US 2004O147559A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0147559 A1 Taveras et al. (43) Pub. Date: Jul. 29, 2004
(54) 3,4-DI-SUBSTITUTED Related U.S. Application Data CYCLOBUTENE-1,2-DIONES AS CXC-CHEMOKINE RECEPTOR LIGANDS (63) Continuation-in-part of application No. 10/241,326, filed on Sep. 11, 2002, which is a continuation-in-part (75) Inventors: Arthur G. Taveras, Denville, NJ (US); of application No. 10/208.412, filed on Jul. 30, 2002, Cynthia J. Aki, Livingston, NJ (US); which is a continuation-in-part of application No. Richard W. Bond, Union, NJ (US); 10/122,841, filed on Apr. 15, 2002, now abandoned. Jianping Chao, Summit, NJ (US); Michael Dwyer, Scotch Plains, NJ (60) Provisional application No. 60/284,026, filed on Apr. (US); Johan A. Ferreira, Bethlehem, 16, 2001. PA (US); Jianhua Chao, Pompton Lakes, NJ (US); Younong Yu, Scotch Publication Classification Plains, NJ (US); John J. Baldwin, Gwynedd Valley, PA (US); Bernd (51) Int. Cl." ...... C07D 277/08; CO7D 263/02; Kaiser, Wallingford, CT (US); Ge Li, CO7D 213/46; A61K 31/4439; Shanghai (CN); J. Robert Merritt, A61K 31/.444 Ewing, NJ (US); Purakkattle J. Biju, (52) U.S. Cl...... 514/332; 514/340; 514/341; Scotch Plains, NJ (US); Kingsley H. 514/365; 514/374; 514/396; Nelson JR., Mebane, NC (US); Laura 514/397; 546/267; 546/270.4; L. Rokosz, Union, NJ (US); James P. 546/272.7: 546/271.4; 548/146; Jakway, Bridgewater, NJ (US); Gaifa 548/215; 548/335.5 Lai, Edison, NJ (US); Minglang Wu, Monmouth Junction, NJ (US); Evan A. (57) ABSTRACT Hecker, Austin, TX (US); Daniel Lundell, Flemington, NJ (US); Jay S. There are disclosed compounds of the formula Fine, Bloomfield, NJ (US) Correspondence Address: (IA) SCHERING-PLOUGH CORPORATION PATENT DEPARTMENT (K-6-1, 1990) 2000 GALLOPING HILL ROAD KENILWORTH, NJ 07033-0530 (US) (73) Assignee: Schering Corporation and Pharma copeia, Inc. or a pharmaceutically acceptable Salt or Solvate thereof (21) Appl. No.: 10/630,258 which are useful for the treatment of chemokine-mediated diseases Such as acute and chronic inflammatory disorders (22) Filed: Jul. 30, 2003 and cancer. US 2004/O147559 A1 Jul. 29, 2004
3,4-DI-SUBSTITUTED CYCLOBUTENE-1,2-DIONES 0006. Many different types of tumors have been shown to AS CXC-CHEMOKINE RECEPTOR LIGANDS produce ELRCXC chemokines and their production has been correlated with a more aggressive phenotype (Inoue et CROSS REFERENCE TO RELATED al. 2000 Clin Cancer Res 6 p. 2104-2119) and poor prog APPLICATION nosis (Yoneda et al. 1998 J Nat Cancer Inst 90 p.447-454). Chemokines are potent chemotactic factors and the 0001. This application is a continuation in part of U.S. ELRCXC chemokines have been shown to induce EC application Ser. No. 10/241326 filed Sep. 11, 2002, which in chemotaxis. Thus, these chemokines probably induce turn is a continuation in part of U.S. application Ser. No. chemotaxis of endothelial cells toward their site of produc 10/208412 filed Jul. 30, 2002, which in turn is a continuation tion in the tumor. This may be a critical Step in the induction in part of U.S. application Ser. No. 10/122841 filed Apr. 15, of angiogenesis by the tumor. Inhibitors of CXCR2 or dual 2002, which in turn claims the benefit U.S. Provisional inhibitors of CXCR2 and CXCR1 will inhibit the angiogenic Application 60/284,026, filed Apr. 16, 2001, the disclosures activity of the ELRCXC chemokines and therefore block the of which are incorporated herein by reference thereto. growth of the tumor. This anti-tumor activity has been demonstrated for antibodies to IL-8 (Arenberg et al. 1996 J FIELD OF THE INVENTION Clin Invest 97 p. 2792-2802), ENA-78 (Arenberg et al. 1998 J Clin Invest 102 p.465-72), and GROC. (Haghnegahdar et 0002 The present invention relates to novel substituted cyclobutenedione compounds, pharmaceutical compositions al. J. Leukoc Biology 2000 67 p. 53-62). containing the compounds, and the use of the compounds 0007 Many tumor cells have also been shown to express and formulations in treating CXC chemokine-mediated dis CXCR2 and thus tumor cells may also stimulate their own CSCS. growth when they secrete ELRCXC chemokines. Thus, along with decreasing angiogenesis, inhibitors of CXCR2 BACKGROUND OF THE INVENTION may directly inhibit the growth of tumor cells. 