Cyclopropylamine derivatives useful as LSD1 inhibitors

Abstract

The invention relates to cyclopropylamine compounds, in particular the compounds of Formula (I), and their use in therapy, including e.g. in the treatment or prevention of cancer, a neurological disease or condition, or viral infection. ##STR00001##

Claims

1. A compound of Formula (I) or an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof: ##STR00147## wherein: E is X.sup.3X.sup.4, and X.sup.1, X.sup.2, X.sup.3 and X.sup.4 are independently C(R2); (G) is an aryl or heterocyclyl group; each (R1) is independently chosen from alkyl, alkenyl, alkynyl, cyclyl, -L1-cyclyl, -L1-amino, -L1-hydroxyl, amino, amido, nitro, halo, haloalkyl, haloalkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, hydroxyl, alkoxy, urea, carbamate, acetyl, and carboxyl; each (R2) is independently chosen from H, alkyl, alkenyl, alkynyl, cyclyl, -L1-cyclyl, -L1-amino, -L1-hydroxyl, amino, amido, nitro, halo, haloalkyl, haloalkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, hydroxyl, alkoxy, urea, carbamate, acyl, and carboxyl, wherein each (R2) group has 1, 2, or 3 independently chosen optional substituents or two (R2) groups can be taken together to form a heterocyclyl or aryl group having 1, 2, or 3 independently chosen optional substituents, wherein said optional substituents are independently chosen from alkyl, alkanoyl, heteroalkyl, heterocyclyl, haloalkyl, cycloalkyl, carbocyclyl, arylalkoxy, heterocyclylalkoxy, aryl, aryloxy, heterocyclyloxy, alkoxy, haloalkoxy, oxo, acyloxy, carbonyl, carboxyl, carboxamido, cyano, halogen, hydroxyl, amino, aminoalkyl, amidoalkyl, amido, nitro, thiol, alkylthio, arylthio, sulfonamide, sulfinyl, sulfonyl, urea, and carbamate; each L1 is independently alkylene or heteroalkylene; and n is 0, 1, 2, 3, 4 or 5; with the proviso that the compound of Formula (I) is not: (1S,2R)-2-([1,1-biphenyl]-4-yl)cyclopropanamine, (1 S,2R)-2-(4-chloro-[1,1biphenyl]-4-yl)cyclopropanamine, (1 S,2R)-2-(3-chloro-4-(trifluoromethyl)-[1,1-biphenyl]-4-yl)cyclopropanamine, 2-(3,4,5-trichloro-[1,1-biphenyl]-4-yl)cyclopropanamine, 2-(3,3,4,5-tetrachloro[1,1-biphenyl]-4-yl)cyclopropanamine, 2-(3,3,4-trichloro-[1,1-biphenyl]-4-yl)cyclopropanamine, or 2-(3,5-dichloro-4-methyl-[1,1-biphenyl]-4-yl)cyclopropanamine.

2. The compound of claim 1 wherein said compound is a compound of Formula (II) or an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof: ##STR00148## wherein: X.sup.1 is CH; (G) is an aryl or heterocyclyl group; each (R1) is independently chosen from alkyl, alkenyl, alkynyl, cyclyl, -L1-cyclyl, -L1-amino, -L1-hydroxyl, amino, amido, nitro, halo, haloalkyl, haloalkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, hydroxyl, alkoxy, urea, carbamate, acetyl, and carboxyl; each (R2) is independently chosen from alkyl, alkenyl, alkynyl, cyclyl, -L1-cyclyl, -L1-amino, -L1-hydroxyl, amino, amido, nitro, halo, haloalkyl, haloalkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, hydroxyl, alkoxy, urea, carbamate, acyl, and carboxyl, wherein each (R2) group has 1, 2, or 3 optional substituents, wherein said optional substituents are independently chosen from alkyl, alkanoyl, heteroalkyl, heterocyclyl, haloalkyl, cycloalkyl, carbocyclyl, arylalkoxy, heterocyclylalkoxy, aryl, aryloxy, heterocyclyloxy, alkoxy, haloalkoxy, oxo, acyloxy, carbonyl, carboxyl, carboxamido, cyano, halogen, hydroxyl, amino, aminoalkyl, amidoalkyl, amido, nitro, thiol, alkylthio, arylthio, sulfonamide, sulfinyl, sulfonyl, urea, and carbamate; each L1 is independently alkylene or heteroalkylene; m is 0, 1, 2 or 3; and n is 0, 1, 2, 3, 4 or 5, provided that n and m are chosen independently such that n+m is greater than zero when (G) is an aryl; with the proviso that the compound of Formula (II) is not: (1S,2R)-2-(4-chloro-[1,1-biphenyl]-4-yl)cyclopropanamine, (1 S,2R)-2-(3-chloro-4-(trifluoromethyl)-[1,1-biphenyl]-4-yl)cyclopropanamine, 2-(3,4,5-trichloro-[1,1-biphenyl]-4-yl)cyclopropanamine, 2-(3,3,4,5-tetrachloro-[1,1-biphenyl]-4-yl)cyclopropanamine, 2-(3,3,4-trichloro-[1,1-biphenyl]-4-yl)cyclopropanamine, or 2-(3,5-dichloro-4-methyl-[1,1-biphenyl]-4-yl)cyclopropanamine.

3. The compound of claim 1 wherein (G) is a heterocyclyl.

4. The compound of claim 1 wherein (G) is phenyl.

5. The compound of claim 1 wherein (G) is a phenyl, thienyl, benzothienyl, indolyl, indolinyl, indolinonyl, pyridinyl, pyridinonyl, benzofuranyl, benzofuranonyl, indazolyl, or carbazolyl group.

6. The compound of claim 1 wherein each (R1) is independently chosen from alkyl, amino, amido, nitro, F, haloalkoxy, cyano, sulfonyl, sulfonamide, and hydroxyl.

7. The compound of claim 1 wherein each (R1) is independently chosen from F, CN, CH.sub.3, OH, C(O)NH.sub.2,NHCOCH.sub.3, NHSO.sub.2CH.sub.3, NHSO.sub.2CH.sub.2CH.sub.3, NHSO.sub.2CH(CH.sub.3)CH.sub.3, NHSO.sub.2-(C.sub.6H.sub.5), NHSO.sub.2-(C.sub.6H.sub.4)CN, NHSO.sub.2CF.sub.3, and S(O).sub.2NHCH.sub.3.

8. The compound of claim 1 wherein each (R2) is H.

9. The compound of claim 1 wherein n is 1, 2, or 3.

10. The compound of claim 1 wherein the compound of formula (I) is: 4-((trans)-2-aminocyclopropyl)biphenyl-4-ol; 4-((trans)-2-aminocyclopropyl)biphenyl-3-ol; 4-((trans)-2-aminocyclopropyl)-4-fluorobiphenyl-3-ol; 4-((trans)-2-aminocyclopropyl)-5-chlorobiphenyl-3-ol; 4-((trans)-2-aminocyclopropyl)-5-chloro-4-fluorobiphenyl-3-ol; N-(4-((trans)-2-aminocyclopropyl)biphenyl-3-yl)benzenesulfonamide; N-(4-((trans)-2-aminocyclopropyl)biphenyl-3-yl)propane-2-sulfonamide; N-(4-((trans)-2-aminocyclopropyl)biphenyl-3-yl)methanesulfonamide; N-(4-((trans)-2-aminocyclopropyl)biphenyl-2-yl)methanesulfonamide; 4-((trans)-2-aminocyclopropyl)-6-methoxybiphenyl-3-carbonitrile; N-(4-((trans)-2-aminocyclopropyl)-6-methoxybiphenyl-3-yl)methanesulfonamide; 4-((trans)-2-aminocyclopropyl)-6-hydroxybiphenyl-3-carbonitrile; N-(4-((trans)-2-aminocyclopropyl)-6-hydroxybiphenyl-3-yl)methanesulfonamide; N-(4-((trans)-2-aminocyclopropyl)-5-chloro-[1,1-biphenyl]-3-yl)methanesulfonamide; N-(4-((trans)-2-aminocyclopropyl)-4-fluoro-[1,1-biphenyl]-3-yl)methanesulfonamide; N-(4-((trans)-2-aminocyclopropyl)-[1,1-biphenyl]-3-yl)-1,1,1-trifluoromethanesulfonamide; 4-((trans)-2-aminocyclopropyl)-6-hydroxy-[1,1-biphenyl]-3-carbonitrile; 4-((trans)-2-aminocyclopropyl)-[1,1-biphenyl]-2-ol; and 4-((trans)-2-aminocyclopropyl)-3-methoxy-[1,1-biphenyl]-3-ol; or a pharmaceutically acceptable salt or solvate thereof.

11. The compound of claim 4 wherein each (R1) is independently chosen from alkyl, amino, amido, nitro, F, haloalkoxy, cyano, sulfonyl, sulfonamide, and hydroxyl.

12. The compound of claim 5 wherein each (R1) is independently chosen from alkyl, amino, amido, nitro, F, haloalkoxy, cyano, sulfonyl, sulfonamide, and hydroxyl.

13. The compound of claim 4 wherein each (R1) is independently chosen from F, CN, CH.sub.3, OH, C(O)NH.sub.2, NHCOCH.sub.3, NHSO.sub.2CH.sub.3, NHSO.sub.2CH.sub.2CH.sub.3, NHSO.sub.2CH(CH.sub.3)CH.sub.3, NHSO.sub.2(C.sub.6H.sub.5), NHSO.sub.2(C.sub.6H.sub.4)CN, NHSO.sub.2CF.sub.3, and S(O).sub.2NHCH.sub.3.

14. A pharmaceutical composition comprising a compound of Formula (I) or an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof: ##STR00149## wherein: E is X.sup.3X.sup.4, and X.sup.2, X.sup.3 and X.sup.4 are independently C(R2); (G) is an aryl or heterocyclyl group; each (R1) is independently chosen from alkyl, alkenyl, alkynyl, cyclyl, -L1-cyclyl, -L1-amino, -L1-hydroxyl, amino, amido, nitro, halo, haloalkyl, haloalkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, hydroxyl, alkoxy, urea, carbamate, acetyl, and carboxyl; each (R2) is independently chosen from H, alkyl, alkenyl, alkynyl, cyclyl, -L1-cyclyl, -L1-amino, -L1-hydroxyl, amino, amido, nitro, halo, haloalkyl, haloalkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, hydroxyl, alkoxy, urea, carbamate, acyl, and carboxyl, wherein each (R2) group has 1, 2, or 3 independently chosen optional substituents or two (R2) groups can be taken together to form a heterocyclyl or aryl group having 1, 2, or 3 independently chosen optional substituents, wherein said optional substituents are independently chosen from alkyl, alkanoyl, heteroalkyl, heterocyclyl, haloalkyl, cycloalkyl, carbocyclyl, arylalkoxy, heterocyclylalkoxy, aryl, aryloxy, heterocyclyloxy, alkoxy, haloalkoxy, oxo, acyloxy, carbonyl, carboxyl, carboxamido, cyano, halogen, hydroxyl, amino, aminoalkyl, amidoalkyl, amido, nitro, thiol, alkylthio, arylthio, sulfonamide, sulfinyl, sulfonyl, urea, and carbamate; each L1 is independently alkylene or heteroalkylene; and n is 0, 1, 2, 3, 4 or 5; and a pharmaceutically acceptable carrier.

15. The pharmaceutical composition of claim 14, wherein the compound of formula (I) is: 4-((trans)-2-aminocyclopropyl)biphenyl-4-ol; 4-((trans)-2-aminocyclopropyl)biphenyl-3-ol; 4-((trans)-2-aminocyclopropyl)-4-fluorobiphenyl-3-ol; 4-((trans)-2-aminocyclopropyl)-5-chlorobiphenyl-3-ol; 4-((trans)-2-aminocyclopropyl)-5-chloro-4-fluorobiphenyl-3-ol; N-(4-((trans)-2-aminocyclopropyl)biphenyl-3-yl)benzenesulfonamide; N-(4-((trans)-2-aminocyclopropyl)biphenyl-3-yl)propane-2-sulfonamide; N-(4-((trans)-2-aminocyclopropyl)biphenyl-3-yl)methanesulfonamide; N-(4-((trans)-2-aminocyclopropyl)biphenyl-2-yl)methanesulfonamide; 4-((trans)-2-aminocyclopropyl)-6-methoxybiphenyl-3-carbonitrile; N-(4-((trans)-2-aminocyclopropyl)-6-methoxybiphenyl-3-yl)methanesulfonamide; 4-((trans)-2-aminocyclopropyl)-6-hydroxybiphenyl-3-carbonitrile; N-(4-((trans)-2-aminocyclopropyl)-6-hydroxybiphenyl-3-yl)methanesulfonamide; N-(4-((trans)-2-aminocyclopropyl)-5-chloro-[1,1-biphenyl]-3-yl)methanesulfonamide; N-(4-((trans)-2-aminocyclopropyl)-4-fluoro-[1,1-biphenyl]-3-yl)methanesulfonamide; N-(4-((trans)-2-aminocyclopropyl)-[1,1-biphenyl]-3-yl)-1,1,1-trifluoromethanesulfonamide; 4-((trans)-2-aminocyclopropyl)-6-hydroxy-[1,1-biphenyl]-3-carbonitrile; 4-((trans)-2-aminocyclopropyl)-[1,1-biphenyl]-2-ol; and 4-((trans)-2-aminocyclopropyl)-3-methoxy-[1,1-biphenyl]-3-ol; or a pharmaceutically acceptable salt or solvate thereof.

16. The pharmaceutical composition of claim 14 wherein (G) is a phenyl, thienyl, benzothienyl, indolyl, indolinyl, indolinonyl, pyridinyl, pyridinonyl, benzofuranyl, benzofuranonyl, indazolyl, or carbazolyl group.

17. The pharmaceutical composition of claim 14 wherein (G) is phenyl.

18. The pharmaceutical composition of claim 14 wherein each (R2) is H.

19. The pharmaceutical composition of claim 16 wherein each (R1) is independently chosen from alkyl, amino, amido, nitro, F, haloalkoxy, cyano, sulfonyl, sulfonamide, and hydroxyl.

20. The pharmaceutical composition of claim 17 wherein each (R1) is independently chosen from alkyl, amino, amido, nitro, F, haloalkoxy, cyano, sulfonyl, sulfonamide, and hydroxyl.

Description

DETAILED DESCRIPTION OF THE INVENTION

Definitions

(1) Any definition herein may be used in combination with any other definition to describe a composite structural group. By convention, the trailing element of any such definition is that which attaches to the parent moiety. For example, the composite group alkylamido would represent an alkyl group attached to the parent molecule through an amido group, and the term alkoxyalkyl would represent an alkoxy group attached to the parent molecule through an alkyl group.

(2) As used herein, the term acyl, refers to a carbonyl attached to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, or any other moiety where the atom attached to the carbonyl is carbon. An acetyl group refers to a C(O)CH.sub.3 group. An alkylcarbonyl or alkanoyl group refers to an alkyl group attached to the parent molecular moiety through a carbonyl group. Examples of such groups include, but are not limited to, methylcarbonyl or ethylcarbonyl. Examples of acyl groups include, but are not limited to, formyl, alkanoyl or aroyl.

(3) As used herein, the term acyloxy, refers to an acyl group attached to the parent moiety through an oxygen atom.

(4) As used herein, the term alkenyl, refers to a straight-chain or branched-chain hydrocarbon group having one or more double bonds and containing from 2 to 20 carbon atoms. A (C2-C6)alkenyl has from 2 to 6 carbon atoms.

(5) As used herein, the term alkenylene, refers to a carbon-carbon double bond system attached at two or more positions such as ethenylene e.g., CHCH. Examples of suitable alkenyl groups include, but are not limited to, ethenyl, propenyl, 2-methylpropenyl, or 1,4-butadienyl.

(6) As used herein, the term alkoxy, refers to an alkyl ether group, wherein the term alkyl is as defined below. Examples of suitable alkyl ether groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, or n-pentoxy.

(7) As used herein, the term alkyl, refers to a straight-chain or branched-chain alkyl group containing from 1 to 20 carbon atoms. A (C1-C10)alkyl has from 1 to 10 carbon atoms and a (C1-C6)alkyl has from 1 to 6 carbon atoms and a (C1-C4)alkyl has from 1 to 4 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neo-pentyl, iso-amyl, hexyl, heptyl, octyl, or noyl.

(8) As used herein, the term alkylene, refers to a saturated aliphatic group having from 1 to 20 carbons and is derived from a straight or branched chain saturated hydrocarbon attached at two or more positions. Alkylene groups include, but are not limited to, methylene (CH.sub.2), ethylene CH.sub.2CH.sub.2, propylene (CH.sub.2CH.sub.2CH.sub.2) or isopropylene (CH(CH.sub.3)CH.sub.2).

(9) As used herein, the term alkylamino, refers to an alkyl group attached to the parent molecular moiety through an amino group. Suitable alkylamino groups may be mono- or dialkylated, forming groups including, but not limited to N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-ethylmethylamino, N,N-diethylamino, N-propylamino, or N,N-methylpropylamino.

(10) As used herein, the term alkylidene, refers to an alkenyl group in which one carbon atom of the carbon-carbon double bond belongs to the moiety to which the alkenyl group is attached.

(11) As used herein, the term alkylthio, refers to an alkyl thioether (RS) group wherein the term R is an alkyl is as defined above wherein the group is attached to the parent molecule through the sulfur group. Examples of suitable alkyl thioether groups include, but are not limited to, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, iso-butylthio, sec-butylthio, or tert-butylthio.

(12) As used herein, the term alkynyl, as used herein, refers to a straight-chain or branched-chain hydrocarbon group having one or more triple bonds and containing from 2 to 20 carbon atoms. A (C2-C6)alkynyl has from 2 to 6 carbon atoms. A (C2-C4)alkynyl has from 2 to 4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, 3-methylbutyn-1-yl, or hexyn-2-yl.

(13) As used herein, the term alkynylene, refers to a carbon-carbon triple bond attached at two positions such as ethynylene (CC).

(14) As used herein, the terms amido and carbamoyl, refer to an amino group as described below attached to the parent molecular moiety through a carbonyl group (e.g., C(O)NRR), or vice versa (N(R)C(O)NR). Amido and carbamoyl encompass C-amido, N-amido and acylamino as defined herein. R and R are as defined herein.

(15) As used herein, the term C-amido, refers to a C(O)NRR group with R and R as defined herein.

(16) As used herein, the term N-amido, refers to a RC(O)NR group, with R and R as defined herein.

(17) As used herein, the term acylamino, refers to an acyl group attached to the parent moiety through an amino group. An example of an acylamino group includes, but is not limited to, acetylamino (CH.sub.3C(O)NH).

(18) As used herein, the term amino, refers to NRR, wherein R and R are independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, aryl, carbocyclyl, and heterocyclyl. Additionally, R and R may be combined to form a heterocyclyl.

