1
`I
`(12) United btates Patent
`Chen et al.
`
`USUU691 6809132
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 6,916,309 B2
`Jul. 12, 2005
`
`(54) HE'I'EROCYCI.IC ACRIIION F. INHIBITORS
`OF [MPDH ENZYME
`
`(75)
`
`lnventors: Ping Chen, Belle Mead, NJ (US); T.C.
`-
`,
`.
`_
`Murall Dhar‘, l\lt:\'\1L)WI1, PA (US),
`.
`.
`.
`.
`ILClWIl‘l J. Iwanowiez, West Windsor, NJ
`H. Wilttersun, I.)CIII1IIIgIOII,
`NJ (US); Henry CII, Bordenlown, NJ
`(US); Yufen Zhao, Pennington, N]
`(US)
`
`(73) Assignee: Bristol-Myers Squibb Company,
`Princeton, NJ (US)
`
`(4) Notice:
`
`Subjeetto any disclaimer, the term ofthis
`patent 15 extended or adjusted under 35
`U.S.(.'. 154(1)) by 2? days.
`
`(21) Appl. No.:
`(77)
`Filed‘
`dd
`'
`(65)
`
`ll]_f32S,009
`Dec 20 2002
`D
`_
`Pf ' P ,1 ll
`Im uncamm am
`US 200340181497 Al Sep. 25, 2003
`
`(60)
`
`Related U-5- /\P[l1iC«'iti01'l "M3
`Provisional application No. 6U,-"343,234_. filed on Dec. 21,
`3991'
`Int. CL7
`
`(51)
`
`C071) 471714; (:07!) 471704;
`A61K 31f4375; A611’ 197'0’_>; A61P 17!U6
`51472395, 514725505;
`.2) Us. Cl.
`5141256; 5147293; 544,-"1(|5; 5447333; 5443405;
`544760; 5447126; 544_.-361; 5447250; 546781;
`,
`340575
`_
`(58) Field of Search
`5443105, 333,
`5447405, 60, 126, 361; 540481; 514;’230.S,
`255 .05, 256, 293; 5407575
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`3_.835_.139 A
`9i_9?4 Pfister et al.
`4,250,182 A
`2)’ 981 Gorvin
`4.374.984 A
`241933 Eiehler el al.
`-’t_.686_.23-’t A
`87-937 Nelson et al.
`4,725,522 A
`27 988 Nelson et al.
`4_.T2'r'_.l'J69 A
`2f_988 Nelson el al.
`4,753,935 A
`6,-" 988 Nelson (:1 ill.
`4,786,631-' A
`11,-" 988 Allison et ill.
`4,808,592 A
`2,! 989 Nelson et al.
`4_.861_.T’6 A
`8,9103‘) Nelson et al.
`4,868,153 A
`9)" 989 Allison et ill.
`4,943,793 A
`37 99:) Allison et al.
`4,952,579 A
`8}, 990 Nelson el al‘
`4_.95.9_.3s7 A
`97-990 Nelson et al.
`4,992,457 A
`27 991 Allison et al.
`5__;g4',t__[)s3 A
`o,r_og3 {gm}; (:1 at,
`5,38tJ,8?9 A
`1,! 995 Sjogrcn
`5.444.972 A
`37' 995 Pflllerwfl el ill‘
`5.-555.-583 A
`91-997 Collar‘ 01 31-
`5r_,8ll7,875 A
`9;’ 998 Armistead et Ell.
`2w4"'m53'g55 M 312004 Iwmlowlcz C‘ al‘
`1-‘OREIGN PA'1‘]:‘,N'1‘ [_)()CUM[;'N'[‘3
`1009576
`:3)" l 977
`101191360
`5)-"197?
`
`CA
`CA
`
`DE
`lil’
`GR
`
`JP
`JP
`W0
`W0
`
`W0
`wo
`W0
`W()
`W0
`
`224399?
`(J 054 812
`1382259
`
`53'-305173
`11-13076?
`W0 94,-"UllU5
`W0 94,121“
`
`3;’ [W3
`611.982
`l,u"l 91-"5
`
`1241983
`5,-"l999
`l/1994
`M1994
`
`W0 g8)15546
`4941998
`wo 93740331
`ogiggp,
`WO 00423415
`442000
`W{) Ull,-‘Z341 6
`44211111]
`W0 (J3flJ59269
`112003
`OTHER PUBLICATIONS
`
`1994 W 593 S97 *
`I M d (‘h
`11]
`(‘h
`'
`'
`1
`'
`' _'
`)‘
`' ("
`C ‘
`‘ cm‘
`' 8" C ‘i
`Stewart, (5. el al., Aust. .l. (Ihem., vol. 37, pp. 1939-1950
`(1984).
`Chemical Abstracts, vol. 123, No. 3 (1995), abstract No.
`32927 gi
`Seiliinder Acridones Listing oi‘ Abstracts.
`Canelos,
`l’.A. el al., Abstract 486: "koliprzun, a Type
`Phosphocliesterase (PDE) Inhibitor, Promotes Induction ot
`Neoantigen Tolerance in Murine '1‘ Cells” (593), J. Allergy
`(flin. lrnmunol. vol. 107, No. 2, p. 3147.
`
`(Continued)
`
`1’rr'mar_v 1:‘xmm'ncr—Mark L Berch
`A-W"-With‘ »'='xwHim'r—Kahsay llablc
`(74) /U_-"0»"»"i<3.3r';
`/'13?‘-"113 0* H-"m—'1‘¢1'°"‘3° 1 B03159 319995“
`B- Davis
`(57)
`
`ABSTRACT
`
`Compounds having the formula (I),
`
`(I)
`
`R
`
`30
`J\
`X1
`_ X7
`X’‘’ “X3
`X“ “X3
`l,,,_ A ,
`l_,,
`L,
`“*'~..x,»-“~».\_/’*~».x, W/’*-.Y/Ox?
`'
`
`R3
`
`1
`30.
`_
`.
`,
`3.
`.
