PCT
`
`Intema~onal Bureau
`
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCr)
`WO 95106030
`
`(11) Internation*l Publication Number:
`
`(51) International Patent Classification 6 :
`C07C 311/29, C07D 213/30, C07C
`317/14, 311/18, C07D 307/79, C07K
`51062, A61K 31/18, 31/44
`
`A1
`
`(43) International Publication Date:
`
`2 March 1995 (02.03.95)
`
`(21) International Application Number: PCT/US94/09139
`
`(22) International Filing Date:
`
`23 August 1994 (23.08.94)
`
`(30) Priority Data:
`081110,911 24 August 1993 (24.08.93)
`081204,827
`2 March 1994 (02.03.94)
`
`US
`US
`
`(60) Parent Applications or Grants
`(63) Related by Continuation
`US
`Filed on
`US
`Filed on
`
`081110,911 (CON)
`24 August 1993 (24.08.93)
`08/204,827 (CON)
`2 March 1994 (02.03.94)
`
`MUI~.I J.h’P,, Richard, A. [US/US]; 562 Stonegate Terrace,
`Glencoe, IL 60022 (US). TAI .I.EY, John, J. [US/US]; 8772
`Pine Avenue, Brentwood, MO 63144 (US). GETMAN,
`Daniel, P. [US/US]; 66 Sunny Hill Court, Chesterfield,
`MO 63017 (US). DECRESCENZO, Gary, A. [US/US];
`536 Schrader Farm Drive, St. Peters, MO 63376 (US).
`FRESKOS, John, N. [US/US]; 7572 York, Clayton, MO
`63105 (US). BERTENSHAW, Deborah, E. [US/US]; 8758
`Pine Avenue, Brentwood, MO 63144 (US). HEINTZ,
`Robert, M. [US/US]; 603 Nancy Place, Ballwin, MO 63021
`(us).
`
`(74) Agents: UNGEMACI-I, Frank, S. et al.; G.D. Searle & Co.,
`Corporate Patent Dept., P.O. Box 5110, Chicago, IL 60680-
`5110 (US).
`
`(71) Applicants (for all designated States except US): G.D. SEARLE
`& CO. [US/US]; Corporate Patent Dept., P.O. Box 5110,
`Chicago, IL 60680-5110 (US). THE MONSANTO COM-
`PANY [US/US]; 800 North Lindbergh Boulevard, St. Louis,
`MO 63167 (US).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): VAZQUE7_., I~.chad,
`L. [US/US]; 233 Saratoga Court, Gurnee, IL 60031 (US).
`
`(81) Designated States: AM, AT, AU, BB, BG, BR, BY, CA, CH,
`CN, CZ, DE, DK, ES, FI, GB, GE, HU, JP, KE, KG, KP,
`IGL KZ, LK, LT, LU, LV, MD, MG, IvlN, MW, NL, NO,
`NZ, PL, PT, RO, RU, SD, SE, SI, SK, TI, Tr, UA, US,
`UZ, VN, European patent (AT, BE, CIL DE, DK, ES, FIL
`GB, GR, IE, IT, LU, MC, NL, PT, SE), OAPI patent (BF,
`B J, CF, CG, CL CM, GA, GN, ML, MR, NE, SN, TD, TG),
`ARIPO patent (KE, MW, SD).
`
`Published
`With international search report.
`
`($4) Title: HYDROXYETHYLAMINO SULPHONAM1DES USEFUL AS RETROVIRAL PROTEASE INHIBITORS
`
`(57) Abstract
`
`Hydroxyethylamino sulphonamid~ compounds
`of formulae (I) and (2), wherein A, R2, R3, R4,
`R6, x, pt and p2 are as defined in claim~ 1 and 8
`are effective as retroviral protease inhibitors, and in
`particular as inhibitom of HIV proteaze.
`
`(1)
`
`(2)
`
`0 0
`
`P~’
`
`pa
`
`N
`I
`OH Ra
`
`R4
`
`Lupin Ex. 1017 (Page 1 of 278)
`
`

`
`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international
`applications under the PCT.
`
`AT
`AU
`BB
`BE
`BF
`BG
`B.]