(19) As used herein, the term aryl, refers a carbocyclic aromatic system containing one ring, or two or three rings fused together where in the ring atoms are all carbon. The term aryl groups includes, but is not limited to groups such as phenyl, naphthyl, or anthracenyl.

(20) As used herein, the term arylalkenyl or aralkenyl, refers to an aryl group attached to the parent molecular moiety through an alkenyl group.

(21) As used herein, the term arylalkoxy or aralkoxy, refers to an aryl group attached to the parent molecular moiety through an alkoxy group. Examples of arylalkoxy groups include, but are not limited to, benzyloxy or phenethoxy.

(22) As used herein, the term arylalkyl or aralkyl, refers to an aryl group attached to the parent molecular moiety through an alkyl group.

(23) As used herein, the term arylalkynyl or aralkynyl, refers to an aryl group attached to the parent molecular moiety through an alkynyl group.

(24) As used herein, the term arylalkanoyl or aralkanoyl or aroyl, refers to an acyl group derived from an aryl-substituted alkanecarboxylic acid including, but not limited to, benzoyl, napthoyl, phenylacetyl, 3-phenylpropionyl (hydrocinnamoyl), 4-phenylbutyryl, (2-naphthyl)acetyl, or 4-chlorohydrocinnamoyl.

(25) As used herein, the term aryloxy, refers to an aryl group attached to the parent molecular moiety through an oxy (O).

(26) As used herein, the terms benzo and benz, refer to the divalent group C.sub.6H.sub.4=derived from benzene. Examples include, but are not limited to, benzothiophene or benzimidazole.

(27) As used herein, the term carbamate, refers to an O-carbamyl or N-carbamyl group as defined herein.

(28) As used herein, the term O-carbamyl refers to a OC(O)NRR, group- with R and R as defined herein.

(29) As used herein, the term N-carbamyl refers to a ROC(O)NR group, with R and R as defined herein.

(30) As used herein, the term carbonyl, when alone includes formyl C(O)H and in combination is a C(O) group.

(31) As used herein, the term carboxyl or carboxy refers to C(O)OH or the corresponding carboxylate anion, such as is in a carboxylic acid salt. An O-carboxy group refers to a RC(O)O group, where R is as defined herein. A C-carboxy group refers to a C(O)OR groups where R is as defined herein.

(32) As used herein, the term cyano refers to CN.

(33) As used herein, the term carbocyclyl refers to a saturated or partially saturated monocyclic or a fused bicyclic or tricyclic group wherein the ring atoms of the cyclic system are all carbon and wherein each cyclic moiety contains from 3 to 12 carbon atom ring members. Carbocyclyl encompasses benzo fused to a carbocyclyl ring system. One group of carbocyclyls have from 5 to 7 carbon atoms. Examples of carbocyclyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, tetrahydronapthyl, indanyl, octahydronaphthyl, 2,3-dihydro-1H-indenyl, or adamantyl.

(34) As used herein, the term cycloalkyl refers to a saturated monocyclic, bicyclic or tricyclic group wherein the ring atoms of the cyclic system are all carbon and wherein each cyclic moiety contains from 3 to 12 carbon atom ring members. One group of cycloalkyls has from 5 to 7 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or adamantyl.

(35) As used herein, the term cycloalkenyl refers to a partially saturated monocyclic, bicyclic or tricyclic group wherein the ring atoms of the cyclic system are all carbon and wherein each cyclic moiety contains from 3 to 12 carbon atom ring members. One group of carboalkenyls have from 5 to 7 carbon atoms. Examples of cycloalkenyl groups include, but are not limited to, cyclobutenyl, cyclopentenyl, or cyclohexenyl.

(36) As used herein, the term cyclyl refers to an aryl, heterocyclyl, or carbocyclyl group as defined herein.

(37) As used herein, the term ester refers to a carboxy group bridging two moieties linked at carbon atoms.

(38) As used herein, the term ether refers to an oxy group bridging two moieties linked at carbon atoms.

(39) As used herein, the term halo or halogen refers to fluorine, chlorine, bromine, or iodine.

(40) As used herein, the term haloalkoxy refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, 2-fluoroethoxy, or 3-chloropropoxy.

(41) As used herein, the term haloalkyl refers to an alkyl group having the meaning as defined above wherein one or more hydrogens are replaced with a halogen. Specifically embraced are monohaloalkyl, dihaloalkyl or polyhaloalkyl groups. A monohaloalkyl group, for one example, may have an iodo, bromo, chloro or fluoro atom within the group. Dihalo or polyhaloalkyl groups may have two or more of the same halo atoms or a combination of different halo groups. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl or dichloropropyl.

(42) As used herein, haloalkylene refers to a haloalkyl group attached at two or more positions. Examples include, but are not limited to, fluoromethylene (CFH), difluoromethylene (CF.sub.2), or chloromethylene (CHCl).

(43) As used herein, the term heteroalkyl refers to a straight or branched alkyl chain, wherein one, two, or three carbons forming the alkyl chain are each replaced by a heteroatom independently selected from the group consisting of O, N, and S, and wherein the nitrogen and/or sulfur heteroatom(s) (if present) may optionally be oxidized and the nitrogen heteroatom(s) (if present) may optionally be quaternized. The heteroatom(s) O, N and S may, for example, be placed at an interior position of the heteroalkyl group, i.e., the heteroalkyl may be bound to the remainder of the molecule via a carbon atom. Up to two heteroatoms may be consecutive, such as, for example, CH.sub.2NHOCH.sub.3.

(44) As used herein, the term heteroalkylene refers to a heteroalkyl group attached at two positions. Examples include, but are not limited to, CH.sub.2OCH.sub.2, CH.sub.2SCH.sub.2, and CH.sub.2NHCH.sub.2, CH.sub.2S, or CH.sub.2NHCH(CH.sub.3)CH.sub.2.

(45) As used herein, the term heteroaryl, refers to a 3 to 7 membered unsaturated monocyclic ring, or a fused monocyclic, bicyclic, or tricyclic ring system in which the rings are aromatic and which at least one ring contains at least one atom selected from the group consisting of O, S, and N. One group of heteroaryls has from 5 to 7 carbon atoms. Examples of heteroaryl groups include, but are not limited to, pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, or furopyridinyl.

(46) As used herein, the term heterocyclyl or hetercycle, each refer to a saturated, partially unsaturated, or fully unsaturated monocyclic, bicyclic, or tricyclic heterocyclic group containing at least one heteroatom as a ring member, wherein each said heteroatom may be independently selected from the group consisting of nitrogen, oxygen, and sulfur wherein the nitron or sulfur atoms may be oxidized (e.g., NO, S(O), or S(O).sub.2). Additionally, 1, 2, or 3 of the carbon atoms of the heterocyclyl may be optionally oxidized (e.g., to give an oxo group or O). One group of heterocyclyls has from 1 to 4 heteroatoms as ring members. Another group of heterocyclyls has from 1 to 2 heteroatoms as ring members. One group of heterocyclyls has from 3 to 8 ring members in each ring. Yet another group of heterocyclyls has from 3 to 7 ring members in each ring. Again another group of heterocyclyls has from 5 to 6 ring members in each ring. Heterocyclyl is intended to encompass a heterocyclyl group fused to a carbocyclyl or benzo ring systems. Examples of heterocyclyl groups include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinylimidazolinyl, or imidazolidinyl. Examples of heteroaryls that are heterocyclyls include, but are not limited to, pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, or furopyridinyl.

(47) As used herein, the term heterocycloalkyl, refers to a heterocyclyl group that is not fully saturated e.g., one or more of the rings systems of a heterocycloalkyl is not aromatic. Examples of heterocycloalkyls include piperazinyl, morpholinyl, piperidinyl, or pyrrolidinyl.

(48) As used herein, the term hydroxyl, as used herein, refers to OH.

(49) As used herein, the term hydroxyalkyl, as used herein, refers to a hydroxyl group attached to the parent molecular moiety through an alkyl group.

(50) As used herein, the phrase in the main chain, refers to the longest contiguous or adjacent chain of carbon atoms starting at the point of attachment of a group to the compounds of any one of the formulas disclosed herein.

(51) As used herein, the term isocyanato, refers to a NCO group.

(52) As used herein, the term isothiocyanato, refers to a NCS group.

(53) As used herein, the term phrase linear chain of atoms refers to the longest straight chain of atoms independently selected from carbon, nitrogen, oxygen and sulfur.

(54) As used herein, the term lower, where not otherwise specifically defined, means containing from 1 to and including 6 carbon atoms.

(55) As used herein, the term lower aryl, means phenyl or naphthyl.

(56) As used herein, the term lower heteroaryl, means either 1)monocyclic heteroaryl comprising five or six ring members, of which between one and four said members may be heteroatoms selected from O, S, or N.

(57) As used herein, the term lower cycloalkyl, refers to a monocyclic cycloalkyl having between three and six ring members. Examples of lower cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

(58) As used herein, the term lower heterocyclyl, refers to a monocyclic heterocyclyls having between three and six ring members, of which between one and four may be heteroatoms selected from the group consisting of O, S, and N wherein the N and S group may be optionally oxidized (e.g., N(O), S(O), and S(O).sub.2)). Examples of lower heterocyclyls include, but are not limited to, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, and morpholinyl. Lower heterocyclyls may be saturated or partially unsaturated which is a lower heterocycloalkyl.

(59) As used herein, the term lower amino, refers to NRR, wherein R and R are independently selected from the group consisting of hydrogen, lower alkyl, and lower heteroalkyl. Additionally, the R and R of a lower amino group may combine to form a five- or six-membered heterocycloalkyl.

(60) As used herein, the term mercaptyl, refers to an RS group, where R is as defined herein.

(61) As used herein, the term nitro, refers to NO.sub.2.

(62) As used herein, the terms oxy or oxa, refer to O.

(63) As used herein, the term oxo, refers to O.

(64) As used herein, the terms sulfonate sulfonic acid and sulfonic, refers to the SO.sub.3H group and its anion as the sulfonic acid is used in salt formation.

(65) As used herein, the term sulfanyl, to S.

(66) As used herein, the term sulfinyl, refers to S(O)(R), with R as defined herein.

(67) As used herein, the term sulfonyl, refers to S(O).sub.2R, with R as defined herein.

(68) As used herein, the term sulfonamide, refers to an N-sulfonamido or S-sulfonamido group as defined herein.

(69) As used herein, the term N-sulfonamido, refers to a RS(O).sub.2N(R) group with R and R as defined herein. Exemplary, non-limiting N-sulfonamido groups are NHSO.sub.2CH.sub.3, NHSO.sub.2CH.sub.2CH.sub.3, NHSO.sub.2(phenyl), NHSO.sub.2(isopropyl), NHSO.sub.2(-phenyl-CN), or NHSO.sub.2CF.sub.3, particularly NHSO.sub.2CH.sub.3, NHSO.sub.2CH.sub.2CH.sub.3, NHSO.sub.2(phenyl), or NHSO.sub.2(isopropyl).

(70) As used herein, the term S-sulfonamido, refers to a S(O).sub.2NRR, group, with R and R as defined herein. An exemplary, non-limiting S-sulfonamido group is S(O).sub.2NHCH.sub.3.

(71) As used herein, the terms thia and thio, refer to a S group or another wherein the oxygen is replaced with sulfur. The oxidized derivatives of the thio group, namely sulfinyl and sulfonyl, are included in the definition of thia and thio.

(72) As used herein, the term thiol, refers to an SH group.

(73) As used herein, the term thiocarbonyl, when alone includes thioformyl C(S)R group with R as defined herein.

(74) As used herein, the term N-thiocarbamyl, refers to an ROC(S)N(R) group, with R and R as defined herein.

(75) As used herein, the term O-thiocarbamyl, refers to a OC(S)NRR group with R and R as defined herein.

(76) As used herein, the term thiocyanato, refers to a SCN group.

(77) As used herein, the term trihalomethanesulfonamido, refers to a X.sub.3CS(O).sub.2N(R) group where X is an independently chosen halogen and R as defined herein.

(78) As used herein, the term trihalomethanesulfonyl, refers to a X.sub.3CS(O).sub.2 group where X is an independently chosen halogen.

(79) As used herein, the term trihalomethoxy, refers to a X.sub.3CO group where X is an independently chosen halogen.

(80) As used herein, the term trisubstituted silyl, refers to a silicone group substituted at its three free valences with groups as listed herein under the definition of for R and R. Examples include, but are not limited to, trimethysilyl, tert-butyldimethylsilyl, or triphenylsilyl.

(81) As used herein, the term urea, refers to a N(R)C(O)N(R) group wherein R and R are as defined herein.

(82) As used herein, the term optionally substituted means the proceeding or anteceding group may be substituted or unsubstituted. When substituted, the substituents of an optionally substituted group may include, without limitation, one or more substituents independently selected from the following groups or a particular designated set of groups, alone or in combination: lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl, lower heterocycloalkyl, lower haloalkyl, lower cycloalkyl, phenyl, aryl, aryloxy, lower alkoxy, lower haloalkoxy, oxo, lower acyloxy, carbonyl, carboxyl, lower alkylcarbonyl, lower carboxyester, lower carboxamido, cyano, hydrogen, halogen, hydroxyl, amino, lower alkylamino, arylamino, aminoalkyl, amido, nitro, thiol, lower alkylthio, lower haloalkylthio, lower perhaloalkylthio, arylthio, sulfonate, sulfonic acid, trisubstituted silyl, N.sub.3, SH, SCH.sub.3, C(O)CH.sub.3, CO.sub.2CH.sub.3, CO.sub.2H, pyridinyl, thiophene, furanyl, carbamate, and urea. Two substituents may be joined together to form a fused five-, six-, or seven-membered carbocyclic or heterocyclic ring consisting of zero to three heteroatoms, for example forming methylenedioxy or ethylenedioxy. An optionally substituted group may be unsubstituted (e.g., CH.sub.2CH.sub.3), fully substituted (e.g. CF.sub.2CF.sub.3), monosubstituted (e.g. CH.sub.2CH.sub.2F) or substituted at a level anywhere in-between fully substituted and monosubstituted (e.g., CH.sub.2CF.sub.3). Where substituents are recited without qualification as to substitution, both substituted and unsubstituted forms are encompassed. Where a substituent is qualified as substituted, the substituted form is specifically intended. Additionally, different sets of optional substituents to a particular moiety may be defined as needed; in these cases, the optional substitution will be as defined, often immediately following the phrase, optionally substituted with. In one specific definition, the optional substituents are chosen from hydroxyl, halo, alkyl, alkoxy, haloalkyl, haloalkoxy, N((C1-C3)alkyl).sub.2, NH((C1-C3)alkyl), NHC(O)((C1-C3)alkyl), C(O)OH, C(O)O((C1-C3)alkyl), C(O)(C1-C3)alkyl), C(O)NH.sub.2, C(O)NH(C1-C3)alkyl), C(O)NH(cycloalkyl), C(O)N(C1-C3)alkyl).sub.2, S(O).sub.2((C1-C3)alkyl), S(O).sub.2NH.sub.2, S(O).sub.2N((C1-C3)alkyl).sub.2, S(O).sub.2NH((C1-C3)alkyl), CHF.sub.2, OCF.sub.3, OCHF.sub.2, SCF.sub.3, CF.sub.3, CN, NH.sub.2, NO.sub.2, or tetrazolyl.

(83) The term R or the term R, appearing by itself and without a number designation, unless otherwise defined, refers to a moiety selected from the group consisting of hydrogen, alkyl, haloalkyl (e.g., CF.sub.3), cycloalkyl, heteroalkyl, aryl, heteroaryl and heterocycloalkyl. Said cycloalkyl, said aryl, said heteroaryl and/or said heterocycloalkyl may each be substituted with 1, 2, 3 or 4 groups (particularly with one group) independently selected from lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl, lower heterocycloalkyl, lower haloalkyl, lower cycloalkyl, phenyl, aryl, aryloxy, lower alkoxy, lower haloalkoxy, lower acyloxy, carbonyl, carboxyl, lower alkylcarbonyl, lower carboxyester, lower carboxamido, cyano, halogen, hydroxyl, amino, lower alkylamino, arylamino, aminoalkyl, amido, nitro, thiol, lower alkylthio, lower haloalkylthio, lower perhaloalkylthio, arylthio, carbamate, or urea, and preferably selected independently from CN, CF.sub.3, or halogen. Accordingly, said aryl (e.g., phenyl) may, e.g., be substituted with 1, 2, 3 or 4 groups (preferably one group) independently selected from CN, CF.sub.3, or halogen (for example, R and/or R may be phenyl substituted with one group CN). It is preferred that said cycloalkyl, said aryl, said heteroaryl and said heterocycloalkyl are each unsubstituted. Most preferably, the term R and the term R, appearing by itself and without a number designation, each refer to a moiety selected from the group consisting of hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl and heterocycloalkyl (wherein said cycloalkyl, said aryl, said heteroaryl and said heterocycloalkyl are each unsubstituted). Whether an R group has a number designation or not, every R group, including R, R and R.sup.p where p=(1, 2, 3, . . . p), every substituent, and every term should be understood to be independent of every other in terms of selection from a group. Should any variable, substituent, or term (e.g., aryl, heterocycle, R, etc.) occur more than one time in a formula or generic structure, its definition at each occurrence is independent of the definition at every other occurrence. Those of skill in the art will further recognize that certain groups may be attached to a parent molecule or may occupy a position in a chain of elements from either end as written. Thus, by way of example only, an unsymmetrical group such as C(O)N(R) may be attached to the parent moiety at either the carbon or the nitrogen.

(84) Asymmetric centers exist in the compounds disclosed herein. These centers are designated by the symbols R or S, depending on the configuration of substituents around the chiral carbon atom. It should be understood that the invention encompasses all stereochemical isomeric forms, including diastereomeric, enantiomeric, and epimeric forms, as well as d-isomers and 1-isomers, and mixtures thereof. Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other appropriate method known in the art. Starting compounds of particular stereochemistry are either commercially available or can be made and resolved by techniques known in the art. Additionally, the compounds disclosed herein may exist as geometric isomers. The present invention includes all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof. Additionally, compounds may exist as tautomers; all tautomeric isomers are provided by this invention. Additionally, the compounds disclosed herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms.

(85) As used herein, the terms (1S,2R) enantiomer and (1R,2S) enantiomer of a compound according to the invention, in particular of a compound of Formula (I), (II), (III), (IV) or (V), refer to the two possible enantiomers of the trans-isomer (in respect of the substituents on the cyclopropyl ring) of the respective compound. In this connection, the 1-position of the cyclopropyl ring refers to the carbon atom of the cyclopropyl ring which is bound to the terminal amino group of the compound and the 2-position of the cyclopropyl ring refers to the carbon atom which is bound to the adjacent cyclic group (i.e., the cyclic group comprising E, X.sup.1 and X.sup.2 in Formula (I)) of the compound, unless defined otherwise by the chemical name of any particular compound.

