Claims for Patent: 8,835,429

Summary for Patent: 8,835,429

Title:	Pyrimidine compounds, their use as mTOR kinase and Pl3 kinase inhibitors, and their syntheses
Abstract:	The invention relates to pyrimidine compounds of the Formula I: or a pharmaceutically acceptable salt thereof, wherein the constituent variables are as defined herein, compositions comprising the compounds, and methods for making and using the compounds. ##STR00001##
Inventor(s):	Curran; Kevin Joseph (Somerville, MA), Kaplan; Joshua Aaron (Seattle, WA), Richard; David James (Littleton, MA), Verheijen; Jeroen Cunera (Westborough, MA), Zask; Arie (New York, NY)
Assignee:	Wyeth LLC (New York, NY)
Application Number:	13/264,776
Patent Claims:	1. A compound of Formula I: ##STR00050## or a pharmaceutically acceptable salt thereof wherein; R.sup.1 is independently C.sub.1-C.sub.6alkyl-, C.sub.6-C.sub.14aryl-, C.sub.1-C.sub.9heteroaryl-, halogen, or hydroxyl; p is 0, 1, 2, 3, or 4; het is a bridged C.sub.5-C.sub.9heterobicyclyl- group containing at least one oxygen atom, at least one nitrogen atom, and optionally additional heteroatoms selected from oxygen, sulfur and nitrogen, and is connected to the pyrimidinyl group through one of the nitrogen atoms; one of A is C--R.sup.5 and the other two are N; Ar is C.sub.6-C.sub.14aryl- or C.sub.1-C.sub.9heteroaryl- wherein the C.sub.6-C.sub.14aryl- or C.sub.1-C.sub.9heteroaryl- is optionally substituted with from 1 to 4 substituents independently selected from C.sub.1-C.sub.6alkyl-, halogen, haloalkyl-, hydroxyl, hydroxyl(C.sub.1-C.sub.6alkyl)-, H.sub.2N--, aminoalkyl-, di(C.sub.1-C.sub.6alkyl)amino-, HO.sub.2C--, (C.sub.1-C.sub.6alkoxy)carbonyl-, (C.sub.1-C.sub.6alkyl)carboxyl-, di(C.sub.1-C.sub.6alkyl)amido-, H.sub.2NC(O)--, (C.sub.1-C.sub.6alkyl)amido-, and O.sub.2N--; and wherein the C.sub.6-C.sub.14aryl- or C.sub.1-C.sub.9heteroaryl- is bonded to the pyrimidine core through a carbon atom of the C.sub.6-C.sub.14aryl- or C.sub.1-C.sub.9heteroaryl-; R.sup.2 is H or C.sub.1-C.sub.6alkyl-; R.sup.3 is R.sup.6, R.sup.7R.sup.8N--, R.sup.9S--, or R.sup.9O--; R.sup.6 is: (a) H; (b) C.sub.1-C.sub.6alkyl- optionally substituted with from 1 to 3 substituents independently selected from: (i) C.sub.1-C.sub.6alkoxy-, (ii) H.sub.2N--, (iii) (C.sub.1-C.sub.6alkyl)amino-, (iv) di(C.sub.1-C.sub.6alkyl)amino-, (v) C.sub.6-C.sub.14aryl-, (vi) C.sub.1-C.sub.9heterocyclyl- optionally substituted by C.sub.1-C.sub.6alkyl-, (vii) and C.sub.1-C.sub.9heteroaryl-; (c) C.sub.1-C.sub.6alkoxy-; (d) C.sub.1-C.sub.9heteroaryl- optionally substituted with from 1 to 3 substituents independently selected from: (i) C.sub.1-C.sub.6alkyl- optionally substituted with H.sub.2N--, (ii) heterocyclyl(C.sub.1-C.sub.6alkyl)-, (iii) halogen, (iv) hydroxyl, (v) H.sub.2N--, (vi) O.sub.2N--, (vii) H.sub.2NSO.sub.2--, (viii) HO.sub.2C--, (ix) (C.sub.1-C.sub.6alkoxy)carbonyl-, (x) (C.sub.1-C.sub.6alkoxy)C(O)NH--, (xi) (C.sub.1-C.sub.6alkyl)amino-, (xii) di(C.sub.1-C.sub.6alkyl)amino-, (xiii) R.sup.10R.sup.11NC(O)--, (xiv) R.sup.10O--, (xv) R.sup.10R.sup.11N--, (xvi) R.sup.10R.sup.11NS(O).sub.2--, (xvii) R.sup.10S(O).sub.2NR.sup.11--, (xviii) R.sup.10R.sup.11NC(O)NH--, (xix) R.sup.10S--, (xx) R.sup.10S(O)--, (xxi) R.sup.10S(O).sub.2--, (xxii) R.sup.10C(O)--, (xxiii) C.sub.1-C.sub.9heterocyclyl- optionally substituted by C.sub.1-C.sub.6alkyl- or C.sub.1-C.sub.6hydroxylalkyl-, (xxiv) C.sub.1-C.sub.6hydroxylalkyl-, (xxv) and perfluoro(C.sub.1-C.sub.6)alkyl-; (e) C.sub.1-C.sub.6hydroxylalkyl-; (f) C.sub.1-C.sub.9heterocyclyl-; (g) C.sub.6-C.sub.14aryl- optionally substituted with from 1 to 3 substituents independently selected from: (i) C.sub.1-C.sub.6alkyl- optionally substituted with H.sub.2N--, (ii) heterocyclyl(C.sub.1-C.sub.6alkyl)-, (iii) halogen, (iv) hydroxyl, (v) H.sub.2N--, (vi) O.sub.2N--, (vii) H.sub.2NSO.sub.2--, (viii) HO.sub.2C--, (ix) (C.sub.1-C.sub.6alkoxy)carbonyl-, (x) (C.sub.1-C.sub.6alkoxy)C(O)NH--, (xi) (C.sub.1-C.sub.6alkyl)amino-, (xii) di(C.sub.1-C.sub.6alkyl)amino-, (xiii) R.sup.10R.sup.11NC(O)--, (xiv) R.sup.10O--, (xv) R.sup.10R.sup.11N--, (xvi) R.sup.10R.sup.11NS(O).sub.2--, (xvii) R.sup.10S(O).sub.2NR.sup.11--, (xviii) R.sup.10R.sup.11NC(O)NH--, (xix) R.sup.10S--, (xx) R.sup.10S(O)--, (xxi) R.sup.10S(O).sub.2--, (xxii) R.sup.10C(O)--, (xxiii) C.sub.1-C.sub.9heterocyclyl- optionally substituted by C.sub.1-C.sub.6alkyl- or C.sub.1-C.sub.6hydroxylalkyl-, (xxiv) C.sub.1-C.sub.6hydroxylalkyl-, (xxv) and perfluoro(C.sub.1-C.sub.6)alkyl-; (h) or