0.003 Chemokines are chemotactic cytokines that are 0008 Hence, the CXC-chemokine receptors represent released by a wide variety of cells to attract macrophages, promising targets for the development of novel anti-inflam T-cells, eosinophils, basophils, neutrophils and endothelial matory and anti-tumor agents. cells to Sites of inflammation and tumor growth. There are 0009. There remains a need for compounds that are two main classes of chemokines, the CXC-chemokines and capable of modulating activity at CXC-chemokine recep the CC-chemokines. The class depends on whether the first tors. For example, conditions associated with an increase in two cystepnes are separated by a single amino acid (CXC IL-8 production (which is responsible for chemotaxis of chemokines) or are adjacent (CC-chemokines). The CXC neutrophil and T-cell Subsets into the inflammatory site and chemokines include interleukin-8 (IL-8), neutrophil-activat growth of tumors) would benefit by compounds that are ing protein-1 (NAP-1), neutrophil-activating protein-2 inhibitors of IL-8 receptor binding. (NAP-2), GROC, GROB, GROY, ENA-78, GCP-2, IP-10, MIG and PF4. CC chemokines include RANTES, MIP-1C., SUMMARY OF THE INVENTION MIP-2B, monocyte chemotactic protein-1 (MCP-1), MCP-2, MCP-3 and eotaxin. Individual members of the chemokine 0010 This invention provides a method of treating a families are known to be bound by at least one chemokine chemokine mediated disease in a patient in need of Such receptor, with CXC-chemokines generally bound by mem treatment comprising administering to Said patient an effec bers of the CXCR class of receptors, and CC-chemokines by tive amount of a compound of formula IA, as described members of the CCR class of receptors. For example, IL-8 below is bound by the CXCR-1 and CXCR-2 receptors. 0011. This invention also provides a method of treating 0004 Since CXC-chemokines promote the accumulation cancer in a patient in need of Such treatment comprising and activation of neutrophils, these chemokines have been administering to Said patient an effective amount of a implicated in a wide range of acute and chronic inflamma compound of formula IA, as described below. tory disorders including psoriasis and rheumatoid arthritis. 0012. This invention also provides a method of treating Baggiolini et al., FEBS Lett. 307, 97 (1992); Miller et al., cancer in a patient in need of Such treatment comprising Crit. Rev. Immunol. 12, 17 (1992); Oppenheim et al., Annu. administering to Said patient an effective amount of a Fev. Immunol. 9, 617 (1991); Seitz et al., J. Clin. Invest. 87, compound of formula IA, as described below, concurrently 463 (1991); Miller et al., Am. Rev. Respir. Dis. 146, 427 or Sequentially with: (a) a microtubule affecting agent, or (b) (1992); Donnely et al., Lancet 341, 643(1993). an antineoplastic agent, or (c) an anti-angiogenesis agent, or 0005 ELRCXC chemokines including IL-8, GROC, (d) a VEGF receptor kinase inhibitor, or (e) antibodies GRO?3, GROY, NAP-2, and ENA-78 (Strieter et al. 1995 against the VEGF receptor, or (f) interferon, and/or g) JBC 270 p. 27348-57) have also been implicated in the radiation. induction of tumor angiogenesis (new blood vessel growth). All of these chemokines are believed to exert their actions by 0013 This invention also provides a method of inhibiting binding to the 7 transmembrane G-protein coupled receptor angiogenesis, in a patient in need of Such treatment, com CXCR2 (also known as IL-8RB), while IL-8 also binds prising administering to Said patient an effective amount of CXCR1 (also known as IL-8RA). Thus, their angiogenic at least one compound of formula IA, as described below. activity is due to their binding to and activation of CXCR2, 0014. This invention also provides a method of treating and possible CXCR1 for IL-8, expressed on the surface of angiogenic ocular disease (e.g., ocular inflammation, retin vascular endothelial cells (ECS) in Surrounding vessels. opathy of prematurity, diabetic retinopathy, macular degen US 2004/O147559 A1 Jul. 29, 2004
eration with the wet type preferred and corneal neovascu of its definition at every other occurrence. Also, combina larization) in a patient in need of Such treatment, comprising tions of Substituents and/or variables are permissible only if administering to Said patient an effective amount of at least Such combinations result in Stable compounds. one compound of formula IA, as described below. 0027. Unless indicated otherwise, the following defini 0.015 This invention also provides a method of treating a tions apply throughout the present specification and claims. disease Selected from the group consisting of gingivitis, These definitions apply regardless of whether a term is used respiratory viruses, herpes viruses, hepatitis viruses, HIV, by itself or in combination with other terms. For example, kaposi's Sarcoma associated virus and atherosclerosis, in a the definition of “alkyl also applies to the “alkyl” portion of patient in need of Such treatment, comprising administering “alkoxy”. to Said patient an effective amount of at least one compound of formula IA, as described below. 0028 “At least one” represents, for example, 1, or 1-2, or 1-3. 