(86) As used herein, the term preventing an increase in a symptom, refers to both not allowing a symptom to increase or worsen, as well as reducing the rate of increase in the symptom. For example, a symptom can be measured as the amount of particular disease marker, i.e., a protein (e.g., cancer biomarker). In another example the symptom can be cognitive decline. Preventing an increase, according to the definition provided herein, means that the amount of symptom (e.g., protein or cognitive decline) does not increase or that the rate at which it increases is reduced.

(87) As used herein, the term treating a disease or disorder, refers to a slowing of or a reversal of the progress of the disease. Treating a disease or disorder includes treating a symptom and/or reducing the symptoms of the disease.

(88) As used herein, the term preventing a disease or disorder, refers to a slowing of the disease or of the onset of the disease or the symptoms thereof. Preventing a disease or disorder can include stopping the onset of the disease or symptoms thereof. As used herein, the term unit dosage form refers to a physically discrete unit, such as a capsule or tablet suitable as a unitary dosage for a human patient. Each unit contains a predetermined quantity of a compound of Formula (I), (II), (III), (TV) or (V) which was discovered or believed to produce the desired pharmacokinetic profile which yields the desired therapeutic effect. The dosage unit is composed of a compound of Formula (I), (II), (III), (IV) or (V) in association with at least one pharmaceutically acceptable carrier, salt, excipient, or combination thereof.

(89) As used herein, the term subject or patient or individual, such as the subject in need of treatment or prevention, may be a eukaryote, an animal, a vertebrate animal, a mammal, a rodent (e.g. a guinea pig, a hamster, a rat, a mouse), a murine (e.g. a mouse), a canine (e.g. a dog), a feline (e.g. a cat), an equine (e.g. a horse), a primate, a simian (e.g. a monkey or ape), a monkey (e.g. a marmoset, a baboon), an ape (e.g. gorilla, chimpanzee, orangutang, gibbon), or a human. The meaning of the terms eukaryote, animal, mammal, etc. is well known in the art and can, for example, be deduced from Wehner und Gehring (1995; Thieme Verlag). In the context of this invention, it is particularly envisaged that animals are to be treated which are economically, agronomically or scientifically important. Scientifically important organisms include, but are not limited to, mice, rats, and rabbits. Lower organisms such as, e.g., fruit flies like Drosophila melagonaster and nematodes like Caenorhabditis elegans may also be used in scientific approaches. Non-limiting examples of agronomically important animals are sheep, cattle and pig, while, for example, cats and dogs may be considered as economically important animals. Preferably, the subject/patient/individual is a mammal; more preferably, the subject/patient/individual is a human or a non-human mammal (such as, e.g., a guinea pig, a hamster, a rat, a mouse, a rabbit, a dog, a cat, a horse, a monkey, an ape, a marmoset, a baboon, a gorilla, a chimpanzee, an orangutang, a gibbon, a sheep, cattle, or a pig); even more preferably, the subject/patient/individual is a human.

(90) As used herein, the term dose or dosage, refers the amount of active ingredient that an individual takes or is administered at one time. For example, a 40 mg dose of a compound of Formula (I), (II), (III), (IV) or (V) refers to, in the case of a twice-daily dosage regimen, a situation where the individual takes 40 mg of a compound of Formula (I), (II), (III), (IV) or (V) twice a day, e.g., 40 mg in the morning and 40 mg in the evening. The 40 mg of a compound of Formula (I), (II), (III), (IV) or (V) dose can be divided into two or more dosage units, e.g., two 20 mg dosage units of a compound of Formula (I), (II), (III), (IV) or (V) in tablet form or two 20 mg dosage units of a compound of Formula (I), (II), (III), (IV) or (V) in capsule form.

(91) As used herein, a pharmaceutically acceptable prodrug is a compound that may be converted under physiological conditions or by solvolysis to the specified compound or to a pharmaceutically acceptable salt of such compound.

(92) As used herein, a pharmaceutically active metabolite is intended to mean a pharmacologically active product produced through metabolism in the body of a specified compound or salt thereof. Metabolites of a compound may be identified using routine techniques known in the art and their activities determined using tests such as those described herein.

(93) As used herein, a pharmaceutically acceptable salt is intended to mean a salt that retains the biological effectiveness of the free acids and bases of the specified compound and that is not biologically or otherwise undesirable. A compound for use in the invention may possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. Exemplary pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a mineral or organic acid or an inorganic base, such as salts including sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrophosphates, dihydrophosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4 dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, gamma-hydroxybutyrates, glycollates, tartrates, methane-sulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, or mandelates.

(94) As used herein, a pharmaceutically acceptable carrier refers to a non-API (API refers to Active Pharmaceutical Ingredient) substances such as disintegrators, binders, fillers, and lubricants used in formulating pharmaceutical products. They are generally safe for administering to humans according to established governmental standards, including those promulgated by the United States Food and Drug Administration and the European Medical Agency.

(95) As is understood by the skilled artisan, certain variables in the list of substituents are repetitive (different name for the same substituent), generic to other terms in the list, and/or partially overlap in content with other terms. In the compounds of the invention, the skilled artisan recognizes that substituents may be attached to the remainder of the molecule via a number of positions and the preferred positions are as illustrated in the Examples.

(96) Additionally, the compound of Formula (I), (II), (III), (IV) or (V) can contain asymmetric carbon atoms and can therefore exist in racemic and optically active forms. Thus, optical isomers or enantiomers, racemates, tautomers, and diastereomers are also encompassed in the compounds of Formula (I), (II), (III), (IV) or (V). The methods of present invention include the use of all such isomers and mixtures thereof. Methods of separation of enantiomeric and diastereomeric mixtures are well known to one skilled in the art. The present invention encompasses any isolated racemic or optically active form of compounds described in Formula (I), (II), (III), (IV) or (V), or any mixture thereof. In one aspect, the compounds of the invention have a trans configuration around the cyclopropyl ring as in trans-phenylcyclopropylamine. In one aspect, the compounds of the invention have a cis configuration around the cyclopropyl ring as in cis-phenylcyclopropylamine. In a preferred aspect, the compounds of Formula (I), (II), (III), (IV) or (V) have the trans configuration.

(97) Typically, compounds according to Formula (I), (II), (III), (IV) or (V) can be effective at an amount of from about 0.01 gig/kg to about 100 mg/kg per day based on total body weight. The active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at predetermined intervals of time. The suitable dosage unit for each administration can be, e.g., from about 1 g to about 2000 mg, preferably from about 5 g to about 1000 mg.

(98) It should be understood that the dosage ranges set forth above are exemplary only and are not intended to limit the scope of this invention. The therapeutically effective amount for each active compound can vary with factors including but not limited to the activity of the compound used, stability of the active compound in the patient's body, the severity of the conditions to be alleviated, the total weight of the patient treated, the route of administration, the case of absorption, distribution, and excretion of the active compound by the body, the age and sensitivity of the patient to be treated, and the like, as will be apparent to a skilled artisan. The amount of administration can be adjusted as the various factors change over time.

(99) For oral delivery, the active compounds can be incorporated into a formulation that includes pharmaceutically acceptable carriers such as binders (e.g., gelatin, cellulose, gum tragacanth), excipients (e.g., starch, lactose), lubricants (e.g., magnesium stearate, silicon dioxide), disintegrating agents (e.g., alginate, Primogel, and corn starch), and sweetening or flavoring agents (e.g., glucose, sucrose, saccharin, methyl salicylate, and peppermint). The formulation can be orally delivered in the form of enclosed gelatin capsules or compressed tablets. Capsules and tablets can be prepared in any conventional techniques. The capsules and tablets can also be coated with various coatings known in the art to modify the flavors, tastes, colors, and shapes of the capsules and tablets. In addition, liquid carriers such as fatty oil can also be included in capsules.

(100) Suitable oral formulations can also be in the form of suspension, syrup, chewing gum, wafer, elixir, and the like. If desired, conventional agents for modifying flavors, tastes, colors, and shapes of the special forms can also be included. In addition, for convenient administration by enteral feeding tube in patients unable to swallow, the active compounds can be dissolved in an acceptable lipophilic vegetable oil vehicle such as olive oil, corn oil and safflower oil.

(101) The active compounds can also be administered parenterally in the form of solution or suspension, or in lyophilized form capable of conversion into a solution or suspension form before use. In such formulations, diluents or pharmaceutically acceptable carriers such as sterile water and physiological saline buffer can be used. Other conventional solvents, pH buffers, stabilizers, anti-bacteria agents, surfactants, and antioxidants can all be included. For example, useful components include sodium chloride, acetates, citrates or phosphates buffers, glycerin, dextrose, fixed oils, methyl parabens, polyethylene glycol, propylene glycol, sodium bisulfate, benzyl alcohol, ascorbic acid, and the like. The parenteral formulations can be stored in any conventional containers such as vials and ampoules.

(102) Routes of topical administration include nasal, bucal, mucosal, rectal, or vaginal applications. For topical administration, the active compounds can be formulated into lotions, creams, ointments, gels, powders, pastes, sprays, suspensions, drops and aerosols. Thus, one or more thickening agents, humectants, and stabilizing agents can be included in the formulations. Examples of such agents include, but are not limited to, polyethylene glycol, sorbitol, xanthan gum, petrolatum, beeswax, or mineral oil, lanolin, squalene, and the like. A special form of topical administration is delivery by a transdermal patch. Methods for preparing transdermal patches are disclosed, e.g., in Brown, et al. (1988) Ann. Rev. Med. 39:221-229 which is incorporated herein by reference.

(103) Subcutaneous implantation for sustained release of the active compounds may also be a suitable route of administration. This entails surgical procedures for implanting an active compound in any suitable formulation into a subcutaneous space, e.g., beneath the anterior abdominal wall. See, e.g., Wilson et al. (1984) J. Clin. Psych. 45:242-247. Hydrogels can be used as a carrier for the sustained release of the active compounds. Hydrogels are generally known in the art. They are typically made by crosslinking high molecular weight biocompatible polymers into a network, which swells in water to form a gel like material. Preferably, hydrogels are biodegradable or biosorbable. For purposes of this invention, hydrogels made of polyethylene glycols, collagen, or poly(glycolic-co-L1-lactic acid) may be useful. See, e.g., Phillips et al. (1984) J. Pharmaceut. Sci., 73: 1718-1720.

(104) The active compounds can also be conjugated, to a water soluble non-immunogenic non-peptidic high molecular weight polymer to form a polymer conjugate. For example, an active compound is covalently linked to polyethylene glycol to form a conjugate. Typically, such a conjugate exhibits improved solubility, stability, and reduced toxicity and immunogenicity. Thus, when administered to a patient, the active compound in the conjugate can have a longer half-life in the body, and exhibit better efficacy. See generally, Burnham (1994) Am. J. Hosp. Pharm. 15:210-218. PEGylated proteins are currently being used in protein replacement therapies and for other therapeutic uses. For example, PEGylated interferon (PEG-INTRON A) is clinically used for treating Hepatitis B. PEGylated adenosine deaminase (ADAGEN) is being used to treat severe combined immunodeficiency disease (SCIDS). PEGylated L-asparaginase (ONCAPSPAR) is being used to treat acute lymphoblastic leukemia (ALL). It is preferred that the covalent linkage between the polymer and the active compound and/or the polymer itself is hydrolytically degradable under physiological conditions. Such conjugates known as prodrugs can readily release the active compound inside the body. Controlled release of an active compound can also be achieved by incorporating the active ingredient into microcapsules, nanocapsules, or hydrogels generally known in the art. Other pharmaceutically acceptable prodrugs of the compounds of this invention include, but are not limited to, esters, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, metal salts and sulfonate esters.

(105) Liposomes can also be used as carriers for the active compounds of the present invention. Liposomes are micelles made of various lipids such as cholesterol, phospholipids, fatty acids, and derivatives thereof. Various modified lipids can also be used. Liposomes can reduce the toxicity of the active compounds, and increase their stability. Methods for preparing liposomal suspensions containing active ingredients therein are generally known in the art. See, e.g., U.S. Pat. No. 4,522,811; Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976).

(106) The active compounds can also be administered in combination with another active agent that synergistically treats or prevents the same symptoms or is effective for another disease or symptom in the patient treated so long as the other active agent does not interfere with or adversely affect the effects of the active compounds of this invention. Such other active agents include but are not limited to anti-inflammation agents, antiviral agents, antibiotics, antifungal agents, antithrombotic agents, cardiovascular drugs, cholesterol lowering agents, anti-cancer drugs, hypertension drugs, and the like.

(107) Examples of antineoplastic agents that can be used in combination with the compounds and methods of the present invention include, in general, and as appropriate, alkylating agents, anti-metabolites, epidophyllotoxins, antineoplastic enzymes, topoisomerase inhibitors, procarbazines, mitoxantrones, platinum coordination complexes, biological response modifiers and growth inhibitors, hormonal/anti-hormonal therapeutic agents and haematopoietic growth factors. Exemplary classes of antineoplastic include the anthracyclines, vinca drugs, mitomycins, bleomycins, cytotoxic nucleosides, epothilones, discodermolides, pteridines, diynenes and podophyllotoxins. Particularly useful members of those classes include, for example, carminomycin, daunorubicin, aminopterin, methotrexate, methopterin, dichloromethotrexate, mitomycin C, porfiromycin, 5-fluorouracil, 6-mercaptopurine, gemcitabine, cytosine arabinoside, podophyllotoxin or podo-phyllotoxin derivatives such as etoposide, etoposide phosphate or teniposide, melphalan, vinblastine, vincristine, leurosidine, vindesine, leurosine, paclitaxel and the like. Other useful antineoplastic agents include estramustine, carboplatin, cyclophosphamide, bleomycin, gemcitibine, ifosamide, melphalan, hexamethyl melamine, thiotepa, cytarabin, idatrexate, trimetrexate, dacarbazine, L-asparaginase, camptothecin, CPT-11, topotecan, ara-C, bicalutamide, flutamide, leuprolide, pyridobenzoindole derivatives, interferons and interleukins.

(108) General Synthetic Route Description

(109) Compounds of Formula (I), (II), (III), (IV) or (V) can be synthesized by the general route described in the Scheme 1, 2 (including Schemes 2(a) and (b) and 3. As is known by the ordinary skilled artisan, other synthetic routes can be employed to arrive at the reactant, intermediates and final products of the invention with the following schemes being preferred routes to the indicated compounds.

(110) ##STR00009##

(111) Commercially availables aldehydes of formula (I) have been subjected to a Horner-Wadsworth-Emmons reaction using triethyl phosphono acetate and potassium tert-butoxide in tetrahydrofuran at 0 C. to give the ethyl acrylate derivative of formula (2) which is subjected to cyclopropanation reaction using trimetilsulfoxonium iodide and sodium hydride in dimethyl sulfoxide as a solvent leading to (trans)-ethyl cyclopropanecarboxylate derivatives of formula (3) (being trans ((1S,2R), (1R,2S)) mixture although the individual diastereoisomers corresponding to (1S, 2R) and (1R,2S) can be used). Hydrolysis to the corresponding (trans)-cyclopropanecarboxylic acid derivatives of formula (4) was performed using NaOH in MeOH. The reaction, first with ethyl chloroformate and triethylamine in acetone and later with sodium azide in water leads to the formation of (trans)-cyclopropanecarbonyl azide derivatives of formula (5). Reaction with tert-butanol results in the formation of tert-butyl (trans)-cyclopropylcarbamate derivatives of formula (6). Their reaction with commercially available boronic acid or boronate ester derivatives of formula (7) using acetonitrile and water as a solvent, potassium carbonate as a base and Tetrakis(triphenylphospine) Paladium (0) as a catalyst leads to the formation of tert-butyl (trans)-cyclopropylcarbamate derivatives of formula (8). Deprotection of the Boc-group using HCl 2M in diethyl ether using diethyl ether as a solvent leads to the formation of the corresponding hydrochloride salt of the (trans)-cyclopropanamine derivatives of formula (9), which are subject of the present invention as defined above.

(112) ##STR00010##

(113) Commercially availables 6-bromonicotinaldehydes of formula (I) (XN), have been subjected to a Horner-Wadsworth-Emmons reaction using triethyl phosphono acetate and potassium tert-butoxide in tetrahydrofurane at 0 C. to get the ethyl acrylate derivative of formula (2) (XN). Their reaction with commercially available boronic acid or boronate ester derivatives of formula (7) using acetonitrile and water as a solvent, potassium carbonate as a base and Tetrakis(triphenylphospine) Paladium (0) as a catalyst leads to the formation of derivatives of formula (10). N-oxidation with meta-chloroperoxybenzoic acid in dichloromethane results in the formation of derivatives of formula (11). Reaction with phosphorus oxychloride provide compounds of formula (12) which are subjected to cyclopropanation reaction using trimetilsulfoxonium iodide and sodium hydride in dimethyl sulfoxide as a solvent leading to (trans)-ethyl cyclopropanecarboxylate derivatives of formula (13) (being trans ((1S, 2R), (1R, 2S)) mixture although the individual isomers corresponding to (1S,2R) and (1R,2S) can be used). Hydrolysis to the corresponding (trans)-cyclopropanecarboxylic acid derivatives of formula (14) was performed using NaOH in MeOH. The reaction, first with ethyl chloroformate and triethylamine in acetone and later with sodium azide in water leads to the formation of (trans)-cyclopropanecarbonyl azide derivatives of formula (15). Reaction with tert-butanol results in the formation of tert-butyl (trans)-cyclopropylcarbamate derivatives of formula (16). Later reaction with commercially available boronic acid or boronate ester derivatives of formula (17) using acetonitrile and water as a solvent, potassium carbonate as a base and Tetrakis(triphenylphospine) Paladium (0) as a catalyst leads to the formation of tert-butyl (trans)-cyclopropylcarbamate derivatives of formula (18). Deprotection of the Boc-group using HCl in dioxane leads to the formation of the corresponding hydrochloride salt of the (trans)-cyclopropanamine derivatives of formula (19), which are also subjects of the present invention.

