BRPI0617534A2 - COMPOUND, PHARMACEUTICAL COMPOSITION, METHOD FOR THE SELECTIVE ACTIVATION / STIMULATION OF A-7 NICOTINIC RECEPTORS IN A PATIENT, METHOD FOR THE TREATMENT OF A PATIENT SUFFERING FROM A PSYCHOTIC DISEASE, A DISEASES AND A NEURODEGENERATIVE DISEASE. OR A CONDITION OF DEGENERATION OF MEMORY AND / OR COGNITION, METHOD FOR THE TREATMENT OF A PATIENT SUFFERING FROM DEMENTIA AND / OR ANOTHER CONDITION WITH LOSS OF MEMORY, METHOD FOR TREATING A PATIENT SUFFERING DEGENERATION OF DEATH MEMORY SOFT COGNITIVE DEGENERATION DUE TO AGING, ALZHEIMER EVIL, SCHIZOPHRENIA, PARKINSON EVIL, HUNTINGTON EVIL, PICK EVIL, CREUTZFELDT-JAKOB EVIL, DEPRESSION, AGING, SICKNESS, HARMONY, HARMONY, ACCIDENT, HEALTH, HEALTH MULTIINFARTO DEMENTIA, HIV AND / OR CARDIOVASCULAR DISEASE, METHOD FOR TREATING AND / OR PREVENTING DEMENTIA IN A PATIENT WITH ALZHEIMER'S EVIL , METHOD FOR THE TREATMENT OF A PATIENT FOR THE WITHDRAWAL OF ALCOHOL OR FOR THE TREATMENT OF A PATIENT WITH ANTI-TOXIC THERAPY, METHOD FOR THE TREATMENT OF A PATIENT TO CONFIRM NEUROPROTECTION AGAINST DAMAGE ASSOCIATED WITH CEREBRAL EARLY ACCIDENT ACCIDENTS GLUTAMATE, METHOD FOR THE TREATMENT OF A PATIENT SUFFERING FROM NICOTIN ADDICTION, PAIN, TIME DIFFERENCE, OBESITY AND / OR DIABETES, METHOD OF INDUCING A PATIENT TO STOP SMOKING, METHOD FOR TREATING A PATIENT WHO SUFFERS SOFT COGNITIVE DEGENERATION (MCI), VASCULAR DEMENTIA (VAD), COGNITIVE DECLINATION ASSOCIATED WITH AGE (AACD), AMNESIA ASSOCIATED WITH OPEN HEART SURGERY, CARDIAC APPRECIATION, GENERAL ANESTHESIA, DEDEYOUS EXPERTISE (DEODOUS EXPERIENCE, DEDEYOUS EXPERIENCE, .) - Google Patents

Abstract

COMPOUND, PHARMACEUTICAL COMPOSITION, METHOD FOR THE SELECTIVE ACTIVATION / STIMULATION OF A-7 NICOTINIC RECEPTORS IN A PATIENT, METHOD FOR THE TREATMENT OF A PATIENT SUFFERING FROM A PSYCHOTIC DISEASE, A DISEASES AND A NEURODEGENERATIVE DISEASE. OR A CONDITION OF DEGENERATION OF MEMORY AND / OR COGNITION, METHOD FOR THE TREATMENT OF A PATIENT SUFFERING FROM DEMENTIA AND / OR ANOTHER CONDITION WITH LOSS OF MEMORY, METHOD FOR TREATING A PATIENT SUFFERING DEGENERATION OF DEATH MEMORY SOFT COGNITIVE DEGENERATION DUE TO AGING, ALZHEIMER'S EVIL, SCHIZOPHRENIA, PARKINSON'S EVIL, HUNTINGTON'S EVIL, PICK'S EVENT, CREUTZFELDT-JAKOB EVIL, DEPRESSION, AGING, SICKNESS, HARMONY, HARMONY, ACCIDENT, HEALTH, HEALTH MULTIINFARTO DEMENTIA, HIV AND / OR CARDIOVASCULAR DISEASE, METHOD FOR TREATING AND / OR PREVENTING DEMENTIA IN A PATIENT WITH ALZHEIMER'S EVIL , METHOD FOR THE TREATMENT OF A PATIENT FOR THE WITHDRAWAL OF ALCOHOL OR FOR THE TREATMENT OF A PATIENT WITH ANTI-TOXIC THERAPY, METHOD FOR THE TREATMENT OF A PATIENT TO CONFIRM NEUROPROTECTION AGAINST DAMAGE ASSOCIATED WITH CEREBRAL EARLY ACCIDENT RESULTS GLUTAMATE, METHOD FOR THE TREATMENT OF A PATIENT SUFFERING FROM NICOTIN ADDICTION, PAIN, TIME DIFFERENCE, OBESITY AND / OR DIABETES, METHOD OF INDUCING A PATIENT TO STOP SMOKING, METHOD FOR TREATING A PATIENT WHO SUFFERS SOFT COGNITIVE DEGENERATION (MCI), VASCULAR DEMENTIA (VAD), COGNITIVE DECLINATION ASSOCIATED WITH AGE (AACD), AMNESIA ASSOCIATED WITH OPEN HEART SURGERY, CARDIAC APPROPRIATION, GENERAL ANESTHESIA, DEHESIA, DEHESIA, HOSPITAL SLEEP INDUCED BY COGNITIVE DEGENERATION, CHRONIC FATIGUE SYNDROME, NARCOLEPSY, AIDS-RELATED DEMENTIA, RELATED COGNITIVE DEGENERATION OF WITH EPILEPSY, DOWN SYNDROME, DEMENTIA RELATED TO ALCOHOLISM, DRUG / SUBSTANCES-DEGENERATION, PUGILISTIC DEMENTIA (BOXEATER SYNDROME), OR ANIMAL DEMENTIA, METHOD FOR TREATING TREATMENT TREATMENT METHOD A PATIENT SUFFERING FROM MEMORY DEGENERATION, METHOD FOR THE TREATMENT OR PROPHYLAXIS OF A DISEASE OR A CONDITION RESULTING FROM THE DISCURSION OF THE TRANSMISSION OF THE NICOTINIC ACETYLINE RECEPTOR IN A PATIENT, METHOD FOR THE TREATMENT OR A PROFILE OF PROFILE RESULTING FROM DEFECTIVE ACETYL CHILLINE NICOTINIC RECEPTORS OR MALFUNCTIONING IN A PATIENT, METHOD FOR TREATING OR PROPHYLAXIS OF A DISEASE OR A CONDITION RESULTING FROM THE DELETED TRANSMISSION OF THE ACETYLINE COLIN RECEIVER TO A NICOTYLINIC TREATMENT INTO A NICOTINIC TREATMENT OR A NICOTININE TREATMENT. A DISEASE OR CONDITION RESULTING FROM THE LOSS OF CHOLINERGIC SYNOPSIS IN A PATIENT, METHOD O FOR THE PROTECTION OF NEURONES IN A PATIENT WITH NEUROTOXICITY INDUCED BY THE ACTIVATION OF A7NACH RECEPTORS, METHOD FOR THE TREATMENT OR PROPHYLAXIS OF A NEURODEGENERATIVE DISORDER THROUGH THE INHIBITION OF THE PEEPIDE CONTAINED WITH AEPETHESIS OF AEPHESIS OF AEPHESIS OF AEPHESIS OF AEPHESIS. TREATMENT OF A PATIENT SUFFERING FROM AN INFLAMMATORY DISEASE The present invention relates generally to the field of ligands for nicotinic acetylcholine receptors (nACh receptors), the activation of nACh receptors, and the treatment of disease conditions associated with defective or malfunctioning nicotinic acetyl choline receptors, especially in the brain. In addition, the present invention relates to new compounds (for example, indazoles and benzothiazoles), which act as ligands for the cx7 nACh receptor subtype, methods of preparing such compounds, compositions containing such compounds, and methods of using them.

Description

COMPOUND, PHARMACEUTICAL COMPOSITION, METHOD FOR ACCEPTANCE / SELECTIVE STIMULATION OF A-7 NICOTINICAL RECEPTORS IN A PATIENT, METHOD FOR TREATMENT OF A PATIENT DISEASE OF A PSYCHOAN DISEASE, NEUROVE DISEASE, A NEUROVE DISEASE DEGENERATION OF MEMORY AND / OR COGNITION, METHOD FOR THE TREATMENT OF A PATIENT SUFFERING FROM DEMENTIA AND / ANY OTHER CONDITION WITH LOSS OF MEMORY, METHOD FOR HANDLING A PATIENT SUFFERED BY DEGENERATION DEVELOPED BY DEVELOPMENT ALZHEIMER, SCHIZOPHRENIA, BAD DEPARKINSON, BAD HUNTINGTON BAD, PICK BAD, BAD DECREUTZFELDT-JAKOB, DEPRESSION, AGING, BRAIN CRACLE, HYPOXIA OF THE CNS, CNS MULTI VARIETY, CERNAL DEEK, CNS HYDROXIA METHOD FOR TREATMENT AND / OR APPRECIATION OF DEMENTIA IN AN ALZHEIMER PATIENT PATIENT, METHOD FOR TREATMENT OF A PATIENT FOR ALCOHOL WITHDRAWAL OR TREATMENT OF A PATIENT WITH ANTI-TOXIC THERAPY, METHOD FOR TREATMENT OF A PATIENT TO AGAINST NEUROPROTECTION DAMAGES ASSOCIATED WITH THE VASCULAR EXTRACTEDUCT AND THE GLASSES BY THE EXTRACTS NICOTINE ADDICTION SUFFER, PAIN, FUSOHORARY TUMBLE, OBESITY AND / OR DIABETES, METHOD FOR INDUCTION OF STOPPING SMOKING, METHOD FOR TREATMENT OF UMPACIENT (DEGENIATION DEGENCIATION) ), COGNITIVE DECLINE WITH AITY (AACD), AMNESIA ASSOCIATED WITH THE HEART SURGERY, HEART APPRECIATION, GENERAL ANESTHESIA, DAMEMIC DEFENSE DEDICATED, NON-DIAGNOSIS DEDICATED, NON-DIAGNOSIS DEDICATED, AIDS, EPILEPSY-COGNITIVE DEGENERATION, SYNDRUS MEASURES DOWN, ALCOHOL-RELATED DEMENTIA, DRUG / SUBSTANCE MEMORY DEGENERATION, PUGILISTIC DEMENTIA (BOXER SYNDROME), OR ANIMAL DEMENTIA, METHOD FOR TREATMENT OF MEMORY LOSS, METHOD DETERMINATION FOR THE TREATMENT OR PROPHILAXY OF A HAZARDOUS OR CONDITION RESULTING FROM DYNAMIC TRANSMISSION RECEIVER TRANSMISSION DYEUNCTION IN A PATIENT, METHOD FOR TREATMENT OR PROPHYLAXIS OF A NONOTHINE RECEPTIENTAL DISEASE OR ACETIC DISEASES , METHOD FOR THE TREATMENT OR PROPHILAXY OF A DISEASE OR CONDITION RESULTING FROM THE SUPPRESSED TRANSMISSION OF THE NACE-SIDE DEACETIL HILL RECEIVER IN A PATIENT, METHOD FOR THE PROTRAILING OR PROPHILAXY FOR A PROPELLANEOUS PERSONAL DISEASE NEURONS IN A PACI ENTE COMEUROTOXICITY INDUCED BY THE ACTIVATION OF DEA 7 NACH RECEPTORS, THE METHOD FOR TREATMENT OR PROPHYLAXIS OF NEURODEGENERATIVE DISTURBUS BY INHIBITION OF PEANIUM RECEPTOR IN A BODY PATIENT IN A DENTAL PATTERN

The present patent application claims the benefit of provisional US patent application no. 60 / 791,881, filed April 14, 2006, and provisional US filing 60 / 719,552, filed September 23, 2005, the full disclosure of which is hereby incorporated by reference.

The present patent application is also related to US patent application no. Serial No. 11 / 089,533, filed March 25, 2005 (claiming benefit of US Patent Application No. 60 / 555,951, filed March 25, 2004, and Provisional Patent Application No. 60 / 616,033, filed October 6, 2004) and U.S. Pat. Serial No. 10 / 669,645, filed September 25, 2003 (filing for provisional US patent application Serial No. 60 / 413,151, filed September 25, 2002, and provisional US patent application Serial No. 60 / 448,469, filed February 21, 2003, the full disclosures of which are hereby incorporated by reference.

FIELD OF INVENTION

The present invention relates generally to the field of nicotinic acetylcholine receptor (nAChR) ligands, the activation of nAChRs, and the treatment of disease conditions associated with defective or malfunctioning nicotinic acetylcholine receptors, especially the brain. Additionally, the present invention relates to novel compounds which act as ligands for the nAChR α7 subtype, methods for preparing such compounds, compositions comprising such compounds, and methods of using them.

BACKGROUND OF THE INVENTION

There are two types of oneurotransmitter receptors, acetylcholine: muscarinic receptors and nicotinic receptors, based on the selectivity of damuscarin and nicotine, respectively. Muscarinic receptors are G-protein coupled receptors. Nicotinic receptors are members of the ligand-joined ion channel family. When activated, the conductance of the ions through the nicotinic ion channels increases. The nicotinic alpha-7 receptor protein forms an in vitro homo-pentameric channel that is highly permeable to a variety of cations (eg, Ca ++). Each nicotinic alpha-7 receptor has four transmembrane domains, called M1, M2, M3, and M4. It has been suggested that the M2 domain forms the wall that lines the channel. Sequence alignment shows that nicotinic alpha-7 is highly conserved during evolution. The M2 domain that lines the channel is identical in the sequence of chicken protein to humans. For discussions on the alpha-7 receptor, see, for example, Revah et al. (1991), Nature, 353, 846-849; Galzi et al. (1992), Nature, 359, 500-505; Fucile et al. (2000), PNAS97 (7), 3643-3648; Briggs et al. (1999), Eur. J. Pharmacol. 366 (2-3), 301-308; and Gopalakrishnan et al. (1995), Eur. J. Pharmacol. 290 (3), 237-246.

The nicotinic alpha-7 receptor channel is expressed in various brain regions and is believed to be involved in many important biological processes in the central nervous system (CNS), including learning and memory. Nicotinic alpha-7 receptors are located at presynaptic and postsynaptic terminals, and it has been suggested that they are involved in modulating synaptic transmission. Therefore, there is an interest in the development of novel compounds which bind to the α7 nACh receptor subtype for the treatment of disease conditions associated with malfunctioning or malfunctioning nicotinic acetylcholine receptors.

BRIEF DESCRIPTION OF THE INVENTION

The present invention relates to novel compounds which act as ligands for the α 7 nACh receptor subtype, methods for the preparation of such compounds, compositions comprising such compounds, and methods of their use.

DETAILED DESCRIPTION OF THE INVENTION The present invention includes compounds of formulas Formula I, II, III, or IV:

<formula> formula see original document page 6 </formula>

on what

A is

<formula> formula see original document page 6 </formula>

X is O or S;

each of X1 to X4 is independently N, CH, CR1, or C-, where C- represents the point of attachment of the group A of the structure of formulas (I), (II), (III) or ( IV) (e.g., each of X1, X2, X3 and X4 is CH or CR1, and group A is joined at position 3 to the remainder of the structure of formulas (I), (II), (III) or (IV), each of X1, X2 and X3 is CH or CR1, X4 is N, and group A is attached at position 3 to the remainder of the structure of formulas (I), (II), (III) or (IV), each of X1, X2 and X4 is CH or CR1, X3 is N, and group A is joined in position 3 to the remainder of the structure of formulas (I), (II), (III) or (IV), or each of X1, X3 and X 4 is CH or CR 11 X 2 is N, and group A is attached at position 3 to the remainder of the structure of formulas (I), (II), (III) or (IV);

each of X5 to X8 is independently N, CH, CR3, or C-, where C- represents the point of attachment of the group A of the structure of formulas (I), (II), (III) or ( IV) (for example, each of X 5, X 6 and X 8 is CH or CR 3 and X 7 is C-, whereby group A is joined at its 5 position on the structure of formulas (I), (II), (III) or (IV), or each of X5, X7 and X8 is CH or CR3 and X6 is C-, whereby group A is joined at its 6 position to the remainder of the structure of formulas (I), (II ), (III) or (IV));

each of X9 to X12 is independently N, CH, CR4, or C-, where C- represents the point of attachment of group A to the remainder of the structure of formulas (I), (II), (III) or

(IV) (e.g., each of X9, X10, X11 and X12 is CH or CR4, and group A is joined at position 3 to the remainder of the structure of formulas (I), (II), (III) or (IV) , each of X9, X10 and X11 is CH or CR4, X12 is N, and group A is joined at position 3 to the remainder of the structure of formulas (I), (II), (III) or (IV), or each one of X9, X10 and X12 is CH or CR4, X11 is N, and group A is joined at position 3 to the remainder of the structure of formulas (I), (II), (III) or (IV), or each of X9, X11 and X12 is CH or CR4, X10 is N, and group A is joined at position 3 to the remainder of the structure of formulas (I), (II), (III) or (IV);

each of X13 to X16 is independently N, CH, CR, or C-, where C- represents the point of attachment of group A to the remainder of the structure of formulas (I), (II), (III) or ( IV) (e.g., each of X13, X14, X15 and X16 is CH or CR, and

group A is joined at position 3 to the remainder of the structure of formulas (I), (II), (III) or (IV), each of X13, X14 and X15 is CH or CR, X16 is N, and group A is joined at the position 3 of the structure of the formulas (I), (II), (III) or (IV), or each of X13, X14 and X16 is CH or CR, X15 is N, and group A is joined at the 3 to the remainder of the structure of formulas (I), (II), (III) or (IV), or each of X13, X15 and X16 is CH or CR, X14 is N, and group A is joined at position 3 the remainder of the structure of formulas (I), (II), (III) or (IV);

R1 is H, alkyl having one to four carbon atoms, halogenated alkyl having one to four carbon atoms, cycloalkyl having three to seven carbon atoms, or cycloalkylalkyl having four to seven carbon atoms;

R is H, F, Cl, Br, I, OH, CN, COH, NR6R7, Carboxy, CONR6R7, NR2COR8, NR2COOR8, NR2CSR8, NR2CONR2R9, NR2CSNR2R9, NR2CONR6R7, NR2R6R, NR2 C1-6-alkyl-0) ^ 2-C1-6-alkyl, NR2-C1-6-alkyl-NR6R7, NR2-C1-alkyl-CONR6R7, NR2-CO-C1-6-alkyl-Ar, NR2 -C 1-6 alkyl-C 0-0 -R 2, NR 2 -C 1-6-N 2 -C 1-6 alkyl-NR 2 (C 0 -R 2) -NR 2 (CO-O-R 2), C 1-6 alkyl NR2, -0-C1-6-alkyl-1-NR6R7, alkyl having one to four carbon atoms, fluorinated alkyl having one to four carbon atoms (e.g. CF3), alkenyl having two to six carbon atoms, alkynyl which has two to six carbon atoms (eg, ethinyl, propynyl, pentenyl), wherein the alkyl, fluorinated alkyl, alkenyl or alkynylation groups are in each case unsubstituted or substituted by Ar or Het (eg phenylacetylene C6H5-C = C-) cycloalkyl having three to seven carbon atoms, cycloalkenyl having five to eight carbon atoms which is unsubstituted or substituted by HCO-, Cl-6- alkoxy, NR6R7, CO-NR6R7, C2-6-alkoxycarbonyl, or -CO-R10 cycloalkylalkyl having four carbon atoms, cycloalkenylalkyl having six to one carbon atoms, alkoxy having one to four carbon atoms (e.g. OCH3), cycloalkoxy having three to seven carbon atoms, cycloalkylalkoxy having four to seven carbon atoms (eg cyclopropylmethoxy), alkylthio having one to four carbon atoms (eg SCH3), fluorinated alkoxy having one to four atoms carbon (e.g. OCF3, OCHF2), hydroxy alkyl having one to four carbon atoms, fluorinated alkyl hydroxy having one to four carbon atoms (e.g. 2,2,2-trifluoro-1-hydroxyl-1- (trifluoromethyl ) ethyl), hydroxy alkoxy having two to four carbon atoms, fluorinated alkoxy hydroxy which has two to four carbon atoms, monoalkylamino having one to four carbon atoms, dialkylamino wherein each alkyl group independently has one to four atoms s carbon, alkoxycarbonyl having two to six carbon atoms, Ar, Het, OAr, OHet, Carbo-O, Ar-C 1-6 alkyl-O-, Het-C 1-6 alkyl-O-, Het-CO -Het-, Het-C1-6-alkyl-NR2-, or Ar-C1-6-alkyl-Het-O- as long as R is not NH2; or

R is one of the following formulas

<formula> formula see original document page 9 </formula>

n ranges from 2 to 4, m ranges from 3 to 5; or two R may together form a fused five membered forward structure containing at least one N atom;

R "1 is H, F, Cl, Br, I, OH, CN, nitro, NH 2, COH, NR" 6R "7, carboxy, CONR" 6R "7, NR" 2COR "8, NR" 2COOR "8, NR "2CSR" 8, NR "2CONR" 2R "9, NR" 2CSNR "2R" 9, NR "2SO2R" 10, NR "2CONR" 6R "7, NR" 2CSNR "6R" 7, NR "2R" 9, SO2R "10, SOR" 10, -O- (C1-6-alkyl-O) 1-2-C1-6-alkyl, NR "2-C1-6-alkyl-NR" 6R "7, NR" 2- C1-6-alkyl-CONR "6R" 7, NR "2-CO-C1-6-alkyl-Ar, NR" 2-C1-6-alkyl-CO-OR "2, NR" 2-C1-6- alkyl-NR "2 (CO-OR" 2), -C1-6-alkyl-NR "2, -O-C1-6-alkyl-NR" 6R "7, alkyl containing one to four carbon atoms, fluorinated alkyl containing one to four carbon atoms (eg CF3), alkenyl containing two to six carbon atoms (eg ethinyl, propynyl, pentenyl), alkynyl containing two to six carbon atoms, wherein the groups alkyl, fluorinated alkyl, alkenyl or alkynylation are in each case unsubstituted or otherwise substituted by Ar or Het (e.g. phenyl acetylene C6H5-C = C -), cycloalkyl containing three to seven carbon atoms, cycloalkenyl containing five to eight carbon atoms, which is unsubstituted or else substituted by HCO-, C1-S-alkoxy, NR6R7, CO-NR6R7, C2-6-alkoxycarbonyl, or -CO-R10 cycloalkylalkyl containing four to seven carbon atoms, containing six to nine carbon atoms. carbon, alkoxy containing one to four carbon atoms (eg OCH3), cycloalkoxy containing three to seven carbon atoms, cycloalkylalkoxy containing four to seven carbon atoms (eg cyclopropyl methoxy), alkylthio containing one carbon atom ( SCH3), alkoxyfluoride containing one to four carbon atoms (eg OCF3, OCHF2), alkyl hydroxy containing one to four carbon atoms, fluorinated alkyl hydroxy containing one to four carbon atoms (e.g. 2,2,2- trifluoro-1-hydroxyl-1- (trifluoromethyl) ethyl), hydroxy alkoxy containing two to four carbon atoms, fluorinated alkoxy hydroxy containing two to four carbon atoms, monoalkylamin containing one to four carbon atoms, dialkyl Each alkyl group independently has one to four carbon atoms, alkoxycarbonyl containing two to six carbon atoms, Ar, Het, OAr, OHet, Carbo-0, Ar-C 1-6 alkyl-O, Het-C 1-6. alkyl-O-, Het-CO-Het-, Het-C1- and -alkyl-NR2-, or Ar-C1-6-alkyl-Het-O-; or

R1 is one of the following formulas <formula> formula see original document page 11 </formula>

Or two R1 may together form a fused five-membered ring structure containing at least one N atom;

R2 is H, alkyl containing one to four carbon atoms, fluorinated alkyl containing one to four carbon atoms, cycloalkyl containing three to seven carbon atoms, cycloalkyl alkyl containing four to seven carbon atoms, C1-4 alkyl-CO-fluorinated, C3-7-cycloalkyl-CO-, C1-4-alkyl-NHCO-, C3-7-cycloalkyl-NH-CO-, Het, Ar-C1-4-alkyl-, Ar-C1-4-alkyl-CO- Ar-C1-4-alkyl-SO2, C1-4-alkyl-O-C1-4-alkyl- (e.g. CH2 CH2 -O-CH3), or Ar-C1-4-alkyl-NH-CO-;

R3 is H, F, Cl, Br, I, OH, CN, nitro, NH2, COH, NR6R7, Carboxy, CONR6R7, NR2COR8, NR2COOR8, NR2CSR8, NR2CONR2R9, NR2SO2R10, NR2R7, NR2R7, NR2R7 O- (C1-6-alkyl-O) ia-C1-4-alkyl, NR2-C1-6-alkyl-NR6R7, NR2-C1-6-alkyl I-CONR6R7, NR2-CO-C1-6-alkyl- Ar, NR2-C-6-alkyl-CO-O-R2, NR2-C1-6-alkyl-NR2 (CO-O-R2), -C1-6-alkyl-NR2, -0-C1-6-alkyl -NR6R7, alkyl containing one to four carbon atoms, fluorinated alkyl containing one to four carbon atoms (eg CF3), alkenyl containing two to six carbon atoms (eg ethinyl, propynyl, pentenyl), alkynyl containing two to four carbon atoms. six carbon atoms, wherein the alkyl, fluorinated alkyl, alkenyl or alkynylation groups are in each case unsubstituted or substituted by Ar or Het (eg phenyl acetylene C6H5-C = C -), cycloalkyl containing three to seven carbon atoms, cycloalkenyl containing five to eight carbon atoms, which is unsubstituted or substituted a by HCO-, C1-6-alkoxy, NR6R7, CO-NR6R7, C2-6-alkoxycarbonyl, or -CO-R10, cycloalkylalkyl containing four to seven carbon atoms, cycloalkenylalkyl containing six to nine carbon atoms, alkoxy containing one to four carbon atoms (eg OCH3), cycloalkoxy containing three to seven carbon atoms, cycloalkylalkoxy containing four to seven carbon atoms (eg cyclopropyl methoxy), alkylthio containing one to four carbon atoms (eg SCH3 ), alkoxyfluoride containing one to four carbon atoms (eg OCF3, OCHF2), hydroxy alkyl containing one to four carbon atoms, fluorinated alkyl hydroxy containing one to four carbon atoms (eg 2,2,2-trifluoro-1- hydroxy-1- (trifluoromethyl) ethyl), hydroxy alkoxy containing four to four carbon atoms, fluorinated alkoxy hydroxy containing two to four carbon atoms, monoalkylamin containing one to four carbon atoms, dialkylamino in which each alkyl group has independently one to four carbon atoms, carbonyl alkoxy containing two to six carbon atoms, Ar, Het, OAr, OHet, Carbo-0, Ar-C 1-6 alkyl-O, Het-C 1-6 alkyl-O, Het-CO-Het-, Het-C1-6-alkyl-NR2-, or Ar-C1-6-alkyl-Het-O-; or

R3 is one of the following formulas

<formula> formula see original document page 12 </formula>

two R 3 may together form a fused five membered ring structure containing at least one N atom;

R4 is H, F, Cl, Br, I, OH, CN, Nitro, NH2, COH, NR6R7, Carboxy, CONR6R7, NR2COR8, NR2COOR8, NR2CSR8, NR2CONR2R9, NR2SO2R10, NR2R6, NR2R6, NR2R7 -O- (C1-6-alkyl-O) 1-2-C1-6-alkyl, NR2-C1-6-alkyl-NR6R7, NR2-C1-6-alkyl-1-CONR6R7, NR2-CO-C1-6 alkyl-Ar, NR2-C1-6-alkyl-CO-O-R2, NR2-C1-6-alkyl-NR2 (C0-0-R2), -C1-6-alkyl-NR2, -0-C1- 6-alkyl-NR6R7, alkyl containing one to four carbon atoms, fluorinated alkyl containing one to four carbon atoms (eg CF3), alkenyl containing two to six carbon atoms (eg ethinyl, propynyl, pentenyl), alkynyl containing two to six carbon atoms, wherein the alkyl, fluorinated alkyl, alkenyl or alkynyl groups are in each case unsubstituted or substituted by Ar or Het (e.g. phenyl acetylene C6H5-C≡C-), cycloalkyl containing three to seven carbon atoms, cycloalkenyl containing five to eight carbon atoms which is unsubstituted or otherwise substituted HCO-, C 1-6 alkoxy, NR 6 R 7, CO-NR 6 R 7, C 2-6 alkoxycarbonyl, or -CO-R 10 cycloalkylalkyl containing four to seven carbon atoms, cycloalkenylalkyl containing six to nine carbon atoms, alkoxy containing one to four carbon atoms (eg OCH3), cycloalkoxy containing three to seven carbon atoms, cycloalkylalkoxy containing four to seven carbon atoms (eg cyclopropyl methoxy), alkylthio contained four carbon atoms (eg SCH3), alkoxyfluoride containing one to four carbon atoms (eg, OCF3, OCHF2), alkyl hydroxy containing one to four carbon atoms, fluorinated alkyl hydroxy containing one to four carbon atoms (eg 2,2,2-trifluoro-1-hydroxyl-1- (trifluoromethyl ) ethyl), hydroxy alkoxy containing four to four carbon atoms, fluorinated alkoxy hydroxy containing two to four carbon atoms, monoalkylamin containing one to four carbon atoms, dialkylamino in which any alkyl group has in dependently one to four carbon atoms, carbonyl alkoxy containing two to six carbon atoms, Ar, Het, OAr, OHet, Carbo-0, Ar-C1-6-alkyl-0-, Het-C1-6-alkyl-0-, Het-CO-Het-, Het-C1-6-alkyl-NR2-, or Ar-C1-6-alkyl-Het-O-; or

R4 is one of the following formulas

two R4 may together form a fused five-membered ring structure containing at least one N atom;

R5 is H, F, Cl, Br, I, OH, CN, nitro, NH2, carboxy, CONR6R7, NR2COR8, NR2CSR8, NR2CONR2R9, NR2SO2R10, NR2CONR6R7, NR2CSNR6R7, NR2CSNR6R7, NR2C10, NR2R10, NR2, R6, R6 carbon, fluorinated alkyl containing one to four carbon atoms (eg CF3), alkenyl containing two to six carbon atoms (eg ethinyl, propynyl, pentenyl), alkynyl containing two to six carbon atoms, wherein alkyl, alkyl fluoridated, alkenyl or alkynyl are in each case unsubstituted or then substituted by Ar or Het (eg phenylacetylene C6H5-C = C-), cycloalkyl containing three to seven carbon atoms, cycloalkenyl containing five to eight carbon atoms, which is not or substituted by HCO-, C1- and alkoxy, NR6R7, CO-NR6R7, C2-6-alkoxycarbonyl, or -CO-R10 cycloalkylalkyl containing four carbon atoms, cycloalkenylalkyl containing six one carbon atoms, alkoxy containing one at four carbon atoms (e.g. OCH3), cycloalkoxy containing three to seven carbon atoms, cycloalkylalkoxy containing four to seven carbon atoms (e.g. cyclopropyl methoxy), alkylthio containing one to four carbon atoms (eg SCH3), fluorinated alkoxy containing one to four carbon atoms (e.g. OCF3, OCHF2), alkyl hydroxy containing one to four carbon atoms, alkyl fluorinated hydroxy containing one to four carbon atoms (e.g. 2,2,2-trifluoro-1-hydroxyl-1- (trifluoromethyl ) ethyl), alkoxy hydroxy containing two to four carbon atoms, fluorinated alkoxy hydroxy containing two to four carbon atoms, monoalkylamino containing one to four carbon atoms, dialkylamino wherein each alkyl group independently has one to four carbon atoms, alkoxycarbonyl containing two to four carbon atoms six carbon atoms, Ar, Het, OAr or OHet;

each of R 5 and R 7 is independently H, alkyl containing one to four carbon atoms, alkoxyalkyl containing two to eight carbon atoms, cycloalkyl containing three to seven carbon atoms; or cycloalkylalkyl containing four to seven carbon atoms, or R 6 and R 7 are together an alkylene group containing four to six carbon atoms forms a ring of the N atom (e.g., pipridinyl, pyrrolidinyl);

R8 is H, alkyl containing one to four carbon atoms, fluorinated alkyl containing one to four carbon atoms (eg CF3), alkenyl containing three to six carbon atoms, alkynyl containing three to six carbon atoms (eg propynyl, pentenyl) wherein the alkyl, fluorinated alkyl, alkenyl or alkynyl groups are each unsubstituted or else substituted by Ar or Het (e.g. phenyl acetylene C6H5-Cs = C-), cycloalkyl containing three to seven carbon atoms, cycloalkenyl containing five to eight atoms carbon, cycloalkylalkyl containing four to seven carbon atoms, cycloalkenylalkyl containing six to nine carbon atoms, hydroxy alkyl containing one to four carbon atoms, fluorinated hydroxy alkyl containing one to four carbon atoms, monoalkylamino containing one to four carbon atoms, dialkylamino in that each alkyl group independently has one to four carbon atoms, Ar, or Het;

R 9 is alkyl having one to four carbon atoms, Ar, Ar-alkyl wherein the alkyl moiety has one to four carbon atoms, or Het;

R10 is alkyl containing one to four carbon atoms, fluorinated alkyl containing one to four carbon atoms (eg CF3), alkenyl containing three to six carbon atoms, alkynyl containing three to six carbon atoms (eg propynyl, pentenyl), whereas the alkyl, fluorinated alkyl, alkenyl or alkynyl groups are each unsubstituted or else substituted by Ar or Het (e.g. phenyl acetylene C6H5-C = C-), cycloalkyl containing three to seven carbon atoms, cycloalkenyl containing five to eight carbon atoms , cycloalkylalkyl containing four to seven carbon atoms, cycloalkenylalkyl containing six to nine carbon atoms, hydroxy alkyl containing two to four carbon atoms, fluorinated hydroxy alkyl containing two to four carbon atoms, monoalkylamino containing one to four carbon atoms, dialkylamino in which each alkyl group independently has one to four carbon atoms., NR 6 R 7, NR 2 R 8, Ar, or Het;

Ar is an aryl group containing six to ten carbon atoms which is unsubstituted or substituted one or more times by alkyl containing one to eight carbon atoms, alkoxy containing one to eight carbon atoms, halogen (F, Cl, Br or I, preferably F or Cl), dialkylamino wherein each of the alkyl moieties has one to eight carbon atoms, amino, cyano, hydroxyl, nitro, halogenated alkyl containing eight carbon atoms, halogenated alkoxy containing one to eight carbon atoms, hydroxy alkyl containing one to eight carbon atoms, hydroxy alkoxy containing two to eight carbon atoms, alkenyloxy containing three to eight carbon atoms, alkylthio containing one to eight carbon atoms, alkylsulfinyl containing one to eight carbon atoms, alkylsulfonyl containing one to eight carbon atoms carbon, monoalkylamino containing one to eight carbon atoms, cycloalkylamino wherein the cycloalkyl group has three to seven carbon atoms and is optionally substituted, ar wherein the aryl moiety contains six to ten carbon atoms (e.g. phenyl, naphthyl, biphenyl) and is optionally substituted arylthio wherein the aryl moiety contains six to ten carbon atoms (e.g. phenyl, naphthyl, biphenyl) and is optionally substituted cycloalkyloxy wherein the group cycloalkyl has three to seven carbon atoms and is optionally substituted, sulfo, sulfonylamino, acylamido (e.g. acetamido), acyloxy (e.g. acetoxy), or combinations thereof; Het is a heterocyclic group which is fully saturated, partially saturated or fully unsaturated, containing five to ten ring atoms wherein at least one ring atom is an atom of 0, 0 or S which is unsubstituted or substituted one or more times by halogen (F, Cl, Br or I, preferably F or Cl), having six to ten carbon atoms (e.g. phenyl, naphthyl, biphenyl) which is optionally substituted, alkyl containing one to eight atoms carbon, alkoxy containing eight carbon atoms, cycloalkyl containing three atoms carbon, cyano, trifluoromethyl, nitro, oxo, OH, alkoxy carbonyl alkyl containing three to eight carbon atoms, amino, monoalkylamino containing one to eight carbon atoms, dialkylamino wherein each alkyl group has one to eight carbon atoms, SO 2 R 11, -CXR 11, piperidinylethyl, or combinations thereof; Carbo is a partially unsaturated carbocyclic group containing five to fourteen carbon atoms, which is unsubstituted or substituted one or more times by halogen, alkyl containing one to eight carbon atoms, alkoxy containing one to eight carbon atoms, hydroxy, nitro, cyano, oxo, or combinations thereof (for example, indanyl, tetrahydronaphenyl, etc.); and

R11 is alkyl containing one to four carbon atoms, halogenated alkyl containing one to four carbon atoms (eg CF3), alkenyl containing three to six carbon atoms, alkynyl containing three to six carbon atoms (eg propynyl, pentenyl), whereas the alkyl, halogenated alkyl, alkenyl or alkynyl groups are each unsubstituted or substituted by Ar or Het (e.g. phenyl acetylene C6H5-C = C-), cycloalkyl containing three to seven carbon atoms, cycloalkenyl containing five to eight carbon atoms , cycloalkylalkyl containing four to seven carbon atoms, cycloalkenylalkyl containing six to nine carbon atoms, hydroxy alkyl containing two to four carbon atoms, fluorinated hydroxy alkyl containing two to four carbon atoms, monoalkylamino containing one to four carbon atoms, dialkylamino in which each alkyl group independently has one to four carbon atoms, or Ar;

and pharmaceutically acceptable salts or solvates (e.g. hydrates) or N-oxides thereof, or pharmaceutically acceptable salts thereof solvates, or pharmaceutically acceptable salts or solvates of their N-oxides.

According to another aspect of the compound and / or method of the invention, the compound is selected from Formulas I, II, III or IV: <formula> formula see original document page 19 </formula>

on what

A is

<formula> formula see original document page 19 </formula>

X is 0 OR S;

each of X1 to X4 is independently N, CH, CR1, or C-, where C- represents the point of attachment of the group A of the structure of formulas (I), (II), (III) or ( IV) (e.g., each of X1, X2, X3 and X4 is CH or CR1, and group A is joined at position 3 to the remainder of the structure of formulas (I), (II), (III) or (IV), each of X1, X2 and X3 is CH or CR1, X4 is N, and group A is attached at position 3 to the remainder of the structure of formulas (I), (II), (III) or (IV), each of X1, X2 and X4 is CH or CR1, X3 is N, and group A is joined in position 3 to the remainder of the structure of formulas (I), (II), (III) or (IV), or each of X1, X3 and X4 is CH or CR1, X2 is N, and group A is attached at position 3 to the remainder of the structure of formulas (I), (II), (III) or (IV);

each of X5 to X8 is independently N, CH, CR3, or C-, where C- represents the point of attachment of the group A of the structure of formulas (I), (II), (III) or ( IV) (for example, each of X5, X6 and X8 is CH or CR3 and X7 is C-, whereby group A is joined at its 5 position along the structure of formulas (I), (II), (III) or (IV), or each of X5, X7 and X8 is CH or CR3 and X6 is C-, whereby group A is joined at its 6 position to the remainder of the structure of formulas (I), (II ), (III) or (IV)), each of X9 to X12 is independently N, CH, CR4, or C-, where C- represents the point of attachment of group A to the remainder of the structure of formulas (I ), (II), (III) or (IV) (for example, each of X9, X10, X11 and X12 is CH or CR4, and group A is joined at position 3 to the remainder of the structure of formulas (I), ( II), (III) or (IV), each of X9, X10 and X11 is CH or CR4, X12 is N, and group A is joined at position 3 of the structure of formulas (I), (II), ( III) the u (IV), or each of X9, X10 and X12 is CH or CR4, X11 is N, and group A is joined at position 3 to the remainder of the structure of formulas (I), (II), (III) or ( IV), or each of X9, X11 and X12 is CH or CR4, X10 is N, and group A is joined at position 3 to the remainder of the structure of formulas (I), (II), (III) or (IV); each of X13 to X16 is independently N, CH, CR, or C-, where C- represents the point of attachment of group A to the remainder of the structure of formulas (I), (II), (III) or ( IV) (for example, each of X13, X14, X15 and X16 is CH or CR, and group A is joined at position 3 to the remainder of the structure of formulas (I), (II), (III) or (IV), each of X13, X14 and X15 is CH or CR, X16 is N, and group A is joined at the 3-position of the structure of formulas (I), (II), (III) or (IV), or each of X13, X14 and X16 is CH or CR, X15 is N, and group A is joined at position 3 to the remainder of the structure of formulas (I), (II), (III) or (IV), or each of X13, X15 and X16 is CH or CR, X14 is N, and the gr A is joined at position 3 to the remainder of the structure of formulas (I), (II), (III) or (IV): R1 is ila, alkyl having one to four carbon atoms, halogenated alkyl having one to four carbon atoms cycloalkyl having three to seven carbon atoms, or cycloalkylalkyl having four to seven carbon atoms;

R is H, F, Cl, Br, I, OH, CN, COH, NR6R7, Carboxy, CONR6R7, NR2COR8, NR2COOR8, NR2CSR8, NR2CONR2R9, NR2CSNR2R9, NR2CONR6R7, NR2R6N, NR2R6 C1-6-alkyl-0) 1-2-C1-6-alkyl, NR2-C1-6-alkyl-NR6R7, NR2-C1.6-alkyl-CONR6R7, NR2-CO-C1-6-alkyl-Ar, NR2-C1-6-alkyl-C0-0-R2, NR2-C1-6-N2-C1-6-alkyl-NR2 (C0-0-R2) -NR2 (CO-O-R2), -C1-6 -alkyl-NR2, -0-C1-6-alkyl-NR6R7, alkyl having one to four carbon atoms, fluorinated alkyl having one to four carbon atoms (e.g. CF3), alkenyl having two to six carbon atoms, alkynyl having from two to six carbon atoms (eg, ethinyl, propynyl, pentenyl), wherein the alkyl, fluorinated alkyl, alkenyl or alkynyl groups are in each case unsubstituted or substituted by Ar or Het (eg phenylacetylene C6H5-C = C -), cycloalkyl having three to seven carbon atoms, cycloalkenyl having five to eight carbon atoms which is unsubstituted or substituted by HCO-, Cl -6-alkoxy, NR6R7, CO-NR6R7, C2.6-alkoxycarbonyl, or -CO-R10, cycloalkylalkyl having four carbon atoms, cycloalkenylalkyl having six to one carbon atoms, alkoxy having one to four carbon atoms ( OCH3), cycloalkoxy having three to seven carbon atoms, cycloalkylalkoxy having four to seven carbon atoms (e.g. cyclopropyl methoxy), alkylthio having one to four carbon atoms (e.g. SCH3), fluorinated alkoxy having one to four carbon atoms (e.g. OCF3, OCHF2), alkyl hydroxy having one to four carbon atoms, fluorinated alkyl hydroxy having one to four carbon atoms (e.g. 2,2,2-trifluoro-1-hydroxyl-1 - (trifluoromethyl) ethyl), hydroxy alkoxy having two to four carbon atoms, fluorinated alkoxy hydroxy having two to four carbon atoms, monoalkylamino having one to four carbon atoms, dialkylamino wherein each alkyl group independently has one to four atoms carbon atoms, carbonyl alkoxy having two to six carbon atoms, Ar, Het, OAr ,. OHet, Carbo-O, Ar-C 1-6 alkyl-O-, Het-C 1-6 alkyl-O-, Het-CO-Het-, Het-C 1-6 alkyl-NR 2 -, or Ar-C 1 .6-alkyl-Het-O-,

provided that R is not NH2; or

R is one of the following formulas

<formula> formula see original document page 22 </formula>

η ranges from 2 to 4;

m ranges from 3 to 5; or

two Rs may together form a fused five membered ring structure containing at least one N atom;

R1 is H, F, Cl, Br, I, OH, CN, nitro, NH2, C0H, NR6R7, Carboxy, CONR6R7, NR2COR8, NR2COOR8, NR2CSR8, NR2CONR2R9, NR2SO2R10, NR2R6, NR2R6, NR2R6, NR2 -O- (C1- and alkyl-O) 1.2-C1.6-alkyl, NR2-C1.6-alkyl-NR6R7, NR2-C1.6-alkyl-1-CONR6R7, NR2-CO-C1.6-alkyl 1 - Ar, NR2 - C1.6 - alkyl-1-CO-O-R2, NR2-C1-6-alkyl-NR2 (CO-O-R2), -C1-and-alkyl-NR2, -O-C1-4 -alkyl1-NR6R7, alkyl containing one to four carbon atoms, fluorinated alkyl containing one to four carbon atoms (eg CF3), alkenyl containing two to six carbon atoms (eg ethinyl, propynyl, pentenyl), alkynyl containing two to six carbon atoms, wherein the alkyl, fluorinated alkyl, alkenyl or alkynylation groups are in each case unsubstituted or substituted by Ar or Het (e.g. phenyl acetylene C6H5-C = C -), cycloalkyl containing three to seven carbon atoms. carbon, cycloalkenyl containing five to eight carbon atoms, aqual is unsubstituted or substituted by HCO-, C 1-6 alkoxy, NR 6 R 7, CO-NR 6 R 7, C 2-6 alkoxycarbonyl, or -CO-R 10 cycloalkylalkyl containing four to seven carbon atoms, cycloalkenylalkyl containing six to nine carbon atoms, alkoxy containing one to four carbon atoms (eg OCH3), cycloalkoxy containing three to seven carbon atoms, cycloalkylalkoxy containing four to seven carbon atoms (eg cyclopropyl methoxy), alkylthio containing one to four carbon atoms (eg , SCH3), alkoxyfluoride containing one to four carbon atoms (eg OCF3, OCHF2), alkyl hydroxy containing one to four carbon atoms, fluorinated alkyl hydroxy containing one to four carbon atoms (eg 2,2,2-trifluoro -1-hydroxyl-1- (trifluoromethyl) ethyl), hydroxy alkoxy containing four to four carbon atoms, fluorinated alkoxy hydroxy containing two to four carbon atoms, monoalkylamino containing one to four carbon atoms, dialkylamino Alkyl group independently has one to four carbon atoms, alkoxycarbonyl containing two to six carbon atoms, Ar, Het, OAr, OHet, Carbo-O, Ar-C1-6-alkyl-O-, Het-C1-6-alkyl- O-, Het-CO-Het-, Het-C1.6-alkyl-NR2-, or Ar-C1.6-alkyl-Het-O-; or

R1 is one of the following formulas

<formula> formula see original document page 23 </formula> Or two R1 may together form a five membered fused ring structure containing at least one atom of N; R2 is H, alkyl containing one to four carbon atoms, fluorinated alkyl containing one. four to seven carbon atoms, cycloalkyl containing three to seven carbon atoms, cycloalkylalkyl containing four to seven carbon atoms, C 1-4 alkyl-CO-fluorinated, C 3-7 cycloalkyl-CO-, C 1-4 alkyl-NHCO -, C 3-7 -cycloalkyl-NH-CO-, Het, Ar-C 1-4 -alkyl-, Ar-C 1-4 -alkyl-CO-, Ar-C 1-4-alkyl-SO 2, C 1-4 O-C 1-4 alkyl-alkyl (e.g. CH 2 CH 2 -O-CH 3) or Ar-C 1-4 alkyl-NH-CO- R 3 is H, F, Cl, Br, I, OH, CN, Nitro, NH2, COH, NR6R7, Carboxy, CONR6R7, NR2COR8, NR2COOR8, NR2CSR8, NR2CONR2R9, NR2CSNR2R9, NR2SO2R10, NR2CRNR6, NR2-R6-R2 .6-alkyl, NR2-C1-6-alkyl-NR6R7, NR2-C1-6-alkyl-CONR6R7, NR2-CO-C1-6-alkyl-Ar, NR2-C1-6-alkyl-CO-O-R2 , NR 2 -C 1-6 alkyl-NR 2 (CO-O-R 2), -C 1 -S-alkyl yl-NR 2, -0-C 1-6 -alkyl-NR 6 R 7, alkyl containing one to four carbon atoms, fluorinated alkyl containing one to four carbon atoms (e.g. CF3), alkenyl containing two to six carbon atoms (for example , ethinyl, propynyl, pentenyl), alkynyl containing two to six carbon atoms, wherein the alkyl, fluorinated alkyl, alkenyl or alkynylation groups are in each case unsubstituted or substituted by Ar or Het (eg phenyl acetylene C6H5-C = C -), cycloalkyl containing three to seven carbon atoms, cycloalkenyl containing five to eight carbon atoms, which is unsubstituted or otherwise substituted by HCO-, C1-6 alkoxy, NR6R7, CO-NR6R7, C2-6-alkoxycarbonyl, or -CO-R10, cycloalkylalkyl containing four to seven carbon atoms, cycloalkenylalkyl containing six to nine carbon atoms, alkoxy containing one to four carbon atoms (e.g. OCH3), cycloalkoxy containing three to seven carbon atoms, cycloalkylalkoxy containing four to seven carbon atoms (e.g. cyclopropyl methoxy), alkylthio containing one to four carbon atoms (e.g. SCH3), alkoxyfluoride containing one to four carbon atoms (eg OCF3, OCHF2), alkyl hydroxy containing one to four carbon atoms. carbon, hydroxy fluorinated alkyl containing one to four carbon atoms (eg 2,2,2-trifluoro-1-hydroxyl-1- (trifluoromethyl) ethyl), hydroxy alkoxy containing two to four carbon atoms, fluorinated alkoxy hydroxy containing two to four carbon atoms, monoalkylamin containing one to four carbon atoms, dialkylamino in each alkyl group independently has one to four carbon atoms, alkoxycarbonyl containing two to six carbon atoms, Ar, Het, OAr, OHet, Carbo-0, Ar-C1- 6-alkyl-O-, Het-C1-6-alkyl-O-, Het-CO-Het-, Het-C1-6-alkyl-NR2-, or Ar-C1-6-alkyl-Het-O-; or

R3 is one of the following formulas

<formula> formula see original document page 25 </formula>

or two R 3 may together form a fused five membered ring structure containing at least one N atom;

R4 is H, F, Cl, Br, I, OH, CN, Nitro, NH2, COH, NR6R7, Carboxy, CONR6R7, NR2COR8, NR2COOR8, NR2CSR8, NR2CONR2R9, NR2SO2R10, NR2R6, NR2R6, NR2R7 -O- (C1-6-alkyl-0) 1-2-C1-6-alkyl, NR2-C1-6-alkyl-NR6R7, NR2-C1-6-alkyl I-CONR6R7, NR2-CO-C1-6 -alkyl-Ar, NR2-C1-6-alkyl-CO-O-R2, NR2-C1-6-alkyl-NR2 (CO-O-R2), -C1-6-alkyl-NR2, -0-C1- 6-alkyl-NR6R7, alkyl containing one to four carbon atoms, fluorinated alkyl containing one to four carbon atoms (eg CF3), alkenyl containing two to six carbon atoms (eg ethinyl, propynyl, pentenyl), alkynyl containing two to six carbon atoms, wherein the alkyl, fluorinated alkyl, alkenyl or alkynyl groups are in each case unsubstituted or substituted by Ar or Het (e.g. phenyl acetylene C6H5-C≡C-), cycloalkyl containing three to seven carbon atoms, cycloalkenyl containing five to eight carbon atoms which is unsubstituted or otherwise substituted HCO-, C 1-6 alkoxy, NR 6 R 7, CO-NR 6 R 7, C 2-6 alkoxycarbonyl, or -CO-R 10 cycloalkylalkyl containing four to seven carbon atoms, cycloalkenylalkyl containing six to nine carbon atoms, alkoxy containing one to four carbon atoms (eg OCH3), cycloalkoxy containing three to seven carbon atoms, cycloalkylalkoxy containing four to seven carbon atoms (e.g. cyclopropyl methoxy), alkylthio contained four carbon atoms (e.g. SCH3), alkoxyfluoride containing one to four carbon atoms (eg, OCF3, OCHF2), alkyl hydroxy containing one to four carbon atoms, fluorinated alkyl hydroxy containing one to four carbon atoms (eg 2,2,2-trifluoro-1-hydroxyl-1- (trifluoromethyl ) ethyl), hydroxy alkoxy containing four to four carbon atoms, fluorinated alkoxy hydroxy containing two to four carbon atoms, monoalkylamin containing one to four carbon atoms, dialkylamino in which any alkyl group has in dependently one to four carbon atoms, alkoxycarbonyl containing two to six carbon atoms, Ar, Het, OAr, OHet, Carbo-0, Ar-C 1-6 alkyl-O, Het-C 1-6 alkyl-O, Het-CO-Het-, Het-C1-6-alkyl-NR2-, or Ar-C1-6-alkyl-Het-O-; or

R4 is one of the following formulas or two R4 may together form a five membered fused ring structure containing at least one N atom;

R5 is H, F, Cl, Br, I, OH, CN, nitro, NH2, carboxy, CONR6R7, NR2COR8, NR2CSR8, NR2CONR2R9, NR2SO2R10, NR2CONR6R7, NR2CSNR6R7, NR2CSNR6R7, NR2C10, NR2R10, NR2, R6, R6 carbon, fluorinated alkyl containing one to four carbon atoms (eg CF3), alkenyl containing two to six carbon atoms (eg ethinyl, propynyl, pentenyl), alkynyl containing two to six carbon atoms, wherein alkyl, alkyl fluoridated, alkenyl or alkynyl are in each case unsubstituted or then substituted by Ar or Het (eg phenylacetylene C6H5-C = C-), cycloalkyl containing three to seven carbon atoms, cycloalkenyl containing five to eight carbon atoms, which is not substituted or substituted by HCO-, C1-6-alkoxy, NR6R7, CO-NR6R7, C2-6-alkoxycarbonyl, or -CO-R10, cycloalkylalkyl containing four carbon atoms, cycloalkenylalkyl containing six one carbon atoms, alkoxy containing one at four carbon atoms (e.g. OCH3), cycloalkoxy containing three to seven carbon atoms, cycloalkylalkoxy containing four to seven carbon atoms (eg cyclopropyl methoxy), alkylthio containing one to four carbon atoms (eg SCH3), fluorinated alkoxy containing one to four carbon atoms (e.g. OCF3, OCHF2), alkyl hydroxy containing one to four carbon atoms, alkyl fluorinated hydroxy containing one to four carbon atoms (e.g. 2,2,2-trifluoro-1-hydroxyl-1- (trifluoromethyl ) ethyl), alkoxy hydroxy containing two to four carbon atoms, fluorinated alkoxy hydroxy containing two to four carbon atoms, monoalkylamino containing one to four carbon atoms, dialkylamino wherein each alkyl group independently has one to four carbon atoms, alkoxycarbonyl containing two to four carbon atoms six carbon atoms, Ar, Het, OAr or OHet;

each of R 6 and R 7 is independently H, alkyl containing one to four carbon atoms, alkoxyalkyl containing two to eight carbon atoms, cycloalkyl containing three to seven carbon atoms; or cycloalkylalkyl containing four to seven carbon atoms, or R 6 and R 7 are together an alkylene group containing four to six carbon atoms forms a ring of the N atom (e.g., pipridinyl, pyrrolidinyl);

R8 is H, alkyl containing one to four carbon atoms, fluorinated alkyl containing one to four carbon atoms (eg CF3), alkenyl containing three to six carbon atoms, alkynyl containing three to six carbon atoms (eg propynyl, pentenyl) wherein the alkyl, fluorinated alkyl, alkenyl or alkynyl groups are each unsubstituted or substituted by Ar or Het (e.g. phenyl acetylene C6H5-CsC-), cycloalkyl containing three to seven carbon atoms, cycloalkenyl containing five to eight carbon atoms , cycloalkylalkyl containing four to seven carbon atoms, cycloalkenylalkyl containing six to nine carbon atoms, hydroxy alkyl containing one to four carbon atoms, fluorinated hydroxy alkyl containing one to four carbon atoms, monoalkylamino containing one to four decarbon atoms, dialkylamino each alkyl group independently has one to four carbon atoms, Ar, or Het; R 9 is alkyl which has an aq four carbon atoms, Ar, Ar-alkyl wherein the alkyl moiety has one to four carbon atoms, or Het;

R10 is alkyl containing one to four carbon atoms, fluorinated alkyl containing one to four carbon atoms (eg CF3), alkenyl containing three to six carbon atoms, alkynyl containing three to six carbon atoms (eg propynyl, pentenyl), whereas the alkyl, fluorinated alkyl, alkenyl or alkynyl groups are in each case unsubstituted or substituted by Ar or Het (e.g. phenyl acetylene C6H5-C = C-), cycloalkyl containing three to seven carbon atoms, cycloalkenyl containing five to eight carbon atoms. carbon, cycloalkylalkyl containing four to seven carbon atoms, cycloalkenylalkyl containing six to nine carbon atoms, hydroxy alkyl containing two to four carbon atoms, fluorinated hydroxy alkyl containing two to four carbon atoms, monoalkylamino containing one to four carbon atoms, dialkylamino each alkyl group independently has one to four carbon atoms, NR 6 R 7, NR 2 R 8, Ar, or Het;

Ar is an aryl group containing six to ten carbon atoms, which is unsubstituted or substituted one or more times by alkyl containing one to eight carbon atoms, alkoxy containing one to eight carbon atoms, halogen (F, Cl, Br or I, preferably F or Cl), dialkylamino in which one of the alkyl moieties has one to eight carbon atoms, amino, cyano, hydroxyl, nitro, halogenated alkyl containing from eight carbon atoms, halogenated alkoxy containing one to eight carbon atoms, hydroxy alkyl containing one to eight carbon atoms, hydroxy alkoxy containing two to eight carbon atoms, alkenyloxy containing three to eight carbon atoms, alkylthio containing one to eight carbon atoms, alkylsulfinyl containing one to eight carbon atoms, alkylsulfonyl containing one to eight atoms monoalkylamino containing one to eight carbon atoms, cycloalkylamino wherein the cycloalkyl group has three to seven carbon atoms and is optionally substituted ar wherein the aryl moiety contains six to ten carbon atoms (e.g. phenyl, naphthyl, biphenyl) and is optionally substituted arylthio wherein the aryl moiety contains six to ten carbon atoms (e.g. phenyl, naphthyl, biphenyl) and is optionally substituted cycloalkyloxy wherein the group cycloalkyl has three to seven carbon atoms and is optionally substituted, sulfo, sulfonylamino, acylamido (e.g. acetamido), acyloxy (e.g. acetoxy), or combinations thereof;

Het is a heterocyclic group which is fully saturated, partially saturated or fully unsaturated containing five to ten ring atoms wherein at least one ring atom is a Ν, 0 or S atom which is unsubstituted or substituted one or more. more often by halogen (F, Cl, Br or I, preferably F or Cl), aryl containing six to ten carbon atoms (e.g. phenyl, naphthyl, biphenyl) which is optionally substituted, alkyl containing one to eight carbon atoms, alkoxy containing eight carbon atoms, cycloalkyl containing three atoms, carbon, cyano, trifluoromethyl, nitro, oxo, OH, alkoxy carbonyl alkyl containing three to eight carbon atoms, amino, monoalkylamino containing one to eight carbon atoms, dialkylamino wherein each alkyl group has one to eight carbon atoms, SO 2 R 11, -CXR 11, piperidinylethyl, or combinations thereof;

Carbo is a partially unsaturated carbocyclic group containing five to fourteen carbon atoms, which is unsubstituted or substituted one or more times by halogen, alkyl containing one to eight carbon atoms, alkoxy containing one to eight carbon atoms, hydroxy, nitro, cyano oxo, or combinations thereof (for example, indanyl, tetrahydronaphthyl, etc.); and

R11 is alkyl containing one to four carbon atoms, halogenated alkyl containing one to four carbon atoms (eg CF3), alkenyl containing three to six carbon atoms, alkynyl containing three to six carbon atoms (eg propynyl, pentenyl), whereas the alkyl, halogenated alkyl, alkenyl or alkynyl groups are each unsubstituted or otherwise substituted by Ar or Het (e.g. phenyl acetylene C6H5-C = C-), cycloalkyl containing three to seven carbon atoms, cycloalkenyl containing five to eight carbon atoms. carbon, cycloalkylalkyl containing four to seven carbon atoms, cycloalkenylalkyl containing six to nine carbon atoms, hydroxy alkyl containing two to four carbon atoms, fluorinated hydroxy alkyl containing two to four carbon atoms, monoalkylamino containing one to four carbon atoms, dialkylamino in that each alkyl group independently has one to four carbon atoms, or Ar;

and their pharmaceutically acceptable salts or solvates (e.g. hydrates) or N-oxides, or pharmaceutically acceptable salts thereof solvates, or pharmaceutically acceptable salts or solvates of their N-oxides;

provided that the 1-azabicyclic group is in the form of a quaternary ammonium salt of the sub-formula:

wherein Z is alkyl having one to four carbon atoms (eg, methyl, ethyl, propyl), halogenated alkyl having one to four carbon atoms (eg chloromethyl, chloroethyl), cycloalkylalkyl having four to seven carbon atoms ( cyclopropylmethyl), or arylalkyl has seven to sixteen carbon atoms (e.g. benzyl), and anion A is, for example, iodide, bromide, chloride, triflate, tosylate, or mesylate.

According to a further aspect of the compound and / or method of the invention, the compound is selected from formulas I-IV, wherein:

R 2, if present, is H, alkyl having four carbon atoms, fluoridated alkyl having four carbon atoms, cycloalkyl having three to seven carbon atoms, cycloalkyl alkyl having four to seven carbon atoms, C1-4 alkyl Fluorinated CO, C 3-7 -cycloalkyl-CO-, Cl-4-alkyl-NH-CO-, C 3-7-cycloalkyl-NH-CO-, Het, Ar-Cl-4-alkyl-, Ar-Cl- 4-C10-alkyl, Ar-Cl-4-alkyl-SO2, Cl-4-alkyl-O-Cl-4-alkyl- (e.g. CH2CH2-0-CH3), or Ar-Cl-4- alkyl-NH-CO-; and

Het is a heterocyclic group which is fully saturated, partially saturated or fully unsaturated containing five to ten ring atoms wherein at least one ring atom is an N, O or S atom which is unsubstituted or substituted one or more times. halogen, aryl that you are afraid of ten carbon atoms which is optionally substituted, alkyl that has one to eight carbon atoms, alkoxy that has one to eight carbon atoms, cycloalkyl that has three to seven carbon atoms, halogenated alkoxy that has one to eight carbon atoms, cycloalkoxy having three to seven carbon atoms, cycloalkylalkoxy having four to seven carbon atoms, alkyl (halogenated alkyl) amino at which each alkyl group has one to eight C atoms, di (alkylhalogenated) amino wherein each alkyl group has one to eight halogenated C (alkyl) amino atoms having one to eight carbon cyano, halogenated alkyl atoms having one eighteen carbon atoms, nitro, oxo, OH, carbonyl alkoxy alkyl having three to eight carbon atoms, amino, monoalkylamino having one to eight carbon atoms, dialkylamino wherein each alkyl group has one to eight C1 SO2R11, -CXR11, piperidinyl ethyl, or combinations thereof.

In formulas I-IV, group A, for example, an indazolyl, benzothiazolyl, benzoisothiazolyl, benzisoxazolyl, pyrazolo [3,4-b] pyridinyl, pyrazolo [4,3-c] pyridinyl group, or isothiazolo [5,4-b ] pyridinyl, may be attached to the rest of the structure through some appropriate point of attachment.

In formula I, when A is an indazolyl group dasub-formula (a), it is preferably attached to the remainder of the compound through its 3, 4 or 7 position, particularly through position 3. When A is a benzothiazolyl group dasub-formula (b) ), it is preferably attached to the remainder of the compound by its 4 or 7 position. When A is a benzoisothiazolyl group of sub-formula (c), it is preferably unidifferent to the remainder of the compound by suppression 3, 4 or 7, particularly through Position 3. When A is a benzisoxazolyl group of sub-formula (d), it is preferably joined to the remainder of the compound by superseding 3, 4 or 7, particularly through position 3.

Similarly, in formula II, when A is an indazolyl group of sub-formula (a), it is preferably attached to the compound of the compound through its 3, 4 or 7 position, particularly through position 3. When A is a group-benzothiazolyl of the sub-formula formula (b), it is preferably unidifferent to the remainder of the compound by suppression 4 or 7. When A is a benzoisothiazolyl group of sub-formula (c), it is preferably attached to the remainder of the compound by its 3, 4 or 7 position, particularly through position 3. When A is a benzisoxazolyl group of the formula (d), it is preferably attached to the remainder of the composition through its position 3, 4 or 7, particularly through position 3.

Furthermore, in formula III, when A is an indazolyl group of sub-formula (a), it is preferably attached to the compound of the compound through its 3, 4 or 7 position, particularly through position 3. When A is a group-benzothiazolyl of the sub-formula. It is preferably unidifferent to the remainder of the compound by suppressing 4 or 7. When A is a benzoisothiazolyl group of sub-formula (c), it is preferably attached to the remainder of the compound by its position 3, 4 or 7. 7, particularly through position 3. When A is a benzisoxazolyl group of the formula (d), it is preferably attached to the remainder of the composition through its position 3, 4 or 7, particularly through position 3.

Additionally, in formula IV, when A is an indazolyl group of sub-formula (a), it is preferably attached to the compound via its 3, 4 or 7 position, particularly via position 3. When A is a group-benzothiazolyl of the sub-formula. It is preferably unidifferent to the remainder of the compound by suppression 4 or 7. When A is a benzoisothiazolyl group of sub-formula (c), it is preferably attached to the remainder of the compound by its 3, 4 or 7 position. , particularly through position 3. When A is a benzisoxazolyl group of the formula (d), it is preferably attached to the remainder of the composition through its position 3, 4 or 7, particularly through position 3.

The following sub-formulas illustrate some preferred linkages between groups A, for example indazole, benzothiazole, benzoisothiazole, benzisoxazole, pyrazolo [3,4-b] pyridinyl, pyrazolo [3,4-c] pyridine, pyrazolo [4,3 -c] pyridinyl, and isothiazolo [5,4-b] pyridinyl, and the remainder of the structure for formula I. In each of the following sub-formulas, the substituent R 7 R 1, R 3 and / or R 4 is generally one, two or three times, preferably once or twice, and most preferably once.

<formula> formula see original document page 35 </formula> <formula> formula see original document page 36 </formula>

The following sub-formulas illustrate some preferred linkages between groups A, for example indazole, benzothiazole, benzoisothiazole, benzisoxazole, pyrazolo [3,4-b] pyridinyl, pyrazolo [3,4-c] pyridine, pyrazolo [4,3 -c] pyridinyl, and isothiazolo [5,4-b] pyridinyl, and the remainder of the structure for formula II. In each of the following sub-formulas, the substituent R, R1, R3 and / or R4 is generally present once, twice or three times, preferably once or twice, and most preferably once.

<formula> formula see original document page 36 </formula> <formula> formula see original document page 37 </formula> <formula> formula see original document page 38 </formula>

The following sub-formulas illustrate some preferred linkages between groups A, for example indazole, benzothiazole, benzoisothiazole, benzisoxazole, pyrazolo [3,4-

b] pyridinyl, pyrazolo [3,4-c] pyridine, pyrazolo [4,3-

c] pyridinyl, and isothiazolo [5,4-b] pyridinyl, and the remainder of the structure for formula III. In each of the following sub-formulas, the substituent R, R1, R3 and / or R4 is generally present once, twice or three times, preferably once or twice, and most preferably once.

<formula> formula see original document page 38 </formula> <formula> formula see original document page 39 </formula> The following sub-formulas will illustrate some of the preferred linkages between groups A, for example indazole, benzothiazole, benzoisothiazole, benzisoxazole , pyrazolo [3,4-b] pyridinyl, pyrazolo [3,4-c] pyridine, pyrazolo [4,3-c] pyridinyl, and isothiazolo [5,4-b] pyridinyl, and the remainder of the structure for formula IV . In each of the following sub-formulas, the substituent R, R1, R3 and / or R4 is generally present once, twice or three times, preferably once or twice, and most preferably once. <formula> formula see original document page 41 </formula>

In all cases, X is preferably 0.

In all cases, R 1 is preferably H, cyclopropyl methyl or CH 3, particularly H. Alkyl throughout refers to a straight chain or branched chain aliphatic hydrocarbon radical having one to eight carbon atoms, preferably one to four carbon atoms. Suitable alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl.

Alkenyl throughout refers to a straight chain or branched chain aliphatic hydrocarbon radical preferably having from two to six carbon atoms. Suitable alkenyl groups include, but are not limited to, ethenyl, propenyl, butentyl epentenyl.

Alkynyl7 is a straight chain or branched chain aliphatic hydrocarbon radical preferably having from two to six carbon atoms. Suitable alkynyl groups include, but are not limited to, etino, propine, butino, etc.

Alkoxy refers to alkyl-O- groups wherein the alkyl moiety has one to eight carbon atoms, preferably one to four carbon atoms. Suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, isobutoxy and sec-butoxy.

Alkoxy alkoxy refers to alkyl-O-alkyl- groups wherein each alkyl moiety independently has one to eight carbon atoms, preferably one to four carbon atoms. Suitable alkyl alkoxy groups include, but are not limited to, methoxy methyl, ethoxy methyl and ethoxy ethyl.

