Claims for Patent: 8,952,043

Summary for Patent: 8,952,043

Title:	Benzoxepin PI3K inhibitor compounds and methods of use
Abstract:	Benzoxepin compounds of Formula I, and including stereoisomers, geometric isomers, tautomers, solvates, metabolites and pharmaceutically acceptable salts thereof, wherein: Z.sup.1 is CR.sup.1 or N; Z.sup.2 is CR.sup.2 or N; Z.sup.3 is CR.sup.3 or N; Z.sup.4 is CR.sup.4 or N; and where (i) X.sup.1 is N and X.sup.2 is S, (ii) X.sup.1 is S and X.sup.2 is N, (iii) X.sup.1 is CR.sup.7 and X.sup.2 is S, (iv) X.sup.1 is S and X.sup.2 is CR.sup.7; (v) X.sup.1 is NR.sup.8 and X.sup.2 is N, (vi) X.sup.1 is N and X.sup.2 is NR.sup.8, (vii) X.sup.1 is CR.sup.7 and X.sup.2 is O, (viii) X.sup.1 is O and X.sup.2 is CR.sup.7, (ix) X.sup.1 is CR.sup.7 and X.sup.2 is C(R.sup.7).sub.2, (x) X.sup.1 is C(R.sup.7).sub.2 and X.sup.2 is CR.sup.7; (xi) X.sup.1 is N and X.sup.2 is O, or (xii) X.sup.1 is O and X.sup.2 is N, are useful for inhibiting lipid kinases including p110 alpha and other isoforms of PI3K, and for treating disorders such as cancer mediated by lipid kinases. Methods of using compounds of Formula I for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed. ##STR00001##
Inventor(s):	Blaquiere; Nicole (San Francisco, CA), Do; Steven (San Jose, CA), Dudley; Danette (Pacifica, CA), Folkes; Adrian (Berkshire, GB), Goldsmith; Richard (Belmont, CA), Heald; Robert (Harlow, GB), Heffron; Timothy (Burlingame, CA), Kolesnikov; Aleksandr (San Francisco, CA), Ndubaku; Chudi (San Francisco, CA), Olivero; Alan G. (Half Moon Bay, CA), Price; Stephen (Harlow, GB), Staben; Steven (San Francisco, CA), Wei; BinQing (Belmont, CA)
Assignee:	Genetech, Inc. (South San Francisco, CA)
Application Number:	14/162,520
Patent Claims:	1. A method of therapeutically treating cancer in a patient comprised of administering to said patient a therapeutically effective amount of a compound selected from Formula I: ##STR00658## and stereoisomers, geometric isomers, tautomers, or pharmaceutically acceptable salts thereof, wherein: Z.sup.1 is CR.sup.1 or N; Z.sup.2 is CR.sup.2 or N; Z.sup.3 is CR.sup.3 or N; Z.sup.4 is CR.sup.4 or N; where (i) X.sup.1 is N and X.sup.2 is S, (ii) X.sup.1 is S and X.sup.2 is N, (iii) X.sup.1 is CR.sup.7 and X.sup.2 is S, (iv) X.sup.1 is S and X.sup.2 is CR.sup.7; (vii) X.sup.1 is CR.sup.7 and X.sup.2 is O, (viii) X.sup.1 is O and X.sup.2 is CR.sup.7, (ix) X.sup.1 is CR.sup.7 and X.sup.2 is C(R.sup.7).sub.2, (x) X.sup.1 is C(R.sup.7).sub.2 and X.sup.2 is CR.sup.7; (xi) X.sup.1 is N and X.sup.2 is O, or (xii) X.sup.1 is O and X.sup.2 is N; R.sup.1 is selected from H, F, Cl, Br, I, --CN, --CF.sub.3, --NO.sub.2, and C.sub.1-C.sub.4 alkyl; R.sup.2, R.sup.3, R.sup.4, and R.sup.7 are independently selected from: H, F, Cl, Br, I, --CN, --COR.sup.10, --CO.sub.2R.sup.10, --C(.dbd.O)N(R.sup.10)OR.sup.11, --C(.dbd.NR.sup.10)NR.sup.10R.sup.11, --C(.dbd.O)NR.sup.10R.sup.11, --NO.sub.2, --NR.sup.10R.sup.11, --NR.sup.12C(.dbd.O)R.sup.10, --NR.sup.12C(.dbd.O)OR.sup.11, --NR.sup.12C(.dbd.O)NR.sup.10R.sup.11, --NR.sup.12C(.dbd.O)(C.sub.1-C.sub.12 alkylene)NR.sup.10R.sup.11, --NR.sup.12(C.sub.1-C.sub.12 alkylene)NR.sup.10R.sup.11, --NR.sup.12(C.sub.1-C.sub.12 alkylene)OR.sup.10, --NR.sup.12(C.sub.1-C.sub.12 alkylene)C(.dbd.O)NR.sup.10R.sup.11, --OR.sup.10, --S(O).sub.2R.sup.10, --C(.dbd.O)NR.sup.10(C.sub.1-C.sub.12 alkylene)NR.sup.10R.sup.11, --C(.dbd.O)NR.sup.10(C.sub.1-C.sub.12 alkylene)NR.sup.10C(.dbd.O)OR.sup.11, --C(.dbd.O)NR.sup.10(C.sub.1-C.sub.12 