3-substituted-1h-indole, 3-substituted-1h-pyrrolo[2,3-b]pyridine and 3-substituted-1h-pyrrolo[3,2-b]pyridine compounds, their use as mtor kinase and pi3 kinase inhibitors, and their syntheses

A compound of Formula 1:

• or a geometric isomer thereof, or a pharmaceutically acceptable salt thereof, wherein:
• A is oxygen or sulfur;
• . . . represents an optional second carbon-to-carbon bond;
• D is C—R6 or N;
• E is C—R9 or N;
• R1, R2, R3, and R4 are each independently H;
• C1-C6alkoxy optionally substituted with from 1 to 3 substituents independently selected from —NH2, (C1-C6alkyl)NH—, and (C1-C6alkyl)(C1-C6alkyl)N—;
• C1-C6alkyl;
• (C1-C6alkoxy)carbonyl;
• R12R13N—;
• R12R13NC(O)NH—;
• R12C(O)NH—;
• R14OC(O)NH—;
• halo;
• OR20;
• or hydroxyl;
• wherein at least one of R1-R4 is OR20, wherein each R29 is independently selected from C(O)R12, CO2R12, CONR12R13, P(O)(OR12)(OR13), P(O)R12(OR13), C(R12R13)OR14, and C(R12R13)NR14R21;
• with the proviso that R12 cannot be H when R29 is C(O)R12 or CO2R12;
• R12, R13, R14 and R21 are each independently H;
• C1-C6alkyl optionally substituted with from 1 to 3 substituents independently selected from OH, —NH2, (C1-C6alkyl)NH—, (C1-C6alkyl)(C1-C6alkyl)N—, C6-C10 aryl, (C1-C6alkyl)oxycarbonyl, and C1-C9 heteroaryl;
• perfluoro(C1-C6)alkyl;
• C1-C9heteroaryl optionally substituted with from 1 to 3 substituents independently selected from C1-C6alkyl, halo, and perfluoro(C1-C6)alkyl;
• C8-C14aryl optionally substituted with from 1 to 3 substituents independently selected from C1-C6alkyl, halo, and perfluoro(C1-C8)alkyl;
• C2-C8 heterocyclyl;
• or C3-C8cycloalkyl;
• or when R29 is CONR12R13, R12 and R13 taken together with the N they are attached to form a 3-10 membered heterocyclyl with 1-3 hetero atoms selected from N, O and S, wherein the 3-10 membered heterocyclyl is optionally substituted with 1-3 substituents selected from straight or branched C1-C6alkyl optionally substituted with fluorine, C6-C14aryl, C3-C8 cycloalkyl, C3-C8 heterocyclyl, CN, ═O, NO2, (CH2)n—, O(C1-C6alkyl), (CH2)n—, —NH2, (C1-C6alkyl)NH—(CH2)n—, and (C1-C6alkyl)(C1-C6alkyl)N—(CH2)n—;
• wherein n is 0 or 1;
• R5 is H;
• C1-C6alkyl;
• C6-C14aryl;
• C3-C8cycloalkyl;
• halo;
• C1-C9heteroaryl;
• C1-C6heterocyclylalkyl;
• C1-C6 perfluoroalkyl-;
• R15R16NC(O)—;
• (C1-C6alkoxy)carbonyl;
• or CO2H;
• R15 and R16 are each independently H;
• C1-C6alkyl optionally substituted with from 1 to 3 substituents independently selected from —NH2, (C1-C6alkyl)NH—, (C1-C6alkyl)(C1-C6alkyl)N—, and C1-C9heteroaryl;
• C1-C9heteroaryl;
• C6-C14aryl optionally substituted with from 1 to 3 substituents independently selected from C1-C6alkyl, halo, and perfluoro(C1-C6)alkyl;
• or C3-C8cycloalkyl;
