ZA200400677B - Cysteine protease inhibitors with 2-cyano-4-amino-pyrimidine structure and cathepsin K inhibitory activity for the treatment of inflammations and other diseases. - Google Patents

Description

CYSTEINE PROTEASE INHIBITORS WITH 2-CYANO-4-AMINO-PYRIMIDINE STRUCTURE AND

CATHEPSIN K INHIBITORY ACTIVITY FOR THE TREATMENT OF INFLAMMATIONS AND OTHER

DISEASES. . This invention relates to inhibitors of cysteine proteases, in particular to heteroaryl nitrile cathepsin K inhibitors and to their pharmaceutical use for the treatment or prophylaxis of diseases or medical conditions in which cathepsin K is implicated.

Cathepsin K is a member of the family of lysosomal cysteine cathepsin enzymes, e.g. cathepsins B, K, L and S, which are implicated in various disorders including inflammation, rheumatoid arthritis, osteoarthritis, osteoporosis, tumors (especially tumor invasion and tumor metastasis), coronary disease, atherosclerosis (including atherosclerotic plaque rupture and destabilization), autoimmune diseases, respiratory diseases, infectious diseases and immunologically mediated diseases (including transplant rejection).

Accordingly the present invention provides a compound of formula I, or a pharmaceutically acceptable salt or ester thereof

R

RA To

LL I i) N Ly

R2 wherein

Ris H, -R4, -OR4 or NR3R4, wherein R3 is H, lower alkyl or C3 to Cg cycloalkyl, and

R4 is lower alkyl or Cj to Cy cycloalkyl, and wherein R3 and R4 are independently, optionally substituted by halo, hydroxy, lower ) alkoxy, CN, NO», or optionally mono- or di-lower alkyl substituted amino;

R1 is -CO-NR5R6, -NH-CO-RS5, -CH,-NH-C(O)-RS5, -CO-RS, -S(0)-R5, -S(0)>-R5,-

CH,-CO-RS5 or -CH;-NR5R6, wherein

RS is aryl, aryl-lower alkyl, C3-Cjocycloalkyl, C3-Cjocycloalkyl-lower alkyl, heterocyclyl or heterocyclyl-lower alkyl, i

R6 is H, aryl, aryl-lower alkyl, aryl-lower-alkenyl, C;-Cjgcycloalkyl, C3-Cjocycloalkyl- lower alkyl, heterocyclyl or heterocyclyl-lower alkyl, or . wherein RS and R6 together with the nitrogen atom to which they attached are joined to form an N-heterocyclyl group, wherein N-heterocyclyl denotes a saturated, partially unsaturated or aromatic nitrogen containing heterocyclic moiety attached via a nitrogen atom thereof having from 3 to 8 ring atoms optionally containing a further 1, 2 or 3 heteroatoms selected from N, NR7, O,

S, S(O) or S(O), wherein R7 is H or optionally substituted (lower alkyl, carboxy. acyl (including both lower alkyl acyl, e.g. formyl, acetyl or propionyl, or aryl acyl, e.g. benzoyl), amido, aryl, S(O) or S(O),), and wherein the N-heterocyclyl is optionally fused in a bicyclic structure, e.g. with a benzene or pyridine ring, and wherein the N- heterocyclyl is optionally linked in a spiro structure with a 3 to 8 membered cycloalkyl or heterocyclic ring wherein the heterocyclic ring has from 3 to 10 ring members and contains from 1 to 3 heteroatoms selected from N, NR6, O, S, S(O) or S(O); wherein R6 is as defined above), and wherein heterocyclyl denotes a ring having from 3 to 10 ring members and containing from 1 to 3 heteroatoms selected from N, NR7, O, S, S(O) or S(O), wherein R7 is as defined above), and wherein R5 and R6 are independently, optionally substituted by one or more groups, e.g. 1-3 groups, selected from halo, hydroxy, oxo, lower alkoxy, CN or NO,, or optionally substituted (optionally mono- or di-lower alkyl substituted amino, lower-alkoxy, aryl, aryl-lower alkyl, N-heterocyclyl or N-heterocyclyl-lower alkyl (wherein the optional substitution comprises from 1 to 3 substituents selected from halo, hydroxy, lower alkoxy, lower alkoxy-lower alkyl, lower alkoxy-carbonyl, CN, NO, N-heterocyclyl or N- heterocyclyl-lower alkyl, or optionally mono- or di-lower alkyl substituted amino; .