`
`Austria
`Australia
`Barbado~
`Belgium
`Bm’kina Faao
`Bulgaria
`Benin
`
`Iklan~
`BY
`~nada
`CA
`CF
`Central African l~9ubli¢
`CG
`Congo
`Swi~erl~d
`CH
`C[ ~ d’Ivoire
`
`CN
`CS
`CZ
`DE
`DK
`ES
`FI
`FR
`GA
`
`China
`Cz~uboslovakia
`Czech RepubUc
`Germsny
`Demnark
`Spain
`F~nl~nd
`Prm~e
`Gabon
`
`GB
`GE
`GN
`GR
`HU
`I!~
`rr
`
`KE
`KG
`KP
`
`KR
`KZ
`
`Uni~:l Kingdo~
`Oec~’gta
`Otfin~a
`Or¢(cid:128)¢(cid:128)
`Hungry
`Ireland
`l~y
`
`Kenya
`KyrT/s~an
`Dcmocra~ Pcopk’s P~:publi¢
`o~ Korea
`Republic of Korea
`g~t~t~n
`
`LK
`$fi Lanka
`Luxcmbourg
`LU
`Lat~
`LV
`Mon~o
`MC
`MD
`Republic of Moldova
`Madag~sc~
`MG
`ML ~
`MN
`Mongolia
`
`MR
`MW
`NE
`NL
`NO
`NZ
`PL
`
`RO
`RU
`SD
`SE
`Sl
`SK
`
`TD
`TG
`TJ
`Tr
`UA
`US
`UZ
`VN
`
`Maufitalfia
`Malawi
`Nig~
`Nctlerlands
`Norway
`New Zealand
`PoI~d
`
`Rom~n~
`lh~ssian Feder~ion
`Sudan
`Swcdce
`Slovcnia
`Slovskis
`
`Cllad
`Togo
`Tajiki.~n
`T~inidad and Tobago
`Ulwaine
`United Stmes of America
`UzbekLqan
`Viet Nam
`
`Lupin Ex. 1017 (Page 2 of 278)
`
`

`
`WO 95/06030
`
`PCT/US94/09139
`
`Hydroxyethylamlno sulphonamides useful as retrovlral protease Inhlbltors
`
`1
`
`5
`
`RELATED APPLICATION
`This application is a continuation in part
`application of co-owned and co-pending U.S. patent
`application Serial No. 08/204,827 filed March 2, 1994,
`which is a continuation in part application of co-owned
`and co-pending PCT/US93/07814, filed August 24, 1993,
`I0 which is a continuation in part application of co-owned
`U.S. patent application Serial No. 07/934,984 filed
`August 25, 1992, now abandoned, each of which is
`incorporated herein by reference in its entirety.
`
`15
`
`BACKGROUND OF THE INVENTION
`
`i. Field of the Invention
`The present invention relates to retroviral
`protease inhibitors and, more particularly, relates to
`novel compounds and a composition and method for
`inhibiting retroviral proteases. This invention, in
`particular, relates to sulfonamide-containing
`hydroxyethylamine protease inhibitor compounds, a
`composition and method for inhibiting retroviral
`proteases such as human immunodeficiency virus (HIV)
`protease and for treating a retroviral infection, e.g.,
`an HIV infection. The subject invention also relates to
`processes for making such compounds as well as to
`intermediates useful in such processes.
`
`2 Related Art
`During the replication cycle of retroviruses,
`gag and gag-pol gene transcription products are translated
`as proteins. These proteins are subsequently processed by
`a virally encoded protease (or proteinase) to yield viral
`enzymes and structural proteins of the virus core. Most
`commonly, the gag precursor proteins are processed into
`
`2O
`
`25
`
`3O
`
`35
`
`Lupin Ex. 1017 (Page 3 of 278)
`
`

`
`WO 95106030
`
`PCT/US94/09139
`
`the core proteins and the pol precursor proteins are
`processed into the viral enzymes, e.g., reverse
`transcriptase and retroviral protease. It has been shown
`that correct processing of the precursor proteins by the
`retroviral protease is necessary for assembly of
`infectious virons. For example, it has been shown that
`frameshift mutations in the protease region of the pol
`gene of HIV prevents processing of the gag precursor
`protein. It has also been shown through site-directed
`mutagenesis of an aspartic acid residue in the HIV
`protease active site that processing of the gag precursor
`protein is prevented. Thus, attempts have been made to
`inhibit viral replication by inhibiting the action of
`retroviral proteases.
`
`Retroviral protease inhibition typically
`involves a transition-state mimetic whereby the retroviral
`protease is exposed to a mimetic compound which binds
`(typically in a reversible manner) to the enzyme in
`competition with the gag and gag-pol proteins to thereby
`inhibit specific processing of structural proteins and the
`release of retroviral protease itself. In this manner,
`retroviral replication proteases can be effectively
`inhibited.
`
`10
`
`15
`
`2O
`
`25
`
`Several classes of compounds have been
`proposed, particularly for inhibition of proteases, such
`as for inhibition of HIV protease. Such compounds
`include hydroxyethy!amine isosteres and reduced amide
`30 isosteres. See, for example, EP 0 346 847; EP 0 342,541;
`Roberts et al, "Rational Design of Peptide-Based
`Proteinas4 Inhibitors, "Science, 248, 358 (1990); and
`Erickson et al, "Design Activity, and 2.8i Crystal
`Structure of a C2 Symmetric Inhibitor Complexed to HIV-I
`35 Protease," Science, 249, 527 (1990).
`
`Lupin Ex. 1017 (Page 4 of 278)
`
`

`
`WO 95106030
`
`PCT/US94/09139
`
`Several classes of compounds are known to be
`useful as inhibitors of the proteolytic enzyme renin.
`See, for example, U.S. No. 4,599,198; U.K. 2,184,730;
`G.B. 2,209,752; EP 0 264 795; G.B. 2,200,115 and U.S. SIR
`5 H725. Of these, G.B. 2,200,115, GB 2,209,752, EP 0
`264,795, U.S. SIR H725 and U.S. 4,599,198 disclose urea-
`containing hydroxyethylamine renin inhibitors. EP 468
`641 discloses renin inhibitors and intermediates for the
`preparation of the inhibitors, which include sulfonamide-
`I0 containing hydroxyethylamine compounds, such as 3-(t-
`butoxycarbonyl)amino-cyclohexyl-l-(phenylsulfonyl)amino-
`2(5)-butanol. G.B. 2,200,115 also discloses sul£amoyl-
`containing hydroxyethylamine renin inhibitors, and EP
`0264 795 discloses certain sulfonamide-containing
`15 hydroxyethylamine renin inhibitors. However, it is known
`that, although renin and HIV proteases are both
`classified as aspartyl proteases, compounds which are
`effective renin inhibitors generally cannot be predicted
`to be effective HIV protease inhibitors.