(114) ##STR00011##

(115) Commercially availables 6-bromonicotinaldehydes of formula (I) (XN), have been subjected to a Horner-Wadsworth-Emmons reaction using triethyl phosphono acetate and potassium tert-butoxide in tetrahydrofuran at 0 C. to get the ethyl acrylate derivative of formula (2) (XN). Their reaction with commercially available boronic acid or boronate ester derivatives of formula (20) using acetonitrile and water as a solvent, potassium carbonate as a base and Tetrakis(triphenylphospine) Paladium (0) as a catalyst leads to the formation of derivatives of formula (10). N-oxidation with meta-chloroperoxybenzoic acid in dichloromethane results in the formation of derivatives of formula (11). Reaction with phosphorus oxychloride provide compounds of formula (12) which are subjected to cyclopropanation reaction using trimethylsulfoxonium iodide and sodium hydride in dimethyl sulfoxide as a solvent leading to (trans)-ethyl cyclopropanecarboxylate derivatives of formula (13) (being trans ((1S,2R), (1R,2S)) mixture although the individual isomers corresponding to (1S, 2R) and (1R,2S) can be used). Hydrolysis to the corresponding (trans)-cyclopropanecarboxylic acid derivatives of formula (14) was performed using NaOH in MeOH. The reaction, first with ethyl chloroformate and triethylamine in acetone and later with sodium azide in water leads to the formation of (trans)-cyclopropanecarbonyl azide derivatives of formula (15). Reaction with tert-butanol results in the formation of tert-butyl (trans)-cyclopropylcarbamate derivatives of formula (16). Later reaction with commercially available boronic acid or boronate ester derivatives of formula (17) using acetonitrile and water as a solvent, potassium carbonate as a base and Tetrakis(triphenylphospine) Paladium (0) as a catalyst leads to the formation of tert-butyl (trans)-cyclopropylcarbamate derivatives of formula (18). Deprotection of the Boc-group using HCl in dioxane or BBr.sub.3 in dichloromethane with later HCl 2M in diethyl ether leads to the formation of the corresponding hydrochloride salt of the (trans)-cyclopropanamine derivatives of formula (19), which are also subjects of the present invention.

(116) ##STR00012##

(117) Commercially availables aldehydes of formula (21) have been subjected to a Horner-Wadsworth-Emmons reaction using triethyl phosphono acetate and potassium tert-butoxide in tetrahydrofurane at 0 C. to get the ethyl acrylate derivative of formula (22) which is subjected to cyclopropanation reaction using trimethylsulfoxonium iodide and sodium hydride in dimethyl sulfoxide as a solvent leading to (trans)-ethyl cyclopropanecarboxylate derivatives of formula (23) (being trans ((1S, 2R), (1R,2S)) mixture although the individual diastereoisomers corresponding to (1S,2R) and (1R,2S) can be used). Hydrolysis to the corresponding (trans)-cyclopropanecarboxylic acid derivatives of formula (24) was performed using NaOH in MeOH. The reaction, first with ethyl chloroformate and triethylamine in acetone and later with sodium azide in water leads to the formation of (trans)-cyclopropanecarbonyl azide derivatives of formula (25). Reaction with tert-butanol results in the formation of tert-butyl (trans)-cyclopropylcarbamate derivatives of formula (26). Their reaction with commercially available boronic acid or boronate ester derivatives of formula (20) using acetonitrile and water as a solvent, potassium carbonate as a base and Tetrakis(triphenylphospine) Paladium (0) as a catalyst leads to the formation of tert-butyl (trans)-cyclopropylcarbamate derivatives of formula (27). Deprotection of the Boc-group using HCl 2M in diethyl ether using diethyl ether as a solvent or BBr.sub.3 in dichloromethane with later HCl 2M in diethyl ether leads to the formation of the corresponding hydrochloride salt of the (trans)-cyclopropanamine derivatives of formula (28), which are also subject of the present invention.

(118) Thus, the invention further relates to methods synthesizing a compound of formula (I) according to the methods described herein.

(119) Furthermore, the invention also relates to an intermediate of formula (1), formula (2), formula (3), formula (4), formula (5), formula (6), formula (7), formula (8), formula (9), formula (10), formula (11), formula (13), formula (14), formula (15), formula (16), formula (17), formula (18), formula (19), formula (20), formula (21), formula (22), formula (23), formula (24), formula (25), formula (26), formula (27), or formula (28) wherein the various R groups are as defined herein.

(120) Furthermore, the invention also relates to a method of preparing an intermediate of formula (1), formula (2), formula (3), formula (4), formula (5), formula (6), formula (7), formula (8), formula (9), formula (10), formula (11), formula (13), formula (14), formula (15), formula (16), formula (17), formula (18), formula (19), formula (20), formula (21), formula (22), formula (23), formula (24), formula (25), formula (26), formula (27), or formula (28) wherein the various R-groups are as defined herein said method comprising contacting the starting materials and reagents under conditions sufficient to catalyze the reaction as illustrated in Scheme 1, 2, or 3.

EXAMPLES

(121) The program used to generate the names corresponding to the structures in the Example compounds below was ChemBioDraw Ultra 11.0.1. This program named the molecules as the (1S,2R) configuration due to the configuration of the input structure and the trans term has been substituted in the place of the (1S,2R) term specified by the program. The structures depicted below for the Example compounds below are shown as having one particular stereochemical configuration around the cyclopropyl carbon atoms of the phenylcyclopropylamine core (1S,2R). All the compounds synthesized in the Examples are mixtures having both configurations (1R,2S) and (1S, 2R), that is to say they are trans in respect to the cyclopropyl ring of the cyclopropyl ring system. This is due to the fact the cyclopropyl derivatives used as starting material are trans. It is contemplated that the cis configuration starting material or the individual diastereomers could be used as starting material, all of which are either commercially or synthetically available. Thus, the invention relates to compounds of Formula (I), (II), (III), (IV) or (V) and those of the examples that have specific stereochemical configurations around the cyclopropyl ring e.g., trans ((1R,2S) and (1S,2R)) and cis ((1R, 2R) and (1S, 2S)). A preferred stereochemical configuration around the cyclopropyl ring is trans.

(122) The compounds of the examples can also be synthesized or provided in a salt form. The skilled artisan is aware and capable of making salt forms and/or converting salt forms of the compounds of the invention, e.g., compounds of Formula (I), (II), (III), (IV) or (V) and those of the Examples. In some cases the compounds of Formula (I), (II), (III), (IV) or (V) and the Examples can be more stable as salt forms as compared to free base.

(123) In reference to the synthetic schemes described herein the following intermediates (and analogous intermediates or derivatives thereof) can be made using the following procedures.

Intermediate A: (E)-ethyl 3-(4-bromophenyl)acrylate

(124) ##STR00013##

(125) A solution of triethyl phosphonoacetate (13.1 g, 0.0589 mol) was added slowly (dropwise) to a solution of Potassium-tert-butoxide (6.59 g, 0.0589 mol), in dry THF (150 mL) at 5 C., stirred for 30-45 mins at the same temperature, then a solution of 4-Bromo benzaldehyde (10 g, 0.054 mol), in dry THF (50 mL) was slowly added dropwise at 5 C. over a period of 15 mins, stirred the reaction mixture for 30 mins at the same temperature. After completion of reaction by TLC, the reaction mixture was poured into ice water (300 mL), extracted with EtOAc (2200 mL). The combined organic extracts were washed with sat NaHCO.sub.3 solution (200 mL), water (200 mL), brine (200 mL) and dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated to get crude (E)-ethyl 3-(4-bromophenyl) acrylate (10 g, 72%) as pale green liquid. This is carried to next step without further purification.

Intermediate B: (Trans)-ethyl 2-(4-bromophenyl)cyclopropanecarboxylate

(126) ##STR00014##

(127) Trimethyl sulfoxonium iodide (5.19 g, 0.0236 mol) was added slowly in small portions over a period of 20 min. to a suspension of sodium hydride (0.44 g, 0.0236 mol) in dry DMSO (80 mL) at rt, stirred for 1 h, till the formation of clear solution. Then a solution of (E)-ethyl 3-(4-bromophenyl) acrylate (Intermediate A, 5 g, 0.01968), in dry DMSO (20 mL) was added slowly dropwise, stirred at rt for 30 mins. After completion of reaction, checked by TLC, the reaction mixture was poured into ice water (200 mL), extracted with EtOAc (2150 mL). Combined organic extracts were washed with ice water (2150 mL), brine (150 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated to get (trans)-ethyl 2-(4-bromophenyl)cyclopropanecarboxylate (4 g, 75.9%) as a green liquid. The crude is carried to next step without further purification.

Intermediate C: (Trans)-2-(4-bromophenyl)cyclopropanecarboxylic acid

(128) ##STR00015##

(129) NaOH 4N (20 mL) was added to a solution of (trans)-ethyl 2-(4-bromophenyl)cyclopropanecarboxylate (Intermediate B, 4 g, 0.0149 mol), in Methanol (40 mL) and stirred at rt for 2 h. After completion of reaction, checked by TLC, the solvent was evaporated and the residue was diluted with water (50 mL), acidified with HCl 4 N solution, the solid formed was filtered and dried to get (trans)-2-(4-bromophenyl)cyclopropanecarboxylic acid (2.59 g, 72%), as a white solid.

Intermediate D: (Trans)-2-(4-bromophenyl)cyclopropanecarbonyl azide

(130) ##STR00016##

(131) Ethyl chloroformate (1.9 mL) was added to a solution of (trans)-2-(4-bromophenyl)cyclopropanecarboxylic acid (Intermediate C, 4 g, 0.0165 mol) and Et.sub.3N (2.51 mL, 0.0199 mol) in acetone (60 mL) at 20 C., stirred at same temperature for 1 h, then a solution of NaN.sub.3 (1.3 g, 0.0199 mol) in water (5 mL), was added and stirred for 30 mins at rt. After completion of reaction, checked by TLC, the solvent was evaporated and crude residue was dissolved in ethyl acetate (100 mL), washed with water (40 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated to get (trans)-2-(4-bromophenyl)cyclopropanecarbonyl azide (4 g). The crude residue is carried to next step without further purification.

Intermediate E: tert-butyl (trans)-2-(4-bromophenyl)cyclopropylcarbamate

(132) ##STR00017##

(133) A solution of (trans)-2-(4-bromophenyl)cyclopropanecarbonyl azide (Intermediate D, 4 g) in tert-Butanol (40 mL) was heated at 90 C. for 16 h. After completion of reaction, checked by TLC, the solvent was evaporated residue was poured into water (50 mL), extracted with EtOAc (250 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated. The crude residue was purified by column chromatography (SiO.sub.2) by eluting with EtOAc: Petroleum ether (2:98), to get tert-butyl (trans)-2-(4-bromophenyl)cyclopropylcarbamate (2.5 g, 48% overall 2 steps) as a white solid. .sup.1H-NMR (CDCl.sub.3, 250 MHz) : 1.07-1.19 (m, 2H), 1.44 (s, 9H); 2.05-1.94 (m, 1H); 2.72-2.62 (m, 1H); 4.85 (br, 1H,); 7.09-6.96 (m, 2H); 7.44-7.33 (m, 2H).

Intermediate F: (E)-ethyl 3-(6-bromopyridin-3-yl)acrylate

(134) ##STR00018##

(135) Triethyl phosphonoacetate (26.6 g, 118.8 mmol) was added slowly dropwise to a mixture of Potassium-tert-butoxide (14.5 g, 129.6 mmol) in dry THF (200 mL) at 5 C., stirred for 20 min and then a solution of 6-bromopyridine-3-carboxaldehyde (20 g, 108 mmol) in dry THF (100 mL) was added slowly dropwise at 5 C. and stirred for 30 min. After completion, the reaction mixture was poured into ice water (350 mL) and extracted with EtOAc (2300 mL). The combined organic extracts were washed with saturated NaHCO.sub.3 solution (250 mL), water (250 mL) and brine (250 mL) and dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated to get (E)-ethyl 3-(6-bromopyridin-3-yl) acrylate (20 g, 72.9%) as brown color liquid. This is carried to next step without further purification.

Intermediate G: (Trans)-ethyl-2-(6-bromopyridin-3-yl)cyclopropanecarboxylate

(136) ##STR00019##

(137) Trimethyl sulfoxonium iodide (20.8 g, 94.7 mmol) was added in small portions to a suspension of sodium hydride (4 g, 170.6 mmol) in dry DMSO (400 mL) at rt., stirred for 1 h until clear solution was obtained. A solution of (E)-ethyl 3-(6-bromopyridin-3-yl) acrylate (Intermediate F, 20 g, 78.7 mmol) in dry DMSO (20 mL) was added and stirred for 4 h. After completion, the reaction mixture was poured into ice water (700 mL), extracted with EtOAc (2350 mL). The combined organic extracts were washed with water (250 mL), brine (250 mL) and dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated to give (trans)-ethyl-2-(6-bromopyridin-3-yl)cyclopropanecarboxylate (10 g, 47%) as brown liquid.

Intermediate H: (Trans)-2-(6-bromopyridin-3-yl)cyclopropanecarboxylic acid hydrochloride

(138) ##STR00020##

(139) NaOH 4N solution (60 mL) was added to a solution of (trans)-ethyl-2-(6-bromopyridin-3-yl)cyclopropanecarboxylate (Intermediate G, 10 g, 37.1 mmol) in methanol (100 mL) and the reaction mixture was stirred at RT for 4 h. After completion, the solvent was evaporated and the residue was diluted with ice water (250 mL) and acidified with 4 N HCl solution, the aqueous layer was extracted with EtOAc (2350 mL). The combined organic extracts were washed with water (250 mL), brine (250 mL) and dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated to give (trans)-2-(6-bromopyridin-3-yl)cyclopropanecarboxylic acid hydrochloride (5 g, 55.8%) as a light brown color solid.

Intermediate I: (Trans)-2-(6-bromopyridin-3-yl)cyclopropanecarbonyl azide

(140) ##STR00021##

(141) Ethyl chloroformate (5.8 mL, 62 mmol) was added to a solution of (trans)-2-(6-bromopyridin-3-yl)cyclopropanecarboxylic acid hydrochloride (Intermediate H, 5 g, 20.7 mmol) and Et.sub.3N (14.2 mL, 103.7 mmol) in Acetone (100 mL) at 5 C., then reaction mixture was stirred at 5 C. for 1 h, then a solution of NaN.sub.3 (2.7 g, 41.4 mmol) in water (10 mL) was added and stirred for 30 mins at RT. After completion the solvent was evaporated under vacuum. The crude residue was dissolved in ethyl acetate (200 mL), washed with water (80 mL), brine (80 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated to get (trans)-2-(6-bromopyridin-3-yl)cyclopropanecarbonyl azide (2.5 g, 45.5%) as a brown color gummy liquid.

Intermediate J: tert-butyl(trans)-2-(6-bromopyridin-3-yl)cyclopropylcarbamate

(142) ##STR00022##

(143) A solution of (trans)-2-(6-bromopyridin-3-yl)cyclopropanecarbonyl azide (Intermediate I, 2.5 g, 9.36 mmol) in tert-butanol (80 mL) was heated at 90 C. for 16 h. After completion, the solvent was evaporated under vacuum and the residue was taken in water (100 mL) and extracted with EtOAc (2100 mL). The combined organic extracts were washed with water (100 mL), brine (100 mL) and dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated. The crude residue was purified by flash column chromatography (SiO.sub.2) by eluting with EtOAc: Hexane (2:8) to get tert-butyl (trans)-2-(6-bromopyridin-3-yl)cyclopropylcarbamate (1.1 g, 37.5%) as a light yellow solid. .sup.1H-NMR (CDCl.sub.3) (ppm): 1.16 (q, 18), 1.23 (quin, 1H), 1.45 (s, 9H), 2.01 (m, 1H), 2.69 (m, 1H), 4.88 (br, 1H), 7.36 (s, 2H), 8.20 (s, 1H).

Example 1: (trans)-2-(3-(trifluoromethyl)biphenyl-4-yl)cyclopropanamine hydrochloride

(144) ##STR00023##
Step 1:

(145) To a solution of tert-butyl (trans)-2-(4-bromophenyl)cyclopropylcarbamate (Intermediate E.sub.[a2]) (1 g, 3.2 mmol), potassium carbonate (1.31 g, 9.6 mmol), 3-(trifluoromethyl)phenylboronic acid (0.73 g, 3.8 mmol) in acetonitrile: water (4:1) were degassed for 30 mins, added tetrakis triphenylphosphine palladium (36 mg, 0.032 mmol), degassed again for 10 mins, heated the reaction mixture at reflux temperature for 5 h. After completion, the reaction mixture was poured in ice water (50 mL), extracted with, ethyl acetate (250 mL). Combined extracts were washed with water (70 mL), brine (70 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated. The crude residue was purified by column chromatography (SiO.sub.2), by using EtOAc: Petroleum ether (2:8) to get tert-butyl (trans)-2-(3-(trifluoromethyl)biphenyl-4-yl)cyclopropylcarbamate (0.8 g, 66%) as a white solid.

(146) Step 2:

(147) To a solution of tert-butyl (trans)-2-(3-(trifluoromethyl)biphenyl-4-yl)cyclopropylcarbamate (200 mg, 0.53 mmol), in diethyl ether (5 mL) at 10 C. was added HCl in diethyl ether (3 mL), slowly dropwise over a period of 10 min, stirred the reaction mixture for 4 h. After completion, the solvent was evaporated, residue was triturated with hexane (5 mL) and diethyl ether (5 mL), and dried under reduced pressure to get (trans)-2-(3-(trifluoromethyl)biphenyl-4-yl)cyclopropanamine hydrochloride (140 mg, 77.8%) as a white solid. .sup.1H-NMR (DMSO-d6) (ppm): 1.27 (q, 1H), 1.46 (quin, 1H), 2.41 (m, 1H), 2.86 (m, 1H), 7.29 (d, 2H), 7.69 (m, 4H), 7.96 (m, 2H), 8.53 (s, 1H), 8.61 (br, 2H). MS (M+H): 278.3

(148) The following compounds can be synthesized following the method described for example 1 using the corresponding commercial available boronic acid/boronate ester.

Example 2: (trans)-2-(terphenyl-4-yl)cyclopropanamine hydrochloride

(149) ##STR00024##

(150) .sup.1H-NMR (DMSO-d6) (ppm): 1.27 (q, 1H), 1.43 (quin, 1H), 2.40 (m, 1H), 2.87 (m, 1H), 7.27 (d, 2H), 7.38 (t, 1H), 7.49 (t, 2H), 7.67 (d, 2H), 7.72 (d, 2H), 7.76 (s, 4H), 8.51 (s, 2H). MS (M+H): 286.4.

Example 3: 4-((trans)-2-aminocyclopropyl)biphenyl-4-ol hydrochloride

(151) ##STR00025##

(152) .sup.1H-NMR (DMSO-d6) (ppm): 1.22 (q, 1H), 1.4 (m, 1H), 2.35 (m, 1H), 2.85 (m, 1H), 6.8 (d, 2H), 7.2 (d, 2H), 7.45 (d, 2H), 7.5 (d, 2H), 8.4 (brs, 3H), 9.6 (s, 1H). MS (M+H): 226.1.

Example 4: 4-((trans)-2-aminocyclopropyl)biphenyl-3-ol hydrochloride

(153) ##STR00026##

(154) .sup.1H-NMR (DMSO-d6) (ppm): 1.24 (q, 2H), 1.43 (quin, 1H), 2.39 (m, 1H), 2.83 (m, 1H), 6.75 (d, 1H), 7.02 (m, 2H), 7.23 (d, 3H), 7.51 (d, 2H), 8.56 (br, 3), 9.54 (s, 1H). MS (M+H): 226.1.