R2 is is independently H, or optionally substituted (lower alkyl, aryl, aryl-lower alkyl, Cs-

Ciocycloalkyl, C3-Cjocycloalkyl-lower alkyl, heterocyclyl or heterocyclyl-lower alkyl), ’ and wherein R2 is optionally substituted by halo, hydroxy, oxo, lower alkoxy, CN, NO,, or optionally mono- or di-lower alkyl substituted amino. . Above and elsewhere in the present description the following terms have the following meanings.

Halo or halogen denote I, Br, Cl or F.

The term “lower” referred to above and hereinafter in connection with organic radicals or compounds respectively defines such as branched or unbranched with up to and including 7, preferably up to and including 5 and advantageously one, two or three carbon atoms.

A lower alkyl group is branched or unbranched and contains 1 to 7 carbon atoms, preferably 1-5 carbon atoms. Lower alkyl represents; for example, methyl, ethyl, propyl, butyl, isopropyl isobutyl, tertiary butyl or neopentyl (2,2 ~-dimethylpropyl).

Halo-substituted lower alkyl is C|-C;lower alkyl substituted by up to 6 halo atoms.

A lower alkoxy group is branched or unbranched and contains 1 to 7 carbon atoms, preferably 1-4 carbon atoms. Lower alkoxy represents for example methoxy, ethoxy, propoxy, butoxy, isopropoxy, isobutoxy or tertiary butoxy.

A lower alkene, alkenyl or alkenyloxy group is branched or unbranched and contains 2 to 7 carbon atoms, preferably 2-4 carbon atoms and contains at least one carbon-carbon double bond. Lower alkene lower alkenyl or lower alkenyloxy represents for example vinyl, prop-1-enyl, allyl, butenyl, isopropenyl or isobutenyl and the oxy equivalents thereof.

A lower alkyne, alkynyl or alkynyloxy group is branched or unbranched and contains 2 to 7 carbon atoms, preferably 2-4 carbon atoms and contains at least one carbon-carbon triple bond. Lower alkyne or alkynyl represents for example ethynyl, prop-1-ynyl, propargyl, butynyl, isopropynyl or isobutynyl and the oxy equivalents thereof.

In the present description, oxygen containing substituents, e.g. alkoxy, alkenyloxy, . alkynyloxy, carbonyl, etc. encompass their sulphur containing homologues, e.g. thioalkoxy, thioalkenyloxy, thioalkynyloxy, thiocarbonyl, sulphone, sulphoxide etc. ; Aryl represents carbocyclic or heterocyclic aryl.

Carbocyclic aryl represents monocyclic, bicyclic or tricyclic aryl, for example phenyl or phenyl mono-, di- or tri-substituted by one, two or three radicals selected from , lower alkyl, lower alkoxy, aryl, hydroxy, halogen, cyano, trifluoromethyl, lower alkylenedioxy and oxy-C,-Cs-alkylene and other substituents, for instance as described in . the examples; or 1- or 2-naphthyl; or 1- or 2-phenanthrenyl. Lower alkylenedioxy is a divalent substituent attached to two adjacent carbon atoms of phenyl, e.g. methylenedioxy or ethylenedioxy. Oxy-C,-Cs-alkylene is also a divalent substituent attached to two adjacent carbon atoms of phenyl, e.g. oxyethylene or oxypropylene. An example for oxy-

C,-Cs-alkylene-phenyl is 2,3-dihydrobenzofuran-5-yl.

Preferred as carbocyclic aryl is naphthyl, phenyl or phenyl optionally substituted, for instance, as described in the examples, e.g. mono- or disubstituted by lower alkoxy, phenyl, halogen, lower alkyl or trifluoromethyl.

Heterocyclic aryl represents monocyclic or bicyclic heteroaryl, for example pyridyl, indolyl, quinoxalinyl, quinolinyl, isoquinolinyl, benzothienyl, benzofuranyl, benzopyranyl, benzothiopyranyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, or any said radical substituted, especially mono- or di-substituted as defined above.

