Claims for Patent: 10,435,414

Summary for Patent: 10,435,414

Title:	Tricyclic PI3K inhibitor compounds and methods of use
Abstract:	Described herein are tricyclic compounds with phosphoinositide-3 kinase (PI3K) modulation activity or function having the Formula I structure: ##STR00001## or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, and with the substituents and structural features described herein. Also described are pharmaceutical compositions and medicaments that include the Formula I compounds, as well as methods of using such PI3K modulators, alone and in combination with other therapeutic agents, for treating diseases or conditions that are mediated or dependent upon PI3K dysregulation.
Inventor(s):	Braun; Marie-Gabrielle (San Francisco, CA), Garland; Keira (South San Francisco, CA), Hanan; Emily (South San Francisco, CA), Purkey; Hans (South San Francisco, CA), Staben; Steven T. (San Francisco, CA), Heald; Robert Andrew (Harlow Essex, GB), Knight; Jamie (Harlow Essex, GB), Macleod; Calum (Harlow Essex, GB), Lu; Aijun (Beijing, CN), Wu; Guosheng (Beijing, CN), Yeap; Siew Kuen (Harlow Essex, GB)
Assignee:	Genentech, Inc. (South San Francisco, CA)
Application Number:	16/044,862
Patent Claims:	1. A method of treating cancer in a patient having a cancer selected from the group consisting of breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, and uterine cancer, comprising administering to said patient a therapeutically effective amount of a compound selected from Formula I: ##STR00545## or stereoisomers, tautomers, and pharmaceutically acceptable salts thereof, wherein: the dotted/solid lines represent a single or double bond; X.sup.a is N; X.sup.b is C and X.sup.c is N; or X.sup.c is C and X.sup.b is N; X.sup.d is CR.sup.2; R.sup.1 is selected from Br, Cl, I, C.sub.2-C.sub.20 heterocyclyl, C.sub.1-C.sub.20 heteroaryl, --NR.sup.3R.sup.4, and -OR.sup.5; R.sup.2 is selected from H, F, Cl, C.sub.1-C.sub.6 alkyl, and --O(C.sub.1-C.sub.6 alkyl); R.sup.3 is selected from H, and C.sub.1-C.sub.6 alkyl; R.sup.4 is selected from H, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.20 heterocyclyl, and C.sub.1-C.sub.20 heteroaryl; or R.sup.3 and R.sup.4 form a 4-membered, 5-membered or 6-membered heterocyclyl ring; R.sup.5 is selected from C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.20 heterocyclyl, and C.sub.1-C.sub.20 heteroaryl; R.sup.6 is independently selected from H, C.sub.1-C.sub.4 alkyl, and F; or two geminal or vicinal R.sup.6 groups can form a 3, 4, or 5 membered-carbocyclic ring; p is 2, 3, or 4; A is selected from C.sub.6-C.sub.20 aryl, --(C.sub.6-C.sub.20 aryl)-(C.sub.6-C.sub.20 aryl), --(C.sub.6-C.sub.20 aryl)-(C.sub.1-C.sub.20 heteroaryl), --(C.sub.6-C.sub.20 aryl)-(C.sub.2-C.sub.20 heterocyclyl), --(C.sub.1-C.sub.20 heteroaryl)-(C.sub.2-C.sub.20 heterocyclyl), --(C.sub.1-C.sub.20 heteroaryl)-(C.sub.1-C.sub.20 heteroaryl), C.sub.2-C.sub.20 heterocyclyl, and C.sub.1-C.sub.20 heteroaryl; and where alkyl, aryl, heterocyclyl and heteroaryl are optionally substituted with one or more groups independently selected from F, Cl, I, --CN, --CH.sub.3, --CH.sub.2CH.sub.3, --CH(CH.sub.3).sub.2, C(CH.sub.3).sub.3, --CH.sub.2CH(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(OH)CH(CH.sub.3).sub.2, --C(CH.sub.3).sub.2CH.sub.2OH, --CH.sub.2CH.sub.2SO.sub.2CH.sub.3, --CH.sub.2OP(O)(OH).sub.2, --CHF.sub.2, --CH.sub.2NH.sub.2, --CH.sub.2NHSO.sub.2CH.sub.3, --CH.sub.2NHCH.sub.3, --CH.sub.2N(CH.sub.3).sub.2, --CF.sub.3, --CH.sub.2CF.sub.3, --CH.sub.2CHF.sub.2, CH(CH.sub.3)CN, --C(CH.sub.3).sub.2CN, --CH.sub.2CN, --CO.sub.2H, --COCH.sub.3, --CO.sub.2CH.sub.3, --CO.sub.2C(CH.sub.3).sub.3, --COCH(OH)CH.sub.3, --CONH.sub.2, --CONHCH.sub.3, --CONHCH.sub.2CH.sub.3, --CONHCH(CH.sub.3).sub.2, --CON(CH.sub.3).sub.2, --C(CH.sub.3).sub.2CONH.sub.2, --NH.sub.2, --NHCH.sub.3, --N(CH.sub.3).sub.2, --NHCOCH.sub.3, --N(CH.sub.3)COCH.sub.3, --NHS(O).sub.2CH.sub.3, --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, --NO.sub.2, .dbd.O, --OH, --OCH.sub.3, --OCH.sub.2CH.sub.3, --OCH.sub.2CH.sub.2OCH.sub.3, --OCH.sub.2CH.sub.2OH, --OCH.sub.2CH.sub.2N(CH.sub.3).sub.2, --OP(O)(OH).sub.2, --S(O).sub.2N(CH.sub.3).sub.2, --SCH.sub.3, --S(O).sub.2CH.sub.3, --S(O).sub.3H, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, cyclopentyl, tetrahydrofuranyl, morpholinyl, piperidyl, piperazinyl, and tetrahydropyranyl. 2. The method of claim 1, wherein the compound is selected from Formulas Ia and Ic: wherein p is 2, or 3. 