alkylene)NR.sup.10C(.dbd.O)R.sup.11, --C(.dbd.O)NR.sup.10(C.sub.1-C.sub.12 alkylene)R.sup.10, C.sub.1-C.sub.12 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, C.sub.3-C.sub.12 carbocyclyl, C.sub.2-C.sub.20 heterocyclyl, C.sub.6-C.sub.20 aryl, C.sub.1-C.sub.20 heteroaryl, --(C.sub.3-C.sub.12 carbocyclyl)-(C.sub.1-C.sub.12 alkyl), --(C.sub.2-C.sub.20 heterocyclyl)-(C.sub.1-C.sub.12 alkyl), --(C.sub.6-C.sub.20 aryl)-(C.sub.1-C.sub.12 alkyl), --(C.sub.1-C.sub.20 heteroaryl)-(C.sub.1-C.sub.12 alkyl), --(C.sub.1-C.sub.12 alkylene)-(C.sub.3-C.sub.12 carbocyclyl), --(C.sub.1-C.sub.12 alkylene)-(C.sub.2-C.sub.20 heterocyclyl), --(C.sub.1-C.sub.12 alkylene)-(C.sub.2-C.sub.20 heterocyclyl)-(C.sub.2-C.sub.20 heterocyclyl), --(C.sub.1-C.sub.12 alkylene)-(C.sub.2-C.sub.20 heterocyclyl)-(C.sub.3-C.sub.12 carbocyclyl), --(C.sub.1-C.sub.12 alkylene)-(C.sub.2-C.sub.20 heterocyclyl)-C(.dbd.O)--(C.sub.2-C.sub.20 heterocyclyl), --(C.sub.1-C.sub.12 alkylene)-(C.sub.1-C.sub.20 heteroaryl), --(C.sub.1-C.sub.12 alkylene)-(C.sub.2-C.sub.20 heterocyclyl)-(C.sub.1-C.sub.12 alkyl), --(C.sub.1-C.sub.12 alkylene)-(C.sub.6-C.sub.20 aryl)-(C.sub.1-C.sub.12 alkyl), --(C.sub.1-C.sub.12 alkylene)-(C.sub.1-C.sub.20 heteroaryl)-(C.sub.1-C.sub.12 alkyl), --(C.sub.1-C.sub.12 alkylene)-C(.dbd.O)--(C.sub.2-C.sub.20 heterocyclyl), --(C.sub.1-C.sub.12 alkylene)C(.dbd.O)OR.sup.10, --(C.sub.1-C.sub.12 alkylene)-NR.sup.10R.sup.11, --(C.sub.1-C.sub.12 alkylene)NR.sup.12C(.dbd.O)R.sup.10, --(C.sub.1-C.sub.12 alkylene)OR.sup.10, --(C.sub.1-C.sub.12 alkylene)-NR.sup.10--(C.sub.1-C.sub.12 alkylene)-(C.sub.1-C.sub.20 heteroaryl), --(C.sub.1-C.sub.12 alkylene)-NR.sup.10--(C.sub.1-C.sub.12 alkylene)-(C.sub.1-C.sub.20 heterocyclyl), --(C.sub.1-C.sub.12 alkylene)-NR.sup.10--(C.sub.1-C.sub.12 alkylene)-NHC(.dbd.O)--(C.sub.1-C.sub.20 heteroaryl), --(C.sub.1-C.sub.12 alkylene)-(C.sub.2-C.sub.20 heterocyclyl)-NR.sup.10R.sup.11, and --(C.sub.1-C.sub.12 alkylene)-(C.sub.2-C.sub.20 heterocyclyl)-(C.sub.1-C.sub.12 alkyl)-NR.sup.10R.sup.11, where Z.sup.2 is CR.sup.2 and R.sup.2 is azetidinyl optionally substituted with one or more groups independently selected from F, Cl, Br, I, R.sup.10, --SR.sup.10, --S(O).sub.2R.sup.10, --S(O).sub.2NR.sup.10R.sup.11, --NR.sup.10R.sup.11, --NR.sup.12C(O)R.sup.10, --CO.sub.2R.sup.10, --C(O)R.sup.10, --CONR.sup.10R.sup.11, oxo, and --OR.sup.10; or Z.sup.3 is CR.sup.3 and R.sup.3 is azetidinyl optionally substituted with one or more groups independently selected from F, C1, Br, I, R.sup.10, --SR.sup.10, --S(O).sub.2R.sup.10, --S(O).sub.2NR.sup.10R.sup.11, --NR.sup.10R.sup.11, --NR.sup.12C(O)R.sup.10, --CO.sub.2R.sup.10, --C(O)R.sup.10, --CONR.sup.10R.sup.11, oxo, and --OR.sup.10; and where alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, R.sup.10, --SR.sup.10, --S(O).sub.2R.sup.10, --S(O).sub.2NR.sup.10R.sup.11, --NR.sup.10R.sup.11, --NR.sup.12C(O)R.sup.10, --CO.sub.2R.sup.10, --C(O)R.sup.10, --CONR.sup.10R.sup.11, oxo, and --OR.sup.10; A is selected from C.sub.2-C.sub.20 heterocyclyl and C.sub.1-C.sub.20 heteroaryl wherein heterocyclyl and heteroaryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, --CN, --COR.sup.10, --CO.sub.2R.sup.10, --C(.dbd.O)N(R.sup.10)OR.sup.11, --C(.dbd.NR.sup.10)NR.sup.10R.sup.11, --C(.dbd.O)NR.sup.10R.sup.11, --NO.sub.2, --NR.sup.10R.sup.11, --NR.sup.12C(.dbd.O)R.sup.10, --NR.sup.12C(.dbd.O)OR.sup.11, --NR.sup.12C(.dbd.O)NR.sup.10R.sup.11, --NR.sup.12C(.dbd.O)(C.sub.1-C.sub.12 alkylene)NR.sup.10R.sup.11, --NR.sup.12(C.sub.1-C.sub.12 alkylene)NR.sup.10R.sup.11, --NR.sup.12(C.sub.1-C.sub.12 