`wherein R -is selected trpm H, 0‘H and NH3, R1
`15 selectccl
`rmf" :0 ‘ml :5» V‘
`1*’
`‘ C-(=9)—3
`5§=0l—= “r
`_—b(0l;—: Of W mtg)? '36 —C-Haj If X 15 —C-(=0)—; X
`is selected from
`(.Il_,_
`,
`N(R )
`, and
`U , except
`that when W is —{TH2—, X is —(.‘[=())—; Y is a bond or
`—(T(R"”}[R"5)—; Q is a linker; Z is optionally substituted
`alkyl, alkenyl, alkynyl, eycloalkyl, aryl, heteroarvl, or het-
`crucyclylé and X1’ X3’ X3’ X4, X5, X5’ X7, X8’ X9, X10 and
`X" are selected such a tricyelie heteroaryl ring, system is
`formed as further defined in the specification.
`
`10140
`
`9 Claims, No Drawings
`
`PENN EX. 2232
`
`CFAD V. UPENN
`IPR20l5-01836
`
`

`
`US 6,916,809 B2
`Page 2
`
`OTHER PUBLICATIONS
`
`Carr, 8.1-‘. ct a1.,"Characlcri7.ation oflluman Type I and'I'ypt:
`II IMP Dehyclrogenascs”, The Journal of Biological Chem-
`istry, vol. 268, No. 36, pp. 27286-27290 (1993).
`Collart, F,R. et a1., "Cloning and Sequence Analysis of the
`Human and Chinese Hamster Inosinc—S'—monophosphatc
`Dchydrogcnasc cDNAs”, The Journal of Biological Chom-
`islry, vol. 263, No. 3, pp. 15769-15772 (1988).
`Jackson, R.C. ct al.,"1MP dehydrogcnase, an enzyme linked
`with proliferation and malignancy”, Nature, vol. 256, pp.
`331-333 (1975).
`
`Konno, Y. ct al., “Expression of Human IMP Dchydrogenase
`Types 1 and II in Esciiericlufa coli and Distribution in Human
`Normal Lymphocytes and Lcukemic Cell Lines”, The Jour-
`nal of Biological Chemistry, vol. 266, 1\'o. 1, pp. 506-509
`(1991).
`
`Natsumerla, Y. ct 211., “Two Distinct CDNAS for Human IMP
`Dehydrogenasc”, The Journal of Biological Chemistry, vol.
`265, No. 9, pp. 5292-5295 (1990).
`
`* cited by examiner
`
`20140
`
`PENN EX. 2232
`
`CFAD V. UPENN
`IPR20l5-01836
`
`

`
`US 6,916,809 B2
`
`1
`HETEROCYCLIC ACRIDONE INHIBITORS
`OF IMPDH ENZYME
`
`RILL/KIILD APPLICATIONS
`
`ilhi-"3 aplllicalihh Claim’? lhh hhhelh UT US‘ P1'UVl-‘iihhhl
`A1Jp1iCi1Ii0l1 N0- 603343.334, T11’-‘ail D60 31, 3001, iflC0f1J0-
`Tiiltld hflrtlifl by rfiftlrtlflcth
`
`5
`
`2
`phenolic acid (“MPA”) and some ofits derivatives as potent,
`uncompetitive, reversible inhibitors of human IMPDII type
`I and type II. MI-‘A has been demonstrated to block the
`response of B and T—cells
`to mitogen or antigen.
`Immunosuppressants, such as MPA and derivatives of MPA,
`are useful drugs in the treatment of transplant rejection and
`autoimmune disorders, psoriasis,
`inflammatory diseases,
`including rheumatoid arthritis, tumors and for the treatment
`of allograll rejection. These are described in U.S. Pat. Nos.
`,0 4,686,234, 4,725,622, 4,727,069, 4,753,935, 4,786,637’,
`FIELD OF THE INVENTION
`4’808’592’ 4’801’7.76’ 4’868‘l53‘ 4’948‘793’ 4’952’579’
`The present invention relates to compounds which inhibit
`4’959’387’ 4’992’4{)7‘ a‘nd_5‘247’O83‘
`IMPDII,
`to methods of making such compounds, and to
`Mycophcnhlaic motclm _sold_ under the lradfz Ham]:
`pharmaceutical compositions containing these compounds.
`CELLCEPT-15 aPr°dr“?»‘lf'h1‘3hhb°r"'l°5 MPAm V“l0- IF 13
`The compounds and pharmaceutical compositions of the
`invcnu-on can be used as lherapeulie agmls [Gr
`|MPD“_ 15 approved fonuse in preventing acute renal allograitrejecti-on
`a_,mCia1ed disorders‘
`tollowing kidney transplantation. The side etieet prohle
`limits the therapeutic potential of this drug. MPA1s rapidly
`rEet::l'l)tili:e](] tolthetinalctive g_l-t.(l‘l(.‘1.trL)l']iLl(idi1']l-]\-'l\«’L)i“ I£1l}'|’i/i\mal%s,
`BACKGROUND 01:‘ THE INVENTION
`I e
`on
`eve s o
`ucuroni e excee
`t at o
`.
`e
`Ih051'h'-3 Yh0h0l3h05l3h'<1h3 ‘h3hYCh'08°h35C (IMPDH) ha5 3“ glucuronide uridergfies enterohepatic recycling causing
`h’-3'-3h 5h0“’h l0 '39 "1 k°Y 5hZYm5 lh ‘h° Wghlalihh Of CC“
`accumulation of MPA in the bile and subsequently in the
`Prohfcralioh and (llE°r°hllall°h- Nucbolldcs am rcqhlrcd
`gastrointestinal tract. This together with the production of
`for '39“-5 10 dhhdc hhd “3l"1iCaW- Ih mammalhs hhclcmldcs
`the inactive glucuronide ellectively lowers the drug’s in vivo
`ma)’ he Syhlhhsized through hhh 0f “V0 Pathway-‘V ‘he ‘13
`potency, while increasing its undesirable gastrointestinal
`novo synthesis pathway or the salvage pathway. The extent Ge Side e[1‘eel5_
`ol‘ utilization of each pathway is dependent on the cell type. Hi
`The Comb,-nalion of agents for pwvemion andyor Heap
`This selectivity has ramifications with regard to therapeutic
`mom of IMPDH_aSS0ciamd disorders’ especially auogmft
`“mill” as described htiklw‘
`rejection, has been investigated.