Preferably, heterocyclic aryl is pyridyl, indolyl, quinolinyl, pyrrolyl, thiazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, or any said radical substituted, especially mono- or di-substituted as defined above.

Cycloalkyl represents a saturated cyclic hydrocarbon optionally substituted by lower alkyl which contains 3 to 10 ring carbons and is advantageously cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl optionally substituted by lower alkyl.

N-heterocyclyl is as defined above. Preferred N-heterocyclic substituents are optionally substituted pyrrolidine, pyrrole, diazole, triazole, tetrazole, imidazole, oxazole, thiazole, pyridine, pyrimidine, triazine, piperidine, piperazine, morpholine, phthalimde, hydantoin, oxazolidinone or 2,6-dioxo-piperazine and, for example, as hereinafter . described in the examples. .

In a further embodiment the invention provides a compound of formula Ila, or . a pharmaceutically acceptable salt or ester thereof

Re" HN SN Ila

R2 N wherein R2 is as defined above and R5”’ and R6™’ are as defined above for R5 and R6 respectively.

R2 is preferably R2’ which is lower alkyl, e.g. straight chain or more preferably branched-chain C;-Cs alkyl, e.g. especially 2-ethylbutyl, isobutyl, or 2,2-dimethylpropyl; or C3-Cgcycloalkyl, especially cyclopropyl, cyclopentyl or cyclohexyl.

R5”’ and R6’’ may be such that R5”” and R6™’ together with the nitrogen atom to which they are joined to form an N-heterocyclyl group

R5” is preferably optionally substituted (aryl-lower-alkyl, heterocyclyl-aryl, N- heterocyclyl-aryl or aryl-N-heterocyclyl (where N-heterocyclyl is as defined above).

RS” is preferably optionally substituted by from 1-4 substituents selected from halo, hydroxy, nitro, cyano, lower-alkyl, lower-alkoxy or lower-alkoxy-lower-akyl.

For example, R5”’ is 4-methoxy-benzyl, 3-methoxy-benzyl, 4-(4-methyl-piperazin- 1-yD)-benzyl, 4-[4-(2-ethoxy-ethyl)-piperazin-1-yl]-benzyl, 1-methyl-1-phenyl-ethyl, 2-(4- methoxy-phenyl)-1,1-dimethyl-ethyl, 2-(4-fluoro-phenyl)-1,1-dimethyl-ethyl, 4-(4- methyl-piperazin-1-yl)-phenyl]-ethyl, 2-[4-(4-isopropyl-piperazin-1-yl)-phenyl]}-1,1- dimethyl-ethyl, 2-{4-[4-(2-methoxy-ethyl)-piperazin-1-yl]-phenyl}-1,1-dimethyl-ethyl, 2- {3-[4-(2-ethoxy-ethyl)-piperazin-1-yl]-phenyl}-1,1-dimethyl-ethyl, 2-[3-(4-ethyl- piperazin-1-yl)-phenyl]-1,1-dimethyl-ethyl, 2-[3-(4-isopropyl-piperazin-1-yl)-phenyl]- 1,1-dimethyl-ethyl, 1,1-dimethyl-2-(3-pyrrolidin-1-yl-phenyl)-ethyl, 2-{3-[4-(2-methoxy- ethyl)-piperazin-1-yl]-phenyl}-1,1-dimethyl-ethyl, 2-(4-methoxy-phenyl)-ethyl . 2-[4-(4-methyl-piperazin- 1-yl)-phenyl]-ethyl, 2-[4-(4-isopropyl-piperazin-1-yl)-phenyl]- ethyl, 2-{4-[4-(2-methoxy-ethyl)-piperazin-1-yl}-phenyl}-ethyl, 2-(3-methoxy-phenyl)- ) ethyl, 2-[3-(4-methyl-piperazin-1-yl)-phenyl]-ethyl, 2-[4-(4-isopropyl-piperazin-1-yl)- phenyl]-ethyl, 2-pyrrol-1-yl-ethyl, 3-piperidin-1-yl-propyl