0016. This invention also provides a method of treating acute inflammatory pain, in a patient in need of Such 0029. “Patient” includes both human and other mammals, treatment, comprising administering to Said patient an effec preferably human. tive amount of at least one compound of formula IA, as 0030) “Mammal” includes a human being, and preferably described below. means a human being. 0.017. This invention also provides a method of treating chronic inflammatory pain, in a patient in need of Such 0031 “Alkyl” means a straight or branched saturated treatment, comprising administering to Said patient an effec hydrocarbon chain having 1 to 20 carbon atoms, preferably tive amount of at least one compound of formula IA, as 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms. described below. 0032) “Alkoxy' means an alkyl-O-group wherein alkyl is 0.018. This invention also provides a method of treating as defined above. Non-limiting examples of alkoxy groups acute neuropathic pain, in a patient in need of Such treat include: methoxy, ethoxy, n-propoxy, iso-propoxy and n-bu ment, comprising administering to Said patient an effective toxy. The bond to the parent moiety is through the ether amount of at least one compound of formula IA, as OXygen. described below. 0033 “Alkenyl' means a straight or branched aliphatic 0019. This invention also provides a method of treating hydrocarbon group having at least one carbon-carbon double chronic neuropathic pain, in a patient in need of Such bond, and 2 to 20 carbon atoms, preferably 2 to 12 carbon treatment, comprising administering to Said patient an effec atoms, and more preferably 2 to 6 carbon atoms. Non tive amount of at least one compound of formula IA, as limiting examples of alkenyl groups include: ethenyl, pro described below. penyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl 0020. This invention also provides a method of treating and decenyl. COPD, in a patient in need of Such treatment, comprising 0034). “Alkynyl' means a straight or branched aliphatic administering to Said patient and effective amount of at least hydrocarbon group having at least one carbon-carbon triple one compound of formula IA as described below. bond, and 2 to 15 carbon atoms, preferably 2 to 12 carbon 0021. This invention also provides a method of treating atoms, and more preferably 2 to 4 carbon atoms. Non acute inflammation, in a patient in need of Such treatment, limiting examples of alkynyl groups include ethynyl, pro comprising administering to Said patient and effective pynyl, 2-butynyl, 3-methylbutynyl, n-pentynyl, and decy amount of at least one compound of formula IA as described nyl. below. 0035 “Aryl” means an aromatic monocyclic or multicy 0022. This invention also provides a method of treating clic ring System, wherein at least one ring is aromatic, chronic inflammation, in a patient in need of Such treatment, comprising about 6 to about 14 carbon atoms, and preferably comprising administering to Said patient and effective about 6 to about 10 carbon atoms. Non-limiting examples of amount of at least one compound of formula IA as described Suitable aryl groups include: phenyl, naphthyl, indenyl, below. tetrahydronaphthyl, indanyl, anthracenyl, and fluorenyl. 0023 This invention also provides a method of treating 0036) “Arylalkyl means an aryl group, as defined above, rheumatoid arthritis, in a patient in need of Such treatment, bound to an alkyl group, as defined above, wherein the alkyl comprising administering to Said patient and effective group is bound to the parent moiety. Non-limiting examples amount of at least one compound of formula IA as described of Suitable arylalkyl groups include benzyl, phenethyl and below. naphthleneylmethyl. 0024. This invention also provides novel compounds of 0037 “Cycloalkyl” means saturated carbocyclic rings formula IA, as described below. having 3 to 10 (e.g., 3 to 7) carbon atoms, preferably 5 to 10 0.025 This invention also provides a pharmaceutical carbon atoms, and more preferably 5 to 7 carbon atoms, and composition comprising at least one (e.g., 1-3, usually 1) having one to three rings. Non-limiting examples of compound of formula IA, as described below, and a phar cycloalkyl groups include: cyclopropyl, cyclopentyl, cyclo maceutically acceptable carrier. hexyl, cycloheptyl, norbornyl, and adamantyl. DETAILED DESCRIPTION OF THE 0038 “Cycloalkylalkyl” means a cycloalkyl group bound INVENTION to the parent moiety through an alkyl group. Non-limiting 0026. When any variable occurs more than one time in examples include: cyclopropylmethyl and cyclohexylm any moiety, its definition on each occurrence is independent ethyl. US 2004/O147559 A1 Jul. 29, 2004