`
`2O
`
`BRIEF DESCRIPTION OF THE INVENTION
`
`The present invention is directed to virus
`25 inhibiting compounds and compositions. More
`particularly, the present invention is directed to
`retroviral protease inhibiting compounds and
`compositions, to a method of inhibiting retroviral
`proteases, to processes for preparing the compounds and
`30 to intermediates useful in such processes. The subject
`compounds are characterized as sulfonamide-containing
`hydroxyethylamine inhibitor compounds.
`
`Lupin Ex. 1017 (Page 5 of 278)
`
`

`
`WO 95/06030
`
`PC"T/US94/09139
`
`4
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`In accordance with the present invention, there
`is provided a retroviral protease inhibiting compound of
`the formula:
`
`RI’ RI" Y R2
`
`R’ RI R6 OH R3
`
`(i)
`
`or a pharmaceutically acceptable salt, prodrug or ester
`thereof, wherein:
`
`I0
`
`R represents hydrogen, alkoxycarbonyl, aralkoxycarbonyl,
`alkylcarbonyl, cycloalkylcarbonyl,
`cycloalkylalkoxycarbonyl, cycloalkylalkanoyl, alkanoyl,
`15 aralkanoyl, aroyl, aryloxycarbonyl, aryloxycarbonylalkyl,
`aryloxyalkanoyl, heterocyclylcarbonyl,
`heterocyclyloxycarbonyl, heterocyclylalkanoy!,
`heterocyclylalkoxycarbonyl, heteroaralkanoyl,
`heteroaralkoxycarbonyl, heteroaryloxycarbonyl,
`20 heteroaroyl, alkyl, alkenyl, alkynyl, cycloalkyl, aryl,
`aralkyl, aryloxyalkyl, heteroaryloxyalkyl, hydroxyalkyl,
`aminocarbonyl, aminoalkanoyl, and mono- and disubstituted
`aminocarbonyl and mono- and disubstituted aminoalkanoyl
`radicals wherein the substituents are selected from
`25 alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,
`heteroaryl, heteroaralkyl, heterocycloalkyl,
`heterocycloalkyalkyl radicals, or where said
`aminocarbonyl and aminoalkanoyl radicals are
`disubstituted, said substituents along with the nitrogen
`30 atom to which they are attached form a heterocycloalkyl
`or heteroaryl radical;
`
`R’ represents hydrogen, radicals as defined for R3 or
`R"S02- wherein R" represents radicals as defined for
`
`Lupin Ex. 1017 (Page 6 of 278)
`
`

`
`WO 95106030
`
`PCT/US94/09139
`
`or R and R’ together with the nitrogen to which they are
`attached represent heterocycloalkyl and heteroaryl
`radicals;
`
`5 R1 represents hydrogen, -CH2SO2NH2, -CH2CO2CH3, -C02CH3,
`-CONH2, -CH2C(O)NHCH3, -C(CH3)2(SH), -C(CH3)2(SCH3),
`-C(CH3)2(S[O]CH3), -C(CH3)2(S[O]2CH3), alkyl, haloalkyl,
`alkenyl, alkynyl and cycloalkyl radicals, and amino acid
`side chains selected from asparagine, S-methyl cysteine
`i0 and the sulfoxide (SO) and sulfone (S02) derivatives
`thereof, isoleucine, allo-isoleucine, alanine, leucine,
`tert-leucine, phenylalanine, ornithine, histidine,
`norleucine, glutamine, threonine, allo-threonine, serine,
`O-alkyl serine, aspartic acid, beta-cyano alanine and
`15 valine side chains;
`
`RI’ and RI" independently represent hydrogen and radicals
`as defined for RI, or one of RI’ and RI", together with
`R1 and the carbon atoms to which RI, RI’ and RI" are
`attached, represent a cycloa!kyl radical;
`
`R2 represents alkyl, aryl, cycloalkyl, cycloalkylalkyl
`and aralkyl radicals, which radicals are optionally
`substituted with a group selected from alkyl and halogen
`radials, -NO2, -CN, -CF3, -OR9 and -SRg, wherein R9
`
`represents hydrogen and alkyl radicals, and halogen
`radicals;
`
`2O
`
`25
`
`R3 represents hydrogen, alkyl, haloalkyl, alkenyl,
`30 alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyi,
`cycloalkylalkyl, heterocycloalkyl, heteroaryl,
`heterocycloalkylalkyl, aryl, aralkyl, heteroaralkyl,
`aminoalkyl and mono- and disubstituted aminoalkyl
`radicals, wherein said substituents are selected from
`35 alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,
`heteroaryl, heteroaralkyl, heterocycloalkyl, and
`heterocycloalkylalkyl radicals, or in the case of a
`
`Lupin Ex. 1017 (Page 7 of 278)
`
`

`
`WO 95106030
`
`PCT/US94/09139
`
`disubstituted aminoalkyl radical, said substituents along
`with the nitrogen atom to which they are attached, form a
`heterocycloalkyl or a heteroaryl radical;
`
`5
`
`R4 represents radicals as defined by R3 except for
`hydrogen;
`
`R6 represents hydrogen and alkyl radicals;
`
`i0 x represents 0, 1 or 2;
`
`t represents either 0 or i; and
`
`Y represents O, S and NRI5 wherein R15 represents
`hydrogen and radicals as defined for R3.
