AU768201B2 - Kinase inhibitors - Google Patents

Kinase inhibitors Download PDF

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AU768201B2
AU768201B2 AU27344/00A AU2734400A AU768201B2 AU 768201 B2 AU768201 B2 AU 768201B2 AU 27344/00 A AU27344/00 A AU 27344/00A AU 2734400 A AU2734400 A AU 2734400A AU 768201 B2 AU768201 B2 AU 768201B2
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cio
alkyl
substituted
independently
coor
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David M Armistead
Jean E. Bemis
Daniel Elbaum
Gregory Habgood
Perry M. Novak
Joseph J. Nunes
Leticia M. Toledo-Sherman
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Amgen Inc
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Amgen Inc
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    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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Description

1 KINASE INHIBITORS Background of the Invention Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of common general knowledge in the field.
The invention relates to inhibitors of-kinases, compositions comprising the inhibitors, and methods of using the inhibitors and inhibitor compositions. The inhibitors and compositions comprising them are useful for treating or modulating disease in which kinases may be involved, symptoms of such disease, or the effect of other physiological events mediated by kinases. The invention also provides for methods of making kinase inhibitor compounds and methods for treating diseases in which kinase activity is involved.
The protein kinases constitute a large family of structurally related enzymes that are responsible for the control of a wide variety of signal transduction processes within the cell. (See, Hardie, G. and Hanks,.S. (1995) The Protein Kinase Facts Book. land II, Academic Press, San Diego, CA). Protein kinases are thought to have evolved from a common ancestral gene due to the conservation of their structure and catalytic function.
25 Almost all kinases contain a similar 250-300 amino acid catalytic domain. The kinases may be categorized into families by the substrates they phosphorylate protein- Styrosine, protein-serine/threonine, lipids, etc.). Sequence motifs have been identified that generally corespond to each of these kinase families (See, for example, Hanks, S.K., Hunter, FASEB 9:576-596 (1995); Knighton et al., Science, 253:407-414 (1991); Hiles et al., Cell, 70:419-429 (1992); Kunz et al, Cell, 73:585-596 (1993); Garcia-Bustos et EMBOJ., 13:2352-2361 (1994)).
Since the structure of the catalytic subunit of cAMP-dependent protein kinase (cAPK) was elucidated, approximately two dozen additional kinase structures have been solved as either apo enzymes or binary and ternary complexes (with ATP, ATP analogs, *i 35 metal ions, ADP, ATP competitive inhibitors in the absence or presence of peptide substrate or peptide inhibitors). These proteins share a structurally conserved catalytic oo WO 00/43373 PCT/US00/01581 domain comprising two lobes that can be further subdivided into twelve subdomains. The N-terminal portion forms the small lobe (including subdomains I-IV) whose architecture is composed of an antiparallel five-strand P-sheet and one a-helix, while the lower Cterminal domain forms another lobe (including subdomains VIA XI) containing mostly a-helical architecture. Subdomain V spans the two lobes. The N-terminal domain is thought to participate in orienting the nucleotide (or other binding entity), while the Cterminal domain is thought to be responsible for binding peptide substrate and initiating phosphotransfer to the hydroxyl group of a serine, threonine, or tyrosine residue.
The N- and C-terminal domains are connected through a single peptide strand, to which the adenine moiety of ATP binds via an eleven membered hydrogen bond cycle, involving the N1 and the N6 amino group, and the backbone carbonyl and NH functions of two nonconsecutive residues. This linker acts as a hinge about which the domains can rotate with respect to each other without disruption of the secondary architecture of the kinase. Several torsion angle changes in the linker backbone allow this movement to occur. The ribose group of ATP is anchored to the enzyme via hydrogen bonds with residues within the ribose-binding pocket. The triphosphate group is held in position via various polar interactions with several variable residues form the glycine rich loop, the conserved DFG motive and the catalytic loop.
Protein kinases may be characterized by their regulation mechanisms. It must be noted, however, that an individual protein kinase may be regulated by more than one mechanism. These mechanisms include, for example, autophosphorylation, transphosphorylation by other kinases, protein-protein interactions, protein-lipid interactions, and protein-polynucleotide interactions.
Kinases regulate many different cell processes including, but not limited to, proliferation, differentiation, apoptosis, motility, transcription, translation and other signaling processes, by adding phosphate groups to target proteins. These phosphorylation events act as molecular on/off switches that can modulate or regulate the target protein biological function. Phosphorylation of target proteins occurs in response to a variety of extracellular signals (hormones, neurotransmitters, growth and differentiation factors, etc.), cell cycle events, environmental or nutritional stresses, etc. The appropriate protein kinase functions in signaling pathways to activate or inactivate (either directly or indirectly), for example, a metabolic enzyme, regulatory protein, receptor, cytoskeletal protein, ion channel or pump, or transcription factor. Uncontrolled signaling due to WO 00/43373 PCT/US00/01581 defective control of protein phosphorylation has been implicated in a number of diseases, including, for example, inflammation, cancer, allergy/asthma, disease and conditions of the immune system, disease and conditions of the central nervous system, and angiogenesis.
Initial interest in protein kinases as pharmacological targets was stimulated by the findings that many viral oncogenes encode structurally modified cellular protein kinases with constitutive enzyme activity. These findings pointed to the potential involvement of proto-oncogene encoded protein kinases in human proliferative disorders. Subsequently, deregulated protein kinase activity, resulting from a variety of more subtle mechanisms, has been implicated in the pathophysiology of a number of important human disorders including cancer and immunologically related diseases. The development of selective protein kinase inhibitors that can block the disease pathologies and/or symptoms resulting from aberrant protein kinase activity has therefore generated much interest.
iSummary nf the Invpntinn The invention relates to compounds of the formula:
X
R 1 1
NH
R N- R2 wherein, I 5 5 R is H; CN; COOR C(O)NR R halo; Cl-C10 alkyl; CI-C10 alkenyl; 56 5 alkyl substituted with 1-3 independent NR R NR R SR or OR or C1-C10 56 5 alkenyl substituted with 1-3 independent NR R NR R SR or OR 2 55 5 5 8 5 8 R is NR R SR OR R aryl; N(R )-N=CH(R N(R )-N=CH(aryl); 5 55 5 5 15 5 56 NR -NR C(O)NR R NR -NR R NR -NR R Cl-C10 alkyl substituted with 1-3 8 5 5 5 55 56 independent aryl, R halo, CF3, SR OR OC(O)R NR R, NR R COOR N02, CN, 55 C(O)R, C(O)NR R, or S(O)2NR R; or Cl-C10 alkenyl substituted with 1-3 8 5 5 5 55 56 independent aryl, R halo, CF3, SR OR OC(O)R NR R ,NR R ,COOR N02, CN, 55 C(O)R C(O)NR R or S(O)2NR R R 3is phenyl substituted with 1-3 independent R 4; R 8; COOR 5; or Cl-C 7 aflkl substituted with 1-3 independent aryl R or Re; X is 0oarS; and the remaining groups are as defined herein.
The invention also relates to compositions comprising these compounds, methods of making these compounds, methods of inhibiting enzyme activity, particularly kinase activity, through use of these compounds, and methods of treaing disease or disease symptoms in a mamnmal, particularly where modulation of enzyme activity, and more particularly kinase activity, can affect disease outcome.
According to a first aspect, the present invention provides a compound of the formula: 0
NC
NH
S N R or a pharmaceutically acceptable salt thereof, wherein R 2 is NH-ary; R3 is phenyl substituted with 1-3 independent R 4 *:Wherein each R4 is independently selected from H, C I-Cl10 alkyl; C2-Cl10 alkenyl; C2-C1O alkynyl; C3-C1O cycloalkyl; C4-C1O cycloallcenyl; aryl; R 8 halo; haloalkyl; SR 5
OR
5
NR
5 R; COOR 5
NO
2 CN; C(O)R 5 C(O)C(O)R 5
C(O)N
5
R
5
OC(O)R
5
S(O)
2
R
5
S(O)
2 NR; NR 5
C(O)NR
5
R
5
NR
5 C(O)C(O)R 5
NR
5
C(O)R
5
NR
5
(COOR
5
NR
5
C(O)R
8
NR
5
S(O)
2
NR
5 R; NR 5
S(O)
2
R
5
N'R
5
S(O)
2
R
8
NR
5
C(O)C(O)NR
5
R
5
NR
5 C(O)C(O)NRR; Ci1-Cl10 alkyl substituted with aryl, R 7 or R;or ClI-C 1 alkenyl substituted with aryl, R7 or 8 .25 Each R 5 is independently H; C-C 10 alkyl; C2-C 10 alkenyl; C2-C 10 alkynyl; C3cycloalkyl; C4-C 10 cycloalkenyl; aryl; R9; C I-Cl10 alkyl substituted with 1-3 independent aryl, R 7 or R9 groups; C3-C 10 cycloalkyl substituted with 1-3 independent aryl, R 7 or R 9 groups; or ClI-C 10 alkenyl substituted with 1-3 independent aryl, R 7 or R9; 4a Each R 6 is independently C(O)R ,COOR ,or S(0)2 R;S Each R7is independently halo, CF3, SR10, OR 10, OC(O)R 10, NR NR1 0 INR"IIRII, COOR 0, N02, CNC(O)R toor C(O)NR Each I"is independently a 5-8 membered inonocyclic, 8-12 membered bicyclic, -or 11-14 membered *tricyclic ring. system comprising 1-w3 hetero~atoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricy cic, said heteroatoms: selected from 0, N, orS, which may be saturated or unsaturate d, and wherein 0, 1. 2 or 3 atoms of each ring may be substituted by a substituent independently selected from Cl- CIO alkyl;- C2-CIO alkenyl; C2-CIO alkynyl, C3-CIO cycloalkyl;. C4-CIO cycloalkeniyl; aryl; R 9 halo; sulfur~ oxygen; haloalkyl; SRS; OR 5 OC(O)Rs; NRSR5; NR 5R;6
RR
NRR COOR; N02; CN; C(O)NR R; CI-CIO alkyl substituted with 1-3 independent R 7 R9 or aryl; or CI-CI0 alkceryl substituted with 1-3 independent R .or aryl; Each Ris independently a 5-8 membered monocyclic, 8-12 memnbered bicyclic. or. 11-14 memnbered tricydlic- ring system comprising.- 1-3 heteroatoms if monocyclic '1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if toicycic, said heteroatoins selected from 0, N, or S, which may be saturated or unauaeand wherein 0, 1, 2 or 3 atoms of each ring-may be substituted by a substituent idpnetyselected from CI- CIO alkyL- C2-CIO alkenyl; C2-CIO alkynyL- C3-CIO cycloalkyl; C4-CIO cycloalknyl; 30 10 10 ~10 10 I I halo; sulfur, oxygen CF3; haloalkl; SR 0; OR 0; NRO R; NR1!R; N,1R R; COR 0 10 10 CR NO2, CN; C(O)p or C(0)WR is independently H, Cl-CIO alkyl; C2-CIO alkenyl; 1 /C2-CIO :alkynyl; C3-ClO cycloalkyl; C4-CIO. cycloalkenl; haloalkyl, Cl-CIO alkyl optionally substituted with 1-3 independent Cl-C 10 alkyl, C2-CIO alkenyl, C2-C10 alkynyl, C3- CIO cycloalkyL,.C4-.CIO cycloalkenyl, halo, CF.3, OR' 3
SR'
3 NR. COOR' 3 N02,1 C(O)R C(O)NR13R1 NHC(O)R 3, or OC(O)R 1; or phenyl optionally substituted with 1-3 independent CI-ClO alkyl, C2-CIO alkenyl, C2-C1O alkynyl, C3-CIO *13 13 13 13 13 N cycloalkyt, C4-CIO cycloalkenyl, hao, CF3, OR SR NR R dOOR ,N02 13 13 13 3 C (O)R ,d(O)NR13R NHC(O)R3 ,or OC(O)R 11 10 10 Each R is independently C(O)R COOR or S(Q)2R 32 Each R is independently H, Cl-CIO alkyl, C2-C1O alkenyl, C2-CIO -4b alkynyl, C3-C1O cycloalkYl, C4-CIO cycloaHkeyl. or phenyl Optionally substituted with 1-3 independent CI-CIO alkyl, C2-CIO alkenyLC2-C1O alkynyl, C3-CIO cycloalkyl, C4-.
13 13 13 13 13 13 CIO cycloalkenyl, halo, CF3, ORI I SR. NR R ,COOR NO2, CN, C(O)R C(O)NR1 R 1, NHC(O)R 1, or OC(O)R3 Each R 1 3 is independently H; CI-CIO alkyl; C2-.CIO'alkenyl; C2-CIO alkcynyl; C3-CIO cycloalkyl; C4-CIO cycloalkenyl; Cl-C 10 alkyl optionally substituted 19 1919 19 with halo, CF3, OR 19 SR NR 9R19 COOR N 102, CN; or phenyl optionally 119 19 substituted with halo, CF3, OR"9, SR9 NR19R COOR NO2, CN; Each R 19 is independently H- CI -ClO0 alkyl; C3-CIO0 cycloalkyl or phenyl; Each haloalkyl is independently a Cl-Cl 0 alkcyl substituted with one or more halogen atoms, selected from F, CL,. Br, or L. wherein the number of halogen atoms may not exceed that number that results in a perhaloalkyl group;.
Each aryl is independently a 6- arbon monocyclic or 10-carbon bicyclic aromatic ring system optionally substituted with 1-3 independent Cl-CIO alkyl; C2-CIO alkenyl; C2-CIO alkyntyl; C3-C1O cycloalkyl; C4-CIO cycioalkenyl; R 9 halo; haloalcyl; OR 2; SR 1; NR2 R I 2; COOR 12;N02;CN; C(O)R 1 C(O)C(O)R 12;C(O)NR 12R1 2 2 12R2 N12C()() 11 12 12S() 1R2 12; OC(O)R NRI C(O)NR A i i C(O)R9; NitSzR R 12 9 12 12 12 NRt S(O)2R; Nit C(O)C(O)NR it Ci-CIO alkyl substituted with 1-3 independent 9 12 12 .212 12 12 12 12 R .'halo, CF3, OR ,SR. NRR, COOK NO2 CMC(O)R ,C(O)NRR NHC(O)R 2, N(COOR 12), S(O)2NR 12R 12, OC(O)R 12; d2-CIO .alkenyl substituted with 1- needn 9 haoC3 12 12 12 12 12 C,()R12 l-3inepenenti~hal dF3OR. ,NR .iR COQR NO2C,C() C(ONit' 12 0H()12' I~CX 1 2 12 12
O()
12 or 12 and provided that:
R
2 is other than unsubstituted phenyl-NHj-, 25(2) when Rt 3 is 4-methoxyphenyl, then Wt is other than 4-methoxyphenyl-NH- or :9*9.4-nitrophenyl-NH-; and when Wt is 2, 4-dichiorophenyl, then R? is other than 4-chlorophenyl-NH-.
According to a second aspect, the present invention provides a pharmaceutical composition comprising a compound according to the first aspect and a pharmaceutically acceptable carrier, adjuvant or vehicle.
According to a third aspect, the present invention provides a method of treating a kinase mediated disease or disease symptoms in a mammal comprising admnfistration to 4c said mammal of a compound according to the first aspect or a pharmaceutical composition according to the second aspect.
According to a fourth aspect, the present invention provides a method of inhibiting kinase activity in a mammal comprising the step of administering to said mammal a compound according to the first aspect-or a pharmaceutical composition according to the second aspect.
According to a fifth aspect, the present invention provides a method of treating disease or disease symptoms in a mammal comprising the step of administering to said mammal a compound according to the first aspect or a pharmaceutical composition according to the second aspect.
According to a sixth aspect, the present invention provides a method of making a pharmaceutically useful composition comprising combining a compound according to the first aspect with one or more pharmaceutically acceptable carriers.
According to a seventh aspect, the present invention provides a method of making a compound according to the first aspect comprising reacting a pyrimidinone of the formula: 0
NC
oo Y NH :R R 2 with an appropriate nucleophilic agent, wherein the groups in said formula are as defined according to the first aspect.
According to an eighth aspect, the present invention provides use of a compound according to the first aspect in the manufacture of a medicament for the treatment of a kinase mediated diseae or disease symptoms in a mammal.
25 Unless the context clearly requires otherwise, throughout the description and the to claims, the words 'comprise', 'comprising', and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the *0 sense of"including, but not limited to".