2-(4-methoxy-phenyl)-2-methyl-propyl, 2-methyl-2-[4~(4-methyl-piperazin-1-yl)-phenyl]- propyl, 2-[4-(4-isopropyl-piperazin-1-yl)-phenyl]-2-methyl-propyl, 2-{4-[4-(2-ethoxy- i ethyl)-piperazin-1-yl]-phenyl} -2-methyl-propyl, 2- {4-[pyrimidin-1-yl]-phenyl}-2-methyl- propyl, 4-(3-methoxy-phenyl)-piperazin-1-yl-methyl, 4-(4-methoxy-phenyl)-piperazin-1- . yl-methyl, 1-methyl-1-(1-phenyl-cyclopropyl)-ethyl,

For example, R5”’ and R6™ together with the nitrogen atom to which they are joined to form an N-heterocyclyl group is 4-(2-pyridin-4-yl-ethyl)-piperazin-1-yl, [4-(2-pyridin-2- yl-ethyl)-piperazin-1-yl, 4-pyridin-4-ylmethyl-piperazin-1-yl, 4-(2-piperidin-1-yl-ethyl)- piperazin-1-yl, 4-(2-pyrrolidin- 1-yl-ethyl)-piperazin- 1-yl, 4-(2-Diethylamino-ethyl)- piperazin-1-yl, 4-(3-Diethylamino-propyl)-piperazin-1-yl, 4-(1-methyl-piperidin-4-yl)- piperazin-1-yl, 4-pyrrolidin-1-yl-piperidin-1-yl, 4-(2-methoxy-ethyl)-piperazin-1-yl

In a preferred embodiment the invention provides a compound of formula II, or a oo pharmaceutically acceptable salt or ester thereof

O

H

HN SN un ho N

R wherein R2 is as defined above and R5’ is as defined above for R5.

R2 is preferably R2’ which is lower alkyl, e.g. straight chain or more preferably branched-chain C;-Cs alkyl, e.g. especially 2-ethylbutyl, isobutyl, or 2,2-dimethylpropyl; or C3-Cgeycloalkyl, especially cyclopropyl, cyclopentyl or cyclohexyl.

R5’ is preferably optionally substituted (aryl-lower-alkyl, heterocyclyl-aryl, N- heterocyclyl-aryl or aryl-N-heterocyclyl (where N-heterocyclyl is as defined above).

R5’ is preferably optionally substituted by from 1-4 substituents selected from halo, ; hydroxy, nitro, cyano, lower-alkyl, lower-alkoxy, lower-alkoxy-carbonyl or lower-alkoxy- lower-akyl. :

For example, R5’ is 4-methoxy-phenyl, 4-(1-propyl-piperidin-4-yl)-phenyl, 4-(4- ) methyl-piperazin-1-yl)-phenyl, 4-[1-(2-methoxy-ethyl)-piperidin-4-yl}-phenyl, 4-(4- propyl-piperazin-1-yl)-phenyl, 3-[4-(4-methyl-piperazin-1-yl)-phenyl]-propionyl, 3-[3-(4- ) methyl-piperazin-1-yl)-phenyl]-propionyl, 4-(4-ethyl-piperazin-1-yl)-phenyl, 4-(4- isopropyl-piperazin- 1-yl)-phenyl, 4-[4-(2-ethoxy-ethyl)-piperazin-1-yl}-phenyl, 4-[4-(2- methoxy-ethyl)-piperazin-1-yl]-phenyl, 4-piperazin-1-yl-phenyl, 4-[4-(carboxylic acid tert-butyl ester) piperazino-1-yl-J-phenyl, 3-[4-(carboxylic acid tert-butyl ester) piperazino-1-yl-]-phenyl, 3-(4-methyl-piperazin-1-yl)-phenyl, 3-(4-ethyl-piperazin-1-yl)- phenyl, 3-(4-isopropyl-piperazin-1-yl)-phenyl, 3-[4-(2-methoxy-ethyl)-piperazin-1-yl}- phenyl, 3-[4-(2-ethoxy-ethyl)-piperazin-1-yl]-phenyl, 3-(2-pyrrolidin-1-yl-ethoxy)-phenyl, 3-(2-dimethylamino-ethoxy)-4-methoxy-phenyl, 4-dimethylaminomethyl-phenyl, 4-(4- methyl-piperazin-1-ylmethyl)-phenyl, 4-[1-(2-methoxy-ethyl)-piperidin-4-ylmethyl]- phenyl, 4-methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl, 3-[4-(4-ethyl-piperazin-1-yl)- phenyl]-2,2-dimethyl-propionyl, 3-[4-(4-propyl-piperazin-1-yl)-phenyl]-propionyl, 3-(4- pyrrolidin-1-yl-phenyl)-propionyl, 3-[3-(4-ethyl-piperazin-1-yl)-phenyl]-2,2-dimethyl- propionyl, 3-{3-{4-(2-methoxy-ethyl)-piperazin- 1-yl]-phenyl}-2,2-dimethyl-propionyl, 3- {3-[4-(2-ethoxy-ethyl)-piperazin-1-yl}-phenyl} -2,2-dimethyl-propionyl, 3-(3-pyrrolidin- 1-yl-phenyl)-propionyl, 2-[4-(4-methyl-piperazin-1-yl}-phenyl]-isobutyl, 2-(4-methoxy- * phenyl)-acetyl, 2-(3-methoxy-phenyl)-acetyl, 2-[4-(4-methyl-piperazin-1-yl)-phenyl}- acetyl, 2-[4-(4-ethyl-piperazin-1-yl)-phenyl]-acetyl, 2-[4-(4-isopropyl-piperazin-1-yl)- phenyl]-acetyl, 2-(4-pyrrolidin-1-yl-phenyl)-acetyl, 2-[4-(2-diethylamino-ethylamino)- phenyl]-isobutyl, 2-(4-pyrrolidin-1-yl-phenyl)-isobutyl.

