NOVEL INHIBITORS

Abstract

The invention relates to a compound of formula (1):

A-B-D-E (1) or a pharmaceutically acceptable salt, solvate or polymorph thereof, including all tautomers and stereoisomers thereof, wherein: A is selected from monocyclic and bicyclic heteroaryl, which may independently substituted by alkyl or amino; B is selected from alkyl, heteroalkyl, alkyl-amino, aryl, heteroaryl, cycloalkyl, heterocyclyl and alkylene, wherein said groups may independently be substituted by alkyl; D is selected from aryl-amino, heteroaryl-amino, cycloalkyl-amino, heterocyclyl, heterocyclyl-amino, urea, thioamide, thiourea, sulfonamide, sulfoximine and sulfamoyl, wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl groups may independently be substituted; and E is selected from aryl, heteroaryl, cycloalkyl, heterocyclyl, wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl groups may independently be substituted.

The compounds of formula (1) are inhibitors of glutaminyl cyclase (QC, EC 2.3.2.5). QC catalyzes the intramolecular cyclization of N-terminal glutamine residues into pyroglutamic acid (5-oxo-prolyl, pGlu*) under liberation of ammonia and the intramolecular cyclization of N-terminal glutamate residues into pyroglutamic acid under liberation of water.

Claims

1. A compound of formula I:
A-B-D-E (1) or a pharmaceutically acceptable salt or solvate thereof, including all tautomers and stereoisomers thereof, wherein: A is selected from monocyclic and bicyclic heteroaryl selected from ##STR00235## B is selected from piperidine, phenyl or ##STR00236## wherein X.sub.1 is CH.sub.2 or S and n is 1 or 2; D is selected from ##STR00237## sulfonamide, sulfoximine and sulfamoyl, wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl groups may independently be substituted with one or more substituents; E is selected from aryl and heteroaryl, wherein said aryl and heteroaryl groups may independently be substituted with one or more substituents; with the proviso that when B is alkyl or heteroalkyl, then D may not be sulfonamide.

2. The compound according to claim 1, wherein B is selected from ##STR00238## wherein X.sub.1 is CH.sub.2 or S, and n is 1 or 2; and ##STR00239## wherein o is 0 or 1; and p is 0 or 1.

3. The compound according to claim 1, wherein D is selected from ##STR00240## wherein wherein R is absent or is hydrogen; or R forms together with the nitrogen atom, to which it is attached a heterocyclic ring of group B; R.sub.2 is hydrogen, alkyl or cycloalkyl; Y.sub.1, Y.sub.2, Y.sub.3 and Y.sub.4 are independently selected from CH, N, S and O; Y.sub.4 is optionally substituted with alkyl or halogen.

4. The compound according to claim 1, wherein E is ##STR00241## wherein Y.sub.5 is C and Y.sub.6-Y.sub.10 are independently selected from CH, N or O, and R.sub.3, R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are independently selected from hydrogen, halogen, alkyl, O-alkyl, O-phenyl and O-cycloalkyl.

5. The compound according to claim 1, which is a compound of formula (IIa): ##STR00242## wherein Z is selected from CH and N; X.sub.1 is selected from alkyl, N, O, S; n is 1 or 2; Y.sub.1 to Y.sub.4 and Y.sub.6, Y.sub.7 and Y.sub.10 are independently selected from CH and N; Y.sub.5 is C; Y.sub.6 and Y.sub.6 are independently selected from C and N; when Y.sub.8 is C, R.sub.5 is selected from halogen, alkyl and O-alkyl, and when Y.sub.8 is N, R.sub.5 is absent; when Y.sub.9 is C, R.sub.6 is selected from hydrogen, alkyl and O-alkyl, and when Y.sub.9 is N, R.sub.6 is absent.

6. The compound according to claim 1, which is a compound of formula (IVa): ##STR00243## wherein Z is selected from CH and N; o is 0 or 1; p is 0 or 1; Y.sub.1 to Y.sub.4 and Y.sub.6, Y.sub.7 and Y.sub.10 are independently selected from CH and N; Y.sub.5 is C; Y.sub.8 and Y.sub.9 are independently selected from C and N; when Y.sub.8 is C, R.sub.5 is selected from halogen, alkyl and O-alkyl, and when Y.sub.8 is N, R.sub.5 is absent; when Y.sub.9 is C, R.sub.6 is selected from hydrogen, alkyl and O-alkyl, and when Y.sub.9 is N, R.sub.6 is absent.

7. The compound according to claim 1, which is a compound a compound of formula (X): ##STR00244## wherein is 0 or 1; p is 0 or 1; R.sub.5 is selected from halogen, alkyl and O-alkyl; and R.sub.6 is selected from hydrogen, alkyl and O-alkyl.

8. The compound according to claim 1, which is a compound of formula (XI): ##STR00245## wherein is 0 or 1; p is 0 or 1; R.sub.2 is selected from alkyl and cycloalkyl; R.sub.5 is selected from halogen, alkyl and O-alkyl; and R.sub.6 is selected from hydrogen, alkyl and O-alkyl.

9. The compound according to claim 3, wherein NR is represented by ##STR00246##

10. The compound according to 3, which is a compound of formula (XIIa): ##STR00247## wherein Z is selected from CH and N; Y.sub.1 to Y.sub.4 and Y.sub.6, Y.sub.7 and Y.sub.8 are independently selected from CH and N; Y.sub.5 is C; Y.sub.8 and Y.sub.9 are independently selected from C and N; when Y.sub.8 is C, R.sub.5 is selected from halogen, alkyl and O-alkyl, and when Y.sub.8 is N, R is absent; when Y.sub.9 is C, R.sub.6 is selected from hydrogen, alkyl and O-alkyl, and when Y.sub.9 is N, R.sub.6 is absent.

11. The compound according to claim 3, which is a compound a compound of formula (XIII): ##STR00248## wherein Z is selected from CH and N; R.sub.5 is selected from halogen, alkyl and O-alkyl; and R.sub.6 is selected from hydrogen, alkyl and O-alkyl.

12. The compound according to claim 1, which is a compound selected from: 5-[3-({4′-fluoro-[1,1′-biphenyl]-2-yl}amino)propyl]-1,3,4-thiadiazol-2-amine; 5-{[2-({4′-fluoro-[1,1′-biphenyl]-2-yl}amino)ethyl]sulfanyl}-1,3,4-thiadiazol-2-amine; 5-{[2-({3′,4′-dimethoxy-[1,1′-biphenyl]-2-yl}amino)ethyl]sulfanyl}-1,3,4-thiadiazol-2-amine; 5-[4-({4′-fluoro-[1,1′-biphenyl]-2-yl}amino)phenyl]-1,3,4-thiadiazol-2-amine; 5-(4-{[2-(3,4-dimethoxyphenyl)phenyl]amino}phenyl)-1,3,4-thiadiazol-2-amine; 5-(4-{[2-(4-methoxyphenyl)phenyl]amino}phenyl)-1,3,4-thiadiazol-2-amine; N-[4-(5-amino-1,3,4-thiadiazol-2-yl)phenyl]-3-(4-methoxyphenyl)pyridin-2-amine; N-[4-(5-amino-1,3,4-thiadiazol-2-yl)phenyl]-3-(4-methoxyphenyl)pyridin-4-amine; N-[4-(5-amino-1,3,4-thiadiazol-2-yl)phenyl]-3-(3,4-dimethoxyphenyl)pyridin-4-amine; N-[4-(5-amino-1,3,4-thiadiazol-2-yl)phenyl]-3-(4-fluorophenyl)pyridin-2-amine; N-[4-(5-amino-1,3,4-thiadiazol-2-yl)phenyl]-3-(4-fluorophenyl)pyrazin-2-amine; 5-(4-{[2-(4-phenoxyphenyl)phenyl]amino}phenyl)-1,3,4-thiadiazol-2-amine; 5-(4-{[2-(4-propoxyphenyl)phenyl]amino}phenyl)-1,3,4-thiadiazol-2-amine; 5-[4-({2-[4-(propan-2-yloxy)phenyl]phenyl}amino)phenyl]-1,3,4-thiadiazol-2-amine; N-[3-(5-amino-1,3,4-thiadiazol-2-yl)propyl]-4-fluorobenzene-1-sulfonamide; N-{2-[(5-amino-1,3,4-thiadiazol-2-yl)sulfanyl]ethyl}-4-fluorobenzene-1-sulfonamide; 5-(3-{[(4-fluorophenyl)(methyl)oxo-λω-sulfanylidene]amino}propyl)-1,3,4-thiadiazol-2-amine; N-[4-(2-amino-1,3-thiazol-5-yl)phenyl]-4-fluorobenzene-1-sulfonamide; N-[4-(2-amino-1,3-thiazol-5-yl)phenyl]-3,4-dimethoxybenzene-1-sulfonamide; 5-(1-{4′-fluoro-[1,1′-biphenyl]-2-yl}piperidin-4-yl)-1,3,4-thiadiazol-2-amine; 5-[1-(4-fluorobenzenesulfonyl)piperdino-4-yl]-1,3-thiazol-2-amine; 5-[1-(4-fluorobenzenesulfonyl)piperidin-4-yl]-1,3,4-thiadiazol-2-amine; or a pharmaceutically acceptable salt or solvate thereof, including all tautomers and stereoisomers.

13. A pharmaceutical composition comprising a compound according to claim 1 optionally in combination with one or more therapeutically acceptable diluents or carriers.

14. The pharmaceutical composition of claim 13, which comprises additionally at least one compound, selected from the group consisting of neuroprotectants, antiparkinsonian drugs, amyloid protein deposition inhibitors, beta amyloid synthesis inhibitors, antidepressants, anxiolytic drugs, antipsychotic drugs and anti-multiple sclerosis drugs.

15. The pharmaceutical composition of claim 13, which comprises additionally at least one compound, selected from the group consisting of PEP-inhibitors, LiCl, inhibitors of inhibitors of DP IV or DP IV-like enzymes, acetylcholinesterase (ACE) inhibitors, PIMT enhancers, inhibitors of beta secretases, inhibitors of gamma secretases, inhibitors of neutral endopeptidase, inhibitors of Phosphodiesterase-4 (PDE-4), TNFalpha inhibitors, muscarinic M1 receptor antagonists, NMDA receptor antagonists, sigma-1 receptor inhibitors, histamine H3 antagonists, immunomodulatory agents, immunosuppressive agents or an agent selected from the group consisting of antegren (natalizumab), Neurelan (fampridine-SR), campath (alemtuzumab), IR 208, NBI 5788/MSP 771 (tiplimotide), paclitaxel, Anergix.MS (AG 284), SH636, Differin (CD 271, adapalene), BAY 361677 (interleukin-4), matrix-metalloproteinase-inhibitors, interferon-tau (trophoblastin) and SAIK-MS.

16. A method of treating a disease selected from the group consisting of Kennedy's disease, duodenal cancer with or without Helicobacter pylori infections, colorectal cancer, Zolliger-Ellison syndrome, gastric cancer with or without Helicobacter pylori infections, pathogenic psychotic conditions, schizophrenia, infertility, neoplasia, inflammatory host responses, cancer, malign metastasis, melanoma, psoriasis, impaired humoral and cell-mediated immune responses, leukocyte adhesion and migration processes in the endothelium, impaired food intake, impaired sleep-wakefulness, impaired homeostatic regulation of energy metabolism, impaired autonomic function, impaired hormonal balance or impaired regulation of body fluids, multiple sclerosis, the Guillain-Barré syndrome and chronic inflammatory demyelinizing polyradiculoneuropathy, said method comprising the step of administering to a subject in need thereof an effective amount of compound according to claim 1.

17. A method of treating a disease selected from the group consisting of mild cognitive impairment, Alzheimer's disease, Familial British Dementia, Familial Danish Dementia, neurodegeneration in Down Syndrome and Huntington's disease, said method comprising the step of administering to a subject in need thereof an effective amount of compound according to claim 1.

18. A method of treating a disease selected from the group consisting of rheumatoid arthritis, atherosclerosis, pancreatitis and restenosis, said method comprising the step of administering to a subject in need thereof an effective amount of compound according to claim 1.

Description

EXAMPLES

[0910] In a further embodiment, the present invention provides compounds of formula (IIa) and (IIb), wherein X.sub.1, n, Z, Y.sub.1, Y.sub.2, Y.sub.3, Y.sub.4, Y.sub.5, Y.sub.6, Y.sub.7, Y.sub.8, Y.sub.9, Y.sub.10, R.sub.5, and R.sub.6 are as defined in examples 1 to 265:

##STR00048##

TABLE-US-00003 Comp X.sub.1 n Z Y.sub.1 Y.sub.2 Y.sub.3 Y.sub.4 Y.sub.5 Y.sub.6 Y.sub.7 Y.sub.8 Y.sub.9 Y.sub.10 R.sub.5 R.sub.6 1 CH.sub.2 1 CH CH CH CH CH C CH CH CH CH CH H H 2 CH.sub.2 1 N CH CH CH CH C CH CH CH CH CH H H 3 S 1 N CH CH CH CH C CH CH CH CH CH H H 4 CH.sub.2 1 CH CH CH CH CH C N CH CH CH CH H H 5 CH.sub.2 1 N CH CH CH CH C N CH CH CH CH H H 6 S 1 N CH CH CH CH C N CH CH CH CH H H 7 CH.sub.2 1 CH CH CH CH CH C CH N CH CH CH H H 8 CH.sub.2 1 N CH CH CH CH C CH N CH CH CH H H 9 S 1 N CH CH CH CH C CH N CH CH CH H H 10 CH.sub.2 1 CH CH CH CH CH C N CH CH CH N H H 11 CH.sub.2 1 N CH CH CH CH C N CH CH CH N H H 12 S 1 N CH CH CH CH C N CH CH CH N H H 13 CH.sub.2 1 CH CH CH CH CH C N N CH CH CH H H 14 CH.sub.2 1 N CH CH CH CH C N N CH CH CH H H 15 S 1 N CH CH CH CH C N N CH CH CH H H 16 CH.sub.2 1 CH CH CH CH CH C CH N CH N CH H absent 17 CH.sub.2 1 N CH CH CH CH C CH N CH N CH H 18 S 1 N CH CH CH CH C CH N CH N CH H 19 CH2 1 CH CH CH CH CH C CH CH N CH N absent H 20 CH2 1 N CH CH CH CH C CH CH N CH N H 21 S 1 N CH CH CH CH C CH CH N CH N H 22 1 C CH CH CH CH H H 23 CH.sub.2 1 CH CH CH CH CH C CH CH N CH CH absent H 24 CH.sub.2 1 N CH CH CH CH C CH CH N CH CH H 25 S 1 N CH CH CH CH C CH CH N CH CH H 26 CH.sub.2 1 CH N CH CH CH C CH CH CH CH CH H H 27 CH.sub.2 1 N N CH CH CH C CH CH CH CH CH H H 28 S 1 N N CH CH CH C CH CH CH CH CH H H 29 CH.sub.2 1 CH N CH CH CH C N CH CH CH CH H H 30 CH.sub.2 1 N N CH CH CH C N CH CH CH CH H H 31 S 1 N N CH CH CH C N CH CH CH CH H H 32 CH.sub.2 1 CH N CH CH CH C CH N CH CH CH H H 33 CH.sub.2 1 N N CH CH CH C CH N CH CH CH H H 34 S 1 N N CH CH CH C CH N CH CH CH H H 35 CH.sub.2 1 CH N CH CH CH C N CH CH CH N H H 36 CH.sub.2 1 N N CH CH CH C N CH CH CH N H H 37 S 1 N N CH CH CH C N CH CH CH N H H 38 CH.sub.2 1 CH N CH CH CH C CH CH N CH N absent H 39 CH.sub.2 1 N N CH CH CH C CH CH N CH N H 40 S 1 N N CH CH CH C CH CH N CH N H 41 CH.sub.2 1 CH N CH CH CH C N CH CH CH CH H H 42 CH.sub.2 1 N N CH CH CH C N CH CH CH CH H H 43 S 1 N N CH CH CH C N CH CH CH CH H H 44 CH.sub.2 1 CH N N CH CH C CH CH N CH N absent H 45 CH.sub.2 1 N N N CH CH C CH CH N CH N H 46 S 1 N N N CH CH C CH CH N CH N H 47 CH.sub.2 1 CH N N CH CH C CH CH CH CH CH H H 48 CH.sub.2 1 N N N CH CH C CH CH CH CH CH H H 49 S 1 N N N CH CH C CH CH CH CH CH H H 50 CH.sub.2 1 CH CH N CH CH C CH CH CH CH CH H H 51 CH.sub.2 1 N CH N CH CH C CH CH CH CH CH H H 52 S 1 N CH N CH CH C CH CH CH CH CH H H 53 CH.sub.2 1 CH CH N CH CH C N CH CH CH CH H H 54 CH.sub.2 1 N CH N CH CH C N CH CH CH CH H H 55 S 1 N CH N CH CH C N CH CH CH CH H H 56 CH.sub.2 1 CH CH N CH CH C CH N CH CH CH H H 57 CH.sub.2 1 N CH N CH CH C CH N CH CH CH H H 58 S 1 N CH N CH CH C CH N CH CH CH H H 59 CH.sub.2 1 CH CH N CH CH C CH N CH N CH H absent 60 CH.sub.2 1 N CH N CH CH C CH N CH N CH H 61 S 1 N CH N CH CH C CH N CH N CH H 62 CH.sub.2 1 CH CH N CH CH C N CH CH N CH H H 63 CH.sub.2 1 N CH N CH CH C N CH CH N CH H H 64 S 1 N CH N CH CH C N CH CH N CH H H 65 CH.sub.2 1 CH CH N CH CH C CH CH N CH N absent H 66 CH.sub.2 1 N CH N CH CH C CH CH N CH N H 67 S 1 N CH N CH CH C CH CH N CH N H 68 CH.sub.2 1 CH CH N CH CH C CH CH N CH CH absent H 69 CH.sub.2 1 N CH N CH CH C CH CH N CH CH H 70 S 1 N CH N CH CH C CH CH N CH CH H 71 CH.sub.2 1 CH N CH N CH C CH CH CH CH CH H H 72 CH.sub.2 1 N N CH N CH C CH CH CH CH CH H H 73 S 1 N N CH N CH C CH CH CH CH CH H H 74 CH.sub.2 1 CH N CH N CH C N CH CH CH CH H H 75 CH.sub.2 1 N N CH N CH C N CH CH CH CH H H 76 S 1 N N CH N CH C N CH CH CH CH H H 77 CH.sub.2 1 CH N CH N CH C CH N CH CH CH H H 78 CH.sub.2 1 N N CH N CH C CH N CH CH CH H H 79 S 1 N N CH N CH C CH N CH CH CH H H 80 CH.sub.2 1 CH CH N CH N C CH CH CH CH CH H H 81 CH.sub.2 1 N CH N CH N C CH CH CH CH CH H H 82 S 1 N CH N CH N C CH CH CH CH CH H H 83 CH.sub.2 1 CH CH CH N N C CH CH CH CH CH H H 84 CH.sub.2 1 N CH CH N N C CH CH CH CH CH H H 85 S 1 N CH CH N N C CH CH CH CH CH H H 86 CH.sub.2 1 CH CH CH CH N C CH CH CH CH CH H H 87 CH.sub.2 1 N CH CH CH N C CH CH CH CH CH H H 88 S 1 N CH CH CH N C CH CH CH CH CH H H 89 CH.sub.2 1 CH CH CH CH N C CH CH N CH CH absent H 90 CH.sub.2 1 N CH CH CH N C CH CH N CH CH H 91 S 1 N CH CH CH N C CH CH N CH CH H 92 CH.sub.2 1 CH CH CH CH CH C CH CH CH CH CH F H 93 CH.sub.2 1 N CH CH CH CH C CH CH CH CH CH F H 94 S 1 N CH CH CH CH C CH CH CH CH CH F H 95 CH.sub.2 1 CH CH CH CH CH C N CH CH CH CH F H 96 CH.sub.2 1 N CH CH CH CH C N CH CH CH CH F H 97 S 1 N CH CH CH CH C N CH CH CH CH F H 98 CH.sub.2 1 CH CH CH CH CH C CH N CH CH CH F H 99 CH.sub.2 1 N CH CH CH CH C CH N CH CH CH F H 100 S 1 N CH CH CH CH C CH N CH CH CH F H 101 CH.sub.2 1 CH CH CH CH CH C N CH CH CH N F H 102 CH.sub.2 1 N CH CH CH CH C N CH CH CH N F H 103 S 1 N CH CH CH CH C N CH CH CH N F H 104 CH.sub.2 1 CH CH CH CH CH C N N CH CH CH F H 105 CH.sub.2 1 N CH CH CH CH C N N CH CH CH F H 106 S 1 N CH CH CH CH C N N CH CH CH F H 107 CH.sub.2 1 CH CH CH CH CH C CH N CH N CH F absent 108 CH.sub.2 1 N CH CH CH CH C CH N CH N CH F 109 S 1 N CH CH CH CH C CH N CH N CH F 110 CH.sub.2 1 CH CH CH CH CH C CH CH N CH N absent 111 CH.sub.2 1 N CH CH CH CH C CH CH N CH N 112 S 1 N CH CH CH CH C CH CH N CH N 113 CH.sub.2 1 CH CH CH CH CH C CH CH N CH CH absent H 114 CH.sub.2 1 N CH CH CH CH C CH CH N CH CH H 115 S 1 N CH CH CH CH C CH CH N CH CH H 116 CH.sub.2 1 CH N CH CH CH C CH CH CH CH CH F H 117 CH.sub.2 1 N N CH CH CH C CH CH CH CH CH F H 118 S 1 N N CH CH CH C CH CH CH CH CH F H 119 CH.sub.2 1 CH N CH CH CH C N CH CH CH CH F H 120 CH.sub.2 1 N N CH CH CH C N CH CH CH CH F H 121 S 1 N N CH CH CH C N CH CH CH CH F H 122 CH.sub.2 1 CH N CH CH CH C CH N CH CH CH F H 123 CH.sub.2 1 N N CH CH CH C CH N CH CH CH F H 124 S 1 N N CH CH CH C CH N CH CH CH F H 125 CH.sub.2 1 CH N CH CH CH C N CH CH CH F H 126 CH.sub.2 1 N N CH CH CH C N CH CH CH F H 127 S 1 N N CH CH CH C N CH CH CH F H 128 CH.sub.2 1 CH N CH CH CH C CH CH N CH N absent H 129 CH.sub.2 1 N N CH CH CH C CH CH N CH N H 130 S 1 N N CH CH CH C CH CH N CH N H 131 CH.sub.2 1 CH N N CH CH C CH CH CH CH CH F H 132 CH.sub.2 1 N N N CH CH C CH CH CH CH CH F H 133 S 1 N N N CH CH C CH CH CH CH CH F H 134 CH.sub.2 1 CH N N CH CH C CH CH N CH N absent H 135 CH.sub.2 1 N N N CH CH C CH CH N CH N H 136 S 1 N N N CH CH C CH CH N CH N H 137 CH.sub.2 1 CH CH N CH CH C CH CH CH CH CH F H 138 CH.sub.2 1 N CH N CH CH C CH CH CH CH CH F H 139 S 1 N CH N CH CH C CH CH CH CH CH F H 140 CH.sub.2 1 CH CH N CH CH C N CH CH CH CH F H 141 CH.sub.2 1 N CH N CH CH C N CH CH CH CH F H 142 S 1 N CH N CH CH C N CH CH CH CH F H 143 CH.sub.2 1 CH CH N CH CH C CH N CH CH CH F H 144 CH.sub.2 1 N CH N CH CH C CH N CH CH CH F H 145 S 1 N CH N CH CH C CH N CH CH CH F H 146 CH.sub.2 1 CH CH N CH CH C CH N CH N CH F absent 147 CH.sub.2 1 N CH N CH CH C CH N CH N CH F 148 S 1 N CH N CH CH C CH N CH N CH F 149 CH.sub.2 1 CH CH N CH CH C N CH CH N CH F absent 150 CH.sub.2 1 N CH N CH CH C N CH CH N CH F 151 S 1 N CH N CH CH C N CH CH N CH F 152 CH.sub.2 1 CH CH N CH CH C CH CH N CH N absent H 153 CH.sub.2 1 N CH N CH CH C CH CH N CH N H 154 S 1 N CH N CH CH C CH CH N CH N H 155 CH.sub.2 1 CH N CH N CH C CH CH CH CH CH F H 156 CH.sub.2 1 N N CH N CH C CH CH CH CH CH F H 157 S 1 N N CH N CH C CH CH CH CH CH F H 158 CH.sub.2 1 CH N CH N CH C N CH CH CH CH F H 159 CH.sub.2 1 N N CH N CH C N CH CH CH CH F H 160 S 1 N N CH N CH C N CH CH CH CH F H 161 CH.sub.2 1 CH N CH N CH C CH N CH CH CH F H 162 CH.sub.2 1 N N CH N CH C CH N CH CH CH F H 163 S 1 N N CH N CH C CH N CH CH CH F H 164 CH.sub.2 1 CH CH N CH N C CH CH CH CH CH F H 165 CH.sub.2 1 N CH N CH N C CH CH CH CH CH F H 166 S 1 N CH N CH N C CH CH CH CH CH F H 167 CH.sub.2 1 CH CH CH N N C CH CH CH CH CH F H 168 CH.sub.2 1 N CH CH N N C CH CH CH CH CH F H 169 S 1 N CH CH N N C CH CH CH CH CH F H 170 CH.sub.2 1 CH CH CH CH N C CH CH CH CH CH F H 171 CH.sub.2 1 N CH CH CH N C CH CH CH CH CH F H 172 S 1 N CH CH CH N C CH CH CH CH CH F H 173 CH.sub.2 1 CH CH CH CH N C CH N CH CH CH F H 174 CH.sub.2 1 N CH CH CH N C CH N CH CH CH F H 175 S 1 N CH CH CH N C CH N CH CH CH F H 176 CH.sub.2 1 CH CH CH CH CH C CH CH CH CH CH OMe OMe 177 CH.sub.2 1 N CH CH CH CH C CH CH CH CH CH OMe OMe 178 S 1 N CH CH CH CH C CH CH CH CH CH OMe OMe 179 CH.sub.2 1 CH CH CH CH CH C N CH CH CH CH OMe OMe 180 CH.sub.2 1 N CH CH CH CH C N CH CH CH CH OMe OMe 181 S 1 N CH CH CH CH C N CH CH CH CH OMe OMe 182 CH.sub.2 1 CH CH CH CH CH C CH N CH CH CH OMe OMe 183 CH.sub.2 1 N CH CH CH CH C CH N CH CH CH OMe OMe 184 S 1 N CH CH CH CH C CH N CH CH CH OMe OMe 185 CH.sub.2 1 CH CH CH CH CH C N CH CH CH N OMe OMe 186 CH.sub.2 1 N CH CH CH CH C N CH CH CH N OMe OMe 187 S 1 N CH CH CH CH C N CH CH CH N OMe OMe 188 CH.sub.2 1 CH CH CH CH CH C N N CH CH CH OMe OMe 189 CH.sub.2 1 N CH CH CH CH C N N CH CH CH OMe OMe 190 S 1 N CH CH CH CH C N N CH CH CH OMe OMe 191 CH.sub.2 1 CH CH CH CH CH C CH N CH N CH OMe absent 192 CH.sub.2 1 N CH CH CH CH C CH N CH N CH OMe 193 S 1 N CH CH CH CH C CH N CH N CH OMe 194 CH.sub.2 1 CH CH CH CH CH C CH CH N CH N absent OMe 195 CH.sub.2 1 N CH CH CH CH C CH CH N CH N OMe 196 S 1 N CH CH CH CH C CH CH N CH N OMe 197 CH.sub.2 1 CH CH CH CH CH C CH CH N CH CH absent OMe 198 CH.sub.2 1 N CH CH CH CH C CH CH N CH CH OMe 199 S 1 N N CH CH CH C CH CH N CH CH OMe 200 CH.sub.2 1 CH N CH CH CH C CH CH CH CH CH OMe OMe 201 CH.sub.2 1 N N CH CH CH C CH CH CH CH CH OMe OMe 202 S 1 N N CH CH CH C CH CH CH CH CH OMe OMe 203 CH.sub.2 1 CH N CH CH CH C N N CH CH CH OMe OMe 204 CH2 1 N N CH CH CH C N CH CH CH CH OMe OMe 205 S 1 N N CH CH CH C N CH CH CH CH OMe OMe 206 CH.sub.2 1 CH N CH CH CH C CH N CH CH CH OMe OMe 207 CH.sub.2 1 N N CH CH CH C CH N CH CH CH OMe OMe 208 S 1 N N CH CH CH C CH N CH CH CH OMe OMe 209 CH.sub.2 1 CH N CH CH CH C N CH CH CH N OMe OMe 210 CH.sub.2 1 N N CH CH CH C N CH CH CH N OMe OMe 211 S 1 N N CH CH CH C N CH CH CH N OMe OMe 212 CH.sub.2 1 CH N CH CH CH C CH CH N CH N absent OMe 213 CH.sub.2 1 N N CH CH CH C CH CH N CH N OMe 214 S 1 N N CH CH CH C CH CH N CH N OMe 215 CH.sub.2 1 CH N CH CH CH C N CH CH CH CH OMe OMe 216 CH.sub.2 1 N N CH CH CH C N CH CH CH CH OMe OMe 217 S 1 N N CH CH CH C N CH CH CH CH OMe OMe 218 CH.sub.2 1 CH N N CH CH C CH CH N CH N absent OMe 219 CH.sub.2 1 N N N CH CH C CH CH N CH N OMe 220 S 1 N N N CH CH C CH CH N CH N OMe 221 CH.sub.2 1 CH N N CH CH C CH CH CH CH CH OMe OMe 222 CH.sub.2 1 N N N CH CH C CH CH CH CH CH OMe OMe 223 S 1 N N N CH CH C CH CH CH CH CH OMe OMe 224 CH.sub.2 1 CH CH N CH CH C CH CH CH CH CH OMe OMe 225 CH.sub.2 1 N CH N CH CH C CH CH CH CH CH OMe OMe 226 S 1 N CH N CH CH C CH CH CH CH CH OMe OMe 227 CH.sub.2 1 CH CH N CH CH C N CH CH CH CH OMe OMe 228 CH.sub.2 1 N CH N CH CH C N CH CH CH CH OMe OMe 229 S 1 N CH N CH CH C N CH CH CH CH OMe OMe 230 CH.sub.2 1 CH CH N CH CH C CH N CH CH CH OMe OMe 231 CH.sub.2 1 N CH N CH CH C CH N CH CH CH OMe OMe 232 S 1 N CH N CH CH C CH N CH CH CH OMe OMe 233 CH.sub.2 1 CH CH N CH CH C CH N CH N CH OMe absent 234 CH.sub.2 1 N CH N CH CH C CH N CH N CH OMe 235 S 1 N CH N CH CH C CH N CH N CH OMe 236 CH.sub.2 1 CH CH N CH CH C N CH CH N CH OMe OMe 237 CH.sub.2 1 N CH N CH CH C N CH CH N CH OMe OMe 238 S 1 N CH N CH CH C N CH CH N CH OMe OMe 239 CH.sub.2 1 CH CH N CH CH C CH CH N CH N absent OMe 240 CH.sub.2 1 N CH N CH CH C CH CH N CH N OMe 241 S 1 N CH N CH CH C CH CH N CH N OMe 242 CH.sub.2 1 CH CH N CH CH C CH CH N CH CH absent OMe 243 CH.sub.2 1 N CH N CH CH C CH CH N CH CH OMe 244 S 1 N CH N CH CH C CH CH N CH CH OMe 245 CH.sub.2 1 CH N CH N CH C CH CH CH CH CH OMe OMe 246 CH.sub.2 1 N N CH N CH C CH CH CH CH CH OMe OMe 247 S 1 N N CH N CH C CH CH CH CH CH OMe OMe 248 CH.sub.2 1 CH N CH N CH C N CH CH CH CH OMe OMe 249 CH.sub.2 1 N N CH N CH C N CH CH CH CH OMe OMe 250 S 1 N N CH N CH C N CH CH CH CH OMe OMe 251 CH.sub.2 1 CH N CH N CH C CH N CH CH CH OMe OMe 252 CH.sub.2 1 N N CH N CH C CH N CH CH CH OMe OMe 253 S 1 N N CH N CH C CH N CH CH CH OMe OMe 254 CH.sub.2 1 CH CH N CH N C CH CH CH CH CH OMe OMe 255 CH.sub.2 1 N CH N CH N C CH CH CH CH CH OMe OMe 256 S 1 N CH N CH N C CH CH CH CH CH OMe OMe 257 CH.sub.2 1 CH CH CH N N C CH CH CH CH CH OMe OMe 258 CH.sub.2 1 N CH CH N N C CH CH CH CH CH OMe OMe 259 S 1 N CH CH N N C CH CH CH CH CH OMe OMe 260 CH.sub.2 1 CH CH CH CH N C CH CH CH CH CH OMe OMe 261 CH.sub.2 1 N CH CH CH N C CH CH CH CH CH OMe OMe 262 S 1 N CH CH CH N C CH CH CH CH CH OMe OMe 263 CH.sub.2 1 CH CH CH CH N C CH CH N CH CH absent OMe 264 CH.sub.2 1 N CH CH CH N C CH CH N CH CH OMe 265 S 1 N CH CH CH N C CH CH N CH CH OMe