4d nPilP riiptinn nf thi. tnvntinn The invention provides compounds useful in inhibiting kinase attvtY ri inhibiting kinases or other polypeptides having sequences or subsequences homologous to kinase sequences or subsequences. In one embodiment, the inhibitory compound has the
X
RN
formula: wherein, R is H; CN; COOR; C(O)NR R; halo; CI-CIO alkyl; CI-CIO alkenyl; CI-CIO alkyl substiftedwith 1-3 independent NRYR,NRR,SR or ORS; or CI-CIO 56 S S alkenyi subsituted with 1-3 independent NR ,NRR,SR or OR 2 55 S R S R isNRR; SR;OR;R ary; N(R)-NCH(R); N(R-N=CH(ary); 5 .5 55 55 5 5 6 NR -NR C(O)NR R; NR -NR R NR -NR R; CI-ClO alkyl substituted with 1-3 independent aryl, R, hao, CF3, SR ORS OC(O)R NRSRS, NR R COOR N02, CN, C(O)R, C(O)NR R, or S(O)2NR R; or CI-CIO alkenyl substituted with 1-3 8 S 5 5 55 56 independent aryl, R ,halo, CF3, SR ,OROC(O)R ,NR R ,NR R ,COOR ,N02, CN, C(O)R ,C(O)NR R ,or S(O)2NR R R is phenyl substituted with 1-3 independent R;R;COOR;or C-CIO 7 a alkcyl substituted with 1-3 independent aryl, R or R; WO 00/43373 PTUO/18 PCT/USOO/01581 X is 0or S; Each R 4is independently selected from H, Ci1-CI10 alkyl; C2-Gl10 alkenyl; C2-ClO alkynyl; C3-ClO cycloalkyl; C4-CIO cycloalkenyl; aryl; R 8; halo; haloalkyl; 5 55 5 CF3; 5R; OR 5 NR R NR 5 R COOR 5 N02; CN; C(O)R C(O)C(O)R5; C(O)NR R; 555 55 5 5 5 OC(O)R5; S(O)2R5; S(O)2NR R NR C(O)NR R5; NR5C(O)C(O)R NR NR 5(COOR5); NR 5 C(O)R 8; NR S(O)2NR 5R5; NR 5S(O)2R5; NP. S(O)2R 8; NR 5C(O)C(O)NR 5R 5; NR 5C(O)C(O)NR 5R6; Cl-C 10 alkyl substituted with aryl, R 7or R ;or C I-Cl10 alkenyl substituted with aryl, R or R8; Each R 5is independently H; Ci-ClO alkyl; C2-ClO alkenyl; C2-CIO alkynyl; C3-ClO cycloalkyl; C4-CLO cycloalkenyl; aryl; R 9 Ci-ClO alkyl substituted with 1-3 independent aryl, R 7or R 9groups; C3-CIO cycloalkyl substituted with 1-3 independent aryl, R 7or R 9groups; or Cl-Cl 0 alkenyl substituted with 1-3 independent aryl, R orRl; 6 5 5 Each R is independently C(O)R COOR or S(0)2 R; 7 10 10 1 0 t Each R is independently halo, CF3, SR OR OC(O)RI NP.RR0 NROR, NRIIRI, COORO, N02,CN,C(O)RI0,orC(O)NRORO; Each R 8is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatomns if tricyclic, said heteroatoms selected from 0, N, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent independently selected from Cl alkyl; C2-C 10 alkenyl; C2-C 10 alkynyl; C3-C 10 cycloalkyl; C4-Cl10 cycloalkenyl; 9 5 5 5 5 5 56 aryl; R halo; sulfur; oxygen; CF3; haloalkyl; SR OR OC(O)R NR. R NR R 6 6 5 5 5 NR. R COOR N02; CN; C(O)R C(O)NR R Ci-CIO alkyl substituted with 1-3 7 9 7 9 independent R R or aryl; or ClI-C 10 alkenyl substituted with 1-3 independent R R or aryl; Each R 9is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatomns if tricyclic, said heteroatoms selected from 0, N, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 WO 00/43373PCUS/O58 PCT/USOO/01581 atoms of each ring may be substituted by a substituent independently selected from ClI CG1 alkyl; C2-C 10 alkenyl; C2-C 10 alkynyl; C3-CI10 cycloalkyl; C4-C 10 cycloalkenyl; halo; sulfur; oxygen; CF3; haloalkyl; SR10; OR1 NR OR1; NRIR R NR 11R COOR1 0 N02; CN; C(O)R 1; or C(O)NR 10R 1 Each R.1 is independently H, CI-ClO alkyl; C2-C1O alkenyl; C2-CIO alkynyl; C3-CIO cycloalkyl; C4-CIO cycloalkenyl; haloalkyl; CI-ClO alkyl optionally substituted with 1-3 independent Cl-GbO alkyl, G2-ClO alkenyl, C2-CIO alkynyl, C3- 13 13 13 13 13 GIO cycloalkyl, G4-GbO cycloalkenyl, halo, GF3, OR 13 SR NR R GOOR N02, CN, G(O)R 1, G(O)NR1 R 1, NHG(O)R 1, or OC(O)R1 or phenyl optionally substituted with 1-3 independent Cl-GbO alkyl, C2-CIO alkenyl, C2-C1O alkynyl, C3-GbO 13 13 13 13 13 cycloalkyl, C4-G 10 cycloalkenyl, halo, GF3, OR SR NR R COOR N02, CN, C(O)R. 1, C(O)NR1 R 1, NHC(O)R 1, or OC(O)R 1 I 1 10 10 Each R is independently C(O)R COOR or S(O)2R Each R 12is independently H, GI-CIC alkyl, C2-G1O alkenyl, C2-G1O alkynyl, G3-G1O cycloalkyl, G4-C1O cycloalkenyl, or phenyl optionally substituted with 1-3 independent GI-GlO alkyl, C2-CIO alkenyl, C2-GIO alkynyl, C3-CIO cycloalkyl, C4- 13 13 13 13 13 13 CIO cycloalkenyl, halo, CF3, OR SR NR R GOOR N02, CN, G(O)R C(O)NR1 R 1, NHC(O)R or OG(O)R 1 Each R 13is independently H; GI-CIO alkyl; C2-CIO alkenyl; C2-CIO alkynyl; C3-CIO cycloalkyl; C4-ClO cycloalkenyl; CI-ClO alkyl optionally substituted 19 19 19 19 19 with halo, CF3, OR SR NR R COOR N02, CN; or phenyl optionally 19 19 19 19 19 substituted with halo, CF3, OR 19 SR NR R GOOR N02, CN; Each R 15is independently Cl-CIO alkyl; G2-CIO alkenyl; G2-ClO alkynyl; C3-G1O cycloalkyl; C4-G1O cycloalkenyl; aryl; R 9; Cl-CIO alkyl substituted with 1-3 independent aryl, R 7or R 9groups; or GI-ClO alkenyl substituted with 1-3 independent aryl, R. or R.
Each R 16is independently Cl-GbO alkyl; C2-ClO alkenyl; C2-GbO alkynyl; G3-CI10 cycloalkyl; C4-C 10 cycloalkenyl; R 9; C I-Cl10 alkyl substituted with 1-3 independent aryl, R. or R 9groups; Cl-GbO alkenyl substituted with 1-3 independent aryl, R 7or R 9; or phenyl substituted with 1-3 independent C I-CGl0 alkyl, C2-C 10 alkenyl, C2- WO 00/43373 WO 0043373PCTIUSOO/01 581 9 12 12 CIO alkynyl, C3-C1O cycloalkyl, C4-C1O cycloalkenyl, R halo, CF3, OR SR NR 12R 1, COOR 1, N02, CN, C(O)R C(O)NR2 R 1, NHC(O)R NH(COOR 1), 12 12 12 9 S(O)2NR R OC(O)R CI-ClO alkyl substituted with 1-3 independent R halo, CF3, 12 12 12 12 12 22 12 12 OR SR NR R COOR N02, CN, C(O)RI C(O)NR1 R NHC(O)R NH(COOR S(O)2NR 12R 1, OC(O)R12 Each R 1 9 is independently H; C I-Cl10 alkyl; C3-C1O0 cycloalkyl or phenyl; Each haloalkyl is independently a CI-ClO alkyl substituted with one or more halogen atoms, selected from F, Cl, Br, or 1, wherein the number of halogen atoms may not exceed that number that results in a perhaloalkyl group; and Each aryl is independently a 6-carbon monocyclic or 10-carbon bicyclic aromatic ring system optionally substituted with 1-3 independent Cl-Cl 0 alkyl; C2-C alkenyl; C2-ClO alkynyl; C3-CIO cycloalkyl; C4-C1O cycloalkenyl;.R 9; halo; haloalkyl; 12 1 2 12 12 12 12 12 12 12 CF3; OR ;SR NR R COOR N02; CN; C(O)R C(O)C(O)R C(O)NR R S()R12 NR12)(R 12 ;NR12)CO 12); NR 12)S02 12; 12 R12; S(O)R 1; NRC(O)R R1; N(R 1 1; N(R 12(O)R ;NR1 S(O)2NR 12R 1 12 1 12 12 12 12 129 12 12 12 1 OCR ao NR3 OR R NRR COCOR N2R C(O)R NR (O)NR R NRCOR1,N(OR S(O)2R1 R 12R C(C(O)N R2 Ci-ClO alkeyl substituted with1-inendt 9 2 1 12 12 12 12 12 12 R- neeetR, halo, CF3, OR SR NR R COOR N02, CN, C(O)R CON CO)N 12 ,NC 12, 12(O 12 O2N 12 R1,O() 2;oR1 Preferred compounds include those of the formula above wherein X is 0.
In another embodiment, the compounds of the formula above are those wherein, R Iis H; COOR 5; C(O)NR 5R 5; halo; C2-C1O alkyl; CI-ClO alkenyl; Cl- CIO alkyl substituted with NR 5R 5, NR 5R6, SR 5or OR; or CI-ClO alkenyl substituted with NRRNR R6,SR' or OR; R2 is NE. R 15; SR 5; OR 5; R 8; aryl; N(R 5)-N=CH(R N(R 5 5 16 5 5 6 8 NR. -NE C(O)NR5R; ;NE.-NE. R NR -NE. R C I-Cl10alkyl substituted with aryl,R halo, CF3, SR5, OR, OC(O)R, NE. R5, NR5 R6, COOR N02, CN, C(O)R 5 5 5 8 C(O)NE. R or S(O)2NR R or Ci-ClO alkenyl substituted with aryl, R halo, CF3, WO 00/43373 WO 0043373PCT/USOO/0I 581 5 5 5 56 5 5 SR OR OC(O)R5, NRR, NRR, COOR N02, CN, C(O)R C(O)NRR5, or S(O)2NR R; 3 4 R is phenyl substituted with 1-3 independent R. R COOR5; or ClI-Cl 0 alkyl substituted with aryl, R 7or R8 X is 0or S; Each R4 is independently selected from Ci-ClO alkyl; C2-CIO0 alkenyl; C2-ClO alkynyl; C3-ClO cycloalkyl; C4-ClO cycloalkenyl; aryl; R 8; halo; haloalkyl; 55 56 5 5 5 5 CF3; SR OR5; NR R5; NR R COOR N02; CN; C(O)R C(O)C(O)R ;C(O)NR R; 5 5 5 5 5 5 5 OC(O)R S(O)2R S(O)2NR R NR C(O)NR R5; NR5C(O)C(O)R; NR C(O)R NRX(COOR 5 NR5 C(O)R8; NR 5S(O)2NR 5R.5; NR 5S(O)2R 5; NR 5S(O)2R 8; NR 5C(O)C(O)NR5R 5; NR5C(O)C(O)NR 5R 6; CI-CIO alkyl substituted with aryl, R 7or R ;or ClI-Cl 10 alkenyl substituted with aryl, R or R8; Each R 5is independently H; CI-ClO0 alkyl; C2-ClO alkenyl; C2-CIO alkynyl; C3-CI0 cycloalkyl; C4-ClO cycloalkenyl; aryl; R 9 CI-C10 alkyl substituted wth ne r tw inepedentary, R7 orR9 gop;C-I yla lsbtttdwt 1 wione or two independent aryl, R or R groups; C 3-Cl yclalkyl substituted withlR7 9 or R 6 5 5 Each R is independently C(O)R COOR or S(0)2 R 7 10 10 1 01 Each R is independently halo, CF3, SR OR OC(0)R 0, NRI R1 10 11 II I 10 10 10 NR R ,NR1R11,COOR N02,CN,C(O)R ,orC(O)NR R Each R 8is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatomns if tricyclic, said heteroatoms selected from 0, N, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent independently selected from Cl CIO alkyl; C2-C1O alkenyl; C2-C10 alkynyl; C3-ClO cycloalkyl; C4-C10 cycloalkenyl; aryl; R 9; halo; sulfur; oxygen; CF3; haloalkyl; SR 5; OR; OC(0)R 5; NR 5R5; NR5 R6; 6 6 5 5 55 7 9 NR. R COOR N02; CN; C(O)R C(O)NRR R; ClI-Cl 10 alkyl substituted with R R 7 9 or aryl; C I-Cl10 alkenyl substituted with R R or aryl; WO 00/43373 PCTUSOO/01581 9 Each R is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from 0, N, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent independently selected from Cl CIO alkyl; C2-C1O alkenyl; C2-C1O alkynyl; C3-C1O cycloalkyl; C4-ClO cycloalkenyl; halo; sulfur; oxygen; CF3; haloalkyl; SR 10; OR 0; NSIR R; NRIR R NR IR 1 COOR 10; N02; CN; C(O)R 10; or C(O)NR 10R 1 Each R 10is independently H, Ci-ClO alkyl; C2-ClO* alkenyl; C2-CIO alkynyl; C3-C1O cycloalkyl; C4-C1O cycloalkenyl; haloalkyl; CI-CIO alkyl optionally substituted with 1-3 independent Cl-GbO alkyl, C2-CIO alkenyl, C2-C1O alkynyl, C3- 13 13 13 13 13 CIO cycloalkyl, C4-C1O cycloalkenyl, halo, CF3, OR SR NR R COOR N02, CN, C(O)R 1, C(O)NR1 R 1, NHC(O)R 1, or OC(O)R 13; or phenyl optionally substituted with 1-3 independent Cl-GbO alkyl, C2-CIO alkenyl, C2-ClO alkynyl, C3-CIO 13 13 13 13 13 cycloalkyl, C4-CLO cycloalkenyl, halo, CF3, OR SR NR R COOR N02, CN, C(O)R 1, C(O)NR1 R 1, NHC(O)R 1, or OC(O)R 1 I 1 10 10 Each R is independently C(O)R COOR or S(O)2R Each R 12is independently H, Cl-CIO alkyl, C2-CIO alkenyl, C2-C1O alkynyl, C3-C1O cycloalkyl, C4-CIO cycloalkenyl, or phenyl optionally substituted with 1-3 independent Cl-CIO alkyl, C2-C1O alkenyl, C2-CIO alkynyl, C3-C1O cycloalkyl, C4- 13 13 13 13 13 13 GIO cycloalkenyl, halo, CF3, OR 13 SR NR R. COOR N02, CN, C(O)R C(O)NR1 R 1, NHC(O)R 3, or OC(O)R 1 Each R 13is independently H; CI-ClO alkyl; C2-CIO alkenyl; C2-CIO alkynyl; C3-CIO cycloalkyl; C4-C10 cycloalkenyl; CI-ClO alkyl optionally substituted 19 19 19 19 19 with halo, CF3, OR SR NR R COOR N02, CN; or phenyl optionally 19 19 19 19 19 substituted with halo, CF3, OR SR NR R GOOR N02, CN; Each R isis independently Cl-Cl 0 alkyl; C2-C 10 alkenyl; C2-C alkynyl; C3-CIO cycloalkyl; G4-CIO cycloalkenyl; aryl; R 9; Cl-CIO alkyl substituted with one or two independent aryl, R 7or R 9groups; or Ci-ClO alkenyl substituted with aryl, R 7orR 9; WO 00/43373 WO 0043373PCTIUSOO/01581 16 Each R is independently Ci-ClO alkyl; C2-C1O alkenyl; C2-CIO alkynyl; C3 -C 10 cycloalkyl; C4-C 10 cycloalkenyl; R 9; C I-Cl10 alkyl substituted with one or two independent aryl, R or R 9groups; C I-Cl10 alkenyl substituted with aryl, R 7or R9 or phenyl substituted with 1-3 independent ClI-CG1 alkyl, C2-CI10 alkenyl, C2-C 9 12 12 12 12 alkynyl, C3-ClO cycloalkyl, C4-CIO cycloalkenyl, R halo, CF3, OR SR NR R 12 22 12 12 12 12 12 COOR N02, CN, C(O)RI C(O)NR2 R NHC(O)R NH(COOR S(O)2NR R OC(O)R 2, ClI-C 1 alkyl substituted with R 9, halo, CF3, OR 12, SR 12, NR 12R 12, COOR 1 N02, CN, C(O)R 1, C(O)NR 12R 12, NI{C(O)R 1, NI-(COOR S(O)2NR 1 R12 12
OC(O)R
to Each R 19 is independently H; C I-CI10 alkyl; C3-C 10 cycloalkyl or phenyl; Each haloalkyl is independently a CI-ClO alkyl substituted with one or more halogen atoms, selected from F, Cl, Br, or 1, wherein the number of halogen atoms may not exceed that number that results in a perhaloalkyl group; Each aryl is independently a 6-carbon monocyclic or 10-carbon bicyclic aromatic ring system optionally substituted with 1-3 independent CI-CIO alkyl; C2-C1O alkenyl; C2-ClO alkynyl; C3-ClO cycloalkyl; C4-CIO cycloalkenyl; R 9; halo; haloalkyl; 12 12 12 12 12 12 12 12 12 CF3; OR]; SR NR. R COOR N02; CN; C(O)R C(O)C(O)R C(O)NR R; S(O)2R 12; N(R 12)C(O)R 12; N(R 1)(COOR N(R 1)S(O)2R 1; S(O)2NR12 R2 OC(O)R 12 NR. 1C(O)NRI R 1; NP. C(O)C(O)R 12; NR 1C(O)R9; NR. 1S(O)2NR 1 R 1 NP. S(O)2R 9; NR. 1C(O)C(O)NR 12R 1; Cl-GbO alkyl substituted with 1-3 independent 9 32 32 12 12 12 12 12 12 R halo, CF3, OR SR NR. R COOR N02, CN, C(O)R C(O)NR R NHC(O)R 1, NH(COORI S(O)2NR 1 R 1, OC(O)R 1; C2-C 10 alkenyl substituted with 9 12 12 32 12 12 32 1-3 independent R halo, CF3, OR SR NR R COOR N02, CN, C(O)R C(O)NP.2 R 1, NHC(O)R 1, NH(COOR S(0)2NR 12R 1, OC(O)R 1; or R 1.Preferred compounds of this embodiment are also those wherein X is 0.