`In one study,
`it was
`IMPDII is involved in the de novo synthesis of guanosine
`ohgerved that eye-lie AMP agr_31'1'i5[5-gj gueh as,
`the Type 4
`nucleotides.
`IMPDH catalyzes the irreversible NAD— 30 Phosphodiesterase [PDE4)
`inhibitor Rolipram [4—[3—
`dependent oxidation Of inosine—5'—monophosphate (“IMP”)
`(cyclnpcntylgxy)-4-mc[h()xy_phcny]]-2-pyrrolidinon(:]
`I0 xanthosinc—5'—monophosphatc (“XMP”), Jackson ct al.,
`(Schering AG), synergized with IMPDH inhibitor MPA bya
`NW“-"6’i 3553331‘-333 (1975)
`cAMP— and IMPDH—dependent mechanism. (P. A. Canelos
`INIPDII
`ubiquitous in cuka_ry(3T_c5;’ ba{_;[cri3_ and p]'[_)[()—
`Cl iil.,J. flt."i"£’l'gy and Ci.I."I.ICi5li hl'ii'.tIfl!I()I()g_y‘_, lU7I593
`zoa. The prokaryotic forms share 30-40% sequence identity 35 The investigators found that cyclic AMP agonists, such as
`with the human enzyme,
`the I-‘Dl_i_4 inhibitor Rolipram (Rol), markedly downregu—
`TWO distinct CDNA.»S encoding IMPDH haw: bccn idem
`lated antigen-specific
`lymphocyte resporises through their
`Iified and isolated. These transcripts are labeled type I and
`"[rcCl’“’" ‘f Vancty “r Slgnahng Palhwa_y‘°" lhc Study dflgned
`type II and are ofidentical size (514 amino acids). Collartet
`‘he P°l_‘’"“‘’l 1‘: "Sc 3 ]"w °_"“°°r}”a““" ‘ff Rd 00- M=
`al.,J. Biol. Cl.=em._. 263:'l5769—t5772(1988); Natsumeda et 4“ 3PI‘“”“"?3“= "-1::)“3-‘*>’Wg”‘= “’"_h 8 "=i"°'Y 0‘ Immune
`al.,J’. Bier. C.It£_’iF.*t._, 255.-5292-5295 (1990), and U.S. Pat. No.
`3“I‘P"=*'~‘““=, «'*.*.=If="‘5 h“_‘h*> _P“>"°m1““ ="1d»“'0f
`'FW'*‘F"1 0'"
`5,665,583 to Collart et al. These isoforms share 84%
`?“0_g‘Ta_fi
`re-l‘j"C“0_n' While hm’; or‘ F10 -‘3}’h°r815h° cflcct 30“
`sequence identity. IMPDH type I and type II form tetramers
`mh‘b“_‘°_“ 0? am‘3°n‘1_nd“C°d prohtcr‘ll 10" ("‘55°55°d_ by H
`in Sole“-On, [he cmymalicany active ,mil_
`Thymidine incorporation) could be demonstrated with cal-
`l3 and T-lymphocytes depend on the de novo, rather than 45
`,3.
`.
`.,
`_
`.
`, .
`x
`(
`9
`I
`.
`.
`.
`.
`ms:'_a*m1m*- Of m>'C°P.h=.-
`d*="‘°"-*'m'r=‘1. with M“ "is
`::1$’.a.i‘;.‘§."$“i§i’.§?c”§','.";i{“i‘.‘I‘...'3.‘..1.li1.“."'..T‘"‘.’3f..i.‘°;?'n°..-1: it. '§3§.lT.,"§$d§?
`"male .mU.k.m] (cenccph Rfwhsy Thlshsmid W51: Stahsge
`antigen. Due to the B and T cell's unique reliance on the de
`Cally Sl.gmhcam.0vcr 4 ordu-S. of magnitude. (lo
`[0 lo
`novo pathway, IMPDII is an attractive target for selectively
`5:: M). This synergism was recapitulated with dibuteryl—cAMP
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`(,x10__;. M a
`roximam IC.
`)md inhibited with the US: of
`inhibiting the immune system without also inhibiting the
`I-I-9
`sungestiii:
`a mechanihlrntinvolving both CAMP and
`pmmcration Of mhcr 06115‘
`pml;,-n iinax
`Inhibitors of IMPDII have also been described in the art.
`Since Ml-‘A is a selective, uncompetitive, and reversible
`$0 9\7""§00,28 and U55‘ Pal‘ 1&0‘ 3’807’876 dawns“ lass
`?N[l;I-3:_,432;?tE]V5S‘t.bm‘1?OhSl'5S_a tfmmmml
`ac‘ .0110‘ 55 inhibitor of IMPDII, a key enzyme in the purine salvage
`'
`tmul 35’ d wrleh 0 helcnmytlll" hubhlllulcd
`pathway the potential for cAMl-’-mediated cross-talk at this
`anilincs as inhibitors of IMPDH‘
`locLLs w’as further investigated.
`It was found that gene
`Tiazollurin, ribavirin and mimribine also inhibit IMPDII.
`expression for IMPDH types 1 and H (assessed by R"[‘_pCp_)
`Thhhh hhdwsidc ahalhg-‘5 5”“ C'3‘mF’c1hlV'h ihhihhmh Or
`remained unallected by the administration of rolipram,
`IMPDH? h0W°V"3Ts lhhhc “gems ihhihh Ulhhr NAD d"'l-‘eh’
`en MP/\, or both at low and high concentrations. However,
`d’-3h‘ °hZY1h°5- This low 1°V°1 of 5°1"~‘°hVhY f0‘ IMPDH
`functional reversal of the synergistic eifect was demon-
`limits the therapeutic application of tiazofurin, ribavirin and
`seated with the use of d,_=,exye_uae05iee_ ,1 Specific am-ageeist
`mizoribine Thus. new agents which have improved sc1-=c-
`of MPA on IMPDH ('72. inhibition ofproliferation 81:16 vs.