0.039 “Cycloalkenyl' means a non-aromatic mono or 0047 N-oxides can form on a tertiary nitrogen present in multicyclic ring System comprising 3 to 10 carbon atoms, an R substituent, or on=N- in a heteroaryl ring substituent and preferably 5 to 10 carbon atoms, and having at least one and are included in the compounds of formula I. carbon-carbon double bond. Preferred cycloalkenyl rings have 5 to 7 carbon atoms. Non-limiting examples of 0048. The term “prodrug,” as used herein, represents cycloalkyl groups include cyclopentenyl, cyclohexenyl, compounds which are rapidly transformed in Vivo to the cycloheptenyl, and norbornenyl. parent compound of the above formula, for example, by 0040 “Halo' means fluoro, chloro, bromo, or iodo hydrolysis in blood. A thorough discussion is provided in T. groupS. Preferred are fluoro, chloro or bromo, and more Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, preferred are fluoro and chloro. Vol. 14 of the A.C.S. Symposium Series, and in Edward B. 0041) “Halogen” means fluorine, chlorine, bromine, or Roche, ed., Bioreversible Carriers in Drug Design, Ameri iodine. Preferred are fluorine, chlorine or bromine, and more can Pharmaceutical Association and Pergamon Press, 1987, preferred are fluorine and chlorine. both of which are incorporated herein by reference. 0.042 “Haloalkyl” means an alkyl group as defined above 0049. As used herein, the term “composition” is intended wherein one or more hydrogen atoms on the alkyl is replaced to encompass a product comprising the Specified ingredients by a halo group defined above. in the Specified amounts, as well as any product which 0043 “Heterocyclyl” or “heterocyclic” or “heterocy results, directly or indirectly, from combination of the Speci cloalkyl means a non-aromatic Saturated monocyclic or fied ingredients in the Specified amounts. multicyclic ring System (i.e., a Saturated carbocyclic ring or ring System) comprising 3 to 10 ring atoms (e.g., 3 to 7 ring 0050 AS used in the methods of this invention, “an atoms), preferably 5 to 10 ring atoms, in which one or more effective amount’ means a therapeutically acceptable of the atoms in the ring System is an element other than amount (i.e., that amount which provides the desired thera carbon, for example nitrogen, oxygen or Sulfur, alone or in peutic effective). combination. There are no adjacent oxygen and/or Sulfur atoms present in the ring System. Preferred heterocyclyls 0051. Also, as used herein, with reference to chemical have 5 to 6 ring atoms. The prefix aza, oxa or thia before the structures or formulas, “Bn” represents benzyl, “Et” repre heterocyclyl root name means that at least a nitrogen, sents ethyl, “Me” represents methyl, and “Ph” represents OXygen or Sulfur atom, respectively, is present as a ring phenyl. atom. The nitrogen or Sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide 0052 Representative embodiments of this invention are or S.S.-dioxide. Non-limiting examples of monocyclic het described below. The embodiments have been numbered for erocyclyl rings include: piperidyl, pyrrolidinyl, piperazinyl, purposes of reference thereto. morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, and 0053. The methods of this invention use a compound of tetrahydrothiopyranyl. formula IA: 0044) The term heterocyclic acidic functional group is intended to include groups Such as, pyrrole, imidazole, (IA) triazole, tetrazole, and the like. O O 0.045 “Heteroaryl' means an aromatic monocyclic or multicyclic ring System comprising 5 to 14 ring atoms, B A. preferably 5 to 10 ring atoms, in which one or more of the n N N1 ring atoms is an element other than carbon, for example H H nitrogen, oxygen or Sulfur, alone or in combination. Pre ferred heteroaryls contain 5 to 6 ring atoms. The prefix aza, oxa or thia before the heteroaryl root name means that at 0054 and the pharmaceutically acceptable salts (e.g., least a nitrogen, oxygen or Sulfur atom respectively, is Sodium or calcium salt) and Solvates thereof, wherein: present as a ring atom. A nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide. Non 0055 A is selected from the group consisting of: limiting examples of heteroaryls include: pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, isoxazolyl, isothiazolyl, Oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, (1) triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinox R7 R8 R7 R8 alinyl, phthalazinyl, imidazol,2-apyridinyl, imidazo2,1- bithiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimida N NN Zolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopy l- l ridyl, isoquinolinyl, benzoaZaindolyl, 1,2,4-triazinyl, and R7 R8 R7 R8 benzothiazolyl. N N 0046) “Heteroarylalkyl means a heteroaryl group, as defined above, bound to an alkyl group, as defined above, where the bond to the parent moiety is through the alkyl 21 2 Na grOup.