3. The method of claim 1, wherein the compound is selected from Formula Ig: ##STR00546## 4. The method of claim 3, wherein the compound is selected from Formulas Ih, Ii and Ij: ##STR00547## 5. The method of claim 1, wherein the compound is selected from Formulas Ik, Il and Im: ##STR00548## 6. The method of claim 4, wherein the compound is selected from Formula In, Io and Ip: ##STR00549## wherein Y is O or NW; and R.sup.7 is selected from H, cyclopropyl, cyclobutyl and C.sub.1-C.sub.6 alkyl optionally substituted with F, Cl, --OCH.sub.3, or --OH; or R.sup.3 and R.sup.7 form a 4-membered, 5-membered or 6-membered heterocyclyl ring. 7. The method of claim 6 wherein Y is NH. 8. The method of claim 6 wherein Y is NR.sup.3, and R.sup.3 and R.sup.7 form a pyrrolidinyl ring. 9. The method of claim 6 wherein Y is O. 10. The method of claim 1 wherein R.sup.1 is Br or substituted pyrazolyl. 11. The method of claim 1 wherein R.sup.1 is selected from: ##STR00550## where the wavy line indicates the site of attachment. 12. The method of claim 1 wherein A is substituted benzo[d]oxazolyl or substituted benzothiazolyl. 13. The method of claim 1 wherein A is selected from the structures: ##STR00551## ##STR00552## where the wavy line indicates the site of attachment. 14. The method of claim 1, wherein the compound is selected from the group consisting of: 5-(4-bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)benzo[d]ox- azol-2-amine; 4-bromo-1-(2-methyloxazolo[4,5-b]pyridin-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-- diazabenzo[cd]azulene; 1-(1-(2-methylbenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[c- d]azulen-4-yl)pyrrolidine-2-carboxamide; (S)-1-(1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenz- o[cd]azulen-4-yl)pyrrolidine-2-carboxamide; (S)-2-((1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazaben- zo[cd]azulen-4-yl)amino)propanamide; (S)-2-(41-phenyl-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amin- o)propanamide; (R)-2-((1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazaben- zo[cd]azulen-4-yl)amino)propanamide; (S)-2-((1-(pyridin-3-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4- -yl)amino)propanamide; (S)-2-((1-(pyrimidin-4-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen- -4-yl)amino)propanamide; (S)-2-((1-(5-cyanopyridin-2-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]a- zulen-4-yl)amino)propanamide; (S)-2-((1-(6-methoxypyridin-3-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd- ]azulen-4-yl)amino)propanamide; (S)-2-((1-(pyridin-2-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4- -yl)amino)propanamide; (S)-2-cyclopropyl-2-((1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-8,9-dihydr- o-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide; (S)-2-((1-(benzo[d][1,3]dioxol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo- [cd]azulen-4-yl)amino)-2-cyclopropylacetamide, (S)-2-cyclopropyl-2-((1-(3-oxoisoindolin-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-- diazabenzo[cd]azulen-4-yl)amino)acetamide; (S)-2-cyclopropyl-2-((1-(quinazolin-7-yl)-8,9-dihydro-7H-6-oxa-2,9a-diaza- benzo[cd]azulen-4-yl)amino)acetamide; (S)-2-cyclopropyl-2-((1-(quinoxalin-6-yl)-8,9-dihydro-7H-6-oxa-2,9a-diaza- benzo[cd]azulen-4-yl)amino)acetamide; (S)-2-((1-(3-cyanophenyl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-- 4-yl)amino)-2-cyclopropylacetamide; (S)-2-cyclopropyl-2-((1-(quinazolin-6-yl)-8,9-dihydro-7H-6-oxa-2,9a-diaza- benzo[cd]azulen-4-yl)amino)acetamide; (S)-2-((1-(2-aminoquinazolin-6-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[c- d]azulen-4-yl)amino)-2-cyclopropylacetamide; (S)-2-cyclopropyl-2-((1-(2-methoxy-6-methylpyrimidin-4-yl)-8,9-dihydro-7H- -6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide; (S)-2-cyclopropyl-2-((1-(4-methylpyridin-3-yl)-8,9-dihydro-7H-6-oxa-2,9a-- diazabenzo[cd]azulen-4-yl)amino)acetamide; (S)-2-cyclopropyl-2-((1-(2-(hydroxymethyl)-6-methylpyrimidin-4-yl)-8,9-di- hydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide; 2-(4-(1-(2-aminobenzo oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)-1H-pyra- zol-1-yl)-2-methylpropanamide; (S)-2-cyclopropyl-2-((1-(pyridazin-4-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazab- enzo[cd]azulen-4-yl)amino)acetamide; (S)-2-cyclopropyl-2-((1-(4-(hydroxymethyl)piperidin-1-yl)-8,9-dihydro-7H-- 