Example 5: (trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropanamine dihydrochloride

(155) ##STR00027##
Step 1:

(156) A solution of tert-butyl (trans)-2-(6-bromopyridin-3-yl)cyclopropylcarbamate (Intermediate J.sub.[a2]) (100 mg, 0.32 mmol), potassium carbonate (132 mg, 0.96 mmol) and 3-trifluoromethylbenzeneboronic acid (72 mg, 0.38 mmol) in CH.sub.3CN: H.sub.2O (4:1) (10 mL) was degassed for 30 mins, added tetrakis triphenylphosphine palladium (37 mg, 0.032 mmol), degassed for 10 mins and heated the reaction mixture at reflux temperature for 2 h. After completion, the reaction mixture was poured in ice water (100 mL), extracted with ethyl acetate (540 mL). The combined extract were washed with water (70 mL), brine (70 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated. The crude residue was purified by column chromatography (SiO.sub.2), by using EtOAc:Petroleum ether (1:9) to get tert-butyl (trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropylcarbamate (70 mg, 58.3%) as a white solid.

(157) .sup.1H-NMR (CDCl.sub.3) (ppm): 1.26 (m, 2H), 1.46 (s, 9H), 2.10 (m, 1H), 2.78 (m, 1H), 4.86 (br, 1H), 7.55 (m, 2H), 7.65 (t, 2H), 8.14 (d, 1H), 8.24 (s, 1H), 8.54 (s, 1H). MS (M+H): 379.1.

(158) Step 2:

(159) To a solution of tert-butyl (trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropylcarbamate (70 mg, 0.185 mmol), in diethyl ether (10 mL) at 0 C. was added HCl in diethyl ether (5 mL) slowly dropwise over a period of 10 mins, stirred the reaction mixture for 2 h. After completion, the reaction mixture was filtered under inert atmosphere and washed with hexane (10 mL) and EtOAC (5 mL), and dried under reduced pressure to get (50 mg, 86.2%) of (trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropanamine dihydrochloride as a pale yellow powder. .sup.1H-NMR (D.sub.2O) S (ppm): 1.52 (q, 1H), 1.63 (quin, H), 2.66 (m, 1H), 3.08 (m, 1H), 7.72 (t, 1H), 7.89 (d, 1H), 7.98 (d, 1H), 8.09 (s, 1H), 8.14 (d, 1H), 8.27 (d, 1H), 8.61 (s, 1H). MS (M+H): 279.1.

(160) The following compounds can be synthesized following the method described for example 5 using the corresponding commercial available boronic acid/boronate ester.

Example 6: (Trans)-2-(6-(3,5-dichlorophenyl)pyridin-3-yl)cyclopropanamine hydrochloride

(161) ##STR00028##

(162) .sup.1H-NMR (D2O) (ppm): 1.58 (q, 2H), 1.69 (quin, 1H), 2.69 (m, 1H), 3.13 (m, 1H), 7.67 (s, 1H), 7.76 (s, 2H), 8.07 (d, 1H), 8.22 (m, 1H), 8.64 (s, 1H). MS (M+H): 279.1.

Example 7: (trans)-2-(6-(4-chlorophenyl)pyridin-3-yl)cyclopropanamine hydrochloride

(163) ##STR00029##

(164) .sup.1H-NMR (CD3OD) (ppm): 1.70-1.75 (m, 2H), 2.75 (m, 1H), 3.2 (m, 1H), 7.69 (d, 2H), 7.93 (d, 2H), 8.3 (m, 1H), 8.45 (s, 1H), 8.8 (s, 1H). MS (M+H): 245.1.

Example 8: (trans)-2-(6-(3-chlorophenyl)pyridin-3-yl)cyclopropanamine hydrochloride

(165) ##STR00030##

(166) .sup.1H-NMR (CD3OD) (ppm): 1.7 (m, 2H), 2.75 (br, 1H), 3.2 (br, 1H), 7.65 (m, 2H), 7.85 (d, 1H), 8.0 (s, 1H), 8.3 (d, 1H), 8.4 (br, 1H), 8.8 (s, 1H). MS (M+H): 245.1.

Example 9: (trans)-2-(6-(4-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropanamine hydrochloride

(167) ##STR00031##

(168) .sup.1H-NMR (CD3OD) (ppm): 1.67-1.73 (m, 2H), 2.78 (br, 1H), 3.21 (br, 1H), 7.97 (d, 2H), 8.14 (d, 2H), 8.35 (m, 1H), 8.45 (m, 1H), 8.88 (s, 1H). MS (M+H): 279.2.

Example 10: (trans)-2-(6-(4-methoxyphenyl)pyridin-3-yl)cyclopropanamine hydrochloride

(169) ##STR00032##

(170) .sup.1H-NMR (CD3OD) (ppm): 1.7-1.75 (m, 2H), 2.75 (m, 1H), 3.2 (m, 1H), 3.92 (s, 3H), 7.21 (d, 1H), 7.95 (d, 2H), 8.3 (d, 1H), 8.40 (d, 1H), 8.71 (s, 1H). MS (M+H): 241.2.

Example 11: (trans)-2-(6-(3-methoxyphenyl)pyridin-3-yl)cyclopropanamine hydrochloride

(171) ##STR00033##

(172) .sup.1H-NMR (CD3OD) (ppm): 1.73 (m, 2H), 2.75 (br, 1H), 3.22 (br, 1H), 3.9 (s, 3H), 7.26 (d, 1H), 7.48 (s, 2H), 7.60 (t, 1H), 8.32 (d, 1H), 8.45 (d, 1H), 8.8 (s, 1H). MS (M+H): 241.1.

Example 12: 4-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)benzonitrile dihydrochloride

(173) ##STR00034##

(174) .sup.1H-NMR (CD3OD) (ppm): 1.6-1.69 (br, 2H), 2.71 (br, 1H), 3.20 (br, 1H), 8.01 (d, 2H), 8.12 (d, 2H), 8.27 (m, 1H), 8.44 (br, 1H), 8.85 (m, 1H). MS (M+H): 236.2.

Example 13: 3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)benzonitrile hydrochloride

(175) ##STR00035##

(176) .sup.1H-NMR (CD3OD) (ppm): 1.65 (m, 2H), 2.73 (br, 1H), 3.18 (br, 1H), 7.82 (m, 1H), 8.02 (m, 1H), 8.23-8.34 (m, 4H), 8.83 (br, 1H). MS (M+H): 236.1.

Example 14: (Trans)-2-(6-p-tolylpyridin-3-yl)cyclopropanamine hydrochloride

(177) ##STR00036##

(178) .sup.1H-NMR (CD3OD) (ppm): 1.64-1.71 (m, 2H), 2.47 (s, 3H), 2.74 (m, 1H), 3.2 (m, 1H), 7.5 (d, 2H), 7.84 (d, 2H), 8.3 (d, 1H), 8.43 (d, 1H), 8.75 (s, 1H). MS (M+H): 225.2.

Example 15: (Trans)-2-(6-m-tolylpyridin-3-yl)cyclopropanamine hydrochloride

(179) ##STR00037##

(180) .sup.1H-NMR (CD3OD) (ppm): 1.63-1.71 (m, 2H), 2.49 (s, 3H), 2.76 (br, 1H), 3.2 (m, 1H), 7.55 (m, 2H), 7.74 (d, 1H), 7.78 (s, 1H), 8.31 (d, 1H), 8.46 (br, 1H), 8.79 (s, 1H). MS (M+H): 225.2.

Example 16: 4-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)phenol hydrochloride

(181) ##STR00038##

(182) .sup.1H-NMR (CD3OD) (ppm): 1.65 (m, 2H), 2.71 (m, 1H), 3.16 (m, 1H), 7.04 (d, 1H), 7.85 (d, 2H), 8.24 (d, 1H), 8.37 (d, 1H), 8.66 (s, 1H). MS (M+H): 227.2.

(183) The following compounds can be synthesized following the methodology described in Scheme 1.

Example 17: 3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)phenol dihydrochloride

(184) ##STR00039##

(185) .sup.1H-NMR (400 MHz, DMSO-D6) : 8.6-8.8 (brd, 4H), 8-7.8 (brs, 2H), 7.43 (s, 2H), 7.3 (s, 1H), 6.9 (brs, 1H), 3.0 (brs, 1H), 2.57 (brs, 1H), 1.6 (brs 1H), 1.4 (brs, 1H). MS (M+H): 227.2.

Example 18: 4-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)benzamide hydrochloride

(186) ##STR00040##

(187) .sup.1H-NMR (400 MHz CD30OD): 8.8 (s, 1H), 8.46-8.33 (m, 2H), 8.14-8.01 (band, 2H), 3.2 (m, 1H), 2.75 (brs, 1H), 1.74-1.64 (m, 2H). MS (M+H): 254.2.

Example 19: 3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)benzamide hydrochloride

(188) ##STR00041##

(189) 1H-NMR (400 MHz CD3OD): 8.83 (s, 1H), 8.45-8.33 (band, 3H), 8.15 (m, 2H), 7.77 (m, 1H), 3.21 (brs, 1H), 2.75 (m, 1H), 1.69 (m, 2H). MS (M+H): 254.2.

Example 20: 2-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)phenol hydrochloride

(190) ##STR00042##

(191) .sup.1H-NMR (400 MHz, D2O) : 8.65 (s, 1H), 8.3 (m, 2H), 7.75 (d, 1H), 7.58 (t, 1H), 7.2 (m, 2H), 3.2 (brs, 1H), 2.88 (brs, 1H), 1.75 (m, 1H), 1.6 (q, 1H). MS (M+H): 227.2.

Example 21: 3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)phenol[a2]

(192) ##STR00043##

Example 22: (trans)-2-(6-(3-methoxy-4-methylphenyl)pyridin-3-yl)cyclopropanamine hydrochloride

(193) ##STR00044##

(194) .sup.1H-NMR (400 MHz, DMSO D6) : 8.8-8.6 (brd, 4H), 8.18 (brs, 1H), 8.0 (brs, 1H), 7.7 (brs, 1H), 7.55 (brs, 1H), 7.3 (brs, 1H), 3.9 (s, 3H), 3.0 (brs, 1H), 2.6 (brs, 1H), 2.2 (s, 3H), 1.6 (brs, 1H), 1.4 (brs, 1H). MS (M+H): 255.2.

Example 23: 5-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-2-fluorophenol hydrochloride

(195) ##STR00045##

(196) .sup.1H-NMR (400 MHz, D2O) : 8.55 (s, 1H), 8.24 (d, 1H), 8.07 (d, 1H), 7.4-7.3 (m, 3H), 3.12-3.08 (m, 1H), 2.69-2.64 (m, 1H), 1.67-1.62 (m, 1H), 1.56-1.51 (m, 1H). MS (M+H): 244.9.

Example 24: 3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-5-fluorophenol hydrochloride

(197) ##STR00046##

(198) .sup.1H-NMR (400 MHz, DMSO D6) : 8.6 (s, 1H), 8.25 (d, 1H), 8.1 (d, 1H), 7.1 (d, 2H), 6.85 (d, 1H), 3.1 (brs, 1H), 2.67 (brs, 1H), 1.68 (m, 1H), 1.55 (q, 1H). MS (M+H): 245.0.

Example 25: 3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-4-fluorophenol hydrochloride

(199) ##STR00047##

(200) .sup.1H-NMR (400 MHz, DMSO D6) : 8.49 (s, 1H), 8.17 (d, 1H), 7.94 (d, 1H), 7.07 (t, 1H), 6.95 (m, 2H), 2.98 (m, 1H), 2.58 (m, 1H), 1.56 (m, 1H), 1.44 (q, 1H). MS (M+H): 244.9.

Example 26: 3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-2-fluorophenol hydrochloride

(201) ##STR00048##

(202) .sup.1H-NMR (400 MHz, D2O) : 8.63 (s, 1H), 8.24 (d, 1H), 8.05 (d, 1H), 7.23-7.14 (m, 3H), 3.1 (m, 1H), 2.7 (t, 1H), 1.63-1.66 (m, 1H), 1.54-1.57 (q, 1H). MS (M+H): 245.0.

Example 27: 3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-2,4-difluorophenol

(203) ##STR00049##

Example 28: 3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-2,4,6-trifluorophenol

(204) ##STR00050##

Example 29: 3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-5-chlorophenol hydrochloride

(205) ##STR00051##

(206) .sup.1H-NMR (400 MHz, D2O) : 8.59 (s, 1H), 8.23 (d, 1H), 8.06 (d, 1H), 7.36 (d, 1H), 7.13 (d, 2H), 3.1 (brs, 1H), 2.68 (brs, 1H), 1.66 (m, 1H), 1.54 (q, 1H). MS (M+H): 260.9.

Example 30: (trans)-2-(6-(2-fluoro-3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropanamine hydrochloride

(207) ##STR00052##

(208) .sup.1H-NMR (400 MHz, D2O) : 8.69 (s, 1H), 8.26 (d, 1H), 8.10 (d, 1H), 7.95 (q, 1H), 7.55 (t, 1H), 3.14 (brs, 1H), 2.71 (brs, 1H), 1.68 (m, 1H), 1.59 (q, 1H). MS (M+H): 296.9.

Example 31: (trans)-2-(6-(5-chlorothiophen-2-yl)pyridin-3-yl)cyclopropanamine hydrochloride

(209) ##STR00053##

(210) .sup.1H-NMR (400 MHz, D2O) : 8.38 (s, 1H), 8.02 (d, 2H), 7.90 (d, 1H), 7.58 (s, 1H), 7.09 (s, 1H), 3.04 (brs, 1H), 2.58 (brs, 1H), 1.62 (m, 1H), 1.51 (q, 1H). MS (M+H): 251.1.

Example 32: (Trans)-2-(6-(5-methylthiophen-2-yl)pyridin-3-yl)cyclopropanamine

(211) ##STR00054##

Example 33: (Trans)-2-(6-(1H-indol-6-yl)pyridin-3-yl)cyclopropanamine

(212) ##STR00055##

Example 34: (trans)-2-(6-(benzo[b]thiophen-5-yl)pyridin-3-yl)cyclopropanamine hydrochloride

(213) ##STR00056##

(214) .sup.1H-NMR (400 MHz, D2O) : 8.52 (S, 1H), 8.24 (brm, 3H), 8.12 (s, 1H), 7.72-7.70 (brm, 2H), 7.49 (d, 1H), 3.10 (brs, 1H), 2.66 (brs, 1H), 1.68 (brs, 1H), 1.57 (q, 1H). MS (M+H): 267.1.

Example 35: 3-(5-((trans)-2-aminocyclopropyl)-3-methylpyridin-2-yl)phenol hydrochloride

(215) ##STR00057##

(216) .sup.1H-NMR (400 MHz, CD.sub.3OD) : 8.6 (m, 1H), 8.30 (brs, 1H), 7.47-7.43 (m, 1H), 7.07-6.98 (m, 3H), 3.24-3.15 (m, 1H), 2.66 (brs, 1H), 2.47 (s, 3H), 1.63-1.66 (2H, m). MS (M+H): 241.2.

Example 36: (trans)-2-(6-(3-chlorophenyl)-5-methylpyridin-3-yl)cyclopropanamine

(217) ##STR00058##

(218) .sup.1H-NMR (400 MHz, CD.sub.3OD) : 8.70 (s, 1H), 8.39 (s, 1H), 7.72-7.57 (band, 4H), 3.21 (m, 1H), 2.73 (brs, 1H), 2.47 (s, 3H), 1.68 (2H, band). MS (M+H): 259.1.

Example 37: (trans)-2-(5-methyl-6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropanamine hydrochloride

(219) ##STR00059##

(220) .sup.1H-NMR (400 MHz, CD.sub.3OD) : 8.73 (brs, 1H), 8.40 (m, 1H), 8.02-8.00 (m, 2H), 7.93-7.85 (m, 2H), 3.20-3.24 (m, 1H), 2.76-2.71 (brs, 1H), 2.46 (s, 3H), 1.72-1.66 (2H, m). MS (M+H): 293.2.

Example 38: (trans)-2-(6-(4-fluoro-3-methoxyphenyl)pyridin-3-yl)cyclopropanamine hydrochloride

(221) ##STR00060##

(222) .sup.1H-NMR (400 MHz, DMSO D6) : 8.8, (m, 4H), 8.1 (m, 1H), 7.9 (2H, m), 7.65 (brs, 1H), 7.4 (t, 1H), 4.0 (s, 3H), 3.0 (brs, 1H), 2.5 (brs, 1H), 1.6 (brs, 1H), 1.4 (q, 1H). MS (M+H): 259.2.

Example 39: (trans)-2-(6-(3-fluoro-5-methoxyphenyl)pyridin-3-yl)cyclopropanamine hydrochloride

(223) ##STR00061##

(224) .sup.1H-NMR (400 MHz, DMSO D6) : 8.8-8.6 (brs, 4H), 8.0 (brs, 1H), 7.8-7.6 (brs, 1H), 7.5 (brs, 2H), 6.9 (brs, 1H), 3.8 (s, 3H), 3.0 (s, 1H), 1.5 (brs, 1H), 1.4 (brs, 1H). MS (M+H): 259.2.

Example 40: (trans)-2-(6-(2-fluoro-5-methoxyphenyl)pyridin-3-yl)cyclopropanamine hydrochloride

(225) ##STR00062##

(226) .sup.1H-NMR (400 MHz, DMSO D6) : 8.9 (d, 4H), 7.8 (s, 2H), 7.45 (s, 1H), 7.3 (t, 1H), 7.07 (brs, 1H), 3.8 (s, 3H), 3.0 (brs, 1H), 2.5 (s, 1H), 1.6 (m, 1H), 1.4 (q, 1H). MS (M+H): 259.2.

Example 41: (trans)-2-(6-(2-fluoro-3-methoxyphenyl)pyridin-3-yl)cyclopropanamine hydrochloride

(227) ##STR00063##

(228) .sup.1H-NMR (400 MHz, D2O) : 8.8 (s, 1H), 8.4 (d, 1H), 8.2 (d, 1H), 7.45 (m, 2H), 7.3 (m, 1H), 4.0 (s, 3H), 3.2 (brs, 1H), 2.8 (brs, 1H), 1.8 (brs, 1H), 1.65 (q, 1H). MS (M+H): 259.2.

Example 42: (trans)-2-(6-(3-chloro-5-methoxyphenyl)pyridin-3-yl)cyclopropanamine hydrochloride

(229) ##STR00064##

(230) .sup.1H-NMR (400 MHz, DMSO D6) : 8.8-8.6 (brd, 4H), 8.1 (m, 1H), 7.8 (m, 2H), 7.6 (s, 1H), 7.17 (s, 1H), 3.8 (s, 3H), 3.0 (brs, H), 2.5 (s, 1H), 1.58 (brs, 1H), 1.4 (q, 1H). MS (M+H): 275.2.