[0911] In a further embodiment, the present invention provides compounds of formula (IIIa) and (IIIb), wherein X.sub.1, n, Y.sub.1, Y.sub.2, Y.sub.3, Y.sub.4, Y.sub.5, Y.sub.6, Y.sub.7, Y.sub.8, Y.sub.9, Y.sub.10, R.sub.5, and R.sub.6 are as defined in examples 266 to 443:

##STR00049##

TABLE-US-00004 Comp X.sub.1 n Y.sub.1 Y.sub.2 Y.sub.3 Y.sub.4 Y.sub.5 Y.sub.6 Y.sub.7 Y.sub.8 Y.sub.9 Y.sub.10 R.sub.5 R.sub.6 266 CH.sub.2 1 CH CH CH CH C CH CH CH CH CH H H 267 S 1 CH CH CH CH C CH CH CH CH CH H H 268 CH.sub.2 1 CH CH CH CH C N CH CH CH CH H H 269 S 1 CH CH CH CH C N CH CH CH CH H H 270 CH.sub.2 1 CH CH CH CH C CH N CH CH CH H H 271 S 1 CH CH CH CH C CH N CH CH CH H H 272 CH.sub.2 1 CH CH CH CH C N CH CH CH N H H 273 S 1 CH CH CH CH C N CH CH CH N H H 274 CH.sub.2 1 CH CH CH CH C N N CH CH CH H H 275 S 1 CH CH CH CH C N N CH CH CH H H 276 CH.sub.2 1 CH CH CH CH C CH N CH N CH H absent 277 S 1 CH CH CH CH C CH N CH N CH H 278 CH.sub.2 1 CH CH CH CH C CH CH N CH N absent H 279 S 1 CH CH CH CH C CH CH N CH N H 280 CH.sub.2 1 CH CH CH CH C CH CH N CH CH absent H 281 S 1 CH CH CH CH C CH CH N CH CH H 282 CH.sub.2 1 N CH CH CH C CH CH CH CH CH H H 283 S 1 N CH CH CH C CH CH CH CH CH H H 284 CH.sub.2 1 N CH CH CH C N CH CH CH CH H H 285 S 1 N CH CH CH C N CH CH CH CH H H 286 CH.sub.2 1 N CH CH CH C CH N CH CH CH H H 287 CH.sub.2 1 N CH CH CH C CH N CH CH CH H H 288 S 1 N CH CH CH C CH N CH CH CH H H 289 CH.sub.2 1 N CH CH CH C N CH CH CH N H H 290 S 1 N CH CH CH C N CH CH CH N H H 291 CH.sub.2 1 N CH CH CH C CH CH N CH N absent H 292 S 1 N CH CH CH C CH CH N CH N H 293 CH.sub.2 1 N CH CH CH C N CH CH CH CH H H 294 S 1 N CH CH CH C N CH CH CH CH H H 295 CH.sub.2 1 N N CH CH C CH CH N CH N absent H 296 CH.sub.2 1 N N CH CH C CH CH N CH N H 297 S 1 N N CH CH C CH CH N CH N H 298 CH.sub.2 1 N N CH CH C CH CH CH CH CH H H 299 S 1 N N CH CH C CH CH CH CH CH H H 300 CH.sub.2 1 CH N CH CH C CH CH CH CH CH H H 301 S 1 CH N CH CH C CH CH CH CH CH H H 302 CH.sub.2 1 CH N CH CH C N CH CH CH CH H H 303 S 1 CH N CH CH C N CH CH CH CH H H 304 CH.sub.2 1 CH N CH CH C CH N CH CH CH H H 305 S 1 CH N CH CH C CH N CH CH CH H H 306 CH.sub.2 1 CH N CH CH C CH N CH N CH H absent 307 S 1 CH N CH CH C CH N CH N CH H 308 CH.sub.2 1 CH N CH CH C N CH CH N CH H H 309 S 1 CH N CH CH C N CH CH N CH H H 310 CH.sub.2 1 CH N CH CH C CH CH N CH N absent H 311 S 1 CH N CH CH C CH CH N CH N H 312 CH.sub.2 1 CH N CH CH C CH CH N CH CH absent H 313 S 1 CH N CH CH C CH CH N CH CH H 314 CH.sub.2 1 N CH N CH C CH CH CH CH CH H H 315 S 1 N CH N CH C CH CH CH CH CH H H 316 CH.sub.2 1 N CH N CH C N CH CH CH CH H H 317 S 1 N CH N CH C N CH CH CH CH H H 318 CH.sub.2 1 N CH N CH C CH N CH CH CH H H 319 S 1 N CH N CH C CH N CH CH CH H H 320 CH.sub.2 1 CH N CH N C CH CH CH CH CH H H 321 S 1 CH N CH N C CH CH CH CH CH H H 322 CH.sub.2 1 CH CH N N C CH CH CH CH CH H H 323 S 1 CH CH N N C CH CH CH CH CH H H 324 CH.sub.2 1 CH CH CH N C CH CH CH CH CH H H 325 S 1 CH CH CH N C CH CH CH CH CH H H 326 CH.sub.2 1 CH CH CH N C CH CH N CH CH absent H 327 S 1 CH CH CH N C CH CH N CH CH H 328 CH.sub.2 1 CH CH CH CH C CH CH CH CH CH F H 329 S 1 CH CH CH CH C CH CH CH CH CH F H 330 CH.sub.2 1 CH CH CH CH C N CH CH CH CH F H 331 S 1 CH CH CH CH C N CH CH CH CH F H 332 CH.sub.2 1 CH CH CH CH C CH N CH CH CH F H 333 S 1 CH CH CH CH C CH N CH CH CH F H 334 CH.sub.2 1 CH CH CH CH C N CH CH CH N F H 335 S 1 CH CH CH CH C N CH CH CH N F H 336 CH.sub.2 1 CH CH CH CH C N N CH CH CH F H 337 S 1 CH CH CH CH C N N CH CH CH F H 338 CH.sub.2 1 CH CH CH CH C CH N CH N CH F absent 339 S 1 CH CH CH CH C CH N CH N CH F 340 CH.sub.2 1 CH CH CH CH C CH CH N CH N absent 341 S 1 CH CH CH CH C CH CH N CH N 342 CH.sub.2 1 CH CH CH CH C CH CH N CH CH absent H 343 S 1 CH CH CH CH C CH CH N CH CH H 344 CH.sub.2 1 N CH CH CH C CH CH CH CH CH F H 345 S 1 N CH CH CH C CH CH CH CH CH F H 346 CH.sub.2 1 N CH CH CH C N CH CH CH CH F H 347 S 1 N CH CH CH C N CH CH CH CH F H 348 CH.sub.2 1 N CH CH CH C CH N CH CH CH F H 349 S 1 N CH CH CH C CH N CH CH CH F H 350 CH.sub.2 1 N CH CH CH C N CH CH CH N F H 351 S 1 N CH CH CH C N CH CH CH N F H 352 CH.sub.2 1 N CH CH CH C CH CH N CH N absent H 353 S 1 N CH CH CH C CH CH N CH N H 354 CH.sub.2 1 N N CH CH C CH CH CH CH CH F H 355 S 1 N N CH CH C CH CH CH CH CH F H 356 CH.sub.2 1 N N CH CH C CH CH N CH N absent H 357 S 1 N N CH CH C CH CH N CH N H 358 CH.sub.2 1 CH N CH CH C CH CH CH CH CH F H 359 S 1 CH N CH CH C CH CH CH CH CH F H 360 CH.sub.2 1 CH N CH CH C N CH CH CH CH F H 361 S 1 CH N CH CH C N CH CH CH CH F H 362 CH.sub.2 1 CH N CH CH C CH N CH CH CH F H 363 S 1 CH N CH CH C CH N CH CH CH F H 364 CH.sub.2 1 CH N CH CH C CH N CH N CH F absent 365 S 1 CH N CH CH C CH N CH N CH F 366 CH.sub.2 1 CH N CH CH C N CH CH N CH F absent 367 S 1 CH N CH CH C N CH CH N CH F 368 CH.sub.2 1 CH N CH CH C CH CH N CH N absent H 369 S 1 CH N CH CH C CH CH N CH N H 370 CH.sub.2 1 N CH N CH C CH CH CH CH CH F H 371 S 1 N CH N CH C CH CH CH CH CH F H 372 CH.sub.2 1 N CH N CH C N CH CH CH CH F H 373 S 1 N CH N CH C N CH CH CH CH F H 374 CH.sub.2 1 N CH N CH C CH N CH CH CH F H 375 S 1 N CH N CH C CH N CH CH CH F H 376 CH.sub.2 1 CH N CH N C CH CH CH CH CH F H 377 S 1 CH N CH N C CH CH CH CH CH F H 378 CH.sub.2 1 CH CH N N C CH CH CH CH CH F H 379 S 1 CH CH N N C CH CH CH CH CH F H 380 CH.sub.2 1 CH CH CH N C CH CH CH CH CH F H 381 S 1 CH CH CH N C CH CH CH CH CH F H 382 CH.sub.2 1 CH CH CH N C CH N CH CH CH F H 383 S 1 CH CH CH N C CH N CH CH CH F H 384 CH.sub.2 1 CH CH CH CH C CH CH CH CH CH OMe OMe 385 S 1 CH CH CH CH C CH CH CH CH CH OMe OMe 386 CH.sub.2 1 CH CH CH CH C N CH CH CH CH OMe OMe 387 S 1 CH CH CH CH C N CH CH CH CH OMe OMe 388 CH.sub.2 1 CH CH CH CH C CH N CH CH CH OMe OMe 389 S 1 CH CH CH CH C CH N CH CH CH OMe OMe 390 CH.sub.2 1 CH CH CH CH C N CH CH CH N OMe OMe 391 S 1 CH CH CH CH C N CH CH CH N OMe OMe 392 CH.sub.2 1 CH CH CH CH C N N CH CH CH OMe OMe 393 S 1 CH CH CH CH C N N CH CH CH OMe OMe 394 CH.sub.2 1 CH CH CH CH C CH N CH N CH OMe absent 395 S 1 CH CH CH CH C CH N CH N CH OMe 396 CH.sub.2 1 CH CH CH CH C CH CH N CH N absent OMe 397 S 1 CH CH CH CH C CH CH N CH N OMe 398 CH.sub.2 1 CH CH CH CH C CH CH N CH CH absent OMe 399 S 1 CH CH CH CH C CH CH N CH CH OMe 400 CH.sub.2 1 N CH CH CH C CH CH CH CH CH OMe OMe 401 S 1 N CH CH CH C CH CH CH CH CH OMe OMe 402 CH.sub.2 1 N CH CH CH C N CH CH CH CH OMe OMe 403 S 1 N CH CH CH C N CH CH CH CH OMe OMe 404 CH.sub.2 1 N CH CH CH C CH N CH CH CH OMe OMe 405 S 1 N CH CH CH C CH N CH CH CH OMe OMe 406 CH.sub.2 1 N CH CH CH C N CH CH CH N OMe OMe 407 S 1 N CH CH CH C N CH CH CH N OMe OMe 408 CH.sub.2 1 N CH CH CH C CH CH N CH N absent OMe 409 S 1 N CH CH CH C CH CH N CH N OMe 410 CH.sub.2 1 N CH CH CH C N CH CH CH CH OMe OMe 411 S 1 N CH CH CH C N CH CH CH CH OMe OMe 412 CH.sub.2 1 N N CH CH C CH CH N CH N absent OMe 413 S 1 N N CH CH C CH CH N CH N OMe 414 CH.sub.2 1 N N CH CH C CH CH CH CH CH OMe OMe 415 S 1 N N CH CH C CH CH CH CH CH OMe OMe 416 CH.sub.2 1 CH N CH CH C CH CH CH CH CH OMe OMe 417 S 1 CH N CH CH C CH CH CH CH CH OMe OMe 418 CH.sub.2 1 CH N CH CH C N CH CH CH CH OMe OMe 419 S 1 CH N CH CH C N CH CH CH CH OMe OMe 420 CH.sub.2 1 CH N CH CH C CH N CH CH CH OMe OMe 421 S 1 CH N CH CH C CH N CH CH CH OMe OMe 422 CH.sub.2 1 CH N CH CH C CH N CH N CH OMe absent 423 S 1 CH N CH CH C CH N CH N CH OMe 424 CH.sub.2 1 CH N CH CH C N CH CH N CH OMe OMe 425 S 1 CH N CH CH C N CH CH N CH OMe OMe 426 CH.sub.2 1 CH N CH CH C CH CH N CH N absent OMe 427 S 1 CH N CH CH C CH CH N CH N OMe 428 CH.sub.2 1 CH N CH CH C CH CH N CH CH OMe absent 429 S 1 CH N CH CH C CH CH N CH CH OMe 430 CH.sub.2 1 N CH N CH C CH CH CH CH CH OMe OMe 431 S 1 N CH N CH C CH CH CH CH CH OMe OMe 432 CH.sub.2 1 N CH N CH C N CH CH CH CH OMe OMe 433 S 1 N CH N CH C N CH CH CH CH OMe OMe 434 CH.sub.2 1 N CH N CH C CH N CH CH CH OMe OMe 435 S 1 N CH N CH C CH N CH CH CH OMe OMe 436 CH.sub.2 1 CH N CH N C CH CH CH CH CH OMe OMe 437 S 1 CH N CH N C CH CH CH CH CH OMe OMe 438 CH.sub.2 1 CH CH N N C CH CH CH CH CH OMe OMe 439 S 1 CH CH N N C CH CH CH CH CH OMe OMe 440 CH.sub.2 1 CH CH CH N C CH CH CH CH CH OMe OMe 441 S 1 CH CH CH N C CH CH CH CH CH OMe OMe 442 CH.sub.2 1 CH CH CH N C CH CH N CH CH absent OMe 443 S 1 CH CH CH N C CH CH N CH CH OMe

[0912] In a further embodiment, the present invention provides compounds of formula (Iva) and (IVb), wherein X.sub.1, o, Z, Y.sub.1, Y.sub.2, Y.sub.3, Y.sub.4, Y.sub.5, Y.sub.6, Y.sub.7, Y.sub.8, Y.sub.9, Y.sub.10, R.sub.5, and R.sub.6 are as defined in examples 444 to 795:

##STR00050##

[0913] In both, formulae (IVa) and (IVb), o is 0.

TABLE-US-00005 Comp p Z Y.sub.1 Y.sub.2 Y.sub.3 Y.sub.4 Y.sub.5 Y.sub.6 Y.sub.7 Y.sub.8 Y.sub.9 Y.sub.10 R.sub.5 R.sub.6 444 0 CH CH CH CH CH C CH CH CH CH CH H H 445 0 N CH CH CH CH C CH CH CH CH CH H H 446 0 CH CH CH CH CH C N CH CH CH CH H H 447 0 N CH CH CH CH C N CH CH CH CH H H 448 0 CH CH CH CH CH C CH N CH CH CH H H 449 0 N CH CH CH CH C CH N CH CH CH H H 450 0 CH CH CH CH CH C N CH CH CH N H H 451 0 N CH CH CH CH C N CH CH CH N H H 452 0 CH CH CH CH CH C N N CH CH CH H H 453 0 N CH CH CH CH C N N CH CH CH H H 454 0 CH CH CH CH CH C CH N CH N CH H absent 455 0 N CH CH CH CH C CH N CH N CH H 456 0 CH CH CH CH CH C CH CH N CH N absent H 457 0 N CH CH CH CH C CH CH N CH N H 458 0 CH CH CH CH CH C CH CH N CH CH absent H 459 0 N CH CH CH CH C CH CH N CH CH H 460 0 CH N CH CH CH C CH CH CH CH CH H H 461 0 N N CH CH CH C CH CH CH CH CH H H 462 0 CH N CH CH CH C N CH CH CH CH H H 463 0 N N CH CH CH C N CH CH CH CH H H 464 0 CH N CH CH CH C CH N CH CH CH H H 465 0 N N CH CH CH C CH N CH CH CH H H 466 0 CH N CH CH CH C N CH CH CH N H H 467 0 N N CH CH CH C N CH CH CH N H H 468 0 CH N CH CH CH C CH CH N CH N absent H 469 0 N N CH CH CH C CH CH N CH N H 470 0 CH N CH CH CH C N CH CH CH CH H H 471 0 N N CH CH CH C N CH CH CH CH H H 472 0 CH N N CH CH C CH CH N CH N absent H 473 0 N N N CH CH C CH CH N CH N H 474 0 CH N N CH CH C CH CH CH CH CH H H 475 0 N N N CH CH C CH CH CH CH CH H H 476 0 CH CH N CH CH C CH CH CH CH CH H H 477 0 N CH N CH CH C CH CH CH CH CH H H 478 0 CH CH N CH CH C N CH CH CH CH H H 479 0 N CH N CH CH C N CH CH CH CH H H 480 0 CH CH N CH CH C CH N CH CH CH H H 481 0 N CH N CH CH C CH N CH CH CH H H 482 0 CH CH N CH CH C CH N CH N CH H absent 483 0 N CH N CH CH C CH N CH N CH H 484 0 CH CH N CH CH C N CH CH N CH H H 485 0 N CH N CH CH C N CH CH N CH H H 486 0 CH CH N CH CH C CH CH N CH N absent H 487 0 N CH N CH CH C CH CH N CH N H 488 0 CH CH N CH CH C CH CH N CH CH absent H 489 0 N CH N CH CH C CH CH N CH CH H 490 0 CH N CH N CH C CH CH CH CH CH H H 491 0 N N CH N CH C CH CH CH CH CH H H 492 0 CH N CH N CH C N CH CH CH CH H H 493 0 N N CH N CH C N CH CH CH CH H H 494 0 CH N CH N CH C CH N CH CH CH H H 495 0 N N CH N CH C CH N CH CH CH H H 496 0 CH CH N CH N C CH CH CH CH CH H H 497 0 N CH N CH N C CH CH CH CH CH H H 498 0 CH CH CH N N C CH CH CH CH CH H H 499 0 N CH CH N N C CH CH CH CH CH H H 500 0 CH CH CH CH N C CH CH CH CH CH H H 501 0 N CH CH CH N C CH CH CH CH CH H H 502 0 CH CH CH CH N C CH CH N CH CH absent H 503 0 N CH CH CH N C CH CH N CH CH H 504 0 CH CH CH CH CH C CH CH CH CH CH F H 505 0 N CH CH CH CH C CH CH CH CH CH F H 506 0 CH CH CH CH CH C N CH CH CH CH F H 507 0 N CH CH CH CH C N CH CH CH CH F H 508 0 CH CH CH CH CH C CH N CH CH CH F H 509 0 N CH CH CH CH C CH N CH CH CH F H 510 0 CH CH CH CH CH C N CH CH CH N F H 511 0 N CH CH CH CH C N CH CH CH N F H 512 0 CH CH CH CH CH C N N CH CH CH F H 513 0 N CH CH CH CH C N N CH CH CH F H 514 0 CH CH CH CH CH C CH N CH N CH F absent 515 0 N CH CH CH CH C CH N CH N CH F 516 0 CH CH CH CH CH C CH CH N CH N absent 517 0 N CH CH CH CH C CH CH N CH N 518 0 CH CH CH CH CH C CH CH N CH CH absent H 519 0 N CH CH CH CH C CH CH N CH CH H 520 0 CH N CH CH CH C CH CH CH CH CH F H 521 0 N N CH CH CH C CH CH CH CH CH F H 522 0 CH N CH CH CH C N CH CH CH CH F H 523 0 N N CH CH CH C N CH CH CH CH F H 524 0 CH N CH CH CH C CH N CH CH CH F H 525 0 N N CH CH CH C CH N CH CH CH F H 526 0 CH N CH CH CH C N CH CH CH N F H 527 0 N N CH CH CH C N CH CH CH N F H 528 0 CH N CH CH CH C CH CH N CH N absent H 529 0 N N CH CH CH C CH CH N CH N H 530 0 CH N N CH CH C CH CH CH CH CH F H 531 0 N N N CH CH C CH CH CH CH CH F H 532 0 CH N N CH CH C CH CH N CH N absent H 533 0 N N N CH CH C CH CH N CH N H 534 0 CH CH N CH CH C CH CH CH CH CH F H 535 0 N CH N CH CH C CH CH CH CH CH F H 536 0 CH CH N CH CH C N CH CH CH CH F H 537 0 N CH N CH CH C N CH CH CH CH F H 538 0 CH CH N CH CH C CH N CH CH CH F H 539 0 N CH N CH CH C CH N CH CH CH F H 540 0 CH CH N CH CH C CH N CH N CH H absent 541 0 N CH N CH CH C CH N CH N CH F 542 0 CH CH N CH CH C N CH CH N CH F absent 543 0 N CH N CH CH C N CH CH N CH F 544 0 CH CH N CH CH C CH CH N CH N absent H 545 0 N CH N CH CH C CH CH N CH N H 546 0 CH N CH N CH C CH CH CH CH CH F H 547 0 N N CH N CH C CH CH CH CH CH F H 548 0 CH N CH N CH C N CH CH CH CH F H 549 0 N N CH N CH C N CH CH CH CH F H 550 0 CH N CH N CH C CH N CH CH CH F H 551 0 N N CH N CH C CH N CH CH CH F H 552 0 CH CH N CH N C CH CH CH CH CH F H 553 0 N CH N CH N C CH CH CH CH CH F H 554 0 CH CH CH N N C CH CH CH CH CH F H 555 0 N CH CH N N C CH CH CH CH CH F H 556 0 CH CH CH CH N C CH CH CH CH CH F H 557 0 N CH CH CH N C CH CH CH CH CH F H 558 0 CH CH CH CH N C CH N CH CH CH F H 559 0 N CH CH CH N C CH N CH CH CH F H 560 0 CH CH CH CH CH C CH CH CH CH CH OMe OMe 561 0 N CH CH CH CH C CH CH CH CH CH OMe OMe 562 0 CH CH CH CH CH C N CH CH CH CH OMe OMe 563 0 N CH CH CH CH C N CH CH CH CH OMe OMe 564 0 CH CH CH CH CH C CH N CH CH CH OMe OMe 565 0 N CH CH CH CH C CH N CH CH CH OMe OMe 566 0 CH CH CH CH CH C N CH CH CH N OMe OMe 567 0 N CH CH CH CH C N CH CH CH N OMe OMe 568 0 CH CH CH CH CH C N N CH CH CH OMe OMe 569 0 N CH CH CH CH C N N CH CH CH OMe OMe 570 0 CH CH CH CH CH C CH N CH N CH OMe absent 571 0 N CH CH CH CH C CH N CH N CH OMe 572 0 CH CH CH CH CH C CH CH N CH N absent OMe 573 0 N CH CH CH CH C CH CH N CH N OMe 574 0 CH CH CH CH CH C CH CH N CH CH absent OMe 575 0 N CH CH CH CH C CH CH N CH CH OMe 576 0 CH N CH CH CH C CH CH CH CH CH OMe OMe 577 0 N N CH CH CH C CH CH CH CH CH OMe OMe 578 0 CH N CH CH CH C N CH CH CH CH OMe OMe 579 0 N N CH CH CH C N CH CH CH CH OMe OMe 580 0 CH N CH CH CH C CH N CH CH CH OMe OMe 581 0 N N CH CH CH C CH N CH CH CH OMe OMe 582 0 CH N CH CH CH C N CH CH CH N OMe OMe 583 0 N N CH CH CH C N CH CH CH N OMe OMe 584 0 CH N CH CH CH C CH CH N CH N absent OMe 585 0 N N CH CH CH C CH CH N CH N OMe 586 0 CH N CH CH CH C N CH CH CH CH OMe OMe 587 0 N N CH CH CH C N CH CH CH CH OMe OMe 588 0 CH N N CH CH C CH CH N CH N absent OMe 589 0 N N N CH CH C CH CH N CH N OMe 590 0 CH N N CH CH C CH CH CH CH CH OMe OMe 591 0 N N N CH CH C CH CH CH CH CH OMe OMe 592 0 CH CH N CH CH C CH CH CH CH CH OMe OMe 593 0 N CH N CH CH C CH CH CH CH CH OMe OMe 594 0 CH CH N CH CH C N CH CH CH CH OMe OMe 595 0 N CH N CH CH C N CH CH CH CH OMe OMe 596 0 CH CH N CH CH C CH N CH CH CH OMe OMe 597 0 N CH N CH CH C CH N CH CH CH OMe OMe 598 0 CH CH N CH CH C CH N CH N CH OMe absent 599 0 N CH N CH CH C CH N CH N CH OMe 600 0 CH CH N CH CH C N CH CH N CH OMe OMe 601 0 N CH N CH CH C N CH CH N CH OMe OMe 602 0 CH CH N CH CH C CH CH N CH N absent OMe 603 0 N CH N CH CH C CH CH N CH N OMe 604 0 CH CH N CH CH C CH CH N CH CH absent OMe 605 0 N CH N CH CH C CH CH N CH CH OMe 606 0 CH N CH N CH C CH CH CH CH CH OMe OMe 607 0 N N CH N CH C CH CH CH CH CH OMe OMe 608 0 CH N CH N CH C N CH CH CH CH OMe OMe 609 0 N N CH N CH C N CH CH CH CH OMe OMe 610 0 CH N CH N CH C CH N CH CH CH OMe OMe 611 0 N N CH N CH C CH N CH CH CH OMe OMe 612 0 CH CH N CH N C CH CH CH CH CH OMe OMe 613 0 N CH N CH N C CH CH CH CH CH OMe OMe 614 0 CH CH CH N N C CH CH CH CH CH OMe OMe 615 0 N CH CH N N C CH CH CH CH CH OMe OMe 616 0 CH CH CH CH N C CH CH CH CH CH OMe OMe 617 0 N CH CH CH N C CH CH CH CH CH OMe OMe 618 0 CH CH CH CH N C CH CH N CH CH absent OMe 619 0 N CH CH CH N C CH CH N CH CH OMe 620 1 CH CH CH CH CH C CH CH CH CH CH H H 621 1 N CH CH CH CH C CH CH CH CH CH H H 622 1 CH CH CH CH CH C N CH CH CH CH H H 623 1 N CH CH CH CH C N CH CH CH CH H H 624 1 CH CH CH CH CH C CH N CH CH CH H H 625 1 N CH CH CH CH C CH N CH CH CH H H 626 1 CH CH CH CH CH C N CH CH CH N H H 627 1 N CH CH CH CH C N CH CH CH N H H 628 1 CH CH CH CH CH C N N CH CH CH H H 629 1 N CH CH CH CH C N N CH CH CH H H 630 1 CH CH CH CH CH C CH N CH N CH H absent 631 1 N CH CH CH CH C CH N CH N CH H 632 1 CH CH CH CH CH C CH CH N CH N absent H 633 1 N CH CH CH CH C CH CH N CH N H 634 1 CH CH CH CH CH C CH CH N CH CH absent H 635 1 N CH CH CH CH C CH CH N CH CH H 636 1 CH N CH CH CH C CH CH CH CH CH H H 637 1 N N CH CH CH C CH CH CH CH CH H H 638 1 CH N CH CH CH C N CH CH CH CH H H 639 1 N N CH CH CH C N CH CH CH CH H H 640 1 CH N CH CH CH C CH N CH CH CH H H 641 1 N N CH CH CH C CH N CH CH CH H H 642 1 CH N CH CH CH C N CH CH CH N H H 643 1 N N CH CH CH C N CH CH CH N H H 644 1 CH N CH CH CH C CH CH N CH N absent H 645 1 N N CH CH CH C CH CH N CH N H 646 1 CH N CH CH CH C N CH CH CH CH H H 647 1 N N CH CH CH C N CH CH CH CH H H 648 1 CH N N CH CH C CH CH N CH N absent H 649 1 N N N CH CH C CH CH N CH N H 650 1 CH N N CH CH C CH CH CH CH CH H H 651 1 N N N CH CH C CH CH CH CH CH H H 652 1 CH CH N CH CH C CH CH CH CH CH H H 653 1 N CH N CH CH C CH CH CH CH CH H H 654 1 CH CH N CH CH C N CH CH CH CH H H 655 1 N CH N CH CH C N CH CH CH CH H H 656 1 CH CH N CH CH C CH N CH CH CH H H 657 1 N CH N CH CH C CH N CH CH CH H H 658 1 CH CH N CH CH C CH N CH N CH H absent 659 1 N CH N CH CH C CH N CH N CH H 660 1 CH CH N CH CH C N CH CH N CH H H 661 1 N CH N CH CH C N CH CH N CH H H 662 1 CH CH N CH CH C CH CH N CH N absent H 663 1 N CH N CH CH C CH CH N CH N H 664 1 CH CH N CH CH C CH CH N CH CH absent H 665 1 N CH N CH CH C CH CH N CH CH H 666 1 CH N CH N CH C CH CH CH CH CH H H 667 1 N N CH N CH C CH CH CH CH CH H H 668 1 CH N CH N CH C N CH CH CH CH H H 669 1 N N CH N CH C N CH CH CH CH H H 670 1 CH N CH N CH C CH N CH CH CH H H 671 1 N N CH N CH C CH N CH CH CH H H 672 1 CH CH N CH N C CH CH CH CH CH H H 673 1 N CH N CH N C CH CH CH CH CH H H 674 1 CH CH CH N N C CH CH CH CH CH H H 675 1 N CH CH N N C CH CH CH CH CH H H 676 1 CH CH CH CH N C CH CH CH CH CH H H 677 1 N CH CH CH N C CH CH CH CH CH H H 678 1 CH CH CH CH N C CH CH N CH CH absent H 679 1 N CH CH CH N C CH CH N CH CH H 680 1 CH CH CH CH CH C CH CH CH CH CH F H 681 1 N CH CH CH CH C CH CH CH CH CH F H 682 1 CH CH CH CH CH C N CH CH CH CH F H 683 1 N CH CH CH CH C N CH CH CH CH F H 684 1 CH CH CH CH CH C CH N CH CH CH F H 685 1 N CH CH CH CH C CH N CH CH CH F H 686 1 CH CH CH CH CH C N CH CH CH N F H 687 1 N CH CH CH CH C N CH CH CH N F H 688 1 CH CH CH CH CH C N N CH CH CH F H 689 1 N CH CH CH CH C N N CH CH CH F H 690 1 CH CH CH CH CH C CH N CH N CH F absent 691 1 N CH CH CH CH C CH N CH N CH F 692 1 CH CH CH CH CH C CH CH N CH N absent 693 1 N CH CH CH CH C CH CH N CH N 694 1 CH CH CH CH CH C CH CH N CH CH absent H 695 1 N CH CH CH CH C CH CH N CH CH H 696 1 CH N CH CH CH C CH CH CH CH CH F H 697 1 N N CH CH CH C CH CH CH CH CH F H 698 1 CH N CH CH CH C N CH CH CH CH F H 699 1 N N CH CH CH C N CH CH CH CH F H 700 1 CH N CH CH CH C CH N CH CH CH F H 701 1 N N CH CH CH C CH N CH CH CH F H 702 1 CH N CH CH CH C N CH CH CH N F H 703 1 N N CH CH CH C N CH CH CH N F H 704 1 CH N CH CH CH C CH CH N CH N absent H 705 1 N N CH CH CH C CH CH N CH N H 706 1 CH N N CH CH C CH CH CH CH CH F H 707 1 N N N CH CH C CH CH CH CH CH F H 708 1 CH N N CH CH C CH CH N CH N absent H 709 1 N N N CH CH C CH CH N CH N H 710 1 CH CH N CH CH C CH CH CH CH CH F H 711 1 N CH N CH CH C CH CH CH CH CH F H 712 1 CH CH N CH CH C N CH CH CH CH F H 713 1 N CH N CH CH C N CH CH CH CH F H 714 1 CH CH N CH CH C CH N CH CH CH F H 715 1 N CH N CH CH C CH N CH CH CH F H 716 1 CH CH N CH CH C CH N CH N CH F absent 717 1 N CH N CH CH C CH N CH N CH F 718 1 CH CH N CH CH C N CH CH N CH F absent 719 1 N CH N CH CH C N CH CH N CH F 720 1 CH CH N CH CH C CH CH N N absent H 721 1 N CH N CH CH C CH CH N N H 722 1 CH N CH N CH C CH CH CH CH CH F H 723 1 N N CH N CH C CH CH CH CH CH F H 724 1 CH N CH N CH C N CH CH CH CH F H 725 1 N N CH N CH C N CH CH CH CH F H 726 1 CH N CH N CH C CH N CH CH CH F H 727 1 N N CH N CH C CH N CH CH CH F H 728 1 CH CH N CH N C CH CH CH CH CH F H 729 1 N CH N CH N C CH CH CH CH CH F H 730 1 CH CH CH N N C CH CH CH CH CH F H 731 1 N CH CH N N C CH CH CH CH CH F H 732 1 CH CH CH CH N C CH CH CH CH CH F H 733 1 N CH CH CH N C CH CH CH CH CH F H 734 1 CH CH CH CH N C CH N CH CH CH F H 735 1 N CH CH CH N C CH N CH CH CH F H 736 1 CH CH CH CH CH C CH CH CH CH CH OMe OMe 737 1 N CH CH CH CH C CH CH CH CH CH OMe OMe 738 1 CH CH CH CH CH C N CH CH CH CH OMe OMe 739 1 N CH CH CH CH C N CH CH CH CH OMe OMe 740 1 CH CH CH CH CH C CH N CH CH CH OMe OMe 741 1 N CH CH CH CH C CH N CH CH CH OMe OMe 742 1 CH CH CH CH CH C N CH CH CH N OMe OMe 743 1 N CH CH CH CH C N CH CH CH N OMe OMe 744 1 CH CH CH CH CH C N N CH CH CH OMe OMe 745 1 N CH CH CH CH C N N CH CH CH OMe OMe 746 1 CH CH CH CH CH C CH N CH N CH OMe absent 747 1 N CH CH CH CH C CH N CH N CH OMe 748 1 CH CH CH CH CH C CH CH N CH N absent OMe 749 1 N CH CH CH CH C CH CH N CH N OMe 750 1 CH CH CH CH CH C CH CH N CH CH absent OMe 751 1 N CH CH CH CH C CH CH N CH CH OMe 752 1 CH N CH CH CH C CH CH CH CH CH OMe OMe 753 1 N N CH CH CH C CH CH CH CH CH OMe OMe 754 1 CH N CH CH CH C N CH CH CH CH OMe OMe 755 1 N N CH CH CH C N CH CH CH CH OMe OMe 756 1 CH N CH CH CH C CH N CH CH CH OMe OMe 757 1 N N CH CH CH C CH N CH CH CH OMe OMe 758 1 CH N CH CH CH C N CH CH CH N OMe OMe 759 1 N N CH CH CH C N CH CH CH N OMe OMe 760 1 CH N CH CH CH C CH CH N CH N absent OMe 761 1 N N CH CH CH C CH CH N CH N OMe 762 1 CH N CH CH CH C N CH CH CH CH OMe OMe 763 1 N N CH CH CH C N CH CH CH CH OMe OMe 764 1 CH N N CH CH C CH CH N CH N absent OMe 765 1 N N N CH CH C CH CH N CH N OMe 766 1 CH N N CH CH C CH CH CH CH CH OMe OMe 767 1 N N N CH CH C CH CH CH CH CH OMe OMe 768 1 CH CH N CH CH C CH CH CH CH CH OMe OMe 769 1 N CH N CH CH C CH CH CH CH CH OMe OMe 770 1 CH CH N CH CH C N CH CH CH CH OMe OMe 771 1 N CH N CH CH C N CH CH CH CH OMe OMe 772 1 CH CH N CH CH C CH N CH CH CH OMe OMe 773 1 N CH N CH CH C CH N CH CH CH OMe OMe 774 1 CH CH N CH CH C CH N CH N CH OMe absent 775 1 N CH N CH CH C CH N CH N CH OMe 776 1 CH CH N CH CH C N CH CH N CH OMe OMe 777 1 N CH N CH CH C N CH CH N CH OMe OMe 778 1 CH CH N CH CH C CH CH N CH N absent OMe 779 1 N CH N CH CH C CH CH N CH N OMe 780 1 CH CH N CH CH C CH CH N CH CH absent OMe 781 1 N CH N CH CH C CH CH N CH CH OMe 782 1 CH N CH N CH C CH CH CH CH CH OMe OMe 783 1 N N CH N CH C CH CH CH CH CH OMe OMe 784 1 CH N CH N CH C N CH CH CH CH OMe OMe 785 1 N N CH N CH C N CH CH CH CH OMe OMe 786 1 CH N CH N CH C CH N CH CH CH OMe OMe 787 1 N N CH N CH C CH N CH CH CH OMe OMe 788 1 CH CH N CH N C CH CH CH CH CH OMe OMe 789 1 N CH N CH N C CH CH CH CH CH OMe OMe 790 1 CH CH CH N N C CH CH CH CH CH OMe OMe 791 1 N CH CH N N C CH CH CH CH CH OMe OMe 792 1 CH CH CH CH N C CH CH CH CH CH OMe OMe 793 1 N CH CH CH N C CH CH CH CH CH OMe OMe 794 1 CH CH CH CH N C CH CH N CH CH absent OMe 795 1 N CH CH CH N C CH CH N CH CH OMe

[0914] In a further embodiment, the present invention provides compounds of formula (IVa) and (IVb), wherein X.sub.1, o, Z, Y.sub.1, Y.sub.2, Y.sub.3, Y.sub.4, Y.sub.5, Y.sub.6, Y.sub.7, Y.sub.8, Y.sub.9, Y.sub.10, R.sub.5, and R.sub.6 are as defined in examples 1289 to 1296:

##STR00051##

[0915] In both, formulae (IVa) and (Vb), o is 0.