Alkylthio refers to alkyl-S- groups wherein the alkyl moiety preferably has one to four carbon atoms. Suitable alkylthio groups include, but are not limited to, methylthio and ethylthio. Cycloalkyl refers to a saturated cyclic, bicyclic or tricyclic hydrocarbon radical of the saturated that has three to seven carbon atoms. Suitable cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Other suitable cycloalkyl groups include, but are not limited to, spiropentyl, bicyclo [2.1.0] pentyl and bicyclo [3.1.0] hexyl.

Cycloalkoxy refers to cycloalkyl-O- groups wherein the cycloalkyl moiety is preferably a cyclic, bicyclic or tricyclic saturated hydrocarbon radical having from three to seven carbon atoms.

Cycloalkylalkyl groups contain four to seven carbon atoms. Suitable cycloalkylalkyl groups include, but are not limited to, for example, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl and cyclopentylmethyl.

Cycloalkylalkoxy groups contain four to seven carbon atoms. Suitable cycloalkylalkoxy groups include, but are not limited to, for example, cyclopropyl methyloxy, cyclopropyl ethyloxy, cyclobutyl methyloxy and cyclopentyl methyloxy.

The cycloalkyl and cycloalkylalkyl structures may be substituted, for example, by C1-4-alkyl, C1-4-alkoxy, hydroxyl, amino, monoalkylamino having one to four carbon atoms, and / or dialkylamino wherein each alkyl group has one to four atoms of carbon.

Aryl as a group or a substituent per se or as part of a group or substituent (for example, Ar, OAr, Ar-C 1-6 alkyl-O- or Ar-C 1-6 alkyl-Het-O- ) refers to an aromatic carbocyclic radical containing six to ten carbon atoms unless otherwise indicated. Suitable aryl groups include, but are not limited to, phenyl, naphthyl and biphenyl. Substituted aryl groups include the above-described aryl groups which are substituted one or more times by halogen, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl alkylthio, alkylsulphinyl, alkylsulphonyl, phenoxy and acyloxy (e.g. acetoxy).

Heterocyclic groups (for example, the Het portions of Het, OHet, Het-C 1-6 alkyl-O-, Het-CO-Het- and Het-C 1-6 alkyl-NR 2) refer to saturated heterocyclic groups, partially saturated and fully unsaturated having one, two or three rings and a total number of five to ten atoms wherein at least one of the ring atoms is an N, O or S atom. Preferably, the heterocyclic group contains one to three atoms. hetero-ring selected from N, 0 and S. The saturated and partially saturated heterocyclic groups include but are limited to dihydropyranyl, tetrahydropyranyl, tetrahydrofuranoyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, morpholinyl, isoxazolinyl, and the like. Suitable heteroaryl groups include, but are not limited to, furyl, thienyl, thiazolyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, indolyl, quinolinyl, isoquinolinyl, naphthyridinyl, and the like. Other examples of suitable heterocyclic groups include 2-furyl, 3-furyl, 2-quinolinyl, 1,3-benzodioxyl, 2-thienyl, 3-thienyl, 1,3-thiazoli-2-yl, 1,3-oxazol-2-yl , pyrrolidin-1-yl, 6-pyrrolidin-1-yl, piperidin-1-yl, 6-piperazin-1-yl, morpholin-4-yl, 2-benzofuranyl, 2-benzothiophenyl, 3-thienyl, 2,3 -dihydro-5-benzofuranyl, 4-indole, 4-pyridyl, 3-quinolinyl, 4-quinolinyl, 1,4-benzodioxan-6-yl, 3-indole, 2-pyrrolyl, tetrahydro-2H-pyran-4-yl 3,6-dihydro-2H-pyran-4-yl, 5-indolyl, 1,5-benzoxepin-8-yl, 3-pyridyl, 6-coumarinyl, 5-benzofuranyl, 2-isoimidazol-4-yl, 3 -pyrazolyl, e3-carbazolyl, hexahydropyrrolo [1,2-a] pyrazin-2- (1H) -yl, octahydro-6H-pyrrolo [3,4-b] pyridin-6-yl, and 1,4-diazepan-2-one 1-ila.

Heterocyclic groups also include substituted and unsubstituted azabicyclo and oxazabicyclic groups, for example 2,5-diazabicyclo [2.2.1] hept-2-yl, methyl-2,5-diazabicyclo [2.2.1] hept-2-yl trifluoroethyl-2,5-diazabicyclo [2.2.1] hept-2-yl, 2-oxa-5-azabicyclo [2.2.1] hept-yl, 5-methyl-2,5-diazabicyclo [2.2.1] hept -2-yl, 1,4-diazabicyclo [3.2.2] ηοη-4-yl, 5-methyl-2,5-diazabicyclo [2.2.2] oct-2-yl, 8-methyl-3,8-diazabicyclo [3.2.1] oct-3-yl, 5-cyclopropyl-2,5-diazabicyclo [2.2.1] hept-2-yl, and 5- (cyclopropylcarbonyl) -2,5-diazabicyclo [2.2.1] heptyl 2-ila.

Substituted heterocyclic groups refer to the heterocyclic groups described above which are substituted at one or more sites, for example, by halogen, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino and / or dialkylamino. Suitable substituted heterocyclic groups include 2-methylpiperazin-1-yl, 3-methylpiperazin-1-yl, 4-methylpiperazin-1-yl, 3,4-dimethylpiperazin-1-yl, 4-methyl-1,4-diazepan-1 -yl, 3-methoxypyrrolidin-1-yl, 1-methylpyrrolidin-3-yl, 1-methyl-4,5-dihydro-1H-imidazol-2-yl, 3- (cyclopropylmethoxy) pyrrolidin-1-yl, 6- chloroisothiazolo [5,4-b] pyridinyl, 4- (cyclopropylcarbonyl) piperazin-1-yl, and 1- (cyclopropylcarbonyl) octahydro-6H-pyrrolo [3,4-b] pyridin-6-yl.

The substituted radicals in each case are substituted one or more times, and preferably have one to three substituents, especially one to two substituents, of the exemplified substituents. These substituents are each independently selected. Thus, the substituents may be the same or different. Halogenated radicals, such as halogenated alkyls, are preferably fluorinated and include, but are not limited to, perhalo radicals such as trifluoromethyl.

According to another aspect of the compound and / or method of the invention, R is not NH 2 or NHCH 3. According to a further aspect of the invention, R is not NH 2, NHCH 3, or N (CH 3) 2. According to a further aspect of the invention, R is not NH 2, monoalkylamino, or dialkylamino.

According to one aspect of the compound and / or method of the invention, R 2 is Het-NH-CO-. According to another aspect of the compound and / or method of the invention, when R2 is Het-NH-CO-, the Het group is preferably an azabicyclo group, for example 1-azabicyclo [2.2.2] oct-3-yl. .

According to one aspect of the compound and / or method of the invention, Het is substituted by cycloalkylalkyl having from four to seven carbon atoms (e.g., cyclopropylamethyl). According to another aspect of the compound and / or method of the invention, when Het is substituted by cycloalkylalkyl, the cycloalkyl moiety preferably has three to five carbon atoms (e.g. cyclopropyl), and the alkyl moiety preferably has one or two carbon atoms. Additionally, the Het group is preferably an azabicyclo group, for example 2,5-diazabicyclo [2.2.1] hept-2-yl.

According to a further aspect of the compound and / or method of the invention, Het is a heterocyclic group which is fully saturated, partially saturated or fully unsaturated containing five to ten ring atoms wherein at least one ring atom is an N atom. O or S, and which is substituted wherein at least one of the substituents is alkoxyhalogen containing one to eight carbon atoms (e.g. OCHF2), cycloalkoxy having three to seven carbon atoms, cycloalkylalkoxy having four to seven carbon atoms. carbon (e.g. cyclopropyl methyloxy), cycloalkylalkyl having four to seven carbon atoms (e.g. cyclopropylmethyl), halogenated alkyl other than trifluoromethyl (e.g. halogenated alkyl having two to eight or three to eight carbon atoms such as trifluoroethyl (trifluoropropyl), alkyl alkoxy having two to eight carbon atoms (e.g. CH3OCH2), alkyl (alkylated halogen) amino wherein each alkyl group has one to one carbon atoms, di (halogenated alkyl) amino wherein each alkyl group has one to eight carbon atoms, or halogenated (alkyl) amino having one to eight carbon atoms.

According to a further aspect of the compound and / or method of the invention, the compound is selected from formulas I-IV wherein at least one group R, R 1, R 3, R 4 and R 5 is Het or OHet in which the Het group is selected, in each case substituted or unsubstituted azabicyclooctyl (eg 1-azabicyclo [2.2.2] oct-3-yl), oxa-azabicycloheptyl (eg 2-oxa-5-azabicyclo [2.2.1] heptyl), diazabicycloheptyl (e.g. 2,5-diazabicyclo [2.2.1] hept-2-yl, 5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl, trifluoroethyl-2,5-diazabicyclo [2.2. 1] hept-2-yl, and 5- (cyclopropylcarbonyl) -2,5-diazabicyclo [2.2.1] hept-2-yl) diazabicyclononyl (e.g. 1,4-diazabicyclo [3.2.2] ηοη-4- ila), diazabicyclooctyl (e.g. 5-methyl-2,5-diazabicyclo [2.2.2] oct-2-yl and 8-methyl-3,8-diazabicyclo [3.2.1] oct-3-yl), pyrazolyl dihydroimidazolyl, 1,4-diazepanyl (e.g. 1,4-diazepan-1-yl and 4-methyl-1,4-diazepan-1-yl), hexahydropyrrolopyrazinyl (e.g. hexahydropyrrolo [1,2-a] pyrazin-2 (I H) -yl), eoctahydropyrrolopyridinyl (e.g. 1- (cyclopropylcarbonyl) -octahydro-6H-pyrrolo [3,4-b] pyridin-6-yl).

According to a further aspect of the compound and / or method of the invention at least one of X1, X2, X3 and X4 is N, at least one of X5, X6, X7 and X8 is N; at least one of X9, X10, X11 and X12 is N; and / or at least one of X13, X14, X15 and X16 is N. According to a further embodiment of this aspect of the invention, at least one of X1, X2, X3 and X4 is N, and one or two of the remaining X1-X4 are CR1. . According to an additional embodiment of this aspect of the invention, at least one of X5, X6, X7 and X8 is N, and one or two of the remaining X5-X8 are CR3. According to a further embodiment of this aspect of the invention, at least one of X9, X10, X11 and X12 is N, and one or two of the remaining X9-X12 are CR4. According to an additional embodiment of this aspect of the invention, at least one of X13, X14, X15 and X16 is N, and one or two of the remaining X13-X16 are CR.

According to a further aspect of the compound and / or method of the invention, X 4 is N and each of X 1, X 2 and X 3 is CH or CR 1. According to a further aspect of the compound and / or method of the invention, X 3 is N and each of X 1, X 2 and X 4 is CH or CR 1.

According to a further aspect of the compound and / or method of the invention, X 12 is N and each of X 9, X 10 and X 11 is CH or CR 4.

According to a further aspect of the compound and / or method of the invention, Het is a heterocyclic group which is fully saturated, partially saturated or fully unsaturated containing five to ten ring atoms wherein at least one ring atom is a de atom. O, or S, and which is substituted wherein at least one of the substituents is halogenated alkoxy containing one to eight carbon atoms (e.g. OCHF2), cycloalkoxy having three to seven carbon atoms, cycloalkylalkoxy having four to seven carbon atoms. carbon (e.g., cyclopropylmethyloxy), halogenated alkyl with the exception of trifluoromethyl (e.g., halogenated alkyl having two to eight or three to eight carbon atoms, such as trifluoromethyl and trifluoropropyl), alkyl alkoxy having two to eight carbon atoms (e.g. CH3OCH2), alkyl (halogenated alkyl) amino wherein each alkyl group has from one to eight carbon atoms, di (halogenated alkyl) amino wherein each alkyl group has one to eight carbon atoms. halogenated C, or (alkyl) amino atoms having one to eight carbon atoms.

According to a further aspect of the compound and / or method of the invention, Het is a heterocyclic group which is fully saturated and substituted wherein at least one of its substituents is halogenated alkoxy containing one to eight C atoms (e.g. OCHF2) cycloalkoxy having three to seven carbon atoms, cycloalkylalkoxy having four to seven carbon atoms (eg cyclopropylmethyloxy), halogenated alkyl other than trifluoromethyl (eg halogenated alkyl having two to eight or three to eight carbon atoms such as trifluoroethyl and trifluoropropyl), alkyl alkoxy having two to eight carbon atoms (e.g. CHOCH2), alkyl (halogenated alkyl) amino wherein each alkyl group has one to eight C, di (alkylhalogenated) amino atoms where each alkyl group has one to eight C atoms, or halogenated (alkyl) amino having one to eight carbon atoms.

According to a further aspect of the compound and / or method of the invention, Het is a heterocyclic group which is fully saturated, partially saturated or fully unsaturated containing five to ten ring atoms wherein at least one ring atom is a de atom. O or S which is substituted wherein at least one of the substituents is halogenated alkoxy containing one to eight carbon atoms (eg OCHF2), cycloalkylalkoxy having four to seven carbon atoms (eg cyclopropylmethyloxy) halogenated alkyl trifluoromethyl (e.g., halogenated alkyl having two to eight or three to eight carbon atoms, such as trifluoroethyl and trifluoropropyl), alkoxyalkyl having two to eight carbon atoms (e.g. CH3OCH2), or alkyl (halogenated alkyl) amino wherein Each alkyl group has one to eight carbon atoms.

According to a further aspect of the compound and / or method of the invention, Het is a fully saturated heterocyclic group which is substituted wherein at least one of the substituents is halogenated alkoxy containing one to eight carbon atoms (e.g. OCHF2), cycloalkylalkoxy which have four to seven carbon atoms (eg, cyclopropylmethyloxy), halogenated alkyl with the exception of trifluoromethyl (eg, halogenated alkyl having two to three to eight carbon atoms, such as trifluoroethyl and trifluoropropyl), alkyl alkoxy having two to eight atoms carbon (e.g. CH 3 OCH 2), or amino (halogenated alkyl) amino wherein each alkyl group has from one to eight carbon atoms.

According to a further aspect of the compound and / or method of the invention, A is of formula (a) which has at least one substituent R1 which is a heterocyclic group which is fully saturated, partially saturated or fully unsaturated, has five to ten carbon atoms. ring wherein at least one ring atom is a Ν, O or S atom and which is substituted wherein at least one of the substituents is halogenated alkoxy containing one to eight carbon atoms (e.g. OCHF2), cycloalkoxy having three at seven carbon atoms, cycloalkylalkoxy having four to seven carbon atoms (e.g. cyclopropylmethyloxy), halogenated alkyl with trifluoromethyl (e.g. halogenated alkyl having two to eight or three to eight carbon atoms such as trifluoroethyl and trifluoropropyl), alkoxyalkyl having two to eight carbon atoms (e.g. CH3OCH2), alkyl (halogenated alkyl) amino wherein each alkyl group has one to eight carbon atoms, di (alkyl halo) genyl) amino wherein each alkyl group has one to eight carbon atoms, or halogenated (alkyl) amino which has one to eight carbon atoms.

According to a further aspect of the compound and / or method of the invention, A is of formula (a) which has at least one substituent R1 which is a fully saturated heterocyclic group which is substituted wherein at least one of the substituents is halogenated alkoxy containing one to one. eight C atoms (eg OCHF2), cycloalkoxy having three to seven carbon atoms, cycloalkylalkoxy having four to seven carbon atoms (eg cyclopropylmethyloxy), halogenated alkyl other than trifluoromethyl (eg halogenated alkyl having two to eight or three to eight carbon atoms such as trifluoroethyl and trifluoropropyl), alkyl alkoxy having two to eight carbon atoms (e.g. CH3OCH2), or alkyl (halogenated alkyl) amino in which alkyl group has one to eight carbon atoms.

According to a further aspect of the compound and / or method of the invention, A is of formula (c) which has at least one substituent R4 which is a heterocyclic group which is fully saturated, partially saturated or fully unsaturated, and has five to ten atoms. wherein at least one ring atom is a Ν, O or S atom which is substituted wherein at least one of the substituents is halogenated alkoxy containing one to eight carbon atoms (eg OCHF2), cycloalkoxy having three to seven carbon atoms, cycloalkylalkoxy having four to seven carbon atoms (e.g. cyclopropylmethyloxy), halogenated alkyl with trifluoromethyl exception (e.g. halogenated alkyl having two to eight or three to eight carbon atoms such as trifluoroethyl and trifluoropropyl) alkoxyalkyl having two to eight carbon atoms (e.g. CH3OCH2), alkyl (halogenated alkyl) amino, where each alkyl group has one to eight carbon atoms, di (alkyl halogen) genetically defined amino amino wherein each alkyl group has one to eight carbon atoms, or halogenated (alkyl) amino which has one to eight carbon atoms.

According to a further aspect of the compound and / or method of the invention, A is of formula (c) having at least one substituent R4 which is a fully saturated heterocyclic group which is substituted wherein at least one of the substituents is halogenated alkoxy containing one to one. eight carbon atoms (eg OCHF2), cycloalkoxy having three carbon atoms, cycloalkylalkoxy having four carbon atoms (eg cyclopropylmethyloxy), halogenated alkyl other than trifluoromethyl (eg halogenated alkyl having two to eight or three to eight carbon atoms such as trifluoroethyl (trifluoropropyl), alkyl alkoxy having two to eight carbon atoms (e.g. CH 3 OCH 2), or alkyl (alkylated halogen) amino wherein each alkyl group has one to eight carbon atoms.

According to a further aspect of the compound and / or method of the invention, A is of formula (d) which has at least one substituent R which is OH, O- (C1-6-alkyl-O) 1-2-C1-6. -alkyl, -0-C1-6-alkyl-NR6R7, alkoxy containing one to four carbon atoms (e.g. OCH3), cycloalkoxy having three to seven carbon atoms, cycloalkylalkoxy having four to seven carbon atoms (e.g. cyclopropyl methoxy ), alkoxyfluoride containing one to four carbon atoms (eg OCF3, OCHF2), alkyl hydroxy containing one to four carbon atoms, fluorinated alkyl hydroxy containing one to four carbon atoms, alkoxy hydroxy having two to four carbon atoms, alkoxy hydroxy fluoride having two carbon atoms, 0Ar, 0Het, Carbo-0, Ar-C 1-6 -alkyl-O, Het-C 1-6 -alkyl-O, or Ar-C 1-6 -alkyl-Het 0-.

According to a further aspect of the compound and / or method of the invention, A is of formula (d) which has at least one substituent of R which is OH, O- (C1-6-alkyl-O) 1-2-C1- 6-alkyl, alkoxy containing one to four carbon atoms (eg OCH3), cycloalkoxy having three to seven carbon atoms, cycloalkylalkoxy having four to seven carbon atoms (eg cyclopropylmethoxy), fluorinated alkoxy containing one to four carbon atoms carbon (e.g., OCF3, OCHF2), alkoxy hydroxy having two to four carbon atoms, or fluorinated alkoxy hydroxy.

According to a further aspect of the compound and / or method of the invention, A is of formula (d) which has at least one substituent of R which is OH, alkoxy containing one to four carbon atoms (e.g. OCH3), fluorinated alkoxy containing one to four carbon atoms (e.g., OCF3, OCHF2), alkoxy hydroxy having two to four carbon atoms, or fluorinated alkoxy hydroxy.

According to a further aspect of the compound and / or method of the invention, A is of formula (a) having at least one R1 substituent which is dihydroimidazolyl.

According to a further aspect of the compound and / or method of the invention, A is of formula (a) having at least one substituent R1 which is Het except thiazolyl, and wherein R2 is alkyl having two to four carbon atoms, fluorinated alkyl having one to four carbon atoms, cycloalkyl having three to seven carbon atoms, cycloalkylalkyl having four to seven carbon atoms, C1-4-alkyl-CO-fluorinated, C3-7-cycloalkyl-CO-, C1-4-alkyl-NH-CO-, C3-7-cycloalkyl-NH-CO-, Het, Ar-C1-4-alkyl-, Ar-C1-4-alkyl-CO-, Ar-C1-4- alkyl-SO2-, C1-4-alkyl-O-C1-4-alkyl- (e.g. CH2CH2-O-CH3), or Ar-C1-4-alkyl-NH-CO-.

According to a further aspect of the compound and / or method of the invention, A is of formula (c) which has at least one R4 substituent which is imidazolyl (e.g. imidazol-1-yl), pyrrolyl, pyrazolyl, C1-8. alkyl pyrazolyl (e.g. 3-methyl-1H-pyrazol-1-yl, 5-methyl-1H-pyrazol-1-yl), oxa-azabicycloheptyl (e.g. 2-oxa-5-azabicyclo [2.2.1] heptyl), diazabicycloheptyl (e.g. 2,5-diazabicyclo [2.2.1] hept-2-yl), C 1-8 alkyl diazabicycloheptyl (e.g. 5-methyl-2,5-diazabicyclo [2.2. 1] hept-2-yl), halogenated C 1-8 alkyl diazabicycloheptyl (e.g. trifluoroethyl-2,5-diazabicyclo [2.2.1] hept-2-yl, piperidinyl substituted by amino, C 1-8 alkylamino NH-), (C 1-8 alkyl) 2 N-) alkylamino (e.g. (4-dimethylamino) piperidin-1-yl), or hydroxy, halogenated alkoxy, cycloalkylalkoxy, amino, C 1-8 monoalkylamino substituted pyrrolidinyl alkyl-NH-), dialkylamino ((C1-8-alkyl) 2N-, alkoxyalkyl, or alkyl (alkylflu) fluorinated amino) (e.g. 3- (cyclopropylmethoxy) pyrrolidin-1-yl, 3- (hydroxy) pyrrolidin-1-yl (such as 3- (3R) -hydroxypyrrolidin-1-yl, 3- (3S) - hydroxypyrrolidin-1-yl), 3- (difluoromethoxy) pyrrolidin-1-yl), 3- (dimethylamino) pyrrolidin-1-yl (such as 3- (3S) - (dimethylamino) pyrrolidin-1-yl, 3- ( 3R) - (dimethylamino) pyrrolidin-1-yl), 3-methylaminopyrrolidin-1-yl, 3- (methoxymethyl) pyrrolidin-1-yl, and 3- [methyl (2,2,2-trifluoroethyl) amino] pyrrolidin-2-one According to a further aspect of the invention, the compound is of formulas I to IV, but the 1-azabicyclic group is in the form of a quaternary ammonium salt of the sub-formula:

<formula> formula see original document page 55 </formula>

wherein Z is alkyl having one to four carbon atoms (eg, methyl, ethyl, propyl), halogenated alkyl having one to four carbon atoms (eg chloromethyl, chloroethyl), cycloalkylalkyl having four to seven carbon atoms ( cyclopropylmethyl), or arylalkyl containing seven to sixteen carbon atoms (e.g. benzyl), and anion A is, for example, iodide, bromide, chloride, triflate, tosylate, or mesylate. In this embodiment, group A is preferably of formula (a) or (c). Furthermore, each of X1 to X4 is preferably CH or CR1, and each of X9 to X12 is preferably CH or CR4.

According to a further aspect of the invention, the compound is selected from the formula Ip according to the following subgenres:

(i) X13-X16 is independently CH or CR wherein at least one of X13-X16 is other than CH; X is O;

R1 is H, alkyl (e.g. CH3 or C2H5, particularly CH3) or cycloalkylalkyl (e.g. cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclopropylmethyl, particularly cyclopropylmethyl); and

at least one R is alkoxy (e.g. OCH 3) or Het (e.g. 3-methoxy-pyrrolidin-1-yl [such as (3R) -3-methoxypyrrolidin-1-yl, (3S) -3-methoxypyrrolidin-2-yl] According to a further aspect of the invention, the compound is selected from formula Ia or Ij according to the following subgenres:

(i) X is O;

one of X1-X4 is N or one of X9-X12 is N and the other of X1-X4 or X9-X12 is CH, CR1 or CR4;

R1 is H, alkyl (e.g. CH3 or C2H5, particularly CH3) or cycloalkylalkyl (e.g. cyclopropyl ethyl, particularly cyclopropylmethyl);

R2 is H; and

R 1 and R 4 are independently selected from H, halogen (e.g. Cl or F), Ar (e.g. phenyl) or Het (e.g. 3-dimethylaminopyrrolidin-1-yl).

According to a further aspect of the compound and / or method of the invention, the compound is selected from the following subgenres:

(a) a compound according to formula I wherein at least one of X1, X2, X3 and X4 is N;

(b) a compound according to formula Ia wherein at least one of X1, X2, X3 and X4 is N;

(c) a compound according to formula Ij wherein at least one of X1, X2, X3 and X4 is N;

(d) a compound according to formula I wherein at least one of X5, X6, X7 and X8 is N;

(e) a compound according to formula I wherein at least one of X9, X10, X11 and X12 is N;

(f) a compound according to formula I wherein at least one of X 13, X 14, X 15 and X 16 is N;

(g) a compound according to formula I wherein at least one of X1, X2, X3 and X4 is N, and one or two of the remaining X1-X4 are CR1; (h) a compound according to formula Ia wherein at least one of X1i X2, X3 and X4 is N, and one or two of the remaining X1-X4 are CR1;

(i) a compound according to formula Ij wherein at least one of X1, X2, X3 and X4 is N, and one or two of X1-X4

remaining are CR1;

(j) a compound according to formula I wherein at least one of X5, X6, X7 and X8 is N, and one or two of the remaining X5-X8 are CR3; (k) a compound according to formula I wherein

at least one of X9f X10, X11 and X12 is N, and one or two of the remaining X9-X12 are CR4;

(1) a compound according to formula I wherein at least one of X13, X147, X15 and X16 is N, and one or two of the remaining X13-X16 are CR;

(m) a compound according to formula I wherein X 4 is N and each of X 1, X 2 and X 3 is CH or CR 1;

(n) a compound according to formula Ia wherein X 4 is N and each of X 1, X 2 and X 3 is CH or CR 1;

(o) a compound according to formula Ij wherein

X12 is N and each of X9, X10 and X11 is CH or CR4;

(p) a compound according to formula Ia wherein X 3 is N and each of X 11 is X 2 and X 4 is CH or CR 1;

(q) a compound according to formula Ia or Ij which has at least one R1 or R4 which is Het substituted and at least one of the substituents of Het is halogenated alkoxy containing one to eight carbon atoms (e.g. OCHF2), cycloalkoxy having three to seven carbon atoms, cycloalkylalkoxy having four to seven carbon atoms

(e.g. cyclopropylmethyloxy), halogenated alkyl with

except trifluoromethyl (eg halogenated alkyl which has two to eight or three to eight carbon atoms, such as trifluoroethyl), alkyl alkoxy having two to eight carbon atoms (eg CH2OCH3), amino (alkylhalogenated) amino, where each alkyl group has one to eight carbon atoms, di (halogenated alkyl) amino wherein each alkyl group has one to eight carbon atoms, or halogenated (alkyl) amino having one to eight carbon atoms; (r) a compound according to formula Ia or Ij which has at least one R1 or R4 which is Het substituted and at least one of the substituents of Het is halogenated alkoxy containing one to eight carbon atoms (e.g. OCHF2), cycloalkylalkoxy having four to seven carbon atoms (eg cyclopropylmethyloxy), halogenated alkyl with the exception of trifluoromethyl (e.g. halogenated alkyl having two to eight or three to eight carbon atoms, such as trifluoroethyl), alkyl alkoxy having two to eight carbon atoms (e.g. CH 2 OCH 3), or alkyl (halogenated alkyl) amino, wherein each alkyl group has one to eight carbon atoms; (s) a compound according to formula Ia or Ij which has at least one R 1 or R 4 which is a group Fully saturated substituted Het (e.g., pyrrolidinyl or piperidinyl) and at least one of the Het substituents is halogenated alkoxy containing one to eight carbon atoms (eg OCHF2), cycloalkoxy having three to seven carbon atoms, cycloalkylalkoxy having four to seven carbon atoms (e.g. cyclopropylmethyloxy), halogenated alkyl other than trifluoromethyl (e.g. halogenated alkyl having two to eight or three to eight carbon atoms, such as trifluoroethyl), alkoxy alkyl having two to eight carbon atoms (e.g. CH2OCH3) , alkyl (halogenated alkyl) amino, wherein each alkyl group has one to eight carbon atoms, di (halogenated alkyl) amino wherein each alkyl group has one to eight carbon atoms, or (a alkyl) halogenated amino having one to eight carbon atoms;

(t) a compound according to formula Ia or Ij which has at least one R1 or R4 which is a fully saturated substituted Het group (e.g. pyrrolidinyl) and at least one of the Het substituents is halogenated alkoxy containing one to eight carbon atoms ( e.g. OCHF2), cycloalkylalkoxy having four to seven carbon atoms (e.g. cyclopropylmethyloxy), halogenated alkyl with trifluoromethyl (e.g. halogenated alkyl having two to eight or three to eight carbon atoms, such as trifluoroethyl), alkoxy alkyl having two to eight carbon atoms (e.g., CH 2 OCH 3), or alkyl (alkylated halogen) amino, wherein each alkyl group has one to eight carbon atoms;

(u) a compound according to IP of formula having at least one substituent which is OH, O- (C1-6-alkyl-0) 1-2-C1-6-alkyl, -0-C1-6-alkyl Alkoxy containing one to four carbon atoms (eg OCH3), cycloalkoxy having three to seven carbon atoms, cycloalkylalkoxy having four to seven carbon atoms (e.g. cyclopropylmethoxy), fluorinated alkoxy containing one to four carbon atoms ( (eg OCF3, OCHF2), hydroxy alkyl having one to four carbon atoms, fluorinated alkyl hydroxy containing one to four carbon atoms, hydroxyalkoxy having two to four carbon atoms, fluorinated hydroxyalkoxy having two to four carbon atoms, OAr, OHet, Carbo-O, Ar-C 1-6 alkyl-O-, Het-C 1-6 alkyl-O-, or Ar-C 1-6 alkyl-Het-O-;

(v) a compound according to formula Ip having at least one substituent of R which is OH, O- (C1-6-alkyl-0) 1-2-C1-6-alkyl, alkoxy containing one to four carbon atoms. carbon (e.g. OCH3), cycloalkoxy having three to seven carbon atoms, cycloalkylalkoxy having four to seven carbon atoms (e.g. cyclopropylmethoxy), fluoridated alkoxy having one to four carbon atoms (e.g. OCF3, OCHF2), hydroxy alkoxy having two to four carbon atoms, or fluorinated alkoxy hydroxy;

(w) a compound according to formula Ip having at least one substituent of R which is OH, alkoxy containing one to four carbon atoms (eg OCH3), alkoxyfluoride containing one to four carbon atoms (eg OCF3, OCHF2 ), alkoxy hydroxy having two to four carbon atoms, or fluorinated alkoxy hydroxy;

(x) a compound according to formula Ia which is at least one substituent of R which is dihydroimidazolyl;

(y) a compound according to formula Ia having at least one substituent R 1 which is Het except for detiazolyl, and wherein R 2 is alkyl having two to four carbon atoms, fluorinated alkyl having one to four carbon atoms, cycloalkyl having has three to seven carbon atoms, cycloalkylalkyl having four to seven carbon atoms, C1-4-alkyl-fluorinated C3-7-cycloalkyl-CO-, C1-4-alkyl-NH-CO-, C3- 7-cycloalkyl-NH-CO-, Het, Ar-C1-4-alkyl-, Ar-C1-4-alkyl-CO-, Ar-C1-4-alkyl-SO2, C1-4-alkyl-O- C 1-4 alkyl- (e.g. CH 2 CH 2 -O-CH 3), or Ar-C 1-4 alkyl-NH-CO-;

(z) a compound according to formula I having at least one R4 substituent which is imidazolyl (e.g. imidazol-1-yl), pyrrolyl, pyrazolyl, C1-8-alkylpyrazolyl (e.g. 3-methyl -1H-pyrazol-1-yl, 5-methyl-1H-pyrazol-1-yl), oxo-azabicycloheptyl (e.g. 2-oxo-5-azabicyclo [2.2.1] heptyl), 2,5-diazabicyclo [ 2.2.1] hept-2-yl, C1-8-alkyl-diazabicycloheptyl (e.g. 5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl), halogenated C1-8-alkyl-diazabicycloheptyl (e.g., trifluoroethyl-2,5-diazabicyclo [2.2.1] hept-2-yl), amino-substituted piperidinyl, (C 1-8 alkyl-NH-) monoalkylamino, or (2 C 1-8 alkyl) dialkylamino -) (e.g. (4-dimethylamino) piperidin-1-yl), or hydroxy, alkoxyhalogenated, cycloalkylalkoxy, amino, C1-8 alkyl-NH-, dialkylamino (C1-8 alkyl) substituted pyrrolidinyl ) 2N-), alkyl alkoxy, or fluorinated alkyl (alkyl) amino (e.g. 3- (cyclopropylmethoxy) pyrrolidin-1-yl, 3- (hydroxy) pyrrole idin-1-yl (such as 3- (3R) -hydroxypyrrolidin-1-yl, 3- (3S) -hydroxypyrrolidin-1-yl), 3- (difluoromethoxy) pyrrolidin-1-yl), 3- (dimethylamino ) pyrrolidin-1-yl (such as 3- (3S) - (dimethylamino) pyrrolidin-1-yl, 3- (3R) - (dimethylamino) pyrrolidin-1-yl), 3-methylaminopyrrolidin-1-yl, 3- (methoxymethyl) pyrrolidin-1-yl, 3- [methyl (2,2,2-trifluoroethyl) amino] pyrrolidin-1-yl);

(aa) a subgenre according to any of the above subgenres (a) - (z) where X is O; and

(ab) a subgenre according to any of the above subgenera (a) - (aa) wherein R1 is H or alkyl, especially H.

According to one aspect of the compound and / or method of the invention, the compound of formulas I-IV is selected from:

1) (3S) -3 - ({[6- (Cyclopropylmethoxy) -1,2-benzisothiazol-3-yl] carbonyl} amino) -1- (cyclopropylamethyl) -1-azoniabicyclic bromide or formate [2.2.2] octane,

2) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] 6- (3-methoxypyrrolidin-1-yl) -1,2-benzisothiazole-3-carboxamide,

3) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5,6-dimethoxy-1H-indazol-3-carboxamide hydroformate,

4) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-propyl-6- (1,3-thiazol-2-yl) -1H-indazol-3-carboxamide,

5) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-isopropyl-6- (1,3-thiazol-2-yl) -1H-indazol-3-carboxamide, 6) N - [(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -6 (tetrahydrofuran-3-yloxy) -1H-indazol-3-carboxaraide hydroformate, 7) N- [Hydroformate (3S) -1-azabicyclo [2.2.2] oct-3-yl] -6 (tetrahydro-2H-pyran-4-yloxy) -1H-indazole-3-carboxamide, 8) N - [(3S) hydroformate -1-azabicyclo [2.2.2] oct-3-yl] -6 [(1-methylpyrrolidin-3-yl) oxy] -1H-indazol-3-carboxamide, 9) N - [(3S) -1 hydroformate -azabicyclo [2.2.2] oct-3-yl] -4-hydroxy-1H-indazol-3-carboxamide, 10) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -hydroformate 5bromo-4-hydroxy-1H-indazol-3-carboxamide, 11) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] 5,7-dibromo-4-hydroxy-1H hydroformate -indazol-3-carboxamide, 12) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5hydroxy-1,2-benzothiazol-3-carboxamide hydroformate, 13) Iodide or (3S) -3 - {[(5-Hydroxy-1,2-benzisothiazol-3-yl) carbonyl] amino} -1-methyl-1-azoniabicyclo [2.2.2] octane, 14) N- [Hydroformate format] ( 3S) -1-azabicyclo [2.2.2] oct-3-yl] -6 (3-furylmethoxy) -1,2-benzisothiazole-3-carboxamide, 15) N - [(3S) -1-azabicyclo [ 2.2.2] oct-3-yl] -1ethyl-6- (2-oxopyrrolidin-1-yl) -1H-indazol-3-carboxamide, 16) N - [(3S) -1-azabicyclo hydroformate [2.2. 2] oct-3-yl] -7hydroxy-1H-indazol-3-carboxamide, 17) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-methoxy-N-methyl hydroformate -IH-indazol-3-carboxamide, 18) N - [(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -1methyl-6 {[(propylamino) carbonyl] amino} -1H hydroformate -indazol-3-carboxamide, 19) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-ethyl-6-methoxy-1Hindazol-3-carboxamide, 20) N- [ (3R) -1-Azabicyclo [2.2.2] oct-3-yl] -1-ethyl-6-methoxy-1H-indazol-3-carboxamide, 21) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1- (difluoromethyl) -6-methoxy-1H-indazol-3-carboxamide,

22) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1- (difluoromethyl) -6- (1,3-thiazol-2-yl) -1H-indazol-3-one carboxamide,

23) N - [(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -6 - [(cyclopropylcarbonyl) amino] -1-methyl-1H-indazol-3-carboxamide hydroformate,

24) N - [(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -6 - [(cyclopropylcarbonyl) amino] -1- (difluoromethyl) -1H-indazol-3-carboxamide hydroformate,

25) N - [(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -1- (difluoromethyl) -6 - {[(propylamino) carbonyl] amino} -1H-indazol-3 hydroformate -carboxamide,

26) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-cyclopropyl-6- (1,3-thiazol-2-yl) -1H-indazol-3-carboxamide,

27) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1,3-thiazol-2-yl) -1- (3-thienyl) -1H-indazol-2-one 3-carboxamide,

28) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -N-methyl-6- (1,3-oxazol-2-yl) -1H-indazol-3-carboxamide,

29) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -N-methyl-6- (1,3-thiazol-2-yl) -1H-indazol-3-carboxamide,

30) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-ethyl-6- (1,3-oxazol-2-yl) -1H-indazol-3-carboxamide,

31) N - [(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -1- (cyclopropylamethyl) -6- (1,3-oxazol-2-yl) -1H-indazol-3-one arboxam i da,

32) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1,3-oxazol-2-yl) -1-propyl-1H-indazol-3-carboxamide,

33) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-ethyl-N-methyl-6- (1,3-oxazol-2-yl) -1H-indazol-2-one 3-carboxamide,

34) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -N-methyl-6- (tetrahydro-2H-pyran-4-yl) -1H-indazol-3-carboxamide, 35) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -N-methyl-5- (tetrahydro-2H-pyran-4-yl) -1H-indazol-3-carboxamide,

36) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5- (difluoromethoxy) -N-methyl-1H-indazol-3-carboxamide,

37) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (difluoromethoxy) -N-methyl-1H-indazol-3-carboxamide,

38) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-cyclopropyl-6 - [(cyclopropylcarbonyl) amino] -1H-indazol-3-carboxamide,

39) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-cyclopropyl-6 - {[(propylamino) carbonyl] amino} -1H-indazol-3-carboxamide,

40) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5-methoxy-N-methyl-1H-indazol-3-carboxamide,

41) N - [(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -6 - [(4S) -4-hydroxy-2-oxopyrrolidin-1-yl] -1H-indazol-hydroformate 3-carboxamide,

42) N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -5-methoxy-N-methyl-1H-indazol-3-carboxamide hydroformate,

43) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -5- (difluoromethoxy) -N-methyl-1H-indazol-3-carboxamide hydroformate,

44) N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -6- (difluoromethoxy) -N-methyl-1H-indazol-3-carboxamide hydroformate,

45) N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -N-methyl-6- (tetrahydro-2H-pyran-4-yl) -1H-indazol-3-hydroformate carboxamide,

46) N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -N-methyl-5- (tetrahydro-2H-pyran-4-yl) -1H-indazol-3-hydroformate carboxamide,

47) N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -N-methyl-6- (1,3-thiazol-2-yl) -1H-indazol-3-hydroformate carboxamide,

48) N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -6-methoxy-N-methyl-1,2-benzisothiazole-3-carboxamide hydroformate,

49) N - [(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -6- (3-methoxypyrrolidin-1-yl) -1,2-benzisothiazole-3-carboxamide hydrochloride,

50) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-hydroxy-1,2-benzisothiazole-3-carboxamide, 51) N - [(3R) -1 hydrochloride -azabicyclo [2.2.2] oct-3-yl] -6-methoxy-1,2-benzisothiazol-3-carboxamide,

52) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-methoxy-1,2-benzisothiazole-3-carboxamide hydrochloride,

53) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7-methoxy-1,2-benzisothiazole-3-carboxamide hydrochloride,

54) N - [(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -6- (2-oxo-3-propylimidazolidin-1-yl) -1,2-benzisothiazole-3-hydrochloride carboxamide,

55) N - [(3S) -1-Oxide-1-azabicyclo [2.2.2] oct-3-yl] -5- (trifluoromethoxy) -1H-indazol-3-carboxamide, e56) 6-Methoxy-N- [(3S) -1-oxido-1-azabicyclo [2.2.2] oct-3-yl] -1,2-benz isothiazol-3-carboxamide,

wherein the salts listed above may also be in free base form or in the form of another pharmaceutically acceptable salt, and the above-listed free base forms may also be in the form of a pharmaceutically acceptable salt,

wherein a compound listed above (in a free base form or in the form of a pharmaceutically acceptable salt) may also be in the form of a solvate (such as a hydrate),

wherein a compound listed above (in free base or pharmaceutically acceptable salt form) may also be in the form of an N-oxide,

wherein a compound listed above (in a free base or solvate form or an N-oxide thereof, or in the form of a pharmaceutically acceptable salt or solvate thereof) may also be in the form of a polymorph, and

wherein if the compound exhibits chirality it may be in the form of a mixture of enantiomers such as a racemate or a mixture of diastereomers, or may be in the form of a single enantiomer or a single diastereomer. According to a further aspect of the compound and / or method of the invention, the compound of formulas I-IV is selected from:

1) (3S) -3 - ({[6- (Cyclopropylmethoxy) -1,2-benzisothiazol-3-yl] carbonyl} amino) -1- (cyclopropylamethyl) -1-azoniabicyclic bromide or formate [2.2.2] octane,

2) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-methoxypyrrolidin-1-yl) -1,2-benzisothiazole-3-carboxamide,

3) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5,6-dimethoxy-1H-indazol-3-carboxamide hydroformate,

4) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-propyl-6- (1,3-thiazol-2-yl) -1H-indazol-3-carboxamide,

5) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-isopropyl-6- (1,3-thiazol-2-yl) -1H-indazol-3-carboxamide,

6) N - [(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -6- (tetrahydrofuran-3-yloxy) -1H-indazol-3-carboxamide hydroformate,

7) N - [(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -6- (tetrahydro-2H-pyran-4-yloxy) -1H-indazol-3-carboxamide hydroformate,

8) N - [(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -6 - [(1-methylpyrrolidin-3-yl) oxy] -1H-indazol-3-carboxamide hydroformate,

9) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -4-hydroxy-1H-indazol-3-carboxamide hydroformate,

10) N - [(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -5-bromo-4-hydroxy-1H-indazol-3-carboxamide hydroformate,

11) N - [(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -5,7-dibromo-4-hydroxy-1H-indazol-3-carboxamide hydroformate,

12) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5-hydroxy-1,2-benzisothiazole-3-carboxamide hydroformate,

13) (3S) -3 - {[(5-Hydroxy-1,2-benzisothiazol-3-yl) carbonyl] amino} -1-methyl-1-azoniabicyclo [2.2.2] octane iodide or formate,

14) N - [(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -6- (3-furylmethoxy) -1,2-benzisothiazole-3-carboxamide hydroformate, 15) N- [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-ethyl-6- (2-oxopyrrolidin-1-yl) -1H-indazol-3-carboxamide,

16) N - [(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -7-hydroxy-1H-indazol-3-carboxamide hydroformate,

17) N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -6-methoxy-N-methyl-1H-indazol-3-carboxamide hydroformate,

18) N - [(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -1-methyl-6 - {[(propylamino) carbonyl] amino} -1H-indazol-3-carboxamide hydroformate,

19) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-ethyl-6-methoxy-1H-indazol-3-carboxamide,

20) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -1-ethyl-6-methoxy-1H-indazol-3-carboxamide,

21) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1- (difluoromethyl) -6-methoxy-1H-indazol-3-carboxamide,

22) N - [(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -1- (difluoromethyl) -6- (1,3-thiazol-2-yl) -1H-indazol-3-one carboxamide,

23) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(cyclopropylcarbonyl) amino] -1-methyl-1H-indazol-3-carboxamide hydroformate,

24) N - [(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -6 - [(cyclopropylcarbonyl) amino] -1- (difluoromethyl) -1H-indazol-3-carboxamide hydroformate,

25) N - [(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -1- (difluoromethyl) -6 - {[(propylamino) carbonyl] amino} -1H-indazol-3 - hydroformate carboxamide,

26) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-cyclopropyl-6- (1,3-thiazol-2-yl) -1H-indazol-3-carboxamide,

27) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1,3-thiazol-2-yl) -1- (3-thienyl) -1H-indazol-2-one 3-carboxamide,

28) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -N-methyl-6- (1,3-oxazol-2-yl) -1H-indazol-3-carboxamide, 29) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -N-methyl-6- (1,3-thiazol-2-yl) -1H-indazol-3-carboxamide,

30) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-ethyl-6- (1,3-oxazol-2-yl) -1H-indazol-3-carboxamide,

31) N - [(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -1- (cyclopropylamethyl) -6- (1,3-oxazol-2-yl) -1H-indazol-3-one carboxamide,

32) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1,3-oxazol-2-yl) -1-propyl-1H-indazol-3-carboxamide,

33) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-ethyl-N-methyl-6- (1,3-oxazol-2-yl) -1H-indazol-2-one 3-carboxamide,

34) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -N-methyl-6- (tetrahydro-2H-pyran-4-yl) -1H-indazol-3-carboxamide,

35) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -N-methyl-5- (tetrahydro-2H-pyran-4-yl) -1H-indazol-3-carboxamide,

36) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5- (difluoromethoxy) -N-methyl-1H-indazol-3-carboxamide,

37) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (difluoromethoxy) -N-methyl-1H-indazol-3-carboxamide,

38) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-cyclopropyl-6 - [(cyclopropylcarbonyl) amino] -1H-indazol-3-carboxamide,

39) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-cyclopropyl-6 - {[(propylamino) carbonyl] amino} -1H-indazol-3-carboxamide,

40) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5-methoxy-N-methyl-1H-indazol-3-carboxamide,

41) N - [(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -6 - [(4S) -4-hydroxy-2-oxopyrrolidin-1-yl] -1H-indazol-hydroformate 3-carboxamide,

42) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -5-methoxy-N-methyl-1H-indazol-3-carboxamide hydroformate,

43) N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -5- (difluoromethoxy) -N-methyl-1H-indazol-3-carboxamide hydroformate, 44) N- [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (difluoromethoxy) -N-methyl-1H-indazol-3-carboxamide,

45) N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -N-methyl-6- (tetrahydro-2H-pyran-4-yl) -1H-indazol-3-hydroformate carboxamide,

46) N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -N-methyl-5- (tetrahydro-2H-pyran-4-yl) -1H-indazol-3-hydroformate carboxamide,

47) N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -N-methyl-6- (1,3-thiazol-2-yl) -1H-indazol-3-hydroformate carboxamide,

48) N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -6-methoxy-N-methyl-1,2-benzisothiazole-3-carboxamide hydroformate,

49) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-methoxypyrrolidin-1-yl) -1,2-benzisothiazole-3-carboxamide hydrochloride, and

50) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-hydroxy-1,2-benzisothiazole-3-carboxamide,

wherein the salts listed above may also be in free base form or in the form of another pharmaceutically acceptable salt, and the above-listed free base forms may also be in the form of a pharmaceutically acceptable salt,

wherein a compound listed above (in free base form or in the form of a pharmaceutically acceptable salt) may also be in the form of a solvate (such as a hydrate),

wherein a compound listed above (in a free base form or a solvate thereof, or in the form of a pharmaceutically acceptable salt or solvate thereof) may also be in the form of a polymorph, and

wherein if the compound exhibits chirality it may be in the form of a mixture of enantiomers such as a racemate or a mixture of diastereomers, or may be in the form of a single enantiomer or a single diastereomer. According to an additional aspect of the compound and / According to the method of the invention, the compound of formulas I-IV is selected from: 57) N - [(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -6-fluoro-1H-pyrazolo [3] hydroformate , 4-b] pyridin-3-carboxamide, 58) N - [(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -6- [3- (cyclopropylmethoxy) pyrrolidin-1-yl hydroformate ] -1H-indazol-3-carboxamide, 59) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1H-pyrazolo [4,3-c] pyridine-3-carboxamide, 60) N - [(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -1H-pyrazolo [3,4-c] pyridine-3-carboxamide hydroformate, 61) N - [( 3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- [3- (cyclopropylmethoxy) pyrrolidin-1-yl] -1H-indazol-3-carboxamide, 62) N - [(3R ) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-methoxypyrrolidin-1-yl) -1H-ind azol-3-carboxamide, 63) N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -6- (2-oxo-3-propylimidazolidin-1-yl) -1H-hydroformate indazol-3-carboxamide, 64) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-pyrrolidin-1-yl-1,2-benzisothiazole-3-carboxamide, 65) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-methyl-2-oxopyrrolidin-1-yl) -1,2-benzisothiazole-3-carboxamide, 66) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (β-pyrrol-1-yl) -1,2-benzisothiazole-3-carboxamide, 67) N- [( 3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-ethyl-2-oxoimidazolidin-1-yl) -1,2-benzisothiazol-3-carboxamide, 68) N- [( 3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- [3- (cyclopropylmethoxy) pyrrolidin-1-yl] -1,2-benzisothiazol-3-carboxamide, 69) N - [(3S ) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-methoxypyrrolidin-1-yl) -1,2-benzisoxazole-3-carboxamide, 70) N - [(3S) -1 -azabicyclo [2.2.2] oct-3-yl] -7- (3-methoxypyrrolidin-1-yl) -1,2-benzisothiazol-3-carboxamide,

71) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-methoxy-1,2-benzisoxazol-3-carboxamide hydrochloride,

72) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-methoxypyrrolidin-1-yl) -1,2-benzisothiazol-3-carboxamide,

73) N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -1-ethyl-6- (1,3-oxazol-2-yl) -1H-indazol-3-hydroformate carboxamide,

74) N - [(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -1-ethyl-6- (1,3-oxazol-2-yl) -1H-indazol-3-hydrochloride carboxamide,

75) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(3R) -3-methoxypyrrolidin-1-yl] -1,2-benzisothiazol-3-carboxamide,

76) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(3S) -3-methoxypyrrolidin-1-yl] -1,2-benzisothiazol-3-carboxamide,

77) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (2-OXO-3-propylimidazolidin-1-yl) -1H-indazol-3-carboxamide,

78) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-hydroxypyrrolidin-1-yl) -1,2-benzisothiazole-3-carboxamide,

79) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- [3- (difluoromethoxy) pyrrolidin-1-yl] -1,2-benzisothiazole-3-carboxamide,

80) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1H-imidazol-1-yl) -1,2-benzisothiazole-3-carboxamide,

81) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1H-pyrazol-1-yl) -1,2-benzisothiazole-3-carboxamide,

82) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-methyl-1H-pyrazol-1-yl) -1,2-benzisothiazole-3-carboxamide,

83) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (5-methyl-1H-pyrazol-1-yl) -1,2-benzisothiazole-3-carboxamide,

84) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(3R) -3-methoxypyrrolidin-1-yl] -1,2-benzisothiazole-3-carboxamide,

85) N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -6 - [(3S) -3-methoxypyrrolidin-1-yl] -1,2-benzisothiazol-3-carboxamide , 86) N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -6-methoxy-1,2-benzisoxazol-3-carboxamide,

87) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-ethoxypyrrolidin-1-yl) -7-fluoro-1,2-benzisothiazol-3-carboxamide,

88) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-phenyl-1H-pyrazolo [3,4-b] pyridine-3-carboxamide,

89) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (4,5-dihydro-1H-imidazol-2-yl) -1H-indazol-3-carboxamide,

90) N - [(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -6- [3- (dimethylamino) pyrrolidin-1-yl] -1H-pyrazolo [3,4-b] pyridine -3-carboxamide,

91) N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -6- [3- (dimethylamino) pyrrolidin-1-yl] -1H-pyrazolo [3,4-b] pyridine -3-carboxamide,

92) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-fluoro-6- (3-methoxypyrrolidin-1-yl) -1,2-benzisothiazol-3-carboxamide,

93) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7-fluoro-6- (3-methoxypyrrolidin-1-yl) -1,2-benzisothiazol-3-carboxamide,

94) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(3R) -3-hydroxypyrrolidin-1-yl] -1,2-benzisothiazole-3-carboxamide,

95) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(3S) -3-hydroxypyrrolidin-1-yl] -1,2-benzisothiazol-3-carboxamide,

96) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(3S) -3- (dimethylamino) pyrrolidin-1-yl] -1,2-benzisothiazol-3 -carboxamide,

97) N - [(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -6 - [(1S, 4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl ] -1,2-benzisothiazole-3-carboxamide,

98) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(3R) -3-hydroxypyrrolidin-1-yl] -1,2-benzisothiazole-3-carboxamide,

99) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(3S) -3-hydroxypyrrolidin-1-yl] -1,2-benzisothiazole-3-carboxamide, 100) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(3S) -3- (dimethylamino) pyrrolidin-1-yl] -1,2-benzisothiazol-3 -carboxamide, 101) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] - 7 - [(3R) -3-hydroxypyrrolidin-1-yl] -1,2-benzisothiazole-3 -carboxamide, 102) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7 - [(3S) -3-hydroxypyrrolidin-1-yl] -1,2-benzisothiazole-3 -carboxamide, 103) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7 - [(3S) -3- (dimethylamino) pyrrolidin-1-yl] -1,2- benzisothiazol-3-carboxamide, 104) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7 - [(1S, 4S) -2-oxa-5-azabicyclo [2.2.1 ] hept-5-yl] -1,2-benzisothiazol-3-carboxamide, 105) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7 - [(3S) -3 - (dimethylamino) pyrrolidin-1-yl] -1,2-benzisothiazol-3-carboxamide, 106) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] isothiazolo [5, 4-b] pyridin-3-carboxamide, 107) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] isothiazolo [5,4-b] pyri hydroformate dina-3-carboxamide, 108) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(3R) -3-methoxypyrrolidin-1-yl] -1,2- benzisoxazol-3-carboxamide, 109) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(3S) -3-methoxypyrrolidin-1-yl] -1,2 benzisoxazole -3-carboxamide, 110) N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -7 - [(3R) -3-methoxypyrrolidin-1-yl] -1,2 hydroformate -benzisothiazol-3-carboxamide, 111) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7 - [(3S) -3-methoxypyrrolidin-1-yl] -1,2 -benzisothiazol-3-carboxamide, 112) N - [(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -7 - [(3R) -3-methoxypyrrolidin-1-yl] -1-hydroformate , 2-benzisothiazol-3-carboxamide, 113) N - [(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -7 - [(3S) -3-methoxypyrrolidin-1-yl] hydroformate -1,2-benzisothiazole-3-carboxamide,

114) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7-fluoro-6-methoxy-1,2-benzisothiazol-3-carboxamide,

115) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-fluoro-6-methoxy-1,2-benzisothiazol-3-carboxamide,

116) N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -6 - [(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2 -yl] -1,2-benzisothiazole-3-carboxamide,

117) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2 -yl] -1,2-benzisothiazole-3-carboxamide,

118) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(1S, 4S) -2,155-diazabicyclo [2.2.1] hept-2-yl] -1, 2-benzisothiazole-3-carboxamide,

119) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(1S, 4S) -2,5-diazabicyclo [2.2.1] hept-2-yl] - 1,2-benzisothiazole-3-carboxamide,

120) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- [3- (methylamino) pyrrolidin-1-yl] -1,2-benzisothiazole-3-carboxamide,

121) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- [3- (methylamino) pyrrolidin-1-yl] -1,2-benzisothiazole-3-carboxamide,

122) N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -6 - [(1S, 4S) -5- (2,2,2-trifluoroethyl) -2,5-diazabicyclo [2.2.1] hept-2-yl] -1,2-benzisothiazol-3-carboxamide,

123) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] - 6- {3- [methyl (2,2,2-trifluoroethyl) amino] pyrrolidin-1-yl} - 1,2-benzisothiazole-3-carboxamide,

124) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- {3- [methyl (2,2,2-trifluoroethyl) amino] pyrrolidin-1-yl} - 1,2-benzisothiazol-3-carboxamide, 125) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- [3- (methoxymethyl) pyrrolidin-1-yl] -1 , 2-benzisothiazole-3-carboxamide,

126) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- [3- (methoxymethyl) pyrrolidin-1-yl] -1,2-benzisothiazole-3-carboxamide,

127) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(3R) -3- (dimethylamino) pyrrolidin-1-yl] -1,2-benzisothiazol-3 -carboxamide,

128) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(3R) -3- (dimethylamino) pyrrolidin-1-yl] -1,2-benzisothiazole-3 -carboxamide,

129) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] 6- [4- (dimethylamino) piperidin-1-yl] -1,2-benzisothiazole-3-carboxamide, and

130) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- [4- (dimethylamino) piperidin-1-yl] -1,2-benzisothiazole-3-carboxamide,

wherein the salts listed above may also be in free base form or in the form of another pharmaceutically acceptable salt, and the above-listed free base forms may also be in the form of a pharmaceutically acceptable salt,

wherein a compound listed above (in free base form or in the form of a pharmaceutically acceptable salt) may also be in the form of a solvate (such as a hydrate),

wherein a compound listed above (in free base or pharmaceutically acceptable salt form) may also be in the form of an N-oxide,

wherein a compound listed above (in a free base form or a solvate or an N-oxide thereof, or in the form of a pharmaceutically acceptable salt or solvate thereof) may also be in the form of a polymorph, and if the compound exhibit chirality it may be in the form of a mixture of enantiomers such as a racemate or a mixture of diastereomers, or may be in the form of a single enantiomer or a single diathereomer. According to a further aspect of the compound and / or method of the invention, compound of the formulas I-IV is: 131) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (2-oxo-3-propylimidazolidin-1-yl) -1, 2-benzisothiazole-3-carboxamide or a pharmaceutically acceptable salt thereof, wherein the compound listed above (in free base form or in the form of a pharmaceutically acceptable salt) may also be in the form of a solvate (such as a hydrate), in that the compound listed above (in free base form or in the form of a pharmaceutically acceptable salt) vel) may also be in the form of an N-oxide, wherein the above listed compound (in free base form or a solvate or N-oxide thereof, or in the form of a pharmaceutically acceptable salt or solvate thereof) It may also be in the form of a polymorph. According to a further aspect of the compound and / or method of the invention, the compound of formulas I-IV is selected from: 132) N - [(3S) -1-azabicyclo [2.2] hydroformate .2] oct-3-yl] -N-methyl-6 - [(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] -1, di-2- benzisothiazol-3-carboxamide, 133) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -N-methyl-6 - [(1S, 4S) -5-methyl-2,5 -diazabicyclo [2.2.1] hept-2-yl] -1, dihydroformate 2-benzisothiazol-3-carboxamide, 134) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(IR, 4R) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] -1,2-benzisothiazole-3-carboxamide,

135) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(IR, 4R) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2 -yl] -1,2-benzisothiazole-3-carboxamide,

136) N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] 6- (1,4-diazabicyclo [3.2.2] non-4-yl) -1,2-benzisothiazole-dihydroformate 3-carboxamide,

137) N - [(3S) -1-Azabicyclo [2.2.2] oct-3-yl] - 6- (1,4-diazabicyclo [3.2.2] ηοη-4-yl) -1,2-dihydroformate benzisothiazole-3-carboxamide,

138) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-pyrrolidin-1-yl-1,2-benzisothiazole-3-carboxamide,

139) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (4-methylpiperazin-1-yl) -1,2-benzisothiazole-3-carboxamide,

140) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (4-methylpiperazin-1-yl) -1,2-benzisothiazole-3-carboxamide,

141) N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -6- (4-methyl-1,4-diazepan-1-yl) -1,2-benzisothiazole-3 carboxamide,

142) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (4-methyl-1,4-diazepan-1-yl) -1,2-benzisothiazole-3 carboxamide,

143) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (hexahydropyrrolo [1,2-a] pyrazin-2 (1H) -yl) -1,2-benzisothiazole -3-carboxamide,

144) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (hexahydropyrrolo [1,2-a] pyrazin-2 (1H) -yl) -1,2-benzisothiazole -3-carboxamide,

145) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (5-methyl-2,5-diazabicyclo [2.2.2] oct-2-yl) -1, 2-benzisothiazol-3-carboxamide, 146) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (5-methyl-2,5-diazabicyclo [2.2.2] oct -2-yl) -1,2-benzisothiazol-3-carboxamide,

147) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (8-methyl-3,8-diazabicyclo [3.2.1] oct-3-yl) -1, 2-benzisothiazole-3-carboxamide,

148) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (8-methyl-3,8-diazabicyclo [3.2.1] oct-3-yl) -1, 2-benzisothiazole-3-carboxamide,

149) N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -6 - [(1S, 4S) -5-cyclopropyl-2,5-diazabicyclo [2.2.1] hept-2 -yl] -1,2-benzisothiazole-3-carboxamide,

150) N - [(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -6 - [(1S, 4S) -5-cyclopropyl-2,5-diazabicyclo [2.2.1] hept-2 -yl] -1,2-benzisothiazole-3-carboxamide,

151) N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -6 - [(1S, 4S) -5- (cyclopropylamethyl) -2,5-diazabicyclo [2.2.1] hept -2-yl] -1,2-benzisothiazol-3-carboxamide,

152) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(1S, 4S) -5- (cyclopropylamethyl) -2,5-diazabicyclo [2.2.1] hept -2-yl] -1,2-benzisothiazol-3-carboxamide,

153) N - [(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -5- (4-methyl-1,4-diazepan-1-yl) -1,2-benzisothiazol-3-one carboxamide,

154) N - [(3R) -1-azabicyclo [2.2.2] oct-3-xl] -5 - [(3R) -3-methoxypyrrolidin-1-yl] -1,2-benzisothiazole-3-carboxamide,

155) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5 - [(3R) -3-methoxypyrrolidin-1-yl] -1,2-benzisothiazol-3-carboxamide,

156) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -5 - [(3S) -3-methoxypyrrolidin-1-yl] -1,2-benzisothiazol-3-carboxamide,

157) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- [thiomethylpyrrolidin-3-yl) oxy] -1,2-benzisothiazole-3-carboxamide,

158) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(1-methylpyrrolidin-3-yl) oxy] -1,2-benzisothiazol-3-carboxamide, 159 ) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1-azabicyclo [2.2.2] oct-3-yloxy) -1H-2-benzisothiazol-3-carboxamide,

160) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1-azabicyclo [2.2.2] oct-3-yloxy) -1,2-benzisothiazole-3 carboxamide,

161) δ, N'-di- (3S) -1-azabicyclo [2.2.2] oct-3-yl-1H-indazol-1,3-dicarboxamide,

162) N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -6- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -1H-indazol-2-one 3-carboxamide, 163) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) - 1H-indazol-3-carboxamide,

164) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5 - [(3S) -3- (cyclopropylmethoxy) pyrrolidin-1-yl] -1H-indazol-3-carboxamide ,

165) (3S) -1- (chloromethyl) -3 - [(1H-indazol-3-ylcarbonyl) amino] -1-azoniabicyclo [2.2.2] octane chloride,

166) N - [(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -5 - [(3S) -3-methoxypyrrolidin-1-yl] -1H-indazol-3-carboxamide dihydroformate,

167) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-chloroisothiazolo [5,4-b] pyridine-3-carboxamide,

168) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-methylpiperazin-1-yl) -1,2-benzisothiazole-3-carboxamide,

169) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (octahydro-6H-pyrrolo [3,4-b] pyridin-6-yl) -1,2- benzisothiazole-3-carboxamide,

170) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (octahydro-6H-pyrrolo [3,4-b] pyridin-6-yl) -1,2- benzisothiazole-3-carboxamide,

171) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-piperazin-1-yl-1,2-benzisothiazol-3-carboxamide,

172) N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -6-piperazin-1-yl-1,2-benzisothiazol-3-carboxamide, 173) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1,4-diazepan-1-yl) -1,2-benzisothiazole-3-carboxamide,

174) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1,4-diazepan-1-yl) -1,2-benzisothiazole-3-carboxamide,

175) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (2-methylpiperazin-1-yl) -1,2-benzisothiazole-3-carboxamide,

176) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (2-methylpiperazin-1-yl) -1,2-benzisothiazole-3-carboxamide,

177) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-Π- (cyclopropylcarbonyl) piperazin-1-yl] -1,2-benzisothiazole-3-carboxamide,

178) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] 6- [4- (cyclopropylcarbonyl) piperazin-1-yl] -1,2-benzisothiazole-3-carboxamide,

179) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] 6- [1- (cyclopropylcarbonyl) octahydro-6H-pyrrolo [3,4-b] pyridin-6-yl] -1,2-benzisothiazole-3-carboxamide,

180) N - [(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -6- [1- (cyclopropylcarbonyl) octahydro-6H-pyrrolo [3,4-b] pyridin-6-yl] -1,2-benzisothiazole-3-carboxamide,

181) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(1S, 4S) -5- (cyclopropylcarbonyl) -2,5-diazabicyclo [2.2.1] hept -2-yl] -1,2-benzisothiazol-3-carboxamide,

182) N - [(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -6 - [(1S, 4S) -5- (cyclopropylcarbonyl) -2,5-diazabicyclo [2.2.1] hept -2-yl] -1,2-benzisothiazol-3-carboxamide,

183) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] 6- (3,4-dimethylpiperazin-1-yl) -1,2-benzisothiazole-3-carboxamide,

184) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-cyano-1H-indazol-3-carboxamide,

185) 3 - [(3S) -1-Azabicyclo [2.2.2] oct-3-ylamino] carbonyl-1H-indazol-6-carboxylic acid hydrochloride, 186) Ν (3) - [(3S) -1- azabicyclo [2.2.2] oct-3-yl] -N (6), N (6) -dimethyl-1H-indazol-3,6-dicarboxamide,

187) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] - 6 - [(4-methylpiperazin-1-yl) carbonyl] -1H-indazol-3-carboxamide,

188) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(3R) -3-methoxypyrrolidin-1-yl] carbonyl-1H-indazol-3-carboxamide,

189) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-methoxyisothiazolo [5,4-b] pyridine-3-carboxamide,

190) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -5- (tetrahydro-2H-pyran-4-yloxy) -1H-indazol-3-carboxamide,

wherein the salts listed above may also be in free base form or in the form of another pharmaceutically acceptable salt, and the above-listed free base forms may also be in the form of a pharmaceutically acceptable salt,

wherein a compound listed above (in free base form or in the form of a pharmaceutically acceptable salt) may also be in the form of a solvate (such as a hydrate),

wherein a compound listed above (in free base form or in the form of a pharmaceutically acceptable salt) may also be in the form of an N-oxide,

wherein a compound listed above (in a free base form or a solvate and or an N-oxide thereof, or in the form of a pharmaceutically acceptable salt or solvate thereof) may also be in the form of a polymorph, and

wherein if the compound exhibits chirality it may be in the form of a mixture of enantiomers such as a racemate or a mixture of diastereomers, or may be in the form of a single enantiomer or a single diastereomer. The following table shows the structures for the selected compounds of the formulas. I-IV according to the present invention:

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Additional aspects include pharmaceutical compositions comprising a compound of the present invention and a pharmaceutically acceptable carrier and, optionally, another active agent as discussed below; a method for stimulating or activating inhibition of nicotinic alpha-7 receptors, for example as determined by a conventional assay or assay described herein, either in vitro or in vivo (in an animal, for example, in an animal model or in a mammal or in a human); a method for treating a neurological syndrome, e.g. memory loss, especially long-term memory, cognitive impairment or impairment, memory impairment, etc., a method for treating an alpha-7 nicotinic activity modulated disease state in a mammal, for example, a human being, for example those mentioned in the present invention.

The compounds of the present invention may be prepared conventionally. Some of the known processes that may be used are described below. All starting materials are known or can be conventionally prepared from the known departmental materials by an element skilled in the art. The acids that were used in the preparation of the bicyclobase amides were either commercially available or prepared by the known procedures described in the literature or as described below. For example, indazole-3-carboxylic acid was commercially available. A variety of single indazol-3-substituted acids, such as bromoindazole acids, was prepared from the corresponding isatins by hydrolysis, peladiazotization and basic reduction (Snyder, HR et al., J. Am. Chem. Soc. 1952, 74 , 2009).

