Macrocyclic compounds as protein kinase inhibitors

Abstract

There is provided compounds of formula I, wherein R1, R.sup.2a, R.sup.2b, R.sup.2c, X, Y, Z, R.sup.3 and ring A/B have meanings given in the description, and pharmaceutically-acceptable esters, amides, solvates or salts thereof, which compounds are useful in the treatment of diseases in which inhibition of a protein or lipid kinase (e.g. PI3-K, particularly class I PI3K, PIM family kinase and/or mTOR) is desired and/or required, and particularly in the treatment of cancer. The invention also relates to combinations containing such compounds. ##STR00001##

Claims

1. A method of treatment of a cancer, by administering to a patient suffering from, or susceptible to the cancer, wherein the cancer is selected from the group consisting of bladder cancer, breast cancer, colon cancer, liver cancer, lung cancer, ovary cancer, pancreatic cancer, stomach cancer, cervical cancer, prostate cancer, squamous cell carcinoma, glioblastoma, melanoma, colon-rectum cancer, oral cancer, B-cell lymphoma, T-cell-lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, Burkett's lymphoma; hematopoietic tumors of myeloid lineage, and tumors of the central and peripheral nervous system, which method comprises administration of a therapeutically effective amount of a compound of formula I: ##STR00757## wherein: ring A and ring B represent a fused bicyclic group of any one of the following formulae: ##STR00758## wherein in formula IA: W.sup.1a is CH, CF or N; W.sup.2a is CH, CF or N; W.sup.3a is CR.sup.4a or N; W.sup.4a is CR.sup.5a or N; W.sup.5a is CR.sup.6a or N; in formula IB: W.sup.1b is CH, CF or N; W.sup.2b is CH, CF or N; W.sup.3b is CR.sup.4b or N; W.sup.4b is C or N; W.sup.5b is CR.sup.6b or N; W.sup.6b is C or N; W.sup.7b is C or N, and wherein when W.sup.3b represents N, W.sup.4b and W.sup.6b represent C and W.sup.5b represents C or N, then R* is hydrogen (in all other cases R* is absent); in formula IC: W.sup.1c is CH, CR.sup.t1, N, NR.sup.q1, O or S; W.sup.2c is CH, CR.sup.t2, N, NR.sup.q2, O or S; W.sup.3c is C or N; W.sup.4c is CR.sup.5c or N; W.sup.5c is CR.sup.6c or N; W.sup.6C is C or N; in formula ID: W.sup.1d is CH, CR.sup.t3, N, NR.sup.q3, O or S; W.sup.2d is CH, CR.sup.t4, N, NR.sup.q4, O or S; W.sup.3d is C or N; W.sup.4d is CR.sup.5d or N; W.sup.5d is C or N; W.sup.6d is C or N; each R.sup.t1, R.sup.t2, R.sup.t3, and R.sup.t4 is independently selected from halo, C.sub.1-3 alkyl or C.sub.3 cycloalkyl, a 3- to 5-membered heterocycloalkyl group, —OR.sup.s1, —CN, —N(R.sup.s2)R.sup.s3, —S(O).sub.w1 CH.sub.3 or —C(O)CH.sub.3; w1 represents 0, 1 or 2; each R.sup.s1, R.sup.s2 and R.sup.3s independently represent hydrogen or C.sub.1-2 alkyl; each R.sup.q1, R.sup.q2, R.sup.q3 and R.sup.q4 is independently selected from C.sub.1-3 alkyl or C.sub.3 cycloalkyl, a 3- to 5-membered heterocycloalkyl group or —C(O)CH.sub.3; each R.sup.1, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.3, R.sup.4a, R.sup.5a, R.sup.6a, R.sup.4b, R.sup.6b, R.sup.5c, R.sup.6c, and R.sup.5d are independently selected from hydrogen or a substituent selected from halo, —CN, —C(O)N(R.sup.f1)R.sup.f2, —C(O)R.sup.f3, —N(R.sup.f4)R.sup.f5, —C(O)OR.sup.f6, —OR.sup.f7, —OC(O)—R.sup.f8, —S(O).sub.w2CH.sup.3, C.sub.1-8 alkyl, C.sub.3-8 cycloalkyl and a 3- to 8-membered heterocycloalkyl groups, which latter three groups are optionally substituted by one or more substituents selected from ═O and E.sup.1; w2 represents 0, 1 or 2; R.sup.f1, R.sup.f2, R.sup.f4, R.sup.f5 and R.sup.f7 independently represent hydrogen, C.sub.1-6 alkyl or C.sub.3-6 cycloalkyl optionally substituted by one or more substituents selected from ═O and E.sup.2; or R.sup.f1 and R.sup.f2 and/or R.sup.f4 and R.sup.f5 may be linked together to form a 4- to 8- membered ring optionally substituted by one or more substituents selected from C.sub.1-3 alkyl, C.sub.3 cycloalkyl and halo; R.sup.f3, R.sup.f6 and R.sup.f8 independently represent C.sub.1-6 alkyl or C.sub.3-6 cycloalkyl optionally substituted by one or more substituents selected from ═O and E.sup.2; X represents a direct bond, —C(R.sup.a)(R.sup.b)—, —O—, —S—, —N(R.sup.c)—, —N(R.sup.d)C(O)—, —C(O)N(R.sup.e)—or —N(R.sup.f)—C(O)—N(R.sup.g)—; Y represents -arylene-, -heteroarylene- (which latter two groups are optionally substituted by one or more substituents selected from E.sup.3), -heterocycloalkylene- or —C.sub.1-12alkylene- (which latter two groups are optionally substituted by one or more substituents selected from ═O and E.sup.4); R.sup.N represents hydrogen or C.sub.1-6 alkyl optionally substituted by one or more substituents selected from ═O and E.sup.5; Z represents -(A.sup.x).sub.1-7-, wherein each A.sup.x independently represents —C(R.sup.x1)(R.sup.x2)—, —N(R.sup.x3)—, —C(O)—, —O—, —S—, —S(O)— or —S(O).sub.2—; R.sup.x1, R.sup.x2 and R.sup.x3 each independently represent hydrogen or a substituent selected from E.sub.x; each E.sub.x independently represents halo, —C(O)R.sup.y1, —N(R.sup.y2)—C(O)—N(R.sup.y3)(R.sup.y4), C.sub.1-6 alkyl or heterocycloalkyl (both of which latter two groups are optionally substituted by one or more halo atoms); R.sup.y1, R.sup.y2, R.sup.y3 and R.sup.y4 each independently represent hydrogen or C.sub.1-3 alkyl optionally substituted by one or more halo atoms; each R.sup.a, R.sup.b, R.sup.c, R.sup.d, R.sup.e, R.sup.f and R.sup.g independently represent hydrogen, C.sub.1-6 alkyl or C.sub.3-6 cycloalkyl optionally substituted by one or more halo atoms; each E.sup.1, E.sup.2, E.sup.3, E.sup.4 and E.sup.5 independently represents, on each occasion when used herein: (i) Q.sup.4; (ii) C.sub.1-12 alkyl or C.sub.3-12 cycloalkyl or heterocycloalkyl, each of which is optionally substituted by one or more substituents selected from ═O and Q.sup.5; any two E.sup.1, E.sup.2, E.sup.3, E.sup.4 and/or E.sup.5 groups, may be linked together to form a 3- to 12-membered ring, optionally containing one or more unsaturations, and which ring is optionally substituted by one or more substituents selected from ═O and J.sup.1; each Q.sup.4 and Q.sup.5 independently represent, on each occasion when used herein: halo, —CN, —N(R.sup.20)R.sup.21, —OR.sup.20, —C(═Y.sup.1)—R.sup.20, —C(═Y.sup.1)—OR.sup.20, —C(═Y.sup.1)N(R.sup.20)R.sup.21, —C(═Y.sup.1)N(R.sup.20)—O—R.sup.21a, —OC(═Y.sup.1)—R.sup.20, —OC(═Y.sup.1)—OR.sup.20, —OC(═Y.sup.1)N(R.sup.20)R.sup.21, —OS(O).sub.2OR.sup.20, —OP(═Y.sup.1)(OR.sup.20)(OR.sup.21), —OP(OR.sup.20)(OR.sup.21), —N(R.sup.22)C(═Y.sup.1)R.sup.21, —N(R.sup.22)C(═Y.sup.1)OR.sup.21, —N(R.sup.22)C(═Y.sup.1)N(R.sup.20)R.sup.21, —NR.sup.22S(O).sub.2 R.sup.20, —NR.sup.22S(O).sub.2N(R.sup.20)R.sup.21, —S(O).sub.2N(R.sup.20)R.sup.21, —SC(═Y.sup.1)R.sup.20, —SC(═Y.sup.1)OR.sup.20, —SC(═Y.sup.1)N(R.sup.20)R.sup.21, —S(O).sub.2R.sup.20, —SR.sup.20, —S(O)R.sup.20, —S(O).sub.2OR.sup.20, C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl or heterocycloalkyl (which latter three groups are optionally substituted by one or more substituents selected from ═O and J.sup.2); each Y.sup.1 independently represents, on each occasion when used herein, ═O, ═S, ═NR.sup.23 or ═N—CN; each R.sup.21a represents C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl or heterocycloalkyl (which latter three groups are optionally substituted by one or more substituents selected from J.sup.4 and ═O); each R.sup.20, R.sup.21, R.sup.22 and R.sup.23 independently represent, on each occasion when used herein, hydrogen, C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl or heterocycloalkyl (which latter three groups are optionally substituted by one or more substituents selected from J.sup.4 and ═O); or any relevant pair of R.sup.20, R.sup.21 and R.sup.22, may be linked together to form a 4- to 20- membered ring, optionally containing one or more heteroatoms, optionally containing one or more unsaturations, and which ring is optionally substituted by one or more substituents selected from J.sup.6 and ═O; each J.sup.1, J.sup.2, J.sup.4 and J.sup.6 independently represents, on each occasion when used herein: (i) Q.sup.7; (ii) C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl or heterocycloalkyl, each of which is optionally substituted by one or more substituents selected from ═O and Q.sup.8; each Q.sup.7 and Q.sup.8 independently represents, on each occasion when used herein: halo, —CN, —N(R.sup.50)R.sup.51, —OR.sup.50, —C(═Y.sup.a)—R.sup.50, —C(═Y.sup.a)—OR.sup.50, —C(═Y.sup.a)N(R.sup.50)R.sup.51, —N(R.sup.52)C(═Y.sup.a)R.sup.51, —NR.sup.52S(O).sub.2R.sup.50, —S(O).sub.2N(R.sup.50)R.sup.51, —N(R.sup.52)—C(═Y.sup.a)—N(R.sup.50)R.sup.51, —S(O).sub.2R.sup.50, —SR.sup.50, —S(O)R.sup.50, C.sub.l-6 alkyl or C.sub.3-6 cycloalkyl (optionally substituted by one or more fluoro atoms) or heterocycloalkyl (optionally substituted by one or more substituents selected from halo, —OR.sup.60 and —N(R.sup.61)R.sup.62); each Y.sup.a independently represents, on each occasion when used herein, ═O, ═S, ═NR.sup.53 or ═N—CN; each R.sup.50, R.sup.51, R.sup.52 and R.sup.53 independently represents, on each occasion when used herein, hydrogen, C.sub.1-6 alkyl, or C.sub.3-6 cycloalkyl optionally substituted by one or more substituents selected from fluoro, —OR.sup.60 and —N(R.sup.61)R.sup.62; or any relevant pair of R.sup.50, R.sup.51 and R.sup.52 may be linked together to form, a 3- to 8-membered ring, optionally containing one or more heteroatoms, optionally containing one or more unsaturations, and which ring is optionally substituted by one or more substituents selected from ═O and C.sub.1-3 alkyl; R.sup.60, R.sup.61 and R.sup.62 independently represent hydrogen, C.sub.1-6 alkyl, or C.sub.3-6 cycloalkyl optionally substituted by one or more fluoro atoms; wherein any heterocycloalkyl group may be selected from non-aromatic monocyclic and bicyclic heterocycloalkyl groups in which one to four of the atoms in the ring system is a heteroatom selected from N, O or S, and in which the total number of atoms in the ring system is from five to ten, wherein the heterocycloalkyl group may be bridged, and wherein the heterocycloalkyl group may be saturated or unsaturated containing one or more double and/or triple bonds, wherein any heteroaryl group may be selected from an aromatic group containing one to four heteroatom(s) selected from N, O or S, wherein the heteroaryl group comprises five to ten atoms in the ring system, and wherein the heteroaryl group is monocyclic, bicyclic or tricyclic, provided that at least one of the rings is aromatic, and that when the heteroaryl group is bicyclic or tricyclic it is linked to the rest of the molecule via an aromatic ring, or a pharmaceutically acceptable salt thereof.

2. A method as claimed in claim 1, wherein the cancer is astrocytoma.

3. A method as claimed in claim 1, wherein the cancer is acute myelogenous leukemias.

4. A method as claimed in claim 1, wherein the cancer is non-small cell lung cancer.

5. A method as claimed in claim 1, wherein the cancer is non-Hodgkin's lymphoma.

6. A method as claimed in claim 1, wherein ring A and ring B represents a fused bicyclic group of the following structure (optional substituents are not shown): ##STR00759##

7. A method as claimed in claim 1, wherein Y represents arylene, heteroarylene, heterocycloalkylene or C.sub.1-6alkylene, all of which groups are optionally substituted by one of the following groups: ##STR00760##

8. A method as claimed in claim 1, wherein X represents —N(R.sup.c)— or a direct bond; and/or Z represents —C(O)-[T.sup.1]- or —C(O)N(R.sup.x3)-[T.sup.1]-, in which T.sup.1 represents —(CH.sub.2).sub.0-4-T.sup.2- and T.sup.2 represents a direct bond or —C(O)—N(H)—CH.sub.2—.

9. A method as claimed in claim 1, wherein the compound is selected from the following: ##STR00761## ##STR00762## ##STR00763## ##STR00764## ##STR00765## ##STR00766## ##STR00767## ##STR00768## ##STR00769## ##STR00770## ##STR00771## ##STR00772## ##STR00773## ##STR00774## ##STR00775## ##STR00776## ##STR00777## ##STR00778## ##STR00779## ##STR00780## ##STR00781## ##STR00782##

Description

EXAMPLES

(1) The following Examples illustrate the invention.

Experimental Part

(2) Hereinafter, the term “DCM” means dichloromethane, “MeOH” means methanol, “THF” means tetrahydrofuran, “DMF” means dimethylformamide, “DME” means 1,2-dimethoxyethane, “EtOAc” means ethyl acetate, “BOP” means (Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate, “HOAt” means 1-hydroxy-7-azabenzotriazole, “PyBOP” means (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate, “DMAP” means 4-dimethylaminopyridine, “HATU” means O-(7-azabenzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, “Pd(PPh.sub.3).sub.4” means tetrakis(triphenylphosphine)palladium, “PdCl.sub.2(dppf)-DCM” means 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride, dichloromethane, “DIPEA” means diisopropylethylamine, “TFA” means trifluoroacetic acid, “min” means minutes, “h” means hours, “RT” means room temperature, “eq” means equivalents, “nBuOH” means n-butanol, “mw” means microwave.

(3) General Procedure

(4) NMR spectra were recorded in a Bruker Avance II 300 spectrometer and Bruker Avance II 700 spectrometer fitted with 5 mm QXI 700 S4 inverse phase, Z-gradient unit and variable temperature controller.

(5) The HPLC measurements were performed using a HP 1100 from Agilent Technologies comprising a pump (binary) with degasser, an autosampler, a column oven, a diode-array detector (DAD) and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector was configured with an electrospray ionization source or API/APCI. Nitrogen was used as the nebulizer gas. Data acquisition was performed with ChemStation LC/MSD quad, software.

(6) Method 1

(7) Reversed phase HPLC was carried out on a Gemini-NX C18 (100×2.0 mm; 5 um).

(8) Solvent A: water with 0.1% formic acid; Solvent B: acetonitrile with 0.1% formic acid. Gradient: 5% to 100% of B within 8 min at 50° C., DAD.

(9) Method 2

(10) Reversed phase HPLC was carried out on a Gemini-NX C18 (100×2.0 mm; 5 um).

(11) Solvent A: water with 0.1% formic acid; Solvent B: acetonitrile with 0.1% formic acid. Gradient: 5% to 40% of B within 8 min at 50° C., DAD.

(12) Method 3

(13) Reversed phase HPLC was carried out on a Gemini-NX C18 (100×2.0 mm; 5 um).

(14) Solvent A: water with 0.1% formic acid; Solvent B: acetonitrile with 0.1% formic acid. Gradient: 0% to 30% of B within 8 min at 50° C., DAD.

(15) Method 4

(16) Reversed phase HPLC was carried out on a Gemini C18 column (50×2 mm, 3 urn).