TABLE-US-00006 Comp p Z Y.sub.1 Y.sub.2 Y.sub.3 Y.sub.4 Y.sub.5 Y.sub.6 Y.sub.7 Y.sub.8 Y.sub.9 Y.sub.10 R.sub.5 R.sub.6 1289 0 N CH CH CH CH C CH CH CH CH CH OMe H 1290 0 N N CH CH CH C CH CH CH CH CH OMe H 1291 0 N CH CH N CH C CH CH CH CH CH OMe H 1292 0 N CH CH N CH C CH CH CH CH CH OMe OMe 1293 0 N N CH CH N C CH CH CH CH CH F H 1294 0 N CH CH CH C CH CH CH CH CH CH O-Phenyl H 1295 0 N CH CH CH CH C CH CH CH CH CH propoxy H 1296 0 N CH CH CH CH C CH CH CH CH CH propan-2-yloxy H

[0916] In a further embodiment, the present invention provides compounds of formula (Va) and (Vb), wherein o, Y.sub.1, Y.sub.2, Y.sub.3, Y.sub.4, Y.sub.5, Y.sub.8, Y.sub.7, Y.sub.8, Y.sub.9, Y.sub.10, R.sub.5, and R.sub.6 are as defined in examples 796 to 971:

##STR00052##

[0917] In both, formulae (Va) and (Vb), o is 0.

TABLE-US-00007 Comp p Y.sub.1 Y.sub.2 Y.sub.3 Y.sub.4 Y.sub.5 Y.sub.6 Y.sub.7 Y.sub.8 Y.sub.9 Y.sub.10 R.sub.5 R.sub.6 796 0 CH CH CH CH C CH CH CH CH CH H H 797 0 CH CH CH CH C N CH CH CH CH H H 798 0 CH CH CH CH C CH N CH CH CH H H 799 0 CH CH CH CH C N CH CH CH N H H 800 0 CH CH CH CH C N N CH CH CH H H 801 0 CH CH CH CH C CH N CH N CH H absent 802 0 CH CH CH CH C CH CH N CH N absent H 803 0 CH CH CH CH C CH CH N CH CH absent H 804 0 N CH CH CH C CH CH CH CH CH H H 805 0 N CH CH CH C N CH CH CH CH H H 806 0 N CH CH CH C CH N CH CH CH H H 807 0 N CH CH CH C N CH CH CH N H H 808 0 N CH CH CH C CH CH N CH N absent H 809 0 N CH CH CH C N CH CH CH CH H H 810 0 N N CH CH C CH CH N CH N absent H 811 0 N N CH CH C CH CH CH CH CH H H 812 0 CH N CH CH C CH CH CH CH CH H H 813 0 CH N CH CH C N CH CH CH CH H H 814 0 CH N CH CH C CH N CH CH CH H H 815 0 CH N CH CH C CH N CH N CH H absent 816 0 CH N CH CH C N CH CH N CH H H 817 0 CH N CH CH C CH CH N CH N absent H 818 0 CH N CH CH C CH CH N CH CH absent H 819 0 N CH N CH C CH CH CH CH CH H H 820 0 N CH N CH C N CH CH CH CH H H 821 0 N CH N CH C CH N CH CH CH H H 822 0 CH N CH N C CH CH CH CH CH H H 823 0 CH CH N N C CH CH CH CH CH H H 824 0 CH CH CH N C CH CH CH CH CH H H 825 0 CH CH CH N C CH CH N CH CH absent H 826 0 CH CH CH CH C CH CH CH CH CH F H 827 0 CH CH CH CH C N CH CH CH CH F H 828 0 CH CH CH CH C CH N CH CH CH F H 829 0 CH CH CH CH C N CH CH CH N F H 830 0 CH CH CH CH C N N CH CH CH F H 831 0 CH CH CH CH C CH N CH N CH F absent 832 0 CH CH CH CH C CH CH N CH N absent 833 0 CH CH CH CH C CH CH N CH CH absent H 834 0 N CH CH CH C CH CH CH CH CH F H 835 0 N CH CH CH C N CH CH CH CH F H 836 0 N CH CH CH C CH N CH CH CH F H 837 0 N CH CH CH C N CH CH CH N F H 838 0 N CH CH CH C CH CH N CH N absent H 839 0 N N CH CH C CH CH CH CH CH F H 840 0 N N CH CH C CH CH N CH N absent H 841 0 CH N CH CH C CH CH CH CH CH F H 842 0 CH N CH CH C N CH CH CH CH F H 843 0 CH N CH CH C CH N CH CH CH F H 844 0 CH N CH CH C CH N CH N CH F absent 845 0 CH N CH CH C N CH CH N CH F absent 846 0 CH N CH CH C CH CH N CH N absent H 847 0 N CH N CH C CH CH CH CH CH F H 848 0 N CH N CH C N CH CH CH CH F H 849 0 N CH N CH C CH N CH CH CH F H 850 0 CH N CH N C CH CH CH CH CH F H 851 0 CH CH N N C CH CH CH CH CH F H 852 0 CH CH CH N C CH CH CH CH CH F H 853 0 CH CH CH N C CH N CH CH CH F H 854 0 CH CH CH CH C CH CH CH CH CH OMe OMe 855 0 CH CH CH CH C N CH CH CH CH OMe OMe 856 0 CH CH CH CH C CH N CH CH CH OMe OMe 857 0 CH CH CH CH C N CH CH CH N OMe OMe 858 0 CH CH CH CH C N N CH CH CH OMe OMe 859 0 CH CH CH CH C CH N CH N CH OMe absent 860 0 CH CH CH CH C CH CH N CH N absent OMe 861 0 CH CH CH CH C CH CH N CH CH absent OMe 862 0 N CH CH CH C CH CH CH CH CH OMe OMe 863 0 N CH CH CH C N CH CH CH CH OMe OMe 864 0 N CH CH CH C CH N CH CH CH OMe OMe 865 0 N CH CH CH C N CH CH CH N OMe OMe 866 0 N CH CH CH C CH CH N CH N absent OMe 867 0 N CH CH CH C N CH CH CH CH OMe OMe 868 0 N N CH CH C CH CH N CH N absent OMe 869 0 N N CH CH C CH CH CH CH CH OMe OMe 870 0 CH N CH CH C CH CH CH CH CH OMe OMe 871 0 CH N CH CH C N CH CH CH CH OMe OMe 872 0 CH N CH CH C CH N CH CH CH OMe OMe 873 0 CH N CH CH C CH N CH N CH OMe absent 874 0 CH N CH CH C N CH CH N CH OMe OMe 875 0 CH N CH CH C CH CH N CH N absent OMe 876 0 CH N CH CH C CH CH N CH CH absent OMe 877 0 N CH N CH C CH CH CH CH CH OMe OMe 878 0 N CH N CH C N CH CH CH CH OMe OMe 879 0 N CH N CH C CH N CH CH CH OMe OMe 880 0 CH N CH N C CH CH CH CH CH OMe OMe 881 0 CH CH N N C CH CH CH CH CH OMe OMe 882 0 CH CH CH N C CH CH CH CH CH OMe OMe 883 0 CH CH CH N C CH CH N CH CH absent OMe 884 1 CH CH CH CH C CH CH CH CH CH H H 885 1 CH CH CH CH C N CH CH CH CH H H 886 1 CH CH CH CH C CH N CH CH CH H H 887 1 CH CH CH CH C N CH CH CH N H H 888 1 CH CH CH CH C N N CH CH CH H H 889 1 CH CH CH CH C CH N CH N CH H absent 890 1 CH CH CH CH C CH CH N CH N absent H 891 1 CH CH CH CH C CH CH N CH CH absent H 892 1 N CH CH CH C CH CH CH CH CH H H 893 1 N CH CH CH C N CH CH CH CH H H 894 1 N CH CH CH C CH N CH CH CH H H 895 1 N CH CH CH C N CH CH CH N H H 896 1 N CH CH CH C CH CH N CH N absent H 897 1 N CH CH CH C N CH CH CH CH H H 898 1 N N CH CH C CH CH N CH N absent H 899 1 N N CH CH C CH CH CH CH CH H H 900 1 CH N CH CH C CH CH CH CH CH H H 901 1 CH N CH CH C N CH CH CH CH H H 902 1 CH N CH CH C CH N CH CH CH H H 903 1 CH N CH CH C CH N CH N CH H absent 904 1 CH N CH CH C N CH CH N CH H H 905 1 CH N CH CH C CH CH N CH N absent H 906 1 CH N CH CH C CH CH N CH CH absent H 907 1 N CH N CH C CH CH CH CH CH H H 908 1 N CH N CH C N CH CH CH CH H H 909 1 N CH N CH C CH N CH CH CH H H 910 1 CH N CH N C CH CH CH CH CH H H 911 1 CH CH N N C CH CH CH CH CH H H 912 1 CH CH CH N C CH CH CH CH CH H H 913 1 CH CH CH N C CH CH N CH CH absent H 914 1 CH CH CH CH C CH CH CH CH CH F H 915 1 CH CH CH CH C N CH CH CH CH F H 916 1 CH CH CH CH C CH N CH CH CH F H 917 1 CH CH CH CH C N CH CH CH N F H 918 1 CH CH CH CH C N N CH CH CH F H 919 1 CH CH CH CH C CH N CH N F absent 920 1 CH CH CH CH C CH CH N CH N absent 921 1 CH CH CH CH C CH CH N CH CH absent H 922 1 N CH CH CH C CH CH CH CH CH F H 923 1 N CH CH CH C N CH CH CH CH F H 924 1 N CH CH CH C CH N CH CH CH F H 925 1 N CH CH CH C N CH CH CH N F H 926 1 N CH CH CH C CH CH N CH N absent H 927 1 N N CH CH C CH CH CH CH CH F H 928 1 N N CH CH C CH CH N CH N absent H 929 1 CH N CH CH C CH CH CH CH CH F H 930 1 CH N CH CH C N CH CH CH CH F H 931 1 CH N CH CH C CH N CH CH CH F H 932 1 CH N CH CH C CH N CH N CH F absent 933 1 CH N CH CH C N CH CH N CH F absent 934 1 CH N CH CH C CH CH N CH N absent H 935 1 N CH N CH C CH CH CH CH CH F H 936 1 N CH N CH C N CH CH CH CH F H 937 1 N CH N CH C CH N CH CH CH F H 938 1 CH N CH N C CH CH CH CH CH F H 939 1 CH CH N N C CH CH CH CH CH F H 940 1 CH CH CH N C CH CH CH CH CH F H 941 1 CH CH CH N C CH N CH CH CH F H 942 1 CH CH CH CH C CH CH CH CH CH OMe OMe 943 1 CH CH CH CH C N CH CH CH CH OMe OMe 944 1 CH CH CH CH C CH N CH CH CH OMe OMe 945 1 CH CH CH CH C N CH CH CH N OMe OMe 946 1 CH CH CH CH C N N CH CH CH OMe OMe 947 1 CH CH CH CH C CH N CH N CH OMe absent 948 1 CH CH CH CH C CH CH N CH N absent OMe 949 1 CH CH CH CH C CH CH N CH CH absent OMe 950 1 N CH CH CH C CH CH CH CH CH OMe OMe 951 1 N CH CH CH C N CH CH CH CH OMe OMe 952 1 N CH CH CH C CH N CH CH CH OMe OMe 953 1 N CH CH CH C N CH CH CH N OMe OMe 954 1 N CH CH CH C CH CH N CH N absent OMe 955 1 N CH CH CH C N CH CH CH CH OMe OMe 956 1 N N CH CH C CH CH N CH N absent OMe 957 1 N N CH CH C CH CH CH CH CH OMe OMe 958 1 CH N CH CH C CH CH CH CH CH OMe OMe 959 1 CH N CH CH C N CH CH CH CH OMe OMe 960 1 CH N CH CH C CH N CH CH CH OMe OMe 961 1 CH N CH CH C CH N CH N CH OMe absent 962 1 CH N CH CH C N CH CH N CH OMe OMe 963 1 CH N CH CH C CH CH N CH N absent OMe 964 1 CH N CH CH C CH CH N CH CH absent OMe 965 1 N CH N CH C CH CH CH CH CH OMe OMe 966 1 N CH N CH C N CH CH CH CH OMe OMe 967 1 N CH N CH C CH N CH CH CH OMe OMe 968 1 CH N CH N C CH CH CH CH CH OMe OMe 969 1 CH CH N N C CH CH CH CH CH OMe OMe 970 1 CH CH CH N C CH CH CH CH CH OMe OMe 971 1 CH CH CH N C CH CH N CH CH absent OMe

[0918] In a further embodiment, the present invention provides compounds of formula (Va) and (Vb), wherein o, Y.sub.1, Y.sub.2, Y.sub.3, Y.sub.4, Y.sub.5, Y.sub.6, Y.sub.7, Y.sub.8, Y.sub.9, Y.sub.10, R.sub.5, and R.sub.6 are as defined in examples 1297 to 1300:

##STR00053##

[0919] In both, formulae (Va) and (Vb), o is 0.

TABLE-US-00008 Comp p Y.sub.1 Y.sub.2 Y.sub.3 Y.sub.4 Y.sub.5 Y.sub.6 Y.sub.7 Y.sub.8 Y.sub.9 Y.sub.10 R.sub.5 R.sub.6 1297 0 CH CH CH CH C CH CH CH CH CH OMe H 1298 0 CH CH CH N C CH CH CH CH CH OMe H 1299 0 CH CH CH CH C CH CH CH CH CH O-Phenyl H 1300 0 CH CH N CH C CH CH CH CH CH OMe OMe

[0920] In a further embodiment, the present invention provides compounds of formula (VI), wherein X.sub.1, n, Z, R.sub.5, and R.sub.6 are as defined in examples 972 to 977:

##STR00054##

TABLE-US-00009 Comp X.sub.1 Z n R.sub.5 R.sub.6 972 CH.sub.2 CH 1 F H 973 CH.sub.2 N 1 F H 974 S N 1 F H 975 CH.sub.2 CH 1 OMe OMe 976 CH.sub.2 N 1 OMe OMe 977 S N 1 OMe OMe

[0921] In a further embodiment, the present invention provides compounds of formula (VII), wherein X.sub.1, n, Z, R.sub.2, R.sub.5, and R.sub.6 are as defined in examples 978 to 54:

##STR00055##

TABLE-US-00010 Comp X.sub.1 Z n R.sub.2 R.sub.5 R.sub.6 978 CH.sub.2 CH 1 Me F H 979 CH.sub.2 N 1 Me F H 980 S N 1 Me F H 981 CH.sub.2 CH 1 Me OMe OMe 982 CH.sub.2 N 1 Me OMe OMe 983 S N 1 Me OMe OMe 984 CH.sub.2 CH 1 Cyclopropyl F H 985 CH.sub.2 N 1 Cyclopropyl F H 986 S N 1 Cyclopropyl F H 987 CH.sub.2 CH 1 Cyclopropyl OMe OMe 988 CH.sub.2 N 1 Cyclopropyl OMe OMe 989 S N 1 Cyclopropyl OMe OMe

[0922] In a further embodiment, the present invention provides compounds of formula (VIII), wherein X.sub.1, n, R.sub.5, and R.sub.6 are as defined in examples 990 to 993:

##STR00056##

TABLE-US-00011 Comp X.sub.1 n R5 R6 990 CH.sub.2 1 F H 991 S 1 F H 992 CH.sub.2 1 OMe OMe 993 S 1 OMe OMe

[0923] In a further embodiment, the present invention provides compounds of formula (IX), wherein X.sub.1, n, R.sub.2, R.sub.5, and R.sub.6 are as defined in examples 994 to 1001:

##STR00057##

TABLE-US-00012 Comp X.sub.1 n R.sub.2 R.sub.5 R.sub.6 994 CH.sub.2 1 Me F H 995 S 1 Me F H 996 CH.sub.2 1 Me OMe OMe 997 S 1 Me OMe OMe 998 CH.sub.2 1 Cyclopropyl F H 999 S 1 Cyclopropyl F H 1000 CH.sub.2 1 Cyclopropyl OMe OMe 1001 S 1 Cyclopropyl OMe OMe

[0924] In a further embodiment, the present invention provides compounds of formula (X), wherein o, R.sub.5, and R.sub.6 are as defined in examples 1002 to 1005:

##STR00058##

TABLE-US-00013 o is 0. Comp p R.sub.5 R.sub.6 1002 0 F H 1003 0 OMe OMe 1004 1 F H 1005 1 OMe OMe

[0925] In a further embodiment, the present invention provides compounds of formula (XI), wherein o, R.sub.2, R.sub.5, and R.sub.6 are as defined in examples 1006 to 1013:

##STR00059##

TABLE-US-00014 o is 0. Comp p R.sub.2 R.sub.5 R.sub.6 1006 0 Me F H 1007 0 Me OMe OMe 1008 0 Cyclopropyl F H 1009 0 Cyclopropyl OMe OMe 1010 1 Me F H 1011 1 Me OMe OMe 1012 1 Cyclopropyl F H 1013 1 Cyclopropyl OMe OMe

[0926] In a further embodiment, the present invention provides compounds of formula (XIIa) and (XIIb), wherein Z, Y.sub.1, Y.sub.2, Y.sub.3, Y.sub.4, Y.sub.5, Y.sub.6, Y.sub.7, Y.sub.8, Y.sub.9, Y.sub.10, R.sub.5, and R.sub.6 are as defined in examples 1014 to 1189:

##STR00060##

TABLE-US-00015 Comp Z Y.sub.1 Y.sub.2 Y.sub.3 Y.sub.4 Y.sub.5 Y.sub.6 Y.sub.7 Y.sub.8 Y.sub.9 Y.sub.10 R.sub.5 R.sub.6 1014 CH CH CH CH CH C CH CH CH CH CH H H 1015 N CH CH CH CH C CH CH CH CH CH H H 1016 CH CH CH CH CH C N CH CH CH CH H H 1017 N CH CH CH CH C N CH CH CH CH H H 1018 CH CH CH CH CH C CH N CH CH CH H H 1019 N CH CH CH CH C CH N CH CH CH H H 1020 CH CH CH CH CH C N CH CH CH N H H 1021 N CH CH CH CH C N CH CH CH N H H 1022 CH CH CH CH CH C N N CH CH CH H H 1023 N CH CH CH CH C N N CH CH CH H H 1024 CH CH CH CH CH C CH N CH N CH H absent 1025 N CH CH CH CH C CH N CH N CH H 1026 CH CH CH CH CH C CH CH N CH N absent H 1027 N CH CH CH CH C CH CH N CH N H 1028 CH CH CH CH CH C CH CH N CH CH absent H 1029 N CH CH CH CH C CH CH N CH CH H 1030 CH N CH CH CH C CH CH CH CH CH H H 1031 N N CH CH CH C CH CH CH CH CH H H 1032 CH N CH CH CH C N CH CH CH CH H H 1033 N N CH CH CH C N CH CH CH CH H H 1034 CH N CH CH CH C CH N CH CH CH H H 1035 N N CH CH CH C CH N CH CH CH H H 1036 CH N CH CH CH C N CH CH CH N H H 1037 N N CH CH CH C N CH CH CH N H H 1038 CH N CH CH CH C CH CH N CH N absent H 1039 N N CH CH CH C CH CH N CH N H 1040 CH N CH CH CH C N CH CH CH CH H H 1041 N N CH CH CH C N CH CH CH CH H H 1042 CH N N CH CH C CH CH N CH N absent H 1043 N N N CH CH C CH CH N CH N H 1044 CH N N CH CH C CH CH CH CH CH H H 1045 N N N CH CH C CH CH CH CH CH H H 1046 CH CH N CH CH C CH CH CH CH CH H H 1047 N CH N CH CH C CH CH CH CH CH H H 1048 CH CH N CH CH C N CH CH CH CH H H 1049 N CH N CH CH C N CH CH CH CH H H 1050 CH CH N CH CH C CH N CH CH CH H H 1051 N CH N CH CH C CH N CH CH CH H H 1052 CH CH N CH CH C CH N CH N CH H absent 1053 N CH N CH CH C CH N CH N CH H 1054 CH CH N CH CH C N CH CH N CH H H 1055 N CH N CH CH C N CH CH N CH H H 1056 CH CH N CH CH C CH CH N CH N absent H 1057 N CH N CH CH C CH CH N CH N H 1058 CH CH N CH CH C CH CH N CH CH absent H 1059 N CH N CH CH C CH CH N CH CH H 1060 CH N CH N CH C CH CH CH CH CH H H 1061 N N CH N CH C CH CH CH CH CH H H 1062 CH N CH N CH C N CH CH CH CH H H 1063 N N CH N CH C N CH CH CH CH H H 1064 CH N CH N CH C CH N CH CH CH H H 1065 N N CH N CH C CH N CH CH CH H H 1066 CH CH N CH N C CH CH CH CH CH H H 1067 N CH N CH N C CH CH CH CH CH H H 1068 CH CH CH N N C CH CH CH CH CH H H 1069 N CH CH N N C CH CH CH CH CH H H 1070 CH CH CH CH N C CH CH CH CH CH H H 1071 N CH CH CH N C CH CH CH CH CH H H 1072 CH CH CH CH N C CH CH N CH CH absent H 1073 N CH CH CH N C CH CH N CH CH H 1074 CH CH CH CH CH C CH CH CH CH CH F H 1075 N CH CH CH CH C CH CH CH CH CH F H 1076 CH CH CH CH CH C N CH CH CH CH F H 1077 N CH CH CH CH C N CH CH CH CH F H 1078 CH CH CH CH CH C CH N CH CH CH F 1079 N CH CH CH CH C CH N CH CH CH F H 1080 CH CH CH CH CH C N CH CH CH N F H 1081 N CH CH CH CH C N CH CH CH N F H 1082 CH CH CH CH CH C N N CH CH CH F H 1083 N CH CH CH CH C N N CH CH CH F H 1084 CH CH CH CH CH C CH N CH N CH F absent 1085 N CH CH CH CH C CH N CH N CH F 1086 CH CH CH CH CH C CH CH N CH N absent 1087 N CH CH CH CH C CH CH N CH N 1088 CH CH CH CH CH C CH CH N CH CH absent H 1089 N CH CH CH CH C CH CH N CH CH H 1090 CH N CH CH CH C CH CH CH CH CH F H 1091 N N CH CH CH C CH CH CH CH CH F H 1092 CH N CH CH CH C N CH CH CH CH F H 1093 N N CH CH CH C N CH CH CH CH F H 1094 CH N CH CH CH C CH N CH CH CH F H 1095 N N CH CH CH C CH N CH CH CH F H 1096 CH N CH CH CH C N CH CH CH N F H 1097 N N CH CH CH C N CH CH CH N F H 1098 CH N CH CH CH C CH CH N CH N absent H 1099 N N CH CH CH C CH CH N CH N H 1100 CH N N CH CH C CH CH CH CH CH F H 1101 N N N CH CH C CH CH CH CH CH F H 1102 CH N N CH CH C CH CH N CH N absent H 1103 N N N CH CH C CH CH N CH N H 1104 CH CH N CH CH C CH CH CH CH CH F H 1105 N CH N CH CH C CH CH CH CH CH F H 1106 CH CH N CH CH C N CH CH CH CH F H 1107 N CH N CH CH C N CH CH CH CH F H 1108 CH CH N CH CH C CH N CH CH CH F H 1109 N CH N CH CH C CH N CH CH CH F H 1110 CH CH N CH CH C CH N CH N CH F absent 1111 N CH N CH CH C CH N CH N CH F 1112 CH CH N CH CH C N CH CH N CH F absent 1113 N CH N CH CH C N CH CH N CH F 1114 CH CH N CH CH C CH CH N CH N absent H 1115 N CH N CH CH C CH CH N CH N H 1116 CH N CH N CH C CH CH CH CH CH F H 1117 N N CH N CH C CH CH CH CH CH F H 1118 CH N CH N CH C N CH CH CH CH F H 1119 N N CH N CH C N CH CH CH CH F H 1120 CH N CH N CH C CH N CH CH CH F H 1121 N N CH N CH C CH N CH CH CH F H 1122 CH CH N CH N C CH CH CH CH CH F H 1123 N CH N CH N C CH CH CH CH CH F H 1124 CH CH CH N N C CH CH CH CH CH F H 1125 N CH CH N N C CH CH CH CH CH F H 1126 CH CH CH CH N C CH CH CH CH CH F H 1127 N CH CH CH N C CH CH CH CH CH F H 1128 CH CH CH CH N C CH N CH CH CH F H 1129 N CH CH CH N C CH N CH CH CH F H 1130 CH CH CH CH CH C CH CH CH CH CH OMe OMe 1131 N CH CH CH CH C CH CH CH CH CH OMe OMe 1132 CH CH CH CH CH C N CH CH CH CH OMe OMe 1133 N CH CH CH CH C N CH CH CH CH OMe OMe 1134 CH CH CH CH CH C CH N CH CH CH OMe OMe 1135 N CH CH CH CH C CH N CH CH CH OMe OMe 1136 CH CH CH CH CH C N CH CH CH N OMe OMe 1137 N CH CH CH CH C N CH CH CH N OMe OMe 1138 CH CH CH CH CH C N N CH CH CH OMe OMe 1139 N CH CH CH CH C N N CH CH CH OMe OMe 1140 CH CH CH CH CH C CH N CH N CH OMe absent 1141 N CH CH CH CH C CH N CH N CH OMe 1142 CH CH CH CH CH C CH CH N CH N absent OMe 1143 N CH CH CH CH C CH CH N CH N OMe 1144 CH CH CH CH CH C CH CH N CH CH absent OMe 1145 N CH CH CH CH C CH CH N CH CH OMe 1146 CH N CH CH CH C CH CH CH CH CH OMe OMe 1147 N N CH CH CH C CH CH CH CH CH OMe OMe 1148 CH N CH CH CH C N CH CH CH CH OMe OMe 1149 N N CH CH CH C N CH CH CH CH OMe OMe 1150 CH N CH CH CH C CH N CH CH CH OMe OMe 1151 N N CH CH CH C CH N CH CH CH OMe OMe 1152 CH N CH CH CH C N CH CH CH N OMe OMe 1153 N N CH CH CH C N CH CH CH N OMe OMe 1154 CH N CH CH CH C CH CH N CH N absent OMe 1155 N N CH CH CH C CH CH N CH N OMe 1156 CH N CH CH CH C N CH CH CH CH OMe OMe 1157 N N CH CH CH C N CH CH CH CH OMe OMe 1158 CH N N CH CH C CH CH N CH N absent OMe 1159 N N N CH CH C CH CH N CH N OMe 1160 CH N N CH CH C CH CH CH CH CH OMe OMe 1161 N N N CH CH C CH CH CH CH CH OMe OMe 1162 CH CH N CH CH C CH CH CH CH CH OMe OMe 1163 N CH N CH CH C CH CH CH CH CH OMe OMe 1164 CH CH N CH CH C N CH CH CH CH OMe OMe 1165 N CH N CH CH C N CH CH CH CH OMe OMe 1166 CH CH N CH CH C CH N CH CH CH OMe OMe 1167 N CH N CH CH C CH N CH CH CH OMe OMe 1168 CH CH N CH CH C CH N CH N CH OMe absent 1169 N CH N CH CH C CH N CH N CH OMe 1170 CH CH N CH CH C N CH CH N CH OMe OMe 1171 N CH N CH CH C N CH CH N CH OMe OMe 1172 CH CH N CH CH C CH CH N CH N absent OMe 1173 N CH N CH CH C CH CH N CH N OMe 1174 CH CH N CH CH C CH CH N CH CH absent OMe 1175 N CH N CH CH C CH CH N CH CH OMe 1176 CH N CH N CH C CH CH CH CH CH OMe OMe 1177 N N CH N CH C CH CH CH CH CH OMe OMe 1178 CH N CH N CH C N CH CH CH CH OMe OMe 1179 N N CH N CH C N CH CH CH CH OMe OMe 1180 CH N CH N CH C CH N CH CH CH OMe OMe 1181 N N CH N CH C CH N CH CH CH OMe OMe 1182 CH CH N CH N C CH CH CH CH CH OMe OMe 1183 N CH N CH N C CH CH CH CH CH OMe OMe 1184 CH CH CH N N C CH CH CH CH CH OMe OMe 1185 N CH CH N N C CH CH CH CH CH OMe OMe 1186 CH CH CH CH N C CH CH CH CH CH OMe OMe 1187 N CH CH CH N C CH CH CH CH CH OMe OMe 1188 CH CH CH CH N C CH CH N CH CH absent OMe 1189 N CH CH CH N C CH CH N CH CH OMe

[0927] In a further embodiment, the present invention provides compounds of formula (XIII), wherein Z, R.sub.5, and R.sub.6 are as defined in examples 1190 to 1193:

##STR00061##

TABLE-US-00016 Comp Z R.sub.5 R.sub.6 1190 CH F H 1191 N F H 1192 CH OMe OMe 1193 N OMe OMe

