of benzyl (2R)-4-[2-methoxyimino-6-[(1-methylcyclopropyl)sulfamoyl]-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazolin-8-yl]piperazine-1-carboxylate

[0642] The title compound was prepared as a light yellow solid following Scheme 1 and in analogy to Example 3 (steps 4-7) using benzyl (2R)-4-[6-bromo-2-chloro-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-quinazolin-8-yl]-2-methyl-piperazine-1-carboxylate, benzyl mercaptan, methoxyamine hydrochloride and 1-methylcyclopropanamine hydrochloride as starting materials.

[0643] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm: 8.59 (s, 1H), 8.03 (d, J=2.0 Hz, 1H), 8.01 (s, 1H), 7.73 (d, J=2.0 Hz, 1H), 7.69 (s, 1H), 7.43 (s, 1H), 7.36 (m, 5H), 5.12 (m, 2H), 4.82 (m, 2H), 4.35 (m, 1H), 4.00 (m, 1H), 3.82 (s, 3H), 3.76 (s, 3H), 3.28 (m, 1H), 2.94 (m, 3H), 2.73 (m, 1H), 1.40 (d, J=6.8 Hz, 3H), 1.03 (s, 3H), 0.58 (m, 2H), 0.37 (m, 2H).

[0644] MS m/z (+ESI): 651.0 [M+H].sup.+.

Step 10: Preparation of 2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(3R)-3-methylpiperazin-1-yl]-1H-quinazoline-6-sulfonamide

[0645] 10% Pd/C (200 mg, 0.19 mmol) was added to a stirred solution of benzyl (2R)-4-[2-methoxyimino-6-[(1-methylcyclopropyl)sulfamoyl]-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazolin-8-yl]piperazine-1-carboxylate (350 mg, 0.48 mmol) in EtOH (5 mL) and EA (5 mL), followed by 37% aqueous HCl (1.4 mL, 16.8 mmol). After 24 h stirring under hydrogen flow, the reaction mixture was diluted with MeOH/DCM (10/1, v/v) and filtered. The filtrate was concentrated and purified by preparative HPLC to afford 2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(3R)-3-methylpiperazin-1-yl]-1H-quinazoline-6-sulfonamide as a light yellow solid (124 mg, 45% yield).

[0646] .sup.1H NMR (400 MHz, DMSO-d.sub.6+D.sub.2O) ppm: 8.01 (d, J=2.0 Hz, 1H), 7.69 (d, J=2.0 Hz, 1H), 7.67 (s, 1H), 7.42 (s, 1H), 4.81 (s, 2H), 3.83 (s, 3H), 3.74 (s, 3H), 3.19 (m, 2H), 3.01 (m, 3H), 2.81 (m, 1H), 2.62 (m, 1H), 1.16 (d, J=6.4 Hz, 3H), 1.01 (s, 3H), 0.57 (m, 2H), 0.37 (m, 2H).

[0647] MS m/z (+ESI): 517.4 [M+H].sup.+.

Step 11: Preparation of 2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(3R)-3-methyl-4-(1-methylcyclopropanecarbonyl)piperazin-1-yl]-1H-quinazoline-6-sulfonamide

[0648] 1-Methylcyclopropanecarboxylic acid (32 mg, 0.31 mmol) was added to a stirred solution of 2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(3R)-3-methylpiperazin-1-yl]-1H-quinazoline-6-sulfonamide (90 mg, 0.16 mmol) in DMF (5 mL), followed by EDCI (62 mg, 0.31 mmol) and HOBt (44 mg, 0.31 mmol). After 3 h stirring, the reaction mixture was concentrated and purified by preparative HPLC to afford 2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(3R)-3-methyl-4-(1-methylcyclopropanecarbonyl)piperazin-1-yl]-1H-quinazoline-6-sulfonamide as a white solid (28 mg, 29% yield).

[0649] .sup.1H NMR (400 MHz, DMSO-d.sub.6+D.sub.2O) ppm: 8.03 (d, J=2.0 Hz, 1H), 7.76 (d, J=2.0 Hz, 1H), 7.69 (s, 1H), 7.43 (s, 1H), 4.82 (s, 2H), 4.61 (m, 1H), 4.26 (m, 1H), 3.82 (s, 3H), 3.76 (s, 3H), 2.96 (m, 3H), 2.67 (m, 2H), 1.41 (br, 3H), 1.25 (s, 3H), 1.01 (s, 3H), 0.83 (m, 2H), 0.57 (m, 4H), 0.37 (m, 2H).

[0650] MS m/z (+ESI): 599.5 [M+H].sup.+.

Preparation of Example 12: (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(3R)-4-acetyl-3-methyl-piperazin-1-yl]-1H-quinazoline-6-sulfonamide

##STR00065##

[0651] To a solution of (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(3R)-3-methylpiperazin-1-yl]-1H-quinazoline-6-sulfonamide (74 mg, 0.13 mmol) in THF (2 mL) was added acetic anhydride (66 mg, 0.64 mmol). The reaction solution was stirred at 30 C. for 1 h. The reaction solution was purified directly by preparative HPLC (ACN/H.sub.2O-0.1% HCOOH) to give the desired product as white solid (32 mg, 44% yield).

[0652] .sup.1H NMR (400 MHz, DMSO-d.sub.6+D.sub.2O) ppm: 8.04 (d, J=2.0 Hz, 1H), 7.71 (d, J=2.0 Hz, 1H), 7.70 (s, 1H), 7.44 (s, 1H), 4.83 (s, 2H), 4.68 and 4.20 (2 m, 1H), 4.39 and 2.61 (2 m, 1H), 3.82 (s, 3H), 3.77 (s, 3H), 3.46 (m, 1H), 2.96 (m, 3H), 2.77 (m, 1H), 2.06 and 2.04 (2s, 3H), 1.46 and 1.34 (2d, J=6.8 Hz, 3H), 1.03 (s, 3H), 0.58 (m, 2H), 0.37 (m, 2H).

[0653] MS m/z (+ESI): 559.3 [M+H].sup.+.

Preparation of Example 13: (R,E)-2-(methoxyimino)-8-(6-methyl-1,2,3,6-tetrahydropyridin-4-yl)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide/(R,E)-2-(methoxyimino)-8-(2-methyl-1,2,3,6-tetrahydropyridin-4-yl)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide

##STR00066##

Step 1: tert-butyl (R)-6-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate/tert-butyl (R)-2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate

[0654] Under argon atmosphere, to a stirred solution of 1,1-dimethylethyl (2R)-2-methyl-4-oxo-1-piperidinecarboxylate (600 mg, 2.76 mmol) in dry THF (20 mL) was added dropwise NaHMDS (2.8 mL, 5.6 mmol, 2M solution in THF) at 78 C. The solution was stirred for 30 min at 78 C. and then treated with a solution of 1,1,1-trifluoro-N-phenyl-N-[(trifluoromethyl)sulfonyl]methanesulfonamide (2.0 g, 5.5 mmol) in dry THF (10 mL). The reaction solution was allowed to slowly warm to room temperature and stirred for another 2 h. The reaction was quenched by aq. NH.sub.4Cl solution, then extracted with EA twice. The combined organic layers were washed with water and brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under vacuum to dryness. The residue was purified by Biotage Combiflash (0-10% EA in PE, collected: 5% EA in PE) to afford the title compound as a colorless oil. (840 mg, 88% yield, a mixture of isomers).

[0655] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm: 5.75 (m, 1H), 4.68 (m, 1H), 4.43 (m, 0.6H), 4.25 (m, 0.4H), 3.65 (m, 0.6H), 3.00 (m, 0.4H), 2.81 (m, 0.6H), 2.59 (m, 0.4H), 2.22 (m, 0.4H), 2.08 (m, 0.6H), 1.49 and 1.48 (2s, 9H), 1.25 and 1.19 (2d, J=6.8 Hz, 3H).

Step 2: tert-butyl (R)-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate/tert-butyl (R)-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[0656] To a solution of a mixture of tert-butyl (R)-6-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate and tert-butyl (R)-2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate (0.84 g, 2.43 mmol) in 1,4-dioxane (10 mL) were added potassium acetate (386 mg, 3.89 mmol), 4,4,4,4,5,5,5,5-octamethyl-2,2-bi-1,3,2-dioxaborolane (756 mg, 2.92 mmol) and 1,1-bis(diphenylphosphino)ferrocene palladium (II) chloride (72 mg, 0.10 mmol). The suspension was evacuated and backfilled with N.sub.2 gas, followed by stirring for 2 h at 100 C. The reaction suspension was concentrated in vacuo. The residue was purified directly by Biotage Combiflash (ACN/H.sub.2O with 0.1% HCOOH; collected: 80% ACN in H.sub.2O) to afford the desired product as a brown oil. (455 mg, 58% yield, a mixture of isomers).

[0657] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm: 6.43 (m, 1H), 4.46 (m, 1H), 4.21 (m, 0.55H), 4.06 (m, 0.45H), 3.61 (m, 0.55H), 2.75 (m, 0.55H), 2.43 (m, 0.45H), 2.15 (m, 1H), 2.05 (m, 0.45H), 1.46 (s, 9H), 1.26 (s, 12H), 1.18 and 1.06 (2d, J=6.8 Hz, 3H).