(17) Solvent A: water with 0.1% formic acid; Solvent B: acetonitrile with 0.1% formic acid. Gradient: 10% to 95% of B within 4 min at 50° C., DAD.

(18) Method 5

(19) Reversed phase HPLC was carried out on a Gemini C18 column (50×2 mm, 3 um). Solvent A: water with 0.1% formic acid; Solvent B: acetonitrile with 0.1% formic acid. Gradient: 0% to 30% of B within 4 min at 50° C., DAD.

(20) “Found mass” refers to the most abundant isotope detected in the HPLC-MS.

(21) The compound names given herein may be generated in accordance with IUPAC using the AutoNom naming program in MDL ISIS Draw.

Preparation of Intermediates

(22) The synthesis of the some intermediates may have already been described in international patent applications WO2009/040552, WO2008/150827 and WO 2010/112874.

Synthesis of Intermediate I-01

(23) ##STR00031##

(24) To a solution of (5-amino-6-methoxypyridin-3-yl)boronic acid pinacol ester (1.0 g, 3.99 mmol) in pyridine (13.3 mL) at 0° C. was added 3-(chlorosulfonyl)benzoic acid (1.11 g, 4.79 mmol). The reaction mixture was stirred at 0° C. for 3 h. The mixture was concentrated and the residue was purified by column chromatography (Biotage, cHex:EtOAc 100:0 to 0:100) to give Intermediate I-01 (1.15 g, 82%).

Synthesis of Intermediate 1-02

(25) ##STR00032##

(26) To a mixture of 5-bromo-2-chloro-3-nitropyridine (5 g, 21.06 mmol) in 2-propanol (60 mL) was added DBU (15.7 mL, 105.3 mmol). The reaction mixture was stirred at 50° C. for 17 h. After cooling to RT, 1N HCl was added and the mixture was concentrated under reduced pressure. Aqueous layer was extracted with EtOAc (×4). Combined organic layers were washed with 1N HCl, dried, filtered and evaporated. The residue was purified on silica gel (Biotage, cHex/EtOAc 100:0 to 90:10) to give Intermediate 1-02 (974 mg, 18%).

Synthesis of Intermediate 1-03

(27) ##STR00033##

(28) To a solution of Intermediate I-02 (978 mg, 3.75 mmol) in a 4:1 mixture of acetic acid/water (10 mL) was added Iron (628 mg, 11.24 mmol). The reaction mixture was stirred at RT for 4 h. EtOAc was added, and the mixture was filtered through a plug of celite. The filtrate was basified by addition of 5N NaOH. The mixture was extracted with EtOAc (×3) and the combined organic layers were dried, filtered and evaporated. The residue was purified on silica gel (Biotage, cHex/EtOAc 100:0, 80:20) to obtain Intermediate I-03 (338 mg, 39%).

Synthesis of Intermediate I-04

(29) ##STR00034##

(30) To a mixture of Intermediate I-03 (338 mg, 1.46 mmol), bis(pinacolato)diboron (446 mg, 1.75 mmol) and KOAc (431 mg, 4.39 mmol) in 1,4-dioxane/DMF (2 mL/0.2 mL) was added PdCl.sub.2(dppf). DCM (121 mg, 0.15 mmol). The reaction mixture was heated under microwave conditions at 150° C. for 10 min. On cooling, the mixture was filtered through a column of silica gel (isolute Si II, 5 g) with a pad of celite on its top eluting with EtOAc. The filtrate was evaporated and the residue was purified on silica gel (Biotage, cHex/EtOAc 90:10 to 0:100) to obtain Intermediate I-04 (169 mg, 42%).

Synthesis of Intermediate I-05

(31) ##STR00035##

(32) A mixture of methyl 3-aminothiophene-2-carboxylate (1 g, 6.362 mmol) and acetonitrile (0.50 mL, 9.542 mmol) in HCl (4M in 1,4-dioxane, 12.70 mL) was placed into a sealed tube and left under sonication at RT for 4 h. The reaction mixture was then heated at 100° C. for 16 h. More HCl (4M in 1,4-dioxane, 2 mL) and CH.sub.3CN (0.25 mL) were added and the mixture was heated at 100° C. for 2 h. NaOH (5 N, 12 mL) was added and the mixture was refluxed for 30 min. On cooling, H.sub.2O was added and the mixture was extracted with EtOAc. The combined organic layers were dried (Na.sub.2SO.sub.4), filtered and concentrated to give Intermediate I-05 (184 mg). The aqueous layer was evaporated under vacuum and the residue was triturated from H.sub.2O to give Intermediate I-05 (463 mg) as a pale yellow solid. Total yield: 61%.

Synthesis of Intermediate I-06

(33) ##STR00036##

(34) To acetic anhydride (18 mL) at 0° C. was added dropwise formic acid (12 mL) followed by the portionwise addition of methyl 3-amino-4-methylthiophene-2-carboxylate (5 g, 29.2 mmol). The reaction mixture was stirred at RT for 18 h. The mixture was poured into a solution of Na.sub.2CO.sub.3 (30 g) in water (100 mL) at 0° C. The resulting white solid was filtered off, washed with water and dried to give Intermediate I-06 (4.69 g, 81%) as a white solid.

(35) .sup.1H NMR (300 MHz, DMSO) δ 9.85 (s, 1H), 8.24 (s, 1H), 7.55 (s, 1H), 3.76 (s, 3H), 2.07 (s, 3H).

Synthesis of Intermediate I-07

(36) ##STR00037##

(37) A mixture of Intermediate I-06 (4.65 g, 23.25 mmol) and ammonium formate (10 g, 200 mmol) in formamide (6 mL) was heated at 160° C. for 18 h. On cooling, the resulting solid was filtered, washed with acetone and dried to give Intermediate I-07 (3.85 g, 99%) as a white solid.

(38) .sup.1H NMR (300 MHz, DMSO) δ 8.18 (s, 1H), 7.81 (d, J=0.7 Hz, 1H), 2.31 (d, J=0.9 Hz, 3H).

Synthesis of Intermediate I-08

(39) ##STR00038##

(40) A mixture of methyl 3-aminothiophene-2-carboxylate (2 g, 12.72 mmol) and isobutyronitrile (1.71 mL, 19.08 mmol) in HCl (4M in 1,4-dioxane, 25 mL) was placed into a seated tube and left under sonication at RT for 4 h. The reaction mixture was then heated at 100° C. for 16 h. More HCl (4M in 1,4-dioxane, 4 mL) and isobutyronitrile (0.9 mL) were added and the mixture was stirred at RT for 20 h. 5N NaOH (24 mL) was added and the mixture was refluxed for 1 h. The solvent was evaporated and H.sub.2O and 6N HCl were added to the residue. The resulting suspension was filtered off and washed with a lot of H.sub.2O and Et.sub.2O to give Intermediate I-08 (2.40 g, 97%).

(41) LC-MS: R.sub.t=2.64 min, [M+H].sup.+=195.0.

(42) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 11.76 (s, 1H), 7.82 (d, J=5.3 Hz, 1H), 7.36 (d, J=5.3 Hz, 1H), 3.09 (m, 1H), 1.43 (d, 6H).

Synthesis of Intermediate I-09

(43) ##STR00039##

(44) A solution of 5-cyano-4-methylthiophene-2-boronic acid (0.2 g, 1.20 mmol) in 7N NH.sub.3 in MeOH was hydrogenated in an H-cube apparatus (Raney Nickel, flow 1 mL/min, 50 bar, 50° C., recirculating mode) for 2 h 45 min. Solvent was evaporated under reduced pressure to give Intermediate I-09 (164 mg, 80%).

(45) Method A-1

Synthesis of Intermediate I-01

(46) ##STR00040##

(47) To a sealed tube charged with 6-Bromo-4-chloro-quinoline 1-00 (2.3 g, 9.48 mmol) in 1,4-dioxane (75 ml), 2-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridin-3-yl amine (2.85 g, 11.38 mmol), K.sub.2CO.sub.3 (aq. sol. 1M) (40 ml) and tetrakis(triphenylphosphine)palladium(0) (1.096 g, 0.948 mmol) were added. The reaction mixture was heated at 100° C. for 1 h. The mixture was concentrated and purified by flash chromatography in a Biotage using cyclohexane-EtOAc gradient to give intermediate I-01 (2.2 g, Y: 81%).

Synthesis of Intermediate II-01

(48) ##STR00041##

(49) To a solution of 2-Bromo-5-iodo-imidazo[2,1-b]-1,3,4-thiadiazole (0.55 g, 1.67 mmol) in 1,4-dioxane (9 mL), 2-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridin-3-yl amine (0.5 g, 2 mmol), Na.sub.2CO.sub.3 (aq. sol. 2M) (5 mL) and PdCl.sub.2(PPh.sub.3).sub.2 (117 mg, 0.167 mmol) were added. The reaction mixture was heated (sand bath) in a sealed tube at 110° C. for 2.5 h. On cooling, water was added and the suspension was filtered and rinsed with H.sub.2O and Et.sub.2O. The solid was purified through a path of silica (EtOAc:DCM 10:90 to 50:50) to give the intermediate II-01 (2.16 g, Y: 23%) as a beige solid.

Synthesis of Intermediate III-02

(50) ##STR00042##

(51) To a solution of 3-bromo-5-chloropyrazolo[1,5-a]pyrimidine (III-01) (0.5 g, 2.151 mmol) in DME (10 mL) was added (5-amino-6-methoxypyridin-3-yl)boronic acid pinacol ester (538 mg, 2.151 mmol), K.sub.2CO.sub.3 2M (3.3 mL, 6.452 mmol) and PdCl.sub.2(PPh.sub.3).sub.2 (45 mg, 0.065 mmol). The reaction mixture was heated in a sealed tube at 80° C. for 30 min. 3-(N-Boc-aminomethyl)pyridine-5-boronic acid pinacol ester (719 mg, 2.151 mmol) and PdCl.sub.2(PPh.sub.3).sub.2 (45 mg, 0.065 mmol) were added and the mixture was heated at 80° C. for 22 h. On cooling, the mixture was diluted with EtOAc and washed with brine. The organic layer was dried, filtered and evaporated. The residue was purified by flash chromatography in a Biotage using MeOH:DCM 4:96 to 10:90 gradient to give intermediate III-02 (545 mg, 56%) as a yellow solid.

Synthesis of Intermediate IV-02

(52) ##STR00043##

(53) To a solution of 3-bromo-6-chloroimidazo[1,2-b]pyridazine (IV-01) (450 mg, 1.936 mmol) in 1,4-dioxane (8 mL) was added 3-(N-Boc-aminomethyl)pyridine-5-boronic acid pinacol ester (679 mg, 2.033 mmol), aq. Na.sub.2CO.sub.3 2M (3 mL, 6 mmol) and PdCl.sub.2(PPh.sub.3).sub.2 (136 mg, 0.194 mmol). The resulting mixture was heated at 80° C. in a sealed tube for 8 h. On cooling, the mixture was diluted with DCM and water. Layers were separated and the aqueous phase was extracted twice with DCM. The combined organic extracts were dried (Na.sub.2SO.sub.4), filtered and concentrated. The residue was purified by flash chromatography (Biotage) using MeOH:DCM 0:100 to 20:80 as eluent to afford intermediate IV-02 (525 mg, 75%).

Synthesis of Intermediate VIII-18

(54) ##STR00044##

(55) To a solution of 4-chloro-6-iodothieno[3,2-d]pyrimidine VIII-01 (30 mg, 0.101 mmol) in 1,2-dioxane (0.81 mL) was added 3-aminopyridine-5-boronic acid, pinacol ester (27 mg, 0.121 mmol), K.sub.2CO.sub.3 1M (0.42 mL) and Pd(PPh.sub.3).sub.4 (12 mg, 0.010 mmol). The reaction mixture was heated at 100° C. for 1 h. Then 3-(N-Boc-aminomethyl)pyridine-5-boronic acid, pinacol ester (50 mg, 0.142 mmol), K.sub.2CO.sub.3 1M (0.42 mL) and Pd(PPh.sub.3).sub.4 (12 mg, 0.010 mmol) were added. The reaction mixture was heated at 100° C. for 1 h. On cooling, the mixture was concentrated and the residue was purified by column chromatography (Biotage, cHex:EtOAc 100:0 to 0:100 and EtOAc:MeOH 100:0 to 80:20) to give intermediate VIII-18 (17 mg, 39%).

(56) Method A-2

(57) ##STR00045##

(58) To a solution of the corresponding 2-methoxy-pyridin-3ylamine intermediate (1 eq.) in pyridine (10 mL/mmol) at 0° C. was added the required sulfonyl chloride (1.2 eq.). The reaction mixture was stirred at 0° C. for 1 h, MeOH was added and the mixture was evaporated. The residue was purified either by flash chromatography in a Biotage using MeOH:EtOAc gradient or by precipitation from MeOH to give the desired sulfonilated product.

Synthesis of Intermediate IX-10

(59) ##STR00046##

(60) A mixture of Intermediate IX-09 (0.7 g, 1.507 mmol), 3-chlorosulfonyl-benzoic acid (0.83 g, 3.773 mmol), pyridine (7 mL) and DCM (35 mL) was stirred at 40° C. overnight. Methanol (20 mL) was added to the reaction mixture. The mixture was concentrated and diluted into 20 mL of 1N NaOH at 0° C. The mixture was extracted with EtOAc. The aqueous phase was adjusted to pH=3 by 1N HCl and extracted with EtOAc. The organic phase was dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by flash chromatography to give Intermediate IX-10 (0.4 g, yield: 41%).

(61) Method A-3

(62) In a sealed tube charged with the halogenated starting material (1 eq.) in 1,4-dioxane (10 mL/mmol), the corresponding boronic acid (1.2 eq.), K.sub.2CO.sub.3 (aq. sol. 1M) (3 eq.) and tetrakis(triphenylphosphine)palladium(0) (0.1 eq.) were added. The reaction mixture was heated at 100° C. for 1-2 h. The mixture was concentrated and the crude was purified by flash chromatography in a Biotage using Cyclohexane/EtOAc followed by EtOAc/MeOH gradient to give the desired product.

Synthesis of Intermediate II-02

(63) ##STR00047##

(64) To a solution of intermediate II-01 (0.54 g, 1.44 mmol) in 1,4-dioxane (7.5 mL), 3-(n-boc-aminomethyl)pyridine-5-boronic acid pinacol ester (0.58 g, 1.73 mmol), Na.sub.2CO.sub.3 (aq. sol. 2M) (2.25 mL) and PdCl.sub.2(PPh.sub.3).sub.2 (102 mg, 0.144 mmol) were added. The reaction mixture was heated (sand bath) in a sealed tube at 110° C. for 2 h. On cooling, water was added and the suspension was filtered off and rinsed with H.sub.2O and Et.sub.2O to give intermediate 3-05 (0.412 g, Y: 63%). The aqueous phase was neutralised with HCl 25% and extracted with DCM. The organic phase was separated, dried (Na.sub.2SO.sub.4), filtered and evaporated. The residue was purified by flash chromatography in a Biotage (MeOH:DCM 2:98 to 10:90) to give intermediate II-02 (0.17 g, Y: 26%), global yield: 89%.

Synthesis of Intermediate VII-07

(65) ##STR00048##

(66) A mixture of intermediate VII-06 (3.76 g, 8.95 mmol), 2-methoxy-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-ylamine (2.35 g, 9.40 mmol), Na.sub.2CO.sub.3 (1.9 g, 17.9 mmol), Pd(dppf)Cl.sub.2 (0.36 g, 0.45 mmol) in H.sub.2O (8 mL) and DME (60 mL) was stirred at 120° C. under N.sub.2 overnight. The mixture was poured into ice water and extracted with EtOAc. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, and concentrated. The residue was purified by column chromatography to give the intermediate VII-07 (3.48 g, 84%).

Synthesis of Intermediate VII-10

(67) ##STR00049##

(68) A mixture of intermediate VII-01 (0.50 g, 2.06 mmol), {2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-ethyl}-carbamic acid tert-butyl ester (0.73 g, 2.16 mmol), Pd(dppf)Cl.sub.2 (84 mg, 0.10 mmol), and Na.sub.2CO.sub.3 (0.65 g, 6.17 mmol) in DME (8 mL) and H.sub.2O (2.5 mL) was heated under microwave irradiation at 140° C. for 40 min. The mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, and concentrated. The residue was purified by chromatography column on silica gel to give intermediate VII-10 (125 mg, 15%).