`
`15
`
`A family of compounds of particular interest
`within Formula I are compounds embraced by Formula II:
`
`R~N
`
`R,F
`
`R4
`
`(II)
`
`2 0
`
`R~
`
`OH
`
`wherein:
`
`R represents hydrogen, alkoxycarbonyl, aralkoxycarbonyl,
`25 alkylcarbonyl, cycloalkylcarbonyl,
`cycloalkylalkoxycarbonyl, cycloalkylalkanoyl, alkanoyl,
`aralkanoyl, aroyl, aryloxycarbonyl, aryloxycarbonylalkyl,
`aryloxyalkanoyl, heterocyclylcarbonyl,
`heterocyclyloxycarbonyl, heterocyclylalkanoyl,
`30 heterocyclylalkoxycarbonyl, heteroaralkanoyl,
`heteroaralkoxycarbonyl, heteroaryloxy-carbonyl,
`heteroaroyl, alkyl, alkenyl, cycloalkyl, aryl, aralkyl,
`aryloxyalkyl, heteroaryloxyalkyl, hydroxyalkyl,
`aminocarbonyl, aminoalkanoyl, and mono- and disubstituted
`
`Lupin Ex. 1017 (Page 8 of 278)
`
`

`
`WO 95/06030
`
`PCT/US94/09139
`
`aminocarbonyl and mono- and disubstituted aminoalkanoyl
`radicals wherein the substituents are selected from
`alkyl, aryl, ara!kyl, cycloalkyl, gycloalkylalkyl,
`heteroaryl, heteroaralkyl, heterocycloalkyl,
`,heterocycloalkyalkyl radicals, or where said
`aminoalkanoyl radical is disubstituted, said substituents
`along with the nitrogen atom to which they are attached
`form a heterocycloalkyl or heteroaryl radical;
`
`10
`
`R’ represents hydrogen and radicals as defined for R3 or
`R and R’ together with the nitrogen to which they are
`attached represent heterocycloalkyl and heteroaryl
`radical;
`
`15 R1 represents hydrogen, -CH2SO2NH2, -CH2CO2CH3, -CO2CH3,
`-CONH2, -CH2C(O)NHCH3, -C(CH3)2(SH), -C(CH3)2(SCH3),
`-C(CH3)2(S[O]CH3), -C(CH3)2(S[O]2CH3), alkyl, haloalkyl,
`alkenyl, alkynyl and cycloalkyl radicals, and amino acid
`side chains selected from asparagine, S-methyl cysteine
`20 and the sulfoxide (SO) and sulfone (SO2) derivatives
`thereof, isoleucine, allo-isoleucine, alanine, leucine,
`tert-leucine, phenylalanine, ornithine, histidine,
`norleucine, glutamine, threonine, allo-threonine, serine,
`O-methyl serine, aspartic acid, beta-cyano alanine and
`25 valine side chains;
`
`R2 represents alkyl, aryl, cycloalkyl, cycloalkylalkyl
`and aralkyl radicals, which radicals are optionally
`substituted with a group selected from alkyl and halogen
`radials, -NO2, -C~N, CF3, -ORg, -SR9, wherein R9
`
`represents hydrogen and alkyl radicals;
`
`R3 represents alkyl, haloalkyl, alkenyl, alkynyl,
`hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl,
`heterocycloalkyl, heteroaryl, heterocycloalkylalkyl,
`aryl, aralkyl, heteroaralkyl, aminoalkyl and mono- and
`disubstituted aminoalkyl radicals, wherein said
`
`30
`
`35
`
`Lupin Ex. 1017 (Page 9 of 278)
`
`

`
`WO 95/06030
`
`PCT/US94/09139
`
`substituents are selected from alkyl, aryl, aralkyl,
`cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl,
`heterocycloalkyl, and heterocycloalkylalkyl radicals, or
`in the case of a disubstituted aminoalkyl radical, said
`substituents along with the nitrogen atom to which they
`are attached, form a heterocycloalkyl or a heteroaryl
`radical; and
`
`R4 represents radicals as defined by R3.