alkylene)OR.sup.10, --NR.sup.12(C.sub.1-C.sub.12 alkylene)C(.dbd.O)NR.sup.10R.sup.11, --OR.sup.10, --S(O).sub.2R.sup.10, --C(.dbd.O)NR.sup.10(C.sub.1-C.sub.12 alkylene)NR.sup.10R.sup.11, --C(.dbd.O)NR.sup.10(C.sub.1-C.sub.12 alkylene)NR.sup.10C(.dbd.O)OR.sup.11, --C(.dbd.O)NR.sup.10(C.sub.1-C.sub.12 alkylene)NR.sup.10C(.dbd.O)R.sup.11, --C(.dbd.O)NR.sup.10(C.sub.1-C.sub.12 alkylene)R.sup.10, C.sub.1-C.sub.12 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, C.sub.3-C.sub.12 carbocyclyl, C.sub.2-C.sub.20 heterocyclyl, C.sub.6-C.sub.20 aryl, C.sub.1-C.sub.20 heteroaryl, --(C.sub.3-C.sub.12 carbocyclyl)-(C.sub.1-C.sub.12 alkyl), --(C.sub.2-C.sub.20 heterocyclyl)-(C.sub.1-C.sub.12 alkyl), --(C.sub.6-C.sub.20 aryl)-(C.sub.1-C.sub.12 alkyl), --(C.sub.1-C.sub.20 heteroaryl)-(C.sub.1-C.sub.12 alkyl), --(C.sub.1-C.sub.12 alkylene)-(C.sub.3-C.sub.12 carbocyclyl), --(C.sub.1-C.sub.12 alkylene)-(C.sub.2-C.sub.20 heterocyclyl), --(C.sub.1-C.sub.12 alkylene)-(C.sub.2-C.sub.20 heterocyclyl)-(C.sub.2-C.sub.20 heterocyclyl), --(C.sub.1-C.sub.12 alkylene)-(C.sub.2-C.sub.20 heterocyclyl)-(C.sub.3-C.sub.12 carbocyclyl), --(C.sub.1-C.sub.12 alkylene)-(C.sub.2-C.sub.20 heterocyclyl)-C(.dbd.O)--(C.sub.2-C.sub.20 heterocyclyl), --(C.sub.1-C.sub.12 alkylene)-(C.sub.1-C.sub.20 heteroaryl), --(C.sub.1-C.sub.12 alkylene)-(C.sub.2-C.sub.20 heterocyclyl)-(C.sub.1-C.sub.12 alkyl), --(C.sub.1-C.sub.12 alkylene)-(C.sub.6-C.sub.20 aryl)-(C.sub.1-C.sub.12 alkyl), --(C.sub.1-C.sub.12 alkylene)-(C.sub.1-C.sub.20 heteroaryl)-(C.sub.1-C.sub.12 alkyl), --(C.sub.1-C.sub.12 alkylene)-C(.dbd.O)--(C.sub.2-C.sub.20 heterocyclyl), --(C.sub.1-C.sub.12 alkylene)C(.dbd.O)OR.sup.10, --(C.sub.1-C.sub.12 alkylene)-NR.sup.10R.sup.11, --(C.sub.1-C.sub.12 alkylene)NR.sup.12C(.dbd.O)R.sup.10, --(C.sub.1-C.sub.12 alkylene)OR.sup.10, --(C.sub.1-C.sub.12 alkylene)-NR.sup.10--(C.sub.1-C.sub.12 alkylene)-(C.sub.1-C.sub.20 heteroaryl), --(C.sub.1-C.sub.12 alkylene)-NR.sup.10--(C.sub.1-C.sub.12 alkylene)-(C.sub.1-C.sub.20 heterocyclyl), --(C.sub.1-C.sub.12 alkylene)-NR.sup.10--(C.sub.1-C.sub.12 alkylene)-NHC(.dbd.O)--(C.sub.1-C.sub.20 heteroaryl), --(C.sub.1-C.sub.12 alkylene)-(C.sub.2-C.sub.20 heterocyclyl)-NR.sup.10R.sup.11, and --(C.sub.1-C.sub.12 alkylene)-(C.sub.2-C.sub.20 heterocyclyl)-(C.sub.1-C.sub.12 alkyl)-NR.sup.10R.sup.11, where alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, R.sup.10, --SR.sup.10, --S(O).sub.2R.sup.10, --NR.sup.10R.sup.11, --NR.sup.12C(O)R.sup.10, --CO.sub.2R.sup.10, --C(O)R.sup.10, --CONR.sup.10R.sup.11, and --OR.sup.10; R.sup.5 is selected from H and C.sub.1-C.sub.12 alkyl optionally substituted with one or more groups independently selected from F, Cl, Br, I, --CN, --CO.sub.2H, --CONH.sub.2, --CONHCH.sub.3, --NH.sub.2, --NO.sub.2, --N(CH.sub.3).sub.2, --NHCOCH.sub.3, --NHS(O).sub.2CH.sub.3, --OH, --OCH.sub.3, --OCH.sub.2CH.sub.3, --S(O).sub.2NH.sub.2, and --S(O).sub.2CH.sub.3; R.sup.6 is selected from C.sub.1-C.sub.12 alkyl, C.sub.3-C.sub.12 carbocyclyl, C.sub.2-C.sub.20 heterocyclyl, C.sub.1-C.sub.20 heteroaryl, and C.sub.6-C.sub.20 aryl, each of which are optionally substituted with one or more groups independently selected from F, Cl, Br, I, --CH.sub.3, --CH.sub.2OH, --CH.sub.2C.sub.6H.sub.5, --CN, --CF.sub.3, --CO.sub.2H, --C(O)CH.sub.3, --NH.sub.2, --NO.sub.2, --N(CH.sub.3).sub.2, --NHCOCH.sub.3, --NHS(O).sub.2CH.sub.3, --OH, oxo, --OCH.sub.3, --OCH.sub.2CH.sub.3, --S(O).sub.2NH.sub.2, --S(O).sub.2CH.sub.3, --C(.dbd.O)NR.sup.10(C.sub.1-C.sub.12 alkylene)NR.sup.10R.sup.11, phenyl, pyridinyl, tetrahydro-furan-2-yl, 