Claims for Patent: 9,546,182

Summary for Patent: 9,546,182

Title:	Tricyclic PI3K inhibitor compounds and methods of use
Abstract:	Tricyclic PI3k inhibitor compounds of Formula I with anti-cancer activity, anti-inflammatory activity, or immunoregulatory properties, and more specifically with PI3 kinase modulating or inhibitory activity are described. Methods are described for using the tricyclic PI3K inhibitor compounds of Formula I for in vitro, in situ, and in vivo diagnosis or treatment of mammalian cells, organisms, or associated pathological conditions. ##STR00001## Formula I compounds include stereoisomers, geometric isomers, tautomers, and pharmaceutically acceptable salts thereof. The dashed lines indicate an optional double bond, and at least one dashed line is a double bond. The substituents are as described.
Inventor(s):	Dotson; Jennafer (Belmont, CA), Heald; Robert Andrew (Harlow, GB), Heffron; Timothy (Burlingame, CA), Jones; Graham Elgin (Harlow, GB), Krintel; Sussie Lerche (Harlow, GB), McLean; Neville James (Harlow, GB), Ndubaku; Chudi (San Francisco, CA), Olivero; Alan G. (Half Moon Bay, CA), Salphati; Laurent (San Francisco, CA), Wang; Lan (Foster City, CA), Wei; BinQuing (Belmont, CA)
Assignee:	Genentech, Inc. (South San Francisco, unknown)
Application Number:	14/524,204
Patent Claims:	1. A method of treating cancer characterized by over expression of PI3 kinase in a patient, the method comprising administering to said patient a therapeutically effective amount of a compound of Formula I: ##STR00191## and stereoisomers, geometric isomers, tautomers, and pharmaceutically acceptable salts thereof, wherein: the dashed lines indicate an optional double bond, and at least one dashed line is a double bond; X.sup.1 is S, O, N, NR.sup.a, CR.sup.1, C(R.sup.1).sub.2, or --C(R.sup.1).sub.2O--; X.sup.2 is C, CR.sup.2 or N; X.sup.3 is C, CR.sup.3 or N; A is a 5, 6, or 7-membered carbocyclyl or heterocyclyl ring fused to X.sup.2 and X.sup.3, optionally substituted with one or more R.sup.5 groups; R.sup.a is selected from H, C.sub.1-C.sub.12 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, --(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(.dbd.O)--(C.sub.2-C.sub.20 heterocyclyl), --(C.sub.1-C.sub.12 alkylene)-(C.sub.6-C.sub.20 aryl), and --(C.sub.1-C.sub.12 alkylene)-(C.sub.1-C.sub.20 heteroaryl), 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, --CH.sub.3, --CH.sub.2CH.sub.3, --C(CH.sub.3).sub.3, --CH.sub.2OH, --CH.sub.2CH.sub.2OH, --C(CH.sub.3).sub.2OH, --CH.sub.2OCH.sub.3, --CN, --CH.sub.2F, --CHF.sub.2, --CF.sub.3, --CO.sub.2H, --COCH.sub.3, --COC(CH.sub.3).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, --NO.sub.2, --NH.sub.2, --NHCH.sub.3, --N(CH.sub.3).sub.2, --NHCOCH.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, .dbd.O, --OH, --OCH.sub.3, --S(O).sub.2N(CH.sub.3).sub.2, --SCH.sub.3, --S(O).sub.2CH.sub.3, cyclopropyl, cyclobutyl, oxetanyl, morpholino, and 1,1-dioxo-thiopyran-4-yl; R.sup.1, R.sup.2, and R.sup.3 are independently selected from H, F, Cl, Br, I, --CH.sub.3, --CH.sub.2CH.sub.3, --C(CH.sub.3).sub.3, --CH.sub.2OH, --CH.sub.2CH.sub.2OH, --C(CH.sub.3).sub.2OH, --CH.sub.2OCH.sub.3, --CN, --CF.sub.3, --CO.sub.2H, --COCH.sub.3, --COC(CH.sub.3).