WO 00/43373 WO 0043373PCT[USOO/01581 In another embodiment, the invention relates to a compound of the formula, x R 17 R NH wherein, R is CN; R 2is NR 5R 15; OR 5; R 8; aryl; N(R 5)-N=CH(R)8 N(R )-N=CH(aryl); NR -_NR 5C(O)NR R 5; NR -NR 5R 16; NR 5-NR 5R 6; C I-Cl10 alkyl substituted with aryl, R 8 5 5 55 56 5 halo, CF3, SR OR OG(O)R NR5 R NRR R, COOR N02, CN, C(O)R C(O)NR5 R 5, or S(O)2NR 5R 5; or GI-ClO alkenyl substituted with aryl, R 8, halo, CF3, 5 5 5 5 56 5 5 SR OR OC(O)R NR R, NRR, COOR N02, CN, C(O)R C(O)NRR5, or
R;
X is 0or S; 4 Each R is independently selected from H, Ci-ClO alkyl; C2-C1O alkenyl; C2-CIO alkynyl; C3-CIO cycloalkyl; C4-ClO cycloalkenyl; aryl; R 8; halo; haloalkyl; CF3; SR OR 5; NR 5R 5; NR 5R 6; COOR 5; N02; CN; C(O)R 5; C(O)C(O)R 5; C(O)NR 5R S(O)2R5; S(O)2NR 5R 5; NR 5C(O)NR 5R 5; NR 5C(O)C(O)R 5; NR NR 5(COOR5); NR 5C(O)R 8; NR 5S(O)2NR 5R 5; NR 5S(O)2R 5; NR 5S(O)2R8; NR 5C(O)C(O)NR 5R5; NR 5C(O)C(O)NR R 6; CI-ClO alkyl substituted with aryl, R 7or R 8; or CI-Cl 0 alkenyl substituted with aryl, R 7or R8; Each R 5is independently H; Ci-ClO alkyl; C2-ClO alkenyl; C2-C1O alkynyl; C3-C1O cycloalkyl; C4-CIO cycloalkenyl; aryl; R 9; Ci-ClO alkyl substituted with one or two independent aryl, R 7or R 9groups; C3-ClO cycloalkyl substituted with WO 00/43373 PCT/US00/01581 7 9 7 one or two independent aryl, R or R groups; or C1-CO10 alkenyl substituted with aryl, R 9 or R 6 5 5 Each R is independently C(O)R COOR or S(0)2 R; 7 10 10 10 10 Each R is independently halo, CF3, SR OR OC(O)R NR R 11 1 11 10 10 10 NR R ,NR R ,COOR ,NO2,CN,C(O)R ,orC(O)NR R 8 Each R is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent independently selected from Cl alkyl; C2-C10 alkenyl; C2-CO10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; 9 5 5 5 55 56 aryl; R; halo; sulfur; oxygen; CF3; haloalkyl; SR OR; OC(O)R NR R NR R 66 5 5 55 7 9 NR R COOR N02; CN; C(O)R C(O)NR R C1-CIO alkyl substituted with R R 79 or aryl; C1-C 10 alkenyl substituted with R R or aryl; Each R is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent independently selected from Cl- C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; 10 10 10 10 I1 I1 11 halo; sulfur; oxygen; CF3; haloalkyl; SR OR NRIO R NRIO R NR R 1010 10 COOR 0 N02; CN; C(O)R or C(O)NR R Each RI 0 is independently H, CI-CIO alkyl; C2-CIO alkenyl; C2-CO10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; haloalkyl; CI-CIO alkyl optionally substituted with 1-3 independent C1-CIO alkyl, C2-CO10 alkenyl, C2-C10 alkynyl, C3- 13 13 13 13 13 cycloalkyl, C4-C10 cycloalkenyl, halo, CF3, OR SR NR R COOR NO2, 13 13 13 13 13 CN, C(O)R C(O)NR R NHC(O)RI or OC(O)R or phenyl optionally substituted with 1-3 independent CI-CIO alkyl, C2-C10 alkenyl, C2-CO10 alkynyl, C3-C10 13 13 13 13 13 cycloalkyl, C4-C10 cycloalkenyl, halo, CF3, OR SRI NR R COOR N02, CN, C(0)R C(O)NR3 R 3, NHC(O)R 3, or OC(O)R I1 10 10 Each R is independently C(O)R COOR or S(O)2R WO 00/43373 PTUO/18 PCTIUSOO/01581 Each R 12is independently H, Cl-cl 0 alkcyl, C2-C 10 alkenyl, C2-C alkynyl, C3-ClO cycloalkyl, C4-ClO cycloalkenyl, or phenyl optionally substituted with 1-3 independent CI-ClO alkyl, C2-C1O alkenyl, C2-C1O alkynyl, C3-CIO cycloalkyl, C4- 13 13 13 13 13 13 CIO cycloalkenyl, halo, CF3, OR SR NR R COOR N02, CN, C(O)RI C(O)NR3 R 1, NIIC(O)R 1, or OC(O)R 1 Each R 13is independently H; Cl-GbO alkyl; C2-C1O alkenyl; C2-ClO alkynyl; C3-GlO cycloalkyl; C4-CIO cycloalkenyl; Ci-CIO alkyl optionally substituted 19 19 19 19 19 with halo, CF3, OR SR NR R COOR N02, CN; or phenyl optionally 19 19 1 91 substituted with halo, CF3, OR SR NR 9R9, COOR 9, N02, CN; Each R 14is each independently selected from Ci-CIO alkyl; C2-ClO alkenyl; C2-CIO alkynyl; C3-ClO cycloalkyl; C4-C1O cycloalkenyl; aryl; R 8; halo; 5 55 5 65 5 haloalkyl; CF3; SR OR5; NR R NR R COOR5; N02; CN; C(O)R C(O)C(O)R 55 5 55 S 5 5
C(O)NR
5 R OC(O)R S(O)2R; S(0)2NR5R; NR C(O)NR R; NR C(O)C(O)R NR 5C(O)R 5; NR 5(COOR5); NR 5C(O)R 8; NR 5S(O)2NR 5R5; MR 5S(O)2R 5; NR S(O)2R8;
NR
5
C(O)C(O)NR
5 R 5 NR 5
C(O)C(O)NR
5 R 6 CI-ClO alkyl substituted with aryl, R 7 or R ;or ClI-CG1 alkenyl substituted with aryl, R 7or R8; Each R 15is independently Ci-ClO alkyl; C2-C1O alkenyl; C2-C1O alkynyl; C3-C1O cycloalkyl; C4-G1O cycloalkenyl; aryl; R 9; CI-ClO alkyl substituted with one or two independent aryl, R 7or R 9groups; or Cl-CIO alkenyl substituted with aryl, R orR 9; Each R 16is independently CI-CIO alkyl; C2-CIO alkenyl; C2-CIO alkynyl; C3-CIO cycloalkyl; G4-CIO cycloalkenyl; R 9 Ci-CIO alkyl substituted with one or two independent aryl, R 7or R9 groups; ClI-Gb1 alkenyl substituted with aryl, R 7or R 9; or phenyl substituted with 1-3 independent CI-GlO alkyl, C2-CIO alkenyl, C2-ClO alkcynyl, C3-ClO cycloalkyl, C4-CIO cycloalkenyl, R9, halo, CF3, OR 2, SRI 2, NRI RI2 COOR 1, N02, GN, C(O)R 1, C(O)NR 12R 12, NHiC(O)R 1, NI{(COOR S(O)2NR 12R 1 12 912 12 12 12 12 OC(O)R. Ci1-Cl10 alkyl substituted with R halo, CF3, OR SR NR R COOR NO2, CN, C(O)R C(O)NRI R 12, NHC(O)R 12, NH(COOR 12), S(O)2NR 12R12 12
OC(O)R.
WO 00/43373PCIS/O58 PCT/USOO/01581 Each R 17is independently selected from H, Cl-cl 0 alkyl; C2-C alkenyl; C2-ClO alkynyl; C3-ClO cycloalkyl; C4-CIO cycloalkenyl; aryl; R 8; halo; 5 5 56 555 haloalkyl; CF3; SR; OR; NR R5; NRR R; COOR; N02; CN; C(O)R5;
C(O)NR
5
R
5 OC(O)R5; S(O)2R5; S(O)2NR R; NR5C(O)NR5 R NR NR 5C(O)R5; NR (COOR5); NR 5C(O)R8; NR 5S'(O)2NR 5R 5; NR 5S(O)2R 5; NR5S(O)2R;8 5 5 5 5 6 7 NR C(O)C(O)NR R; NR C(O)C(O)NR R Cl-CIO alkyl substituted with aryl, R or R ;or C I-Cl10 alkenyl substituted with aryl, R 7or R 8; Each R 19is independently H; Cl1-C 10 alkyl; C3 -C 10 cycloalkyl or phenyl; Each haloalkyl is independently a Cl-Cl 0 alkyl substituted with one or more halogen atoms, selected from F, Cl, Br, or I, wherein the number of halogen atoms may not exceed that number that results in a perhaloalkyl group; Each aryl is independently a 6-carbon monocyclic or 1 0-carbon bicyclic aromatic ring system optionally substituted with 1-3 independent Cl-Cl 0 alkyl; C2-C alkenyl; C2-CIO alkynyl; C3-C10 cycloalkyl; C4-ClO cycloalkenyl; R 9; halo; haloalkyl; 12 12 12 12 12 12 12 12 12 CF3; OR ;SR NR R COOR N02; CN; C(O)R C(O)C(O)R C(O)NR R S(O)2R 12 N(R 1)C(O)R 12; N(R 1)(COOR N(R 1)S(O)2R 12; S(O)2NR 12R12 OC(O)R 12 NR 1C(O)NR] R 1; NR12C(O)C(O)R 12; NR 12C(O)R9; NR 1S(O)2NR 12R12 NR 12S(O)2R9; NR 1C(O)C(O)NR 12R 1; CI-ClO alkyl substituted with 1-3 independent R 9, halo, CF3, OR 12, SR 12, NR 12R 12, COOR 12, N02, CN, C(O)R 1, C(O)NR 12R12 NHC(O)R 1, NI{(COORI S(O)2NR 12R 1, OC(O)R 1; C2-C 10 alkenyl substituted with 9 12 12 12 12 12 12 1-3 independent R halo, CF3, OR SR NR, R COOR N02, CN, C(O)RI C(O)NR2 R 1, NHC(O)R 1, NH(COOR S(O)2NR 12R 1, OC(O)R 1; or R 1 wherein when all R4 and R 17are simultaneously H, R 14may not be Me, Cl, or OMe; and wherein R 14and R 17may not simultaneously be Cl. Preferred compounds of this embodiment are also those wherein X is 0. Alternatively, the compound has the formula directly above wherein each R 14is independently selected from C2-CIO alkyl; C2-C1O alkenyl; C2-CIO alkynyl; C3-C1O cycloalkyl; C4-ClO cycloalkenyl; aryl; R 8; I; Br; F; CF,; SR 5
OR
2 5
NR
5 R 5
NR
5
R
6 COOR 5
NO
2 CN; C(O)R 5
C(O)C(O)R
5
C(O)NR
5 R 5
S(O)
2
NR
5
R
5
NR
5
C(O)NR
5 R 5
NR
5 C(O)C(O)R 5
NR
5
C(O)R
8
NR'S(O)
2
NR
5
R
5
NR
5
S(O)
2 R 5
NR
5
S(O)
2 R 8
NR
5
C(O)C(O)NR
5
R
5
NR
5
C(O)C(O)NR
5 CI-CIO alkyl WO 00/43373 PCT/US00/01581 substituted with aryl, R 7 or R 8 or C1-C10 alkenyl substituted with aryl, R 7 or R 8 and each
R
25 is independently H; C2-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R 9 C1-C10 alkyl substituted with one or two independent aryl, R 7 or R 9 groups; C3-C10 cycloalkyl substituted with one or two independent aryl, R 7 or R 9 groups; or Cl-C10 alkenyl substituted with aryl, R 7 or R 9 Alternatively, the compound has the formula directly above wherein each R 14 is independently selected from NR R NR R; NRSC(O)NRRS NR C(O)C(O)RS; 5 5 5 8 5 5 5 5 8
NRSC(O)R
5 NRS(COOR); NRSC(O)R; NRS(0)2NR R; NRSS(O)2RS; NR S(0)2R; 55 5 5 6 NR C(0)C(0)NR R or NR C(O)C(O)NR R In alternate embodiments, the compound is of any of the formulae above, wherein at least two of R 4 and/or R 17 are independently H. Preferred compounds of these embodiments are also those wherein X is O.
In an alternate embodiment, the inhibitory compound has the formula:
X
R'
R 4 NH R 4 R N R R' R 1 4 wherein, R is CN; 2 515 5 8 5 8 R is NR R OR R 8 aryl; N(R N(R )-N=CH(aryl); 5 55 5 5 16 5 56 8 NR -NR C(O)NR R NR -NR R NR -NR R CI-C10 alkyl substituted with aryl, R 5 5 55 56 5 halo, CF3, SR 5 OR OC(O)R 5 NR R, NR R, COOR, N02, CN, C(O)R 5 55 8 C(O)NR R or S(0)2NR R or C1-C10 alkenyl substituted with aryl, R halo, CF3, 5 5 55 56 5 5
SR
5
OR
5
OC(O)R
5 NR R NR R, COOR N02, CN, C(O)R C(O)NR R or S(0)2NRR; X is O or S; 4 Each R is independently selected from H, C1-C10 alkyl; C2-C10 alkenyl; 8 C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R 8 halo; haloalkyl; 5 5 5 5 5 CF3; SR OR NR R NR R COOR NO2; CN; C(O)R C(O)C(O)R5; C(O)NR WO 00/43373 PCT/US00/01581 5 55 5 55 5 5 5 OC(O)R S(0)2R S(0)2NR R NR C(O)NR R; NR C(O)C(O)R NR C(O)R 5 5 8 5 55 5 5 5 8 NR (COOR); NR C(O)R8; NR S(O)2NR R NR S(0)2R; NR S(0)2R 55 5 56 7 NR C(O)C(O)NR R; NR C(O)C(O)NR R C1-CIO alkyl substituted with aryl, R or 8 7 8 R ;or CI-CO10 alkenyl substituted with aryl, R or R Each RS 5 is independently H; Ci-CIO alkyl; C2-CO10 alkenyl; C2-CO10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R CI-CIO alkyl substituted 7 9 with one or two independent aryl, R or R groups; C3-C10 cycloalkyl substituted with 7 9 7 one or two independent aryl, R or R groups; or C1-CIO alkenyl substituted with aryl, R 9 or R; 5 Each R is independently C(O)RS, COOR or S(0)2 R; 7 10 10 10 10 Each R is independently halo, CF3, SR OR OC(O)R NR R 11 11 II 10 10 10 NR R ,NR R ,COOR ,NO2,CN,C(O)R ,orC(O)NR R Each R is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent independently selected from Cl alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; 9 5 5 5 5 56 aryl; R; halo; sulfur; oxygen; CF3; haloalkyl; SR OR OC(O)R NR R; NR R; 66 5 5 55 7 9 NR R COOR NO2; CN; C(O)R C(O)NR R C1-CO10 alkyl substituted with R R 79 or aryl; Cl-C1O alkenyl substituted with R R or aryl; Each R is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent independently selected from Clalkyl; C2-C10 alkenyl; C2-CO10 alkynyl; C3-C10 cycloalkyl; C4-CO10 cycloalkenyl; 10 10 10 10 11 11 11 halo; sulfur; oxygen; CF3; haloalkyl; SR OR NRIO R NR IOR NRIIRII 10 COOR N02; CN; C(O)R or C(O)NR R WO 00/43373 WO 0043373PCTUSOO/01 581 Each R is independently H, Ci-CIO alkyl; C2-C1O alkenyl; C2-C1O alkynyl; C3-C1O cycloalkyl; C4-ClO cycloalkenyl; haloalkyl; Ci-ClO alkyl optionally substituted with 1-3 independent Ci-ClO alkyl, C2-CIO alkenyl, C2-C1O alkynyl, C3- 13 13 13 13 13 CIO cycloalkyl, C4-C1O cycloalkenyl, halo, CF3, OR SR NR R COOR N02, 13 13 13 13 13 CN, C(O)R C(O)NR R NHC(O)R or OC(O)R or phenyl optionally substituted with 1-3 independent Ci-CIO alkyl, C2-C1O alkenyl, C2-CIO alkynyl, C3-CIO 13 13 13 13 13 cycloalkyl, C4-CIO cycloalkenyl, halo, CF3, OR SR NR R COOR N02, CN, 13,CON 13 13 13 13 C(O)R ()RR ,NHC(O)R or OC(O)R 10 10 Each R 1 is independently G(O)R COOR or S(O)2R Each R 12is independently H, CI-ClO alkyl, C2-C1O alkenyl, C2-CIO alkynyl, C3-Cl10 cycloalkyl, C4-C 10 cycloalkenyl, or phenyl optionally substituted with 1-3 independent CI-ClO alkyl, C2-ClO alkenyl, C2-ClO alkynyl, C3-ClO cycloalkyl, C4- 13 13 13 13 13 13 CIO cycloalkenyl, halo, CF3, OR SR NR R COOR N02, CN, C(O)R
C(O)NR
3 R 1 3 NHC(O)R 1, or OC(O)R 1 Each R 13is independently H; CI-ClO alkyl; C2-C1O alkenyl; C2-C1O alkynyl; C3-C1O cycloalkyl; C4-ClO cycloalkenyl; Ci-CIO alkyl optionally substituted 19 19 19 19 19 with halo, CF3, OR SR NR R COOR N02, CN; or phenyl optionally 19 19 19 19 19 substituted with halo, CF3, OR SR NR R COOR N02, CN; Each R 14is independently selected from CI-CIO alkyl; C2-ClO alkenyl; C2-C1O alkynyl; C3-CIO cycloalkyl; C4-C1O cycloalkenyl; aryl; R 8; halo; haloalkyl; 5 5 5 6 5 5 5 CF3; SR OR NR R NR5R COOR5; NO2; CN; C(O)R C(O)C(O)R C(O)NR R; 5 55 5 5 5 5 5 5 OC(O)R S(O)2R S(O)2NR R5; NR C(O)NR R NR C(O)C(O)R; NR NR 5(COOR5); NR 5C(O)R 8; NR 5S(O)2NR 5R 5; NR5S(O)2R 5; NR 5S(O)2R8; NR 5C(O)C(O)NR R NR5 C(O)C(O)NkR 6; Cl-GbO alkyl substituted with aryl R 7or R8; or ClI-C 1 alkenyl substituted with aryl, R 7orR R Each R 15is independently CI-ClO alkyl; C2-CIO alkenyl; C2-C1O alkynyl; C3-C1O cycloalkyl; C4-CLO cycloalkenyl; aryl; R 9; Cl-GbO alkyl substituted with one or two independent aryl, R 7or R 9groups; or Cl-Cl 0 alkenyl substituted with aryl, R 7orR9; WO 00/43373 WO 0043373PCTLJSOO/01581 Each R 16is independently CI-C1O alkyl; C2-C1O alkenyl; C2-Clo alkynyl; C3-C1O cycloalkyl; C4-CIO cycloalkenyl; R 9; C I-Cl10 alkyl substituted with one or two independent aryl, R or R 9groups; Cl-Gb0 alkenyl substituted with aryl, R 7or R9 or phenyl substituted with 1-3 independent Cl-Gb0 alkyl, C2-ClO alkenyl, C2-CIO 9 12 12 12 12 alkynyl, C3-CIO cycloalkyl, C4-ClO cycloalkenyl, R halo, CF3, OR SR NR R COOR 1, N02, CN, C(O)R 1, C(O)NR1 R 1, NHC(O)R 1, NH(COOR S(O)2NR 12R12 12 9 12 12 12 12 12 OC(O)R Ci-ClO alkyl substituted with R ,halo, CF3, OR ,SR ,NRRC R N02, CN, C(O)R 1, C(O)NRI R 1, NHC(O)R 1, NH(COOR S(O)2NR 12R1 12
OC(O)R
Each R 19is independently H; C I-CL10 alkyl; C3 -C 10 cycloalkyl or phenyl; Each haloalkyl is independently a Cl-cl 0 alkyl substituted with one or more halogen atoms, selected from F, Cl, Br, or I, wherein the number of halogen atoms may not exceed that number that results in a perhaloalkyl group; Each aryl is independently a 6-carbon monocyclic or 1 0-carbon bicyclic aromatic ring system optionally substituted with 1-3 independent Cl-Gb0 alkyl; C2-CIO alkenyl; C2-ClO alkynyl; C3-C1O cycloalkyl; C4-ClO cycloalkenyl; R 9; halo; haloalkyl; 12 12 12 12 12 12 12 12 12 CF3; OR ;SRI NR R COOR N02; CN; C(O)R C(O)C(O)R C(O)NR R; S()R12 NR12)(R 12 ;NR12)CO 12) 12)S02 12 ;S02R12 R12; (O)R 12 NR C(O)R 1; NR(R )(OR 1; N(R NR1S(O)2NR 12R 1 9 2 1 12 12 12 12 129 12 12 12 RC(O) hao NR3 OR R NR R (O)C(OR N2 C(O)R; NR S (O)NR R CO) 12NR(O 2) S(O)2 12 NR 12(O)C(O)N R2 Cl-Cl 0 alkeyl substituted with1-inendt 992 1 12 12 12 12 12 12 R- neeetR, halo, CF3, OR SR NR R COOR N02, CN, C(O)R CON C()2R1,NHC(O)R 1, NH(COOR S(O)2NR 1 R 1, OC(O)R 12 C2; 10 Ry susttue wit wherein when all R4 are H, R 14may not be Me or OMe. Preferred compounds of this embodiment are also those wherein X is 0. Alternatively, the compound has the formula directly above wherein each R 1 4 is independently selected from C2-CIO alkyl; C2-C1O alkenyl; C2-C1O alkynyl; C3-C1O cycloalkyl; C4-C1O cycloalkenyl; aryl; R 8 halo; CF 3 SR'; OR 2 1; NR 5
R
5
NR
5
R
6 COOR 5
NO
2 CN; C(O)R 5
C(O)C(O)R
5
C(O)NR
5
R
5
S(O)
2
NR
5
R
5
NR
5
C(O)NR
5
R
5
NR
5
C(O)C(O)R
5
NR
5 C(O)R 8
NR
5 S(0) 2
NR
5
R
5 WO 00/43373 PCT/US00/01581 NRSS(O)2R 5 NRSS(0)2RS; NR'C(O)C(O)NRRS; NR'C(O)C(O)NR R; C1-C10 alkyl substituted with aryl, R 7 or R or Cl-C10 alkenyl substituted with aryl, R 7 or R and each R is independently H; C2-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R9; Cl-C10 alkyl substituted with one or two independent aryl, R 7 or R 9 groups; C3-C10 cycloalkyl substituted with one or two independent aryl, R 7 or R 9 groups; or Cl-C10 alkenyl substituted with aryl, R 7 or R 9 Alternatively, the compound has the formula directly above wherein each R is 56 5 55 5 independently selected from NR R NR R; NR C(0)NR R NR C(O)C(O)R 5 5 5 5 8 5 55 5 5 5 8 NR C(O)R NR (COOR); NR C(O)R NR S(0)2NR R NR S(O)2R NR S(O)2R 55 5 56 NR C(O)C(O)NR R or NR C(O)C(O)NR R In alternate embodiments, the compound is of any of the formulae above, wherein at least two of the R are independently H.