[0658] MS m/z (+ESI): 324.2 [M+H].sup.+; 268.1 [M+H-Bu].sup.+.

Step 3: tert-butyl (2R)-2-methyl-4-[(2E)-2-methoxyimino-6-[(1-methylcyclopropyl)sulfamoyl]-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazolin-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylate/tert-butyl (6R)-4-[(2E)-2-methoxyimino-6-[(1-methylcyclopropyl)sulfamoyl]-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazolin-8-yl]-6-methyl-3,6-dihydro-2H-pyridine-1-carboxylate

[0659] To a solution of (2E)-8-bromo-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonamide and (300 mg, 0.54 mmol) in 1,4-dioxane (10 mL) and water (1 mL) were added a mixture of tert-butyl (2R)-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate and tert-butyl (6R)-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (421 mg, 1.30 mmol), potassium phosphate tribasic (351 mg, 1.63 mmol), 2-(dicyclohexylphosphino)-2,4,6-tri-i-propyl-1,1-biphenyl (53 mg, 0.11 mmol) and dipalladium-tris(dibenzylideneacetone) chloroform complex (57 mg, 0.05 mmol). The resulting solution was evacuated and backfilled with N.sub.2 gas, followed by stirring at 75 C. for 3.5 h. The suspension was concentrated under vacuum to dryness. The residue was purified by Biotage Combiflash (10-80% EA in PE, collected: 60% EA in PE) to afford the desired product as a yellow solid. (150 mg, 45% yield, a mixture of isomers).

[0660] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm: 8.58 (s, 0.6H, NH, isomer 2), 8.34 (s, 0.4H, NH, isomer 1), 8.18 (d, J=2.0 Hz, 0.4H, isomer 1), 8.17 (d, J=2.0 Hz, 0.6H, isomer 2), 8.06 (s, 0.4H, SO.sub.2NH, isomer 1), 8.03 (s, 0.6H, SO.sub.2NH, isomer 2), 7.76 (d, J=2.0 Hz, 0.6H, isomer 2), 7.70 (m, 1.4H), 7.43 (s, 1H), 6.06 (m, 0.6H, isomer 2), 6.03 (m, 0.4H, isomer 1), 4.82 (s, 2H), 4.53 (m, 1H), 4.28 (m, 0.4H, isomer 1), 4.09 (m, 0.6H, isomer 2), 3.81 (s, 1.8H, isomer 2), 3.80 (s, 1.2H, isomer 1), 3.77 (s, 3H), 3.70 (m, 0.6H, isomer 2), 3.04 (m, 0.4H, isomer 1), 2.71 (m, 0.4H, isomer 1), 2.54 (m, 0.6H, isomer 2), 2.09 (m, 1H), 1.45 (s, 9H), 1.25 (d, J=6.8 Hz, 1.8H, isomer 2), 1.25 (d, J=6.8 Hz, 1.2H, isomer 1), 1.06 (s, 3H), 0.60 (m, 2H), 0.39 (m, 2H).

[0661] MS m/z (+ESI): 614.3 [M+H].sup.+.

Step 4: (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(2R)-2-methyl-1,2,3,6-tetrahydropyridin-4-yl]-1H-quinazoline-6-sulfonamide/(2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(6R)-6-methyl-1,2,3,6-tetrahydropyridin-4-yl]-1H-quinazoline-6-sulfonamide

[0662] To a solution of a mixture of tert-butyl (2R)-2-methyl-4-[(2E)-2-methoxyimino-6-[(1-methylcyclopropyl)sulfamoyl]-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazolin-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylate and tert-butyl (6R)-6-methyl-4-[(2E)-2-methoxyimino-6-[(1-methylcyclopropyl)sulfamoyl]-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazolin-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (117 mg, 0.19 mmol) in DCM (9 mL) was added trifluoroacetic acid (9 mL 115 mmol) and then the reaction was stirred at 25 C. for 1 h. The volatiles were removed under vacuum to give the crude product which was purified by preparative HPLC (ACN/H.sub.2O with 0.1% HCOOH) to give the product as a white solid. (42 mg, 43.0% yield, a mixture of isomers).

[0663] .sup.1H NMR (400 MHz, DMSO-d.sub.6+D.sub.2O) ppm: 8.26 (s, 0.8H, HCOOH), 8.18 (d, J=2.0 Hz, 1H), 7.77 (d, J=2.0 Hz, 0.64H), 7.73 (d, J=2.0 Hz, 0.36H), 7.70 (s, 1H), 7.44 (s, 1H), 6.07 (m, 0.36H), 5.97 (m, 0.64H), 4.82 (s, 2H), 3.82 (s, 1.1H), 3.81 (s, 1.9H), 3.77 (s, 3H), 3.65 (m, 0.64H), 3.55 (m, 1H), 3.22 (m, 0.64H), 3.08 (m, 0.36H), 2.97 (m, 0.64H), 2.32 (m, 1H), 2.8 (m, 0.36H), 2.14 (m, 0.36H), 1.24 (d, J=6.8 Hz, 1.9H), 1.19 (d, J=6.8 Hz, 1.1H), 1.06 (s, 3H), 0.60 (m, 2H), 0.39 (m, 2H); mixture of two isomers (36:64).

[0664] MS m/z (+ESI): 514.5 [M+H].sup.+.

Preparation of Example 14: (E)-4-(2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-4-oxo-1,2,3,4-tetrahydroquinazolin-8-yl)-N,N,2-trimethylbenzamide

##STR00067##

[0665] N,N,2-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide ester (303 mg, 1.05 mmol) was added at 25 C. to a stirred solution of (2E)-8-chloro-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonamide (100 mg, 0.21 mmol), potassium phosphate tribasic (226 mg, 1.05 mmol), 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (21 mg, 0.04 mmol) and dipalladium-tris(dibenzylideneacetone) chloroform complex (22 mg, 0.02 mmol) in 1,4-dioxane (8 mL) and water (1 mL). The reaction solution was evacuated and backfilled with N.sub.2 gas and then stirred at 85 C. for 2 hours. The reaction was cooled to room temperature, and then filtered. The filtrate was submitted to preparative HPLC purification to afford the desired product as white solid (39 mg, 32% yield).

[0666] .sup.1H NMR (400 MHz, DMSO-d.sub.6+D.sub.2O) ppm: 8.28 (d, J=2.0 Hz, 1H), 7.84 (d, J=2.0 Hz, 1H), 7.70 (s, 1H), 7.47 (s, 1H), 7.44 (s, 1H), 7.40 (m, 2H), 4.82 (s, 2H), 3.77 (s, 3H), 3.71 (s, 3H), 3.04 (s, 3H), 2.79 (s, 3H), 2.28 (s, 3H), 1.09 (s, 3H), 0.63 (m, 2H), 0.41 (m, 2H).

[0667] MS m/z (+ESI): 580.5 [M+H].sup.+.

Preparation of Example 20: (E)-6-(2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-4-oxo-1,2,3,4-tetrahydroquinazolin-8-yl)-N,N-dimethylnicotinamide: Step 1: (2E)-N,N-dimethyl-6-(tributylstannyl)nicotinamide

##STR00068##

[0668] To a solution of 6-bromo-N,N-dimethyl-pyridine-3-carboxamide (1.30 g, 4.82 mmol) in 1,4-dioxane (6 mL) were added lithium chloride (1.24 g, 28.9 mmol), tricyclohexyl phosphine (418 mg, 1.45 mmol), tris(dibenzylideneacetone)dipalladium-chloroform adduct (451 mg, 0.48 mmol) and hexabutyldistannane (2.98 mL, 5.79 mmol). The suspension was stirred at 125 C. for 2 h. The reaction suspension was combined with another batch and purified by Biotage Combiflash eluting with 0-100% EA in PE, collected: 60% EA in PE) to give the desired product as yellow oil (900 mg, 27.6% yield).

[0669] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm: 8.70 (dd, J=2.0 Hz, 0.8 Hz, 1H), 7.64 (dd, J=7.6 Hz, 2.0 Hz, 1H), 7.53 (dd, J=7.6 Hz, 0.8 Hz, 1H), 2.99 (s, 3H), 2.92 (s, 3H), 1.53 (m, 6H), 1.28 (m, 6H), 1.08 (m, 6H), 0.84 (t, J=7.2 Hz, 9H).

[0670] MS m/z (+ESI): 441.1 [M+H].sup.+.

[0671] Step 2: (E)-6-(2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-4-oxo-1,2,3,4-tetrahydroquinazolin-8-yl)-N,N-dimethylnicotinamide: A sealed tube was charged with (2E)-8-chloro-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonamide (100 mg, 0.21 mmol), N,N-dimethyl-6-tributylstannyl-pyridine-3-carboxamide (205 mg, 0.42 mmol), palladium(0) tetrakis(triphenylphosphine) (25 mg, 0.02 mmol) and THF (2 mL). The reaction solution was heated to 100 C. and stirred for 16 h under N.sub.2 atmosphere. The reaction solution was purified directly by preparative HPLC eluting with MeOH/H.sub.2O (0.1% HCOOH) to afford the desired product as a yellow solid (21 mg, 17.4% yield).