C.sub.3-C.sub.8cycloalkyl-; R.sup.10 and R.sup.11 are each independently H, C.sub.1-C.sub.6alkoxy-, C.sub.1-C.sub.6alkyl-, C.sub.1-C.sub.6alkoxy(C.sub.2-C.sub.6alkylene)-, (C.sub.1-C.sub.6alkyl)amino-C.sub.2-C.sub.6alkylene-, di(C.sub.1-C.sub.6alkyl)amino-C.sub.2-C.sub.6alkylene-, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.6-C.sub.14aryl-, (C.sub.6-C.sub.14aryl)alkyl-, C.sub.3-C.sub.8cycloalkyl-, C.sub.1-C.sub.9heteroaryl-, (C.sub.1-C.sub.9heteroaryl)alkyl-, C.sub.1-C.sub.9heterocyclyl- optionally substituted by C.sub.1-C.sub.6alkyl-, or heterocyclyl(C.sub.1-C.sub.6alkyl-); or R.sup.10 and R.sup.11, when taken together with the nitrogen to which they are attached, form a 3- to 7- membered heterocycle wherein up to two of the carbon atoms of the heterocycle are optionally replaced with --N(H)--, --N(C.sub.1-C.sub.6alkyl)-, --N(C.sub.3-C.sub.8cycloalkyl)-, --N(C.sub.6-C.sub.14aryl)-, --N(C.sub.1-C.sub.9heteroaryl)-, --S--, --SO--, --S(O).sub.2--, or --O-- and wherein any carbon atom of the heterocycle is optionally substituted with from 1 or 2 substituents independently selected from C.sub.1-C.sub.6alkyl-, H.sub.2N--, (C.sub.1-C.sub.6alkyl)amino-, di(C.sub.1-C.sub.6alkyl)amino-, and C.sub.1-C.sub.9heterocyclyl-; R.sup.7 and R.sup.8 are each independently selected from: (a) H; (b) C.sub.1-C.sub.6alkyl- optionally substituted with from 1 to 3 substituents independently selected from: (i) C.sub.1-C.sub.8acyl- (ii) C.sub.1-C.sub.6alkoxy- optionally substituted with --NH.sub.2, (iii) (C.sub.1-C.sub.6alkoxy)carbonyl-, (iv) H.sub.2N--, (v) (C.sub.1-C.sub.6alkyl)amino-, (vi) di(C.sub.1-C.sub.6alkyl)amino-, (vii) (C.sub.1-C.sub.6alkyl)carboxyamido-, optionally substituted with A) H.sub.2N--, B) (C.sub.1-C.sub.6alkyl)amino-, C) or di(C.sub.1-C.sub.6alkyl)amino-, (viii) C.sub.6-C.sub.14aryl-, (ix) C.sub.3-C.sub.8cycloalkyl- (x) halogen, (xi) C.sub.1-C.sub.9heterocyclyl- optionally substituted by C.sub.1-C.sub.6alkyl-, (xii) HO.sub.2C--, (xiii) NC--, (xiv) R.sup.10C(O)NR.sup.11--, (xv) R.sup.10R.sup.11NC(O)--, (xvi) and C.sub.1-C.sub.9heteroaryl-; (c) C.sub.1-C.sub.6alkoxy-; (d) C.sub.1-C.sub.9heteroaryl- optionally substituted with from 1 to 3 substituents independently selected from: (i) C.sub.1-C.sub.6alkoxy- optionally substituted with A) H.sub.2N--, B) (C.sub.1-C.sub.6alkyl)amino-, C) di(C.sub.1-C.sub.6alkyl)amino-, D) C.sub.1-C.sub.9heterocyclyl- optionally substituted by C.sub.1-C.sub.6alkyl-, E) and hydroxyl, (ii) (C.sub.1-C.sub.6alkoxy)carbonyl-, (iii) (C.sub.1-C.sub.6alkoxy)C(O)NH--, (iv) C.sub.1-C.sub.6alkyl- optionally substituted with A) H.sub.2N--, B) (C.sub.1-C.sub.6alkyl)amino-, C) or di(C.sub.1-C.sub.6alkyl)amino-, (v) (C.sub.1-C.sub.6alkyl)amino-, (vi) di(C.sub.1-C.sub.6alkyl)amino-, (vii) (C.sub.1-C.sub.6alkyl)amido- optionally substituted with A) H.sub.2N--, B) (C.sub.1-C.sub.6alkyl)amino-, C) or di(C.sub.1-C.sub.6alkyl)amino-, (viii) (C.sub.1-C.sub.6alkyl)carboxyamido-, (ix) C.sub.1-C.sub.9heterocyclyl- optionally substituted by C.sub.1-C.sub.6alkyl- or C.sub.1-C.sub.6hydroxylalkyl-, (x) heterocyclyl(C.sub.1-C.sub.6alkyl)- optionally substituted by C.sub.1-C.sub.6alkyl-, (xi) halogen, (xii) hydroxyl, (xiii) C.sub.1-C.sub.6hydroxylalkyl-, (xiv) perfluoro(C.sub.1-C.sub.6)alkyl-, (xv) H.sub.2N--, (xvi) O.sub.2N--, (xvii) H.sub.2NSO.sub.2--, (xviii) HO.sub.2C--, (xix) NC--, (xx) R.sup.10R.sup.11NC(O)--, (xxi) R.sup.10R.sup.11NNHC(O)--, (xxii) R.sup.10O--, (xxiii) R.sup.10R.sup.11N--, (xxiv) R.sup.10R.sup.11NS(O).sub.2--, (xxv) R.sup.10S(O).sub.2NR.sup.11--, (xxvi) R.sup.10R.sup.11NC(O)NH--, (xxvii) R.sup.10S--, (xxviii) R.sup.10S(O)--, (xxix) R.sup.10S(O).sub.2--, (xxx) and R.sup.10C(O)--; (e) C.sub.1-C.sub.6hydroxylalkyl-; (f) C.sub.1-C.sub.9heterocyclyl- optionally substituted with from 1 to 3 substituents independently selected from: (i) C.sub.1-C.sub.6alkyl-, (ii) heterocyclyl(C.sub.1-C.sub.6alkyl)-, (iii) (C.sub.6-C.sub.14aryl)alkyl-, (iv) C.sub.1-C.sub.6acyl-, (v) (C.sub.1-C.sub.6alkoxy)carbonyl-, (vi) (C.sub.1-C.sub.6alkyl)carboxyl-, (vii) halogen, (viii) C.sub.1-C.sub.6haloalkyl-, (ix) hydroxyl, (x) C.sub.1-C.sub.6hydroxyalkyl-, (xi) H.sub.2N--, (xii) (C.sub.1-C.sub.6alkyl)amino-, (xiii) di(C.sub.1-C.sub.6alkyl)amino-, (xiv) HO.sub.2C--, (xv) (C.sub.1-C.sub.6alkoxy)carbonyl-, (xvi) (C.sub.1-C.sub.6alkyl)carboxyl-, (xvii) (C.sub.1-C.sub.6alkyl)amido-, (xviii) H.sub.2NC(O)--, (xix) (C.sub.1-C.sub.6alkyl)carboxyamido-, (xx) and --NO.sub.2; (g) C.sub.6-C.sub.14aryl- optionally substituted with from 1 to 3 substituents