Preferred compounds of these embodiments are also those wherein X is O.
In an alternate embodiment, the inhibitory compound has the formula,
X
R NH
R
4
R
17
R
14
R
4 wherein, R is CN; 2 5 15 5 8 5 8 R is NR R OR; R; aryl; N(R N(R )-N=CH(aryl); 5 5 5 5 5 16 5 5 6 8 NR -NR C(O)NR R ;NR -NR R ;NR -NR R C1-C10 alkyl substituted with aryl, R 5 5 55 56 5 halo, CF3, SR OR, OC(O)R, NR R, NR R, COOR, N02, CN, C(O)R 5 55 8 C(O)NR R or S(0)2NR R or CI-C10 alkenyl substituted with aryl, R halo, CF3, 5 5 55 56 5 5 SR, OR, OC(O)R, NR R, NR R, COOR, N02, CN, C(O)R, C(O)NR R, or S(0)2NR R X is O or S; WO 00/43373 PCTIUS00/01581 Each R is independently selected from H, C-C 10 alkyl; C2-C10 alkenyl; 8 C2-CO10 alkynyl; C3-C10 cycloalkyl; C4-CO10 cycloalkenyl; aryl; R halo; haloalkyl; CF3; SR S; OR5; NRSRS; NR R6; COOR N02; CN; C(O)RS; C(O)C(O)R C(O)NRSRS; 5 55 5 55 5 5 5 OC(O)R S(0)2R S(O)2NR R NR C(O)NRR NR C(O)C(O)R NR C(O)R 55 8 5 8 NRS (COOR); NR C(O)R NR sS(0)2NRSR NR S(O)2R NR S(0)2R 5 5 5 56 7 NR C(O)C(O)NR R; NR C(O)C(O)NRR CI-CIO alkyl substituted with aryl, R or 8 7 8 R or CI-CO10 alkenyl substituted with aryl, R or R Each R is independently H; CI-CO10 alkyl; C2-C10 alkenyl; C2-CO10 alkynyl; C3-CO10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R9; C1-ClO alkyl substituted with one or two independent aryl, R or R 9 groups; C3-CO10 cycloalkyl substituted with 7 9 7 one or two independent aryl, R or R groups; or Cl-CO10 alkenyl substituted with aryl, R 9 or R 6 5 5 Each R is independently C(O)R COOR or S(0)2 R; 7 10 10 10 10 Each R is independently halo, CF3, SR OR OC(O)R NR1 R 11 II 11 10 10 10 NR R ,NR R ,COOR ,N02,CN,C(O)R ,orC(O)NR R Each R is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent independently selected from Clalkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; 9 5 5 5 5 5 5 6 aryl; R halo; sulfur; oxygen; CF3; haloalkyl; SR OR OC(O)R NR R NR R; 66 5 5 55 7 9 NR R COOR N02; CN; C(O)R C(O)NR R CI-CO10 alkyl substituted with R R 79 or aryl; Cl-C10 alkenyl substituted with R R or aryl; Each R9 is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from 0, N, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent independently selected from Cl CO10 alkyl; C2-CO10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; WO 00/43373 WO 0043373PCT/USOO/01581 halo; sulfur; oxygen; CF3; haloalkyl; SR 10; OR 0; NIR R; NRI. R NRIR R G00R 10 N02; CN; C(O)R 10; or C(O)NR 10R 1 Each R 10is independently H, Ci-ClO alkyl; C2-C1O alkenyl; C2-CIO alkynyl; C3-ClO cycloalkyl; C4-C1O cycloalkenyl; haloalkyl; Ci-ClO alkyl optionally substituted with 1-3 independent CI-ClO alkyl, C2-ClO alkenyl, C2-C1O alkynyl, C3- 13 13 13 13 13 CIO cycloalkyl, C4-CIO cycloalkenyl, halo, CF3, OR SR NR R COOR N02, CN, C(O)R 1, C(O)NR3 R 1, NHC(O)R 1, or OC(O)R 13; or phenyl optionally substituted with 1-3 independent CI-ClO alkyl, C2-CIO alkenyl, C2-C1O alkynyl, C3-ClO 13 13 13 13 13 cycloalkyl, C4-ClO cycloalkenyl, halo, CF3, OR SR NR. R COOR N02, CN, C(O)R 3, C(O)NR1 R 1, NI{C(O)R 3, or OC(O)R 1 I 1 10 10 Each R is independently C(O)R COOR or S(O)2R Each R 12is independently H, Cl-CIO alkyl, C2-CIO alkenyl, C2-ClO alkynyl, C3 -C 10 cycloalkyl, C4-C 10 cycloalkenyl, or phenyl optionally substituted with 1-3 independent C I-C 10 alkyl, C2-CI10 alkenyl, C2-CI10 alkynyl, C3-CI10 cycloalkyl, C4- 13 13 13 13 13 13 Cl10 cycloalkenyl, halo, CF3, OR 13 SR NR. R COOR N02, CN, C(O)RI C(O)NRP. R 1, NHC(O)R 1, or OC(O)R 1 13 Each R is independently H; Cl-GbO alkyl; C2-CIO alkenyl; C2-CIO alkynyl; C3-C1O cycloalkyl; C4-C1O cycloalkenyl; CI-CIO alkyl optionally substituted 19 19 19 19 19 with halo, CF3, OR SR NP R COOR NO2, CN; or phenyl optionally 19 19 19 19 19 substituted with halo, CF3, OR SR NR R COOR N02, CN; Each R 14is independently selected from CI-ClO alkyl; C2-C1O alkenyl; C2-C1O alkynyl; C3-C1O cycloalkyl; C4-CIO cycloalkenyl; aryl; R 8; halo; haloalkyl; 5 5 5 5 CF3; SR OR NR R NP. R COOR5; N02; CN; C(O)R C(O)C(O)R C(O)NR 555 5 55 5 5 OC(O)R S(O)2RS; S(O)2NR R5; NR C(O)NR R5; NR C(O)C(O)R5; NP. C(O)R NP. (COOR5); NR5 C(O)R;8 NRP. S(O)2NR. R; NR 5 S(O)2R5; NP. S(O)2R'; 55 5 5 6 7 NR. C(O)C(O)NP. R5; NR. C(O)C(O)NP. Cl-cl 0 alkyl substituted with aryl, R or P.8 or C I-C 10 alkenyl substituted with aryl, R7 or R8; Each P.1 is independently Ci-ClO alkyl; C2-CIO alkenyl; C2-C1O alkynyl; C3-C1O cycloalkyl; C4-CIO cycloalkenyl; aryl; R.
9 Cl-GbO alkyl substituted WO 00/43373 WO 0043373PCTIUSOO/01581 with one or two independent aryl, R 7or R 9groups; or ClI-C 10 alkenyl substituted with aryl, R orR 9; Each R 16is independently H; Ci-ClO alkyl; C2-C1O alkenyl; C2-C1O alkynyl; C3-C1O cycloalkyl; C4-GIO cycloalkenyl; aryl; R 9; CI-ClO alkyl substituted with one or two independent aryl, R 7or R 9groups; or C I-Cl10 alkenyl substituted with aryl, R 7or R9; Each R 17is independently selected from H, Cl-Cl 0 alkyl; C2-C alkenyl; C2-ClO alkynyl; C3-ClO cycloalkyl; C4-ClO cycloalkenyl; aryl; R 8; halo; 5 55 56 5 haloalkyl; CF3; SR OR5; NR R NER R; COOR N02; CN; C(O)R5; C(O)C(O)R C(O)NR5 R5; OC(O)R 5; S(O)2R5; S(O)2NR R; NR 5C(O)NR R5; NE. NR 5C(O)R5; NE. (COOR5); NE. 5CO)R 8; NR 5S(O)2NR R 5; NR 5S(O)2R 5; NR 5S(O)2R8; 55 5 5 6 7 NR. C(0)C(O)NR R5; NR. C(O)C(O)NR R Ci-ClO alkyl substituted with aryl, R or R ;or C I-Cl10 alkenyl substituted with aryl, R 7or R8; Each R 19is independently H; C I-Cl10 alkyl; C3 -Cl10 cycloalkyl or phenyl; Each haloalkyl is independently a CI-ClO alkyl substituted with one or more halogen atoms, selected from F, Cl, Br, or I, wherein the number of halogen atoms may not exceed that number that results in a perhaloalkyl group; Each aryl is independently a 6-carbon monocyclic or 10-carbon bicyclic aromatic ring system optionally substituted with 1-3 independent CI-CIO alkyl; alkenyl; C2-C 10 alkynyl; C3-C 10 cycloalkyl; C4-Cl10 cycloalkenyl; R 9; halo; haloalkyl; 12 12 12 12 12 12 12 12 12 CF3; OR ;SR NE. R COOR N02; CN; C(O)R C(O)C(O)R C(O)NE. R; S(0)2R 12 N(R 1)C(O)R 12; N(R 1)(COOR N(R 1)S(O)2R 1; S(O)2NRE. R 1 OC(O)R 12 NE. 1C(O)NR2 R 1; NE. C(O)C(O)R 12; NR 12C(O)R9; NE. 1S(O)2NRI RI 12 9 12 12 12 NE. S(O)2R NE. C(O)C(O)NE. R ;CI-ClO alkyl substituted with 1-3 independent 912 12 12 12 12 12 12 12 R9,halo, CF3, OR SR NR R ,COOR N02, CN, C(O)R C(O)NR R NHC(O)R 12, NH(COOR 12), S(O)2NR 12R 12, OC(O)R 12; C2-C 10 alkenyl substituted with 9 12 12 12 12 12 1 2 1-3 independent R halo, CF3, OR SR NE. R COOR N02, CN, C(O)R C(O)NR2 R 1, NHC(O)R 1, NH(COOR S(O)2NR12 R 1, OC(O)R 2; or R 1 wherein R 1 4 and R 1 7 may not simultaneously be Cf. Preferred compounds of this embodiment are also those wherein X is 0. Alternatively, the compound has the formula WO 00/43373 WO 0043373PCTUSOO/0I 581 directly above wherein each R'1 7 is independently selected from from H, Gi-ClO alkyl; C2-ClO alkenyl; C2-C1O alkynyl; C3-ClO cycloalkyl; C4-C1O cycloalkenyl; aryl; R 8
I;
Br; F; CF 3
SR
5
OR
5
NR
5
R
5
NR
5 R 6 COOR 5
NO
2 CN; C(O)R 5 C(O)C(O)R 5
C(O)NR
5
S(O)
2
NR
5 R 5
NR
5
C(O)NR
5
R
5
NR
5
C(O)C(O)R
5
NR
5 C(O)R 8
NR'S(O)
2
NR
5
R
5
NR'S(O)
2 R 5
NR'S(O)
2 R 8
NIC(O)C(O)NR
5
R
5 CI-ClO alkyl substituted with aryl, R 7 or R 8 or Ci-ClO alkenyl substituted with aryl, R 7 or R 8 Alternatively, the compound has the formula directly above wherein each R 14is 55 5 6 5 55 5 independently selected from NR 5 R NR R NR C(O)NR R5; NR C(O)C(O)R 5 5 5 5 8 5 5 5 5 5 8 NR C(O)R NR (COOR NR C(O)R NR S(O)2NR R NR S(O)2R NR5S(O)2R NR5C(O)C(O)NR5 R 5; or NR 5C(O)C(O)NR R 6. In alternate embodiments, the compound is of any of the formulae above, wherein at least two of R 4and/or R 17are independently H. Preferred compounds of these embodiments are also those wherein X is 0.