[0672] .sup.1H NMR (400 MHz, DMSO-d.sub.6+D.sub.2O) ppm: 8.79 (d, J=2.0 Hz, 1H), 8.59 (d, J=2.0 Hz, 1H), 8.34 (d, J=2.0 Hz, 1H), 8.23 (d, J=8.4 Hz, 1H), 8.15 (dd, J=8.4 Hz, 2.0 Hz, 1H), 7.71 (s, 1H), 7.45 (s, 1H), 4.86 (s, 2H), 3.90 (s, 3H), 3.76 (s, 3H), 3.04 (s, 3H), 2.99 (s, 3H), 1.06 (s, 3H), 0.64 (m, 2H), 0.40 (m, 2H).

[0673] MS m/z (+ESI): 567.4 [M+H].sup.+.

Preparation of Example 21: (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(3R)-3,4-dimethylpiperazin-1-yl]-1H-quinazoline-6-sulfonamide

##STR00069##

[0674] To a solution of (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(3R)-3-methylpiperazin-1-yl]-1H-quinazoline-6-sulfonamide (120 mg, 0.21 mmol) in methanol (2 mL) were added sodium cyanoborohydride (69 mg, 1.05 mmol) and formaldehyde (85 mg, 1.05 mmol, 37% aq. solution). The reaction solution was stirred at 25 C. for 1 h. The reaction solution was directly purified by preparative HPLC (ACN/H.sub.2O-0.1% HCOOH) to give the desired product as white solid (44 mg, 38% yield).

[0675] .sup.1H NMR (400 MHz, DMSO-d.sub.6+D.sub.2O) ppm: 8.01 (d, J=2.0 Hz, 1H), 7.71 (m, 2H), 7.44 (s, 1H), 4.82 (s, 2H), 3.85 (s, 3H), 3.77 (s, 3H), 2.89 (m, 4H), 2.54 (m, 1H), 2.35 (m, 2H), 2.29 (s, 3H), 1.06 (d, J=6.4 Hz, 3H), 1.02 (s, 3H), 0.58 (m, 2H), 0.37 (m, 2H).

[0676] MS m/z (+ESI): 531.4 [M+H].sup.+.

Preparation of Example 22: (E)-8-(4-(1-hydroxy-2-oxocyclobutyl)phenyl)-2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide

##STR00070##

[0677] Step 1: tert-butyl N-[1-[4-(2E)-2-methoxyimino-6-[(1-methylcyclopropyl) sulfamoyl]-3-[(1-methylpyrazol-4-yl]methyl]-4-oxo-1H-quinazolin-8-yl]benzoyl]cyclopropyl]carbamate:

[0678] To a solution of tert-butyl N-[1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]cyclopropyl]carbamate (654 mg, 1.01 mmol) in 1,4-dioxane (5 mL) and water (1 mL) were added (2E)-8-bromo-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonamide (140 mg, 0.25 mmol), 1,1-bis(diphenylphosphino) ferrocene palladium (II) chloride (19 mg, 0.025 mmol) and potassium carbonate (78 mg, 0.56 mmol). The reaction solution was stirred at 75 C. for 2 h under N.sub.2 atmosphere. The solution was concentrated in vacuo, and the residue was purified by Biotage Combiflash eluting with 0-60% EA in PE (EA/PE=1/1, R.sub.f=0.5) to afford the desired product as brown solid (160 mg, 83.9% yield, 90%).

[0679] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm: 8.56 (d, J=1.6 Hz, 1H), 8.23 (s, 1H), 7.92 (m, 2H), 7.88 (d, J=1.6 Hz, 1H), 7.69 (s, 1H), 7.58 (s, 1H), 7.49 (m, 2H), 5.30 (br s, 1H, BocNH), 4.96 (s, 2H), 3.89 (s, 3H), 3.80 (s, 3H), 1.80 (m, 2H), 1.27 (m, 11H), 1.24 (s, 3H), 0.80 (m, 2H), 0.51 (m, 2H).

[0680] MS m/z (+ESI): 678.1 [M+H].sup.+.

Step 2: (2E)-8-[4-(1-hydroxy-2-oxo-cyclobutyl)phenyl]-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl) methyl]-4-oxo-1H-quinazoline-6-sulfonamide

[0681] To a solution of tert-butyl N-[1-[4-[(2E)-2-methoxyimino-6-[(1-methylcyclopropyl)sulfamoyl]-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazolin-8-yl]benzoyl]cyclopropyl]carbamate (160 mg, 0.21 mmol) in DCM (1 mL) was added trifluoroacetic acid (1.49 g, 13.1 mmol) at 25 C. The solution was stirred at 25 C. for 0.5 h. The reaction solution was concentrated under vacuum, and the residue was purified by preparative HPLC eluting with ACN/H.sub.2O (0.1% HCOOH). The collected fractions were subjected to standing for 24 h at room temperature followed by lyophilization to afford the product 22 (22 mg, 17.2% Yield).

[0682] .sup.1H NMR (400 MHz, DMSO-d.sub.6+D.sub.2O) ppm: 8.27 (d, J=2.0 Hz, 1H), 7.79 (d, J=2.0 Hz, 1H), 7.68 (m, 3H), 7.57 (d, J=8.4 Hz, 2H), 7.44 (s, 1H), 4.82 (s, 2H), 3.76 (s, 3H), 3.70 (s, 3H), 3.11 (m, 1H), 3.01 (m, 1H), 2.66 (m, 1H), 2.32 (m, 1H), 1.08 (s, 3H), 0.62 (m, 2H), 0.39 (m, 2H).

[0683] MS m/z (+ESI): 579.3 [M+H].sup.+.

Preparation of Example 23: (E)-5-(2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-4-oxo-1,2,3,4-tetrahydroquinazolin-8-yl)-N,N-dimethyl-1H-imidazole-2-carboxamide

##STR00071##

Step 1: ethyl (E)-4-(2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-4-oxo-1,2,3,4-tetrahydroquinazolin-8-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxylate

[0684] To a solution of (2E)-8-bromo-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonamide (400 mg, 0.72 mmol) in 1,4-dioxane (15 mL) and water (3 mL) were added [2-ethoxycarbonyl-1-(2-trimethylsilylethoxymethyl)imidazol-4-yl]boronic acid (1.82 g, 2.90 mmol), potassium phosphate tribasic (800 mg, 3.62 mmol), dipalladium-tris(dibenzylideneacetone)chloroform complex (76 mg, 0.07 mmol) and 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (71 mg, 0.15 mmol). The resulting solution was evacuated and backfilled with N.sub.2 gas, followed by stirring at 90 C. for 1.5 h. The reaction solution was directly purified by Biotage Combiflash eluting with ACN/H.sub.2O (0.1% HCOOH) to afford the desired product as a yellow solid (380 mg, 68.8% yield).

[0685] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm: 12.54 (s, 1H), 8.55 (s, 1H), 8.32 (d, J=2.0 Hz, 1H), 8.20 (d, J=2.0 Hz, 1H), 8.05 (s, 1H), 7.72 (s, 1H), 7.46 (s, 1H), 5.81 (s, 2H), 4.87 (s, 2H), 4.43 (q, J=7.2 Hz, 2H), 3.88 (s, 3H), 3.77 (s, 3H), 3.61 (t, J=7.6 Hz, 2H), 1.37 (t, J=7.2 Hz, 3H), 1.08 (s, 3H), 0.87 (t, J=7.6 Hz, 2H), 0.63 (m, 2H), 0.38 (m, 2H), 0.06 (s, 9H).

[0686] MS m/z (+ESI): 687.5 [M+H].sup.+.

Step 2: 4-[(2E)-2-methoxyimino-6-[(1-methylcyclopropyl) sulfamoyl]-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazolin-8-yl]-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxylic acid

[0687] To a solution of ethyl 4-[(2E)-2-methoxyimino-6-[(1-methylcyclopropyl)sulfamoyl]-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazolin-8-yl]-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxylate (200 mg, 0.26 mmol) in methanol (2 mL) and water (2 mL) was added sodium hydroxide (32 mg, 0.79 mmol). The solution was stirred at 25 C. for 16 h. The reaction solution was acidified to pH=5 with 1N HCl and then purified by Biotage Combiflash eluting with ACN/H.sub.2O (0.1% HCOOH) to afford the desired product as a yellow solid (160 mg, 74.1% yield).

[0688] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm: 13.06 (s, 1H), 8.45 (s, 1H), 8.32 (d, J=2.0 Hz, 1H), 8.17 (d, J=1.6 Hz, 1H), 8.03 (s, 1H), 7.71 (s, 1H), 7.45 (s, 1H), 5.83 (s, 2H), 4.86 (s, 2H), 3.83 (s, 3H), 3.77 (s, 3H), 3.60 (t, J=8.0 Hz, 2H), 1.08 (s, 3H), 0.87 (t, J=8.0 Hz, 2H), 0.63 (m, 2H), 0.38 (m, 2H), 0.06 (s, 9H).

[0689] MS m/z (+ESI): 659.4 [M+H].sup.+.