`hV'hY £01’ IMPDH W0‘-11(lh3Ph35‘3hl ‘<1 Sit-lhlhcahl hhPF0V°h1"~'hl
`35:12, p<0.05). Finally, despite a marked synergistic etfect
`0V” the hucleoshlh hha10g5-
`65 on inhibition oi‘ proliferation, no signilicant downregulation
`U.S. Pat. Nos. 5,380,879 and 5,444,072 and PCT publi-
`in the generation of proinllamrnatory cytokines (IL-2, IL-4,
`cations W0 94,=‘(lllU5 and WC] 94;’l2l84 describe myco-
`and IliN, each assessed by RT-PCR), could be detected with
`PENN EX. 2232
`
`_.
`
`3 of 40
`
`CFAD V. UPENN
`IPR20l5-01836
`
`

`
`US 6,916,809 B2
`
`3
`the administration of Rol 10"? M, Ml-’/\ 10"” M, or the
`combination.
`It was concluded that Rol demonstrates
`
`marked synergy with MP/\ by a cAMl-’- and IlVIPI)II-
`dependent mechanism. The utility of this combination of
`agents for the induction ofT cell tolerance was suggested by
`the specificity of the observed elfect for proliferation, with-
`out the abrogation of eytokjne generation and early signaling
`processes.
`
`10
`
`"I5
`
`Unlike type I, type II mRNA is preferentially upregulated
`in human leukemic cell lines K562 and I-II.—(i0. Welier, J’.
`Him’. C:'rerii., 266: 506-509 (1991). In addition, cells from
`human ovarian tumors and leukemic cells from patients with
`chronic granulocytic, lymphocytic and acute myeloid leu-
`kemias also display an up regulation type II rnRNA. This
`disproportionate increase in IMPDII activity in malignant
`cells may be addressed through the use of an appropriate
`IMPDH inhibitor. IMPDH has also been shown to play a
`role in the proliferation of smooth muscle cells, indicating
`that
`inhibitors of IMPDII may be useful
`in preventing
`restenosis or other hyperproliferative vascular diseases.
`IMPDH has been shown to play a role in viral replication
`in some viral cell
`lines. Carr, J. Biol. C.‘l1'em_,
`2ti8:272,86—27290 ["1993]. The IMPDH inhibitor \/‘X-497, is
`currently being evaluated for the treatment of hepatitis (T
`virus in humans. Ribavirin has also been used in the treat— "
`
`ll]
`
`4
`X" is selected from CR1, N, NR2, () and S;
`X5 is CR‘ or N;
`X5 is selected from CR5, N, NR2, 0, and S;
`X7 is selected from a bond, CR1 and N;
`X3, X9, X10 and X“ are independently selected from (T
`and N;
`Provided, however, that at least one of X1, X3, X3, X4, X5,
`X6, X7, X3, X9, X10 and X“ is N, NR3, U or S; and provided
`further that X1, X3, X3, X4, X5, X6, X7, X3, X9, X10 and X”
`are selected such that a tricyclic heteroaryl ring system is
`formed;
`;orW may
`S(O)2
`,or
`S[—O)
`,
`Wis C(—0)
`be —CH2— if X is —C[—O)—, —S(=O)—, or
`—3(0]2~;
`O ,
`, and
`N(R")
`,
`CH3
`X is selected from
`, X is selected from
`except
`that when W is —CH2
`C(—())
`,
`Sf—())
`, or
`3(0):
`;
`Y is a bond or —(T[R4U)[R'l5)—;
`Q is selected from a bond, —C(R“‘)(R’”‘)—,
`C(—O)
`,
`CH2 0 ,
`CH2 0 CH2
`,
`CH2
`,
`(:0, NR"
`(:11, co,
`,
`(.‘(—())NR"
`, and
`—c11=C(R=°)—;
`Z is selected from alkyl, substituted alkyl, alkenyl, sub-
`stituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,
`substituted cycloalkyl, aryl, substituted aryl, heteroaryl, sub-
`stituted heteroaryl, heterocyclyl and substituted
`heterocyclyl, and when Y is —(T[R"°)(R"5)— and Q is a
`bond or —C(R3°)(R4°)—, Z may be C0211 or CO2alkyl;
`R' is the same or different and is selected from hydrogen,
`halogen, cyano, alkyl, substituted alkyl, alkenyl, substituted
`alkenyl, alkynyl, substituted alkynyl, O—R7, —(C=0)R7,
`—(C=O)—O R7, NRSRQ, —(C—O)NR3R'°, —SR°'°,
`—S(=O)R2“, %OZR23 and —CEC—Si(0H_,)3;
`R: is selected from hydrogen, alkyl, substituted alkyl,
`aryl, substituted aryl, heteroaryl, substituted heteroaryl,
`heterocyclyl and substituted heterocyclyl;
`R7’ is selected from II, ()II and NII3;
`R4 is selected from H, OH and CH alkyl,
`R7 is selected from hydrogen, alkyl, substituted alkyl,
`alkenyl, alkynyl, cycloalkyl, substituted eycloalkyl, (T(—(])
`alkyl, C(=O)Lsubstituted alkyl, C(=O)cycloalkyl, C(=O)
`substituted cycloalkyl, C(=0)aryl, C[=0)substituted aryl,
`(f(=())()-alkyl, (I(=[))[)-substituted alkyl, C(=(])
`heterocyclo, —C(=0)—NR“R°, C(—O)heteroaryl, aryl,
`substituted aryl, heterocyclo, substituted heterocyclo, het-
`eroaryl and substituted heteroaryl;
`RR and R9 are independently selected from hydrogen,
`OR7, alkyl, substituted alkyl, cycloalkyl, substituted
`cycloalkyl, C(—0)alkyl, C[=O)substituted alkyl, C(=0)
`cycloalkyl, (T(=())substituted cycloalkyl, C(=(]]aryl,
`C(=O)substituted aryl, C(=0)0—alkyl, C(=0)O—
`substituted alkyl, (I(=[))heterocyclo, (.'(=()]heteroaryl,
`aryl, substituted aryl, heterocyclyl, substituted heterocyclyl,
`55 heteroaryl and substituted heteroaryl, or R" and R9 are taken
`together with the nitrogen atom to which they are attached
`to fonrt a substituted or unsubstituted heterocyclic ring of3
`to-8 atoms, or substituted or unsubstituted heteroaryl ring of
`5 ‘iii???’