independently selected from: (i) C.sub.1-C.sub.6alkoxy- optionally substituted with A) H.sub.2N--, B) (C.sub.1-C.sub.6alkyl)amino-, C) di(C.sub.1-C.sub.6alkyl)amino-, D) C.sub.1-C.sub.9heterocyclyl- optionally substituted by C.sub.1-C.sub.6alkyl-, E) and hydroxyl, (ii) (C.sub.1-C.sub.6alkoxy)carbonyl-, (iii) (C.sub.1-C.sub.6alkoxy)C(O)NH--, (iv) C.sub.1-C.sub.6alkyl- optionally substituted with A) H.sub.2N--, B) (C.sub.1-C.sub.6alkyl)amino-, C) or di(C.sub.1-C.sub.6alkyl)amino-, (v) (C.sub.1-C.sub.6alkyl)amino-, (vi) di(C.sub.1-C.sub.6alkyl)amino-, (vii) (C.sub.1-C.sub.6alkyl)amido- optionally substituted with A) H.sub.2N--, B) (C.sub.1-C.sub.6alkyl)amino-, C) or di(C.sub.1-C.sub.6alkyl)amino-, (viii) (C.sub.1-C.sub.6alkyl)carboxyamido-, (ix) C.sub.1-C.sub.9heterocyclyl- optionally substituted by C.sub.1-C.sub.6alkyl- or C.sub.1-C.sub.6hydroxylalkyl-, (x) heterocyclyl(C.sub.1-C.sub.6alkyl)- optionally substituted by C.sub.1-C.sub.6alkyl-, (xi) halogen, (xii) hydroxyl, (xiii) C.sub.1-C.sub.6hydroxylalkyl-, (xiv) perfluoro(C.sub.1-C.sub.6)alkyl-, (xv) H.sub.2N--, (xvi) O.sub.2N--, (xvii) H.sub.2NSO.sub.2--, (xviii) HO.sub.2C--, (xix) NC--, (xx) R.sup.10R.sup.11NC(O)--, (xxi) R.sup.10R.sup.11NNHC(O)--, (xxii) R.sup.10O--, (xxiii) R.sup.10R.sup.11N--, (xxiv) R.sup.10R.sup.11NS(O).sub.2--, (xxv) R.sup.10S(O).sub.2NR.sup.11--, (xxvi) R.sup.10R.sup.11NC(O)NH--, (xxvii) R.sup.10S--, (xxviii) R.sup.10S(O)--, (xxix) R.sup.10S(O).sub.2--, (xxx) and R.sup.10C(O)--; (h) and C.sub.3-C.sub.8cycloalkyl- optionally substituted with from 1 to 3 substituents independently selected from: (i) C.sub.1-C.sub.6alkyl- optionally substituted with halogen, (ii) (C.sub.1-C.sub.6alkoxy)carbonyl-, (iii) (C.sub.1-C.sub.6alkyl)amido-, (iv) (C.sub.1-C.sub.6alkyl)carboxyamido-, (v) (C.sub.1-C.sub.6alkyl)carboxyl-, (vi) C.sub.1-C.sub.6alkoxy-, (vii) H.sub.2N--, (viii) (C.sub.1-C.sub.6alkyl)amino-, (ix) di(C.sub.1-C.sub.6alkyl)amino-, (x) hydroxyl, (xi) H.sub.2NC(O)--, (xii) HO.sub.2C--, (xiii) and --NO.sub.2; wherein any two hydrogen atoms on the same carbon atom of the C.sub.3-C.sub.8cycloalkyl- ring can be replaced by an oxygen atom to form an oxo (.dbd.O) substituent, and wherein any two hydrogen atoms on the same carbon atom of the C.sub.3-C.sub.8cycloalkyl- ring can be replaced by an alkylenedioxy group so that the alkylenedioxy group, when taken together with the carbon atom to which it is attached, forms a 5- to 7-membered heterocycle containing two oxygen atoms; or R.sup.7 and R.sup.8, when taken together with the nitrogen to which they are attached, form a 3- to 7- membered heterocycle wherein up to two of the carbon atoms of the heterocycle are optionally replaced with --N(H)--, --N(C.sub.1-C.sub.6alkyl)-, --N(C.sub.6-C.sub.14aryl)-, --S--, --SO--, --S(O).sub.2--, or --O--; R.sup.9 is C.sub.1-C.sub.6alkyl-, C.sub.6-C.sub.14aryl-, (C.sub.6-C.sub.14aryl)alkyl- optionally substituted by H.sub.2N--, C.sub.1-C.sub.9heterocyclyl- optionally substituted by C.sub.1-C.sub.6alkyl-, C.sub.3-C.sub.8cycloalkyl-, C.sub.1-C.sub.6hydroxylalkyl-, or C.sub.1-C.sub.6perfluoroalkyl-; R.sup.4 is: a) hydrogen; b) C.sub.1-C.sub.6acyl-; c) C.sub.1-C.sub.6alkyl-; d) H.sub.2N-- optionally substituted with C.sub.1-C.sub.9heterocycle, e) (C.sub.1-C.sub.6alkyl)amino- optionally substituted with (C.sub.1-C.sub.6alkyl)SO.sub.2--, f) di(C.sub.1-C.sub.6alkyl)amino- optionally substituted with (C.sub.1-C.sub.6alkyl)SO.sub.2--, g) (C.sub.1-C.sub.6alkyl)amino-C.sub.1-C.sub.6alkylene-, h) di(C.sub.1-C.sub.6alkyl)amino-C.sub.1-C.sub.6alkylene-, i) amino(C.sub.1-C.sub.6alkyl)-; j) C.sub.3-C.sub.8cycloalkyl-; k) C.sub.6-C.sub.14aryl- optionally substituted with a substituent selected from: i) HO.sub.2C--, ii) C.sub.1-C.sub.6hydroxylalkyl-, iii) R.sup.12R.sup.13NC(O)--, iv) and (C.sub.1-C.sub.6alkoxy)carbonyl-; l) C.sub.1-C.sub.9heterocycle optionally substituted with C.sub.1-C.sub.6alkyl-; m) (C.sub.1-C.sub.6heteroaryl)alkyl-; n) heterocyclyl(C.sub.1-C.sub.6alkyl)-; o) (C.sub.6-C.sub.14aryl)alkyl-; p) heterocyclyl(C.sub.1-C.sub.6alkyl); q) (C.sub.1-C.sub.6heteroaryl)alkyl-; r) (C.sub.6-C.sub.14aryl)alkyl-; s) C.sub.1-C.sub.6hydroxylalkyl-; t) C.sub.1-C.sub.6perfluoroalkyl-; u) C.sub.1-C.sub.9heteroaryl- optionally substituted with a substituent selected from: i) HO.sub.2C--, ii) C.sub.1-C.sub.6hydroxylalkyl-, iii) R.sup.12R.sup.13NC(O)--, iv) and (C.sub.1-C.sub.6alkoxy)carbonyl-; v) R.sup.3C(O)--N(R.sup.2)--Ar--; w) R.sup.12R.sup.13NC(O)--; x) R.sup.14OC(O)--; y) or R.sup.14S(O).sub.2--; R.sup.5 is: a) hydrogen; b) C.sub.1-C.sub.6acyl-; c) C.sub.1-C.sub.6alkyl-; d) amino(C.sub.1-C.sub.6alkyl)-; e) C.sub.3-C.sub.8cycloalkyl-; f) C.sub.6-C.sub.14aryl- optionally substituted with a substituent selected from: i) HO.sub.2C--, ii) C.sub.1-C.sub.6hydroxylalkyl-, iii) R.sup.12R.sup.13NC(O)--, iv) and (C.sub.1-C.sub.6alkoxy)carbonyl-; g) halogen; h) C.sub.1-C.sub.9heterocycle optionally substituted with C.sub.1-C.sub.6alkyl-; i) (C.sub.1-C.sub.9heteroaryl)alkyl-; j) heterocyclyl(C.sub.1-C.sub.6alkyl)-; k) (C.sub.6-C.sub.14aryl)alkyl-; l) heterocyclyl(C.sub.1-C.sub.6alkyl); m) (C.sub.1-C.sub.9heteroaryl)alkyl-; n) (C.sub.6-C.sub.14aryl)alkyl-; o) C.sub.1-C.sub.6hydroxylalkyl-; p) C.sub.1-C.sub.6perfluoroalkyl-; q) C.sub.1-C.sub.9heteroaryl- optionally substituted with a substituent selected from: i) HO.sub.2C--, ii) C.sub.1-C.sub.6hydroxylalkyl-, iii) R.sup.12R.sup.13NC(O)--, iv) and (C.sub.1-C.sub.6alkoxy)carbonyl-; r) R.sup.12R.sup.13NC(O)--; s) R.sup.14OC(O)--; t) or R.sup.14S(O).sub.2--; R.sup.12 and R.sup.13 are each independently H, C.sub.1-C.sub.6alkyl-, C.sub.3-C.sub.8cycloalkyl-, C.sub.6-C.sub.14aryl-, C.sub.1-C.sub.9heteroaryl-, (C.sub.1-C.sub.9heteroaryl)alkyl-, heterocyclyl(C.sub.1-C.sub.6alkyl)-, (C.sub.6-C.sub.14aryl)alkyl-, or C.sub.1-C.sub.9heterocyclyl- optionally substituted by C.sub.1-C.sub.6alkyl-; or R.sup.12 and R.sup.13, when taken together with the nitrogen to which they are attached, form a 3- to 7- membered heterocycle wherein up to two of the carbon atoms of the heterocycle are optionally replaced with --N(H)--, --N(C.sub.1-C.sub.6alkyl)-, --N(C.sub.6-C.sub.14aryl)-, --S--, --SO--, --S(O).sub.2--, or --O--; R.sup.14 is C.sub.1-C.sub.6alkyl-, C.sub.6-C.sub.14aryl-, (C.sub.6-C.sub.14aryl)alkyl-, C.sub.1-C.sub.9heterocyclyl- optionally substituted by C.sub.1-C.sub.6alkyl-, C.sub.3-C.sub.8cycloalkyl-, C.sub.1-C.sub.6hydroxylalkyl-, or C.sub.1-C.sub.6perfluoroalkyl-. 2. A compound of claim 1 of the Formula II: ##STR00051## or a pharmaceutically acceptable salt thereof. 3. A compound of claim 2 of the Formula III: ##STR00052## or a pharmaceutically acceptable salt thereof. 4. A compound of claim 2 of the Formula IV: ##STR00053## or a pharmaceutically acceptable salt thereof. 5. A compound of claim 1 of the Formula V: ##STR00054## or a pharmaceutically acceptable salt thereof. 6. A compound of claim 5 of the Formula VI: ##STR00055## or a pharmaceutically acceptable salt thereof. 7. A compound of claim 1 wherein p is 0. 8. A compound of claim 1 wherein R.sup.2 is H. 9. A compound of claim 1 wherein R.sup.3 is R.sup.7R.sup.8N--. 10. A compound of claim 9 wherein R.sup.7 is 4-pyridyl-. 11. A compound of claim 1 wherein R.sup.8 is H. 12. A compound of claim 1 wherein R.sup.4 is C.sub.1-C.sub.9heterocyclyl-. 13. A compound of claim 1 wherein R.sup.5 is H. 14. A compound of claim 1 selected from the group consisting of: 1-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-(isopropylamino)pyrimid- in-2-yl]phenyl}-3-pyridin-4-ylurea; 1-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-(isopropylamino)pyrimid- in-2-yl]phenyl}-3-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}urea; 1-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-(isopropylamino)pyrimid- in-2-yl]phenyl}-3-[4-(4-methylpiperazin-1-yl)phenyl]urea; 1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-{4-[4-(3,7-dioxa-9-azabicyclo[3.3- .1]non-9-yl)-6-(isopropylamino)pyrimidin-2-yl]phenyl}urea; 1-methyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-phenylpyrimidin-2-- yl]phenyl}urea; 2-hydroxyethyl {4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-phenylpyrimidin-2-yl]phenyl}c- arbamate; 1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-(8-oxa-3-azabicyclo- [3.2.1]oct-3-yl)-6-phenylpyrimidin-2-yl]phenyl}urea; 1-ethyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-phenylpyrimidin-2-y- l]phenyl}urea; 1-cyclopropyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-phenylpyrimid- in-2-yl]phenyl}urea; 1-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-phenylpyrimidin-2-yl]phenyl- }-3-pyridin-4-ylurea; 1-[4-(hydroxymethyl)phenyl]-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6- -phenylpyrimidin-2-yl]phenyl}urea; 1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]o- ct-3-yl)-6-phenylpyrimidin-2-yl]phenyl}urea; 2-hydroxyethyl {4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl]phenyl}carbamate; 1-methyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl]phenyl- }urea; 