US 2004/O147559 A1 Jul. 29, 2004
0056 wherein the above rings of said A groups are -continued substituted with 1 to 6 substituents each independently R7 R8 R7 R8 Selected from the group consisting of R groups; N n N (3) 21 2NN R7 R8 R7 R8 s O, O S R7 R8 R7 R8 1 1 vic -O 2n R7 R8 R7 R8
W6Ns, 7(No. NM Qu s s R7 R8 R7 R8 O O / (No. (NNH R7 R8 R7 R8
S e-N, s R7 R8 R7 R8 N
X 2 s R8 N
X )p
X, s R8 s C.S. R8 R8 R7 R8 R12 R7 R8 , and A N) ", &M N). NN N NF C.S. R7 R8 R7 R8 4NO 4NS ( ( s eN, 2N, R7 R8 R7 R8 R12 0057 wherein one or both of the above rings of said A A. \ ^ N1 groups are Substituted with 1 to 6 Substituents each inde ( N, Vl s pendently selected from the group consisting of R groups; N=/ R7 R8 (4) )z
OD R8 and
O and US 2004/O147559 A1 Jul. 29, 2004
-continued -continued
O R9
0.058 wherein the above phenyl rings of said A groups are substituted with 1 to 3 substituents each independently R R6 R N O Selected from the group consisting of: R groups; and
R11 \ s R3 2 s
N-NH OH (5) 11 R7 R8 R R7 R8 N 2 Sp O s o 9 N N 2-R R9 r N
R7 R8 R7 R8 R9 NS 2 2 i. s FN R9
R7 R8 R7 R8 9 Sir R. S s X-RR N/N R7 R8 R' R7 R8 '^ N NRs. R and O R13 M N Y!.
0059 B is selected from the group consisting of
R5 R5 R R6 R R6 / S R S and s s R le s R3 N 3 \ f W R2 N- N R2 R3 R2 US 2004/O147559 A1 Jul. 29, 2004
0060) n is 0 to 6; 6) substituents on said substituted RandR groups, wherein each Substitutent is independently Selected from the group 0061 p is 1 to 5; consisting of: 0062 X is O, NH, or S; 0069 a) halogen, 0063 Z is 1 to 3; 0070 b) –CF, 0064 R is selected from the group consisting of hydro gen, OH, -C(O)OH, -SH, -SONR'R'', -NH 0071 c)-COR', C(O)R', -NHSONR'R'', -NHSOR,-NR'R''- 0072 d) -OR, C(O)NR'R'', -C(O)NHOR, -C(O)NR'OH, -S(O)OH, -OC(O)R', an unsubstituted heterocyclic 0.073 e) -NR'R'' acidic functional group, and a Substituted heterocyclic acidic 0074 f)-NO, functional group; wherein there are 1 to 6 Substituents on Said Substituted heterocyclic acidic functional group each 0075 g) –CN, Substituent being independently Selected from the group consisting of: R groups; 0.076 h) -SOOR, 0065 each R and R' is independently selected from the 0077 i) -Si(alkyl), wherein each alkyl is indepen group consisting of hydrogen, cyano, halogen, alkyl, dently Selected, alkoxy, -OH, CF, OCF, -NO, C(O)R', 0078 j) -Si(aryl), wherein each alkyl is indepen –C(O)OR, –C(O)NHR'7, -C(O)NR'R'', dently Selected, –SONR'R'', -SOR", –C(O)NR'OR', unsubsti tuted or substituted aryl, unsubstituted or substituted het 0079 k) –(R)-R'Si, wherein each R" is inde eroaryl, pendently Selected, 0080 l) –COR',
31 13 0081 m) -C(O)NR'R'', 0082 n) -SONR'R'', P-R31, R141 N and O 0083) o) –SOR, so-N 0084) p) –OC(O)R', OR 13 0085) q)-OC(O)NR'R'', 0.086 r)-NRC(O)R', and 0087 s)-NRCOR'; 0088 (fluoroalkyl is one non-limiting example of an alkyl group that is Substituted with halogen); 0.066 wherein there are 1 to 6 substituents on said Substituted aryl group and each Substituent is independently 0089 R is selected from the group consisting of: hydro selected from the group consisting of R groups; and gen, alkyl, cycloalkyl and cycloalkylalkyl, wherein there are 1 to 6 substituents on said Substituted heteroaryl group and each Substituent is independently 0090 each R is independently selected from the group Selected from the group consisting of: R groups; consisting of: 0067 each R and R are the same or different and are 0091) a) –R', independently Selected from the group consisting of hydro 0092) b) halogen, gen, halogen, alkyl, alkoxy, -CF, -OCF, -NO, –C(O)R', –C(O)OR', -C(O)NR'R'', 0093 c) –CF, –SONR'R'', -C(O)NR'OR'', cyano, unsubstituted 0094 d) -COR', or substituted aryl, and unsubstituted or substituted het eroaryl group; wherein there are 1 to 6 Substituents on Said O095) e) -OR', Substituted aryl group and each Substituent is independently Selected from the group consisting of R groups; and 0096) f)-NR'R'' wherein there are 1 to 6 substituents on said Substituted 0097 g) -NO, heteroaryl group and each Substituent is independently Selected from the group consisting of: R groups; 0.098 h) –CN, 0068 each R7 and R is independently selected from the 0099) i) -SOR, group consisting of H, unsubstituted or Substituted alkyl, 01.00) ) -SONR'R'', unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or Substituted arylalkyl, unsubsti 01.01 k) – NRCOR'', tuted or substituted heteroarylalkyl, unsubstituted or substi 0102) 1) -CONR'R'' tuted cycloalkyl, unsubstituted or Substituted cycloalkyla lkyl, -COR', -CONR'R'', alkynyl, alkenyl, and 0103 m) - NRCOR'', cycloalkenyl; and wherein there are one or more (e.g., 1 to 01.04 n) –COR', US 2004/O147559 A1 Jul. 29, 2004