6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide; (S)-2-cyclopropyl-2-((1-(piperidin-1-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazab- enzo[cd]azulen-4-yl)amino)acetamide; (S)-2-cyclopropyl-2-((1-(2-methoxypyrimidin-5-yl)-8,9-dihydro-7H-6-oxa-2,- 9a-diazabenzo[cd]azulen-4-yl)amino)acetamide; (S)-2-cyclopropyl-2-((1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-8,9-di- hydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide, (S)-2-((1-(5-chloro-6-methoxypyridin-3-yl)-8,9-dihydro-7H-6-oxa-2,9a-diaz- abenzo[cd]azulen-4-yl)amino)-2-cyclopropylacetamide; (S)-2-cyclopropyl-2-((1-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-8- ,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide; (S)-2-((1-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-8,9-dihydro-7H-6-oxa-2,9a-- diazabenzo[cd]azulen-4-yl)amino)-2-cyclopropylacetamide; (S)-2-((1-(1H-indazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azule- n-4-yl)amino)-2-cyclopropylacetamide; (S)-2-cyclopropyl-2-((1-(pyrimidin-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazab- enzo[cd]azulen-4-yl)amino)acetamide; (S)-2-((1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazaben- zo[cd]azulen-4-yl)amino)-2-cyclopropylacetamide; (S)-2-cyclopropyl-2-((1-(thiazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazaben- zo[cd]azulen-4-yl)amino)acetamide; (S)-2-cyclopropyl-2-((1-(4-(methylsulfonyl)phenyl)-8,9-dihydro-7H-6-oxa-2- ,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide; (S)-2-cyclopropyl-2-((1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-8,9-dihydro- -7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide; (S)-2-((1-((R)-3-(hydroxymethyl)piperidin-1-yl)-8,9-dihydro-7H-6-oxa-2,9a- -diazabenzo[cd]azulen-4-yl)amino)propanamide; (S)-2-((1-(4-(hydroxymethyl)piperidin-1-yl)-8,9-dihydro-7H-6-oxa-2,9a-dia- zabenzo[cd]azulen-4-yl)amino)propanamide; (S)-2-cyclopropyl-2-(41-morpholino-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[c- d]azulen-4-yl)amino)acetamide; (S)-2-cyclopropyl-2-((1-(oxazol-2-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenz- o[cd]azulen-4-yl)amino)acetamide; (S)-2-cyclopropyl-2-((1-(3-(difluoromethoxy)phenyl)-8,9-dihydro-7H-6-oxa-- 2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide; (S)-2-cyclopropyl-2-((1-(2-fluoro-4-methoxyphenyl)-8,9-dihydro-7H-6-oxa-2- ,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide; (S)-2-cyclopropyl-2-((1-(2,4-difluorophenyl)-8,9-dihydro-7H-6-oxa-2,9a-di- azabenzo[cd]azulen-4-yl)amino)acetamide; (S)-3-(4-((2-amino-1-cyclopropyl-2-oxoethyl)amino)-8,9-dihydro-7H-6-oxa-2- ,9a-diazabenzo[cd]azulen-1-yl)benzamide; (S)-2-cyclopropyl-2-((1-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-8,9-dihy- dro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide; (S)-2-cyclopropyl-2-((1-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)-8,9- -dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide; (S)-2-((1-(2-amino-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)-8,9-dihyd- ro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)-2-cyclopropylacetamide; (S)-2-cyclopropyl-2-((1-(4-(difluoromethoxy)phenyl)-8,9-dihydro-7H-6-oxa-- 2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide; (S)-4-(4-((2-amino-1-cyclopropyl-2-oxoethyl)amino)-8,9-dihydro-7H-6-oxa-2- ,9a-diazabenzo[cd]azulen-1-yl)picolinamide; 2-(4-(1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo- [cd]azulen-4-yl)-1H-pyrazol-1-yl)ethan-1-ol; 5-(4-(1-methyl-1H-pyrazol-4-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]a- zulen-1-yl)benzo[d]oxazol-2-amine; 2-(4-(1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo- [cd]azulen-4-yl)-1H-pyrazol-1-yl)-N,2-dimethylpropanamide; (S)-2-cyclopropyl-2-((1-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-8,9-dihydr- o-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide; (S)-2-((1-([1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-8,9-dihydro-7H-6-oxa-2,9- a-diazabenzo[cd]azulen-4-yl)amino)-2-cyclopropylacetamide; (S)-5-(4-((2-amino-1-cyclopropyl-2-oxoethyl)amino)-8,9-dihydro-7H-6-oxa-2- ,9a-diazabenzo[cd]azulen-1-yl)-2-fluorobenzamide; methyl (S)-5-(4-((2-amino-1-cyclopropyl-2-oxoethyl)amino)-8,9-dihydro-7H-6-oxa-2- ,9a-diazabenzo[cd]azulen-1-yl)-2-methoxybenzoate; (S)-2-cyclopropyl-2-((1-(2-(methylsulfonyl)pyridin-4-yl)-8,9-dihydro-7H-6- -oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide; (S)-2-cyclopropyl-2-((1-(1,3-dimethyl-1H-pyrazol-4-yl)-8,9-dihydro-7H-6-o- xa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide; (S)-2-cyclopropyl-2-((1-(5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-- yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide; (S)-2-((1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazaben- zo[cd]azulen-4-yl)oxy)propanamide; (S)-2-cyclopropyl-2-((1-(3-(difluoromethoxy)-4-methoxyphenyl)-8,9-dihydro- -7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide; (S)-5-(4-((2-amino-1-cyclopropyl-2-oxoethyl)amino)-8,9-dihydro-7H-6-oxa-2- ,9a-diazabenzo[cd]azulen-1-yl)-2-methoxybenzamide; (S)-2-cyclopropyl-2-((1-(pyridin-4-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazaben- zo[cd]azulen-4-yl)amino)acetamide; (S)-2-cyclopropyl-2-((1-(1-methyl-1H-pyrazol-4-yl)-8,9-dihydro-7H-6-oxa-2- ,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide; (S)-2-cyclopropyl-2-((1-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-8,9- -dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide; (S)-2-(4-bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)benzo[- d]oxazol-2-yl)methanol; (S)-2-((1-(1H-pyrazolo[3,4-b]pyridin-4-yl)-8,9-dihydro-7H-6-oxa-2,9a-diaz- abenzo[cd]azulen-4-yl)amino)-2-cyclopropylacetamide; (S)-2-((1-(2-aminobenzo[d]thiazol-6-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabe- nzo[cd]azulen-4-yl)amino)-2-cyclopropylacetamide; (S)-2-((1-(2-aminobenzo[d]oxazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-di- azacycloocta[cd]inden-4-yl)amino)-2-cyclopropylacetamide; 5-(4-bromo-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-1-yl)b- enzo[d]oxazol-2-amine; (S)-2-cyclopropyl-2-((1-(2-methoxyquinoxalin-6-yl)-8,9-dihydro-7H-6-oxa-2- ,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide; 2-((1-(3-cyanopiperidin-1-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azu- len-4-yl)amino)-2-cyclopropylacetamide, (S)-2-cyclopropyl-2-((1-(5-(methylsulfonyl)pyridin-3-yl)-8,9-dihydro-7H-6- -oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide; (S)-2-((1-(3H-imidazo[4,5-b]pyridin-7-yl)-8,9-dihydro-7H-6-oxa-2,9a-diaza- benzo[cd]azulen-4-yl)amino)-2-cyclopropylacetamide; (S)-2-cyclopropyl-2-((1-(thieno[2,3-b]pyridin-4-yl)-8,9-dihydro-7H-6-oxa-- 2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide; (S)-2-((1-(benzo[d]thiazol-6-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]- azulen-4-yl)amino)-2-cyclopropylacetamide; (S)-2-cyclopropyl-2-((1-(7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)-8,9-di- hydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide; (S)-2-((1-(1,4-oxazepan-4-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azu- len-4-yl)amino)-2-cyclopropylacetamide; (S)-2-(4-(4-(2-amino-1-cyclopropyl-2-oxoethyl)amino)-8,9-dihydro-7H-6-oxa- -2,9a-diazabenzo[cd]azulen-1-yl)-1H-pyrazol-1-yl)-2-methylpropanamide; (S)-2-cyclopropyl-2-((1-(3-hydroxypiperidin-1-yl)-8,9-dihydro-7H-6-oxa-2,- 9a-diazabenzo[cd]azulen-4-yl)amino)acetamide; (S)-2-cyclopropyl-2-((1-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-7H-6- -oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide; (S)-2-((1-(2-aminobenzo[d]thiazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabe- nzo[cd]azulen-4-yl)amino)-2-cyclopropylacetamide; (S)-2-((1-(2-(methylamino)benzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-- diazabenzo[cd]azulen-4-yl)amino)propanamide; (S)-1-(1-(2-(methylamino)benzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-d- iazabenzo[cd]azulen-4-yl)pyrrolidine-2-carboxamide; (S)-2-((1-(2-aminoquinoxalin-6-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[c- d]azulen-4-yl)amino)-2-cyclopropylacetamide; (S)-4-(4-((2-amino-1-cyclopropyl-2-oxoethyl)amino)-8,9-dihydro-7H-6-oxa-2- ,9a-diazabenzo[cd]azulen-1-yl)-2-fluorobenzamide; (S)-2-cyclopropyl-2-((1-(3-hydroxyquinolin-6-yl)-8,9-dihydro-7H-6-oxa-2,9- a-diazabenzo[cd]azulen-4-yl)amino)acetamide; (S)-2-((1-(4-(1H-1,2,4-triazol-3-yl)phenyl)-8,9-dihydro-7H-6-oxa-2,9a-dia- zabenzo[cd]azulen-4-yl)amino)-2-cyclopropylacetamide; (S)-5-(4-((2-amino-1-cyclopropyl-2-oxoethyl)amino)-8,9-dihydro-7H-6-oxa-2- ,9a-diazabenzo[cd]azulen-1-yl)picolinamide; 1-(2-aminobenzo[d]oxazol-5-yl)-N-(3,3-difluorocyclobutyl)-8,9-dihydro-7H-- 6-oxa-2,9a-diazabenzo[cd]azulen-4-amine; 