Several substituted indazole-3 acids have been prepared by modifying existing indazole acids or esters. For example, N (I) and N (2) protected indazole acids were prepared from the ester by methylation with methoxyethoxymethyl chloride (MEM-Cl) or trimethylsilylethoxymethyl chloride (SEM-Cl) and hydride or diisopropylethylamine. N (1) -alkylated indazol-3-carboxylic acids were prepared from the corresponding indazole esters by standard alkylation or Mitsunobu procedures. N (1) -arylated indazole-3-carboxylic acids were prepared from corresponding deindazole esters by means of copper-mediated cross-couplings with boronic acids. Heterocyclic nonaromatic derivatives were prepared from corresponding debris by metal-halogen exchange, capture of indole aryl lithiums with ketones, followed by reduction or acid mediated elimination. Aromatic substituted indazole-3 acids were prepared from corresponding bromides by palladium-mediated cross-coupling with boronic acids or ten-aryl reagents (Reeder, M.R .; et.al., Org. Proc. Res. Deveri.2003, 7, 696). Indazole amino acids were prepared using a palladium-mediated cross coupling reaction with secondary arainas. Phenol derivatives were prepared from corresponding methoxy acids using boron tribromide. 6-Amino- and 6-phenyl-7-azaindazole-3-carboxylic acids were prepared from commercially available 6-fluoro material by reaction with a secondary amine or nickel-mediated cross-coupling with aryla Grignard reagents. Substituted indazole-3 were prepared from benzene derivatives. For example, 5-difluoromethoxyindazole-3 acid was prepared from 3-bromo-4-nitrophenol by reaction with ethyl difluoroacetate, reaction with diethyl malonate, decarboxylating aponification, esterification, nitro group reduction and diazotization. 6-Difluoromethoxyindazole-3-acid was prepared in a manner similar to 2-bromo-5-difluoromethoxynitrobenzene. 2-Bromo-5-difluoromethoxynitrobenzene was prepared from 4-nitrophenol by ether formation, concomitant nitro reduction as amide, nitration, amide hydrolysis and a Sandmeyer reaction with copper (I) bromide. 6-Benzyloxyindazole-3-carboxylic acid and ester were prepared from 4-methoxynitrobenzene by concomitant protection such as amide, nitration, amide hydrolysis, Sandmeyer's reaction with copper (I) bromine and demethylation. Benzyl brometode alkylated phenol and aryl bromide were subjected to reaction with diethylmalonate, decarboxylating saponification, esterification, nitro group reduction and diazotization. The 5-benzyloxy analog was prepared in a similar manner to 4-benzyloxy-2-bromonitrobenzene (Parker, A.A.; Mindt, TLOg. Lett. 2002, 4, 4265.) The benzyl group was removed by hydrogenolysis and the resulting phenol. was transformed into ether derivatives through Mitsunobu alkylation or darning conditions. Acid 4-methoxyindazole was prepared from 4-methoxy aniline by amide formation, pellitanation, starch hydrolysis, Sandmeyer reaction with copper (I) bromide, nitroreduction, deisatin formation and rearrangement for indazole, followed by hydrogenolytic removal of bromine. 5-azaindazole-3-acid was prepared from 4-chloropyridine by metallation and diethyloxalate capture, cyclization with hydrazine and sponification. 6-Azaindazole-3-acid was prepared from 4-chloro-3-nitropyridine by reaction with a demalonate anion, decarboxylation, nitro reduction, diazotization and saponification.

Benziosoxazole esters were prepared from simple benzene derivatives using similar techniques. For example, 6-bromobenzisoxazole-3-carboxylate ethyl was prepared from 2-nitro-1,4-dibromobenzene by reaction with dimethyl malonate, a deconification / decarboxylation sequence, esterification and isoamyl nitrite reaction under basic conditions. The 6-methoxybenzisoxazole ester compound was prepared analogously from 2,4-dinitrochlorobenzene. Reduction of the resulting S-nitro group followed by diazotization and oxidation resulted in 6-hydroxy compound. Ether was obtained by simple alkylation.

Benzisothiazole carboxylic acids were also prepared using similar strategies outlined for indazole acids. For example, S-methoxybenzisothiazole-3-carboxylic acid was prepared from 3-methoxythiophenol by reaction with oxalyl chloride and aluminum chloride followed by treatment with hydroxylamine, hydrogen peroxide and desodium hydroxide. Substituted benzisothiazole amino acids were prepared from the necessary bromide by a palladium-mediated cross-coupling reaction with secondary amino or benzophenone imine. The secondary secondary amines generated in this manner serve as intermediates for other ligands. For example, amines have been transformed into tertiary amines and amides using standard amination and acylation reducing reactions practiced by those skilled in the art. 7-Azabenzisothiazole-3-carboxylic acid was prepared from 2-chloronicotinoyl chloride by anion reaction and diethyl malonate carboxylation followed by deacetone reaction with sulfur, ammonium hydroxide and ammonia to quench the 7-aza-nucleus. 3-methylbenzisothiazole. The acid was installed using benzyl N-bromosuccinamide oxidation and hydrolysis, followed by basic oxidation. alcohol permanganate. 7-aza-6-chlorobenzisothiazole-3 acid was synthesized from the 7-aza-3-methylbenzisothiazole nucleus by pyridine ring nitrogen oxidation followed by a triphosphene-mediated rearrangement reaction to install a chlorine atom at position 6. Synthesis was terminated by benzyl oxidation in a similar manner to unsubstituted azabenzisothiazole acid.

Bicycloamines, 3-aminoquinuclidine and ReS osenantiomers thereof used in the preparation of bicyclobase amides were commercially available. N-alkylated quinquinuclidines were prepared by acylation of 3-aminoquinuclidine followed by amide reduction.

Bicyclobase amides were prepared from acids and bicycloamines using standard peptide coupling agents such as O- (benzotriazol-1-yl) -Ν, Ν, Ν *, N'-tetramethyluronium (HBTU) hexafluorophosphate, O- (7-azabenzotriazol-1-yl) -Ν, Ν, Ν1, N'-tetramethyluronium (HATU), O- (benzotriazol-1-yl) tetrafluoroborate -Ν, Ν, Ν ', N1-tetramethyluronium (TBTU) ), hydroxybenzotriazole (HOBt) and N- (3-dimethylaminopropyl) -N1-ethylcarbodiimide (EDCI), carbonyl diimidazole (CDI) and 2-chloro-1,3-dimethylimidazolinium (CIP) or when converting the acids to the corresponding acid chloride followed by bicyclamine reaction (Macor, JE; Gurley, D .; Lanthorn, T.; Loch, J .; Mack, RA; Mullen, G .; Tran, o; Wright, N .; and JE Macor et al., " The 5-HT3-AntagonistTropisetron (ICS 205-930) was a Potent and Selective t-7Nicotinic Partial Receptor AgonistBioorg. Med. Chem. Lett.2001, 9, 319-321) The couplings were performed generally at temperatu at room temperature for 18-24 hours. The resulting adducts were isolated and purified by standard techniques practiced by elements skilled in the art, such as chromatography or recrystallization.

Nicotinic ligands may alternatively be prepared by modifying other nicotinic ligands. For example, the urea cyclic ligand was prepared from the corresponding bromine ligand by a palladium-catalyzed cross coupling reaction. Amino-substituted ligands were prepared by similar palladium mediated coupling reactions with secondary amines or benzophenoneimine. The primary and secondary amines thus generated serve as intermediates for other ligands as understood by those skilled in the art. 5-Alkoxybenzisothiazole ligands were prepared by palladium-mediated cross-coupling with the depinacolborane dimer followed by oxidation and alkylation. In some cases, indazol quinuclidine carboxamides were derivatized into indazole nitrogen under Mitsunobu conditions or through copper-mediated coupling with boronic acids. Quaternary quinuclidine salts were prepared by reaction of the final product with alkylating agents. N-oxides were prepared by reaction of the final product with oxidants.

One skilled in the art will recognize that the compounds of Formulas I-IV may exist in different isomeric, tautomeric and geometric forms. All of these compounds, including useful isomers, trans isomers, diastereomeric mixtures, racemates, non-rheumatic enantiomer mixtures, substantially pure entantiomers and pure enantiomers, are within the scope of the present invention. Substantially pure enantiomers contain no more than 5% by weight / weight of the corresponding opposite enantiomer, preferably more than 2%, and most preferably more than 1%.

Optical isomers may be obtained by defining racemic mixtures according to conventional procedures, for example, by formation of isomeric diastereoisomer salts using an optically active acid or base or formation of covalent diastereomers.

Examples of suitable acids include tartaric acid, diacetyl tartaric acid, dibenzoyl tartaric acid, ditholuoyltartaric acid and camphorsulfonic acid. Mixtures of diastereoisomers may be separated into their individual diastereomers based on their physical and / or chemical differences by methods known to those skilled in the art, for example by chromatography or fractional crystallization. The optically active bases or acids are then released from the separated diastereomeric salts. A different process for the separation of optical isomers involves the use of chiral chromatography (for example chiral HPLC columns), with or without conventional adhesion, ideally chosen to maximize enantiomer separation. Suitable HPLC columns are manufactured by Diacel, for example Chiracel OD and Chiracel OJ among many others, all routinely selectable. Enzymatic separations, such as without derivatization, are also useful. The optically active compounds of Formulas I-IV may likewise be obtained using optically active starting materials and chiral synthesis processes under reaction conditions that do not cause racemization.

In addition, one skilled in the art will recognize that the compounds may be used in different enriched isotopic forms, for example, enriched to 2H, 3H, 11C, 13C and / or 14C content. In a particular embodiment, the compounds are deuterated. Such deuterated forms may be obtained by the procedure described in U.S. Pat. 5,846,514 and 6,334,997. As described in U.S. Pat. 5,846,514 and 6,334,997, de-activation can increase the effectiveness and increase the duration of drug action.

Deuterium substituted compounds can be synthesized using various methods as described in: Dean, Dennis C .; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and

Development [In: Curr., Pharm. Des., 2000; 6 (10)] (2000), 110 pp. CAN 133: 68895 AN 2000: 473538 CAPLUS; Kabalka, George W.; Varma, Rajender S. The synthesis of radiolabeled compounds via organometallic intermediates. Tetrahedron (1989), 45 (21), 6601-21, CODEN: TETRAB ISSN: 0040-4020. CAN112: 20527 AN 1990: 20527 CAPLUS; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem. (1981), 64 (1-2), 9-32. CODEN: JRACBN ISSN: 0022-4081, CAN95: 76229 ANT 1981: 476229 CAPLUS.

Where applicable, the present invention also provides useful forms of the compounds as described in the present invention, such as pharmaceutically acceptable salts or prodrugs of all compounds of the present invention for which salts or prodrugs may be prepared. Pharmaceutically acceptable salts include those obtained by reaction of the parent compound, acting as a base, with an inorganic or inorganic acid to form a salt, for example, hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphor sulfonic acid, oxalic, malic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid and carbonic acid. Pharmaceutically acceptable salts also include those wherein the major compounds function as an acid and react with a base suitable for the formation, for example, of sodium, potassium, calcium, magnesium, ammonium and choline salts. The skilled artisan will also recognize that the acid addition salts of the claimed compounds may be prepared by reacting the compounds with the appropriate inorganic or organic acid by any method of a number of known methods. Alternatively, alkali demetal salts and alkaline earth metal salts may be prepared by reacting the compounds of the invention with an appropriate base by a variety of known methods.

The following are additional examples of acidic salts that may be obtained by reaction with inorganic or organic acids: acetates, adipates, alginates, citrates, aspartates, benzoates, benzenesulfonates, bisulfates, butyrates, camphorates, digluconates, cyclopentane propionates, dodecyl sulfates, ethane sulfonates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, fumarates, hydrobromides, hydroiodides, 2-hydroxyethane sulfonates, lactates, maleates, methanes, sulfonates, nicotinates, 2-naphthalene sulfonates, oxalates, palmoates, phephionates, phepropionates , picarates, pivalates, propionates, succinates, tartrates, thiocyanates, tosylates, mesylates and hendecanoates.

For example, the pharmaceutically acceptable salt may be a hydrochloride, a hydrobromide, a hydrochloride or a maleate.

Salts of the present invention also include the quaternary ammonium salts obtained by reacting the nucleophilic parent compound with nucleofugal carrier groups. Examples of such agents include, but are not limited to, methyl iodide, methyl bromide, methyl chloride, methyl triflate, methyl tosylate, methyl mesylate, ethyl iodide, ethyl bromide, ethyl chloride, ethyl triflate, tosylate deethyl, ethyl mesylate, propyl iodide, depropyl bromide, propyl chloride, cyclopropylmethyl bromide, benzyl bromide, methylene chloride and dichloroethane. The skilled artisan will recognize that the list of agents in the examples presented is non-exhaustive and may be expanded rationally.

For example, the quaternary ammonium salt may be formed on the N atom of the azabicyclic structure as shown in the following formula:

<formula> formula see original document page 105 </formula>

wherein Z is, for example, methyl, chloromethyl, ethyl, chloroethyl, propyl, cyclopropylmethyl or benzyl and the corresponding anion A is, for example, iodide, bromide, chloride, triflate, tosylate or mesylate. See, for example, compounds 1, 13 and 165.

Preferably, the salts formed are pharmaceutically acceptable for mammalian administration.

However, the pharmaceutically unacceptable salts of the compounds are suitable as intermediates, for example, to isolate the compound as a salt and then convert the salt back to the free compound by treatment with an alkaline reagent. For example, alkyl halide addition salts (for example, salts formed by reaction with methyl iodide) may be provided. The free base may then, if desired, be converted to a pharmaceutically acceptable acid addition salt.

One skilled in the art will also recognize that any of the compounds of Formulas I, II, III and IV may exist in different polymorphic forms. As known in the art, polymorphism is the ability of a compound to crystallize as more than one crystalline species. or distinct "polymorphic". A polymorph is a solid crystalline phase of a compound with at least two different arrangements or polymorphic forms of such a molecule composed in the solid state. The polymorphic forms of any compound are defined by the same formula or chemical composition and are as distinct in chemical structure as the crystal structures of two different chemical compounds.

One skilled in the art will further recognize that the compounds of Formulas I, II, III and IV may exist in different solvate forms. Solvates of the compounds of the invention may also form when solvent molecules are incorporated into the crystalline structure of the atom distribution arrangement of the compound molecule during the crystallization process.

Numerous standard references are available which describe procedures for preparing various formulations suitable for administration of the compounds according to the invention. Examples of potential formulations and preparations are contained, for example, in the Handbookof Pharmaceutical Excipients, American Pharmaceutical Association (current edition); Pharmaceutical Dosage Forms: Tablets (Lieberman, Lachman and Schwartz, editors) current edition, published by Mareei Dekker, Inc., as well as in Remington1S Pharmaceutical Sciences (Arthur Osol, editor), 1553-1593 (current edition).

In view of their alpha-7 stimulating activity and, preferably, by their high high degree of selectivity, the compounds of the present invention may be administered to anyone requiring alpha-7 receptor stimulation. Administration may be performed according to the needs of the patients, for example orally, nasally, parenterally (subeutaneously, intravenously, intramuscularly, intrasternally and by infusion) by inhalation, rectally, vaginally, topically and by ocular administration.

Various solid oral dosage forms may be used for the administration of the compounds of the invention including solid forms such as tablets, ice capsules, capsules, coated capsules, granules, lozenges and powders. The compounds of the present invention may be administered alone or in combination with various carriers, diluents (such as sucrose, mannitol, lactose, starches) and pharmaceutically acceptable excipients known in the art, including, but not limited to, suspending agents, solubilizers, sizing agents, binders, disintegrants, preservatives, dyes, flavorings, lubricants and the like. Time-release capsules, tablets and the like are also advantageous in administering the compounds of the present invention.

Various liquid oral dosage forms may also be used for the administration of the inventive compounds, including non-aqueous, syrupy solutions, emulsions, suspensions; and elixirs. Such dosage forms may also contain appropriate inert diluents known in the art, such as water and appropriate art-known excipients, such as preservatives, wetting agents, sweeteners, flavorings, as well as emulsifying and / or suspending agents. compounds of the invention. The compounds of the present invention may be injected, for example, intravenously, in the form of a sterile isotonic solution. Other preparations are also possible.

Suppositories for rectal administration of the compounds of the present invention may be prepared by mixing the compound with an appropriate excipient such as cocoa butter, salicylates and polyethylene glycols.

Formulations for vaginal administration may be in the form of a pessary, buffer, cream, gel, paste, foam or a spray formula containing, in addition to the active ingredient, suitable carriers as known in the art.

For topical administration, the pharmaceutical composition may be in the form of creams, ointments, ointments, lotions, emulsions, suspensions, gels, solutions, pastes, powders, sprays and drops suitable for administration to the skin, eyes, ears or nose. Topical administration may also involve transdermal administration through means such as transdermal patches.

Aerosol formulations suitable for administration by inhalation may also be obtained.

For example, for the treatment of airway disorders, the compounds according to the invention may be administered by inhalation in the form of a powder (e.g., micronized) or in the form of atomized solutions or de-suspensions. The aerosol formulation may be placed in an acceptable pressurized propellant.

The compounds may be administered as the sole active agent or in combination with other pharmaceutical agents such as other agents used to treat cognitive degeneration and / or memory loss, for example, other α-7 agonists, PDE4 inhibitors, calcium channel blockers, mle m2 muscarinic modulators, adenosine receptor modulators, amphacin NMDA-R modulators, mGluR modulators, dedopamine modulators, serotonin modulators, decanabinoid modulators and cholinesterase inhibitors (e.g., donepezil, rivastigimine and glantanamine). In such combinations, each active ingredient may be administered according to its usual dosage range or a dose below its usual dosage range.

The compounds of the invention may be used in conjunction with "positive modulators" that enhance the efficacy of nicotinic receptor agonists. See, for example, the positive modulators described in patent applications WO 99/56745, WO 01/32619 and WO 01/32622. Combinatorial taltherapy may be used in the treatment of conditions / diseases associated with nicotinic-reduced transmission. In addition, the compounds may be used in conjunction with compounds which bind to the APe peptides thereby inhibiting the binding of peptides to the subtype 7nACh. See, for example, patent application WO 99/62505.

The present invention further includes treatment methods involving activation of nicotinic α-7 receptors. Accordingly, the present invention includes methods of selective activation / stimulation of α-7-nicotinic receptors in animals (e.g., a mammal, such as a human), wherein such activation / stimulation has a therapeutic effect, such as where such activation may alleviate conditions. involving neurological syndromes, such as memory impairment, especially long-term memory. Such methods include administering to a patient in need of treatment (e.g., a mammal, such as a human) an effective amount of a compound of Formula I. IV alone or as part of a formulation as described in the present invention.

According to one aspect of the method of the invention, there is provided a method for treating a patient (e.g., a mammal such as a human) suffering from a disease state (e.g., memory degeneration), which comprises administering to the patient of a compound according to Formulas I-IV. Preferably, the finger state involves decreased cholinanicotinic acetyl receptor activity.

According to one aspect of the method of the invention, there is provided a method for the treatment or prophylaxis of a disease or condition resulting from nicotinic acetylcholine receptor transmission dysfunction in a mammal, for example, a human, which comprises administering a effective amount of a compound according to Formulas I-IV. According to one aspect of the method of the invention, there is provided a method for the treatment or prophylaxis of a disease or condition resulting from defective or malfunctioning nicotinic deacetylcholine receptors, particularly α7nACh receptors, in a patient (e.g., a mammal such as a human) which comprises administering an effective amount of a compound according to Formulas I-IV.

According to one aspect of the method of the invention, there is provided a method for treating or prophylaxis of a disease or condition resulting from the suppressed nicotinic acetylcholine receptor transmission in a patient (e.g., a mammal, such as a human) which comprises administering an amount of a compound according to Formulas I-IV effective to activate α7nACh receptors.

According to another aspect of the invention method, a method for treating or prophylaxis of a psychotic disorder, cognitive degeneration (e.g. memory degeneration) or neurodegenerative disease in a patient (e.g. a mammal such as a which comprises administering an effective amount of a compound according to Formulas I-IV.

According to another aspect of the inventive method, there is provided a method for treating or aprophylaxis of a disease or condition resulting from the loss of cholinergic synapses in a patient (e.g., a mammal, such as a human), which comprises administering an effective amount of a compound according to Formulas I-IV.

According to another aspect of the inventive method, there is provided a method for the treatment or prophylaxis of a neurodegenerative disorder by activating α7nACh receptors in a patient (e.g., a mammal, such as a human), which comprises administering a effective amount of a compound according to Formulas I-IV.

According to another aspect of the invention method, a method for protecting neurons in a patient (e.g., a mammal, such as a human) is presented against neurotoxicity induced by activation of α7nACh receptors, which comprises administering an effective amount. of a compound according to Formulas I-IV.

According to another aspect of the invention method, a method for treating or aprophylaxis of a neurodegenerative disorder by inhibiting the attachment of AR peptides to α7nACh receptors in a patient (e.g., a mammal, such as a human) is presented, which comprises administering an effective amount of a compound according to Formulas I-IV.

According to another aspect of the invention method, a method for protecting neurons in a patient (e.g., a mammal such as a human) against RA-induced neurotoxicity is disclosed which comprises administering an effective amount of a neuron. compound according to Formulas I-IV.

According to another aspect of the inventive method, a method for alleviating inhibition of cholinergic dysfunction induced by AR peptides in a patient (e.g., a mammal, such as a human being) is disclosed which comprises administering an effective amount. A subject or patient for whom the administration of the therapeutic compound is an effective therapeutic regimen for a disease or disorder is preferably a human, but may be any animal, including a laboratory animal in the context of a given compound. a clinical or experimental experience of selection or activity. Thus, as can be readily appreciated by a skilled artisan, the methods, compounds and compositions of the present invention are particularly suited for administration to any animal, particularly a mammal and include, but are not limited to, humans, domestic animals, such as dogs and dogs, farm animals such as, but not limited to, cattle, horses, goats, sheep and swine, wild animals (in the jungle or in a zoo), research animals such as mice, rats, rabbits, goats, sheep, pigs, dogs, cats, etc., avian species such as chickens, turkeys, songbirds, etc., ie for veterinary medical use.

The compounds of the present invention are nicotinic alpha-7 ligands, preferably agonists, especially partial agonists, for the alpha-7 nicotinic acetylcholine receptor. Assays for determining nicotinic acetylcholine activity are known in the art. See, for example, Davies, A.R., et al. , Characterization of the binding of [3H] methyllycaconitine: a new radioligand forlabelling alpha 7-type neuronal nicotinic acetylcholinereceptors. Neuropharmacology, 1999.38 (5): pages 679-90.

As agonists for α-7 nAChRs, the compounds are useful in the prophylaxis and treatment of a variety of diseases and conditions associated with the central nervous system. Nicotinic acetylcholine receptors are the docanal ion receptors of the gastrol ligand that are composed of five protein subunits that form an ionscentral conductive pore. There are currently eleven known nAChR neuronal subunits (α2-α9 and β2-β4). There are also five additional subunits expressed in the peripheral nervous system (α1, β1, γ, δ, ε).

The nAChR receptor subtypes may be homopentameric or heteropentameric. The subtype that received considerable attention was the a-7 doreceptor homopentamer subtype formed from five a7 subunits. 0a7nAChrs exhibits high affinity for nicotine (agonist) and α-bungarotoxin (antagonist). Studies have shown that a7-nAChR agonists may be useful in treating psychotic disorders, neurodegenerative disorders, and cognitive impairment, among other things. Although nicotinase is a known agonist, there is a need for the development of other a7-nAChR agonists, especially selective agonists that are less toxic or exhibit fewer side effects than nicotine.

The anabasein compound, ie 2- (3-pyridyl) -3,4,5,6-tetrahydropyridine, is a toxin that occurs naturally in certain marine worms (worms) and ants. See, for example, Kern et al. , Toxicon, 9:23, 1971. Anabasein is a potent activator of mammalian nicotinic receptors. See, for example, Kem, Amer. Zoologist, 25, 99, 1985. Certain deanabasein analogs such as anabasine and DMAB (3- [4- (dimethylamino) benzylidene] -3,4,5,6-tetrahydro-2 ', 3'-bipyridine) are also agonists of known nicotinic receptor. See, for example, U.S. Patent no. 5,602,257 and patent application WO 92/15306. A particular analogue of anabasein, (E-3- [2,4-dimethoxybenzylidene] anabasein, also known as GTS-21 and DMXB (see, for example, US Patent No. 5,741,802), is a selective selective agonist of a7- For example, abnormal sensory inhibition is a deficit of sensory processing in schizophrenics, and GTS-21 has been found to increase sensory inhibition through interaction with al -nAChRs, see, for example, Stevens et al., Psychopharmacology, 136 : 320-27 (1998).

Another compound that is known to be selective ocl-nAChR umagonist is Tropisetron, i.e. IaH, 5aH-tropan-3a-yl indol-3-carboxylate. See I. E. Macor et al., The 5-HT3-Antagonist Tropisetron (ICS 205-930) is a Potentand Selective A 7 Nicotinic Partial Agonist Receptor. Bioorg.Med. Chem. Lett. 2001, 319-321).

Agents that bind to nicotinic acetylcholine receptors have been specified as useful in the prophylaxis and / or treatment of various diseases and conditions, particularly psychotic disorders, neurodegenerative disorders that involve cholinergic system dysfunction and conditions of memory and / or cognition degeneration, including, for example schizophrenia, anxiety, mania, depression, manic depression [examples of psychotic disorders], Tourette's syndrome, Parkinson's disease, Huntington's disease [examples of neurodegenerative diseases], cognitive disorders (such as Alzheimer's disease, dementia with Lewy bodies, amyotrophic lateral sclerosis, memory degeneration, memory loss, cognitive impairment, attention deficit, Attention Deficit Disorder) and other uses such as treatment of denicotin addiction, induction of smoking cessation, pain management (ie, use of analgesics), the provision of neuroprotection , the treatment of time zone dizziness, inflammation or sepsis. See, for example, WO 97/30998 patent applications; WO 99/03850; WO 00/42044; WO 01/36417; Holladayet al., J. Med. Chem., 40: 26,4169-94 (1997); Schmitt et al., Annual Reports Med. Chem., Chapter 5, 41-51 (2000); Stevenset al., Psychopharmacology, (1998) 136: 320-27 (1998); eShytle et al., Molecular Psychiatry, (2002), 7, pages 525-535.

Thus, according to the invention, there is provided a method for treating a patient, especially a human being, suffering from psychotic disorders, neurodegenerative disorders involving dysfunction of the cholinergic system and conditions of cognitive and / or memory impairment, including, eg schizophrenia, anxiety, mania, depression, manic depression [examples of psychotic disorders], Tourette's syndrome, Parkinson's disease, Huntington's disease [examples of neurodegenerative disorders] and / or cognitive disorders (such as Alzheimer's disease, dementia with Lewy bodies amyotrophic lateral sclerosis, memory degeneration, memory loss, cognitive impairment, attention deficit, Attention Deficit Disorder), which comprises administering to the patient an effective amount of a compound according to Formulas I-IV.

Neurodegenerative disorders included in the methods of the present invention include, but are not limited to, prophylaxis and / or treatment of Alzheimer's disease, Pick's disease, diffuse Lewy body disease, progressive supranuclear palsy (SteelRichardson's syndrome), multivessel degeneration. systemic disease (Shy-Drager syndrome), diseases including amyotrophic lateral sclerosis, degenerative ataxias, neuromotor diseases, cortical basal degeneration, ALS-Parkinson-Guam complex dementia, Huntington's disease, Huntington's disease, Parkinson's disease, synucleinopathies, primary progressive aphasia, striatonigral degeneration, Machado-Joseph disease / type 3 cerebrospinal ataxia, spinocerebellar ataxia, cerebellopontine degeneration, Gilles De La Tourette's disease, pseudobulbar paralysis, spinal muscular atrophy, spinobulbar atrophy, Kennel's disease, familial lateral sclerosis, familial spastic paraplegia , Kugelberg-Welander evil, Tay-evil Sach, Sandhoff's Disease, Familial Spastic Disease, Wohlfart-Kugelberg-Welander Disease, Spastic Paraparesis, Progressive Multifocal Leukoencephalopathy, Prion Diseases (such as Creutzf eld-Jakob Disease, Gerstmann-Straussler-Scheinker Disease, Kuru and Fatal Familial Insomnia) neurodegenerative disorders resulting from cerebral ischemia or infarction, including embolic occlusion and thrombotic occlusion as well as intracranial hemorrhage of any kind (including but not limited to epidural, subdural, subarachnoid and intracerebral hemorrhage) and intracranial and intraventricular lesions (including but not limited to them) limited, occlusion, penetration, cutting, compression and laceration).

In addition, α7-nAChRs receptor agonists, such as the compounds of the present invention, may be used in the treatment of age-related dementia and other memory-depleting conditions including age-related memory loss, asenility, vascular dementia, diffuse white matter disease (Binswanger's disease), dementia of endocrine or metabolic origin, dementia due to traumatic brain injury and diffuse brain damage, dementia and frontal lobe dementia. See, for example, patent application WO 99/62505. Accordingly, according to the invention, there is provided a method for treating a patient, especially a human, suffering from age-related dementia and other memory-dementing conditions, which comprises administering to the patient an effective amount of a compound of according to Formulas I-IV.

Thus, according to a further embodiment, the present invention includes methods for treating patients suffering from memory degeneration, for example due to mild cognitive impairment due to aging, Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeld-Jakob's disease, depression, aging, head injury, cerebrovascular accident, CNS hypoxia, cerebral senility, multi-infarct dementia and other neurological conditions, as well as HIV and cardiovascular disease, which includes administration of an effective amount of a compound according to Formulas I-IV.

Amyloid precursor protein (APP) and AR-peptides derived therefrom, e.g. ββ.40, ββ-42 and other fragments, are known to be involved in the pathology of Alzheimer's disease. Peptides A (3142) are implicated not only in neurotoxicity but are also known to inhibit cholinergic transmitter function.

Additionally, it has been determined that the AR peptides select nAChRs a-7. Thus, agents that block RA peptide from being targeted to nAChRs a-7 are useful for treating neurodegenerative diseases. See, for example, patent application WO 99/62505. In addition, a-7 stimulating nAChRs can protect neurons against apeptide-associated acitotoxicity. See, for example, Kihara, T. et al., Ann. Neurol., 1997, 42, 159.

Thus, according to one embodiment of the invention, a method for treating and / or preventing dementia in an Alzheimer's patient is disclosed which comprises administering to the patient a therapeutically effective amount of a compound according to Formulas I-IV to inhibit the binding of a betaamyloid peptide (preferably A (31_42) with nAChRs, preferably nChRs o-7, most preferably human a-7 nAChRs (as well as a method for treating and / or preventing other clinical manifestations of the disease). Alzheimer's, including, but limited to, language-cognitive deficits, apraxias, depression, delusions, and other symptoms and neuropsychiatric signs and movement and gait abnormalities).

The present invention also provides methods for treating other amyloid diseases, for example, hereditary cerebral angiopathy, hereditary non-neuropathic amyloid disease, Down syndrome, macroglobulinemia, secondary familial febredo, Muckle-Wells syndrome, multiple myeloma, ecardiac pancreatic amyloidosis, chronic hemodialysis, anthropathy and amyloidosis from Finland and Iowa.

In addition, nicotinic receptors have been implicated as playing a role in the body's response to alcohol intake. Thus, a7-nAChR agonists may be used in the treatment of alcohol withdrawal and detoxification therapy. Accordingly, according to one embodiment of the invention, a method for treating a patient for suspending alcohol or treating a patient with detoxification therapy is provided, which comprises administering to the patient an effective amount of a compound according to the present invention. Formulas I-IV.

Agonists for α-7nAChR receptor subtypes may also be used for neuroprotection against damage associated with stroke and ischemia and glutamate-induced excitotoxicity. Accordingly, according to one embodiment of the invention, a method for treatment is disclosed. of a patient to provide neuroprotection against damage associated with stroke and glutamate-induced ischemia and ecotoxicity, which comprises administering to the patient an effective amount of a compound according to Formulas I-IV.

As noted above, agonists for α-7nAChR receptor subtypes may also be used in the treatment of nicotine addiction, induction of smoking cessation, treatment of pain in the treatment of time zone dizziness, obesity, dediabetes, inflammation and sepsis. Thus, according to one embodiment of the invention, there is provided a method for treating a patient suffering from denicotin, pain, time zone dizziness, diabetes, deobesity and / or a method for inducing a patient. smoking trim, which comprises administering to the patient an effective amount of a compound according to Formulas I-IV.

The inflammatory reflex is an autonomic nervous system response to an inflammatory signal. Upon detecting an inflammatory stimulus, the autonomic nervous system responds through the vagus nerve by releasing acetylcholine and activating nicotinic α-7 receptors in macrophages. These macrophages in turn release cytokines. The dysfunctions in this truck were linked to human inflammatory diseases including rheumatoid arthritis, diabetes and septicemia. Macrophages express the nicotinic α-7 receptor and this receptor is likely to measure the cholinergic antiinflammatory response.

Therefore, macrophage -0.7nACh receptor affinity compounds may be useful for human inflammatory diseases including rheumatoid arthritis, diabetes and asepticemia. See, for example, Czura, CJ et al., J. Intern.Med., 2005, 257 (2), 156-66. Accordingly, according to one embodiment of the invention, a method of treating a patient (e.g. example, a mammal, such as a human) suffering from an inflammatory disease, such as, but not limited to, rheumatoid arthritis, diabetes or septicemia, which comprises administering to the patient an effective amount of a compound according to the invention. with Formulas I-IV.

In addition, because of their affinity for cx7nACh receptors, labeled derivatives of the compounds of Formulas I-IV (e.g., derivatives labeled Cl1 or F18) may be used in generating receptor neuroimagery within, for example, the brain. Thus, the use of such labeled agents in in vivo imaging of receptors can be performed using, for example, PET imaging.

The condition of memory degeneration is manifested by the degeneration of the ability to learn new information and / or the inability to recall previously learned information. Memory degeneration is a primary symptom of dementia and may also be a symptom associated with diseases such as Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeld-Jakob disease, HIV disease. cardiovascular and traumatic brain injury as well as cognitive decline related to age.

Thus, according to one embodiment of the invention there is provided a method of treating a patient who suffers, for example, from mild cognitive degeneration (MCI), vascular dementia (VaD), age-associated cognitive decline (AACD), amnesia associated with open heart surgery, cardiac arrest and / or general anesthesia, memory deficits from previous exposure to anesthetic agents, sleep deprivation-induced cognitive degeneration, chronic fatigue syndrome, narcolepsy, AIDS-related dementia, epilepsy-related cognitive degeneration, Down's syndrome , alcohol-related dementia, drug / substance-induced memory degeneration, boxer dementia (Boxer's Syndrome) and animal dementia (eg dogs, cats, horses, etc.), which comprises administering to the patient an effective amount of a drug. compound according to Formulas I-IV.

Dosages of the compounds of the present invention depend on a variety of factors including the particular syndrome to be treated, the severity of symptoms, the route of administration, the frequency of dosing interval, the particular compound used, the efficacy, the toxicological profile, the pharmacokinetic profile of the compound. and the presence of all deleterious side effects, among other considerations.

The compounds of the invention may be administered to patients, e.g. mammals, particularly humans, at typical dosage levels customary for nicotinic α-7 receptor agonists such as the above-mentioned nicotinic α-7 receptor agonist compounds.

For example, the compounds may be administered in single or multiple doses by oral administration at a dosage level of for example 0.0001-10 mg / kg / day, for example 0.01-10 mg / kg / day. day. Unit dosage forms may contain, for example, 1-200 mg of active compound. For intravenous administration, the compounds may be administered in single or multiple dosages.

In practicing the procedures of the present invention, it should naturally be understood that references to buffers, media, reagents, cells, particular culture conditions, and the like are not yet intended as limiting, but should be read to include all related materials that an element skilled in the art should be aware of. as being of interest or value in the particular context in which this discussion is presented. For example, it is usually possible to replace one buffering system or culture medium with another and still achieve similar results when not identical. Those skilled in the art should have sufficient knowledge of such systems and methodologies to be able, without self-experimentation, to make substitutions to serve their purposes of use of the methods and procedures described in the present invention.

The present invention will now be further described by means of the following non-limiting examples. In applying the description of these examples, it should be clearly borne in mind that other embodiments and embodiments other than the methods described in accordance with the present invention will undoubtedly suggest to yourself those elements skilled in the relevant art.

In the above and in the following examples, all temperatures are determined uncorrected in degrees Celsius; and unless otherwise indicated, all parts and percentages are by weight.

The entire descriptions of all applications, patents and publications, cited above and below, are incorporated by reference into the present invention.

Using the following procedures and additional procedures described below, the following compounds were prepared. Other examples of synthesis are described in U.S. Patent Application Nos. 11 / 089,533 and 10 / 669,645, incorporated herein by reference.

All spectra were recorded at 300 MHz on a Bruker Instruments NMR unless otherwise specified. Coupling constants (J) are in Hertz (Hz) and peaks are listed relative to TMS (δ0.00 ppm). Microwave reactions were performed using 2.5 ml or 5 ml Personal ChemistryOptimizer ™ microwave reactor flasks. All reactions were performed at 200 ° C for 600 seconds with the fixed control time on unless otherwise specified. Sulfonic acid ion exchange resins (SCX) were purchased from Varian Technologies. Analytical HPLC was performed on 4.6 mm χ 100 mm XterraRP18 3.5 μ columns using a gradient of 20/80 to 80/20 water (0.1% formic acid) / acetonitrile (0.1% formic acid) for six minutes.

Preparative HPLC was performed on 30mm χ 100mm Xterra Prep RPi8 5μ columns using (i) an 8 minute gradient of 20/80 to 80/20 acetonitrile (0.1% formic acid) / water (0 ° C). 1% formic acid) (compounds 1-50, 54-57, 59, 60, 63-77, 79-131 and 149-185), (ii) a 30 minute gradient of 5/95 to 95/5 of acetonitrile (0.05% trifluoroacetic acid) / water (0.05% trifluoroacetic acid) (compounds 51-53), (iii) an 8 minute gradient of 10/90 to 60/40 acetonitrile (0.1% formic acid) / water (0.1% formic acid) (compounds 58, 61, 62.78 and 132-137), (iv) an 8 minute gradient of 5/95 to 60/40 acetonitrile (0.1% acid water (0.1% formic acid) (compounds 18 6-190) or (v) an 8 minute gradient of 10/90 to 80/20 acetonitrile (0.1% formic acid) / water ( 0.1% formic acid) (compounds 138-148).

Acid Preparations. The following procedures (1-29) detail the preparation of indazole, benzisoxazole and benzisothiazole acids and esters that were not commercially available.

Procedure 1

Procedure 1 provides a preparation of substituted benzisothiazole-3-carboxylic acids from corresponding dostiophenols.

To a solution of 3-methoxythiophenol (26.7 mmol) ether (20 mL) was added oxalyl chloride (43 mmol) by dripping. The mixture was heated at reflux for one hour, cooled to room temperature (RT) and concentrated in vacuo. The resulting yellow oil was dissolved in dichloromethane (50 mL), cooled to 0 ° C and treated with aluminum chloride (32.0 mmol) in portions. The mixture was refluxed for 30 minutes, cooled to room temperature and poured into ice water with stirring.

The organic layer was separated and washed successively saturated aqueous sodium combicarbonate, water and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography (4/1 ethyl acetate / hexane), thereby yielding 6-methoxy-1-benzothiophene-2,3-dione in 47% yield as an orange solid.

To a mixture of dione (0.44 mmol) in a 30% aqueous solution of ammonium hydroxide (2.0 mL), 35% hydrogen peroxide in aqueous solution (0.2 mL) was added and the reaction mixture was maintained. for twelve hours. The precipitated pink solids were isolated by filtration, washed with water and dried under high vacuum, thereby resulting in the amide in 42% yield.

To a solution of amide (5.46 mmol) in methanol (100 ml) was added 10 N sodium hydroxide (12 ml). The mixture was heated at reflux for twelve hours, cooled to room temperature, and acidified to pH <2 by the slow addition of concentrated hydrochloric acid. The organic layer was extracted with dichloromethane (twice) and dried over sodium sulfate. The crude product was purified by chromatography (300/50/1 dichloromethane / methanol / formic acid), thereby resulting in 89% acid as a pink solid.

The following acids were prepared using this method:

6-Bromobenzisothiazole-3-carboxylic acid. 5-Bromobenzisothiazole-3-carboxylic acid. 6-Methoxybenzisothiazole-3-carboxylic acid. 7-Bromobenzisothiazole-3-carboxylic acid.

The following esters were prepared from the acid using ethanol and sulfuric acid: ethyl 6-bromobenzisothiazole-3-carboxylate. Ethyl 6-methoxybenzisothiazole-3-carboxylate.5-bromo-1,2-benzisothiazole-3-carboxylate butyl.

The following procedure was used to prepare tert-butyl esters from benzisothiazole:

Di-tert-butyldicarbonate (128 mmol) was added to a suspension of 6-bromo-1,2-benzisothiazole-3-carboxylic acid (46.5 mmol) and 4-dimethylaminopyridine (4.26 mmol) in tert-butyl alcohol ( 40.0 ml) and tetrahydrofuran (40.0 ml), and the reaction mixture was heated at 65 ° C for sixteen hours. There was a vigorous evolution of carbon dioxide that gradually decreased as the mixture became homogeneous. The reaction mixture was concentrated and the residue was dissolved in dichloromethane. The dichloromethane solution was filtered through silica gel (approximately 50 g) and the eluent was concentrated to give the ester product a 99% yield. The following ester was prepared using this method:

Tert-Butyl 6-bromo-1,2-benzisothiazole-3-carboxylate.

Procedure 2

Procedure 2 presents a method for preparing isatins from anilines and converting isatins to corresponding indazol-3-carboxylic acids.

A solution of substituted aniline (565 ml) in 6 N hydrochloric acid (106 ml) was added to a suspension of 2,2,2-trichloro-1-ethoxyethanol (678 ml) and sodium sulfate (3.15 mol) in water ( 1.4 liter) and the reaction mixture was vigorously stirred for one hour. The solution of hydroxylamine hydrochloride (2.08 mol) in water (650 ml) was added in one portion and the reaction mixture was heated at 80 ° C for one and a half hours. This reaction mixture was cooled to 10 ° C and precipitated solids were collected by filtration, washed with water and dried to give the amide a yield of 91%.

The amide was added to sulfuric acid (1.9 liter) and the reaction mixture was heated to 60 ° C for 6 hours. The reaction mixture was placed to cool to room temperature and carefully poured into ice (7kg). Precipitated solids were collected by filtration, washed with water and dried to yield naisatin in 61% yield.

Conversion of the substituted isatines to corresponding indazole-3-carboxylic acids is essentially the same as that described for indazole-3-carboxylic acid: Snyder, H.R., et. al. J. Am. Chem. Sound. 1952.74, 2009. Substituted isatin (22.1 mmol) was diluted with 1 N sodium hydroxide (24 mL) and heated to 50 ° C by trinminutes. The burgundy solution was placed to cool to room temperature and held for one hour. The reaction mixture was cooled to 0 ° C and treated with a 0 ° C solution of sodium nitrite (22.0 mmol) in water (5.5 mL). This solution was added via a submerged pipette below the surface of a vigorously stirred solution of sulfuric acids (2.3 mL) in water (45 mL) at 0 ° C. The addition took fifteen minutes and the reaction was continued for another thirty minutes. A cold (0 ° C) solution of dihydrated tin (II) chloride (52.7 mmol) in concentrated hydrochloric acid (20ml) was added to the reaction mixture for ten minutes and the reaction mixture was maintained for sixty minutes. Precipitated solids were isolated by filtration, washed with water and dried to yield a quantitative mass balance. This material was of sufficient purity (1 H NMR and LC / MS) to be used for the next step without further purification. Alternatively, the acid was recrystallized from acetic acid to yield pure material.

The following acids were prepared using this method:

6-bromo-1H-indazol-3-acid.

5-methoxy-1H-indazol-3-acid.

6-methoxy-1H-indazol-3-acid.

Procedure 3

Procedure 3 presents a method for the capture of indole aryl lithium with ketones and coupling with 3-aminoquinuclidine for the formation of heterocyclic derivatives.

Tert-Butyl 6-bromoindazole-3-carboxylate was prepared from the acid by reaction with a two-fold excess of tert-butyldicarbonate followed by treatment with sodium hydroxide. To a suspension of sodium hydride (60% dispersion in mineral oil) (4.8 mmol) in tetrahydrofuran (40 mL) at 0 ° C was slowly added a solution of tert-butyl 6-bromoindazole-3-carboxylate (4%). 0.0 mmol) in tetrahydrofuran (4 ml). After stirring for half an hour at 0 ° C, the mixture was cooled to -780 ° C and a 1.7 M solution of tert-butyl lithium in pentane (5.1 mmol) was added. After half an hour at -78 ° C, a solution of dripetrahydropyran-4-one (5 mmol) in tetrahydrofuran (1 ml) was added dropwise. The mixture was stirred at -7 ° C for one hour and heated to 0 ° C. The reaction mixture was quenched with saturated aqueous ammonium chloride and the mixture was partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layer was separated, washed with brine (50 mL), dried (magnesium sulfate). ) and concentrated. The residue was purified by chromatography (70/30 dehexanes / ethyl acetate) to give 6- (4-hydroxytetrahydropyran-4-yl) -1H-indazol-3-carboxylic acid tert-butyl ester (68%) as a colorless solid.

6- (4-Hydroxytetrahydropyran-4-yl) -1H-indazol-3-carboxylic acid tert-butyl ester (0.86mmol) was dissolved in trifluoroacetic acid (3 ml) and the mixture was kept at room temperature for sixteen hours. . The solvent was removed in vacuo and the residue was triturated with ethyl acetate to give 6- (3,6-dihydro-2H-pyran-4-yl) -1H-indazol-3-carboxylic acid (76%). The acids were coupled with quinuclidine amine according to procedure A.

6- (4-Hydroxytetrahydropyran-4-yl) -1H-indazol-3-carboxylic acid tert-butyl ester (1.0mmol) was extracted into trifluoroacetic acid (5 ml), triethylsilane (2 ml) and dichloromethane (3 ml) and the mixture was refluxed for sixteen hours. The solvent was removed in vacuo and the residue was triturated with ethyl acetate to give 6- (tetrahydropyran-4-yl) -1H-indazol-3-carboxylic acid (60%) as a brownish solid.

The following acids and esters were prepared using this method:

5- (Tetrahydro-2H-pyran-4-yl) -1H-indazol-3-carboxylic acid.

6- (Tetrahydro-2H-pyran-4-yl) -1H-indazol-3-carboxylic acid.

Tert-Butyl 6-formyl-1H-indazol-3-carboxylic acid-tert-butyl-1H-indazol-3-carboxylate acid.

Procedure 4

Procedure 4 provides a method for preparing W-1-alkylated indazole-3-carboxylic acids from the corresponding indazole ester.

To a solution of deethyl 5-methoxyindazole-3-carboxylate (1.50 mmol) in acetonitrile (15 mL) was added potassium carbonate (5.99 mmol) and methyl iodide (3.00 mmol). The reaction was heated at 600 ° C for four hours, placed to cool to room temperature and partitioned between water (50 ml) and ethyl acetate (50 ml). The layers were separated and the organic layer was washed with brine (25ml), dried (magnesium sulfate) and concentrated. The residue was purified by chromatography using a 95/5 to 80/20 gradient of hexanes / ethyl acetate to yield 2-substituted indazole (17%) and 1-substituted indazole (44%). 1-substituted indazole (61 mg, 0.26 mmol) was suspended in ethanol (5.0 mL) and heated to facilitate dissolution. An aliquot of a 5.0 M solution of sodium hydroxide in water (2.00 ml) was added and the reaction mixture was kept at room temperature for sixteen hours. The reaction mixture was diluted with water (50 ml) and acidified with 6.0 clor hydrochloric acid. The aqueous layer was extracted with ethyl comacetate (3 x 50 ml) and the combined organic layers were washed with brine (25 ml), dried (magnesium sulfate) and concentrated, resulting in an acidic yield of 95%.

The following acids were prepared using this method:

6-Bromo-1-methyl-1H-indazol-3-carboxylic acid.-6-Bromo-1-ethyl-1H-indazol-3-carboxylic acid. 1-Ethyl-6-methoxy-1H-indazol-3-carboxylic acid .

Procedure 5

Procedure 5 presents a method for preparing 5-difluoromethoxyindazole-3-acid from 3-bromo-4-nitrophenol.

3-Bromo-4-nitrophenol (10.0 mmol) was added to a suspension of sodium hydroxide (29.0 mmol) in N, N-dimethyl formamide (15 mL) and the suspension was kept for fifteen minutes at room temperature. The reaction mixture was cooled to 0 ° C and treated with chlorodifluoroacetate deethyl (20.0 mmol). The reaction mixture was heated at 70 ° C for sixteen hours and concentrated. The residue was diluted with ice water (200 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried (magnesium sulfate) and concentrated to yield 75% yield as a yellow oil.

Diethyl malonate (328 mmol) was added dropwise to a suspension of sodium hydride (328 mmol) in dimethyl sulfoxide (40 mL) at 0 ° C. The reaction mixture was cooled to 60 ° C and kept for half an hour. A solution of dimethyl fluoromethyl ether (149 mmol) in dimethyl sulfoxide (80 mL) was added dropwise and the reaction mixture was cooled to 100 ° C for five hours. The cooling solution was poured into ice water and the aqueous layer extracted with dichloromethane (3 x 100 ml). The combined organic layers were dried (magnesium sulfate) and concentrated to yield crude diester in 112% yield as an oil. The diester (167 mmol), sodium hydroxide (500 mmol) and water (35 mL) were combined and heated to 60 ° C for one hour. The reaction mixture was placed to cool to room temperature and the aqueous layer was washed with dichloromethane (3 x 100 ml). The pH of the aqueous layer was cautiously adjusted to 1 with concentrated hydrochloric acid and the reaction mixture was heated at 60 ° C for one hour. The suspension was cooled to 50 ° C and the solids were collected through filtration and dried to yield the acid at 61% yield.

Acetyl chloride (203 mmol) was added dropwise to ethanol (300 mL) at 0 ° C. After half an hour, the acid (101 mmol) was added and the reaction mixture was heated at reflux for fifteen hours. The reaction mixture was concentrated and the residue was partitioned between dichloromethane (200ml) and saturated sodium bicarbonate (100ml). The aqueous layer was extracted further with dichloromethane (2 x 200 ml) and the combined organic layers were dried (magnesium sulfate) and concentrated to give the ester at 60% yield as a brown oil.

The ester (60.4 mmol) was dissolved in ethanol (103 mL), diluted with water (71 mL) and treated with deamonium chloride (243 mmol) and iron powder (301 mmol). The reaction mixture was heated at reflux for ten minutes and the suspension was filtered through Celite and the filter cake was washed with ethanol three times. The filtered material was concentrated, the residue was suspended in 2N hydrochloric acid and stirred vigorously for half an hour. The aqueous layer was washed with ethyl comacetate (3 x 50 ml) and the pH adjusted to 9-10 with 5 sódio sodium hydroxide. The aqueous layer was extracted with chloroform (3 x 100ml) and the combined organic layers were dried (magnesium sulfate). Acetic anhydride (392mmol), isoamyl nitrite (291mmol) and potassium acetate (5.1mmol) were added to the organic layer and the suspension was heated at reflux for sixteen hours. The solution was evaporated and the residue was partitioned between saturated sodium bicarbonate (50 mL) and dichloromethane (100 mL). The aqueous layer was extracted further with dichloromethane (2 x 100 ml) and the combined organic layers were dried (magnesium sulfate) and concentrated to yield the N-acetylindazole ester in 79% yield as a brown oil.

The ester (63.8 mmol), sodium hydroxide (193 mmol) and water (65 mL) were combined and the reaction was maintained for 24 hours at 60 ° C. After cooling to room temperature, the aqueous layer was washed with dichloromethane (3 χ 50ml). The aqueous layer was adjusted to pH 1 with concentrated hydrochloric acid. Precipitated solids were collected by filtration, washed with edichloromethane water and dried to yield the acid at 27% yield.

The following acid was prepared according to this method:

5- (Difluoromethoxy) -1H-indazole-3-carboxylic acid.Procedure 6

Procedure 6 presents a method for preparing 6-difluoromethoxyindazole-3-acid from 4-nitrophenol.

4-Nitrophenol (162 mmol) was added to a suspension of sodium hydroxide (485 mmol) in NfN-dimethylformamide (150 mL) and the suspension was maintained for fifteen minutes at room temperature. The reaction mixture was cooled to 0 ° C and treated with ethyl chlorodifluoroacetate (329 mmol). The reaction mixture was heated to 70 ° C for sixteen hours and concentrated. The residue was diluted with water ice (200 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried (magnesium sulfate) and concentrated to yield the oleifluoromethyl in 59% yield as a yellow oil.

Nitro ether (149 mmol) was dissolved in ethanol (37.5 mL), diluted with water (25 mL) and treated with ammonium chloride (84.7 mmol) and iron powder (105 mmol). The reaction mixture was heated at reflux for thirty minutes and the suspension was filtered through Celite. The filter cake was washed with ethanol three times and the combined filtered materials were concentrated. The residue was dissolved in water and the pH adjusted to 9-10 with 5% sodium hydroxide. The aqueous layer was extracted with ethyl acetate (3 x 100 ml) and the combined organic layers were dried (magnesium sulfate) and concentrated to a yellow oil. The oil was dissolved in acetic anhydride (23.5 mmol) and the reaction mixture was kept at room temperature for sixteen hours. The reaction mixture was diluted with water (50 ml) and neutralized with solid sodium bicarbonate. The precipitated solids were isolated by filtration, washed with water and dried to give acetamide in 62% yield as a light yellow solid.

Acetic anhydride (19.6 mmol) was added to a solution of acetamide (13.2 mmol) in chloroform (20 mL) and the reaction mixture was heated to reflux. Nitric-fuming acid (16.0 mmol) was added by dripping and the reaction mixture was refluxed for thirty minutes. The cooling solution was diluted with water (20 ml) and aqueous layer was extracted with dichloromethane (3 x 10 ml). The combined organic layers were dried (magnesium sulfate) and concentrated to give nitro amide in 83% yield.

The amide (11.0 mmol), sodium hydroxide (43.8 mmol) and water (10 mL) were combined and the reaction mixture was kept for one and a half hours at 60 ° C. The reaction was placed to cool to room temperature and the precipitated solids were isolated by filtration and washed with water and dried to yield aniline at 98% yield as a light yellow solid.

The aniline (15.7 mmol) was mixed with 40% hydrobromic acid (14.3 g) and water (10 ml) and the reaction mixture was heated to 80-90 ° C to completely dissolve the aniline. The reaction mixture was cooled to 0 ° C and a solution of sodium nitrite (23.2 mmol) in water (5.3 mL) was added over a period of fifteen minutes.

The solution was kept for forty minutes at 0-5 ° C filtered. Copper (I) bromide (18.8 mmol) was dissolved in 40% hydrobromic acid (21 ml) and cooled to 0 ° C. The diazo salt solution was slowly added to the copper solution and the mixture was kept for 30 minutes at 0-10 ° C. The reaction mixture was heated at 60 ° C for thirty minutes and at 100 ° C for ten minutes to then ensure completion. The reaction mixture was placed to cool to room temperature and extracted with dichloromethane (3 x 40ml). The combined organic layers were washed with 1 M sodium hydroxide, water, 1 N hydrochloric acid and water. The organic layer was dried (magnesium sulfate) and concentrated to give nitrobromide in 76% yield as a light yellow solid.

Diethyl malonate (25.7 mmol) was added dropwise to a suspension of sodium hydride (25.8 mmol) in dimethyl sulfoxide (5 mL) at 0 ° C. The reaction mixture was heated to 60 ° C and held for thirty minutes. A solution of nitro bromide (11.7 mmol) in dimethyl sulfoxide (7 mL) was added dropwise and the reaction mixture was heated at 100 ° C for five hours. The cooling solution was poured into ice water and the aqueous layer was extracted with dichloromethane (3 x 100 ml). The combined organic layers were dried (magnesium sulfate) and concentrated to yield crude diester as an oil. Diester (11.7mmol), sodium hydroxide (35mmol) and water (20ml) were combined and heated at 60 ° C for one hour. The reaction mixture was placed to cool to room temperature and the aqueous layer was washed with dichloromethane (3 x 100 ml).

The pH of the aqueous layer was cautiously adjusted to 1 concentrated hydrochloric acid and the reaction mixture was heated to 60 ° C for one hour. The suspension was cooled to 0 ° C and the solids were collected by filtration and dried to yield the acid in 64% yield.

Acetyl chloride (15.3 mmol) was added dropwise to ethanol (50 mL) at 0 ° C. After thirty minutes, the acid (7.69 mmol) was added and the reaction mixture was refluxed for fifteen hours. The reaction mixture was concentrated and the residue was partitioned between dichloromethane (20ml) and saturated sodium bicarbonate (10ml). The aqueous layer was extracted further with dichloromethane (2 x 20 ml) and the combined organic layers were dried (magnesium sulfate) and concentrated to yield the ester at 94% yield as a brown oil.

Acetic anhydride (6.0 ml) was added to. an ester suspension (3.64 mmol) and acetic acid (7.0 mL) at 0 ° C. Zinc powder (14.6 mmol) was added portionwise over fifteen minutes and the reaction mixture was kept for thirty minutes at 0 ° C and then for one and a half hours at room temperature. Additional zinc powder (6.15 mmol) was added and the reaction was maintained for three hours. The suspension was filtered through Celite and the filtered material concentrated. The residue was partitioned between saturated sodium bicarbonate (10 mL) and ethyl acetate (20 mL). The aqueous layer was extracted further with ethyl acetate (3 x 20ml) and the combined organic layers were dried (magnesium sulfate) and concentrated to give acetamide in 92% yield as a brown oil.

Acetic anhydride (13.7 mmol), isoamyl nitrite (13.7 mmol) and potassium acetate (2.04 mmol) were added to a solution of acetamide (3.92 mmol) in chloroform (20 mL) and the suspension was heated at reflux for sixteen hours. The solution was evaporated and the residue was partitioned between saturated sodium bicarbonate (10 mL) and dichloromethane (20 mL). The aqueous layer was extracted further with dichloromethane (2 x 20 ml) and the combined organic layers were dried (magnesium sulfate) and concentrated to yield the crude W-acetylindazole ester as a brown oil.

The ester (3.36 mmol), sodium hydroxide (10 mmol) and water (5 mL) were combined and the reaction was held for 24 hours at 60 ° C. After cooling to room temperature, the aqueous layer was washed with dichloromethane (3 x 30ml). The aqueous layer was adjusted to pH 1 with concentrated hydrochloric acid and precipitated solids were collected by filtration, washed with water and dichloromethane and dried to yield the acid in 26% yield.

The following acid was prepared according to this method:

6- (Difluoromethoxy) -1H-indazole-3-carboxylic acid.

Procedure 7

Procedure 7 provides a method for coupling between benzisothiazole-3-carboxylic brominated esters and indazole-3-carboxylic esters and brominated Grignard reagents for formation of substituted heteroaromatic acids.

A 0.5 M solution of Grignard reagent (75.0mmol) in tetrahydrofuran was diluted with tetrahydrofuran (150ml), cooled to 5 ° C and treated with solid zinc chloride (165 mmol). The reaction mixture was placed to warm to room temperature and brominated (28.2 mmol) ethanes (triphosphine) palladium (0) ester (1.64 mmol) was added. The suspension was heated at 650 ° C for sixteen hours and concentrated. The reaction was partitioned between ethyl acetate (250 mL) and 7 M ammonium chloride (500 mL). The aqueous layer was extracted with ethyl acetate (3 x 250 ml) and the combined extracts were dried over sodium sulfate and concentrated to dryness. The residue was purified by chromatography using a gradient of 100/0 to 97/3 decloroform / methanol to give the ester in 80% yield. The ester was suspended in methanol (100 mL) and treated with 8 M sodium hydroxide (30 mL). The mixture was heated at 60 ° C for three hours, cooled to room temperature, filtered and acidified to pH <2 by the slow addition of concentrated hydrochloric acid. The aqueous layer was concentrated and the residue was triturated with water. The resulting solid was recrystallized from water to give the acid at 81% yield.

Thignol Grignard reagent is commercially available. Alternatively, aryl lithium and the corresponding ten-aryl reagent may be generated according to the procedure outlined by Reeder, M.R .; et.al., Org. Proc.Res. Owe. 2003, 7, 696. Oxazole zinc reagent was prepared according to this procedure.

The following acids were prepared using this method:

6- (1,3-Thiazol-2-yl) -1H-indazol-3-carboxylic acid.

6- (1,3-oxazol-2-yl) -1H-indazol-3-carboxylic acid.

1-Ethyl-6- (1,3-oxazol-2-yl) -1H-indazol-3-carboxylic acid.

Procedure 8

Procedure 8 presents a method for preparing β-methoxyethoxymethyl and N-trimethylsilylethoxymethyl protected deindazole acids and esters from the corresponding indazole esters using alkylation conditions.

Representative Procedure for N (I) -alkylation: A solution of ethyl 5- (benzyloxy) -1H-indazol-3-carboxylate (2.70 mmol) in tetrahydrofuran (10 mL) was added dropwise to a suspension at 0 ° C of sodium hydride (60% mineral oil dispersion, 8.1 mmol) in tetrahydrofuran (54.0 ml). The reaction was kept at 0 ° C for one hour. [Β- (trimethylsilyl) ethoxy] methyl chloride (3.2 mmol) was added and the reaction mixture was maintained for one hour. The reaction was partitioned between water (50 mL) and ethyl acetate (50 mL) and organic layer was washed with brine (25 mL), dried (magnesium sulfate) and concentrated. The residue was purified by chromatography (95/5 to 85/15 hexanes / ethyl acetate) to yield the protected indazole in 89% yield.

Representative Procedure for N (2) -alkylation: 2-Methoxyethoxymethyl chloride (48.0 mmol) was slowly added to a suspension of ethyl 6-bromo-β-indazol-3-carboxylate (40.0 mmol) and N, N diisopropylethylamine (80.0 mmol) in methylene chloride (80.0 mL). The reaction became homogeneous and was kept for four hours at room temperature. The reaction mixture was concentrated and the residue was partitioned between water (50 mL) and ethyl acetate (100 mL). The layers were separated and the organic layer was washed with brine (25ml), dried (magnesium sulfate) and concentrated to give sufficiently pure product (89%) as a 2/1 mixture of N (2) - and N (I) - regioisomers. like a yellow oil.

5.0 M sodium hydroxide (52 ml) was added to a solution of ethyl 6-bromo-1 - [(2-methoxyethoxy) methyl] -1H-indazol-3-carboxylate (18.2mmol) and the mixture of The reaction was maintained for sixteen hours. The solution was diluted with 50 ml of water (50 ml) and acidified with 6.0 clor hydrochloric acid. The slurry was extracted with ethyl acetate (50 mL) and the organic layer was washed with brine (25 mL), dried (magnesium sulfate) and concentrated. The residue was recrystallized from toluene to give a colorless solid (82%) as a mixture of regioisomers.

The following esters and acids were prepared using this method:

6-Bromo-1 - [(2-methoxyethoxy) methyl] -1H-indazole-3-carboxylic acid.

6-Bromo-1 - [(2-methoxyethoxy) methyl] -1H-indazol-3-carboxylate deethyl.

Ethyl 6-benzyloxy-1 - [(2-methoxyethoxy) methyl] -1H-indazol-3-carboxylate.

6-Bromo-1 - {[2- (trimethylsilyl) ethoxy] methyl} -1H-indazol-3-carboxylic acid.

Ethyl 6-bromo-1 - {[2- (trimethylsilyl) ethoxy] methyl} -1H-indazole-3-carboxylic acid.

5-Bromo-1 - {[2- (trimethylsilyl) ethoxy] methyl} -1H-indazol-3-carboxylic acid.

6-Bromo-2 - {[2- (trimethylsilyl) ethoxy] methyl} -1H-indazol-3-carboxylic acid.

5-Bromo-2 - {[2- (trimethylsilyl) ethoxy] methyl} -1H-indazol-3-carboxylic acid.

Ethyl 6-bromo-2- {[2- (trimethylsilyl) ethoxy] methyl} -1H-indazole-3-carboxylic acid.

5-bromo-2 - {[2- (trimethylsilyl) ethoxy] methyl} -1H-indazol-3-carboxylic acid.

5-Bromo-1 - {[2- (trimethylsilyl) ethoxy] methyl} -1H-indazole-3-carboxylic acid ethyl.

Procedure 9

Procedure 9 provides a method for preparing alkoxy indazole acids from the corresponding benzyloxy indazole esters using Mitsunobu conditions.

Ethyl 6-benzyloxy-1 - [(2-methoxyethoxy) methyl] -1H-indazol-3-carboxylate (9.38 mmol) was added to a suspension of 10% palladium on carbon (249 mg) in ethanol (66 , 7 ml). The reaction was stirred under a hydrogen atmosphere (50 psi) for four hours. The reaction was filtered through Celite and concentrated to yield phenol at 87% yield as a white solid.

Diisopropyl azodicarboxylate (0.841 mmol) was added dropwise to a solution of ethyl 6-hydroxy-1 - [(2-methoxyethoxy) methyl] -1H-indazol-3-carboxylate (0.765 mmol), 1-methyl-3-pyrrolidinol (0.917 mmol) and triphenylphosphine (1.15 mmol) in tetrahydrofuran (4.6 mL). The reaction was held for sixteen hours and concentrated. The residue was purified by chromatography (100/0 to 90/10 ethyl acetate / [70/03/2 ethyl acetate / methanol / dimethylethylamine] to give the ether product in 28% yield. to result in the acid which was coupled to the bicyclobase using procedure C.

The following acids were prepared using this method:

6-Hydroxy-1 - [(2-methoxyethoxy) methyl] -1H-indazol-3-carboxylate ethyl

1 - [(2-Methoxyethoxy) methyl] -6 - [(1-methylpyrrolidin-3-yl) oxy] -1H-indazol-3-carboxylic acid.

1 - [(2-Methoxyethoxy) methyl] -6- (tetrahydrofuran-3-yloxy) -1H-indazol-3-carboxylic acid.

1 - [(2-Methoxyethoxy) methyl] -6- (tetrahydro-2H-pyran-4-yloxy) -1H-indazol-3-carboxylic acid.

6 - [(1-Methylpyrrolidin-3-yl) oxy] -1,2-benzisothiazol-3-carboxylic acid 6- (1-azabicyclo [2,2,2] oct-3-yloxy) -1,2 -benzisothiazole-3-carboxylic acid.

Procedure 10

Procedure 10 presents a method for preparing 4-methoxyindazole acid from 4-methoxyaniline.

A solution of 4-methoxy aniline (1.63 mol) in acetic acid (244 ml) was treated with acetic anhydride (244 ml) and zinc epoxide (30.8 mmol) and the reaction mixture was heated at reflux for thirty minutes. The suspension was placed to cool to room temperature, and was filtered and concentrated. The residue was diluted with water (200 ml) and the pH of the solution was adjusted to 8 with 1.0% sodium hydroxide. Precipitated solids were collected by filtration, washed with water (1 liter) and dried to obtain acetaminophen. 94% yield as a purple solid.

Concentrated nitric acid (210 ml) was added dropwise to a solution of acetamide (1.52 mol) in dichloromethane (1.5 liter) at room temperature. The reaction mixture was heated at reflux for one hour and placed to cool to room temperature. The reaction mixture was washed with water (1.0 liter), saturated sodium carbonate (1.0 liter) and water (1.0 liter). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain anithroacetamide in 83% yield as an orange solid.

A solution of nitroacetamide (1.27 mol) in water (1.27 liter) was treated with sodium hydroxide (5.07 mol) and the reaction mixture was heated at 600 ° C for two hours. Precipitated solids were collected by filtration, washed with water and dried to obtain 85% nitroaniline as an orange solid. A solution of sodium nitrite (1.4 mol) in water (250 ml) was added to a cold solution (0-5 ° C) denitroaniline (1.08 mol) in hydrobromic acid (4.87 mol) (prepared by heating the reaction mixture to 90 ° C for two hours). The reaction mixture was maintained for forty minutes and filtered. The filtered material was added dropwise to a cold (0-5 ° C) solution of copper (I) bromide (1.81 mol) in hydrobromic acid (640 ml) and the stirring mixture was maintained for thirty minutes. The reaction mixture was heated to 60 ° C and held for thirty minutes. The reaction mixture was heated at reflux and maintained for one hour. The reaction mixture was diluted with water (2 liters) and extracted with dichloromethane (3 χ 1 liter). The combined organic layers were washed with 10% sodium hydroxide (1.0 liter), water (2.0 liter), 10% hydrochloric acid (1.6 liter) and water (2.0 liter), dried (sodium sulfate). magnesium) and concentrated. The residue was recrystallized from ethanol to obtain bromide in 50% yield as a yellow solid.

Iron powder (1.08 mol) and ammonium chloride (862mmol) were added to a solution of bromide (216 mmol) in ethanol (200 ml) and water (140 ml) and the reaction mixture cooled to reflux for one hour. . The suspension was filtered and concentrated and the residue was extracted with ethyl acetate (3 x 200 ml). The combined organic layers were dried (sodium sulfate) and concentrated to obtain bromoaniline in 96% yield as a yellow liquid.

A solution of bromoaniline (208 mmol) in 50% hydrochloric acid (40 mL) was added to a solution of trichloroacetaldehyde hydrate (312 mmol) and sodium sulfate (967 mmol) in water (450 mL) and the reaction mixture was kept by one hour. The solution of hydroxylamine hydrochloride (793mmol) in water (240ml) was added and the reaction mixture was heated at 60 ° C for two hours. The aqueous layer was decanted and the residual solidifying red oil was purified by chromatography (6/6/1 petroleum ether / dichloromethane / ethyl acetate) to give α-oxime amide in 29% yield as a solid. light yellow.

Α-Oxime amide (58.6 mmol) was added in one portion to warm (40 ° C) 90% sulfuric acid (16 ml) and the reaction mixture was heated at 60 ° C for thirty minutes. The reaction mixture was placed to cool to room temperature and poured into ice water. The precipitated orange solids were collected by filtration and dried. The crude product was purified by chromatography (15/1 petroleum ether / ethyl acetate) to obtain isatin in 57% yield as a yellow solid.