`
`I0
`
`A more preferred family of compounds within
`Formula II consists of compounds wherein:
`
`R represents hydrogen, alkoxycarbonyl, aralkoxycarbonyl,
`15 alkylcarbonyl, cycloalkylcarbonyl,
`cycloalkylalkoxycarbonyl, cycloalkylalkanoyl, alkanoyl,
`aralkanoyl, aroyl, aryloxycarbonyl, aryloxycarbonylalkyl,
`aryloxyalkanoyl, heterocyclylcarbonyl,
`heterocyclyloxycarbonyl, heterocyclylalkanoyl,
`20 heterocyclylalkoxycarbonyl, heteroaralkanoyl,
`heteroaralkoxycarbonyl, heteroaryloxy-carbonyl,
`heteroaroy!, alkyl, alkenyl, cycloalkyl, aryl, aralkyl,
`aryloxyalkyl, heteroaryloxyalkyl, hydroxyalkyl,
`aminocarbonyl, aminoalkanoyl, and mono- and disubstituted
`25 aminocarbonyl and mono- and disubstituted aminoalkanoyl
`radicals wherein the substituents are selected from
`alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,
`heteroaryl, heteroaralkyl, heterocycloalkyl,
`heterocycloalkyalkyl radicals, or where said
`30 aminoalkanoyl radical is disubstituted, said substituents
`along with the nitrogen atom to which they are attached
`form a heterocycloalkyl or heteroaryl radical;
`
`35
`
`R’ represents hydrogen and radicals as defined for R3 or
`R and R’ together with the nitrogen to which they are
`attached represent heterocycloalkyl and heteroaryl
`radical;
`
`Lupin Ex. 1017 (Page 10 of 278)
`
`

`
`WO 95106030
`
`PCT/US94/09139
`
`R1 represents CH2C(O)NHCH3, C(CH3)2(SCH3),
`C(CH3)2(S[O]CH3), C(CH3)2(S[O]2CH3), alkyl, alkenyl and
`alkynyl radicals, and amino acid side chains selected
`from the group consisting of asparagine, valine,
`thre0nine, allo-threonine, isoleucine, tert-leucine,
`S-methyl cysteine and the sulfone and sulfoxide
`derivatives thereof, alanine, and allo-isoleucine;
`
`i0 R2 represents alkyl, cycloalkylalkyl and aralkyl
`radicals, which radicals are optionally substituted with
`halogen radicals and radicals represented by the formula
`-OR9 and -SR9 wherein R9 represents alkyl radicals; and
`
`15 R3 and R4 independently represent alkyl, alkenyl,
`alkoxyalkyl, cycloalkyl, cycloalkylalkyl,
`heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl
`and heteroaralkyl radicals.
`
`2O
`
`Of highest interest are compounds within
`Formula II wherein
`
`R represents alkoxycarbonyl, aralkoxycarbonyl,
`alkylcarbonyl, cycloalkylcarbonyl,
`25 cycloalkylalkoxycarbonyl, cycloalkylalkanoyl, alkanoyl,
`aralkanoyl, aroyl, aryloxycarbonyl, aryloxycarbonylalkyl,
`aryloxyalkanoyl, heterocyclylcarbonyl,
`heterocyclyloxycarbonyl, heterocyclylalkanoyl,
`heterocyclylalkoxycarbonyl, heteroaralkanoyl,
`30 heteroaralkoxycarbonyl, heteroaryloxy-carbonyl,
`heteroaroyl, aminocarbonyl, aminoalkanoyl, and mono- and
`disubstituted aminocarbonyl and mono- and disubstituted
`aminoalkanoyl radicals wherein the substituents are
`selected from alkyl, aryl, aralkyl, cycloalkyl,
`35 cycloalkylalkyl, heteroaryl, heteroaralkyl,
`heterocycloalkyl, heterocycloalkyalkyl radicals, or where
`said aminoalkanoyl radical is disubstituted, said
`
`Lupin Ex. 1017 (Page 11 of 278)
`
`

`
`WO 95/06030
`
`PCT/US94/09139
`
`10
`
`substituents along with the nitrogen atom to which they
`are attached form a heterocycloalkyl or heteroaryl
`radical;
`
`R’ represents hydrogen and radicals as defined for R3 or
`R and R’ together with the nitrogen to which they are
`attached represent heterocycloalkyl and heteroaryl
`radical;
`
`I0 R1 represents CH2C(O)NHCH3, C(CH3)2(SCH3),
`C(CH3)2(S[O]CH3), C(CH3)2(S[O]2CH3), methyl, propargyl,
`t-butyl, isopropyl and sec-butyl radicals, and amino acid
`side chains selected from the group consisting of
`asparagine, valine, S-methyl cysteine, allo-iso-leucine,
`15 iso-leucine, and beta-cyano alanine side chains;
`
`R2 represents CH3SCH2CH2-, iso-butyl, n-butyl, benzyl,
`4-fluorobenzyl, 2-naphthylmethyl and cyclohexylmethyl
`radicals;
`
`20
`
`R3 represents isoamyl, n-butyl, isobutyl and cyclohexyl
`radicals; and
`
`R4 represents phenyl, substituted phenyl and methyl
`radicals.