5-(4-bromo-3-fluoro-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)b- enzo[d]oxazol-2-amine; (S)-1-(2-aminobenzo[d]oxazol-5-yl)-3-fluoro-8,9-dihydro-7H-6-oxa-2,9a-dia- zabenzo[cd]azulen-4-yl)pyrrolidine-2-carboxamide; (S)-2-((1-([1,3]dioxolo[4,5-b]pyridin-7-yl)-8,9-dihydro-7H-6-oxa-2,9a-dia- zabenzo[cd]azulen-4-yl)amino)-2-cyclopropylacetamide; (S)-2-cyclopropyl-2-((1-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-8,9-dihydr- o-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide; (S)-2-((1-(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-8,9-dihydro-7H-6-- oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)-2-cyclopropylacetamide; (6-(4-bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)quinoxali- n-2-yl)methanol; (S)-1-(1-(1H-benzo[d]imidazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[- cd]azulen-4-yl)pyrrolidine-2-carboxamide; (S)-1-(1-(1H-benzo[d][1,2,3]triazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diaza- benzo[cd]azulen-4-yl)pyrrolidine-2-carboxamide; (S)-2-((1-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-8,9-dihydro-7H-6-o- xa-2,9a-diazabenzo[cd]azulen-4-yl)amino)-2-cyclopropylacetamide; 1-(2-aminobenzo[d]oxazol-5-yl)-N-((1r,3r)-3-fluorocyclobutyl)-8,9-dihydro- -7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-amine; 1-(2-aminobenzo[d]oxazol-5-yl)-N-((1s,3s)-3-fluorocyclobutyl)-8,9-dihydro- -7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-amine; (S)-2-((1-(2-aminobenzo[d]oxazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-di- azacycloocta[cd]inden-4-yl)oxy)propanamide, (S)-2-((1-(2-amino-7-methylbenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a- -diazabenzo[cd]azulen-4-yl)amino)-2-cyclopropylacetamide; (S)-1-(1-(3H-[1,2,3]triazolo[4,5-b]pyridin-7-yl)-8,9-dihydro-7H-6-oxa-2,9- a-diazabenzo[cd]azulen-4-yl)pyrrolidine-2-carboxamide; (S)-2-((1-(2-aminobenzo[d]oxazol-6-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazaben- zo[cd]azulen-4-yl)amino)-2-cyclopropylacetamide; (S)-2-((2-(2-aminobenzo[d]oxazol-5-yl)-3,4-dihydro-5-oxa-1,2a-diazaacenap- hthylen-7-yl)amino)-2-cyclopropylacetamide; (S)-2-((1-(2-amino-7-chlorobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a- -diazabenzo[cd]azulen-4-yl)amino)-2-cyclopropylacetamide; (S)-2-cyclopropyl-2-((1-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)-8,9-dihydro-7H-- 6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide; (S)-2-cyclopropyl-2-((1-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-8,9-dihydro-- 7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide; (S)-2-((1-(1H-pyrazol-4-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azule- n-4-yl)amino)-2-cyclopropylacetamide; (S)-2-cyclopropyl-2-((1-(6-methoxypyridin-3-yl)-1,7,8,9-tetrahydrooxepino- [4,3,2-cd]indazol-4-yl)amino)acetamide; (S)-2-((1-(2-aminobenzo[d]thiazol-6-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-d- iazacycloocta[cd]inden-4-yl)amino)-2-cyclopropylacetamide; (S)-2-cyclopropyl-2-((1-(8-fluoroquinoxalin-6-yl)-8,9-dihydro-7H-6-oxa-2,- 9a-diazabenzo[cd]azulen-4-yl)amino)acetamide; (R)-2-(4-(1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazab- enzo[cd]azulen-4-yl)-1H-pyrazol-1-yl)butanamide; (S)-2-(4-(1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazab- enzo[cd]azulen-4-yl)-1H-pyrazol-1-yl)butanamide; (R)-2-(4-(1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazab- enzo[cd]azulen-4-yl)-1H-pyrazol-1-yl)propanamide; (S)-2-(4-(1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazab- enzo[cd]azulen-4-yl)-1H-pyrazol-1-yl)propanamide, (S)-1-(1-(2-oxo-3,4-dihydro-2H-benzo[4,5] oxazolo[3,2-a]pyrimidin-7-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azu- len-4-yl)pyrrolidine-2-carboxamide; (S)-1-(1-(4-(1H-1,2,4-triazol-3-yl)phenyl)-8,9-dihydro-7H-6-oxa-2,9a-diaz- abenzo[cd]azulen-4-yl)pyrrolidine-2-carboxamide; (S)-1-(1-(3-chloro-4-(1H-1,2,4-triazol-3-yl)phenyl)-8,9-dihydro-7H-6-oxa-- 2,9a-diazabenzo[cd]azulen-4-yl)pyrrolidine-2-carboxamide; (S)-1-(1-(6-(1H-pyrazol-4-yl)pyridin-3-yl)-8,9-dihydro-7H-6-oxa-2,9a-diaz- abenzo[cd]azulen-4-yl)pyrrolidine-2-carboxamide; (S)-1-(1-(2-amino-7-ethylbenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-d- iazabenzo[cd]azulen-4-yl)pyrrolidine-2-carboxamide; (S)-2-((1-(2-amino-7-ethylbenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-- diazabenzo[cd]azulen-4-yl)amino)-2-cyclopropylacetamide; (5)-1-(1-(5-(1H-1,2,4-triazol-3-yl)pyridin-2-yl)-8,9-dihydro-7H-6-oxa-2,9- a-diazabenzo[cd]azulen-4-yl)pyrrolidine-2-carboxamide; (S)-1-(1-(4-(1,2,4-thiadiazol-3-yl)phenyl)-8,9-dihydro-7H-6-oxa-2,9a-diaz- abenzo[cd]azulen-4-yl)pyrrolidine-2-carboxamide; (S)-2-cyclopropyl-2-((1-(pyrazolo[1,5-a]pyrimidin-5-yl)-8,9-dihydro-7H-6-- oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide; (S)-1-(1-(4-(1H-pyrazol-3-yl)phenyl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo- [cd]azulen-4-yl)pyrrolidine-2-carboxamide; S)-2-(4-(1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabe- nzo[cd]azulen-4-yl)-1H-pyrazol-1-yl)-2-cyclopropylacetamide; (R)-2-(4-(1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazab- enzo[cd]azulen-4-yl)-1H-pyrazol-1-yl)-2-cyclopropylacetamide; (R)-2-(4-(1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazab- enzo[cd]azulen-4-yl)-1H-pyrazol-1-yl)-3-methoxy-2-methylpropanamide; (S)-2-(4-(1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazab- enzo[cd]azulen-4-yl)-1H-pyrazol-1-yl)-3-methoxy-2-methylpropanamide; (S)-1-(1-(4-(2-oxoimidazolidin-1-yl)phenyl)-8,9-dihydro-7H-6-oxa-2,9a-dia- zabenzo[cd]azulen-4-yl)pyrrolidine-2-carboxamide, (S)-2-((1-(2-amino-7-(trifluoromethyl)benzo[d]oxazol-5-yl)-8,9-dihydro-7H- -6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)-2-cyclopropylacetamide; (S)-1-(1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenz- o[cd]azulen-4-yl)-N-(4-methoxybenzyl)pyrrolidine-2-carboxamide; (S)-1-(1-(3-oxo-2,3-dihydrobenzo[d]isoxazol-6-yl)-8,9-dihydro-7H-6-oxa-2,- 9a-diazabenzo[cd]azulen-4-yl)pyrrolidine-2-carboxamide; (S)-2-4(R)-2-(2-aminobenzo[d]oxazol-5-yl)-4-methyl-3,4-dihydro-5-oxa-1,2a- -diazaacenaphthylen-7-yl)amino)-2-cyclopropylacetamide; (5)-1-(1-(2-aminobenzo[d]thiazol-6-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-di- azacycloocta[cd]inden-4-yl)pyrrolidine-2-carboxamide; (S)-2-((1-(2-aminobenzo[d]oxazol-5-yl)-3-fluoro-8,9-dihydro-7H-6-oxa-2,9a- -diazabenzo[cd]azulen-4-yl)oxy)propanamide; (S)-2-((1-(2-amino-4-fluorobenzo[d]oxazol-5-yl)-7,8,9,10-tetrahydro-6-oxa- -2,10a-diazacycloocta[cd]inden-4-yl)oxy)propanamide; (S)-2-((1-(2-amino-4-fluorobenzo[d]thiazol-6-yl)-7,8,9,10-tetrahydro-6-ox- a-2,10a-diazacycloocta[cd]inden-4-yl)oxy)propanamide; (S)-2-((1-(4-(1H-1,2,4-triazol-3-yl)phenyl)-7,8,9,10-tetrahydro-6-oxa-2,1- 0a-diazacycloocta[cd]inden-4-yl)oxy)propanamide, and (S)-2-((1-(2-aminoquinoxalin-6-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazac- ycloocta[cd]inden-4-yl)oxy)propanamide; or a pharmaceutically acceptable salt thereof. 15. The method of claim 1, wherein the compound is selected from the group consisting of: (R)-2-((1-(2-aminobenzo[d]oxazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-di- azacycloocta[cd]inden-4-yl)oxy)propanamide; (S)-2-((1-(2-Aminobenzo[d]thiazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-d- iazacycloocta[cd]inden-4-yl)amino)-2-cyclopropylacetamide; (S)-1-(1-(2-aminobenzo[d]oxazol-5-yl)-3-fluoro-7,8,9,10-tetrahydro-6-oxa-- 2,10a-diazacycloocta[cd]inden-4-yl)pyrrolidine-2-carboxamide, (S)-2-((1-(2-aminobenzo[d]thiazol-6-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-d- iazacycloocta[cd]inden-4-yl)oxy)propanamide; (S)-2-((1-(2-amino-7-fluorobenzo[d]oxazol-5-yl)-'7,8,9,10-tetrahydro-6-ox- a-2,10a-diazacycloocta[cd]inden-4-yl)oxy)propanamide; (S)-1-(1-(2-aminobenzo[d]oxazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-dia- zacycloocta[cd]inden-4-yl)pyrrolidine-2-carboxamide; (R)-2-(((R)-2-(2-aminobenzo[d]oxazol-5-yl)-4-methyl-3,4-dihydro-5-oxa-1,2- a-diazaacenaphthylen-7-yl)oxy)propanamide; (S)-2-4(R)-2-(2-aminobenzo[d]oxazol-5-yl)-4-methyl-3,4-dihydro-5-oxa-1,2a- -diazaacenaphthylen-7-yl)oxy)propanamide; 5-(4-bromo-8,9-dihydrooxepino[4,3,2-cd]indazol-1(7H)-yl)benzo[d]oxazol-2-- amine; (S)-2-((1-(2-aminobenzo[d]oxazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,- 10a-diazacycloocta[cd]inden-4-yl)(methyl)amino)propanamide; (S)-2-((1-(2-aminobenzo[d]thiazol-6-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-d- iazacycloocta[cd]inden-4-yl)(methyl)amino)propanamide; (S)-2-((1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazaben- zo[cd]azulen-4-yl)oxy)butanamide; (R)-2-((1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazaben- zo[cd]azulen-4-yl)oxy)butanamide; (S)-2-((1-(2-amino-7-fluorobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a- -diazabenzo[cd]azulen-4-yl)oxy)propanamide; (R)-2-((1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazaben- zo[cd]azulen-4-yl)oxy)-2-cyclopropylacetamide; (S)-2-((1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazaben- zo[cd]azulen-4-yl)oxy)-2-cyclopropylacetamide; (S)-2-((1-(2-amino-4,7-difluorobenzo[d]oxazol-5-yl)-7,8,9,10-tetrahydro-6- -oxa-2,10a-diazacycloocta[cd]inden-4-yl)oxy)propanamide; (S)-4-(1-(2-aminobenzo[d]thiazol-6-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-di- azacycloocta[cd]inden-4-yl)morpholine-3-carboxamide, (R)-2-((1-(2-Amino-7-fluorobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a- -diazabenzo[cd]azulen-4-yl)oxy)propanamide, (S)-2-((1-(2-amino-7-fluorobenzo[d]oxazol-5-yl)-'7,8,9,10-tetrahydro-6-ox- a-2,10a-diazacycloocta[cd]inden-4-yl)(methyl)amino)propanamide, (S)-2-((1-(2-aminothiazolo[5,4-b]pyridin-5-yl)-7,8,9,10-tetrahydro-6-oxa-- 