substituents on the ring formed when the RandR'groups are taken together with the nitrogen to which they are bound) O) and each Substituent is independently Selected from the group consisting of alkyl, aryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, arylalkyl, fluoroalkyl, cycloalkyl, 4N cycloalkylalkyl, heteroaryl, heteroarylalkyl, amino, W –C(O)OR', -C(O)NR'R'', - SONR'R'', N-N M —C(O)R', -SOR" provided that R is not H, H -NHC(O)NR'R'', -NHC(O)OR', halogen, and a het erocycloalkenyl group (i.e., a heterocyclic group that has at least one, and preferably one, double bond in a ring, e.g., 0105 p) alkyl substituted with one or more (e.g., one) -OH groups (e.g., -(CH2), OH, wherein q is 1-6, usually 1 to 2, and preferably 1), 0106 q) alkyl substituted with one or more (e.g., one) —NR'R'' group (e.g., -(CH.)NR'R'', wherein q is 1-6, usually 1 to 2, and preferably 1), and 01.07 r)-N(R')SOR' (e.g., R is H and R' is 0112 each R" and R' is independently selected from the alkyl, Such as methyl); group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl and 0108) each R'' and R'' is independently selected from heteroaryl; the group consisting of R', hydrogen, alkyl (e.g., C to C, 0113 R'7 is selected from the group consisting of: such as methyl), halogen, -CF, -OCF, -NR'R'', -SO-alkyl, -SOaryl, -SOcycloalkyl, and -SO-heteroaryl; 0114) R' is selected from the group consisting of H, alkyl, aryl, heteroaryl, -C(O)R', -SOR'' and -C(O)NR'R''; 0109) R' is selected from the group consisting of hydro gen, -C(O)OR', unsubstituted or substituted aryl, unsub 0115 each R'' and R is independently selected from the stituted or substituted heteroaryl, unsubstituted or substi group consisting of alkyl, aryl and heteroaryl; tuted arylalkyl, unsubstituted or Substituted cycloalkyl, 0116) R' is selected from the group consisting of: alkyl, unsubstituted or substituted alkyl, unsubstituted or substi cycloalkyl, -CN, -NO, or -SOR" provided that R' is tuted cycloalkylalkyl, and unsubstituted or Substituted het not H; eroarylalkyl group; wherein there are 1 to 6 Substituents on 0117 each R is independently selected from the group the Substituted R' groups and each Substituent is indepen consisting of unsubstituted alkyl, unsubstituted or Substi dently selected from the group consisting of R groups; tuted aryl, unsubstituted or Substituted heteroaryland unsub 0110 each RandR'' is independently selected from the stituted or substituted cycloalkyl; wherein there are 1 to 6 group consisting of H, unsubstituted or Substituted alkyl, Substituents on said Substituted R' groups and each Sub unsubstituted or substituted aryl, unsubstituted or substituted Stituent is independently Selected from the group consisting heteroaryl, unsubstituted or Substituted arylalkyl, unsubsti of alkyl, halogen and -CF, tuted or substituted heteroarylalkyl, unsubstituted or substi 0118 each R" is independently selected from the group tuted cycloalkyl, unsubstituted or Substituted cycloalkyla consisting of H, alkyl and cycloalkyl, and lkyl, unsubstituted or Substituted heterocyclic, unsubstituted or substituted fluoroalkyl, and unsubstituted or substituted 0119) t is 0, 1 or 2. heterocycloalkylalkyl (wherein “heterocyloalkyl” means 0.120. An embodiment of the present invention is directed heterocyclic); wherein there are 1 to 6 Substituents on said to a method of treating a chemokine mediated disease in a substituted R' and R' groups and each substituent is patient in need of Such treatment (e.g., a mammal, preferably independently Selected from the group consisting of alkyl, a human being) comprising administering to Said patient a -CF, -OH, alkoxy, aryl, arylalkyl, fluroalkyl, cycloalkyl, therapeutically effective amount of at least one (e.g., 1-3, cycloalkylalkyl, heteroaryl, heteroarylalkyl, -N(R"), and usually one) compound of formula IA, or a pharmaceu –C(O)OR, -C(O)NR'R'', -S(O)NR'R'', tically acceptable Salt or Solvate thereof. -C(O)R', -SOR" provided that R is not H, halogen, 0121 Examples of chemokine mediated diseases include: and -NHC(O)NR'R''; or acute inflammation, chronic inflammation, rheumatoid 0111) R' and R' taken together with the nitrogen they arthritis, acute inflammatory pain, chronic inflammatory are attached to in the groups -C(O)NR'R'' and pain, acute neuropathic pain, chronic neuropathic pain, -SONR'R'' form an unsubstituted or substituted satu pSoriasis, atopic dermatitis, asthma, COPD, adult respiratory rated heterocyclic ring (preferably a 3 to 7 membered disease, arthritis, inflammatory bowel disease, Crohn's dis heterocyclic ring), Said ring optionally containing one addi