Synthesis of Intermediate VIII-09

(69) ##STR00050##

(70) To a mixture of Intermediate VIII-02 (2 g, 6.8 mmol), {2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-ethyl}-carbamic acid tert-butyl ester (2.2 g, 6.8 mmol) and K.sub.2CO.sub.3 (2.8 g, 20.4 mmol) in dioxane (20 mL) and H.sub.2O (10 mL) was added Pd(dppf)Cl.sub.2 (0.5 g, 0.7 mmol) under N.sub.2. The mixture was heated to 85° C. and stirred 2 h. The reaction mixture was cooled to RT, poured into water, and extracted with CH.sub.2Cl.sub.2 (50 mL×4). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by column chromatography to give Intermediate VIII-09 (1.7 g, 53%) as a yellow solid.

Synthesis of Intermediate XVII-03

(71) ##STR00051##

(72) A mixture of Intermediate XVII-02 (233 mg, 0.49 mmol), 5-(Boc-aminomethyl)thiophene-2-boronic acid (159 mg, 0.62 mmol), K.sub.3PO.sub.4 (178 mg, 0.80 mmol), tricyclohexylphosphine (28 mg, 0.11 mmol) and Pd(dba).sub.2 (47 mg) in degassed dioxane (10 mL) and water (0.6 mL) was heated for 3 h at 120° C. under microwave irradiation. On cooling, the mixture was evaporated and the residue was purified by column chromatography (hexanes/EtOAc, 90:10 to 0:100) to give the ester intermediate as a brown solid (205 mg). By eluting the column with EtOAc/MeOH 80:20 the acid Intermediate XVII-03 was obtained (50 mg).

(73) The ester (205 mg) was dissolved in EtOH (10 mL), the mixture was cooled to 0° C., 4N KOH (10 mL) was added and the mixture was stirred for 4 h at RT. The EtOH was carefully removed, water (5 mL) was added, and the mixture was cooled to 0° C. Acetic acid was added until the solution had a pH of ˜4, and the resulting solid was filtered, washed with water and dried to give the acid as a grey solid (183 mg). Both collected acids (50 mg+183 mg) were combined and purified by column chromatography (EtOAc/MeOH, 100:0 to 80:20) to give Intermediate XVII-03 as a brown solid (193 mg, 61%).

(74) Method A-4

Synthesis of Intermediate I-03

(75) ##STR00052##

(76) In a sealed tube charged with intermediate I-02 (250 mg, 0.532 mmol) in 1-methyl-2-pyrrolidinone (4.5 ml), 4-(tert-butoxycarbonylaminomethyl)piperidine (238 mg, 1.064 mmol) was added. The reaction mixture was heated at 150° C. for 1 h. The mixture was concentrated. The crude was purified by flash chromatography in a Biotage using Cyclohexane/AcOEt gradient followed by AcOEt/MeOH gradient to give intermediate I-03 (154 mg, Y: 45%).

Synthesis of Intermediate I-04

(77) ##STR00053##

(78) In a sealed tube charged with intermediate I-02 (260 mg, 0.553 mmol) in 1-methyl-2-pyrrolidinone (3 ml), N-boc-1,4-diaminobutane (214 mg, 1.107 mmol) was added. The reaction mixture was heated at 150° C. for 1.5 h. The mixture was concentrated. The crude was purified by flash chromatography in a Biotage using Cyclohexane/AcOEt gradient followed by AcOEt/MeOH gradient to give intermediate I-04 (137 mg, Y: 40%).

Synthesis of Intermediate VII-06

(79) ##STR00054##

(80) To a solution of intermediate VII-01 (2.08 g, 8.56 mmol) in ClCH.sub.2CH.sub.2CI (40 mL) was added 4-(tert-butoxycarbonylaminomethyl)piperidine (1.92 g, 8.99 mmol) and Et.sub.3N (1.73 g, 17.12 mmol) at 0° C. The mixture was stirred at RT overnight. The mixture was poured into ice water and extracted with EtOAc. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, and concentrated to give the intermediate VII-06 (3.45 g, crude), which was used in the next step with no further treatment.

Synthesis of Intermediate VIII-12

(81) ##STR00055##

(82) To a solution of intermediate VIII-02 (0.6 g, 2.05 mmol) and Et.sub.3N (0.62 g, 0.15 mmol) in n-Butanol (30 mL) was added 4-(tert-butoxycarbonylaminomethyl)piperidine (0.66 g, 3.08 mmol). The mixture was heated to reflux and stirred for 3 h. On cooling, the reaction mixture was concentrated. The residue was purified by column chromatography to give Intermediate VIII-12 (0.8 g, 83%) as a yellow solid.

(83) Method A-5

Synthesis of Intermediates I-07 & I-08

(84) ##STR00056##

(85) To a solution of intermediate I-06 (620 mg, 0.966 mmol) in dioxane (8 ml) at 0° C. was added dropwise a solution of HCl (4 N in water) (8 ml). The reaction mixture was stirred for 2 h. Additional amount of HCl (4 N) (8 ml) was added and the mixture was stirred at RT for 2 h. The reaction was evaporated till dryness. The residue, mixture of intermediates I-07 and I-08, was used in the next step without further purification.

Synthesis of Intermediates II-04 & II-05

(86) ##STR00057##

(87) To a solution of intermediate II-03 (80 mg, 0.125 mmol) in dioxane (1.25 mL) was added HCl (4 M in dioxane) (1.25 mL). Two more additions of HCl (1 mL) were made and the mixture was finally stirred at RT over the weekend. The reaction was concentrated in vacuo and coevaporated with toluene. The residue, mixture of intermediates II-04 and II-05, was used in the next step without further purification.

Synthesis of Intermediate VIII-24

(88) ##STR00058##

(89) To a suspension of Intermediate VIII-04 (200 mg, 0.308 mmol) in 1,4-dioxane (3 mL) was added HCl 4N in dioxane (3.85 mL, 15.415 mmol). The reaction mixture was heated in a pressure tube at 100° C. for 4 h. On cooling, the mixture was filtered and washed with Et.sub.2O to give Intermediate VIII-24 (200 mg, quant.) contaminated with aprox. 5% of the methoxy-derivative.

(90) Method A-6

Synthesis of Intermediate II-10

(91) ##STR00059##

(92) To a suspension of the corresponding Boc-amino (1 eq.) in DCM (5 mL/mmol) was added TFA (5 mL/mmol). The solution was stirred at RT for 1-18 h. The mixture was concentrated and coevaporated with toluene three times to give the desired product as trifluoroacetic salt. It was used in the next experiment without further purification. Quantitative yield was assumed.

Synthesis of Intermediate XIII-38

(93) ##STR00060##

(94) The corresponding acid (1 eq.) was suspended in DCE (5 mL/mmol), the mixture cooled to 0° C. and TFA (5 mL/mmol) was added. The mixture was stirred for 4 h at room temperature and the solvents were removed in vacuo to give the desired compound as trifluoroacetic salt. It was used in subsequent reactions without further purification. A quantitative yield was assumed.

(95) Method A-7

Synthesis of Intermediate II-08

(96) ##STR00061##

(97) To a solution of Intermediate II-07 (trifluoroacetic salt, raw material, 290 mg, 0.436 mmol) in DCM (8 mL) and DMF (1 mL) was added DIPEA (0.38 mL, 2.18 mmol), Boc-Gly-OH (153 mg, 0.871 mmol), BOP (385 mg, 0.871 mmol) and DMAP (5 mg, 0.044 mmol). The mixture was stirred at RT for 2 h and evaporated. The residue was taken up in EtOAc and washed with H.sub.2O and HCl 1.2 M. The organic layer was dried, filtered and evaporated to give Intermediate II-08 (510 mg). It was used in the next experiment with no further treatment. Quantitative yield was assumed.

(98) Method A-8

Synthesis of Intermediate II-09

(99) ##STR00062##

(100) To a solution of Intermediate II-08 (raw material, 310 mg, 0.437 mmol) in MeOH (8 mL) was added LiOH.H.sub.2O (184 mg, 4.37 mmol). The reaction mixture was stirred at RT for 8 h and more LiOH H.sub.2O (184 mg) was added. The mixture was stirred overnight and evaporated to give Intermediate II-09. It was used in the next experiment with no further treatment. Quantitative yield was assumed.

Synthesis of Intermediate VIII-22

(101) ##STR00063##

(102) To a mixture of Intermediate VIII-21 (157 mg, 0.225 mmol) in 1,4-dioxane/water (3:1, 4 mL) was added potassium carbonate. The reaction was heated at 100° C. for 5 h. On cooling, the mixture was evaporated, water was added, and the pH was adjusted to 5 with 1N HCl. The mixture was extracted with EtOAc. The aqueous layer was further acidified until pH 3 and extracted with 1:1 CHCl.sub.3/.sup.iPrOH. All the organic layers were combined, dried and filtered to give Intermediate VIII-22 (127 mg, 83%).

Synthesis of Intermediate VIII-65

(103) ##STR00064##

(104) To a solution of Intermediate VIII-64 (275 mg, 0.41 mmol) in 1,4-dioxane (3 mL) was added 2M KOH (1 mL, 2 mmol). The reaction mixture was stirred at RT for 4.5 h. The mixture was partially evaporated under reduced pressure without heating. Water was added and pH was adjusted to pH 2 with 2M HCl. The aqueous layer was extracted twice with EtOAc, dried, filtered and evaporated to afford Intermediate VIII-65 (248 mg, 92%).

(105) Method A-9

Synthesis of Intermediate V-02

(106) ##STR00065##

(107) To a solution of 5-bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine V-01 (1.58 g, 4.64 mmol) in DCM (47 mL) was added benzenesulfonyl chloride (1.32 mL, 10.22 mmol), tetrabutylammonium hydrogen sulfate (55% in water, 0.75 mL, 1.16 mmol) and NaOH (50% aq., 14 mL). The reaction mixture was stirred at RT for 12 h. The mixture was quenched with brine and the aqueous layer was extracted with DCM (2×20 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and evaporated. Ice-cold methanol was added to the residue and the mixture was stirred at 0° C. for 1 h. The suspension was filtered off and the solid was washed with ice-cold methanol to afford Intermediate V-02 (1.72 g, 80%) as a pale yellow solid.

(108) Method A-10

Synthesis of Intermediate XII-01

(109) ##STR00066##

(110) A mixture of Intermediate I-05 (647 mg, 3.893 mmol) and POCl.sub.3 (32 mL) was refluxed for 5 h. The reaction mixture was cooled down to RT and poured very carefully into sat. Na.sub.2CO.sub.3. The aqueous layer was extracted with EtOAc. The combined organic layers were dried (Na.sub.2SO.sub.4), filtered and evaporated to give Intermediate XII-01 (518 mg, 72%) as a pale brown solid.

Synthesis of Intermediate XIII-01

(111) ##STR00067##

(112) A mixture of Intermediate 1-07 (4.85 g, 24.34 mmol) and POCl.sub.3 (20 mL) was refluxed for 3 h. On cooling, the solvents were removed in vacuo, the residue was suspended in water and the suspension was cooled to 0° C. Aqueous saturated Na.sub.2CO.sub.3 was added dropwise at 0° C. up to pH˜8. The resulting solid was filtered, washed with water and dried to give Intermediate XIII-01 (1.1 g, 20%) as a white solid.

(113) .sup.1H NMR (300 MHz, DMSO) δ 9.01 (s, 1H), 8.19 (q, J=1.1 Hz, 1H), 2.39 (d, J=1.1 Hz, 3H).

Method A-11

Synthesis of Intermediate XII-02

(114) ##STR00068##

(115) To a mixture of Intermediate XII-01 (429 mg, 2.323 mmol) in THF (12 mL) was added LDA (1.8 M in THF/heptane/ethylbenzene, 1.55 mL, 2.788 mmol) at −78° C. After stirring at −78° C. for 1 h, a solution of I.sub.2 (737 mg, 2.904 mmol) in THF (2.6 mL) was slowly added. The reaction mixture was stirred at −78° C. for 2 h. EtOAc was added to the mixture at −78° C. followed by the addition of H.sub.2O. The aqueous layer was extracted with EtOAc and the combined organic layers were dried (Na.sub.2SO.sub.4), filtered and concentrated. The residue was triturated from MeCN to give Intermediate XII-02 (515 mg, 71%) as a pale brown solid.