1-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl]phenyl}-3- -pyridin-4-ylurea; 1-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-ylpyrimidin-2-yl)phenyl]-3-me- thylurea; 1-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-ylpyrimidin-2-yl)phe- nyl]-3-pyridin-4-ylurea; 1-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-ylpyrimidin-2-yl)phenyl]-3-[4- -(4-methylpiperazin-1-yl)phenyl]urea; 1-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-ylpyrimidin-2-yl)phenyl]-1-et- hyl-3-pyridin-4-ylurea; 1-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-ylpyrimidin-2-yl)phenyl]-1-et- hyl-3-[4-(4-methylpiperazin-1-yl)phenyl]urea; bis(2-hydroxyethyl) {[6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidine-2,4-diyl]di-4,1-phenyle- ne}biscarbamate; N',N'''-{[6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidine-2,4-diyl]di-4,1- -phenylene}bis(1-methylurea); N',N'''-{[6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidine-2,4-diyl]di-4,1- -phenylene}bis(1-ethylurea); N',N'''-{[6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidine-2,4-diyl]di-4,1- -phenylene}bis(1-cyclopropylurea); N,N''-{[6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidine-2,4-diyl]di-4,1-p- henylene}bis(3-pyridin-3-ylurea); N,N''-{[6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidine-2,4-diyl]di-4,1-p- henylene}bis(3-pyridin-4-ylurea); N',N'''-{[6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidine-2,4-diyl]di-4,1- -phenylene}bis{1-[4-(4-methylpiperazin-1-yl)phenyl]urea}; 4,4'-{[6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidine-2,4-diyl]bis(4,1-p- henylenecarbamoylimino)}dibenzamide; 1-methyl-3-{4-[4-(1-methylethoxy)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)py- rimidin-2-yl]phenyl}urea; 1-cyclopropyl-3-{4-[4-(1-methylethoxy)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-- yl)pyrimidin-2-yl]phenyl}urea; 1-{4-[4-(1-methylethoxy)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2- -yl]phenyl}-3-pyridin-4-ylurea; 1-{4-[4-(1-methylethoxy)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2- -yl]phenyl}-3-[4-(4-methylpiperazin-1-yl)phenyl]urea; 1-methyl-3-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3- -yl)pyrimidin-2-yl}phenyl)urea; 1-cyclopropyl-3-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]- oct-3-yl)pyrimidin-2-yl}phenyl)urea; 1-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrim- idin-2-yl}phenyl)-3-pyridin-4-ylurea; 1-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrim- idin-2-yl}phenyl)-3-[4-(4-methylpiperazin-1-yl)phenyl]urea; N.about.3.about.,N.about.3.about.-dimethyl-N-(4-[(1-methylethyl)amino]-6-- (8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-2-{4-[(pyridin-3-ylcarbamoyl)amino]phe- nyl}pyrimidin-5-yl)-beta-alaninamide; 1-methyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(trifluoromethyl)p- yrimidin-2-yl]phenyl}urea; 1-cyclopropyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(trifluoromet- hyl)pyrimidin-2-yl]phenyl}urea; 2-hydroxyethyl {4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(trifluoromethyl)pyrimidin-2-- yl]phenyl}carbamate; 1-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(trifluoromethyl)pyrimidin-- 2-yl]phenyl}-3-pyridin-4-ylurea; 1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oc- t-3-yl)-6-(trifluoromethyl)pyrimidin-2-yl]phenyl}urea; tert-butyl methyl(4-{[(4-{4-[(methylsulfonyl)methyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct- -3-yl)pyrimidin-2-yl}phenyl)carbamoyl]amino}benzyl)carbamate; 1-methyl-3-(4-{4-[(methylsulfonyl)methyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct- -3-yl)pyrimidin-2-yl}phenyl)urea; 1-ethyl-3-(4-{4-[(methylsulfonyl)methyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-- 3-yl)pyrimidin-2-yl}phenyl)urea; 1-cyclopropyl-3-(4-{4-[(methylsulfonyl)methyl]-6-(8-oxa-3-azabicyclo[3.2.- 1]oct-3-yl)pyrimidin-2-yl}phenyl)urea; 1-(4-{4-[(methylsulfonyl)methyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyr- imidin-2-yl}phenyl)-3-phenylurea; 1-(4-{4-[(methylsulfonyl)methyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyr- imidin-2-yl}phenyl)-3-pyridin-3-ylurea; 1-(4-{4-[(methylsulfonyl)methyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyr- imidin-2-yl}phenyl)-3-pyridin-4-ylurea; 1-[4-(4-methylpiperazin-1-yl)phenyl]-3-(4-{4-[(methylsulfonyl)methyl]-6-(- 8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phenyl)urea; 1-(4-{4-[(methylsulfonyl)methyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyr- imidin-2-yl}phenyl)-3-(4-piperazin-1-ylphenyl)urea; 