In a further preferred embodiment the invention provides a compound of formula

IIT or a pharmaceutically acceptable salt or ester thereof 0

A i) . i N SY

R2

Claims (16)

1. A compound of formula I, or a pharmaceutically acceptable salt or ester thereof . R HN Poe SN R2 wherein Ris H, -R4, -OR4 or NR3R4, wherein R3 is H, lower alkyl or C; to Cj cycloalkyl, and R4 is lower alkyl or C; to Cy cycloalkyl, Co wherein R3 and R4 are independently, optionally substituted by halo, hydroxy, lower alkoxy, CN, NO, or optionally mono- or di-lower alkyl substituted amino; R1 is —CO-NRS5R6, -NH-CO-RS, -CH,-NH-C(O)-R5, -CO-RS, -S(O)-R5, -S(O),- RS5,-CH2-CO-R5 or -CH;-NR5R6, wherein R5 is aryl, aryl-lower alkyl, C3-Cjocycloalkyl, Cs-C,cycloalkyl-lower alkyl, heterocyclyl or heterocyclyl-lower alkyl, R6 is H, aryl, aryl-lower alkyl, aryl-lower-alkenyl, C3-Cjocycloalkyl, Cs- Cjocycloalkyl-lower alkyl, heterocyclyl or heterocyclyl-lower alkyl, or wherein R5 and R6 together with the nitrogen atom to which they attached are joined to form an N-heterocyclyl group, wherein N-heterocyclyl denotes a saturated, partially unsaturated or aromatic nitrogen containing heterocyclic moiety attached via a nitrogen atom thereof having from 3 to 8 ring atoms optionally containing a further 1, 2 or 3 heteroatoms selected

. from N, NR7, O, S, S(O) or S(O), wherein R7 is H or optionally substituted (lower ) alkyl, carboxy, acyl (including both lower alkyl acyl, e.g. formyl, acetyl or ’ propionyl, or aryl acyl, e.g. benzoyl), amido, aryl, S(O) or S(O);), and wherein the N-heterocyclyl is optionally fused in a bicyclic structure, e.g. with a benzene or pyridine ring, and wherein the N-heterocyclyl is optionally linked in a spiro structure with a 3 to 8 membered cycloalkyl or heterocyclic ring wherein the } heterocyclic ring has from 3 to 10 ring members and contains from 1 to 3 heteroatoms selected from N, NR6, O, S, S(O) or S(O); wherein R6 is as defined above), and wherein heterocyclyl denotes a ring having from 3 to 10 ring members and containing from 1 to 3 heteroatoms selected from N, NR7, O, S, S(O) or S(O), wherein R7 is as defined above), and wherein R5 and R6 are independently, optionally substituted by one or more groups, e.g. 1-3 groups, selected from halo, hydroxy, oxo, lower alkoxy, CN or NO, or optionally substituted (optionally mono- or di-lower alkyl substituted amino, lower alkoxy, aryl, aryl-lower alkyl, N-heterocyclyl or N-heterocyclyl-lower alkyl (wherein the optional substitution comprises from 1 to 3 substituents selected from halo, hydroxy, lower alkoxy, lower alkoxy-lower alkyl, lower alkoxy-carbonyl CN, NO, optionally mono- or di-lower alkyl substituted amino, N-heterocyclyl or N-heterocyclyl-lower alkyl or optionally mono- or di-lower alkyl substituted amino; R2 is is independently H, or optionally substituted (lower alkyl, aryl, aryl-lower alkyl, C3-C cycloalkyl, Cs-Cocycloalkyl-lower alkyl, heterocyclyl or heterocyclyl- lower alkyl), and wherein R2 is optionally substituted by halo, hydroxy, oxo, lower alkoxy, CN, NO, or optionally mono- or di-lower alkyl substituted amino.