(116) TABLE-US-00001 TABLE 1 Intermediates Starting Yield No. R1 R2 Material Method % I-02 0 Cl I-01 A-2 54 I-05 Cl I-01 A-2 43 I-06 I-02 A-3 84 I-09 I-02 A-3 82 I-10 I-02 A-3 57 I-11 I-02 A-3 62 I-12 0 I-05 A-3 66 I-13 I-09 A-6 Quant. I-14 I-03 A-6 Quant. I-15 I-04 A-6 Quant. I-16 I-12 A-6 Quant. I-17 0 I-10 A-6 Quant. I-18 I-02 A-3 73 I-19 I-18 A-6 Quant. I-02 Cl I-00 A-1 Quant. I-20 I-02 A-1 88 I-21 00 I-20 A-6 Quant. I-22 01 02 I-02 A-4 64 I-23 03 04 I-22 A-6 Quant. I-24 05 06 I-05 A-3 65 I-25 07 08 I-24 A-6 Quant. I-26 09 0 I-01 A-1 83 I-27 I-26 A-2 31 I-28 I-27 A-6 Quant. I-29 Cl I-00 A-1 83 I-30 Cl I-29 A-2 47 I-31 I-30 A-1 90 I-32 0 I-31 A-6 Quant. Starting Yield No. R1 R2 Material Method % II-03 II-02 A-2 45 II-06 II-02 A-2 20 II-07 II-06 A-6 Quant. II-10 II-09 A-6 Quant. II-11 0 II-01 A-3 53 II-12 II-11 A-2 44 II-13 II-12 A-6 Quant. II-14 II-01 A-3 26 II-15 II-14 A-2 Quant. II-16 0 II-15 A-6 Quant. Starting Yield No. R1 R2 Material Method % III- 03 III-02 A-2 71 III- 04 III-03 A-6 Quant. III- 05 III-01 A-1 29 III- 06 0 III-05 A-2 72 III- 07 III-06 A-6 Quant. III- 08 Br III-01 A-1 98 III- 09 III-08 A-1 25 III- 10 III-09 A-2 40 III- 11 III-10 A-6 Quant. III- 12 0 III-08 A-1 50 III- 13 III-12 A-2 46 III- 14 III-13 A-6 Quant. III- 15 III-05 A-2 48 III- 16 III-15 A-8 50 III- 17 0 III-16 A-6 Quant. III- 18 III-06 A-5 Quant. Starting Yield No. R1 R2 Material Method % IV- 03 IV-02 A-3 67 IV- 04 IV-03 A-2 57 IV- 05 0 IV-04 A-6 Quant. IV- 06 Cl IV-01 A-1 90 IV- 07 IV-06 A-3 83 IV- 08 IV-07 A-2 75 IV- 09 IV-08 A-6 Quant. IV- 10 Cl IV-01 A-1 62 IV- 11 0 IV-10 A-3 94 IV- 12 IV-11 A-2 65 IV- 13 IV-12 A-6 Quant. IV- 14 Cl IV-01 A-1 90 IV- 15 IV-14 A-1 72 IV- 16 IV-15 A-2 84 IV- 17 00 01 IV-16 A-6 Quant. 02 Starting Yield No. R1 R2 Material Method % V-03 Br 03 V-02 A-1 60 V-04 04 05 V-03 A-1 62 V-05 06 07 V-04 A-6 Quant. 08 Starting Yield No. R1 R2 Material Method % VI-02 09 Cl 0 VI-01 Commercially Available A-1 20 VI-03 VI-02 A-1 89 VI-04 VI-03 A-6 Quant. VI-05 Cl VI-01 A-1 67 VI-06 VI-05 A-1 78 VI-07 VI-06 A-2 49 VI-08 0 VI-07 A-6 Quant. Starting Yield No. R1 R2 Material Method % VII- 02 Br VII-01 Commerically A-1 68 Available VII- 03 VII-02 A-1 95 VII- 04 VII-03 A-2 62 VII- 05 0 VII-04 A-6 Quant. VII- 06 Br VII-01 A-4 Quant. VII- 07 VII-06 A-3 84 VII- 08 VII-07 A-2 37 VII- 09 VII-08 A-6 Quant. VII- 10 Br VII-01 A-3 15 VII- 11 0 VII-10 A-3 61 VII- 12 VII-11 A-2 43 VII- 13 VII-12 A-6 Quant. VII- 14 Br VII-01 A-3  4 VII- 15 VII-14 A-3 95 VII- 16 VII-15 A-2 31 VII- 17 0 VII-16 A-6 Quant. Starting Yield No. R1 R2 Material Method % VIII-  02 Cl VIII-01  Commercially A-1  79 Available VIII-  03 VIII-02  A-3  63 VIII-  04 VIII-03  A-2  37 VIII-  05 0 VIII-04  A-6 Quant. VIII-  06 VIII-02  A-1  64 VIII-  07 VIII-06  A-2  62 VIII-  08 VIII-07  A-6 Quant. VIII-  09 VIII-02  A-3  53 VIII-  10 0 VIII-09  A-2  61 VIII-  11 VIII-10  A-6 Quant. VIII-  12 VIII-02  A-4  83 VIII-  13 VIII-12  A-2  63 VIII-  14 VIII-13  A-6 Quant. VIII-  15 0 VIII-02  A-3  54 VIII-  16 VIII-15  A-2  42 VIII-  17 VIII-16  A-6 Quant. VIII-  18 VIII-01  A-1  39 VIII-  19 VIII-18  A-2  26 VIII-  20 0 VIII-19  A-6 Quant. VIII-  21 VIII-03  A-2  54 VIII-  22 VIII-21  A-8  83 VIII-  23 VIII-22  A-6 Quant. VIII-  24 VIII-04  A-5 Quant. VIII-  25 Cl VIII-02  A-2  28 VIII-  26 00 01 VIII-25  A-3  43 VIII-  27 02 03 VIII-03  A-2  70 VIII-  28 04 05 VIII-27  A-6 Quant. VIII-  29 06 Cl VIII-01  A-3  98 VIII-  30 07 08 VIII-29  A-3  57 VIII-  31 09 0 VIII-30  A-2  62 VIII-  32 VIII-31  A-6 Quant. VIII-  33 VIII-03  A-2  44 VIII-  34 VIII-33  A-6 Quant. VIII-  35 VIII-03  A-2  37 VIII-  36 0 VIII-35  A-6 Quant. VIII-  37 VIII-02  A-1  61 VIII-  38 VIII-37  A-2  64 VIII-  39 VIII-38  A-6 Quant. VIII-  40 Cl VIII-01  A-1  63 VIII-  41 VIII-40  A-1  74 VIII-  42 0 VIII-41  A-6 Quant. VIII-  43 VIII-29  A-1  56 VIII-  44 VIII-43  A-2  34 VIII-  45 VIII-44  A-6 Quant. VIII-  46 VIII-02  A-4  75 VIII-  47 0 VIII-46  A-2  71 VIII-  48 VIII-47  A-6 Quant. VIII-  49 VIII-02  A-1  45 VIII-  50 VIII-49  A-2  40 VIII-  51 VIII-50  A-6 Quant. VIII-  52 0 VIII-02  A-4  75 VIII-  53 VIII-52  A-2  65 VIII-  54 VIII-53  A-6 Quant. VIII-  55 VIII-02  A-1  80 VIII-  56 VIII-55  A-2  57 VIII-  57 0 VIII-56  A-6 Quant. VIII-  58 VIII-02  A-4  93 VIII-  59 VIII-58  A-2  74 VIII-  60 VIII-59  A-6 Quant. VIII-  61 VIII-02  A-1 100 VIII-  62 0 VIII-61  A-2  18 VIII-  63 VIII-62  A-6 Quant. VIII-  64 Cl VIII-02  A-2  67 VIII-  65 VIII-64  A-1  71 VIII-  66 VIII-65  A-8  92 VIII-  67 0 VIII-66  A-6 Quant. VIII-  68 VIII-02  A-4  84 VIII-  69 VIII-68  A-2  80 VIII-  70 VIII-69  A-6 Quant. VIII-  71 VIII-02  A-4  91 VIII-  72 0 VIII-71  A-2  68 VIII-  73 VIII-72  A-6 Quant. VIII-  74 VIII-64  A-1  32 VIII-  75 VIII-74  A-8 Quant. VIII-  76 VIII-75  A-6 Quant. VIII-  77 00 VIII-64  A-1 Quant. VIII-  78 01 02 VIII-77  A-8  16 VIII-  79 03 04 VIII-78  A-6 Quant. VIII-  80 05 06 VIII-37  A-2  50 VIII-  81 07 08 VIII-80  A-6 Quant. VIII-  82 09 0 VIII-02  A-4  91 VIII-  83 VIII-82  A-2  78 VIII-  84 VIII-83  A-6 Quant. VIII-  85 VIII-02  A-4  93 VIII-  86 VIII-85  A-2  77 VIII-  87 0 VIII-86  A-6 Quant. VIII-  88 VIII-02  A-4  80 VIII-  89 VIII-88  A-2  85 VIII-  90 VIII-89  A-6 Quant. VIII-  91 VIII-02  A-4  86 VIII-  92 0 VIII-91  A-2  90 VIII-  93 VIII-92  A-6 Quant. VIII-  94 VIII-64  A-1 Quant. VIII-  95 VIII-94  A-8  95 VIII-  96 VIII-02  A-1  17 VIII-  97 0 VIII-96  A-2  74 VIII-  98 VIII-97  A-6  25 VIII-  99 VIII-02  A-1  77 VIII- 100 VIII-99  A-2  75 VIII- 101 VIII-100 A-6 Quant. VIII- 102 0 VIII-99 A-2  56 VIII- 103 VIII-102 A-6 Quant. VIII- 104 VIII-99  A-2  60 VIII- 105 VIII-104 A-6 Quant. Starting Yield No. R1 R2 Material Method % IX- 02 Br IX-01 Commercially Available A-3 57 IX- 03 0 IX-02 A-3 72 IX- 04 IX-03 A-2 71 IX- 05 IX-04 A-6 Quant. IX- 06 IX-02 A-3 69 IX- 07 IX-06 A-2 58 IX- 08 0 IX-07 A-6 Quant. IX- 09 IX-02 A-1 66 IX- 10 IX-09 A-2 41 IX- 11 IX-10 A-6 Quant. Starting Yield No. R1 R2 Material Method % X- 02 Cl 0 X-01 Commercially A-1 80 Available X- 03 Cl X-02 A-2 24 X- 04 X-03 A-1 51 X- 05 X-04 A-6 Quant. X- 06 X-03 A-1 70 X- 07 X-06 A-6 Quant. X- 08 0 X-02 A-1 18 X- 09 X-08 A-2 31 X- 10 X-09 A-8 48 X- 11 X-10 A-6 Quant. Starting Yield No. R1 R2 Material Method % XI-02 Cl 00 XI-01 Commercially A-1 92 Available XI-03 01 02 XI-02 A-1 Quant. XI-04 03 04 XI-03 A-2 96 XI-05 05 06 XI-04 A-6 Quant. 07 Starting Yield No. R1 R2 Material Method % XII- H Cl 1-05 A-10  72 01 XII- I Cl XII-01 A-11  71 02 XII- 03 08 Cl XII-02 A-1  83 XII- 04 09 0 XII-03 A-1 100 XII- 05 XII-04 A-2  41 XII- 06 XII-05 A-6 Quant. Starting Yield No. R1 R2 Material Method % XIII- H Cl 1-07 A-10 20 01 XIII- I Cl XIII-01 A-11 77 02 XIII- 03 Cl XIII-02 A-1 70 XIII- 04 XIII-03 A-1 50 XIII- 05 0 XIII-04 A-2 66 XIII- 06 XIII-05 A-6 Quant. XIII- 07 XIII-03 A-1 64 XIII- 08 XIII-07 A-2 56 XIII- 09 XIII-08 A-6 Quant. XIII- 10 0 XIII-03 A-1 64 XIII- 11 XIII-10 A-2 76 XIII- 12 XIII-11 A-6 Quant. XIII- 13 XIII-10 A-2 19 XIII- 14 XIII-13 A-6 Quant. XIII- 15 Cl XIII-03 A-2 50 XIII- 16 0 XIII-15 A-1 Quant. XIII- 17 XIII-16 A-8 95 XIII- 18 XIII-03 A-4 85 XIII- 19 XIII-18 A-2 93 XIII- 20 XIII-19 A-8 Quant. XIII- 21 0 XIII-20 A-6 Quant. XIII- 22 XIII-03 A-1 Quant. XIII- 23 XIII-22 A-2 95% XIII- 24 XIII-23 A-8 97% XIII- 25 XIII-24 A-6 Quant. XIII- 26 0 XIII-03 A-4 98 XIII- 27 XIII-26 A-2 80 XIII- 28 XIII-27 A-8 86 XIII- 29 XIII-28 A-6 Quant. XIII- 30 XIII-03 A-1 98 XIII- 31 0 XIII-30 A-2 66 XIII- 32 XIII-31 A-6 Quant. XIII- 33 XIII-03 A-4 98 XIII- 34 XIII-33 A-2 82 XIII- 35 XIII-34 A-8 Quant. XIII- 36 0 XIII-35 A-6 Quant. XIII- 37 XIII-10 A-2 56 XIII- 38 XIII-37 A-6 Quant. XIII- 39 XIII-10 A-2 80 XIII- 40 XIII-39 A-8 95 XIII- 41 0 XIII-40 A-6 Quant. Starting Yield No. R1 R2 Material Method % XIV- H Cl 1-08 A-10 91 01 XIV- I Cl XIV-01 A-11 90 02 XIV- 03 Cl XIV-02 A-1 74 XIV- 04 XIV-03 A-1 99 XIV- 05 XIV-04 A-2 40 XIV- 06 XIV-05 A-6 Quant. XIV- 07 00 01 XIV-03 A-1 81 XIV- 08 02 03 XIV-07 A-2 30 XIV- 09 04 05 XIV-08 A-6 Quant. 06 Starting Yield No. R1 R2 Material Method % XV- 02 H Cl 07 A-10 78 XV-01 Commercially Available XV- I Cl XV-02 A-11 88 03 XV- 04 08 Cl XV-03 A-1 79 XV- 05 09 0 XV-04 A-1 85 XV- 06 XV-05 A-2 44 XV- 07 XV-06 A-6 Quant. XV- 08 XV-05 A-2 32 XV- 09 XV-08 A-6 Quant. XV- 10 0 XV-04 A-1 43 XV- 11 XV-10 A-2 82 XV- 12 XV-11 A-6 Quant. Starting Yield No. R1 R2 Material Method % XVI- 02 I Cl A-11 23 XVI-01 Commercially Available XVI- 03 XVI-02 A-1 96 XVI- 04 0 XVI-03 A-2 57 XVI- 05 XVI-04 A-6 Quant. Starting Yield No. R1 R2 Material Method % XVII- 02 Cl XVII-01 Commercially Available A-1 44 XVII- 03 XVII-02 A-3 61 XVII- 04 XVII-03 A-6 Quant. XVII- 05 0 XVII-02 A-3 35 XVII- 06 XVII-05 A-6 Quant. Starting Yield No. R1 R2 Material Method % XVIII- 02 I Cl A-11 86 XVIII-01 Commercially Available XVIII- 03 Cl XVIII-02 A-1 84 XVIII- 04 XVIII-03 A-3 Quant. XVIII- 05 0 XVIII-04 A-2 48 XVIII- 06 XVIII-05 A-8 82 XVIII- 07 XVIII-06 A-6 Quant.

(117) The final examples of compounds of the invention were prepared according to the general methods B-1 to B-4 described hereinafter.

EXAMPLES

(118) General Method B-1

(119) The corresponding aminoacid intermediate (1 eq.) was dissolved in DMF (50 mL/mmol) and DI PEA (5 eq.) was added. The mixture was added using a syringe pump (2 mL/h) to a solution of PyBOP (1.1 eq.) and DMAP (1.1 eq.) in DMF (150 mL/mmol). After the addition, the mixture was stirred for 18 h and evaporated till dryness. The residue was purified by flash chromatography in a Biotage using cyclohexane/AcOEt gradient followed by AcOEt/MeOH gradient to give the expected compound.

(120) General Method B-2

(121) A solution of the indicated aminoacid intermediate (1 eq.) in DMF (50 mL/mmol) and DIPEA (5 eq.) was added via syringe pump (2 mL/h) to a solution of HATU (2 eq.) and HOAt (0.5 M in DMF, 2 eq.) in DMF (150 mL/mmol). The resulting mixture was stirred overnight under Ar. The mixture was concentrated under vacuum. The residue was purified by flash chromatography in a Biotage using DCM/MeOH gradient to give the expected compound.

(122) General Method B-3

(123) A solution of the indicated aminoacid intermediate (1 eq.) in DMF (50 mL/mmol) and DIPEA (5 eq.) was added via syringe pump (2 mL/h) to a solution of PyBroP (2 eq.) in DMF (150 mL/mmol). The resulting mixture was stirred overnight under Ar. The mixture was concentrated under vacuum. The residue was purified by flash chromatography in a Biotage using DCM/MeOH gradient to give the expected compound.

(124) Method B-4

(125) Synthesis of Final Product 46

(126) To a solution of Final Product 27 (30 mg, 0.06 mmol) in DMF (0.6 mL) and DIPEA (10 μL 0.06 mmol) was added MeI (4 μL, 0.06 mmol) at 0° C. The mixture was stirred from 0° C. to rt. More DIPEA (10 μL) and MeI (5 μL) were added and the reaction was stirred at rt for 6 h. Water was added and the mixture was extracted with DCM. The organic layer was dried (Na.sub.2SO.sub.4), filtered and concentrated. The residue was purified by prep HPLC to give Final Product 46 (4 mg, 13%) and the dimethylated product (3 mg, 9%).

(127) TABLE-US-00002 TABLE 2 Final products Cpd. Starting General Yield Nr. Structure Material Method %  1 I-07 B-1 12  2 I-08 B-1 23  3 I-13 B-1 31  4 I-17 B-1 57  5 I-11 B-1 20  6 0 I-14 B-1 38  7 I-15 B-1 73  8 II-04 B-2 19  9 II-05 B-2 21  10 I-16 B-1 26  11 III-04 B-2 40  12 IV-05 B-2 53  13 IV-09 B-2 43  14 II-10 B-2 1  15 I-19 B-1 14  16 0 III-07 B-2 18  17 II-13 B-2 43  18 IV-13 B-2 12  19 I-21 B-1 5  20 V-05 B-1 5  21 VI-04 B-2 3  22 VII-05 B-2 36  23 IV-17 B-2 4  24 I-23 B-3 6  25 III-11 B-2 4  26 0 III-14 B-2 30  27 VIII-05 B-2 31  28 VIII-08 B-2 19  29 I-25 B-1 47  30 IX-05 B-2 15  31 X-05 B-2 18  32 VII-09 B-2 53  33 VII-13 B-2 51  34 IX-08 B-2 38  35 X-07 B-2 32  36 0 VIII-11 B-2 18  37 VI-08 B-2 8  38 VIII-14 B-2 6  39 I-28 B-2 34  40 IX-11 B-2 21  41 VII-17 B-2 29  42 VIII-17 B-2 30  43 VIII-20 B-2 10  44 VIII-23 B-2 19  45 VIII-24 B-2 10  46 00 27 B-4 13  47 01 VIII-26 B-2 14  48 02 VIII-28 B-2 38  49 03 I-32 B-1 11  50 04 VIII-32 B-2 19  51 05 XI-05 B-2 7  52 06 VIII-34 B-2 34  53 07 VIII-36 B-2 35  54 08 XII-06 B-2 29  55 09 VIII-39 B-2 20  56 0 XIII-06 B-2 36  57 XIII-09 B-2 25  58 VIII-42 B-2 13  59 VIII-45 B-2 19  60 XIV-06 B-2 22  61 XIV-09 B-2 13  62 XV-07 B-2 33  63 XV-09 B-2 42  64 VIII-48 B-2 27  65 VIII-50 B-2 59  66 0 VIII-54 B-2 29  67 III-17 B-2 29  68 XIII-12 B-2 4  69 VIII-57 B-2 15  70 VIII-60 B-2 20  71 X-11 B-2 9  72 VIII-63 B-2 17  73 XVI-05 B-2 34  74 VIII-67 B-2 16  75 VIII-70 B-2 3  76 0 VIII-73 B-2 43  77 VIII-76 B-2 9  78 XVII-04 B-2 26  79 VIII-79 B-2 52  80 XV-12 B-2 18  81 XVII-06 B-2 19  82 VIII-81 B-2 33  83 VIII-84 B-2 25  84 VIII-87 B-2 32  85 III-18 B-2 3  86 0 VIII-90 B-2 20  87 VIII-93 B-2 27  88 VIII-95 B-2 4  89 VIII-98 B-2 25  90 XIII-14 B-2 16  91 XIII-21 B-2 49  92 XIII-25 B-2 37  93 VIII-101 B-2 24  94 XIII-29 B-2 42  95 XIII-32 B-2 29  96 0 II-16 B-2 1  97 VIII-103 B-2 17  98 VIII-105 B-2 16  99 XIII-36 B-2 29 100 XIII-38 B-2 25 101 XVIII-07 B-2 31 102 XIII-41 B-2 26

(128) Certain exemplary compounds of the invention described herein were prepared, characterised and assayed for their PI3Kα, PIM-1 and mTOR enzymatic activities.