1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-(4-{4-[(methylsulfonyl)methyl]-6-- (8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phenyl)urea; 1-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}-3-(4-{4-[(methylsulfonyl)met- hyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phenyl)urea; 1-{4-[(methylamino)methyl]phenyl}-3-(4-{4-[(methylsulfonyl)methyl]-6-(8-o- xa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phenyl)urea; 1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)phenyl]-3-py- ridin-4-ylurea; 1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-[4-(4,6-di-3-oxa-8-azabicyclo[3.2- .1]oct-8-ylpyrimidin-2-yl)phenyl]urea; 1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)phenyl]-3-[4- -(4-methylpiperazin-1-yl)phenyl]urea; 1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)phenyl]-3-{4- -[(4-methylpiperazin-1-yl)methyl]phenyl}urea; 1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)phenyl]-3-{4- -[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea; 1-{4-[4-(isopropylamino)-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2- -yl]phenyl}-3-pyridin-4-ylurea; 1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-{4-[4-(isopropylamino)-6-(3-oxa-8- -azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phenyl}urea; 1-{4-[4-(isopropylamino)-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2- -yl]phenyl}-3-[4-(4-methylpiperazin-1-yl)phenyl]urea; 1-{4-[4-(isopropylamino)-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2- -yl]phenyl}-3-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}urea; 1-{4-[4-(isopropylamino)-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2- -yl]phenyl}-3-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]urea; 1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)phenyl]-3-py- ridin-3-ylurea; 1-[4-(5-chloro-4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)phe- nyl]-3-pyridin-3-ylurea; 1-[4-(5-chloro-4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)phe- nyl]-3-[4-(4-methylpiperazin-1-yl)phenyl]urea; 1-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-ylam- ino)pyrimidin-2-yl]phenyl}-3-pyridin-4-ylurea; 1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oc- t-8-yl)-6-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-2-yl]phenyl}urea; 1-{4-[4-{[2-(methylsulfonyl)ethyl]amino}-6-(3-oxa-8-azabicyclo[3.2.1]oct-- 8-yl)pyrimidin-2-yl]phenyl}-3-pyridin-3-ylurea; 1-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}-3-{4-[4-{[2-(methylsulfonyl)- ethyl]amino}-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phenyl}ur- ea; 1-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-y- lamino)pyrimidin-2-yl]phenyl}-3-pyridin-3-ylurea; 1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]o- ct-8-yl)-6-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-2-yl]phenyl}urea; 1-{4-[4-{[2-(methylsulfonyl)ethyl]amino}-6-(3-oxa-8-azabicyclo[3.2.1]oct-- 8-yl)pyrimidin-2-yl]phenyl}-3-pyridin-4-ylurea; 1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-{4-[4-{[2-(methylsulfonyl)ethyl]a- mino}-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phenyl}urea; 1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-{[2-(methylsulfonyl)ethyl]am- ino}-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phenyl}urea; 1-{4[(4-methylpiperazin-1-yl)methyl]phenyl}-3-{4-[4-(3-oxa-8-azabicyclo[3- .2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-2-yl]phenyl}urea- ; 1-{4-[4-(diethylamino)-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-- yl]phenyl}-3-pyridin-4-ylurea; 1-{4-[4-(diethylamino)-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-y- l]phenyl}-3-[4-(4-methylpiperazin-1-yl)phenyl]urea; 1-(4-{4-[(1-methylethyl)amino]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrim- idin-2-yl}phenyl)-3-[4-(pyrrolidin-1-ylmethyl)phenyl]urea; 1-(4-{4-[(1-methylethyl)amino]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrim- idin-2-yl}phenyl)-3-pyridin-3-ylurea; 1-{4-[(dimethylamino)methyl]phenyl}-3-(4-{4-[(1-methylethyl)amino]-6-(3-o- xa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)urea; 1-(4-{4-[(1-methylethyl)amino]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrim- idin-2-yl}phenyl)-3-[4-(2-pyrrolidin-1-ylethoxy)phenyl]urea; 1-(4-{4-[(dimethylamino)methyl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyri- midin-2-yl}phenyl)-3-pyridin-3-ylurea; 1-(4-{4-[(dimethylamino)methyl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyri- midin-2-yl}phenyl)-3-methylurea; 