In another embodiment, the inhibitory compound has the formula, x 3)
NHR
wherein R is CN; R is NR 5R 15; OR 5; R 8; aryl; N(R 5)-N=CH(R8); N(R 5 5 5 5 5 16 5 56 8 NR -NR C(O)NR R NR -NR R NR -NR R C I-Cl10alkyl substituted with aryl,R halo, CF3, SR5, OR5, OC(O)R5, NRR5, NRR6, COOR N02, CN, 555 5 8 C(O)NR R or S(O)2NR R or CI-ClO alkenyl substituted with aryl, R halo, CF3, 5 5 55 565 5 SR OR OC(O)R NR R, NRR, COOR', N02, CN, C(0)R C(O)NRR or S(O)2NR R; R 3is R 8; COOR 5; or Ci-ClO alkyl substituted with R 7, R 8, or phenyl substituted with 1-3 independent Ci-ClO alkyl, C2-C1O alkenyl, C2-ClO alkynyl, C3- 912 12 12 12 12 cycloalkyl, C4-CIO cycloalkenyl, R, halo, CF3, OR SR NR R COOR N02, CN, C(O)R C(O)NR2 R 1, NI{C(0)R 1, NII(COOR S(O)2NR 12R12 WO 00/43373 WO 0043373PCTIUSOO/O1 581 12 9 12 12 12 12 12 OC(O)R C I-Cl10 alkyl substituted with R halo, CF3, OR SR NR R COOR N02, CN, C(O)R C(O)NR2 R 1, NHC(O)R 2, NH(COOR S(O)2NR 12R12 12 3 OC(O)R wherein R is not unsubstituted fiiranyl, unsubstituted thienyl or unsubstituted pyridyl; X is 0or S; Each R 4is independently selected from H, ClI-C 1 alkyl; C2-CI10 alkenyl; C2-ClO alkynyl; C3-C1O cycloalkyl; C4-CIO cycloalkenyl; aryl; R 8; halo; haloalkyl; CF3; SR 5; OR 5; NR R NR5R COOR'; N02; CN; C(O)R C(O)C(O)R C(O)NR 5 5 55 5 5 5 S(O)2R S(O)2NR5R5; NR C(O)NR R; NR C(O)C(O)R; NR C(O)R; NR 5(COOR5); NR 5C(O)R;8 NR 5S(O)2NR 5R5; NR 5S(O)2R;5 NR S(O)2R8; 5 5 5 6 7 NR C(O)C(O)NR R NR C(O)C(O)NR R CI-ClO alkyl substituted with aryl, R or R ;or C I-Cl10 alkenyl substituted with aryl, R 7or R8; Each R 5is independently H; Ci-CIO alkyl; C2-C1O alkenyl; C2-C1O alkynyl; C3-ClO cycloalkyl; C4-C1O cycloalkenyl; aryl; R 9; CI-ClO alkyl substituted with one or two independent aryl, R 7or R 9groups; C3-C1O cycloalkyl substituted with one or two independent aryl, R 7or R 9groups; or C I-Cl10 alkenyl substituted with aryl, R7 9 orR; 6 5 5 Each R is independently C(O)R COOR or S(0)2 R Each R 7is independently halo, CF3, SR 0, OR 0, OC(O)R ,j NR OR1 10 11 11 II1 10 10 NR R NR RI 1,COOR N02, CN, C(O)R 1, or (O)NR R Each R 8is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatomrs if tricyclic, said heteroatoms selected from 0, N, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent independently selected from Cl- CIO alkyl; C2-CIO alkenyl; C2-C1O alkynyl; C3-C1O cycloalkyl; C4-C1O cycloalkenyl; aryl; R 9; halo; sulfur; oxygen; CF3; haloalkyl; SR.5; OR5; OC(O)R 5; NR5R5; NR 5R6; NR 6k6; COOR 5; N02; CN; C(O)R C(O)NR5 CI-ClO alkyl substituted with R 7, R9 7 9 or aryl; ClI-C O alkenyl substituted with R R or aryl; WO 00/43373 WO 0043373PCT/USOO/01581 Each R 9is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatomns if tricyclic, said heteroatoms selected from 0, N, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent independently selected from Cl CIO alkyl; C2-ClO alkenyl; C2-CIO alkynyl; C3-C1O0 cycloalkyl; C4-ClO cycloalkenyl; halo; sulfur; oxygen; CF3; haloalkyl; SR 10; OR1 NRI R NR 10R II; NR 11R COOR1 0 N02; CN; C(O)R 10; or C(O)NR I Each R 10is independently H, Ci-ClO alkyl; C2-CIO alkenyl; C2-C1O alkynyl; C3-CIO cycloalkyl; C4-CIO cycloalkenyl; haloalkyl; Ci-CIO alkyl optionally substituted with 1-3 independent CI-CIO alkyl, C2-ClO alkenyl, C2-ClO alkynyl, C3- 13 13 13 13 13 CIO cycloalkyl, C4-CIO cycloalkenyl, halo, CF3, OR SR NR R COOR N02, 13,CON 13 13, 13, 13 CN, C(O)R (ON R ,NHC(O)R ,or OC(O)R or phenyl optionally substituted with 1-3 independent CI-CIO alkyl, C2-CIO alkenyl, G2-ClO alkynyl, C3-CIO 13 13 13 13 13 cycloalkyl, C4-CIO cycloalkenyl, halo, CF3, OR SR NR R COOR N02, CN, C(O)R 1, C(O)NR1 R 1, NHC(O)R 1, or OC(O)R 1 I1 10 10 Each R is independently C(O)R COOR or S(O)2R Each R 12is independently H, CI-CIO alkyl, C2-C1O alkenyl, C2-CIO alkynyl, C3-C 10 cycloalkyl, C4-C 10 cycloalkenyl, or phenyl optionally substituted with 1-3 independent Cl-ClO alkyl, C2-CIO alkenyl, C2-CIO alkynyl, C3-CIO cycloalkyl, C4- 13 13 13 13 13 13 CIO cycloalkenyl, halo, CF3, OR SR NR R COOR N02, CN, C(O)R C(O)NR3 R 1, NIIC(0)R 1, or OC(O)R 1 Each R 13is independently H; Cl-C!O alkyl; C2-C1O alkenyl; C2-CIO alkynyl; C3-CIO cycloalkyl; C4-CIO cycloalkenyl; Cl-CIO alkyl optionally substituted 19 19 19 19 19 with halo, CF3, OR SR NR R COOR N02, CN; or phenyl optionally 19 19 19 19 19 substituted with halo, CF3, OR SR NR R COOR N02, CN; Each R isis independently Cl-GbO alkyl; C2-CIO alkenyl; C2-G1O alkynyl; C3-GbO cycloalkyl; C4-CIO cycloalkenyl; aryl; R 9; CI-ClO alkyl substituted with one or two independent aryl, R 7or R 9groups; or Cl-cl 0 alkenyl substituted with aryl, R orR 9; WO 00/43373 PCT/US00/01581 Each R16 is independently CI-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 9 cycloalkyl; C4-C10 cycloalkenyl; R CI-CO10 alkyl substituted with one or two 7 9 7 9 independent aryl, R or R groups; CI-CO10 alkenyl substituted with aryl, R or R or phenyl substituted with 1-3 independent CI-CO10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, 9 12 12 12 12 12 s C3-C10 cycloalkyl, C4-CO10 cycloalkenyl, R halo, CF3, OR SR NR R COOR NO2, CN, C(O)R 12, C(O)NRI2 R 12, NHC(O)RI 2, NH(COOR S(O)2NR 12R2 12 9 12 12 12 12 12 OC(O)R CI-C10 alkyl substituted with R halo, CF3, OR SR NR R COOR, 12 12 12 12 12 12 12 N02, CN, C(O)R C(O)NR R NHC(O)R NH(COOR S(O)2NR R 12
OC(O)RI
Each R19 is independently H; CI-CO10 alkyl; C3-C10 cycloalkyl or phenyl; Each haloalkyl is independently a CI-C10 alkyl substituted with one or more halogen atoms, selected from F, Cl, Br, or I, wherein the number of halogen atoms may not exceed that number that results in a perhaloalkyl group; Each aryl is independently a 6-carbon monocyclic or 10-carbon bicyclic aromatic ring system optionally substituted with 1-3 independent Cl-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; R halo; haloalkyl; 12 12 12 12 12 12 12 12 12 CF3; OR SR NR R COOR N02; CN; C(O)R C(O)C(O)R C(O)NR R 12 12 12 12 12 12 12 12 12 S(O)2R ;1 N(R )C(O)R N(R )(COOR N(R 1)S(O)2R 12; S(0)2NR12 R12 12 12 12 12 12 12 12 9 12 12 12 OC(O)R NR 12C(O)NR12 R 12; NR 1C(O)C(O)R2 NR 12C(O)R9; NR 12S(0)2NR1 R; 12 9 12 12 12 NR S(0)2R NR C(O)C(O)NR R C1-C10 alkyl substituted with 1-3 independent 9 12 12 12 12 12 12 12 12 R halo, CF3, OR SR NR R COOR N02, CN, C(O)R C(O)NR R 12 12 12 12 12 NHC(O)R NH(COOR S(O)2NR12 R 12, OC(O)R C2-C10 alkenyl substituted with 9 12 12 12 12 12 12 1-3 independent R, halo, CF3, OR SR NR R COOR NO2, CN, C(O)R 12 12 12 12 12 12 12 12 C(O)N R 1, NHC(O)R NH(COOR S(0)2NR R OC(O)R or R 3 8 Alternatively, the compound has the formula directly above wherein each R is R and alternatively, wherein R is R that is attached by a nitrogen atom in the R ring system.
Preferred compounds of these embodiments are also those wherein X is O.
WO 00/43373 PCT/USOO/01581 In another embodiment, the inhibitory compound has the formula, R 1 8 R
-X
wherein, R 2is NR 5R 5; SR5; OR5; R 8 aryl; N(R )-N=CH(R N(R NR5-NR5C(O)NR5 R 5; NR -NR 5R 15; NR 5-NR 5R6; ClI-Gb1 alkyl. substituted with aryl, R 8 5 5 5 5 5 6 5 halo, CF73, SR OR OC(O)R NR R NR R COOR N02, CN, C(O)R 5 5 5 8 C(O)NR R or S(O)2NR R or Cl-Gb0 alkenyl substituted with aryl, R halo, CF3, 5 5 5 5 56 5 5 5 SR OR OC(O)R NR R, NPRR, COOR N02, CN, C(O)R C(O)NR R, or S(O)2NRR
R;
X is 0or S; 4 R is one, two, or three substituents, each independently selected from H, Cl-cl 0 alkyl; C2-C 10 alkenyl; C2-C 10 alkynyl; C3-C 10 cycloalkyl; C4-C 8 5 5 5 5 561 cycloalkenyl; aryl; R halo; haloalkyl; CF73; SR OR NR R NR R COOR N02; 5 5 5 5 5 5 5 CN; C(O)R; C(O)C(O)R; C(O)NR R; OC(O)R; S(O)2R; S(O)2NR R;
NR
5 C(O)NR 5 R 5
NR
5 C(O)C(O)R 5 NR 5 C(O)R 5 NR 5 (COOR 5
NR'
5 C(O)R 8 5 5 5 5 8 5 5 NR S(O)2NR R; NR S(O)2R5; NR S(O)2R NR C(O)C(O)NR R; 5 6 7 8 NR C(O)C(O)NR R Cl-C1O alkyl substituted with aryl, R or R or Ci-ClO alkenyl substituted with aryl, R 7or R8; Each R 5is independently H; Cl-Cl 0 alkyl; C2-C 10 alkenyl; C2-C alkynyl; C3-C1O cycloalkyl; C4-C1O cycloalkenyl; aryl; R 9; Cl-Gb0 alkyl substituted with one or two independent aryl, R 7or R 9groups; C3-C10 cycloalkyl substituted with one or two independent aryl, R 7or R 9groups; or C I-CI10 alkenyl substituted with aryl, R7 9 orR; 6 5 5 Each R is independently C(O)R dOOR or S(0)2 R WO 00/43373 PCT/US00/01581 710 10 10 10 Each R is independently halo, CF3, SR OR OC(O)R NR R 11 11 11 10 10 10 NR R ,NR R ,COOR ,N02,CN,C(O)R ,orC(O)NR R 8 Each R is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from 0, N, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent independently selected from Cl CIO alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-CO10 cycloalkyl; C4-C10 cycloalkenyl; 9 5 5 5 5 5 6 aryl; R halo; sulfur; oxygen; CF3; haloalkyl; SR OR OC(O)R5; NR R5; NR R; 6 5 5 5 7 9 NR R COOR N02; CN; C(O)R C(O)NR R CI-C10 alkyl substituted with R R 79 or aryl; C1-C10 alkenyl substituted with R R or aryl; 9 Each R is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent independently selected from Cl- CIO alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; 10 10 10 10 11 11 I1 halo; sulfur; oxygen; CF3; haloalkyl; SR OR NR R10 NR R NR R 10 10 COOR N02; CN; C(O)R or C(O)NR R Each RI 0 is independently H, CI-CIO alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; haloalkyl; CI-CIO alkyl optionally substituted with 1-3 independent Cl-C10 alkyl, C2-C10 alkenyl, C2-CO10 alkynyl, C3- 13 13 13 13 13 cycloalkyl, C4-C10 cycloalkenyl, halo, CF3, OR SR NR R COOR N02, CN, C(O)R C(O)NR R NHC(O)RI 3, or OC(O)R 3; or phenyl optionally substituted with 1-3 independent C1-CIO alkyl, C2-CO10 alkenyl, C2-CO10 alkynyl, C3-C10 13 13 13 13 13 cycloalkyl, C4-C10 cycloalkenyl, halo, CF3, OR SR NR R COOR N02, CN, 13 13 13 13 13 C(O)R C(O)NR R NHC(O)R or OC(O)R I1 10 10 Each Rl is independently C(O)R IO, COOR IO, or S(0)2RIO Each R12 is independently H, Cl-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, or phenyl optionally substituted with 1-3 independent C1-CIO alkyl, C2-CO10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4- WO 00/43373 PCT/US00/01581 13 13 13 13 13 13 cycloalkenyl, halo, CF3, OR 1 3 SR 3 NR R COOR N02, CN, C(O)R 3 C(O)NR R NHC(O)R 13 or OC(O)R 13 Each R is independently H; C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; CI-C10 alkyl optionally substituted 19 19 19 19 19 with halo, CF3, OR SR NR R COOR N02, CN; or phenyl optionally 19 19 19 19 19 substituted with halo, CF3, OR SR NR R COOR N02, CN; Each R8 is independently C1-C10 alkyl or both R 1 s may be taken together 18 as a C2-C7 alkyl chain; wherein any R may optionally be substituted with 1-3 7 8 independent R or R Each R 19 is independently H; C1-C10 alkyl; C3-C10 cycloalkyl or phenyl; Each haloalkyl is independently a C1-C10 alkyl substituted with one or more halogen atoms, selected from F, Cl, Br, or I, wherein the number of halogen atoms may not exceed that number that results in a perhaloalkyl group; Each aryl is independently a 6-carbon monocyclic or 10-carbon bicyclic aromatic ring system optionally substituted with 1-3 independent C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; R halo; haloalkyl; 12 12 12 12 12 12 12 12 CF3; OR SR NR R COOR N02; CN; C(O)R C(O)C(O)R C(O)NR R 12 12 12 12 12 12 12 12 12 S()2R N(R )C(O)R N(R )(COOR N(R )S(0)2R S(O)2NR R 12 2 12 12 12 9 12 12 12 OC(O)R 12; NR C(O)NR R 2 NR C(O)C(O)R2 NR C(O)R 9 NR S(0)2NR2 R 12 9 12 12 12 NR S(O)2R NR C(O)C(O)NR R C1-C10 alkyl substituted with 1-3 independent 9 12 12 12 12 12 12 12 12 R, halo, CF3, OR SR NR R COOR 1 N02, CN, C(O)R C(O)NR R2 12 12 12 12 12 NHC(O)R NH(COOR S(O)2NR R OC(O)R C2-C10 alkenyl substituted with 9 12 12 12 12 12 12 1-3 independent R, halo, CF3, OR SR NR R COOR NO2, CN, C(O)R 12 12 12 12 12 12 12 12 C(O)NR R NHC(O)R NH(COOR S(O)2NR R OC(O)R 1 2 or R Preferred compounds of this embodiment are also those wherein X is O.
The invention also relates to methods of inhibiting enzyme or polypeptide activity, particularly of an enzyme or polypeptide described herein, such as a kinase, in a mammal comprising the step of administering to said mammal a compound of any of the formulae described herein or a composition comprising a compound of any of the formulae described herein. In one embodiment, the invention relates to a method of inhibiting kinase activity in a mammal comprising the step of administering to said mammal a WO 00/43373 PCT/US00/01581 compound, or a composition comprising a compound, of any one of the formulae described herein. Preferably, the mammal is a human.
In another embodiment, the invention relates to a method of inhibiting enzyme activity in a mammal comprising the step of administering to said mammal a compound, or a composition comprising a compound, of any of the formulae described herein.
Preferably, the mammal is a human.
The invention also relates to methods of treating disease and/or disease symptoms, particularly those mediated by an enzyme or polypeptide described herein, such as kinase mediated disease or disease symptoms, in a mammal comprising the step of administering to said mammal a compound of any of the formulae described herein or a composition comprising a compound of any of the formulae described herein. Such diseases or disease symptoms are described herein. "Kinase mediated" disease or disease symptoms refers to disease or disease symptoms in which kinase activity is involved. In one embodiment, this invention relates to a method of treating disease or disease symptoms, particularly kinase mediated disease or disease symptoms, in a mammal comprising the step of administering to said mammal a compound, or a composition comprising a compound, of any of the formulae described herein. Preferably, the mammal is a human.
In an alternate embodiment, this invention relates to a method of treating disease or disease symptoms in a mammal comprising the step of administering to said mammal a compound, or a composition comprising a compound, of any of the formulae described herein. Preferably, the mammal is a human.
In the compounds described herein, the term "halo" refers to any radical of fluorine, chlorine, bromine or iodine. The terms "alkyl", "alkenyl" and "alkynyl" refer to hydrocarbon chains that may be straight-chain or branched-chain, containing the indicated number of carbon atoms. For example, C1-CIO indicates the group may have from 1 to 10 (inclusive) carbon atoms in it. The terms "ring" and "ring system" refer to a ring comprising the delineated number of atoms, said atoms being carbon or, where indicated, a heteroatom such as nitrogen, oxygen or sulfur. The ring itself, as well as any substitutents thereon, may be attached at any atom that allows a stable compound to be formed.
In the methods described herein, said mammal is preferably a human. The inhibitors described herein, however, are useful in inhibiting kinase activity in human cells and useful in murine and other species used as surrogates for investigating activity in vitro and in vivo in humans and against human kinases. The inhibitors described herein WO 00/43373 PCT/US00/01581 are also useful for investigating inhibition and activity of kinases originating from species other than humans.
The compounds and compositions described herein are useful for inhibition of kinase activity of one or more enzymes. Kinases include, for example, protein kinases, lipid kinases phosphatidylinositol kinases PI-3, PI-4) and carbohydrate kinases.
Further information relating to kinase structure, function and and their role in disease or disease symptoms is available at the Protein Kinase Resource web site (http://www.sdsc.edu/Kinases/pk home.html). Kinases may be of prokaryotic, eukaryotic, bacterial, viral, fungal or archaea origin. Specifically, the compounds described herein are useful as inhibitors of tyrosine, serine/threonine or histidine protein kinases. Examples of kinases that are inhibited by the compounds and compositions described herein and against which the methods described herein are useful include, but are not limited to, LCK, IRK INSR Insulin receptor), IGF-1 receptor, SYK, IRAKI, IRAK2, BLK, BMX, BTK, FRK, FGR, FYN, HCK, ITK, LYN, TEC, TXK, YES, ABL, SRC, EGF-R ErbB-1), ErbB-2 NEU HER2), ErbB-3, ErbB-4, FAK, FGF1R FGR-1), FGF2R FGR-2), IKK-1 IKK-ALPHA CHUK), IKK-2 IKK-BETA), MET c-MET), NIK, PDGF receptor ALPHA, PDGF receptor BETA, TIE1, TIE2 TEK), VEGFR1 FLT-1), VEGFR2 KDR), FLT-3, FLT-4, KIT, CSK, JAKI, JAK2, JAK3, TYK2, RIP, RIP-2, LOK, TAK1, RET, ALK, MLK3, COT, TRKA, PYK2, EPHB4, RON, GSK3, UL13, ORF47, ATM, CDK (including all subtypes), PKA, PKB (including all PKB subtypes) (=AKT-1, AKT-2, AKT-3), PKC (including all PKC subtypes), and bARKI (=GRK2) (and other G-protein coupled receptor kinases (GRKs)), and all subtypes of these kinases. The compounds and compositions of the invention are therefore also particularly suited for treatment of diseases and disease symptoms that involve one or more of the aforementioned protein kinases. In one embodiment, the compounds, compositions or methods of this invention are particularly suited for inhibition of or treatment of disease or disease symptoms mediated by LCK, ZAP, LYN, EGFR, ERB-B2, KDR, ITK, BTK, or SYK. In another embodiment, the compounds, compositions or methods of this invention are particularly suited for inhibition of or treatment of disease or disease symptoms mediated by src-family kinases. In another embodiment, the compounds, compositions or methods of this invention are particularly suited for inhibition of or treatment of disease or disease symptoms mediated by kinases in one of the kinase families defined by Hardie Hanks, ed. supra. The compounds and compositions are also suited for regulating or modulating signal transduction in signal WO 00/43373 PCT/US00/01581 transduction pathways that involve one or more kinases, thus affecting events in a cell, and are therefor useful in methods for regulating or modulating signal transduction.