(129) TABLE-US-00003 TABLE 3 Analytical data and PI3K alpha, PIM-1 and mTOR activities Cpd. .sup.1H NMR (300 MHz; δ in Nr. R.sub.t [M + 1].sup.+ Meth. PI3K mTOR PIM1 ppm, J in Hz) 1 3.67 524.3 1 *** *** * DMSO-d.sub.6 δ 9.86 (s, 1H), (2) (64) 9.40 (t, J = 5.7 Hz, 1H), 9.01 (d, J = 4.4 Hz, 1H), 8.73 (m, 2H), 8.21 (d, J = 8.7 Hz, 1H), 8.14 (m, 1H), 8.06 (m, 3H), 7.98 (m, 2H), 7.71 (m, 3H), 7.60 (d, J = 4.4 Hz, 1H), 4.56 (d, J = 5.5 Hz, 2H), 3.76 (s, 3H). 2 3.11 510.0 1 ** * * DMSO-d.sub.6 δ 11.96 (very broad s, 1H), 9.41 (t, J = 5.6 Hz, 1H), 8.99 (d, J = 4.4 Hz, 1H), 8.73 (d, J = 1.7 Hz, 1H), 8.72 (d, J = 1.9 Hz, 1H), 8.17 (m, 3H), 8.06 (m, 2H), 7.89 (dd, J = 8.7, 1.8 Hz, 1H), 7.70 (t, J = 7.8 Hz, 1H), 7.58 (m, 3H), 7.21 (d, J = 2.1 Hz, 1H), 4.54 (d, J = 5.5 Hz, 2H). 3 4.21 523.1 1 *** ** * DMSO-d.sub.6 δ 9.84 (broad s, (1.6) 1H), 9.37 (t, J = 5.9 Hz, 1H), 8.97 (d, J = 4.4 Hz, 1H), 8.18 (d, J = 8.7 Hz, 1H), 8.03 (m, 3H), 7.91 (m, 2H), 7.70 (m, 2H), 7.62 (m, 2H), 7.58 (d, J = 7.3 Hz, 1H), 7.51 (m, 3H), 4.50 (d, J = 5.7 Hz, 2H), 3.73 (s, 3H). 4 4.69 541.1 1 *** ** * DMSO-d.sub.6 δ 9.86 (s, 1H), (3) 9.31 (t, J = 5.8 Hz, 1H), 9.00 (d, J = 4.4 Hz, 1H), 8.20 (d, J = 8.7 Hz, 1H), 8.20 (m, 4H), 7.70 (t, J = 7.9 Hz, 1H), 7.58 (m, 5H), 7.43 (dd, J = 9.7, 8.5 Hz, 1H), 4.46 (m, 2H), 3.73 (s, 3H). 5 4.55 541.1 1 *** ** * DMSO-d.sub.6 δ 9.83 (s, 1H), (23) 9.35 (m, 1H), 9.02 (d, J = 4.3 Hz, 1H), 8.19 (d, J = 8.7 Hz, 1H), 8.13 (m, 1H), 8.03 (m, 3H), 7.97 (dd, J = 8.7, 1.9 Hz, 1H), 7.70 (m, 3H), 7.51 (m, 3H), 7.40 (t, J = 7.5 Hz, 1H), 4.69 (dd, J = 13.7, 6.5 Hz, 1H), 4.36 (dd, J = 13.9, 3.3 Hz, 1H), 3.80 (s, 3H). 6 2.90 530.2 1 *** *** * DMSO-d.sub.6 δ 10.16 (broad s, (11) (72) 1H), 8.93 (t, J = 6.2 Hz, 1H), 8.71 (d, J = 4.9 Hz, 1H), 8.31 (m, 1H), 8.24 (m, 2H), 8.01 (m, 2H), 7.95 (d, J = 2.2 Hz, 1H), 7.91 (m, 2H), 7.79 (t, J = 7.8 Hz, 1H), 7.05 (d, J = 4.9 Hz, 1H), 3.94 (s, 3H), 3.50 (m, 2H), 3.37 (m, 2H), 2.77 (m, 2H), 1.81 (m, 3H), 1.65 (m, 2H). 7 3.07 504.1 1 * * * DMSO-d.sub.6 δ 8.92 (m, 1H), 8.82 (t, J = 5.5 Hz, 1H), 8.62 (m, 2H), 8.53 (d, J = 7.1 Hz, 1H), 8.31 (d, J = 2.2 Hz, 1H), 8.24 (dd, J = 8.8, 1.4 Hz, 1H), 8.17 (m, 2H), 7.94 (d, J = 8.8 Hz, 1H), 7.88 (d, J = 2.2 Hz, 1H), 7.77 (t, J = 7.8 Hz, 1H), 6.94 (d, J = 7.2 Hz, 1H), 4.01 (s, 3H), 3.60 (m, 2H), 3.37 (m, 2H), 1.83 (m, 2H), 1.62 (m, 2H). 8 3.87 520.2 1 *** * * DMSO-d.sub.6 δ 10.56 (s, 1H), (7) 9.70 (t, J = 5.8 Hz, 1H), 8.95 (s, 1H), 8.79 (s, 1H), 8.57 (s, 1H), 8.34 (d, J = 2.0 Hz, 1H), 8.21 (m, 2H), 8.16 (d, J = 7.8 Hz, 1H), 7.97 (s, 1H), 7.89 (d, J = 2.1 Hz, 1H), 7.80 (t, J = 7.8 Hz, 1H), 4.68 (d, J = 5.6 Hz, 2H), 4.02 (s, 3H). 9 3.14 506.0 1 ** * ** DMSO-d.sub.6 δ 9.60 (t, J = 5.5 Hz, 1H), 8.93 (d, J = 2.1 Hz, 1H), 8.64 (s, 1H), 8.55 (d, J = 1.9 Hz, 1H), 8.17 (t, J = 1.8 Hz, 1H), 8.12 (m, 1H), 8.04 (m, 1H), 7.90 (s, 1H), 7.72 (m, 1H), 7.59 (m, 1H), 7.35 (m, 1H), 4.66 (d, J = 5.5 Hz, 2H). 10 3.94 560.1 1 *** *** * DMSO-d.sub.6 δ 10.47 (s, 1H), (0.03) (22) 9.14 (t, J = 5.4 Hz, 1H), 9.02 (d, J = 4.4 Hz, 1H), 8.74 (m, 2H), 8.22 (d, J = 8.7 Hz, 1H), 7.99 (m, 3H), 7.72 (m, 3H), 7.60 (d, J = 4.4 Hz, 1H), 7.55 (d, J = 1.8 Hz, 1H), 4.52 (d, J = 5.5 Hz, 2H), 3.77 (s, 3H). 11 3.27 514.1 1 *** *** * DMSO-d.sub.6 δ 9.97 (s, 1H), (0.4) (4) 9.68 (t, J = 5.8 Hz, 1H), 9.23 (d, J = 7.4 Hz, 1H), 8.94 (d, J = 1.3 Hz, 1H), 8.81 (s, 1H), 8.74 (m, 2H), 8.49 (d, J = 1.3 Hz, 1H), 8.34 (t, J = 1.8 Hz, 1H), 8.15 (d, J = 2.2 Hz, 1H), 8.09 (m, 1H), 8.03 (m, 1H), 7.70 (t, J = 7.8 Hz, 1H), 7.65 (d, J = 7.5 Hz, 1H), 4.60 (d, J = 5.6 Hz, 2H), 4.02 (s, 3H). 12 3.32 514.1 1 *** *** * DMSO-d.sub.6 δ 9.93 (broad s, (0.4) (5) 1H), 9.56 (t, J = 5.6 Hz, 1H), 8.95 (d, J = 1.8 Hz, 1H), 8.60 (d, J = 1.6 Hz, 1H), 8.48 (m, 1H), 8.37 (m, 3H), 8.04 (m, 2H), 7.92 (d, J = 2.1 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.67 (d, J = 9.5 Hz, 1H), 4.56 (d, J = 5.5 Hz, 2H), 3.91 (s, 3H). 13 4.09 513.1 1 *** *** * DMSO-d.sub.6 δ 9.91 (broad s, (0.4) (10) 1H), 9.46 (t, J = 5.7 Hz, 1H), 8.37 (m, 2H), 8.27 (d, J = 9.4 Hz, 1H), 8.14 (s, 1H), 8.03 (m, 3H), 7.88 (d, J = 2.2 Hz, 1H), 7.69 (m, 2H), 7.61 (d, J = 9.5 Hz, 1H), 7.50 (t, J = 7.6 Hz, 1H), 7.40 (m, 1H), 4.54 (d, J = 5.6 Hz, 2H), 3.88 (s, 3H). 14 3.37 577.1 1 ** * ** DMSO-d.sub.6 δ 10.04 (broad s, 1H), 8.96 (t, J = 5.9 Hz, 1H), 8.92 (d, J = 2.0 Hz, 1H), 8.57 (t, J = 5.8 Hz, 1H), 8.50 (m, 2H), 8.44 (m, 1H), 8.16 (d, J = 2.2 Hz, 1H), 8.10 (m, 3H), 7.94 (s, 1H), 7.75 (m, 1H), 4.36 (d, J = 5.9 Hz, 2H), 3.84 (d, J = 5.8 Hz, 2H), 3.77 (s, 3H). 15 3.89 524.1 1 *** ** * DMSO-d.sub.6 δ 9.87 (broad s, (20) 1H), 9.49 (t, J = 5.8 Hz, 1H), 9.02 (d, J = 4.4 Hz, 1H), 8.75 (d, J = 5.1 Hz, 1H), 8.19 (d, J = 8.7 Hz, 1H), 8.15 (m, 1H), 8.09 (d, J = 7.8 Hz, 1H), 8.00 (m, 2H), 7.91 (dd, J = 8.7, 1.8 Hz, 1H), 7.70 (m, 2H), 7.65 (s, 1H), 7.57 (m, 2H), 7.51 (d, J = 2.0 Hz, 1H), 4.68 (d, J = 5.8 Hz, 2H), 3.79 (s, 3H). 16 4.87 513.1 1 *** *** * DMSO-d.sub.6 δ 9.90 (s, 1H), (0.9) (4) 9.57 (t, J = 5.7 Hz, 1H), 9.18 (d, J = 7.4 Hz, 1H), 8.72 (m, 2H), 8.62 (s, 1H), 8.12 (d, J = 2.0 Hz, 1H), 8.08 (d, J = 7.5 Hz, 1H), 7.99 (m, 2H), 7.69 (d, J = 7.8 Hz, 1H), 7.65 (m, 1H), 7.59 (d, J = 7.5 Hz, 1H), 7.43 (t, J = 7.6 Hz, 1H), 7.27 (m, 1H), 4.58 (d, J = 5.7 Hz, 2H), 4.01 (s, 3H). 17 4.97 519.0 1 *** ** * DMSO-d.sub.6 δ 10.52 (s, 1H), (9) 9.67 (t, J = 5.8 Hz, 1H), 8.79 (s, 1H), 8.31 (s, 1H), 8.16 (t, J = 8.0 Hz, 2H), 7.94 (s, 1H), 7.91 (d, J = 2.0 Hz, 1H), 7.82- 7.73 (m, 2H), 7.68 (d, J = 7.8 Hz, 1H), 7.47 (t, J = 7.7 Hz, 1H), 7.35 (d, J = 7.6 Hz, 1H), 4.64 (d, J = 5.7 Hz, 2H), 4.01 (s, 3H). 18 3.29 517.2 1 *** *** * DMSO-d.sub.6 δ 10.36 (s, 1H), (5) (67) 8.75 (t, J = 5.4 Hz, 1H), 8.62 (d, J = 1.9 Hz, 1H), 8.51 (m, 1H), 8.23 (d, J = 4.7 Hz, 2H), 8.18 (d, J = 9.5 Hz, 1H), 8.02 (m, 2H), 7.85 (d, J = 2.1 Hz, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.76 (d, J = 9.7 Hz, 1H), 7.59 (t, J = 7.8 Hz, 1H), 4.48 (s, 2H), 4.04 (s, 3H), 3.72 (s, 2H). 19 3.24 527.1 1 *** *** * DMSO-d.sub.6 δ 10.28 (bs, 1H), (4) (21) 8.86 (d, J = 4.5 Hz, 2H), 8.34 (s, 1H), 8.30 (s, 1H), 8.21 (s, 1H), 8.13-8.05 (m, 3H), 8.05-7.94 (m, 2H), 7.90 (s, 1H), 7.75-7.62 (m, 2H), 7.50 (d, J = 4.5 Hz, 1H), 4.43 (s, 2H), 3.95 (s, 3H), 3.78 (s, 2H). 20 3.18 513.0 1 *** ** * DMSO-d.sub.6 δ 12.26 (s, 1H), (80) 10.12 (s, 1H), 9.62 (t, J = 5.6 Hz, 1H), 8.85 (d, J = 2.0 Hz, 1H), 8.81 (s, 1H), 8.50 (d, J = 2.0 Hz, 1H), 8.46 (d, J = 1.7 Hz, 1H), 8.22-8.11 (m, 4H), 8.07 (d, J = 1.8 Hz, 1H), 7.81- 7.74 (m, 1H), 7.74 (d, J = 2.2 Hz, 1H), 4.61 (d, J = 5.5 Hz, 2H), 3.94 (s, 3H). 21 4.44 531.1 1 *** * ** DMSO-d.sub.6 δ 9.56 (t, J = 5.3 (85) Hz, 1H), 9.16 (s, 1H), 9.09 (s, 1H), 9.02 (s, 1H), 8.80 (s, 1H), 8.44 (s, 1H), 8.13 (m, 3H), 7.74 (m, 3H), 4.68 (d, J = 5.2 Hz, 2H), 3.94 (s, 3H). 22 4.67 524.1 1 *** *** * DMSO δ 9.87 (s, 1H), 9.42 (t, (0.1) (30) J = 5.5 Hz, 1H), 9.38 (s, 1H), 8.18 (s, 2H), 8.14 (s, 1H), 8.04 (m, 3H), 7.93 (s, 1H), 7.72 (m, 2H), 7.80 (m, 2H), 7.63 (m, 2H), 4.53 (d, J = 5.5 Hz, 2H), 3.76 (s, 3H). 23 0.41 532.2 1 *** *** * DMSO δ 8.59 (t, J = 5.5 Hz, (5) (22) 1H), 8.52 (d, J = 1.8 Hz, 1H), 8.16 (s, 1H), 8.13 (d, J = 9.6 Hz, 1H), 8.04 (m, 1H), 7.96 (d, J = 2.0 Hz, 1H), 7.92 (m, 1H), 7.78 (d, J = 9.6 Hz, 1H), 7.75 (s, 1H), 7.65 (t, J = 7.8 Hz, 1H), 6.42 (m, 1H), 4.02 (s, 3H), 3.49 (m, 2H), 3.36 (m, 2H), 2.82 (t, J = 5.2 Hz, 2H), 2.76 (m, 2H), 2.61 (s, 2H). 24 2.88 544.2 1 *** *** * DMSO δ 8.62 (d, J = 4.8 Hz, (3) (4) 1H), 8.15 (s, 1H), 8.02 (m, 2H), 7.96 (m, 2H), 7.67 (m, 4H), 6.91 (d, J = 4.9 Hz, 1H), 4.02 (s, 3H), 3.40 (m, 4H), 3.05 (s, 3H), 2.73 (m, 2H), 1.94 (m, 1H), 1.71 (m, 2H), 0.95 (m, 2H). 25 2.71 522.3 1 *** *** * DMSO δ 8.87 (d, J = 7.5 Hz, (20) (54) 1H), 8.68 (t, J = 5.3 Hz, 1H), 8.51 (s, 1H), 8.22 (s, 1H), 8.18 (s, 1H), 7.98 (d, J = 1.6 Hz, 1H), 7.91 (m, 2H), 7.56 (m, 2H), 6.20 (m, 1H), 3.9 (s, 3H), 3.48 (m, 2H), 3.34 (m, 2H), 2.90 (m, 2H), 2.77 (m, 2H), 2.60 (m, 2H). 26 3.99 517.3 1 *** *** * DMSO δ 10.14 (s, 1H), 9.07 (4) (40) (d, J = 7.5 Hz, 1H), 8.84 (t, J = 5.2 Hz, 1H), 8.80 (d, J = 1.7 Hz, 1H), 8.71 (s, 1H), 8.49 (s, 1H), 8.00 (s, 1H), 7.96 (m, 1H), 7.86 (m, 1H), 7.81 (s, 1H), 7.75 (d, J = 2.1 Hz, 1H), 7.56 (m, 2H), 4.45 (m, 2H), 4.04 (s, 3H), 3.66 (s, 2H). 27 4.18 531.1 1 ** * *** DMSO δ 10.74 (s, 1H), 9.90 (40) (t, J = 6.0 Hz, 1H), 9.29 (s, 1H), 9.26 (d, J = 1.9 Hz, 1H), 8.88 (m, 2H), 8.67 (s, 1H), 8.49 (m, 1H), 8.28 (d, J = 7.7 Hz, 1H), 8.21 (m, 2H), 7.83 (m, 1H), 7.44 (s, 1H), 4.73 (d, J = 5.8 Hz, 2H), 4.03 (s, 3H). 28 4.92 530.2 1 ** * ** DMSO δ 10.71 (s, 1H), 9.90 (t, J = 5.7 Hz, 1H), 9.24 (s, 1H), 8.93 (s, 1H), 8.64 (s, 1H), 8.27 (d, J = 7.5 Hz, 1H), 8.19 (m, 4H), 7.81 (m, 1H), 7.65 (d, J = 4.5 Hz, 2H), 7.46 (d, J = 1.8 Hz, 1H), 4.70 (d, J = 5.6 Hz, 2H), 4.02 (s, 3H). 29 4.51 559.3 1 *** ** * DMSO δ 10.46 (s, 1H), 9.13 (6) (t, J = 5.7 Hz, 1H), 8.98 (d, J = 4.4 Hz, 1H), 8.20 (d, J = 8.6 Hz, 1H), 7.97 (dd, J = 8.7, 1.9 Hz, 1H), 7.94 (d, J = 2.2 Hz, 1H), 7.74 (d, J = 2.2 Hz, 1H), 7.58 (m, 8H), 4.46 (m, 2H), 3.76 (s, 3H). 30 2.58 513.1 1 *** *** * DMSO δ 9.40 (t, J = 5.2 Hz, (11) (49) 1H), 8.73 (d, J = 2.1 Hz, 1H), 8.69 (s, 1H), 8.61 (m, 2H), 8.44 (t, J = 1.9 Hz, 1H), 8.22- 8.04 (m, 3H), 7.96 (s, 1H), 7.91 (d, J = 2.2 Hz, 1H), 7.82- 7.66 (m, 2H), 7.59 (dd, J = 9.4, 1.5 Hz, 1H), 4.59 (d, J = 5.2 Hz, 2H), 3.93 (s, 3H). 31 3.57 525.1 1 *** *** * DMSO δ 9.83 (s, 1H), 9.26 (t, (2) (23) J = 6.1 Hz, 1H), 9.09 (d, J = 4.4 Hz, 1H), 8.83 (m, 1H), 8.67 (m, 1H), 8.59 (d, J = 8.7 Hz, 1H), 8.32-8.17 (m, 2H), 8.08-7.93 (m, 4H), 7.91 (d, J = 4.4 Hz, 1H), 7.72 (t, J = 7.8 Hz, 1H), 7.59 (m, 1H), 4.50 (d, J = 5.9 Hz, 2H), 3.50 (s, 3H). 32 2.83 531.2 1 *** *** * DMSO δ 10.09 (s, 1H), 8.85 (2) (5) (t, J = 6.1 Hz, 1H), 8.62 (s, 1H), 8.37-8.26 (m, 2H), 8.16 (m, 1H), 8.05 (m, 2H), 7.85 (d, J = 8.7 Hz, 1H), 7.81- 7.65 (m, 3H), 4.05 (m, 2H), 3.98 (s, 3H), 3.59-3.44 (m, 2H), 3.04 (t, J = 11.9 Hz, 2H), 2.01 (m, 1H), 1.93- 1.61 (m, 4H). 33 4.16 528.2 1 *** *** * DMSO δ 10.23 (s, 1H), 9.19 (1.3) (4.8) (s, 1H), 8.98 (t, J = 5.8 Hz, 1H), 8.69 (s, 1H), 8.42 (t, J = 1.9 Hz, 1H), 8.30-8.00 (m, 7H), 7.72 (t, J = 7.8 Hz, 1H), 7.67 (d, J = 2.2 Hz, 1H), 4.42 (m, 2H), 3.97 (s, 3H), 3.77 (m, 2H). 34 3.14 516.1 1 *** *** * DMSO δ 10.15 (s, 1H), 9.02 (7.6) (66) (t, J = 5.7 Hz, 1H), 8.49 (m, 1H), 8.36 (s, 1H), 8.21 (s, 1H), 8.19-8.08 (m, 3H), 7.85 (s, 1H), 7.78-7.62 (m, 3H), 7.56 (d, J = 2.2 Hz, 1H), 7.47 (dd, J = 9.2, 1.8 Hz, 1H), 4.39 (m, 2H), 3.96 (s, 3H), 3.81-3.60 (m, 2H). 