`
`25
`
`Another family of compounds of .particular
`interest within Formula I are compounds embraced by
`Formula III:
`
`30
`
`(TTT)
`
`wherein:
`R represents hydrogen, alkoxycarbonyl, aralkoxycarbonyl,
`alkylcarbonyl, cycloalkylcarbonyl,
`
`35
`
`Lupin Ex. 1017 (Page 12 of 278)
`
`

`
`WO 95106030
`
`PCTFOS94/09139
`
`11
`
`cycloalkylalkoxycarbonyl, cycloalkylalkanoyl, alkanoyl,
`aralkanoyl, aroyl, aryloxycarbonyl, aryloxycarbonylalkyl,
`aryloxyalkanoyl, heterocyclylcarbonyl,
`heterocyclyloxycarbonyl, heterocyclylalkanoyl,
`5 heterocyclylalkoxycarbonyl, heteroaralkanoyl,
`heteroaralkoxycarbonyl, heteroaryloxy-carbonyl,
`heteroaroyl, alkyl, alkenyl, cycloalkyl, aryl, aralkyl,
`aryloxyalkyl, heteroaryloxyalkyl, hydroxyalkyl,
`aminocarbonyl, aminoalkanoyl, and mono- and disubstituted
`i0 aminocarbonyl and mono- and disubstituted aminoalkanoyl
`radicals wherein the substituents are selected from
`alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,
`heteroaryl, heteroaralkyl, heterocycloalkyl,
`heterocycloalkyalkyl radicals, or where said
`15 aminoalkanoyl radical is disubstituted, said substituents
`along with the nitrogen atom to which they are attached
`form a heterocycloalkyl or heteroaryl radical;
`
`2O
`
`R’ represents hydrogen and radicals as defined for R3 or
`R and R’ together with the nitrogen to which they are
`attached represent heterocycloalkyl and heteroaryl
`radical;
`
`R1 represents hydrogen, -CH2SO2NH2, -CH2CO2CH3, -C02CH3,
`25 -CONH2, -CH2C(O)NHCH3, -C(CH3)2(SH), -C(CH3)2(SCH3),
`-C(CH3)2(S[O]CH3), -C(CH3)2(S[O]2CH3), alkyl, haloalkyl,
`alkenyl, aikynyl and cycloalkyl radicals, and amino acid
`side chains selected from asparagine, S-methyl cysteine
`and the sulfoxide (SO) and sulfone (SO2) derivatives
`30 thereof, isoleucine, allo-isoleucine, alanine, leucine,
`tert-leucine, phenylalanine, ornithine, histidine,
`norleucine, glutamine, threonine, allo-threonine, serine,
`aspartic acid, beta-cyano alanine and valine side
`chains;
`
`35
`
`R2 represents alkyl, aryl, cycloalkyl, cycloalkylalkyl
`and aralkyl radicals, which radicals are optionally
`
`Lupin Ex. 1017 (Page 13 of 278)
`
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`WO 95/06030
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`PCTRIS94/09139
`
`12
`
`substituted with a group selected from alkyl and halogen
`radicals, -NO2, -C=N, CF3, -ORg, -sRg, wherein R9
`
`represents hydrogen and alkyl;
`
`5 R3 represents alkyl, haloalkyl, alkenyl, alkynyl,
`hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl,
`heterocycloalkyl, heteroaryl, heterocycloalkylalkyl,
`aryl, aralkyl, heteroaralkyl, aminoalkyl and mono- and
`disubstituted aminoalkyl radicals, wherein said
`i0 substituents are selected from alkyl, aryl, aralkyl,
`cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl,
`heterocycloalky!, and heterocycloalkylalkyl radicals, or
`in the case of a disubstituted aminoalkyl radical, said
`substituents along with the nitrogen atom to which they
`15 are attached, form a heterocycloalkyl or a heteroaryl
`radical; and
`
`R4 represents radicals as defined by R3.
`
`20
`
`A more preferred family of compounds within
`Formula III consists of compounds wherein
`
`R represents hydrogen, alkoxycarbonyl, aralkoxycarbonyl,
`alkylcarbonyl, cycloalkylcarbonyl,
`25 cycloalkylalkoxycarbonyl, cycloalkylalkanoyl, alkanoyl,
`aralkanoyl, aroyl, aryloxycarbonyl, aryloxycarbonylalkyl,
`aryloxyalkanoyl, heterocyclylcarbonyl,
`heterocyclyloxycarb0nyl, heterocyclylalkanoyl,
`heterocyclylalkoxycarbonyl, heteroaralkanoyl,
`30 heteroaralkoxycarbonyl, heteroaryloxy-carbonyl,
`heteroaroyl, alkyl, alkenyl, cycloalkyl, aryl, aralkyl,
`aryloxyalkyl, heteroaryloxyalkyl, hydroxyalkyl,
`aminocarbonyl, aminoalkanoyl, and mono- and disubstituted
`aminocarbonyl and mono- and disubstituted aminoalkanoyl
`35 radicals wherein the substituents are selected from
`alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,
`heteroaryl, heteroaralkyl, heterocycloalkyi,
`
`Lupin Ex. 1017 (Page 14 of 278)
`
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`13
`
`heterocycloalkyalkyl radicals, or where said
`aminoalkanoyl radical is disubstituted, said substituents
`along with the nitrogen atom to which they are attached
`form a heterocycloalkyl or heteroaryl radical;
`
`R’ represents hydrogen and radicals as defined for R3 or
`R and R’ together with the nitrogen to which they are
`attached represent heterocycloalkyl and heteroaryl
`radical;
`
`R1 represents hydrogen, alkyl and alkenyl radicals, and
`amino acid side chains selected from the .group consisting
`of asparagine, valine, threonine, allo-threonine,
`isoleucine, tert-leucine, S-methyl cysteine and the
`sulfone and sulfoxide derivatives thereof, alanine, and
`allo-isoleucine;
`
`R2 represents alkyl, cycloalkylalkyl and aralkyl
`radicals, which radicals are optionally substituted with
`halogen radicals and radicals represented by the formula
`-OR9 and -SR9 wherein R9 represents hydrogen and alkyl
`and halogen radicals; and
`
`R3 and R4 independently represent alkyl, alkenyl,
`alkoxyalkyl, cycloalkyl, cycloalkylalkyl,
`heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl,
`heteroaryl and heteroaralkyl radicals.