2,10a-diazacycloocta[cd]inden-4-yl)oxy)propanamide, (S)-2-((1-(2-aminooxazolo[4,5-b]pyridin-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-d- iazabenzo[cd]azulen-4-yl)oxy)propanamide, (R)-2-((1-(4-(1H-1,2,4-triazol-3-yl)phenyl)-7,8,9,10-tetrahydro-6-oxa-2,1- 0a-diazacycloocta[cd]inden-4-yl)oxy)butanamide, (S)-2-((1-(4-(1H-1,2,4-triazol-3-yl)phenyl)-7,8,9,10-tetrahydro-6-oxa-2,1- 0a-diazacycloocta[cd]inden-4-yl)oxy)butanamide, (S)-2-((1-(3-fluoro-4-(1H-1,2,4-triazol-3-yl)phenyl)-7,8,9,10-tetrahydro-- 6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)oxy)propanamide, (S)-2-((1-(2-amino-4-fluorobenzo[d]oxazol-5-yl)-'7,8,9,10-tetrahydro-6-ox- a-2,10a-diazacycloocta[cd]inden-4-yl)(methyl)amino)propanamide, (S)-2-((1-(2-aminobenzo[d]oxazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-di- azacycloocta[cd]inden-4-yl)oxy)butanamide, (S)-2-((1-(2-amino-7-fluorobenzo[d]oxazol-5-yl)-'7,8,9,10-tetrahydro-6-ox- a-2,10a-diazacycloocta[cd]inden-4-yl)oxy)butanamide, (S)-2-((1-(2-amino-4-fluorobenzo[d]thiazol-6-yl)-7,8,9,10-tetrahydro-6-ox- a-2,10a-diazacycloocta[cd]inden-4-yl)oxy)butanamide; (S)-2-((1-(2-aminobenzo[d]thiazol-6-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabe- nzo[cd]azulen-4-yl)oxy)propanamide, (R)-2-((1-(2-aminobenzo[d]thiazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-d- iazacycloocta[cd]inden-4-yl)oxy)propanamide, (S)-2-((1-(2-aminobenzo[d]thiazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-d- iazacycloocta[cd]inden-4-yl)oxy)propanamide, (S)-2-((1-(2-amino-5-fluorobenzo[d]thiazol-6-yl)-7,8,9,10-tetrahydro-6-ox- a-2,10a-diazacycloocta[cd]inden-4-yl)oxy)propanamide, (R)-2-((1-(2-amino-5-fluorobenzo[d]thiazol-6-yl)-7,8,9,10-tetrahydro-6-ox- a-2,10a-diazacycloocta[cd]inden-4-yl)oxy)propanamide, (R)-2-((1-(2-amino-4-fluorobenzo[d]thiazol-6-yl)-7,8,9,10-tetrahydro-6-ox- a-2,10a-diazacycloocta[cd]inden-4-yl)oxy)-2-cyclopropylacetamide, (S)-2-((1-(2-amino-4-fluorobenzo[d]thiazol-6-yl)-7,8,9,10-tetrahydro-6-ox- a-2,10a-diazacycloocta[cd]inden-4-yl)oxy)-2-cyclopropylacetamide, (S)-2-((1-(2-aminobenzo[d]thiazol-6-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-d- iazacycloocta[cd]inden-4-yl)oxy)-2-cyclopropylacetamide, (R)-2-((1-(2-aminobenzo[d]thiazol-6-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-d- iazacycloocta[cd]inden-4-yl)oxy)-2-cyclopropylacetamide, (R)-2-((1-(2-aminobenzo[d]oxazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-di- azacycloocta[cd]inden-4-yl)oxy)-2-cyclopropylacetamide, (S)-2-((1-(2-aminobenzo[d]oxazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-di- azacycloocta[cd]inden-4-yl)oxy)-2-cyclopropylacetamide, (S)-2-((1-(2-amino-7-fluorobenzo[d]thiazol-5-yl)-7,8,9,10-tetrahydro-6-ox- a-2,10a-diazacycloocta[cd]inden-4-yl)oxy)propanamide, (S)-2-((1-(2-amino-7-fluorobenzo[d]thiazol-6-yl)-7,8,9,10-tetrahydro-6-ox- a-2,10a-diazacycloocta[cd]inden-4-yl)oxy)propanamide, (R)-2-((1-(2-amino-7-fluorobenzo[d]thiazol-6-yl)-7,8,9,10-tetrahydro-6-ox- a-2,10a-diazacycloocta[cd]inden-4-yl)oxy)propanamide, (R)-2-((1-(2-amino-7-fluorobenzo[d]oxazol-5-yl)-'7,8,9,10-tetrahydro-6-ox- a-2,10a-diazacycloocta[cd]inden-4-yl)oxy)-2-cyclopropylacetamide, (S)-2-((1-(2-amino-7-fluorobenzo[d]oxazol-5-yl)-'7,8,9,10-tetrahydro-6-ox- a-2,10a-diazacycloocta[cd]inden-4-yl)oxy)-2-cyclopropylacetamide, (S)-2-((2-(2-amino-4-fluorobenzo[d]thiazol-6-yl)-3,4-dihydro-5-oxa-1,2a-d- iazaacenaphthylen-7-yl)oxy)-2-cyclopropylacetamide, (R)-2-((2-(2-amino-4-fluorobenzo[d]thiazol-6-yl)-3,4-dihydro-5-oxa-1,2a-d- iazaacenaphthylen-7-yl)oxy)-2-cyclopropylacetamide, (S)-2-((1-(3-aminobenzo[e][1,2,4]triazin-7-yl)-7,8,9,10-tetrahydro-6-oxa-- 2,10a-diazacycloocta[cd]inden-4-yl)oxy)propanamide, (S)-2-((1-(2-fluoro-4-(1H-1,2,4-triazol-5-yl)phenyl)-7,8,9,10-tetrahydro-- 