35 4.69 524.3 1 *** *** * DMSO δ 9.81 (s, 1H), 9.20 (t, (5) (16) J = 6.0 Hz, 1H), 9.04 (d, J = 4.4 Hz, 1H), 8.56 (d, J = 8.8 Hz, 1H), 8.21 (d, J = 8.7 Hz, 1H), 8.07 (d, J = 2.3 Hz, 1H), 8.02-7.93 (m, 3H), 7.81 (m, 1H), 7.76 (d, J = 4.4 Hz, 1H), 7.74-7.58 (m, 3H), 7.53 (t, J = 7.5 Hz, 1H), 7.44(m, 1H), 4.45 (d, J = 6.0 Hz, 2H), 3.52 (s, 3H). 36 4.11 534.2 1 ** * ** DMSO δ 10.76 (s, 1H), 9.20 (t, J = 5.4 Hz, 1H), 9.06 (s, 1H), 8.90 (m, 1H), 8.65 (d, J = 2.3 Hz, 1H), 8.52 (s, 1H), 8.19 (s, 1H), 8.14 (m, 2H), 8.09 (s, 1H), 7.73 (t, J = 7.8 Hz, 1H), 7.25 (d, J = 2.2 Hz, 1H), 4.61 (m, 2H), 4.03 (s, 3H), 3.70 (m, 2H). 37 5.23 530.0 1 *** * * DMSO δ 10.34 (s, 1H), 9.63 (20) (t, J = 4.8 Hz, 1H), 9.14 (s, 1H), 9.11 (s, 1H), 8.21 (m, 3H), 8.05 (s, 1H), 7.97 (m, 1H), 7.88 (s, 1H), 7.83 (d, J = 2.2 Hz, 1H), 7.79 (t, J = 7.8 Hz, 1H), 7.63 (m, 2H), 4.65 (d, J = 4.9 Hz, 2H), 3.99 (s, 3H). 38 3.15 537.2 1 * * * DMSO δ 10.49 (s, 1H), 8.64 (m, 1H), 8.53 (m, 2H), 8.41 (s, 1H), 7.97 (d, J = 8.5 Hz, 1H), 7.90 (d, J = 8.5 Hz, 1H), 7.62 (m, 2H), 6.85 (s, 1H), 4.38 (m, 2H), 4.01 (s, 3H), 3.50 (m, 2H), 3.23 (m, 2H), 2.14 (m, 1H), 1.67 (m, 2H), 1.25 (d, J = 7.0 Hz, 2H). 39 4.47 549.3 1 *** *** * DMSO δ 10.18 (s, 1H), 8.91 (0.05) (0.3) (d, J = 4.4 Hz, 1H), 8.45 (d, J = 2.1 Hz, 1H), 8.16 (m, 2H), 7.96 (m, 1H), 7.91 (s, 1H), 7.75 (m, 3H), 7.66 (d, J = 2.2 Hz, 1H), 7.47 (m, 3H), 7.43 (s, 1H), 4.54 (s, 2H), 4.02 (s, 3H), 3.93 (m, 2H), 3.08 (m, 2H). 40 1.19 531.3 1 *** *** * DMSO δ 10.55 (broad s, 1H), (3) (36) 8.62 (t, J = 5.5 Hz, 1H), 8.40 (m, 1H), 8.19 (d, J = 2.3 Hz, 1H), 8.06 (m, 2H), 8.00 (s, 1H), 7.70 (t, J = 7.8 Hz, 1H), 7.63 (d, J = 9.4 Hz, 1H), 7.53 (m, 3H), 6.04 (m, 1H), 3.97 (s, 3H), 3.53 (m, 2H), 3.25 (m, 2H), 2.76 (m, 4H), 2.39 (m, 2H). 41 3.96 525.0 1 *** *** * DMSO δ 9.88 (broad s, 1H), (3) (16) 9.44 (m, 2H), 8.95 (d, J = 1.8 Hz, 1H), 8.82 (d, J = 1.5 Hz, 1H), 8.25 (m, 4H), 8.08 (m, 3H), 7.99 (s, 1H), 7.84 (d, J = 2.1 Hz, 1H), 7.73 (t, J = 7.8 Hz, 1H), 4.59 (d, J = 5.3 Hz, 2H), 3.82 (s, 3H). 42 4.42 531.0 1 ** * ** DMSO δ 10.76 (s, 1H), 9.97 (s, 1H), 9.33 (s, 1H), 8.92 (s, 1H), 8.84 (d, J = 5.2 Hz, 1H), 8.66 (s, 1H), 8.32-8.17 (m, 3H), 8.13 (m, 2H), 7.83 (t, J = 7.7 Hz, 1H), 7.43 (s, 1H), 4.77 (d, J = 5.6 Hz, 2H), 4.02 (s, 3H). 43 3.75 501.1 1 *** * *** DMSO δ 9.86 (m, 1H), 9.32 (44) (41) (s, 1H), 9.26 (s, 1H), 8.93- 8.79 (m, 3H), 8.51 (s, 1H), 8.30 (s, 2H), 8.22 (m, 1H), 8.01 (d, J = 7.9 Hz, 1H), 7.76 (t, J = 7.8 Hz, 1H), 7.48 (m, 1H), 4.73 (d, J = 5.5 Hz, 2H). DMSO δ 11.24 (s, 1H), 9.38 (m, 1H), 9.30 (s, 1H), 9.21 (d, J = 1.9 Hz, 1H), 8.83 (s, 1H), 8.68 (m, 1H), 8.61 (t, J = 44 4.26 567.0 1 ** * * 7.9 Hz, 1H), 8.40 (m, 1H), 8.23 (s, 1H), 7.85 (t, J = 10.3 Hz, 1H), 7.36 (d, J = 1.9 Hz, 1H), 4.73 (d, J = 5.3 Hz, 2H), 4.01 (s, 3H). 45 3.38 517.1 1 * * ** DMSO δ 9.87 (s, 1H), 9.25 (d, J = 2.0 Hz, 1H), 9.24 (s, 1H), 8.84 (s, 2H), 8.46 (s, 1H), 8.21 (t, J = 7.5 Hz, 2H), 8.03 (s, 1H), 8.01 (s, 1H), 7.80 (t, J = 7.8 Hz, 1H), 7.07 (s, 1H), 4.72 (d, J = 5.5 Hz, 2H). 46 4.46 545.0 1 * * * DMSO δ 9.74 (t, J = 5.5 Hz, 1H), 9.30 (m, 2H), 8.97 (d, J = 2.1 Hz, 1H), 8.83 (m, 1H), 8.67 (m, 1H), 8.50 (s, 1H), 8.40 (d, J = 7.6 Hz, 1H), 8.26 (m, 1H), 8.23 (s, 1H), 7.89 (t, J = 7.9 Hz, 1H), 7.44 (d, J = 2.1 Hz, 1H), 4.73 (d, J = 5.4 Hz, 2H), 4.07 (s, 3H), 3.19 (s, 3H). 47 4.09 517.0 1 *** *** * DMSO δ 10.86 (broad s, 1H), (99) (8.5) 10.62 (s, 1H), 9.24 (s, 1H), 8.96 (d, J = 2.1 Hz, 1H), 8.76 (d, J = 2.3 Hz, 1H), 8.56 (d, J = 2.3 Hz, 1H), 8.48 (m, 1H), 8.31 (t, J = 2.2 Hz, 1H), 8.03 (s, 1H), 7.85 (m, 1H), 7.60 (m, 2H), 7.21 (d, J = 2.3 Hz, 1H), 4.04 (s, 3H). 48 4.29 549.1 1 *** * *** DMSO δ 10.74 (s, 1H), 9.47 (48) (52) (m, 1H), 9.29 (s, 1H), 9.22 (d, J = 2.2 Hz, 1H), 8.84 (d, J = 2.1 Hz, 1H), 8.66 (d, J = 2.2 Hz, 1H), 8.56 (dd, J = 6.4, 2.6 Hz, 1H), 8.44 (t, J = 2.2 Hz, 1H), 8.22 (m, 2H), 7.75 (dd, J = 10.2, 8.8 Hz, 1H), 7.46 (d, J = 2.2 Hz, 1H), 4.73 (d, J = 5.7 Hz, 2H), 4.03 (s, 3H). 49 3.39 494.1 1 *** ** * DMSO δ 10.32 (s, 1H), 9.35 (68) (t, J = 5.7 Hz, 1H), 9.03 (d, J = 4.4 Hz, 1H), 8.79 (d, J = 2.0 Hz, 1H), 8.73 (d, J = 2.1 Hz, 1H), 8.52 (d, J = 2.0 Hz, 1H), 8.46 (d, J = 2.3 Hz, 1H), 8.22 (d, J = 8.7 Hz, 1H), 8.01 (m, 5H), 7.67 (m, 2H), 7.61 (d, J = 4.4 Hz, 1H), 7.52 (t, J = 2.3 Hz, 1H), 4.50 (d, J = 5.7 Hz, 2H). 50 4.91 559.2 1 * * * DMSO δ 10.54 (s, 1H), 9.90 (m, 1H), 9.27 (m, 2H), 8.88 (d, J = 12.0 Hz, 2H), 8.65 (d, J = 2.0 Hz, 1H), 8.49 (s, 1H), 8.25 (m, 3H), 7.84 (t, J = 7.8 Hz, 1H), 7.42 (d, J = 2.0 Hz, 1H), 5.37 (m, 1H), 4.74 (d, J = 5.4 Hz, 2H), 1.40 (d, J = 6.2 Hz, 6H). 51 3.84 518.2 1 ** * * DMSO δ 10.19 (s, 1H), 9.07 (t, J = 4.7 Hz, 1H), 8.89 (s, 1H), 8.83 (m, 2H), 8.32 (s, 1H), 8.28 (s, 1H), 8.01 (d, J = 7.8 Hz, 1H), 7.85 (d, J = 7.9 Hz, 1H), 7.70 (s, 1H), 7.56 (t, J = 7.8 Hz, 1H), 7.35 (d, J = 1.7 Hz, 1H), 4.52 (m, 2H), 4.04 (s, 3H), 3.67 (m, 2H). 52 4.24 549.1 1 ** * ** DMSO δ 11.16 (s, 1H), 9.90 (t, J = 5.6 Hz, 1H), 9.29 (s, 1H), 9.26 (d, J = 2.1 Hz, 1H), 8.92 (m, 1H), 8.85 (s, 1H), 8.66 (s, 1H), 8.45 (s, 1H), 8.37 (m, 1H), 8.21 (s, 1H), 7.67 (t, J = 9.2 Hz, 1H), 7.37 (d, J = 2.1 Hz, 1H), 4.73 (d, J = 5.5 Hz, 2H), 4.01 (s, 1H). 53 4.88 599.1 1 * * * DMSO δ 10.78 (broad s, 1H), 10.12 (t, J = 5.6 Hz, 1H), 9.29 (s, 1H), 9.25 (d, J = 1.8 Hz, 1H), 9.18 (s, 1H), 8.88 (s, 1H), 8.71 (s, 1H), 8.64 (s, 1H), 8.61 (s, 1H), 8.51 (s, 1H), 8.22 (s, 1H), 7.42 (d, J = 1.9 Hz, 1H), 4.77 (d, J = 5.4 Hz, 2H), 4.04 (s, 3H). 54 4.34 545.2 1 ** * * DMSO δ 10.73 (s, 1H), 9.88 (t, J = 5.5 Hz, 1H), 9.24 (d, J = 2.1 Hz, 1H), 8.88 (m, 1H), 8.84 (d, J = 1.9 Hz, 1H), 8.63 (d, J = 2.2 Hz, 1H), 8.46 (t, J = 2.0 Hz, 1H), 8.28 (d, J = 8.0 Hz, 1H), 8.21 (d, J = 8.4 Hz, 1H), 8.11 (s, 1H), 7.83 (t, J = 7.8 Hz, 1H), 7.42 (d, J = 2.2 Hz, 1H), 4.73 (d, J = 5.7 Hz, 2H), 4.02 (s, 3H), 2.79 (s, 3H). 55 4.65 536.0 1 ** * *** DMSO δ 10.82 (s, 1H), 9.88 (12) (t, J = 5.8 Hz, 1H), 9.11 (s, 1H), 8.67 (m, 2H), 8.23 (m, 2H), 8.10 (s, 1H), 7.87 (m, 2H), 7.44 (d, J = 2.2 Hz, 1H), 7.26 (d, J = 3.7 Hz, 1H), 4.85 (d, J = 5.7 Hz, 2H), 4.05 (s, 3H). 56 4.46 545.1 1 *** ** *** DMSO δ 10.69 (broad s, 1H), (13) (56) 9.83 (t, J = 5.3 Hz, 1H), 9.36 (s, 1H), 9.28 (d, J = 2.1 Hz, 1H), 8.85 (d, J = 1.7 Hz, 1H), 8.80 (s, 1H), 8.54 (t, J = 2.0 Hz, 1H), 8.20 (m, 3H), 7.79 (t, J = 7.8 Hz, 1H), 7.53 (s, 1H), 4.71 (d, J = 5.4 Hz, 2H), 4.01 (s, 3H), 2.58 (s, 3H). 57 4.44 548.1 1 *** ** ** DMSO δ 10.68 (broad s, 1H), (0.8) 9.21 (t, J = 5.1 Hz, 1H), 9.13 (s, 1H), 8.80 (s, 1H), 8.41 (s, 1H), 8.32 (s, 1H), 8.20 (m, 2H), 8.11 (d, J = 8.1 Hz, 1H), 7.75 (t, J = 7.8 Hz, 1H), 7.33 (d, J = 2.1 Hz, 1H), 4.59 (d, J = 5.0 Hz, 2H), 4.03 (s, 3H), 3.71 (m, 2H), 2.54 (s, 3H). 58 4.20 535.0 1 *** * ** DMSO δ 11.12 (broad s, 1H), (3.6) 9.90 (t, J = 4.9 Hz, 1H), 9.34 (s, 1H), 9.27 (s, 1H), 8.91 (m, 3H), 8.49 (s, 1H), 8.42 (s, 1H), 8.28 (m, 2H), 7.85 (t, J = 7.7 Hz, 1H), 7.53 (s, 1H), 4.74 (d, J = 4.7 Hz, 2H). 59 4.89 562.1 1 * * * DMSO δ 10.58 (s, 1H), 9.19 (t, J = 5.4 Hz, 1H), 9.05 (s, 1H), 8.90 (t, J = 1.7 Hz, 1H), 8.63 (d, J = 2.3 Hz, 1H), 8.51 (s, 1H), 8.15 (m, 3H), 8.07 (s, 1H), 7.75 (t, J = 7.8 Hz, 1H), 7.24 (d, J = 2.2 Hz, 1H), 5.37 (hept, J = 6.2 Hz, 1H), 4.61 (m, 2H), 3.71 (m, 2H), 1.41 (d, J = 6.2 Hz, 6H). 60 5.32 573.1 1 * * * DMSO δ 10.70 (broad s, 1H), 9.87 (t, J = 5.9 Hz, 1H), 9.29 (d, J = 2.1 Hz, 1H), 8.87 (m, 1H), 8.84 (d, J = 1.7 Hz, 1H), 8.59 (s, 1H), 8.46 (m, 1H), 8.25 (d, J = 7.6 Hz, 1H), 8.18 (d, J = 8.1 Hz, 1H), 8.14 (s, 1H), 7.81 (t, J = 7.8 Hz, 1H), 7.40 (d, J = 2.0 Hz, 1H), 4.72 (d, J = 5.5 Hz, 2H), 4.00 (s, 3H), 3.32 (m, 1H), 1.40 (d, J = 6.9 Hz, 6H). 61 5.17 576.1 1 * * * DMSO δ 10.74 (s, 1H), 9.19 (t, J = 5.1 Hz, 1H), 8.89 (m, 1H), 8.64 (d, J = 2.1 Hz, 1H), 8.47 (s, 1H), 8.15 (m, 3H), 8.05 (s, 1H), 7.75 (t, J = 7.9 Hz, 1H), 7.25 (d, J = 2.1 Hz, 1H), 4.61 (m, 2H), 4.04 (s, 3H), 3.71 (m, 2H), 3.22 (m, 1H), 1.34 (d, J = 6.9 Hz, 3H). 62 4.14 530.0 1 ** * *** DMSO δ 10.62 (broad s, 1H), (31) 9.84 (t, J = 5.8 Hz, 1H), 8.89 (d, J = 2.3 Hz, 1H), 8.81 (m, 1H), 8.78 (m, 2H), 8.58 (d, J = 2.3 Hz, 1H), 8.39 (t, J = 2.2 Hz, 1H), 8.22 (m, 2H), 8.12 (s, 1H), 7.80 (t, J = 7.8 Hz, 1H), 7.69 (d, J = 4.9 Hz, 1H), 7.37 (d, J = 2.2 Hz, 1H), 4.68 (d, J = 5.7 Hz, 2H), 4.00 (s, 3H). 63 4.19 548.0 1 *** * *** DMSO δ 10.64 (s, 1H), 9.52 (15) (47) (t, J = 5.9 Hz, 1H), 8.86 (d, J = 2.2 Hz, 1H), 8.78 (m, 2H), 8.61 (d, J = 2.2 Hz, 1H), 8.44 (dd, J = 6.5, 2.4 Hz, 1H), 8.37 (t, J = 2.2 Hz, 1H), 8.21 (m, 1H), 8.16 (s, 1H), 7.72 (t, J = 9.4 Hz, 1H), 7.66 (d, J = 4.8 Hz, 1H), 7.40 (d, J = 2.2 Hz, 1H), 4.65 (d, J = 5.8 Hz, 2H), 4.00 (s, 3H). 64 3.37 539.2 1 * * ** DMSO δ 10.61 (s, 1H), 9.37 (m, 1H), 8.85 (s, 1H), 8.52 (s, 1H), 8.21 (m, 2H), 7.89 (s, 1H), 7.80 (t, J = 7.8 Hz, 2H), 7.46 (s, 1H), 4.80 (d, J = 14.0 Hz, 1H), 4.61 (d, J = 12.3 Hz, 1H), 4.01 (m, 4H), 3.64 (m, 2H), 3.42 (m, 2H), 3.25 (m, 1H), 3.12 (m, 1H). 65 5.24 548.1 1 ** * * DMSO δ 10.71 (s, 1H), 9.89 (m, 1H), 9.23 (s, 1H), 8.94 (s, 1H), 8.66 (s, 1H), 8.23 (m, 5H), 7.82 (m, 1H), 7.54 (m, 1H), 7.43 (s, 1H), 4.70 (d, J = 4.5 Hz, 2H), 4.02 (s, 3H). 66 3.39 539.2 1 ** * *** DMSO δ 10.62 (broad s, 1H), (88) 9.37 (t, J = 5.4 Hz, 1H), 8.84 (s, 1H), 8.51 (s, 1H), 8.48 (s, 1H), 8.20 (d, J = 7.4 Hz, 2H), 7.88 (s, 1H), 7.80 (t, J = 7.9 Hz, 1H), 7.46 (s, 1H), 4.80 (d, J = 13.4 Hz, 1H), 4.61 (d, J = 13.7 Hz, 1H), 4.02 (m, 4H), 3.65 (m, 2H), 3.42 (m, 2H), 3.24 (m, 1H), 3.11 (m, 1H). 67 5.02 549.1 1 *** *** * DMSO δ 10.56 (s, 1H), 9.44 (0.5) (12) (t, J = 6.0 Hz, 1H), 9.19 (d, J = 7.3 Hz, 1H), 8.54 (m, 2H), 8.24 (t, J = 7.7 Hz, 1H), 8.14 (d, J = 2.1 Hz, 1H), 7.80 (m, 1H), 7.69 (t, J = 10.0 Hz, 1H), 7.62 (m, 1H), 7.52 (d, J = 7.5 Hz, 1H), 7.44 (t, J = 7.6 Hz, 1H), 7.28 (d, J = 7.5 Hz, 1H), 4.49 (d, J = 5.8 Hz, 2H), 3.97 (s, 3H). 68 4.99 550.1 1 *** *** *** DMSO δ 10.79 (broad s, 1H), (2.5) (90) (28) 9.89 (t, J = 5.5 Hz, 1H), 9.17 (s, 1H), 8.60 (s, 1H), 8.36 (m, 1H), 8.26 (d, J = 7.8 Hz, 1H), 8.19 (d, J = 7.8 Hz, 1H), 7.91 (d, J = 3.7 Hz, 1H), 7.85 (t, J = 7.6 Hz, 1H), 7.61 (s, 1H), 7.25 (d, J = 3.6 Hz, 1H), 4.83 (d, J = 4.8 Hz, 2H), 4.05 (s, 3H), 2.60 (s, 3H). 69 4.53 520.0 1 ** * ** DMSO δ 10.60 (s, 1H), 9.83 (t, J = 5.7 Hz, 1H), 9.05 (s, 1H), 8.99 (m, 1H), 8.64 (d, J = 2.1 Hz, 1H), 8.26 (d, J = 7.8 Hz, 1H), 8.17 (d, J = 8.0 Hz, 1H), 8.07 (s, 1H), 7.80 (t, J = 7.8 Hz, 1H), 7.54 (d, J = 3.5 Hz, 1H), 7.43 (d, J = 2.1 Hz, 1H), 6.74 (d, J = 3.5 Hz, 1H), 4.79 (d, J = 5.5 Hz, 3H), 4.02 (s, 3H). 70 2.73 497.1 1 * * ** DMSO δ 10.49 (broad s, 1H), 9.26 (t, J = 5.8 Hz, 1H), 8.84 (s, 1H), 8.48 (d, J = 1.6 Hz, 1H), 8.30 (s, 1H), 8.18 (m, 2H), 7.91 (t, J = 7.0 Hz, 1H), 7.79 (m, 2H), 7.51 (d, J = 2.2 Hz, 1H), 3.98 (s, 3H), 3.66 (m, 2H), 3.45 (m, 2H), 1.85 (m, 2H). 