[0928] In a further embodiment, the present invention provides compounds of formula (XIV), wherein R.sub.5, and R.sub.6 are as defined in examples 1194 to 1195:

##STR00062##

TABLE-US-00017 Comp R.sub.5 R.sub.6 1194 F H 1195 OMe OMe

[0929] In a further embodiment, the present invention provides compounds of formula (XVa) and (XVb), wherein Y.sub.1, Y.sub.2, Y.sub.3, Y.sub.4, Y.sub.5, Y.sub.6, Y.sub.7, Y.sub.8, Y.sub.9, Y.sub.10, R.sub.5, and R.sub.6 are as defined in examples 1196 to 1282:

##STR00063##

TABLE-US-00018 Comp Y.sub.1 Y.sub.2 Y.sub.3 Y.sub.4 Y.sub.5 Y.sub.6 Y.sub.7 Y.sub.8 Y.sub.9 Y.sub.10 R.sub.5 R.sub.6 1196 CH CH CH CH C CH CH CH CH CH H H 1197 CH CH CH CH C N CH CH CH CH H H 1198 CH CH CH CH C CH N CH CH CH H H 1199 CH CH CH CH C N CH CH CH N H H 1200 CH CH CH CH C N N CH CH CH H H 1201 CH CH CH CH C CH N CH N CH H absent 1202 CH CH CH CH C CH CH N CH N absent H 1203 CH CH CH CH C CH CH N CH CH absent H 1204 N CH CH CH C CH CH CH CH CH H H 1205 N CH CH CH C N CH CH CH CH H H 1206 N CH CH CH C CH N CH CH CH H H 1207 N CH CH CH C N CH CH CH N H H 1208 N CH CH CH C CH CH N CH N absent H 1209 N CH CH CH C N CH CH CH CH H H 1210 N N CH CH C CH CH N CH N absent H 1211 N N CH CH C CH CH CH CH CH H H 1212 CH N CH CH C CH CH CH CH CH H H 1213 CH N CH CH C N CH CH CH CH H H 1214 CH N CH CH C CH N CH CH CH H H 1215 CH N CH CH C CH N CH N CH H absent 1216 CH N CH CH C N CH CH N CH H H 1217 CH N CH CH C CH CH N CH N absent H 1218 CH N CH CH C CH CH N CH CH absent H 1219 N CH N CH C CH CH CH CH CH H H 1220 N CH N CH C N CH CH CH CH H H 1221 N CH N CH C CH N CH CH CH H H 1222 CH N CH N C CH CH CH CH CH H H 1223 CH CH N N C CH CH CH CH CH H H 1224 CH CH CH N C CH CH CH CH CH H H 1225 CH CH CH N C CH CH N CH CH absent H 1226 CH CH CH CH C CH CH CH CH CH F H 1227 CH CH CH CH C N CH CH CH CH F H 1228 CH CH CH CH C CH N CH CH CH F H 1229 CH CH CH CH C N CH CH CH N F H 1230 CH CH CH CH C N N CH CH CH F H 1231 CH CH CH CH C CH N CH N CH F absent 1232 CH CH CH CH C CH CH N CH N absent 1233 CH CH CH CH C CH CH N CH CH absent H 1234 N CH CH CH C CH CH CH CH CH F H 1235 N CH CH CH C N CH CH CH CH F H 1236 N CH CH CH C CH N CH CH CH F H 1237 N CH CH CH C N CH CH CH N F H 1238 N CH CH CH C CH CH N CH N absent H 1239 N N CH CH C CH CH CH CH CH F H 1240 N N CH CH C CH CH N CH N absent H 1241 CH N CH CH C CH CH CH CH CH F H 1242 CH N CH CH C N CH CH CH CH F H 1243 CH N CH CH C CH N CH CH CH F H 1244 CH N CH CH C CH N CH N CH F absent 1245 CH N CH CH C N CH CH N CH F absent 1246 CH N CH CH C CH CH N CH N absent H 1247 N CH N CH C CH CH CH CH CH F H 1248 N CH N CH C N CH CH CH CH F H 1249 N CH N CH C CH N CH CH CH F H 1250 CH N CH N C CH CH CH CH CH F H 1251 CH CH N N C CH CH CH CH CH F H 1252 CH CH CH N C CH CH CH CH CH F H 1253 CH CH CH N C CH N CH CH CH F H 1254 CH CH CH CH C CH CH CH CH CH OMe OMe 1255 CH CH CH CH C N CH CH CH CH OMe OMe 1256 CH CH CH CH C CH N CH CH CH OMe OMe 1257 CH CH CH CH C N CH CH CH N OMe OMe 1258 CH CH CH CH C N N CH CH CH OMe OMe 1259 CH CH CH CH C CH N CH N CH OMe absent 1260 CH CH CH CH C CH CH N CH N absent OMe 1261 CH CH CH CH C CH CH N CH CH absent OMe 1262 N CH CH CH C CH CH CH CH CH OMe OMe 1263 N CH CH CH C N CH CH CH CH OMe OMe 1264 N CH CH CH C CH N CH CH CH OMe OMe 1265 N CH CH CH C N CH CH CH N OMe OMe 1266 N CH CH CH C CH CH N CH N absent OMe 1267 N CH CH CH C N CH CH CH CH OMe OMe 1268 N N CH CH C CH CH N CH N absent OMe 1269 N N CH CH C CH CH CH CH CH OMe OMe 1270 CH N CH CH C CH CH CH CH CH OMe OMe 1271 CH N CH CH C N CH CH CH CH OMe OMe 1272 CH N CH CH C CH N CH CH CH OMe OMe 1273 CH N CH CH C CH N CH N CH OMe absent 1274 CH N CH CH C N CH CH N CH OMe OMe 1275 CH N CH CH C CH CH N CH N absent OMe 1276 CH N CH CH C CH CH N CH CH absent OMe 1277 N CH N CH C CH CH CH CH CH OMe OMe 1278 N CH N CH C N CH CH CH CH OMe OMe 1279 N CH N CH C CH N CH CH CH OMe OMe 1280 CH N CH N C CH CH CH CH CH OMe OMe 1281 CH CH N N C CH CH CH CH CH OMe OMe 1282 CH CH CH N C CH CH CH CH CH OMe OMe

[0930] In a further embodiment, the present invention provides compounds of formula (XVa) and (XVb), wherein Y.sub.1, Y.sub.2, Y.sub.3, Y.sub.4, Y.sub.5, Y.sub.6, Y.sub.7, Y.sub.8, Y.sub.9, Y.sub.10, R.sub.5, and R.sub.6 are as defined in examples 1310 to 1319:

##STR00064##

TABLE-US-00019 Comp Y.sub.1 Y.sub.2 Y.sub.3 Y.sub.4 Y.sub.5 Y.sub.6 Y.sub.7 Y.sub.8 Y.sub.9 Y.sub.10 R.sub.5 R.sub.6 1301 CH CH CH CH C CH CH CH CH CH OMe H 1302 CH CH CH N C CH CH CH CH CH OMe H 1303 N CH CH CH C CH CH CH CH CH OMe H 1304 CH CH N CH C CH CH CH CH CH OMe H 1305 CH N CH CH C CH CH CH CH CH OMe H 1306 N CH N CH C CH CH CH CH CH OMe H 1307 N CH CH N C CH CH CH CH CH OMe H 1308 CH CH N CH C CH CH CH CH CH OMe OMe 1309 N CH CH N C CH CH CH CH CH OMe OMe 1310 N CH CH N C CH CH CH CH CH F H 1311 CH CH CH CH C CH CH CH CH CH O-phenyl H 1312 CH CH CH CH C CH CH CH CH CH O-cyclohexyl H 1313 CH CH CH CH C CH CH CH CH CH propyloxy H 1314 CH CH CH CH C CH CH CH CH CH propan-2-yloxy H 1315 CH CH CH CH subst. C CH CH CH CH CH OMe H with Me 1316 CH CH CH CH subst. C CH CH CH CH CH OMe OMe with Me 1317 CH CH CH CH subst. C CH CH CH CH CH Cl OMe with F 1318 CH CH CH CH subst. C CH CH CH CH CH OMe OMe with F 1319 CH CH CH CH subst. C CH CH CH CH CH F H with F

[0931] In a further embodiment, the present invention provides compounds of formula (XVI), wherein R.sub.5, and R.sub.6 are as defined in examples 1283 to 1284:

##STR00065##

TABLE-US-00020 Comp R5 R6 1283 F H 1284 OMe OMe

[0932] In a further embodiment, the present invention provides compounds of formula (XVII), wherein R.sub.2, R.sub.5, and R.sub.6 are as defined in examples 1285 to 1288:

##STR00066##

TABLE-US-00021 Comp R2 R5 R6 1285 Me F H 1286 Me OMe OMe 1287 Cyclopropy F H 1288 Cyclopropy OMe OMe

[0933] In a further embodiment, the present invention provides compounds of formula (XVIII), wherein X.sub.1, n, R.sub.5, and R.sub.6 are as defined in examples 1320 to 1323:

##STR00067##

TABLE-US-00022 Comp X.sub.1 n R5 R6 1320 CH.sub.2 1 F H 1321 S 1 F H 1322 CH.sub.2 1 OMe OMe 1323 S 1 OMe OMe

[0934] In a preferred embodiment, the present invention provides compounds of formula (I), or a pharmaceutically acceptable salt, solvate or polymorph thereof, including all tautomers and stereoisomers thereof, wherein said compound of formula (I) is selected from:

TABLE-US-00023 Exam- Syn- hQC hQC ple thesis K.sub.i K.sub.i Com- Exam- Mol [μM] [μM] pound ple Compound Name Structure Formula Weight pH6 pH8 93 A2 5-[3-({4′-fluoro-[1,1′-biphenyl]- 2-yl}amino)propyl]-1,3,4- thiadiazol-2-amine [00068] embedded image C.sub.17H.sub.17FN.sub.4S 328.40 2.6 1102 94 A3 5-{[2-({4′-fluoro-[1,1′-biphenyl]- 2-yl}amino)ethyl]sulfanyl}-1,3,4- thiadiazol-2-amine [00069] C.sub.16H.sub.15FN.sub.4S.sub.2 346.44 2.97 11.51 178 A4 5-{[2-({3′,4′-dimethoxy-[1,1′- biphenyl]-2- yl}amino)ethyl]sulfanyl}-1,3,4- thiadiazol-2-amine [00070] embedded image C.sub.18H.sub.20N.sub.4O.sub.2S.sub.2 388.50 1.10 0.97 328 B1 4′-fluoro-N-[3-(4-methyl-4H- 1,2,4-triazol-3-yl)propyl]-[1,1′- biphenyl]-2-amine [00071] C.sub.18H.sub.19FN.sub.4 310.36 1.97 2.86 384 B3 3′,4′-dimethoxy-N-[3-(4-methyl- 4H-1,2,4-triazol-3-yl)propyl]- [1,1′-biphenyl]-2-amine [00072] embedded image C.sub.20H.sub.24N.sub.4O.sub.2 352.43 0.13 0.26 505 C2 5-[4-({4′-fluoro-[1,1-biphenyl]- 2-yl}amino)phenyl]-1,3,4- thiadiazol-2-amine [00073] C.sub.20H.sub.15FN.sub.4S 362.42 1.52 1.81 561 C3 5-(4-{[2-(3,4- dimethoxyphenyl)phenyl]amino} phenyl)-1,3,4-thiadiazol-2- amine [00074] C.sub.22H.sub.20N.sub.4O.sub.2S 404.48 0.42 1.09 1289 C4 5-(4-{[2-(4- methoxyphenyl)phenyl]amino} phenyl)-1,3,4-thiadiazol-2-amine [00075] embedded image C.sub.21H.sub.18N.sub.4OS 374.46 1.87 1.48 1290 C5 N-[4-(5-amino-1,3,4-thiadiazol- 2-yl)phenyl]-3-(4- methoxyphenyl)pyridin-2-amine [00076] C.sub.20H.sub.17N.sub.5O.sub.S 375.44 4.17 4.70 1291 C6 N-[4-(5-amino-1,3,4-thiadiazol 2-yl)phenyl]-3-(4- methoxyphenyl)pyridin-4-amine [00077] C.sub.20H.sub.17N.sub.5OS 375.44 7.16 4.22 1292 C7 N-[4-(5-amino-1,3,4-thiadiazol- 2-yl)phenyl]-3-(3,4- dimethoxyphenyl)pyridin-4- amine [00078] embedded image C.sub.21H.sub.19N.sub.5O.sub.2S 405.47 54.69 7.46 521 C8 N-[4-(5-amino-1,3,4-thiadiazol- 2-yl)phenyl]-3-(4- fluorophenyl)pyridin-2-amine [00079] C.sub.19H.sub.14FN.sub.5S 363.41 2.69 4.27 1293 C9 N-[4-(5-amino-1,3,4-thiadiazol- 2-yl)phenyl]-3-(4- fluorophenyl)pyrazin-2-amine [00080] C.sub.18H.sub.13FN.sub.6S 364.39 1.66 6.89 1294 C10 5-(4-{[2-(4- phenoxyphenyl)phenyl]amino} phenyl)-1,3,4-thiadiazol-2-amine [00081] embedded image C.sub.26H.sub.20N.sub.4OS 436.52 4.37 2.23 1295 C11 5-(4-{[2-(4- propoxyphenyl)phenyl]amino} phenyl)-1,3,4-thiadiazol-2-amine [00082] C.sub.23H.sub.22N.sub.4OS 402.51 2.15 2.36 1296 C12 5-[4-({2-[4-(propan-2- yloxy)phenyl]phenyl}amino)phe- nyl]-1,3,4-thiadiazol-2-amine [00083] C.sub.23H.sub.22N.sub.4OS 402.51 1.51 3.27 826 D1 4′-fluoro-N-[4-(4-methyl-4H- 1,2,4-triazol-3-yl)phenyl]-[1,1‘- biphenyl]-2-amine [00084] embedded image C.sub.21H.sub.17FN.sub.4 344.38 1.44 1.74 854 D2 3′,4′-dimethoxy-N-[4-(4-methyl- 4H-1,2,4-triazol-3-yl)phenyl]- [1,1′-biphenyl]-2-amine [00085] C.sub.23H.sub.22N.sub.4O.sub.2 386.45 0.44 1.48 1297 D3 N-[2-(4- methoxyphenyl)phenyl]-4-(4- methyl-4H-1,2,4-triazol-3- yl)aniline [00086] embedded image C.sub.22H.sub.20N.sub.4O 356.42 0.99 1.69 1298 D4 2-(4-methoxyphenyl)-N-[4-(4- methyl-4H-1,2,4-triazol-3- yl)phenyl]pyridin-3-amine [00087] C.sub.21H.sub.19N.sub.5O 357.40 1.70 3.37 852 D5 2-(4-fluorophenyl)-N-[4-(4- methyl-4H-1,2,4-triazol-3- yl)phenyl]pyridin-3-amine [00088] C.sub.20H.sub.16FN.sub.5 345.37 2.69 5.05 1299 D6 4-(4-methyl-4H-1,2,4-triazol-3- yl)-N-[2-(4- phenoxyphenyl)phenyl]aniline [00089] embedded image C.sub.27H.sub.22N.sub.4O 418.48 1.33 1.81 1300 D7 3-(3,4-dimethoxyphenyl)-N-[4- (4-methyl-4H-1,2,4-triazol-3- yl)phenyl]pyridin-4-amine [00090] C.sub.22H.sub.21N.sub.5O.sub.2 387.43 Not deter- mined 10.07 973 E2 N-[3-(5-amino-1,3,4-thiadiazol- 2-yl)propyl]-4-fluorobenzene-1- sulfonamide [00091] embedded image C.sub.11H.sub.13FN.sub.4O.sub.2S.sub.2 316.37 18.08 9.38 974 E3 N-{2-[(5-amino-1,3,4-thiadiazol- 2-yl)sulfanyl]ethyl}-4- fluorobenzene-1-sulfonamide [00092] C.sub.10H.sub.11FN.sub.4O.sub.2S.sub.3 334.41 19.91 26.48 979 F2 5-(3-{[(4- fluorophenyl)(methyl)oxo-λω- sulfanylidene]amino}propyl)- 1,3,4-thiadiazol-2-amine [00093] embedded image C.sub.12H.sub.15FN.sub.4OS.sub.2 314.40 11.41 11.70 990 G1 4-fluoro-N-[3-(4-methyl-4H- 1,2,4-triazol-3- yl)propyl]benzene-1- sulfonamide [00094] C.sub.12H.sub.15FN.sub.4O.sub.2S 298.33 — — 991 G2 4-fluoro-N-{2-[(4-methyl-4H- 1,2,4-triazol-3- yl)sulfanyl]ethyl}benzene-1- sulfonamide [00095] embedded image C.sub.11H.sub.13FN.sub.4O.sub.2S.sub.2 316.37 8.84 11.49 1332 G5 [(3,4- dimethoxyphenyl)sulfamoyl]({2- [(4-methyl-4H-1,2,4-triazol-3- yl)sulfanyl]ethyl})amine [00096] C.sub.13H.sub.19N.sub.5O.sub.4S.sub.2 373.45 13.63 11.76 1002 I1 N-[4-(2-amino-1,3-thiazol-5- yl)phenyl]-4-fluorobenzene-1- sulfonamide [00097] embedded image C.sub.15H.sub.12FN.sub.3O.sub.2S.sub.2 349.40 2.93 2.64 1003 I2 N-[4-(2-amino-1,3-thiazol-5- yl)phenyl]-3,4- dimethoxybenzene-1- sulfonamide [00098] C.sub.17H.sub.17N.sub.3O.sub.4S.sub.2 391.46 0.20 0.34 1075 L2 5-(1-{4′-fluoro-[1,1′-biphenyl]-2- yl}piperidin-4-yl)-1,3,4- thiadiazol-2-amine [00099] embedded image C.sub.19H.sub.19FN.sub.4S 354.44 0.09 0.248 1190 M1 5-[1-(4- fluorobenzenesulfonyl)piperidin- 4-yl]-1,3-thiazol-amine [00100] C.sub.14H.sub.16FN.sub.3O.sub.2S.sub.2 341.42 1.32 1.70 1191 M2 5-[1-(4- fluorobenzenesulfonyl)piperidin- 4-yl]-1,3,4-thiadiazol-2-amine [00101] C.sub.13H.sub.15FN.sub.4O.sub.2S.sub.2 342.41 1.18 1.60 1194 N1 1-(4-fluorobenzenesulfonyl)-4- (4-methyl-4H-1,2,4-triazol-3- yl)piperidine [00102] embedded image C.sub.14H.sub.17FN.sub.4O.sub.2S 324.37 3.05 3.30 1226 O1 N-[(1H-1,3-benzodiazol-5- yl)methyl]-4′-fluoro-[1,1′- biphenyl]-2-amine [00103] C.sub.20H.sub.16FN.sub.3 317.35 5.91 5.29 1254 O2 N-[(1H-1,3-benzodiazol-5- yl)methyl]-3′,4′-dimethoxy-[1,1′- biphenyl]-2-amine [00104] C.sub.22H.sub.21N.sub.3O.sub.2 359.42 0.12 0.27 1301 O3 N-(1H-1,3-benzodiazol-5- ylmethyl)-2-(4- methoxyphenyl)amine [00105] embedded image C.sub.21H.sub.19N.sub.3O 329.39 1.44 1.65 1302 O4 N-(1H-1,3-benzodiazol-5- ylmethyl)-2-(4- methoxyphenyl)pyridin-3-amine [00106] C.sub.20H.sub.18N.sub.4O 330.38 9.52 2.96 1303 O5 N-(1H-1,3-benzodiazol-5- ylmethyl)-3-(4- methoxyphenyl)pyridin-2-amine [00107] C.sub.20H.sub.18N.sub.4O 330.38 2.74 2.41 1304 O6 N-(1H-1,3-benzodiazol-5- ylmethyl)-3-(4- methoxyphenyl)pyridin-4-amine [00108] embedded image C.sub.20H.sub.18N.sub.4O 330.38 15.05 10.85 1305 O7 N-(1H-1,3-benzodiazol-5- ylmethyl)-4-(4- methoxyphenyl)pyridin-3-amine [00109] C.sub.20H.sub.18N.sub.4O 330.38 11.14 4.24 1306 O8 N-(1H-1,3-benzodiazol-5- ylmethyl)-5-(4-methoxyphenyl) pyrimidin-4-amine [00110] C.sub.19H.sub.17N.sub.5O 331.37 Not deter- mined 18.31 1307 O9 N-(1H-1,3-benzodiazol-5- ylmethyl)-3-(4- methoxyphenyl)pyrazin-2- amine [00111] embedded image C.sub.19H.sub.17N.sub.5O 331.37 1.90 2.21 1308 O10 N-(1H-1,3-benzodiazol-5- ylmethyl)-3-(3,4- dimethoxyphenyl)pyridin-4- amine [00112] C.sub.21H.sub.20N.sub.4O.sub.2 360.40 1.63 0.88 1262 O11 N-(1H-1,3-benzodiazol-5- ylmethyl)-3-(3,4- dimethoxyphenyl)pyridin-2- amine [00113] C.sub.21H.sub.20N.sub.4O.sub.2 360.40 0.10 0.23 1309 O12 N-(1H-1,3-benzodiazol-5- ylmethyl)-3-(3,4- dimethoxyphenyl)pyrazin-2- amine [00114] embedded image C.sub.20H.sub.19N.sub.5O.sub.2 361.39 0.13 0.42 1252 O13 N-(1H-1,3-benzodiazol-5- ylmethyl)-2-(4- fluorophenyl)pyridin-3-amine [00115] C.sub.19H.sub.15FN.sub.4 318.34 145.42 21.96 1234 O14 N-(1H-1,3-benzodiazol-5- ylmethyl)-3-(4- fluorophenyl)pyridin-2-amine [00116] C.sub.19H.sub.15FN.sub.4 318.34 58.79 12.28 1310 O15 N-(1H-1,3-benzodiazol-5- ylmethyl)-3-(4- fluorophenyl)pyrazin-2-amine [00117] embedded image C.sub.18H.sub.14FN.sub.5 319.33 10.52 11.74 1311 O16 N-(1H-1,3-benzodiazol-5- ylmethyl)-2-(4- phenoxyphenyl)aniline [00118] C.sub.26H.sub.21N.sub.3O 391.46 4.34 2.11 1312 O17 N-(1H-1,3-benzodiazol-5- ylmethyl)-2-[4- (cyclohexyloxy)phenyl]aniline [00119] C.sub.26H.sub.27N.sub.3O 397.51 2.03 4.17 1313 O18 N-(1H-1,3-benzodiazol-5- ylmethyl)-2-(4- propoxyphenyl)aniline [00120] embedded image C.sub.23H.sub.23N.sub.3O 357.44 3.59 2.64 1314 O19 N-(1H-1,3-benzodiazol-5- ylmethyl)-2-[4-(propan-2- yloxy)phenyl]aniline [00121] C.sub.23H.sub.23N.sub.3O 357.44 1.53 3.39 1315 O20 N-(1H-1,3-benzodiazol-5- ylmethyl)-2-(4-methoxyphenyl)- 3-methylaniline [00122] C22H21N3O 343.42 2.38 1.64 1316 O21 N-(1H-1,3-benzodiazol-5- ylmethyl)-2-(3,4- dimethoxyphenyl)-3- methylaniline [00123] embedded image C23H23N3O2: 373.45 0.43 0.42 1317 O22 N-(1H-1,3-benzodiazol-5- ylmethyl)-2-(4-chlorophenyl)-3- fluoroaniline [00124] C20H15ClFN3 351.8 4.89 6.83 1318 O23 N-(1H-1,3-benzodiazol-5- ylmethyl)-2-(3,4- dimethoxyphenyl)-3- fluoroaniline [00125] C22H20FN3O2 377.41 0.055 0.10 1319 O24 N-(1H-1,3-benzodiazol-5- ylmethyl)-3-fluoro-2-(4- fluoropheny)aniline [00126] embedded image C20H15F2N3 335.35 5.81 9.41 1283 P1 N-[(1H-1,3-benzodiazol-5- yl)methyl]-4-fluorobenzene-1- sulfonamide [00127] C.sub.14H.sub.12FN.sub.3O.sub.2S 305.32 38.34 24.74 1285 Q1 [(1H-1,3-benzodiazol-5- yl)methyl][(4- fluorophenyl)(methyl)oxo-λω- sulfanylidene]amine [00128] C.sub.15H.sub.14FN.sub.3OS 303.35 8.05 5.18

SYNTHESIS OF THE EXAMPLES

[0935] Synthesis Method A

##STR00129##

[0936] 4-({4′-fluoro-[1,1′-biphenyl]-2-yl}amino)butanenitrile 4′-fluoro-[1,1′-biphenyl]-2-amine (0.5 g, 2.7 mmol), sodium cyanoborohydride (0.25 g, 4.0 mmol) and 4-oxobutanenitrile (0.44 g, 5.3 mmol) were dissolved in dry MeOH (15 mL) and acetic acid was added (0.5 mL). Reaction was stirred over 2 h until full consumption of amine was observed via UPLC analysis. After this time reaction mixture was diluted with saturated sodium bicarbonate solution (40 mL) and extracted with ethyl acetate (3×20 mL). Combined organic layers were dried over sodium sulfate, filtered and evaporated and purified via column chromatography using ethyl acetate in hexanes 10-20% as eluent to give pure title compound (0.17 g, 12%).

[0937] 5-[3-({4′-fluoro-[1,1′-biphenyl]-2-yl}amino)propyl]-1,3,4-thiadiazol-2-amine (A2) 4-({4′-fluoro-[1,1′-biphenyl]-2-yl}amino)butanenitrile (0.16 g, 0.6 mmol) and tiosemicarbazide (0.06 g, 0.7 mmol) were dissolved in trifluoroacetic acid (1.3 mL). Reaction was monitored via UPLC analysis. After completion of the reaction, solvent was removed in vacuo and crude material was purified via column chromatography using MeOH in DCM 0-2% as eluent to give pure title compound (70 mg, 33%). LCMS-Method 10 (200 nm); RT=5.81 min, 95.2% purity, [M+1]=329.2, .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 7.46-7.36 (m, 2H), 7.32-7.23 (m, 2H), 7.20-7.11 (m, 1H), 7.05-6.89 (m, 3H), 6.76-6.55 (m, 2H), 4.61 (t, J=5.9 Hz, 1H), 3.10 (q, J=6.6 Hz, 2H), 2.82 (t, J=7.5 Hz, 2H), 1.85 (p, J=7.2 Hz, 2H).

[0938] Synthesis Method B

##STR00130##

[0939] Step 1

##STR00131##

[0940] 2-substituted aniline (1.0 eq.), sodium cyanoborohydride (1.5 eq.) and t-butyldimethylsilyloxyacetaldehyde (2.0 eq.) were dissolved in dry MeOH (30.0 vol.) and acetic acid was added (1.0 vol.). Reaction was stirred over 1-2 h until full consumption of amine was observed via UPLC analysis. After this time reaction mixture was diluted with saturated sodium bicarbonate solution (40 mL) and extracted with ethyl acetate (3×20 mL). Combined organic layers were dried over sodium sulfate, filtered and evaporated, used in next step without further purification.

[0941] Step 2

##STR00132##

[0942] Product from step 1 (1.0 eq.) and tetrabutylammonium fluoride trihydrate (1.05 eq.) were dissolved in THF (40.0 vol.). Reaction was monitored via UPLC analysis. After completion the reaction, solvent was removed in vacuo and crude material was taken to step 3.

[0943] 5-{[2-({4′-fluoro-[1,1′-b]phenyl]-2-yl}amino)ethyl]sulfanyl}-1,3,4-thiadiazol-2-amine (A3). To solution of 2-({4′-fluoro-[1,1′-biphenyl]-2-yl}amino)ethan-1-ol (0.58 g, 2.5 mmol), 2-amino-5-mercapto-thiadiazole (0.50 g, 3.8 mmol) and triphenylphosphine (1.18 g, 4.5 mmol) in anhydrous THF (16.0 mL) diethyleneazodicarboxylate (0.66 g, 3.8 mmol) was added dropwise. Reaction mixture was stirred overnight at room temperature. After this time solvents were removed in vacuo. Crude product was purified via column chromatography using 0-3% MeOH in DCM and additional repurified via preparative TLC method using MeOH in DCM as eluent. Final re-purification was performed via preparative HPLC method to give pure product (40 mg. 7%) LCMS-Method 7 (200 nm): RT=5.81 min, 98.7% purity, [M]=346.0, .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 7.48-7.31 (m, 1H), 7.27-7.10 (m, 2H), 7.01 (dd, J=7.4, 1.6 Hz, 1H), 6.84-6.52 (m, 1H), 3.47 (t, J=6.6 Hz, 1H), 3.26 (t, J=6.6 Hz, 1H).

[0944] 5-{[2-({3′,4′-dimethoxy-[1,1′-biphenyl]-2-yl}amino)ethyl]sulfanyl}-1,3,4-thiadiazol-2-amine (A4). To solution of 2-({3′,4′-dimethoxy-[1,1′-biphenyl]-2-yl}amino)ethan-1-ol (0.9 g, 8.3 mmol), 2-amino-5-mercapto-thiadiazole (1.0 g, 7.5 mmol) and triphenylphosphine (2.17 g, 8.3 mmol) in anhydrous THF (10.0 mL) diethyleneazadicarboxylate (2.25 g, 9.8 mmol) was added dropwise in 5 mL of anhydrous tetrahydrofurane. Reaction mixture was stirred overnight at room temperature. After this time solvents were removed in vacuo. Crude product was purified via column chromatography using 0-3% MeOH in DCM and re-purified via preparative HPLC method to give pure product (80 mg, 7%) LCMS-Method 7 (205 nm): RT=5.27 min, 98.1% purity, [M]=386.9. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 7.30 (s, 1H), 7.14 (td, J=7.8, 7.3, 1.7 Hz, 1H), 7.09-6.96 (m, 2H), 6.89 (dd, J=8.2, 2.0 Hz, 0H), 6.75-6.61 (m, 1H), 4.94 (t, J=6.0 Hz, 1H), 3.79 (d, J=1.8 Hz, 3H), 3.38 (d, J=6.5 Hz, 1H), 3.24 (t, J=6.4 Hz, 1H).

[0945] Synthesis Method C

##STR00133##

[0946] Step 1

##STR00134##

[0947] To the solution of amine (4.27 mmol) in MeOH (25.0 mL) methyl 4-oxobutanoate (0.99 g, 8.54 mmol) and acetic acid (0.8 mL) was added. The reaction mixture was stirred for 1.5 hours at ambient temperature. After that time NaBH.sub.3CN (0.40 mg, 6.41 mmol) was added and the mixture was stirred for 1 h. Reaction was quenched with saturated solution of NaHCO.sub.3. The water layer was extracted with DCM (3×20 mL). Combined organic layers were dried over sodium sulfate, filtered, evaporated to provide the product.

[0948] methyl 4-(4′-fluoro-[1,1′-biphenyl]-2-yl)amino)butanoate (0.875 g, 71%) 4′-fluoro-[1,1′-biphenyl]-2-amine was used. Crude (1.47 g) was purified via column chromatography using 100% DCM as eluent. UPLC (254 nm): RT=4.14 min, 76% purity, [M+H]=288.20.

[0949] methyl 4-((3′,4′-dimethoxy-[1,1′-biphenyl]-2-yl)amino)butanoate (1.00 g, 71%) 3′,4′-dimethoxy-[1,1′-biphenyl]-2-amine was used. Crude product was purified via column chromatography using 0-20% EA in hexane as eluent.

[0950] Step 2

##STR00135##

[0951] To the solution of corresponding starting material (3.04 mmol) in EtOH (30 mL) 50% hydrazine in H.sub.2O (5.0 eq) was added. Reaction mixture was stirred for 18 hour at 80° C. After that time the solvent was evaporated to give pure compound.

[0952] 4-(4′-fluoro-[1,1′-biphenyl]-2-yl)amino)butanehydrazide (0.85 g, 96%). Methyl 4-({4′-fluoro-[1,1′-biphenyl]-2-yl}amino)butanoate (0.875 g. 3.04 mmol) as starting material was used. UPLC (254 nm): RT=3.06 min, [M+H]=288.35.

[0953] 4-({3′,4′-dimethoxy-[1,1′-biphenyl]-2-yl}amino)butanehydrazide (0.97 g, 97%). Methyl 4-({3′,4′-dimethoxy-[1,1′-biphenyl]-2-yl}amino)butanoate (1.0 g, 3.04 mmol) as starting material was used. UPLC (254 nm): RT=2.82 min, [M+H]=330.30.

[0954] Step 3

##STR00136##

[0955] To the solution of corresponding starting material (2.6 mmol) in MeOH (8 mL) N,N-dimethylformamide dimethylacetal (311 mg, 2.6 mmol) was added. Reaction mixture was stirred for 1 hour at 80° C. After that time solvent was evaporated to obtain desired product.

[0956] N′-[(1E)-(dimethylamino)methylidene]-4-({4′-fluoro-[1,1′-biphenyl]-2-yl}amino)butane-hydrazide (0.894 g, 100%). 4-({4′-fluoro-[1,1′-biphenyl]-2-yl}amino)butanehydrazide (0.75 g, 2.61 mmol) was used as starting material. UPLC (254 nm): RT=3.40 min, [M+H]=343.15.