`1
`td f
`11,
`1
`d
`1
`1‘:
`1 a 11,
`1
`“1sseece
`roma'y an S1.l)Sll.lC a'y;
`R25 is the same or different and is selec1ed from hydrogen,
`halogen, nitro, cyano, alkyl, substituted alkyl, alkenyl, sub-
`stituted alkenyl, alkynyl, substituted alkynyl, 0
`R7,
`NRSR9, SR7, S(O)R7, SOZR7, S03R7, S02NR8R°,
`55 —C(=0)R7, C0 R7, C(=0)NR“R°, and —C=C s1
`((“_]13)_,;
`2
`R3” is selected from =0 and =S;
`
`ment of hepatitis (3 and I3 viruses and when used in
`combination with interferon an enhancement in activity was
`observed. The IMPDH inhibitor ribavirin is limited by its
`lack of a sustained response in monotherapy and broad
`cellular toxicity.
`There remains a need for potent selective inhibitors of
`IMPDH with improved pharmacological properties, physi-
`cal properties and fewer side effects. Such inhibitors would
`have therapeutic potential as immunosuppressants, anti-
`cancer agents, anti—vascular hyperproliferative agents, anti-
`inllammatory agents, antifungal agents, antipsoriatic and
`anti—viral agents. The compounds of the present invention
`are effective inhibitors of IMPDII. Inhibitors of IMPDII
`
`enzyme are also described in U.S. patent application Ser.
`No.
`'10f324,306,
`titled "Acridone Inhibitors of IMPDH
`Enzyme,” having the same assignee as the present invention
`and filed concomitantly herewith,
`the entire contents of
`which is incorporated herein by reference. Said application
`also claims priority to US. patent application Ser. No.
`60;’343,?.34, liled Dec. ?.l, 2001.
`
`SUMMARY OF THE INVENTION
`
`The present invention provides compounds of the follow-
`ing formula (I), their enantiomers, diastereomers, tautomers
`and pharmaceutically acceptable salts and solvates thereof,
`for use as IMPDH inhibitors:
`
`(I )
`
`R3“
`X7 J\ X,
`X5’ “X3
`xawX:
`Q
`LSOLIJ
`L10 A X
`3"’. X‘/i xx’
`“”/ \"/ T7
`'
`'
`ll:
`
`whcrcm
`d N
`d CR1
`I
`df
`1
`X1 _
`'
`4
`3“
`15 9° “*0 mm 3 ‘On -
`-
`X: is selected from CR”, N, NR2, 0 and S;
`X3 is selected from CR1, N, NR2, O and 5;
`
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`US 6,916,809 B2
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`6
`preferably 3 to 7 carbon atoms. Also included in this
`definition are bieyclic rings where the cyeloalkyl ring as
`defined above has a bridge of one, two or three carbon atoms
`in the bridge, or a second ring attached in a fused or spiro
`fashion, i.e., a fused aryl, substituted aryl, eycloalkyl, sub-
`stituted cycloalkyl, heterocyclo, substituted heterocyclo,
`heteroaryl or substituted heteroaryl ring, or a spiroeyeloalkyl
`or spiroheterocycloalkyl ring, provided that
`the point of
`attachment is in the cycloalkyl ring.
`Thus,
`the term “cycloalkyl" includes cyclopropyl,
`cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
`cyclooctyl, etc., as well as the following ring systems,
`
`{Q
`:J&,
`Ax.
`
`/
`
`Q S
`
`Q,
`2
`
`AA
`
`37"
`
`@.
`
`em.
`
`and so forth.
`
`The term “substituted cycloalkyl" refers to such
`cycloalkyl groups as defined above having one, two or three
`substituents attached to any available carbon atom of a
`monocyclic ring or any available carbon or nitrogen atom of
`a bicyclic ring, wherein said substituents are selected from
`the group consisting of halogen, nitro, alkyl, substituted
`alkyl, alkenyl, cyano, cycloalkyl, aryl, heterocyclo,
`heteroaryl, oxo (=0), —OR5,
`CO,_R5, —C(—O)
`NR5R°“,
`OC(—0)R5,
`0C(—O)R5,
`OC(—O)
`ORf'R"', —OCH3C03R5, C(=O)R5, NR5Rfi", —NR'°C
`(—o)R-‘, NR“’(:(—o)oR-‘,
`NR"’(I(—(J)(T(—())()R5,
`—NR'”C(=0)C(=0)NR“R“”, —NR"’C(=0)C(=0)
`alkyl, —NR'”(?{N(IN)()R5, NR“’(I(=[))NR“R°", —NR'-"
`(NCN)NR“'R“"',
`—NR'”C[NR"]NR“R°",
`—NR""s(),NR“'R“"', —NR“’so,R5, —SR5, —S(())R5,
`—so.__R-“, —so_,R-‘, —S()2NR"R"", —NII()R5,
`—NR1°Nl{“l{“", —N[C(=O)R5][0Rm], —N(CO3RS)
`OR”), —C(=O)NR1°(CR”'R13), R5, —C(—0)(CRl3R13) ,
`()((?R“R‘5)q(?(),R5, —(I(=())((IR"'R”),()R5, —(:(=o§
`(CRIZRJ3)PO(CRl4Rl5)‘!R5’ TC(:O)(CRl2Rl3)’NRGR(i(:’
`—()(?(=())()((IR‘3R”)m NR“R°“, —()(I(=0]N((fR”-
`R13),R5, —O(CR‘2R”),,, NR6R°",
`NR“’C(=0)
`((:R'=R‘3),R-"', —NR‘°(I(=(?)((IR‘2R’3),(JR5, NR’°(f
`(:NC}(CRl2Rl3)rRS! TNR1[)C(:0)(CR12Rl3]rNR6R6n’
`PENN EX. 2232
`
`5
`)6
`R and R” are independently selected from hydrogen,
`C1__,alkyl, hydroxy, halogen, hydroxyC1__,alkyl, haloC1_4
`alkyl, and heterocyclo(.',_,,alkyl, or taken together fonn a
`C_,,,cycloa].kyl ring; and
`R4” and R45 are independently selected from hydrogen,
`cyano, alkyl, substituted alkyl, alkenyl, substituted alkenyl,
`alkynyl, substituted alkynyl, cycloalkyl, substituted
`cycloalkyl, aryl, substituted aryl, heterocyelo, substituted
`heterocyclo, heteroaryl and substituted heteroaryl, or R40
`and R45 are taken together to form a substituted or unsub-
`stituted cycloalkyl ring of 3 to 8 atoms or a substituted or
`unsubstituted heterocyclo ring of 3 to 8 atoms.