71 3.85 561.2 1 *** *** * DMSO-d6 δ 10.44 (s, 1H), (0.15) (25) 9.14 (t, J = 6.2 Hz, 1H), 9.09 (d, J = 4.4 Hz, 1H), 8.82 (d, J = 2.2 Hz, 1H), 8.66 (d, J = 2.2 Hz, 1H), 8.60 (d, J = 8.7 Hz, 1H), 8.28 (d, J = 8.8 Hz, 1H), 8.09 (m, 3H), 7.90 (d, J = 4.5 Hz, 1H), 7.68 (t, J = 10.1 Hz, 1H), 7.33 (t, J = 7.2 Hz, 1H), 4.50 (d, J = 6.1 Hz, 2H), 3.64 (m, 3H). 72 5.28 548.1 1 * * ** DMSO-d6 δ 10.71 (s, 1H), 9.92 (t, J = 5.8 Hz, 1H), 9.26 (s, 1H), 8.94 (s, 1H), 8.66 (d, J = 2.2 Hz, 1H), 8.28 (d, J = 7.8 Hz, 1H), 8.21 (m, 2H), 8.05 (s, 1H), 7.91 (m, 1H), 7.82 (t, J = 7.8 Hz, 1H), 7.58 (m, 1H), 7.46 (d, J = 2.2 Hz, 1H), 4.70 (d, J = 5.8 Hz, 2H), 4.03 (s, 3H). 73 5.13 560.0 1 * * *** DMSO-d6 δ 9.86 (t, J = 5.6 (45) Hz, 1H), 9.04 (s, 1H), 8.66 (d, J = 1.9 Hz, 1H), 8.63 (m, 1H), 8.22 (m, 1H), 8.20 (m, 2H), 7.85 (m, 2H), 7.69 (d, J = 3.7 Hz, 1H), 7.32 (m, 2H), 4.78 (d, J = 5.7 Hz, 2H), 4.03 (s, 3H). 74 4.74 536.0 1 * ** DMSO-d6 δ 10.76 (s, 1H), 9.86 (t, J = 5.7 Hz, 1H), 9.13 (s, 1H), 8.80 (m, 1H), 8.67 (d, J = 2.1 Hz, 1H), 8.43 (d, J = 1.5 Hz, 1H), 8.28 (d, J = 7.8 Hz, 1H), 8.23 (d, J = 7.8 Hz, 1H), 8.14 (s, 1H), 7.87 (t, J = 7.8 Hz, 1H), 7.76 (d, J = 1.4 Hz, 1H), 7.42 (d, J = 2.1 Hz, 1H), 4.77 (d, J = 5.4 Hz, 2H), 4.04 (s, 3H). 75 3.40 523.1 1 * * DMSO-d6 δ 10.16 (bs, 1H), 9.08 (d, J = 7.8 Hz, 1H), 8.55 (m, 3H), 8.29 (d, J = 7.6 Hz, 1H), 8.01 (d, J = 8.5 Hz, 1H), 7.79 (t, J = 7.8 Hz, 1H), 7.71 (s, 1H), 6.83 (d, J = 2.2 Hz, 1H), 4.47 (m, 1H), 4.35 (m, 1H), 4.23 (m, 1H), 3.98 (s, 3H), 3.43 (m, 1H), 3.03 (m, 1H), 2.03 (m, 3H), 1.70 (m, 1H). 76 3.41 523.1 1 * ** DMSO-d6 δ 10.16 (bs, 1H), 9.08 (d, J = 7.8 Hz, 1H), 8.56 (m, 3H), 8.31 (d, J = 7.6 Hz, 1H), 8.02 (d, J = 8.1 Hz, 1H), 7.80 (t, J = 7.8 Hz, 1H), 7.71 (s, 1H), 6.84 (d, J = 2.0 Hz, 1H), 4.46 (m, 1H), 4.35 (m, 1H), 4.24 (m, 1H), 3.99 (s, 3H), 3.42 (m, 1H), 3.02 (m, 1H), 2.01 (m, 3H), 1.70 (m, 1H). 77 4.82 536.1 1 ** * *** DMSO-d6 δ 10.76 (broad s, (17) 1H), 9.77 (t, J = 5.5 Hz, 1H), 9.09 (s, 1H), 8.83 (s, 1H), 8.68 (s, 1H), 8.29 (d, J = 7.7 Hz, 1H), 8.22 (d, J = 7.6 Hz, 1H), 8.15 (s, 1H), 7.92 (s, 1H), 7.87 (t, J = 7.9 Hz, 2H), 7.82 (s, 1H), 7.39 (d, J = 1.8 Hz, 1H), 4.63 (d, J = 5.5 Hz, 2H), 4.04 (s, 3H). 78 4.15 518.0 1 ** * ** DMSO-d6 δ 12.41 (s, 1H), 10.61 (s, 1H), 9.83 (t, J = 5.9 Hz, 1H), 8.66 (s, 1H), 8.42 (s, 1H), 8.22 (m, 3H), 7.86 (t, J = 7.7 Hz, 1H), 7.58 (d, J = 3.6 Hz, 1H), 7.50 (s, 1H), 7.39 (d, J = 5.1 Hz, 1H), 7.13 (d, J = 3.5 Hz, 1H), 6.86 (s, 1H), 4.80 (d, J = 5.6 Hz, 2H), 4.01 (s, 3H). 79 4.66 537.0 1 ** * * DMSO-d6 δ 10.65 (broad s, 1H), 9.96 (t, J = 5.7 Hz, 1H), 9.14 (s, 1H), 9.01 (s, 1H), 8.77 (s, 1H), 8.61 (s, 1H), 8.22 (m, 2H), 8.07 (s, 1H), 7.81 (t, J = 7.8 Hz, 1H), 7.54 (d, J = 1.9 Hz, 1H), 5.02 (d, J = 5.5 Hz, 2H), 4.02 (s, 3H). 80 4.26 535.0 1 ** * *** DMSO-d6 δ 10.72 (broad s, (15) 1H), 9.83 (t, J = 5.9 Hz, 1H), 8.64 (m, 3H), 8.22 (m, 2H), 8.05 (s, 1H), 7.86 (t, J = 7.8 Hz, 1H), 7.64 (m, 2H), 7.39 (d, J = 2.2 Hz, 1H), 7.20 (d, J = 3.6 Hz, 1H), 4.80 (d, J = 5.3 Hz, 2H), 4.03 (s, 3H). 81 3.74 513.1 1 ** * ** DMSO-d6 δ 12.44 (s, 1H), 10.41 (s, 1H), 9.77 (t, J = 5.4 Hz, 1H), 9.02 (s, 1H), 8.87 (s, 1H), 8.71 (s, 1H), 8.42 (m, 1H), 8.32 (d, J = 4.9 Hz, 1H), 8.22 (m, 3H), 7.78 (t, J = 7.6 Hz, 1H), 7.57 (s, 1H), 7.38 (d, J = 5.0 Hz, 1H), 6.68 (s, 1H), 4.70 (d, J = 5.0 Hz, 2H), 3.97 (s, 3H). 82 4.84 554.0 1 *** * *** DMSO-d6 δ 10.83 (broad s, (57) (13) 1H), 9.51 (m, 1H), 9.12 (s, 1H), 8.67 (d, J = 2.2 Hz, 1H), 8.56 (dd, J = 6.4, 2.5 Hz, 1H), 8.27 (m, 1H), 8.11 (s, 1H), 7.87 (d, J = 3.7 Hz, 1H), 7.79 (t, J = 9.5 Hz, 1H), 7.57 (d, J = 2.2 Hz, 1H), 7.24 (d, J = 3.7 Hz, 1H), 4.86 (s, 2H), 4.05 (s, 3H). 83 3.40 537.1 1 * * ** DMSO-d6 δ 10.61 (s, 1H), 9.40 (m, 1H), 8.91 (s, 1H), 8.60 (s, 1H), 8.51 (s, 1H), 8.19 (t, J = 7.0 Hz, 3H), 7.83 (s, 1H), 7.78 (t, J = 7.8 Hz, 1H), 7.51 (s, 1H), 5.14 (d, J = 12.7 Hz, 1H), 4.69 (d, J = 13.0 Hz, 1H), 3.99 (s, 3H), 3.42 (m, 1H), 3.23 (m, 2H), 2.98 (m, 1H), 1.97 (m, 1H), 1.88 (m, 2H), 1.46 (m, 2H). 84 3.40 537.1 1 * * ** DMSO-d6 δ 10.62 (broad s, 1H), 9.41 (t, J = 5.7 Hz, 1H), 8.91 (s, 1H), 8.63 (s, 1H), 8.51 (d, J = 2.1 Hz, 1H), 8.19 (t, J = 7.5 Hz, 2H), 7.83 (s, 1H), 7.78 (t, J = 7.8 Hz, 1H), 7.51 (d, J = 2.2 Hz, 1H), 5.15 (d, J = 13.3 Hz, 1H), 4.69 (d, J = 13.2 Hz, 1H), 3.99 (s, 3H), 3.42 (m, 1H), 3.21 (m, 2H), 2.99 (m, 1H), 1.98 (m, 1H), 1.88 (m, 2H), 1.48 (m, 2H). 85 4.22 499.1 1 ** * * Methanol-d4 δ 8.84 (d, J = 7.3 Hz, 1H), 8.47 (m, 1H), 8.38 (s, 1H), 8.18 (d, J = 7.7 Hz, 1H), 8.10 (m, 2H), 7.97 (s, 1H), 7.74 (m, 2H), 7.64 (d, J = 8.0 Hz, 1H), 7.46 (t, J = 7.6 Hz, 1H), 7.30 (m, 1H), 7.22 (d, J = 7.3 Hz, 1H), 4.61 (s, 2H). 86 2.82 523.1 1 * * ** DMSO-d6 δ 10.61 (broad s, 1H), 9.07 (d, J = 7.1 Hz, 1H), 8.69 (s, 1H), 8.55 (d, J = 2.1 Hz, 1H), 8.35 (s, 1H), 8.22 (d, J = 7.7 Hz, 1H), 8.15 (m, 1H), 7.84 (t, J = 7.8 Hz, 1H), 7.79 (s, 1H), 7.31 (d, J = 2.1 Hz, 1H), 4.06 (m, 1H), 4.00 (s, 3H), 3.88 (m, 3H), 3.54 (m, 1H), 3.33 (m, 1H), 2.78 (m, 1H), 2.18 (m, 1H), 1.74 (m, 1H). 87 2.82 523.1 1 * * ** DMSO-d6 δ 10.61 (broad s, 1H), 9.07 (d, J = 7.2 Hz, 1H), 8.69 (s, 1H), 8.55 (d, J = 2.0 Hz, 1H), 8.35 (s, 1H), 8.22 (d, J = 7.7 Hz, 1H), 8.15 (m, 1H), 7.84 (t, J = 7.8 Hz, 1H), 7.78 (s, 1H), 7.31 (d, J = 2.1 Hz, 1H), 4.06 (m, 1H), 4.00 (s, 3H), 3.87 (m, 3H), 3.56 (m, 1H), 3.33 (m, 1H), 2.79 (m, 1H), 2.18 (m, 1H), 1.74 (m, 1H). 88 4.82 550.0 1 ** * *** .sup.1H NMR (300 MHz, DMSO- (69) d6) δ 10.82 (s, 1H), 9.84 (t, J = 5.7 Hz, 1H), 9.09 (s, 1H), 8.68 (m, 1H), 8.65 (m, 1H), 8.25 (m, 2H), 8.09 (s, 1H), 7.89 (t, J = 7.8 Hz, 1H), 7.76 (s, 1H), 7.45 (d, J = 2.1 Hz, 1H), 4.75 (d, J = 5.4 Hz, 2H), 4.05 (s, 3H), 2.30 (s, 3H). 89 3.95 531.1 1 * * * .sup.1H NMR (300 MHz, DMSO- d6) δ 10.45 (broad s, 1H), 9.43 (t, J = 3.5 Hz, 1H), 9.30 (s, 1H), 8.85 (d, J = 5.2 Hz, 1H), 8.78 (m, 1H), 8.70 (s, 1H), 8.56 (d, J = 1.9 Hz, 1H), 8.14 (s, 1H), 8.04 (m, 2H), 7.80 (m, 2H), 7.70 (t, J = 7.8 Hz, 1H), 4.47 (dd, J = 13.6, 2.4 Hz, 1H), 3.93 (s, 3H), 3.89 (dd, J = 13.6, 4.3 Hz, 1H). 90 5.21 568.1 1 *** *** *** .sup.1H NMR (300 MHz, DMSO) δ (1.8) (56) (27) 10.80 (broad s, 1H), 9.58 (t, J = 5.2 Hz, 1H), 9.18 (s, 1H), 8.48 (dd, J = 6.4, 2.5 Hz, 1H), 8.37 (s, 1H), 8.32 (m, 1H), 7.93 (d, J = 3.7 Hz, 1H), 7.78 (d, J = 9.5 Hz, 1H), 7.73 (d, J = 2.0 Hz, 1H), 7.24 (d, J = 3.7 Hz, 1H), 4.85 (d, J = 4.8 Hz, 2H), 4.05 (s, 3H), 2.61 (s, 3H). 91 3.78 553.2 1 *** ** *** DMSO-d6 δ 10.55 (s, 1H), (10) (47) 9.29 (s, 1H), 8.71 (s, 1H), 8.55 (s, 1H), 8.17 (m, 2H), 7.79 (m, 1H), 7.56 (s, 1H), 4.77 (d, J = 13.6 Hz, 1H), 4.57 (d, J = 12.6 Hz, 1H), 4.04 (s, 1H), 3.98 (s, 3H), 3.73 (broad s, 1H), 3.61 (m, 1H), 3.46 (s, 2H), 3.16 (m, 3H), 2.43 (s, 3H). 92 5.46 562.1 1 *** * * DMSO-d6 δ 10.64 (s, 1H), (15) 9.85 (t, J = 5.9 Hz, 1H), 9.34 (s, 1H), 8.84 (s, 1H), 8.24 (m, 2H), 8.09 (s, 1H), 7.93 (d, J = 9.6 Hz, 1H), 7.81 (t, J = 7.8 Hz, 1H), 7.56 (m, 2H), 4.67 (d, J = 5.6 Hz, 2H), 4.02 (s, 3H), 2.57 (s, 3H). 93 4.91 610.1 1 ** *** * DMSO-d6 δ 10.64 (s, 1H), (32) 9.16 (t, J = 6.1 Hz, 1H), 9.11 (s, 1H), 8.66 (d, J = 2.2 Hz, 2H), 8.16 (d, J = 8.8 Hz, 1H), 8.10 (s, 1H), 7.85 (d, J = 3.7 Hz, 1H), 7.58 (d, J = 8.9 Hz, 1H), 7.46 (d, J = 2.1 Hz, 1H), 7.23 (d, J = 3.7 Hz, 1H), 4.89 (s, 2H), 4.44 (m, 2H), 4.04 (s, 3H), 3.79 (m, 2H), 3.29 (s, 3H). 94 2.98 537.2 1 *** * *** DMSO-d6 δ 10.57 (s, 1H), (26) (65) 9.06 (d, J = 7.2 Hz, 1H), 8.64 (s, 1H), 8.42 (s, 1H), 8.20 (m, 3H), 7.83 (t, J = 7.8 Hz, 1H), 7.40 (d, J = 1.9 Hz, 1H), 4.01 (s, 3H), 3.91 (d, J = 6.9 Hz, 3H), 3.77 (dd, J = 21.3, 12.6 Hz, 1H), 3.59 (m, 1H), 3.23 (m, 1H), 2.80 (s, 1H), 2.43 (s, 3H), 2.16 (s, 1H), 1.75 (dd, J = 12.3, 8.1 Hz, 1H). 95 5.26 624.3 1 *** * ** DMSO-d6 δ 10.64 (s, 1H), (20) 9.16 (s, 2H), 8.56 (d, J = 2.5 Hz, 1H), 8.30 (s, 1H), 8.17 (d, J = 9.1 Hz, 1H), 7.90 (d, J = 3.7 Hz, 1H), 7.59 (s, 1H), 7.53 (d, J = 9.0 Hz, 1H), 7.22 (d, J = 3.7 Hz, 1H), 4.86 (s, 2H), 4.42 (s, 2H), 4.04 (s, 3H), 3.79 (m, 2H), 3.29 (s, 3H), 2.60 (s, 3H). 96 7.40 520.0 3 *** ** DMSO-d6 δ 9.75 (t, J = 6.2 (8.8) Hz, 1H), 8.81 (s, 1H), 8.57 (d, J = 5.4 Hz, 1H), 8.13 (m, 5H), 7.98 (s, 1H), 7.80 (s, 1H), 7.74 (d, J = 4.4 Hz, 2H), 4.67 (d, J = 5.7 Hz, 2H), 3.97 (s, 3H). 97 5.37 566.1 1 ** * *** DMSO-d6 δ 10.61 (s, 1H), (62) 9.26 (t, J = 6.0 Hz, 1H), 9.11 (s, 1H), 8.66 (m, 2H), 8.17 (d, J = 9.2 Hz, 1H), 8.10 (s, 1H), 7.84 (d, J = 3.7 Hz, 1H), 7.54 (d, J = 8.9 Hz, 1H), 7.47 (d, J = 2.1 Hz, 1H), 7.21 (d, J = 3.7 Hz, 1H), 4.85 (s, 2H), 4.04 (s, 3H), 4.03 (s, 3H). 98 5.05 570.1 1 *** * *** DMSO-d6 δ 10.90 (s, 1H), (37) (13) 9.73 (t, J = 5.9 Hz, 1H), 9.14 (s, 1H), 8.67 (d, J = 2.0 Hz, 1H), 8.35 (d, J = 2.2 Hz, 1H), 8.18 (dd, J = 8.6, 2.2 Hz, 1H), 8.10 (s, 1H), 7.98 (d, J = 8.6 Hz, 1H), 7.89 (d, J = 3.7 Hz, 1H), 7.82 (d, J = 2.1 Hz, 1H), 7.26 (d, J = 3.7 Hz, 1H), 4.86 (s, 2H), 4.05 (s, 3H). 99 3.17 537.2 1 *** * *** DMSO-d6 δ 10.57 (s, 1H), (43) (53) 9.06 (d, J = 7.1 Hz, 1H), 8.64 (s, 1H), 8.43 (s, 1H), 8.21 (m, 3H), 7.83 (t, J = 7.8 Hz, 1H), 7.40 (d, J = 2.1 Hz, 1H), 4.01 (s, 3H), 3.91 (d, J = 7.0 Hz, 3H), 3.77 (dd, J = 21.4, 12.3 Hz, 1H), 3.60 (m, 1H), 3.27 (s, 1H), 2.81 (d, J = 6.3 Hz, 1H), 2.43 (s, 3H), 2.16 (s, 1H), 1.76 (m, 1H). 100 5.11 580.0 1 *** * *** DMSO-d6 δ 10.61 (m, 1H), (3.3) (31) 9.25 (t, J = 5.7 Hz, 1H), 9.16 (s, 1H), 8.56 (d, J = 2.2 Hz, 1H), 8.31 (s, 1H), 8.20 (d, J = 8.7 Hz, 1H), 7.90 (d, J = 3.6 Hz, 1H), 7.61 (s, 1H), 7.50 (d, J = 8.9 Hz, 1H), 7.21 (d, J = 3.5 Hz, 1H), 4.84 (s, 2H), 4.04 (s, 3H), 4.02 (s, 3H), 2.60 (s, 3H). 101 4.80 549.1 1 *** * *** DMSO-d6 δ 10.69 (s, 1H), (26) (21) 9.83 (t, J = 6.0 Hz, 1H), 8.71 (d, J = 5.0 Hz, 1H), 8.59 (d, J = 1.6 Hz, 1H), 8.29 (dd, J = 10.1, 5.0 Hz, 2H), 8.16 (d, J = 7.9 Hz, 1H), 7.84 (t, J = 7.8 Hz, 1H), 7.73 (d, J = 5.0 Hz, 1H), 7.67 (d, J = 3.7 Hz, 1H), 7.60 (d, J = 2.1 Hz, 1H), 7.20 (d, J = 3.7 Hz, 1H), 4.78 (d, J = 5.6 Hz, 2H), 4.04 (s, 3H), 2.62 (s, 3H). 102 5.31 584.1 1 *** *** *** DMSO-d6 δ 10.84 (s, 1H), (0.1) (28) (9.5) 9.79 (t, J = 5.8 Hz, 1H), 9.19 (s, 1H), 8.41 (d, J = 2.0 Hz, 1H), 8.29 (d, J = 2.2 Hz, 1H), 8.25 (dd, J = 8.6, 2.3 Hz, 1H), 8.02 (d, J = 2.1 Hz, 1H), 7.97 (d, J = 8.5 Hz, 1H), 7.93 (d, J = 3.7 Hz, 1H), 7.25 (d, J = 3.7 Hz, 1H), 4.83 (s, 2H), 4.05 (s, 3H), 2.62 (s, 3H). R.sub.t means retention time (in minutes), [M + H].sup.+ means the protonated mass of the compound, method refers to the method used for (LC)MS. Biological activity in PI3K alpha, PIM-1 and mTOR for certain examples is represented in Table 3 by semi-quantative results: IC50 >1 μM (*), IC50 <100 nM (***), 100 nM < IC50 < 1 μM (**). Quantitative data is also presented, in parentheses, depicting the actual IC.sub.50 values (nM) for representative examples.