The isatin (20.7 mmol) was mixed with IM sodium hydroxide (23 mL) and the reaction mixture was heated at 30-40 ° C for thirty minutes. The reaction mixture was cooled to 0 ° C and treated with a solution of sodium nitrite (20.7mmol) in water (5.1ml) and kept for twenty minutes. The solution was added by dripping to a cold (0-5 ° C) solution of concentrated sulfuric acid (2.24 ml) in water (43.3 ml) and the reaction mixture was kept for half an hour. A solution of tin (II) chloride (50.5 mmol) in concentrated hydrochloric acid (19.6 mL) was added dropwise and the reaction mixture was kept at 0-5 ° C for one hour. Precipitated solids were isolated by filtration and dried to obtain indazole acid as a yellow solid (100 wt%).

Acetyl chloride (18 mL) was added to methanol (180 mL) at 0 ° C and the reaction mixture was kept for one hour. Indazole acid (21.8 mmol) was added and the reaction mixture was heated at reflux for three hours. The solution was concentrated to dryness and the residue was suspended in water and the pH adjusted to 7 with saturated hydrogenated sodium carbonate. The mixture was extracted with ethyl comacetate (3 x 100 ml) and the combined organic layers were dried (magnesium sulfate) and concentrated. The crude product was purified by decromatography (2/1 petroleum ether / ethyl acetate) to obtain indazole ester in 5% yield (two steps) as a yellow solid.

Indazole ester (1.02 mmol) was combined with 10% carbon calcium (30 mg) and methanol (20 ml) under a hydrogen gas atmosphere for thirty minutes at room temperature. The catalyst was removed by filtration and the eluent was concentrated to obtain the brominated indazoldes ester in 24% yield as an orange solid.

1 M sodium hydroxide (1.5 ml) was added to a solution of debrominated indazole ester (0.243 mmol) in methanol (3.0 ml) and the reaction mixture was heated at 60 ° C for three hours. The solution was concentrated, the pH was adjusted to 1-2 and the solids were collected by filtration to obtain indazole acid in 100% yield as a yellow solid.

The following acid was prepared using this procedure:

4-Methoxy-1H-indazol-3-carboxylic acid.

Procedure 11

Procedure 11 presents a method for preparing benzyloxy-substituted acids and deindazole-3-carboxylic esters from the corresponding nitrobenzene-bromers. Acetic anhydride (34 ml) and zinc powder (4.59 mmol) were added to a solution of 4- methoxynitrobenzene (230mmol) in glacial acetic acid (34 ml) and the reaction mixture was heated at reflux for half an hour. The reaction mixture was poured into water (340 ml) and the pH of the solution was adjusted to 10% with sodium hydroxide. Precipitated solids were isolated by filtration, washed with water (100ml) and dried to yield acetamide in 88% yield.

65% nitric acid (22 ml) was added dropwise over half an hour to a solution of acetamide (200 mmol) in dichloromethane (200 ml). The reaction mixture was kept for one hour at room temperature and heated at reflux for one hour. The reaction mixture was washed with water (200 mL), saturated sodium carbonate solution (100 mL) and water (200 mL). The combined organic layers were dried (magnesium sulfate) and concentrated to yield 90% nanitroacetamide as a yellow solid.

Nitroacetamide (180 mmol) was added 4 M sodium hydroxide (180 mL) and the reaction mixture was kept for two hours at 60 ° C. The precipitated solids were isolated by filtration, washed with water and dried to yield nitroaniline in 70% yield as a red solid.

A solution of sodium nitrite (11.8 g) in water (28 ml) was added by dripping for half an hour to a solution of nitroaniline (125 mmol) in 40% hydrobromic acid (110 g) at 10 ° C. The reaction mixture was kept for forty minutes at 0-10 ° C and filtered. The filtered material was added dropwise over one hour at 0 ° C to a purple solution of copper (I) bromide (209 mmol) in hydrobromic acid (74 ml). The reaction mixture was placed to warm and kept at room temperature for thirty minutes, kept at 60 ° C for half an hour and heated at reflux for one hour. The reaction mixture was partitioned between water (2.0 liters) and dichloromethane (600 ml) and the aqueous layer further extracted with dichloromethane (300 ml). The combined organic layers were washed with 10% sodium hydroxide (200 ml), water (600 ml), 10% hydrochloric acid (300 ml) and water (600 ml), dried (magnesium sulfate) and concentrated to give the nitrobromide a. a yield of 83% as a yellow oil.

A solution of boron tribromide (250 mmol) in dichloromethane (200 mL) was added by dripping for one hour to a solution of nitrobromide (100 mmol) in dichloromethane (250 mL) at -78 ° C. The reaction mixture was placed to warm to room temperature and maintained for thirty hours. The reaction mixture was cooled to 0 ° C, quenched with water (300 ml) and the aqueous layer extracted with ethyl acetate (2 x 300 ml). The combined organic layers were washed with saturated sodium bicarbonate (2 x 300 ml), dried (magnesium sulfate) and concentrated to yield nitrophenol in a yield of 87% as a brown crystalline solid.

Benzyl bromide (131 mmol) and depotassium carbonate (130 mmol) were added to a solution of denitrophenol (87.0 mmol) in 2/1 acetonitrile / acetone (840 ml). The reaction mixture was heated at reflux for seventeen hours and concentrated to dryness. The residue was taken up in filtered ethyl acetate (756 ml) and the organic layer was washed with water (567 ml), 1 M hydrochloric acid (2 x 567 ml) and brine (567 ml). The organic layer was dried (magnesium sulfate) and concentrated in benzyl ether in 78% yield.

Diethyl malonate (890 mmol) was added dropwise over one hour to a suspension of disodium hydride (520 mmol) in dimethyl sulfoxide (100 mL) at 0 ° C. Benzyl ether (44.0 mmol) was added and the mixture The reaction was heated to 100 ° C for five hours. The mixture was poured into ice water and extracted with ethyl acetate (3 x 70 ml). The combined organic layers were dried (magnesium sulfate) and concentrated to yield the product of the addition of diethyl malonate. The diethyl malonate addition product was diluted with a 4 M sodium hydroxide solution (100 ml) and the reaction mixture was heated at 600 ° C for six hours. The solution was extracted with dichloromethane (3 x 50 ml) and the aqueous layer was adjusted to pH 1 with concentrated hydrochloric acid. The reaction mixture was heated at 60 ° C for one hour, placed to cool to room temperature and extracted with ethyl acetate (3 x 50 ml). The combined organic layers were dried (magnesium sulfate) and concentrated to yield phenylphenic acid in 78% yield as a solid.

Phenylacetic acid (350 mmol) was added to a freshly prepared solution of ethanolic hydrochloric acid [acetyl chloride (5 mL) was added to ethanol (100 mL)] and the reaction mixture was heated at reflux for twenty hours. The reaction mixture was concentrated to dryness and the residue was partitioned between saturated sodium bicarbonate (200ml) and ethyl acetate (150ml). The aqueous layer was extracted with ethyl acetate (2 x 50 ml) and the combined organic layers were dried (magnesium sulfate), filtered and concentrated to yield the ester in 77% yield.

The nitro ester (27.0 mmol) was dissolved in acetic acid (60 mL) and acetic anhydride (44 mL) and cooled to 0 ° C. Zinc powder (153 mmol) was added and the mixture was placed to warm to room temperature and kept for two hours. Additional amounts of zinc dust (2 x 45.9 mmol) were added over a period of three hours. After one hour, the reaction mixture was filtered and the filter cake was washed with ethanol (100 ml). The combined filtered materials were concentrated and the residue was partitioned between saturated sodium bicarbonate and ethyl acetate (50 ml). The solution was extracted with ethyl acetate (2 x 50 ml) and the combined organic layers were dried (magnesium sulfate), filtered and concentrated to afford acetamide in 82% yield.

Isoamyl nitrite (47.2g) was added dropwise over thirty minutes to a solution of acetamide (21.0 mmol) in chloroform (80ml) and acetic anhydride (45ml). Solid potassium acetate (7.13 mmol) was added in several portions and the reaction mixture was heated at reflux for one and a half hours. The reaction mixture was washed with water (2 x 80 ml) and brine (80 ml), dried (magnesium sulfate) and concentrated to yield indazolacetyl ester in 68% yield.

Acetylated indazole ester (15.0 mmol) was suspended in 2 M sodium hydroxide (35 mL) and the reaction mixture was heated at 60 ° C for 24 hours. The pH of the solution was adjusted to 1-2 with concentrated hydrochloric acid and the solids were collected by filtration and dried to give 6-benzyloxy-1H-indazol-3-carboxylic acid at a yield of 28% as a yellow solid.

6-Benzyloxy-1H-indazole-3-carboxylic acid (1.85mmol) was added to a freshly prepared solution of ethanolic hydrochloric acid [prepared from ethanol (20ml) and acetylchloride (5ml)] and the mixture of The reaction was heated at reflux for 25 hours and concentrated. The residue was partitioned between saturated sodium bicarbonate (20 mL) and ethyl acetate (20 mL) and the layers separated. The aqueous layer was extracted with ethyl acetate (2 x 20 ml) and the combined organic layers were dried (magnesium sulfate) and concentrated. The residue was purified by chromatography (300/1 dichloromethane / methanol) to yield the product in 36.4% yield. Alternatively, the ester may be obtained from the acetylated indazole ester by keeping the acetylated material in 2 M ammonia in methanol for thirty minutes.

The following acids were prepared using this method:

6-Benzyloxy-1H-indazol-3-carboxylic acid. 5-Benzyloxy-1H-indazol-3-carboxylic acid (from 4-benzyloxy-2-bromonitrobenzene: see Parker, KA; Mindt, TLOg. Lett., 2002, 4, 4265).

Ethyl 6-benzyloxy-1H-indazol-3-carboxylate.5-benzyloxy-1H-indazol-3-carboxylate of ethyl.

Procedure 12

Procedure 12 presents a method for preparing N (1) -difluoromethylindazole acids from the corresponding 3-carboxylic indazole acids.

Acetyl chloride (141 mmol) was added dropwise to a solution of 6-methoxy-3-indazolecarboxylic acid (26.0 mmol) in ethanol (200 mL) and the reaction mixture was heated at reflux for sixteen hours. The reaction mixture was placed to cool to ambient temperature and concentrated. The residue was dissolved in ethyl acetate (300 mL) and washed with aqueous sodium bicarbonate (2 x 50 mL). The combined aqueous layers were again extracted with ethyl acetate (2 x 200 ml). The combined organic layers were washed with brine (50 mL), dried (sodium sulfate), concentrated and dried under vacuum to yield 4.91 g (86%) of the ester as a solid.

A solution of ethyl 6-methoxy-1H-indazol-3-carboxylate (4.54 mmol) in NfN-dimethyl formamide (6.11 ml) was added dropwise to a suspension of disodium hydride (5.45 mmol) and N, N-dimethyl formamide (12.2 ml) and reaction mixture was kept at room temperature for thirty minutes. Chlorodifluoromethane (17.0 mol) was bubbled into the reaction and the mixture was heated to 800 ° C and held for two hours. The mixture was diluted with water (200 mL) and precipitates were collected to yield a white solid. The solid was dissolved in ethanol (20.0 mL) and a 5.0 M sodium hydroxide solution (3.6 mL) was added. . The reaction mixture was kept at room temperature for two hours, diluted with water (50 ml) and acidified with 6.0 N hydrochloric acid. The precipitate was collected and dried to yield the acid in 65% yield.

The following acids were prepared using this method:

1- (Difluoromethyl) -6-methoxy-1H-indazol-3-carboxylic acid. 6-Bromo-1- (difluoromethyl) -1H-indazole-3-carboxylic acid.

Procedure 13

Procedure 13 presents a preparation of 5-azaindazole-3-carboxylic acid from 4-chloropyridine.

A saturated aqueous sodium bicarbonate solution was carefully added to a solution of 4-chloropyridine hydrochloride (56.7 mmol) in water (20 mL) until the basic solution became. The mixture was extracted with hexanes (3 x 25 ml). The combined organic layers were dried over magnesium sulfate and concentrated to a volume of approximately 25 ml to give a free base solution.

N-butyl lithium (2.0 M in pentane, 68 mmol) was added dropwise to a solution of N, N-diisopropylamine (62.3 mmol) in tetrahydrofuran (61.6 mmol) at 0 ° C and the reaction mixture was held for thirty minutes. Reaction mixture was cooled to -78 ° C and 4-chloropyridine hexane solution was added by dripping and the mixture was maintained for one hour. Diethyl oxalate (56.7mmol) was added to the orange homogeneous solution and the mixture was placed to warm to room temperature. LC / MS analysis revealed that the main product was not ethyl oxoxate but N, JV-diisopropylamide. The reaction was divided between water (50 ml) and ethyl acetate (50 ml). The layers were separated and the organic layers were washed with brine (25 ml), dried (magnesium sulfate) and concentrated. The residue was dissolved in ethanol (50.0 mL), treated with hydrazine (160 mmol) and the mixture was heated at reflux for one hour. The reaction mixture was concentrated and the residue was titrated with dichloromethane to yield 1.20 g (8.6%) of the hydrazone product.

A mixture of N, N-diisopropyl-1H-pyrazolo [4,3-c] pyridine-3-carboxamide (0.800 g, 0.00325 mol) and aqueous hydrogen chloride (10 M, 3.00 mL) in a The microwave reaction was heated at 120 ° C for ten minutes. The mixture must be heated to a high absorbance setting to prevent pressure buildup. The reaction was diluted with water and neutralized with 3 sódio sodium hydroxide. The resulting white precipitate was collected, and was found to be a mixture of acid (47%) and monoisopropylamide (25%). The mixture was used without further purification.

The following acid was prepared using this method:

1H-pyrazolo [4,3-c] pyridine-3-carboxylic acid.

Procedure 14

Procedure 14 presents a preparation of 6-azaindazole-3-carboxylic acid from 4-chloro-3-nitropyridine.

T-butyl ethyl propane-1,3-dioate (26.6 mmol) was added to a suspension of sodium hydride (1.11 g) in tetrahydrofuran (50.0 ml) at 0 ° C. The reaction mixture was placed to warm to room temperature and maintained for thirty minutes. The reaction mixture was then cooled to 0 ° C and a solution of 4-chloro-3-nitropyridine (12.6 mmol) in tetrahydrofuran / N, N-dimethyl formamide (9/1, 10 ml) was added dropwise. The mixture was placed to warm to room temperature and held for one hour. Areaation was quenched with water (50 ml) and neutralized with acetic acid to a pH of 5 (the color changed from dark brown to yellow on neutralization). The mixture was extracted with ethyl acetate (50 mL) and the combined organic layers were washed with brine (25 mL), dried (magnesium sulfate) and concentrated to yield 94% yield.

Crude tert-butyl ethyl (3-nitropyridin-4-yl) malonate (12.6 mmol) was dissolved in 4/1 dedichloromethane / trifluoroacetic acid (25.0 mL) and the mixture was heated at reflux for two hours. The reaction mixture was concentrated and the residue was partitioned between saturated aqueous sodium bicarbonate (50 mL) and ethyl acetate (50 mL). The layers were separated and the ethyl acetate layer was washed with brine (25 ml), dried (magnesium sulfate) and concentrated. The residue was purified by chromatography (95/5 dichloromethane / ethyl acetate) to give the product in 77% yield.

Ethyl (3-nitropyridin-4-yl) acetate (9.66 mmol) and 10% palladium on carbon (2.10 g) were diluted with ethanol (25.0 mL) in a Parr pressure reactor. The reaction mixture was stirred under a hydrogen atmosphere (30 psi) for three hours. The reaction mixture was filtered (Celite) and concentrated to yield the product in 97% yield.

Amyl nitrite (18.9 mmol) was added to a solution of ethyl (3-aminopyridin-4-yl) acetate (9.43 mmol), potassium acetate (11.3) and acetic anhydride (28.3 mmol) Chloroform (10.0 ml) and the reaction was heated at 60 ° C for sixteen hours. The cooled reaction mixture was carefully diluted with aqueous sodium bicarbonate and extracted with dichloromethane (2 x 50 ml). The combined organic layers were washed with brine (25 mL), dried (magnesium sulfate) and concentrated. The residue was pre-purified by chromatography (50/50 to 0/100 hexanes / ethyl acetate) to yield a complex mixture of products. The mixture was dissolved in ethanol (10.0 mL), diluted with 5.0 M sodium hydroxide (5.00 mL) and the reaction mixture was kept for sixteen hours. The reaction mixture was concentrated to ~ 5 ml, diluted with water (20 ml) and neutralized with acetic acid. The yellow solid was collected by filtration to yield the desired product at 18% yield.

The following acid was prepared using this method:

1H-pyrazolo [3,4-c] pyridine-3-carboxylic acid.

Procedure 15

Procedure 15 presents a preparation of aminobenzisothiazole-3-carboxylic acids from the ester.

Cesium carbonate (3.18 mmol), palladium (II) acetate (0.24 mmol) and 2-dicyclohexylphosphino-2 ', 41,6'-tri-i-propyl-1,1'-biphenyl (O, 24 mmol) were combined in a microwave container and the container was flushed with nitrogen. A solution of (R) - (+) -3-pyrrolidinol (3.18 mol) and tert-butyl 6-bromo-1,2-benzisothiazole-3-carboxylate (1.59mol) in tetrahydrofuran (20.0 ml ) has been added. The container was sealed and heated at 1350 ° C for thirty minutes.

The reaction mixture was filtered through Celite (ethyl acetate) and the filtered material was concentrated. The residue was purified by chromatography (70/30 to 50/50 dehexanes / ethyl acetate) to give the purified ester.

The ester was dissolved in dichloromethane / trifluoroacetic acid (4: 1, 2.00 ml) and held for sixteen hours. The reaction mixture was concentrated to yield the product in 23% yield. The product was used without further purification.

Alternatively, when ethyl 6-bromo-1,2-benzisothiazole-3-carboxylate was used, an etherethanol solution was saponified using 5% sodium hydroxide. Acid was collected by filtration after dilution with water and neutralization with acetic acid.

The following acids and esters were prepared using this method:

6 - [(3R) -3-Hydroxypyrrolidin-1-yl] -1,2-benzisothiazole-3-carboxylic acid.

6 - [(35) -3-hydroxypyrrolidin-1-yl] -1,2-benzisothiazole-3-carboxylic acid.

6 - [(3R) -3-Methoxypyrrolidin-1-yl] -1,2-benzisothiazole-3-carboxylic acid.

6 - [(3S) -3-Methoxypyrrolidin-1-yl] -1,2-benzisothiazole-3-carboxylic acid.

6- (3-Methoxypyrrolidin-1-yl) -1,2-benzisothiazole-3-carboxylic acid.

6 - [(3S) -3-Dimethylaminopyrrolidin-1-yl] -1,2-benzisothiazole-3-carboxylic acid.

6 - [(3R) -3-Dimethylaminopyrrolidin-1-yl] -1,2-benzisothiazole-3-carboxylic acid.

6- (3-Ethoxypyrrolidin-1-yl) -1,2-benzisothiazole-3-carboxylic acid.

6 - [(1S, 4S) -2-Oxa-5-azabicyclo [2,2,1] hept-5-yl] -1,2-benzisothiazole-3-carboxylic acid.

Tert-Butyl 7-bromo-1,2-benzisothiazole-3-carboxylate.

7 - [(3 ') -3-hydroxypyrrolidin-1-yl] -1,2-benzisothiazol-3-carboxylic acid 7 - [(3S) -3-hydroxypyrrolidin-1-yl] -1,2-benzisothiazole acid -3-carboxylic acid.

6 - [(1S, 4S) -5- (tert-Butoxycarbonyl) -2,5-diazabicyclo [2,2,1] hept-2-yl] -1,2-benzisothiazole-3-carboxylic acid 6 - [( 1S, 4S) -5-methyl-2,5-diazabicyclo [2,2,1] hept-2-yl] -1,2-benzisothiazole-3-carboxylic acid

6- [3 - [(tert-Butoxycarbonyl) (methyl) amino] pyrrolidin-1-yl] -1,2-benzisothiazole-3-carboxylic acid

6- [3- (methoxymethyl) pyrrolidin-1-yl] -1,2-benzisothiazole-3-carboxylic acid

6- [4- (dimethylamino) piperidin-1-yl] -1,2-benzisothiazole-3-carboxylic acid

6- (1,4-Diazabicyclo [3,2,2] ηοη-4-yl) -1,2-benzisothiazole-3-carboxylic acid.

6 - [(1S, 4S) -5-Methyl-2,5-diazabicyclo [2,2,1] hept-2-yl] -1,2-benzisothiazole-3-carboxylic acid.

6 - [(L1,4R) -5-methyl-2,5-diazabicyclo [2,2,1] hept-2-yl] -1,2-benzisothiazole-3-carboxylic acid.

6- (Pyrrolidin-1-yl) -1,2-benzisothiazol-3-carboxylic acid. 6- (4-Methylpiperazin-1-yl) -1,2-benzisothiazol-3-carboxylic acid.

6- (4-Methyl-1,4-diazepan-1-yl) -1,2-benzisothiazole-3-carboxylic acid.

6- (hexahydropyrrolo [1,2-a] pyrazin-2 (1H) -yl) -1,2-benzisothiazole-3-carboxylic acid.

6- (5-Methyl-2,5-diazabicyclo [2,2,2] oct-2-yl) -1,2-benzisothiazole-3-carboxylic acid.

6- (8-Methyl-3,8-diazabicyclo [3,2,1] oct-3-yl) -1,2-benzisothiazole-3-carboxylic acid.

5- (4-Methyl-1,4-diazepan-1-yl) -1,2-benzisothiazole-3-carboxylic acid.

5 - [(3R) -3-Methoxypyrrolidin-1-yl] -1,2-benzisothiazol-3-carboxylic acid 5 - [(3S) -3-Methoxypyrrolidin-1-yl] -1,2-benzisothiazole 3-carboxylic acid.

5 - [(3S) -3- (cyclopropylmethoxy) pyrrolidin-1-yl] -2 - {[2- (trimethylsilyl) ethoxy] methyl} -1H-indazol-3-carboxylic acid.

5 - [(3S) -3- (Methoxy) pyrrolidin-1-yl] -2 - {[2- (trimethylsilyl) ethoxy] methyl} -1H-indazol-3-carboxylic acid.

5 - ((3R) -3 - {[2- (trimethylsilyl) ethoxy] methoxy} pyrrolidin-1-yl) -1,2-benzisothiazole-3-carboxylic acid.

5 - ((3S) -3 - {[2- (trimethylsilyl) ethoxy] methoxy} pyrrolidin-1-yl) -1,2-benzisothiazole-3-carboxylic acid.

6- [4- (tert-Butoxycarbonyl) -3-methylpiperazin-1-yl] -1,2-benzisothiazole-3-carboxylic acid.

6- [1- (tert-Butoxycarbonyl) octahydro-6H-pyrrolo [3,4-b] pyridin-6-yl] -1,2-benzisothiazole-3-carboxylic acid.

5 - [(3S) -3-Methoxypyrrolidin-1-yl] -1 - {[2- (trimethylsilyl) ethoxy] methyl} -1H-indazol-3-carboxylic acid.

6- [4- (tert-Butoxycarbonyl) -3-methylpiperazin-1-yl] -1,2-benzisothiazole-3-carboxylic acid.

6- [1- (tert-Butoxycarbonyl) octahydro-6H-pyrrolo [3,4-b] pyridin-6-yl] -1,2-benzisothiazole-3-carboxylic acid.

6- [4- (tert-Butoxycarbonyl) piperazin-1-yl] -1,2-benzisothiazole-3-carboxylic acid.

Ethyl 6- [4- (tert-butoxycarbonyl) -1,4-diazepan-1-yl] -1,2-benzisothiazole-3-carboxylate.

6- [4- (tert-Butoxycarbonyl) -2-methylpiperazin-1-yl] -1,2-benzisothiazole-3-carboxylic acid.

6- (3,4-Dimethylpiperazin-1-yl) -1,2-benzisothiazole-3-carboxylic acid.

Ethyl 6- [3 - [(tert-butoxycarbonyl) (methyl) amino] pyrrolidin-1-yl] -1,2-benzisothiazole-3-carboxylate.

The following esters were prepared from the N-Boc intermediates using trifluoroacetic acid: 6 - [(1S, 4S) -2,5-diazabicyclo [2,2,1] hept-2-yl] -1,2-benzisothiazole-3 ethylcarboxylate.

Ethyl 6- (octahydro-6H-pyrrolo [3,4-b] pyridin-6-yl) -1,2-benzisothiazole-3-carboxylate.

Ethyl 6-piperazin-1-yl-1,2-benzisothiazole-3-carboxylate.

Procedure 16

Procedure 16 presents a preparation of 6-amino-7-azaindazole-3-carboxylic acids from tert-butyl 6-fluoro-1H-pyrazolo [3,4-b] pyridine-3-carboxylate.

3-pyrrolidinol (24.7 mmol) was added to a solution of tert-butyl 6-fluoro-1H-pyrazolo [3,4-b] pyridine-3-carboxylate (4.22 mmol) in toluene (4.00 mL) in a microwave reaction vessel. The reaction mixture was subjected to microwave irradiation at 120 ° C for 300 seconds. The reaction mixture was partitioned between water (100ml) and ethyl acetate (200ml) and the layers separated.

The organic layer was washed with water (2 x 50 mL) and brine (25 mL) and was filtered through silica gel (50 g). The silica was washed with 100 ml EtOAc and the combined EtOAc solutions were concentrated to yield the product in 63% yield.

Methanesulfonyl chloride (5.52 mmol) was added dropwise to a cold (at 0 ° C) solution of 6- (3-hydroxypyrrolidin-1-yl) -1H-pyrazolo [3,4-b] pyridine-3-carboxylate of tert-butyl (2.63 mmol) and triethylamine (6.57 mmol) in dichloromethane (2.7 mL). The reaction mixture was kept at room temperature for sixteen hours and diluted with water (25 ml). The dichloromethane layer was separated and transferred to a silica gel column. The column was eluted using a gradient of 90/10 to 0/100 dehexanes / ethyl acetate to give the bis mesylate 60% yield and the monomesilate 28% yield. 1- (methylsulfonyl) -6-3- tert-Butyl [(methylsulfonyl) oxide] pyrrolidin-1-yl-1H-pyrazolo [3,4-b] pyridine-3-carboxylate (0.380 mmol) was diluted with a 2.0 M solution of dimethylamine in tetrahydrofuran (5.0 ml) in a microwave container. The reaction mixture was subjected to microwave irradiation at 135 ° C for eighty minutes. The reaction mixture was concentrated and the residue was purified by chromatography {100/0 to 90/10 ethyl acetate / [((50/50/2) ethyl acetate / methanol / dimethylethylamine]} to give the purified ester. The ester was dissolved in 4/1 dedichloromethane / trifluoroacetic acid (5.00 ml) and the mixture was kept at room temperature for sixteen hours. The volatiles were removed and the residue was dissolved in water.

The mixture was neutralized with half of the saturated sodium bicarbonate and the solid precipitate was collected by filtration to yield the product in 79% yield.

The following acid was prepared using this method.

6- [3- (dimethylamino) pyrrolidin-1-yl] -1H-pyrazolo [3,4-b] pyridine-3-carboxylic acid.

Procedure 17

Procedure 17 shows a preparation of fluorinated benzisothiazole-3-carboxylic acids from the corresponding benzisothiazole-3-carboxylic acid ester.

1-Fluoro-2,6-dichloropyridinium triflate (2.25mmol) was added to a solution of ethyl 6- (3-methoxypyrrolidin-1-yl) -1,2-benzisothiazole-3-carboxylate (1.87 mmol ) in dichloromethane (20.0 ml) and the reaction mixture was kept at room temperature for six hours. The reaction mixture was filtered through silica gel (10 g, dichloromethane wash) and the eluent was concentrated. The residue was purified by chromatography (90/10 to 70/30 dehexanes / ethyl acetate) to yield the product at 22% yield.

A solution of ethyl 7-fluoro-6- (3-methoxypyrrolidin-1-yl) -1,2-benzisothiazole-3-carboxylate (0.177 mmol) in ethanol (1.5 mL) was treated with a sodium hydroxide solution. 1.0 M (3.0 mmol). Within minutes, a gelatinous solid was precipitated. The reaction mixture was diluted with water (50 ml) and acidified with 6.0 clor hydrochloric acid. The precipitate was collected by filtration to yield the product in 80% yield. The acid was used without further purification.

The following acids were prepared using this method:

7-Fluoro-6- (3-methoxypyrrolidin-1-yl) -1,2-benzisothiazole-3-carboxylic acid.

7-Fluoro-6- (3-ethoxypyrrolidin-1-yl) -1,2-benzisothiazole-3-carboxylic acid.

7-Fluoro-6-methoxy-1,2-benzisothiazole-3-carboxylic acid. Procedure 18

procedure 18 presents a preparation of tert -6-phenyl-1H-pyrazolo [3,4-b] pyridine-3-carboxylic acid from tert -6-phenyl-1H-pyrazolo [3,4-b] pyridine-3-carboxylate butyl

[1,3-Bis (diphenylphosphino) propane] nickel (II) chloride (0.0999 mmol) and tert-butyl 6-fluoro-1H-pyrazolo [3,4-b] pyridine-3-carboxylate (0.999 mmol) ) were dissolved in tetrahydrofuran (20.0 ml) and the reaction mixture was cooled to 0 ° C. A 1.00 M solution of phenylmagnesium bromide in tetrahydrofuran (2.40 ml) was added and the stirring mixture was placed to warm to room temperature and maintained for four hours. The reaction was partitioned between water (50 ml) and ethyl acetate (50 ml). The layers were separated and the organic layers were washed with brine (25 mL), dried (magnesium sulfate) and concentrated. The residue was purified by chromatography (95/5 to 85/15 hexanes / ethyl acetate)) to give the product a 56% yield.

Det-butyl 6-phenyl-1H-pyrazolo [3,4-b] pyridine-3-carboxylate (0.555 mmol) was dissolved in a 4/1 solution of dichloromethane / trifluoroacetic acid (2.00 ml) and the reaction was maintained for 2 hours. sixteen hours at room temperature. The reaction mixture was concentrated and the residue was diluted with water (5 ml). The reaction mixture was neutralized to pH 5-7, stirred vigorously for one hour and the precipitated solids were collected by filtration to yield the acid in 92% yield.

The following acid was prepared using this method:

6-Phenyl-1H-pyrazolo [3,4-b] pyridine-3-carboxylic acid. Procedure 19

Procedure 19 details the preparation of ethyl 6-bromobenzisoxazole-3-carboxylate from 2,5-dibromonitrobenzene.

Diethyl malonate (12.6 g, 79 mmol) was added to a suspension of sodium hydride (3.16 g, 132 mmol) in dimethyl sulfoxide (60 mL) for 30 minutes. The reaction temperature rose to 60 ° C and the mixture was clarified. 1,4-dibromo-2-nitrobenzene (10 g, 36.0 mmol) was added and the solution was kept for two hours at 100 ° C. The reaction mixture was cooled to room temperature and poured into ice (300g - 400g). Precipitated solids were isolated by filtration and dried to yield 11.0 g of product (89%).

The ester (11.0 g, 32.0 mmol) was diluted with a 2 N sodium hydroxide solution (32 mL, 63 mmol) and the reaction mixture was kept at room temperature for sixteen hours. The aqueous layer was extracted with dichloromethane (20 mL) and acidified. Precipitated solids were isolated by filtration and dried to yield 7.00 g of acid (89%).

Sulfuric acid (1 mL) was added to a solution of acid (7.00 g, 27.0 mmol) in ethanol (60 mL). The reaction mixture was heated to reflux, kept for two hours and concentrated under reduced pressure. The residue was partitioned between ethyl acetate (250 mL) and saturated sodium carbonate (50 mL) and the organic layer was washed with saturated sodium carbonate (50 mL) and brine (50 mL). The organic layer was dried (sodium sulfate) and concentrated to yield 8.00 g (98%) of the ester as a liquid.

Isoamyl nitrite (225 ml) was added to a solution of ester (420 g, 1.46 mol) in ethanol (3 liters) in a 10-neck round bottom flask with three necks and the mixture was heated to 60 ° C. A solution of disodium ethoxide prepared from metallic sodium (33.5 g, 1.46 mmol) in ethanol (1 liter) was added by dripping and the reaction mixture was kept for two hours. The reaction mixture was placed to cool to room temperature and neutralized with 2 clor hydrochloric acid. The reaction mixture was extracted with ethyl acetate (4x2 liters) and the combined organic layers were washed with water (2x1 liter) and brine (2x1 liter) and dried (sodium sulfate). The residue was purified by chromatography (1/1 to 0/1 hexane / ethyl acetate) to yield 110 g of product (28%).

See, for example, International Patent Publication No. WO. 2004/010995.

The following ester was prepared using this method:

Ethyl 6-bromo-1,2-benzisoxazole-3-carboxylate.Procedure 20

Procedure 20 details the preparation of ethyl 6-methoxybenzisoxazole-3-carboxylate from 1-chloro-2,4-dinitrobenzene.

Sodium hydride (417 mmol) was added to a solution of ethyl 3-oxobutanoate (129 mmol) in tetrahydrofuran (350 mL). 1-Chloro-2,4-dinitrobenzene (123mmol) was added and the resulting suspension was kept for 24 hours at room temperature. The pH was adjusted to 5 by the addition of 3 M hydrochloric acid and the resulting solution extracted with diethyl ether (300 ml). The organic layer was washed with water (3 x 300 ml), dried (magnesium sulfate) and concentrated to give ethyl 2- (2,4-dinitrophenyl) -3-oxobutanoate in 98% yield as a brown solid.

Propan-1-amine (136 mmol) was added to a solution of ethyl 2- (2,4-dinitrophenyl) -3-oxobutanoate (135mmol) in chloroform (500 mL). The reaction mixture was kept for twelve hours at room temperature and concentrated.

The residue was purified by chromatography (20/1 dehexane / ethyl acetate) to give ethyl 2- (2,4-dinitrophenyl) acetate in 99% yield as a brown oil.

A solution of ethyl 2- (2,4-dinitrophenyl) acetate (18.1 mmol) and 3-methylbutanyl nitrite (73.5 mmol) in ethanol (70 mL) was heated to 60 ° C. A solution of sodium ethoxide prepared from sodium (21.7 mmol) and ethanol (70 mL) was added and the reaction mixture was kept for one hour. The reaction mixture was cooled to 0 ° C and the pH adjusted to 7 by the addition of 5% hydrochloric acid. The resulting solution was diluted with water (500 mL) and extracted with ethyl acetate (200 mL). The organic layer was washed with brine (4 x 200 ml), dried (magnesium sulfate) and concentrated. The residue was purified by chromatography (30/1 petroleum ether / ethyl acetate) to give 6-nitrobenzo [d] isoxazole-3-carboxylate deethyl in 70% yield as an orange solid.

Ethyl 6-nitrobenzo [d] isoxazole-3-carboxylate (12.7 mmol), iron (53.6 mmol) and ammonium chloride (56.1mmol) were combined and diluted with ethanol (150 mL) and water (20 ml). The resulting suspension was heated at reflux with vigorous comagitation for two hours. The reaction mixture was filtered through Celite, diluted with brine (200 mL) and the resulting solution was extracted with ethyl acetate (200 mL). The organic layer was washed with brine (3 x 200 mL), dried (magnesium sulfate) and concentrated. The residue was purified by chromatography (20/1 petroleum ether / ethyl acetate) to give ethyl 6-aminobenzo [d] isoxazole-3-carboxylate at 49.6% yield as an orange solid.

Ethyl 6-aminobenzo [d] isoxazole-3-carboxylate (2.43 mmol) was diluted with a solution of sulfuric acid (2.5 mL) in water (2.5 mL) and the resulting mixture was kept at room temperature. for thirty minutes. A solution of sodium nitrite (2.67 mmol) in water (2.5 mL) was added by dripping at 0 ° C and the resulting mixture was kept for 30 minutes at 0 ° C. This aqueous solution was added to a cold (0 ° C) solution of copper (II) nitrate (149 mmol) in water (80 mL) and the reaction mixture was placed to warm to room temperature. After five minutes, copper (I) oxide (2.78 mmol) was added to the mixture and the stirring mixture was kept for one hour at room temperature. The reaction mixture was extracted with ethyl acetate (3 x 100ml) and the combined organic layers were dried (magnesium sulfate) and concentrated to yield crude ethyl 6-hydroxybenzo [d] isoxazole-3-carboxylate at 99% yield as a brown oil.

Potassium carbonate (9.42 mmol) and iodomethane (8.45 mmol) were added to a solution of crude ethyl 6-hydroxybenzo [d] isoxazole-3-carboxylate (2.42mmol) in N, N-dimethyl formamide ( 30 ml) and the reaction mixture was kept for 48 hours at room temperature in the dark. The reaction mixture was diluted with water (100 ml) and extracted with ethyl acetate (2 χ 100 ml). The combined organic layers were washed with brine (3 x 100 ml), dried (magnesium sulfate) and concentrated. The residue was purified by chromatography (30/1 petroleum ether / ethyl acetate) to give ethyl 6-methoxybenzo [d] isoxazole-3-carboxylate at 19% yield as a yellow solid.

The following ester was prepared using this method:

Ethyl 6-methoxybenzo [d] isoxazole-3-carboxylate.

Procedure 21

Procedure 21 presents a preparation of 7-azabenzisothiazole-3-carboxylic acid from 2-chloronicotinic acid.

2-Chloronicotinic acid (317 mmol) was diluted with oxalyl chloride (130 mL) and the resulting solution was refluxed for eighteen hours. Volatile components were removed by evaporation to yield 2-chloronicotinoyl chloride in 98% yield as a white solid.

Magnesium chloride (221 mmol) and triethylamine (752 mmol) were added to a solution of diethyl malonate (375 mmol) in toluene (250 mL) and the reaction mixture was kept for one hour at 25 ° C. A solution of 2-chloronicotinoyl chloride (313 mmol) in toluene (80 ml) was added by dripping over the two hour period. The reaction mixture was kept at room temperature for three hours and quenched with cold water (500 ° C). The resulting solution was extracted with ethyl acetate (500 ml) and the organic layers were combined. The organic layer was washed with brine (3 x 300 ml), dried (sodium sulfate) and concentrated to give diethyl 2- (2-chloronicotinoyl) malonate in 85% yield as a brown oil.

A solution of 2- (2-chloronicotinoyl) dediethyl malonate (267 mmol) in dimethyl sulfoxide (100 ml) was added by drip for one and a half hours to a solution of water at 130 ° C (10 ml) in dimethyl sulfoxide (260 ml) ). The reaction mixture was kept at 1300 ° C for a further two hours and was placed to cool to room temperature. The reaction mixture was diluted with cold water (0 ° C) (500 ml) and extracted with ethyl acetate (3 χ 200 ml). The combined organic layers were washed with brine (5 x 200 ml), dried (sodium sulfate) and concentrated. The residue was purified by chromatography (10/1 petroleum ether / ethyl acetate) to give 1- (2-chloropyridin-3-yl) ethanone in 52% yield as a yellow oil.

A solution of 1- (2-chloropyridin-3-yl) ethanone (129mmol) in ammonium hydroxide (130 ml) and ethanol (500 ml) was added to a 1 liter high pressure steel vessel under an ammonia atmosphere. Sulfur (129 mmol) was added to the reaction mixture, the vessel was sealed and the reaction mixture was heated at 130 ° C for sixteen hours. The reaction mixture was filtered through celite and the eluent was extracted with ethyl acetate (300 ml). The organic layer was washed with brine (100 mL), dried (sodium sulfate) and concentrated. The residue was purified by chromatography (20/1 petroleum ether / ethyl acetate) to give 3-methylisothiazolo [5,4-b] pyridine at 22% yield as a white solid.

N-Bromosuccinamide (10.7 mmol) was added to a solution of 3-methylisothiazolo [5,4-b] pyridine (10.0 mmol) in tetracarbon chloride (20 mL). Benzoyl peroxide (0.82mmol) was added and the reaction mixture was heated at reflux for 48 hours. The reaction mixture was filtered through Celite (ethyl acetate) and the eluent was concentrated to yield crude 3- (bromomethyl) isothiazolo [5,4-b] pyridine as a yellow solid.

A solution of crude 3- (bromomethyl) isothiazolo [5,4-b] pyridine (3.49 mmol) in dimethyl sulfoxide (20 mL) was treated with water (4 mL) and the reaction mixture cooled to 80 ° C. for an hour and a half. The reaction mixture was diluted with water (100 mL), filtered through Celite and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with water, dried (magnesium sulfate) and concentrated to yield isothiazolo [5,4-b] pyridin-3-ylmethanol in 31% yield as a yellow oil.

Potassium permanganate (2.25 mmol) and potassium hydroxide (1.79 mmol) were added to a solution of deisothiazolo [5,4-b] pyridin-3-ylmethanol (1.0 mmol) in water (4ml) and the solution The resulting mixture was reacted for three hours at room temperature. The reaction mixture was filtered through Celite and extracted with ethyl acetate (3 x 10 ml). The pH of the combined aqueous layers was adjusted by 2 by the addition of 0.6 clor hydrochloric acid. The slurry was stirred for five minutes and the solids were collected by filtration to give isothiazolo [5,4-b] pyridine-3-carboxylic acid in 42% yield as a light yellow solid. The following acid was prepared using this method:

Isothiazolo [5,4-b] pyridine-3-carboxylic acid.

Procedure 22

The following procedure presents a method for preparing substituted 2,2,2-trifluoroethyl acids.

A mixture of ethyl 6 - [(15,45) -5- (tert-butoxycarbonyl) -2,5-diazabicyclo [2,2,1] hept-2-yl] -1,2-benzisothiazole-3-carboxylate (1.16 mmol) in 4/1 methylene chloride / trifluoroacetic acid (10.00 mL) was kept at room temperature for sixteen hours. The reaction mixture was concentrated and the residue was loaded onto a SCX column (10 g) and leveled with 5 volumes of methanol. The partially purified product was then eluted using 2.0 M ammonia in methanol to yield the amine in 68% yield.

2,2,2-Trifluoroethyl methanesulfonate (0.330 mmol) was added to a solution of 6 - [(15,45) -2,5-diazabicyclo [2,2,1] hept-2-yl] -1,2-benzisothiazole Ethyl 3-carboxylate (0.165 mmol) in N, N-diisopropylethylamine (0.20 mL) and acetonitrile (15 mL) and the resulting mixture was kept for sixteen hours at room temperature. The reaction mixture was concentrated and the residue was purified by chromatography (90/10 to 70/30 hexanes / ethyl acetate) to give the purified ester. The ester was dissolved in ethanol (5.0 mL) and an aqueous sodium hydroxide solution (5.0 M, 2.0 mL) was added. The reaction was kept at room temperature for four hours, then diluted with water (50 ml) and neutralized with acetic acid. The precipitate was collected by filtration to yield 6 - [(15,45) -5- (2,2,2-trifluoroethyl) -2,5-diazabicyclo [2,2,1] hept-2-yl] - 1,2-benzisothiazole-3-carboxylic acid in 29% yield. The following acid was prepared using a similar procedure:

6- {3- [Methyl (2,2,2-trifluoroethyl) amino] pyrrolidin-1-yl} -1,2-benzisothiazole-3-carboxylic acid.

Procedure 23

Procedure 23 presents a preparation of amidine-substituted indazole-3-carboxylic acids from the corresponding aldehydes.

N-Methyl-1,2-ethanediamine (4.7 mmol) was added to a solution of tert-butyl 6-formyl-1H-indazol-3-carboxylate (4.2 mmol) in tert-butanol (40 mL) and The mixing mixture was kept for thirty minutes. Potassium carbonate (10 mmol) and iodine (5.3 mmol) were added and the paste was heated to 70 ° C for three hours. The reaction mixture was placed to cool to room temperature and quenched with aqueous sodium thiosulfate (40 ml). The aqueous layer was extracted with 9/1 dichloromethane / methanol and the combined organic layers were dried (magnesium sulfate) and concentrated. The residue was purified by chromatography [100/0 to 60/40 dichloromethane / (8/1/1 dichloromethane / methanol / 7M ammonia in methanol) to give naamidine in 51% yield.

Tert-Butyl 6- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -1H-indazol-3-carboxylate (2.2 mmol) was diluted with trifluoroacetic acid (3.7 mL) and The reaction mixture was kept for sixteen hours at room temperature. The precipitated product was isolated by filtration to give the acid in 93% yield.

The following acid was prepared using this method:

6- (1-Methyl-4,5-dihydro-1H-imidazol-2-yl) -1H-indazol-3-carboxylic acid.

Procedure 24 Procedure 24 provides a preparation of N-alkyl aminobenzisothiazole-3-carboxylic acids from the corresponding aminobenzisothiazole-3-carboxylic esters.

Sodium cyanoborohydride (8.57 mmol) was added to a solution of 6 - [(IS, 4S) -2,5-diazabicyclo [2,2,1] hept-2-yl] -1,2-benzisothiazole-3 ethyl carboxylate (0.260 g, 0.857 mmol) and 1-ethoxy-1- (trimethylsilyloxy) cyclopropane (8.57 mmol) in ethanol (11.2 mL) and the reaction mixture was heated at 600 ° C for six hours. The reaction mixture was diluted with water (50ml) and extracted with ethyl acetate (2 x 50ml). The combined organic layers were washed with brine (25 mL), dried (magnesium sulfate) and concentrated. The residue was purified by chromatography (ethyl acetate) to yield the ester. A solution of 5.0 M sodium hydroxide in water (4.00 ml) was added to a solution of ester in ethanol (10.0 ml) and the reaction mixture was kept for sixteen hours. The reaction was neutralized with acetic acid and loaded onto an SCX column. The column was flushed with water (200 mL) and methanol (100 mL) and the product was eluted with 2.0 M ammonia in methanol (60 mL) to yield the acid at 56% yield. The acid was used without further purification.

The following acid was prepared using this method:

6 - [(1S, 4S) -5-Cyclopropyl-2,5-diazabicyclo [2,2,1] hept-2-yl] -1,2-benzisothiazole-3-carboxylic acid.

Procedure 25

Procedure 25 shows a preparation of N-alkyl aminobenzisothiazole-3-carboxylic acids from corresponding aminobenzisothiazole-3-carboxylic esters. Cyclopropylmethyl bromide (1.71) was added to a suspension of 6 - [(1S, 45) -2,5- ethyl diazabicyclo [2.2.1] hept-2-yl] -1,2-benzisothiazol-3-carboxylate (0.857 mmol) and sodium bicarbonate (3.43 mmol) in acetonitrile (10.0 mL) and the mixture of The reaction was heated at 60 ° C for six hours. Acetonitrile was decanted from the solids and the solids were washed with acetonitrile (2 x 5 ml). The deacetonitrile solution was transferred to a silica gel column and the mixture was purified by chromatography (9/1 to 7/3 ethyl acetate / [(50/50/2) ethyl acetate / methanol / dimethylethylamine]} to result in esterified. A solution of 5.0 M sodium hydroxide in water (2.00 ml) was added to a solution of ester in ethanol (5.0 ml) and the reaction mixture was maintained for sixteen hours. The reaction was neutralized with acetic acid and the reaction mixture was transferred to an SCX column (10 g). The column was flushed with water (200 ml) and methanol (100 ml) and the product was eluted with 2.0 M ammonia in methanol to give the product in 50% yield. The acid was used without further purification.

The following acid was prepared using this method:

6 - [(1S, 4S) -5- (cyclopropylmethyl) -2,5-diazabicyclo [2,2,1] hept-2-yl] -1,2-benzisothiazole-3-carboxylic acid.

Procedure 26

Procedure 26 shows a preparation of 6-hydroxybenzisothiazole-3-carboxylic acid and ester from the corresponding anisole.

A 1.0 M solution of methylene boron tribromide (20.00 ml) was added by dripping to a 0 ° C solution of ethyl 6-methoxy-1,2-benzisothiazole-3-carboxylate (12.6 ml). ) in methylene chloride (30.0 ml). The reaction mixture was placed to warm to room temperature and maintained for sixteen hours. The reaction mixture was poured into 100 ml of ice water and 2 N sodium hydroxide and the mixture was stirred vigorously for twenty minutes. Precipitated solids were removed by filtration and the eluent was washed with ethyl acetate (2 x 50ml). The aqueous layer was neutralized with 6N hydrochloric acid and the precipitated brownish solid was collected by filtration to give a mixture of methoxy acids (~ 48% yield) and hydroxy (~ 37% yield).

Thionyl chloride (27.0) was added dropwise to a round bottom flask containing ethanol (50.0 ml) at 0 ° C. The reaction mixture was placed to warm to room temperature and the mixture of hydroxy acid and methoxy was added after thirty minutes. The reaction mixture was heated at 950 ° C for four hours and concentrated to approximately 25 ml. The reaction mixture was partitioned between ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate (100 mL) and the organic layer was washed with brine and concentrated. The residue was purified by chromatography using a gradient of 80/20 to 60/40 dehexanes / ethyl acetate to yield the product at 82% yield.

The following acids and esters were prepared using this method:

6-Hydroxy-1,2-benzisothiazole-3-carboxylic acid. 6-Methoxybenzo [d] isothiazole-3-carboxylic acid.

Ethyl 6-hydroxy-1,2-benzisothiazole-3-carboxylate.

Procedure 27

Procedure 27 shows a preparation of 7-aza-6-chlorobenzisothiazole-3-carboxylic acid from 2-chloronicotinoyl chloride. Metallic magnesium (1.25 mol) was diluted with ethanol (250 ml) and carbon tetrachloride (5 ml) and the suspension was heated to 70 ° C-80 ° C for one hour. A solution of diethyl malonate (1.21 mol) in toluene (200 ml) was added dropwise and the reaction mixture was kept for two hours. The reaction mixture was cooled to 0 ° C and a solution of 2-chloronicotinoyl chloride ( 313 mmol) in toluene (200 mL) was added dropwise while the temperature was maintained at 0 ° C to 5 ° C. The resulting solution was placed to warm to room temperature and held for two hours. The reaction mixture was diluted with 50 ml of water and precipitated solids were collected by filtration to yield 104 g of crude 2- (2-chloronicotinoyl) malonate as a pink solid.

Water (1.3 mL) was added to a solution of diethyl 2- (2-chloronicotinoyl) malonate (31.7 mmol) in dimethyl sulfoxide (50 mL). The pH of the reaction mixture was added and adjusted to 5-6 by the addition of hydrochloric acid and the reaction mixture was heated at 130 ° C for two hours. The reaction mixture was then quenched with ice water (300 ml) and the aqueous layer was extracted with ethyl acetate (3 x 50 ml). The combined organic layers were washed with brine, dried (sodium sulfate) and concentrated. The residue was purified by chromatography (1/20 ethyl deacetate / petroleum ether) to give 1- (2-chloropyridin-3-yl) ethanone in 56% yield as a pale yellow oil.

Ammonium hydroxide (388 mL) was added to a mixture of sulfur (386 mmol) and 1- (2-chloropyridin-3-yl) ethanone (350 mmol) and the slurry was diluted with methanol (960 mL). Gaseous ammonia was bubbled through the reaction mixture for ten minutes and the reaction mixture was heated at 110 ° C for 24 hours. The reaction mixture was concentrated to dryness and the residue was extracted with water (3 x 500 ml). The aqueous layer was extracted with ethyl acetate (5 x 500 ml) and the combined organic layers were dried (magnesium sulfate) and concentrated. The residue was purified by chromatography (1/25 ethyl acetate / petroleum ether) to give 3-methylisothiazolo [5,4-b] pyridine at 67% yield as a pale yellow solid.

A solution of m-chloroperbenzoic acid (160 mmol) in acetic acid (200 mL) was added dropwise to a solution of 3-methylisothiazolo [5,4-b] pyridine (107 mmol) in dichloromethane (200 mL). The reaction mixture was kept for six hours at 25 ° C. The reaction mixture was diluted with water (100 mL), the pH adjusted to 8 with 10% sodium hydroxide and the layers separated. The aqueous layer was extracted with ethyl acetate (10 x 100 ml) and the combined organic layers were dried (magnesium sulfate) and concentrated to yield 3-methylisothiazolo [5,4-b] pyridine-N-oxide in 62% yield as a yellow solid.

A solution of triphosgene (190 mmol) in dichloromethane (200 ml) was added by dripping for twenty minutes to a solution of 3-methylisothiazolo [5.4-b] pyridine-N-oxide (47.4) in dichloromethane (150 ml) at -20 ° C. ° C.

A solution of diisopropylamine (190 mmol) in dichloromethane (200 mL) was added dropwise over one hour. The reaction mixture was placed to warm to ambient temperature and maintained for sixteen hours. The reaction mixture was quenched with water (40 ml) and the pH adjusted to 7 by the addition of 10% sodium hydroxide. The organic layer was washed with water (100 ml). The combined aqueous layers were extracted with dichloromethane (10 x 100 ml) and the combined organic layers were dried (magnesium sulfate) and concentrated. The residue was purified by chromatography (1/80 ethyl acetate / petroleum ether) to give 6-chloro-3-methylisothiazolo [5,4-b] pyridine in 46% yield as a colorless solid.

AIBN (1.35 mmol) was added to a solution of 6-chloro-3-methylisothiazolo [5,4-b] pyridine (13.5 mmol) and N-bromosuccinamide (27.1 mmol) in carbon tetrachloride ( 25ml). The reaction mixture was heated at 80 ° C for six hours, placed to cool to room temperature and precipitated solids were removed by filtration. The filtrate was concentrated to yield crude 3- (bromomethyl) -6-chloroisothiazolo [5,4-b] pyridine as a yellow oil.

Water (8 ml) was added to a solution of 3- (bromomethyl) -6-chloroisothiazolo [5,4-b] pyridine (19.0 mmol) in dimethyl sulfoxide (40 ml) and the reaction mixture was cooled to 800 ° C by a half hour. The reaction mixture was then quenched with water (50 ml) and the resulting solution was extracted with ethyl acetate (3 x 40 ml). The combined organic layers were dried (magnesium sulfate) and concentrated to yield crude methanol (6-chloroisothiazolo [5,4-b] pyridin-3-yl) as a yellow solid.

Potassium permanganate (1.69) was added in several batches to a solution of (6-chlorobenzo [d] isothiazol-3-yl) methanol (2.50 mmol) in water (3ml). Potassium carbonate (2.90 mmol) was added and the reaction mixture was maintained for thirty minutes at 25 ° C. Insoluble materials were removed by filtration and aqueous layer was extracted with ethyl acetate (3 x 10 ml).

The pH of the aqueous layer was adjusted to 3-4 by the addition of 1N hydrochloric acid and the reaction mixture was kept for ten minutes. The solids were collected by filtration to give 6-chlorobenzo [d] isothiazole-3-carboxylic acid in 15% yield as a white solid. The following acid was made using this method: 6-Chloroisothiazole [5,4-b acid ] pyridine-3-carboxylic acid.

Procedure 28

Procedure 28 shows a preparation of N-acylated aminobenzisothiazole-3-carboxylic acids from the corresponding aminobenzisothiazole-3-carboxylic esters.

Cyclopropanecarbonyl chloride (0.37 mmol) and N, N-diisopropylethylamine (0.49 mmol) were added to a solution of ethyl 6-piperazin-1-yl-1,2-benzisothiazole-3-carboxylate (0.12 mmol) in methylene chloride (3.0 ml) and reaction mixture was kept for one hour at room temperature. The reaction mixture was quenched with methanol (10 mL) and the mixture was held for an additional 30 minutes. The reaction mixture was poured onto a 5 g SCS column and the product was eluted with methanol (20 ml). A solution of 5.0 M sodium hydroxide in water (1.2 ml) was added to the methanol solution and the mixture was kept for two hours. The reaction mixture was diluted with water (50 mL) and neutralized with a 6 N hydrochloric acid solution (1.5 mL). The pH was further adjusted between 5 and 7 with acetic acid. Precipitated solids were collected by filtration to yield the acid in 88% yield.

The following acids were prepared using this method:

6- [4- (Cyclopropylcarbonyl) piperazin-1-yl] -1,2-benzisothiazole-3-carboxylic acid.

6- [1- (Cyclopropylcarbonyl) octahydro-6H-pyrrolo [3,4-b] pyridin-6-yl] -1,2-benzisothiazole-3-carboxylic acid.

6 - [(1S, 4S) -5- (cyclopropylcarbonyl) -2,5-diazabicyclo [2,2,1] hept-2-yl] -1,2-benzisothiazole-3-carboxylic acid.

Procedure 29 Procedure 29 provides a preparation of nitrile-substituted indazole-3-carboxylic acids from the corresponding bromoindazole-3-carboxylic esters.

Zinc cyanide (1.00 mmol) was added to a solution of ethyl 6-bromo-1H-indazol-3-carboxylate (0.502mmol) and tetrakis (triphenylphosphine) palladium (0) (0.0502 mmol) in JV, JV- dimethyl formamide (5.00 ml) and the reaction mixture was heated at 100 ° C for sixteen hours. The reaction mixture was diluted with ethyl acetate and water and the layers were separated. The aqueous layer was extracted with ethyl acetate (2 times) and the combined organic layers were washed with brine and dried (sodium sulfate). The residue was purified by chromatography (70/30 to 50/50 hexane / ethyl acetate) to yield nitrile at 65% yield. The ester was hydrolyzed with sodium hydroxide in ethanol to yield the acid.

The following acid and ester were prepared using this procedure:

Ethyl 6-cyano-1H-indazol-3-carboxylate.

6-Cyano-1H-indazol-3-carboxylic acid.

Base Preparations

The following procedures (30-35) detail the preparation of bicyclobases and amines that were not commercially available.

Procedure 30

Procedure 30 provides a method for preparing N-alkylated 3-aminoquinuclidines from 3-aminoquinuclidine.

Acetyl chloride (12) was added dropwise to a solution of (R) -3-aminoquinuclidine (10mmol) and N, N-diisopropylethylamine (30 mmol) in dichloromethane (100 mL). The resulting solution was kept at room temperature for four hours and evaporated to dryness. The starch was dissolved in tetrahydrofuran (150 ml) and treated with lithium aluminum hydride (66 mmol) in small portions. The reaction mixture was quenched with sodium sulfate dihydrate and the resulting slurry was diluted with tetrahydrofuran and filtered through Celite. The filtered material was concentrated and the residue was then diluted with freshly prepared methanolic hydrogen chloride (generated by dripping by the addition of 3 ml deacetyl chloride in 30 ml methanol) and kept at room temperature for fifteen minutes. The residue obtained by removing the volatile components was recrystallized (2-propanol / methanol) to give the secondary amine in 41% yield as a colorless solid.

The following bases were prepared using this method:

(3R) -N- (Methyl) quinuclidin-3-amine dihydrochloride.

(3S) -N- (Methyl) quinuclidin-3-amine dihydrochloride.

Procedure 31

Procedure 31 presents a method for preparing cyclic urea from diamines.

Carbonic acid and dimethyl ester (10.0 mmol) were added dropwise to a mixture of 2,7-propyl-1,2-ethanediamine (10.0 mmol) and cesium carbonate (2.00 mmol) and the mixture of The reaction was heated to 70 ° C for one hour. The reaction mixture was concentrated and the residue was heated at 130 ° C for three hours. The reaction mixture was concentrated and the residue was purified by chromatography [(50/50 to 0/100) hexane / ethyl acetate] to afford the product (60%) as an oil.

The following cyclic ureas were prepared using this method:

1-propylimidazolidin-2-one.l-ethylimidazolidin-2-one.Procedure 32

Procedure 32 presents a method for preparing 3-alkoxypyrrolidines from N-Boc-3-hydroxypyrrolidine.

1-boc-3-hydroxypyrrolidine (16.1 mmol) was added portionwise to a suspension of sodium hydride (22.0 mmol) in tetrahydrofuran (40 mL) at 0 ° C. The reaction mixture was diluted with tetrahydrofuran (60 ml) and placed to warm to room temperature. Methyl iodide (21.0 mmol) was added to the cloudy suspension after one hour and the reaction mixture was kept at room temperature for six hours. The reaction mixture was concentrated and again dissolved in ethyl acetate (100 ml). The extract was washed with saturated ammonium chloride (20 mL), water (20 mL) and brine (20 mL) and dried (sodium sulfate). The residue was purified by chromatography (1/4 ethyl acetate / hexane) to give the ether. W-Boc product was dissolved in tetrahydrofuran (30 mL) and 6 N hydrochloric acid (20 mL) was added. The resulting mixture was stirred for one hour and concentrated to yield an oil. Toluene (10ml) and ethanol (10ml) were added and the mixture concentrated to yield 1.79g of a very hygroscopic brownish solid. The solid was suspended in vigorously stirred ethyl acetate for twelve hours. The solids were collected quickly by filtration and dried under high vacuum to yield the product (81%) as a colorless solid.

An alternative procedure used for removal of N-Boc groups involves exposure to trifluoroacetic acid for four hours, followed by concentration of the reaction mixture. This procedure may be useful for producing the amine as a free base. The following amine was prepared using this procedure:

3-Methoxypyrrolidine hydrochloride.

The free base was obtained by neutralizing salt with saturated sodium carbonate (5 ml), extracting with 9/1 dichloromethane / methanol (3 x 20 ml), drying (potassium carbonate) and concentration, followed by amine uptake. a column of SCX and elution with 2 M daphony in methanol:

3-methoxypyrrolidine.3-ethoxypyrrolidine. (3R) -3-methoxypyrrolidine. (3S) -3-methoxypyrrolidine.3- (methoxymethyl) pyrrolidine

Procedure 33

Procedure 33 shows a preparation of SEM protected hydroxypyrrolidines from hydroxypyrrolidine.

A solution of 1-Boc-3-hydroxypyrrolidine (26.7mmol) in tetrahydrofuran (20ml) was slowly added to a suspension of sodium hydride (30.8mmol) in tetrahydrofuran (78ml) and the reaction mixture was added. maintained for thirty minutes. A solution of [β- (trimethylsilyl) ethoxy] methyl chloride (30.7 mmol) in tetrahydrofuran (4.4 mL) was added and the reaction mixture was kept for eighteen hours. The reaction was partitioned between water (50 ml) and ethyl acetate (50 ml) and the layers separated. The organic layer was washed with brine (25 mL), dried (magnesium sulfate) and concentrated. The residue was purified by chromatography (95/5 to 80/20 hexanes / ethyl acetate) to yield the Boc protected product. The residue was heated neat at 350 ° C for three hours. The resulting brown oil was purified by chromatography [100/0 to 80/20 ethyl acetate / (50/50/2 ethyl acetate / methanol / dimethylethylamine)] to give a brown oil after concentration. The oil was dissolved in ethanol and the solution was treated with activated carbon, filtered and concentrated to yield the product in 52% yield.

The following amine was prepared using this method:

3 - {[2- (trimethylsilyl) ethoxy] methoxy} pyrrolidine.

Procedure 34

Procedure 34 presents a preparation of 3-trifluoromethoxypyrrolidine from hydroxypyrrolidine.

A solution of I-Boc-3-hydroxypyrrolidine (26.7mmol) in tetrahydrofuran (20ml) was slowly added to a suspension of sodium hydride (30.8mmol) in tetrahydrofuran (78ml) at 0 ° C. Chlorodifluoromethane (30.7mmol) was added to the reaction and the reaction mixture was placed to warm to room temperature, which was maintained for eighteen hours. The reaction was partitioned between water (50 mL) and ethyl acetate (50 mL) and the layers separated. The organic layer was washed with brine (25 mL), dried (magnesium sulfate) and concentrated. The residue was purified by chromatography (95/5 to 80/20 dehexanes / ethyl acetate) to yield the Boc protected product. The purified product (approximately 2 g) was dissolved in a 4/1 mixture of dichloromethane / trifluoroacetic acid (20.0 ml) and kept for four hours. The solvent was removed and the residue was purified by chromatography [100/0 to 90/10 ethyl acetate / (50/50/2 ethyl deacetate / methanol / dimethylethylamine)]. The product became unexpectedly volatile and much of it was lost in concentration. The final yield for the product was 2%. The following amine was prepared using this

method:

3- (difluoromethoxy) pyrrolidine.

Procedure 35

Procedure 35 shows a preparation of 3-cyclopropylmethoxypyrrolidine from hydroxypyrrolidine.

A solution of 3-hydroxypyrrolidine hydrochloride (162 mmol) in tetrahydrofuran (100 ml) was treated with potassium carbonate (210 mmol) and a solution of benzyl dechloroformate (210 mmol) in tetrahydrofuran (50 ml). The resulting solution was kept for sixteen hours at room temperature. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate (200 mL). The solution was washed with brine (3 x 100 ml), dried (magnesium sulfate) and concentrated to give the protected amine in 90% yield as a yellow liquid.

Sodium hydride (280 mmol) was added portionwise to a cold (CO) solution of benzyl 3-hydroxypyrrolidine-1-carboxylate (76.9 mmol) in N, N-dimethyl formamide (100 mL). The mixture was maintained for sixty minutes and was then treated with a solution of (bromomethyl) cyclopropane (231 mmol) in N, N-dimethyl formamide (100 mL) and depotassium iodide (0.66 mmol). The reaction mixture was placed to warm to room temperature, which was held for thirty minutes. The reaction mixture was subjected to microwave irradiation for two hours at 90 ° C. The reaction mixture was concentrated and the residue was diluted with ethyl acetate (200 mL) and water (200 mL) and the layers separated. The aqueous layer was extracted with ethyl acetate (3 x 200 mL) and the combined organic layers. They were washed with brine (2 x 200 ml) and dried (magnesium sulfate). The residue was purified by chromatography (20/1 petroleum ether / ethyl acetate) to give the product in 81% yield.

A suspension of benzyl 3- (cyclopropylmethoxy) pyrrolidine-1-carboxylate (17.4 mmol) and 10% palladium on carbon (600 mg) in ethyl acetate (20 ml) and methanol (20 ml) was placed under a gas atmosphere. hydrogen. The reaction mixture was maintained for sixteen hours and was filtered through Celite. The filtered material was concentrated to yield the product in 86% yield as a yellow liquid.

The following amine was prepared using this method:

3- (cyclopropylmethoxy) pyrrolidine.

Representative Procedures

The following procedures (A-AA) detail the preparation of bicyclobase analogs.

Procedure A

Procedure A provides a method for coupling between 3-aminoquinuclidine and benzisoxazole carboxylic esters for the formation of decarboxamide derivatives.

Suspension of (S) -3-aminoquinuclidine hydrochloride (3.50 mmol) in ethanol (5 mL) was treated with N, N-diisopropylethylamine (4.00 mmol). Ethyl 6-bromo-1,2-benzisoxazole-3-carboxylate (1.86 mmol) was added and the suspension was heated at 85 ° C for three days. The reaction mixture was placed to cool to room temperature, diluted with dichloromethane (30 ml) and washed with 10 ml saturated sodium bicarbonate. The aqueous layer was extracted again with dichloromethane (30 mL) and the combined organic layers were washed with dried brine (sodium sulfate). The organic layer was loaded onto a 10 g SCX column. The column was washed with methanol (50 mL), 2 M ammonia in methanol (60 mL) and the ammonia wash concentrated. The residue was purified by chromatography [40/60 to 0/100 ethyl acetate / (70/30/1 ethyl deacetate / methanol / ammonium hydroxide)] to give the product in 63% yield as a colorless oil .

The following compound was prepared using this method:

86) N - [(3R) -1-azabicyclo [2,2,2] oct-3-yl] -6-methoxy-1,2-benzisoxazol-3-carboxamide, 1H NMR (CD3OD) δ 7.94 ( d, 1H, J = 8.8), 7.24 (d, 1H, J = 2), 7.06 (dd, 1H, J = 2.1, 8.7), 4.51 (m, 1H ), 3.91 (s, 1H), 3.84 (m, 1H), 3.38 (m, 1H), 2.38 (m, 1H), 2.22 (m, 1H), 2.09 (m, 2H), 1.94 (m, 1H); LC / MS (EI) t R3.37, m / z 302.1 (M + +1);

N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -6-bromo-1,2-benzisoxazol-3-carboxamide.

Procedure B

Procedure B provides a method for coupling between 3-aminoquinuclidine and benzisothiazole carboxylic acids for the formation of decarboxamide derivatives.

To a solution of benzisothiazole-3-carboxylic acid (0.30 mmol) in a mixture of 5/1 detetrahydrofuran / N, N-dimethyl formamide (12 ml) was added diisopropylethylamine (1.1 mmol) and dihydrochloride (R) -3-aminoquinuclidine (0.6 mmol). The mixture was cooled to 0 ° C and HATU (0.3 mmol) was added in one portion. The reaction mixture was placed to warm to room temperature and held for sixteen hours. The mixture was partitioned between the saturated aqueous potassium carbonate solution and a 95/5 mixture of dichloromethane / methanol. The aqueous layer was extracted with 95/5 dichloromethane / methanol (2X) and the combined organic layers were washed with brine and dried over sodium sulfate. Alternatively, the reaction mixture was loaded onto a 10 g SCX column and the column was washed with methanol (50 mL), 2 M ammonia in methanol (60 mL) and the ammonia wash concentrated. The crude product was purified by chromatography [100/0 to 30/70 ethyl acetate / [(50/50/2) ethyl acetate / methanol / dimethylethylamine] or by preparative HPLC, thereby resulting in the amide at a yield. 75% as a colorless solid.