Step 3: (E)-4-(2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-4-oxo-1,2,3,4-tetrahydroquinazolin-8-yl)-N,N-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxamide

[0690] To a solution of 4-[(2E)-2-methoxyimino-6-[(1-methylcyclopropyl)sulfamoyl]-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazolin-8-yl]-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxylic acid (150 mg, 0.18 mmol) in DCM (1 mL) were added 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (107 mg, 0.27 mmol), Hunig's base (71 mg, 0.55 mmol) and dimethylamine (0.46 mL, 0.91 mmol, 2M THF solution) at 25 C. The reaction solution was stirred at 25 C. for 2 h. The reaction solution was concentrated under vacuum, and the residue was purified by Biotage Combiflash eluting with ACN/H.sub.2O (0.1% HCOOH) to afford the desired product as a yellow solid (80 mg, 57.5% yield).

[0691] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm: 12.51 (s, 1H), 8.37 (s, 1H), 8.32 (d, J=2.0 Hz, 1H), 8.18 (s, 1H), 8.05 (s, 1H), 7.71 (s, 1H), 7.45 (s, 1H), 5.60 (s, 2H), 4.86 (s, 2H), 3.86 (s, 3H), 3.77 (s, 3H), 3.54 (t, J=8.0 Hz, 2H), 3.21 (s, 3H), 3.09 (s, 3H), 1.08 (s, 3H), 0.85 (t, J=8.0 Hz, 2H), 0.63 (m, 2H), 0.39 (m, 2H), 0.06 (s, 9H).

[0692] MS m/z (+ESI): 686.1 [M+H].sup.+.

Step 4: (E)-5-(2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-4-oxo-1,2,3,4-tetrahydroquinazolin-8-yl)-N,N-dimethyl-1H-imidazole-2-carboxamide

[0693] To a solution of 4-[(2E)-2-methoxyimino-6-[(1-methylcyclopropyl)sulfamoyl]-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazolin-8-yl]-N,N-dimethyl-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide (50 mg, 0.06 mmol) in DCM (1 mL) was added trifluoroacetic acid (0.83 mL, 10.9 mmol). The solution was stirred at 25 C. for 2 h. The solution was concentrated under vacuum, and the residue was treated with methanol (2 mL) and 25% ammonium hydroxide (0.2 mL). The resulting solution was stirred at 25 C. for another 1 h. The volatiles were removed under vacuum, and the residue was combined with another batch and purified by preparative HPLC eluting with ACN/H.sub.2O (0.1% HCOOH) to give the desired compound as a white solid (27 mg, 28.5% yield)

[0694] .sup.1H NMR (400 MHz, DMSO-d.sub.6+D.sub.2O) ppm: 8.34 (d, J=2.0 Hz, 1H), 8.17 (d, J=2.0 Hz, 1H), 8.09 (s, 1H), 7.71 (s, 1H), 7.46 (s, 1H), 4.86 (s, 2H), 3.85 (s, 3H), 3.76 (s, 3H), 3.51 (s, 3H), 3.08 (s, 3H), 1.06 (s, 3H), 0.63 (m, 2H), 0.39 (m, 2H).

[0695] MS m/z (+ESI): 556.4 [M+H].sup.+.

Preparation of Example 24: (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(2R)-2-methyl-4-piperidyl]-1H-quinazoline-6-sulfonamide

##STR00072##

[0696] To a solution of a mixture of (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(2R)-2-methyl-1,2,3,6-tetrahydropyridin-4-yl]-1H-quinazoline-6-sulfonamide and (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(6R)-6-methyl-1,2,3,6-tetrahydropyridin-4-yl]-1H-quinazoline-6-sulfonamide (130 mg, 0.26 mmol) in ethyl acetate (3 mL) and ethanol (9 mL) was added platinum(IV) oxide (293 mg, 1.27 mmol). The suspension was stirred at 25 C. under hydrogen balloon atmosphere for 24 h. The catalysts were filtered off. The filtrate was purified by preparative HPLC (ACN-H.sub.2O with 0.1% TFA) and (ACN-H.sub.2O with 0.1% HCOOH) to afford the desired product as a white solid. (46 mg, 34% yield).

[0697] .sup.1H NMR (400 MHz, DMSO-d.sub.6+D.sub.2O) ppm: 8.38 (s, 1H, HCOOH), 8.16 (d, J=2.0 Hz, 1H), 7.78 and 7.74 (2d, J=2.0 Hz, 1H, epimers), 7.69 (s, 1H), 7.44 (s, 1H), 4.84 (s, 2H), 3.84 and 3.83 (2s, 3H, epimers), 3.76 (s, 3H), 3.24 (m, 2H), 3.11 (m, 1H), 2.94 (m, 1H), 1.86 (m, 2H), 1.59 (m, 1H), 1.39 (m, 1H), 1.17 (d, J=6.4 Hz, 3H), 1.02 (s, 3H), 0.57 (m, 2H), 0.36 (m, 2H).

[0698] MS m/z (+ESI): 516.4 [M+H].sup.+.

Preparation of Example 25: (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(2R)-1,2-dimethyl-4-piperidyl]-1H-quinazoline-6-sulfonamide

##STR00073##

[0699] To a solution of (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(2R)-2-methyl-4-piperidyl]-1H-quinazoline-6-sulfonamide (120 mg, 0.17 mmol) in methanol (3 mL) were added formaldehyde (76 mg, 0.93 mmol, 37% aq. solution) and sodium cyanoborohydride (37 mg, 0.56 mmol). The reaction solution was stirred at 25 C. for 1 h. The reaction solution was purified directly by preparative HPLC (ACN/H.sub.2O with 0.1% HCOOH) to afford the desired product as a white solid. (36 mg, 36% yield).

[0700] .sup.1H NMR (400 MHz, DMSO-d.sub.6+D.sub.2O) ppm: 8.22 (s, 1H, HCOOH), 8.15 (d, J=2.0 Hz, 1H), 7.80 (d, J=2.0 Hz, 1H), 7.69 (s, 1H), 7.43 (s, 1H), 4.83 (s, 2H), 3.84 and 3.83 (2s, 3H, epimers), 3.76 (s, 3H), 2.98 (m, 2H), 2.69 (m, 1H), 2.32 (m, 1H), 2.29 (s, 3H), 1.78 (m, 2H), 1.64 (m, 1H), 1.37 (m, 1H), 1.14 and 1.08 (2d, J=6.8 Hz, 3H), 1.01 and 1.00 (2s, 3H, epimers), 0.57 (m, 2H), 0.36 (m, 2H).

[0701] MS m/z (+ESI): 530.5 [M+H].sup.+.

Preparation of Example 26: (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(2R)-1-acetyl-2-methyl-4-piperidyl]-1H-quinazoline-6-sulfonamide

##STR00074##

[0702] To a solution of (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(2R)-2-methyl-4-piperidyl]-1H-quinazoline-6-sulfonamide (125 mg, 0.19 mmol) in THF (3 mL) was added acetic anhydride (100 mg, 0.97 mmol). The reaction solution was stirred for 2 h at 25 C. The reaction solution was purified directly by preparative HPLC eluting with MeOH/H.sub.2O (0.1% HCOOH) to afford the desired product as a white solid. (29 mg, 26% yield).

[0703] .sup.1H NMR (400 MHz, DMSO-d.sub.6+D.sub.2O) ppm: 8.15 (d, J=2.0 Hz, 1H), 7.83 (d, J=2.0 Hz, 1H), 7.69 (s, 1H), 7.43 (s, 1H), 4.83 (s, 2H), 4.17 (m, 1H), 3.84 (s, 3H), 3.76 (s, 3H), 3.28 (m, 1H), 3.12 (m, 2H), 2.22 (m, 1H), 2.04 (s, 3H), 1.87 (m, 1H), 1.73 (m, 1H), 1.44 (m, 1H), 1.14 (d, J=6.4 Hz, 3H), 1.01 (s, 3H), 0.58 (m, 2H), 0.37 (m, 2H).

[0704] MS m/z (+ESI): 558.5 [M+H].sup.+.

Preparation of Example 27: (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(2R)-2-methyl-1-(1-methylcyclopropanecarbonyl)-4-piperidyl]-1H-quinazoline-6-sulfonamide

##STR00075##

[0705] To a solution of (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(2R)-2-methyl-4-piperidyl]-1H-quinazoline-6-sulfonamide (150 mg, 0.23 mmol) in DMF (6 mL) were added 1-methylcyclopropanecarboxylic acid (37 mg, 0.35 mmol), 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (137 mg, 0.35 mmol) and Hunig's base (91 mg, 0.70 mmol). The solution was stirred at 25 C. for 2 h. The reaction solution was directly purified by preparative HPLC (ACN-H.sub.2O with 0.1% HCOOH) to afford the desired product as a white solid. (65 mg, 46% yield.

[0706] .sup.1H NMR (400 MHz, DMSO-d.sub.6+D.sub.2O) ppm: 8.14 (d, J=2.0 Hz, 1H), 7.78 (d, J=2.0 Hz, 1H), 7.69 and 7.68 (2s, 1H, epimers), 7.44 and 7.43 (2s, 1H, epimers), 4.83 and 4.82 (2s, 2H, epimers), 4.74 and 4.32 (m, 1H, epimers), 4.21 (m, 1H), 4.05 (m, 1H), 3.84 and 3.81 (2s, 3H, epimers), 3.76 and 3.75 (2s, 3H, epimers), 3.10 (m, 1H), 2.32 (m, 1H), 1.91 (m, 1H), 1.76 (m, 1H), 1.38 (m, 1H), 1.27 and 1.23 (2s, 3H, epimers), 1.12 (d, J=6.4 Hz, 3H), 1.01 and 0.98 (2s, 3H, epimers), 0.88 (m, 1H), 0.75 (m, 1H), 0.57 (m, 4H), 0.36 (m, 2H).