`
`5
`
`10
`
`15
`
`2O
`
`25
`
`Of highest interest are compounds within
`Formula III wherein
`
`3O
`
`R represents hydrogen, alkoxycarbonyl, aralkoxycarbonyl,
`alkylcarbonyl, cycloalkylcarbonyl,
`cycloalkylalkoxycarbonyl, cycloalkylalkanoyl, alkanoyl,
`aralkanoyl, aroyl, aryloxycarbonyl, aryloxycarbonylalkyl,
`aryloxyalkanoyl, heterocyclylcarbonyl,
`heterocyclyloxycarbonyl, heterocyclylalkanoyl,
`
`35
`
`Lupin Ex. 1017 (Page 15 of 278)
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`
`14
`
`heterocyclylalkoxycarbonyl, heteroaralkanoyl,
`heteroaralkoxycarbonyl, heteroaryloxy-carbonyl,
`heteroaroyl, aminocarbonyl, aminoalkanoyl, and mono- and
`disubstituted aminocarbonyl and mono- and disubstituted
`aminoalkanoyl radicals wherein the substituents are
`selected from alkyl, aryl, aralkyl, cycloalkyl,
`cycloalkylalkyl, heteroaryl, heteroaralkyl,
`heterocycloalkyl, heterocycloalkyalkyl radicals, or where
`said aminoalkanoyl radical is disubstituted, said
`substituents along with the nitrogen atom to which they
`are attached form a heterocycloalkyl or heteroaryl
`radical;
`
`R’ represents hydrogen and radicals as defined for R3 or
`R and R’ together with the nitrogen to which they are
`attached represent heterocycloalkyl and heteroaryl
`radical;
`
`R1 represents hydrogen, methyl, propargyl, t-butyl,
`isopropyl and sec-butyl radicals, and amino acid side
`chains selected from the group consisting of asparagine,
`valine, S-methyl cysteine, allo-iso-leucine, iso-leucine,
`threonine, serine, aspartic acid, beta-cyano alanine, and
`allo-threonine side chains;
`
`R2 represents CH3SCH2CH2-, iso-butyl, n-butyl, benzyl,
`4-fluorobenzyl, 2-naphthylmethyl and cyclohexylmethyl
`radicals; and
`
`10
`
`15
`
`2O
`
`25
`
`3O R3 represents alkyl, cyclohexyl, isobutyl, isoamyl, and
`n-butyl radicals; and
`
`R4 represents methyl, phenyl and substituted phenyl
`radicals wherein the substituents are selected from halo,
`alkoxy, hydroxy, nitro and amino substituents.
`
`Lupin Ex. 1017 (Page 16 of 278)
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`15
`
`Another family of compounds of particular
`interest within Formula I are compounds embraced by
`Formula IV:
`
`aI’
`
`a2
`
`R,/
`
`R1
`
`N
`
`N/S~ R4
`I
`OH Ra
`
`(IV)
`
`wherein:
`
`R represents hydrogen, alkoxycarbonyl, aralkoxycarbonyl,
`alkylcarbonyl, cycloalkylcarbonyl,
`i0 cycloalkylalkoxycarbonyl, cycloalkylalkanoyl, alkanoyl,
`aralkanoyl, aroyl, aryloxycarbonyl, aryloxycarbonylalkyl,
`aryloxyalkanoyl, heterocyclylcarbonyl,
`heterocyclyloxycarbonyl, heterocyclylalkanoyl,
`heterocyclylalkoxycarbonyl, heteroaralkanoyl,
`15 heteroaralkoxycarbonyl, heteroaryloxy-carbonyl,
`heteroaroyl, alkyl, alkenyl, cycloalkyl, aryl, aralkyl,
`aryloxyalkyl, heteroaryloxyalkyl, hydroxyalkyl,
`aminocarbonyl, aminoalkanoyl, and mono- and disubstituted
`aminocarbonyl and mono- and disubstituted aminoalkanoyl
`20 radicals wherein the substituents are selected from
`alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,
`heteroaryl, heteroaralkyl, heterocycloalkyl,
`heterocycloalkyalkyl radicals, or where said
`aminoalkanoyl radical is disubstituted, said substituents
`25 along with the nitrogen atom to which they are attached
`form a heterocycloalkyl or heteroaryl radical;
`
`R’ represents hydrogen and radicals as defined for R3 or
`R and R’ together with the nitrogen to which they are
`attached represent heterocycloalkyl and heteroaryl
`radical;
`
`3O
`
`R1 represents hydrogen, -CH2SO2NH2, -CH2CO2CH3, -C02CH3,
`-CONH2, -CH2C(O)NHCH3, -C(CH3)2(SH)I -C(CH3)2(SCH3) ,
`-C(CH3)2(S[O]CH3), -C(CH3)2(S[©]2CH3), alkyl, haloalkyl,
`
`35
`
`Lupin Ex. 1017 (Page 17 of 278)
`
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`WO 95/06030
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`PCTRIS94/09139
`
`16
`
`alkenyl, alkynyl and cycloalkyl radicals, and amino acid
`side chains selected from asparagine, S-methyl cysteine
`and the sulfoxide (SO) and sulfone (S02) derivatives
`thereof, isoleucine, allo-isoleucine, alanine, leucine,
`tert-leucine, phenylalanine, ornithine, histidine,
`norleucine, glutamine, threonine, allo-threonine, serine,
`aspartic acid, beta-cyano alanine and valine side
`chains;