The following compounds were prepared using this method:

84) N - [(3R) -1-azabicyclo [2,2,2] oct-3-yl] -6 - [(3R) -3-methoxypyrrolidin-1-yl] -1,2-benzisothiazol-3 carboxamide, 1HNMR (CD 3 OD) δ 8.47 (d, J = 9.1, 1H); 6.98 (d, J = 1.9, 1H); 6.88 (dd, J "= 2.0 / 9.2, 1H); 4.30 (m, 1H); 4.16 (m, 1H); 3.60-3.35 (m, 5H); 3.38 (s, 3H); 3.3-2.95 (m, 5H); 2.30-2.00 (m, 4H) 1.92 (m, 2H); 1.61 (m, 1H); LC / MS (EI) t R 3.84, m / z 387.2 (M + +1);

85) N - [(3R) -1-Azabicyclo [2,2,2] oct-3-yl] -6 - [(3S) -3-methoxypyrrolidin-1-yl] -1,2-benzisothiazol-3 carboxamide, LC / MS (EI) t R 3.91, m / z 387.2 (M + +1);

87) N - [(3S) -1-Azabicyclo [2,2,2] oct-3-yl] -6- (3-ethoxypyrrolidin-1-yl) -7-fluoro-1,2-benzisothiazol-3 carboxamide, LC / MS (EI) t R 4.82, m / z 419.1 (M + +1);

92) N - [(3R) -1-Azabicyclo [2,2,2] oct-3-yl] -7-fluoro-6- (3-methoxypyrrolidin-1-yl) -1,2-benzisothiazol-3 carboxamide, LC / MS (EI) t R 5.11, m / z 405.2 (M + +1);

93) N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -7-fluoro-6- (3-methoxypyrrolidin-1-yl) -1,2-benzisothiazol-3 carboxamide, LC / MS (EI) t R 5.08, m / z 405.2 (M + +1);

94). N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -6 - [(3R) -3-hydroxypyrrolidin-1-yl] -1,2-benzisothiazole-3-carboxamide, LC / MS (EI) t R 4.25, m / z 373.1 (M + +1); 95) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] - 6 - [(35) -3-hydroxypyrrolidin-1-yl] -1,2-benzisothiazole-3-carboxamide, LC / MS (EI) t R 4.23, m / z 373.1 (M + +1);

96) N - [(35) -1-azabicyclo [2,2,2] oct-3-yl] -6 - [(35) -3- (dimethylamino) pyrrolidin-1-yl] -1,2-benzisothiazole -3-carboxamide, LC / MS (EI) t R 1.92, m / z 400.2 (M + +1);

97) N - [(35) -1-azabicyclo [2,2,2] oct-3-yl] -6 - [(15,45) -2-oxa-5-azabicyclo [2,2,1] hept - 5-yl] -1,2-benzisothiazol-3-carboxamide, LC / MS (EI) t R 4.26, m / z 385.1 (M + +1);

98) N - [(3R) -1-azabicyclo [2,2,2] oct-3-yl] -6 - [(3R) -3-hydroxypyrrolidin-1-yl] -1,2-benzisothiazole-3 carboxamide, LC / MS (EI) t R 4.27, m / z 373.1 (M + +1);

99) N - [(3R) -1-Azabicyclo [2,2,2] oct-3-yl] -6 - [(35) -3-hydroxypyrrolidin-1-yl] -1,2-benzisothiazole-3 carboxamide, LC / MS (EI) t R 4.23, m / z 373.1 (M + +1);

100) N - [(3R) -1-azabicyclo [2,2,2] oct-3-yl] -6 - [(35) -3- (dimethylamino) pyrrolidin-1-yl] -1,2-benzisothiazole -3-carboxamide, LC / MS (EI) t R 1.89, m / z 400.2 (M + +1);

101) N - [(35) -1-azabicyclo [2,2,2] oct-3-yl] -7 - [(3R) -3-hydroxypyrrolidin-1-yl] -1,2-benzisothiazol-3 carboxamide, LC / MS (EI) t R 4.27, m / z 373.1 (M + +1);

102) N - [(35) -1-azabicyclo [2,2,2] oct-3-yl] - 7 - [(35) -3-hydroxypyrrolidin-1-yl] -1,2-benzisothiazole-3 carboxamide, LC / MS (EI) t R 4.26, m / z 373.1 (M + +1);

103) N - [(35) -1-azabicyclo [2,2,2] oct-3-yl] -7 - [(35) -3- (dimethylamino) pyrrolidin-1-yl] -1,2-benzisothiazole -3-carboxamide, LC / MS (EI) t R 1.92, m / z 400.2 (M + +1);

104) N - [(35) -1-azabicyclo [2,2,2] oct-3-yl] -7 - [(15,45) -2-oxa-5-azabicyclo [2,2,1] hept -5-yl] -1,2-benzisothiazol-3-carboxamide, LC / MS (EI) t R 4.36, m / z 385.1 (M + +1);

105) N - [(3 ') -1-azabicyclo [2,2,2] oct-3-yl] -7 - [(35) -3- (dimethylamino) pyrrolidin-1-yl] -1,2- benzisothiazole-3-carboxamide, LC / MS (EI) t R 1.81, m / z 400.2 (M + +1); 106) N - [(3S) -1-azabicyclohydroformate [2.2.2 ] oct-3-yl] isothiazolo [5,4-b] pyridine-3-carboxamide, LC / MS (EI) t R 2.71, m / z 289.1 (M + +1);

107) N - [(3R) -1-Azabicyclo [2,2,2] oct-3-yl] isothiazolo [5,4-b] pyridine-3-carboxamide hydroformate, LC / MS (EI) t R 2.48 m / z 289.1 (M + +1);

114) N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -7-fluoro-6-methoxy-1,2-benzisothiazol-3-carboxamide, LC / MS (EI) t R 3.8, m / z 336.1 (M + +1);

115) N - [(3R) -1-azabicyclo [2,2,2] oct-3-yl] -7-fluoro-6-methoxy-1,2-benzisothiazol-3-carboxamide, LC / MS (EI) t R 3.81, m / z 336.1 (M + + 1);

116) N - [(3R) -1-azabicyclo [2,2,2] oct-3-yl] -6 - [(1S, AS) -5-methyl-2,5-diazabicyclo [2.2.1 ] hept-2-yl] -1,2-benzisothiazol-3-carboxamide, LC / MS (EI) t R 1.84, m / z 398.2 (M + +1);

117) N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -6 - [(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1 ] hept-2-yl] -1,2-benzisothiazol-3-carboxamide, LC / MS (EI) t R 1.87, m / z 398.2 (M + +1);

122) N - [(3R) -1-Azabicyclo [2,2,2] oct-3-yl] -6 - [(1S, 4S) -5- (2,2,2-trifluoroethyl) -2,5 -diazabicyclo [2.2.1] hept-2-yl] -1,2-benzisothiazol-3-carboxamide, LC / MS (EI) t R 4.69, m / z466.1 (M + +1);

123) N - [(3R) -1-azabicyclo [2,2,2] oct-3-yl] -6- {3- [methyl (2,2,2-trifluoroethyl) amino] pyrrolidin-1-yl} -1,2-benzisothiazole-3-carboxamide, LC / MS (EI) t R 4.77, m / z 468.1 (M + +1);

124) N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -6- {3- [methyl (2,2,2-trifluoroethyl) amino] pyrrolidin-1-yl} -1,2-benzisothiazole-3-carboxamide, LC / MS (EI) t R 4.75, m / z 468.1 (M + +1);

125) N - [(35) -1-azabicyclo [2,2,2] oct-3-yl] -6- [3- (methoxymethyl) pyrrolidin-1-yl] -1,2-benzisothiazole-3-carboxamide LC / MS (EI) t R 4.98, m / z 401.1 (M + +1); 126) N - [(3 R) -1-azabicyclo [2.2.2] oct-3-yl] -6- [3- (methoxymethyl) pyrrolidin-1-yl] -1,2-benzisothiazole-3-carboxamide, LC / MS (EI) t R 4.94, m / z 401.1 (M + +1);

127) N - [(3R) -1-azabicyclo [2,2,2] oct-3-yl] -6 - [(3 ') -3- (dimethylamino) pyrrolidin-1-yl] -1,2- benzisothiazole-3-carboxamide, LC / MS (EI) t R 1.55, m / z 400.2 (M + +1);

128) N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] - 6 - [(3R) -3- (dimethylamino) pyrrolidin-1-yl] -1,2-benzisothiazole -3-carboxamide, LC / MS (EI) t R 1.55, m / z 400.1 (M + +1);

129) N - [(3S) -1-Azabicyclo [2,2,2] oct-3-yl] -6- [4- (dimethylamino) piperidin-1-yl] -1,2-benzisothiazole-3-carboxamideLC MS (EI) t R 1.59, m / z 414.1 (M + +1);

130) N - [(3R) -1-azabicyclo [2,2,2] oct-3-yl] -6- [4- (dimethylamino) piperidin-1-yl] -1,2-benzisothiazole-3-carboxamide LC / MS (EI) t R 1.61, m / z 414.2 (M + +1);

177) N - [(3R) -1-Azabicyclo [2,2,2] oct-3-yl] -6- [4- (cyclopropylcarbonyl) piperazin-1-yl] -1,2-benzisothiazole-3-carboxamide LC / MS (EI) t R 3.30, m / z 440 (M + +1);

178) N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -6- [4-

(Cyclopropylcarbonyl) piperazin-1-yl] -1,2-benzisothiazol-3-carboxamide, LC / MS (EI) t R 3.30, m / z 440 (M + +1);

179) N - [(3R) -1-azabicyclo [2,2,2] oct-3-yl] -6- [1- (cycloprop.ylcarbonyl) octahydro-6H-pyrrolo [3,4-b] pyridin-2-one 6-yl] -1,2-benzisothiazol-3-carboxamide, LC / MS (EI) t R 3.81, m / z 480 (M + +1);

180) N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -6- [1- (cyclopropylcarbonyl) octahydro-6H-pyrrolo [3,4-b] pyridin-6 yl] -1,2-benzisothiazole-3-carboxamide, LC / MS (EI) t R 3.85, m / z 480 (M + + 1);

181) N - [(3R) -1-azabicyclo [2,2,2] oct-3-yl] -6 - [(1S, 4S) -5- (cyclopropylcarbonyl) -2,5-diazabicyclo [2.2 , 1] hept-2-yl] -1,2-benzisothiazol-3-carboxamide, LC / MS (EI) t R 3.97, m / z 452 (M + + 1); -182) N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -6 - [(1S, AS) -5- (cyclopropylcarbonyl) -2,5-diazabicyclo [2,2,1] hept-2-yl ] -1,2-benzisothiazole-3-carboxamide, LC / MS (EI) t R 3.04, m / z 452 (M + +1);

-183) N - [(3R) -1-azabicyclo [2,2,2] oct-3-yl] -6- (3,4-dimethylpiperazin-1-yl) -1,2-benzisothiazole-3-carboxamide LC / MS (EI) t R 1.30, m / z 400 (M + +1);

-132) N - [(3S) -1-Azabicyclo [2,2,2] oct-3-yl] -1H-methyl-6 - [(1S, 4S) -5-methyl-2,5-dihydroformate diazabicyclo [2.2.1] hept-2-yl] -1,2-benzisothiazol-3-carboxamide, LC / MS (EI) t R 3.27, m / z 412.2 (M + +1);

-133) N - [{3R) -1-Azabicyclo [2,2,2] oct-3-yl] -W-methyl-6 - [(1H14S) -5-methyl-2,5-diazabicyclo dihydroformate [ 2,2,1] hept-2-yl] -1,2-benzisothiazol-3-carboxamide, LC / MS (EI) t R 3.19, m / z 412.2 (M + +1);

-134) N - [(3 ') - 1-azabicyclo [2,2,2] oct-3-yl] -6 - [(li', 4R) -5-methyl-2,5-diazabicyclo [2, 2.1] hept-2-yl] -1,2-benzisothiazol-3-carboxamide, LC / MS (EI) t R 3.26, m / z 398.2 (M + +1);

-135) N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -6 - [(li ', 4') -5-methyl-2,5-diazabicyclo [2, 2.1] hept-2-yl] -1,2-benzisothiazol-3-carboxamide, LC / MS (EI) t R 3.2, m / z 398.2 (M + +1);

-136) N - [(3R) -1-Azabicyclo [2,2,2] oct-3-yl] 6- (1,4-diazabicyclo [3,2,2] non4-yl) -1-dihydroformate 2-benzisothiazole-3-carboxamide, LC / MS (EI) t R 1.61, m / z 412.2 (M + +1);

-137) N - [(3S) -1-Azabicyclo [2,2,2] oct-3-yl] -6- (1,4-diazabicyclo [3,2,2] non4-yl) -1-dihydroformate , 2-benzisothiazole-3-carboxamide, LC / MS (R) t R 3.51, m / z 412.1 (M + +1);

-138) N - [(3R) -1-azabicyclo [2,2,2] oct-3-yl] -6-pyrrolidin-1-yl-1,2-benzisothiazole-3-carboxamide, LC / MS (EI ) t R 4.66, m / z 357.2 (M + +1);

-139) N - [(3R) -1-azabicyclo [2,2,2] oct-3-yl] -6- (4-methylpiperazin-1-yl) -1,2-benzisothiazole-3-carboxamide, LC MS (EI) t R 1.67, m / z 386.2 (M + +1); 140) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6 - (4-methylpiperazin-1-yl) -1,2-benzisothiazol-3-carboxamide, LC / MS (EI) t R 1.63, m / z 386.2 (M + +1);

141) N - [(3R) -1-azabicyclo [2,2,2] oct-3-yl] -6- (4-methyl-1,4-diazepan-1-yl) -1,2-benzisothiazole-1 3-carboxamide, LC / MS (EI) t R 1.8, m / z 400.2 (M + +1);

142) N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -6- (4-methyl-1,4-diazepan-1-yl) -1,2-benzisothiazole 3-carboxamide, LC / MS (EI) t R 1.84, m / z 400.2 (M + +1);

143) N - [(3R) -1-azabicyclo [2,2,2] oct-3-yl] -6- (hexahydropyrrolo [1,2-a] pyrazin-2 (1H) -yl) -1,2 -benzisothiazole-3-carboxamide, LC / MS (EI) t R 1.79, m / z 412.1 (M + +1);

144) N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] 6- (hexahydropyrrolo [1,2-a] pyrazin-2 (1H) -yl) -1,2 -benzisothiazole-3-carboxamide, LC / MS (EI) t R 1.81, m / z 412.2 (M + +1);

145) N - [(3R) -1-azabicyclo [2,2,2] oct-3-yl] -6- (5-methyl-2,5-diazabicyclo [2,2,2] oct-2-yl ) -1,2-benzisothiazole-3-carboxamide, LC / MS (EI) t R 1.88, m / z 412.2 (M + +1);

146) N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -6- (5-methyl-2,5-diazabicyclo [2,2,2] oct-2-yl ) -1,2-benzisothiazole-3-carboxamide, LC / MS (EI) t R 1.88, m / z 412.2 (M + +1);

147) N - [(3R) -1-azabicyclo [2,2,2] oct-3-yl] -6- (8-methyl-3,8-diazabicyclo [3,2,1] oct-3-yl ) -1,2-benzisothiazole-3-carboxamide, LC / MS (EI) t R 1.95, m / z 412.2 (M + +1);

148) N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -6- (8-methyl-3,8-diazabicyclo [3,2,1] oct-3-yl ) -1,2-benzisothiazole-3-carboxamide, LC / MS (EI) t R 1.93, m / z 412.2 (M + +1);

149) N - [(3R) -1-Azabicyclo [2,2,2] oct-3-yl] -6 - [(1S, 4S) -5-cyclopropyl-2,5-diazabicyclo [2.2.1 ] hept-2-yl] -1,2-benzisothiazol-3-carboxamide, LC / MS (EI) t R 3.08, m / z 424.1 (M + +1);

150) N - [(33) -1-azabicyclo [2,2,2] oct-3-yl] -6 - [(15,4S) -5-cyclopropyl-2,5-diazabicyclo [2.2.1 ] hept-2-yl] -1,2-benzisothiazol-3-carboxamide, LC / MS (EI) t R 3.24, m / z 424.1 (M + +1);

151) N - [(3R) -1-Azabicyclo [2,2,2] oct-3-yl] -6 - [(1S, 4S) -5- (cyclopropylmethyl) -2,5-diazabicyclo [2.2 , 1] hept-2-yl] -1,2-benzisothiazol-3-carboxamide, LC / MS (EI) t R 1.31, m / z 438.2 (M + +1);

152) N - [(3S) -1-Azabicyclo [2,2,2] oct-3-yl] -6 - [(1S, 4S) -5- (cyclopropylmethyl) -2,5-diazabicyclo [2.2 , 1] hept-2-yl] -1,2-benzisothiazol-3-carboxamide, LC / MS (EI) t R 1.31, m / z 438.2 (M + +1);

153) N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -5- (4-methyl-1,4-diazepan-1-yl) -1,2-benzisothiazol-2-one 3-carboxamide, LC / MS (EI) t R 2.14, m / z 400.2 (M + +1);

154) N - [(3R) -1-Azabicyclo [2,2,2] oct-3-yl] -5 - [(3R) -3-methoxypyrrolidin-1-yl] -1,2-benzisothiazol-3 carboxamide, LC / MS (EI) t R 3.57, m / z 387.2 (M + +1);

155) N - [(35) -1-azabicyclo [2,2,2] oct-3-yl] -5 - [(3R) -3-methoxypyrrolidin-1-yl] -1,2-benzisothiazol-3 carboxamide, LC / MS (EI) t R 3.57, m / z 387.2 (M + +1);

156) N - [(3 ') -1-azabicyclo [2,2,2] oct-3-yl] -5 - [(3S) -3-methoxypyrrolidin-1-yl] -1,2-benzisothiazole-3 carboxamide, LC / MS (EI) t R 3.56, m / z 387.2 (M + +1);

157) N - [(3R) -1-azabicyclo [2,2,2] oct-3-yl] -6 - [(1-methylpyrrolidin-3-yl) oxy] -1,2-benzisothiazol-3-carboxamide LC / MS (EI) t R 1.25, m / z 387.2 (M + +1);

158) N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -6 - [(1-methylpyrrolidin-3-yl) oxy] -1,2-benzisothiazol-3-carboxamide LC / MS (EI) t R 1.25, m / z 387.2 (M + +1);

159) N - [(3R) -1-Azabicyclo [2,2,2] oct-3-yl] -6- (1-azabicyclo [2,2,2] oct-3-yloxy) -1,2- benzisothiazole-3-carboxamide, LC / MS (EI) t R 1.33, m / z 413.2 (M + +1); 160) N - [(3S) -1-azabicyclo [2.2.2] oct -3-yl] -6- (1-azabicyclo [2,2,2] oct-3-yloxy) -1,2-benzisothiazol-3-carboxamide, LC / MS (EI) t R 1.32, m / z 413.2 (M + +1); N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5- (bromo) -1,2-benzisothiazole-3-carboxamide;

N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -6- (bromo) -1,2-benzisothiazol-3-carboxamide;

N - [(3R) -1-azabicyclo [2,2,2] oct-3-yl] -6- (bromo) -1,2-benzisothiazole-3-carboxamide;

N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -6- (methoxy) -1,2-benzisothiazole-3-carboxamide.

The following compounds were prepared using this procedure, followed by treatment with trifluoroacetic acid, ion exchange isolation and purification by chromatography or preparative HPLC as described above:

118) N - [(3R) -1-azabicyclo [2,2,2] oct-3-yl] -6 - [(1S, 4S) -2,5-diazabicyclo [2,2,1] hept-2 -yl] -1,2-benzisothiazole-3-carboxamide, LC / MS (EI) t R 1.87, m / z 3 84.1 (M + +1);

119) N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -6 - [(1S, 4S) -2,5-diazabicyclo [2,2,1] hept-2 -yl] -1,2-benzisothiazole-3-carboxamide, LC / MS (EI) t R 1.87, m / z 384.1 (M + +1);

120) N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -6- [3- (methylamino) pyrrolidin-1-yl] -1,2-benzisothiazole-3-carboxamide LC / MS (EI) t R 1.96, m / z 386.1 (M + +1);

121) N - [(3R) -1-azabicyclo [2,2,2] oct-3-yl] -6- [3- (methylamino) pyrrolidin-1-yl] -1,2-benzisothiazole-3 carboxamide, LC / MS (EI) t R 1.94, m / z 386.2 (M + +1);

168) N - [(3R) -1-Azabicyclo [2,2,2] oct-3-yl] 6- (3-methylpiperazin-1-yl) -1,2-benzisothiazole-3-carboxamide, LC / MS (EI) t R 1.28, m / z 386.2 (M + +1); 169) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (octahydro-6H-pyrrolo [3,4-b] pyridin-6-yl) -1,2-benzisothiazole-3-carboxamide, LC / MS (EI) t R 1.33, m / z 412.2 (M + +1);

170) N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -6- (octahydro-6H-pyrrolo [3,4-b] pyridin-6-yl) -1, 2-benzisothiazole-3-carboxamide, LC / MS (EI) t R 1.35, m / z 412.2 (M + +1);

171) N - [(3S) -1-Azabicyclo [2,2,2] oct-3-yl] -6-piperazin-1-yl-1,2-benzisothiazol-3-carboxamide, LC / MS (EI) t R 1.29, m / z 372 (M + +1);

172) N - [(3R) -1-Azabicyclo [2,2,2] oct-3-yl] -6-piperazin-1-yl-1,2-benzisothiazol-3-carboxamide, LC / MS (EI) t R 1.47, m / z 372 (M + +1);

173) W - [(3 ') -1-azabicyclo [2,2,2] oct-3-yl] 6- (1,4-diazepan-1-yl) -1,2-benzisothiazole-3-carboxamide LC / MS (EI) t R 1.74, m / z 386 (M + +1);

174) W - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -6- (1,4-diazepan-1-yl) -1,2-benzisothiazole-3-carboxamide, LC / MS (EI) t R 1.70, m / z 386 (M + +1);

175) N - [(3R) -1-Azabicyclo [2,2,2] oct-3-yl] -6- (2-methylpiperazin-1-yl) -1,2-benzisothiazole-3-carboxamide, LC / MS (EI) t R 1.57, m / z 386 (M + +1);

176) N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -6- (2-methylpiperazin-1-yl) -1,2-benzisothiazole-3-carboxamide, LC / MS (EI) t R 1.55, m / z 386 (M + +1).

Procedure C

Procedure C provides a method for coupling between 3-aminoquinuclidine and carboxylic acids for the formation of carboxamide derivatives.

To a solution of carboxylic acid (16.1 mmol) in N, N-dimethyl formamide (65 ml) was added HBTU (16.1 mmol), a catalytic amount of dimethylaminopyridine, NfN-diisopropylethylamine (96.6 mmol) and 4 µm molecular sieves. It is activated (2.6 g). The reaction mixture was kept at room temperature for two hours under 3-aminoquinuclidine nitrogen hydrochloride (16.1 mmol) was then added. After eighteen hours, the solvent was removed under reduced pressure. The oily residue was partitioned between saturated aqueous sodium bicarbonate (25 mL) and dichloromethane (100 mL). The aqueous layer was further extracted with 9/1 dichloromethane / methanol (5 x 100 ml) and the combined organic layers were concentrated. The residue was purified by chromatography [90/10/1 dedichloromethane / methanol / ammonium hydroxide or 1/1 to 0/1 ethyl deacetate / (70/30/1 ethyl acetate / methanol / ammonium hydroxide)] or by preparative HPLC, thereby resulting in the product in 30-70% yield.

The following compounds were prepared using this method:

42) N - [(3R) -1-Azabicyclo [2,2,2] oct-3-yl] -5-methoxy-N-methyl-1H-indazol-3-carboxamide hydroformate. 1H NMR (CD3OD) δ8.42 (br s, 1H), 7.49 (d, J = 9.1, 1H), 7.38 (d, J = 2.1.1H), 7.09 (dd , J = 9.1, 2.4, 1H), 4.89 (m, 1H), 3.85 (s, 3H), 3.83 (m, 2H), 3.60-3.46 (m 1H), 3.38-3.30 (m, 2H), 2.57 (m, 2H), 2.36-2.30 (m, 1H), 2.10-1.97 (m, 3H ); LC / MS (EI) t R 2.56, m / z 315 (M + +1);

43) N - [(31 ') -1-Azabicyclo [2,2,2] oct-3-yl] -5- (difluoromethoxy) -N-methyl-1H-indazol-3-carboxamide hydroformate. LC / MS (EI) t R 2.82, m / z 351 (M + +1);

44) N - [(3R) -1-Azabicyclo [2,2,2] oct-3-yl] -S- (difluoromethoxy) -N-methyl-1H-indazol-3-carboxamide hydroformate. LC / MS (EI) t R 2.9, m / z 351 (M + +1);

45) N - [(3R) -1-Azabicyclo [2,2,2] oct-3-yl] -N-methyl-6- (tetrahydro-2H-pyran-4-yl) -1H-indazol-hydroformate 3-carboxamide.

LC / MS (EI) t R 2.55, m / z 369 (M + +1); 46) N - [(3R) -1-Azabicyclo [2,2,2] oct-3-yl] -hydroformate N-methyl-5- (tetrahydro-2H-pyran-4-yl) -1H-indazol-3-carboxamide.LC/MS (EI) t R 2.89, m / z 369 (M + +1);

47) N - [(3R) -1-Azabicyclo [2,2,2] oct-3-yl] -N-methyl-6- (1,3-thiazol-2-yl) -1H-indazol-hydroformate 3-carboxamide. LC / MS (EI) t R 3.33, m / z 368 (M + +1);

48) N - [(3R) -1-Azabicyclo [2,2,2] oct-3-yl] -S-methoxy-N-methyl-1,2-benzisothiazole-3-carboxamide hydroformate. LC / MS (EI) t R3.21, m / z 348 (M + +1);

N - [(35) -1-azabicyclo [2,2,2] oct-3-yl] -7-methoxy-1H-indazol-3-carboxamide.

Procedure D

Procedure D presents a method for coupling between 3-aminoquinuclidine and carboxylic acids15 for the formation of carboxamide derivatives.

To a solution of carboxylic acid (4.77 mmol) in N, N-dimethyl formamide (14 mL) was added N1N-diisopropylethylamine (19 mmol) and 3-aminoquinuclidine dihydrochloride (4.29 mmol). The reaction mixture was kept at room temperature for thirty minutes under nitrogen and HATU (4.76 mol) was then added. After eighteen hours, the reaction mixture was filtered through Cellite (rinse with methanol) and equally divided between three SCX columns. The columns were washed with methanol25 (100 ml each) and the basic components were eluted with 2 M ammonia in methanol (100 ml each) and concentrated. The residue was purified by chromatography [1/1 to 0/1 ethyl deacetate / (70/30/1 ethyl acetate).

ethyl / methanol / ammonium hydroxide] or by preparative HPLC 30, thereby resulting in the product at a yield of 15% -50%.

The following compounds were prepared using this method: 3) N - [(35) -1-Azabicyclo [2,2,2] oct-3-yl] -5,6-dimethoxy-1H-indazol-3-carboxamide hydroformate. 1H NMR (CD3OD) δ 8.3 3 (bs, 2H), 7.55 (s, 1H), 7.05 (s, 1H), 4.52 (m, 1H), 3.87 (s, 3H ), 3.86 (s, 3H), 3.79 (m, 1H), 3.37 (m, 6H), 2.38 (m, 4H), 2.11 (m, 5H); LC / MS (EI) t R 2.48, m / z 331 (M + +1);

17) N - [(3R) -1-Azabicyclo [2,2,2] oct-3-yl] -6-methoxy-N-methyl-1 H -indazol-3-carboxamide hydroformate. LC / MS (EI) t R 2.53, m / z 315 (M + +1);

19) N - [(35) -1-azabicyclo [2,2,2] oct-3-yl] -1-ethyl-6-methoxy-1H-indazol-3-carboxamide. LC / MS (EI) t R 3.55, m / z 329 (M + +1);

20) N - [(3R) -1-Azabicyclo [2,2,2] oct-3-yl] -1-ethyl-6-methoxy-1H-indazol-3-carboxamide. LC / MS (EI) t R 3.54, m / z 329 (M + +1);

21) N - [(35) -1-azabicyclo [2,2,2] oct-3-yl] -1- (difluoromethyl) -6-methoxy-1H-indazol-3-carboxamide. LC / MS (EI) t R 3.75, m / z 351 (M + +1);

28) N - [(35) -1-azabicyclo [2,2,2] oct-3-yl] -N-methyl-6- (1,3-oxazol-2-yl) -1H-indazol-3-one carboxamide. LC / MS (EI) t R 3.09, m / z 352 (M + +1);

29) N - [(35) -1-azabicyclo [2,2,2] oct-3-yl] -N-methyl-6- (1,3-thiazol-2-yl) -1H-indazol-3-one carboxamide. LC / MS (EI) t R 3.33, m / z 368 (M + +1);

34) N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -N-methyl-6- (tetrahydro-2H-pyran-4-yl) -1H-indazol-3-one carboxamide. LC / MS

(EI) t R 2.52, m / z 369 (M + +1); 35) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -N-methyl-5 - (tetrahydro-2H-pyran-4-yl) -1H-indazol-3-carboxamide. LC / MS (EI) t R 2.85, m / z 369 (M + +1);

36) N - [(3S) -1-Azabicyclo [2,2,2] oct-3-yl] -5- (difluoromethoxy) -N-methyl-1H-indazol-3-carboxamide. LC / MS (EI) t R 3.4, m / z 351 (M + +1);

37) N - [(35) -1-azabicyclo [2,2,2] oct-3-yl] -6- (difluoromethoxy) -N-methyl-1H-indazol-3-carboxamide. LC / MS (EI) t R 3.48, m / z 351 (M + +1); 40) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5- methoxy-N-methyl-1H-indazol-3-carboxamide. LC / MS (EI) t R 2.51, m / z 315 (M + +1); 57) N - [(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -hydroformate 6-fluoro-1H-pyrazolo [3,4-b] pyridine-3-carboxamide, LC / MS (EI) t R 2.47, m / z 290 (M + +1);

59) N - [(33) -1-azabicyclo [2,2,2] oct-3-yl] -1H-pyrazolo [4,3-c] pyridine-3-carboxamide, LC / MS (EI) t R 1 , 29, m / z 272.2 (M + +1);

60) N - [{3S) -1-Azabicyclo [2,2,2] oct-3-yl] -1H-pyrazolo [3,4-c] pyridine-3-carboxamide hydroformate, LC / MS (EI) t R 1.59, m / z 272.2 (M + +1);

73) N - [(3R) -1-Azabicyclo [2,2,2] oct-3-yl] -1-ethyl-6- (1,3-oxazol-2-yl) -1H-indazol-hydroformate 3-carboxamide, LC / MS (EI) t R 3.13, m / z 366 (M + +1);

88) N - [(3S) -1-Azabicyclo [2,2,2] oct-3-yl] -6-phenyl-1H-pyrazolo [3,4-b] pyridine-3-carboxamide, LC / MS ( EI) t R 4.18, m / z 348.1 (M + +1);

90) N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -6- [3- (dimethylamino) pyrrolidin-1-yl] -1H-pyrazolo [3,4-b ] pyridine-3-carboxamide, LC / MS (EI) t R 2.64, m / z 384.2 (M + +1);

91) N - [(3R) -1-azabicyclo [2,2,2] oct-3-yl] -6- [3- (dimethylamino) pyrrolidin-1-yl] -1H-pyrazolo [3,4-b ] pyridine-3-carboxamide, LC / MS (EI) t R 2.62, m / z 384.2 (M + +1);

N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -6- (bromo) -1H-indazol-3-carboxamide;

N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -4-methoxy-1H-indazol-3-carboxamide.

N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -6-bromo-1-ethyl-1H-indazol-3-carboxamide;

N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -6-bromo-1-methyl-1H-indazol-3-carboxamide;

N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -6-bromo-1-difluoromethyl-1H-indazol-3-carboxamide; N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -6- (1,3-thiazol-2-yl) -1H-indazol-3-carboxamide;

N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -6- (1,3-oxazol-2-yl) -1H-indazol-3-carboxamide;

N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -6-bromo-1 - [(2-methoxyethoxy) methyl] -1H-indazol-3-carboxamide;

N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -6-bromo-1 - {[2- (trimethylsilyl) ethoxy] methyl} -1H-indazol-3-carboxamide;

N - [{3R) -1-azabicyclo [2,2,2] oct-3-yl] -6-bromo-1 - {[2- (trimethylsilyl) ethoxy] methyl} -1H-indazol-3-carboxamide;

N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -6-bromo-2 - {[2- (trimethylsilyl) ethoxy] methyl} -1H-indazol-3-carboxamide;

N - [(3R) -1-azabicyclo [2,2,2] oct-3-yl] -6-bromo-2- {[2- (trimethylsilyl) ethoxy] methyl} -1H-indazol-3-carboxamide.

The following compounds were prepared using this procedure, followed by removal of the protecting group using 6 N hydrochloric acid, ion exchange isolation, and preparative HPLC purification:

6) N - [(3S) -1-Azabicyclo [2,2,2] oct-3-yl] -6- (tetrahydrofuran-3-yloxy) -1H-indazol-3-carboxamide hydroformate. LC / MS (EI) t R 2.68, m / z 357 (M + +1);

7) N - [(3S) -1-Azabicyclo [2,2,2] oct-3-yl] -6- (tetrahydro-2H-pyran-4-yloxy) -1H-indazol-3-carboxamide hydroformate. LC / MS (EI) t R 2.73, m / z 371 (M + +1);

8) N - [(3S) -1-Azabicyclo [2,2,2] oct-3-yl] -6 - [(1-methylpyrrolidin-3-yl) oxy] -1H-indazol-3-carboxamide hydroformate . LC / MS (EI) t R 1.4, m / z 370 (M + +1).

The following compound was prepared using this procedure, followed by treatment with detetrabutylammonium fluoride:

164) N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -5 - [(3S) -3- (cyclopropylmethoxy) pyrrolidin-1-yl] -1H-indazol-3 carboxamide, LC / MS (EI) t R 3.67, m / z 410 (M + +1); 166) N - [(3S) -1-azabicyclo [2.2.2] oct-3-dihydroformate yl] -5 - [(3S) -3-methoxypyrrolidin-1-yl] -1H-indazol-3-carboxamide, LC / MS (EI) t R 2.44, m / z 369 (M + +1).

[PAGE 156]

Procedure E

Procedure E presents a method for coupling 3-aminoquinuclidine and carboxylic acids, amines and indazoles for the formation of amide and urea derivatives.

A mixture of 6- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -1H-indazol-3-carboxylic acid (0.500 mmol), TBTU (0.624 mmol) and (3R) - dihydrochloride Quinuclidin-3-amine (0.706 mmol) was diluted with N, N-dimethyl formamide (4 mL) and N, N-diisopropylethylamine (2.34 mmol) was added. The reaction mixture was maintained for sixteen hours at room temperature. The reaction mixture was loaded onto an SCX column (10g) and washed with methanol (100ml). The partially purified product was then eluted using 2.0 M ammonia in methanol (60 ml). The solvent was removed and the residue was purified by preparative HPLC, thereby resulting in the product in 20% yield.

The following compounds were prepared using this method:

162) N - [(3R) -1-Azabicyclo [2,2,2] oct-3-yl] -6- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -1H- indazol-3-carboxamide, 1 H NMR (CD 3 OD) δ 8.53 (s, 2H), 8.46 (d, J = 8.5, 1H, rotamer), 8.40 (d, J = 8.4, 1H, rotamer), 8.06 (s, 1H, rotamer), 7.90 (s, 1H, rotamer), 7.50 (d, J = 8.3, 1H, rotamer), 7.35 (d, J = 8.4, 1H, rotamer), 4.91 (s, 1H), 4.20 (m, 3H), 4.03 (m, 3H), 3.82 (m, 1H), 3.33 (m, 6H), 3.19 (s, 3H), 2.39 (m, 1H), 2.38 (m, 1H), 2.11 (m, 2H), 1.22 (m, 1H) ; LC / MS (EI) t R 1.43, m / z 352 (M + +1); 163) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- ( 1-methyl-4,5-dihydro-1H-imidazol-2-yl) -1H-indazol-3-carboxamide, LC / MS (EI) t R 1.26, m / z 352 (M + +1);

167) N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -6-chloroisothiazolo [5,4-b] pyridine-3-carboxamide, LC / MS (EI) t R 2, 46, m / z 322 (M + +1);

184) N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -6-cyano-1H-indazol-3-carboxamide, LC / MS (EI) t R 2.50, m / z 2.96 (M + +1).

Procedure F

Procedure F provides a method for coupling 3-aminoquinuclidine with carboxylic acids, amines and indazoles for the formation of amide and urea derivatives.

NfN-carbonyldiimidazole (0.62 mmol) was added to a solution of (S) 3-aminoquinuclidine hydrochloride (0.500 mmol) in N, W-dimethyl formamide (3.0 mL). N, N-diisopropylethylamine (1.48 mmol) was added dropwise and the reaction mixture was kept for two hours at room temperature. N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -1H-indazol-3-carboxamide (0.370 mmol) was added and the reaction mixture was maintained for sixteen hours. The reaction mixture was transferred to an SCX column (10 g) and the column was washed with 5 volumes of methanol. The partially purified product was then eluted using 5% dimethylethylamine in methanol. The residue was purified by chromatography using 50/50 to 30/70 ethyl acetate / [(50/50/2) ethyl acetate / methanol / dimethylethylamine] to give urea at 61% yield.

The following compound was prepared using this method:

161) N, N'-di- (35) -1-azabicyclo [2.2.2] oct-3-yl-1H-indazol-1,3-dicarboxamide, 1H NMR (CD3OD) δ 8.34 (d , J = 8.5, 1H); 8.27 (d, J = 8.2,1H); 7.57 (t, J = 7.3, 1H); 7.40 (t, J = 7,3,1H); 4.21 (m, 1H); 4.11 (m, 1H); 3.39 (m, 2H); 3.1-2.7 (m, 10H); 2.12 (m, 2H); 1.97 (m, 2H); 1.81 (m, 4H); 1.59 (m, 2H); LC / MS (EI) t R 1.38, m / z 423.2 (M + +1);

N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -6- (bromo) -1,2-benzisothiazole-3-carboxamide.

N - [(3R) -1-azabicyclo [2,2,2] oct-3-yl] -5- (tetrahydro-2H-pyran-4-yloxy) -1- [2- (trimethylsilyl) ethoxy] methyl] 1H-indazol-3-carboxamide

The following compound was prepared using this procedure, followed by treatment with tetrabutylammonium fluoride:

190) N - [(3R) -1-azabicyclo [2,2,2] oct-3-yl] -5- (tetrahydro-2H-pyran-4-yloxy) -1H-indazol-3-carboxamide); LC / MS (EI) t R 4.46, m / z 370.4 (M + +1);

Procedure G

Procedure G provides a method for coupling 3-aminoquinuclidine and carboxylic acids to form carboxamide derivatives.

The coupling reaction and purification were performed according to procedure A (benzisoxazoles), procedures Β, E or F (benzisothiazoles) or procedures C, D, E or F (indazoles). The free base was dissolved in methanol (3.5 ml / mmol of starting acid) and treated with 1 N hydrochloric acid in ether (3.5 ml / mmol of starting acid). The resulting suspension was diluted with ether (7 ml / mmol of the starting acid) and kept at room temperature for two hours.

The solids were collected by filtration, rinsed with ether and dried, thereby resulting in the hydrochloride salt in a yield of 40-60%.

The following compounds were prepared using this method: 71) N - [(35) -1-Azabicyclo [2,2,2] oct-3-yl] -S-methoxy-1,2-benzisoxazol-3-carboxamide hydrochloride, 1H NMR (CD3OD) δ 7.93 (d, J = 8.7, 1H), 7.23 (s, 1H), 7.05 (d, J = 8.7, 1H), 4.47 (m 1H), 3.91 (s, 3H), 3.82-3.69 (m, 1H), 3.35-3.25 (m, 5H), 2.32 (m, 1H), 2, 16 (m, 1 H), 2.04 (m, 2H), 1.86 (m, 2H); LC / MS (EI) t R 2.75, m / z 302 (M + +1);

74) N - [(3S) -1-Azabicyclo [2,2,2] oct-3-yl] -1-ethyl-6- (1,3-oxazol-2-yl) -1H-indazol-hydrochloride 3-carboxamide, LC / MS (EI) t R 3.07, m / z 366 (M + +1);

51) N - [(3R) -1-Azabicyclo [2,2,2] oct-3-yl] -6-methoxy-1,2-benzisothiazole-3-carboxamide hydrochloride. LC / MS (EI) t R 14.4, m / z 318 (M + +1);

52) N - [(3S) -1-Azabicyclo [2,2,2] oct-3-yl] -S-methoxy-1,2-benzisothiazole-3-carboxamide hydrochloride. LC / MS (EI) t R 14.35, m / z 318 (M + +1);

53) N - [(3S) -1-Azabicyclo [2,2,2] oct-3-yl] -7-methoxy-1,2-benzisothiazole-3-carboxamide hydrochloride. LC / MS (EI) t R 15.36, m / z 318 (M + +1),

Procedure H

Procedure H presents a method for coupling brominated 3-aminoquinuclidinecarboxamides and Grignard reagents for the formation of substituted dealkyl derivatives.

A 5 ml microwave reaction vessel was charged with bis (triphenylphosphine) palladium (II) chloride (0.030 mmol, 0.1 equiv.) And bromide (0.30 mmol). The container was evacuated and refilled with argon gas. In a separate reaction vessel, the Grignard solution (1.2mmol, 4 equiv.) Was added to a solution of 0.5 M zinc decloride (1.2 mmol, 4 equiv.) In tetrahydrofuran at room temperature. The suspension was held for 30 minutes and the entire contents were transferred to the reaction vessel by cannula. The container was microwaved and subjected to microwave irradiation at 100 ° C for 600 seconds with a pre-stirring time of 60 seconds. Sandation was quenched with acetic acid (0.5 ml), diluted with methanol and transferred to an SCX column. The column was washed with methanol (50 mL) and the product was eluted with 2 M ammonia in methanol (50 mL) and concentrated. The residue was purified by chromatography [90/10/1 Dichloromethane / methanol / ammonium hydroxide or 1/1 to 0/1 ethyl deacetate / (70/30/1 ethyl acetate / methanol / ammonium hydroxide)] or by preparative HPLC, thereby resulting in the product in a 20-50% yield.

The following compound was prepared using this method:

22) N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -1- (difluoromethyl) -6- (1,3 -1iazol-2-yl) -1H-indazol-2-one 3-carboxamide. 1H NMR (CD3OD) δ 8.46 (s, 1H); 8.40 (d, J = 8.6,1H); 8.05 (d, J = 8.6, 1H); 7.98 (t, J = 58.3, 1H); 7.97 (d, J = 3.3, 1H); 7.73 (d, J = 3.3, 1H); 4.57 (m, 1H); 3.86 (m, 1H); 3.60-3.20 (m, 5H); 2.43 (m, 1H); 2.26 (m, 1H); 2.16 (m, 2H); 1.95 (m, 1H); LC / MS (EI) t R 4.04, m / z 404 (M + +1).

Procedure I

Procedure I provides a method for the coupling between aminoquinuclidinecarboxamides which support aniline or phenol and alkylating agents for forming aniline or ether substituted secondary derivatives.

To a solution of N - [(35) -1-azabicyclo [2,2,2] oct-3-yl] -6-hydroxy-1,2-benzisothiazole-3-carboxamide (0.400 mol) in N, N-dimethyl formamide (6 ml) were added depotassium carbonate (2.00 mol) and cyclopropylmethyl bromide (0.47 mmol). The reaction was maintained for sixteen hours and the solvent was removed in vacuo. The residue was extracted with 10/1 dedichloromethane / methanol (3 times) and the combined extracts were concentrated. The residue was purified by preparative HPLC using an eight minute gradient of 95/5 to 20/80 of water (0.1% formic acid) / acetonitrile (0.1% formic acid), thereby yielding the product to a yield. 32%.

The following compounds were prepared using this method:

N - [(3S) -1-Azabicyclo [2,2,2] oct-3-yl] -6- (cyclopropylmethoxy) -1,2-benzisothiazole-3-carboxamide hydroformate;

13) (3S) -3 - {[(5-Hydroxy-1,2-benzisothiazol-3-yl) carbonyl] amino} -1-methyl-1-azoniabicyclo [2,2,2] octane iodide or formate. LC / MS (EI) t R 2.55, m / z 318 (M + +1);

N - [(3S) -1-Azabicyclo [2,2,2] oct-3-yl] -5-methoxy-1,2-benzisothiazole-3-carboxamide hydroformate.

The following compound may be prepared using this method:

1) (35) -3 - ({[6- (Cyclopropylmethoxy) -1,2-benzisothiazol-3-yl] carbonyl} amino) -1- (cyclopropylmethyl) -1-azoniabicyclo [2.2, bromide or formate] 2] octane. LC / MS (EI) t R 5.76, m / z 412 (M + +1).

Procedure J

Procedure J presents a method for the coupling between brominated benzisothiazoles 3-aminoguinuclidine and cyclic amines for the formation of deaniline derivatives.

Pyrrolidine (0.361 mmol), N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-bromo-1,2-benzisothiazole-3-carboxamide (0.259 mmol), palladium (0.021 mmol), 2-dicyclohexylphosphino-2 ', 4', 6'-tri-i-propyl-1,1'-biphenyl (0.049mmol) and cesium carbonate (0.586 mmol) were combined in a microwave container . The vial was evacuated freshly filled under an argon atmosphere. Tetrahydrofuran (3.7 ml) was added and the vial was foiled. The reaction was subjected to microwave irradiation at 135 ° C for thirty minutes. The reaction mixture was filtered through Celite and the residue was purified by chromatography [100/0 to 80/20 ethyl acetate / (50/50/2 ethyl acetate / methanol / dimethylethylamine)] or preparative HPLC to yield the product. at a yield of 34%.

The following compounds were prepared using this method:

2) N - [(3S) -1-Azabicyclo [2,2,2] oct-3-yl] -6- (3-methoxypyrrolidin-1-yl) -1,2-benzisothiazole-3-carboxamide, 1HNMR ( CD 3 OD) δ 7.91 (d, J = 8.9, 1H); 7.77 (s, 1H); 7.09 (d, J = 8.9, 1H); 4.3-4.1 (m, 2H); 3.7-3.3 (m, 8H); 3.1-2.8 (m, 5H); 2.20 (m, 2H); 2.09 (m, 1H); 1.98 (m, 1H); 1.83 (m, 2H); 1.60 (m, 1H); LC / MS (EI) t R 3.7, m / z 387 (M + +1);

64) N- [13S) -1-Azabicyclo [2,2,2] oct-3-yl] -6-pyrrolidin-1-yl-1,2-benzisothiazol-3-carboxamide, LC / MS (EI) t R 4.13, m / z 357.2 (M + +1);

66) N - [(3S) -1-Azabicyclo [2,2,2] oct-3-yl] -6- (β-pyrrol-1-yl) -1,2-benzisothiazole-3-carboxamide, LC / MS (EI) t R 4.04, m / z 353.1 (M + +1);

68) N - [(3S) -1-Azabicyclo [2,2,2] oct-3-yl] -6- [3- (cyclopropylmethoxy) pyrrolidin-1-yl] -1,2-benzisothiazole-3-carboxamide LC / MS (EI) t R 4.31, m / z 427.2 (M + +1);

69) N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -6- (3-methoxypyrrolidin-1-yl) -1,2-benzisoxazole-3-carboxamide, LC / MS (EI) t R 3.57, m / z 371.2 (M + +1);

70) N - [(3S) -1-Azabicyclo [2,2,2] oct-3-yl] -7- (3-methoxypyrrolidin-1-yl) -1,2-benzisothiazole-3-carboxamide, LC / MS (EI) t R 3.83, m / z 387.2 (M + +1);

72) N - [(3R) -1-Azabicyclo [2,2,2] oct-3-yl] -6- (3-methoxypyrrolidin-1-yl) -1,2-benzisothiazole-3-carboxamide, LC / MS (EI) t R 3.8, m / z 387.2 (M + +1); 75) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -S- t (3R) -3-methoxypyrrolidin-1-yl] -1,2-benzisothiazol-3-carboxamide, LC / MS (EI) t R 3.74, m / z 387.2 (M + +1);

76) N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -6 - [(3S) -3-methoxypyrrolidin-1-yl] -1,2-benzisothiazol-3 carboxamide, LC / MS (EI) t R 3.77, m / z 387.2 (M + +1);

79) N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -6- [3- (difluoromethoxy) pyrrolidin-1-yl] -1,2-benzisothiazol-3 carboxamide, LC / MS (EI) t R 4.22, m / z 423.2 (M + +1);

108) N - [(3S) -1-Azabicyclo [2,2,2] oct-3-yl] -6 - [(3 ') -3-methoxypyrrolidin-1-yl] -1,2-benzisoxazol-3 carboxamide, LC / MS (EI) t R 4.5, m / z 371.1 (M + +1);

109) N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -6 - [(3S) -3-methoxypyrrolidin-1-yl] -1,2-benzisoxazol-3-one carboxamide, LC / MS (EI) t R 4.5, m / z 371.1 (M + +1);

110) Benzisothiazol-N - [(3R) -1-azabicyclo [2,2,2] oct-3-yl] -7 - [{3R) -3-methoxypyrrolidin-1-yl] -1,2-hydroformate 3-carboxamide, LC / MS (EI) t R 3.92, m / z 387.1 (M + +1);

111) N - [(3R) -1-azabicyclo [2,2,2] oct-3-yl] - 7 - [(35) -3-methoxypyrrolidin-1-yl] -1,2-benzisothiazol-3-one carboxamide, LC / MS (EI) t R 3.91, m / z 387.1 (M + +1);

112) Benzisothiazole-N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -7 - [(3R) -3-methoxypyrrolidin-1-yl] -1,2-hydroformate 3-carboxamide, LC / MS (EI) t R 3.91, m / z 387.1 (M + +1);

113) Benzisothiazol-N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -7 - [(3S) -3-methoxypyrrolidin-1-yl] -1,2-hydroformate 3-carboxamide, LC / MS (EI) t R 3.94, m / z 387.1 (M + +1).

The following compound was prepared from 3 - [(2-trimethylsilylethoxy) methoxy] pyrrolidine using this method followed by treatment with 6 N hydrochloric acid, preparative HPLC purification and isolation using SCX ion atrocation: 78) N-H3S) -1 -azabicyclo [2,2,2] oct-3-yl] 6- (3-hydroxypyrrolidin-1-yl) -1,2-benzisothiazol-3-carboxamide, LC / MS (EI) t R 4.44, m / z 373.1 (M + +1).

Procedure K

Procedure K provides a method for coupling brominated 3-aminoquinuclidine indazoles and cyclic amines for the formation of aniline derivatives.

2-Dicyclohexylphosphino-2 ', 4', 6'-triisopropyl-1,1'-biphenyl (0.0450 mmol), palladium (II) acetate (0.0150 mmol), cesium carbonate (2.25 mmol) and 3- (cyclopropylmethoxy) pyrrolidine (2.25 mmol) were combined in one vial. A solution of N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -6-bromo-2- [2- (trimethylsilyl) ethoxy] methyl-1H-indazol-3-carboxamide (0.751 mmol) in toluene (6.36 mL) was added and the mixture was heated at 80 ° C for three days. The reaction mixture was filtered through Celite, loaded onto a column of RediSep (silica gel) and eluted using a gradient of 100/0 to 80/20 ethyl acetate / (50/50/2 ethyl deacetate / methanol / dimethylethylamine) . The residue was transferred to an SCX column (10 g) and the column was washed with methanol (5 volumes), 2.0 M ammonia in methanol (most of the SEM was removed by this process) and the ammonia eluent was concentrated. The residue was purified by preparative HPLC [90/10 to 50/50 water (0.1% formic acid) / acetonitrile (0.1% formic acid) for ten minutes] to give the desired product in a yield of 7%. %.

The following acids were prepared using this method:

58) N - [(3S) -1-Azabicyclo [2,2,2] oct-3-yl] -6- [3- (cyclopropylmethoxy) pyrrolidin-1-yl] -1H-indazol-3-carboxamide hydroformate 1H NMR (CD3OD) δ 8.44 (Br s, 1H); 7.95 (d, J = 9.0,1H); 6.75 (d, J = 9.0, 1H); 6.46 (s, 1H); 4.50 (m, 1H); 4.30 (m, 1H); 3.81 (m, 1Η); 3.60-3.20 (m, 9Η); 3.36 (d, J = 6.9, 2H); 2.37 (m, 1H); 2.26 (m, 1H); 2.17 (m, 2H); 2.09 (m, 2H); 1.92 (m, 1H); 1.05 (m, 1H); 0.52 (m, 2H); 0.22 (m, 2H); LC / MS (EI) t R 4.48, m / z 410.2 (M + +1);

61) N - [{3R) -1-Azabicyclo [2,2,2] oct-3-yl] -6- [3- (cyclopropylmethoxy) pyrrolidin-1-yl] -1H-indazol-3-carboxamide hydroformate LC / MS (EI) t R 4.49, m / z 410.2 (M + +1); 62) N - [(3 R) -1-azabicyclo [2.2.2] oct-3-hydroformate yl] -6- (3-methoxypyrrolidin-1-yl) -1H-indazol-3-carboxamide, LC / MS

(EI) t R 4.1, m / z 370.3 (M + +1).

Procedure L

Procedure L provides a method for coupling brominated aminoquinuclidinecarboxamides and cyclic amines for the formation of aniline derivatives.

A mixture of 3-methoxypyrrolidine hydrochloride (6.27 mmol), N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -6-bromo-1,2-benzisothiazol-3 carboxamide (4.42 mmol), 2-

dicyclohexylphosphino-2 ', 4', 6'-tri-i-propyl-1,11-biphenyl (0.845mmol), palladium acetate (0.363 mmol) and cesium carbonate (9.97 mmol) was evacuated and refilled with an argon atmosphere. Tetrahydrofuran (60 ml) was added and the reaction was heated at reflux for 67 hours. The reaction mixture was placed to cool to room temperature and was filtered through Celite (MeOH) and concentrated. The residue was partitioned between 9/1 dichloromethane / methanol (100ml) and sodium salt bicarbonate (40ml) and the layers separated. The aqueous layer was extracted with 9/1 dedichloromethane / methanol (3 x 50 ml) and the combined organic layers were washed with brine and dried (sodium sulfate). The residue was purified by chromatography (70/30/1 ethyl acetate / methanol / ammonium hydroxide) to give the free base (84%) as a yellow foam. The monohydrochloride salt was prepared from methanolic hydrogen chloride [acetyl chloride (0.95 eq) in methanol (5 ml)] and was recrystallized from domethanol / ethyl acetate.

The following compound was prepared using this procedure:

49) N - [(3S) -1-Azabicyclo [2,2,2] oct-3-yl] -S- (3-methoxypyrrolidin-1-yl) -1,2-benzisothiazole-3-carboxamide hydrochloride. 1 H NMR (CD 3 OD) δ 8.48 (d, J = 9.1, 1H), 7.02 (d, J = 1.9, 1H), 6.91 (dd, J = 9.2, 2.1 , 1H), 4.52-4.48 (m, 1H), 4.20-4.17 (m, 1H), 3.87-3.78 (m, 1H), 3.58 (dd, J = 11.0, 4.7, 1H), 3.50-3.42 (m, 3H), 3.38 (s, 3H), 3.36-3.34 (m, 3H), 2.40 -2.37 (m, 1H), 2.26-2.08 (m, 3H), 1.95-1.87 (m, 1H); LC / MS (EI) t R 3.47, m / z 387 (M + +1).

Procedure M

Procedure M provides a method for coupling brominated aminoquinuclidinecarboxamides to imine benzophenone for the formation of deaniline derivatives.

The mixture of bromide (6.30 mmol), depalladium acetate (1.0 mmolO) and 9,9-dimethyl-4,5-bis (diphenylphosphino) xanthene (Xantphos) (0.700 mmol) was evacuated and refilled with argon. The solids were diluted with tetrahydrofuran (150 mL) and treated with cesium carbonate (7.00 mmol) and benzophenonone imine (6.80 mmol). The reaction mixture was heated at reflux for sixteen hours. The reaction mixture was concentrated and redissolved in a mixture of tetrahydrofuran (90ml) and 3N hydrochloric acid (30ml). The reaction mixture was kept for two hours and concentrated. 0 The residue was purified by chromatography using a 70/30/1 mixture of ethyl acetate / methanol / ammonium hydroxide, thereby resulting in aniline in 79% yield. Aniline was used directly in subsequent reactions. The following compounds were prepared using this method:

6-amino-N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -1- (methyl) -1H-indazol-3-carboxamide;

6-amino-N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -1- (difluoromethyl) -1H-indazol-3-carboxamide;

6-amino-N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -1-cyclopropyl-1H-indazol-3-carboxamide;

Procedure N

Procedure N presents a method for the coupling between aminoquinuclidinecarboxamides and acylating agents for the formation of decarboxamide derivatives.

To a solution of aniline (0.42 mmol) in pyridine (2ml) and Ν, N-dimethyl formamide (2ml) was added acid chloride (0.55mmol). The mixture was kept at room temperature for sixteen hours and concentrated in vacuo. The residue was purified by preparative HPLC, thereby resulting in the product in 30-80% yield.

The following compounds were prepared using this method:

23) N - [(3S) -1-Azabicyclo [2,2,2] oct-3-yl] -6 - [(cyclopropylcarbonyl) amino] -1-methyl-1H-indazol-3-carboxamide hydroformate, 1H NMR (CD 3 OD) δ 8.40 (Br s, 1H); 8.18 (s, 1H); 8.07 (d, J = 8.7, 1H); 7.20 (d, J = 8.7,1H); 4.50 (m, 1H); 4.09 (s, 3H); 3.81 (m, 1H); 3.60-3.20 (m, 5H); 2.37 (m, 1H); 2.26 (m, 1H); 2.11 (m, 2H); 1.92 (m, 1H); 1.81 (m, 1H); 0.99 (m, 2H); 0.91 (m, 2H); LC / MS (EI) t R 3.15, m / z 368 (M + +1);

24) N - [(3S) -1-Azabicyclo [2,2,2] oct-3-yl] -6 - [(cyclopropylcarbonyl) amino] -1- (difluoromethyl) -1H-indazol-3-hydroformate carboxamide. LC / MS (EI) t R 3.79, m / z 404 (M + +1); 38) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1- cyclopropyl-6 - [(cyclopropylcarbonyl) amino] -1H-indazol-3-carboxamide. LC / MS (EI) t R 3.65, m / z 394 (M + +1).

Procedure O

Procedure O presents a method for coupling aminoquinuclidinecarboxamides and osisocyanates for the formation of urea derivatives.

To the aniline (0.40 mmol) in a mixture of pyridine (2 ml) and N, N-dimethyl formamide (1 ml) was added isocyanate (0.53 mmol). The reaction mixture was kept at room temperature for sixteen hours and concentrated in vacuo. The residue was purified by preparative HPLC, thereby resulting in the product in 50-80% yield.

The following compounds were prepared using this method:

18) N - [(3S) -1-Azabicyclo [2,2,2] oct-3-yl] -1-methyl-6 - {[(propylamino) carbonyl] amino} -1H-indazol-3 - hydroformate carboxamide, 1 H NMR (CD 3 OD) δ 8.50 (Br s, 1H); 8.00 (d, J = 8.7, 1H); 7.92 (s, 1H); 7.01 (d, J = 8.7,1H); 4.50 (m, 1H); 4.06 (s, 3H); 3.81 (m, 1H); 3.60-3.30 (m, 5H); 3.20 (t, J = 7.1, 2H); 2.37 (m, 1H); 2.26 (m, 1H); 2.11 (m, 2H); 1.92 (m, 1H); 1.58 (m, J = 7.1, 2H); 0.98 (t, J = 7.3, 2H); LC / MS (EI) t R 3.36, m / z 385 (M + + 1);

25) N - [(3S) -1-Azabicyclo [2,2,2] oct-3-yl] -1- (difluoromethyl) -6 - {[(propylamino) carbonyl] amino} -1H-indazol-hydroformate 3-carboxamide. LC / MS (EI) t R 3.81, m / z 421 (M + +1);

39) N - [(3S) -1-Azabicyclo [2,2,2] oct-3-yl] -1-cyclopropyl-6 {[(propylamino) carbonyl] amino} -1H-indazol-3-carboxamide. LC / MS (EI) t R 3.71, m / z 411 (M + +1).

Procedure P

Procedure P presents a method for the adhesion of methoxy substituted quinuclidinecarboxamides for formation of phenol derivatives. Boron tribromide (20.0 mmol) was added to a solution of N - [(35) -1-azabicyclo [2,2,2 ] oct-3-yl] -6-methoxy-1,2-benzisothiazol-3-carboxamide (3.80 mmol) in dichloromethane (100ml) at 0 ° C. The reaction mixture was placed to warm to room temperature and held for three days. The reaction mixture was quenched with saturated potassium carbonate solution (50 ml) and the layers separated. The aqueous layer was extracted further with (10/1) dichloromethane / methanol (50 ml) and the organic layers were combined and concentrated. The residue was purified by chromatography [(70/30/1) ethyl acetate / methanol / ammonium hydroxide] to yield the product at 70% yield.

The following compounds were prepared using this procedure:

9) N - [(35) -1-Azabicyclo [2,2,2] oct-3-yl] -4-hydroxy-1H-indazol-3-carboxamide hydroformate. 1H NMR (CD3 OD) δ 8.3 9 (s, 1H), 7.28 (t, J = 8.3, 1H), 7.00 (d, J = 8.4, 1H), 6.54 ( d, J = 7.6, 1H), 4.57 (m, 1H), 3.83 (t, J = 11.4, 1H), 3.52-3.31 (m, 5H), 2, 42-2.39 (m, 1H), 2.27 (m, 1H), 2.12-2.07 (m, 2H), 1.98-1.90 (m, 1H); LC / MS (EI) t R 3.18, m / z 287 (M + +1);

10) N - [(35) -1-Azabicyclo [2,2,2] oct-3-yl] -5-bromo-4-hydroxy-1H-indazol-3-carboxamide hydroformate. LC / MS (EI) t R 3.9, m / z 365/367 (M + +1);

11) N - [(35) -1-Azabicyclo [2,2,2] oct-3-yl] -5,7-dibromo-4-hydroxy-1H-indazol-3-carboxamide hydroformate. LC / MS (EI) t R4.26, m / z 443/445/447 (M + +1);

16) N - [(3S) -1-Azabicyclo [2,2,2] oct-3-yl] -7-hydroxy-1H-indazol-3-carboxamide hydroformate. LC / MS (EI) t R 2.48, m / z 287 (M + +1);

50) N - [(35) -1-azabicyclo [2,2,2] oct-3-yl] -6-hydroxy-1,2-benzisothiazole-3-carboxamide. LC / MS (EI) t R 2.58, m / z 304 (M + +1). Procedure Q

Procedure Q presents a method for preparing cyclic amide derivatives from the corresponding brominated quinuclidine derivatives.

Palladium (ii) acetate (0.09 mmol) was added to a solution of 2,21-bis (diphenylphosphino) -1,1'-binaftyl (0.14 mmol) in toluene (10 ml) and the reaction mixture was kept. until contents are completely dissolved. The resulting yellow solution was transferred to a mixture of bromide (0.33 mmol), cesium carbonate (0.60 mmol) and amide (1.0 mmolO) under a nitrogen gas atmosphere and the reaction mixture was heated to 100 ° C for sixteen hours. The reaction mixture was filtered through celite and concentrated. The residue was purified by HPLC, thereby yielding the product in 72% yield.

The following compounds were prepared using this method:

15) N - [(3S) -1-Azabicyclo [2,2,2] oct-3-yl] -1-ethyl-6- (2-oxopyrrolidin-1-yl) -1H-indazol-3-hydroformate carboxamide, 1HNMR (CD 3 OD) δ 8.40 (Br s, 1H); 8.15 (d, J = 8.9, 1H); 7.88 (s, 1H); 7.54 (d, J = 8.9, 1H); 4.55 (m, 1H); 4.49 (q, J = 7.2, 2H); 3.99 (t, J = 7.0, 2H); 3.81 (m, 1H); 3.60-3.30 (m, 5H); 2.63 (t, J = 8.1, 2H); 2.38 (m, 1H); 2.26 (m, 1H); 2.19 (m, 2H); 2.10 (m, 2H); 1.92 (m, 1H); 1.51 (t, J = 7.2, 3H); LC / MS (EI) t R 2.59, m / z 382 (M + +1);

65) N - [(35) -1-azabicyclo [2,2,2] oct-3-yl] -6- (3-methyl-2-oxopyrrolidin-1-yl) -1,2-benzisothiazole-3 carboxamide, LC / MS (EI) t R 2.93, m / z 385.2 (M + +1).

The following compound was prepared using this procedure, followed by removal of the protecting groups using 6 N hydrochloric acid: 41) N - [(35) -1-azabicyclo [2,2,2] oct-3-yl] -6- [ (4S) -4-hydroxy-2-oxopyrrolidin-1-yl] -1H-indazol-3-carboxamide. LC / MS (EI) t R 1.39, m / z 370 (M + +1);

Procedure R

Procedure R presents a method for the coupling between aminoquinuclidinecarboxamides and alcohols through Mitsunobu conditions for the formation of N (1) -alkylated derivatives.

Diisopropyl azodicarboxylate (0.212 mmol) was added dropwise to a solution of N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] 6- (1,3-oxazol-2-yl) ) -1H-indazol-3-carboxamide (0.141 mmol), cyclopropyl carbinol (0.283 mmol), triphenylphosphine (0.283 mmol) and N, N-dimethyl formamide (1.00 mL). The reaction mixture was kept for sixteen hours at room temperature and loaded onto a column on desilyl gel. The mixture was purified by chromatography {95/5 to 85/15 ethyl acetate / [(50/50/2) ethyl acetate / methanol / dimethylethylamine]} to give the product (20%) as a solid. The product contained approximately 7% of the 2-cyclopropylmethyl isomer.

The following compounds were prepared using this procedure:

4) N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -1-propyl-6- (1,3-thiazol-2-yl) -1H-indazol-3-one carboxamide, 1H NMR (CD3OD) δ 8.44 (Br s, 1H); 8.27 (d, J = 8.6,1H); 8.25 (s, 1H); 7.94 (d, J = 3.3, 1H); 7.85 (d, J = 8.5, 1H); 7.68 (d, J = 3.3, 1H); 4.55 (m, 1H); 4.53 (t, J = 7.0, 2H); 3.83 (m, 1H); 3.60-3.25 (m, 5H); 2.40 (m, 1H) / 2.25 (m, 1H); 2.12 (m, 2H); 2.08 (m, 2H); 2.00 (m, 1H); LC / MS (EI) t R 4.02, m / z 396 (M + +1);

5) N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -1-isopropyl-6- (1,3-thiazol-2-yl) -1H-indazol-3-one carboxamide. LC / MS (EI) t R 3.9, m / z 396 (M + +1); 30) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-ethyl 6- (1,3-oxazol-2-yl) -1H-indazol-3-carboxamide. LC / MS (EI) t R 3.61, m / z. 366 (M + +1);

31) N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -1- (cyclopropylmethyl) -S- (1,3-oxazol-2-yl) -1H-indazol-2-one 3-carboxamide. LC / MS (EI) t R 3.88, m / z 392 (M + +1);

32) N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -6- (1,3-oxazol-2-yl) -1-propyl-1H-indazol-3-one carboxamide. LC / MS (EI) t R 3.79, m / z 380 (M + +1);

33) N - [(3S) -1-Azabicyclo [2,2,2] oct-3-yl] -1-ethyl-N-methyl-6- (1,3-oxazol-2-yl) -1H- indazol-3-carboxamide. LC / MS (EI) t R3.79, m / z 380 (M + +1).

Procedure S

Procedure S presents a method for forming ether derivatives from corresponding phenols using Mitsunobu conditions.

Diisopropyl azodicarboxylate (0.618 mmol) was added dropwise to a solution of N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -6-hydroxy-1,2-benzisothiazole-3-one carboxamide (0.594 mmol), 3-furan methanol (0.594 mmol) ethenylphosphine (0.594 mmol) in N1N-dimethyl formamide (3.40 ml). The reaction mixture was kept for sixteen hours and concentrated. The residue was purified by chromatography {100/0 to 90/10 ethyl acetate / [(70/30/2) ethyl acetate / methanol / dimethylethylamine]} to give the product in 26% yield.

The following compound was prepared using this procedure:

14) N - [(3S) -1-Azabicyclo [2,2,2] oct-3-yl] -6- (3-furylmethoxy) -1,2-benzisothiazole-3-carboxamide hydroformate. 1H NMR (CD3OD) δ 8.5-8.41 (m, 1H), 7.86-7.80 (m, 1H), 7.70-7.69 (m, 1H), 7.27-7 , 22 (m, 1H), 7.01-6.93 (m, 1H), 6.64-6.59 (m, 1H), 4.52 (m, 1H), 4.30 (m, 2H ), 3.98-3.89 (m, 1H), 3.56-3.38 (m, 5Η), 2.41-2.39 (m, 1Η), 2.29 (m, 2Η), 2.15-2.13 (m, 1 H), 2.00 (m, 1H); LC / MS (δ) t R 3.58, m / z 384 (M + +1).