2,3-dihydro-benzofuran-2-yl, 1-isopropyl-pyrrolidin-3-ylmethyl, morpholin-4-yl, piperidin-1-yl, piperazinyl, piperazin-4-yl-2-one, piperazin-4-yl-3-one, pyrrolidin-1-yl, thiomorpholin-4-yl, S-dioxothiomorpholin-4-yl, --C.ident.CR.sup.13, --CH.dbd.CHR.sup.13, and --C(.dbd.O)NR.sup.10R.sup.11; or R.sup.5 and R.sup.6 together with the nitrogen atom to which they are attached form C.sub.2-C.sub.20 heterocyclyl or C.sub.1-C.sub.20 heteroaryl, optionally substituted with one or more groups selected from F, Cl, Br, I, --CH.sub.3, --C(CH.sub.3).sub.3, --CH.sub.2OH, --CH.sub.2CH.sub.2OH, --CH.sub.2C.sub.6H.sub.5, pyridin-2-yl, 6-methyl-pyridin-2-yl, pyridin-4-yl, pyridin-3-yl, pyrimidin-2-yl, pyrazin-2-yl, tetrahydro-furan-carbonyl, 2-methoxy-phenyl, benzoyl, cyclopropylmethyl, (tetra-furan-2-yl)methyl, 2,6-dimethyl-morpholin-4-yl, 4-methyl-piperazine-carbonyl, pyrrolidine-1-carbonyl, cyclopropanecarbonyl, 2,4-difluoro-phenyl, pyridin-2-ylmethyl, morpholin-4-yl, --CN, --CF.sub.3, --CO.sub.2H, --CONH.sub.2, --CONHCH.sub.3, --CON(CH.sub.3).sub.2, --COCF.sub.3, --COCH.sub.3, --COCH(CH.sub.3).sub.2, --NO.sub.2, --NHCH.sub.3, --N(CH.sub.3).sub.2, --N(CH.sub.2CH.sub.3).sub.2, --NHCOCH.sub.3, --NCH.sub.3COCH.sub.3, --NHS(O).sub.2CH.sub.3, --OH, --OCH.sub.3, --OCH.sub.2CH.sub.3, --CH.sub.2OCH.sub.3, --CH.sub.2CH.sub.2OCH.sub.3, --CH.sub.2S(O).sub.2NHCH.sub.3, --CH.sub.2S(O).sub.2CH.sub.2CH.sub.3, --S(O).sub.2NHCH.sub.3, --S(O).sub.2CH.sub.2CH.sub.3, --S(O).sub.2NH.sub.2, --S(O).sub.2N(CH.sub.3).sub.2 and --S(O).sub.2CH.sub.3; R.sup.10, R.sup.11 and R.sup.12 are independently selected from H, C.sub.1-C.sub.12 alkyl, --(C.sub.1-C.sub.12 alkylene)-(C.sub.2-C.sub.20 heterocyclyl), --(C.sub.1-C.sub.12 alkylene)-(C.sub.6-C.sub.20 aryl), --(C.sub.1-C.sub.12 alkylene)-(C.sub.3-C.sub.12 carbocyclyl), C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, C.sub.3-C.sub.12 carbocyclyl, C.sub.2-C.sub.20 heterocyclyl, C.sub.6-C.sub.20 aryl, and C.sub.1-C.sub.20 heteroaryl, each of which are optionally substituted with one or more groups independently selected from F, Cl, Br, I, --CH.sub.3, --CH.sub.2CH.sub.3, --CH(CH.sub.3).sub.2, --CH.sub.2OH, --CH.sub.2OCH.sub.3, --CH.sub.2CH.sub.2OH, --C(CH.sub.3).sub.2OH, --CH.sub.2C(CH.sub.3).sub.2OH, --CH.sub.2CH(CH.sub.3)OH, --CH.sub.2CO.sub.2H, --CH.sub.2CO.sub.2CH.sub.3, --CH.sub.2NH.sub.2, --(CH.sub.2).sub.2N(CH.sub.3).sub.2, --CH.sub.2C.sub.6H.sub.5, --CN, --CF.sub.3, --CO.sub.2H, --C(O)CH.sub.3, --C(O)CH(OH)CH.sub.3, --CO.sub.2CH.sub.3, --CONH.sub.2, --CONHCH.sub.3, --CON(CH.sub.3).sub.2, --C(CH.sub.3).sub.2CONH.sub.2, --NH.sub.2, --NO.sub.2, --N(CH.sub.3).sub.2, --N(CH.sub.3)C(CH.sub.3).sub.2CONH.sub.2, --N(CH.sub.3)CH.sub.2CH.sub.2S(O).sub.2CH.sub.3, --NHCOCH.sub.3, --NHS(O).sub.2CH.sub.3, .dbd.O (oxo), --OH, --OCH.sub.3, --OCH.sub.2CH.sub.3, --OCH.sub.2CH.sub.2OH, --OP(O)(OH).sub.2, --SCH.sub.3, --S(O).sub.2CH.sub.3, --S(O).sub.2NH.sub.2, --S(O).sub.2N(CH.sub.3).sub.2, --CH.sub.2S(O).sub.2NHCH.sub.3, --CH.sub.2S(O).sub.2CH.sub.2CH.sub.3, --S(O).sub.2NHCH.sub.3, --S(O).sub.2CH.sub.2CH.sub.3, pyrrolidin-1-yl, 2-oxopyrrolidin-1-yl, cyclopropyl, cyclopentyl, oxetanyl, 4-methylpiperazin-1-yl, and 4-morpholinyl; or R.sup.10 and R.sup.11 together with the nitrogen atom to which they are attached form a C.sub.2-C.sub.20 heterocyclyl ring, optionally substituted with one or more groups independently selected from