The inhibitors described herein are also useful for inhibiting the biological activity of any enzyme comprising greater than 90%, alternatively greater than 85%, or alternatively greater than 70% sequence homology with a kinase sequence, including the kinases mentioned herein. The inhibitors described herein are also useful for inhibiting the biological activity of any enzyme comprising a subsequence, or variant thereof, of any enzyme that comprises greater than 90%, alternatively greater than 85%, or alternatively greater than 70% sequence homology with a kinase subsequence, including subsequences of the kinases mentioned herein. Such subsequence preferably comprises greater than alternatively greater than 85%, or alternatively greater than 70% sequence homology with the sequence of an active site or subdomain of a kinase enzyme. The subsequences, or variants thereof, comprise at least about 300, or alternatively at least about 200, amino acids.
The inhibitors described herein are useful for inhibiting the biological activity of any enzyme that binds ATP and thus for treating disease or disease symptoms mediated by any enzyme that binds ATP. The inhibitors described herein are also useful for inhibiting the biological activity of any enzyme that is involved in phosphotransfer and thus for treating disease or disease symptoms mediated by any enzyme that is involved in phosphotransfer. The inhibitors described herein are also useful for inhibiting the biological activity of a polypeptide or enzyme having sequence homology with a kinase sequence and thus for treating disease or disease symptoms mediated by such polypeptide or enzyme. Such polypeptides or enzymes may be identified by comparison of their sequence with kinase sequences and kinase catalytic domain sequences. For example, one method of comparison involves the database PROSITE (http://expasy.hcuge.ch), containing "signatures" or sequence patterns (or motifs) or profiles of protein families or domains. Thus, the inhibitors described herein are useful for inhibiting the biological activity of a polypeptide or enzyme comprising a sequence that comprises a "signature" or sequence pattern or profile derived for, and identified in PROSITE as relating to kinases, and for treating disease or disease symptoms mediated by such polypeptide or enzyme.
Examples of such PROSITE motifs or consensus patterns identified as relating to kinases include PS00107, PS00108, PS00109, PS50011, PS00915, and PS00916.
The compounds, compositions and methods described herein are useful in inhibiting kinase activity. As such, the compounds, compositions and methods of this WO 00/43373 PCT/US00/01581 invention are useful in treating kinase-mediated disease or disease symptoms in a mammal, particularly a human. Kinase mediated diseases are those wherein a protein kinase is involved in signaling, mediation, modulation, or regulation of the disease process. Kinase mediated diseases are exemplified by the following disease classes: cancer, autoimmunological, metabolic, inflammatory, infection (bacterial, viral, yeast, fungal, etc.), diseases of the central nervous system, degenerative neural disease, allergy/asthma, angiogenesis, neovascularization, vasculogenesis, cardiovascular, and the like.
The compounds, compositions and methods described herein are useful in treating or preventing diseases or their symptoms, including, transplant rejection kidney, liver, heart, lung, pancreas (islet cells), bone marrow, cornea, small bowel, skin allografts or xenografts), graft versus host disease, osteoarthritis, rheumatoid arthritis, multiple sclerosis, diabetes, diabetic retinopathy, asthma, inflammatory bowel disease (Crohn's disease, ulcerative colitis), renal disease, cachexia, septic shock, lupus, diabetes mellitus, myasthenia gravis, psoriasis, dermatitis, eczema, seborrhea, Alzheimer's disease, Parkinson's disease, stem cell protection during chemotherapy, ex vivo selection or ex vivo purging for autologous or allogeneic bone marrow transplantation, leukemia (acute myeloid, chronic myeloid, acute lymphoblastic, etc.), cancer (breast, lung, colorectal, ovary, prostate, renal, squamous cell, prostate, glioblastoma, melanoma, pancreatic, Kaposi's sarcoma, etc.), occular disease, retinopathies, macular degeneration, diabetic retinopathy), corneal disease, glaucoma, bacterial infections, viral infections, fungal infections and heart disease, including but not limited to, restenosis. In one embodiment, the compositions and methods described herein are useful in treating or preventing rheumatoid arthritis, transplant rejection, asthma or allergy, or their symptoms.
Another embodiment envisioned by this invention relates to the use of the kinase inhibitory compounds described herein for use as reagents that effectively bind to kinases.
As reagents, the compounds of this invention, and their derivatives, may be derivatized to bind to a stable resin as a tethered substrate for affinity chromatography applications.
The compounds of this invention, and their derivatives, may also be modified radiolabelled or affinity labelled, etc.) in order to utilize them in the investigation of enzyme or polypeptide characterization, structure, and/or function. These and other uses that characterize kinase inhibitors will be evident to those of ordinary skill in the art.
In another embodiment, the inhibitors described herein are useful for crystallizing or co-crystallizing with a protein kinase. Such crystals or crystal complexes may WO 00/43373 PCTIUS00/01581 additionally comprise additional peptides and or metal ions. The crystals or crystal complexes may be used for investigation and determination of enzyme characteristics including, for example, structure of the kinase enzyme, enzyme active site domains, and inhibitor-enzyme interactions. This information is useful in developing inhibitor compounds with modified characteristics and for understanding structure-function relationships of the enzymes and their enzyme-inhibitor interactions.
In an alternate embodiment, the inhibitory compounds described herein may be used as platforms or scaffolds which may be utilized in combinatorial chemistry techniques for preparation of derivatives and/or chemical libraries of compounds. Such derivatives and libraries of compounds have kinase inhibitory activity and are useful for identifying and designing compounds possessing kinase inhibitory activity.
Combinatorial techniques suitable for utilizing the compounds described herein are known in the art as exemplified by Obrecht, D. and Villalgrodo, Solid-Supported Combinatorial and Parallel Synthesis of Small-Molecular-Weight Compound Libraries, Pergamon-Elsevier Science Limited (1998), and include those such as the "split and pool" or "parallel" synthesis techniques, solid-phase and solution-phase techniques, and encoding techniques (see, for example, Czamik, Curr. Opin. Chem. Bio., (1997) 1, Thus, one embodiment relates to a method of using the compounds described in the formulae herein for generating derivatives or chemical libraries comprising: 1) providing a body comprising a plurality of wells; 2) providing one or more compounds of the formulae described herein in each well; 3) providing an additional one or more chemicals in each well; 4) isolating the resulting one or more products from each well. An alternate embodiment relates to a method of using the compounds described in the formulae herein for generating derivatives or chemical libraries comprising: 1) providing one or more compounds of the formulae described herein attached to a solid support; 2) treating the one or more compounds of the formulae described herein attached to a solid support with one or more additional chemicals; 3) isolating the resulting one or more products from the solid support. In the methods described above, "tags" or identifier or labeling moieties may be attached to and/or detached from the compounds of the formulae herein or their derivatives, to facilitate tracking, identification or isolation of the desired products or their intermediates. Such moieties are known in the art. The chemicals used in the aforementioned methods may include, for example, solvents, reagents, catalysts, protecting group and deprotecting group reagents and the like. Examples of such WO 00/43373 PCT/US00/01581 chemicals are those that appear in the various synthetic and protecting group chemistry texts and treatises referenced herein.
The compounds of the formulae herein may be used to study the mechanism and role of proteins in biological pathways and processes involving kinases. The compounds of the formulae herein may also be used as probes to identify new kinase enzymes or polypeptides with sequence homology to kinases. The inhibitor compounds may be tethered to a support or modified tagged, radiolabeled or other identifiable detection method) such that the compound may be detected and isolated in the presence of the kinase enzyme or polypeptide. Thus, another embodiment relates to a method of identifying and/or isolating a kinase enzyme or polypeptide with sequence homology to a kinase enzyme sequence or subsequence, comprising, contacting a tethered or modified compound of any of the formulae herein with one or more polypeptides, isolating a polypeptide/inhibitor complex, and identifying or isolating the sequence of the polypeptide in the polypeptide/inhibitor complex. The identification of the polypeptide sequence may be performed while in the polypeptide/inhibitor complex or after the polypeptide is decomplexed from the tethered or modified compound of any of the formulae herein.
Table 1 lists representative individual compounds of the invention and compounds employed in the compositions and methods of this invention.
WO 00/43373 WO 0043373PCTUSOO/O1 581 Table 1 2 NH cl NN
N"C
H
0
NHN
N~ ;ii HI N "C NH ci N N Nj i;
H
~NH
I N
H
N N'aN~ I H 0, 78 No 0 Ij), N
I
0~
H
N4C
H
WO 00/43373 PCT/USOO/01581 11 12
N
c C NH N N N
H,
N N 0 0H 13 14 0
N
4 NH C -C C! *l NH N N N- N I H
H
0- N+ H 16 N 4 c 0 I
N
4 0 c
NNN
H H Br 17 18 N 0 N H N N' N NN"f 0 0 0 N CN NH l
H
N01M
H
H 0) 1 WO 00/43373 WO 0043373PCT/USOO/01581 21N 0 H l2
N
4 0c N 21 NariC 22 N N
H
3 C 23 24 N Oc N01 cl NNH
CI
HN N N N N OC NH 26 Noc 0 H N H N ,t N H N 27 N 0 28 N 4 0 CN H
INH
N NN NN NN N' H N~ N 29 0 30 H~ 29 NI H 3
N
0 H
H
WO 00/43373 WO 0043373PCTIUSOO/01581 N N CH3 I&
H
N
OC
NN
0H 33 37 39
-NH
'N N 0
N
H K 0 WO 00/43373 WO 0043373PCTUSOO/01581 41 0
H
47 "'0
S.'
"N
0
H
49
HN'
(N_ I WO 00/43373PC/SO058 PCT/USOO/01581 52NH 0 N N N N&
H
IH
54 0NHc 0 N H
HH
56
H
3
C
Nc 0 57 -C N H N 0 N K- H H
H
59 Nc OC
NH
0 N N' H
NJ;
H
CI
N N
H
WO 00/43373PCISO058 PCTIUSOO/01581 61 0
H
N
63
H
H cl
H
HN~
WO 00/43373PCIS/I58 PCT/USOO/01581 IH l SNi:)
H
73 Nc cI 0 HO N
NH
2
H
WO 00/43373 WO 0043373PCT/USOO/01581 81 0
H
2
N')N'
H
NOC,
LNH cl I Na
H
I.
HN,
NCH3Nc
NH-
HN
-J I H
N
WO 00/43373 PCTUSOO/01581 91 H N KI 92 F o=s=o
K
H H
H
3 C
H
CI
93 0 94 N 0 c NH ~CI NH ja-' c NNA N N H H HN NH HNy-,.NH 2 0 0 0 Nc clN, N H 96 CI 96H N N H 'H N N I H
HNH
HN NH 2 N NH 0 H Nc 98 N c NH 97 NH cl NH
NN
N N' a
NHN
I Ht 2 N NHHN 0 0 N 00 C NH 100 N 0 N NNH
HN
N Nj H I H HNN 0C WO 00/43373 WO 0043373PCTUSOO/01 581 101 NC NHIl12N)
NN
H 0. N H NP H3C
VN
I
H
NH N N N N N H
H
3 C 0\ N H 0N0
SNS
0 0 i-NH NH ci 106 NNHCc
NN
NANNa N H H H N X NH HN0 00 N c c 107 N N N 18N H N
H
HN 0 CH3
N
H
3 C -N00
H
3 C CH 3 N RC N HfjCI 109 N~ _zrA 110 1N WO 00/43373 WO 0043373PCTUSOO/01 581
H
H
3 C 113 114 F iN N 1 lS H 115 116 I~ N S Na- K-0 117 118 N a
NH
N N C
H
119 120
H
3
C.
WO 00/43373 WO 0043373PCT/USOO/OI 581 121 0 122 0 NH NH N N' H N 1 -1N' H IH 123 124 C~O NHNHI NN NN I H N N I H
N
F F F
H
3
C
125 126 I~ HIN~ N: NN> 0KI
H
3 C I H <N
H
3 C CH 3 (0; 127 128 NH, c N~ -C N C: NHN N N H I H N~F
F
129 130 N 0 N 0 c J -l r WO 00/43373 PTUO/18 PCT/USOO/01581 132 N "c.
CI
H
134 NH
C
N
H
C
ul
N
135 136
CI
137 138 N Oc
NHCI
I H
N
0
H
139
H
CI
0 YI H WO 00/43373 WO 0043373PCT/USOO/01581 .f CI
H
0 HO N
H
143 146 ci 0 2
N.
150
H
YO 0
HN
0 WO 00/43373 WO 0043373PCT/USOO/01 581 'Ni
H
N0 2 156
NN
H
CI
0 H2N
N
YI-H
0 159
"Y
WO 00/43373 WO 0043373PCTUSOO/01581 162 N. N N~f: I H
N
HN
/\O
0a 165 167 166 H l
SN"(
H
168 170 *NH l
N
H
WO 00/43373 WO 0043373PCT/USOO/01581 171 N C 1 0 N l172 N ,C 0 N N~ N C Nc N NH N 0 N N' NN
N
NN H rya OMe 0 OMe 173 N -1 NH c 174 N c 0 H NAN NI H 0 N N 0 I H H Nr N 0 0 175 176 1 NH, C NH N N*N aN H 0 NN Na 0 N' N HN N H 0 177 178 -c N H N I10C N ci H H Nj OMe
N
HN aMO&
H
0 179 180 NN H c 0 H ci N N' H 0 N NN I H HN H 0 Br Br WO 00/43373 WO 0043373PCTIUSOO/01 581 181 N 0 NH I 182 N,,C 0
NN
N H 0 N HN N H N O 1 183 N C 0N 14N" 0 18 NN0 H
N
HN /\NHH
N
o H N0 2 N0 2 1 8 Ic 0 N l1 8 6 N 0 N NN 0 N H
NN
O H 187 1880 N N 0 'l do N HH
HNH
0N 0 189 190
I
HN
WO 00/43373PCIS /058 PCTIUSOO/01581 192
H
194 196 0 Me N'
H
198
H
200 0 0 e WO 00/43373 WO 0043373PCT/USOO/01581 202 0
N'
203 204 205 NH
I
N N N
N
I H
HN
o OMe N N N I H HN N '-r-O-OMe 0 OMe 0 N N
IH
H I c SN'j
H
208 209 210 N 0 N
H
HNI
0 0 N
N
N H WO 00/43373 WO 0043373PCTUSOO/OI 581 213 *1 c *Ni
H
-I -s CI
N
H
H
215 216 217 219 220 N 0AN NN N
H
0
H
N.c 0 4 NH -s Ci 0 N N'J I H N. N N H
H
WO 00/43373 WO 0043373PCTIUSOO/O1 581 H l Nf
H
222
N.
I
H
224 0 N NiN)
H
0 2 N Nj~:
HN-N
226 225 N
-C,
227 228 'NH c CI N
OC.
CI
N
H
229 0 0 2 N N r S e WO 00/43373 PCTIUSOO/O1 581 232 N NH l 0 N N I H I H 234 N 4c NH~~
CI
0 N N J I H 0 2 N '\N \I H 236 235 238 240 NH l SN N J I H HN,, s 0 IH cl
H
0 -S
H
WO 00/43373 WO 0043373PCTIUSOO/OI 581 -1C NH l
HN
_N I Y-1H 0
NH
245 246
NOC.
0
S/-
247 248
CI
'Ni
H
249 N c N H
C
HNH
N 0 0 0 N W0
N.
Io
H
0 WO 00/43373 WO 0043373PCTUSOO/O1 581 LNH l I Na
H
NC
NHCI
U0 N N
H
N
H
'NH l Na
H
0
H
255 256 ao 258 N
'C,
H
y
NNH
259 N N N S MeG NN
H
MeG WO 00/43373 WO 0043373PCTIUSOO/01 581 N~ N -p MeO 1 No<N
N
N OMe N OMe
H
264 N 0 NH SMe
H
MeO ,OMe 269
NH
2 WO 00/43373 WO 0043373PCT/USOO/0I 581 N, 0 NH N N OH
H
MeO 274 275 OMe N -C NHNIII SMe
H
MeO -t 280
NN
MeOj~ WO 00/43373 WO 0043373PCTIUSOO/01581 0 OMe 283 284
.NIZU
H
286 'N~aF
H
N C I NH _p 'N N) MeO H c 290 WO 00/43373 WO 0043373PCTIUSOO/01581 294 N
-C.
N OBr pZ I 1 C F NH
J
N~ N 5 N MeO
H
298
NH
N NCN
H
MeO -l 299
H
N~ ome 0 WO 00/43373 WO 0043373PCTIUSOO/01581 301 302 Nc NH Nc 0 NH
NH
MeOj; MeO;-
H
303 304 N C HN c NH -OMe SN NP <N MeO HSMe Ne N 305 306 N NN I H O N -N H
H
307 308 N N H r i c I C, c HCI NNNN H N N I oI H i H t NH 2 N N H H 309 310 No 0N H CI N c 0NH CI N N~ N N' H
H
NH
2 Ho-- H N N H 0 o") WO 00/43373 WO 0043373PCT/USOO/O1 581 311 312 N O H HlNOCc ON ON'c H
H
3 1 3 N Ho 3 1 4 N I Hc N N cia NN- N N N H N JN H
H
HN HN 0 0 3157 316 N 0 Br NH
BNN
N: H N NH I H WO 00/43373 PCT/US00/01581 Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds. The term "stable", as used herein, refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein therapeutic or prophylactic administration to a mammal or for use in affinity chromatography applications). Typically, such compounds are stable at a temperature of 40 oC or less, in the absence of excessive moisture for at least one week.
As used herein, the compounds of this invention, including the compounds of formulae described herein, are defined to include pharmaceutically acceptable derivatives or prodrugs thereof. A "pharmaceutically acceptable derivative or prodrug" means any pharmaceutically acceptable salt, ester, salt of an ester, or other derivative of a compound of this invention which, upon administration to a recipient, is capable of providing (directly or indirectly) a compound of this invention. Particularly favored derivatives and prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a mammal by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment the brain or lymphatic system) relative to the parent species. Preferred prodrugs include derivatives where a group which enhances aqueous solubility or active transport through the gut membrane is appended to the structure of formulae described herein.
Pharmaceutically acceptable salts of the compounds of this invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases.
Examples of suitable acid salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, tosylate and undecanoate.
Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts. Salts derived WO 00/43373 PCT/US00/01581 from appropriate bases include alkali metal sodium), alkaline earth metal magnesium), ammonium and N-(alkyl)4 salts. This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quatemrnization.
The compounds of this invention may be synthesized using conventional techniques. Advantageously, these compounds are conveniently synthesized from readily available starting materials. In general, the compounds of the formulae described herein are conveniently obtained via methods illustrated in General Synthetic Schemes I-IV and the Examples herein. These general schemes are also exemplified by the specific methods described in the Examples section below.