`'Ihe present invention also relates to pharmaceutical com-
`positions containing compounds of formula (I), and methods
`for treating IMI-‘Dll-associated disorders using the com-
`pounds of formula (I), alone or in combination with PDE4
`inhibitors.
`
`l)l_-"l'AI[_l_-ll) [)l_".S(TRlP'l'l()N Ul" Till."
`INVl_".N'l'I()N
`
`The following are definitions of the terms as used
`throughout this specification and claims. The initial defini-
`tion provided for a group or term herein applies to that group
`or term throughout the present specification, individually or
`as part of another group, unless otherwise indicated.
`'Ihe term "alkyl" refers to straight or branched chain
`hydrocarbon groups having 1
`to 12 carbons atoms, prefer-
`ably l to 8 carbon atoms, and most preferably 1 to 4 carbon
`atoms. The term "lower alkyl” refers to an alkyl group of 1
`to 4 carbon atoms.
`
`The term "substituted alkyl” refers to an alkyl group as
`defined above, having one,
`two, or
`three substituents
`selected from the group consisting of halo, cyano, ()—R5,
`S R5, NRf‘R"", nitro, oxo, cycloalkyl, substituted
`cycloalkyl, aryl, substituted aryl, heterocyclo, substituted
`heterocyclo, heteroaryl, substituted heteroaryl, (TOQRS, S(())
`R5, SUQRS, S()3Rs, S()3NRf'R°", C(=()) NRfiR6",
`NR“'(:t),R°"', c:,NR°'NR°"' and (T(=(])R5.
`'Ihe term “alkenyl" refers to straight or branched chain
`hydrocarbon groups having 2 to 12 carbon atoms and one,
`two or three double bonds, preferably 2 to 6 carbon atoms
`and one double bond.
`
`'Ihe term “substituted alkenyl" refers to an alkenyl group
`as defined above having one,
`two, or three substituents
`selected from the group consisting of halo, eyano, 0—R5,
`S—R5, NR°R°", nitro, oxo, cycloalkyl, substituted
`cycloalkyl, aryl, substituted aryl, heterocyclo, substituted
`heterocyclo, heteroaryl, substituted heteroaryl, (TOZR5, S(())
`R5, SOZR5, SOSR5, SO:NR°R6", C(=O)NR5R°",
`NR“(:t),R"’", c:t),NR“R“" and (?(=o)R-“.
`The term "al.kynyl” refers to straight or branched chain
`hydrocarbon group having 2 to 12 carbon atoms and one,
`two or three triple bonds, preferably 2 to 6 carbon atoms and
`one triple bond.
`'Ihe term "substituted alkynyl" refers to an alkynyl group
`as defined above having one,
`two or three substituents
`selected from the group consisting of halo, cyano, ()—R5,
`S—R5, NR“Rfi", nitro, cycloalkyl, substituted cycloalkyl,
`oxo, aryl, substituted aryl, heterocyclo, heteroaryl, COSRS,
`S([))R5, SOZRS, S()3R5, SO3NR°Rd“, C(=(})NR6R°”, and
`C(=O)R5.
`The term “halo” refers to chloro, brorno, tiuoro, and iodo,
`with chloro, bromo and fluoro being preferred.
`The term "cycloalkyl” refers to fully saturated and par-
`tially unsaturated monocyclic hydrocarbon rings of 3 to 9,
`
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`—NR'”[(IR'2R‘3),,,()R5, —NR‘”(C'2R‘7’),.(T()2R5, —NR'”
`(CRl2Rl3)nlNRfiRfir!’ TNR1(](CRl2Rl3‘) lSOq(CRlIlRl5)( R5,
`—(:(=o)NR‘"(c:R”R”),,s(J,((:“'tt 5) R‘, —so,N‘R‘“
`(CR12Rl3)rlC0[CRlI|R15)fZ1'{5’ l(l'](CRl2Rl3)"'DR5’
`and —SO;._NRw (CRER "],,Si(alkyl)3.
`When a substituted cycloalkyl is substituted with a second
`ring, including an aryl, heterocyclo, or heteroaryl ring, or a
`second cycloalkyl ring, said second ring in turn is optionally
`substituted with one to three R17 groups as defined below.
`It should be understood that a “substituted eycloalkyl”
`may have a substituent attached to any atom of the
`cycloalkyl ring, including its point of attachment to another
`group. Thus, for example, a cyeloalkyl group substituted
`with a group “R” may comprise,
`
`10
`
`ll]
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`and so forth, where R is a substituent on a cycloalkyl group
`as defined above.
`
`l-naphthyl, and
`The term “aryl” refers to the phenyl,
`2—naphthyl, preferably phenyl, as well as an aryl ring having *
`a fused cycloalkyl, substituted cycloalkyl, heterocyclo, sub-
`stituted heterocyclo, heteroaryl, or substituted heteroaryl
`ring, provided that the point of attachment is in the aryl ring.
`Thus, examples of aryl groups include Thus, examples of
`aryl groups include:
`
`30
`
`|\
`
`|\
`
`—'/
`
`|\ O
`
`|\
`
`I\\
`
`|\
`
`—'/"i
`—'/ N
`4 \ 2
`
`'/N/’ '/N'’’'
`
`+ \
`
`'/N”
`
`'/ /’
`
`'/ /9
`
`|\\ Ix”
`_'/
`_'/ 0'"
`
`andsoforth.