ease, ulcerative colitis, Septic shock, endotoxic shock, gram tional heteroatom Selected from the group consisting of O, negative Sepsis, toxic shock Syndrome, Stroke, cardiac and S and NR'; wherein there are 1 to 3 substituents on the renal reperfusion injury, glomerulonephritis, thrombosis, substituted cyclized R' and R' groups (i.e., there is 1 to 3 Alzheimer's disease, graft VS. host reaction, allograft rejec US 2004/O147559 A1 Jul. 29, 2004 tions, malaria, acute respiratory distreSS Syndrome, delayed in a patient in need of Such treatment (e.g., a mammal, type hyperSensitivity reaction, atherosclerosis, cerebral and preferably a human being) comprising administering to said cardiac ischemia, osteoarthritis, multiple Sclerosis, restino patient a therapeutically effective amount of at least one sis, angiogenesis, osteoporosis, gingivitis, respiratory (e.g., 1-3, and usually one) compound of formula IA, or a Viruses, herpes viruses, hepatitis viruses, HIV, Kaposi's pharmaceutically acceptable Salt or Solvate thereof. Sarcoma associated virus, meningitis, cystic fibrosis, pre term labor, cough, pruritis, multi-organ dysfunction, trauma, 0127. Another embodiment of the present invention is Strains, sprains, contusions, psoriatic arthritis, herpes, directed to a method of treating acute neuropathic pain, in a encephalitis, CNS vasculitis, traumatic brain injury, CNS patient in need of Such treatment (e.g., a mammal, preferably tumors, Subarachnoid hemorrhage, post Surgical trauma, a human being) comprising administering to Said patient a interstitial pneumonitis, hyperSensitivity, crystal induced therapeutically effective amount of at least one (e.g., 1-3, arthritis, acute and chronic pancreatitis, acute alcoholic and usually one) compound of formula IA, or a pharmaceu hepatitis, necrotizing enterocolitis, chronic Sinusitis, angio tically acceptable Salt or Solvate thereof. genic ocular disease, ocular inflammation, retinopathy of 0128. Another embodiment of the present invention is prematurity, diabetic retinopathy, macular degeneration with directed to a method of treating chronic neuropathic pain, in the wet type preferred and corneal neovascularization, poly a patient in need of Such treatment (e.g., a mammal, pref myositis, vasculitis, acne, gastric and duodenal ulcers, celiac erably a human being) comprising administering to said disease, esophagitis, gloSSitis, airflow obstruction, airway patient a therapeutically effective amount of at least one hyperresponsiveness, bronchiectasis, bronchiolitis, bronchi (e.g., 1-3, and usually one) compound of formula IA, or a olitis obliterans, chronic bronchitis, cor pulmonae, cough, pharmaceutically acceptable Salt or Solvate thereof. dyspnea, emphysema, hypercapnea, hyperinflation, hypox emia, hyperoxia-induced inflammations, hypoxia, Surgical 0129. Another embodiment of the present invention is lung Volume reduction, pulmonary fibrosis, pulmonary directed to a method of treating COPD, in a patient in need hypertension, right ventricular hypertrophy, peritonitis asso of Such treatment (e.g., a mammal, preferably a human ciated with continuous ambulatory peritoneal dialysis being) comprising administering to said patient a therapeu (CAPD), granulocytic ehrlichiosis, Sarcoidosis, Small air tically effective amount of at least one (e.g., 1-3, and usually way disease, ventilation-perfusion mismatching, wheeze, one) compound of formula IA, or a pharmaceutically accept colds, gout, alcoholic liver disease, lupus, bum therapy, able Salt or Solvate thereof. periodontitis, transplant reperfusion injury and early trans 0.130. Another embodiment of the present invention is plantation rejection. directed to a method of treating acute inflammation, in a 0122) An embodiment of the present invention is directed patient in need of Such treatment (e.g., a mammal, preferably to a method of treating cancer in a patient (e.g., a mammal, a human being) comprising administering to Said patient a Such as a human being) in need of Such treatment, compris therapeutically effective amount of at least one (e.g., 1-3, ing administering to Said patient, concurrently or Sequen and usually one) compound of formula IA, or a pharmaceu tially, a therapeutically effective amount of (a) at least one tically acceptable Salt or Solvate thereof. (e.g., 1-3, and usually one) compound of formula IA, and (b) 0131) Another embodiment of the present invention is a microtubule affecting agent or antineoplastic agent or directed to a method of treating chronic inflammation, in a anti-angiogenesis agent or VEGF receptor kinase inhibitor patient in need of Such treatment (e.g., a