Example 43: (trans)-2-(6-(2-chloro-5-methoxyphenyl)pyridin-3-yl)cyclopropanamine hydrochloride

(231) ##STR00065##

(232) .sup.1H-NMR (400 MHz, DMSO D6) : 8.9-8.6 (brd, 4H), 8.0-7.8 (brd, 2H), 7.5 (m, 1H), 7.2-7.1 (brd, 2H), 3.9 (s, 3H), 3.0 (brs, 1H), 2.6 (brs, 1H), 1.6 (brs, 1H), 1.4 (brs, 1H). MS (M+H): 274.9.

Example 44: (trans)-2-(6-(3-methoxy-5-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropanamine hydrochloride

(233) ##STR00066##

(234) .sup.1H-NMR (400 MHz, DMSO 136) : 8.7-8.4 (brd, 4H), 8.10 (d, 1H), 8.02 (s, 1H), 7.92 (s, 1H), 7.71 (d, 1H), 7.31 (s, 1H), 3.94 (s, 3H), 3.0 (brs, 1H), 2.42 (brs, 1H), 1.50 (brs, 1H), 1.38 (q, 1H). MS (M+H): 309.1.

Example 45: 3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-5-methoxybenzonitrile hydrochloride

(235) ##STR00067##

(236) .sup.1H-NMR (400 MHz, D2O) : 8.65 (s, 1H), 8.27 (br, 1H), 8.10 (br, 1H), 7.73 (br, 1H), 7.61 (br, 1H), 7.53 (br, 1H), 3.90 (s, 3H) 3.12 (brs, 1H), 2.7 (brs, 1H), 1.69 (quin, 1H), 1.57 (q, 1H). MS (M+H): 266.2.

Example 46: 5-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-2-methylphenol hydrochloride

(237) ##STR00068##

(238) .sup.1H-NMR (400 MHz, DMSO D6) : 8.55 (s, 1H), 8.25 (d, 1H), 8.1 (d 1H), 7.37-7.23 (m, 3H), 3.09-3.11 (brs, 1H), 2.67 (brs, 1H), 2.23 (s, 3H), 1.66 (brs, 1H), 1.53 (q, 1H). MS (M+H): 241.0.

Example 47: 3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-4-chlorophenol hydrochloride

(239) ##STR00069##

(240) .sup.1H-NMR (400 MHz, DMSO D6) : 8.69 (s, 1H), 8.31 (d, 1H), 8.03 (d, 1H), 7.45 (d, 1H), 7.04 (m 2H), 3.12 (brs, 1H), 2.72 (brs, 1H), 1.73 (brs, 1H), 1.58 (q, 1H). MS (M+H): 260.9.

Example 48: 3-(5-((trans)-2-amninocyclopropyl)pyridin-2-yl)-5-(trifluoromethyl)phenol hydrochloride

(241) ##STR00070##

(242) .sup.1H-NMR (400 MHz, D2O) : 8.62 (s, 1H), 8.24 (d, 1H), 8.12 (d, 1H), 7.67 (s, 1H), 7.48 (s, 1H), 7.38 (s, 1H), 3.12 (brs, 1H), 2.69 (brs, 1H), 1.67 (brs, 1H), 1.57 (q, 1H). MS (M+H): 295.1.

Example 49: (trans)-2-(6-(2-fluoro-5-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropanamine hydrochloride

(243) ##STR00071##

(244) .sup.1H-NMR (400 MHz, D2O) : 8.73 (s, 1H), 8.34 (d, 1H), 8.15 (d, 1H), 8.09 (d, 1H), 7.9 (q, 1H), 7.5 (q, 1H), 3.18 (brs, 1H), 2.74 (brs, 1H), 1.71 (brs, 1H), 1.62 (q, 1H); MS (M+H): 296.9.

Example 50: (trans)-2-(6-(2-chloro-5-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropanamine hydrochloride

(245) ##STR00072##

(246) .sup.1H-NMR (400 MHz, D.sub.2O) : 8.72 (s, 1H), 8.32 (d, 1H), 8.04 (d, 1H), 7.9 (d, 1H), 7.81 (d, 2H), 3.14 (brs, 1H), 2.73 (m, 1H), 1.69 (brs, 1H), 1.59 (q, 1H). MS (M+H): 312.9.

Example 51: (trans)-2-(6-(3,5-bis(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropanamine hydrochloride

(247) ##STR00073##

(248) .sup.1H-NMR (400 MHz, D.sub.2O D6) : 8.68 (s, 1H), 8.41 (s, 2H), 8.29 (s, 1H), 8.18 (q, 2H), 3.14 (brs, 1H), 2.69 (brs, 1H), 1.69 (brs, 1H), 1.60 (q, 1H). MS (M+H): 346.8.

Example 52: N-(3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)phenyl)acetamide hydrochloride

(249) ##STR00074##

(250) .sup.1H-NMR (400 MHz, D2O) : 8.62 (s, 1H), 8.30 (d, 1H), 8.16 (d, 1H), 7.98 (s, 1H), 7.7-7.5 (m, 3H), 3.10 (brs, 4H), 2.69 (brs, 1H), 2.18 (s, 3H), 1.69 (m, 1H), 1.57 (q, 1H). MS (M+H): 268.2

Example 53: N-(3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)phenyl)methanesulfonamide hydrochloride

(251) ##STR00075##

(252) .sup.1H-NMR (400 MHz, D2O) : 8.64 (s, 1H), 8.30 (d, 1H), 8.14 (d, 1H), 7.68-7.56 (m, 1H), 7.46 (d, 1H), 3.10 (brs, 4H), 2.68 (brs, 1H), 1.68 (m, 1H), 1.58 (q, 1H). MS (M+H): 304.1.

Example 54: (trans)-2-(6-(benzo[b]thiophen-2-yl)pyridin-3-yl)cyclopropanamine hydrochloride

(253) ##STR00076##

(254) .sup.1H-NMR (400 MHz, D2O) : 8.23 (d, 1H), 7.89-7.90 (brm, 5H), 7.42 (d, 2H), 2.97 (brs, 1H), 2.46 (brs, 1H), 1.58 (m, 1H), 1.44 (q, 1H). MS (M+H): 267.1.

Example 55: (trans)-2-(6-(benzo[b]thiophen-3-yl)pyridin-3-yl)cyclopropanamine hydrochloride

(255) ##STR00077##

(256) .sup.1H-NMR (400 MHz, D2O) : 8.63 (S, 1H), 8.32 (d, 1H), 8.19 (s, 1H), 8.13 (d, 1H), 8.06 (d, 1H), 7.92 (d, 1H), 7.53 (d, 2H), 3.15 (m, 1H), 2.71 (m, 1H), 1.64 (m, 1H), 1.57 (q, 1H). MS (M+H): 267.1.

Example 56: 5-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)thiophene-2-carbonitrile hydrochloride

(257) ##STR00078##

(258) .sup.1H-NMR (400 MHz, D2O) : 8.35 (S, 1H), 7.8 (brs, 1H), 7.79 (s, 1H), 7.69 (s, 1H), 7.57 (s, 1H), 3.0 (brs, 1H), 2.53 (brs, 1H), 1.56 (brs, 1H), 1.48 (q, 1H); Mass (M+H): 242.1.

Example 57: (trans)-2-(6-(4-methylthiophen-3-yl)pyridin-3-yl)cyclopropanamine hydrochloride

(259) ##STR00079##

(260) .sup.1H-NMR (400 MHz, D2O) : 8.6 (s, 1H), 8.35 (d, 1H), 8.0 (d, 1H), 7.85 (d, 1H), 7.35 (d, 1H), 3.15 (m, 1H), 2.7 (m, 1H), 2.3 (s, 3H), 1.65 (m, 1H), 1.55 (q, 1H). MS (M+H): 231.1.

Example 58: (Trans)-2-(6-(3,4-difluoro-5-methoxyphenyl)pyridin-3-yl)cyclopropanamine hydrochloride

(261) ##STR00080##

(262) .sup.1H-NMR (400 MHz, DMSO-d6) : 8.60-8.66 (m, 4H), 8.07 (brs, 1H), 7.74 (brs, 3H), 3.99 (s, 3H), 2.97 (brs, 1H), 2.47 (brs, 1H), 1.52 (brs, 1H), 1.37 (q, 1H). MS (M+H): 277.1.

Example 59: 5-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-2,3-difluorophenol hydrochloride

(263) ##STR00081##

(264) .sup.1H-NMR (400 MHz, D2O) : 8.60 (s, 1H), 8.23 (d, 4H), 8.05 (brs, 1H), 7.22 (m, 2H), 3.10 (m, 1H), 2.67 (m, 1H), 1.66 (quin, 1H), 1.55 (q, 1H), MS (M+H): 263.1.

Example 60: (Trans)-2-(6-(1H-indazol-6-yl)pyridin-3-yl)cyclopropanamine hydrochloride

(265) ##STR00082##

(266) .sup.1H-NMR (400 MHz, D2O) : 8.64 (brs, 1H), 8.35 (m, 1H), 8.25 (m, 2H), 8.07 (m, 2H), 7.56 (br, 1H), 3.15 (brs, 1H), 2.72 (brs, 1H), 1.70 (quin, 1H), 1.58 (q, 1H). MS (M+H): 251.1.

Example 61: (Trans)-2-(6-(9H-carbazol-2-yl)pyridin-3-yl)cyclopropanamine hydrochloride

(267) ##STR00083##

(268) .sup.1H-NMR (400 MHz, DMSO-d6) : 8.70 (s, 1H), 8.32 (d, 1H), 8.16-8.24 (m, 3H), 8.04 (d, 1H), 7.82 (d, 1H), 7.58 (d, 1H), 7.49 (t, 1H), 7.24 (t, 1H), 3.03 (brs, 1H), 2.57 (brs, 1H), 1.56 (brs, 1H), 1.44 (brs, 1H). MS (M+H): 300.1.

Example 62: 6-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)indolin-2-one hydrochloride

(269) ##STR00084##

(270) .sup.1H-NMR (400 MHz, DMSO-d6) : 8.62 (s, 1H), 7.96 (d, 1H), 7.80 (d, 1H), 7.62 (d, 1H), 7.51 (s, 1H), 7.33 (d, 1H), 2.98 (brs, 1H), 2.47 (brs, 1H), 1.51 (quin, 1H), 1.39 (q, 1H). MS (M+H): 266.1.

Example 63: Enantiomers of 4-((trans)-2-aminocyclopropyl)biphenyl-3-ol hydrochloride

(271) ##STR00085##

(272) Each of these compounds corresponds to each of the possible trans-isomers [(1R,2S) and (1S,2R)] of the product described in Example 4. The synthetic procedure used for their synthesis was similar to the one described in Example 4. Chiral HPLC resolution of the diastereomeric mixture was performed at the N-Boc stage, followed by final carbamate deprotection of each of these two enantiomers.

(273) The conditions used to perform this chiral separation are:

(274) Separation by chiral preparative HPLC: Every injection is prepared from 40 mg of the racemic mixture dissolved in a mixture of EtOH, Hexane, THF and diethylamine. These injections were separated on a Chiral Pak-IC (25030 mm ID) 5 m at ambient temperature eluting with 0.2% DEA in 93/7 hexane/EtOH at 35 ml/min. The solutions from the chiral separation were concentrated in vacuum to afford the resolved enantiomers.

(275) Analytical determination of enantiomeric excess (ee): ChiralCel OD-H 2504.6 mm ID, 5 m, 0.1% TFA in 75/25 hexane/EtOH at 1 mL/min at ambient temperature, with UV analysis at 260 nm. Enantiomers eluted at 4.93 and 7.90 min, each with >98% enantiomeric excess.

(276) Analytical purity: Acquity UPLC BEH C18 1002.1 mm ID, 1.71 m, 0.025% TFA in a gradient H2O:ACN (T/% B, 0/10, 4/80, 6/80, 6.1/10) at 0.3 mL/min at ambient temperature, with UV analysis at 259 nm. Elution at 2.40 min, each with >99.5% purity. Without being bound by theory, it is believed that mixtures, e.g., racemates corresponding to a compound of Formula (I), (II), (III), (IV) or (V) can be resolved in the individual enantiomers or an enantiomer substantially free of the other enantiomer. Thus, the skilled artisan, in view of the disclosure described herein can isolate or purify enantiomers from racemates or mixtures of enantiomers in view of the disclosure herein utilizing standard organic chemistry techniques for separating enantiomers.

Example 64: N-(3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)phenyl)benzenesulfonamide hydrochloride

(277) ##STR00086##

(278) .sup.1H-NMR (400 MHz, CD3OD) : 8.74 (s, 1H), 8.34 (m, 1H), 8.14 (m, 1H), 7.82 (d, 2H), 7.73 (br, 1H), 7.58 (t, 2H), 7.49 (t, 3H), 7.30 (t, 1H), 3.17 (m, 1H), 2.68 (m, 1H), 1.65 (m, 2H). MS (M+H): 366.0.

Example 65: N-(3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)phenyl)propane-2-sulfonamide hydrochloride

(279) ##STR00087##

(280) .sup.1H-NMR (400 MHz, CD3OD) : 8.77 (s, 1H), 8.31 (d, 1H), 8.19 (d, 1H), 7.83 (s, 1H), 7.55-7.65 (m, 2H), 7.48 (d, 1H), 3.38 (m, 1H), 3.17 (m, 1H), 2.70 (m, 1H), 1.65 (m, 2H), 1.36 (d, 6H). MS (M+H): 332.3.

Example 66: 4-((trans)-2-aminocyclopropyl)-4-fluorobiphenyl-3-ol hydrochloride

(281) ##STR00088##

(282) .sup.1H-NMR (400 MHz, D2O) : 7.56 (m, 2H), 7.2-7.32 (m, 4H), 7.1-7.2 (m, 1H), 2.90 (m, 1H), 2.45 (m, 1H), 1.45 (quin, 1H), 1.37 (q, 1H). MS (M+H): 242.1.

Example 67: 4-((trans)-2-aminocyclopropyl)-5-chlorobiphenyl-3-ol hydrochloride

(283) ##STR00089##

(284) .sup.1H-NMR (400 MHz, D2O) : 7.2-7.4 (m, 2H), 6.86-7.15 (m, 3H), 6.65-6.85 (m, 2H), 2.72 (brs, 1H), 2.28 (brs, 1H), 1.29 (brs, 1H), 1.18 (brs, 1H). MS (M+H): 258.1.

Example 68: N-(4-((trans)-2-aminocyclopropyl)biphenyl-3-yl)benzenesulfonamide hydrochloride

(285) ##STR00090##

(286) .sup.1H-NMR (400 MHz, DMSO-d6) : 10.45 (s, 1H), 8.42 (brs, 3H), 7.80 (d, 2H), 7.61 (m, 1H), 7.57 (q, 2H), 7.43 (d, 2H), 7.32 (m, 3H), 7.24 (d, 2H), 7.06 (m, 1H), 2.85 (m, 1H), 2.35 (m, 1H), 1.42 (quin, 1H), 1.26 (q, 1H). MS (M+H): 363.3.

Example 69: N-(4-((trans)-2-aminocyclopropyl)biphenyl-3-yl)propane-2-sulfonamide hydrochloride

(287) ##STR00091##

(288) .sup.1H-NMR (400 MHz, DMSO-d6) : 7.55 (d, 2H), 7.47 (s, 1H), 7.43 (t, 1H), 7.36 (d, 1H), 7.26 (d, 2H), 7.22 (d, 1H), 3.31 (m, 1H), 2.84 (m, 1H), 2.33 (m, 1H), 1.40 (m, 1H), 1.25 (d, 7H). MS (M+H): 329.0

Example 70: N-(4-((trans)-2-aminocyclopropyl)biphenyl-3-yl)methanesulfonamide hydrochloride

(289) ##STR00092##

(290) .sup.1H-NMR (400 MHz, D2O) : 7.55 (d, 2H), 7.47 (d, 3H), 7.23 (d, 3H), 3.07 (s, 3H), 2.90 (m, 1H), 2.45 (m, 1H), 1.46 (quin, 1H), 1.37 (q, 1H). MS (M+H): 301.2.

Example 71: N-(2-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)phenyl)methanesulfonamide hydrochloride

(291) ##STR00093##

(292) .sup.1H-NMR (400 MHz, DMSO-d6) : 8.63 (s, 1H), 8.01 (d, 1H), 7.86 (t, 1H), 7.54 (m, 2H), 7.33 (t, 1H), 2.99 (m, 1H), 2.94 (s, 3H), 2.47 (m, 1H), 1.40-1.55 (m, 2H). MS (M+H): 304.0.

Example 72: 3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-4-methoxybenzonitrile hydrochloride

(293) ##STR00094##

(294) .sup.1H-NMR (400 MHz, CD3OD) : 8.83 (s, 1H), 8.40 (d, 1H), 8.20 (d, 1H), 8.15 (s, 1H), 8.05 (dd, 1H), 7.46 (d, 1H), 4.01 (s, 3H), 3.21 (m, 1H), 2.74 (m, 1H), 1.60-1.75 (m, 2H). MS (M+H): 266.3.

Example 73: N-(4-((trans)-2-aminocyclopropyl)biphenyl-2-yl)methanesulfonamide hydrochloride

(295) ##STR00095##

(296) .sup.1H-NMR (400 MHz, DMSO-d6) : 7.37-7.42 (m, 5H), 7.34 (d, 1H), 7.24 (d, 2H), 2.85 (m, 1H), 2.75 (s, 3H), 2.37 (m, 1H), 1.42 (quin, 1H), 1.31 (q, 1H). MS (MH): 301.2.