F, Cl, Br, I, --CH.sub.3, --CH.sub.2OH, --CH.sub.2C.sub.6H.sub.5, --CN, --CF.sub.3, --CO.sub.2H, --CONH.sub.2, --CONHCH.sub.3, --NO.sub.2, --N(CH.sub.3).sub.2, --NHCOCH.sub.3, --NHS(O).sub.2CH.sub.3, --OH, oxo, --OCH.sub.3, --OCH.sub.2CH.sub.3, --S(O).sub.2NH.sub.2, --S(O).sub.2CH.sub.3, --CH(CH.sub.3).sub.2, --CH.sub.2CF.sub.3, --CH.sub.2CH.sub.2OH and --C(CH.sub.3).sub.2OH; and R.sup.13 is selected from H, F, Cl, Br, I, --CH.sub.3, --CH.sub.2CH.sub.3, --CN, --CF.sub.3, --CH.sub.2N(CH.sub.3).sub.2, --CH.sub.2OH, --CO.sub.2H, --CONH.sub.2, --CON(CH.sub.3).sub.2, --NO.sub.2, and --S(O).sub.2CH.sub.3; wherein the cancer is selected from breast, colon, glioma, lung, melanoma, ovarian and prostate. 2. The method of claim 1 selected from Formulas Ii and Iii: ##STR00659## 3. The method of claim 1 selected from Formulas Iiii and Iiv: ##STR00660## 4. The method of claim 1 selected from Formulas Ivii and Iviii: ##STR00661## 5. The method of claim 1 selected from Formulas Iix and Ix: ##STR00662## 6. The method of claim 1 selected from Formulas Ixi and Ixii: ##STR00663## 7. The method of claim 1 wherein Z.sup.1 is CR.sup.1; Z.sup.2 is CR.sup.2; Z.sup.3 is CR.sup.3; and Z.sup.4 is CR.sup.4. 8. The method of claim 1 wherein Z.sup.1 is N; Z.sup.2 is CR.sup.2; Z.sup.3 is CR.sup.3; and Z.sup.4 is CR.sup.4. 9. The method of claim 1 wherein Z.sup.1 is CR.sup.1; Z.sup.2 is N; Z.sup.3 is CR.sup.3; and Z.sup.4 is CR.sup.4. 10. The method of claim 1 wherein Z.sup.1 is CR.sup.1; Z.sup.2 is CR.sup.2; Z.sup.3 is N; and Z.sup.4 is CR.sup.4. 11. The method of claim 1 wherein Z.sup.1 is CR.sup.1; Z.sup.2 is CR.sup.2; Z.sup.3 is CR.sup.3; and Z.sup.4 is N. 12. The method of claim 1 wherein A is C.sub.2-C.sub.20 heterocyclyl or C.sub.1-C.sub.20 heteroaryl substituted with --CH.sub.2OH, --CH.sub.2CO.sub.2H, --CH(CH.sub.3)CH.sub.2OCH.sub.3, --CH.sub.3, --CH(CH.sub.3).sub.2, --CH.sub.2CH(CH.sub.3).sub.2, --CH.sub.2CF.sub.3, --C(.dbd.O)CH.sub.3, --C(.dbd.O)NHCH.sub.3, --C(.dbd.O)N(CH.sub.3).sub.2, --CO.sub.2H, --CO.sub.2CH.sub.3, --CH.sub.2CO.sub.2CH.sub.3, --NH.sub.2, --NHC(.dbd.O)CH.sub.3, --OH, --OCH.sub.3, --S(O).sub.2CH.sub.3, 1-methylpiperid-4-yl, 4-methylpiperazin-1-yl, 4-morpholinyl, (4-methylpiperazin-1-yl)carboxamide, --CH.sub.2(1H-1,2,4-triazol-5-yl), cyclopropyl, cyclopropylmethyl, or cyclobutyl. 13. The method of claim 12 wherein A is a C.sub.1-C.sub.20 heteroaryl selected from pyridyl, isoxazolyl, imidazolyl, pyrazolyl, pyrrolyl, thiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxazolyl, oxadiazolyl, 1,3,4-oxadiazol-2(3H)-one, furanyl, thienyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,4-triazol-5(4H)-one, 4,5-dihydro-1,2,4-triazin-6(1H)-one, tetrazolyl, pyrrolo[2,3-b]pyridinyl, indazolyl, 3,4-dihydroquinolinyl, and benzo[d]thiazole. 14. The method of claim 1 wherein A is selected from the structures: ##STR00664## ##STR00665## where R.sup.9 is independently selected from H, F, Cl, Br, I, --CH.sub.3, --CH.sub.2CH.sub.3, --CH(CH.sub.3).sub.2, --CH.sub.2CH(CH.sub.3).sub.2, --CH.sub.2OH, --CH.sub.2CO.sub.2H, --CH(CH.sub.3)CH.sub.2OCH.sub.3, --CN, --CF.sub.3, --CH.sub.2CF.sub.3, --CH.sub.2NH.sub.2, --CH.sub.2CH.sub.2NH.sub.2, --C(.dbd.O)CH.sub.3, --CH.sub.2C(.dbd.O)NHCH.sub.3, --C(.dbd.O)NHCH.sub.3, --CO.sub.2H, --CH.sub.2CO.sub.2CH.sub.3, --NH.sub.2, --OH, --OCH.sub.3, --SCH.sub.3, --S(O).sub.2CH.sub.3, 1-methylpiperid-4-yl, 4-methylpiperazin-1-yl, 4-morpholinyl, morpholin-4-yl-ethyl, benzyl, and phenyl, where benzyl and phenyl are optionally substituted with one or more groups selected from F, Cl, Br, I, --CH.sub.2OH, --CH.sub.2CO.sub.2H, --CN, --CH.sub.2NH.sub.2, --CH.sub.3, --C(.dbd.O)CH.sub.3, --C(.dbd.O)NHCH.sub.3, --CO.sub.2H, --CH.sub.2CO.sub.2CH.sub.3, --NH.sub.2, --OCH.sub.3, --S(O).sub.2CH.sub.3, 1-methylpiperid-4-yl, 4-methylpiperazin-1-yl, and 4-morpholinyl; and where the wavy line indicates the site of attachment. 