[0707] MS m/z (+ESI): 598.6 [M+H].sup.+.

Preparation of Example 28: (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(2R)-1,2-dimethyl-3,6-dihydro-2H-pyridin-4-yl]-1H-quinazoline-6-sulfonamide/(2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(6R)-1,6-dimethyl-3,6-dihydro-2H-pyridin-4-yl]-1H-quinazoline-6-sulfonamide

##STR00076##

[0708] To a solution of a mixture of (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(2R)-2-methyl-1,2,3,6-tetrahydropyridin-4-yl]-1H-quinazoline-6-sulfonamide and (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(6R)-6-methyl-1,2,3,6-tetrahydropyridin-4-yl]-1H-quinazoline-6-sulfonamide (50 mg, 0.097 mmol) in methanol (5 mL) were added formaldehyde (20 mg, 0.24 mmol, 37% aqueous solution) and sodium cyanoborohydride (6 mg, 0.097 mmol). The reaction was stirred at 25 C. for 1 h. The reaction solution was purified by preparative HPLC (ACN/H.sub.2O with 0.1% HCOOH) to give the desired product as a white solid (22 mg, 43% yield).

[0709] .sup.1H NMR (400 MHz, DMSO-d.sub.6+D.sub.2O) ppm: 8.18 (m, 1H), 8.16 (s, 0.7H, HCOOH), 7.78 (d, J=2.0 Hz, 0.57H), 7.73 (d, J=2.0 Hz, 0.43H), 7.70 (s, 1H), 7.44 (s, 1H), 6.00 (m, 0.43H), 5.90 (m, 0.57H), 4.82 (s, 2H), 3.82 (s, 1.3H), 2.81 (s, 1.7H), 3.77 (s, 3H), 3.36 (m, 0.6H), 3.15 (m, 0.4H), 2.99 (m, 1H), 2.82 (m, 0.4H), 2.58 (m, 0.6H), 2.47-2.30 (m, 1.6H), 2.16 (m, 0.4H), 1.22 (d, J=6.8 Hz, 1.7H), 1.12 (d, J=6.8 Hz, 1.3H), 1.06 (s, 3H), 0.60 (m, 2H), 0.39 (m, 2H); mixture of two isomers (40:60).

[0710] MS m/z (+ESI): 528.3 [M+H].sup.+.

Preparation of Example 29: (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(2R)-1-acetyl-2-methyl-3,6-dihydro-2H-pyridin-4-yl]-1H-quinazoline-6-sulfonamide/(2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(6R)-1-acetyl-6-methyl-3,6-dihydro-2H-pyridin-4-yl]-1H-quinazoline-6-sulfonamide

##STR00077##

[0711] To a solution of a mixture of (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(2R)-2-methyl-1,2,3,6-tetrahydropyridin-4-yl]-1H-quinazoline-6-sulfonamide and (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(6R)-6-methyl-1,2,3,6-tetrahydropyridin-4-yl]-1H-quinazoline-6-sulfonamide (50 mg, 0.097 mmol) in THF (5 mL) was added acetic anhydride (15 mg, 0.14 mmol) and then the reaction was stirred at 25 C. for 1 h. The reaction solution was purified by preparative HPLC (ACN/H.sub.2O with 0.1% HCOOH) to give the desired product as a white solid (22 mg, 41% yield).

[0712] .sup.1H NMR (400 MHz, DMSO-d.sub.6+D.sub.2O) ppm: 8.18 (d, J=2.0 Hz, 0.4H, isomer 1), 8.16 (d, J=2.0 Hz, 0.6H, isomer 2), 7.74 (m, 0.6H, isomer 2), 7.69 (m, 1.4H), 7.43 (s, 1H), 6.06 (m, 0.6H, isomer 2), 6.03 (m, 0.4H, isomer 1), 4.91 (m, 0.4H, isomer 1), 4.82 (s, 2H), 4.57 (m, 0.6H, isomer 2), 4.33 (m, 0.4H, isomer 1), 3.92 (m, 0.6H, isomer 2), 3.80 (m, 3H), 3.76 (s, 3H), 3.55-3.30 (m, 1H, overlapped with H.sub.2O peak), 2.83 (m, 0.4H), 2.67 (m, 0.6H), 2.07 (m, 4H), 1.35-1.15 (4d, J=6.8 Hz, 3H, isomers), 1.05 (s, 3H), 0.59 (m, 2H), 0.38 (m, 2H); mixture of two isomers (40:60).

[0713] MS m/z (+ESI): 556.3 [M+H].sup.+.

Preparation of Example 30: (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(2R)-2-methyl-1-(1-methylcyclopropanecarbonyl)-3,6-dihydro-2H-pyridin-4-yl]-1H-quinazoline-6-sulfonamide/(2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(6R)-6-methyl-1-(1-methylcyclopropanecarbonyl)-3,6-dihydro-2H-pyridin-4-yl]-1H-quinazoline-6-sulfonamide

##STR00078##

[0714] To a solution of a mixture of (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(2R)-2-methyl-1,2,3,6-tetrahydropyridin-4-yl]-1H-quinazoline-6-sulfonamide and (2E)-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-8-[(6R)-6-methyl-1,2,3,6-tetrahydropyridin-4-yl]-1H-quinazoline-6-sulfonamide (70 mg, 0.14 mmol) in DMF (5 mL) were added 1-methylcyclopropanecarboxylic acid (14 mg, 0.14 mmol), N-hydroxybenzotriazole (HOBt) (28 mg, 0.20 mmol), Hunig's base (36 mg, 0.27 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (40 mg, 0.20 mmol). Then the reaction was stirred at 25 C. for 1 h. The reaction solution was directly purified by preparative HPLC (ACN/H.sub.2O with 0.1% HCOOH) to give the desired product as a white solid (37 mg, 44% yield).

[0715] .sup.1H NMR (400 MHz, DMSO-d.sub.6+D.sub.2O) ppm: 8.19 (d, J=2.0 Hz, 0.42H, isomer 1), 8.18 (d, J=2.0 Hz, 0.58H, isomer 2), 7.80 (d, J=2.0 Hz, 0.58H, isomer 2), 7.73 (d, J=2.0 Hz, 0.42H, isomer 1), 7.70 (s, 1H), 7.44 (s, 1H), 6.09 (m, 0.58H, isomer 2), 6.05 (m, 0.42H, isomer 1), 4.86 (m, 1H), 4.82 (s, 2H), 4.63 (m, 0.42H, isomer 1), 4.36 (m, 0.58H, isomer 2), 3.81 (s, 1.7H, isomer 2), 3.80 (s, 1.3H, isomer 1), 3.77 (s, 3H), 3.38 (m, 1.42H, overlapped with H.sub.2O peak), 2.75 (m, 0.58H, isomer 2), 2.10 (m, 1H), 1.28 (m, 6H), 1.06 (s, 3H), 0.93 (m, 1H), 0.78 (m, 1H), 0.60 (m, 4H), 0.39 (m, 2H); mixture of two isomers (40:60).

[0716] MS m/z (+ESI): 596.4 [M+H].sup.+.

Preparation of Example 32: (R,E)-2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-8-(3-methyl-4-(1-(trifluoromethyl)cyclopropane-1-carbonyl)piperazin-1-yl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide

##STR00079##

[0717] To a stirred solution of 1-(trifluoromethyl)cyclopropane-1-carboxylic acid (28.5 mg, 0.186 mmol) in DMF (3 mL) were added HATU (88 mg, 0.232 mmol) followed by DIPEA (59 mg, 0.464 mmol) at 0 C. The resulting reaction mixture was stirred for 5 min at 0 C. prior to the addition of (R,E)-2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-N-(1-methylcyclopropyl)-8-(3-methylpiperazin-1-yl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide (80 mg, 0.155 mmol). The resulting reaction mixture was allowed to attain room temperature and stirred for 6 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (35 mL). Combined organic layers were washed with cold water (25 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and the filtrate was evaporated under reduced pressure to get crude product which was purified by prep-HPLC (10 mM NH.sub.4HCO.sub.3 in H.sub.2O/ACN) to afford the desired product as an off-white solid (13.8 mg, 14% yield).

[0718] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm: 8.63 (s, 1H), 8.04 (d, J=1.6 Hz, 1H), 8.01 (s, 1H), 7.77 (d, J=1.6 Hz, 1H), 7.70 (s, 1H), 7.44 (s, 1H), 4.87-4.79 (m, 2H), 4.64 (bs, 1H), 4.30-4.23 (m, 1H), 3.83 (s, 3H), 3.77 (s, 3H), 3.52-3.50 (m, 1H), 2.99-2.96 (m, 3H), 2.67-2.66 (m, 1H), 1.42-1.23 (m, 7H), 1.03 (s, 3H), 0.60-0.57 (m, 2H), 0.38-0.36 (m, 2H).

[0719] MS m/z (+ESI): 651.3 [M+H].sup.+.