Procedure T

Procedure T presents a method for preparing phenol-substituted quinuclidinecarboxamides from bromide derivatives.

Potassium acetate (0.600 mmol), depalladium acetate (0.060 mmol), bis (pinacolate) diboro (0.800 mmol) and 2-dicyclohexylphosphino-2 ', 4', 6'-tri-propyl-1,1'-biphenyl (0.200mmol) was added to a suspension of N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5-bromo-1,2-benzisothiazole-3-carboxamide (0.500 mmol ) in toluene (8 ml). The reaction mixture was subjected to microwave irradiation (150 ° C) for five minutes. The reaction mixture was placed at room temperature, filtered through Celite (methanol), and the filtered material was concentrated. The residue was purified by preparative HPLC to yield the product at 60% yield.

Hydrogen peroxide (0.500 mmol) was added to a solution of N - [(35) -1-azabicyclo [2,2,2] oct-3-yl] -5- (4,4,5,5-tetramethyl-1 3,2-dioxaborolan-2-yl) -1,2-benzisothiazol-3-carboxamide (0.200 mmol) in acetone (3 ml). The reaction mixture was kept for two hours at room temperature and diluted with water (2 ml). The product was extracted with (9/1) dichloromethane / methanol and the extract was concentrated to yield the product in 70% yield. Phenol was used directly in subsequent reactions.

The following compounds were prepared using this procedure:

12) N - [(3S) -1-Azabicyclo [2,2,2] oct-3-yl] -5-hydroxy-1,2-benzisothiazole-3-carboxamide hydroformate. 1H NMR (CD3OD) δ 8.55 (d, 1H, t1 = 9), 7.36 (d, 1H, J = 2), 7.05 (dd, 1H, J = 2.9), 4.51 ( m, 1H), 3.83 (m, 1H), 3.38 (m, 5H), 2.40 (m, 1H), 2.38 (m, 1Η), 2.12 (m, 2Η), 1.94 (m, 1H); LC / MS (δ) t R 2.58, m / z 304 (M + +1);

(3 - [(3S) -1-azabicyclo [2,2,2] oct-3-ylamino] carbonyl-1,2-benzisothiazol-5-yl) boronic acid;

(3 - [(3S) -1-Azabicyclo [2,2,2] oct-3-ylamino] carbonyl-1,2-benzisothiazol-6-yl) boronic acid.

Procedure U

Procedure U presents a method for coupling benzisothiazolboronic 3-aminoquinuclidine acids to form aromatic aniline derivatives.

3 - [(3S) -1-Azabicyclo [2,2,2] oct-3-ylamino] carbonyl-1,2-benzisothiazol-6-yl) boronic acid (0.604 mmol), 1H-imidazole (1.8 mmol ), cupric acetate (1.21 mmol), triethylamine (3.0 mmol), pyridine (4.8 mmol) and tetrahydrofuran (8.5 mL) were combined in a microwave oven container. The reaction mixture was subjected to demi-microwave irradiation at 1400 ° C for 600 seconds. The reaction mixture was concentrated and the residue was purified by chromatography [95/5 to 85/15 ethyl acetate / (1/1 / 0.1 ethyl deacetate / methanol / dimethylethylamine)] to yield the pre-purified product as a yellow oil. The residue was further purified by preparative HPLC and fractions containing the desired product were pooled and loaded onto a 5 g SCX column. The column was washed with methanol (120 ml), 2.0 M ammonia in methanol and ammonia eluent concentrated to give the product in 14% yield a white solid.

The following compounds were prepared using this method:

80) N - [(3S) -1-Azabicyclo [2,2,2] oct-3-yl] -6- (1H-imidazol-1-yl) -1,2-benzisothiazole-3-carboxamide, 1H NMR (CD 3 OD) δ 8.87 (d, J = 8.9, 1H); 8.35 (m, 2H); 7.81 (d, J = 8.9, 1H); 7.75 (s, 1H); 7.22 (s, 1H); 4.20 (m, 1H); 3.35 (m, 1H); 3.20-2.75 (m, 5Η); 2.09 (m, 1Η); 1.95 (m, 1Η); 1.82 (m, 2Η); 1.56 (m, 1H); LC / MS (EI) t R 1.7, m / z 354.1 (M + +1);

81) N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -6- (β-pyrazol-1-yl) -1,2-benzisothiazole-3-carboxamide, LC / MS (EI) t R 3.27, m / z 354.1 (M + +1);

82) N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -6- (3-methyl-1H-pyrazol-1-yl) -1,2-benzisothiazole-3 carboxamide, LC / MS (EI) t R3.85, m / z 368.1 (M + +1);

83) N - [(3S) -1-Azabicyclo [2,2,2] oct-3-yl] -6- (5-methyl-1H-pyrazol-1-yl) -1,2-benzisothiazole-3 carboxamide, LC / MS (EI) t R 3.47, m / z 368.1 (M + +1).

Procedure V

Procedure V presents a method for coupling indazol quinuclidinecarboxamides and boronic acids for the formation of arylated N (1) -alkylamide carboxamide derivatives.

A mixture of N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -6- (1,3-thiazol-2-yl) -1H-indazol-3-carboxamide (0.280 mmol), cyclopropylboronic acid (0.840 mmol) and copper (II) acetate (5.60 mmol) was diluted with triethylamine (1.40 mmol), pyridine (2.2 mmol) and tetrahydrofuran (3.00 mL). The reaction mixture was subjected to microwave irradiation at 140 ° C for 600 seconds. The reaction mixture was filtered and transferred to an SCX column. The column was washed with methanol (five volumes) and the product was then eluted using 2.0 M ammonia in methanol, thereby resulting in a light yellow solid. The residue was purified by chromatography {90/10 to 80/20 ethyl acetate / [((50/50/2) ethyl acetate / methanol / dimethylethylamine]} to give the product in 22% yield. The final product contained approximately 3% of the regioisomer.

The following compounds were prepared using this method: 26) N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -1-cyclopropyl-6- (1,3-thiazol-2-one) yl) -1H-indazol-3-carboxamide, 1H NMR (CD3OD) δ8.28 (S, 1H); 8.21 (d, J = 8.6,1H); 7.91 (d, J = 3.3, 1H) 7.80 (d, J = 8.6, 1H); 7.65 (d, J = 3.3, 1H); 4.20 (m, 1H);

3.82 (m, 1H); 3.35 (m, 1H); 3.20-2.80 (m, 5H); 2.07 (m, 1H); 1.95 (m, 1H); 1.81 (m, 2H); 1.57 (m, 1H); 1.25 (m, 4H); LC / MS (EI) t R 3.9, m / z 394 (M + +1);

27). N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -6- (1,3-thiazol-2-yl) -1- (3-thienyl) -1H-indazol-2-one 3-carboxamide LC / MS (EI) t R 4.28, m / z 436 (M + +1);

N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -6-bromo-1-cyclopropyl-1H-indazol-3-carboxamide.

Procedure W

Procedure W presents a method for the coupling between cyclic bromine aminoquinuclidine benzisothiazoles for the formation of urea derivatives.

A mixture of 1-propylimidazolidin-2-one (19.0mmol), N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -6-bromo-1,2-one

benzisothiazol-3-carboxamide (10.0 mmol), palladium (II) acetate (1.00 mmol) and di-tert-butyl (2 ', 4', 6'-triisopropylbiphenyl-2-yl) phosphine (2, 00 mmol) was diluted with toluene (100 mL) etetrahydrofuran (50 mL). The reaction mixture was heated at 100 ° C for sixteen hours and the reaction mixture was filtered through Celite (methanol) and concentrated. The residue was transferred to an SCX column and washed with methanol (100ml). The crude product was eluted with 7 M ammonia in methanol (100 mL) and the combined product fractions were concentrated. The residue was purified by chromatography [(70/35/1) ethyl acetate / methanol / ammonium hydroxide] to yield the product at 90% yield. The monohydrochloride salt was prepared from methanolic hydrogen chloride [acetyl chloride (0.95 equiv.) In methanol (5 ml)] and was recrystallized from domethanol / ethyl acetate.

Alternative Method: A mixture of 1-ethylimidazolidin-2-one (41.2 mg, 0.000361 mol), N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6 -bromo-1,2-benzisothiazole-3-carboxamide (95.0 mg, 0.000259 mol), palladium (II) acetate (4.8 mg, 0.000021mol), 2-dicyclohexylphosphine-21.4 ', 61-Tri-i-propyl-1,11-biphenyl (23.2 mg, 0.0000488 mol) and cesium carbonate (191 mg, 0.000586 mol) in a microwave tube were evacuated and filled under argon atmosphere. Tetrahydrofuran (3.7 ml, 0.045 mol) was added, the container was sealed and the reaction mixture was subjected to microwave irradiation at 1350 ° C for thirty minutes. Reaction mixture was filtered through concentrated Celite. The residue was purified by chromatography [100/0 to 80/20 ethyl acetate / (50/50/2 ethyl deacetate / methanol / dimethylethylamine)] to yield the product in 24% yield.

The following compounds were prepared using this method:

67) N - [(3S) -1-Azabicyclo [2,2,2] oct-3-yl] -6- (3-ethyl-2-oxoimidazolidin-1-yl) -1,2-benzisothiazol-3 carboxamide, 1 H NMR (CD 3 OD) δ 8.64 (d, J = 9.1, 1H); 8.16 (d, J = 1.8, 1H); 7.93 (dd, J = 1.9 / 9.1, 1H); 4.20 (m, 1H); 3.98 (m, 2H); 3.61 (m, 2H); 3.60-3.35 (m, 1H); 3.37 (q, J = 7.3, 2H); 3.1-2.75 (m, 5H); 2.08 (m, 1H); 1.92 (m, 1H); 1.81 (m, 2H); 1.55 (m, 1H); 1.20 (t, J = 7.3, 3H); LC / MS (EI) t R 3.25, m / z 400.2 (M + +1); 131) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] - 6- (2-OXO-3-propylimidazolidin-1-yl) -1,2-benzisothiazol-3-carboxamide, LC / MS (EI) t R 3.76, m / z 414.2 (M + +1);

54) N - [(35) -1-Azabicyclo [2,2,2] oct-3-yl] -6- (2-oxo-3-propylimidazolidin-1-yl) -1,2-benzisothiazole hydrochloride 3-carboxamide. LC / MS (EI) t R 3.68, m / z 414 (M + +1). Procedure X

Procedure X presents a method for coupling bromine aminoquinuclidine indazole and urea cyclic for the formation of urea derivatives.

A mixture of 1-propylimidazolidin-2-one (0.5684mmol), N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -6-bromo-2- [2- ( trimethylsilyl) ethoxy] methyl-1H-indazol-3-carboxamide (0.409mmol), palladium acetate (0.034 mmol), 2-dicyclohexylphosphino-21,4 ', 6'-tri-propyl-1,11-biphenyl (0.0768 mmol) and cesium carbonate (0.924 mmol) in a microwave tube was evacuated again filled under an argon atmosphere. Tetrahydrofuran (5.8 mL) was added and the flask was sealed. The reaction mixture was subjected to demicrowave irradiation at 1350 ° C for thirty minutes. The reaction mixture was filtered through celite and concentrated. The residue was purified by chromatography [100/0 to 80/20 ethyl deacetate / (50/50/2 ethyl acetate / methanol / dimethylethylamine)] to yield the product protected by purified SEM. The residue was dissolved in tetrahydrofuran (5 mL) and 6 N hydrochloric acid (5 mL) and the reaction mixture was subjected to microwave irradiation at 140 ° C for 600 seconds. The reaction mixture was transferred to an SCX column (10 g) and the column was flushed with methanol (120 mL) and 2.0 M ammonia in methanol (60 mL) and the ammonia eluent was concentrated. The residue was purified by preparative HPLC and the fractions containing the desired product were pooled and transferred to an SCX column (10 g). The column was flushed with methanol (120 mL) and 2.0 M ammonia in methanol (60 mL) and the ammonia eluent was concentrated to yield the product in 28% yield.

The following compounds were prepared using this method: 77) N - [(35) -1-azabicyclo [2,2,2] oct-3-yl] -6- (2-oxo-3-propylimidazolidin-1-yl) - 1H-indazol-3-carboxamide, 1H NMR (CD3OD) δ 8.09 (d, J = 9.0, 1H); 7.72 (s, 1H); 7.51 (d, J = 9.0, 1H); 4.18 (m, 1H); 3.90 (m, 2H); 3.51 (m, 2H); 3.35 (m, 1H); 3.23 (t, J = 7.2, 2H); 3.15-2.75 (m, 5H); 2.05 (m, 1H); 1.95 (m, 1H); 1.79 (m, 2H); 1.60 (m, 1H); 1.59 (m, J = 7,3,2H); 0.95 (t, J = 7.3, 3H); LC / MS (EI) t R 3.03, m / z 397.2 (M + +1);

63) N - [(3 ') -1-azabicyclo [2,2,2] oct-3-yl] 6- (2-oxo-3-propylimidazolidin-1-yl) -1H-indazol-3-carboxamide LC / MS (EI) t R 4.14, m / z 397.3 (M + +1).

Procedure Y

Procedure Y presents a method for quinuclidinecarboxamide oxidation for the formation of N-oxide derivatives.

M-chloroperbenzoic acid (0.266 mmol) was added portionwise to a -78 ° C suspension of dequinuclidine amide (0.21 mmol) in dichloromethane (3 mL) and the reaction mixture was placed to warm to room temperature and maintained for sixteen hours. . The reaction mixture was diluted with methanol and loaded onto an SCX column. The column was washed with methanol (50 mL), 2 M ammonia in methanol (60 mL) and the ammonia wash concentrated. The product was purified by preparative HPLC, thereby yielding 26 mg (38%) of the product.

The following compounds were prepared using this method:

55) N - [(3S) -1-Oxide-1-azabicyclo [2,2,2] oct-3-yl] -5- (trifluoromethoxy) -1H-indazol-3-carboxamide, 1H NMR (CD3OD) δ8 31 (Br m, 1H), 8.08 (s, 1H), 7.69 (d, J = 9.1, 1H), 7.36 (dd, J = 9.0, 1.3, 1H ), 4.72-4.69 (m, 1H), 4.13-4.04 (m, 1H), 3.80-3.63 (m, 5Η), 2.45-2.35 (m , 3Η), 2.28-2.25 (m, 1Η), 2.15-2.11 (m, 1Η); LC / MS (δ) t R 3.99, m / z 371 (M + +1); 56) 6-methoxy-N - [(3S) -1-oxide-1-azabicyclo [2.2.2] oct -3-yl] -1,2-benzisothiazol-3-carboxamide, LC / MS (EI) t R 3.65, m / z 334 (M + +1).

Z Procedure

Procedure Z presents a method for converting aminoquinuclidinecarboxamide nitriles to the formation of dihydroimidazole derivatives using diamines.

Hydrogen sulfide was bubbled through a solution of 6-cyano-N- (quinuclidin-3-yl) -1H-indazole-3-carboxamide (90 mg, 0.31 mmol) in ethanol (6 mL) in a pressure tube. 0 ° C for thirty minutes. The vessel was sealed and the reaction mixture was heated at 80 ° C for sixteen hours and concentrated. The residue was diluted with ethylenediamine (4 ml) and heated at 100 ° C for sixteen hours. The reaction mixture was concentrated to yield 110 mg (94%) of dihydroimidazole as a brown solid.

The following compound was prepared using this method:

89) N - [(3R) -1-Azabicyclo [2,2,2] oct-3-yl] -6- (4,5-dihydro-1H-imidazol-2-yl) -1H-indazol-3-one carboxamide, 1 H NMR (CD 3 OD) δ8.27 (d, J = Q, 5, 1H), 8.08 (s, 1H), 7.66 (d, J = 8.5, 1H), 4.22 ( m, 1H), 3.87 (s, 3H), 3.69 (s, 1H), 3.37 (m, 6H), 2.91 (m, 8H), 2.08 (m, 2H), 1.82 (m, 2H), 1.55 (m, 1H); LC / MS (EI) t R 1.63, m / z 339.2 (M + +1).

AA procedure

Procedure AA presents a method for the reaction of 3-aminoquinuclidine carboxamides with electrophiles for forming quaternary ammonium salt derivatives.

N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -1H-indazol-3-carboxamide (3.26 mmol) was dissolved in dichloromethane (50.0ml) and the mixture of The reaction was kept at room temperature for three days. After a few minutes the mixture turned dark and after an hour a white precipitate became evident. The precipitated solid was collected by filtration, washed with dichloromethane and ethyl acetate and dried to yield the product in 92% yield as a colorless solid. Analytical LC / MS analysis showed that the product was contaminated with some of the starting material (approximately 5%).

To a solution of (3S) -1- (chloromethyl) -3 - [(1H-indazol-3-ylcarbonyl) amino] -1-azoniabicyclo [2.2.2] octane chloride (0.999 mmol) in methanol (10 , 0 ml) were added PM-diisopropylethylamine (415 mmol / g loading; 41.5mol) and PM-carbonate (3.5 mmol / g loading; 0.050 mmol).

The reaction mixture was stirred for 24 hours and solid support reagents were removed by filtration. The solvent was evaporated to approximately 3 ml and ethyl acetate (15 ml) was added. The precipitated solid was collected to give the product in 94% yield.

The following compound was prepared using this method:

165) (3S) -1- (Chloromethyl) -3 - [(1H-indazol-3-ylcarbonyl) amino] -1-azoniabicyclo [2.2.2] octane chloride, 1H NMR (CD3OD) δ 8.19 (d, J = 8.2,1H); 7.60 (d, J = 8.5,1H); 7.43 (t, J = 8.5,1H); 7.26 (t, J = 8.2,1H); 5.23 (s, 2H); 4.63 (m, 1H); 4.10 (m, 1H); 3.55-3.85 (m, 5H); 2.48 (m, 1H); 2.41 (m, 1H); 2.23 (m, 2H); 2.09 (m, 1H); LC / MS (EI) t R 2.38, m / z321 / 319 (M + +1).

AB procedure

Procedure AB presents a method for hydrolysis of 3-aminoquinuclidine nitriles to carboxylic acids and subsequent coupling with amines to form amide derivatives. Potassium hydroxide (7.0 mmol) was added to a solution of N - [(35) - 1-azabicyclo [2,2,2] oct-3-yl] -6-cyano-1H-indazol-3-carboxamide (2.3 mmol) in 1,2-ethanediol (6 ml) and the reaction mixture was heated at 1400C for seven hours. Sandation was placed to cool to room temperature and treated with 6 ml of 1 Μ hydrochloric acid. The formed precipitate was isolated by filtration and dried under vacuum to yield the product in 45% yield as the HCl salt.

3 - [(3S) -1-Azabicyclo [2,2,2] oct-3-ylamino] carbonyl-1H-indazol-6-carboxylic hydrochloride (0.3 mmol), TBTU (0 4 mmol) and dimethylamine (0.432 mmol). N, N-dimethyl formamide (2 ml) and N, N-diisopropylethylamine (0.249 ml, 1.43 mmol) were added and the reaction mixture was kept for sixteen hours at room temperature. The reaction mixture was loaded onto an SCX column (10 g) and flushed with methanol (200 mL). The partially purified product was then eluted using 7.0 M ammonia in methanol (60 ml). The residue was purified by preparative HPLC and the product fractions were blown off and loaded onto an SCX column (10 g). The column was flushed with methanol (200 mL) followed by 7.0 mM ammonia methanol (60 mL). The ammonia layer was evaporated to yield the amide in 30% yield.

The following compounds were prepared using this method:

185) 3 - [(3S) -1-Azabicyclo [2,2,2] oct-3-ylamino] carbonyl-1H-indazol-6-carboxylic acid hydrochloride, LC / MS (EI) t R 1.50, m 315 (M + +1);

186) N (3) - [(3S) -1-Azabicyclo [2,2,2] oct-3-yl] -N (6), N (6) -dimethyl-1H-indazol-3,6-dicarboxamide 1H NMR (CD3OD) δ 8.22 (s, 1H), 7.74 (s, 1H), 7.25 (s, 1H), 4.78 (s, 6H), 4.58 (m, 1H) ), 3.67 (m, 1H), 3.33 (m, 6H), 2.39 (m, 1H), 2.38 (m, 1H), 2.11 (m, 2Η), 1.22 (m, 1Η); LC / MS (δ) t R 2.50, m / z 342 (M + +1);

187) N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -6-t (4-methylpiperazin-1-yl) carbonyl] -1H-indazol-3-carboxamide, LC MS (EI) t R 2.40, m / z 397 (M + +1);

188) N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] - 6 - [(3R) -3-methoxypyrrolidin-1-yl] carbonyl-1H-indazol-3-one carboxamide, LC / MS (EI) t R 2.50, m / z 398 (M + +1).

AC procedure

Procedure AC presents a method for producing 7-azabenzisothiazole ether derivatives from the corresponding chloride.

Sodium methoxide (30.0 mmol) was added to a solution of N - [(3S) -1-azabicyclo [2,2,2] oct-3-yl] -6-chloroisothiazolo [5,4-b] pyridine 3-carboxamide (0.3 mmol) in methanol (2 mL) and the reaction mixture was heated at reflux for sixteen hours. The reaction mixture was cooled to room temperature, quenched with methanol and concentrated. The residue was purified by preparative HPLC and the product fractions were pooled and loaded onto an SCX column (10 g). The column was flushed with methanol (200 mL) followed by 7.0 M ammonia in methanol (60 mL). The ammonia layer was evaporated to yield the product in 30% yield.

The following compound was prepared using this method:

189) N - [(33) -1-azabicyclo [2,2,2] oct-3-yl] -6-methoxyisothiazolo [5,4-b] pyridine-3-carboxamide, LC / MS (EI) t R3, 25, m / z 319 (M + +1).

Binding Example: MLA Binding [3H]

Materials:

Mouse Brain: Pel-Freez Biologicals, CAT No. 56004-2Protease Inhibitor Cocktail Table: Roche, CAT No. 1697498

Membrane Preparation

Mouse brains at 20 vol (weight / volume) 0.32 M protease inhibitor ice cold (one tablet per 50 ml) were homogenized with a polytron for ten seconds in configuration 11 and then centrifuged for ten minutes at 1,000 g, 4 °. Ç. The supernatant was centrifuged again for twenty minutes at 20,000 g, 4 ° C. The pellets were resuspended in binding buffer (200 mM TRIS-HCl, 20 mM HEPES, pH 7.5, 144 mM NaCl, 1.5 mM KCl, 1 mM MgSO 4, 2 mM CaCl 2, 0.1 % (weight / volume) of BSA) and membrane preparation was stored at -80 ° C.

For the saturation assay, the 200 μl binding buffer assay mixture contains 200 μg of membrane protein, 0.2 to 44 nM MLA [3H]. Non-specific binding was defined using LAμLA of MLA. The competition assay was performed with 2 nM MLA [3H] and a desirable decomposed range. The assay mixture was incubated at 22 ° C for two hours, and was then collected with pre-soaked GF / B filter with 0.3% PEI in binding buffer using the Tomtec collector. The filter was washed three times with binding buffer. and radioactivity was counted with Trilux.

The binding affinities for the preferred compounds of the invention are from 2 nM to 25 μΜ, especially from 2 nM to 2.5 μΜ.

The foregoing examples may be repeated with similar success in substituting the generally described or specifically described reagents and / or operating conditions of the present invention for those used in the preceding examples.

Claims (65)