15. The method of claim 14 wherein R.sup.9 is selected from H, --CH.sub.3, --NH.sub.2, 2-chlorophenyl, 2,4-difluorophenyl, and --CH(CH.sub.3).sub.2. 16. The method of claim 14 wherein A is substituted 1H-1,2,4-triazol-5-yl. 17. The method of claim 14 wherein A is selected from the structures: ##STR00666## ##STR00667## ##STR00668## where the wavy line indicates the site of attachment. 18. The method of claim 1 wherein the Formula I compound is selected from: 8-Azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-- 6-oxa-3-thia-1-aza-benzo[e]azulene; 3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-- benzo[e]azulen-9-yl]-azetidine-1-carboxylic acid tert-butyl ester; 2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-(1-methanesulfonyl-azetidin-3-yl- )-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene; (R)-2-Hydroxy-1-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-- oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-propan-1-one; 2-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-a- za-benzo[e]azulen-8-yl]-azetidin-1-yl}-acetamide; 2-(2Isopropyl-2H-[1,2,4]triazol-3-yl)-8-[1-(2-methanesulfonyl-ethyl)-azet- idin-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene; 2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-[1-(propane-2-sulfonyl)-azetidin- -3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene; 2-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-a- za-benzo[e]azulen-8-yl]-azetidin-1-yl}-ethanol; (S)-2-Hydroxy-1-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-- oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-propan-1-one; 2-Hydroxy-1-(3-{4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-o- xa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-azetidin-1-yl)-propan-1- -one; (S)-2-Hydroxy-1-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihyd- ro-6-oxa-3-thia-1-aza-benzo[e]azulen-9-yl]-azetidin-1-yl}-propan-1-one; 1-(3-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-ox- a-1-thia-10-aza-benzo[e]azulen-9-ylamino}-azetidin-1-yl)-ethanone; {2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-t- hia-10-aza-benzo[e]azulen-9-yl}-(1-methanesulfonyl-azetidin-3-yl)-amine; N-(1-Acetyl-azetidin-3-yl)-N-{2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazo- l-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-acetamide; 5-(8-Azetidin-3-yl-4,5-dihydro-6-oxa-1-thia-benzo[e]azulen-2-yl)-1-isopro- pyl-1H-[1,2,4]triazole; 2-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-a- za-benzo[e]azulen-9-yl]-azetidin-1-yl}-acetamide; 9-[1-(2,4-Difluoro-benzyl)-azetidin-3-yl]-2-(2-isopropyl-2H-[1,2,4]triazo- l-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene; 9-[1-(2-Chloro-benzyl)-azetidin-3-yl]-2-(2-isopropyl-2H-[1,2,4]triazol-3-- yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene; 2-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-a- za-benzo[e]azulen-9-yl]-azetidin-1-yl}-ethanol; 1-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-a- za-benzo[e]azulen-9-yl]-azetidin-1-yl}-2-methyl-propan-2-ol; (S)-1-(3-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-- 6-oxa-1-thia-10-aza-benzo[e]azulen-9-ylamino}-azetidin-1-yl)-2-hydroxy-pro- pan-1-one; 2-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-- 3-thia-1-aza-benzo[e]azulen-9-yl]-azetidine-1-sulfonyl}-ethanol; 2-Hydroxy-1-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-- 