Preparation of Example 36: (R,E)-8-(4-(3,3-difluoropyrrolidine-1-carbonyl)-3-methylpiperazin-1-yl)-2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide

##STR00080##

[0720] To a stirred solution of (R,E)-2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-N-(1-methylcyclopropyl)-8-(3-methylpiperazin-1-yl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide (90 mg, 0.174 mmol) in DCM (2.5 mL) were added Et.sub.3N (73 mg, 0.52 mmol), and triphosgene (64 mg, 0.203 mmol) at 0 C. and the resulting reaction mixture was stirred for 5 min at 0 C. prior to the addition of compound 3,3-difluoropyrrolidine (24 mg, 0.174 mmol). The resulting reaction mixture was allowed to attain room temperature and stirred for 6 h. The reaction mixture was diluted with water (10 mL) and extracted with DCM (320 mL). Combined organic layers were washed with cold water (25 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and the filtrate was evaporated under reduced pressure to get the crude product which was purified by prep-HPLC (10 mM NH.sub.4HCO.sub.3 in H.sub.2O/ACN) to afford the desired product as an off-white solid (9.0 mg, 8% yield).

[0721] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm: 8.60 (s, 1H), 8.03 (d, J=1.6 Hz, 1H), 8.00 (s, 1H), 7.75 (d, J=2.0 Hz, 1H), 7.70 (s, 1H), 7.44 (s, 1H), 4.82 (s, 2H), 4.02-4.01 (m, 1H), 3.83 (s, 3H), 3.77-3.70 (m, 5H), 3.60-3.57 (m, 3H), 3.36-3.26 (m, 1H), 2.99-2.88 (m, 3H), 2.76-2.72 (m, 1H), 2.45-2.32 (m, 2H), 1.44-1.42 (m, 3H), 1.03 (s, 3H), 0.60-0.58 (m, 2H), 0.38-0.36 (m, 2H).

[0722] MS m/z (+ESI): 650.5 [M+H].sup.+.

Preparation of Example 42: (R,E)-2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-8-(3-methyl-4-(2,2,2-trifluoroacetyl)piperazin-1-yl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide

##STR00081##

[0723] To a stirred solution of (R,E)-2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-N-(1-methylcyclopropyl)-8-(3-methylpiperazin-1-yl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide (0.200 g, 0.368 mmol) and ethyl 2,2,2-trifluoroacetate (1.3 g, 9.67 mmol) in THF (4 mL), was added 1.0 M LiHMDS in THF (6.0 mL, 5.834 mmol) at 10 C. dropwise and the reaction mixture was warmed to room temperature and stirred for 16 h. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (210 mL). Combined organic layers were washed with saturated brine solution (10 mL), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to get the crude product which was purified by prep-HPLC (10 mM NH.sub.4HCO.sub.3 in H.sub.2O/ACN) to afford the desired product as an off-white solid (10 mg, 4% yield).

[0724] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm: 8.60 (brs, 1H), 8.04-8.00 (m, 2H), 7.78 (brs, 1H), 7.69 (s, 1H), 7.43 (s, 1H), 4.86-4.78 (m, 2H), 4.65-4.26 (m, 2H), 3.82-3.68 (m, 7H), 3.06-2.81 (m, 4H), 1.60-1.48 (m, 3H), 1.03 (s, 3H), 0.60-0.59 (m, 2H), 0.36-0.35 (m, 2H).

[0725] MS m/z (+ESI): 613.3 [M+H].sup.+.

Preparation of Intermediate used in Preparation of Example 13 and Example 22: (E)-8-bromo-2-(methoxyimino)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-N-(1-methylcyclopropyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide

##STR00082##

Step 1: Preparation of 8-bromo-2-chloroquinazolin-4(3H)-one

[0726] To a stirred suspension of 8-bromo-2,4-dichloroquinazoline (2.5 g, 8.7 mmol) in THF (15 mL) was added a solution of sodium hydroxide (0.87 g, 21.8 mmol) in water (20 mL) at 25 C. The reaction suspension turned into a clear solution after 10 min. Stirring was continued for another 3 h at 25 C. The reaction solution was acidified to pH=5 with AcOH and the resulting suspension was filtered. The filter cake was rinsed with H.sub.2O, dried in vacuo to afford the target product as a light-yellow solid. (2.04 g, 81.1% yield).

[0727] MS m/z (+ESI): 259.0, 261.0 [M+H].sup.+.

Step 2: Preparation of 8-bromo-2-chloro-3-((1-methyl-1H-pyrazol-4-yl)methyl)quinazolin-4(3H)-one

[0728] To a solution of 8-bromo-2-chloro-3H-quinazolin-4-one (6.4 g, 22.2 mmol) in NMP (100 mL) were added 4-(chloromethyl)-1-methyl-pyrazole (7.2 g, 44.4 mmol), potassium carbonate (9.4 g, 66.6 mmol) and Hunig's base (8.8 g, 66.6 mmol). The reaction solution was stirred at 25 C. for 16 h. The reaction was diluted with EA and water. The organic phase was separated and evaporated under vacuum to give the crude product, which was purified by column chromatography eluting with PE/EA=1:1 to give the desired product as a white solid. (6.0 g, 68% yield).

[0729] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm: 8.21 (dd, J=8.0 Hz, 1.2 Hz, 1H), 8.02 (dd, J=8.0 Hz, 1.2 Hz, 1H), 7.64 (s, 1H), 7.57 (s, 1H), 7.35 (t, J=8.0 Hz, 1H), 5.54 (s, 2H), 3.87 (s, 3H).

[0730] MS m/z (+ESI): 352.9 & 354.9 [M+H].sup.+.

Step 3: (2E)-8-bromo-2-methoxyimino-3-[(1-methylpyrazol-4-yl)methyl]-1H-quinazolin-4-one

[0731] To a solution of 8-bromo-2-chloro-3-[(1-methylpyrazol-4-yl)methyl]quinazolin-4-one (6.0 g, 15.3 mmol) in DMA (100 mL) were added methoxyamine hydrochloride (3.3 g, 38.2 mmol) and triethylamine (6.3 g, 61.1 mmol). The reaction was heated to 100 C. for 3 h. The reaction was poured into 500 mL of water with vigorous stirring. The precipitated solid was collected by filtration, rinsed with water, dried under vacuum to give the desired product as a white solid (6.0 g, 97.1% yield).

[0732] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm: 8.29 (s, 1H), 8.01 (dd, J=8.0 Hz, 1.2 Hz, 1H), 7.68 (m, 2H), 7.57 (s, 1H), 6.95 (t, J=8.0 Hz, 1H), 4.97 (s, 2H), 3.95 (s, 3H), 3.87 (s, 3H).

[0733] MS m/z (+ESI): 364.0, 366.0 [M+H].sup.+.

Step 4: (2E)-8-bromo-2-methoxyimino-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonyl chloride

[0734] In a sealed tube, a solution of (2E)-8-bromo-2-methoxyimino-3-[(1-methylpyrazol-4-yl)methyl]-1H-quinazolin-4-one (500 mg, 1.24 mmol) in chlorosulfonic acid (2.01 mL, 30.9 mmol) was stirred at 80 C. for 20 h. The reaction solution was poured into ice and then extracted with DCM. The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and directly used in the next step without further purification MS m/z (+ESI): 461.8, 463.8 [M+H].sup.+.

Step 5: (2E)-8-bromo-2-methoxyimino-N-(1-methylcyclopropyl)-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonamide

[0735] To a suspension of 1-methylcyclopropylamine hydrochloride (489 mg, 4.46 mmol) in DCM (10 mL) was added triethylamine (1.26 mL, 8.92 mmol). After stirring at 25 C. for 10 min, (2E)-8-bromo-2-methoxyimino-3-[(1-methylpyrazol-4-yl)methyl]-4-oxo-1H-quinazoline-6-sulfonyl chloride (550 mg, 0.89 mmol) solution in DCM was added dropwise at 25 C. The reaction solution was stirred at 25 C. for 1 h. The crude product combined with another batch was purified by Biotage Combiflash eluting with 0-70% EA in PE (EA/PE=1/2, R.sub.f=0.2) to afford the desired product as a yellow solid (600 mg, 81.3% yield).

[0736] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm: 8.41 (s, 1H, NH), 8.22 (d, J=1.6 Hz, 1H), 8.19 (s, 1H, SO.sub.2NH), 8.15 (d, J=1.6 Hz, 1H), 7.70 (s, 1H), 7.44 (s, 1H), 4.83 (s, 2H), 3.88 (s, 3H), 3.77 (s, 3H), 1.08 (s, 3H), 0.60 (m, 2H), 0.41 (m, 2H).

[0737] MS m/z (+ESI): 496.9, 498.9 [M+H].sup.+.

Preparation of Intermediate as used in Preparation of Example 22: tert-butyl (1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)cyclopropyl)carbamate

##STR00083##

[0738] To a solution of tert-butyl N-[1-(4-chlorobenzoyl)cyclopropyl]carbamate (450 mg, 1.37 mmol) in 1,4-dioxane (5 mL) were added 4,4,4,4,5,5,5,5-octamethyl-2,2-bi-1,3,2-dioxaborolane (710 mg, 2.74 mmol), potassium acetate (407 mg, 4.11 mmol), 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (135 mg, 0.27 mmol) and dipalladium-tris(dibenzylideneacetone)chloroform complex (145 mg, 0.14 mmol). The suspension was evacuated and backfilled with N.sub.2 gas, followed by stirring at 110 C. for 2 h. The suspension was concentrated under vacuum, and the residue was purified by Biotage Combiflash eluting with 0-40% EA in PE (EA/PE=1/4, R.sub.f=0.5) to afford the desired product as brown oil (650 mg, 98.1% yield.