`The term "substituted aryl” refers to such aryl groups as
`defined above having one, two, or three substituents selected
`from the group consisting of halogen, nitro, alkyl, substi-
`tuted alkyl, alkenyl, cyano, eycloalkyl, aryl, heterocyclo,
`heteroaryl,
`()R5,
`CIOQR5,(T(=())NR“R“",—()(f(=())
`R5, —[)C(=())()R5, —(]C(=O)NR6Rfi", —()(fIl2CU2R5,
`—C(=0)R5, NR“R5". —NR1°C(=O)R5, —NR1°C(=O)
`OR5, _—NR10C(=O)C(=0)0R5, —NR1°C(=0)C(=0)
`NR‘:R°", —NR1°c:{=o)(tt=())a1ky1, —NR‘°(I(I\_"(f1'_\l)
`OR’, NRmC(=O)NR°R°“, —NR1°C(NCN)NR°R°",
`—NR1°t7(NR“)NR°'R°"', —NR‘°S()2NR"R"",
`—NRmSO3R5, —SR5, —S(O)R5 —SO2R5, —SO3R5,
`—S[):NR“R“", —NlI()R5, —NR‘BNR‘;R“",
`N[(f(=())
`R5][ORm], —N[CO2R5)ORm, —C(=O)NR'"(CR12R'3),
`
`35
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`
`R5, —(f(=())((TR‘2R‘7’)Pt)[(IR“R” ),,(.‘(J2R5, —(?(=())
`((“_R”Rl3)r0R5, —C(=0)(CR12R13]p0(CR“R”),R5,
`—(f(=())((IR'2R‘7’),NR°R°", —[)(.‘(=())0((TR'2R{7’),,,
`NR“R“”, —0C{'=0)N['CR'2R”),R5. —O(CR'2R”),,,
`NRf'R“", —NR‘”C[=O)[CR'2R”),R5, —NR'“C(=O)
`(CR”R13),OR5, —NR1°C(=NC)(CR”'R13),_R5, —NR1°C
`{=0)(CRl2l{13),NR“R“", —NRl°(CR":l{‘3),,,0l{5, —NR'°
`(CR”R13),CO3R5, —NR1°(CR13R13)mNR°R°“, —NR1°
`((IR13R13) S().((IR1“R:5) R5, —(I(=())NR1°((IRl3R13)
`so,(cR”1'i15);R5, 4o:NR1°tcR”R”),,co(cRl“tt15):’
`R5, —S():NR‘”[(IR':R‘3)’”()R5, and —S()2NR'6
`(C'R”R13),,Si(alkyl)3, as well as pentalluorophenyl.
`When a substituted aryl is substituted with a second ring,
`including a cycloalkyl, heterocyclo, or heteroaryl ring, or a
`second aryl
`ring, said second ring in turn is optionally
`substituted with one to three R”’ groups as defined below.
`The term “heterocyclo” refers to saturated or partially
`saturated monocyelie rings of 3 to 7" members and bicyelie
`rings ol‘ 7 to 11 members having one or two () or S atoms
`andfor one to four N atoms, provided that the total number
`of heteroatoms is four or less and that the heterocyclo ring
`contains at least one carbon atom. The nitrogen and sulfur
`atoms may optionally be oxidized, and the nitrogen atoms
`may optionally be quaternized. The bicyelie heterocyclo
`ring may also contain a bridge of one, two or three carbon
`atoms between available carbon or nitrogen atoms. The
`bicyelic heterocyclo rings may also have a cyeloalkyl,
`substituted cycloalkyl, aryl, substituted aryl, heterocyclo,
`substituted heterocyclo, heteroaryl, or substituted heteroaryl
`ring fused to the monoeyelie ring provided that the point of
`attachment is through an available carbon or nitrogen atom
`of the heterocyclo ring. Also included are heterocyclo rings
`having a second ring attached thereto in a spire fashion
`The term “substituted heterocyclo” refers to a heterocyclo
`ring or ring system as defined above having one, two or three
`substituents on available carbon or nitrogen atom(.-5) selected
`from the group consisting of halogen, nitro, alkyl, substi-
`tuted alkyl, alkenyl, cyano, cycloalkyl, aryl, heterocyclo,
`heteroaryl, oxo (=0), —OR5, —CO;._R5, —C(=O)
`NR"R°“,
`()(I(=())R5, —[)(T(=[))()R5,
`()(I(=(])
`NIt°11°“,_t)(?H,(:t),R5, _c:(—o)R5, NR°R°“, _Ntt*"t:
`(—O)R5, NR‘”C(—O)0R5, NR'”C(—0)C(—O)0R5,
`NR‘°C(—O)C(=0)NR°R°“,
`NR1°C[=0]C(=0)a1kyl,
`—NR'”C(N(TN)()R5, NR'”(T(=())NRf‘R°", —NR'”(T
`(NCN)NRf'Rf"',
`—NR'”C(NR")NR°R°",
`—NR1°SO2NR5R5", —NR1°S0;._R5, —SR5, —S(O)RS,
`—S().__R5, —S()3R5, —S(),2NR"R““,
`NIIUR5,
`—NR“-’NR“R‘"‘, —N[C(=0)R5][OR‘°], —N(CO2R5)
`ORIU’ :C(:O)NR1()[CRl2Rl3)r 5, Tc(:0)(CR12R!3)p
`0(CR”R‘5)qC0:R5, —C(=O)[CR1:R”),OR5, —(“_(=0)
`((?R‘3R'7’) ()((IR"'R'5) R5, —(T(=())((.‘R‘2R”),NR,,R°",
`—OC(=Cf)(CR“R'3),,:i\IR“R“", —0C(=O)N(CR‘2R'“),
`R5, —()((:R”R”),,_NR“R'-‘"', —NR’"c:(=(J)((?R‘“R‘“),R5,
`—NR1°C(=()){(IR”R13)r()R5, —NR1°(I(=N(I)
`{cRI2R13)’l{S, TNRl()C(l0)(CaRl2Rl3)’NR6Rfifl, TNRZEJ
`((fR‘3R13)m()R5, —NR1°((TR”'R1'"‘),(I(J3R5, —NR1°
`((fR'3R‘3),,,NRf'R“”, —NR‘”[(IR‘QR'3),,S()2((IR"‘R'5),,R5,
`—C(=)NR1°(CR”R13),,SO3(CR“R”),R5, —SO3NR1°
`((TRERJ3),,(T()((IR“‘R‘5), R5, —S[)2NR1E’((TR”'R13),,,()R5,
`and —SOQNR“"(CR”R‘;),,Si(alkyl)3.