[0957] 4-({3′,4′-dimethoxy-[1,1′-biphenyl]-2-yl}amino)-N′-[(1E)-(dimethylamino)methylidene]-butanehydrazide (1.014 g, 100%). 4-({3′,4′-dimethoxy-[1,1′-biphenyl]-2-yl}amino)butane-hydrazide (0.869 g, 2.64 mmol) was used as starting material. UPLC (254 nm): RT=3.40 min, [M+H]=385.30.

[0958] Step 4

##STR00137##

[0959] MeNH.sub.2 2M in THF (20 eq) was added to the solution of corresponding starting material in anhydrous THF (10.0 mL) under argon atmosphere. Reaction mixture was cooled to 0° C. and acetic acid (2 mL) was carefully added. Reaction mixture was stirred for 18 hours at 100° C. After that time reaction was cooled to room temperature and water (5 mL) was added. Layers were separated and water layer was extracted three times with EA (3×20 mL). Combined organic layers were dried over sodium sulfate, filtered and evaporated. Crude product was purified via column chromatography using 0-4% MeOH in DCM as eluent and then re-purified via preparative HPLC. Fraction containing the title compound in pure form was concentrated to give the product.

[0960] 4′-fluoro-N-[3-(4-methyl-4H-1,2,4-triazol-3-yl)propyl]-[1,1′-biphenyl]-2-amine (B1) (101 mg, 11%) N′-[(1E)-(dimethylamino)methylidene]-4-({4′-fluoro-[1,1′-biphenyl]-2-yl}amino)butane-hydrazide (1.00 g, 2.92 mmol) was used as starting material. LCMS-Method 2 (220 nm): RT=4.78 min, 98.89% purity. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 8.32 (s, 1H), 7.46-7.36 (m, 2H), 7.32-7.21 (m, 2H), 7.21-7.14 (m, 1H), 6.95 (d, J=1.7 Hz, 1H), 6.72-6.61 (m, 2H). 4.10 (q, J=5.3 Hz, 2H), 3.54 (s, 3H). 2.69 (d, J=7.5 Hz, 2H), 1.95-1.84 (m, 2H).

[0961] 3′,4′-dimethoxy-N-[3-(4-methyl-4H-1,2,4-triazol-3-yl)propyl]-[1,1′-biphenyl]-2-amine (B3) (5 mg, 0.4%). 4-({3′,4′-dimethoxy-[1,1′-biphenyl]-2-yl}amino)-N′-[(1E)-(dimethylamino)-methylidene]-butanehydrazide (1.10 g, 2.86 mmol) was used as starting material. LCMS-Method 8 (210 nm): RT=12.12 min, 99.45% purity. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 8.32 (s, 1H), 7.09-6.84 (m, 4H), 6.66 (d, J=7.9 Hz, 2H), 4.11 (q, J=5.4 Hz, 2H), 3.79 (d, J=5.4 Hz, 3H), 3.53 (s, 3H), 3.40 (t, J=7.0 Hz, 2H), 3.18 (d, J=5.3 Hz, 3H), 1.89-1.96 (m, 2H).

##STR00138##

[0962] Step 1

##STR00139##

[0963] N-[5-(4-bromophenyl)-1,3,4-thiadiazol-2-yl]acetamide 5-(4-bromophenyl)-1,3,4-thiadiazol-2-amine (0.5 g, 2.0 mmol), triethylamine (0.54 mL, 4.0 mmol), were dissolved in DCM (5 mL) and acetyl chloride (0.17 g, 2.15 mmol) was added dropwise at 5° C., reaction was stirred at room temperature over 1h, after this time another portion of triethylamine and acetyl chloride was added at 5° C. and reaction mixture was stirred over additional 30 min. The mixture was diluted with DCM (15.0 mL) and washed with sat. solution of sodium bicarbonate (20 mL), water (20 mL). Title compound was obtained as 1:1 mixture of acetylated (UPLC (254 nm): RT=3.13 min[M+H]=297.9) and diacetylated amine (UPLC (254 nm): RT=3.58 min[M+H]=338.9). (0.40 g, 60%). Used in next step without purification.

[0964] Step 2

##STR00140##

[0965] N-(5-[4-({4′-fluoro-[1,1′-biphenyl]-2-yl}amino)phenyl]-1,3,4-thiadiazol-2-yl)acetamide N-[5-(4-bromophenyl)-1,3,4-thiadiazol-2-yl]acetamide (0.2 g, 0.67 mmol), 4′-fluoro-[1,1′-biphenyl]-2-amine (0.12 g, 0.56 mmol), sodium tert-butanolate (0.15 mg, 1.56 mmol) and XantPhos (40 mg, 0.07 mmol) were suspended in 1,4-dioxane (6 ml), Reaction mixture was degassed with argon flow over 20 min and tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (35 mg, 0.035 mmol) was added. Reaction was stirred overnight at 100° C. After that time reaction mixture was cooled to room temperature, Filtered thru celite, evaporated and purified via column chromatography using MeOH in DCM 0-3% as aluent to give pure product (0.24 g, 88%). UPLC (254 nm): RT=3.78 min. 85% purity, [M+H]=404.8.

##STR00141##

[0966] 5-[4-({4′-fluoro-[1,1′-biphenyl]-2-yl}amino)phenyl]-1,3,4-thiadiazol-2-amine (C.sub.2) To solution of N-{5-[4-({4′-fluoro-[1,1′-biphenyl]-2-yl}amino)phenyl]-1,3,4-thiadiazol-2-yl}acetamide (0.17 g, 0.42 mmol) in methanol (2.5 mL) concentrated hydrochloric acid (2.5 mL) was added dropwise. Reaction mixture was refluxed overnight. After this time reaction was diluted with saturated sodium bicarbonate solution (20 mL) and extracted with DCM (6×15 mL), organic layers were combined, dried over sodium sulfate, filtered and evaporated. Crude product was purified via preparative HPLC method to give pure product (40 mg, 25%) LCMS-Method 6 (200 nm): RT=20.57 min, 91.6% purity, [M+H]=363.14, LCMS (340 nm): RT=20.57 min, 99.2% purity, [M+H]=363.14, 1H NMR (300 MHz, DMSO-d6) δ 7.82 (s, 1H), 7.59-7.33 (m, 7H), 7.27-7.04 (m, 5H), 6.89-6.54 (m, 2H).

##STR00142##

[0967] N-{5-(4-{[2-(3,4-dimethoxyphenyl)phenyl]amino}phenyl)-1,3,4-thiadiazol-2-yl}acetamide N-[5-(4-bromophenyl)-1,3,4-thiadiazol-2-yl]acetamide (100 mg, 0.34 mmol), 2-(3,4-dimethoxyphenyl)aniline (60 mg, 0.28 mmol), sodium tert-butanolate (75 mg, 1.56 mmol) and XantPhos (40 mg, 0.035 mmol) were suspended in 1,4-dioxane (3 ml), Reaction mixture was degassed with argon flow over 20 min and tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (17 mg, 0.017 mmol) was added. Reaction was stirred overnight at 100° C. After that time reaction mixture was cooled to room temperature, Filtered through celite, evaporated and purified via column chromatography using MeOH in DCM 0-3% as aluent to give pure product (0.2 g, 80%). UPLC (254 nm): RT=3.64 min, 85% purity, [M+H]=447.15.

##STR00143##

[0968] 5-(4-([2-(3,4-dimethoxyphenyl)phenyl]amino)phenyl)-1,3,4-thiadiazol-2-amine (C3). To solution of N-{5-(4-{[2-(3,4-dimethoxyphenyl)phenyl]amino}phenyl)-1,3,4-thiadiazol-2-yl}acetamide (0.20 g, 0.42 mmol) in methanol (3.0 mL) concentrated hydrochloric acid (3.0 mL) was added dropwise. Reaction mixture was refluxed overnight. After this time reaction was diluted with saturated sodium bicarbonate solution (20 mL) and extracted with DCM (6×15 mL), organic layers were combined, dried over sodium sulfate, filtered and evaporated. Crude product was purified via preparative HPLC method to give pure product (44 mg, 25%) LCMS (LCMS-Method 10, 200 nm), RT=5.22 min, 96.1% purity, [M+H]=405.11, 1H NMR (300 MHz, DMSO-d6) δ 7.87 (s, 1H), 7.55-7.31 (m, 6H), 7.37-7.13 (m, 5H), 6.81-6.64 (m, 2H), 3.53 (s, 3H), 3.50 (s, J=7.0 Hz, 3H).

##STR00144##

[0969] N-[5-(4-{[2-(4-methoxyphenyl)phenyl]amino}phenyl)-1,3,4-thiadiazol-2-yl]acetamide. N-[5-(4-bromophenyl)-1,3,4-thiadiazol-2-yl]acetamide (128 mg, 0.43 mmol), 2-(4-methoxyphenyl)aniline (102 mg, 0.51 mmol), cesium carbonate (279 mg, 0.86 mmol) and XantPhos (50 mg, 0.09 mmol) were suspended in 1,4-dioxane (3.8 mL). Reaction mixture was degassed with argon flow over 20 min and tris(dibenzylideneacetone)dipalladium(0) (35 mg. 0.04 mmol) was added. Reaction was stirred at 100° C. for 96 hours. After that time reaction mixture was cooled to room temperature, Filtered thru celite, evaporated and purified via column chromatography using DCM/MeOH 1:0.fwdarw.98:2 as a eluent to give product as a yellow solid (62.5 mg, 35.01%). UPLC (254 nm): RT=7.14 min, 80.9% purity, [M+H]=417.10.

##STR00145##

[0970] 5-(4-{[2-(4-methoxyphenyl)phenyl]amino}phenyl)-1,3,4-thiadiazol-2-amine C4. To solution of N-[5-(4-{[2-(4-methoxyphenyl)phenyl]amino}phenyl)-1,3,4-thiadiazol-2-yl]acetamide (63 mg, 0.15 mmol) in methanol (1.0 mL) concentrated hydrochloric acid (1.0 mL) was added dropwise. Reaction mixture was refluxed overnight. After this time reaction was diluted with saturated sodium bicarbonate solution (20 mL), methanol was evaporated and extraction with ethyl acetate (2×10 mL) was made. Combined organic layers were dried over sodium sulfate, filtered and evaporated. Crude product was purified via preparative TLC eluted with Hex/EtOAc/MeOH 70:25:5 to give desired product as a yellow solid (19.6 mg, 35%). LCMS (LCMS-Method 11, 200 nm): RT=2.75 min, 98.9% purity, [M+H]=375.21. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 7.74 (s, 1H), 7.50-7.43 (m, 2H), 7.40-7.28 (m, 5H), 7.23-7.14 (m, 3H), 6.98-6.91 (m, 2H), 6.84-6.78 (m, 2H), 3.75 (s, 3H).

##STR00146##

[0971] N-[5-(4-([3-(4-methoxyphenyl)pyridin-2-yl)]amino)phenyl)-1,3,4-thiadiazol-2-yl]acetamide. N-[5-(4-bromophenyl)-1,3,4-thiadiazol-2-yl]acetamide (87 mg, 0.29 mmol), 3-(4-methoxyphenyl)pyridin-2-amine (70 mg, 0.35 mmol), cesium carbonate (190 mg, 0.58 mmol) and XantPhos (34 mg, 0.06 mmol) were suspended in 1,4-dioxane (2.6 mL). Reaction mixture was degassed with argon flow over 20 min and tris(dibenzylideneacetone)dipalladium(0) (24 mg, 0.03 mmol) was added. Reaction was stirred at 100° C. for 72 hours. After that time reaction mixture was cooled to room temperature, Filtered thru celite, evaporated and purified via column chromatography using DCM/MeOH 1:0.fwdarw.95:5 as a eluent to give product as a pale-yellow solid (114 mg, 93.6%). UPLC (254 nm): RT=5.35 min. 65% purity, [M+H]=418.70.

##STR00147##

[0972] N-[4-(5-amino-1,3,4-thiadiazol-2-yl)phenyl]-3-(4-methoxyphenyl)pyridin-2-amine (C5). To solution of N-[5-(4-{[3-(4-methoxyphenyl)pyridin-2-yl]amino}phenyl)-1,3,4-thiadiazol-2-yl]acetamide (114 mg, 0.27 mmol) in methanol (1.7 mL) concentrated hydrochloric acid (1.7 mL) was added dropwise. Reaction mixture was refluxed overnight. After this time reaction was diluted with saturated sodium bicarbonate solution (20 mL), methanol was evaporated and extraction with ethyl acetate (2×15 mL) was made. Combined organic layers were dried over sodium sulfate, filtered and evaporated. Crude product was purified via preparative TLC eluted with DCM/MeOH 9:1 to give desired product as a yellowish solid (16.4 mg, 16%). LCMS-Method 5 (200 nm): RT=1.75 min, 99.3% purity, [M+H]=376.19. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 8.20 (dd, J=4.9, 1.9 Hz, 1H), 7.96 (s, 1H), 7.67-7.56 (m, 4H), 7.53 (dd, J=7.4, 1.9 Hz, 1H), 7.47-7.40 (m, 2H), 7.25 (s, 2H), 7.10-7.04 (m, 2H), 6.98 (dd, J=7.4, 4.9 Hz, 1H), 3.82 (s, 3H).

##STR00148##

[0973] N-[5-(4-{[3-(4-methoxyphenyl)pyridin-4-yl]amino}phenyl)-1,3,4-thiadiazol-2-yl]acetamide. N-[5-(4-bromophenyl)-1,3,4-thiadiazol-2-yl]acetamide (100 mg, 0.34 mmol), 3-(4-methoxyphenyl)pyridin-4-amine (81 mg, 0.40 mmol), cesium carbonate (219 mg, 0.67 mmol) and XantPhos (39 mg, 0.07 mmol) were suspended in 1,4-dioxane (3 mL). Reaction mixture was degassed with argon flow over 20 min and tris(dibenzylideneacetone)dipalladium(0) (27 mg, 0.03 mmol) was added. Reaction was stirred at 100° C. for 72 hours. After that time reaction mixture was cooled to room temperature, Filtered thru celite, evaporated and purified via column chromatography using DCM/MeOH 1:0.fwdarw.95:5 as a eluent to give product as a yellow solid (75 mg, 53.6%). UPLC (310 nm): RT=3.96 min, 93% purity, [M+H]=418.95.

##STR00149##

[0974] N-[4-(5-amino-1,3,4-thiadiazol-2-yl)phenyl]-3-(4-methoxyphenyl)pyridin-4-amine (C6). To solution of N-[5-(4-{[3-(4-methoxyphenyl)pyridin-4-yl]amino}phenyl)-1,3,4-thiadiazol-2-yl]acetamide (75 mg, 0.18 mmol) in methanol (1.12 mL) concentrated hydrochloric acid (1.12 mL) was added dropwise. Reaction mixture was refluxed overnight. After this time reaction was diluted with saturated sodium bicarbonate solution (20 mL), methanol was evaporated and extraction with ethyl acetate (2×15 mL) was made. Combined organic layers were dried over sodium sulfate, filtered and evaporated. Crude product was purified via preparative TLC eluted with DCM/MeOH 9:1. Re-purification was performed via preparative TLC eluted with DCM/MeOH 9:1 to give desired product as a whitish solid (32.0 mg, 47%). LCMS-Method 3 (200 nm): RT=3.01 min, 99.8% purity, [M+H]=376.18. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 8.26-8.20 (m, 2H). 8.00 (s, 1H), 7.66-7.61 (m, 2H), 7.45-7.40 (m, 2H), 7.32-7.18 (m, 5H), 7.07-7.02 (m, 2H), 3.80 (s, 3H).

##STR00150##

[0975] N-[5-(4-{[3-(3,4-dimethoxyphenyl)pyridin-4-yl]amino}phenyl)-1,3,4-thiadiazol-2-yl]acetamide. N-[5-(4-bromophenyl)-1,3,4-thiadiazol-2-yl]acetamide (100 mg, 0.34 mmol), 3-(3,4-dimethoxyphenyl)pyridin-4-amine (93 mg, 0.40 mmol), cesium carbonate (219 mg, 0.67 mmol) and XantPhos (39 mg, 0.07 mmol) were suspended in 1,4-dioxane (3 mL). Reaction mixture was degassed with argon flow over 20 min and tris(dibenzylideneacetone)dipalladium(0) (27 mg, 0.03 mmol) was added. Reaction was stirred at 100° C. for 72 hours. After that time reaction mixture was cooled to room temperature, Filtered thru celite, evaporated and purified via column chromatography using DCM/MeOH 1:0.fwdarw.95:5 as a eluent to give product as a pale-yellow solid (49 mg, 32.7%). UPLC (310 nm): RT=4.72 min, 100% purity, [M+H]=448.15.

##STR00151##

[0976] N-[4-(5-amino-1,3,4-thiadiazol-2-yl)phenyl]-3-(3,4-dimethoxyphenyl)pyridin-4-amine (C7). To solution of N-[5-(4-{[3-(3,4-dimethoxyphenyl)pyridin-4-yl]amino}phenyl)-1,3,4-thiadiazol-2-yl]acetamide (49 mg, 0.11 mmol) in methanol (0.75 mL) concentrated hydrochloric acid (0.75 mL) was added dropwise. Reaction mixture was refluxed overnight. After this time reaction was diluted with saturated sodium bicarbonate solution (10 mL), methanol was evaporated and extraction with ethyl acetate (2×10 mL) was made. Combined organic layers were dried over sodium sulfate, filtered and evaporated. Crude product was purified via preparative TLC eluted with DCM/MeOH 95:5 to give desired product as a light yellow solid (11 mg, 24.8%). LCMS-Method 3 (200 nm): RT=2.90 min, 99.6% purity, [M+H]=406.17. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 8.28-8.22 (m, 2H), 8.01 (s, 1H), 7.67-7.60 (m, 2H), 7.33-7.17 (m, 5H), 7.09-6.99 (m, 3H), 3.77 (d, J=12.1 Hz, 6H).

##STR00152##

[0977] N-[5-(4-{[3-(4-fluorophenyl)pyridin-2-yl]amino}phenyl)-1,3,4-thiadiazol-2-yl]acetamide. N-[5-(4-bromophenyl)-1,3,4-thiadiazol-2-yl]acetamide (100 mg, 0.34 mmol), 3-(4-fluorophenyl)pyridin-2-amine (52 mg, 0.28 mmol), cesium carbonate (219 mg, 0.67 mmol) and XantPhos (39 mg, 0.07 mmol) were suspended in 1,4-dioxane (3 mL). Reaction mixture was degassed with argon flow over 20 min and tris(dibenzylideneacetone)dipalladium(0) (27 mg, 0.03 mmol) was added. Reaction was stirred at 100° C. for 72 hours. After that time reaction mixture was cooled to room temperature, Filtered thru celite, evaporated and purified via column chromatography using DCM/MeOH 1:0.fwdarw.99:1 as a eluent to give product as a yellowish solid (75 mg, 55.6%). UPLC (254 nm): RT=5.92 min, 96.8% purity, [M+H]=406.95.

##STR00153##

[0978] N-[4-(5-amino-1,3,4-thiadiazol-2-yl)phenyl]-3-(4-fluorophenyl)pyridin-2-amine (C.sub.8). To solution of N-[5-(4-{[3-(4-fluorophenyl)pyridin-2-yl]amino}phenyl)-1,3,4-thiadiazol-2-yl]acetamide (75 mg, 0.18 mmol) in methanol (1.2 mL) concentrated hydrochloric acid (1.2 mL) was added dropwise. Reaction mixture was refluxed overnight. After this time reaction was diluted with saturated sodium bicarbonate solution (20 mL), methanol was evaporated and extraction with ethyl acetate (2×15 mL) was made. Combined organic layers were dried over sodium sulfate, filtered and evaporated. Crude product was purified via preparative TLC eluted with DCM/MeOH 95:5. Re-purification was performed via preparative TLC eluted with DCM/MeOH 95:5 to give desired product as a yellowish solid (4.3 mg, 6.4%). LCMS-Method 2 (200 nm): RT=4.69 min, 98.9% purity, [M+H]=364.18. .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 8.22 (dd, J=5.0, 1.9 Hz, 1H), 7.68-7.61 (m, 2H), 7.60-7.47 (m, 5H), 7.30-7.20 (m, 2H), 7.02 (dd, J=7.4, 5.0 Hz, 1H).

##STR00154##

[0979] N-[5-(4-{[3-(4-fluorophenyl)pyrazin-2-yl]amino}phenyl)-1,3,4-thiadiazol-2-yl]acetamide. N-[5-(4-bromophenyl)-1,3,4-thiadiazol-2-yl]acetamide (100 mg, 0.34 mmol), 3-(4-fluorophenyl)pyrazin-2-amine (76 mg, 0.40 mmol), cesium carbonate (219 mg, 0.67 mmol) and XantPhos (39 mg, 0.07 mmol) were suspended in 1,4-dioxane (3 mL). Reaction mixture was degassed with argon flow over 20 min and tris(dibenzylideneacetone)dipalladium(0) (27 mg, 0.03 mmol) was added. Reaction was stirred at 100° C. for 72 hours. After that time reaction mixture was cooled to room temperature. Filtered thru celite, evaporated and purified via column chromatography using DCM/MeOH 1:0.fwdarw.97:3 as a eluent to give product as a yellowish solid (68 mg, 49.8%). UPLC (254 nm): RT=5.88 min, 95.5% purity, [M+H]=407.05.

##STR00155##

[0980] N-[4-(5-amino-1,3,4-thiadiazol-2-yl)phenyl]-3-(4-fluorophenyl)pyrazin-2-amine (C9). To solution of N-[5-(4-{[3-(4-fluorophenyl)pyrazin-2-yl]amino}phenyl)-1,3,4-thiadiazol-2-yl]acetamide (68 mg, 0.17 mmol) in methanol (1 mL) concentrated hydrochloric acid (1 mL) was added dropwise. Reaction mixture was refluxed overnight. After this time reaction was diluted with saturated sodium bicarbonate solution (20 mL), methanol was evaporated and extraction with ethyl acetate (2×15 mL) was made. Combined organic layers were dried over sodium sulfate, filtered and evaporated. Crude product was purified via preparative TLC eluted with DCM/MeOH 9:1. Re-purification was performed via preparative TLC eluted with DCM/MeOH 95:5 to give desired product as a yellow solid (20.2 mg, 33.2%). LCMS-Method 4 (328 nm): RT=2.44 min, 97.0% purity, [M+H]=365.15. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 8.70 (s, 1H), 8.19 (s, 2H), 7.86-7.79 (m, 2H), 7.64 (s, 4H), 7.46-7.27 (m, 4H).

##STR00156##

[0981] N-[5-(4-{[2-(4-phenoxyphenyl)phenyl]amino}phenyl)-1,3,4-thiadiazol-2-yl]acetamide. N-[5-(4-bromophenyl)-1,3,4-thiadiazol-2-yl]acetamide (100 mg, 0.34 mmol), 2-(4-phenoxyphenyl)aniline (105 mg, 0.40 mmol), cesium carbonate (219 mg, 0.67 mmol) and XantPhos (39 mg, 0.07 mmol) were suspended in 1,4-dioxane (3 mL). Reaction mixture was degassed with argon flow over 20 min and tris(dibenzylideneacetone)dipalladium(0) (27 mg, 0.03 mmol) was added. Reaction was stirred at 100° C. for 72 hours. After that time reaction mixture was cooled to room temperature, Filtered thru celite, evaporated and purified via column chromatography using DCM/MeOH 1:0.fwdarw.98:2 as a eluent to give product as a yellow solid (115 mg, 71.7%). UPLC (254 nm): RT=7.96 min, 88.6% purity, [M+H]=479.15.

##STR00157##

[0982] 5-(4-{[2-(4-phenoxyphenyl)phenyl]amino}phenyl)-1,3,4-thiadiazol-2-amine (C10). To solution of N-[5-(4-{[2-(4-phenoxyphenyl)phenyl]amino}phenyl)-1,3,4-thiadiazol-2-yl]acetamide (95 mg, 0.20 mmol) in methanol (1.4 mL) concentrated hydrochloric acid (1.4 mL) was added dropwise. Reaction mixture was refluxed overnight. After this time reaction was diluted with saturated sodium bicarbonate solution (20 mL), methanol was evaporated and extraction with ethyl acetate (2×15 mL) was made. Combined organic layers were dried over sodium sulfate, filtered and evaporated. Crude product was purified via preparative TLC eluted with DCM/MeOH 8:2. Re-purification was performed via preparative TLC eluted with Hex/EtOAc/MeOH 70:25:5 to give desired product as a yellowish solid (17.2 mg, 19.9%). LCMS-Method 11 (200 nm): RT=3.57 min, 97.5% purity, [M+H]=437.16. .sup.1H NMR (300 MHz. Methanol-d.sub.4) δ 7.52-7.43 (m, 2H), 7.41-7.15 (m, 8H), 7.10-7.01 (m, 1H), 6.97-6.84 (m, 4H), 6.82-6.72 (m, 2H).

##STR00158##

[0983] N-[5-(4-([2-(4-propoxyphenyl)phenyl]amino)phenyl)-1,3,4-thiadiazol-2-yl]acetamide. N-[5-(4-bromophenyl)-1,3,4-thiadiazol-2-yl]acetamide (120 mg, 0.40 mmol), 2-(4-propoxyphenyl)aniline (110 mg, 0.48 mmol), cesium carbonate (262 mg, 0.80 mmol) and XantPhos (47 mg, 0.08 mmol) were suspended in 1,4-dioxane (3.6 mL). Reaction mixture was degassed with argon flow over 20 min and tris(dibenzylideneacetone)dipalladium(0) (33 mg, 0.04 mmol) was added. Reaction was stirred at 100° C. for 72 hours. After that time reaction mixture was cooled to room temperature, Filtered thru celite, evaporated and purified via column chromatography using DCM/MeOH 1:0.fwdarw.97:3 as a eluent to give product as a yellowish solid (55.7 mg, 31.1%). UPLC (254 nm): RT=8.07 min, 86.8% purity, [M+H]=445.30.

##STR00159##

[0984] 5-(4-([2-(4-propoxyphenyl)phenyl]amino)phenyl)-1,3,4-thiadiazol-2-amine (C11). To solution of N-[5-(4-{[2-(4-propoxyphenyl)phenyl]amino}phenyl)-1,3,4-thiadiazol-2-yl]acetamide (56 mg, 0.13 mmol) in methanol (0.84 mL) concentrated hydrochloric acid (0.84 mL) was added dropwise. Reaction mixture was refluxed overnight. After this time reaction was diluted with saturated sodium bicarbonate solution (10 mL), methanol was evaporated and extraction with ethyl acetate (2×10 mL) was made. Combined organic layers were dried over sodium sulfate, filtered and evaporated. Crude product was purified via preparative TLC eluted with Hex/EtOAc/MeOH 70:25:5. Re-purification was performed via maceration with diethyl ether to give desired product as a light brown solid (11 mg, 22%). LCMS-Method 4 (200 nm): RT=3.67 min, 98.9% purity, [M+H]=403.19. .sup.1H NMR (300 MHz. Methanol-d.sub.4) δ 7.56-7.47 (m, 2H), 7.41-7.27 (m, 5H), 7.17 (td, J=7.3, 1.5 Hz, 1H), 6.96-6.81 (m, 4H), 3.94 (t, J=6.5 Hz, 2H), 1.79 dtd, J=13.8, 7.4, 6.4 Hz, 2H), 1.04 (t, J=7.4 Hz, 3H).

##STR00160##

[0985] N-(5-[4-(2-[4-(propan-2-yloxy)phenyl]phenyl)amino)phenyl]-1,3,4-thiadiazol-2-yl)acetamide. N-[5-(4-bromophenyl)-1,3,4-thiadiazol-2-yl]acetamide (100 mg, 0.34 mmol), 2-[4-(propan-2-yloxy)phenyl]aniline (91 mg, 0.40 mmol), cesium carbonate (219 mg, 0.67 mmol) and XantPhos (39 mg, 0.07 mmol) were suspended in 1,4-dioxane (3 mL). Reaction mixture was degassed with argon flow over 20 min and tris(dibenzylideneacetone)dipalladium(0) (27 mg, 0.03 mmol) was added. Reaction was stirred at 100° C. for 72 hours. After that time reaction mixture was cooled to room temperature. Filtered thru celite, evaporated and purified via column chromatography using DCM/MeOH 1:0.fwdarw.97:3 as a eluent to give product as a yellowish solid (87.4 mg, 58.6%). UPLC (254 nm): RT=7.59 min, 87.6% purity, [M+H]=445.15.

##STR00161##

[0986] 5-[4-({2-[4-{propan-2-yloxy)phenyl]phenyl}amino)phenyl]-1,3,4-thiadiazol-2-amine (C12). To solution of N-{5-[4-((2-[4-(propan-2-yloxy)phenyl]phenyl}amino)phenyl]-1,3,4-thiadiazol-2-yl}acetamide (87 mg, 0.20 mmol) in methanol (1.3 mL) concentrated hydrochloric acid (1.3 mL) was added dropwise. Reaction mixture was refluxed overnight. After this time reaction was diluted with saturated sodium bicarbonate solution (15 mL), methanol was evaporated and extraction with ethyl acetate (2×15 mL) was made. Combined organic layers were dried over sodium sulfate, filtered and evaporated. Crude product was purified via preparative TLC eluted with Hex/EtOAc/MeOH 70:25:5. Re-purification was performed via maceration with methanol, to give desired product as a yellow solid (7 mg, 8.8%). LCMS-Method 4 (200 nm): RT=3.54 min, 97.4% purity, [M+H]=403.20. .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 7.55-7.47 (m, 2H), 7.41-7.27 (m, 5H), 7.18 (td, J=7.3, 1.5 Hz, 1H), 6.94-6.81 (m, 4H), 4.59 (dq, J=12.1, 6.1 Hz, 1H), 1.30 (d, J=6.0 Hz, 6H).

[0987] Synthesis Method E

##STR00162##

[0988] To a solution of 4-(chlorophenyl)-4-methyl-4-H-1,2,4-triazole (100 mg, 0.52 mmol) and corresponding base (1.20 mmol, 2.3 eq) in 1,4-dioxane (3.0 mL) amine (1.0 eq) was added. Reaction mixture was degassed for 30 minutes. Then xantphos (30 mg, 0.05 mmol) and corresponding catalyst were added and the mixture was stirred at 100° C. for 5 days. The reaction mixture was filtrated throw cellite, the filtrate was concentrated and purified via column chromatography using 0-10% MeOH in DCM as eluent. Fractions containing the title compound were combined and concentrated. Product was re-purified via P-TLC using 4% MeOH in DCM as an eluent.

[0989] 4′-fluoro-N-[4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl]-[1,1′-biphenyl]-2-amine (D1) (34 mg, 19%). 4′-fluoro-[1,1′-biphenyl]-2-amine (97 mg, 0.52 mmol), t-BuONa (115 mg, 1.2 mmol), chloroform adduct of tris(dibenzylideneacetone)dipalladium(0) (26 mg 0.05 mmol), tetrakis(triphenylphosphine)palladium(0) (30 mg, 0.05 mmol) were used. LCMS-Method 2 (200 nm): RT=5.54 min, 97.6% purity, [M+H]=345.15. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 8.46 (s, 1H), 7.82 (s, 1H), 7.45-7.49 (m, 4H), 7.34-7.40 (m, 3H), 7.17-7.25 (m, 3H), 6.88 (d, J=9.0 Hz, 2H), 3.69 (s, 3H).

[0990] 3′,4′-dimethoxy-N-[4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl]-[1,1′-biphenyl]-2-amine (D2) (45 mg, 28%). 3′,4′-dimethoxy-[1,1′-biphenyl]-4-amine (120 mg, 0.52 mmol), Cs.sub.2CO.sub.3 (396 mg, 1.2 mmol), chloroform adduct of tris(dibenzylideneacetone)dipalladium(0) (26 mg 0.05 mmol) were used. LCMS-Method 2 (200 nm) RT=4.8 min, 98.7% purity, [M+H]=387.14. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 8.46 (s, 1H), 7.74 (s, 1H), 7.47 (d, J=9 Hz, 2H), 7.31-7.42 (m, 3H), 7.19-7.25 (m, 1H), 6.99 (d, 2H, J=6 Hz), 6.88 (d, 2H, J=9 Hz), 3.76 (s, 3H), 3.68 (s, 3H), 3.62 (s, 3H).