1. A compound characterized in that it is in accordance with formulas I, II, III or IV: <formula> formula see original document page 228 </formula> where <formula> formula see original document page 228 </formula> X is 0 or S, each of X1 to X4 is independently N, CH, CR17or C-, where C- is the point of attachment of group A of the structure of formulas (I), (II), (III ) or (IV): each of X5 to X8 is independently N, CH, CR3, or C-, where C- represents the point of attachment of group A of the structure of formulas (I), (II) (III) or (IV): each of X9 to X12 is independently N, CH, CR4, or C-, where C- represents the point of attachment of group A to the remainder of the structure of formulas (I), (II), (III) or (IV): each of X13 to X16 is independently N, CH, CR, or C-, where C- represents the point of attachment of group A to the remainder of the structure of the formulas ( I), (II), (III) or (IV): R1 is H, alkyl having one to four carbon atoms, alkyl hal which has one to four carbon atoms, cycloalkyl having three to seven carbon atoms, or cycloalkylalkyl having four to seven carbon atoms; R is H, F, Cl, Br, I, OH, CN, COH, NR6 R7, carboxy , CONR6R7, NR2COR8, NR2COOR8, NR2CSR8, NR2CONR2R9, NR2CSNR2R9, NR2SO2R10, NR2CONR6R7, NR2CSNR6R7, NR2R9, SO2R10, S1-10-C1-6-C6-6 -alkyl-NR6R7, NR2-C1-6-alkyl-CONR6R7, NR2-CO-C1-6-alkyl-Ar, NR2-C1-6-alkyl-C0-0-R2, NR2-C1-S-N2-C1 -6-alkyl-NR2 (CO-O-R2) -NR2 (CO-O-R2), -C1-alkyl-NR2, -0-C1-6 alkyl-NR6R7, alkyl having one to four atoms decarbon, fluorinated alkyl having one to four carbon atoms decarbon, alkenyl having two to six carbon atoms, alkynyl having two to six carbon atoms, wherein the alkyl, fluorinated alkyl, alkenyl or alkynylation groups are in each case unsubstituted or substituted by Ar or Het, cycloalkyl having three to seven carbon atoms, cycloalkenyl having five to eight carbon atoms carbon which is unsubstituted or substituted by HCO-, Cl-6-alkoxy, NR6R7, CO-NR6R7, C2-6-alkoxycarbonyl, or -CO-R10 cycloalkylalkyl has four to seven carbon atoms, cycloalkenylalkyl having six to nine atoms carbon, alkoxy having one to four carbon atoms, cycloalkoxy having three to seven carbon atoms, cycloalkylalkoxy having four to seven carbon atoms, alkylthio having one to four carbon atoms, fluorinated alkoxy having one to four carbon atoms, alkyl hydroxy having one to four carbon atoms, fluorinated alkyl hydroxy having one to four carbon atoms, alkoxy hydroxy having two to four carbon atoms, fluorinated alkoxy hydroxy having two to four carbon atoms, monoalkylamino having one to four carbon atoms , dialkylamino wherein each alkyl group independently has one to four carbon atoms, alkoxycarbonyl having two to six carbon atoms, Ar, Het, OAr, OHet, Carbo-O, Ar-C 1-4. 6-alkyl-O-, Het-C 1-6 -alkyl-O-, Het-CO-Het-, Het-C 1-6 -alkyl-NR 2 -, or Ar-C 1-6 -alkyl-Het-O-, provided that R is not NH2; or R is one of the following formulasη ranges from 2 to 4. m ranges from 3 to 5; or R 2 may together form a fused five membered ring structure containing at least one N atom; R 1 is H, F, Cl, Br, I, OH, CN, nitro, NH 2, COH, NR 6 R 7, carboxy, CONR 6 R 7, NR 2 COR 8, NR2COOR8, NR2CSR8, NR2CONR2R9, NR2CSNR2R9, NR2SO2R10, NR2CONR6R7, NR2CSNR6R7, NR2R9, SO2R10, SOR10, -0- (C1-6-alkyl-0) -1- C1-6-C1-6 alkyl NR6R7, NR2-C1- and -alkyl-CONR6R7, NR2-CO-C1.6-alkyl-Ar, NR2-C1-6-alkyl-CO-O-R2, NR2-Ca-6-alkyl-NR2 (C0- O-R2), -C1-6 alkyl-NR2, -O-C1-S-alkyl-NR6R7, alkyl containing one to four carbon atoms, fluorinated alkyl containing one to four carbon atoms, alkenyl containing two to six atoms alkynyl containing two to six carbon atoms, wherein the alkyl, fluorinated alkyl, alkenyl or alkynyl groups are in each case unsubstituted or substituted by Ar or Het, cycloalkyl containing three to seven carbon atoms, cycloalkenyl containing five to eight carbon atoms. carbon, which is unsubstituted or then substituted by HCO-, C1-6-alkoxy, NR6R7, CO-NR6R7, C2-6-alkoxycarbonyl, or -CO-R10, cycloalkylalkyl containing four to seven carbon atoms, cycloalkenylalkyl containing six to nine carbon atoms, alkoxy containing one to four carbon atoms, cycloalkoxy containing three to seven carbon atoms, cycloalkylalkoxy containing four to seven carbon atoms, alkylthio containing four carbon atoms, fluorinated alkoxy containing one to four carbon atoms, hydroxy alkyl containing one to four carbon atoms, fluorinated alkyl hydroxy containing four carbon atoms, alkoxy hydroxy containing two carbon atoms, fluorinated alkoxy hydroxy containing four carbon atoms, monoalkylamino containing one four carbon atoms, dialkylamino wherein each alkyl group independently has one to four carbon atoms alkoxycarbonyl containing two to six carbon atoms, Ar, Het, OAr, OHet, Carbo-O, Ar-C 1-6 alkyl-O-, Het-C 1-6-alkyl-O-, Het-CO-Het-, Het-C 1-6 alkyl-NR 2 -, or Ar-C 1-6 alkyl-Het-0-; or R1 is one of the following formulas <formula> formula see original document page 231 </formula> two R1 may together form a fused five-membered ring structure containing at least one N atom, R2 is H, alkyl containing one to four carbon atoms fluorinated alkyl containing one to four carbon atoms, cycloalkyl containing three to seven carbon atoms, cycloalkylalkyl containing four to seven carbon atoms, C1-4-alkyl-CO-fluorinated, C3-7-cycloalkyl-CO-, C1-4 -alkyl-NHCO-, C3-7-cycloalkyl-NH-CO-, Het, Ar-C1-4-alkyl-, Ar-C1-4-alkyl-CO-, Ar-C1-4-alkyl-SO2, C1-4-alkyl-O-C1-4-alkyl- (e.g. CH2CH2 -O-CH3), Ar-C1-4-alkyl-NH-CO-, or Het-NH-CO-; R3 is H, F , Cl, Br, I, OH, CN, Nitro, NH2, COH, NR6R7, Carboxy, CONR6R7, NR2COR8, NR2COOR8, NR2CSR8, NR2CONR2R9, NR2SO2R10, NR2SO2R7, NR2CONR6R7, NR2RR3 -6-alkyl-0) iz-Cx-g-alkyl, NR2-C1-6alkyl-NR6R7, NR2-C1-6-alkyl-1-CONR6R7, NR2-CO-C1-6-alkyl-Ar, NR2-C1- 6-alkyl 1-CO-O-R2, NR2-C1-6-alkyl-NR2 (CO-O-R2), -C1-6-alkyl-NR2, -0-C1-6-alkyl-NR6R7, alkyl containing one to four carbon atoms, fluorinated alkyl containing one to four carbon atoms, alkenyl containing two to six carbon atoms, alkynyl containing two to six carbon atoms, wherein the alkyl, fluorinated alkyl, alkenyl or alkynyl groups are each unsubstituted or substituted. by Ar or Het, cycloalkyl containing three to seven carbon atoms, cycloalkenyl containing five to eight carbon atoms, which is unsubstituted or otherwise substituted by HCO-, C1-6-alkoxy, NR6R7, CO-NR6R7, C2-6-alkoxy carbonyl, or -CO-R10, cycloalkylalkyl containing four to seven carbon atoms, cycloalkenylalkyl containing six to nine carbon atoms, alkoxy containing one to four carbon atoms, cycloalkoxy containing three to seven carbon atoms, cycloalkylalkoxy containing four to seven carbon atoms , alkylthio contained four atoms of ca carbon, fluorinated alkoxy containing four carbon atoms, hydroxy alkyl containing four carbon atoms, fluorinated alkyl hydroxy containing four carbon atoms, hydroxy alkoxy containing two carbon atoms, fluorinated alkoxy hydroxy containing four carbon atoms, monoalkylamino containing one to four carbon atoms, dialkylamino wherein each alkyl group independently has one to four carbon atoms, alkoxycarbonyl containing two to six carbon atoms, Ar, Het, OAr, OHet, Carbo-O, Ar-C1-6-alkyl -0-, Het-C1-6-alkyl-O-, Het-CO-Het-, Het-C1-6-alkyl-NR2-, or Ar-C1-6-alkyl-Het-0-; or R 3 is one of the following formulas; R 3 may together form a five member fused ring structure containing at least one N atom; R 4 is H, F, Cl, Br, I, OH, CN 7 nitro, NH 2, COH, NR 6 R 7, carboxy, CONR6R7, NR2COR8, NR2COOR8, NR2CSR8, NR2CONR2R9, NR2CSNR2R9, NR2SO2R10, NR2CONR6R7, NR2CSNR6R7, NR2R9, SO2R10, SOR10, -1-2-C1-6-C1-6-C1-6 6-alkyl-NR6R7, NR2-C1-6-alkyl-CONR6R7, NR2-CO-C1-6-alkyl-Ar, NR2-C1-6-alkyl-CO-O-R2, NR2-C1-6-alkyl- NR2 (CO-O-R2), -C1-6-alkyl-NR2, -0-C1-6-alkyl-NR6R7, alkyl containing one to four carbon atoms, fluorinated alkyl containing one to four carbon atoms, alkenyl containing two to six carbon atoms, alkynyl containing two to six carbon atoms, wherein the groups alkyl, fluorinated alkyl, alkenyl or alkynylation are in each case unsubstituted or substituted by Ar or Het, cycloalkyl containing three to seven carbon atoms, cycloalkenyl containing five to eight carbon atoms, the which is unsubstituted or substituted by HCO-, C1-6-alkoxy, NR6R7, CO-NR6R7, C2-6-alkoxycarbonyl, or -CO-R10 cycloalkylalkyl containing four to seven carbon, cycloalkenylalkyl atoms containing six to nine carbon atoms alkoxy containing one to four carbon atoms, cycloalkoxy containing three to seven carbon atoms, cycloalkylalkoxy containing four to seven carbon atoms, alkylthio containing one to four carbon atoms, alkoxyfluoride containing one to four carbon atoms, hydroxyalkyl containing one to four carbon atoms, four carbon atoms, fluorinated hydroxyalkyl containing one to four carbon atoms, alkoxy hydroxy containing two to four carbon atoms, fluorinated alkoxy hydroxy containing two to four carbon atoms, monoalkylamino containing one to four carbon atoms, dialkylamino in which each alkyl group is independently dependent one to four carbon atoms, alkoxycarbonyl containing two to six carbon atoms, Ar, Het, OAr, OHet, C arbo-0, Ar-C1-6-alkyl-0-, Het-C1-6-alkyl-0-, Het-CO-Het-, Het-C1-e-alkyl-NR2-, or Ar-C1-6 alkyl-Het-O-; or R4 is one of the following formulas <formula> formula see original document page 234 </formula> two R4 may together form a fused five-membered ring structure containing at least one N atom; R5 is H, F, Cl, Br, I , OH, CN, nitro, NH2, carboxy, CONR6R7, NR2COR8, NR2CSR8, NR2CONR2R9, NR2CSNR2R97 NR2SO2R10, NR2CONR6R7, NR2CSNR6R7, NR2R9. containing two to six carbon atoms, alkynyl containing two to six carbon atoms, wherein the alkyl, fluorinated alkyl, alkenyl or alkynyl groups are in each case unsubstituted or then substituted by Ar or Het, cycloalkyl containing three to seven carbon atoms, cycloalkenyl containing five eighteen carbon atoms, which is unsubstituted or substituted by HCO-, C1-6-alkoxy, NR6R7, CO-NR6R7, C2-6-alkoxycarbonyl, or -CO-R10, cycloalkylalkyl containing four atoms carbon, cycloalkenylalkyl containing six to nine carbon atoms, alkoxy containing one to four carbon atoms, cycloalkoxy containing three to seven carbon atoms, cycloalkylalkoxy containing four to seven carbon atoms, alkylthio containing one to four carbon atoms, alkoxyfluoride containing one to four carbon atoms, four to four carbon atoms, hydroxyalkyl containing one to four carbon atoms, fluorinated hydroxyalkyl containing one to four carbon atoms, alkoxy hydroxy containing two to four carbon atoms, fluorinated alkoxy hydroxy containing two to four carbon atoms, monoalkylamino containing one to four carbon atoms, dialkylamino wherein each alkyl group independently has one to four carbon atoms, alkoxycarbonyl containing two to six carbon atoms, Ar, Het, OAr or OHet, each of R 6 and R 7 is independently H, alkyl containing one to four carbon atoms, alkoxyalkyl containing two to eight carbon atoms, contendot cycloalkyl three to seven carbon atoms; or cycloalkylalkyl containing four to seven carbon atoms, or R 6 and R 7 are together an alkylene group containing four to six carbon atoms forms a ring with the atom of N; R 8 is H, alkyl containing one to four carbon atoms, fluorinated alkyl containing one to six carbon atoms. four carbon atoms, alkenyl containing three to six carbon atoms, alkynyl containing three to six carbon atoms, wherein the alkyl, fluorinated alkyl, alkenyl or alkynyl groups are in each case unsubstituted or substituted by Ar or Het, cycloalkyl containing three to seven decarbonyl atoms, cycloalkenyl containing five to eight decarbonyl atoms, cycloalkylalkyl containing four to seven decarbonyl atoms, cycloalkenylalkyl containing six to nine decarbonyl, hydroxyalkyl containing one to four decarbonyl atoms, fluorinated alkyl hydroxy containing one to four carbon atoms, monoalkylamino four carbon atoms, dialkylamino wherein each alkyl group bark independently one to four carbon atoms, Ar, or Het; R 9 is alkyl having one to four carbon atoms, Ar, Ar-alkyl wherein the alkyl moiety has one to four carbon atoms, or Het; R 10 is alkyl containing one to four carbon atoms. four carbon atoms, fluorinated alkyl containing one to four carbon atoms, alkenyl containing three to six carbon atoms, alkynyl containing three to six carbon atoms, wherein the groups alkyl, fluorinated alkyl, alkenyl or alkynylation are in each case unsubstituted or otherwise substituted. substituted by Ar or Het, cycloalkyl containing three to seven decarbon atoms, cycloalkenyl containing five to eight decarbon atoms, cycloalkylalkyl containing four to seven decarbon atoms, cycloalkenylalkyl containing six to nine decarbon, hydroxyalkyl containing two to four decarbonyl fluids, hydroxyalkyl-containing alkyl two to four carbon atoms, monoalkylamino containing one to four carbon atoms, dialkylamino wherein c Each alkyl group independently has one to four carbon atoms, NR 6 R 7, NR 2 R 8, Ar, or Het; Ar is an aryl group having six to ten carbon atoms that is unsubstituted or substituted one or more times by alkyl having one to eight carbon atoms. C, alkoxy containing one to eight C atoms, halogen, dialkylamino wherein each alkyl moiety has one to eight C atoms, amino, cyano, hydroxyl, nitro, halogenated alkyl having one eight C atoms, halogenated alkoxy containing one to eight C atoms, hydroxy alkyl containing one to eight C atoms, hydroxy alkoxy having two to eight C atoms, alkenyloxy has three to eight C atoms, alkylthio having one to eight C atoms, alkylsulfinyl having one to eight C atoms, alkylsulfonyl having one to eight C1-monoalkylamino atoms having one to eight C atoms, cycloalkylamino wherein the cycloalkyl group has three to seven C atoms and is optionally substituted by alkyl having one to four carbon atoms. carbon, alkoxy containing one to four carbon atoms, hydroxyl, amino, monoalkylamino having one to four carbon atoms, dialkylamino wherein each alkyl group has one to four carbon atoms, or combinations thereof, aryloxy wherein the aryl moiety has six atoms carbon atoms and is optionally substituted by halogen, alkyl having one to eight carbon atoms, hydroxy, alkoxy containing one to eight carbon atoms, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino having one eighteen carbon atoms, dialkylamino in whereas each alkyl group has one to eight carbon atoms, hydroxy alkyl containing one to eight carbon atoms, alkoxy hydroxy having one to eight carbon atoms, carboxy, cyano, acyl, alkoxycarbonyl wherein the alkoxy group has one to eight carbon atoms, alkylthio, alkylsulphinyl having one to eight carbon atoms, alkylsulphonyl having one to eight carbon atoms, phenoxy, acyloxy, or combinations thereof, arylthio in which aryl moiety has six to ten carbon atoms and is optionally substituted by halogen, alkyl having one to eight carbon atoms, hydroxy, alkoxy containing one to eight carbon atoms, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino having one to eight carbon atoms. carbon, dialkylamino wherein each alkyl group has one to eight carbon atoms, hydroxy alkyl having one to eight carbon atoms, alkoxy hydroxy having one to eight carbon atoms, carboxy, cyano, acyl, carbonyl alkoxy wherein the alkoxy group has one to eight carbon atoms eight carbon atoms, alkylthio, alkylsulphinyl having one to eight carbon atoms, alkylsulphonyl having one to eight carbon atoms, phenoxy, or acyloxy, or combinations thereof, cycloalkyloxy wherein the group cycloalkyl has three to seven C atoms and is optionally substituted by alkyl having one to four carbon atoms, alkoxy containing one to four carbon atoms, hydroxy, amino, monoalkylamino having one to four carbon atoms and carbon, dialkylamino wherein each alkyl group has four carbon atoms, or combinations thereof, sulfo, sulfonylamino, acylamido, acyloxy, or combinations thereof; Het is a heterocyclic group which is fully saturated, partially saturated or fully unsaturated, containing five to ten ring atoms wherein at least one ring atom is a Ν, O or S atom which is unsubstituted or substituted one or more times by halogen, aryl having six to ten carbon atoms which is optionally substituted halogen, alkyl having one to eight carbon atoms, hydroxy, alkoxy containing one to eight carbon atoms, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino having one to eight carbon atoms, dialkylamino wherein each alkyl group has one to eight carbon atoms, hydroxy alkyl containing one to eight carbon atoms, alkoxy hydroxy having one to eight carbon atoms, carboxy, cyano, acyl, carbonyl alkoxy wherein the alkoxy group have one to eight carbon atoms, alkylthio, alkylsulfinyl having one to eight carbon atoms, alkylsulfonyl having one to eight carbon atoms, phenoxy, acyloxy, or combinations thereof, alkyl having one to eight C atoms, alkoxy containing one to eight carbon atoms eight C atoms, cycloalkyl having three to seven carbon atoms, cycloalkyl alkyl having four to seven carbon atoms, halogenated alkoxy containing eight C atoms, cycloalkoxy having three to seven carbon atoms, cycloalkylalkoxy having four to seven carbon atoms, alkyl alkoxy having from two to eight carbon, alkyl (halogenated alkyl) amino atoms wherein each alkyl group has one to eight C, di (alkylhalogenated) amino atoms where each alkyl group has one to eight halogenated C (alkyl) amino atoms which has one to eight C, cyano, halogenated alkyl atoms which have one to eight carbon atoms, nitro, oxo, OH, alkoxy carbonyl alkyl which has three to eight carbon atoms, amino, monoalkylamino which has one to eight C atoms, dialkylamino wherein each alkyl group has one to eight atoms of C, SO 2 R 11, -CXR 11, piperidinylethyl, or combinations thereof; Carbo is a partially unsaturated carbocyclic group having five to fourteen carbon atoms, which is unsubstituted or substituted one or more times by halogen, alkyl having one to eight C atoms, alkoxy containing one to eight C atoms, hydroxy, nitro, cyano, oxo, or combinations thereof; eR11 is alkyl containing one to four carbon atoms, halogenated alkyl containing one to four carbon atoms, alkenyl containing three to six carbon atoms, alkynyl containing three to six carbon atoms, wherein the groups alkyl, halogenated alkyl, alkenyl or alkynyl are each unsubstituted or else substituted by Ar or Het, cycloalkyl containing three to seven carbon atoms, cycloalkenyl containing five to eight carbon atoms, cycloalkylalkyl containing four to seven carbon atoms, cycloalkenylalkyl containing six to nine carbon atoms, hydroxy alkyl containing two to to four carbon atoms, fluorinated alkyl hydroxy containing two to four carbon atoms, monoalkylamino containing one to four carbon atoms, dialkylamino wherein each alkyl group independently has one to four carbon atoms, or Ar, and their salts or solvates or N-oxides pharmaceutically or solvates of their pharmaceutically acceptable salts, or pharmaceutically acceptable salts or solvates of their N-oxides, wherein said compound may also be in the form of a polymorph, wherein if said compound exhibits chirality it may be in the form of a mixture of enantiomers or a mixture of diastereomers, or may be in the form of a single enantiomer or single diastereomer, and wherein at least one group R, R1, R3, R4 and R5 is Hetou OHet wherein the Het group is selected, in each case substituted or unsubstituted, from azabicyclooctyl, oxa-azabicycloheptyl, diazabicycloheptyl , diazabicyclononyl, diazabicyclooctyl, pyrazolyl, dihydroimidazolyl, 1,4-diazepanyl, hexahydropyrrolopyrazinyl, eoctahydropyrrolopyridinyl. A compound according to claim 1, characterized in that at least one group R, R 1, R 3, R 4 and R 5 is 1-azabicyclo [2.2.2] oct-3-yloxy, 2-oxa-5-one. azabicyclo [2.2.1] heptyl), diazabicycloheptyl (e.g. -2,5-diazabicyclo [2.2.1] hept-2-yl, 5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl trifluoroethyl-2,5-diazabicyclo [2.2.1] hept-2-yl, 5- (cyclopropylcarbonyl) -2,5-diazabicyclo [2.2.1] hept-2-yl, 1,4-diazabicyclo [3.2 .2] non-4-yl), 5-methyl-2,5-diazabicyclo [2.2.2] oct-2-yl, 8-methyl-3,8-diazabicyclo [3.2.1] oct-3-yl) , pyrazolyl, dihydroimidazolyl, -1,4-diazepan-1-yl, 4-methyl-1,4-diazepan-1-yl, hexahydropyrrolo [1,2-a] pyrazin-2 (1H) -yl), or 1 - (cyclopropylcarbonyl) octahydro-6H-pyrrolo [3,4-b] pyridin-6-yl). A compound according to claim 1, wherein Het is a heterocyclic group which is fully saturated, partially saturated or fully unsaturated, containing five to ten ring atoms wherein at least one ring atom is a atom. of Ν, 0 or S, which is unsubstituted or substituted one or more times by halogen, aryl having six to ten carbon atoms which is optionally substituted by halogen, alkyl having one eighteen carbon atoms, hydroxy, alkoxy containing a to eight carbon atoms, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino having one to eight carbon atoms, dialkylamino wherein each alkyl group has one to eight carbon atoms, hydroxy alkyl containing one to eight carbon atoms, alkoxy hydroxy having one to eight carbon atoms, carboxy, cyano, acyl, carbonyl alkoxy wherein the alkoxy group have one to eight carbon atoms, alkylthio, alkylsulfinyl having one to eight carbon atoms, alkylsulfonyl having one to eight carbon atoms, phenoxy, acyloxy, or combinations thereof, alkyl having one to eight C atoms, alkoxy containing one to eight C atoms, cycloalkyl having three to seven carbon atoms, cycloalkylalkyl having four to seven carbon atoms, halogenated alkoxy contained eight to C atoms, cycloalkoxy having three to seven carbon atoms, cycloalkylalkoxy having four to seven carbon atoms, alkyl alkoxy having two to eight carbon atoms, alkyl (halogenated alkyl) at which each alkyl group has one to eight C 1 di (halogenated alkyl) amino atoms wherein each alkyl group has one to eight C 1 (halo) alkyl amino amino atoms having one to eight C 8 cyano, halogenated alkyl atoms having one to eight carbon atoms , nitro, oxo, OH, alkoxy carbonyl alkyl which has three to eight carbon atoms, amino, monoalkylamino which has one to eight C atoms, dialkylamino wherein each alkyl group has one to eight C atoms , SO2R11, -CXR11, piperidinylethyl, or combinations thereof R2 is H, alkyl having one to four carbon atoms, fluorinated alkyl having one to four carbon atoms, cycloalkyl having three to seven carbon atoms, cycloalkyl alkyl having four to seven carbon atoms, C1-4-alkyl-CO-fluorinated, C3-7-cycloalkyl-CO-, C1-4-alkyl-NH-CO-, C3-7-cycloalkyl-NH-CO-, Het, Ar-C1-4-alkyl-, Ar-C1-4-alkyl-CO-, Ar-C1-4-alkyl-SO2, C1.4-alkyl-O-C1-4-alkyl- (e.g. CH2CH2- O-CH 3), or Ar-C 1-4 alkyl-NH-CO -; and at least one group R, R 1, R 3, R 4 and R 5 is substituted or unsubstituted oxyazabicycloheptyl or oxaazabicycloheptyl. A compound according to claim 3, characterized in that at least one group R, R 1, R 3, R 4 and R 5 is 2,5-diazabicyclo [2.2.1] hept-2-yl, methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl, trifluoroethyl-2,5-diazabicyclo [2.2.1] hept-2-yl, or 2-oxa-5-azabicyclo [2.2.1] heptyl. 5. A compound, wherein it is in accordance with formulas I, II, III or IV: <formula> formula see original document page 242 </formula> where <formula> formula see original document page 243 </formula> X is Each of X1 to X4 is independently N, CH, CR1, or C-, where C- is the point of attachment of the group A of the structure of formulas (I), (II), ( III) or (IV): each of X9 to X12 is independently N, CH, CR4, or C-, where C- is the point of attachment of group A to the remainder of the structure of formulas (I), (II). ), (III) or (IV): R1 is H, alkyl having one to four carbon atoms, halogenated alkyl having one to four carbon atoms, cycloalkyl having three to seven carbon atoms, or cycloalkylalkyl having four to seven carbon atoms: R1 is H, F, Cl, Br, I, OH, CN, COH, NR6R7, carboxy, CONR6R7, NR2COR8, NR2COOR8, NR2CSR8, NR2CONR2R9, NR2SO2R10, NR2R7, NR2R6, NR2R7 0- (C1-6-alkyl-O) 1-2-C1-6 alkyl, NR2-C1-6-alkyl-NR6R7, NR2-C1-6-alkyl-CONR6R7, NR2-CO-C1-6-alkyl-Ar, NR2-C1-6-alkyl-C0-0-R2, NR2 -C1-6-N2-C1-6-alkyl-NR2 (CO-O-R2) -NR2 (CO-O-R2), -C1-6-alkyl-NR2, -0-C1-6-alkyl-NR6R7 , alkyl having one to four carbon atoms, fluorinated alkyl having one to four carbon atoms, alkenyl having two to six carbon atoms, alkynyl having two to six carbon atoms, wherein the groups alkyl, fluorinated alkyl, alkenyl or alkynylylation is in each case unsubstituted or substituted by Ar or Het, cycloalkyl having three to seven carbon atoms, cycloalkenyl having five to eight carbon atoms which is unsubstituted or substituted by HCO-, Cl-6-alkoxy, NR6R7, CO -NR6R7, C2-6-alkoxycarbonyl, or -CO-R10, cycloalkylalkyl having four to seven carbon atoms, cycloalkenylalkyl having six to nine carbon atoms, alkoxy having one to four carbon atoms, cycloalkoxy having three to seven carbon atoms carbon cycloalkylalkyl xi having four to seven carbon atoms, alkylthio having one to four carbon atoms, fluorinated alkoxy having one to four carbon atoms, alkyl hydroxy having one to four carbon atoms, fluorinated alkyl hydroxy having one to four carbon atoms, hydroxy alkoxy having two to four carbon atoms, fluorinated hydroxy alkoxy having two four carbon atoms, monoalkylamino having one to four carbon atoms, dialkylamino wherein each group independently alkylates one to four carbon atoms, alkoxy carbonyl having two to six carbon atoms, Ar, Het, OAr, OHet, Carbo-O, Ar-C 1-6 -alkyl-O, Het-C 1-6 -alkyl-O, Het-CO-Het-, Het-C 1-6 -alkyl-NR2-, or Ar-C1-6-alkyl-Het-O-; a five membered fused ring containing at least one N; R1 atom is one of the following formulas <formula> formula see original document page 244 </formula> two R1 may together form a structure of R2 is H, alkyl containing one to four atoms decarbon, fluorinated alkyl containing one to four carbon atoms decarbon, cycloalkyl containing three to seven carbon atoms, cycloalkylalkyl containing four to seven carbon atoms, C1-4-alkyl-CO-fluoridated, C3-V-Cycloalkyl-CO-, C1- 4-alkyl-NHCO-, C 3-7 -cycloalkyl-NH-CO-, Het, Ar-C 1-4 alkyl-, Ar-C 1-4 alkyl-CO-, Ar-C 1-4-alkyl-SO 2, C 1-4 alkyl-O-C 1-4 alkyl- (e.g. CH 2 CH 2 -O-CH 3), Ar-C 1-4 alkyl-NH-CO-, or Het-NH-CO-; R 4 is H, F , Cl, Br, I, OH, CN, Nitro, NH2, COH, NR6R7, Carboxy, CONR6R7, NR2COR8, NR2COOR8, NR2CSR8, NR2CONS2R9i g-alkyl-O) iz-Cx-e-alkyl, NR2-C1-6-alkyl-NR6R7, NR2-C1-6-alkyl-1-CONR6R7, NR2-CO-C1-6-alkyl-Ar, NR2-C1 -Salt kil-CO-O-R2, NR2-C1-6-alkyl-NR2 (CO-O-R2), -C1-6-alkyl-NR2, -0-C1-6-alkyl-NR6R7, alkyl containing one to four carbon atoms, fluorinated alkyl containing one to four carbon atoms, alkenyl containing two to six carbon atoms, alkynyl containing two to six carbon atoms, wherein the alkyl, fluorinated alkyl, alkenyl or alkynyl groups are each unsubstituted or substituted by Ar or Het, cycloalkyl containing three to seven carbon atoms, cycloalkenyl containing five to eight carbon atoms, which is unsubstituted or otherwise substituted by HCO-, C1-6 alkoxy, NR6R7, CO-NR6R7, C2-6-alkoxycarbonyl, or - CO-R10, cycloalkylalkyl containing four to seven carbon atoms, cycloalkenylalkyl containing six to nine carbon atoms, alkoxy containing one to four carbon atoms, cycloalkoxy containing three to seven carbon atoms, cycloalkylalkyl containing four to seven carbon atoms, alkylthio containing a four c atoms carbon, fluorinated alkoxy containing one to four carbon atoms, hydroxy alkyl containing one to four carbon atoms, fluorinated alkyl hydroxy containing four carbon atoms, hydroxy alkoxy containing two to four carbon atoms, fluorinated alkoxy hydroxy containing four to four carbon atoms, monoalkylamino containing one to four carbon atoms, dialkylamino wherein each alkyl group independently has one to four carbon atoms, alkoxycarbonyl containing two to six carbon atoms, Ar, Het, OAr, OHet, Carbo-0, Ar-C1-6-alkyl -0-, Het-C 1-6 -alkyl-O-, Het-CO-Het-, Het-C 1-6 -alkyl-NR 2 -, or Ar-C 1-6 -alkyl-Het-O-; or R4 is one of the following formulas <formula> formula see original document page 246 </formula> two R4 may together form a fused five-membered ring structure containing at least one N atom, each of R6 and R7 is independently H alkyl containing one to four carbon atoms, alkoxyalkyl containing two to eight carbon atoms, cycloalkyl containing three to seven carbon atoms; or cycloalkylalkyl containing four to seven carbon atoms, or R 6 and R 7 are together an alkylene group containing four to six carbon atoms forms a ring with the atom of N; R 8 is H, alkyl containing one to four carbon atoms, fluorinated alkyl containing one to six carbon atoms. four carbon atoms, alkenyl containing three to six carbon atoms, alkynyl containing three to six carbon atoms, wherein the alkyl, fluorinated alkyl, alkenyl or alkynyl groups are in each case unsubstituted or substituted by Ar or Het, cycloalkyl containing three to seven decarbonyl atoms, cycloalkenyl containing five to eight decarbonyl atoms, cycloalkylalkyl containing four to seven decarbonyl atoms, cycloalkenylalkyl containing six to nine decarbonyl, hydroxyalkyl containing one to four decarbonyl atoms, fluorinated alkyl hydroxy containing one to four carbon atoms, monoalkylamino four carbon atoms, dialkylamino wherein each alkyl group bark independently one to four carbon atoms, Ar, or Het; R 9 is alkyl having one to four carbon atoms, Ar, Ar-alkyl wherein the alkyl moiety has one to four carbon atoms, or Het; R 10 is alkyl containing one to four carbon atoms. four carbon atoms, fluorinated alkyl containing one to four carbon atoms, alkenyl containing three to six carbon atoms, alkynyl containing three to six carbon atoms, wherein the groups alkyl, fluorinated alkyl, alkenyl or alkynylation are in each case unsubstituted or otherwise substituted. substituted by Ar or Het, cycloalkyl containing three to seven decarbon atoms, cycloalkenyl containing five to eight decarbon atoms, cycloalkylalkyl containing four to seven decarbon atoms, cycloalkenylalkyl containing six to nine decarbon, hydroxyalkyl containing two to four decarbonyl atoms, hydroxyalkyl-containing alkyl two to four carbon atoms, monoalkylamino containing one to four carbon atoms, dialkylamino wherein c Each alkyl group independently has one to four carbon atoms, NR 6 R 7, NR 2 R 8, Ar, or Het; Ar is an aryl group having six to ten carbon atoms that is unsubstituted or substituted one or more times by alkyl having one to eight carbon atoms. C, alkoxy containing one to eight C atoms, halogen, dialkylamino wherein each alkyl moiety has one to eight C atoms, amino, cyano, hydroxyl, nitro, halogenated alkyl having one eight C atoms, halogenated alkoxy containing one to eight C atoms, hydroxy alkyl containing one to eight C atoms, alkoxy hydroxy having two to eight C atoms, alkenyloxy has three to eight C atoms, alkylthio having one to eight C atoms, alkylsulfinyl having one to eight atoms of C, alkylsulfonyl having one to eight C atoms, monoalkylamino having one to eight C atoms, cycloalkylamino wherein the cycloalkyl group has three to seven C atoms and is optionally substituted by alkyl having one to four carbon atoms one, alkoxy containing one to four carbon atoms, hydroxyl, amino, monoalkylamino having one to four carbon atoms, dialkylamino wherein each alkyl group has one to four carbon atoms, or combinations thereof, aryloxy wherein the aryl moiety has six atoms carbon and is optionally substituted by halogen, alkyl having one to eight carbon atoms, hydroxy, alkoxy containing one to eight carbon atoms, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino having one eighteen carbon atoms, dialkylamino where each alkyl group having one to eight carbon atoms, hydroxy alkyl containing one to eight carbon atoms, alkoxy hydroxy having one to eight carbon atoms, carboxy, cyano, acyl, alkoxycarbonyl wherein the alkoxy group has one to eight carbon atoms, alkylthio, alkylsulfinyl which has one to eight carbon atoms, alkylsulfonyl having one to eight carbon atoms, phenoxy, acyloxy, or combinations thereof, arylthio Aryl has six to ten carbon atoms and is optionally substituted by halogen, alkyl having one to eight carbon atoms, hydroxy, alkoxy containing one to eight carbon atoms, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino having one to eight carbon atoms. carbon, dialkylamino wherein each alkyl group has one to eight carbon atoms, hydroxy alkyl having one to eight carbon atoms, alkoxy hydroxy having one to eight carbon atoms, carboxy, cyano, acyl, carbonyl alkoxy wherein the alkoxy group has one to eight carbon atoms eight carbon atoms, alkylthio, alkylsulphinyl having one to eight carbon atoms, alkylsulphonyl having one to eight carbon atoms, phenoxy, or acyloxy, or combinations thereof, cycloalkyloxy wherein the group cycloalkyl has three to seven C atoms and is optionally substituted. for alkyl having one to four carbon atoms, alkoxy containing one to four carbon atoms, hydroxyl, amino, monoalkylamino having one to four carbon atoms carbon, dialkylamino wherein each alkyl group has four carbon atoms, or combinations thereof, sulfo, sulfonylamino, acylamido, acyloxy, or combinations thereof, Het is a heterocyclic group which is fully saturated, partially saturated or fully unsaturated containing five to ten ring atoms wherein at least one ring atom is an atom of 0, 0 or S which is unsubstituted or substituted one or more times by halogen, aryl having six to ten carbon atoms which is optionally substituted by halogen, alkyl having one to eight carbon atoms, hydroxy, alkoxy containing one to eight carbon atoms, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino having one to eight carbon atoms, dialkylamino wherein each alkyl group has one to eight carbon atoms, hydroxy alkyl containing one to eight carbon atoms, alkoxy hydroxy having one to eight carbon atoms, carboxy, cyano, acyl, alkoxy carbonyl wherein the alkoxy group one to eight carbon atoms, alkylthio, alkylsulfinyl having one to eight carbon atoms, alkylsulfonyl having one to eight carbon atoms, phenoxy, acyloxy, or combinations thereof, alkyl having one to eight C atoms, alkoxy containing one to eight C atoms, cycloalkyl having three to seven carbon atoms, cycloalkylalkyl having four to seven carbon atoms, halogenated alkoxy containing eight C atoms, cycloalkoxy having three to seven carbon atoms, cycloalkylalkoxy having four to seven atoms decarbonyl, alkyl alkoxy having two to eight alkyl, halogenated (alkyl) halogen atoms where each alkyl group has one to eight C, di (alkylhalogenated) amino atoms where each alkyl group has one to eight C (alkyl) atoms halogenated amino having one to eight C, cyano, alkyl halogen atoms having one to eight carbon atoms, nitro, oxo, OH, alkoxy carbonyl alkyl having three to eight carbon atoms, amino, monoalkylamino Inoque has one to eight C atoms, dialkylamino wherein each alkyl group has one to eight C atoms, SO 2 R 11, -CXR 11, piperidinylethyl, or combinations thereof; Carbo is a partially unsaturated carbocyclic group having five to fourteen carbon atoms, which is unsubstituted or substituted one or more times by halogen, alkyl having one to eight C atoms, alkoxy containing one to eight C atoms, hydroxy, nitro, cyano, oxo, or combinations thereof; eR11 is alkyl containing one to four carbon atoms, halogenated alkyl containing one to four carbon atoms, alkenyl containing three to six carbon atoms, alkynyl containing three to six carbon atoms, wherein the groups alkyl, halogenated alkyl, alkenyl or alkynyl are each unsubstituted or else substituted by Ar or Het, cycloalkyl containing three to seven carbon atoms, cycloalkenyl containing five to eight carbon atoms, cycloalkylalkyl containing four to seven carbon atoms, cycloalkenylalkyl containing six to nine carbon atoms, hydroxy alkyl containing two to four carbon atoms, fluorinated alkyl hydroxy containing two to four carbon atoms, monoalkylamino containing one to four carbon atoms, dialkylamino wherein each alkyl group independently has one to four carbon atoms, or Ar, and their salts or solvates or N-oxides pharmaceutically or solvates of their pharmaceutically acceptable salts, or pharmaceutically acceptable salts or solvates of their N-oxides, wherein said compound may also be in the form of a polymorph, wherein if said compound exhibits chirality it may be in the form of a mixture of enantiomers or a mixture of diastereomers, or may be in the form of a single enantiomer or single diastereomer, provided that: A is of formula (a) and has at least one substituent R1 which is Het with the exception of thiazolyl, and R2 is alkyl which has two to four carbon atoms having an a four carbon atoms, cycloalkyl having three to seven carbon atoms, cycloalkyl alkyl having four to seven carbon atoms, C1-4-alkyl-CO-fluoridated, C3-7-cycloalkyl-CO-, C1-4-alkyl- NH-CO-, C3-7-cycloalkyl-NH-CO-, Het, Ar-C1-4-alkyl-, Ar-C1-4-alkyl-CO-, Ar-C1-4-alkyl-SO2, C1 -4-C 1-4 alkyl-alkyl-, or Ar-C 1-4 alkyl-NH-CO-; or A is of formula (c) and has at least one R 4 substituent which is imidazolyl, pyrrolyl, pyrazolyl, C 1-8 alkylpyrazol, oxa-azabicycloheptyl, diazabicycloheptyl, C 1-8 alkyl diazabicycloheptyl, C 1-8 alkyl diazabicycloheptyl halogenated, amino-substituted piperidinyl, C1-8-alkyl-NH-, or (C1-8-alkyl) 2N-, or hydroxy substituted, hydroxy, halogenated alkoxy, cycloalkylalkoxy, amino, (C1-8-alkyl-NH-) monoalkylamino, dialkylamino ((C 1-8 alkyl) 2 N-), alkyl alkoxy, or alkyl (fluorinated alkyl) amino. A compound according to claim 5 wherein Het is a heterocyclic group which is fully saturated, partially saturated or fully unsaturated, containing five to ten ring atoms wherein at least one ring atom is a ring atom. 0, 0 or S, which is unsubstituted or substituted one or more times by halogen, aryl having six to ten carbon atoms which is optionally substituted by halogen, alkyl having one eighteen carbon atoms, hydroxy, alkoxy containing one to eight carbon atoms, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino having one to eight carbon atoms, dialkylamino wherein each alkyl group has one to eight carbon atoms, hydroxyalkyl containing one to eight carbon atoms, hydroxy alkoxy having one to eight carbon atoms, carboxy, cyano, acyl, alkoxycarbonyl wherein the alkoxy group has one to eight carbon atoms, alkylthio, alkylsulfinyl having one to eight carbon atoms, al alkylsulfonyl having one to eight carbon atoms, phenoxy, acyloxy, or combinations thereof, alkyl having one to eight C atoms, alkoxy containing one to eight C atoms, cycloalkyl having three to seven carbon atoms, cycloalkylalkyl having four to seven carbon atoms, halogenated alkoxy contained eight to C atoms, cycloalkoxy having three to seven carbon atoms, cycloalkylalkoxy having four to seven carbon atoms, alkyl alkoxy having two to eight carbon atoms, alkyl (halogenated alkyl) at which each alkyl group has one to eight C 1 di (halogenated alkyl) amino atoms wherein each alkyl group has one to eight C 1 (halo) alkyl amino amino atoms having one to eight C 8 cyano, halogenated alkyl atoms having one to eight carbon atoms , nitro, oxo, OH, alkoxycarbonylalkyl having three to eight carbon atoms, amino, monoalkylamino which has one to eight C, dialkylamino wherein each alkyl group has one to eight C, S atoms O 2 R 11, -CXR 11, piperidinylethyl, or combinations thereof; eR2 H, alkyl having one to four carbon atoms, fluorinated alkyl having one to four carbon atoms, cycloalkyl having three to seven carbon atoms, cycloalkyl alkyl having four to seven carbon atoms, C1-4-alkyl-CO- C3-7-cycloalkyl-CO-, C1-4-alkyl-NH-CO-, C3-7-cycloalkyl-NH-CO-, Het, Ar-C1-4-alkyl-, Ar-C1-4- alkyl-CO-, Ar-C1-4-alkyl-SO2-, C1-4-alkyl-0-C1-4-alkyl- (e.g. CH2CH2-O-CH3), or Ar-C1-4-alkyl-NH -C0-. Compound according to claim 5 or claim 6, characterized in that the dictocompound is of formula I. Compound according to claim 5 or claim 6, characterized in that the dictocompound is of formula II. Compound according to claim 5 or claim 6, characterized in that the dictocompound is of formula III. Compound according to claim 5 or claim 6, characterized in that the dictocompound is of formula IV. Compound according to any one of claims 5 to 10, characterized in that A is of the formula (a) and is joined to the remainder of the compound by its 3, 4 or 7 position. Compound according to any one of claims 5 to 11, characterized in that A is sub-formula (c) and is joined to the remainder of the compound by its 3, 4 or 7 position. Compound according to Claim 11, characterized in that A is from sub-formula (a) and is joined to the remainder of the compound by its 3-position. Compound according to Claim 12, characterized in that A is of sub-formula (c) and is joined to the remainder of the compound by its 3-position. 15. A compound characterized in that it is in accordance with formulas I, II, III, or IV: <formula> formula see original document page 254 </formula> whereA and <formula> formula see original document page 254 </formula> X is O or S, each of X1 to X4 is independently N, CH, CR1, or C-, where C- is the point of attachment of the group A of the structure of formulas (I), (II) (III) or (IV): each of X5 to X8 is independently N, CH, CR3, or C-, where C- is the point of attachment of group A of the structure of formulas (I), (II), (III) or (IV): each of X9 to X12 is independently N, CH, CR4, or C-, where C- is the point of attachment of group A to the remainder of the structure of the formulas ( I), (II), (III) or (IV): each of X13 to X16 is independently N, CH, CR, or C-, where C- represents the point of attachment of the remaining group A to the structure. of formulas (I), (II), (III) or (IV): R1 is H, alkyl having one to four carbon atoms, halogenated alkyl having one to four carbon atoms, cycloalkyl having three to seven carbon atoms, or cycloalkylalkyl having four to seven carbon atoms; R is H, F, Cl, Br, I, OH, CN, COH, NR6 R7, carboxy, CONR6R7, NR2COR8, NR2COOR8, NR2CSR8, NR2CONR2R9, NR2CSNR2R9, NR2SO2R10, NR2CONR6R7, NR2CSNR6R7, NR2R9, SO2R10, S1-10-C1-6-C1-6 6-alkyl-NR6R7, NR2-C-6-alkyl-CONR6R7, NR2-CO-C1-6-alkyl-Ar, NR2-C1-6-alkyl-C0-0-R2, NR2-C1-6-N2- C1-6-alkyl-NR2 (CO-O-R2) -NR2 (CO-O-R2), -C1-6-alkyl-NR2, -O-C1-6-alkyl-NR6R7, alkyl having one to four carbon atoms, fluorinated alkyl having one to four carbon atoms, alkenyl having two to six carbon atoms, alkynyl having two to six carbon atoms, wherein the unsubstituted alkyl, fluorinated alkyl, alkenyl or alkynyl groups are in each case or substituted by Ar or Het, cycloalkyl having three to seven carbon atoms, cycloalkenyl having five to eight carbon atoms which is unsubstituted or substituted by HCO-, Cl-6-alkoxy, NR6R7, CO-NR6R7, C2-s-alkoxycarbonyl, or -CO-R10 cycloalkylalkyl has four to seven carbon atoms, cycloalkenylalkyl having six to nine carbon atoms. carbon, alkoxy having one to four carbon atoms, cycloalkoxy having three to seven carbon atoms, cycloalkylalkoxy having four to seven carbon atoms, alkylthio having one to four carbon atoms, fluorinated alkoxy having one to four carbon atoms, hydroxy alkyl having one to four carbon atoms, hydroxy fluorinated alkyl having one to four carbon atoms, hydroxy alkoxy having two to four carbon atoms, fluorinated alkoxy hydroxy having two four carbon atoms, monoalkylamino having one to four carbon atoms dialkylamino wherein each alkyl group independently has one to four carbon atoms, alkoxycarbonyl having two to six carbon atoms, Ar, Het, OAr, OHet, Carbo-O, Ar-C1-6-alkyl yl-O-, Het-C1-6-alkyl-O-, Het-CO-Het-, Het-C1-6-alkyl-NR2-, or Ar-C1-6-alkyl-Het-O- as long as R is not NH2; orR is one of the following formulas <formula> formula see original document page 256 </formula> η ranges from 2 to 4, m ranges from 3 to 5; or two R may together form a fused five-membered ring structure containing at least one N atom, R 1 is H, F, Cl, Br, I, OH, CN, nitro, NH 2, CO, NR 6 R 7, carboxy, CONR 6 R 7, NR 2 COR 8, NR2COOR8, NR2CSR8, NR2CONR2R9, NR2CSNR2R9, NR2SO2R10, NR2CONR6R7, NR2CSNR6R7, NR2R9, SO2R10, SOR10, -O- (C1-6-alkyl-0) XS-C1R6-C1-6-C1-6 NR2 - C1.6-alkyl-CONR6R7, NR2-CO-C1-6-alkyl-Ar, NR2-C1-6-alkyl-CO-O-R2, NR2-C1-6-alkyl-NR2 (CO-O- R2), -C1-6-alkyl-NR2, -O-C1-6-alkyl-NR6R7, alkyl containing one to four carbon atoms, fluorinated alkyl containing one to four carbon atoms, alkenyl containing two to six carbon atoms alkynyl containing two to six carbon atoms, wherein the alkyl, fluorinated alkyl, alkenyl or alkynyl groups are in each case unsubstituted or substituted by Ar or Het, cycloalkyl containing three to seven carbon atoms, cycloalkenyl containing five to eight carbon atoms, which is not replaced or Unsubstituted by HCO-, C1-6-alkoxy, NR6R7, CO-NR6R7, C2-6-alkoxycarbonyl, or -CO-R10, cycloalkylalkyl containing four to seven carbon atoms, cycloalkenylalkyl containing six to nine carbon atoms, alkoxy containing one to four carbon atoms, cycloalkoxy containing three to seven carbon atoms, cycloalkylalkoxy containing four to seven carbon atoms, alkylthio containing four carbon atoms, fluorinated alkoxy containing one to four carbon atoms, hydroxy alkyl containing one to four carbon atoms, fluorinated alkyl hydroxy containing four carbon atoms, alkoxy hydroxy containing two four carbon atoms, fluorinated alkoxy hydroxy containing four carbon atoms, monoalkylamino containing one four carbon atoms, dialkylamino wherein each alkyl group independently has one to four carbon atoms alkoxycarbonyl containing two to six carbon atoms, Ar, Het, OAr, OHet, Carbo-0, Ar-C1-e-alkyl-O-, Het -C 1-6 alkyl-O-, Het-CO-Het-, Het-C 1-6 alkyl-NR 2 -, or Ar-C 1-6 alkyl-Het-O-; or R1 is one of the following formulas <formula> formula see original document page 257 </formula> Or two R1 may together form a fused five membered ring structure containing at least one atom of N7-R2 is H, alkyl containing one to four atoms decarbon, fluorinated alkyl containing one to four carbon atoms, cycloalkyl containing three to seven carbon atoms, cycloalkylalkyl containing four to seven carbon atoms, C1-4-alkyl-CO-fluoridated, C3-7-cycloalkyl-CO-, C1- 4-alkyl-NHCO-, C 3-7 -cycloalkyl-NH-CO-, Het, Ar-C 1-4 alkyl-, Ar-C 1-4 alkyl-CO-, Ar-C 1-4 alkyl-SO 2 - C1-4-alkyl-O-C1-4-alkyl- (e.g. CH2 CH2 -O-CH3), Ar-C1-4-alkyl-NH-CO-, or Het-NH-CO-; F, Cl, Br, I, OH, CN, Nitro, NH2, COH, NR6R7, Carboxy, CONR6R7, NR2COR87 NR2COOR8, NR2CSR8, NR2CONR2R9, NR2SO2R107 NR2CONR6R7, NR2-7 6-alkyl-0) i-2-C1-6-alkyl, NR2-C1-6-alkyl-NR6R7, NR2-C1-6-alkyl-1-CONR6R7, NR2-CO-C1-6-alkyl-1-Ar, NR2-C1-6 alkyl-CO-O-R2, NR2-C1-6-alkyl-NR2 (CO-O-R2), -C1-6-alkyl-NR2, -0-C1-6-alkyl-NR6R7, alkyl containing one to four carbon atoms, fluorinated alkyl containing one to four carbon atoms, alkenyl containing two to six carbon atoms, alkynyl containing two to six carbon atoms, wherein the alkyl, fluorinated alkyl, alkenyl or alkynyl groups are each unsubstituted or otherwise substituted. substituted by Ar or Het, cycloalkyl containing three to seven carbon atoms, cycloalkenyl containing five to eight carbon atoms, which is unsubstituted or otherwise substituted by HCO-, C1-S-alkoxy, NR6R7, CO-NR6R7i C2-s-alkoxy carbonyl, or -CO-R10, cycloalkylalkyl containing four to seven carbon atoms, cycloalkenylalkyl containing six to nine carbon atoms, alkoxy containing one to four carbon atoms, cycloalkoxy containing three to seven carbon atoms, cycloalkylalkoxy containing four to seven carbon atoms Alkylium contended for four atoms carbon, fluorinated alkoxy containing four carbon atoms, hydroxy alkyl containing one four carbon atoms, fluorinated alkyl hydroxy containing four carbon atoms, alkoxy hydroxy containing two four carbon atoms, fluorinated alkoxy hydroxy containing four carbon atoms, monoalkylamino containing one to four carbon atoms, dialkylamino wherein each alkyl group independently has one to four carbon atoms, alkoxycarbonyl containing two to six carbon atoms, Ar, Het, OAr, OHet, Carbo-0, Ar-C1-6- alkyl-O-, Het-C1-6-alkyl-O-, Het-CO-Het-, Het-C1-6-alkyl-NR2-, or Ar-C1-6-alkyl-Het-0-; or R3 is one of the following formulas <formula> formula see original document page 259 </formula> or two R3 may together form a fused five-membered ring structure containing at least one atom of N; NR6R7, carboxy, CONR6R7, NR2COR8, NR2COOR8, NR2CSR8, NR2CONR2R9, NR2CSNR2R9, NR2SO2R10, NR2CONR6R7, NR2CSNR6R7, NR2R9, SO2R10, SOR10, -O- (C1-6-alkyl-0) I-2-C1-6-C1-6 alkyl-NR6 NR2-C1-6-alkyl-CONR6R7, NR2-CO-C1.6-alkyl-Ar, NR2-C1-S-alkyl-CO-O-R27 NR2-C1.6-alkyl-NR2 (CO-O-R2 ), -C 1-6 alkyl-NR 2, -0-C 1-6 alkyl-NR 6 R 7, alkyl containing one to four carbon atoms, fluorinated alkyl containing one to four carbon atoms, alkenyl containing two to six carbon atoms, alkynyl containing two to six carbon atoms, wherein the groups alkyl, fluorinated alkyl, alkenyl or alkynylation are in each case unsubstituted or substituted by Ar or Het, cycloalkyl containing three to seven carbon atoms, cycloalkenyl containing five to eight atoms which is unsubstituted or substituted by HCO-, C1-6 alkoxy, NR6R7, CO-NR6R7, C2.6-alkoxycarbonyl, or -CO-R10 cycloalkylalkyl containing four to seven decarbonyl cycloalkenylalkyl atoms containing six to nine carbon atoms, alkoxy containing one to four carbon atoms, cycloalkoxy containing three to seven carbon atoms, cycloalkylalkoxy containing four to seven carbon atoms, alkylthio containing one to four carbon atoms, alkoxyfluoride containing one to four carbon atoms, hydroxyR4 is H, F, Cl, Br, I, OH, CN, nitro, NH 2, COH, alkyl containing one to four carbon atoms, fluorinated hydroxyalkyl containing one to four carbon atoms, alkoxy hydroxy containing two to four carbon atoms, fluorinated alkoxy hydroxy containing two to four carbon atoms, monoalkylamino containing one to four carbon atoms, dialkylamino wherein each alkyl group independently has one to four carbon atoms, alkoxycarbonyl and containing two to six carbon atoms, Ar, Het, OAr, OHet, Carbo-O, Ar-C 1-6 alkyl-O-, Het-C 1-6 alkyl-O-, Het-CO-Het-, Het C1-6-alkyl-NR2-, or Ar-C1-6-alkyl-Het-O-; or R4 is one of the following formulas <formula> formula see original document page 260 </formula> or two R4 may together form a five membered fused ring structure containing at least one atom of N; R5 is H, F, Cl, Br, I, OH, CN, nitro, NH2, carboxy, CONR6R7i NR2COR8, NR2CSR8, NR2CONR2R97 NR2CSNR2R9, NR2SO2R10, NR2CONR6R7, NR2CSNR6R7, NR2R9f one carbon alkyl containing four alkyl atoms, NR2CR6, NR2CR6, NR2C6 alkyl, carbon atoms, four carbon atoms two to six carbon atoms, alkynyl containing two to six carbon atoms, wherein the alkyl, fluorinated alkyl, alkenyl or alkynyl groups are in each case unsubstituted or then substituted by Ar or Het, cycloalkyl containing three to seven carbon atoms, cycloalkenyl containing five eight carbon atoms, which is unsubstituted or substituted by HCO-, C1-6-alkoxy, NR6R7, CO-NR6R7, C2-6-alkoxycarbonyl, or -CO-R10, four-membered cycloalkylalkyl carbon atoms, cycloalkenylalkyl containing six to one carbon atoms, alkoxy containing one to four carbon atoms, cycloalkoxy containing three to seven carbon atoms, cycloalkylalkoxy containing four to seven carbon atoms, alkylthio containing one to four carbon atoms, alkoxyfluoride containing one to four carbon atoms one to four carbon atoms, hydroxyalkyl containing one to four carbon atoms, fluorinated hydroxyalkyl containing one to four carbon atoms, alkoxy hydroxy containing two to four carbon atoms, fluorinated alkoxy hydroxy containing two to four carbon atoms, monoalkylamino containing one to four carbon atoms carbon atoms, dialkylamino wherein each alkyl group independently has one to four carbon atoms, alkoxycarbonyl containing two to six carbon atoms, Ar, Het, OAr or OHet, each of R 6 and R 7 is independently H, alkyl containing one to four carbon atoms, alkoxyalkyl containing two to eight carbon atoms, cycloalkyl containing dotred to seven carbon atoms; or cycloalkylalkyl containing four to seven carbon atoms, or R 6 and R 7 are together an alkylene group containing four to six carbon atoms forms a ring with the atom of N; R 8 is H, alkyl containing one to four carbon atoms, fluorinated alkyl containing one to six carbon atoms. four carbon atoms, alkenyl containing three to six carbon atoms, alkynyl containing three to six carbon atoms, wherein the alkyl, fluorinated alkyl, alkenyl or alkynyl groups are in each case unsubstituted or substituted by Ar or Het, cycloalkyl containing three to seven decarbonyl atoms, cycloalkenyl containing five to eight decarbonyl atoms, cycloalkylalkyl containing four to seven decarbonyl atoms, cycloalkenylalkyl containing six to nine decarbonyl, hydroxyalkyl containing one to four decarbonyl atoms, fluorinated alkyl hydroxy containing one to four carbon atoms, monaylaminoamino four carbon atoms, dialkylamino wherein each alkyl group bark independently one to four carbon atoms, Ar, or Het; R 9 is alkyl having one to four carbon atoms, Ar, Ar-alkyl wherein the alkyl moiety has one to four carbon atoms, or Het; R 10 is alkyl containing one to four carbon atoms, fluorinated alkyl containing one to four carbon atoms, alkenyl containing three to six carbon atoms, alkynyl containing three to six carbon atoms, wherein the groups alkyl, fluorinated alkyl, alkenyl or alkynylation are in each case unsubstituted or then substituted by Ar or Het, cycloalkyl containing three to seven carbon atoms, cycloalkenyl containing five to eight carbon atoms, cycloalkylalkyl containing four to seven carbon atoms, cycloalkenylalkyl containing six to nine carbon atoms, hydroxyalkyl containing two to four carbon atoms, hydroxyalkyl containing two to four carbon atoms, monoalkylamino containing one to four carbon atoms, dialkylamino wherein each alkyl group independently has one to four carbon atoms, NR6 R7, NR2 R8, Ar, or Het; Ar is an aryl group having six to ten carbon atoms that is unsubstituted or substituted one or more times by alkyl having one to eight carbon atoms. C, alkoxy containing one to eight C atoms, halogen, dialkylamino wherein each of the alkyl moieties has one to eight C atoms, amino, cyano, hydroxyl, nitro, halogenated alkyl having one to eight C atoms, halogenated alkoxy containing one to C eight C atoms, hydroxy alkyl containing one to eight C atoms, hydroxy alkoxy having two to eight C atoms, alkenyloxy has three to eight C atoms, alkylthio having one to eight C atoms, alkylsulfinyl having one to eight atoms of C, alkylsulfonyl having one to eight C atoms, monoalkylamino having one to eight C atoms, cycloalkylamino wherein the cycloalkyl group has three to seven C atoms and is optionally substituted by alkyl having one to four carbons alkoxy containing one to four carbon atoms, hydroxyl, amino, monoalkylamino having one to four carbon atoms, dialkylamino wherein each alkyl group has one to four carbon atoms, or combinations thereof, aryloxy wherein the aryl moiety has six atoms carbon and is optionally substituted by halogen, alkyl having one to eight carbon atoms, hydroxy, alkoxy containing one to eight carbon atoms, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino having one eighteen carbon atoms, dialkylamino where each alkyl group having one to eight carbon atoms, hydroxy alkyl containing one to eight carbon atoms, alkoxy hydroxy having one to eight carbon atoms, carboxy, cyano, acyl, alkoxycarbonyl wherein the alkoxy group has one to eight carbon atoms, alkylthio, alkylsulfinyl which has one to eight carbon atoms, alkylsulfonyl having one to eight carbon atoms, phenoxy, acyloxy, or combinations thereof, arylthioem Aryl has six to ten carbon atoms and is optionally substituted by halogen, alkyl having one to eight carbon atoms, hydroxy, alkoxy containing one to eight carbon atoms, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino having one to eight carbon atoms. carbon, dialkylamino wherein each alkyl group has one to eight carbon atoms, hydroxy alkyl having one to eight carbon atoms, alkoxy hydroxy having one to eight carbon atoms, carboxy, cyano, acyl, carbonyl alkoxy wherein the alkoxy group has one to eight carbon atoms eight carbon atoms, alkylthio, alkylsulphinyl having one to eight carbon atoms, alkylsulphonyl having one to eight carbon atoms, phenoxy, or acyloxy, or combinations thereof, cycloalkyloxy wherein the group cycloalkyl has three to seven C atoms and is optionally substituted by alkyl having one to four carbon atoms, alkoxy containing one to four carbon atoms, hydroxyl, amino, monoalkylamino having one to four carbon atoms ono, dialkylamino wherein each alkyl group has four carbon atoms, or combinations thereof, sulfo, sulfonylamino, acylamido, acyloxy, or combinations thereof, Het is a heterocyclic group which is fully saturated, partially saturated or fully unsaturated containing five to ten ring atoms wherein at least one ring atom is an atom of O, O or S which is unsubstituted or substituted one or more times by halogen, aryl having six to ten carbon atoms which is optionally substituted by halogen, alkyl having one to eight carbon atoms, hydroxy, alkoxy containing one to eight carbon atoms, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino having one to eight carbon atoms, dialkylamino wherein each alkyl group has one to eight atoms carbon, hydroxy alkyl containing one to eight carbon atoms, hydroxy alkoxy having one to eight carbon atoms, carboxy, cyano, acyl, carbonyl alkoxy wherein the alkoxy group is Eight carbon atoms, alkylthio, alkylsulfinyl having one to eight carbon atoms, alkylsulfonyl having one to eight carbon atoms, phenoxy, acyloxy, or combinations thereof, alkyl having one to eight C atoms, alkoxy containing one to eight atoms C, cycloalkyl having three to seven carbon atoms, cycloalkylalkyl having four to seven carbon atoms, halogenated alkoxy contained eight carbon atoms, cycloalkoxy having three to seven carbon atoms, cycloalkylalkoxy having four to seven carbon atoms, alkyl alkoxy which has two to eight amino, alkyl (halogenated alkyl) amino atoms wherein each alkyl group has one to eight C, di (alkylhalogenated) amino atoms wherein each alkyl group has one to eight halogenated (alkyl) amino amino atoms having one to eight C, cyano, halogenated alkyl atoms having one to eight carbon atoms, nitro, oxo, OH7 alkoxycarbonylalkyl having three to eight carbon atoms, amino, monoalkylamino t one to eight C atoms, dialkylamino wherein each alkyl group has one to eight atoms of C, SO 2 R 11, -CXR 11, piperidinylethyl, or combinations thereof; Carbo is a partially unsaturated carbocyclic group having five to fourteen carbon atoms, which is unsubstituted or substituted one or more times by halogen, alkyl having one to eight C atoms, alkoxy containing one to eight C atoms, hydroxy, nitro, cyano, oxo, or combinations thereof; eR11 is alkyl containing one to four carbon atoms, halogenated alkyl containing one to four carbon atoms, alkenyl containing three to six carbon atoms, alkynyl containing three to six carbon atoms, wherein the groups alkyl, halogenated alkyl, alkenyl or alkynyl are each unsubstituted or else substituted by Ar or Het, cycloalkyl containing three to seven carbon atoms, cycloalkenyl containing five to eight carbon atoms, cycloalkylalkyl containing four to seven carbon atoms, cycloalkenylalkyl containing six to nine carbon atoms, hydroxy alkyl containing two to four carbon atoms, fluorinated alkyl hydroxy containing two to four carbon atoms, monoalkylamino containing one to four carbon atoms, dialkylamino wherein each alkyl group independently has one to four carbon atoms, or Ar, and their salts or solvates or N-oxides pharmaceutically pharmaceutically acceptable salts or solvates thereof, or pharmaceutically acceptable salts or solvates of their N-oxides, wherein said compound may also be in the form of a polymorph, wherein if said compound exhibits chirality it may be in the form of a mixture of enantiomers or a mixture of diastereomers, or may be in the form of said single enantiomer or single diastereomer, and wherein said compound has at least one Het group which is fully saturated, partially saturated and fully unsaturated, containing five to ten ring atoms wherein at least one ring atom is a de O atom. or S, and is substituted wherein at least one of the substituents is alkoxyhalogen containing one to eight C atoms, cycloalkoxy having three to seven carbon atoms, cycloalkylalkoxy having four to seven carbon atoms, cycloalkylalkyl having four to seven carbon atoms, halogenated alkyl having two to eight carbon atoms, alkoxyalkyl having two to eight carbon atoms, alkyl (halogenated alkyl) amin wherein each alkyl group has one to eight C 1, di (halogenated alkyl) amino atoms wherein each alkyl group has one to eight C 7 atoms or (halogenated alkyl) amino having one to eight C atoms. Compound according to claim 15, characterized in that said compound has at least one Het group which is fully saturated, partially saturated or fully unsaturated, containing five to ten ring atoms wherein at least one ring atom is a compound. ode, O or S, and is substituted, wherein at least one of the substituents is halogenated alkoxy containing one to eight carbon atoms, cycloalkoxy having three to seven carbon atoms, cycloalkylalkoxy having four to seven carbon atoms, halogenated alkyl which has two to eight carbon atoms, alkyl alkoxy having two to eight carbon atoms, alkyl (halogenated alkyl) amino wherein each alkyl group has one to eight C, di (halogenated alkyl) amino at which alkyl group has one to one. eight C atoms, or (alkylhalogenated) amino having one to eight C atoms. Compound according to claim 15 or claim 16, characterized in that R 2 is H, alkyl having one to four carbon atoms, fluorinated alkyl having one to four carbon atoms, cycloalkyl having three to seven carbon atoms, cycloalkylalkyl having four to seven carbon atoms, C1-4-alkyl-CO-fluorinated, C3-7-cycloalkyl-CO-, C1-4-alkyl-NH-CO-, C3-7-cycloalkyl -NH-CO-, Het, Ar-C1-4-alkyl-, Ar-C1-4-alkyl-CO-, Ar-C1-4-alkyl-SO2, C1-4-C1-4-alkyl -alkyl- or Ar-C 1-4 alkyl-NH-CO-. 18. A compound characterized in that it is in accordance with formulas I, II, III, or IV: <formula> formula see original document page 267 </formula> whereA is <formula> formula see original document page 267 </formula> X is O or S; each of X1 to X4 is independently N, CH1 CR1, or C-, where C- represents the point of attachment of the group A of the structure of formulas (I), (II), (III) or (IV): each of X5 to X8 is independently N, CH, CR3, or C-, where C- is the point of attachment of the group A of the structure of formulas (I), ( II), (III) or (IV): each of X9 to X12 is independently N, CH, CR4, or C-, where C- is the point of attachment of group A to the remainder of the structure of formulas (I ), (II), (III) or (IV): each of X13 to X16 is independently N, CH, CR, or C-, where C- represents the point of attachment of group A to the remainder of the structure. (I), (II), (III) or (IV): R 1 is H, alkyl having one to four carbon atoms, alkyl hal which has one to four carbon atoms, cycloalkyl having three to seven carbon atoms, or cycloalkylalkyl having four to seven carbon atoms; R is H, F, Cl, Br, I, OH, CN, COH, NR6 R7, carboxy , CONR6R7, NR2COR8, NR2COOR8, NR2CSR8, NR2CONR2R9, NR2CSNR2R9, NR2SO2R10, NR2CONR6R7, NR2CSNR6R7, NR2R9, SO2R10, -1-C1 -6-C1-6 -S-alkyl-NR6R7, NR2-C1-6-alkyl-CONR6R7, NR2-CO-C1-6-alkyl-Ar, NR2-C1-6-alkyl-C0-0-R2, NR2-C1-S-N2 -C1-6-alkyl-NR2 (CO-O-R2) -NR2 (CO-O-R2), -C1-6-alkyl-NR2, -0-C1-6-alkyl-NR6R7, alkyl having one a four carbon atoms, fluorinated alkyl having one to four carbon atoms, alkenyl having two to six carbon atoms, alkynyl having two to six carbon atoms, wherein the groups alkyl, fluorinated alkyl, alkenyl or alkynylation are in each case unsubstituted. or substituted by Ar or Het, cycloalkyl having three to seven carbon atoms, cycloalkenyl having five to eight carbon atoms which is unsubstituted or substituted by HCO-, C 1-6 alkoxy, NR 6 R 7 CO 2 NR 6 R 7, C 2-6 alkoxycarbonyl, or -CO-R 10 cycloalkylalkyl has four to seven carbon atoms, cycloalkenylalkyl having six to nine carbon atoms, alkoxy having one to four carbon atoms, cycloalkoxy having three to seven carbon atoms, cycloalkylalkoxy having four to seven carbon atoms, alkylthio having one to four carbon atoms, fluorinated alkoxy having one to four carbon atoms, alkyl hydroxy having one to four carbon atoms, fluorinated alkyl hydroxy having one to four carbon atoms, alkoxy hydroxy having two to four carbon atoms, fluorinated alkoxy hydroxy having two to four carbon atoms, monoalkylamino having one to four carbon atoms, dialkylamino in which each alkyl group independently has one to four carbon atoms, alkoxycarbonyl having two to six carbon atoms, Ar, Het, OAr, OHet, Carbo-0, Ar-C1-6-a alkyl-O-, Het-C1-6-alkyl-O-, Het-CO-Het-, Het-C1-6-alkyl-NR2-, or Ar-C1-6-alkyl-Het-0- as long as R is not NH2; orR is one of the following formulas <formula> formula see original document page 269 </formula> η ranges from 2 to 4, m ranges from 3 to 5; or two R may together form a fused five membered ring structure containing at least one N atom, R 1 is H, F, Cl, Br, I, OH, CN, nitro, NH 2, COH, NR 6 R 7, carboxy, CONR 6 R 7, NR 2 COR 8, NR2COOR8i NR2CSR8, NR2CONR2R9, NR2CSNR2R97 NR2SO2R10, NR2CONR6R7, NR2CSNR6R7, NR2R9, SO2R10, SOR10, -O- (C1-6-alkyl-O) 1-2-N-6-C1 -6-C1-6 NR2 - C1-6-alkyl-CONR6R7, NR2-CO-C1-6-alkyl-Ar, NR2-C1-6-alkyl-CO-O-R2, NR2-C1-6-alkyl-NR2 (C0-0-R2) -C1-6-alkyl-NR2, -0-C1-6-alkyl-NR6R7, alkyl containing one to four carbon atoms, fluorinated alkyl containing one to four carbon atoms, alkenyl containing two to six carbon atoms, alkynyl containing two to six carbon atoms, wherein the alkyl, fluorinated alkyl, alkenyl or alkynyl groups are each unsubstituted or otherwise substituted by Ar or Het7 cycloalkyl containing three to seven carbon atoms, cycloalkenyl containing five to eight carbon atoms, which is non-substituted. replaced the u is then substituted by HCO-, C 1-6 alkoxy, NR 6 R 7, CO-NR 6 R 7, C 2-6 alkoxycarbonyl, or -CO-R 10 cycloalkylalkyl containing four to seven carbon atoms, cycloalkenylalkyl containing six to nine carbon atoms, alkoxy containing one to four carbon atoms, cycloalkoxy containing three to seven carbon atoms, cycloalkylalkoxy containing four to seven carbon atoms, alkylthio containing four carbon atoms, fluorinated alkoxy containing one to four carbon atoms, hydroxy alkyl containing one to four carbon atoms carbon, fluorinated alkyl hydroxy containing four carbon atoms, alkoxy hydroxy containing two four carbon atoms, fluorinated alkoxy hydroxy containing four carbon atoms, monoalkylamino containing one four carbon atoms, dialkylamino wherein each alkyl group independently has one to four carbon atoms, alkoxycarbonyl containing two to six carbon atoms, Ar, Het, OAr, OHet, Carbo-0, Ar-C1-6-alkyl- O-, Het-C 1-6 -alkyl-O-, Het-CO-Het-, Het-C 1-6 -alkyl-NR 2 -, or Ar-C 1-6 -alkyl-Het-O-; or R1 is one of the following formulas <formula> formula see original document page 270 </formula> two R1 may together form a fused five-membered ring structure containing at least one N atom, R2 is H, alkyl containing one to four carbon atoms fluorinated alkyl containing one to four carbon atoms, cycloalkyl containing three to seven carbon atoms, cycloalkylalkyl containing four to seven carbon atoms, C1-4-alkyl-CO-fluorinated, C3-7-cycloalkyl-CO-, C1-4 -alkyl-NHCO-, C3-7-cycloalkyl-NH-CO-, Het, Ar-C1-4-alkyl-, Ar-C1-4-alkyl-CO-, Ar-C1-4-alkyl I-SO2- C1-4-alkyl-O-C1-4-alkyl- (e.g. CH2 CH2 -O-CH3), Ar-C1-4alkyl-NH-CO-, or Het-NH-CO-; R3 is H, F, Cl, Br, I, OH, CN, Nitro, NH2, COH, NR6R7, Carboxy, CONR6R7, NR2COR8, NR2COOR8, NR2CSR8, NR2CONR2R9, NR2CSNR2R9, NR2CONR6R7, NR2-R6-6, NR2 6-alkyl-O) 1-2-C1-6-alkyl, NR2-C1.6-alkyl-NR6R7, NR2-C1-6-alkyl-1-CONR6R7, NR2-CO-C1-6-alkyl-1-Ar, NR2 - C1 - 6 - alkyl-CO-O-R2, NR2-C1-6-alkyl-NR2 (CO-O-R2), -C1-6-alkyl-NR2, -O-C1-S-alkyl-NR6R7, alkyl containing one to four carbon atoms, fluorinated alkyl containing one to four carbon atoms, alkenyl containing two to six carbon atoms, alkynyl containing two to six carbon atoms, wherein the alkyl, fluorinated alkyl, alkenyl or alkynyl groups are not otherwise substituted or otherwise substituted by Ar or Het, cycloalkyl containing three to seven carbon atoms, cycloalkenyl containing five to eight carbon atoms, which is unsubstituted or otherwise substituted by HCO-, C1-6-alkoxy, NR6R7, CO-NR6R7, C2 -6-alkoxycarbonyl, or -CO-R10, cycloalkylalkyl containing four to seven carbon atoms, cycloalkenylalkyl containing six to nine carbon atoms, alkoxy containing one to four carbon atoms, cycloalkoxy containing three to seven carbon atoms, cycloalkylalkoxy containing four to seven carbon atoms seven carbon atoms, alkylthio contended for four carbon atoms, fluorinated alkoxy containing one to four carbon atoms, hydroxy alkyl containing one to four carbon atoms, fluorinated alkyl hydroxy containing four carbon atoms, alkoxy hydroxy containing two to four carbon atoms, fluorinated alkoxy hydroxy containing four to atoms monoalkylamino containing one to four carbon atoms, dialkylamino wherein each alkyl group independently has one to four carbon atoms, alkoxycarbonyl containing two to six carbon atoms, Ar, Het, OAr, OHet, Carbo-0, Ar-C1-6 -alkyl-O-, Het-C 1-6 alkyl-O-, Het-CO-Het-, Het-C 1-6 alkyl-NR 2 -, or Ar-C 1-6 alkyl-Het-0-; or R3 is one of the following formulas or two R3s may together form a five membered fused ring structure containing at least one N atom; R4 is H, F, Cl, Br, I, OH, CN, Nitro, NH2, COH, NR6R7, Carboxy, CONR6R7, NR2COR8, NR2COOR8, NR2CSR8, NR2CONR2R9, NR2CSNR2R10, NR2SO2R10, NR2CONR6R7, NR2CS-N6-2R6 -C6 0) is-C1-6 alkyl, NR2-C1-6-alkyl-NR6R7, NR2-C1.6-alkyl I-CONR6R7, NR2-CO-C1-6-alkyl-Ar, NR2-C1-6-alkyl -CO-O-R2, NR2-C1-6-alkyl-NR2 (CO-O-R2), -C1-6-alkyl-NR2, -0-C1-6-alkyl-NR6R7, alkyl containing one to four atoms decarbon, fluorinated alkyl containing one to four carbon atoms decarbon, alkenyl containing two to six carbon atoms, alkynyl containing two to six carbon atoms, wherein the alkyl, fluorinated alkyl, alkenyl or alkynyl groups are in each case unsubstituted or substituted by Ar or Het, cycloalkyl containing three to seven decar atoms carbon, cycloalkenyl containing five to eight carbon atoms which is unsubstituted or substituted by HCO-, C1-6-alkoxy, NR6R7, CO-NR6R7, C2-6-alkoxycarbonyl, or -CO-R10 cycloalkylalkyl containing four to seven carbon atoms, cycloalkenylalkyl containing six to nine carbon atoms, alkoxy containing one to four carbon atoms, cycloalkoxy containing three to seven carbon atoms, cycloalkylalkoxy containing four to seven carbon atoms, alkylthio containing one to four carbon atoms, alkoxyfluoride containing one to four carbon atoms, hydroxyalkyl containing one to four carbon atoms, fluorinated hydroxyalkyl containing one to four carbon atoms, alkoxy hydroxy containing two to four carbon atoms, fluorinated alkoxy hydroxy containing two to four carbon atoms, monoalkylamino containing one to four carbon atoms four carbon atoms, dialkylamino wherein each alkyl group independently has one to four carbon atoms, alkoxycarbonyl It contains two to six carbon atoms, Ar, Het, OAr, OHet, Carbo-O, Ar-C 1-6 alkyl-O-, Het-C 1-6 alkyl-O, Het-CO-Het-, Het-C 1-6 alkyl-NR 2 -, or Ar-C 1-6 alkyl-Het-O-; or R4 is one of the following formulas <formula> formula see original document page 273 </formula> two R4 may together form a fused five-membered ring structure containing at least one N atom; R5 is H, F, Cl, Br, I , OH, CN, nitro, NH2, carboxy, CONR6R7, NR2COR8, NR2CSR8, NR2CONR2R9, NR2CSNR2R9, NR2CONR6R7, NR2CONSNR6R7, NR2R9, SO2R10 alkyl containing one carbon atoms, four carbon atoms, four alkyl atoms alkenyl containing two to six carbon atoms, alkynyl containing two to six carbon atoms, wherein the alkyl, fluorinated alkyl, alkenyl or alkynyl groups are in each case unsubstituted or then substituted by Ar or Het, cycloalkyl containing three to seven carbon atoms, cycloalkenyl containing five eighteen carbon atoms, which is unsubstituted or substituted by HCO-, C1-6-alkoxy, NR6R7, CO-NR6R7, C2-6-alkoxycarbonyl, or -CO-R10, cycloalkylalkyl containing four atoms carbon, cycloalkenylalkyl containing six to one carbon atoms, alkoxy containing one to four carbon atoms, cycloalkoxy containing three to seven carbon atoms, cycloalkylalkoxy containing four to seven carbon atoms, alkylthio containing one to four carbon atoms, alkoxyfluoride containing one to four carbon atoms one to four carbon atoms, hydroxyalkyl containing one to four carbon atoms, fluorinated hydroxyalkyl containing one to four carbon atoms, alkoxy hydroxy containing two to four carbon atoms, fluorinated alkoxy hydroxy containing two to four carbon atoms, monoalkylamino containing one to four carbon atoms carbon atoms, dialkylamino wherein each alkyl group independently has one to four carbon atoms, alkoxycarbonyl containing two to six carbon atoms, Ar, Het, OAr or OHet, each of R 6 and R 7 is independently H, alkyl containing one to four carbon atoms, alkoxyalkyl containing two to eight carbon atoms, contendot cycloalkyl three to seven carbon atoms; or cycloalkylalkyl containing four to seven carbon atoms, or R 6 and R 7 are together an alkylene group containing four to six carbon atoms forms a ring with the atom of N; R 8 is H, alkyl containing one to four carbon atoms, fluorinated alkyl containing one or two carbon atoms. to four carbon atoms, alkenyl containing three to six carbon atoms, alkynyl containing three to six carbon atoms, wherein the alkyl, fluorinated alkyl, alkenyl or alkynyl groups are in each case unsubstituted or substituted by Ar or Het, cycloalkyl containing three to six carbon atoms. seven carbon atoms, cycloalkenyl containing five to eight carbon atoms, cycloalkylalkyl containing four to seven carbon atoms, cycloalkenylalkyl containing six to nine carbon atoms, hydroxy alkyl containing one to four carbon atoms, fluorinated alkyl hydroxy containing one to four carbon atoms, monoalkylamino to four carbon atoms, dialkylamino where each group independently having one to four carbon atoms, Ar, or Het; R 9 is alkyl having one to four carbon atoms, Ar, Ar-alkyl wherein the alkyl moiety has one to four carbon atoms, or Het; R 10 is alkyl containing one to four carbon atoms, fluorinated alkyl containing one to four carbon atoms, alkenyl containing three to six carbon atoms, alkynyl containing three to six carbon atoms, wherein the unsubstituted alkyl, fluorinated alkyl, alkenyl or alkynylation groups are in each case unsubstituted. or substituted by Ar or Het, cycloalkyl containing three to seven carbon atoms, cycloalkenyl containing five to eight carbon atoms, cycloalkylalkyl containing four to seven carbon atoms, cycloalkenylalkyl containing six to nine carbon atoms, hydroxy alkyl containing two to four carbon atoms, hydroxy fluoridated alkyl containing two to four carbon atoms, monoalkylamino containing one to four carbon atoms, dialkylamino in whereas each alkyl group independently has one to four carbon atoms, NR6R7, NR2R8, Ar, or Het; Ar is an aryl group having six to ten carbon atoms that is unsubstituted or substituted one or more times by alkyl having one to eight C atoms, alkoxy containing one to eight C atoms, halogen, dialkylamino wherein each alkyl moiety has one to eight C atoms, amino, cyano, hydroxyl, nitro, halogenated alkyl having one eight C atoms, halogenated alkoxy containing one to eight C atoms, hydroxy alkyl containing one to eight C atoms, hydroxy alkoxy having two to eight C atoms, alkenyloxy has three to eight C atoms, alkylthio having one to eight C atoms, alkylsulfinyl having one to eight C atoms, alkylsulfonyl having one to eight C atoms, monoalkylamino having one to eight C atoms, cycloalkylamino wherein the cycloalkyl group has three to seven C atoms and is optionally substituted by alkyl having one to four C atoms. carbon, alkoxy containing one to four carbon atoms, hydroxyl, amino, monoalkylamino having one to four carbon atoms, dialkylamino wherein each alkyl group has one to four carbon atoms, or combinations thereof, aryloxy wherein the aryl moiety has six atoms optionally substituted by halogen, alkyl having one to eight carbon atoms, hydroxy, alkoxy containing one to eight carbon atoms, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino having one eighteen carbon atoms, dialkylamino wherein each alkyl group has one to eight carbon atoms, hydroxy alkyl containing one to eight carbon atoms, hydroxy alkoxy having one to eight carbon atoms, carboxy, cyano, acyl, alkoxycarbonyl wherein the alkoxy group has one to eight carbon atoms, alkylthio, alkylsulfinyl having one to eight carbon atoms, alkylsulfonyl having one to eight carbon atoms, phenoxy, acyloxy, or combinations thereof, arylthioem which the aryl moiety has six to ten carbon atoms and is optionally substituted by halogen, alkyl having one to eight carbon atoms, hydroxy, alkoxy containing one to eight carbon atoms, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino having one to eight atoms dialkylamino wherein each alkyl group has one to eight carbon atoms, alkyl hydroxy having one to eight carbon atoms, alkoxy hydroxy having one to eight carbon atoms, carboxy, cyano, acyl, carbonyl alkoxy wherein the alkoxy group has one to eight carbon atoms, alkylthio, alkylsulphinyl having one to eight carbon atoms, alkylsulphonyl having one to eight carbon atoms, phenoxy, or acyloxy, or combinations thereof, cycloalkyloxy wherein the group cycloalkyl has three to seven C atoms and is optionally substituted. per alkyl having one to four carbon atoms, alkoxy containing one to four carbon atoms, hydroxy, amino, monoalkylamino having one to four atom carbon, dialkylamino wherein each alkyl group has four carbon atoms, or combinations thereof, sulfo, sulfonylamino, acylamido, acyloxy, or combinations thereof; Het is a heterocyclic group which is fully saturated, partially saturated or fully unsaturated, containing five to ten ring atoms wherein at least one ring atom is a de, O or S1 atom which which is unsubstituted or substituted one or more times by halogen, aryl having six to ten carbon atoms which is optionally substituted by halogen, alkyl having one to eight carbon atoms, hydroxy, alkoxy containing one to eight carbon atoms, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino having one to eight carbon atoms, dialkylamino wherein each alkyl group has one to eight atoms carbon, hydroxy alkyl containing one to eight carbon atoms, hydroxy alkoxy having one to eight carbon atoms, carboxy, cyano, acyl, carbonyl alkoxy wherein the alkoxy group one to eight carbon atoms, alkylthio, alkylsulphinyl having one to eight carbon atoms, alkylsulphonyl having one to eight carbon atoms, phenoxy, acyloxy, or combinations thereof, alkyl having one to eight C atoms, alkoxy containing one to eight carbon atoms eight C atoms, cycloalkyl having three to seven carbon atoms, cycloalkyl alkyl having four to seven carbon atoms, halogenated alkoxy containing eight C atoms, cycloalkoxy having three to seven carbon atoms, cycloalkylalkoxy having four to seven carbon atoms, alkyl alkoxy having from two to eight carbon, alkyl (halogenated alkyl) amino atoms wherein each alkyl group has one to eight C, di (alkylhalogenated) amino atoms where each alkyl group has one to eight halogenated C (alkyl) amino atoms which has one to eight C, cyano, halogenated alkyl atoms that have one to eight carbon atoms, nitro, oxo, OH, alkoxy carbonyl alkyl which has three to eight carbon atoms, amino, monoalkylamino which has one to eight C atoms, dialkylamino wherein each alkyl group has one to eight C atoms, SO 2 R 11, -CXR 11, piperidinylethyl, or combinations thereof; Carbo is a partially unsaturated carbocyclic group having five to fourteen carbon atoms, which is unsubstituted or substituted one or more times by halogen, alkyl having one to eight C atoms, alkoxy containing one to eight C atoms, hydroxy, nitro, cyano, oxo, or combinations thereof; eR11 is alkyl containing one to four carbon atoms, halogenated alkyl containing one to four carbon atoms, alkenyl containing three to six carbon atoms, alkynyl containing three to six carbon atoms, wherein the groups alkyl, halogenated alkyl, alkenyl or alkynyl are each unsubstituted or else substituted by Ar or Het, cycloalkyl containing three to seven carbon atoms, cycloalkenyl containing five to eight carbon atoms, cycloalkylalkyl containing four to seven carbon atoms, cycloalkenylalkyl containing six to nine carbon atoms, hydroxy alkyl containing two to four carbon atoms, fluorinated alkyl hydroxy containing two to four carbon atoms, monoalkylamino containing one to four carbon atoms, dialkylamino wherein each alkyl group independently has one to four carbon atoms, or Ar, and their salts or solvates or N-oxides pharmaceutically pharmaceutically acceptable salts or solvates thereof, or pharmaceutically acceptable salts or solvates of their N-oxides, wherein said compound may also be in the form of a polymorph, wherein if said compound exhibits chirality it may be in the form of a mixture of enantiomers or a mixture of diastereomers, or may be in the form of a single enantiomer or single diastereomer, wherein at least one of X1, X2, X3 and X4 is N; at least one of X5, X6, X7 and X8 is N; at least one of X9, X10, X11 and X12 is N; or at least one of X13, X14, X15 and X16 is N. A compound according to claim 18 wherein Het is a heterocyclic group which is fully saturated, partially saturated or fully unsaturated containing five to ten ring atoms wherein at least one ring atom is a atom. of Ν, 0 or S, which is unsubstituted or substituted by one or more halides, aryl having six to ten carbon atoms which is optionally substituted by halogen, alkyl having one eighteen carbon atoms, hydroxy, alkoxy containing one to eight carbon atoms, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino having one to eight carbon atoms, dialkylamino wherein each alkyl group has one to eight carbon atoms, hydroxy alkyl containing one to eight carbon atoms, hydroxy alkoxy having one to eight carbon atoms, carboxy, cyano, acyl, alkoxycarbonyl wherein the alkoxy group have one to eight carbon atoms, alkylthio, alkylsulfinyl having one to eight carbon atoms, the alkylsulfonyl having one to eight carbon atoms, phenoxy, acyloxy, or combinations thereof, alkyl having one to eight C atoms, alkoxy containing one to eight C atoms, cycloalkyl having three to seven carbon atoms, halogenated alkoxy containing one to eight C atoms, cycloalkoxy having three to seven decarbon atoms, cycloalkylalkoxy having four to seven decarbon atoms, alkyl alkoxy having two to eight decarbon atoms, alkyl (halogenated alkyl) amino wherein each alkyl group has one to eight C atoms, di (halogenated alkyl) aminoem wherein each alkyl group has one to eight C, (halogenated alkyl) amino atoms having one to eight C, cyano, halogenated alkyl atoms having one to eight carbon atoms, nitro, oxo, OH, alkoxycarbonylalkyl having three to eight carbon atoms, amino, monoalkylamino having one to eight C atoms, dialkylamino wherein each alkyl group has one to eight C atoms, SO 2 R 11, -CXR 11, piperidinylethyl, or combinations thereof; eR2 is H, alkyl having one to four carbon atoms, fluorinated alkyl having one to four carbon atoms, cycloalkyl having three to seven carbon atoms, cycloalkyl alkyl having four to seven carbon atoms, C1-4-C0-alkyl -fluorinated, C3-7-cycloalkyl-CO-, C1-4-alkyl-NH-CO-, C3-7-cycloalkyl-NH-CO-, Het, Ar-C1-4-alkyl-, Ar-C1-4 C1-4 alkyl-Ar-C1-4-alkyl-SO2, C1.4-alkyl-0-C1-4-alkyl- (e.g. CH2CH2-O-CH3), or Ar-C1-4-alkyl- NH-CO-. Compound according to Claim 18 or Claim 19, characterized in that at least one of X1, X2, X3 and X4 is N, and one or two of the remaining X1-X4 are CR1, at least one of X5, X6. X7 and X8 is N, and one or two of the remaining X5-X8 are CR3, at least one of X9, X10, X11 and X12 is N7 and one or two of the remaining X9-X12 are CR4; or at least one of X13i X14, X15 and X16 is N, and one or two of the remaining X13-X16 are CR. Compound according to any one of Claims 1 to 20, characterized in that A is from sub-formula (a) and is joined to the remainder of the composition by its positions 3, 4 or 7, A is from sub-formula ( b), and is joined to the remainder of the compound by its positions 4 or 7, A is of the sub-formula (c) and is joined to the remainder of the compound by its positions 3, 4 or 7, or A is of the sub-formula (d ) and is joined to the rest of the composite by its positions 3, 4 or 7. Compound according to claim 21, characterized in that said compound is of formula I. Compound according to claim 21, characterized in that said compound is of formula II. Compound according to claim 21, characterized in that said compound is of formula III. Compound according to claim 21, characterized in that said compound is of formula IV. Compound according to any one of claims 1 to 25, characterized in that A is sub-formula (a) and is joined to the remainder of the compound by its 3, 4 or 7 position. Compound according to any one of claims 1 to 25, characterized in that A is of formula (c) and is joined to the remainder of the compound by its position 3, 4 or 7. Compound according to Claim 26, characterized in that A is of sub-formula (a) and is joined to the remainder of the compound by its 3-position. Compound according to Claim 27, characterized in that A is of sub-formula (c) and is joined to the remainder of the compound by its 3-position. Compound according to Claim 21, characterized in that A is from sub-formula (a), (c), or (d) and is joined to the remainder of the compound by suppression. 