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, --NO.sub.2, --NH.sub.2, --NHCH.sub.3, --N(CH.sub.3).sub.2, --NHCOCH.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, .dbd.O, --OH, --OCH.sub.3, --S(O).sub.2N(CH.sub.3).sub.2, --SCH.sub.3, --S(O).sub.2CH.sub.3, cyclopropyl, cyclobutyl, oxetanyl, morpholino, and 1,1-dioxo-thiopyran-4-yl; R.sup.4 is selected from C.sub.6-C.sub.20 aryl, C.sub.2-C.sub.20 heterocyclyl and C.sub.1-C.sub.20 heteroaryl, each of which are optionally substituted with one or more R.sup.6 groups independently selected from 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.2CN, --CN, --CF.sub.3, --CH.sub.2OH, --CO.sub.2H, --CONH.sub.2, --CONH(CH.sub.3), --CON(CH.sub.3).sub.2, --NO.sub.2, --NH.sub.2, --NHCH.sub.3, --NHCOCH.sub.3, --OH, --OCH.sub.3, --OCH.sub.2CH.sub.3, --OCH(CH.sub.3).sub.2, --SH, --NHC(.dbd.O)NHCH.sub.3, --NHC(.dbd.O)NHCH.sub.2CH.sub.3, --NHC(.dbd.O)NHCH(CH.sub.3).sub.2, --NHS(O).sub.2CH.sub.3, --N(CH.sub.3)C(.dbd.O)OC(CH.sub.3).sub.3, --S(O).sub.2CH.sub.3, benzyl, benzyloxy, morpholinyl, morpholinomethyl, and 4-methylpiperazin-1-yl; and R.sup.5 is independently selected from C.sub.1-C.sub.12 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, --(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(.dbd.O)--(C.sub.2-C.sub.20 heterocyclyl), --(C.sub.1-C.sub.12 alkylene)-(C.sub.6-C.sub.20 aryl), and --(C.sub.1-C.sub.12 alkylene)-(C.sub.1-C.sub.20 heteroaryl); or two geminal R.sup.5 groups form a 3, 4, 5, or 6-membered carbocyclyl or heterocyclyl ring, 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, --CH.sub.3--CH.sub.2CH.sub.3, --C(CH.sub.3).sub.3, --CH.sub.2OH, --CH.sub.2CH.sub.2OH, --C(CH.sub.3).sub.2OH, --CH.sub.2OCH.sub.3, --CN, --CH.sub.2F, --CHF.sub.2, --CF.sub.3, --CO.sub.2H, --COCH.sub.3, --COC(CH.sub.3).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, --NO.sub.2, --NH.sub.2, --NHCH.sub.3, --N(CH.sub.3).sub.2, --NHCOCH.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, .dbd.O, --OH, --OCH.sub.3, --S(O).sub.2N(CH.sub.3).sub.2, --SCH.sub.3, --S(O).sub.2CH.sub.3, cyclopropyl, cyclobutyl, oxetanyl, morpholino, and 1,1-dioxo-thiopyran-4-yl; mor is selected from: ##STR00192## wherein mor is optionally substituted with one or more R.sup.7 groups independently selected from F, Cl, Br, I, --CH.sub.3, --CH.sub.2CH.sub.3, --CH.sub.2CH.sub.2CH.sub.3, --CH(CH.sub.3).sub.2, --C(CH.sub.3).sub.3, --CH.sub.2OCH.sub.3, --CHF.sub.2, --CN, --CF.sub.3, --CH.sub.2OH, --CH.sub.2OCH.sub.3, --CH.sub.2CH.sub.2OH, --CH.sub.2C(CH.sub.3).sub.2OH, --CH(CH.sub.3)OH, --CH(CH.sub.2CH.sub.3)OH, --CH.sub.2CH(OH)CH.sub.3, --C(CH.sub.3).sub.2OH, --C(CH.sub.3).sub.2OCH.sub.3, --CH(CH.sub.3)F, --C(CH.sub.3)F.sub.2, --CH(CH.sub.2CH.sub.3)F, --C(CH.sub.2CH.sub.3).sub.2F, --CO.sub.2H, --CONH.sub.2, --CON(CH.sub.2CH.sub.3).sub.2, --COCH.sub.3, --CON(CH.sub.3).sub.2, --NO.sub.2, --NH.sub.2, --NHCH.sub.3, --N(CH.sub.3).sub.2, --NHCH.sub.2CH.sub.3, --NHCH(CH.sub.3).sub.2, --NHCH.sub.2CH.sub.2OH, --NHCH.sub.2CH.sub.2OCH.sub.3, NHCOCH.sub.3, --NHCOCH.sub.2CH.sub.3, --NHCOCH.sub.2OH, --NHS(O).sub.2CH.sub.3, --N(CH.sub.3)S(O).sub.2CH.sub.3, .dbd.O, --OH, --OCH.sub.3, --OCH.sub.2CH.sub.3, --OCH(CH.sub.3).sub.2, --SH, --NHC(.dbd.O)NHCH.sub.3, --NHC(.dbd.O)NHCH.sub.2CH.sub.3, --S(O)CH.sub.3, --S(O)CH.sub.2CH.sub.3, --S(O).sub.2CH.sub.3, --S(O).sub.2NH.sub.2, --S(O).sub.2NHCH.sub.3, --S(O).sub.2N(CH.sub.3).sub.2, and --CH.sub.2S(O).sub.2CH.sub.3; and wherein the cancer is characterized by over expression of PI3 kinase and is selected from breast, ovary, cervix, prostate, testis, genitourinary tract, esophagus, larynx, glioblastoma, neuroblastoma, stomach, skin, keratoacanthoma, lung, epidermoid carcinoma, large cell carcinoma, non-small cell lung carcinoma (NSCLC), small cell carcinoma, lung adenocarcinoma, bone, colon, adenoma, pancreas, adenocarcinoma, thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma and biliary passages, kidney carcinoma, renal, pancreatic, myeloid disorders, lymphoma, hairy cells, buccal cavity, naso-pharyngeal, pharynx, lip, tongue, mouth, small intestine, colon-rectum, large intestine, rectum, brain and central nervous system, Hodgkin's and leukemia. 2. The method of claim 1 wherein the cancer is a brain cancer. 3. The method of claim 1 further comprising administering to the patient an additional therapeutic agent selected from a chemotherapeutic agent, an anti-angiogenesis therapeutic 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. 4. The method of claim 3 wherein the additional therapeutic agent is bevacizumab. 5. The method of claim 1 wherein the PI3 kinase is p110 alpha. 6. The method of claim 1 wherein: the bond between X.sup.1 and X.sup.3 is a double bond and the bond between X.sup.2 and X.sup.3 is a single bond; X.sup.1 is selected from N and CR.sup.1; X.sup.2 is N; X.sup.3 is C; A is a 5- or 6-membered carbocyclyl or heterocyclyl optionally substituted with one or more R.sup.5 groups; R.sup.1 is H; R.sup.4 is selected from C.sub.6-C.sub.20 aryl and C.sub.5-C.sub.6 heteroaryl each of which are optionally substituted with one or more R.sup.6 groups independently selected from --CH.sub.3, --CH.sub.2CH.sub.3, --CH(CH.sub.3).sub.2, --CH.sub.2CH(CH.sub.3).sub.2, --CF.sub.3, --NH.sub.2, --NHC(.dbd.O)NHCH.sub.3, --NHC(.dbd.O)NHCH.sub.2CH.sub.3 and --NHC(.dbd.O)NHCH(CH.sub.3).sub.2; R.sup.5 is C.sub.1-C.sub.12 alkyl or two germinal R.sup.5 groups forma a 3-, 4-, 5- or 6-membered carbocyclyl or heterocyclyl ring optionally substituted with one or more groups selected from F, Cl, Br, I and --OH; and mor is: ##STR00193## wherein mor is optionally substituted with one or more R.sup.7 groups independently selected from --CH.sub.3, --CH.sub.2CH.sub.3, --CH.sub.2CH.sub.2CH.sub.3, --CH(CH.sub.3).sub.2 and --C(CH.sub.3).sub.3. 7. The method of claim 1 wherein the compound of Formula I is selected from: ##STR00194## ##STR00195## ##STR00196## ##STR00197## ##STR00198## 8. The method of claim 7 wherein the compound of Formula I is: ##STR00199##

Details for Patent 9,546,182

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	AVASTIN	bevacizumab	Injection	125085	02/26/2004		2039-02-26