##STR00163##

[0991] N-[2-(4-methoxyphenyl)phenyl]-4-(4-methyl-4H-1,2,4-triazol-3-yl)aniline (D3). To a solution of 4-(chlorophenyl)-4-methyl-4-H-1,2,4-triazole (73 mg, 0.38 mmol) and Cs.sub.2CO.sub.3 (285 mg, 0.87 mmol) in 1,4-dioxane (2.25 mL) 2-(4-methoxyphenyl)aniline (75 mg, 0.38 mmol) was added. Reaction mixture was degassed for 30 minutes. Then xantphos (22 mg, 0.04 mmol) and chloroform adduct of tris(dibenzylideneacetone)dipalladium(0) (19 mg 0.02 mmol) were added and the mixture was stirred at 100° C. overnight. The reaction mixture was filtrated through cellite, washed with MeOH. Filtrate was concentrated and purified via column chromatography using 0-10% MeOH in DCM as eluent. Fractions containing the title compound were combined and concentrated. Product was re-purified via P-TLC using 4% MeOH in DCM as an eluent to give desired product as an orange solid (13 mg, 10%). LCMS-Method 2 (200 nm): RT=5.38 min, 94.03% purity, [M+H]=357.21. .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 8.48 (s, 1H), 7.45 (d, J=8.8 Hz, 2H), 7.39 (s, 1H), 7.37-7.28 (m, 4H), 7.29-7.13 (m, 1H), 6.94 (dd, J=8.8, 3.3 Hz, 4H), 3.80 (s, 3H), 3.78 (s, 3H).

##STR00164##

[0992] 2-(4-methoxyphenyl)-N-[4(4-methyl-4H-1,2,4-triazol-3-yl)phenyl]pyridin-3-amine (D4). To a solution of 4-(chlorophenyl)-4-methyl-4-H-1,2,4-triazole (68 mg, 0.35 mmol) and Cs.sub.2CO.sub.3 (264 mg, 0.81 mmol) in 1,4-dioxane (2.10 mL) 2-(4-methoxyphenyl)pyridin-3-amine (70 mg, 0.35 mmol) was added. Reaction mixture was degassed for 30 minutes. Then xantphos (20 mg, 0.03 mmol) and chloroform adduct of tris(dibenzylideneacetone)dipalladium(0) (18 mg 0.02 mmol) were added and the mixture was stirred at 100° C. overnight. The reaction mixture was filtrated through cellite, washed with MeOH. Filtrate was concentrated and purified via column chromatography using 0-10% MeOH in DCM as eluent. Fractions containing the title compound were combined and concentrated. Product was re-purified via P-TLC using 4% MeOH in DCM as an eluent to give desired product as white solid (35 mg, 28%). LCMS-Method 1 (200 nm): RT=5.58 min, 96.3% purity, [M+H]=358.22. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 8.67 (s, 1H), 8.43 (d, J=5.9 Hz, 1H), 8.24 (s, 1H), 7.84 (d, J=8.8 Hz, 1H), 7.71 (d, J=8.8 Hz, 2H), 7.54 (d, J=8.3 Hz, 2H), 7.39 (dd, J=8.1, 4.7 Hz, 3H), 6.98 (t, J=9.1 Hz, 4H), 3.78 (s. 3H), 3.74 (s, 3H).

##STR00165##

[0993] 2-(4-fluorophenyl)-N-[4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl]pyridin-3-amine (D5). To a solution of 4-(chlorophenyl)-4-methyl-4-H-1,2,4-triazole (77 mg, 0.40 mmol) and Cs.sub.2CO.sub.3 (301 mg, 0.92 mmol) in 1,4-dioxane (2.25 mL) 2-(4-fluorophenyl)pyridin-3-amine (75 mg, 0.40 mmol) was added. Reaction mixture was degassed for 30 minutes. Then xantphos (23 mg, 0.04 mmol) and chloroform adduct of tris(dibenzylideneacetone)dipalladium(0) (20 mg 0.02 mmol) were added and the mixture was stirred at 100° C. overnight. The reaction mixture was filtrated through cellite, washed with MeOH. Filtrate was concentrated and purified via column chromatography using 0-10% MeOH in DCM as eluent. Fractions containing the title compound were combined and concentrated. Product was re-purified via P-TLC using 4% MeOH in DCM as an eluent to give desired product as light orange solid (5 mg, 4%). LCMS-Method 1 (205 nm): RT=5.82 min, 99.46% purity, [M+H]=346.22. .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 8.50 (s, 1H), 8.37 (dd, J=4.7, 1.5 Hz, 1H), 7.89 (d, J=7.2 Hz, 1H), 7.70 (dd, J=9.1, 5.6 Hz, 2H), 7.51 (d, J=8.8 Hz, 2H), 7.42 (dd, J=8.2, 4.7 Hz, 1H), 7.16 (t, J=8.7 Hz, 2H), 7.01 (d, J=8.8 Hz, 2H), 3.78 (s, 3H).

##STR00166##

[0994] 4-(4-methyl-4H-1,2,4-triazol-3-yl)-N-[2-(4-phenoxyphenyl)phenyl]aniline (D6). To a solution of 4-(chlorophenyl)-4-methyl-4-H-1,2,4-triazole (74 mg, 0.38 mmol) and Cs.sub.2CO.sub.3 (289 mg, 0.89 mmol) in 1,4-dioxane (3.00 mL) 2-(4-phenoxyphenyl)aniline (100 mg, 0.38 mmol) was added. Reaction mixture was degassed for 30 minutes. Then xantphos (22 mg, 0.04 mmol) and chloroform adduct of tris(dibenzylideneacetone)dipalladium(0) (20 mg 0.02 mmol) were added and the mixture was stirred at 100° C. overnight. The reaction mixture was filtrated through celite, washed with MeOH. Filtrate was concentrated and purified via column chromatography using 0-5% MeOH in DCM as eluent. Fractions containing the title compound were combined and concentrated. Product was re-purified via P-TLC using 4% MeOH in DCM as an eluent to give desired product as white solid (25 mg, 16%). LCMS-Method 5 (200 nm): RT=2.25 min, 99.51% purity. [M+H]=419.20. .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 8.47 (s, 1H), 7.74-7.14 (m, 11H), 7.09 (t, J=7.9 Hz, 1H), 7.09-6.77 (m, 6H), 3.75 (s, 3H).

##STR00167##

[0995] 3-(3,4-dimethoxyphenyl)-N-[4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl]pyridin-4-amine (D7). To a solution of 4-(chlorophenyl)-4-methyl-4-H-1,2,4-triazole (59 mg, 0.30 mmol) and Cs.sub.2CO.sub.3 (230 mg, 0.71 mmol) in 1,4-dioxane (2.10 mL) 3-(3,4-dimethoxyphenyl)pyridin-4-amine (70 mg, 0.30 mmol) was added. Reaction mixture was degassed for 30 minutes. Then xantphos (18 mg, 0.03 mmol) and chloroform adduct of tris(dibenzylideneacetone)dipalladium(0) (16 mg 0.02 mmol) were added and the mixture was stirred at 100° C. overnight. The reaction mixture was filtrated through celite, washed with MeOH. Filtrate was concentrated and purified via column chromatography using 0-10% MeOH in DCM as eluent. Fractions containing the title compound were combined and concentrated. Product was re-purified via P-TLC using 4% MeOH in DCM as an eluent to give desired product as white solid (20 mg, 16%). LCMS-Method 3 (305 nm): RT=2.69 min, 98.21% purity, [M+H]=388.24. .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 8.55 (s, 1H), 8.26-8.19 (m, 2H), 7.72-7.58 (m, 2H). 7.43-7.25 (m. 3H), 7.09 (d, J=4.2 Hz, 3H). 3.89 (s, 3H), 3.85 (s, 3H), 3.82 (s. 3H).

[0996] Synthesis Method F

##STR00168##

[0997] 5-(3-bromopropyl)-1,3,4-thiadiazol-2-amine. Phosphoryl chloride (7.37 mL, 79.0 mmol) was added to aminothiourea (2.185 g, 24.0 mmol) and 4-bromobutanoic acid. The mixture was stirred at 85° C. overnight, cooled and poured into ice. Solution of saturated sodium biscarbonate was added the solution and the water layer was extracted three times with EA (3×80 mL). Combined organic layers were dried over sodium sulfate, filtered and evaporated. Crude product was purified via column chromatography using 0-10% DCM in MeOH as eluent. Fractions containing the title compound were combined and concentrated (3.301 g, 62%). UPLC (254 nm): RT=1.91 min, 68% purity, [M−H]=223.7.

##STR00169##

[0998] N-[5-(3-bromopropyl)-1,3,4-thiadiazol-2-yl]acetamide. To the solution of 5-(3-bromopropyl)-1,3,4-thiadiazol-2-amine (3.3 g, 14.8 mmol) in anhydrous DCM (35 mL), under argon atmosphere, trietylamine (4.14 mL, 29.7 mmol) and acetylchloride (1.16 mL, 16.3 mmol) were added. Reaction mixture was stirred for 6 hours at ambient temperature. After that time 1M HCl was added (50 mL) and the water layer was extracted three times with DCM (3×80 mL). Combined organic layers were dried over sodium sulfate, filtered, evaporated to provide the pure product (3.144 g, 80%). UPLC (254 nm): RT=2.43 min. 89% purity, [M+H]=265.65.

##STR00170##

[0999] N-[5-(3-azidopropyl)-1,3,4-thiadiazol-2-yl]acetamide. To the solution of N-[5-(3-bromopropyl)-1,3,4-thiadiazol-2-yl]acetamide (1.0 g, 3.8 mmol) in anhydrous DMF (20.0 mL), under argon atmosphere, sodium azide (0.37 g, 5.7 mmol) was added. Reaction mixture was stirred for 2 hours. After that time water (10 mL) was added and the water layer was extracted with DCM (3×80 mL). Combined organic layers were dried over sodium sulfate, filtered and evaporated to provide the pure product (0.6 g, 71%). UPLC (254 nm): RT=2.29 min, 98% purity, [M+H]=227.0.

##STR00171##

[1000] N-[5-(3-aminopropyl)-1,3,4-thiadiazol-2-yl]acetamide. Solution of methyl N-[5-(3-azidopropyl)-1,3,4-thiadiazol-2-yl]acetamide (0.6 g, 2.7 mmol) in anhydrous tetrahydrofuran (7 mL was dropped to the suspension of LAH pellets (0.1 g, 2.8 mmol) in anhydrous THF (5 mL) under argon atmosphere. Reaction mixture was stirred 1h at ambient temperature. After that time LAH (0.1 g. 2.8 mmol) was added. The stirring was continued for 2 hours. After that time 0.2 mL of water was added, followed by addition of 0.4 mL of 20% NaOH and 0.6 mL of water. The suspension was filtered throw cellite and washed with DCM/MeOH 9:1. Evaporation of solvents gave titled compound (0.22 g, 41%). UPLC (254 nm): RT=1.17 min, 57% purity, [M−H]=201.2.

##STR00172##

[1001] N-{5-[3-(4-fluorobenzenesulfonamido)propyl]-1,3,4-thiadiazol-2-yl}acetamide. To the solution of 3,4-dichlorobenzenosulfonyl chloride (165 mg, 0.85 mmol) in the mixture of solvents DCM (1.0 mL) and pyridine (1.0 mL) N-[5-(3-aminopropyl)-1,3,4-thiadiazol-2-yl]acetamide (170 mg, 0.85 mmol) was added. The reaction mixture was stirred for 18 hours at ambient temperature. After that time solvents were evaporated and to the residues 1M HCl was added and the water layer was extracted with DCM (3×20 mL). Combined organic layers were dried over sodium sulfate, filtered, evaporated to provide the product (0.02 g, 7%). UPLC (254 nm): RT=2.56 min, 98% purity, [M+H]=358.85.

##STR00173##

[1002] N-[3-(5-amino-1,3,4-thiadiazol-2-yl)propyl]-4-fluorobenzene-1-sulfonamide (E2). N-{5-[3-(4-fluorobenzenesulfonamido)propyl]-1,3,4-thiadiazol-2-yl}acetamide (20 mg, 0.06 mmol) was dissolved in the solution of HCl (2 mL) and MeOH (2 mL). The reaction mixture was stirred for 18 hours at 80° C. After that time solution of sodium biscarbonate was added and the water layer was extracted with DCM (3×10 mL). Combined organic layers were dried over sodium sulfate, filtered and evaporated. Purification of crude product via P-TLC using 4% methanol in dichloromethane as an eluent gave desired product (3 mg, 17%). LCMS-Method 1 (200 nm): RT=2.56 min, 96.0% purity. [M+H]=317.15. .sup.1H NMR (300 MHz, MeOH-d.sub.4) δ 7.87-7.94 (m, 2H), 7.29-7.39 (m, 2H), 2.86-2.97 (m, 4H), 1.82-1.91 (m, 2H).

[1003] Synthesis Method G

##STR00174##

[1004] N-(2-chloroethyl)-4-fluorobenzene-1-sulfonamide 2-chloroethylamine hydrochloride (0.25 g, 2.2 mmol), 4-fluorobenzenesulfonyl chloride (0.42 g, 2.2 mmol), were dissolved in DCM (2.5 mL) and pyridine (2.5 mL). Reaction was stirred at room temperature overnight. The mixture was diluted with DCM (15.0 mL) and washed with 1M solution of hydrochloric acid (20 mL). Organic layer was dried over sodium sulfate, filtered and evaporated. Title compound was obtained as yellow oil (0.5 g, 86% yield). .sup.1H NMR (300 MHz, CDCl.sub.3) δ 7.82-7.95 (m, 2H), 7.25-7.33 (m, 2H), 4.92 (t, 1H), 3.54-3.64 (t, 2H), 3.32-3.44 (dt, 2H).

##STR00175##

[1005] N-{2-[(5-amino-1,3,4-thiadiazol-2-yl)sulfanyl]ethyl}-4-fluorobenzene-1-sulfonamide (E3) N-(2-chloroethyl)-4-fluorobenzene-1-sulfonamide (0.18 g, 0.75 mmol), 2-Amino-5-mercapto-1,3,4-thiadiazole (0.10 g, 0.75 mmol), potassium carbonate (0.31 g, 2.25 mmol) were dissolved in acetonitrile (2.0 mL) and stirred at 80° C. overnight. After that time reaction mixture was cooled to room temperature, filtered thru celite, evaporated and purified via column chromatography using MeOH in DCM 0-5% as aluent to give pure product (120 mg, 48%) LCMS-Method 2 (200 nm): RT=4.24 min, 99.71% purity, [M+H]=334.97, .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 7.92 (br s, 1H), 7.80-7.90 (m, 2H), 7.37-7.47 (m, 2H), 7.30 (br s. 2H), 3.07 (m, 4H).

##STR00176##

[1006] 4-fluoro-N-{2-[(4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]ethyl}benzene-1-sulfonamide (G2) N-(2-chloroethyl)-4-fluorobenzene-1-sulfonamide (0.21 g, 0.87 mmol), 3-mercapto-4-methyl-4H-1,2,4-triazole (0.10 g, 0.87 mmol), potassium carbonate (0.36 g, 2.61 mmol) were dissolved in acetonitrile (2.0 mL) and stirred at 80° C. overnight. After that time reaction mixture was cooled to room temperature, filtered thru celite, evaporated and purified via column chromatography using MeOH in DCM 0-5% as eluent to give pure product (200 mg, 73%) LCMS-Method 2 (200 nm): RT=3.79 min, 97.39% purity, [M+H]=317.05, 1H NMR (300 MHz, DMSO-d6) δ 8.53 (s, 1H), 7.97 (s, 1H), 7.88-7.77 (m, 2H). 7.49-7.35 (m, 2H), 3.53 (s, 3H), 3.21-2.99 (m, 4H).

[1007] Synthesis Method H

##STR00177##

[1008] N-[5-(3-bromopropyl)-1,3,4-thiadiazol-2-yl]acetamide was synthesized according to the procedure described for E2.

##STR00178##

[1009] N-[5-(3-{[(4-fluorophenyl)(methyl)oxo-λ.sup.6-sulfanylidene]amino}propyl)-1,3,4-thiadiazol-2-yl]acetamide. To the solution of (4-fluorophenyl)(imino)methyl-λ.sub.6-sulfanone (0.1 g, 0.58 mmol) in anhydrous DMSO (4 mL), under argon atmosphere, KOH (0.065 g, 1.15 mmol) was added. The suspension was stirred for 1.5 hours at ambient temperature. After that time solution of N-[5-(3-bromopropyl)-1,3,4-thiadiazol-2-yl]acetamide (0.229 g, 0.87 mmol) in anhydrous DMSO (4 mL) was slowly (1.5 hours) dropped. The reaction was quenched with water (5 mL) immediately after the dropping was completed. The water layer was extracted with DCM (10 mL) and after that extracted 5 times with mixture of chloroform/isopropyl alcohol 3:1 (5×20 mL). Combined organic layers were dried over sodium sulfate, filtered, evaporated to provide the pure product (0.06 g, 29%). UPLC (254 nm): RT=2.2 min, 61% purity, [M+H]=357.2

##STR00179##

[1010] 5-(3-{[(4-fluorophenyl)(methyl)oxo-λ.sup.6-sulfanylidene]amino}propyl)-1,3,4-thiadiazol-2-amine (F2). N-[5-(3-{[(4-fluorophenyl)(methyl)oxo-λ.sup.6-sulfanylidene]amino}propyl)-1,3,4-thiadiazol-2-yl]acetamide (20 mg, 0.06 mmol) was dissolved in the solution of HCl (2 mL) and MeOH (2 mL). The reaction mixture was stirred for 3 hours at 80° C. After that time solution of sodium biscarbonate was added and the water layer was extracted with DCM (3×10 mL). Combined organic layers were dried over sodium sulfate, filtered and evaporated. Purification of crude product via P-TLC using 4% methanol in dichloromethane as an eluent gave desired product (5 mg, 9%). LCMS (245 nm): RT=5.91 min, 98.88% purity. [M+H]=315.17 .sup.1H NMR (300 MHz. CDCl.sub.3) δ 7.98-7.87 (m, 2H), 7.22-7.26 (m, 2H), 5.21 (s, 2H), 3.11 (s, 2H), 2.89-3.09 (m, 2H), 1.97-2.00 (m, 2H).

[1011] Synthesis Method I

##STR00180##

[1012] Methyl-4-(4-fluorobenzenesulfonamido)butanoate. To the solution of 3,4-dichlorobenzenosulfonyl chloride (633 mg, 3.25 mmol) in DCM (3.0 mL) trietylamine (1.3 mL, 9.76 mmol) and methyl-4-aminobutanoate hydrochloride (500 mg, 3.25 mmol) was added. The reaction mixture was stirred for 18 hours at ambient temperature. After that time 1M HCl (5 mL) was added and the water layer was extracted with DCM (3×5 mL). Combined organic layers were dried over sodium sulfate, filtered, evaporated to provide the product (0.605 g, 68%). UPLC (254 nm): RT=2.89 min, [M+H]=275.85.

##STR00181##

[1013] 4-Fluoro-N-[3-(hydrazinecarbonyl)propyl]benzene-1-sulfonamide. To the solution of methyl-4-(4-fluorobenzenesulfonamido)butanoate (605 mg, 2.09 mmol) in EtOH (10 mL) 50% hydrazine in H.sub.2O (0.65 mL, 10.4 mmol) was added. Reaction mixture was stirred for 1 hour at 80° C. After that time the reaction mixture was cooled, water (20 mL) was added and water layer was extracted three times with EA (3×10 mL). Combined organic layers were dried over sodium sulfate, filtered and evaporated to provide the pure product (180 mg, 31%). UPLC (254 nm): RT=1.88 min, 65% purity, [M+H]=276.2.

##STR00182##

[1014] N-(3-(N′-[(1-dimethylamino)methylidene]hydrazinecarbonyl)propyl)-4-fluorobenzene-1-sulfonamide. To the solution of 4-fluoro-N-[3-(hydrazinecarbonyl)propyl]benzene-1-sulfonamide (180 mg, 0.65 mmol) in MeOH (2 mL) N,N-dimethylformamide dimethylacetal (78 mg, 0.65 mmol) was added. Reaction mixture was stirred for 1 hour at 80° C. After that time solvent was evaporated to obtain desired product. (216 mg, 100%). UPLC (254 nm): RT=1.78 min. 60% purity, [M+H]=331.3.

##STR00183##

[1015] 4-fluoro-N-[3-(4-methyl-4H-1,2,4-triazol-3-yl)propyl]benzene-1-sulfonamide (G1). MeNH.sub.2 2M in THF (32 mL, 3.3 mmol) was added to the solution of N-(3-{N′-[(1-dimethylamino)methylidene]hydrazinecarbonyl}propyl)-4-fluorobenzene-1-sulfonamide (216 mg, 0.63 mmol) in anhydrous THF (5.0 mL) under argon atmosphere. Reaction mixture was cooled to 0° C. and acetic acid (2 mL) was carefully added. Reaction mixture was stirred for 1 hour at 100° C. After that time reaction was cooled to room temperature and water (5 mL) was added and water layer was extracted three times with EA (3×20 mL). Combined organic layers were dried over sodium sulfate, filtered and evaporated. Crude product was purified via column chromatography using 0-4% MeOH in DCM as eluent. Obtained 40 mg of product was re-purified via P-TLC using 4% MeOH in DCM as an eluent and then re-purified via preparative HPLC. Fraction containing the title compound in pure form was concentrated (3 mg, 2%). LCMS-Method 1 (200 nm): RT=6.17 min, 99.5% purity, [M+H]=299.2. .sup.1H NMR (300 MHz, CDCl.sub.3) δ 8.09 (s, 1H). 7.84-7.90 (m, 2H), 7.15-7.23 (m, 2H), 5.62 (t. J=5.6 Hz, 1H), 3.64 (s. 3H), 3.12 (q, J=3.1 Hz, 2H), 2.85 (t, J=6.6 Hz, 2H) 2.06-2.15 (m, 2H).

[1016] Synthesis Method K

##STR00184##

[1017] N-(2-chloroethyl)sulfamoyl chloride 2-chloroethylamine hydrochloride (0.50 g, 4.3 mmol), sulfuryl chloride (3.49 g, 2.10 mL. 25.8 mmol), were dissolved in acetonitrile (5.0 mL) Reaction was stirred at 80° C. overnight. The mixture was concentrated and used directly into next step. Title compound was obtained as yellow oil (0.5 g, 86% yield). .sup.1H NMR (300 MHz, d.sub.6-DMSO) δ 11.0 (bs, 1H), 3.83 (t, 2H), 3.36 (t, 2H)

##STR00185##

[1018] (2-chloroethyl)[(3,4-dimethoxyphenyl)sulfamoyl]amine N-(2-chloroethyl)sulfamoyl chloride (0.14 g, 0.78 mmol) and 3,4-dimetoxyaniline (0.12 g, 0.78 mmol) were dissolved in DCM (1.2 mL) and pyridine (1.2 mL). Reaction was stirred at room temperature overnight. After that time reaction mixture was cooled to room temperature. The mixture was diluted with DCM (15.0 mL) and washed with 1M solution of hydrochloric acid (20 mL). Organic layer was dried over sodium sulfate, filtered and evaporated. Title compound was obtained as yellow oil (0.23 g. 100% yield). Compound was used in the next step without further purification. UPLC (280 nm): RT=3.14 min, 11% purity. [M+H]=294.95

##STR00186##

[1019] [(3,4-dimethoxyphenyl)sulfamoyl]((2-[(4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]ethyl))amine (G5) (2-chloroethyl)[(3,4-dimethoxyphenyl)sulfamoyl]amine (0.085 g, 0.74 mmol), 3-mercapto-4-methyl-4H-1,2,4-triazole (0.22 g, 0.74 mmol), potassium carbonate (0.31 g, 2.21 mmol) were dissolved in acetonitrile (1.7 mL) and stirred at 80° C. for 3 hours. After that time reaction mixture was cooled to room temperature, filtered thru celite, evaporated and purified via column chromatography using MeOH in DCM 0-5% as eluent to give pure product (8 mg, 3%) LCMS-Method 2 (200 nm): RT=3.08 min, 99.1% purity, [M+H]=374.03, 1H NMR (400 MHz, DMSO-d6) δ 7.57 (s, 1H), 6.96-6.75 (m, 2H), 6.72-6.63 (m, 1H), 3.71 (d, J=2.7 Hz, 6H), 3.51 (s, 3H), 3.23-3.08 (m, 4H).

[1020] Synthesis Method L

##STR00187##

[1021] [4-(4-fluorobenzenesulfonamido)phenyl]boronic acid 4-aminophenylboronic acid (1.5 g, 8.7 mmol), and 4-fluorophenylsulfonyl chloride (1.53 g, 7.9 mmol) were dissolved in pyridine (43 mL). The mixture was stirred at 5000 overnight, cooled to room temperature and solvent was removed in vacuo. Crude product was used in next step without any further purification (5.4 g, 200%). UPLC (254 nm): RT=2.88 min, 50% purity, [M-2H]=293.5.

##STR00188##

[1022] [4-(3,4-dimethoxybenzenesulfonamdo)phenyl]boronic acid 4-aminophenylboronic acid (2.35 g, 11.6 mmol), and 3,4-dimethoxyphenylsulfonyl chloride (1.53 g, 7.9 mmol) were dissolved in pyridine (80 mL). The mixture was stirred at 50° C. overnight, cooled to room temperature and solvent was removed in vacuo. Crude product was used in next step without any further purification (8.1 g, 200%). UPLC (254 nm): RT=2.77 min, 50% purity, [M-2H]=335.6.

##STR00189##

[1023] N-[4-(2-amino-1,3-thiazol-5-yl)phenyl]-4-fluorobenzene-1-sulfonamide (11). Solution of [4-(4-fluorobenzenesulfonamido)phenyl]boronic acid (2.75 g, 9.2 mmol), 2-amino-5-bromo-thiazole hydrobromide (2.00 g, 7.7 mmol) and potassium carbonate (3.21 g, 23.1 mmol) in 1,4-dioxane (40.0 mL) and water (4.0 mL) was degassed with argon flow over 20 min and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (0.84 g, 1.2 mmol) was added as one portion. Reaction mixture was stirred overnight at 130° C. After this time reaction was filtered thru celite, which was washed with DCM, water (40 mL) was added, layers were separated and water layer was extracted three with DCM (3×25 mL), organic layers were combined, dried over sodium sulfate, filtered and evaporated. Crude product was purified via column chromatography using Methanol in DCM (0-3%) as eluent, and fraction containing product was additional re-purified via preparative HPLC method to give the pure product as red solid (48 mg, 2%). LCMS-Method 1 (254 nm): RT=6.73 min, 99.6% purity, [M+H]=349.7. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 10.36 (s, 1H), 7.84-7.76 (m, 2H), 7.45-7.36 (m, 2H), 7.28 (dd, J=6.6, 2.0 Hz, 3H), 7.14-6.97 (m, 4H).

##STR00190##

[1024] N-[4-(2-amino-1,3-thiazol-5-yl)phenyl]-3,4-dimethoxybenzene-1-sulfonamide (12). Solution [4-(3,4-dimethoxybenzenesulfonamido)phenyl]boronic acid (1.64 g, 5.5 mmol), 2-amino-5-bromo-thiazole hydrobromide (1.20 g, 4.6 mmol) and potassium carbonate (3.21 g, 23.1 mmol) in 1,4-dioxane (40.0 mL) and water (4.0 mL) was degassed with argon flow over 20 min and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (0.51 g, 0.7 mmol) was added as one portion. Reaction mixture was stirred overnight at 130° C. After this time reaction was filtered thru celite, which was washed with DCM, water (40 mL) was added, layers were separated and water layer was extracted three with DCM (3×25 mL), organic layers were combined, dried over sodium sulfate, filtered and evaporated. Crude product was purified via column chromatography using Methanol in DCM (0-3%) as eluent, and fraction containing product was additional re-purified via preparative HPLC method to give the pure product as orange solid (45 mg, 3%). LCMS-Method 2 (200 nm): RT=2.99 min, 99.9% purity, [M+H]=392.0. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 8.16 (s, 1H), 7.34-7.22 (m, 5H), 7.13-6.95 (m, 5H), 3.79 (s, 3H), 3.76 (s, 3H).

[1025] Synthesis Method M

##STR00191##

[1026] 2-bromo-4′-fluoro-1,1′-biphenyl Solution of 1,2-dibromobenzene (8.26 g, 35.0 mmol), 4-flurophenylboronic acid (2.5 g, 17.9 mmol) and sodium carbonate (3.79 g, 35.0 mmol) in ethanol (35.0 mL), toluene (35.0 mL) and water (35.0 mL) was degassed with argon flow over 20 min and tetrakis(triphenylphosphine) palladium(0) (1.00 g. 0.9 mmol) was added as one portion. Reaction mixture was stirred overnight at 100° C. After this time reaction was filtered thru celite, layers were separated and water layer was extracted twice with ethyl acetate (2×15 mL), organic layers were combined, dried over sodium sulfate, filtered and evaporated. Crude product was purified via column chromatography using hexanes as eluent to give the title product (5.50 g, 122%). UPLC (254 nm): RT=4.33 min, 91% purity, [M+H]=not observed.

##STR00192##

[1027] 1-{4′-fluoro-[1,1′-biphenyl]-2-yl}piperidine-4-carbonitrile Solution of 2-bromo-4′-fluoro-1,1′-biphenyl (0.3 g. 1.2 mmol), piperidine-4-carbonitrile (0.2 g, 1.8 mmol), XantPhos (0.14 g. 0.24 mmol) and cesium carbonate (0.78 g, 2.4 mmol) in anhydrous 1,4-dioxane (3.0 mL), was degassed with argon flow over 20 min and tris(dibenzylideneacetone)dipalladium(0) (0.11 g, 0.12 mmol) was added as one portion. Reaction mixture was stirred overnight at 100° C. After this time reaction was filtered thru celite, washed with ethyl acetate and evaporated. Crude product was purified via column chromatography using ethyl acetate in hexanes (0-4%) as eluent to give the title product (0.18 g, 54%). UPLC (254 nm): RT=4.25 min, 90% purity, [M+H]=281.4.

##STR00193##

[1028] 5-(1-{4′-fluoro-[1,1′-biphenyl]-2-yl}piperidin-4-yl)-1,3,4-thiadiazol-2-amine (L2) Solution of 1-{4′-fluoro-[1,1′-biphenyl]-2-yl}piperidine-4-carbonitrile (0.18 g, 0.7 mmol) and thiosemicarbazide (0.09 g, 1.05 mmol) trifluoroacetic acid (1.5 mL) was stirred at 65° C. over 2 hours. After this time reaction was cooled to room temperature diluted with saturated sodium bicarbonate solution (15 mL) and extracted with DCM (3×15 mL), organic layers were combined, dried over sodium sulfate, filtered and evaporated. Crude product was triturated with ethyl acetate (1 mL) filtered off and dried under vacuum to give pure product (100 mg, 45%) LCMS (LCMS method: LCMS-002-20-80-95-12-05-25 (Gemini-BCM)-UV, 200 nm): RT=4.97 min, 96.7% purity, [M+H]=355.2. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 7.70-7.58 (m, 2H), 7.38-7.17 (m. 4H), 7.16-6.89 (m, 4H), 3.05 (d, J=11.8 Hz, 2H), 2.87 (ddd, J=11.5, 7.6, 3.9 Hz, 1H), 2.62 (t, J=11.3 Hz, 2H), 1.86 (d, J=12.7 Hz, 2H), 1.54 (qd, J=12.0, 3.8 Hz, 2H).

[1029] Synthesis Method N

##STR00194##

[1030] tert-Butyl-4-(2-amino-1,3-thiazol-5-yl)piperidine-1-carboxylate was synthesized in two steps according to the literature (overall yield: 60%).

##STR00195##

[1031] tert-Butyl-4-(2-acetamido-1,3-thiazol-5-yl)piperidine-1-carboxylate. To the solution of tert-butyl-4-(2-amino-1,3-thiazol-5-yl)piperidine-1-carboxylate (3.75 g, 13.23 mmol) in anhydrous DCM (35 mL), under argon atmosphere, trietylamine (3.69 mL, 26.4 mmol) and acetylchloride (1.00 mL, 14.6 mmol) were added. Reaction mixture was stirred for 48 hours at ambient temperature. After that time water was added (50 mL) and the water layer was extracted five times with DCM (5×80 mL). Combined organic layers were dried over sodium sulfate, filtered and evaporated to provide the pure product (4.175 g, 97%). UPLC (254 nm): RT=4.27 min. [M+H]=326.25.

##STR00196##

[1032] N-[5-(piperidin-4-yl)-1,3-thiazol-2-yl]acetamide. To the solution of tert-butyl 4-(2-acetamido-1,3-thiazol-5-yl)piperdino-1-carboxylate (4.175 g, 12.83 mmol) in THF (90.0 mL), 4M HCl in dioxane (10 mL) was added. Reaction mixture was stirred for 18 hours. After that time reaction mixture was filtered, the precipitation was washed with EA (2×40 mL) and dried under reduced pressure to give pure product (2.752 g, 82%). UPLC (254 nm): RT=2.1 min, [M+H]=226.25.

##STR00197##

[1033] N-{5-[1-(4-fluorobenzenesulfonyl)piperidin-4-yl]-1,3-thiazol-2-yl}acetamide. To a solution of 3,4-dichlorobenzenosulfonyl chloride (182 mg, 0.94 mmol) in the mixture of solvents DCM (3.0 mL) and pyridine (3.0 mL) N-[5-(piperidin-4-yl)-1,3-thiazol-2-yl]acetamide (211 mg, 0.94 mmol) was added. The reaction mixture was stirred for 48 hours at ambient temperature. After that time solvents were evaporated and crude was taken to the next step.