31. A compound characterized in that it is in accordance with formulas I, II, III, or IV: <formula> formula see original document page 282 </formula> where <formula> formula see original document page 282 </formula> X is 0 or S, each of X1 to X4 is independently N, CH, CR1, or C-, where C- is the point of attachment of the group A of the structure of formulas (I), (II), (III) or (IV): each of X5 to X8 is independently N, CH, CR3, or C-, where C- is the point of attachment of the group A of the structure of formulas (I), ( II), (III) or (IV): each of X9 to X12 is independently N, CH, CR4, or C-, where C- is the point of attachment of group A to the remainder of the structure of formulas (I ), (II), (III) or (IV): each of X13 to X16 is independently N, CH, CR, or C-, where C- represents the point of attachment of group A to the remainder of the structure. (I), (II), (III) or (IV): R 1 is H, alkyl having one to four carbon atoms, alkyl hal which has one to four carbon atoms, cycloalkyl having three to seven carbon atoms, or cycloalkylalkyl having four to seven carbon atoms; R is H, F, Cl, Br, I, OH, CN, COH, NR6 R7, carboxy , CONR6R7, NR2COR8, NR2COOR8, NR2CSR8, NR2CONR2R9, NR2CSNR2R9, NR2SO2R10, NR2CONR6R7, NR2CSNR6R7, NR2R9, SO2R10, S1-10-C1-C6-6 -alkyl-NR6R7, NR2-C1-6-alkyl-CONR6R7, NR2-CO-C1.g-alkyl-Ar, NR2-C1-6 -Silkyl-CO-O-R2, NR2-C1-6-N2-C1. 6-alkyl-NR2 (CO-O-R2) -NR2 (CO-O-R2), -C1-6-alkyl-NR2, -0-C1.6-alkyl-NR6R7, alkyl having one to four carbon atoms , fluorinated alkyl having one to four carbon atoms, alkenyl having two to six carbon atoms, alkynyl having two to six carbon atoms, wherein the groups alkyl, fluorinated alkyl, alkenyl or alkynylation are in each case unsubstituted or substituted by Ar orHet, cycloalkyl having three to seven carbon atoms, cycloalkenyl having five to eight carbon atoms which is unsubstituted or substituted by HCO-, Cl-6-alkoxy, NR6 R7 CO-NR6 R77 C2-6 alkoxycarbonyl, or -CO-R10 cycloalkylalkyl has four to seven carbon atoms, cycloalkenylalkyl having six to nine carbon atoms, alkoxy having one to four carbon atoms, cycloalkoxy having three to seven carbon atoms, cycloalkylalkoxy having four to seven carbon atoms, alkylthio having one to four carbon atoms, fluorinated alkoxy having one to four carbon atoms, alkyl hydroxy having one to four carbon atoms, fluorinated alkyl hydroxy having one to four carbon atoms, alkoxy hydroxy having two to four carbon atoms, fluorinated alkoxy hydroxy having two to four carbon atoms, monoalkylamino having one to four carbon atoms, dialkylamino in which each alkyl group independently has one to four carbon atoms, alkoxycarbonyl having two to six carbon atoms, Ar, Het, OAr, OHet, Carbo-0, Ar-C 1-6 -alkyl H-O-, Het-C 1-6 -alkyl-O-, Het-CO-Het-, Het-C 1-6 -alkyl-NR2-, or Ar-C 1-6 -alkyl-Het-O- as long as R is not NH2; or R is one of the following formulasη ranges from 2 to 4. m ranges from 3 to 5; or two R may together form a fused five membered ring structure containing at least one N atom, R 1 is H, F, Cl, Br, I, OH, CN, nitro, NH 2, COH, NR 6 R 7, carboxy, CONR 6 R 7, NR 2 COR 8, NR2COOR8, NR2CSR8, NR2CONR2R9, NR2CSNR2R9, NR2SO2R10, NR2CONR6R7, NR2CSNR6R7, NR2R9, SO2R10, SOR10, -O- (C1-6-alkyl-0) -1-2-C1-C6-2 NR6R7, NR2-C1-6-alkyl I-CONR6R7, NR2-CO-C1-6-alkyl-Ar, NR2-C1-6-alkyl-CO-O-R2, NR2-C1-6-alkyl-NR2 (C0 -0-R2), -Cx-g-alkyl-NR2, -0-C1-6-alkyl-NR6R7, alkyl containing one to four carbon atoms, fluorinated alkyl containing one to four carbon atoms, alkenyl containing two to six carbon atoms, alkynyl containing two to six carbon atoms, wherein the alkyl, fluorinated alkyl, alkenyl or alkynyl groups are each unsubstituted or otherwise substituted by Ar or Het, cycloalkyl containing three to seven carbon atoms, cycloalkenyl containing five to eight atoms carbon, which is unsubstituted or substituted by HCO-, C 1-6 alkoxy, NR 6 R 7, CO-NR 6 R 7, C 2-6 alkoxycarbonyl, or -CO-R 10 cycloalkylalkyl containing four to seven carbon atoms, cycloalkenylalkyl containing six to nine carbon atoms, alkoxy containing one to four carbon atoms, cycloalkoxy containing three to seven carbon atoms, cycloalkylalkoxy containing four to seven carbon atoms, alkylthio containing four carbon atoms, fluorinated alkoxy containing one to four carbon atoms, hydroxy alkyl containing one to four carbon atoms, fluorinated alkyl hydroxy containing four carbon atoms, alkoxy hydroxy containing two carbon atoms, fluorinated alkoxy hydroxy containing four carbon atoms, monoalkylamino containing one four carbon atoms, dialkylamino wherein each alkyl group independently has one to four carbon atoms alkoxycarbonyl containing two to six carbon atoms, Ar, Het, OAr, OHet, Carbo-0, Ar-C1-6-alkyl-O-, Het-C1 -6-alkyl-O-, Het-CO-Het-, Het-C1-6-alkyl-NR2-, or Ar-C1-6-alkyl-Het-O-; or R1 is one of the following formulas <formula> formula see original document page 286 </formula> two R1 may together form a fused five-membered ring structure containing at least one N atom, R2 is H, alkyl containing one to four carbon atoms. carbon, fluorinated alkyl containing one to four carbon atoms, cycloalkyl containing three to seven carbon atoms, cycloalkyl alkyl containing four to seven carbon atoms, C1-4-alkyl-CO-fluorinated, C3-7-cycloalkyl-CO-, C1 -4-alkyl-NHCO-, C3-7-cycloalkyl-NH-CO-, Het, Ar-C1-4-alkyl-, Ar-C1-4-alkyl-CO-, Ar-C1-4-alkyl-SO2 -, C1-4-alkyl-O-C1-4-alkyl- (e.g. CH2 CH2 -O-CH3), Ar-C1-4-alkyl-NH-CO-, or Het-NH-CO-; R3 is H, F , Cl, Br, I, OH, CN, Nitro, NH2, COH, NR6R7, Carboxy, CONR6R7, NR2COR8, NR2COOR8, NR2CSR8, NR2CSNR2R9, NR2SO2R10, NR2CONR6R7, NR2CONR6-7, NR2CONR6 -g-alkyl-O) iz-Cx-g-alkyl, NR2-C1-6-alkyl-NR6R7, NR2 -C1-6-alkyl-CONR6R7, NR2-CO-C1-S-alkyl-1-Ar, NR2 - C1 - 6 - alkyl-CO-O-R2, NR2-C1-6-alkyl-NR2 (CO-O-R2), -C1-6-alkyl-NR2, -0-C1-6-alkyl-NR6R7, alkyl containing one to four carbon atoms, fluorinated alkyl containing one to four carbon atoms, alkenyl containing two to six carbon atoms, alkynyl containing two to six carbon atoms, wherein the alkyl, fluorinated alkyl, alkenyl or alkynyl groups are not otherwise substituted or otherwise substituted by Ar or Het, cycloalkyl containing three to seven carbon atoms, cycloalkenyl containing five to eight carbon atoms, which is unsubstituted or otherwise substituted by HCO-, C1-6-alkoxy, NR6R7, CO-NR6R7, C2 -6-alkoxycarbonyl, or -CO-R10, cycloalkylalkyl containing four to seven carbon atoms, cycloalkenylalkyl containing six to nine carbon atoms, alkoxy containing one to four carbon atoms, cycloalkoxy containing three to seven carbon atoms, cycloalkylalkoxy containing four to seven carbon atoms seven carbon atoms, alkylthio contended for four carbon atoms, fluorinated alkoxy containing one to four carbon atoms, hydroxy alkyl containing one to four carbon atoms, fluorinated alkyl hydroxy containing four carbon atoms, alkoxy hydroxy containing two to four carbon atoms, fluorinated alkoxy hydroxy containing four to four carbon atoms monoalkylamino containing one to four carbon atoms, dialkylamino wherein each alkyl group independently has one to four carbon atoms, alkoxycarbonyl containing two to six carbon atoms, Ar, Het, OAr, OHet, Carbo-O, Ar-C1 -C6 -alkyl-O-, Het-C 1-6 alkyl-O-, Het-CO-Het-, Het-C 1-6 alkyl-NR 2 -, or Ar-C 1-6 alkyl-Het-O-; or R3 is one of the following formulas <formula> formula see original document page 287 </formula> two R3 may together form a fused five-membered ring structure containing at least one N atom; R4 is H, F, Cl, Br, I , OH, CN, nitro, NH2, COH, NR6R7, carboxy, CONR6R7, NR2COR8, NR2COOR8, NR2CSR8, NR2CONR2R9, NR2CSNR2R9, NR2SO2R10, NR2CONR6R7, NR2CSNR6-N6 O6 -R6 ) ia-C1-6 alkyl, NR2-C1-S-alkyl-NR6R7, NR2-C1-S-alkyl-1-CONR6R7, NR2-CO-C1-6-alkyl, NR2-C1-6-alkyl- CO-O-R2, NR2-C1-6-alkyl-NR2 (CO-O-R2), -C1-6-alkyl-NR2, -0-C1-6-alkyl-NR6R7, alkyl containing one to four carbon atoms, alkyl fluorine containing one to four carbon atoms, alkenyl containing two to six carbon atoms, alkynyl containing two to six carbon atoms, wherein the alkyl, fluorinated alkyl, alkenyl or alkynyl groups are in each case unsubstituted or substituted by Ar or Het, cycloalkyl containing three to seven carbon atoms, cycloalkenyl containing five to eight carbon atoms, which is unsubstituted or substituted by HCO-, Ca-e-alkoxy, NR6R7, CO-NR6R7, C2-6-alkoxycarbonyl, or -CO-R10 cycloalkylalkyl containing four seven to seven carbon atoms, cycloalkenylalkyl containing six to nine carbon atoms, alkoxy containing one to four carbon atoms, cycloalkoxy containing three to seven carbon atoms, cycloalkylalkoxy containing four to seven carbon atoms, alkylthio containing one to four carbon atoms, alkoxyfluoride containing one to four carbon atoms, hydroxyalkyl containing one to four carbon atoms, fluorinated hydroxyalkyl containing one to four carbon atoms, alkoxy hydroxy containing two to four carbon atoms, fluorinated alkoxy hydroxy containing two to four carbon atoms, monoalkylamino containing one to four carbon atoms to four carbon atoms, dialkylamino wherein each alkyl group independently has one to four carbon atoms, al carbon dioxide containing two to six carbon atoms, Ar, Het, OAr, OHet, Carbo-O, Ar-C 1-6 -alkyl-O-, Het-C 1-6 -alkyl-O, Het-CO-Het-, Het-C 1-6 alkyl-NR 2 -, or Ar-C 1-6 alkyl-Het-O-; or R4 is one of the following five membered fused ring formulas containing at least one N atom; <formula> formula see original document page 288 </formula> two R4 may together form a structure of R5 is F, F, Cl, Br, I , OH, CN, nitro, NH2, carboxy, CONR6R7, NR2COR8, NR2CSR8, NR2CONR2R9, NR2CSNR2R9, NR2SO2R10, NR2CONRsR7, NR2CSNR6R7, NR2R9, one carbon atoms containing four alkyl atoms, S02R10, NR2C6, NR2 alkyl, carbon atoms. alkenyl containing two to six carbon atoms, alkynyl containing two to six carbon atoms, wherein the alkyl, fluorinated alkyl, alkenyl or alkynyl groups are in each case unsubstituted or then substituted by Ar or Het, cycloalkyl containing three to seven carbon atoms, cycloalkenyl containing five eighteen carbon atoms which is unsubstituted or then substituted by HCO-, C1-6 alkoxy, NR6R7, CO-NR6R7, C2.6-alkoxycarbonyl, or -CO-R10 cycloalkylalkyl containing four sides carbon atoms, cycloalkenylalkyl containing six to nine carbon atoms, alkoxy containing one to four carbon atoms, cycloalkoxy containing three to seven carbon atoms, cycloalkylalkoxy containing four to seven carbon atoms, alkylthio containing one to four carbon atoms, alkoxyfluoride containing one to four carbon atoms, hydroxyalkyl containing one to four carbon atoms, fluorinated hydroxyalkyl containing one to four carbon atoms, alkoxy hydroxy containing two to four carbon atoms, fluorinated alkoxy hydroxy containing two to four carbon atoms, monoalkylamino containing one to four carbon atoms four carbon atoms, dialkylamino wherein each alkyl group independently has one to four carbon atoms, alkoxycarbonyl containing two to six carbon atoms, Ar, Het, OAr or OHet, each of R 6 and R 7 is independently H, alkyl containing one to four carbon atoms, alkoxyalkyl containing two to eight carbon atoms, cycloalkyl contains endotres to seven carbon atoms; or cycloalkylalkyl containing four to seven carbon atoms, or R 6 and R 7 are together an alkylene group containing four to six carbon atoms forms a ring with the atom of N; R 8 is H, alkyl containing one to four carbon atoms, fluorinated alkyl containing one to six carbon atoms. four carbon atoms, alkenyl containing three to six carbon atoms, alkynyl containing three to six carbon atoms, wherein the alkyl, fluorinated alkyl, alkenyl or alkynyl groups are in each case unsubstituted or substituted by Ar or Het, cycloalkyl containing three to seven decarbonyl atoms, cycloalkenyl containing five to eight decarbonyl atoms, cycloalkylalkyl containing four to seven decarbonyl atoms, cycloalkenylalkyl containing six to nine decarbonyl, hydroxyalkyl containing one to four decarbonyl atoms, fluorinated alkyl hydroxy containing one to four carbon atoms, monoalkylamino four carbon atoms, dialkylamino wherein each alkyl group bark independently one to four carbon atoms, Ar, or Het; R 9 is alkyl having one to four carbon atoms, Ar, Ar-alkyl wherein the alkyl moiety has one to four carbon atoms, or Het; R 10 is alkyl containing one to four carbon atoms, fluorinated alkyl containing one to four carbon atoms, alkenyl containing three to six carbon atoms, alkynyl containing three to six carbon atoms, wherein the groups alkyl, fluorinated alkyl, alkenyl or alkynylation are in each case unsubstituted or then substituted by Ar or Het, cycloalkyl containing three to seven carbon atoms, cycloalkenyl containing five to eight carbon atoms, cycloalkylalkyl containing four to seven carbon atoms, cycloalkenylalkyl containing six to nine carbon atoms, hydroxyalkyl containing two to four carbon atoms, hydroxyalkyl containing two to four carbon atoms, monoalkylamino containing one to four carbon atoms, dialkylamino wherein each alkyl group independently has one to four carbon atoms, NR6 R7, NR2 R8, Ar, or Het; Ar is an aryl group having six to ten carbon atoms that is unsubstituted or substituted one or more times by alkyl having one to eight carbon atoms. C 1-6 alkoxy containing one to eight C atoms, halogen, dialkylamino wherein each alkyl moiety has one to eight C atoms, amino, cyano, hydroxyl, nitro, halogenated alkyl having one to eight C atoms, halogenated alkoxy containing one to eight atoms C, hydroxy alkyl containing one to eight C atoms, hydroxy alkoxy having two to eight C atoms, alkenyloxy has three to eight C atoms, alkylthio having one to eight C atoms, alkylsulfinyl having one to eight atoms of C, alkylsulfonyl having one to eight C atoms, monoalkylamino having one to eight C atoms, cycloalkylamino wherein the cycloalkyl group has three to seven C atoms and is optionally substituted by alkyl having one to four carbon atoms bono, alkoxy containing one to four carbon atoms, hydroxyl, amino, monoalkylamino having one to four carbon atoms, dialkylamino wherein each alkyl group has one to four carbon atoms, or combinations thereof, aryloxy wherein the aryl moiety has six atoms carbon and is optionally substituted by halogen, alkyl having one to eight carbon atoms, hydroxy, alkoxy containing one to eight carbon atoms, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino having one eighteen carbon atoms, dialkylamino where each alkyl group having one to eight carbon atoms, hydroxy alkyl containing one to eight carbon atoms, alkoxy hydroxy having one to eight carbon atoms, carboxy, cyano, acyl, alkoxycarbonyl wherein the alkoxy group has one to eight carbon atoms, alkylthio, alkylsulfinyl which has one to eight carbon atoms, alkylsulfonyl having one to eight carbon atoms, phenoxy, acyloxy, or combinations thereof, arylthio The aryl moiety has six to ten carbon atoms and is optionally substituted by halogen, alkyl having one to eight carbon atoms, hydroxy, alkoxy containing one to eight carbon atoms, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino having one to eight carbon atoms. carbon, dialkylamino wherein each alkyl group has one to eight carbon atoms, hydroxy alkyl having one to eight carbon atoms, alkoxy hydroxy having one to eight carbon atoms, carboxy, cyano, acyl, carbonyl alkoxy wherein the alkoxy group has one to eight carbon atoms eight carbon atoms, alkylthio, alkylsulphinyl having one to eight carbon atoms, alkylsulphonyl having one to eight carbon atoms, phenoxy, or acyloxy, or combinations thereof, cycloalkyloxy wherein the group cycloalkyl has three to seven C atoms and is optionally substituted. per alkyl having one to four carbon atoms, alkoxy containing one to four carbon atoms, hydroxy, amino, monoalkylamino having one to four carbon atoms carbon, dialkylamino wherein each alkyl group has four carbon atoms, or combinations thereof, sulfo, sulfonylamino, acylamido, acyloxy, or combinations thereof, Het is a heterocyclic group which is fully saturated, partially saturated or fully unsaturated containing five to ten ring atoms wherein at least one ring atom is a Ν, O or S atom, which is unsubstituted or substituted one or more times by halogen, aryl having six to ten carbon atoms which is optionally substituted by halogen, alkyl having one to eight carbon atoms, hydroxy, alkoxy containing one to eight carbon atoms, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino having one to eight carbon atoms, dialkylamino wherein each alkyl group has one to eight atoms carbon, hydroxy alkyl containing one to eight carbon atoms, hydroxy alkoxy having one to eight carbon atoms, carboxy, cyano, acyl, carbonyl alkoxy wherein the alkoxy group One to eight carbon atoms, alkylthio, alkylsulfinyl having one to eight carbon atoms, alkylsulfonyl having one to eight carbon atoms, phenoxy, acyloxy, or combinations thereof, alkyl having one to eight C atoms, alkoxy containing one to eight carbon atoms eight C atoms, cycloalkyl having three to seven carbon atoms, cycloalkyl alkyl having four to seven carbon atoms, halogenated alkoxy containing eight C atoms, cycloalkoxy having three to seven carbon atoms, cycloalkylalkoxy having four to seven carbon atoms, alkyl alkoxy having from two to eight carbon, alkyl (halogenated alkyl) amino atoms wherein each alkyl group has one to eight C, di (alkylhalogenated) amino atoms where each alkyl group has one to eight halogenated C (alkyl) amino atoms which has one to eight C, cyano, halogenated alkyl atoms which have one to eight carbon atoms, nitro, oxo, OH, alkoxy carbonyl alkyl which has three to eight carbon atoms, amino, monoalkylamino which has one to eight C atoms, dialkylamino wherein each alkyl group has one to eight atoms of C, SO 2 R 11, -CXR 11, piperidinylethyl, or combinations thereof; Carbo is a partially unsaturated carbocyclic group having five to fourteen carbon atoms, which is unsubstituted or substituted one or more times by halogen, alkyl having one to eight C atoms, alkoxy containing one to eight C atoms, hydroxy, nitro, cyano, oxo, or combinations thereof; eR11 is alkyl containing one to four carbon atoms, halogenated alkyl containing one to four carbon atoms, alkenyl containing three to six carbon atoms, alkynyl containing three to six carbon atoms, wherein the groups alkyl, halogenated alkyl, alkenyl or alkynyl are each unsubstituted or else substituted by Ar or Het, cycloalkyl containing three to seven carbon atoms, cycloalkenyl containing five to eight carbon atoms, cycloalkylalkyl containing four to seven carbon atoms, cycloalkenylalkyl containing six to nine carbon atoms, hydroxy alkyl containing two fluorinated alkyl hydroxy containing two to four carbon atoms, monoalkylamino containing one to four carbon atoms, dialkylamino wherein each alkyl group independently has one to four carbon atoms, or Ar, and their salts or solvates or N- pharmaceutically acceptable oxides, or solvates of their pharmaceutically acceptable salts, or pharmaceutically acceptable salts or solvates of their N-oxides, wherein said compound may also be in the form of a polymorph, wherein if said compound exhibits chirality it may be in the form of a mixture of enantiomers or a mixture of diastereomers, or may be in the form of a single enantiomer or single diastereomer, provided that the 1-azabicyclic group is in the form of a quaternary ammonium salt of the sub-formula: wherein Z is alkyl having one to four carbon atoms, halogenated alkyl having a to four carbon atoms, cycloalkylalkyl having four to seven carbon atoms, or arylalkyl having seven to sixteen carbon atoms, and anion A is iodide, bromide, chloride, triflate, tosylate, ormesylate.31. Compound according to claim 30, characterized in that A is of formula (a) or (c). Compound according to claim 31, characterized in that each of X1 to X4 is CH or CR1, or each of X9 to X12 is CH or CR4. Compound according to any one of claims 1 to 32, characterized in that X is 0. A compound according to any one of claims 1 to 33, wherein R 1 is H, cyclopropylmethyl, or CH 3. 35. Compound, characterized in that it is selected from: -1) (3S) -3 - ({[6- (Cyclopropylmethoxy) -1,2-benzisothiazol-3-yl] carbonyl} amino) -1-bromide or formate - (cyclopropylmethyl) -1-azoniabicyclo [2.2.2] octane, -2) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-methoxypyrrolidin-1 - yl) -1,2-benzisothiazol-3-carboxamide, -3) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5,6-dimethoxy-1H-indazol hydroformate -3-carboxamide, -4) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-propyl-6- (1,3-thiazol-2-yl) -1H- indazol-3-carboxamide, -5) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-isopropyl-6- (1,3-thiazol-2-yl) -1H -indazol-3-carboxamide, -6) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (tetrahydrofuran-3-yloxy) -1H-indazol-3-hydroformate carboxamide, -7) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (tetrahydro-2H-pyran-4-yloxy) -1H-indazol-3-carboxamide hydroformate , -8) N - [(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -6 - [(1-methylpyrrolidin-3-yl) oxy] -1H-indazol-3-carboxamide hydroformate , -9) N - [(3S) hydroformate -1-azabicyclo [2.2.2] oct-3-yl] -4-hydroxy-1H-indazol-3-carboxamide, - 10) N - [(3S) -1-azabicyclo [2.2.2] octane hydroformate 3-yl] -5-bromo-4-hydroxy-1H-indazol-3-carboxamide, - 11) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5 hydroformate 7-dibromo-4-hydroxy-1H-indazol-3-carboxamide, - 12) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5-hydroxy-1 hydroformate, 2-benzisothiazol-3-carboxamide, - 13) (3S) -3 - {[(5-hydroxy-1,2-benzisothiazol-3-yl) carbonyl] amino} -1-methyl-1-azoniabicyclic iodide or formate [2.2.2] octane, - 14) N - [(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -6- (3-furylmethoxy) -1,2-benzisothiazole-3-hydroformate carboxamide, - 15) N - [(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -1-ethyl-6- (2-oxopyrrolidin-1-yl) -1H-indazol-3 hydroformate 16) N - [(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -7-hydroxy-1H-indazol-3-carboxamide hydroformate, - 17) N- [Hydroformate (3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-methoxy-N-methyl-1H-indazol-3-carboxamide, - 18) N - [(3S) -1-azabicyclohydroformate [2.2.2] oct-3-yl] -1-methyl-6 - {[(propylamino) carbonyl] amino} -1H-indazol-3-carboxamide, - 19) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] - 1-ethyl-6-methoxy-1H-indazol-3-carboxamide, - 20) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -1-ethyl-6-methoxy-1H -indazol-3-carboxamide, - 21) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1- (difluoromethyl) -6-methoxy-1H-indazol-3-carboxamide , - 22) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1- (difluoromethyl) 6- (1,3-thiazol-2-yl) -1H-indazol-2-one 3-carboxamide, - 23) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(cyclopropylcarbonyl) amino] -1-methyl-1H-indazol-3-hydroformate carboxamide, -24) N - [(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -6 - [(cyclopropylcarbonyl) amino] -1- (difluoromethyl) -1H-indazol-3 hydroformate -carboxamide, -25) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1- (difluoromethyl) -6 - {[(propylamino) carbonyl] amino} -1H hydroformate -indazol-3-carboxamide, -26) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-cyclopropyl-6- (1,3-thiazol-2-yl) -IH-indazol-3-carboxamide, -27) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1,3-thiazol-2-yl) -1- (3-thienyl) -1H-indazol-3-carboxamide, -28) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -N-methyl-6- (1,3-oxazol-2-yl) -1H-indazol-3-carboxamide, -29) N - [(3S) -1-azabicyclo [2.2.2 ] oct-3-yl] -N-methyl-6- (1,3-thiazol-2-yl) -1H-indazol-3-carboxamide, -30) N - [(3S) -1-azabicyclo [2.2. 2] oct-3-yl] -1-ethyl-6- (1,3-oxazol-2-yl) -1H-indazol-3-carboxamide, -31) N - [(3S) -1-azabicyclo [2.2 .2] oct-3-yl] -1- (cyclopropylmethyl) -6- (1,3-oxazol-2-yl) -1H-indazol-3-carboxamide, -32) N - [(3S) -1- azabicyclo [2.2.2] oct-3-yl] -6- (1,3-oxazol-2-yl) -1-propyl-1H-indazol-3-carboxamide, -33) N - [(3S) -1 -azabicyclo [2.2.2] oct-3-yl] -1-ethyl-N-methyl-6- (1,3-oxazol-2-yl) -1H-indazol-3-carboxamide, -34) N- [ (3S) -1-azabicyclo [2.2.2] oct-3-yl] -N-methyl-6- (tetrahydro-2H-pyran-4-yl) -1H-indazol-3-carboxamide, -35) N- [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -N-methyl-5- (tetrahydro-2H-pyran-4-yl) -1H-indazol-3-carboxamide, -36) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5- (difluoromethoxy) -N-methyl-1H-indazol-3-carboxamide, -37) N - [(3S) - 1-azabici clo [2.2.2] oct-3-yl] -6- (difluoromethoxy) -N-methyl-1H-indazol-3-carboxamide, -38) N - [(3S) -1-azabicyclo [2.2.2] oct -3-yl] -1-cyclopropyl-6 - [(cyclopropylcarbonyl) amino] -1H-indazol-3-carboxamide, 39) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-cyclopropyl-6 - {[(propylamino) carbonyl] amino} -1H-indazol-3-carboxamide, -40) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] - 5-Methoxy-N-methyl-1H-indazol-3-carboxamide, -41) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(4S) - hydroformate 4-hydroxy-2-oxopyrrolidin-1-yl] -1H-indazol-3-carboxamide, -42) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -5-hydroformate methoxy-N-methyl-1H-indazol-3-carboxamide, -43) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -5- (difluoromethoxy) -N- methyl-1H-indazol-3-carboxamide, -44) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (difluoromethoxy) -N-methyl-1H-hydroformate indazol-3-carboxamide, -45) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -N-methyl-6- (tetrahydro-2H-pyran-4-yl) hydroformate -IH-indazole-3-carboxamide, -46) N - [(3R) - hydroformate 1-azabicyclo [2.2.2] oct-3-yl] -N-methyl-5- (tetrahydro-2H-pyran-4-yl) -1H-indazol-3-carboxamide, -47) N - [( 3R) -1-azabicyclo [2.2.2] oct-3-yl] -N-methyl-6- (1,3-thiazol-2-yl) -1H-indazol-3-carboxamide, -48) N hydroformate - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-methoxy-N-methyl-1,2-benzisothiazol-3-carboxamide, -49) N - [(3S) hydrochloride -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-methoxypyrrolidin-1-yl) -1,2-benzisothiazol-3-carboxamide, -50) N - [(3S) -1- azabicyclo [2.2.2] oct-3-yl] -6-hydroxy-1,2-benzisothiazol-3-carboxamide, -51) N - [(3R) -1-azabicyclo [2.2.2] oct-3 hydrochloride -yl] -6-methoxy-1,2-benzisothiazol-3-carboxamide, -52) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-methoxy-1 hydrochloride , 2-benzisothiazol-3-carboxamide, -53) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7-methoxy-1,2-benzisothiazole-3-carboxamide hydrochloride, - 54) N - [(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -6- (2-oxo-3-propylimidazolidin-1-yl) -1,2-benzisothiazole-3 hydrochloride 55) N - [(3S) -1-oxide-1-azabicyclo [2.2.2] oct-3-yl ] -5- (trifluoromethoxy) -1H-indazol-3-carboxamide, - 56) 6-Methoxy-N - [(3S) -1-oxido-1-azabicyclo [2.2.2] oct-3-yl] - 1,2-benzisothiazol-3-carboxamide, - 57) N - [(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -6-fluoro-1H-pyrazolo [3,4-b] hydroformate ] pyridine-3-carboxamide, - 58) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- [3- (cyclopropylmethoxy) pyrrolidin-1-yl] -1H hydroformate -indazol-3-carboxamide, -59) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1H-pyrazolo [4,3-c] pyridine-3-carboxamide, -60 ) N - [(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -1H-pyrazolo [3,4-c] pyridine-3-carboxamide hydroformate, - 61) N - [( 3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- [3- (cyclopropylmethoxy) pyrrolidin-1-yl] -1H-indazol-3-carboxamide, - 62) N - [( 3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-methoxypyrrolidin-1-yl) -1H-indazol-3-carboxamide, - 63) N - [(3R) - hydroformate 1-azabicyclo [2.2.2] oct-3-yl] -6- (2-oxo-3-propylimidazolidin-1-yl) -1H-indazol-3-carboxamide, - 64) N - [(3S) -1 -azabicyclo [2.2.2] oct-3-yl] -6-pyrrolidin-1 H 1-- 1,2-benzisothiazol-3-carboxamide, - 65) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-methyl-2-oxopyrrolidin-1 -yl) -1,2-benzisothiazol-3-carboxamide, - 66) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (β-pyrrol-1-yl) ) - 1,2-benzisothiazol-3-carboxamide, - 67) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-ethyl-2-oxoimidazolidin-1 -yl) -1,2-benzisothiazole-3-carboxamide, -68) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- [3- (cyclopropylmethoxy) pyrrolidin-1 -yl] -1,2-benzisothiazol-3-carboxamide, -69) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-methoxypyrrolidin-1-yl) -1,2-benzisoxazol-3-carboxamide, -70) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7- (3-methoxypyrrolidin-1-yl) -1, 2-benzisothiazol-3-carboxamide, -71) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-methoxy-1,2-benzisoxazol-3-carboxamide-72 hydrochloride ) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-methoxypyrrolidin-1-yl) -1,2-benzisothiazole-3-carboxamide, -73) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -1-ethyl-6- (1,3-oxazol-2-yl) -1H-indazol-3-carboxamide , -74) N - [(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -1-ethyl-6- (1,3-oxazol-2-yl) -1H-indazol-hydrochloride 3-carboxamide, -75) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(3R) -3-methoxypyrrolidin-1-yl] -1,2- benzisothiazol-3-carboxamide, -76) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(3S) -3-methoxypyrrolidin-1-yl] -1, 2-benzisothiazol-3-carboxamide, -77) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (2-β-3-propylimidazolidin-1-yl) -1H - indazol-3-carboxamide, -78) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-hydroxypyrrolidin-1-yl) -1,2-benz isot iazol-3-carboxamide, -79) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- [3- (difluoromethoxy) pyrrolidin-1-yl] -1,2- benzisothiazol-3-carboxamide, -80) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1H-imidazol-1-yl) -1,2-benzisothiazole-3 -81 carboxamide, -81) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1H-pyrazol-1-yl) -1,2-benzisothiazole-3-carboxamide, -82) N - [(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -6- (3-methyl-1H-pyrazol-1-yl) -1,2-benzisothiazole-3-carboxamide , - 83) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (5-methyl-1H-pyrazol-1-yl) -1,2-benzisothiazole-3-carboxamide, - 84) N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -6 - [(3R) -3-methoxypyrrolidin-1-yl] -1,2-benzisothiazole-3-carboxamide , - 85) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] - 6 - [(3S) -3-methoxypyrrolidin-1-yl] -1,2-benzisothiazol-3-one carboxamide, - 86) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-methoxy-1,2-benzisoxazol-3-carboxamide, - 87) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-ethoxypyrrolidin-1-yl) -7-fluoro-1,2-benzisothiazol-3-carboxamide, - 88) N - [(3S ) -1-azabicyclo [2.2.2] oct-3-yl] -6-phenyl-1H-pyrazolo [3,4-b] pyridine-3-carboxamide, - 89) N - [(3R) -1-azabicyclo [2.2. 2] oct-3-yl] -6- (4,5-dihydro-1H-imidazol-2-yl) -1H-indazol-3-carboxamide, - 90) N - [(3S) -1-azabicyclo [2.2 .2] oct-3-yl] -6- [3- (dimethylamino) pyrrolidin-1-yl] -1H-pyrazolo [3,4-b] pyridine-3-carboxamide, -91) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- [3- (dimethylamino) pyrrolidin-1-yl] -1H-pyrazolo [3,4-b] pyridine-3-carboxamide, -92) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-fluoro-6- (3-methoxypyrrolidin-1-yl) -1,2-benzisothiazol-3-carboxamide, - 93 ) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7-fluoro-6- (3-methoxypyrrolidin-1-yl) -1,2-benzisothiazol-3-carboxamide, - 94) N - [(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -6 - [(3R) -3-hydroxypyrrolidin-1-yl] -1,2-benzisothiazol-3-carboxamide 95) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(3S) -3-hydroxypyrrolidin-1-yl] -1,2-benzisothiazole-3-one carboxamide, - 96) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(3S) -3- (dimethylamino) pyrrolidin-1-yl] -1,2- benzisothiazol-3-carboxamide, -97) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(1S, 4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl] -1,2-benzisothiazol-3-carboxamide, -98) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(3R) -3-hydroxypyrrolidin-1-yl] -1,2-benzisothiazol-3-carboxamide, -99) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] - 6 - [(3S) -3-hydroxypyrrolidin-1-yl] -1,2-benzisothiazol-3-carboxamide, -100) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(3S) -3- (dimethylamino) pyrrolidin-1-yl] -1,2-benzisothiazole-3-carboxamide, -101) N - [(3S) -1-azabicyclo [2.2.2] oct 3-yl] -7 - [(3R) -3-hydroxypyrrolidin-1-yl] -1,2-benzisothiazol-3-carboxamide, -102) N - [(3S) -1-azabicyclo [2.2.2] oct -3-yl] -7 - [(3S) -3-hydroxypyrrolidin-1-yl] -1,2-benzisothiazol-3-carboxamide, -103) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7 - [(3S) -3- (dimethylamino) pyrrolidin-1-yl] -1,2-benzisothiazol-3-carboxamide, -104) N - [(3S) -1-azabicyclo [ 2.2.2] oct-3-yl] -7 - [(1S, 4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl] -1,2-benzisothiazole-3-carboxamide, -105) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7 - [(3S) -3- (dimethylamino) pyrrolidin-1-yl] -1,2-benzisothiazol-2-one 3-carbo xamide, -106) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] isothiazolo [5,4-b] pyridine-3-carboxamide hydroformate, -107) N- [hydroformate (3R) -1-azabicyclo [2.2.2] oct-3-yl] isothiazolo [5,4-b] pyridine-3-carboxamide, -108) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(3R) -3-methoxypyrrolidin-1-yl] -1,2-benzisoxazol-3-carboxamide, -109) N - [(3S) -1-azabicyclo [2.2. 2] oct-3-yl] -6 - [(3S) -3-methoxypyrrolidin-1-yl] -1,2-benzisoxazol-3-carboxamide, -110) N - [(3R) -1-azabicyclohydroformate [2.2.2] oct-3-yl] -7 - [(3R) -3-methoxypyrrolidin-1-yl] -1,2-benzisothiazol-3-carboxamide, -111) N - [(3R) -1- azabicyclo [2.2.2] oct-3-yl] -7 - [(3S) -3-methoxypyrrolidin-1-yl] -1,2-benzisothiazol-3-carboxamide, -112) N - [(3S) hydroformate -1-azabicyclo [2.2.2] oct-3-yl] -7 - [(3R) -3-methoxypyrrolidin-1-yl] -1,2-benzisothiazol-3-carboxamide, -113) N- [Hydroformate (3S) -1-azabicyclo [2.2.2] oct-3-yl] -7 - [(3S) -3-methoxypyrrolidin-1-yl] -1,2-benzisothiazol-3-carboxamide, -114) N- C (3 S) -1-azabicyclo [2.2.2] oct-3-yl] -7-fluoro-6-methoxy-1 , 2-benzisothiazol-3-carboxamide, -115) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-fluoro-6-methoxy-1,2-benzisothiazol-3-one carboxamide, -116) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] -1,2-benzisothiazol-3-carboxamide, -117) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(1S, S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] -1,2-benzisothiazol-3-carboxamide, -118) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(1S, 4S) -2,5-diazabicyclo [2.2.1] hept-2-yl] -1,2-benzisothiazol-3-carboxamide, -119) N- [ (3S) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(1S, 4S) -2,5-diazabicyclo [2.2.1] hept-2-yl] -1,2- benzisothiazol-3-carboxamide, -120) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- [3- (methylamino) pyrrolidin-1-yl] -1,2- benzisothiazol-3-carboxamide, -121) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] 6- [3- (methylamino) pyrrolidin-1-yl] -1,2- benzisothiazol-3-carboxamide, -122) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(1S, 4S) -5- (2,2,2-trifluoroethyl ) -2,5-diazabicyclo [2.2.1] hept-2- yl] -1,2-benzisothiazol-3-carboxamide, -123) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- {3- [methyl (2,2, 2-trifluoroethyl) amino] pyrrolidin-1-yl} -1,2-benzisothiazol-3-carboxamide, - 124) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- {3- [Methyl (2,2,2-trifluoroethyl) amino] pyrrolidin-1-yl} -1,2-benzisothiazol-3-carboxamide, -125) N - [(3S) -1-azabicyclo [2.2.2 ] oct-3-yl] 6- [3- (methoxymethyl) pyrrolidin-1-yl] -1,2-benzisothiazol-3-carboxamide, - 126) N - [(3R) -1-azabicyclo [2.2.2 ] oct-3-yl] 6- [3- (methoxymethyl) pyrrolidin-1-yl] -1,2-benzisothiazol-3-carboxamide, - 127) N - [(3R) -1-azabicyclo [2.2.2 ] oct-3-yl] -6 - [(3R) -3- (dimethylamino) pyrrolidin-1-yl] -1,2-benzisothiazol-3-carboxamide, -128) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(3R) -3- (dimethylamino) pyrrolidin-1-yl] -1,2-benzisothiazol-3-carboxamide, -129) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] - 6- [4- (dimethylamino) piperidin-1-yl] -1,2-benzisothiazol-3-carboxamide, - 130) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- [4- (dimethylamino) piperidin-1-yl] -1,2-benzisothiazole-3-carboxy amide, - 131) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (2-OXO-3-propylimidazolidin-1-yl) -1,2-benzisothiazole-3 - carboxamide, - 132) N - [(3S) -1-azabicyclo [2.2.2 dihydroformate]. 2] oct-3-yl] -N-methyl-6 - [(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] -1,2-benzisothiazol-3 N-[(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -N-methyl-6 - [(1S, 4S) -5-methyl-2,5-dihydroformate -diazabicyclo [2.2.1] hept-2-yl] -1,2-benzisothiazol-3-carboxamide, -134) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(IR, 4R) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] -1,2-benzisothiazole-3-carboxamide, -135) N - [(3S) -1 -azabicyclo [2.2.2] oct-3-yl] -6 - [(IR, 4R) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] -1,2-benzisothiazole-2-one 3-carboxamide, -136) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] 6- (1,4-diazabicyclo [3.2.2] ηοη-4-yl) dihydroformate -1,2-benzisothiazole-3-carboxamide, -137) N - [(3S) -1-Azabicyclo [2.2.2] oct-3-yl] 6- (1,4-diazabicyclo [3.2.2] dihydroformate ] ηοη-4-yl) -1,2-benzisothiazol-3-carboxamide, -138) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-pyrrolidin-1-yl -1,2-benzisothiazol-3-carboxamide, -139) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (4-methylpiperazin-1-yl) -1 2,2-benzisothiazole -3-carboxamide, -140) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (4-methylpiperazin-1-yl) -1,2-benzisothiazole-3 carboxamide, -141) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (4-methyl-1,4-diazepan-1-yl) -1,2- benzisothiazol-3-carboxamide, -142) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (4-methyl--1,4-diazepan-1-yl) - 1,2-benzisothiazol-3-carboxamide, -143) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (hexahydropyrrolo [1,2-a] pyrazin-2 ( 1H) -yl) -1,2-benzisothiazol-3-carboxamide, -144) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (hexahydropyrrolo [1,2- a] pyrazin-2 (1H) -yl) -1,2-benzisothiazole-3-carboxamide, -145) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- ( 5-methyl-2,5-diazabicyclo [2.2.2] oct-2-yl) -1,2-benzisothiazol-3-carboxamide, -146) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (5-methyl-2,5-diazabicyclo [2.2.2] oct-2-yl) -1,2-benzisothiazol-3-carboxamide, -147) N - [(3R ) -1-azabicyclo [2.2.2] oct-3-yl] -6- (8-methyl-3,8-diazabicyclo [3.2.1] oct-3-yl) -1,2-benzisothiazole-3-one carboxamide, -148) N - [(3S) -1-azabicyclo [2.2.2] oct-3-i 1] -6- (8-methyl-3,8-diazabicyclo [3.2.1] oct-3-yl) -1,2-benzisothiazole-3-carboxamide, -149) N - [(3R) -1- azabicyclo [2.2.2] oct-3-yl] -6 - [(1S, 4S) -5-cyclopropyl-2,5-diazabicyclo [2.2.1] hept-2-yl] -1,2-benzisothiazole-3 -carboxamide, -150) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(1S, 4S) -5-cyclopropyl-2,5-diazabicyclo [2.2.1 ] hept-2-yl] -1,2-benzisothiazol-3-carboxamide, -151) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(1S, 4S ) -5- (cyclopropylmethyl) -2,5-diazabicyclo [2.2.1] hept-2-yl] -1,2-benzisothiazole-3-carboxamide, -152) N - [(3S) -1-azabicyclo [2.2 .2] oct-3-yl] -6 - [(1S, 4S) -5- (cyclopropylmethyl) -2,5-diazabicyclo [2.2.1] hept-2-yl] -1,2-benzisothiazole-3 carboxamide, -153) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5- (4-methyl-1,4-diazepan-1-yl) -1,2- benzisothiazol-3-carboxamide, -154) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -5 - [(3R) -3-methoxypyrrolidin-1-yl] -1,2 -benzisothiazol-3-carboxamide, -155) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5 - [(3R) -3-methoxypyrrolidin-1-yl] -1, 2-benzisothiazole-3-carboxamide, -156) N - [(3R) - 1-azabicyclo [2.2.2] oct-3-yl] -5 - [(3S) -3-methoxypyrrolidin-1-yl] -1,2-benzisothiazol-3-carboxamide, -157) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(1-methylpyrrolidin-3-yl) oxy] -1,2-benzisothiazol-3-carboxamide, - 158) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(1-methylpyrrolidin-3-yl) oxy] -1,2-benzisothiazol-3-carboxamide, - 159) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1-azabicyclo [2.2.2] oct-3-yloxy) -1,2-benzisothiazol-3-carboxamide, -160) N- [ (3S) -1-azabicyclo [2.2.2] oct-3-yl] 6- (1-azabicyclo [2.2.2] oct-3-yloxy) -1,2-benzisothiazole-3-carboxamide, - 161) Δ, N'-di- (3S) -1-azabicyclo [2.2.2] oct-3-yl-1H-indazol-1,3-dicarboxamide, - 162) N - [(3R) -1-azabicyclo [2.2 .2] oct-3-yl] -6- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -1H-indazol-3-carboxamide, -163) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -1H-indazol-3-carboxamide, -164) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5 - [(3S) -3- (cyclopropylmethoxy) pyrrolidin-1-yl] -1H-indazol-3-carboxamide, - 165) Chloride (3S) -1- (chloromethyl) -3 - [(1H-indazol-3-ylcarbonyl) amino] -1-azoniabicyclo [2.2.2] octane, - 166) N - [(3S) -1-azabicyclo dihydroformate [2.2.2] oct-3-yl] -5 - [(3S) -3-methoxypyrrolidin-1-yl] -1H-indazol-3-carboxamide, - 167) N - [(3S) -1-azabicyclo [ 2.2.2] oct-3-yl] -6-chloroisothiazolo [5,4-b] pyridin-3-carboxamide, - 168) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl ] -6- (3-methylpiperazin-1-yl) -1,2-benzisothiazol-3-carboxamide, -169) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6 - (octahydro-6H-pyrrolo [3,4-b] pyridin-6-yl) -1,2-benzisothiazole-3-carboxamide, - 170) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (octahydro-6H-pyrrolo [3,4-b] pyridin-6-yl) -1,2-benzisothiazol-3-carboxamide, -171) N - [(3S) - 1-azabicyclo [2.2.2] oct-3-yl] -6-piperazin-1-yl-1,2-benzisothiazol-3-carboxamide, -172) N - [(3R) -1-azabicyclo [2.2.2 ] oct-3-yl] -6-piperazin-1-yl-1,2-benzisothiazol-3-carboxamide, -173) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1,4-diazepan-1-yl) -1,2-benzisothiazol-3-carboxamide, -174) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] - 6- (1,4-diazep an-1-yl) -1,2-benzisothiazol-3-carboxamide, -175) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (2-methylpiperazin-1 -1yl) -1,2-benzisothiazol-3-carboxamide, -176) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (2-methylpiperazin-1-yl) -1,2-benzisothiazol-3-carboxamide, -177) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- [4- (cyclopropylcarbonyl) piperazin-1-yl] -1,2-benzisothiazol-3-carboxamide, -178) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- [4- (cyclopropylcarbonyl) piperazin-1-yl] -1,2-benzisothiazol-3-carboxamide, -179) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- [1- (cyclopropylcarbonyl) octahydro-6H-pyrrolo [ 3,4-b] pyridin-6-yl] -1,2-benzisothiazol-3-carboxamide, -180) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [1- (cyclopropylcarbonyl) octahydro-6H-pyrrolo [3,4-b] pyridin-6-yl] -1,2-benzisothiazol-3-carboxamide, -181) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(1S, 4S) -5- (cyclopropylcarbonyl) -2,5-diazabicyclo [2.2.1] hept-2-yl] -1,2-benzisothiazole -3-carboxamide, -182) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(1S, 4S) -5 - (cyclopropylcarbonyl) -2,5-diazabicyclo [2.2.1] hept-2-yl] -1,2-benzisothiazole-3-carboxamide, -183) N - [(3R) -1-azabicyclo [2.2.2 ] oct-3-yl] -6- (3,4-dimethylpiperazin-1-yl) -1,2-benzisothiazol-3-carboxamide, - 184) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-cyano-1H-indazol-3-carboxamide, - 185) 3 - [(3S) -1-Azabicyclo [2.2.2] oct-3-ylamino] carbonyl-1H-acid hydrochloride indazol-6-carboxylic, - 186) N (3) - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -N (6), N (6) -dimethyl-1H-indazol-2-one 3,6-dicarboxamide, - 187) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(4-methylpiperazin-1-yl) carbonyl] -1H-indazol-2-one 188-N) [- (3S) -1-Azabicyclo [2.2.2] oct-3-yl] -6 - [(3R) -3-methoxypyrrolidin-1-yl] carbonyl-1H-indazol-3-carboxamide 3-carboxamide, -189) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-methoxyisothiazolo [5,4-b] pyridine-3-carboxamide, and-190) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -5- (tetrahydro-2H-pyran-4-yloxy) -1H-indazol-3-carboxamide, wherein the salts listed above may also be in free base form or of another pharmaceutically acceptable salt, and the above-listed free base forms may also be in the form of a pharmaceutically acceptable salt, wherein a compound listed above, in a free base form or in the form of a pharmaceutically acceptable salt, may also be in the form of a pharmaceutically acceptable salt. A solvate, wherein a compound listed above, in free-base form or in the form of a pharmaceutically acceptable salt, may also be in the form of an N-oxide, wherein a compound listed above, in free-base form or a solvate. or an N-oxide thereof, or in the form of a pharmaceutically acceptable salt or solvate thereof, may also be in the form of a polymorph, and if the compound exhibits chirality it may be in the form of a mixture of enantiomers or a mixture of diastereomers. , or may be in the form of a single enantiomer or a single diastereomer. Compound according to claim 35, characterized in that said compound is selected from: - 2) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-methoxypyrrolidin-1-yl) -1,2-benzisothiazol-3-carboxamide, - 3) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5 hydroformate, 6-dimethoxy-1H-indazol-3-carboxamide, -4) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-propyl-6- (1,3-thiazol-2-yl) 2-yl) -1H-indazol-3-carboxamide, - 5) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-isopropyl-6- (1,3-thiazole -2-yl) -1H-indazol-3-carboxamide, - 6) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (tetrahydrofuran-3-yloxy) hydroformate -IH-indazol-3-carboxamide, - 7) N - [(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -6- (tetrahydro-2H-pyran-4-yloxy) -hydroformate 1H-indazol-3-carboxamide, 8) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(1-methylpyrrolidin-3-yl) oxy] hydroformate 1H-indazol-3-carboxamide, - 9) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -4-hydroxy-1H-indazol-3-carboxamide hydroformate, - 10) N - [(3S) -1-az hydroformate abicyclo [2.2.2] oct-3-yl] -5-bromo-4-hydroxy-1H-indazol-3-carboxamide, - 11) N - [(3S) -1-azabicyclo [2.2.2] oct hydroformate -3-yl] -5,7-dibromo-4-hydroxy-1H-indazol-3-carboxamide, -12) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl hydroformate ] -5-hydroxy-1,2-benzothiazol-3-carboxamide, - 13) (3S) -3 - {[(5-hydroxy-1,2-benzisothiazol-3-yl) carbonyl iodide or formate] amino} -1-methyl-1-azoniabicyclo [2.2.2] octane, - 14) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-furylmethoxy) hydroformate ) -1,2-benz isothiazol-3-carboxamide, - 15) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-ethyl-6- (2-oxopyrrolidin hydroformate) -1-yl) -1H-indazol-3-carboxamide, - 16) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7-hydroxy-1H-indazol-3 hydroformate 17) N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -6-methoxy-N-methyl-1H-indazol-3-carboxamide hydroformate, - 18) N - [(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -1-methyl-6 - {[(propylamino) carbonyl] amino} -1H-indazol-3-carboxamide hydroformate, - 19 ) N - [(3S) -1-aza bicycle [2. 2 . 2] oct-3-yl] -1-ethyl-6-methoxy-1H-indazol-3-carboxamide, - 20) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] - 1-ethyl-6-methoxy-1H-indazol-3-carboxamide, - 21) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1- (difluoromethyl) -6- methoxy-1H-indazol-3-carboxamide, - 22) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1- (difluoromethyl) -6- (1,3-thiazole -2-yl) -1H-indazol-3-carboxamide, - 23) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(cyclopropylcarbonyl) amino] - hydroformate 1-methyl-1H-indazol-3-carboxamide, - 24) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(cyclopropylcarbonyl) amino] -1- (difluoromethyl) -1H-indazol-3-carboxamide, - 25) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1- (difluoromethyl) -6- {[] hydroformate (propylamino) carbonyl] amino} -1H-indazol-3-carboxamide, - 26) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-cyclopropyl-6- (1 , 3-thiazol-2-yl) -1H-indazol-3-carboxamide, - 27) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1,3- thiazol-2-yl) -1- (3-thienyl) -1H-indazol-3-carboxamide, - 28) N - [(3S) -1-azabicyclo [2.2.2] oc t-3-yl] -N-methyl-6- (1,3-oxazol-2-yl) -1H-indazol-3-carboxamide, -29) N - [(3S) -1-azabicyclo [2.2.2 ] oct-3-yl] -N-methyl-6- (1,3-thiazol-2-yl) -1H-indazol-3-carboxamide, -30) N - [(3S) -1-azabicyclo [2.2 .2] oct-3-yl] -1-ethyl-6- (1,3-oxazol-2-yl) -1H-indazol-3-carboxamide, 31) N - [(3S) -1-azabicyclo [2.2 .2] oct-3-yl] -1- (cyclopropylmethyl) -6- (1,3-oxazol-2-yl) -1H-indazol-3-carboxamide, -32) N - [(3S) -1- azabicyclo [2.2.2] oct-3-yl] -6- (1,3-oxazol-2-yl) -1-propyl-1H-indazol-3-carboxamide, -33) N - [(3S) -1 -azabicyclo [2.2.2] oct-3-yl] -1-ethyl-N-methyl-6- (1,3-oxazol-2-yl) -1H-indazol-3-carboxamide, -34) N- [ (3S) -1-azabicyclo [2.2.2] oct-3-yl] -N-methyl-6- (tetrahydro-2H-pyran-4-yl) -1H-indazol-3-carboxamide, -35) N- [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -N-methyl-5- (tetrahydro-2H-pyran-4-yl) -1H-indazol-3-carboxamide, -36) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5- (difluoromethoxy) -N-methyl-1H-indazol-3-carboxamide, -37) N - [(3S) -1 -azabicyclo [2.2.2] oct-3-yl] -6- (difluoromethoxy) -N-methyl-1H-indazol-3-carboxamide, -38) N- [(3S) -1-azabicyclo [2. 2 . 2] oct-3-yl] -1-cyclopropyl-6 - [(cyclopropylcarbonyl) amino] -1H-indazol-3-carboxamide, -39) N - [(3S) -1-azabicyclo [2.2.2] oct 3-yl] -1-cyclopropyl-6- {[(propylamino) carbonyl] amino} -1H-indazol-3-carboxamide, -40) N - [(3S) -1-azabicyclo [2.2.2] oct-3 -yl] -5-methoxy-N-methyl-1H-indazol-3-carboxamide, -41) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- [ (4S) -4-Hydroxy-2-oxopyrrolidin-1-yl] -1H-indazol-3-carboxamide, -42) N - [(3R) -1-Azabicyclo hydroformate [2. 2 . 2] oct-3-yl] -5-methoxy-N-methyl-1H-indazol-3-carboxamide, -43) N - [(3R) -1-azabicyclo hydroformate [2. 2 . 2] oct-3-yl] -5- (difluoromethoxy) -N-methyl-1H-indazol-3-carboxamide, - 44) N - [(3R) -1-azabicyclo [2.2.2] oct hydroformate -3-yl] -6- (difluoromethoxy) -N-methyl-1H-indazol-3-carboxamide, - 45) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl hydroformate ] -N-methyl-6- (tetrahydro-2H-pyran-4-yl) -1H-indazol-3-carboxamide, - 46) N - [(3R) -1-azabicyclo [2.2.2] oct. 3-yl] -N-methyl-5- (tetrahydro-2H-pyran-4-yl) -1H-indazol-3-carboxamide, - 47) N - [(3R) -1-azabicyclo hydroformate [2.2.2 ] oct-3-yl] -N-methyl-6- (1,3-thiazol-2-yl) -1H-indazol-3-carboxamide, - 48) N - [(3R) -1-azabicyclo hydroformate [ 2.2.2] oct-3-yl] -6-methoxy-N-methyl-1,2-benzisothiazole-3-carboxamide, - 49) N - [(3S) -1-azabicyclo [2.2.2] oct hydrochloride -3-yl] -6- (3-methoxypyrrolidin-1-yl) -1,2-benzisothiazol-3-carboxamide, - 50) N - [(3S) -1-azabicyclo [2.2.2] oct-3 yl] -6-hydroxy-1,2-benzisothiazol-3-carboxamide, - 51) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-methoxy-1 hydrochloride, 2-benzisothiazole-3-carboxamide, - 52) N - [(3S) -1-a hydrochloride zabicyclo [2.2.2] oct-3-yl] -6-methoxy-1,2-benzisothiazol-3-carboxamide, - 53) N - [(3S) -1-azabicyclo [2.2.2] oct-3 hydrochloride -yl] -7-methoxy-1,2-benzisothiazol-3-carboxamide, - 54) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (2-) hydrochloride oxo-3-propylimidazolidin-1-yl) -1,2-benzisothiazol-3-carboxamide, - 55) N - [(3S) -1-oxide-1-azabicyclo [2.2.2] oct-3-yl] - 5- (trifluoromethoxy) -1H-indazol-3-carboxamide, and- 56) 6-Methoxy-N - [(3S) -1-oxido-1-azabicyclo [2.2.2] oct-3-yl] -1 2-benzisothiazole-3-carboxamide, wherein the salts listed above may also be in free base form or in the form of another pharmaceutically acceptable salt, and the above-listed free base forms may also be in the form of a pharmaceutically acceptable salt, wherein A compound listed above, in free base form or in the form of a pharmaceutically acceptable salt, may also be in the form of a solvate, wherein a compound listed above, in a free base form or in the form of a pharmaceutically acceptable salt. It may also be in the form of an N-oxide, wherein a compound listed above in a free base form or a solvate or an N-oxide thereof, or in the form of a pharmaceutically acceptable salt or solvate thereof, also It may be in the form of a polymorph, and if the compound exhibits chirality it may be in the form of a mixture of enantiomers or a mixture of diastereomers, or may be in the form of a single enantiomer or a single diastereomer. Compound according to claim 35, characterized in that said compound is selected from: -2) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- ( 3-Methoxypyrrolidin-1-yl) -1,2-benzisothiazol-3-carboxamide, -20 3) N - [(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -, 6- hydroformate dimethoxy-1H-indazol-3-carboxamide, -4) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-propyl-6- (1,3-thiazol-2-one yl) -1H-indazol-3-carboxamide, -5) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-isopropyl-6- (1,3-thiazol-2 -yl) -1H-indazol-3-carboxamide, -6) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (tetrahydrofuran-3-yloxy) hydroformate ) - 1H - indazol-3-carboxamide, -7) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (tetrahydro-2H-pyran-4-yloxy) hydroformate - 1H-indazol-3-carboxamide, - 8) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(1-methylpyrrolidin-3-yl) oxy] hydroformate -IH-indazol-3-carboxamide, -9) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -4-hydroxy-1H-indazol-3-carboxamide hydroformate, -10 ) Hydroformate - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5-bromo-4-hydroxy-1H-indazol-3-carboxamide, - 11) N - [(3S) hydroformate -1-azabicyclo [2.2.2] oct-3-yl] - 5,7-dibromo-4-hydroxy-1H-indazol-3-carboxamide, - 12) N - [(3S) -1-azabicyclohydroformate [2.2.2] oct-3-yl] -5-hydroxy-1,2-benzisothiazol-3-carboxamide, - 13) (3S) -3 - {[(5-hydroxy-1,2-iodide) or iodide benzisothiazol-3-yl) carbonyl] amino} -1-methyl-1-azoniabicyclo [2.2.2] octane, - 14) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl hydroformate ] -6- (3-furylmethoxy) -1,2-benzisothiazol-3-carboxamide, - 15) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-ethyl hydroformate -6- (2-oxopyrrolidin-1-yl) -1H-indazol-3-carboxamide, - 16) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7-hydroformate hydroxy-1H-indazol-3-carboxamide, - 17) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-methoxy-N-methyl-1H-indazole hydroformate (18) N - [(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -1-methyl-6 - {[(propylamino) carbonyl] amino} -1H- hydroformate indazol-3-carboxamide, - 19) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-ethyl-6-methoxy-1H-indazol-3-carboxamide, - 20) N - [(3R) - 1-azabicyclo [2.2.2] oct-3-yl] -1-ethyl-6-methoxy-1H-indazol-3-carboxamide, - 21) N - [(3S) -1-azabicyclo [2.2.2] oct -3-yl] -1- (difluoromethyl) -6-methoxy-1H-indazol-3-carboxamide, - 22) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] - 1- (difluoromethyl) 6- (1,3-thiazol-2-yl) -1H-indazol-3-carboxamide, - 23) N - [(3S) -1-azabicyclo [2.2.2] oct hydroformate -3-yl] -6 - [(cyclopropylcarbonyl) amino] -1-methyl-1H-indazol-3-carboxamide, - 24) N - [(3S) -1-azabicyclo [2.2.2] oct-3 hydroformate -yl] -6 - [(cyclopropylcarbonyl) amino] -1- (difluoromethyl) -1H-indazole-3-carboxamide, - 25) N - [(3S) -1-azabicyclo [2.2.2] octane hydroformate 3-yl] -1- (difluoromethyl) -6- {[(propylamino) carbonyl] amino} -1H-indazol-3-carboxamide, - 26) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-cyclopropyl-6- (1,3-thiazol-2-yl) -1H-indazol-3-carboxamide, - 27) N - [(3S) -1-azabicyclo [2.2.2 ] oct-3-yl] -6- (1,3-thiazol-2-yl) -1- (3-thienyl) -1H-indazol-3-carboxamid a, - 28) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -N-methyl-6- (1,3-oxazol-2-yl) -1H-indazol-3 29) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -N-methyl-6- (1,3-thiazol-2-yl) -1H-indazol-2-yl 3-carboxamide, -30) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-ethyl-6- (1,3-oxazol-2-yl) -1H-indazole -3-carboxamide, - 31) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1- (cyclopropylmethyl) -6- (1,3-oxazol-2-yl) - 1H-indazol-3-carboxamide, - 32) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1,3-oxazol-2-yl) -1-propyl -IH-indazol-3-carboxamide, -33) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-ethyl-N-methyl-6- (1,3-oxazole -2-yl) -1H-indazol-3-carboxamide, - 34) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -N-methyl-6- (tetrahydro-2H- pyran-4-yl) -1H-indazol-3-carboxamide, -35) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -N-methyl-5- (tetrahydro-2H -pyran-4-yl) -1H-indazol-3-carboxamide, -36) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5- (difluoromethoxy) -N-methyl -IH-indazol-3-carboxamide, - 37) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (difluoromethoxide) i) -N-methyl-1H-indazol-3-carboxamide, - 38) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-cyclopropyl-6 - [(cyclopropylcarbonyl) amino] -1H-indazol-3-carboxamide, - 39) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-cyclopropyl-6 {[(propylamino) carbonyl] amino } -1H-indazol-3-carboxamide, - 40) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5-methoxy-N-methyl-1H-indazol-3 - carboxamide, - 41) N - [(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -6 - [(4S) -4-hydroxy-2-oxopyrrolidin-1-yl] -1H hydroformate -indazol-3-carboxamide, - 42) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -5-methoxy-N-methyl-1H-indazol-3-carboxamide hydroformate, - 43) N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -5- (difluoromethoxy) -N-methyl-1H-indazol-3-carboxamide hydroformate, - 44) N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -6- (difluoromethoxy) -N-methyl-1H-indazol-3-carboxamide hydroformate, - 45) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -N-methyl-6- (tetrahydro-2H-pyran-4-yl) -1H-indazol-3-carboxamide, ) N - [(3R) -1-azabicic hydroformate lo [2.2.2] oct-3-yl] -N-methyl-5- (tetrahydro-2H-pyran-4-yl) -1H-indazol-3-carboxamide, - 47) N - [(3R) hydroformate -1-azabicyclo [2.2.2] oct-3-yl] -N-methyl-6- (1,3-thiazol-2-yl) -1H-indazol-3-carboxamide, - 48) N- [Hydroformate (3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-methoxy-N-methyl-1,2-benzisothiazol-3-carboxamide, - 49) N - [(3S) -1 hydrochloride -azabicyclo [2.2.2] oct-3-yl] -6- (3-methoxypyrrolidin-1-yl) -1,2-benzisothiazol-3-carboxamide, and-50) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-hydroxy-1,2-benzisothiazol-3-carboxamide, wherein the salts listed above may also be in free base form or in the form of another pharmaceutically acceptable salt, and The above listed base forms may also be in the form of a pharmaceutically acceptable salt, wherein a compound listed above, in a free base form or in the form of a pharmaceutically acceptable salt, may also be in the form of a solvate, wherein a listed compound above in a free base form or in the form of a pharmaceutically acceptable salt. It may also be in the form of an N-oxide, wherein a compound listed above, in a free base form or a solvate or an N-oxide thereof, or in the form of a pharmaceutically acceptable salt or solvate thereof, It may also be in the form of a polymorph, and if the compound exhibits chirality it may be in the form of a mixture of enantiomers or a mixture of diastereomers, or may be in the form of a single enantiomer or a single diastereomer. Compound according to claim 35, characterized in that said compound is selected from: -57) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6 hydroformate -fluoro-1H-pyrazolo [3,4-b] pyridin-3-carboxamide, -58) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- [3] hydroformate - (cyclopropylmethoxy) pyrrolidin-1-yl] -1H-indazol-3-carboxamide, -59) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1H-pyrazolo [4, 3-c] pyridine-3-carboxamide, -60) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1H-pyrazolo [3,4-c] pyridine-3-hydroformate -61) N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -6- [3- (cyclopropylmethoxy) pyrrolidin-1-yl] -1H-indazol-hydroformate 3-carboxamide, -62) N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -6- (3-methoxypyrrolidin-1-yl) -1H-indazol-3-hydroformate carboxamide, -63) N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -6- (2-oxo-3-propylimidazolidin-1-yl) -1H-indazol-hydroformate 3-carboxamide, -64) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-pyrrolidin-1-yl-1,2-benzisothiazole-3-carboxamide 65) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-methyl-2-oxopyrrolidin-1-yl) -1,2-benzisothiazole-3 66) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (β-pyrrol-1-yl) -1,2-benzisothiazole-3-carboxamide , - 67) N - [(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -6- (3-ethyl-2-oxoimidazolidin-1-yl) -1,2-benzisothiazole-3 carboxamide, - 68) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- [3- (cyclopropylmethoxy) pyrrolidin-1-yl] -1,2-benzisothiazole-3 69) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-methoxypyrrolidin-1-yl) -1,2-benzisoxazol-3-carboxamide, - 70) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7- (3-methoxypyrrolidin-1-yl) -1,2-benzisothiazole-3-carboxamide, - 71) Hydrochloride N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-methoxy-1,2-benzisoxazol-3-carboxamide, - 72) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-methoxypyrrolidin-1-yl) -1,2-benzisothiazol-3-carboxamide, - 73) N - [(3R) -1-azabicyclo [ 2.2.2] oct-3-yl] -1-ethyl-6- (1,3-oxazol-2-yl) -1H-indazol-3-carboxamide, - 74) N - [(3S) hydrochloride ) -1-azabicyclo [2.2.2] oct-3-yl] -1-ethyl-6- (1,3-oxazol-2-yl) -1H-indazol-3-carboxamide, - 75) N- [( 3S) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(3R) -3-methoxypyrrolidin-1-yl] -1,2-benzisothiazol-3-carboxamide, -76) N- [ (3S) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(3S) -3-methoxypyrrolidin-1-yl] -1,2-benzisothiazol-3-carboxamide, - 77) N- [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (2-oxo-3-propylimidazolidin-1-yl) -1H-indazol-3-carboxamide, - 78) N- [ (3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-hydroxypyrrolidin-1-yl) -1,2-benzisothiazole-3-carboxamide, - 79) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- [3- (difluoromethoxy) pyrrolidin-1-yl] -1,2-benzisothiazol-3-carboxamide, -80. N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1H-imidazol-1-yl) -1,2-benzisothiazole-3-carboxamide, -81. N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1H-pyrazol-1-yl) -1,2-benzisothiazole-3-carboxamide, -82. N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-methyl-1H-pyrazol-1-yl) -1,2-benzisothiazole-3-carboxamide, -83 . N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (5-methyl-1H-pyrazol-1-yl) -1,2-benzisothiazole-3-carboxamide, -84 . N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(3R) -3-methoxypyrrolidin-1-yl] -1,2-benzisothiazol-3-carboxamide, -85 . N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(3S) -3-methoxypyrrolidin-1-yl] -1,2-benzisothiazol-3-carboxamide, -86 . N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-methoxy-1,2-benzoxoxazol-3-carboxamide, -87. N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-ethoxypyrrolidin-1-yl) -7-fluoro-1,2-benzisothiazol-3-carboxamide, -88 . N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-phenyl-1H-pyrazolo [3,4-b] pyridine-3-carboxamide, -89. N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (4,5-dihydro-1H-imidazol-2-yl) -1H-indazol-3-carboxamide, -90 . N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- [3- (dimethylamino) pyrrolidin-1-yl] -1H-pyrazolo [3,4-b] pyridine-3 -carboxamide, -91. N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- [3- (dimethylamino) pyrrolidin-1-yl] -1H-pyrazolo [3,4-b] pyridine-3 -carboxamide, -92. N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-fluoro-6- (3-methoxypyrrolidin-1-yl) -1,2-benzisothiazol-3-carboxamide, -93 . N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7-fluoro-6- (3-methoxypyrrolidin-1-yl) -1,2-benzisothiazol-3-carboxamide, -94 . N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(3R) -3-hydroxypyrrolidin-1-yl] -1,2-benzisothiazole-3-carboxamide, -95 ) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(3S) -3-hydroxypyrrolidin-1-yl] -1,2-benzisothiazole-3-carboxamide, - 96) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(3S) -3- (dimethylamino) pyrrolidin-1-yl] -1,2-benzisothiazol-3 --carboxamide, -97) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(1S, 4S) -2-oxa-5-azabicyclo [2.2.1 ] hept-5-yl] -1,2-benzisothiazol-3-carboxamide, -98) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(3R) - 3-hydroxypyrrolidin-1-yl] -1,2-benzisothiazol-3-carboxamide, -99) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(3S ) -3-hydroxypyrrolidin-1-yl] -1,2-benzisothiazol-3-carboxamide, -100) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [( 3S) -3- (dimethylamino) pyrrolidin-1-yl] -1,2-benzisothiazol-3-carboxamide, -101) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] - 7 - [(3R) -3-hydroxypyrrolidin-1-yl] -1,2-benzisothiazol-3-carboxamide, -102) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7 - [(3S) -3-hydroxypi rrolidin-1-yl] -1,2-benzisothiazol-3-carboxamide, -103) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7 - [(3S) -3 - (dimethylamino) pyrrolidin-1-yl] -1,2-benzisothiazol-3-carboxamide, -104) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7 - (( 1S, 4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl] -1,2-benzisothiazole-3-carboxamide, -105) N - [(3R) -1-azabicyclo [2.2. 2] oct-3-yl] -7 - [(3S) -3- (dimethylamino) pyrrolidin-1-yl] -1,2-benzisothiazol-3-carboxamide, -106) N - [(3S) - hydroformate 1-azabicyclo [2.2.2] oct-3-yl] isothiazolo [5,4-b] pyridin-3-carboxamide, -107) N - [(3R) -1-azabicyclo hydroformate [2. 2. 2] oct-3-yl] isothiazolo [4,4-b] pyridin-3-carboxamide, -108) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(3R) -3-methoxypyrrolidin-1-yl] -1,2-benzisoxazole -3-carboxamide, -109) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] - 6 - [(3S) -3-methoxypyrrolidin-1-yl] -1,2-benzisoxazol-3-carboxamide, - 110) N - [(3R) -1-azabicyclo [2.2.2] oct-3- hydroformate yl] -7 - [(3R) -3-methoxypyrrolidin-1-yl] -1,2-benzisothiazol-3-carboxamide, - 111) N - [(3R) -1-azabicyclo [2.2.2] oct-3 -yl] -7 - [(3S) -3-methoxypyrrolidin-1-yl] -1,2-benzisothiazole-3-carboxamide, - 112) N - [(3S) -1-azabicyclo [2.2. 2] oct-3-yl] -7 - [(3R) -3-methoxypyrrolidin-1-yl] -1,2-benzisothiazol-3-carboxamide, - 113) N - [(3S) -1-azabicyclohydroformate [2.2.2] oct-3-yl] -7 - [(3S) -3-methoxypyrrolidin-1-yl] -1,2-benzisothiazol-3-carboxamide, - 114) N - [(3S) -1- azabicyclo [2.2.2] oct-3-yl] -7-fluoro-6-methoxy-1,2-benzisothiazol-3-carboxamide, - 115) N - [(3R) -1-azabicyclo [2.2.2] oct -3-yl] -7-fluoro-6-methoxy-1,2-benzisothiazol-3-carboxamide, - 116) N - [(3 R) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] -1, 2-benzisothiazol-3-carboxamide, - 117) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(1S, 4S) -5-methyl-2,5-yl diazabicyclo [2.2.1] hept-2-yl] -1,2-benzisothiazol-3-carboxamide, - 118) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(1S, 4S) -2,5-diazabicyclo [2.2.1] hept-2-yl] -1,2-benzisothiazole-3-carboxamide, - 119) N - [(3S) -1-azabicyclo [2.2 .2] oct-3-yl] -6 - [(1S, 4S) -2,5-diazabicyclo [2.2.1] hept-2-yl] -1,2-benzisothiazol-3-carboxamide, - 120) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] 6- [3- (methylamino) pyrrolidin-1-yl] -1,2-benzisothiazole-3-carboxamide, -121) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- [3- (methylamino) pyrrolidin-1-yl] -1,2-benzisothiazole-3-carboxamide, 122) N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -6 - [(1S, 4S) -5- (2,2,2-trifluoroethyl) -2,5-diazabicyclo [2.2.1] hept-2-yl] -1,2-benzisothiazol-3-carboxamide, -123) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- { 3- [methyl (2,2,2-trifluoroethyl) amino] pyrrolidin-1-yl } -1,2-benzisothiazol-3-carboxamide, -124) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- {3 - [methyl (2,2, 2-trifluoroethyl) amino] pyrrolidin-1-yl} -1,2-benzisothiazol-3-carboxamide, -125) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- [3- (methoxymethyl) pyrrolidin-1-yl] -1,2-benzisothiazol-3-carboxamide, -126) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6 [3- (methoxymethyl) pyrrolidin-1-yl] -1,2-benzisothiazol-3-carboxamide, -127) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6 [(3R) -3- (dimethylamino) pyrrolidin-1-yl] -1,2-benzisothiazol-3-carboxamide, -128) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl ] -6 - [(3R) -3- (dimethylamino) pyrrolidin-1-yl] -1,2-benzisothiazol-3-carboxamide, -129) N - [(3S) -1-azabicyclo [2.2.2 ] oct-3-yl] -6- [4- (dimethylamino) piperidin-1-yl] -1,2-benzisothiazol-3-carboxamide, and-130) N - [(3R) -1-azabicyclo [2.2. 2] oct-3-yl] -6- [4- (dimethylamino) piperidin-1-yl] -1,2-benzisothiazol-3-carboxamide, wherein the salts listed above may also be in free base form or in the form of another pharmaceutically acceptable The above-listed free base forms may also be in the form of a pharmaceutically acceptable salt, wherein a compound listed above in free base form or in the form of a pharmaceutically acceptable salt may also be in the form of a solvate, in whereas a compound listed above, in free base form or in the form of a pharmaceutically acceptable salt, may also be in the form of an N-oxide, wherein a compound listed above, in free base form, or a solvate or N- The oxide thereof, or in the form of a pharmaceutically acceptable salt or solvate thereof, may also be in the form of a polymorph, and if the compound exhibits chirality it may be in the form of a mixture of enantiomers or a mixture of diastereomers, or may be in the form of a single enantiomer or a single diastereomer. Compound according to Claim 35, characterized in that said compound is selected from: - 131) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] - 6 - ( 2-oxo-3-propylimidazolidin-1-yl) -1,2-benzisothiazole-3-carboxamide, and their pharmaceutically acceptable salts, wherein the salts listed above may also be in free base form or in the form of another pharmaceutically acceptable salt, and the above listed base forms may also be in the form of a pharmaceutically acceptable salt, wherein a compound listed above, in a free base form or in the form of a pharmaceutically acceptable salt, may also be in the form of a solvate, wherein a The above listed compound, in free base form or in the form of a pharmaceutically acceptable salt, may also be in the form of an N-oxide, wherein a above listed compound, in free base form, or a solvate or N-oxide of the same, or in the form of a pharmaceutically acceptable salt or solvate thereof, may also be and being in the form of a polymorph, and if the compound exhibits chirality it may be in the form of a mixture of enantiomers or a mixture of diastereomers, or may be in the form of a single enantiomer or a single diastereomer. Compound according to claim 35, characterized in that said compound is selected from: -1) (3S) -3- ({[6- (Cyclopropylmethoxy) -1,2-benzisothiazole bromide or formate) -3-yl] carbonyl} amino) -1- (cyclopropylmethyl) -1-azoniabicyclo [2.2.2] octane, -132) N - [(3S) -1-azabicyclo [2.2.2] oct-3 dihydroformate -yl] -N-methyl-6 - [(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] -1,2-benzisothiazole-3-carboxamide, -133 ) N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -N-methyl-6 - [(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2. 1] hept-2-yl] -1,2-benzisothiazol-3-carboxamide, -134) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(IR , 4R) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] -1,2-benzisothiazole-3-carboxamide, -5) N - [(3S) -1-azabicyclo [2.2 .2] oct-3-yl] -6 - [(IR, 4R) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] -1,2-benzisothiazole-3-carboxamide , -136) N - [(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -6- (1,4-diazabicyclo [3.2.2] non-4-yl) -1,2-dihydroformate benzisothiazole-3-carboxamide, -137) Dihydroform N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1,4-diazabicyclo [3.2.2] non-4-yl) -1,2-benzisothiazole-3-yl ester carboxamide, - 138) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-pyrrolidin-1-yl-1,2-benzisothiazole-3-carboxamide, - 139) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (4-methylpiperazin-1-yl) -1,2-benzisothiazole-3-carboxamide, - 140) N- [ (3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (4-methylpiperazin-1-yl) -1,2-benzisothiazole-3-carboxamide, - 141) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (4-methyl-1,4-diazepan-1-yl) -1,2-benzisothiazol-3-carboxamide, - 142) N- [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (4-methyl-1,4-diazepan-1-yl) -1,2-benzisothiazole-3-carboxamide, 143) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (hexahydropyrrolo [1,2-a] pyrazin-2 (1H) -yl) -1,2-benzisothiazole -3-carboxamide, -144) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (hexahydropyrrolo [1,2-a] pyrazin-2 (1H) -yl) -1,2-benzisothiazol-3-carboxamide, - 145) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (5-methyl-2,5-diazabicyclo [ 2.2.2] oct-2-yl) -1,2-benziso thiazol-3-carboxamide, - 146) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (5-methyl-2,5-diazabicyclo [2.2.2] oct -2-yl) -1,2-benzisothiazol-3-carboxamide, -147) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (8-methyl-3 , 8-diazabicyclo [3.2.1] oct-3-yl) -1,2-benzisothiazol-3-carboxamide, - 148) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (8-methyl-3,8-diazabicyclo [3.2.1] oct-3-yl) -1,2-benzisothiazole-3-carboxamide, -149) N - [(3R) -1-azabicyclo [ 2.2.2] oct-3-yl] -6 - [(1S, 4S) -5-cyclopropyl-2,5-diazabicyclo [2.2.1] hept-2-yl] -1,2-benzisothiazole-3-carboxamide , - 150) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(1S, 4S) -5-cyclopropyl-2,5-diazabicyclo [2.2.1] hept -2-yl] -1,2-benzisothiazol-3-carboxamide, -151) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(1S, 4S) - 5- (cyclopropylmethyl) -2,5-diazabicyclo [2.2.1] hept-2-yl] -1,2-benzisothiazole-3-carboxamide, - 152) N - [(3S) -1-azabicyclo [2.2.2 ] oct-3-yl] -6 - [(1S, 4S) -5- (cyclopropylmethyl) -2,5-diazabicyclo [2.2.1] hept-2-yl] -1,2-benzisothiazole-3-carboxamide, - 153) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5- (4-methyl-1,4-diazepan-1-yl) -1,2-benzisothiazol-3-carboxamide, -154) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -5 - [(3R) -3-methoxypyrrolidin-1-yl] -1,2-benzisothiazol-3-carboxamide, -155) N - [(3S ) -1-azabicyclo [2.2.2] oct-3-yl] -5 - [(3R) -3-methoxypyrrolidin-1-yl] -1,2-benzisothiazol-3-carboxamide, -156) N- [( 3R) -1-azabicyclo [2.2.2] oct-3-yl] -5 - [(3S) -3-methoxypyrrolidin-1-yl] -1,2-benzisothiazol-3-carboxamide, - 157) N- [ (3R) -1-Azabicyclo [2.2.2] oct-3-yl] -6 - [(1-methylpyrrolidin-3-yl) oxy] -1,2-benzisothiazol-3-carboxamide, - 158) N- [ (3S) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(1-methylpyrrolidin-3-yl) oxy] -1,2-benzisothiazol-3-carboxamide, -155) N- [ (3R) -1-Azabicyclo [2.2.2] oct-3-yl] -6- (1-azabicyclo [2.2.2] oct-3-yloxy) -1,2-benzisothiazole-3-carboxamide, -160) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1-azabicyclo [2.2.2] oct-3-yloxy) -1,2-benzisothiazole-3-carboxamide, - 161) N, N'-di- (3S) -1-azabicyclo [2.2.2] oct-3-yl-1H-indazol-1,3-dicarboxamide, - 162) N - [(3R) -1- azabicycle [2 .2.2] oct-3-yl] -6- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -1H-indazol-3-carboxamide, -163) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -1H-indazol-3-carboxamide, 164.N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5 - [(3S) -3- (cyclopropylmethoxy) pyrrolidin-1-yl] -1H-indazol-3-carboxamide, 165. (3S) -1- (Chloromethyl) -3 - [(1H-indazol-3-ylcarbonyl) amino] -1-azoniabicyclo [2.2.2] octane chloride, 166. N - [(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -5 - [(3S) -3-methoxypyrrolidin-1-yl] -1H-indazol-3-carboxamide dihydroformate, 167. N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-chloroisothiazolo [5,4-b] pyridine-3-carboxamide, 168. N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-methylpiperazin-1-yl) -1,2-benzisothiazole-3-carboxamide, 169. N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (octahydro-6H-pyrrolo [3,4-b] pyridin-6-yl) -1,2-benzisothiazole-2-one 3-carboxamide, 170. N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (octahydro-6H-pyrrolo [3,4-b] pyridin-6-yl) -1,2-benzisothiazole-2-one 3-carboxamide, 171. N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-piperazin-1-yl-1,2-benzisothiazol-3-carboxamide, 172. N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-piperazin-1-yl-1,2-benzothiazol-3-carboxamide, 173. N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] 6- (1,4-diazepan-1-yl) -1,2-benzisothiazole-3-carboxamide, 174. N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1,4-diazepan-1-yl) -1,2-benzisothiazole-3-carboxamide, 175. N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (2-methylpiperazin-1-yl) -1,2-benzisothiazole-3-carboxamide, 176. N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (2-methylpiperazin-1-yl) -1,2-benzisothiazole-3-carboxamide, 177. N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] 6- [4- (cyclopropylcarbonyl) piperazin-1-yl] -1,2-benzisothiazol-3-carboxamide, -178) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- [4- (cyclopropylcarbonyl) piperazin-1-yl] -1,2-benzisothiazole-3-carboxamide, -179) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- [1- (cyclopropylcarbonyl) octahydro-6H-pyrrolo [3,4-b] pyridin-6-yl] - -1,2-benzisothiazol-3-carboxamide, -180) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- [1- (cyclopropylcarbonyl) octahydro-6H-pyrrolo [ 3,4-b] pyridin-6-yl] -1,2-benzisothiazol-3-carboxamide, -181) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(1S, 4S) -5- (cyclopropylcarbonyl) -2,5-diazabicyclo [2.2.1] hept-2-yl] -1,2-benzisothiazole-3-carboxamide, -182) N - [(3S ) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(1S, 4S) -5- (cyclopropylcarbonyl) -2,5-diazabicyclo [2.2.1] hept-2-yl] -1 -2-benzisothiazol-3-carboxamide, -183) N - [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3,4-dimethylpiperazin-1-yl) -1 , 2-benzisothiazol-3-carboxamide, -184) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-cyano no-1H-indazol-3-carboxamide, -185) 3 - [(3S) -1-azabicyclo [2.2.2] oct-3-ylamino] carbonyl-1H-indazol-6-carboxylic acid hydrochloride, -186) N (3) - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -N (6) -, N (6) dimethyl-1H-indazol-3,6-dicarboxamide, - 187) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(4-methylpiperazin-1-yl) carbonyl] -1H-indazol-3-carboxamide, -188) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6 - [(3R) -3-methoxypyrrolidin-1-yl] carbonyl-1H-indazol-3-carboxamide, -189) N - [(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-methoxyisothiazolo [5,4-b] pyridine-3-carboxamide, and-190) N - [(3R) - 1-azabicyclo [2.2.2] oct-3-yl] -5- (tetrahydro-2H-pyran-4-yloxy) -1H-indazol-3-carboxamide wherein the salts listed above may also be in free base or in the form of another pharmaceutically acceptable salt, and the above-listed free base forms may also be in the form of a pharmaceutically acceptable salt, wherein a compound listed above, in a free base form or in the form of a pharmaceutically acceptable salt. It may also be in the form of a solvate, wherein a compound listed above, in free base form or in the form of a pharmaceutically acceptable salt, may also be in the form of an N-oxide, wherein a compound listed above, in a free base form or a solvate or an N-oxide thereof, or in the form of a pharmaceutically acceptable salt or solvate thereof, may also be in the form of a polymorph, and if the compound exhibits chirality it may be in the form of a polymorph. a mixture of enantiomers or a mixture of diastereomers, or may be in the form of a single enantiomer or a single diastereomer. Pharmaceutical composition, characterized in that it comprises a compound according to any one of claims 1 to 40 and a pharmaceutically acceptable carrier. Pharmaceutical composition according to claim 41, characterized in that said composition further comprises at least one additional pharmaceutical agent selected from other α-7 agonists, PDE4 inhibitors, calcium channel blockers, muscarinic ml modulators, m2 modulators. muscarinics, adenosine receptor modulators, ampacins, NMDA-R modulators, mGluR modulators, dedopamine modulators, serotonin modulators, decannabinoid modulators, and cholinesterase inhibitors. 43. A method for selective activation / stimulation of a-7 nicotinic receptors in a patient, wherein such activation / stimulation has a therapeutic effect, characterized in that it comprises administering to the patient in need of an effective amount of a compound according to any given condition. one of claims 1 to 40. 44. A method for treating a patient suffering from a psychotic disorder, a neurodegenerative disorder involving cholinergic system dysfunction, and / or a condition of degeneration of memory and / or cognition, characterized in that it comprises patient administration of an amount of a compound according to any one of claims 1 to 40. 45. The method of claim 44 wherein said patient is suffering from schizophrenia, anxiety, mania, depression, manic depression, Tourette's syndrome, Parkinson's disease, Huntington's disease, Alzheimer's disease, dementia. Lewi, amyotrophic lateral sclerosis, memory degeneration, lost memory, cognition deficit, attention deficit, and / or attention deficit hyperactivity disorder. A method for treating a patient suffering from dementia and / or another condition with memory loss, comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 40. 47. Method for treating a patient who has memory degeneration due to mild cognitive degeneration due to aging, Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, Dick's disease, Creutzfeldt-Jakob disease, depression, aging, trauma in the head, stroke, CNS hypoxia, brain senility, multi-infarction dementia, HIV and / or cardiovascular disease, characterized in that it comprises administering to the patient an effective amount of a compound according to any one of claims 1 to 40. A method for treating and / or preventing dementia in a patient with Alzheimer's disease, characterized in that it comprises administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 40 to inhibit beta-binding. -amyloid peptide with nACh receptors. Method for the treatment of a patient for alcohol withdrawal or for the treatment of a patient with anti-poisoning therapy, characterized in that it comprises the administration to the patient of an effective amount of a compound according to any one of claims 1 to 40. A method for treating a patient to provide neuroprotection against damage associated with cerebral vascular accident and glutamate-induced ischemia and excitotoxicity, which comprises administering to the patient an effective amount of a compound according to any one of claims 1 to 40. Method for the treatment of a patient with nicotine addiction, pain, time zone dizziness, obesity and / or diabetes, characterized in that it comprises the administration to the patient of an effective amount of a compound according to any one of claims 1 to 4. 40 A method of inducing a patient to quit, comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 40. 53. Method for treating a patient who has mild cognitive degeneration (MCI), vascular dementia (VaD), age-associated cognitive decline (AACD), amnesia associated with open heart surgery, cardiac arrest, general anesthesia, heart failure. memory due to exposure to anesthetic agents, cognitive degeneration-induced lack of sleep, chronic fatigue syndrome, narcolepsy, AIDS-related dementia, epilepsy-related cognitive degeneration, Down syndrome, alcohol-related dementia, drug / substance-induced memory degeneration , Boxer's Syndrome (Boxer's Syndrome), or animal dementia, characterized in that it comprises administering to the patient an effective amount of a compound according to any one of claims 1 to 40. A method for treating memory loss, comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 40. A method for treating a patient who has memory degeneration disorder, which comprises administering to the patient a compound according to any one of claims 1 to 40. A method according to claim 55, characterized in that said memory degeneration is due to decreased activity of the deacetyl choline nicotinic receptor. A method for the treatment or prophylaxis of a disease or condition resulting from transmission dysfunction of the nicotinic acetylcholine receptor in a patient, comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 6. 40 A method for the treatment or prophylaxis of a disease or condition resulting from defective or malfunctioning nicotinic acetylcholine receptors in a patient, comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 6. 40 A method for the treatment or prophylaxis of a disease or condition resulting from the suppressed transmission of the nicotinic acetylcholine receptor in a patient, comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 40. . A method for the treatment or prophylaxis of a disease or condition resulting from the loss of synapsescolinergic in a patient, which comprises administering to the patient an effective amount of a compound according to any one of claims 1 to 40. A method for the protection of neurons in a patient with α7nACh receptor activation-induced neurotoxicity, comprising administering to said patient an effective amount of a compound according to any one of claims 1 to 40. A method for the treatment or prophylaxis of a neurodegenerative disorder by inhibiting the binding of β-peptides to α7nACh receptors in a patient, which comprises administering to the patient an effective amount of a compound according to any of the claims. 1 to 40. A method for treating a patient suffering from an inflammatory disease comprising administering to said patient an effective amount of a compound according to any one of claims 1 to 40. A method according to claim 63, characterized in that said inflammatory disease is rheumatoid arthritis, diabetes or sepsis. 65. A method according to any one of claims 40 to 64, characterized in that the dictapatient is a human being.