Thus, one embodiment relates to a method of making a compound of the formulae described herein, comprising synthesizing any one or more intermediates illustrated in the synthetic schemes herein and then converting that intermediate(s) to a compound of the formulae described herein. Another embodiment relates to a method of making a compound of the formulae described herein, comprising synthesizing any one or more intermediates illustrated in the examples herein and then converting that intermediate(s) to a compound of the formulae described herein. Another embodiment relates to a method of making a compound of the formulae described herein, comprising synthesizing any one or more intermediates illustrated in the synthetic schemes herein and then converting that intermediate(s) to a compound of the formulae described herein utilizing one or more of the chemical reactions described in the synthetic schemes or examples herein.
Nucleophilic agents are known in the art and are described in the chemical texts and treatises referred to herein. The chemicals used in the aforementioned methods may include, for example, solvents, reagents, catalysts, protecting group and deprotecting group reagents and the like. The methods described above may also additionally comprise steps, either before or after the steps described specifically herein, to add or remove suitable protecting groups in order to ultimately allow synthesis of the compound of the formulae described herein.
WO 00/43373PCUS /058 PCTIUSOO/01581 General Synthetic Scheme I
NC,,CO
2 Et CHO
NH
2 L) N Si 0 0 NC NH NC NH N SMe N .*R Pyridine RNH H General Synthetic Scheme 11 NCC0 2 Et SCHO
NH
2 r 1 X MeS NH x
P
S4 0 0 NC NH NC H A N IlkSMe A N NR Pyridine /-RNH 2 H x x 'P S5 -P S6 Deprotection 0 NC~r
NH
N N ,N'
H
x S8 0 NC
NH
alkylation or N N N* acylation etc. H
(H)
S7 Where X N, 0, S; P suitable protecting group and alkyl or acyl WO 00/43373 WO 0043373PCT/USOO/01581 General Synthetic Scheme III 0 0 S9 R 3 >A-0Et
A
R1NH 2 Pyridine MeSl, NH 0 R' N SMe
A
RNH
2 0 R1INH
YK),R
R
3 N N*
H
511 510 General Synthetic Scheme IV 0 0 S9 R 3 A(lkoEt R1NH 2
H
2 N -LS
A
NaOEt Ethanol 1) K2C0 3 Mel
DMF
2) RNH 2 0
R
1 N<IkNH A Nj, R R ~N N
H
S12 WO 00/43373 PCT/US00/01581 In General Synthetic Scheme I, an appropriate benzaldehyde (SI) is converted to pyrimidinone S2 by reaction with an appropriate cyanoacetate (or equivalent) Smethylisothiouronium sulphate. Pyrimidinone S2 may be reacted with a substituted aniline or amine to form pyrimidinone S3.
In a similar fashion, as illustrated in General Synthetic Scheme II, a protected benzaldehyde (S4) may be reacted under the same conditions to provide pyrimidinone Pyrimidinone S5 can be subsequently reacted with an aniline, amine or other appropriate heteroatom nucleophile to provide pyrimidinone S6. Subsequent deprotection (S7) and functionalization of the resultant heteroatom provides S8.
Alternatively, as shown in General Synthetic Scheme III, an appropriately substituted p-ketoester (S9) can be condensed under similar conditions with Smethylisothiouronium sulphate to afford pyrimidinone S10. Nucleophilic addition to then provides S11. Additionally, as illustrated in General Synthetic Scheme IV, an appropriately substituted 0 -ketoester (S9) can be condensed with thiourea to afford S12.
Subsequent sulfur alkylation and nucleophilic addition provides pryimidinone S13.
Thus, one embodiment relates to a method of making a compound of the formulae described herein, comprising 1) the step of reacting an aldehyde (or equivalent) with a cyanoacetate (or equivalent) and an alkylisothiouronium salt to form a pyrimidinone; 2) reacting said pyrimidinone with a nucleophilic agent an aniline or amine) to form the compound of the formulae described herein. Nucleophilic agents are known in the art and are described in the chemical texts and treatises referred to herein. Such agents may have carbon or a heteroatom N, O, S) as the nucleophilic atom. In an alternate embodiment, the method of making a compound of the formulae described herein, comprises 1) preparation of a thio-substituted pyrimidone intermediate (as exemplified by S2, S5, S10 and S12 in the General Synthetic Schemes); and 2) reacting the pyrimidinone of step 1 with another chemical to form the compound of the formulae described herein.
The chemicals used in the aforementioned methods may include, for example, solvents, reagents, catalysts, protecting group and deprotecting group reagents and the like. The methods described above may also additionally comprise steps, either before or after steps 1 and 2 described above, to add or remove suitable protecting groups in order to ultimately allow synthesis of the compound of the formulae described herein.
As can be appreciated by the skilled artisan, the above synthetic schemes are not intended to comprise a comprehensive list of all means by which the compounds WO 00/43373 PCT/US00/01581 described and claimed in this application may be synthesized. Further methods will be evident to those of ordinary skill in the art. Additionally, the various synthetic steps described above may be performed in an alternate sequence or order to give the desired compounds. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the inhibitor compounds described herein are known in the art and include, for example, those such as described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia ofReagents for Organic Synthesis, John Wiley and Sons (1995).
The compounds of this invention may be modified by appending appropriate functionalities to enhance selective biological properties. Such modifications are known in the art and include those which increase biological penetration into a given biological compartment blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.
The novel compounds of the present invention are excellent ligands for protein kinases, subsequences thereof, and homologous polypeptides. Accordingly, these compounds are capable of targeting and inhibiting kinase enzyme and subsequences thereof. Inhibition can be measured by various methods, including, for example, those methods illustrated in the examples below. The compounds described herein may be used in assays, including radiolabelled, antibody detection and fluorometric, for the isolation, identification, or structural or functional characterization of enzymes, peptides or polypeptides. Such assays include any assay wherein a nucleoside or nucleotide are cofactors or substrates of the peptide of interest, and particularly any assay involving phosphotransfer in which the substrates and or cofactors are ATP, GTP, Mg, Mn, peptides or polymeric amino acids.
Pharmaceutical compositions of this invention comprise a compound of the formulae described herein or a pharmaceutically acceptable salt thereof; an additional agent selected from an immunosuppressant, an anticancer agent, an anti-viral agent, antiinflammatory agent, antifungal agent, antibiotic, or an anti-vascular hyperproliferation compound; and any pharmaceutically acceptable carrier, adjuvant or vehicle. Alternate WO 00/43373 PCT/US00/01581 compositions of this invention comprise a compound of the formulae described herein or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier, adjuvant or vehicle. Such compositions may optionally comprise additional therapeutic agents, including, for example, immunosuppressants, anti-cancer agents, anti-viral agents, antiinflammatory agents, antifungal agents, antibiotics, or anti-vascular hyperproliferation compounds.
The term "pharmaceutically acceptable carrier or adjuvant" refers to a carrier or adjuvant that may be administered to a patient, together with a compound of this invention, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound.
Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-a-tocopherol polyethyleneglycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
Cyclodextrins such as and y-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-p-cyclodextrins, or other solubilized derivatives may also be advantageously used to enhance delivery of compounds of the formulae described herein.
The pharmaceutical compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir, preferably by oral administration or administration by injection. The pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles. In some cases, the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to WO 00/43373 PCTIUSOO/01581 enhance the stability of the formulated compound or its delivery form. The term parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasteral, intrathecal, intralesional and intracranial injection or infusion techniques.
The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents.
The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and or suspensions. Other commonly used surfactants such as Tweens or Spans and/or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
The pharmaceutical compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions and/or emulsions are administered orally, the active ingredient may be suspended or dissolved in an oily phase is combined with emulsifying and/or suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.
WO 00/43373 PCT/US00/01581 The pharmaceutical compositions of this invention may also be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.
Topical administration of the pharmaceutical compositions of this invention is especially useful when the desired treatment involves areas or organs readily accessible by topical application. For application topically to the skin, the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier with suitable emulsifying agents. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The pharmaceutical compositions of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topicallytransdermal patches are also included in this invention.
The pharmaceutical compositions of this invention may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques wellknown in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
Dosage levels of between about 0.01 and about 100 mg/kg body weight per day, alternatively between about 0.5 and about 75 mg/kg body weight per day of the kinase inhibitory compounds described herein are useful in a monotherapy and/or in combination therapy for the prevention and treatment of kinase mediated disease.
Typically, the pharmaceutical compositions of this invention will be administered from about 1 to about 6 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy. The amount of active ingredient WO 00/43373 PCT/US00/01581 that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. A typical preparation will contain from about 5% to about 95% active compound Alternatively, such preparations contain from about 20% to about 80% active compound.
When the compositions of this invention comprise a combination of a kinase inhibitor of the formulae described herein and one or more additional therapeutic or prophylactic agents, both the kinase inhibitor and the additional agent should be present at dosage levels of between about 10 to 100%, and more preferably between about 10 to of the dosage normally administered in a monotherapy regimen. The additional agents may be administered separately, as part of a multiple dose regimen, from the compounds of this invention. Alternatively, those agents may be part of a single dosage form, mixed together with the compounds of this invention in a single composition.
According to one embodiment, the pharmaceutical compositions of this invention comprise an additional immunosuppression agent. Examples of additional immunosuppression agents include, but are not limited to, cyclosporin A, FK506, rapamycin, leflunomide, deoxyspergualin, prednisone, azathioprine, mycophenolate mofetil, OKT3, ATAG, interferon and mizoribine.
According to an alternate embodiment, the pharmaceutical compositions of this invention may additionally comprise cytotoxic or hormonal anti-cancer agents or combinations thereof. Examples of anti-cancer agents include, but are not limited to, cisplatin, actinomycin D, doxorubicin, vincristine, vinblastine, etoposide, amsacrine, mitoxantrone, tenipaside, taxol, taxotere, colchicine, cyclosporin A, phenothiazines, interferons, thioxantheres, anti-estrogens tamoxifen), aromatase inhibitors, antiandrogens, and LHRH antagonists.
According to another alternate embodiment, the pharmaceutical compositions of this invention may additionally comprise an anti-viral agent. Examples of anti-viral agents include, but are not limited to, Cytovene, Ganciclovir, trisodium phosphonoformate, Ribavirin, d4T, ddl, AZT, amprenavir and acyclovir.
Upon improvement of a patient's condition, a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary.
Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level, treatment should cease. Patients may, WO 00/43373 PCT/US00/01581 however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.
As the skilled artisan will appreciate, lower or higher doses than those recited above may be required. Specific dosage and treatment regimens for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition or symptoms, the patient's disposition to the disease, condition or symptoms, and the judgment of the treating physician.
In an alternate embodiment, this invention provides methods of treating, preventing, or relieving symptoms of disease in a mammal comprising the step of administrating to said mammal any of the pharmaceutical compositions and combinations described above. Preferably, the mammal is a human. If the pharmaceutical composition only comprises the inhibitor of this invention as the active component, such methods may additionally comprise the step of administering to said mammal an additional therapeutic agent, such as an antiinflammatory agent, immunosuppressant, an anti-cancer agent, an anti-viral agent, or an anti-vascular hyperproliferation compound. Such additional agent may be administered to the mammal prior to, concurrently with, or following the administration of the inhibitor composition.
The compounds of this invention may contain one or more asymmetric centers and thus occur as racemates and racemic mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures. All such isomeric forms of these compounds are expressly included in the present invention. The compounds of this invention may also be represented in multiple tautomeric forms, for example, as illustrated below: X XH
X
R R N R1 NH NN R N R2 R N.:<R2 R N R
H
in such instances, the invention expressly includes all tautomeric forms of the compounds described herein. The compounds may also occur in cis- or trans- or E- or Z- double WO 00/43373 PCT/US00/01581 bond isomeric forms. All such isomeric forms of such compounds are expressly included in the present invention. All crystal forms of the compounds described herein are expressly included in the present invention.
Substituents on ring moieties phenyl, thienyl, etc.) may be attached to specific atoms, whereby they are intended to be fixed to that atom, or they may be drawn unattached to a specific atom (see below), whereby they are intended to be attached at any available atom that is not already substituted by an atom other than H (hydrogen). For example, a structure drawn as: is intended to encompass all of the following structures:
RB
115 B 15 15 1 All references cited herein, whether in print, electronic, computer readable storage media or other form, are expressly incorporated by reference in their entirety, including but not limited to, abstracts, articles, journals, publications, texts, treatises, intemrnet web sites, databases, patents, and patent publications.
In order that the invention described herein may be more readily understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this invention in any manner. NMR and MS spectra obtained for compounds described in the examples below and those described herein were consistent with that of the compounds of the formulae herein.
WO 00/43373 PCT/US00/01581 Example 1
O
CHO NH NC NH OC 2N+ S e
NCCO
2 Et Pyridine
H
2 N SMe NaOAc N S To a mixture of 1.39g (5 mmol) S-methylisothiouronium sulphate and 1.36g (1.22mL; 10 mmol) in 50 mL of dry pyridine is added 1.13g (1.06 mL; 10 mmol) of ethylcyano acetate and 5 g (61mmol) of anhydrous sodium acetate. The mixture is refluxed (135 0 C) under calcium carbonate for 4 hours. The resultant mixture is cooled and filtered under vacuum and the filtrate evaporated under high-vac. The solid product is suspended in glacial acetic acid and the resulting suspension was evaporated under high-vac. The solid is then suspended in dichloromethane, filtered, and is washed with excess dichloromethane to provide product of purity sufficient for subsequent manipulations.
WO 00/43373 PCT/US00/01581 Example 2 O O NC NH NC N c1 SN .S p-Chloroaniline NC NH A mixture of 25 mg (.09 mmol) of the product from Example 1 and 200 mg of pchloroaniline is heated by heat gun until a homogeneous solution is obtained. The reaction is heated at 170 0 C until such time as the solution solidifies. The product is broken up and suspended in dichloromethane and filtered while washing with excess dichloromethane.
Example 3
O
0 0 0 NH 2 Pyridine NH I 'A OEt HN-SMe NaOAc N SMe 0 "IO To a solution of 360 mg (1.6 mmol) of ketoester in 5 mL of anhydrous pyridine is added 451 mg (1.6 mmol) of S-methylisothiouronium sulphate and 1.33 g (16.2 mmol) of anhydrous sodium acetate. The mixture is refluxed (135 0 C) under calcium carbonate for 7 hours. The resultant mixture is cooled and filtered under vacuum and the filtrate evaporated under high-vac. The solid product is suspended in glacial acetic acid and the resulting suspension is evaporated under high-vac. The solid is then re-suspended in diethylether, filtered, and washed with excess diethylether to provide product of purity sufficient for subsequent manipulations.
WO 00/43373 PCT/US00/01581 Example 4
O
00 OE NH 2 NaOEt NH N X j 0 8
H
2 N S
H
A dry two-necked flask fitted with reflux condenser is charged, under argon, with 126 mg (5.5 mmol) sodium metal and 3 mL absolute ethanol. The sodium is dissolved with mild heating over about one hour. To this solution is added 292 mg (3.8 mmol) of thiourea. After brief stirring, 646 mg (2.7 mmol) ketoester in one mL absolute ethanol is added followed by an additional one mL of absolute ethanol containing residual ketoester from the transfer vessel. The solution is refluxed for five hours at which time it is cooled and evaporated to dryness. The residue is taken up in water, neutralized with glacial acetic acid, and extracted into ethyl acetate (2 X 25mL). The organic layer is separated, dried over magnesium sulfate, filtered, and evaporated under vacuum. The residue is recrystallized from ethanol to yield pure product.
Example O
O
NH NH H Y -Mel To a solution of 161 mg (0.65 mmol) of pyrimidinone in 5 mL of DMF is added 90 mg (0.65 mmol) pulverized potassium carbonate and 44 (0.70 mmol) of methyl iodide. The suspension is stirred under argon for one hour at which point it is added to water (5 mL). The water is extracted with ethyl acetate (2 X 25 mL) and the organic layer is dried over magnesium sulfate, filtered and evaporated under vacuum. The resulting residue is of sufficient purity to be utilized directly in subsequent reactions.
WO 00/43373 PCT/US00/01581 Example 6 0 0 O O H 1 H To a solution of 39 mg (0.12 mmol) pyrimidinone in 1 mL of DMF is added 21 mg (0.12 mmol) N-bromosuccinimide. After stirring for 5 minutes, the reaction is quenched with a few drops of saturated aqueous sodium bisulfite. The solution is then diluted with ethyl acetate and the resulting precipitate is filtered to provide pure bromide.
The ethyl acetate is washed with water (2 X 2 mL), dried over magnesium sulfate, filtered, and evaporated under vacuum to provide additional crude product.
Example 7 The inhibitor compounds described herein are screened in the following manner.
Kinases suitable for use in the following protocol to determine kinase activity of the compounds described herein include, but are not limited to: Lck, Lyn, Src, Fyn, Syk, Zap- Itk, Tec, Btk, EGFR, ErbB2, Kdr, Fit-i, Flt-3, Tek, c-Met, InsR.
Kinases are expressed as either kinase domains or full length constructs fused to glutathione S-transferase (GST) or polyHistidine tagged fusion proteins in either E. coli or Baculovirus-High Five expression systems. They are purified to near homogeneity by affinity chromatography essentially as previously described (Lehr et al., 1996; Gish et al., 1995). In some instances, kinases are co-expressed or mixed with purified or partially purified regulatory polypeptides prior to measurement of activity.
Kinase activity and inhibition are measured essentially by established protocols (Braunwalder et al., 1996). Briefly, The transfer of 33 P0 4 from ATP to the synthetic substrates poly(Glu, Tyr) 4:1 or poly(Arg, Ser) 3:1 attached to the bioactive surface of microtiter plates serves as the basis to evaluate enzyme activity. After an incubation period, the amount of phosphate transferred is measured by first washing the plate with phosphoric acid, adding liquid scintillant, and then counting in a liquid scintillation WO 00/43373 PCT/US00/01581 detector. The ICso is determined by the concentration of compound that causes a reduction in the amount of 33 incorporated onto the substrate bound to the plate.
Other similar methods whereby phosphate is transferred to peptide or polypeptide substrate containing tyrosine, serine, threonine, or histidine, either alone, in combination, or in combination with other amino acids, in solution or immobilized solid phase) are also useful. Alternatively, kinase activity can be measured using antibody-based methods whereby an antibody or polypeptide is used as a reagent to detect phosphorylated target polypeptide. The compounds of the invention described herein are potent and selective kinase inhibitors as demonstrated by representative compounds described herein that inhibit one or more kinases with ICso values at less than about 5 PiM or greater, at less than about 1 ptM, or at less than about 300 nM.