##STR00198##

[1034] 5-[1-(4-fluorobenzenesulfonyl)piperidin-4-yl]-1,3-thiazol-2-amine (M1). N-{5-[1-(4-fluorobenzenesulfonyl)piperidin-4-yl]-1,3-thiazol-2-yl}acetamide (300 mg, 0.78 mmol) was dissolved in the solution of HCl (12 mL) and MeOH (12 mL). The reaction mixture was stirred for 18 hours at 80° C. After that time solution of saturated sodium biscarbonate was added and the water layer was extracted with DCM (3×10 mL). Combined organic layers were dried over sodium sulfate, filtered, evaporated and purified via column chromatography using 0-10% MeOH in DCM as eluent. Fractions containing the title compound were combined and concentrated. Product was re-purified via P-TLC using 4% MeOH in DCM as an eluent (16 mg, 6%). LCMS-Method 1 (220 nm): RT=6.37 min, 95.99% purity, [M+H]=342.07. .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.85-7.90 (m, 2H), 7.35-7.41 (m, 2H), 6.7 (s, 1H), 3.82 (d, J=12.0 Hz, 2H), 2.61-2.73 (m, 1H), 2.40-2.49 (m, 2H), 1.98-2.04 (m, 2H), 1.60-1.75 (m, 2H).

##STR00199##

[1035] 1-(4-fluorobenzenesulfonyl)piperidine-4-carbonitrile. To a solution of piperidine-4-carbonitrile (500 mg, 4.54 mmol) in the mixture of solvents DCM (5.0 mL) and pyridine 4-fluorobenzenesulfonyl chloride (880 mg, 4.54 mmol) was added. The reaction mixture was stirred for 16 hours at ambient temperature. Reaction mixture was diluted with 1M HCl (50 ml) and DCM (50 ml) and layers were separated. Organic layer was washed twice with 1M HCl (2×50 ml) and concentrated to give desired product as beige solid. .sup.1H NMR (400 MHz, Chloroform-d) δ 7.98-7.66 (m, 2H), 7.36-7.12 (m, 2H), 3.29-3.06 (m, 4H), 2.91-2.71 (m, 1H), 2.17-1.89 (m, 4H).

##STR00200##

[1036] 5-[1-(4-fluorobenzenesulfonyl)piperidin-4-yl]-1,3,4-thiadiazol-2-amine (M2). 1-(4-fluorobenzenesulfonyl)piperidine-4-carbonitrile (500 mg, 1.86 mmol) and thisemicarbazide (190 mg, 2.05 mmol) were dissolved in TFA (4.0 mL) and the reaction mixture was stirred for 2 hours at 60° C. After that time solvent was concentrated and residue was suspended in DCM:MeOH (4.0 ml, 95:5; vol:vol) solution and precipitate was filtered to afford desired compound as white solid (610 mg, 96.0%). LCMS-Method 2 (method: LCMS Method 2 (Gemini BCM)-UV, 200 nm): RT=4.29 min, 97.59% purity, [M+H]=343.13. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 8.20-7.71 (m, 2H), 7.51 (t, J=8.8 Hz, 2H), 3.66 (dt, J=12.2, 3.7 Hz, 2H), 2.95 (ddd, J=11.3, 7.5, 3.8 Hz, 1H), 2.43 (dd. J=11.8, 2.6 Hz, 2H), 2.10-1.91 (m, 2H), 1.76-1.43 (m, 2H).

[1037] Synthesis Method O

##STR00201##

[1038] tert-butyl 4-(N′-[(1E)-(dimethylamino)methylidene]hydrazinecarbonyl)piperidine-1-carboxylate. To the solution tert-butyl 4-(hydrazinecarbonyl)piperdino-1-carboxylate (500 mg, 2.05 mmol) in DMF (5 mL) N,N-dimethylforamide dimethylacetal (245 mg, 2.05 mmol) was added. Reaction mixture was stirred for 18 hour at 100° C. After that time solvent was evaporated to obtain desired product (601 mg, 98%).

##STR00202##

[1039] tert-butyl 4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidine-1-carboxylate. MeNH.sub.2 2M in THF (15 mL, 40.2 mmol) was added to the solution of tert-butyl 4-{N′-[(1E)-(dimethylamino)methylidene]hydrazinecarbonyl}piperidine-1-carboxylate (600 mg, 2.01 mmol) in anhydrous THF (6.0 mL) under argon atmosphere. Reaction mixture was cooled to 0° C. and acetic acid (2 mL) was carefully added. Reaction mixture was stirred for 18 hour at 100° C. After that time reaction was cooled to room temperature and water (20 mL) was added and water layer was extracted three times with EA (3×50 mL). Combined organic layers were dried over sodium sulfate, filtered and evaporated to give crude compound (511 mg, 95%).

##STR00203##

[1040] 4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidine. To the solution of tert-butyl 4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidine-1-carboxylate (511 mg, 1.71 mmol) in THF (5.0 mL), 4M HCl in dioxane (6.0 mL) was added. Reaction mixture was stirred for 18 hours. After that time reaction mixture was filtered, the precipitate was washed with EA (2×40 mL) and dried under reduced pressure to give product (347 mg, 100%).

##STR00204##

[1041] 1-(4-fluorobenzenesulfonyl)-4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidine (N1). To a solution of 4-fluorobenzenosulfonyl chloride (117 mg, 0.60 mmol) in pyridine (1.0 mL) 4-(4-methyl-4H-1,2,4-triazol-3-yl)piperadine (100 mg, 0.60 mmol) was added. The reaction mixture was stirred for 18 hours at ambient temperature. After that time solvent was evaporated and 1 M HCl (5 mL) was added and the water layer was extracted with DCM (3×10 mL). Combined organic layers were dried over sodium sulfate, filtered and evaporated. Product was purified via P-TLC using 5% MeOH in DCM as an eluent (6 mg, 3%). LCMS-Method 2 (220 nm): RT=3.63 min, 96.34% purity, [M+H]=325.11 .sup.1H NMR (300 MHz, CDCl.sub.3) δ 8.05 (s, 1H), 7.77-7.90 (m, 2H), 7.20-7.28 (m, 2H), 7.78-7.83 (m, 1H), 3.62 (s, 3H), 2.60-2.86 (m, 4H), 2.02-2.15 (m, 4H).

[1042] Synthesis Method P

##STR00205##

[1043] tert-butyl 5-methyl-1H-1,3-benzodiazole-1-carboxylate 5-methyl-1H-1,3-benzodiazole (0.5 g, 7.6 mmol), Boc anhydride (2.44 g, 11.4 mmol), DMAP (92 mg, 0.76 mmol) and triethylamine (2.11 mL, 15 mmol) were dissolved in acetonitrile (10 mL). The mixture was stirred at 80° C. overnight, cooled and solvent was removed in vacuo. Crude product was purified via column chromatography using DCM as eluent. Fractions containing the title compound were combined and concentrated (0.80 g, 46%). UPLC (254 nm): RT=3.75 min, 93.2% purity, [M+H]=233.2.

##STR00206##

[1044] tert-butyl 5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate, tert-butyl 5-methyl-1H-1,3-benzodiazole-1-carboxylate (0.8 g, 3.44 mmol), N-bromosuccimide (0.64 g, 3.62 mmol), dibenzoyl peroxide (22 mg, 0.1 mmol) were suspended in tetrachloromethane (16 ml), Reaction mixture was stirred overnight at 90° C. After that time reaction mixture was cooled to 0° C., precipitate was filtered off and filtrate was concentrated in vacuo to give desired product as pale yellow oil. (0.95 g, 89%). UPLC (254 nm): RT=3.75 min, 80% purity, [M+H]=312.75.

##STR00207##

[1045] 4′-fluoro-[1,1′-biphenyl]-2-amine. Solution of 2-bromoaniline (1.5 g, 8.7 mmol), 4-flurophenylboronic acid (1.46 g, 10.5 mmol) and potassium carbonate (4.16 g, 30.1 mmol) in 1,4-dioxane (15.0 mL) and water (15.0 mL) was degassed with argon flow over 20 min and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (0.43 g, 0.5 mmol) was added as one portion. Reaction mixture was stirred overnight at 100° C. After this time reaction was filtered thru celite, layers were separated and water layer was extracted twice with ethyl acetate (2×15 mL), organic layers were combined, dried over sodium sulfate, filtered and evaporated. Crude product was purified via column chromatography using 10% ethyl acetate in hexanes as eluent to give the pure product (1.65 g, 100%). UPLC (254 nm): RT=3.31 min, 99% purity, [M+H]=187.9.

##STR00208##

[1046] N-[(1H-1,3-benzodiazol-5-yl)methyl]-4′-fluoro-[1,1′-biphenyl]-2-amine (01). To the solution of 4′-fluoro-[1,1′-biphenyl]-2-amine (100 mg, 0.53 mmol) and tert-butyl 5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (244 mg, 0.59 mmol) in DMF (1.0 mL) sodium carbonate (170 mg, 1.6 mmol) was added. The reaction mixture was stirred overnight at 80° C. After that time reaction mixture was diluted with ethyl acetate (15.0 mL) and washed with semi-saturated brine (3×20 mL). Organic layer were dried over sodium sulfate, filtered, evaporated to provide the crude product, which was purified via column chromatography using MeOH in DCM 0-2% as an eluent to give desired product as off white solid (48 mg, 22%) LCMS-Method 2 (200 nm): RT=4.13 min, 97.2% purity. [M+H]=318.25. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 8.15 (s, 1H), 7.62-7.43 (m, 3H), 7.32 (t, J=8.9 Hz, 2H), 7.18 (d, J=8.2 Hz, 1H), 7.05 (ddd, J=8.5, 7.4, 1.6 Hz, 1H), 6.97 (dd, J=7.5, 1.6 Hz, 1H), 6.70-6.44 (m, 2H), 5.32 (s, 1H), 4.40 (d, J=5.9 Hz, 2H).

##STR00209##

[1047] 3′,4′-dimethoxy-[1,1′-biphenyl]-2-amine. Solution of 2-bromoaniline (3.0 g, 17.4 mmol), 3,4-dimethoxyphenylboronic acid (3.81 g, 20.9 mmol) and potassium carbonate (8.32 g, 30.1 mmol) in 1,4-dioxane (30.0 mL) and water (30.0 mL) was degassed with argon flow over 20 min and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (0.85 g, 1.1 mmol) was added as one portion. Reaction mixture was stirred overnight at 100° C. After this time reaction was filtered thru celite, layers were separated and water layer was extracted twice with ethyl acetate (2×15 mL), organic layers were combined, dried over sodium sulfate, filtered and evaporated. Crude product was purified via column chromatography using ethyl acetate in hexanes 2-10% as eluent to give the pure product (3.2 g, 80%). UPLC (254 nm): RT=3.25 min, 90% purity, [M+H]=229.9.

##STR00210##

[1048] N-[(1H-1,3-benzodiazol-5-yl)methyl]-3′,4′-dimethoxy-[1,1′-biphenyl]-2-amine(O2). To the solution of 3′,4′-dimethoxy-[1,1′-biphenyl]-2-amine (200 mg, 0.87 mmol) and tert-butyl 5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (0.398 g, 0.96 mmol) in DMF (1.0 mL) sodium carbonate (277 mg, 2.62 mmol) was added. The reaction mixture was stirred overnight at 80° C. After that time reaction mixture was diluted with ethyl acetate (15.0 mL) and washed with semi-saturated brine (3×20 mL). Organic layer were dried over sodium sulfate, filtered, evaporated to provide the crude product, which was purified via column chromatography using MeOH in DCM 0-2% as an eluent to give desired product as off white solid (70 mg, 17%) LCMS-Method 2 (205 nm): RT=3.66 min. 96.5% purity, [M+H]=360.1. .sup.1H NMR (300 MHz. DMSO-d.sub.6) δ 8.16 (s, 1H), 7.52 (d, J=8.3 Hz, 2H), 7.20 (dd, J=8.3, 1.6 Hz, 1H), 7.12-6.87 (m, 5H), 6.61 (ddd, J=8.3, 5.9, 1.2 Hz, 2H), 5.26 (t, J=5.9 Hz, 1H), 4.40 (d, J=5.9 Hz, 2H).

##STR00211##

[1049] N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-methoxyphenyl)aniline (03). To the solution of 2-(4-methoxyphenyl)aniline (90 mg, 0.45 mmol) and tert-butyl 5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (156 mg, 0.50 mmol) in DMF (1.0 mL) sodium carbonate (144 mg, 1.36 mmol) was added. The reaction mixture was stirred overnight at 80° C. After that time reaction mixture was cooled down to RT and filtered through celite. Celite pad was washed with MeOH. Filtrate was evaporated to provide the crude product, which was purified via column chromatography using DCM/MeOH 100:0.fwdarw.98:2. Re-purification was performed via preparative TLC eluted with DCM/MeOH 95:5 to give desired product as off white solid (35 mg, 23%). LCMS-Method 2 (230 nm): RT=3.90 min, 96.6% purity, [M+H]=330.24. .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 8.13 (s, 1H), 7.56 (d, J=5.5 Hz, 2H), 7.36 (d, J=8.8 Hz, 2H), 7.25 (dd, J=8.4, 1.2 Hz, 1H), 7.15-6.93 (m, 4H), 6.75-6.63 (m, 2H), 4.45 (s, 2H), 3.84 (s, 3H).

##STR00212##

[1050] N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-methoxyphenyl)pyridin-3-amine (04). To the solution of 2-(4-methoxyphenyl)pyridin-3-amine (90 mg, 0.45 mmol) and tert-butyl 5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (155 mg, 0.50 mmol) in DMF (1.0 mL) sodium carbonate (143 mg, 1.36 mmol) was added. The reaction mixture was stirred overnight at 80° C. After that time reaction mixture was cooled down to RT and filtered through celite. Celite pad was washed with MeOH. Filtrate was evaporated to provide the crude product, which was purified via column chromatography using DCM/MeOH/NH.sub.3 100:0:0.fwdarw.9:1:0.1. Re-purification was performed via preparative TLC eluted with DCM/MeOH/NH.sub.3 95:5:0.1 to give desired product as off white solid (10 mg, 7%). LCMS-Method 1 (205 nm): RT=4.66 min, 97.8% purity, [M+H]=331.27. .sup.1H NMR (300 MHz. Methanol-d.sub.4) δ 8.14 (s, 1H), 7.81 (d, J=5.7 Hz, 1H), 7.58 (t, J=3.9 Hz, 4H), 7.27 (d, J=9.6 Hz, 1H), 7.20-6.97 (m, 4H), 4.49 (s, 2H), 3.86 (s, 3H).

##STR00213##

[1051] N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(4-methoxyphenyl)pyridin-2-amine (05). To the solution of 3-(4-methoxyphenyl)pyridin-2-amine (100 mg, 0.50 mmol) and tert-butyl 5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (202 mg, 0.65 mmol) in DMF (1.0 mL) sodium carbonate (159 mg, 1.50 mmol) was added. The reaction mixture was stirred overnight at 80° C. After that time reaction mixture was cooled down to RT and filtered through celite. Celite pad was washed with MeOH. Filtrate was evaporated to provide the crude product, which was purified via column chromatography using DCM/MeOH/NH.sub.3 95:5:0.fwdarw.9:1:0.1. Re-purification was performed via preparative TLC eluted with DCM/MeOH/NH.sub.3 95:5:0.fwdarw.9:1:0.1 to give desired product as white solid (4 mg, 2.5%). LCMS-Method 3 (200 nm): RT=2.66 min, 96.3% purity, [M+H]=331.11. .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 8.12 (s, 1H), 7.97 (dd, J=5.2, 1.8 Hz, 1H). 7.62-7.51 (m, 2H). 7.35 (t, J=8.7 Hz, 3H), 7.25 (d, J=9.7 Hz, 1H). 7.03 (d, J=8.8 Hz, 2H), 6.69 (dd, J=7.2, 5.2 Hz, 1H), 4.69 (s, 2H), 3.83 (s, 3H).

##STR00214##

[1052] N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(4-methoxyphenyl)pyridin-4-amine (06). To the solution of 3-(4-methoxyphenyl)pyridin-4-amine (100 mg, 0.50 mmol) and tert-butyl 5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (172 mg, 0.55 mmol) in DMF (1.0 mL) sodium carbonate (159 mg, 1.50 mmol) was added. The reaction mixture was stirred overnight at 80° C. After that time reaction mixture was cooled down to RT and filtered through celite. Celite pad was washed with MeOH. Filtrate was evaporated to provide the crude product, which was purified via column chromatography using DCM/MeOH/NH.sub.3 95:5:0.fwdarw.9:1:0.1. Re-purification was performed via preparative TLC eluted with DCM/MeOH/NH.sub.3 95:5:0.fwdarw.9:1:0.1 to give desired product as white solid (12 mg, 7%). LCMS-Method 3 (245 nm): RT=2.36 min, 97.4% purity, [M+H]=331.25. .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 8.28 (s, 1H), 8.26-8.18 (m, 2H), 7.77-7.67 (m, 2H), 7.42-7.32 (m, 3H), 7.11 (d, J=6.7 Hz, 2H), 6.98 (d, J=7.1 Hz, 1H), 5.52 (s, 2H), 3.87 (s, 3H).

##STR00215##

[1053] N-(1H-1,3-benzodiazol-5-ylmethyl)-4-(4-methoxyphenyl)pyridin-3-amine 07. To the solution of 4-(4-methoxyphenyl)pyridin-3-amine (100 mg, 0.50 mmol) and tert-butyl 5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (172 mg, 0.55 mmol) in DMF (1.0 mL) sodium carbonate (159 mg, 1.50 mmol) was added. The reaction mixture was stirred overnight at 80° C. After that time reaction mixture was cooled down to RT and filtered through celite. Celite pad was washed with MeOH. Filtrate was evaporated to provide the crude product, which was purified via column chromatography using DCM/MeOH/NH.sub.3 95:5:0.fwdarw.9:1:0.1. Re-purification was performed via preparative HPLC to give desired product as white solid (5 mg, 4%). LCMS (LCMS-Method 3, 245 nm): RT=2.43 min, 73.7% purity, [M+H]=331.25. .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 8.36 (s, 1H), 8.30 (s, 1H), 8.23 (d, J=6.0 Hz, 1H), 7.91 (s, 1H), 7.73 (d, J=8.3 Hz, 1H), 7.67-7.51 (m, 4H), 7.44 (d, J=8.3 Hz, 1H), 7.12 (d, J=8.8 Hz, 2H), 6.92 (d, J=8.4 Hz, 1H), 5.77 (s, 2H), 3.88 (s, 3H).

##STR00216##

[1054] N-(1H-1,3-benzodiazol-5-ylmethyl)-5-(4-methoxyphenyl)pyrimidin-4-amine (08). To the solution of 5-(4-methoxyphenyl)pyrimidin-4-amine (50 mg, 0.25 mmol) and tert-butyl 5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (86 mg, 0.28 mmol) in DMF (0.5 mL) sodium carbonate (79 mg, 0.75 mmol) was added. The reaction mixture was stirred overnight at 80° C. After that time reaction mixture was cooled down to RT and filtered through celite. Celite pad was washed with MeOH. Filtrate was evaporated to provide the crude product, which was purified via preparative HPLC to give desired product as yellowish solid (1.96 mg, 1.8%). LCMS-Method 12 (200 nm): RT=4.5 min, 100.0% purity, [M+H]=332.20. .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 8.86 (d, J=1.9 Hz, 1H), 8.30 (s, 1H), 8.22 (d, J=1.9 Hz, 1H), 7.80 (s. 1H), 7.72 (d, J=8.3 Hz, 1H), 7.44-7.35 (m, 3H), 7.14-7.06 (m, 2H), 5.51 (s, 2H), 3.87 (s, 3H).

##STR00217##

[1055] N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(4-methoxyphenyl)pyrazin-2-amine (09). To the solution of 3-(4-methoxyphenyl)pyrazin-2-amine (140 mg, 0.70 mmol) and tert-butyl 5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (240 mg, 0.77 mmol) in DMF (1.0 mL) sodium carbonate (221 mg, 2.09 mmol) was added. The reaction mixture was stirred overnight at 80° C. After that time reaction mixture was cooled down to RT and filtered through celite. Celite pad was washed with MeOH. Filtrate was evaporated to provide the crude product, which was purified via column chromatography using DCM/MeOH/NH.sub.3 95:5:0.fwdarw.9:1:0.1. Re-purification was performed via preparative TLC eluted with DCM/MeOH/NH.sub.3 95:5:0.fwdarw.9:1:0.1 to give desired product as off white solid (5 mg, 2%). LCMS-Method 3 (270 nm): RT=3.04 min, 87.4% purity, [M+H]=332.24. .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 8.13 (s, 1H), 7.96 (d, J=2.9 Hz, 1H), 7.76 (d, J=2.9 Hz, 1H), 7.58 (dd, J=12.8, 8.6 Hz, 4H), 7.29 (dd, J=8.3, 1.4 Hz, 1H), 7.09 (d, J=8.8 Hz, 2H), 4.73 (s, 2H), 3.86 (s, 3H).

##STR00218##

[1056] N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(3,4-dimethoxyphenyl)pyridin-4-amine (010). To the solution of 3-(3,4-dimethoxyphenyl)pyridin-4-amine (100 mg, 0.43 mmol) and tert-butyl 5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (214 mg, 0.69 mmol) in DMF (1.0 mL) sodium carbonate (137 mg, 1.30 mmol) was added. The reaction mixture was stirred overnight at 80° C. After that time reaction mixture was cooled down to RT and filtered through celite. Celite pad was washed with MeOH. Filtrate was evaporated to provide the crude product, which was purified via column chromatography using DCM/MeOH 95:5.fwdarw.9:1. Fractions containing product were collected and evaporated. Residue was suspended in MeOH and filtered to give desired product as white solid (11 mg, 7%). LCMS-Method 9 (200 nm): RT=2.8 min, 95.2% purity, [M+H]=361.16. .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 8.28 (d, J=2.2 Hz, 2H), 8.21 (dd, J=7.2, 1.9 Hz, 1H), 7.75 (s, 2H), 7.37 (dd, J=8.4, 1.5 Hz, 1H), 7.13 (d, J=8.2 Hz, 1H), 7.07-6.94 (m, 3H), 5.52 (s, 2H), 3.90 (s, 3H), 3.88 (s, 3H).

##STR00219##

[1057] N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(3,4-dimethoxyphenyl)pyridin-2-amine (011). To the solution of 3-(3,4-dimethoxyphenyl)pyridin-2-amine (100 mg, 0.43 mmol) and tert-butyl 5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (150 mg, 0.48 mmol) in DMF (1.0 mL) sodium carbonate (138 mg, 1.30 mmol) was added. The reaction mixture was stirred overnight at 80° C. After that time reaction mixture was cooled down to RT and filtered through celite. Celite pad was washed with MeOH. Filtrate was evaporated to provide the crude product, which was purified via column chromatography using DCM/MeOH/NH.sub.3 95:5:0.fwdarw.9:1:0.1. Re-purification was performed via preparative TLC eluted with DCM/MeOH/NH.sub.3 95:5:0.fwdarw.9:1:0.1 to give desired product as off white solid (11 mg, 7%). LCMS-Method 1 (200 nm): RT=4.98 min, 93.2% purity, [M+H]=361.25. .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 8.13 (s, 1H), 7.98 (dd, J=5.2, 1.8 Hz, 1H), 7.55 (d, J=8.7 Hz, 2H), 7.37 (dd, J=7.2, 1.8 Hz, 1H), 7.27 (dd, J=8.3, 1.4 Hz, 1H), 7.09-6.91 (m, 3H), 6.69 (dd, J=7.2, 5.2 Hz, 1H), 4.70 (s, 2H), 3.85 (s, 3H), 3.79 (s, 3H).

##STR00220##

[1058] N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(3,4-dimethoxyphenyl)pyrazin-2-amine (012). To the solution of 3-(3,4-dimethoxyphenyl)pyrazin-2-amine (100 mg, 0.43 mmol) and tert-butyl 5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (175 mg, 0.56 mmol) in DMF (1.0 mL) sodium carbonate (137 mg, 1.30 mmol) was added. The reaction mixture was stirred overnight at 80° C. After that time reaction mixture was cooled down to RT and filtered through celite. Celite pad was washed with MeOH. Filtrate was evaporated to provide the crude product, which was purified via column chromatography using DCM/MeOH/NH.sub.3 95:5:0.fwdarw.9:1:0.1. Re-purification was performed via preparative TLC eluted with DCM/MeOH/NH.sub.3 95:5:0.fwdarw.9:1:0.1 to give desired product as off white solid (8 mg, 5%). LCMS-Method 3 (200 nm): RT=2.97 min, 87.7% purity, [M+H]=362.21. .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 8.14 (s, 1H), 7.98 (d, J=2.8 Hz, 1H), 7.77 (d, J=2.8 Hz, 1H), 7.65-7.44 (m, 2H), 7.37-7.20 (m, 3H), 7.09 (d, J=8.2 Hz, 1H), 4.73 (s, 2H), 3.89 (s, 3H), 3.85 (s, 3H).

##STR00221##

[1059] N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-fluorophenyl)pyridin-3-amine (013). To the solution of 2-(4-fluorophenyl)pyridin-3-amine (110 mg, 0.58 mmol) and tert-butyl 5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (202 mg, 0.65 mmol) in DMF (1.0 mL) sodium carbonate (186 mg, 1.75 mmol) was added. The reaction mixture was stirred overnight at 80° C. After that time reaction mixture was cooled down to RT and filtered through celite. Celite pad was washed with MeOH. Filtrate was evaporated to provide the crude product, which was purified via column chromatography using DCM/MeOH/NH.sub.3 95:5:0.fwdarw.9:1:0.1. Re-purification was performed via preparative TLC eluted with DCM/MeOH/NH.sub.3 95:5:0.fwdarw.9:1:0.1 to give desired product as off white solid (8 mg, 4%). LCMS-Method 1 (200 nm): RT=3.04 min, 96.1% purity, [M+H]=319.23. .sup.1H NMR (300 MHz, .sup.1H NMR (300 MHz,) δ 8.20 (s, 1H), 7.84 (d, J=4.5 Hz, 1H), 7.77-7.51 (m, 4H), 7.30 (t, J=8.6 Hz, 3H), 7.23-7.01 (m, 2H), 4.53 (s, 2H).

##STR00222##

[1060] N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(4-fluorophenyl)pyridin-2-amine (014). To the solution of 3-(4-fluorophenyl)pyridin-2-amine (70 mg, 0.37 mmol) and tert-butyl 5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (128 mg, 0.41 mmol) in DMF (0.7 mL) sodium carbonate (118 mg, 1.12 mmol) was added. The reaction mixture was stirred overnight at 80° C. After that time reaction mixture was cooled down to RT and filtered through celite. Celite pad was washed with MeOH. Filtrate was evaporated to provide the crude product, which was purified via preparative HPLC. Re-purification was performed via preparative TLC eluted with DCM/MeOH/NH.sub.3 95:5:0.1 to give desired product as a white solid (7.7 mg, 4.95%). LCMS-Method 1 (200 nm): RT=5.04 min, 97.1% purity, [M+H]=319.23. .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 8.09 (s, 1H), 8.00 (dd, J=5.2, 1.8 Hz, 1H), 7.58-7.41 (m, 4H), 7.34 (dd. J=7.2, 1.8 Hz, 1H), 7.25-7.14 (m, 3H), 6.70 (dd, J=7.2, 5.2 Hz, 1H), 4.69 (s, 2H).

##STR00223##

[1061] N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(4-fluorophenyl)pyrazin-2-amine (015). To the solution of 3-(4-fluorophenyl)pyrazin-2-amine (100 mg, 0.53 mmol) and tert-butyl 5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (214 mg, 0.69 mmol) in DMF (1.0 mL) sodium carbonate (137 mg, 1.30 mmol) was added. The reaction mixture was stirred overnight at 80° C. After that time reaction mixture was cooled down to RT and filtered through celite. Celite pad was washed with MeOH. Filtrate was evaporated to provide the crude product, which was purified via column chromatography using DCM/MeOH/NH.sub.3 95:5:0.fwdarw.9:1:0.1. Re-purification was performed via preparative TLC eluted with DCM/MeOH/NH.sub.3 95:5:0.fwdarw.9:1:0.1 to give desired product as off white solid (3 mg, 2%). LCMS-Method 1 (202 nm): RT=3.08 min, 95.4% purity, [M+H]=320.22. .sup.1H NMR (300 MHz. Methanol-d.sub.4) δ 8.13 (s, 1H). 8.00 (d, J=2.8 Hz, 1H), 7.79 (d, J=2.8 Hz, 1H), 7.70 (dd, J=8.8, 5.4 Hz, 2H), 7.62-7.51 (m, 2H), 7.33-7.23 (m, 3H). 4.73 (s, 2H).

##STR00224##

[1062] N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-phenoxyphenyl)aniline (016). To the solution of 2-(4-phenoxyphenyl)aniline (100 mg, 0.38 mmol) and tert-butyl 5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (132 mg, 0.42 mmol) in DMF (1.0 mL) sodium carbonate (122 mg, 1.15 mmol) was added. The reaction mixture was stirred overnight at 80° C. After that time reaction mixture was cooled down to RT and filtered through celite. Celite pad was washed with MeOH. Filtrate was evaporated to provide the crude product, which was purified via column chromatography using DCM/MeOH 1:0.fwdarw.96:4. Re-purification was performed via preparative TLC eluted with DCM/MeOH/NH.sub.3 95:5:0.1 to give desired product as a white solid (25 mg, 16.7%). LCMS-Method 2 (205 nm): RT=4.99 min, 99.6% purity, [M+H]=392.26. .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 8.13 (s, 1H), 7.57 (d, J=8.1 Hz, 2H), 7.47-7.33 (m, 4H), 7.27 (dd, J=8.5, 1.5 Hz, 1H), 7.17-7.02 (m, 7H), 6.71 (ddd, J=7.8, 6.2, 1.2 Hz, 2H), 4.48 (s, 2H).

##STR00225##

[1063] N-(1H-1,3-benzodiazol-5-ylmethyl)-2-[4-(cyclohexyloxy)phenyl]aniline (017). To the solution of 2-[4-(cyclohexyloxy)phenyl]aniline (100 mg, 0.37 mmol) and tert-butyl 5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (129 mg, 0.42 mmol) in DMF (1.0 mL) sodium carbonate (119 mg, 1.12 mmol) was added. The reaction mixture was stirred overnight at 80° C. After that time reaction mixture was cooled down to RT and filtered through celite. Celite pad was washed with MeOH. Filtrate was evaporated to provide the crude product, which was purified via preparative TLC eluted with DCM/MeOH 95:5. Re-purification was performed via preparative TLC eluted with DCM/MeOH 95:5 to give desired product as a white solid (4.9 mg, 3.3%). LCMS-Method 2 (200 nm): RT=5.17 min, 100% purity, [M+H]=398.26. .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 8.12 (s, 1H), 7.55 (d, J=7.9 Hz, 2H), 7.37-7.21 (m, 3H), 7.11-6.96 (m, 4H), 6.68 (ddd, J=8.6, 5.5, 1.3 Hz, 2H), 4.44 (s, 2H), 4.34 (tt, J=8.4, 3.6 Hz, 1H), 2.06-1.75 (m, 4H), 1.66-1.28 (m, 6H).

##STR00226##

[1064] N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-propoxyphenyl)aniline (018). To the solution of 2-(4-propoxyphenyl)aniline (100 mg, 0.44 mmol) and tert-butyl 5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (152 mg, 0.49 mmol) in DMF (1.0 mL) sodium carbonate (140 mg, 1.32 mmol) was added. The reaction mixture was stirred overnight at 80° C. After that time reaction mixture was cooled down to RT and filtered through celite. Celite pad was washed with MeOH. Filtrate was evaporated to provide the crude product, which was purified via column chromatography using DCM/MeOH 1:0.fwdarw.98:2. Re-purification was performed via preparative TLC eluted with DCM/MeOH 95:5 to give desired product as a white solid (34.4 mg, 21.9%). LCMS-Method 2 (200 nm): RT=4.58 min, 100% purity, [M+H]=358.25. .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 8.09 (s, 1H), 7.53 (d, J=7.8 Hz, 2H), 7.36-7.25 (m, 2H), 7.20 (dd, J=8.4, 1.5 Hz, 1H), 7.10-6.89 (m, 4H), 6.66 (t, J=7.3 Hz, 2H), 4.37 (s, 2H), 3.90 (t, J=6.5 Hz, 2H), 1.77 (dtd, J=13.8, 7.4, 6.4 Hz, 2H), 1.02 (t, J=7.4 Hz, 3H).

##STR00227##

[1065] N-(1H-1,3-benzodiazol-5-ylmethyl)-2-[4-(propan-2-yloxy)phenyl]aniline (019). To the solution of 2-[4-(propan-2-yloxy)phenyl]aniline (100 mg, 0.44 mmol) and tert-butyl 5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (152 mg, 0.49 mmol) in DMF (1.0 mL) sodium carbonate (140 mg, 1.32 mmol) was added. The reaction mixture was stirred overnight at 80° C. After that time reaction mixture was cooled down to RT and filtered through celite. Celite pad was washed with MeOH. Filtrate was evaporated to provide the crude product, which was purified via column chromatography using DCM/MeOH 1:0.fwdarw.99:1. Re-purification was performed via preparative TLC eluted with DCM/MeOH 95:5 to give desired product as a white solid (24.3 mg, 15.5%). LCMS-Method 4 (200 nm): RT=2.42 min, 97.3% purity, [M+H]=358.26. .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ8.10 (s, 1H), 7.54 (d, J=7.9 Hz, 2H), 7.37-7.26 (m, 2H), 7.21 (dd, J=8.4, 1.5 Hz, 1H), 7.10-6.91 (m, 4H), 6.66 (t, J=7.3 Hz, 2H), 4.57 (hept, J=12.0, 6.0 Hz, 1H), 4.39 (s, 2H), 1.31 (d, J=6.0 Hz, 6H).