[0739] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm: 7.83 (d, J=8.0 Hz, 2H), 7.67 (m, 2H), 5.24 (br s, 1H, NH), 1.72 (m, 2H), 1.35 (s, 12H), 1.26 (m, 11H).

[0740] MS m/z (+ESI): 288.2 [M+H-Boc]+& 332.1 [M+H-.sup.tBu].sup.+.

Preparation of Intermediate-III used in the preparation of Example 18: (1-methylcyclopropyl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone

##STR00084##

[0741] Under argon atmosphere, to a suspension of (4-bromophenyl)-(1-methylcyclopropyl)methanone (350 mg, 1.32 mmol) in dioxane (5 mL) were added bis(pinacolato)diboron (683 mg, 2.63 mmol), 1,1-bis(diphenylphosphino)ferrocene palladium (II) chloride (98 mg, 0.13 mmol), 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (129 mg, 0.26 mmol) and potassium acetate (392 mg, 3.95 mmol). The suspension was stirred at 90 C. for 2 h under argon atmosphere. The reaction suspension was directly used in the next step without any workup and purification.

[0742] MS m/z (+ESI): 287.1 [M+H].sup.+.

Biological Examples

PARG Enzymatic Assay

[0743] Inhibition of PARG enzymatic activity by compounds was determined as follows: Recombinant His-tagged human PARG protein expressed in Sf21 insect cells (Adipogen AG, #40T-0022) was aliquoted and stored at 80 C. until use. The artificial enzyme substrate 4-(trifluoromethyl)umbelliferone (TFMU)-ADPr was prepared essentially as described (Drown B S et al, Cell Chemical Biology 2018) and stored at 20 C. as 10 mM stock solutions in DMSO (dimethyl sulfoxide) until use. For reactions, typical final concentration of the enzyme was 1 nM and of the TFMU-ADPr 200 M. Reactions were carried out in black 384-well low volume round bottom assay plates (Corning, #4514) in a final volume of 10 L. To this end, PARG was diluted to 1.67 nM in reaction buffer (50 mM K.sub.2HPO.sub.4, 50 mM KCl, 10 mM -mercaptoethanol, pH 7.4) and 6 L were dispensed per assay well using a multichannel pipette. Then compound was dispensed into each well using an Echo dispenser (BeckmanCoulter) to yield the pre-specified final concentration of the range of concentrations to be tested (typically 8-point serial concentrations ranging from either from 0.01 to 10 M, or from 0.001 to 1 M, or from 0.0001 to 0.1 M), and being volume-corrected with 100% DMSO (0.5% final DMSO concentration in reaction mixtures). Plates were mixed, and after 15 minutes 4 L TFMU-ADPr was added into each well using a multichannel pipette followed by brief mixing. Fluorescence intensity signals were then measured after 30 minutes on an EnVision microplate reader (PerkinElmer) using 380/10 nm and 535/25 nm filters for the excitation and emission, respectively (gain: 150). The assay window was set using DMSO control (top) and a control containing no PARG enzyme (bottom). Delta values were plotted as concentration-response curves fitted to a sigmoidal 4-parameter logistic model to calculate IC.sub.50 values (Scigilian Analyze).

PARG NanoBRET-Based Cellular Target Engagement Assay

[0744] PARG Nano-luciferase construct: The PARG-NanoLuc fusion vector was generated by Promega, by inserting the full length human PARG cDNA sequence encoding the 976 amino acid protein (Gene ID: 8505, UniProt: Q86W56) into the pNLF1-C [CMV/Hygro] vector (C-terminal fusions with NanoLuc enzyme).

[0745] PARG target engagement tracer synthesis: The NanoBRET tracer for PARG was prepared following a previously reported general tracer synthesis procedure.

[0746] PARG Probe Displacement Assay Using NanoBRET: HEK293T (DSMZ #ACC 635) cells transiently transfected with the PARG-NanoLuc fusion construct were resuspended in phenol red-free OptiMEM (Gibco #11058-021) to a concentration of 2.410.sup.5 cells/mL. 9 L per well were then added to a white 384-well low volume microplate (Greiner #784080) and incubated for 24 hours under standard growth conditions.

[0747] Then compound was dispensed into each well using an Echo dispenser (BeckmanCoulter) to yield the pre-specified final concentration of the range of concentrations to be tested (typically 8-point serial concentrations ranging from either from 0.01 to 10 M, or from 0.001 to 1 M, or from 0.0001 to 0.1 M), and being volume-corrected with 100% DMSO (0.5% final DMSO concentration in reaction mixtures).

[0748] After mixing and an incubation at room temperature for 15 min 1 l of the NanoBRET probe (at 0.89 M final concentration) was added to the microplate using a multichannel pipette. The plate was mixed and incubated in a 5% CO.sub.2 environment at 37 C. for 2 hours, and then 5 L per well of a solution consisting of a 1:31.25 dilution of Nano-Glo substrate (Promega) and a 1:500 dilution of NanoLuc extracellular inhibitor (Promega) in phenol red-free OptiMEM was added to each well followed by another mixing step. Filtered luminescence was measured on an EnVision plate reader (PerkinElmer) equipped with a 460 nm filter (donor) and a 645 nm filter (acceptor). BRET ratios were plotted as concentration-response curves fitted to a sigmoidal 4-parameter logistic model to calculate IC.sub.50 values (Scigilian Analyze). Results are shown in Table 2 below.

Detection of Cellular PAR Levels by Western Blotting

[0749] Kuramochi high grade serous ovarian cancer (HGSOC) (JCRB, #JCRB0098) or NCI-H.sub.1650 non-small cell lung cancer (NSCLC) (ATCC, #CRL-5883) cells were cultured in RPMI (BioConcept, #1-41F03-I) containing 10% FCS (Sigma #F9665) and 1% Penicillin-Streptomycin (BioConcept, #4-01F00-H). When cells reached a density of 70% in 6-well plates (TPP, #92006), they were treated either with the test compound vehicle DMSO, or with test compounds at indicated final concentrations for either 4, 6 or 8 hours. Thereafter, the culture medium was removed and cells were collected by scraping in Lysis Buffer (20 mM Tris HCl pH 7.5, 150 mM NaCl, 1 mM EGTA, 1 mM EDTA, 1% Triton and 1% NP-40) containing protease and phosphatase inhibitors (Halt Protease&Phosphatase inhibitor cocktail 100 ThermoScientific, #1861281) and 1 mM PMSF (Fluka, #93482). Cleared lysates were stored in Eppendorf Tubes at 80 C. until use, and protein concentration in lysates was determined using Pierce 660 nm Protein Assay Reagent (ThermoScientific, #22660). 20 g proteins were diluted in 4 Laemmli buffer (Biorad, #161-0747) containing 10% -mercaptoethanol, separated by SDS-PAGE using 10% gels, and then transferred to PVDF membranes (Trans Blot Turbo Transfer Pack BioRad, #1704156) by Trans-Blot Turbo System semidry blotting methodology (BioRad). Primary antibodies were incubated in TBS-0.1% Tween-20 buffer containing 3% bovine serum albumin (Millipore, #81-053-3) overnight at 4 C. The following primary antibodies were used: anti-PAR (Ab-1) mouse monoclonal antibody (10H) (Millipore, #AM80-100UG), Poly/Mono-ADP ribose (PAR/MAR) (E6F6A) rabbit monoclonal antibody (Cell Signaling, #83732), and rabbit anti-GAPDH clone 14C10 (Cell Signaling, #2118S) diluted 1:2000 or mouse -tubulin (Sigma, #T5168) diluted 1:5000 to control for equal protein loading. Horseradish peroxidase (HRP)-conjugated secondary antibodies were incubated one hour at room temperature diluted 1:5000 in TBS-0.1% Tween-20 buffer containing 5% nonfat-dried bovine milk (Sigma, #M7409). The following secondary antibodies were used: Goat anti-mouse-HRP (Jackson, #115-035-146) and goat anti-rabbit-HRP (Jackson, #111-035-144). Membranes were incubated with enhanced chemiluminescence (ECL) Prime Western Blot Detection Reagent (Amersham, #RPN2236) to detect specific signals using the Fusion SOLO S imaging system (Vilber Lourmat). Results are shown in FIG. 1.