• or R15 and R16 when taken together with the nitrogen to which they are attached can form a 3- to 7-membered nitrogen containing heterocycle wherein up to two of the carbon atoms of the heterocycle can be replaced with —N(H)—, —N(C1-C6alkyl)-, —N(C6-C14aryl)-, —S—, —SO—, —S(O)2—, or —O—;
• R6—R9 are each independently:
• (a) H;
• (b) C1-C6alkoxy-;
• (c) C1-C6alkyl-optionally substituted by C6-C14aryl-;
• (d) C2-C6alkenyl-optionally substituted by C6-C14aryl-;
• (e) C2-C6alkynyl-optionally substituted by C6-C14aryl-;
• (f) (C1-C6alkyl)amido-;
• (g) C1-C6alkylcarboxy-;
• (h) (C1-C6alkyl)carboxyamido-;
• (i) (C1-C6alkyl)SO2—;
• (j) C6-C14aryl-optionally substituted with from 1 to 3 substituents independently selected from:
• (i) C1-C6acyl-, (ii) C1-C6alkyl-, which is optionally substituted with from 1 to 3 substituents independently selected from:
• A) H2N—, B) (C1-C6alkyl)NH—, C) (C1-C6alkyl)(C1-C6alkyl)N—, and D) C1-C9heterocyclyl-, (iii) (C1-C6alkyl)amido-, (iv) (C1-C6alkyl)carboxy-, (v) (C1-C6alkyl)carboxyamido-, (vi) C1-C6alkoxy-optionally substituted by C1-C6alkoxy or C1-C9heteroaryl, (vii) (C1-C6alkoxy)carbonyl-, (viii) (C6-C14aryl)oxy-, (ix) C3-C8cycloalkyl-, (x) halo, (xi) C1-C6haloalkyl-, (xii) C1-C9heterocyclyl-optionally substituted by C1-C6alkyl- or C1-C6hydroxylalkyl-, (xiii) hydroxyl, (xiv) C1-C6hydroxylalkyl-, (xv) C1-C6 perfluoroalkyl-, (xvi) C1-C6 perfluoroalkyl-O—, (xvii) R17R18N—, (xviii) NC—, (xix) HOOC—, (xx) R17R18NC(O)—, (xxi) R17C(O)NH—, (xxii) R17R18NS(O)2— (xxiii) R17R18NC(O)NH—, (xxiv) R19OC(O)NH—, (xxv) (C1-C6alkyl)S(O)2NH—, (xxvi) R19S(O)2—, (xxvii) —C(═N—(OR17))—(NR17R18), and (xxviii) O2N—;
• (k) (C6-C14aryl)alkyl-O—;
• (l) halo;
• (m) O1—C9heteroaryl optionally substituted with from 1 to 3 substituents independently selected from:
• (i) O1—C8acyl-, (ii) O1—C6alkyl-, which is optionally substituted with from 1 to 3 substituents independently selected from:
• A) H2N—, B) (C1-C6alkyl)NH—, C) (C1-C6alkyl)(C1-C6alkyl)N—, and D) C1-C9heterocyclyl-, (iii) (C1-C6alkyl)amido-, (iv) (C1-C6alkyl)carboxy, (v) (C1-C6alkyl)carboxyamido-, (vi) C1-C6alkoxy-optionally substituted by C1-C6alkoxy- or C1-C9heteroaryl-, (vii) (C1-C6alkoxy)carbonyl-, (viii) (C6-C14aryl)oxy-, (ix) C3-C8cycloalkyl-, (x) halo, (xi) C1-C6haloalkyl-, (xii) C1-C9heterocyclyl-optionally substituted by C1-C6alkyl- or C1-C6hydroxylalkyl-, (xiii) hydroxyl, (xiv) C1-C6hydroxylalkyl-, (xv) C1-C6 perfluoroalkyl-, (xvi) C1-C6 perfluoroalkyl-O—, (xvii) R17R18N—, (xviii) NC—, (xix) HOOC—, (xx) R17R18NC(O)—, (xxi) R17C(O)NH—, (xxii) R17R18NS(O)2— (xxiii) R17R18NC(O)NH—, (xxiv) R19OC(O)NH—, (xxv) (C1-C6alkyl)S(O)2NH—, (xxvi) R19S(O)2—, (xxvii) —C(═N—(OR17))—(NR17R18), and (xxviii) O2N—;
• (n) hydroxyl;
• (o) C1-C9 heterocyclyl-optionally substituted by:
• (i) C1-C6alkyl-, which is optionally substituted with from 1 to 3 substituents independently selected from:
• A) H2N—, B) (C1-C6alkyl)NH—, and C) (C1-C6alkyl)(C1-C6alkyl)N—, (ii) R17R18NC(O)—, (iii) hydroxyl, or (iv) R17R18N—;
• (p) C1-C6 perfluoroalkyl-;
• (q) NC—;
• (r) (C1-C6alkoxy)carbonyl-;
• (s) HOOC—;
• or (t) O2N—;
• R17 and R18 are each independently H;
• C1-C6alkyl optionally substituted with from 1 to 3 substituents independently selected from C1-C6alkoxy, —NH2, (C1-C6alkyl)NH—, (C1-C6alkyl)(C1-C6alkyl)N—, C6-C14aryl, and C1-C9heteroaryl;
• C1-C9heteroaryl;
• C6-C14aryl optionally substituted with from 1 to 3 substituents independently selected from C1-C6alkyl, halo, and perfluoro(C1-C6)alkyl;
• or C3-C8cycloalkyl;
• or R17 and R18 when taken together with the nitrogen to which they are attached can form a 3- to 7-membered nitrogen containing heterocycle wherein up to two of the carbon atoms of the heterocycle can be replaced with —N(H)—, —N(C1-C6alkyl)-, —N(C6-C14aryl)-, —S—, —SO—, —S(O)2—, or —O—;
• R19 is C1-C6alkyl or C6-C14aryl;
• or R7 and R8 when taken together can be replaced by an alkylenedioxy group so that the alkylenedioxy group, when taken together with the two carbon atoms to which it is attached, forms a 5- to 7-membered heterocycle containing two oxygen atoms;
• R19 is H;
• C1-C6alkyl optionally substituted with from 1 to 3 substituents independently selected from halogen, —NH2, (C1-C6alkyl)NH—, (C1-C6alkyl)(C1-C6alkyl)N—, —N(C1-C3alkyl)C(O)(C1-C6alkyl), —NHC(O)(C1-C6alkyl), —NHC(O)H, —C(O)NH2, —C(O)N(C1-C6alkyl)(C1-C6alkyl), —CN, hydroxyl, C1-C6alkoxy, C1-C6alkyl, —C(O)OH, —C(O)O(C1-C6alkyl), —C(O)(C1-C6alkyl), O6—C14aryl, C1-C9heteroaryl, C3-C8cycloalkyl, C1-C6haloalkyl-, C1-C6-aminoalkyl-, —OC(O)(C1-C6alkyl), C1-C6-carboxyamidoalkyl-, NO2, and C1-C9heterocyclyl-, each C1-C9heterocyclyl-optionally substituted with C1-C6alkyl;
• C2-C10 alkenyl;
• C6-C14aryl;
• C3-C8cycloalkyl;
• C1-C9heteroaryl;
• or C1-C6heterocyclylalkyl group optionally substituted with from 1 to 3 substituents independently selected from halogen, —NH2, (C1-C6alkyl)NH—, (C1-C6alkyl)(C1-C6alkyl)N—, —N(C1-C3alkyl)C(O)(C1-C6alkyl), —NHC(O)(C1-C6alkyl), —NHC(O)H, —C(O)NH2, —C(O)NH(C1-C6alkyl), —C(O)N(C1-C6alkyl)(C1-C6alkyl), —CN, hydroxyl, C1-C6hydroxylalkyl-, C1-C6alkoxy, O1—C6alkyl, —C(O)OH, —C(O)O(C1-C6alkyl), —C(O)(C1-C6alkyl), 4- to 7-membered monocyclic heterocycle, C6-C14aryl C1-C9heteroaryl, C1-C6heterocyclylalkyl, and C3-C8cycloalkyl;
• or R5 and R19 taken together with the atoms connecting them form a fused C5-C8 heterocyclic ring containing 2-3 hetero atoms selected from N, O, and S, and optionally substituted with halogen, hydroxy, O—C1-C6 alkoxy, CN, ═O, C1-C6alkyl, NO2, NH2, NHC1-C6alkyl, N(C1-C6alkyl)2, C(O)C1-C6alkyl, CO2C1-C6alkyl, CONH2, CONHC1-C6alkyl, or CON(C1-C6alkyl)2;
• and
• R11 is H or C1-C6alkyl.