Example 74: 4-((trans)-2-aminocyclopropyl)-6-methoxybiphenyl-3-carbonitrile hydrochloride

(297) ##STR00096##

(298) .sup.1H-NMR (400 MHz, DMSO-d6) : 8.82 (d, 1H), 7.69 (s, 1H), 7.44 (d, 2H), 7.30 (d, 1H), 7.24 (d, 2H), 3.84 (s, 3H), 2.84 (m, 1H), 2.36 (m, 1H), 1.40 (quin, 1H), 1.31 (q, 1H). MS (M+H): 265.3

Example 75: N-(4-((trans)-2-aminocyclopropyl)-6-methoxybiphenyl-3-yl)methanesulfonamide hydrochloride

(299) ##STR00097##

(300) .sup.1H-NMR (400 MHz, DMSO-d6) : 9.47 (s, 1H), 8.38 (brs, 3H), 7.37 (d, 2H), 7.20 (t, 3H), 7.05-7.18 (m, 2H), 3.73 (s, 3H), 2.92 (s, 3H), 2.84 (m, 1H), 2.34 (m, 1H), 1.39 (quin, 1H), 1.25 (q, 1H). MS (MH): 331.3

(301) The following compounds can be synthesized following the methodology described in Scheme 2

Example 76: (trans)-2-(2-chloro-6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropanamine hydrochloride

(302) ##STR00098##
Step 1:

(303) A solution of (E)-ethyl 3-(6-bromopyridin-3-yl)acrylate (Int-F) (20 g, 78.125 mmol), 3-trifloro methyl boronic acid (17.7 g, 93.75 mmol) and K.sub.2CO.sub.3 (32 g, 234 mmol) in ACN: H.sub.2O (4:1), was degassed for 20 minutes. Pd (PPh.sub.3).sub.4 (900 mg, 0.078 mmol) was added and heated at reflux for 4 h. After completion, the reaction mixture was poured into water (200 mL) and extracted with EtOAc (2200 mL). The combined extracts were washed with water (100 mL), brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated. The crude residue was purified by column chromatography (SiO.sub.2) by using EtOAc: Pet ether (2:8) to afford (E)-ethyl 3-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)acrylate (13 g, 52%) as yellow solid.

(304) Step 2:

(305) m-CPBA (13.9 g, 80.97 mmol) was added portion wise to a solution of trans-ethyl 3-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)acrylate (13 g, 40.47 mmol) in DCM (150 mL) at 0 C. over a period of 30 min. and stirred at RT for 16 h. After completion, the reaction mixture was poured into ice water (100 mL), extracted with DCM (2100 mL). Combined organic extracts were treated with sodium metabisulphite, washed with water (100 mL), brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated. The crude residue was purified by column chromatography (SiO.sub.2) by using MeOH: chloroform (1:99) to afford (9 g, 66%) (E)-5-(3-ethoxy-3-oxoprop-1-enyl)-2-(3-(trifluoromethyl)phenyl)pyridine 1-oxide as yellow solid.

(306) Step 3:

(307) A solution of (E)-5-(3-ethoxy-3-oxoprop-1-enyl)-2-(3-(trifluoromethyl)phenyl)pyridine 1-oxide (9 g, 26.7 mmol) in POCl.sub.3 (45 mL) was stirred at 80 C. for 5 h. After completion, reaction mixture was poured into ice water (150 mL), extracted with EtOAc (2100 mL), combined extracts were treated with NaHCO.sub.3 solution, washed with water (100 mL), brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated. The crude residue was purified by column chromatography by using (SiO.sub.2) EtOAc: Pct ether (2:98) to afford (E)-ethyl 3-(2-chloro-6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)acrylate (6.3 g, 67%) as yellow solid.

(308) Step 4:

(309) Trimethyl sulfoxonium iodide (4.6 g, 21.25 mmol) was added slowly in small portions over a period of 20 min, to a suspension of sodium hydride (850 mg, 21.25 mmol) in dry DMSO (120 mL) at RT stirred for 1 h, till the formation of clear solution. A solution of (E)-ethyl 3-(2-chloro-6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)acrylate (6.3 g, 17.71 mmol) in dry DMSO (100 mL) was added slowly dropwise and stirred at RT for 30 mins. After completion, the reaction mixture was poured into ice water (100 mL), extracted with EtOAc (2100 mL). The combined extracts were washed with ice water (2100 mL), brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated to afford trans-ethyl 2-(2-chloro-6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropanecarboxylate (crude) (5.5 g) as reddish brown liquid. The crude was carried to next step without further purification.

(310) Step 5:

(311) 4N NaOH solution (20 mL) was added to a solution of trans-ethyl 2-(2-chloro-6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropanecarboxylate (5.5 g, 14.90 mmol), in Methanol (50 mL) and stirred at RT for 2 h. After completion, the solvent was evaporated and the residue was diluted with water (50 mL), acidified with 4 N HCl solution, extracted with EtOAc (250 mL). The combined extracts were washed with water (250 mL), brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated to afford trans-2-(2-chloro-6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropanecarboxylic acid (4.9 g), as a yellow liquid. The crude was carried to next step without further purification.

(312) Step 6:

(313) Ethyl chloroformate (1.8 mL, 18.86 mmol) was added to a solution of trans-2-(2-chloro-6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropane carboxylic acid (4.9 g, 14.36 mmol), TEA (2.9 mL, 21.54 mmol) in acetone (70 mL) at 20 C. and stirred at for 1 h, then a solution of NaN.sub.3 (1.86 g, 28.71 mmol), in water (10 mL) was added and stirred for 30 mins at RT. After completion, the solvent was evaporated and crude residue was dissolved in ethyl acetate (100 mL), washed with water (40 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated to afford trans-2-(2-chloro-6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropanecarbonyl azide (5 g). The crude was carried to next step without further purification.

(314) Step 7:

(315) A solution of trans-2-(2-chloro-6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropanecarbonyl azide (5 g, 13.66 mmol) in tert-Butanol (100 mL) was heated at 90 C. for 16 h. After completion, the solvent was evaporated residue was taken in water (100 mL), extracted with EtOAc (250 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated. The crude residue was purified by column chromatography by using (SiO.sub.2) EtOAc: Pet ether (2:98) to afford tert-butyl (trans)-2-(2-chloro-6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropylcarbamate (1.6 g, 28.5%) as a white solid.

(316) Step 8:

(317) HCl in dioxane (1 mL) was added to a solution of tert-butyl (trans)-2-(2-chloro-6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropylcarbamate (100 mg, 0.242 mmol) in dioxane (2 mL) at 0 C. and stirred for 3 h at RT. After completion, the solvent was evaporated, residue was triturated with Et2O and dried to afford trans-2-(2-chloro-6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropanamine hydrochloride (80 mg, 95%) as white solid.

(318) .sup.1H-NMR (400 MHz, DMSO D6) : 8.8-8.6 (brs, 3H), 8.4 (d, 2H), 8.2 (d, 1H), 7.85-7.78 (m, 3H), 3.05 (brs, 1H), 2.65 (brs, 1H), 1.55 (brs, 1H), 1.4 (q, 1N). MS (M+H): 313.1.

Example 77: (trans)-2-(2-(4-chlorophenyl)-6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropanamine hydrochloride

(319) ##STR00099##

(320) This compound could be synthesized following the method described for example 77 but previous to the Boc-deprotection (step 8) a Suzuki coupling (step 8) is performed to get the desired product.

(321) Step 8:

(322) A solution of tert-butyl (trans)-2-(2-chloro-6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropylcarbamate (150 mg, 0.364 mmol), 4-chlorophenylboronic acid (67.3 mg, 0.432 mmol) and K.sub.2CO.sub.3 (149 mg, 1.09 mmol) in acetonitrile: water (4:1) was degassed for 20 min. Tetrakis triphenylphosphine palladium (4.2 mg, 0.00364 mmol) was added and the reaction mixture was heated at reflux for 16 h. After completion, the reaction mixture was poured into ice water (25 mL) and extracted with EtOAc (225 mL). The combined extracts were washed with water (25 mL), brine (25 mL) and dried over anhydrous Na.sub.2SO.sub.4 filtered and evaporated. The crude residue was purified by column chromatography (SiO.sub.2) using EtOAc: Pet ether (1:9) to afford tert-butyl (trans)-2-(2-(4-chlorophenyl)-6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropylcarbamate (140 mg, 79%) as white solid.

(323) Step 9:

(324) HCl in dioxane (2 mL) was added to a solution of tert-butyl (trans)-2-(2-(4-chlorophenyl)-6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropylcarbamate (130 mg, 0.315 mmol) in dioxane (2 mL) at 0 C. and stirred for 3 h at RT. After completion, the solvent was evaporated and the residue was triturated with Et2O to afford (trans)-2-(2-(4-chlorophenyl)-6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropanamine hydrochloride (80 mg, 70.7%) as pale yellow solid. .sup.1H-NMR (400 MHz, DMSO D6) : 8.6-8.5 (brs, 3H), 8.45 (d, 2H), 8.1 (d, 1H), 7.7-7.8 (m, 5H), 7.6 (d, 2H), 3.1 (brs, 1H), 2.4 (brs, 1H), 1.4-1.35 (m, 2H). MS (M+H): 389.1

(325) The following compounds could be synthesized following the method described for example 77 using the corresponding commercially available boronic acid/boronate ester.

Example 78: 4-(3-((trans)-2-aminocyclopropyl)-6-(3-(trifluoromethyl)phenyl)pyridin-2-yl)phenol hydrochloride

(326) ##STR00100##

(327) .sup.1H-NMR (400 MHz, DMSO D6) : 8.6 (brs, 3H), 8.45 (s, 2H), 7.85-7.7 (m, 2H), 7.6 (m, 3H), 6.97 (d, 2H), 3.1 (brs, 1H), 2.5 (brs, 1H), 1.37 (m, 1H), 1.3 (q, 18). MS (M+H): 371.2.

Example 79: 4-(3-((trans)-2-aminocyclopropyl)-6-(3-(trifluoromethyl)phenyl)pyridin-2-yl)benzamide hydrochloride

(328) ##STR00101##

(329) .sup.1H-NMR (400 MHz, DMSO D6) : 8.5 (brs, 3H), 8.45 (s, 2H), 8.15 (m, 2H), 8.1 (d, 2H), 7.8-7.7 (m, 5H), 7.5 (brs, 1H), 3.1 (brs, 18), 2.45 (brs, 1H), 1.3 (m, 2H). MS (M+H): 398.1.

Example 80: (trans)-2-(2-methyl-6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropanamine hydrochloride

(330) ##STR00102##

(331) .sup.1H-NMR (400 MHz, DMSO D6) : 8.75 (brs, 3H), 8.4 (s, 1H), 8.35 (d, 1H), 8.0 (s, 1H), 7.85 (d, 1H), 7.8-7.7 (m, 2H), 2.87 (brs, 1H), 2.8 (s, 3H), 2.65 (brs, 1H), 1.5 (m, 1H), 1.4 (q, 1H). MS (M+H): 293.1.

(332) The following compounds can be synthesized following the methodology described in Schemes 1 and 2.

Example 81: 3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-5-hydroxybenzonitrile hydrochloride

(333) ##STR00103##

5-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-2,3-difluorophenol hydrochloride

Example 82: (Trans)-2-(6-(3-chloro-4-fluoro-5-methoxyphenyl)pyridin-3-yl)cyclopropanamine hydrochloride

(334) ##STR00104##

Example 83: 5-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-3-chloro-2-fluorophenol hydrochloride

(335) ##STR00105##

Example 84: 6-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)benzofuran-2(3H)-one hydrochloride

(336) ##STR00106##

Example 85: 4-(5-((trans)-2-aminocyclopropyl)pyridin-2(1H)-one hydrochloride

(337) ##STR00107##

Example 86: 4-((trans)-2-aminocyclopropyl)-5-chloro-4-fluorobiphenyl-3-ol hydrochloride

(338) ##STR00108##

Example 87: 4-((trans)-2-aminocyclopropyl)-6-hydroxybiphenyl-3-carbonitrile hydrochloride

(339) ##STR00109##

(340) .sup.1HNMR (400 MHz, DMSO-d6, D2O Exchange) : 7.67 (s, 1H), 7.64 (d, J=8 Hz, 1H), 7.50 (d, J=8 Hz, 2H), 7.22 (d, J=8 Hz, 2H), 7.08 (d, J=8 Hz, 1H), 2.82-2.90 (m, 1H), 2.33-2.40 (m, 18), 1.38-1.45 (m, 1H), 1.30 (q, J=7 Hz, 1H); Mass (MH): 249.3

Example 88: N-(4-((trans)-2-aminocyclopropyl)-6-hydroxybiphenyl-3-yl)methanesulfonamide hydrochloride

(341) ##STR00110##

(342) .sup.1HNMR (400 MHz, D2O) : 7.53 (d, J=8 Hz, 2H), 7.31 (d, J=8 Hz, 2H), 7.20-7.28 (m, 2H), 7.06 (d, J=8 Hz, 1H), 3.10 (s, 1H), 2.94-3.04 (m, 1H), 2.48-2.58 (m, 1H), 1.48-1.58 (m, 1H), 1.44 (q, J=7 Hz, 1H); Mass (MH): 317

Example 89: 3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-4-hydroxybenzonitrile hydrochloride

(343) ##STR00111##

(344) .sup.1HNMR (400 MHz, D2O) : 8.45 (s, 1H), 8.03-8.13 (m, 1H), 7.92-8.02 (m, 2H), 7.66 (d, J=9 Hz, 1H), 7.03 (d, J=8 Hz, 1H), 3.02-3.10 (m, 1H), 2.56-2.64 (m, 1H), 1.57-1.67 (m, 1H), 1.45-1.56 (m, 1H); Mass (MH): 250.0

Example 90: N-(3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-4-hydroxyphenyl)methanesulfonamide hydrochloride

(345) ##STR00112##

(346) .sup.1HNMR (400 MHz, DMSO-d6, D2O Exchange) : 8.60 (s, 1H), 8.06 (d, J=9 Hz, 1H), 7.95 (d, J=9 Hz, 1H), 7.67 (s, 1H), 7.24 (d, =9 Hz, 1H), 7.00 (d, J=9 Hz, 1H), 2.96-3.06 (m, 1H), 2.94 (s, 1H), 2.45-2.55 (m, 1H), 1.48-1.58 (m, 1H), 1.41 (q, J=7 Hz, 1H); Mass (MH): 318.0

Example 91: N-(3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-5-(trifluoromethyl)phenyl)ethanesulfonamide hydrochloride

(347) ##STR00113##

Example 92: N-(3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-5-(trifluoromethyl)phenyl)methanesulfonamide hydrochloride

(348) ##STR00114##

Example 93: N-(3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-4-methoxyphenyl)methanesulfonamide hydrochloride

(349) ##STR00115##

(350) .sup.1HNMR (400 MHz, CD3OD) : 8.79 (s, 1H), 8.41 (d, J=8 Hz, 1H), 8.18 (d, J=8 Hz, 1H), 7.58 (s, 1H), 7.50 (d, J=9 Hz, 1H), 7.30 (d, J=9 Hz, 1H), 3.93 (s, 3H), 3.17-3.23 (m, 1H), 2.98 (s, 3H), 2.67-2.78 (m, 1H), 1.62-1.77 (m, 2H); Mass (MH): 332.3

Example 94: N-(4-((trans)-2-aminocyclopropyl)-5-chloro-[1,1-biphenyl]-3-yl)methanesulfonamide hydrochloride

(351) ##STR00116##

(352) .sup.1HNMR (400 MHz, D2O) : 7.53 (brs, 2H), 7.47 (brs, 1H), 7.32 (brs, 1H), 7.25 (brs, 3H), 3.09 (s, 3H), 2.83-2.94 (m, 1H), 2.40-2.49 (m, 1H), 1.42-1.53 (m, 1H), 1.30-1.41 (m, 1H); Mass (MH): 335.0

Example 95: N-(3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-5-chlorophenyl)methanesulfonamide hydrochloride

(353) ##STR00117##

(354) .sup.1HNMR (400 MHz, D2O) : 8.44 (s, 1H), 8.00 (d, J=8 Hz, 1H), 7.85 (d, J=8 Hz, 1H), 7.42-7.52 (brs, 1H), 7.30-7.40 (brs, 1H), 7.22-7.30 (brs, 1H), 2.98 (s, 3H), 2.92-3.02 (m, 1H), 2.50-2.58 (m, 1H), 1.45-1.58 (m, 1H), 1.36-1.44 (m, 1H); Mass (MH): 336.3

Example 96: N-(4-((trans)-2-aminocyclopropyl)-4-fluoro-[1,1-biphenyl]-3-yl)methanesulfonamide hydrochloride

(355) ##STR00118##

(356) .sup.1HNMR (400 MHz, D2O) : 7.63 (d, J=8 Hz, 1H), 7.50-7.60 (m, 3H), 7.25-7.36 (m, 1H), 7.27 (d, J=8 Hz, 2H), 3.15 (s, 3H), 2.88-2.95 (m, 1H), 2.42-2.55 (m, 1H), 1.42-1.55 (m, 1H), 1.39 (q, J=7 Hz, 1H); Mass (MH): 319.3

Example 97: N-(5-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-2-fluorophenyl)methanesulfonamide hydrochloride

(357) ##STR00119##

(358) .sup.1HNMR (400 MHz, D2O) : 8.65 (s, 1H), 8.33 (d, J=8 Hz, 1H), 8.16 (d, J=8 Hz, 1H), 7.85-7.94 (brs, 1H), 7.71-7.80 (brs, 1H), 7.50 (t, J=9 Hz, 1H), 3.19 (s, 3H), 2.68-2.80 (m, 1H), 1.65-1.78 (m, 1H), 1.58-1.65 (m, 1H); Mass (M+H): 322.10

Example 98: N-(3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)phenyl)ethanesulfonamide hydrochloride

(359) ##STR00120##

(360) .sup.1HNMR (400 MHz, DMSO-d6, D2O exchange) : 8.61 (s, 1H), 7.93 (d, J=8 Hz, 1H), 7.88 (s, 1H), 7.80 (d, J=8 Hz, 1H), 7.72 (d, J=8 Hz, 1H), 7.50 (t, J=8 Hz, 1H), 7.32 (d, J=8 Hz, 1H), 3.15 (q, J=7 Hz, 2H), 2.90-3.00 (m, 1H), 2.46-2.56 (m, 1H), 1.48-1.58 (m, 1H), 1.42 (q, J=7 Hz, 1H), 1.23 (t, J=7 Hz, 3H); Mass (MH): 316.3

Example 99: N-(3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)phenyl)-4-cyanobenzenesulfonamide hydrochloride

(361) ##STR00121##

(362) .sup.1HNMR (400 MHz, D2O) : 8.66 (s, 1H), 8.28 (d, J=8 Hz, 1H), 8.08 (d, J=8 Hz, 1H), 7.93 (s, 4H), 7.69 (d, J=6 Hz, 1H), 7.63 (s, 1H), 7.56 (t, J=8 Hz, 1H), 7.31 (d, J=8 Hz, 1H), 3.15-3.25 (m, 1H), 2.72-2.80 (m, 1H), 1.71-1.80 (m, 1H), 1.62 (q, J=7 Hz, 1H); Mass (MH): 389.3

Example 100: N-(3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)phenyl)-3-cyanobenzenesulfonamide hydrochloride

(363) ##STR00122##

(364) .sup.1HNMR (400 MHz, D2O) : 8.58 (s, 1H), 8.18-8.26 (m, 1H), 8.11 (brs, 1H), 8.00 (d, J=8 Hz, 2H), 7.91-8.01 (m, 1H), 7.60-7.71 (m, 2H), 7.55 (s, 1H), 7.44-7.52 (m, 1H), 7.24 (brs, 1H), 3.08-3.18 (m, 1H), 2.63-2.73 (m, 1H), 1.63-1.73 (m, 1H), 1.55 (q, J=7 Hz, 1H); Mass (MH): 389.3