Cell Proliferation Assays

[0750] For Examples 1-11, RMUG-S mucinous cystadenocarcinoma (JCRB, #IF050320) and TOV-112D endometrioid adenocarcinoma (ATCC, #CRL-11731) ovarian cancer cell lines were grown in DMEM/F-12 with glutamine (BioConcept, #1-26F09-I) and RPMI with glutamine (BioConcept, #1-41F03-1), respectively, and both media containing 10% FBS (Sigma-Aldrich, #F9665) and supplemented with 1% Penicillin-Streptomycin (BioConcept, #4-01F00-H) using standard cell culture techniques. RMUG-S and TOV-112D ovarian cancer cell lines were selected as highly PARG dependent and having low PARG dependency, respectively, based on their publically available PARG shRNA (short hairpin ribonucleic acid) dropout profiles in the Cancer Dependency Map (DepMap) data portal (Broad Institute DepMap Project; Cheung H W et al, Proceedings of the National Academy of Sciences 2011; Cowley G S et al, Scientific Data 2014; McDonald E R et al, Cell 2017). PARG dependency of these cell lines was independently verified and confirmed by genetic and pharmacological means using shRNA-mediated PARG depletion, and the previously reported cell-permeable quinazolinedione PARG inhibitor tool compound PDD00017273 (Pillay N et al, Cancer Cell 2019). Thus, growth inhibition of the RMUG-S cell line serves as a functional on-target inhibition readout, while observing potent growth inhibition of TOV-112D is indicative of compound off-target activity. Cells were seeded in 96-well plates with clear bottom (Huberlab, #7.655 090) at a seeding density of 5000 cells per well in 100 L of medium, and the plates were incubated overnight at 37 C. with 5% CO.sub.2 prior to treatment with compounds. Experimental compounds were prepared in DMSO at a concentration of 10 mM. Compounds were distributed at the desired final concentrations using the Tecan D300e Digital Dispenser (TECAN) and normalized to the highest DMSO volume. The plates were incubated for 120 hours and cell numbers were then measured using CellTiter-Glo (Promega, #G9241), essentially as recommended by the manufacturer. Briefly, for the CellTiter-Glo proliferation readout, 50 L of the reconstituted CellTiter-Glo 2.0 Reagent were added to 100 L of medium containing cells. The plates were incubated at room temperature for 10 minutes to stabilize the luminescent signal, and luminescence intensity signals were then measured with a Synergy 4 microplate reader (BioTek Instruments). Relative proliferation values were calculated by normalizing the raw data using DMSO-treated cells (100% proliferation) and the signals obtained from cells that were evaluated at the time of compound addition (0% proliferation). The concentration-response data were fitted to a sigmoidal 4-parameter logistic model with the maximum constrained to 100%. GI.sub.50 values were calculated from the curves as the compound concentrations reducing proliferation to 50%. Results are shown in Table 2 below.

[0751] The cell proliferation assay protocol was modified and used for RMUG-S for Examples 12-44, and subsequently used to test Examples 1-44 in the NCI-H1650 cell line.

Modified Cell Proliferation Assays

[0752] NCI-H1650 (ATCC, #CRL-5883) or RMUG-S were seeded on day 1 at 300 cells per well in a 384-well plate (Greiner, #781080) that assure assay linearity and optimal signal intensity in 25 L of RPMI1640 media (Pan Biotech, #P04-22100) containing 10% FCS (Capricorn, #FBS-11A; Lot. CP22-5141) and 1% Glutamine (Pan Biotech, #P04-80100). After incubation for 24 h in humidified chambers at 37 C./5% CO.sub.2, compounds/DMSO were dispensed at different concentrations using an Echo 520 (Beckman Coulter). Cells were further incubated for 120 h at 37 C. and 5% CO.sub.2. Cells treated with the compound vehicle DMSO were used as negative controls and cells treated with 10 M Staurosporine (LC Laboratories, #S-9300) served as positive controls.

[0753] At day 6 the CellTiter Glo Reagent was prepared according to the instructions of the kit (Promega Inc.): Reagent was mixed 1:1 with cell culture medium. Thereon, mixture and assay plates were equilibrated at room temperature for 20 min. Equal volumes of the reagent-medium-mixture were added to the volume of culture medium present in each well. The plates were mixed at 200 rpm for 2 minutes on an orbital shaker (Timix5, Edmund Buehler GmbH). The microplates were then incubated at room temperature for 10 minutes for stabilization of the luminescent signal. Following incubation, the luminescence was recorded on a Victor X5 microplate reader (Perkin Elmer) using a 200 ms integration time. The data was then analyzed with Excel using the XLFIT Plugin (dose response Fit 205) for determination of the concentration necessary for half-maximal inhibition (i.e. the inflection point of the fitted curve).

[0754] As quality control the Z-factor was calculated from 16 positive and negative control values. Only assay results showing a Z-factor0.5 were used for further analysis.

TABLE-US-00004 TABLE 2 PARG biochemical enzyme inhibition, intra-cellular PARG target engagement (TE), and growth inhibition of RMUG-S (high PARG dependency), NCI-H1650 (high PARG dependency) and TOV-112D (low PARG dependency) ovarian cancer cell lines. RMUG-S NCI-H1650 TOV-112D PARG GI.sub.50 GI.sub.50 GI.sub.50 PARG TE (high PARG (high PARG (low PARG Example IC.sub.50 IC.sub.50 dependency) dependency) dependency) 1 +++ ++ ++ ++ 2 ++ + + ++ 3 +++ + + + 4 +++ ++ ND + ND 5 +++ +++ ++ + 6 + + ND ND ND 7 +++ +++ ++ +++ 8 +++ +++ +++ +++ ++ 9 +++ ++ ND + ND 10 +++ ++ ND ++ ND 11 +++ ++ ND ND ND 12 +++ +++ ND +++ ND 13 +++ ++ ND ++ ND 14 +++ +++ ND +++ ND 15 +++ ++ ND + ND 16 +++ +++ ND + ND 17 ++ + ND + ND 18 +++ +++ ND ++ ND 19 +++ +++ ND ++ ND 20 +++ +++ ND ++ ND 21 +++ ++ ++ ++ ND 22 +++ ++ ND ND ND 23 +++ +++ ND ++ ND 24 +++ + + + ND 25 +++ ++ ++ ++ ND 26 +++ +++ + ++ ND 27 +++ +++ +++ +++ ND 28 +++ +++ ++ +++ ND 29 +++ +++ ++ ++ ND 30 +++ +++ +++ +++ ND 31 +++ +++ ND +++ ND 32 +++ +++ ND +++ ND 33 +++ +++ ND +++ ND 34 +++ +++ ND +++ ND 35 +++ +++ ND +++ ND 36 +++ +++ ND +++ ND 37 +++ +++ ND +++ ND 38 +++ +++ ND +++ ND 39 +++ +++ ND +++ ND 40 +++ +++ ND +++ ND 41 +++ +++ ND +++ ND 42 +++ +++ ND ND ND 43 +++ +++ ND ND ND 44 +++ +++ ND ND ND For PARG IC.sub.50 (nM): +++ when <30, ++ when 30-99, + when 100-1000. For PARG TE IC.sub.50 (nM): +++ when <30, ++ when 30-99, + when 100-1000. For RMUG-S GI.sub.50 (nM): +++ when <500, ++ when 500-1999, + when 2000-8999. Highest concentration tested is 9000 nM. ND: Not determined. For NCI-H1650 GI50 (nM): +++ when <500, ++ when 500-1999, + when >2000. Highest concentration tested is 30000 nM. ND: Not determined. For TOV-112D GI.sub.50 (nM): +++ when <500, ++ when 500-1999, + when 2000-8999, when 9000. Highest concentration tested is 9000 nM. ND: Not determined.

LITERATURE REFERENCES

Ordered as Citations Appear in the Text

[0755] Hanahan D, Cancer Discovery 2022, 12(1):31-46 [0756] Gaillard H et al, Nature Reviews Cancer 2015, 15(5):276-89 [0757] Brown J S et al, Cancer Discovery 2017, 7(1):20-37 [0758] Curtin N J, Nature Reviews Cancer 2012, 12(12):801-17 [0759] Hartwell L H et al, Science 1997, 278(5340):1064-8 [0760] Farmer H et al, Nature 2005, 434(7035):917-21 [0761] Bryant H E et al, Nature 2005, 434(7035):913-7 [0762] Turner N et al, Nature Reviews Cancer 2004, 4(10):814-9 [0763] Hottiger M O et al, Trends in Biochemical Sciences 2010, 35(4):208-19 [0764] Leung A K L, Trends in Cell Biology 2020, 30(5):370-383 [0765] Barkauskaite E at al, Nature Communications 2013, 4:2164 [0766] Pourfarjam Y et al, Biochemical and Biophysical Research Communications 2020, 527(3):818-823 [0767] Marques M et al, Oncogene 2019, 38(12):2177-2191 [0768] Pillay N et al, Cancer Cell 2019, 35(3):519-533 [0769] Coulson-Gilmer C et al, Journal of Experimental & Clinical Cancer Research 2021, 40(1):323 [0770] Prokhorova E et al, Molecular Cell, 2021, 81(12):2640-2655 [0771] Chen SH and Yu X, Science Advances 2019, 5(4):eaav4340 [0772] Slade D, Genes & Development 2020, 34(5-6):360-394 [0773] Houl J H et al, Nature Communications 2019, 10(1):5654 [0774] Wuts P. G. M, Greene's Protective Groups in Organic Synthesis, 5.sup.th Edition, Publisher: John Wiley & Sons, 2014 [0775] Drown B S et al, Cell Chemical Biology 2018, 25(12):1562-1570 [0776] Cheung H W et al, Proceedings of the National Academy of Sciences USA 2011, 108(30):12372-7 [0777] Cowley G S et al, Scientific Data 2014, 1:140035 [0778] McDonald E R et al, Cell 2017, 170(3):577-592