3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-ethanone; (R)-2-Hydroxy-1-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-- oxa-3-thia-1-aza-benzo[e]azulen-9-yl]-azetidin-1-yl}-propan-1-one; 8-(1-Azetidin-3-yl-1H-pyrazol-4-yl)-2-(2-isopropyl-5-methyl-2H-[1,2,4]tri- azol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene; 2-(5-Amino-2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1- -aza-benzo[e]azulene-8-carboxylic acid (1-methyl-azetidin-3-yl)-amide; 1-{4-[2-(1-azetidin-3-yl-1H-imidazol-2-yl)-4,5-dihydro-6-oxa-3-thia-1-aza- -benzo[e]azulen-8-yl]-pyrazol-1-yl}-2-methyl-propan-2-ol; 2-hydroxy-1-[3-(2-{8-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-4,5-- dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl}-imidazol-1-yl)-azetidin-1-- yl]-propan-1-one; 1-[3-(2-{8-[1-(2-Hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-4,5-dihydro-6-- oxa-3-thia-1-aza-benzo[e]azulen-2-yl}-imidazol-1-yl)-azetidin-1-yl]-ethano- ne; 5-(8-azetidin-3-yl-4,5-dihydro-6-oxa-1-thia-benzo[e]azulen-2-yl)-1-(2,- 4-difluoro-phenyl)-1H-[1,2,4]triazole; 1-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-a- za-benzo[e]azulen-8-yl]-azetidin-1-yl}-2-methyl-propan-2-ol; 2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-[1-(2,2,2-trifluoro-ethyl)-azeti- din-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene; 8-(1-Isopropyl-azetidin-3-yl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-- dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene; (S)-3-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia- -1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-propane-1,2-diol; (1-Amino-cyclopropyl)-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihy- dro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-methanone; 2-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-a- za-benzo[e]azulen-8-yl]-azetidin-1-yl}-2-methyl-propan-1-ol; {2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-t- hia-10-aza-benzo[e]azulen-9-yl}-(1-methyl-azetidin-3-yl)-amine; {2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-t- hia-10-aza-benzo[e]azulen-9-yl}-oxetan-3-yl-amine; Azetidin-3-yl-{2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dih- ydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-amine; 2-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-a- za-benzo[e]azulen-8-yl]-azetidin-1-yl}-ethanesulfonic acid dimethylamide; 2-Hydroxy-1-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-- 3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-2-methyl-propan-1-one; 2-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-a- za-benzo[e]azulen-8-yl]-azetidine-1-sulfonyl}-ethanol; 2-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-a- za-benzo[e]azulen-8-yl]-azetidin-1-yl}-isobutyramide; 2-{4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-a- za-benzo[e]azulen-8-yl]-pyrazol-1-yl}-N-(1-methyl-azetidin-3-yl)-isobutyra- mide; 8-{1-[2-(3,3-Difluoro-azetidine-1-sulfonyl)-ethyl]-azetidin-3-yl}-2-- (2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[- e]azulene; (2-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa- -3-thia-1-aza-benzo[e]azulen-8-yl]-azetidine-1-sulfonyl}-ethyl)-dimethyl-a- mine; 1-[3-(5-Chloro-2-{8-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-4-yl]-- 4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl}-imidazol-1-yl)-azetidi- n-1-yl]-ethanone; 2-(3-{4-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-ox- a-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-azetidin-1-yl)-ethanol; 