`
`RI’ and RI" independently represent hydrogen and radicals
`as defined for R!, or one of RI’ and RI", together with
`R1 and the carbon atoms to which RI, RI’ and RI" are
`attached, represent a cycloalkyl radical;
`
`R2 represents alkyl, aryl, cycloalkyl, cycloalkylalkyl
`and aralkyl radicals, which radicals are optionally
`substituted with a group selected from alkyl and halogen
`radials, -NO2, -C~N, CF3, -OR9 and -sRg, wherein R9
`represents hydrogen and alkyl radicals;
`
`R3 represents alkyl, haloalkyl, alkenyl, alkynyl,
`hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl,
`heterocycloalkyl, heteroaryl, heterocycloalkylalkyl,
`aryl, aralkyl, heteroaralkyl, aminoalkyl and mono- and
`disubstituted aminoalkyl radicals, wherein said
`substituents are selected from alkyl, aryl, aralkyl,
`cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl,
`heterocycloalkyl, and heterocycloa!kylalkyl radicals, or
`in the case of a disubstituted aminoalkyl radical, said
`substituents along with the nitrogen atom to which they
`are attached, form a heterocycloalkyl or a heteroaryl
`radical; and
`
`R4 represents radicals as defined by R3.
`
`A more preferred family of compounds within
`Formula IV consists of compounds wherein
`
`i0
`
`15
`
`2O
`
`25
`
`30
`
`35
`
`Lupin Ex. 1017 (Page 18 of 278)
`
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`PCT/US94/09139
`
`17
`
`represents an arylalkanoyl, heteroaroyl,
`aryloxyalkanoyl, aryloxycarbonyl, alkanoyl,
`aminocarbonyl, mono-substituted aminoalkanoyl, or
`disubstituted aminoalkanoyl, or mono-or
`dialkylaminocarbonyl radical;
`
`R’ represents hydrogen and radicals as defined for R3 or
`R and R’ together with the nitrogen to which they are
`attached represent a heterocycloalkyl or heteroaryl
`radical;
`
`Rl, RI’ and RI" independently represent hydrogen and
`alkyl radicals having from 1 to about 4 carbon atoms,
`alkenyl, alkynyl, aralkyl radicals, and radicals
`represented by the formula -CH2C(O)R" or -C(O)R" wherein
`R" represents R38, -NR38R39 and OR38 wherein R38 and R39
`independently represent hydrogen and alkyl radicals
`having from 1 to about 4 carbon atoms;
`
`R2 represents alkyl, cycloalkylalkyl and aralkyl
`radicals, which radicals are optionally substituted with
`halogen radicals and radicals represented by the formula
`-OR9 and -SR9 wherein R9 represents hydrogen and alkyl
`radicals; and
`
`R3 and R4 independently represent alkyl, alkenyl,
`alkoxyalkyl, cycloalkyl, cycloalkylalkyl,
`heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl,
`heteroaryl and heteroaralkyl radicals.
`
`l0
`
`15
`
`2O
`
`25
`
`30
`
`Of highest interest are compounds of Formula IV
`
`wherein:
`
`35 R represents an arylalkanoyl, aryloxycarbonyl,
`aryloxyalkanoyl, alkanoyl, aminocarbonyl, mono-
`
`Lupin Ex. 1017 (Page 19 of 278)
`
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`
`18
`
`substituted aminoalkanoyl, or disubstituted
`aminoalkanoyl, or mono-or dialkylaminocarbonyl radica!;
`
`R’ represents hydrogen and radicals as defined for R3 or
`R and R’ together with the nitrogen to which they are
`attached represent a heterocycloalkyl or heteroaryl
`radical;
`
`RI, Rl’ and RI’’ independently represent hydrogen~ methyl,
`ethyl, benzyl, phenylpropyl and propargyl radicals;
`
`10
`
`R2 represents CH3SCH2CH2-, iso-butyl, n-butyl, benzyl,
`4-fluorobenzyl, 2-naphthylmethyl and cyclohexylmethyl
`radicals;
`
`R3 represents alkyl, cyclohexyl, isobutyl, isoamyl and
`n-butyl radicals; and
`
`R4 represents methyl, phenyl and substituted phenyl
`radicals wherein the substituents are selected from halo)
`alkoxy, amino and nitro substituents.
`
`15
`
`2O
`
`As utilized herein, the term "alkyl", alone or
`in combination, means a straight-chain or branched-chain
`25 alkyl radical containing from 1 to about i0 carbon atoms,
`preferably from 1 to about 8 carbon atoms, more
`preferably 1-5 carbon atoms. Examples of such radicals
`include methyl, ethyl, n-propyl, isopropyl, n-butyl,
`isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl,
`30 octyl and the like. The term "alkenyl", alone or in
`combination, means a straight-chain or branched-chain
`hydrocarbon radial having one or more double bonds an