6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)oxy)propanamide; (2R,3S)-1-(1-(2-aminobenzo[d]oxazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a- -diazacycloocta[cd]inden-4-yl)-3-fluoropyrrolidine-2-carboxamide; (S)-2-((1-(2,5-difluoro-4-(1H-1,2,4-triazol-5-yl)phenyl)-7,8,9,10-tetrahy- dro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)oxy)butanamide; (S)-2-((1-(5-(1H-1,2,4-triazol-5-yl)pyridin-2-yl)-7,8,9,10-tetrahydro-6-o- xa-2,10a-diazacycloocta[cd]inden-4-yl)oxy)propanamide; (S)-2-((1-(2-aminobenzo[d]oxazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-di- azacycloocta[cd]inden-4-yl)oxy)propanoic acid; (S)-2-(4-(1-(2-aminothiazolo[5,4-b]pyridin-5-yl)-7,8,9,10-tetrahydro-6-ox- a-2,10a-diazacycloocta[cd]inden-4-yl)-1H-pyrazol-1-yl)butanamide; (R)-2-(4-(1-(2-aminothiazol o[5,4-b]pyridin-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]i- nden-4-yl)-1H-pyrazol-1-yl)butanamide; (2S,3R)-1-(1-(2-aminobenzo[d]thiazol-6-yl)-7,8,9,10-tetrahydro-6-oxa-2,10- a-diazacycloocta[cd]inden-4-yl)-3-methoxypyrrolidine-2-carboxamide; (S)-2-(4-(1-(2-aminooxazolo[4,5-b]pyridin-5-yl)-7,8,9,10-tetrahydro-6-oxa- -2,10a-diazacycloocta[cd]inden-4-yl)-1H-pyrazol-1-yl)butanamide; (R)-2-(4-(1-(2-aminooxazolo[4,5-b]pyridin-5-yl)-7,8,9,10-tetrahydro-6-oxa- -2,10a-diazacycloocta[cd]inden-4-yl)-1H-pyrazol-1-yl)butanamide; (S)-2-((1-(2-aminobenzo[d]thiazol-6-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-d- iazacycloocta[cd]inden-4-yl)oxy)-3-methoxypropanamide; (R)-2-((1-(2-aminobenzo[d]thiazol-6-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-d- iazacycloocta[cd]inden-4-yl)oxy)-3-methoxypropanamide; (S)-2-cyclopropyl-2-((1-(3-fluoro-4-(1H-1,2,4-triazol-5-yl)phenyl)-7,8,9,- 10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)oxy)acetamide; (R)-2-cyclopropyl-2-((1-(3-fluoro-4-(1H-1,2,4-triazol-5-yl)phenyl)-7,8,9,- 10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)oxy)acetamide; (S)-2-((1-(5-fluoro-6-(1H-1,2,4-triazol-5-yl)pyridin-3-yl)-7,8,9,10-tetra- hydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)oxy)propanamide; (2S,3S)-1-(1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diaza- benzo[cd]azulen-4-yl)-3-methylpyrrolidine-2-carboxamide; (2S,3S)-1-(1-(2-aminobenzo[d]oxazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a- -diazacycloocta[cd]inden-4-yl)-3-methylpyrrolidine-2-carboxamide; (2S,3R)-1-(1-(2-aminobenzo[d]oxazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a- -diazacycloocta[cd]inden-4-yl)-3-methoxypyrrolidine-2-carboxamide; (S)-2-(4-(1-(2-aminooxazolo[4,5-b]pyridin-5-yl)-8,9-dihydro-7H-6-oxa-2,9a- -diazabenzo[cd]azulen-4-yl)-1H-pyrazol-1-yl)butanamide; (R)-2-(4-(1-(2-aminooxazolo[4,5-b]pyridin-5-yl)-8,9-dihydro-7H-6-oxa-2,9a- -diazabenzo[cd]azulen-4-yl)-1H-pyrazol-1-yl)butanamide; (S)-2-((1-(2-aminobenzo[d]oxazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-di- azacycloocta[cd]inden-4-yl)oxy)butanoic acid; (R)-2-((1-(2-aminothiazolo[5,4-b]pyridin-5-yl)-7,8,9,10-tetrahydro-6-oxa-- 2,10a-diazacycloocta[cd]inden-4-yl)oxy)-3-methoxypropanamide; and (S)-2-((1-(2-aminothiazolo[5,4-b]pyridin-5-yl)-7,8,9,10-tetrahydro-6-oxa-- 2,10a-diazacycloocta[cd]inden-4-yl)oxy)-3-methoxypropanamide; or a pharmaceutically acceptable salt thereof. 16. The method of claim 1 further comprising administering to the patient a therapeutic agent selected from 5-FU, docetaxel, eribulin, gemcitabine, cobimetinib, ipatasertib, paclitaxel, tamoxifen, fulvestrant, GDC-0810, dexamethasone, palbociclib, bevacizumab, pertuzumab, trastuzumab emtansine, trastuzumab and letrozole. 17. The method of claim 1 wherein the cancer is breast cancer. 18. The method of claim 17 wherein the breast cancer is estrogen receptor positive (ER+) breast cancer. 19. The method of claim 1 wherein the breast cancer subtype is Basal or Luminal. 20. The method of claim 1 wherein the cancer expresses a PIK3CA mutant selected from E542K, E545K, Q546R, H1047L and H1047R. 21. The method of claim 1 wherein the cancer expresses a PTEN mutant. 22. The method of claim 1 wherein the cancer is hormone receptor positive (HR+). 23. The method of claim 1 wherein the patient is HER2 negative, ER (estrogen receptor) negative, and PR (progesterone receptor) negative.

Details for Patent 10,435,414

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	09/25/1998		2035-09-08
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	02/10/2017		2035-09-08
Genentech, Inc.	AVASTIN	bevacizumab	Injection	125085	02/26/2004		2035-09-08
Genentech, Inc.	PERJETA	pertuzumab	Injection	125409	06/08/2012		2035-09-08
Genentech, Inc.	HERCEPTIN HYLECTA	trastuzumab and hyaluronidase-oysk	Injection	761106	02/28/2019		2035-09-08