References: Braunwalder AF, Yarwood DR, Hall T, Missbach M, Lipson KE, Sills MA. (1996). A solid-phase assay for the determination of protein tyrosine kinase activity of c-src using scintillating microtitration plates. Anal. Biochem. 234(1):23-26.
Gish G, McGlone ML, Pawson T, Adams JA. (1995). Bacterial expression, purification and preliminary kinetic description of the kinase domain of v-fps._Protein Eng. 8(6):609- 614.
Lehr RV, Ma YG, Kratz D, Brake PG, Wang S, Faltynek CR, Wang XM, Stevis PE (1996). Production, purification and characterization of non-myristylated human T-cell protein tyrosine kinase in a baculovirus expression system. Gene 169(2):27527-9.
Example 8 The cellular activities of the inhibitor compounds described herein may be assessed in a number of assays known to those skilled in the art, some of which are exemplified as described below. Typical sources for cells include, but are not limited to, human bone marrow or peripheral blood lymphocytes, or their equivalents, or rodent spleen cells. Transformed cell lines that have been reported as cytokine- and growth factor-dependent cells are available from standard cell banks such as The American Type Culture Collection (Bethesda, MD). Cells genetically manipulated to express a particular kinase or kinases are also suitable for use in assaying cellular activity. These cells are WO 00/43373 PCT/US00/01581 grown in various standard tissue culture media available from suppliers such as GIBCO/BRL (Grand Island, NY) supplemented with fetal bovine serum. Cellular activity may also be measured using bacterial, yeast, or virally infected mammalian cells.
Standard inhibitors of cell activation include mycophenolic acid (SIGMA, St. Louis, MO), staurosporine (Calbiochem, San Diego, CA), wortmannin (Calbiochem), cyclosporine, FK-506, and steroids corticosteroids).
The compound(s) are tested for activity in cellular assays of T or B cell activation.
For example, the receptor-induced production of cytokines and/or cell proliferation is a useful measure. This assay is performed similarly to techniques described in the literature and involves antibody-, antigen-, mitogen-, or antigen presenting cell-mediated crosslinking of the T cell or B cell receptor with or without engagement of co-stimulatory receptors.
The compound(s) are tested for activity in cellular assays of allergic mediator release. For example, the receptor-induced degranulation in mast cells or basophils leading to histamine release and the production of cytokines is a useful measure. This assay is performed similarly to techniques described in the literature and involves crosslinking of antigen-specific IgE on cells leading to degranulation and or cytokine production.
The compound(s) are tested for activity in cellular assays of growth factor effects.
For example, growth factor receptor-induced signaling in a cell leading to intracellular signaling events such as kinase autophosphorylation, phosphorylation of relevant kinase substrates, phosphorylation of MAP kinases, or induction of gene expression. Also, for example, growth factor-induced functional events in cells such as DNA synthesis, proliferation, migration, or apoptosis. These assays are performed similarly to techniques described in the literature and involve addition of growth factor to responsive cells followed by monitoring of signaling or functional events.
The compound(s) are tested for activity in cellular assays of cytokine activation.
For example, cytokine-induced intracellular signaling events and/or cell proliferation and/or cytokine production are a useful measure. This assay is performed similarly to techniques described in the literature and involves addition of cytokine to responsive cells followed by monitoring intracellular signaling events and/or cell proliferation and/or cytokine production.
References: WO 00/43373 PCT/US00/01581 1. Shuji, et al. Activation of p21-CDC42/Rac-activated kinases by CD28 signaling: p21-activated kinase (PAK) and MEK kinase 1 (MEKK1) may mediate the interplay between CD3 and CD28 signals. J. Immunol. 160: 4182-4189 (1998).
2. Satterthwaite, et al., Independent and opposing roles for Btk and Lyn in B cell and myeloid signaling pathways. J. Exp. Med. 188: 833-844 (1998).
3. Stephan, et al. FcRl-induced protein tyrosine phosphorylation of pp72 in rat basophilic leukemia cells (RBL-2H3). J. Biol. Chem. 267 5434-5441 (1992).
4. Olayioye, et al. ErbB-1 and ErbB-2 acquire distinct signaling properties dependent upon their dimerization partner. Molecular and Cellular Biology. 18(9): 5042-5051 (1998).
5. Buchdunger, et al. Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative. CancerRes. 56;101-104 (1996).
6. Yoshida, A. et al., Differential endothelial migration and proliferation to basic fibroblast growth factor and vascular endothelial growth factor. Growth Factors.
13:57-64 (1996).
7. Brunet, et al., Akt promotes cell survival by phosphorylating and inhibiting a forkhead transcription factor. Cell. 96:857-868 (1999).
8. Liu, et al. Janus kinases in interleukin-2-mediated signaling: JAK1 and JAK3 are differentially regulated by tyrosine phosphorylation. Current Biology. 7 817-826 (1997).
While we have described a number of embodiments of this invention, it is apparent that our basic examples may be altered to provide other embodiments that utilize the products and processes of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the claims rather than by the specific embodiments that have been represented by way of example.

Claims (1)

  1. 87- THE CLAIMS DEFINING TBlE INVENTION ARE AS FOLLOWS:- 1 A compound of the formula: or a pharmaceutically acceptable salt thereof, wherein R is NH-ary; R 3 is phenyl substituted with 1-3 independent R 4 wherein each R 4 is independently selected from H, Ci-ClO alkyl; C2-ClO alkenyl; C2-ClO alkynyl; C3- CIO cycloalkyl; C4-C1O cycloallcenyl; aryl; R 8 halo; haloalkyl; S5; ORW; NR 5 R; dOOR 5 NO 2 CN; C(O)R 5 C(O)C(O)R 5 C(O)NR 5 R 5 OC(O)R 5 S(O) 2 R 5 S(O) 2 NR 5 R 5 NR 5 C(O)NR 5 R 5 NR 5 C(O)d(O)R 5 NR 5 C(O)R 5 NR 5 (COOR'); NR 5 C(O)R 8 NR 5 S(O) 2 NRR; NR 5 S(O) 2 R 5 NR 5 S(O) 2 R 8 -7 0 88 S NR 5 CO)C()NR N C(QC()R R; Cl-C 10 alkyl substituted with aryl, R7 or R ;or ClI-C 1 alkenyl subs tituted with aryl, R7 or R;9 Each R 5 is indePendently Cl-Cia alkyl; C2-CIO alkenyl; C2-CIO alkynyl; C3-CIO cycloalkyl; C4.-CIO cycloalkenyl; aryl; R 9 ;C CIakysustte with 1-3 independent aryl, R or R 9 gro~ups; C3-CIO cycloalkcyl substituted with 1-3- independent aryl, R 7or R 9groups; or CI-CIO alkenyl subst ituted with 1-3 independent 7 9 aryl, Ror R 6 5 5 Each R is independently C(O)R COOR or S(0)2 R; 7 10 10 10 -10 Each Ris independently halo, CF3, SR OR OC(O)jR ,NR R If 11 .11 10 0O 10 NR R.,NR R COOR N02, CN, C(O)R ,orC(O)NR R.; Each R is independently a 5-8 'membered monocyclic, 8-12 membered bic'yclic, 'or I 1- 14 membered *tricyclic ring. system comprisig 1-3 heteroatomns if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricy clic, said heteroatoms selected from 0, N, orS, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent independently selected from ClI alkyl; CZ.*CIO alkenyl; C2-CIO affkynyl; C3-ClO cycloalkyl;, C4-CIO cycloalkenyl; aryl; R9; halo; sulfur oxygen; haloalkyl; SR;S OR5; OC(O)R5; NRSRS; NR 5R;6 NR COOR;5 N02; CN; C(O)RS; C(O)NRSR5; 'Cl-CO alkyl1 substituted with 1-3 7 9 79 independent R R or aryl; or CI-CXO0 alkenyl substituted with 1-3 independent R R9 or aryl; 9 Each R is independently a 5-8 membered monocyclic, 8-12 membered *'.:bicyclic, or. 11-14 membered tricyciec- ring system comprising.- 1-3 heteroatorns if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatorns if tricycic, said heteroatolns selected from 0, N, or Swhich may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring-may be substituted by a substituent independently selected from C1-7 CIO alkcyl; C2-CIO alkenyl; C2-CIO alkeynyl; C3-CIO cycloalkyl; C4-C1O cycloalkenyl; 100 J t 0I II halo; sutlur, oxygen; CF3; haloalkyl; SRI OR O; NR OR NR NkIR R1 COOR 0 10100 COR N02; CC(O)R ;or C(O)NPLR. .9..10* Each R is independently HC-l ly;C-l ley;C2-C1O 30 alkynyl; C3-CIO cycloalkyl; C4-CIO. cycloalkenyl; haloalkyl; CI-ClO alkyl optionally substituted with 1-3 independent CI-ClO alkcyL C2-CIO alkenyl, C2-CjO alkynyl, C3- 89 13 13 13 13 13 CIO cycloalkyl,. C4-CIO cycloalkenyl, halo, CF3, OR SR ,NR. R. COOR N02, CN, C(O)R 13. C(O)NR1. R 1, NHC(O)R 1, or OC(O)R 3; or phenyl optionally substitutcd with 1 -3 independent CI-ClO alkyl, C2-CIO alkenyl, C2-CIO alkcynyl, C3-CIO cycloalkyl, C4-CIO cycloalkenyl, halo, CF3, OR SR NR 'R'1 3 COOR' 3 NO29 CN, 13 13 13 13 13 C(O)R C(O)NR R ,NHC(O)R or OC(O)Rk I11 10 Each R 1 is independently C(O)R 1, COOR or S(O)2R Each R.is independently H, Cl-CIO alkyl, C2-C1O alkenyl, C2-ClO alkynyl, C-Cl10 cycloalkyl, C4-C 10 cycloalkenyl, or phenyl optionally substituted with 1-3 independent CI-CIO alkyl, C2-C1O alkenyl, C2-CIO alkynyl, C3-C1O cycloalkyl, C4- 13 13 13 13 13 13 CIO cycloalkenyl. halo, CF3, OR SR NR R ,COOR N02, CN, C(O)R' C(O)NR1 3 R 13 NI{C(O)R 1, or OC(O)R 1 Each R 13 is independently H; Cl-CIO alkyl; C2-CIO'alkenyl; C2-ClO alkynyl; C3-CIO cycloalkyl; C4-CIO cycloalkenyl; CI-CIO alkyl optionally substituted 9 919 19 19 with halo, CF3, OR ,SR. NR 9R. COOR N02, CN;. or phenyl optionally 19 19 19 19 19 substituted with halo, CF3, OR SR NR R COOR N02, CN; Each R 9is independently H; CI-CIO alkyl; C3-CIO cycloalkyl or phenyl; *00 90 Each haloalkyl is independently a CI-ClO0 alkyl substituted with one or more halogen atoms, selected from F, CI,. Br, or L, wherein the number of halogen atoms may not exceed that number that results in a perhaloalkyl group; Each aryl is independently a 6-carbon monocyclic or 10-carbon bicyclic aromatic ring system optionally substituted with 1 -3 independent ClI-C 10 alkyl; 'C2-C alkenyl; C2-CIO alkynyl; C3-CIO cycloalkyl; C4-CIO cycloalkenyl; halo; haloalkyl; OR 12 SR 12; NR2 R 12; COOR1 N02; CN; C(O)R. C(O)C(O)R 2; C(O)NR2 R12 S0212; 12 12 N(12)(O 12) N(12SO)12; 12 12 S()2 ;N(R )C(O)R ;NR)CO SOz S(O)2NR RI OC(O)R 12 NR 12C(O)NR 12R 12; NR 12C(O)C(O)R 12; NR 12C(O)R;9 NR 12S(O)INR 12R1 12 9 12 12 12 NR S(O)2R NR. C(O)C(O)NR CI-ClO ailkyl substituted with 1-3 independent 912, 12, 12 12, C 12 2 )N12 R1 .2 Rhalo, CF3, OR ,SR NR R O IN"2 C C(O)R CON NHC(O)R 1, NH(COOR 12), S(O)2NR 12R 12, OC(O)R 12; C2-CIO .alkenyl substituted with 912 12 12 12 12 12 1-3 independent halo, CF3, OR SR, NR. R COOR NO2, CN, C(O)R C )N12 12, 12, 12) 1()2R2 12, 12; 12 C()RR NHC(O)R, ,NH(COOR )S()NR IOC(O)R ;or RI and provided that: R 2 is other than unsubstituted phenyl-N-H-; when R 3 is 4-methoxyphenyl, then W 2 is other than 4-methoxyphenyl-NH- or 4-nitrophenyl-NH-; and when R 3 is 2, 4-dichiorophenyl, then W 2 is other than 4-chlorophenyl-NH-. -91- 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is naphthyl-NH- or phenyl-NH-, wherein the phenyl is substituted by 1-3 radicals independently selected from the group consisting of R 9 R12; halo; CF 3 OR12; SR1 2 NR1 2 R 2 COOR12; NO 2 CN; C(O)NR1 2 R1 2 S(0) 2 NR 2 R1 2 and C1-C10 alkyl substituted with OR 12 3. The compound of claim 2 or a pharmaceutically acceptable salt thereof; wherein R 3 is a phenyl substituted with 1-3 independent R 4 wherein each R 4 is independently selected from H; C1-C10 alkyl; R 8 halo; CF 3 OR 5 NRSRS; COOR 5 NO 2 CN; NR 5 C(O)NRR 5 NR 5 C(O)C(O)R 5 NRSC(O)R 5 NR 5 C(O)R 8 NR 5 S(0) 2 NR 5 R 5 NR 5 S(O) 2 R 5 NRSS(O) 2 R 8 NRsC(0)C(O)NR 5 R 5 or NR 5 C()C(O)NR 5 R 6 each R 5 is independently H; C1-C10 alkyl; C2-C10 alkenyl; aryl; R 9 C1-C10 alkyl substituted with 1-3 independent aryl, R 7 or R 9 groups; or C3-C10 cycloalkyl substituted with R 7 each R 6 is independently C(O)R 5 each R 7 is independently halo, OR'O, N' 1 R' 0 or COOR 1 0 each R 8 is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6 20 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituted independently selected from C1-C10 alkyl; aryl; R 9 halo; sulfur; oxygen; SR5; NRSR 6 NO 2 or C(O)R 5 each R 9 is independently a 5-8 membered monocyclic ring system having 1-3 heteroatoms selected from O, N, or S, which may be saturated or unsaturated, and optionally substituted by NO z each R 1 0 is independently H, C1-C10 alkyl; C1-C10 alkyl substituted with OR1 3 or phenyl; 0: each R 12 is independently H, C1-C10 alkyl, or phenyl; each R' 3 is independently C1-C10 alkyl; or C -C10 alkyl optionally substituted with OR' 9 each R' 9 is independently C1-C10 alkyl; and -nrI -92- each aryl is independently a 6-carbon monocyclic or 10-carbon bicyclic aromatic ring system optionally substituted with 1-3 independent halo; OR 12 NR' 2 R 2 NO 2 N(R' 2 )C(O)R12; or R 12 4. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein R 2 is naphthyl-NH- or phenyl-NH-, wherein the phenyl is substituted by 1-3 radicals independently selected from the group consisting of halo; CF 3 NO 2 CN; C(O)NH 2 S(0) 2 NH 2 hydroxy; methoxy; phenoxy, methylthio; C1-C4 alkyl; phenyl; hydroxy methyl; hydroxyethyl; dimethylamino; and a 5-8 membered monocyclic ring system having 1-3 heteroatoms selected from O, N, or S, which may be saturated or unsaturated. A pharmaceutical composition comprising a compound according to any of claims 1-4 and a pharmaceutically acceptable carrier, adjuvant or vehicle. 6. The composition according to claim 5, further comprising an additional therapeutic agent. 7. A method of treating a kinase mediated disease or disease symptoms in a 20 mammal comprising administration to said mammal of a compound of any one of claims i: 1-4 or a pharmaceutical composition according to claim 5 or claim 6. 8. The method of claim 7, wherein the mammal is a human. 9. A method of inhibiting kinase activity in a mammal comprising the step of administering to said mammal a compound of any one of claims 1-4 or a pharmaceutical composition according to claim 5 or claim 6. *fee S" 10. The method of claim 9, wherein said mammal is a human. 0d -93- 12. The method of claim 11, wherein said mammal is a human. 13. A method of making a pharmaceutically useful composition comprising combining a compound of any one of claims 1-4 with one or more pharmaceutically acceptable carriers. 14. The method of claim 13, further comprising combining an additional therapeutic agent. A method of making a compound of claim 1 comprising reacting a pyrimidinone of the formula: "NH -4 R2 N R with an appropriate nucleophilic agent, wherein the groups in said formula are as defined in claim 1. 16. The method of claim 15, wherein R 5 is Me. 17. Use of a compound of any one of claims 1-4 in the manufacture of a medicament for the treatment of a kinase mediated disease or disease symptoms in a mammal. 18. Use according to claim 17 wherein the mammal is a human. 19. A compound of the formula: tr**-^rl -94- 19. A compound of the formula: 0 NC H NH R N R 2 substantially as herein described with reference to any one or more of the examples but excluding comparative examples. A method of treating kinase mediated disease or disease symptoms, substantially as herein described with reference to any one or more of the examples but excluding comparative examples. 21. A method of inhibiting kinase activity in a mammal comprising the step of administering to said mammal a compound, substantially as herein described with reference to any one or more of the examples but excluding comparative examples. S *22. A method of treating disease or disease symptoms in a mammal comprising the step of administering to said mammal a compound, substantially as S: herein described with reference to any one or more of the examples but excluding comparative examples. 23. A method of making a pharmaceutically useful composition, substantially as herein described with reference to any one or more of the examples but excluding comparative examples: S" 25 24. A method of making a compound of the formula: o 0 NC NH 3 2 R N R 2 substantially as herein described with reference to any one or more of the examples but excluding comparative examples. Use of a compound of any one of claims 1 to 4 in the manufacture of a medicament, substantially as herein described with reference to any one or more of the examples but excluding comparative examples. DATED this 8 th day of October 2003 BALDWIN SHELSTON WATERS Attorneys for: AMGEN INC. *o o o.* e o0.:g 0
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