Example 101: N-(3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)phenyl)-2-cyanobenzenesulfonamide hydrochloride

(365) ##STR00123##

(366) .sup.1HNMR (400 MHz, D2O) : 8.59 (s, 1H), 8.20 (d, J=8 Hz, 1H), 8.08 (d, J=8 Hz, 1H), 8.01 (d, J=9 Hz, 2H), 7.89 (d, J=8 Hz, 1H), 7.83 (t, J=8 Hz, 1H), 7.75 (t, J=8 Hz, 1H), 7.62-7.68 (m, 2H), 7.48 (t, J=8 Hz, 1H), 7.20 (d, J=8 Hz, 1H), 3.08-3.16 (m, 1H), 2.64-2.72 (m, 1H), 1.63-1.74 (m, 1H), 1.55 (q, J=7 Hz, 1H); Mass (MH): 389.3

Example 102: N-(3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-5-(trifluoromethyl)phenyl)-4-cyanobenzenesulfonamide hydrochloride

(367) ##STR00124##

(368) .sup.1HNMR (400 MHz, D2O) : 8.59 (brs, 1H), 8.04-8.14 (m, 1H), 7.78-7.97 (m, 6H), 7.68-7.78 (m, 1H), 7.42-7.50 (m, 1H), 3.08-3.18 (m, 1H), 2.60-2.70 (m, 1H), 1.61-1.72 (m, 1H), 1.50-1.60 (m, 1H); Mass (M+H): 459.2

Example 103: N-(4-((trans)-2-aminocyclopropyl)-[1,1-biphenyl]-3-yl)-1,1,1-trifluoromethanesulfonamide hydrochloride

(369) ##STR00125##

(370) .sup.1HNMR (400 MHz, D2O) : 7.30-7.60 (brs, 5H), 7.10-7.30 (m, 3H), 2.80-2.92 (m, 1H), 2.38-2.48 (m, 1H), 1.40-1.50 (m, 1H), 1.22-1.40 (m, 1H); Mass (MH): 355.3

Example 104: 4((trans)-2-aminocyclopropyl)-6-hydroxy-[1,1-biphenyl]-3-carbonitrile hydrochloride

(371) ##STR00126##

(372) .sup.1HNMR (400 MHz, D2O) : 8.73 (s, 1H), 8.34 (brs, 2H), 8.23 (d, J=8 Hz, 1H), 8.17 (d, J=8 Hz, 1H), 8.13 (d, J=8 Hz, 1H), 7.92 (t, J=8 Hz, 1H), 3.18-3.28 (m, 1H), 2.74-2.84 (m, 1H), 2.64 (s, 3H), 1.72-1.82 (m, 1H), 1.65 (q, J=7 Hz, 1H); Mass (MH): 302.3

Example 105: 4-((trans)-2-aminocyclopropyl)-[1,1-biphenyl]-2-ol hydrochloride

(373) ##STR00127##

(374) .sup.1HNMR (400 MHz, D2O) : 7.46 (brs, 2H), 7.20-7.35 (m, 4H), 6.94-7.04 (m, 2H), 2.84-2.95 (m, 1H), 2.41-2.50 (m, 1H), 1.40-1.52 (m, 1H), 1.34-1.43 (m, 1H); Mass (M+H): 226.18

Example 106: 4-((trans)-2-aminocyclopropyl)-3-methoxy-[1,1-biphenyl]-3-ol hydrochloride

(375) ##STR00128##

(376) .sup.1HNMR (400 MHz, D2O) : 7.39-7.49 (m, 1H), 7.20-7.34 (m, 3H), 7.08-7.20 (m, 2H), 6.92-7.00 (m, 1H), 3.99 (s, 3H), 2.85-2.94 (m, 1H), 2.52-2.62 (m, 1H), 1.42-1.52 (m, 1H), 1.35-1.43 (m, 1H); Mass (M+H): 256.0

(377) The following compounds can be synthesized following the methodology described in Scheme 3.

Example 107: 3-(6-((trans)-2-aminocyclopropyl)pyridin-3-yl)phenol hydrochloride

(378) ##STR00129##

Example 108: (Trans)-2-(5-(3-methoxyphenyl)pyridin-2-yl)cyclopropanamine hydrochloride

(379) ##STR00130##

Example 109: 4-(6-((trans)-2-aminocyclopropyl)pyridin-3-yl)phenol hydrochloride

(380) ##STR00131##

Example 110: 2-(6-((trans)-2-aminocyclopropyl)pyridin-3-yl)phenol hydrochloride

(381) ##STR00132##

Example 111: 2-(5-((trans)-2-aminocyclopropyl)thiophen-2-yl)phenol hydrochloride

(382) ##STR00133##

Example 112: 3-(5-((trans)-2-aminocyclopropyl)thiophen-2-yl)phenol hydrochloride

(383) ##STR00134##

Example 113: 3-(5-((trans)-2-aminocyclopropyl)thiophen-2-yl)phenol trihydrochloride

(384) ##STR00135##

(385) .sup.1HNMR (400 MHz, D2O) : 7.15-7.36 (m, 3H), 7.10 (brs, 1H), 6.80-6.92 (m, 2H), 2.88-2.98 (m, 1H), 2.58-2.64 (m, 1H), 1.46-1.58 (m, 1H), 1.40 (q, J=7 Hz, 1H); Mass (M+H): 232.2

Example 114: 4-(5-((trans)-2-aminocyclopropyl)thiophen-2-yl)phenol hydrochloride

(386) ##STR00136##

Example 115: 2-(5-((trans)-2-aminocyclopropyl)thiazol-2-yl)phenol hydrochloride

(387) ##STR00137##

Example 116: 3-(5-((trans)-2-aminocyclopropyl)thiazol-2-yl)phenol hydrochloride

(388) ##STR00138##

(389) .sup.1HNMR (400 MHz, DMSO-d6, D2O Exchange) : 7.68 (s, 1H), 7.31 (s, 3H), 6.89 (brs, 1H), 2.88-2.96 (m, 1H), 2.58-2.64 (m, 1H), 1.48-1.58 (m, 1H), 1.36 (q, J=7 Hz, 1H); Mass (M+H): 233.3

Example 117: 4-(5-((trans)-2-aminocyclopropyl)thiazol-2-yl)phenol hydrochloride

(390) ##STR00139##

Example 118: 2-(2-((trans)-2-aminocyclopropyl)thiazol-5-yl)phenol hydrochloride

(391) ##STR00140##

Example 119: 3-(2-((trans)-2-aminocyclopropyl)thiazol-5-yl)phenol hydrochloride

(392) ##STR00141##

Example 120: 2-(2-((trans)-2-aminocyclopropyl)thiazol-5-yl)phenol hydrochloride

(393) ##STR00142##

Example 121: 3-(2-((trans)-2-aminocyclopropyl)thiazol-5-yl)phenol hydrochloride

(394) ##STR00143##

Example 122: 3-(5-((trans)-2-aminocyclopropyl)pyrimidin-2-yl)phenol hydrochloride

(395) ##STR00144##

Example 123: 4-(5-((trans)-2-aminocyclopropyl)pyrimidin-2-yl)phenol hydrochloride

(396) ##STR00145##

Example 124: N-(3-(5-((trans)-2-aminocyclopropyl)thiazol-2-yl)phenyl)-2-cyanobenzenesulfonamide dihydrochloride

(397) ##STR00146##

(398) .sup.1HNMR (400 MHz, D2O) : 8.05 (d, J=8 Hz, 1H), 7.76-7.88 (m, 2H), 7.67-7.75 (m, 1H), 7.56 (s, 1H), 7.45 (brs, 2H), 7.25-7.34 (m, 1H), 7.09 (d, J=8 Hz, 1H), 2.94-3.03 (m, 1H), 2.60-2.68 (m, 1H), 1.46-1.58 (m, 1H), 1.40 (q, J=7 Hz, 1H); Mass (MH): 395.0

Example 125: Biological Assays

(399) The compounds of the invention can be tested for their ability to inhibit LSD1. The ability of the compounds of the invention to inhibit LSD1 can be tested as follows. Human recombinant LSD1 protein was purchased from BPS Bioscience Inc. In order to monitor LSD1 enzymatic activity and/or its inhibition rate by our inhibitor(s) of interest, di-methylated H3-K4 peptide (Millipore) was chosen as a substrate. The demethylase activity was estimated, under aerobic conditions, by measuring the release of H.sub.2O.sub.2 produced during the catalytic process, using the Amplex Red peroxide/peroxidase-coupled assay kit (Invitrogen).

(400) Briefly, a fixed amount of LSD1 was incubated on ice for 15 minutes, in the absence and/or in the presence of various concentrations of inhibitor (e.g., from 0 to 75 M, depending on the inhibitor strength). Tranylcypromine (Biomol International) was used as a control for inhibition. Within the experiment, each concentration of inhibitor was tested in triplicate. After leaving the enzyme interacting with the inhibitor, 12.5 M of di-methylated H3-K4 peptide was added to each reaction and the experiment was left for 1 hour at 37 C. in the dark. The enzymatic reactions were set up in a 50 mM sodium phosphate, pH 7.4 buffer. At the end of the incubation, Amplex Red reagent and horseradish peroxidase (HPR) solution were added to the reaction according to the recommendations provided by the supplier (Invitrogen), and left to incubate for 30 extra minutes at room temperature in the dark. A 1 M H.sub.2O.sub.2 solution was used as a control of the kit efficiency. The conversion of the Amplex Red reagent to resorufin due to the presence of H.sub.2O.sub.2 in the assay, was monitored by fluorescence (excitation at 540 nm, emission at 590 nm) using a microplate reader (Infinite 200, Tecan). Arbitrary units were used to measure level of H.sub.2O.sub.2 produced in the absence and/or in the presence of inhibitor.

(401) The maximum demethylase activity of LSD1 was obtained in the absence of inhibitor and corrected for background fluorescence in the absence of LSD1. The Ki (IC50) of each inhibitor was estimated at half of the maximum activity.

(402) The results presented in Table I below show the results of the LSD1 inhibition studies for a number of the Example compounds. Parnate (2-trans phenylcyclopropylamine) was found to have a Ki (IC50) of from about 15 to 35 micromolar depending on the enzyme preparation. The studies show that the compounds of the invention have unexpectedly potent LSD1 inhibition.

Example 126: Biological Assays-Monoamine Oxidase Assays for Determining the Selectivity of the Compounds of the Invention for LSD1

(403) Human recombinant monoamine oxidase proteins MAO-A and MAO-B were purchased from Sigma Aldrich. MAOs catalyze the oxidative deamination of primary, secondary and tertiary amines. In order to monitor MAO enzymatic activities and/or their inhibition rate by inhibitor(s) of interest, a fluorescent-based (inhibitor)-screening assay was set up. 3-(2-Aminophenyl)-3-oxopropanamine (kynuramine dihydrobromide, Sigma Aldrich), a non fluorescent compound was chosen as a substrate. Kynuramine is a non-specific substrate for both MAOs activities. While undergoing oxidative deamination by MAO activities, kynuramine is converted into 4-hydroxyquinoline (4-HQ), a resulting fluorescent product.

(404) The monoamine oxidase activity was estimated by measuring the conversion of kynuramine into 4-hydroxyquinoline. Assays were conducted in 96-well black plates with clear bottom (Corning) in a final volume of 100 L. The assay buffer was 100 mM HEPES, pH 7.5. Each experiment was performed in triplicate within the same experiment.

(405) Briefly, a fixed amount of MAO (0.25 g for MAO-A and 0.5 g for MA-B) was incubated on ice for 15 minutes in the reaction buffer, in the absence and/or in the presence of various concentrations of inhibitor (e.g., from 0 to 50 M, depending on the inhibitor strength). Tranylcypromine (Biomol International) was used as a control for inhibition.

(406) After leaving the enzyme(s) interacting with the inhibitor, 60 to 90 M of kynuramine was added to each reaction for MAO-B and MAO-A assay respectively, and the reaction was left for 1 hour at 37 C. in the dark. The oxidative deamination of the substrate was stopped by adding 50 L (v/v) of NaOH 2N. The conversion of kynuramine to 4-hydroxyquinoline, was monitored by fluorescence (excitation at 320 nm, emission at 360 nm) using a microplate reader (Infinite 200, Tecan). Arbitrary units were used to measure levels of fluorescence produced in the absence and/or in the presence of inhibitor.

(407) The maximum of oxidative deamination activity was obtained by measuring the amount of 4-hydroxyquinoline formed from kynuramine deamination in the absence of inhibitor and corrected for background fluorescence in the absence of MAO enzymes. The Ki (IC50) of each inhibitor was determined at Vmax/2.

(408) TABLE-US-00001 TABLE 1 Summary of Data from MAO-A, MAO-B, and LSD1 Inhibition Studies Example MAO-A MAO-B LSD1 No. (Ki) (Ki) (Ki) 1 I I II 2 I II II 3 I I II 4 I I III 5 I II II 6 I II II 7 I II II 8 I II II 9 I III II 10 I I II 11 I I II 12 I I II 13 I I III 14 I I II 15 I I II 16 I I II 17 I I III 18 I I I 19 I I II 20 I I III 21 I I III 22 I I II 23 I I III 24 I I III 25 I I III 26 I I II 29 I I III 30 I I II 31 I I III 34 I I II 36 I I I 37 I I I 38 I I II 39 I I II 40 I I II 41 I I II 42 I I II 43 I I II 44 I I II 45 I I II 46 I I III 47 I I II 48 I I III 49 I I II 50 I I II 51 I I II 52 I I II 53 I I III 54 I I II 55 I I II 56 I I III 57 I I II 58 I I II 59 nd I III 60 I I II-III 61 I I I 62 I I II 63 I I III 63 I I III 64 I I III 65 I I III 66 I I III 67 I I III 68 I I III 69 I I III 70 I I III 71 I I II 72 I I II 73 I I II-III 74 I I II-III 75 I I III 76 I I II 77 I I I 78 I I I 79 I I I 80 I I II 87 II I II 88 I I III 89 II I III 90 I I III 93 I I II 94 II II III 95 II I III 96 II I III 97 I I II 98 I I III 99 II I III 100 II I III 101 I I III 102 I I III 103 nd nd II 104 II I II 105 I nd II 106 II I II 113 II II III 116 III I III 124 I I III

(409) The ranges for the Ki value reported in Table I are for MAO-A, MAO-B and LSDI-I=between 1 M and 40 M; II=between 0.1 M and 1 M; III between 0.001 M and 0.1 M. nd means not determined.

(410) Generally compounds of Examples were found to have Ki (IC50) values for MAO-A and MAO-B greater than the LSD1 Ki values, whereas LSD1 Ki values were generally lower than 0.5 M.

(411) Thus the compounds of the invention are unexpectedly potent LSD1 inhibitors and unexpectedly selective for LSD1 as compared to MAO-A and MAO-B, or the compounds are dual inhibitors of LSD and MAO-B.

(412) Some compounds of the Examples have been tested for antiproliferative/cytotoxic activity and been found to have activity in the micromolar to low micromolar range against cancer cell lines including HCT-116.

(413) Previous reports of LSD1 have found that it is involved in cell proliferation and growth. Some studies have implicated LSD1 as a therapeutic target for cancer. Huang et al. (2007) PNAS 104:8023-8028 found that polyamine inhibitors of LSD1 modestly cause the reexpression of genes aberrantly silenced in cancer cells and particularly colorectal cancer (Huang et al. Clin Cancer Res. (2009) December 1; 15(23):7217-28. Epub 2009 November 24. PMID: 19934284). Scoumanne et al. ((2007) J. Biol. Chem. May 25; 282(21):15471-5) found that deficiency in LSD1 leads to a partial cell cycle arrest in G2/M and sensitizes cells to growth suppression induced by DNA damage. Kahl et al. ((2006) Cancer Res. 66(23):11341-7.) found that LSD1 expression is correlated with prostate cancer aggressiveness. Metzger et al. reported that LSD1 modulation by siRNA and pargyline regulates androgen receptor (AR) and may have therapeutic potential in cancers where AR plays a role, like prostate, testis, and brain cancers. Lee et al. ((2006) Chem. Biol. 13:563-567) reported that tranylcypromine derepresses Egr-1 gene expression in some cancer lines. A body of evidence is accumulating that Egr-1 is a tumor suppressor gene in many contexts (see e.g., Calogero et al. (2004) Cancer Cell International 4:1 exogenous expression of EGR-1 resulted in growth arrest and eventual cell death in primary cancer cell lines; Lucerna et al. (2006) Cancer Research 66, 6708-6713 show that sustained expression of Egr-1 causes antiangiogeneic effects and inhibits tumor growth in some models; Ferraro et al. ((2005) J. Clin. Oncol. March 20; 23(9):1921-6) reported that Egr-1 is downregulated in lung cancer patients with a higher risk of recurrence and may be more resistant to therapy. Thus, increasing Egr-1 expression via inhibition of LSD1 is a therapeutic approach for some cancers. Recent studies have also implicated LSD1 in brain cancer (Schulte et al. (2009) Cancer Res. March 1; 69(5):2065-71). Other studies have implicated LSD1 in breast cancer (Lims et al. Carcinogenesis. PMID: 20042638).

(414) Thus, a body of evidence has implicated LSD1 in a number of cancers, which suggests that LSD1 is a therapeutic target for cancer. The instant inventors have discovered a class of LSD1 inhibitors that can be used to treat diseases where LSD1 is implicated as a therapeutic target like cancer. Accordingly, the phenylcyclopropylamine compounds of the invention can be used to treat such diseases.

(415) Recent studies have also implicated LSD1 in viral infection and reactivation. In particular it was shown that pharmacological inhibitors of LSD1 like parnate and siRNA knock down of LSD1 caused reduced viral infectivity and reduced reactivation after latency (Liang et al. (2009) Nat. Med. 15:1312-1317). Therefore it is believed that the compounds of the invention can be used for treating or preventing viral infection. Furthermore, it is believed that the compounds of the invention can treat or prevent viral reactivation after latency.

(416) Thus, without wishing to be bound by theory, the inventors have identified a new class of substituted heterocyclylcyclopropylamines, phenylcyclopropylamines, and pyridinylcyclopropanamine containing LSD1 inhibitors with unexpected potency and selectivity for LSD1 a biologically relevant target in oncology and other diseases and/or LSD1/MAO-B.

(417) All publications and patent applications mentioned in the specification are indicative of the level of those skilled in the art to which this invention pertains. All publications and patent applications are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. The mere mentioning of the publications and patent applications does not necessarily constitute an admission that they are prior art to the instant application.

(418) Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be obvious that certain changes and modifications may be practiced within the scope of the appended claims.