`When a substituted heterocyclo is substituted with a
`second ring, including an aryl, cyeloalkyl, or heteroaryl ring,
`or a heterocyclo ring, said second ring in turn is optionally
`substituted with one to three R” groups as defined below.
`Exemplary monocyclic heterocyclo groups include
`pyrrolidinyl, pyrrolinyl, pyrazolinyl, pyrazolidinyl,
`oxetanyl,
`imidazolinyl,
`imidazolidinyl, oxazolidinyl,
`PENN EX. 2232
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`isothiamlidinyl, isoxazolinyl, thiamlidinyl, tetrahydrofuryl,
`piperidinyl, pipe razinyl,
`tetrahydrothiopyranyl,
`tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamor-
`pholinyl sulfoxide,
`thiamorpholinyl sulfone,
`tetrahydrothiopyranylsulfone,
`l,3—dioxolanyl, tetrahydro—1,
`l-dioxothienyl, dioxanyl,
`thietanyl,
`thiiranyl,
`triaviolinyl,
`Iriazolidinyl, etc.
`Exemplary bicyclic heterocyclo groups include indolinyl,
`quinuclidinyl,
`tetrahydroisoquinolinyl, benzimidaviolinyl,
`chromanyl, dihydrobenzofuran, dihydrol'uro[3,4-b]
`pyridinyl, dihydroisoindolyl, dihydroquinazolinyl (such as
`3,4-dihydro-4-oxo-quinaxolinyl), benzofurazanyl,
`benzotriazolinyl, dihydrobenzofuryl, dihydrobenzothienyl,
`dihydrobenzothiopyranyl, dihydrobenzothiopyranyl
`sulfone, dihydrobenicopyranyl, isoindolinyl, isochromanyl,
`benmdioxolyl, tetrahydroquinolinyl, etc.
`Exemplary spirocyclic heterocyclo groups include I-aza
`[4.5]spirodeeane, 2—aza[4.3]spirodecane, 1—aza[5.5]
`spiroundeeane, 2—aza[5,5]spiroundecane, 3—aza[5.5]
`spiroundecane, etc.
`The term "heteroaryl" refers to aromatic 5 or 6 membered
`rnonocyclic groups and 9 or 10 membered bicyclic groups
`which have at least one heteroatom ((3, S or N) in at least one
`oi‘ the rings. Each ring of the heteroaryl group containing a
`heteroatom can contain one or two 0 and S atoms andfor
`from one to four N atoms, provided that the total number of .1.
`heteroatorns in each ring is four or less. The bicyclic
`heteroaryl rings are formed by fusing a cyeloalkyl, substi-
`tuted cycloalkyl, aryl, substituted aryl, heterocyclo, substi-
`tuted heterocyclo, heteroaryl or substituted heteroaryl group
`to the monoeyelic heteroaryl ring as defined above. The
`heteroaryl group is attached via an available carbon or
`nitrogen atom in the aromatic heteroaryl ring. The nitrogen
`and sulfur atoms may optionally be oxidized and the nitro-
`gen atoms may optionally be quaternixed.
`The term “substituted heteroaryl” refers to a heteroaryl
`ring or ring system as defined above having one, two or three
`substituents on available carbon or nitrogen atom(s) selected
`from the group consisting of halogen, nitro, alkyl, substi-
`tuted alkyl, alkenyl, cyano, cycloalkyl, aryl, heterocyclo,
`heteroaryl, —[)R5, —(.‘()3R5, —(I(
`())NR"R"“, —()(T
`(—())R5, —()(I(—())()R5, —(](3(—(})NR°R°"',
`—OCH2C02R5, —C(=O)R5, NR“R°", —NR'”C(=O)R5,
`—NR1°C‘(=0)0R5, —NRl°C(=)C(=O)0R5, —NR1°C
`[=[))(I[=())NR"R'”', —NR‘”(I[=())(f(=())a]ky],
`—NR'”C(NCN)OR5, NR'”C(=0)NR”R“"NR'”C(NCN)
`NR°R"", —NR1°C(NR“)NR‘5R‘5“, —NR1°SO3NR°R°",
`—NR1°S[)2R5, —SR5, —S(())R5, —S(}:R5, —S()3R5,
`—S02NR“R“", —NII0R5, —NR‘°NR‘iR“”,
`N[C(—O)
`R-‘f][oR‘“], —N(co,R-f)oR‘“, —C(=O)NR'“(CR‘2R'3),
`R’, 4:(—o)(CR”R1-‘),o(cR1“R15)(702125, 4“_{=o)
`I
`4
`[(IR‘2R‘3),()R5, —(I(=(J]((TR‘2R")p()((IR"'R'5) R5,
`—C(=0)(CR‘2R”),NR“‘R"”, —oC(=o)o(CR'=R 3),"
`NR*fR'-‘_"', —o(7(=o)N(c:R‘“R‘“),.R5, —()((:R‘=R‘3),,,
`NR°R"“, —NR1°c:(=(J)(c:R19R13),R5,
`NR1°(:(—o)
`(CR1:R”’),OR5, —NRmC(=NC](CR'2R'3),R5, —NRmC
`[
`())[(TR”'R13),NR°R““, —NRl°((IR”R13)m()R5, —NR1°
`[(TR12R17’),.(T[)2R5, —NR”’((IRl2R'3)mNRf‘Rf"°, —NR‘"
`(CRl2R13)’rsO:(CRl4Rl5JqI{5‘ TC(:0)NR10(CR12R13)’l
`S():[(TR1“R15)qR5, —S()2NRl°((TR12R13),,(T()((IR“R15)
`m
`R’, —SO2NR“"[(.‘R”R”) OR’, and —S02NR13
`[CR1:R‘7’),,Si(alkyl)_._.
`When a substituted heteroaryl is substituted with a second
`ring, including an aryl, cyeloalkyl, or heterocyclo ring, or a
`second heteroaryl ring, said second ring in turn is optionally
`substituted with one to three Rm groups as delined below.
`Exemplary rnonocyclic heteroaryl groups include
`pyrrolyl, pyrazolyl,
`iniidamlyl, oxazolyl,
`isoxamlyl,
`
`45
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`lhiamlyl, thiadia