(130) TABLE-US-00004 TABLE 4 Pharmacokinetic parameters for some selected compounds. Administration I.V P.O Parameter Dose AUC inf T½ Cl Vd MRT Dose C max Tmax AUC inf Example (mg/Kg) (h*ng/ml) last (L/h/Kg) (L/Kg) (h) (mg/Kg) F % (ng/ml) (h) (h*ng/ml) 3 5.00 23709.33 1.41 0.36 0.46 1.27 10.00 101.00 12403.41 0.25 48082.44 10 5.00 9467.60 0.57 0.53 0.28 0.53 10.00 39.94 3389.29 0.25 7563.83 16 5.00 23568.46 2.23 0.27 0.99 3.33 10.00 123.00 4820.00 0.50 29157.84 22 5.00 66912.04 3.42 0.07 0.37 4.94 10.00 33.50 14950.90 0.16 44830.22 33 5.00 9159.37 2.91 0.60 1.12 1.87 10.00 48.08 1266.30 0.16 8808.30 31 5.00 8930.77 0.39 0.69 0.56 0.81 10.00 34.00 1635.18 0.25 6083.27 39 1.00 4455.10 1.66 0.25 0.59 2.39 3.00 26.79 962.27 0.50 3580.16 68 5.00 16596.24 3.15 0.04 0.49 10.89 10.00 34.51 2929.00 0.25 57280.69 The parameters estimated are: area under the curve (AUC); plasmatic half life of the product (t½); plasmatic clearance (Cl); volume of distribution (Vd); MRT (Mean residence time); bioavailability (F %); maximum plasma concentration after oral administration (Cmax); and time at which the Cmax occurs (Tmax).

ABBREVIATIONS

(131) DCM dichloromethane MeOH methanol THF tetrahydrofuran dba dibenzylideneacetone DMF dimethylformamide DME 1,2-dimethoxyethane DMSO dimethylsulfoxide dppf diphenylphosphinoferrocene EtOAc ethyl acetate BOP (Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate HOAt 1-hydroxy-7-azabenzotriazole PyBOP (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate PyBroP bromotripyrrolidinophosphonium hexafluorophosphate DMAP 4-dimethylaminopyridine HATU O-(7-azabenzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate Pd(PPh.sub.3).sub.4 tetrakis(triphenylphosphine)palladium PdCl.sub.2(dppf).DCM 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride, dichloromethane DIPEA diisopropylethylamine TFA trifluoroacetic acid min minutes h hours RT room temperature eq equivalents nBuOH n-butanol mw microwave