1-(4-{4-[(dimethylamino)methyl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyri- midin-2-yl}phenyl)-3-ethylurea; 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((dimethylamino)methyl)py- rimidin-2-yl)phenyl)-3-cyclopropylurea; 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((dimethylamino)methyl)py- rimidin-2-yl)phenyl)-3-(4-(4-methyl piperazin-1-yl)phenyl)urea; 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((dimethylamino)methyl)py- rimidin-2-yl)phenyl)-3-(4-(2-(dimethylamino)ethoxy)phenyl)urea; 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((dimethylamino)methyl)py- rimidin-2-yl)phenyl)-3-(4-((dimethylamino)methyl)phenyl)urea; 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((dimethylamino)methyl)py- rimidin-2-yl)phenyl)-3-phenylurea; 1-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-yl)p- yrimidin-2-yl]phenyl}-3-pyridin-3-ylurea; 1-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-yl)p- yrimidin-2-yl]phenyl}-3-pyridin-4-ylurea; 1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oc- t-8-yl)-6-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-yl]phenyl}urea; 1-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-3-{4-[4-(3-oxa-8-azabicyclo[3.- 2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-yl]phenyl}urea; 1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-{4-[4-(3-oxa-8-azabicycl- o[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-yl]phenyl}urea; 1-(4-{[4-(1-methylethyl)piperazin-1-yl]carbonyl}phenyl)-3-{4-[4-(3-oxa-8-- azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-yl]phen- yl}urea; 1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-{4-[4-(3-oxa-8-azabicyclo- [3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-yl]phenyl}urea; 1-(4-{4-[(3R)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-y- l)pyrimidin-2-yl}phenyl)-3-pyridin-4-ylurea; 1-(4-{4-[(3R)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-y- l)pyrimidin-2-yl}phenyl)-3-[4-(4-methylpiperazin-1-yl)phenyl]urea; 1-(4-{4-[(3R)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-y- l)pyrimidin-2-yl}phenyl)-3-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]urea; 1-(4-{4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]- oct-8-yl)pyrimidin-2-yl}phenyl)-3-pyridin-4-ylurea; 1-(4-{4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]- oct-8-yl)pyrimidin-2-yl}phenyl)-3-[4-(4-methylpiperazin-1-yl)phenyl]urea; 1-(4-{4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]- oct-8-yl)pyrimidin-2-yl}phenyl)-3-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]- urea; 1-(4-{4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3- .2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-{4-[(4-methylpiperazin-1-yl)carbony- l]phenyl}urea; 1-(4-{4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]- oct-8-yl)pyrimidin-2-yl}phenyl)-3-(4-{[4-(1-methylethyl)piperazin-1-yl]car- bonyl}phenyl)urea; 1-(4-{4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-6-(3-oxa-8-azabicycl- o[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-pyridin-4-ylurea; 1-[4-(4-methylpiperazin-1-yl)phenyl]-3-(4-{4-[(1S,4S)-2-oxa-5-azabicyclo[- 2.2.1]hept-5-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}pheny- l)urea; 1-{4-[(dimethylamino)methyl]phenyl}-3-(4-{4-[(1S,4S)-2-oxa-5-azabi- cyclo[2.2.1]hept-5-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl- }phenyl)urea; 1-(4-{4-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-6-(3-oxa-8-azabicycl- o[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-pyridin-4-ylurea; 1-[4-(4-methylpiperazin-1-yl)phenyl]-3-(4-{4-[(1R,4R)-2-oxa-5-azabicyclo[- 2.2.1]hept-5-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}pheny- l)urea; 1-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}-3-(4-{4-[(1R,4R)-2-ox- a-5-azabicyclo[2.2.1]hept-5-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrim- idin-2-yl}phenyl)urea; 1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-(4-{4-[(1R,4R)-2-oxa-5-azabicyclo- [2.2.1]hept-5-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phen- yl)urea; 1-(4-{4-[(3R)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1- ]oct-8-yl)pyrimidin-2-yl}phenyl)-3-pyridin-3-ylurea; 1-(4-{4-[(3R)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-y- l)pyrimidin-2-yl}phenyl)-3-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}urea; 1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-(4-{4-[(3R)-3-methylmorpholin-4-y- l]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)urea; N,N-dimethyl-4-{[(4-{4-[(3R)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicycl- o[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)carbamoyl]amino}benzamide; 