2. A compound according to claim 1 of formula II, or a pharmaceutically acceptable salt or ester thereof Oo es HN SN n Re N wherein R2 is as defined above and R5’ is as defined above for RS in claim 1.

/

A

3. A compound according to claim 1 of formula Ila, or a pharmaceutically acceptable ‘ salt or ester thereof R m a IIa 6 HN PN SN R2 wherein R2 is as defined above and R5™ and R6™” is as defined above for RS and R6 respectivly in claim 1.

4. A compound according to claim 1 of formula III or a pharmaceutically acceptable salt or ester thereof Oo R [1] . N | ~ N A mt Hn N SY R2 wherein R2 is as defined above and R5” is as defined above for RS in claim 1.

5. A compound according to claim 1, or a pharmaceutically acceptable salt or ester thereof, selected from any one of the Examples.

6. A compound according to claim 1 for use as a pharmaceutical.

7. A pharmaceutical composition comprising a compound according to claim 1 as an . active ingredient.

¥ - »

8. A compound according to claim 1 for treating a patient suffering from or susceptible to a disease or medical condition in which cathepsin K is implicated.

9. The use of a compound according to claim 1 for the preparation of a medicament for therapeutic or prophylactic treatment of a disease or medical condition in which cathepsin K is implicated.

10. A process for the preparation of a compound of Formula II or a pharmaceutically acceptable salt or ester thereof Oo R MN all I a x BQ HN N C SN R2 wherein R2 and R5’ are as defined above, comprising cyanation of a 2-chloro precursor of formula IV O Det NS HI Ci Iv R2 wherein R2 and R5’ are as defined above, and thereafter, if desired, converting the product obtained into a further compound of formula II, or into a salt or ester thereof

11 A process for the preparation of a compound of Formula ha or a pharmaceutically acceptable salt or ester thereof 56 AMENDED SHEET

Bb bs oN ZN IIa , Rs" ~ Me HN N Cx

NN . R2 wherein R2, R5°’ and R6™ are as defined above, comprising cyanation of a 2-chloro precursor of formula IVa R LIL] ONT YON Rg" ~ BR

Lo. N Cl IVa R2 wherein R2, R5°’ and R6”’ are as defined above, and thereafier, if desired, converting the product obtained into a further compound of formula Ila, or into a salt or ester thereof.

12. A process for the preparation of a compound of Formula III or a pharmaceutically acceptable salt or ester thereof 0) R ” A mI i) N NY R2 wherein R2 and R5” are as defined above, comprising either cyanation of a 2-chloro precursor of formula V 0] R ” ’ PY v i) N Cl . R2 or coupling of a carboxylic acid precursor of formula VI with a corresponding amine of formula vil Q R " va SNH, + HO HN N AF R2 wherein the R2 and R5” are as defined above, and thereafter, if desired, converting the product obtained into a further compound of formula Ill, or into a salt or ester thereof.

13. A compound according to claim 1, substantially as herein described and exemplified.

14. A pharmaceutical composition according to claim 7, substantially as herein described and exemplified.

15. The use according to claim 9, substantially as herein described and exemplified.

16. A process according to any one of claims 10-12, substantially as herein described and exemplified. 58 AMENDED SHEET