##STR00228##

[1066] N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-methoxyphenyl)-3-methylaniline (020). To the solution of 2-(4-methoxyphenyl)-3-methylaniline (100 mg, 0.47 mmol) and tert-butyl 5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (162 mg, 0.52 mmol) in DMF (1.0 mL) sodium carbonate (149 mg, 1.41 mmol) was added. The reaction mixture was stirred overnight at 80° C. After that time reaction mixture was cooled down to RT and filtered through celite. Celite pad was washed with MeOH. Filtrate was evaporated to provide the crude product, which was purified via column chromatography using DCM/MeOH 1:0.fwdarw.97:3. Re-purification was performed via preparative TLC eluted with DCM/MeOH 9:1 to give desired product as a white solid (40.7 mg, 25.3%). LCMS (LCMS-Method 4, 205 nm): RT=2.14 min, 98.9% purity, [M+H]=344.27. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.33 (d, J=11.8 Hz, 1H), 8.14 (s, 1H), 7.57-7.36 (m, 2H), 7.18-7.05 (m, 5H), 6.93 (t, J=7.8 Hz, 1H), 6.54-6.38 (m, 2H), 4.44 (d, J=17.8 Hz, 1H), 4.34 (d, J=5.1 Hz, 2H), 3.81 (s, 3H), 1.88 (s, 3H).

##STR00229##

[1067] N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(3,4-dimethoxyphenyl)-3-methylaniline (021). To the solution of 2-(3,4-dimethoxyphenyl)-3-methylaniline (100 mg, 0.41 mmol) and tert-butyl 5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (142 mg, 0.46 mmol) in DMF (1.0 mL) sodium carbonate (131 mg, 1.23 mmol) was added. The reaction mixture was stirred overnight at 80° C. After that time reaction mixture was cooled down to RT and filtered through celite. Celite pad was washed with MeOH. Filtrate was evaporated to provide the crude product, which was purified via column chromatography using DCM/MeOH 1:0.fwdarw.97:3. Re-purification was performed via preparative TLC eluted with DCM/MeOH 95:5 to give desired product as a white solid (47.5 mg, 31%). LCMS (LCMS-Method 4, 205 nm): RT=1.99 min, 97.3% purity, [M+H]=374.27. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.33 (s, 1H), 8.14 (s, 1H), 7.52 (s, 1H), 7.41 (s, 1H), 7.10 (t, J=7.8 Hz, 2H), 6.93 (t, J=7.8 Hz, 1H), 6.79-6.71 (m, 2H), 6.47 (dd, J=15.8, 7.8 Hz, 2H), 4.55 (s, 1H), 4.34 (d, J=6.0 Hz, 2H), 3.79 (d, J=9.0 Hz, 6H), 1.92 (s, 3H).

##STR00230##

[1068] N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-chlorophenyl)-3-fluoroaniline(O22). To the solution of 2-(4-chlorophenyl)-3-fluoroaniline (100 mg, 0.45 mmol) and tert-butyl 5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (156 mg, 0.50 mmol) in DMF (1.0 mL) sodium carbonate (143 mg, 1.35 mmol) was added. The reaction mixture was stirred overnight at 80° C. After that time reaction mixture was cooled down to RT and filtered through celite. Celite pad was washed with MeOH. Filtrate was evaporated to provide the crude product, which was purified via column chromatography using DCM/MeOH 1:0.fwdarw.97:3. Re-purification was performed via preparative TLC eluted with DCM/MeOH 95:5 to give desired product as a white solid (40.6 mg, 25.6%). LCMS (LCMS-Method 4, 200 nm): RT=2.29 min, 94.2% purity, [M+H]=344.27. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.33 (d, J=17.3 Hz, 1H), 8.15 (d, J=4.1 Hz, 1H), 7.58 (dd, J=8.8, 7.0 Hz, 3H), 7.50-7.36 (m, 3H), 7.20-7.10 (m, 1H). 7.05 (td, J=8.3, 6.8 Hz, 1H), 6.46-6.34 (m, 2H), 5.48 (dt, J=16.2, 6.0 Hz, 1H), 4.38 (t, J=6.0 Hz, 2H).

##STR00231##

[1069] N-(1H-1,3-benzodiazol-5-ylmethyl)-2-(3,4-dimethoxyphenyl)-3-fluoroaniline (023). To the solution of 2-(3,4-dimethoxyphenyl)-3-fluoroaniline (100 mg, 0.40 mmol) and tert-butyl 5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (140 mg, 0.45 mmol) in DMF (1.0 mL) sodium carbonate (129 mg, 1.21 mmol) was added. The reaction mixture was stirred overnight at 80° C. After that time reaction mixture was cooled down to RT and filtered through celite. Celite pad was washed with MeOH. Filtrate was evaporated to provide the crude product, which was purified via column chromatography using DCM/MeOH 1:0.fwdarw.97:3. Re-purification was performed via preparative TLC eluted with DCM/MeOH 9:1 to give desired product as a white solid (29.3 mg, 19.2%). LCMS (LCMS-Method 4, 200 nm): RT=1.92 min, 90.1% purity, [M+H]=378.23. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.38 (s, 1H), 8.16 (s, 1H), 7.50 (s, 2H), 7.21-6.98 (m, 3H), 6.93-6.85 (m, 2H), 6.45-6.37 (m, 2H), 5.27 (s, 1H), 4.39 (d, J=6.0 Hz, 2H), 3.80 (d, J=7.1 Hz, 6H).

##STR00232##

[1070] N-(1H-1,3-benzodiazol-5-ylmethyl)-3-fluoro-2-(4-fluorophenyl)aniline (024). To the solution of 3-fluoro-2-(4-fluorophenyl)aniline (100 mg, 0.49 mmol) and tert-butyl 5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (168 mg, 0.54 mmol) in DMF (1.0 mL) sodium carbonate (155 mg, 1.46 mmol) was added. The reaction mixture was stirred overnight at 80° C. After that time reaction mixture was cooled down to RT and filtered through celite. Celite pad was washed with MeOH. Filtrate was evaporated to provide the crude product, which was purified via column chromatography using DCM/MeOH 1:0.fwdarw.97:3. Re-purification was performed via preparative TLC eluted with DCM/MeOH 9:1 to give desired product as a white solid (29.3 mg, 19.2%). LCMS (LCMS-Method 4, 205 nm): RT=2.12 min, 96.6% purity, [M+H]=336.23. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.32 (s, 1H), 8.15 (s, 1H), 7.55 (s, 1H), 7.45-7.32 (m, 5H), 7.15 (s, 1H), 7.10-6.99 (m, 1H), 6.46-6.36 (m, 2H), 5.37 (s, 1H), 4.39 (d, J=6.0 Hz, 2H).

[1071] Synthesis Method Q

##STR00233##

[1072] N-[(1H-1,3-benzodiazol-5-yl)methyl]-4-fluorobenzene-1-sulfonamide (P1) (1H-1,3-benzodiazol-5-yl)methanamine dihydrochloride (0.25 g, 1.15 mmol) was dissolved in pyridine (7 mL) and stirred at room temperature over 30 min. Then 4-fluorophenylsulfonyl chloride (0.21 g, 1.08 mmol), was added and reaction mixture was heated to 70° C. and stirred overnight. The mixture was quenched with 10 mL of 20% aqueous solution of sodium hydroxide and stirred at 70° C. for another night. Layers were separated and Pyridine was evaporated in vacuo. Crude product was purified via column chromatography using MeOH in DCM (0-3%) as eluent. Fractions containing the title compound were combined and concentrated (55 mg, 19%). LCMS-Method 1 (200 nm): RT=5.81 min, 93.2% purity, [M+ACN]=347.27. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 8.17 (s, 1H), 8.04-7.66 (m, 2H), 7.56-7.31 (m, 4H), 7.05 (d, J=8.4 Hz, 1H), 4.10 (s, 2H).

[1073] Synthesis Method R

##STR00234##

[1074] [(1H-1,3-benzodiazol-5-yl)methyl][(4-fluorophenyl)methyl)oxo-λ.sup.6-sulfanylidene]amine (Q1) (4-fluorophenyl)(imino)methyl-λ.sup.6-sulfanone (250 mg, 1.5 mmol) and potassium hydroxide (234 mg, 2.18 mmol) in DMSO (13.0 mL) were stirred at 50° C. over 1h. After this time reaction was cooled to room temperature and tert-butyl 5-(bromomethyl)-1H-1,3-benzodiazole-1-carboxylate (650 mg, 2.10 mmol) was added. Reaction was stirred overnight, and after this time water (50 mL) was added and extracted with DCM (5×30 mL). Combined organic layers were dried over sodium sulfate, filtered, evaporated to provide the solution of crude product in DMSO, which was purified preparative HPLC method to give title compound as colorless oil. (26 mg, 5%) LCMS-Method 1 (200 nm): RT=5.72 min, 96.3% purity, [M+H]=304.15. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 8.14 (s, 1H). 8.03-7.91 (m. 2H). 7.54 (s, 1H), 7.51-7.42 (m, 3H), 7.12 (dd, J=8.3, 1.6 Hz, 1H), 4.15 (d, J=14.4 Hz, 1H), 3.98 (d, J=14.5 Hz, 1H), 3.25 (s, 3H).

[1075] Analytical Methods

[1076] NMR

[1077] The .sup.1H NMR-Spectra (300 MHz) were recorded at a BRUKER FOURIER 300. The solvent was DMSO-De, unless otherwise specified. Chemical shifts are expressed as parts per million (ppm) downfiled from tetramethylsilan. Splitting patterns have been designated as follows: s (singulet), d (doublet), dd (doublet of doublet), t (triplet), m (multiplet) and br (broad signal).

[1078] HPLC-MS

[1079] LCMS-Method 1

[1080] Apparatus: Dionex UHPLC Ultimate 3000 with DAD detector/Thermo Scientific MSQ Plus

[1081] Column: Gemini-NX 3μ C18 (4.6×50 mm), 110A, column no. OOB-4453-EO, internal column no. 002

[1082] Reagents:—Formic acid ≥98%, Sigma-Aldrich [1083] Acetonitrile for HPLC UV/gradient grade, Baker [1084] μQ-water for LCMS

[1085] HPLC conditions:—Wavelength range: (190-340) nm±4 nm [1086] Flow: 0.5 ml/min [1087] Column temperature: 25° C. [1088] Autosampler temperature: 20° C. [1089] Injection volume: 2.0 μl [1090] Analysis time: 14 min [1091] Elution: gradient

TABLE-US-00024 Time [min] Mobile phase A [%] Mobile phase B [%] Flow [ml/min] 0.0 95 5 0.5 2.0 95 5 0.5 9.5 20 80 0.5 10.5 20 80 0.5 12.0 95 5 0.5 14.0 95 5 0.5 [1092] Mobile phase A: 0.1% v/v water solution of formic acid [1093] Mobile phase B: 0.1% v/v acetonitrile solution of formic acid [1094] Solution for syringe washing: 20% MeOH

[1095] MS conditions:—Mass range: 100-1000 m/z [1096] Ionization: alternate [1097] Scan speed: 12 000 amu/sec

[1098] LCMS-Method 2

[1099] Apparatus: Dionex UHPLC Ultimate 3000 with DAD detector/Thermo Scientific MSQ Plus

[1100] Column: Gemini-NX 3μ C18 (4.6×50 mm), 110A, column no. OOB-4453-EO, internal column no. 002

[1101] Reagents:—Formic acid ≥98%, Sigma-Aldrich [1102] Acetonitrile for HPLC UV/gradient grade, Baker [1103] μQ-water for LCMS

[1104] HPLC conditions:—Wavelength range: (190-340) nm±4 nm [1105] Flow: 0.5 ml/min [1106] Column temperature: 25° C. [1107] Autosampler temperature: 20° C. [1108] Injection volume: 2.0 μl [1109] Analysis time: 12 min [1110] Elution: gradient

TABLE-US-00025 Time [min] Mobile phase A [%] Mobile phase B [%] Flow [ml/min] 0.0 80 20 0.5 6.7 20 80 0.5 7.5 20 80 0.5 7.8 5 95 0.5 9.5 5 95 0.5 10.0 80 20 0.5 12.0 80 20 0.5 [1111] Mobile phase A: 0.1% v/v water solution of formic acid [1112] Mobile phase B: 0.1% v/v acetonitrile solution of formic acid [1113] Solution for syringe washing: 20% MeOH

[1114] MS conditions:—Mass range: 100-1000 m/z [1115] Ionization: alternate [1116] Scan speed: 12 000 amu/sec

[1117] LCMS-Method 3

[1118] Apparatus: Dionex UHPLC Ultimate 3000 with DAD detector/Thermo Scientific MSQ Plus

[1119] Column: Kinetex® 2.6 μm XB-C18 (4.6×50 mm), 110A, column no. OOB-4496-EO, internal column no. 019

[1120] Reagents:—Formic acid a 98%, Sigma-Aldrich [1121] Acetonitrile for HPLC UV/gradient grade, Baker [1122] μQ-water for LCMS

[1123] HPLC conditions:—Wavelength range: (190-340) nm±4 nm [1124] Flow: 1.0 ml/min [1125] Column temperature: 25° C. [1126] Autosampler temperature: 20° C. [1127] Injection volume: 2.0 μl [1128] Analysis time: 7 min [1129] Elution: gradient

TABLE-US-00026 Time [min] Mobile phase A [%] Mobile phase B [%] Flow [ml/min] 0.0 95 5 1.0 1.0 95 5 1.0 4.75 20 80 1.0 5.25 20 80 1.0 6.0 95 5 1.0 7.0 95 5 1.0 [1130] Mobile phase A: 0.1% v/v water solution of formic acid [1131] Mobile phase B: 0.1% v/v acetonitrile solution of formic acid [1132] Solution for syringe washing: 20% MeOH

[1133] MS conditions:—Mass range: 100-1000 m/z [1134] Ionization: alternate [1135] Scan speed: 12 000 amu/sec

[1136] LCMS-Method 4

[1137] Apparatus: Dionex UHPLC Ultimate 3000 with DAD detector/Thermo Scientific MSQ Plus

[1138] Column: Kinetex® 2.6 μm XB-C18 (4.6×50 mm), 110A, column no. OOB-4496-EO, internal column no. 019

[1139] Reagents:—Formic acid ≥98%, Sigma-Aldrich [1140] Acetonitrile for HPLC UV/gradient grade, Baker [1141] μQ-water for LCMS

[1142] HPLC conditions:—Wavelength range: (190-340) nm±4 nm [1143] Flow: 1.0 ml/min [1144] Column temperature: 25° C. [1145] Autosampler temperature: 20° C. [1146] Injection volume: 2.0 μl [1147] Analysis time: 6 min [1148] Elution: gradient

TABLE-US-00027 Time [min] Mobile phase A [%] Mobile phase B [%] Flow [ml/min] 0.0 80 20 1.0 3.35 20 80 1.0 3.75 20 80 1.0 3.9 5 95 1.0 4.75 5 95 1.0 5.0 80 20 1.0 6.0 80 20 1.0 [1149] Mobile phase A: 0.1% v/v water solution of formic acid [1150] Mobile phase B: 0.1% v/v acetonitrile solution of formic acid [1151] Solution for syringe washing: 20% MeOH

[1152] MS conditions:—Mass range: 100-1000 m/z [1153] Ionization: alternate [1154] Scan speed: 12 000 amu/sec

[1155] LCMS-Method 5

[1156] Apparatus: Dionex UHPLC Ultimate 3000 with DAD detector/Thermo Scientific MSQ Plus

[1157] Column: Kinetex® 2.6 μm XB-C18 (4.6×50 mm), 110A, column no. OOB-4496-EO, internal column no. 019

[1158] Reagents:—Formic acid ≥98%, Sigma-Aldrich [1159] Acetonitrile for HPLC UV/gradient grade. Baker [1160] μQ-water for LCMS

[1161] HPLC conditions:—Wavelength range: (190-340) nm±4 nm [1162] Flow: 1.0 ml/min [1163] Column temperature: 25° C. [1164] Autosampler temperature: 20° C. [1165] Injection volume: 2.0 μl [1166] Analysis time: 7 min [1167] Elution: gradient

TABLE-US-00028 Time [min] Mobile phase A [%] Mobile phase B [%] Flow [ml/min] 0.0 80 20 1.0 2.0 20 80 1.0 2.35 20 80 1.0 2.45 5 95 1.0 4.25 5 95 1.0 5.0 80 20 1.0 7.0 80 20 1.0 [1168] Mobile phase A: 0.1% v/v water solution of formic acid [1169] Mobile phase B: 0.1% v/v acetonitrile solution of formic acid [1170] Solution for syringe washing: 20% MeOH

[1171] MS conditions:—Mass range: 100-1000 m/z [1172] Ionization: alternate [1173] Scan speed: 12 000 amu/sec

[1174] HPLC-Method 6

[1175] Apparatus: HPLC—MERCK CHROMASTER with gradient pump and DAD detector

[1176] Column: XBridge C18 3.5μ (4.6×150 mm), column no. 186003034, internal column no. 009

[1177] Reagents: [1178] Methanol for HPLC Ultra Gradient HPLC Grade. Baker [1179] Boric acid ≥99.5%, Sigma-Aldrich [1180] Sodium hydroxide analytical grade, Eurochem BGD [1181] purified water for HPLC

[1182] HPLC conditions: [1183] Wavelength: 210.0 nm±4.0 nm [1184] Flow: 0.5 mL/min [1185] Column temperature: 25° C. [1186] Autosampler temperature: 20° C. [1187] Injection volume: 5 μL [1188] Analysis time: 30 min [1189] Elution: gradient

TABLE-US-00029 Time [min] Mobile phase A [%] Mobile phase B [%] Flow [mL/min] 0.0 50 50 0.5 22.0 5 95 0.5 25.0 5 95 0.5 27.0 50 50 0.5 30.0 50 50 0.5

[1190] Mobile phase A: [1191] Borate buffer c=5 mM, pH=9.6 [1192] Preparation: 0.618 g of boric acid placed in 2 L volumetric flask were dissolved in 1.5 L [1193] purified water. pH value was adjusted to 9.6 using 1M solution of NaOH (6 mL). [1194] Finally, solution was diluted to the mark using purified water.

[1195] Mobile phase B: [1196] 1 L MeOH with the analogous amount of 1M NaOH as in phase A (3 mL).

[1197] Solution for syringe washing: acetonitrile

[1198] LCMS-Method 7

[1199] Apparatus: Dionex UHPLC Ultimate 3000 with DAD detector/Thermo Scientific MSQ Plus

[1200] Column: Gemini-NX 3μ C18 (4.6×50 mm), 110A, column no. OOB-4453-EO, internal column no. 002

[1201] Reagents:—Formic acid a 98%, Sigma-Aldrich [1202] Acetonitrile for HPLC UV/gradient grade, Baker [1203] μQ-water for LCMS

[1204] HPLC conditions:—Wavelength range: (190-340) nm±4 nm [1205] Flow: 0.5 ml/min [1206] Column temperature: 25° C. [1207] Autosampler temperature: 20° C. [1208] Injection volume: 2.0 μl [1209] Analysis time: 12 min [1210] Elution: gradient

TABLE-US-00030 Time [min] Mobile phase A [%] Mobile phase B [%] Flow [ml/min] 0.0 60 40 0.5 6.7 20 80 0.5 7.5 20 80 0.5 7.8 5 95 0.5 9.5 5 95 0.5 10.0 60 40 0.5 12.0 60 40 0.5 [1211] Mobile phase A: 0.1% v/v water solution of formic acid [1212] Mobile phase B: 0.1% v/v acetonitrile solution of formic acid [1213] Solution for syringe washing: 20% MeOH

[1214] MS conditions:—Mass range: 100-1000 m/z [1215] Ionization: alternate [1216] Scan speed: 12 000 amu/sec

[1217] LCMS-Method 8

[1218] Apparatus: Dionex UHPLC Ultimate 3000 with DAD detector/Thermo Scientific MSQ Plus

[1219] Column: Gemini-NX 3μ C18 (4.6×50 mm), 110A, column no. OOB-4453-EO, internal column no. 002

[1220] Reagents:—Formic acid ≥98%, Sigma-Aldrich [1221] Acetonitrile for HPLC UV/gradient grade, Baker [1222] μQ-water for LCMS

[1223] HPLC conditions:—Wavelength range: (190-340) nm±4 nm [1224] Flow: 0.5 ml/min [1225] Column temperature: 25° C. [1226] Autosampler temperature: 20° C. [1227] Injection volume: 2.0 μl [1228] Analysis time: 28 min [1229] Elution: gradient

TABLE-US-00031 Time [min] Mobile phase A [%] Mobile phase B [%] Flow [ml/min] 0.0 95 5 0.5 4.0 95 5 0.5 19.0 20 80 0.5 21.0 20 80 0.5 24.0 95 5 0.5 28.0 95 5 0.5 [1230] Mobile phase A: 0.1% v/v water solution of formic acid [1231] Mobile phase B: 0.1% v/v acetonitrile solution of formic acid [1232] Solution for syringe washing: 20% MeOH

[1233] MS conditions:—Mass range: 100-1000 m/z [1234] Ionization: alternate [1235] Scan speed: 12 000 amu/sec

[1236] LCMS-Method 9

[1237] Apparatus: Dionex UHPLC Ultimate 3000 with DAD detector/Thermo Scientific MSQ Plus

[1238] Column: Kinetex XB-C18 2.6 μm (4.6×50 mm), 100A, column no. OOB-4496-EO, internal column no. 019

[1239] Reagents:—Formic acid ≥98%, Sigma-Aldrich [1240] Acetonitrile for HPLC UV/gradient grade, Baker [1241] μQ-water for LCMS

[1242] HPLC conditions:—Wavelength range: (190-340) nm±4 nm [1243] Flow: 1.0 ml/min [1244] Column temperature: 25° C. [1245] Autosampler temperature: 20° C. [1246] Injection volume: 2.0 μl [1247] Analysis time: 7 min [1248] Elution: gradient

TABLE-US-00032 Time [min] Mobile phase A [%] Mobile phase B [%] Flow [ml/min] 0.0 100 0 1.0 1.0 95 5 1.0 4.0 80 20 1.0 4.75 20 80 1.0 5.25 20 80 1.0 6.0 95 5 1.0 7.0 100 0 1.0 [1249] Mobile phase A: 0.1% v/v water solution of formic acid [1250] Mobile phase B: 0.1% v/v acetonitrile solution of formic acid [1251] Solution for syringe washing: 20% MeOH

[1252] MS conditions:—Mass range: 100-1000 m/z [1253] Ionization: alternate [1254] Scan speed: 12 000 amu/sec

[1255] LCMS-Method 10

[1256] Apparatus: Dionex UHPLC Ultimate 3000 with DAD detector/Thermo Scientific MSQ Plus

[1257] Column: Gemini-NX 3μ C18 (4.6×50 mm), 110A, column no. OOB-4453-EO, internal column no. 002

[1258] Reagents:—Formic acid a 98%, Sigma-Aldrich [1259] Acetonitrile for HPLC UV/gradient grade, Baker [1260] μQ-water for LCMS

[1261] HPLC conditions:—Wavelength range: (190-340) nm t 4 nm [1262] Flow: 0.5 ml/min [1263] Column temperature: 25° C. [1264] Autosampler temperature: 20° C. [1265] Injection volume: 2.0 μl [1266] Analysis time: 12 min [1267] Elution: gradient

TABLE-US-00033 Time [min] Mobile phase A [%] Mobile phase B [%] Flow [ml/min] 0.0 70 30 0.5 6.7 20 80 0.5 7.5 20 80 0.5 7.8 5 95 0.5 9.5 5 95 0.5 10.0 70 30 0.5 12.0 70 30 0.5 [1268] Mobile phase A: 0.1% v/v water solution of formic acid [1269] Mobile phase B: 0.1% v/v acetonitrile solution of formic acid [1270] Solution for syringe washing: 20% MeOH

[1271] MS conditions:—Mass range: 100-1000 m/z [1272] Ionization: alternate [1273] Scan speed: 12 000 amu/sec

[1274] LCMS-Method 11

[1275] Apparatus: Dionex UHPLC Ultimate 3000 with DAD detector/Thermo Scientific MSQ Plus

[1276] Column: Kinetex® 2.6 μm XB-C18 (4.6×50 mm), 110A, column no. OOB-4496-EO, internal column no. 019

[1277] Reagents:—Formic acid a 98%, Sigma-Aldrich [1278] Acetonitrile for HPLC UV/gradient grade, Baker [1279] μQ-water for LCMS

[1280] HPLC conditions:—Wavelength range: (190-340) nm t 4 nm [1281] Flow: 1.0 ml/min [1282] Column temperature: 25° C. [1283] Autosampler temperature: 20° C. [1284] Injection volume: 2.0 μl [1285] Analysis time: 6 min [1286] Elution: gradient

TABLE-US-00034 Time [min] Mobile phase A [%] Mobile phase B [%] Flow [ml/min] 0.0 30 70 1.0 3.35 20 80 1.0 3.75 20 80 1.0 3.9 5 95 1.0 4.75 5 95 1.0 5.0 30 70 1.0 6.0 30 70 1.0 [1287] Mobile phase A: 0.1% v/v water solution of formic acid [1288] Mobile phase B: 0.1% v/v acetonitrile solution of formic acid [1289] Solution for syringe washing: 20% MeOH

[1290] MS conditions:—Mass range: 100-1000 m/z [1291] Ionization: alternate [1292] Scan speed: 12 000 amu/sec

[1293] LCMS-Method 12

[1294] Apparatus: Dionex UHPLC Ultimate 3000 with DAD detector/Thermo Scientific MSQ Plus

[1295] Column: Gemini-NX 3μ C18 (4.6×50 mm), 110A, column no. OOB-4453-EO, internal column no. 002

[1296] Reagents:—Formic acid ≥98%, Sigma-Aldrich [1297] Acetonitrile for HPLC UV/gradient grade, Baker [1298] μQ-water for LCMS

[1299] HPLC conditions:—Wavelength range: (190-340) nm±4 nm [1300] Flow: 0.5 ml/min [1301] Column temperature: 25° C. [1302] Autosampler temperature: 20° C. [1303] Injection volume: 2.0 μl [1304] Analysis time: 14 min [1305] Elution: gradient

TABLE-US-00035 Time [min] Mobile phase A [%] Mobile phase B [%] Flow [ml/min] 0.0 100 0 0.5 2.0 95 5 0.5 8.0 80 20 0.5 9.5 20 80 0.5 10.5 20 80 0.5 12.0 95 5 0.5 14.0 100 0 0.5 [1306] Mobile phase A: 0.1% v/v water solution of formic acid [1307] Mobile phase B: 0.1% v/v acetonitrile solution of formic acid [1308] Solution for syringe washing: 20% MeOH

[1309] MS conditions:—Mass range: 100-1000 m/z [1310] Ionization: alternate [1311] Scan speed: 12 000 amu/sec

[1312] UPLC-MS

[1313] Apparatus: Shimadzu LCMS-2020 Single Quadrupole Liquid Chromatograph Mass Spectrometer

[1314] Column: Acquity UPLC 1.8 μm C18 (2.1×50 mm), 100 Å, column no. 186003532, internal column no. Pur CC—MS001

[1315] Reagents: [1316] Formic acid≥98%, Sigma-Aldrich, [1317] Acetonitrile for HPLC UV/gradient grade, Baker, [1318] purified water for HPLC.

[1319] UPLC conditions: [1320] Wavelength: 254 nm and 280 nm [1321] Flow: 0.5 ml/min [1322] Column temperature: 25° C. [1323] Autosampler temperature: 20° C. [1324] Injection volume: 3 μl [1325] Analysis time: 6.0 min [1326] Elution: gradient

TABLE-US-00036 Time [min] Mobile phase A [%] Mobile phase B [%] Flow [ml/min] 0.01 95 5 0.5 4.00 5 95 0.5 5.00 5 95 0.5 5.20 95 5 0.5 6.00 95 5 0.5 [1327] Mobile phase A [1328] 0.1% v/v water solution of formic acid [1329] Mobile phase B: [1330] 0.1% v/v acetonitrile solution of formic acid [1331] Solution for syringe washing: [1332] 100% acetonitrile

[1333] MS Conditions: [1334] Mass range: 50-1000 m/z [1335] Ionization: alternate [1336] Scan speed: 7500 u/sec

[1337] Activity Screening

[1338] Glutaminyl Cyclase, Assay Determination of IC50 Values and Calculation of KI Values

[1339] 10 mM compound stock solutions were prepared in DMSO. For IC50 determination compound stocks were serially diluted (1:3) in DMSO.

[1340] All measurements were performed with an EnSpire Perkin Elmer multimode reader using glutaminyl-7-amino-4-methylcoumarin (H-Gin-AMC) as substrate and recombinant pyroglutamyl aminopeptidase (pGAP) as auxiliary enzyme. Reactions were carried out at ambient temperature in black 96-well half area microplates. Each sample consisted of 1 μl test compound solution or solvent (DMSO) and 49 μl QC appropriately diluted in assay buffer (50 mM Tris/HCl, pH 8.0 or 50 mM MES buffer, pH=6.0). After a 10 min preincubation at ambient temperature the enzyme reaction was started by adding 50 μl of Gln-AMC-substrate/pGAP mixture in assay buffer. Final substrate concentrations were 50 and 200 μM for measurement at pH 8.0 or 6.0, respectively. Release of flourogenic AMC were recorded at excitation/emission wavelengths of 380/460 nm. Initial velocity of the enzyme reaction was calculated by linear regression of the first 10 data points using the Enspire Manager software. Final evaluation and calculation of IC50s were performed using GraphPad Prism software. IC.sub.50 values were calculated from normalized data (QC activity without inhibitor=100%) by nonlinear regression according to a 4-parameter logistic equation.

[1341] Ki-values were calculated according to the following formula: Ki=IC50/(1+[S]/Km), where:

[1342] [S] reflects to the concentration of substrate in the assay (200 μM for pH 6.0, 50 μM for pH 8.0) and Km is the respective Michaelis-Menten constant (390 μM at pH 6.0, 62 μM at pH 8.0).

[1343] MALDI-TOF Mass Spectrometry

[1344] Matrix-assisted laser desorption/ionization mass spectrometry was carried out using the Hewlett-Packard G2025 LD-TOF System with a linear time of flight analyzer. The instrument was equipped with a 337 nm nitrogen laser, a potential acceleration source (5 kV) and a 1.0 m flight tube. Detector operation was in the positive-ion mode and signals are recorded and filtered using LeCroy 9350M digital storage oscilloscope linked to a personal computer. Samples (5 μl) were mixed with equal volumes of the matrix solution. For matrix solution DHAP/DAHC was used, prepared by solving 30 mg 2′,6′-dihydroxyacetophenone (Aldrich) and 44 mg diammonium hydrogen citrate (Fluka) in 1 ml acetonitrile/0.1% TFA in water (1/1, v/v). A small volume (≈1 μl) of the matrix-analyte-mixture was transferred to a probe tip and immediately evaporated in a vacuum chamber (Hewlett-Packard G2024A sample prep accessory) to ensure rapid and homogeneous sample crystallization.

[1345] For long-term testing of Glu.sup.1-cyclization. Aβ-derived peptides were incubated in 100 μl 0.1 M sodium acetate buffer, pH 5.2 or 0.1 M Bis-Tris buffer, pH 6.5 at 30° C. Peptides were applied in 0.5 mM [Aβ(3-11)a] or 0.15 mM [Aβ(3-21)a] concentrations, and 0.2 U QC is added all 24 hours. In case of Aβ(3-21)a, the assays contained 1% DMSO. At different times, samples are removed from the assay tube, peptides extracted using ZipTips (Millipore) according to the manufacturer's recommendations, mixed with matrix solution (1:1 v/v) and subsequently the mass spectra recorded. Negative controls either contain no QC or heat deactivated enzyme. For the inhibitor studies the sample composition was the same as described above, with exception of the inhibitory compound added (5 mM or 2 mM of a test compound of the invention).

[1346] Compounds and combinations of the invention may have the advantage that they are, for example, more potent, more selective, have fewer side-effects, have better formulation and stability properties, have better pharmacokinetic properties, be more bioavailable, be able to cross blood brain barrier and are more effective in the brain of mammals, are more compatible or effective in combination with other drugs or be more readily synthesized than other compounds of the prior art.

[1347] Throughout the specification and the claims which follow, unless the context requires otherwise, the word ‘comprise’, and variations such as ‘comprises’ and ‘comprising’, will be understood to imply the inclusion of a stated integer, step, group of integers or group of steps but not to the exclusion of any other integer, step, group of integers or group of steps.

[1348] All patents and patent applications mentioned throughout the specification of the present invention are herein incorporated in their entirety by reference.

[1349] The invention embraces all combinations of preferred and more preferred groups and embodiments of groups recited above.

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Abstract