1-(4-{4-[(3R)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-y- l)pyrimidin-2-yl}phenyl)-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}ure- a; 1-(4-{[4-(1-methylethyl)piperazin-1-yl]carbonyl}phenyl)-3-(4-{4-[(3R)-3- -methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl- }phenyl)urea; 1-(4-{4-[(dimethylamino)methyl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyri- midin-2-yl}phenyl)-3-methylurea; 1-[4-(2,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-ylpyrimidin-4-yl)phenyl]-3-me- thylurea; 1-[4-(2,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-ylpyrimidin-4-yl)phe- nyl]-3-pyridin-4-ylurea; 1-[4-(2,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-ylpyrimidin-4-yl)phenyl]-3-[4- -(4-methylpiperazin-1-yl)phenyl]urea; 1-cyclopropyl-3-[4-(2,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-ylpyrimidin-4-y- l)phenyl]urea; 4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl]aniline; 4-[4-chloro-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl]aniline; 4-[2-chloro-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-4-yl]aniline; 8,8'-[2-(4-nitrophenyl)pyrimidine-4,6-diyl]bis(3-oxa-8-azabicyclo[3.2.1]o- ctane); 4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)aniline; 4-{4-[(methylsulfonyl)methyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimi- din-2-yl}aniline; 4-(5-chloro-4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)anilin- e; 9-(6-chloro-2-(4-nitrophenyl)pyrimidin-4-yl)-3,7-dioxa-9-azabicyclo[3.3- .1]nonane; 6-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-N-isopropyl-2-(4-ni- trophenyl)pyrimidin-4-amine; 2-(4-aminophenyl)-6-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-N-isopropyl- pyrimidin-4-amine; 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-2-(4-nitrophenyl)-N-(tetrahydro-2- H-pyran-4-yl)pyrimidin-4-amine; 2-(4-aminophenyl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-(tetrahydro-2- H-pyran-4-yl)pyrimidin-4-amine; 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-(2-(methylsulfonyl)ethyl)-2-(4-- nitrophenyl)pyrimidin-4-amine; 2-(4-aminophenyl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-(2-(methylsul- fonyl)ethyl)pyrimidin-4-amine; 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N,N-diethyl-2-(4-nitrophenyl)pyri- midin-4-amine; 2-(4-aminophenyl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N,N-diethylpyri- midin-4-amine; 4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((dimethylamino)methyl)pyrim- idin-2-yl)aniline; 8-[6-(3,6-dihydro-2H-pyran-4-yl)-2-(4-nitrophenyl)pyrimidin-4-yl]-3-oxa-8- -azabicyclo[3.2.1]octane; and 4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-yl)pyri- midin- 2-yl]aniline. 15. A composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier. 16. A composition comprising a compound of claim 1; a second compound selected from the group consisting of a topoisomerase I inhibitor, procarbazine, dacarbazine, gemcitabine, capecitabine, methotrexate, taxol, taxotere, mercaptopurine, thioguanine, hydroxyurea, cytarabine, cyclophosphamide, ifosfamide, nitrosoureas, cisplatin, carboplatin, mitomycin, dacarbazine, procarbizine, etoposide, teniposide, campathecins, bleomycin, doxorubicin, idarubicin, daunorubicin, dactinomycin, plicamycin, mitoxantrone, L-asparaginase, doxorubicin, epirubicin, 5-fluorouracil, docetaxel, paclitaxel, leucovorin, levamisole, irinotecan, estramustine, etoposide, nitrogen mustards, BCNU, carmustine, lomustine, vinblastine, vincristine, vinorelbine, cisplatin, carboplatin, oxaliplatin, imatinib mesylate, Avastin (bevacizumab), hexamethylmelamine, topotecan, tyrosine kinase inhibitors, tyrphostins, herbimycin A, genistein, erbstatin, lavendustin A, hydroxyzine, glatiramer acetate, interferon beta-1a, interferon beta-1b, and natalizumab and lavendustin A; and a pharmaceutically acceptable carrier. 17. The composition of claim 16, wherein the second compound is Avastin. 18. The compound of claim 1 used for treating breast cancer.

Details for Patent 8,835,429

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Recordati Rare Diseases, Inc.	ELSPAR	asparaginase	For Injection	101063	01/10/1978		2029-04-17
Bayer Healthcare Pharmaceuticals Inc.	BETASERON	interferon beta-1b	For Injection	103471	07/23/1993		2029-04-17
Biogen Inc.	AVONEX	interferon beta-1a	For Injection	103628	05/17/1996		2029-04-17
Biogen Inc.	AVONEX	interferon beta-1a	Injection	103628	05/28/2003		2029-04-17