1-Isopropyl-5-{8-[1-(2-methanesulfonyl-ethyl)-azetidin-3-yl]-4,5-dihydro-- 6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl}-1H-[1,2,4]triazol-3-ylamine; 2-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-a- za-benzo[e]azulen-8-yl]-azetidin-1-yl}-N-methyl-isobutyramide; 2-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-a- za-benzo[e]azulen-8-yl]-azetidin-1-yl}-ethanesulfonic acid methylamide; 2-Amino-1-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-- thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-2-methyl-propan-1-one; N-Isopropyl-2-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-ox- a-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-acetamide; 2-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-a- za-benzo[e]azulen-8-yl]-azetidin-1-yl}-1-morpholin-4-yl-ethanone; N-(2-Hydroxy-2-methyl-propyl)-2-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl- )-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-aceta- mide; 1-(3-{4-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro- -6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-azetidin-1-yl)-2-me- thyl-propan-2-ol; 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-(1-oxazol-2-ylmethyl-azetidin-3-- yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene; (S)-2-Hydroxy-1-{3-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-d- ihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-propan-1-one- ; 2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-[1-(2-methanesulfonyl-- ethyl)-azetidin-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene; (S)-3-{3-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-o- xa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-propane-1,2-diol; 2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-[1-(2-methoxy-ethyl)-az- etidin-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene; 2-{3-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3- -thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-ethanol; 1-{3-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3- -thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-3-methoxy-propan-2-ol; 8-[1-(2-Fluoro-ethyl)-azetidin-3-yl]-2-(2-isopropyl-5-methyl-2H-[1,2,4]tr- iazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene; 3-{3-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3- -thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-propan-1-ol; and N-Isopropyl-2-{3-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dih- ydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-acetamide. 19. The method of claim 1, further comprising administering to the patient a therapeutic agent selected from a chemotherapeutic agent, an anti-inflammatory agent, an immunomodulatory agent, a neurotropic factor, an agent for treating cardiovascular disease, an agent for treating liver disease, an anti-viral agent, an agent for treating blood disorders, an agent for treating diabetes, and an agent for treating immunodeficiency disorders. 20. The method of claim 19 wherein the therapeutic agent is selected from trastuzumab, pertuzumab, letrozole, fulvestrant, paclitaxel, and docetaxel. 21. The method of claim 1 wherein the cancer is breast cancer.

Details for Patent 8,952,043

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	09/25/1998		2039-02-26
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	02/10/2017		2039-02-26
Genentech, Inc.	PERJETA	pertuzumab	Injection	125409	06/08/2012		2039-02-26
Genentech, Inc.	HERCEPTIN HYLECTA	trastuzumab and hyaluronidase-oysk	Injection	761106	02/28/2019		2039-02-26