mammal, preferably or antibodies against the VEGF receptor or interferon, a human being) comprising administering to Said patient a and/or c) radiation. therapeutically effective amount of at least one (e.g., 1-3, 0123. In further embodiments directed to the treatment of and usually one) compound of formula IA, or a pharmaceu cancer, at least one (e.g., 1-3, and usually one) compound of tically acceptable Salt or Solvate thereof. formula IA is administered in combination with antineoplas 0132) Another embodiment of the present invention is tic agents (e.g., one or more, Such as one, or Such as one or directed to a method of treating rheumatoid arthritis, in a two), Selected from the group consisting of gemcitabine, patient in need of Such treatment (e.g., a mammal, preferably paclitaxel (Taxol.B), 5-Fluorouracil (5-FU), cyclophospha a human being) comprising administering to Said patient a mide (Cytoxan(E), temozolomide, taxotere and Vincristine. therapeutically effective amount of at least one (e.g., 1-3, 0.124. In another embodiment the present invention pro and usually one) compound of formula IA, or a pharmaceu vides a method of treating cancer in a patient (e.g., a tically acceptable Salt or Solvate thereof. mammal, Such as a human being) in need of Such treatment, comprising administering, concurrently or Sequentially, an 0133. In another embodiment of the methods of this effective amount of (a) a compound of formula IA, and (b) invention B is Selected from the group consisting of: a microtubule affecting agent (e.g., paclitaxel). 0.125. Another embodiment of the present invention is directed to a method of treating acute inflammatory pain, in a patient in need of Such treatment (e.g., a mammal, pref erably a human being) comprising administering to said patient a therapeutically effective amount of at least one (e.g., 1-3, and usually one) compound of formula IA, or a pharmaceutically acceptable Salt or Solvate thereof. 0.126 Another embodiment of the present invention is directed to a method of treating chronic inflammatory pain, US 2004/O147559 A1 Jul. 29, 2004 10
-continued -continued R5 R7 R8 R7 R8 R R6 N
s and 2 2 N N R7 R8 R7 R8
)- NH O, N s R10 R5 nN.1 s 2 2 R R6 R7 R8 R7 R8 R7 R8 S
7 s a s 1\ s R11 \ (No. N ØNo w&D N-NH Ku \l R7 R8 R7 R8 0134) wherein all substituents are as defined for formula s Q IA. Q-N 0135) In another embodiment of the methods of this R7 R8 invention B is:
0141 wherein the above rings are unsubstituted or Sub stituted, as described for formula IA: and 0136 wherein: 0137) R, R", R and R are as defined for formula IA; (b) and R7 R8 R7 R8 R9 0138 R is selected from the group consisting of hydro gen, cyano, halogen, alkyl, alkoxy, -OH, -CF, -OCF, R8a, and -NO, -C(O)R', –C(O)OR', –C(O)NHR'7, –SONR'R'', -SOR, —C(O)NR'OR', unsubsti R7 R8 tuted or substituted aryl, unsubstituted or substituted het R9 eroaryl, wherein there are 1 to 6 Substituents on Said Substituted aryl group and each Substituent is independently Selected from the group consisting of R groups; and wherein there are 1 to 6 substituents on said Substituted heteroaryl group and each Substituent is independently 0142 wherein in (a) and (b) above: each R7 and R is selected from the group consisting of: R groups. independently Selected from the group consisting of H, 0139) In the methods of this invention: unsubstituted or substituted alkyl, unsubstituted or substi tuted aryl, unsubstituted or Substituted heteroaryl, unsubsti 0140 (1) substituent A in formula IA is preferably tuted or substituted arylalkyl, unsubstituted or substituted Selected from the group consisting of: heteroarylalkyl, unsubstituted or Substituted cycloalkyl, unsubstituted or substituted cycloalkylalkyl, -COR', (a) -CONR'R'', fluoroalkyl, alkynyl, alkenyl, and cycloalk enyl, wherein said substituents on said R7 and Rsubstituted groups are Selected from the group consisting of: a) cyano, b) –COR', c) –C(O)NR'R'', d) -SONR'R'', e) -NO, f) -CF, g) —OR', h) -NR 'R'', i) –OC(O)R',j)-OC(O)NR'R'', and k) halogen; and R. and R are as defined in formula IA; and US 2004/O147559 A1 Jul. 29, 2004
0143 (2) Substituent B in formula IA is preferably 0145. In the methods of this invention: Selected from the group consisting of: 0146 (1) Substituent A in formula IA is more pref erably Selected from the group consisting of:
R5 R5 (a) R R6 R R6 R7 R8 R7 R8
R3 N 2N 2 R2 W -N N Yi R7 R8 R7 R8 N R5 S. , N s Rt. R6 2 2 N R7 R8 R7 R8
N O N nN.1 s n s )- NH R10 2 21 R7 R8 R7 R8 R5 R4 R R6 1. ANO % No N21 7 s N s le le R11 \ -hyN R7 R8 S R7 R8 N-NH OH N R12 R8 R7 R8 R4 e' O N R4 R ANO w s and e-N Cly DC/ O OH OH O R12 R8 R9 R N R10 )p R8
0147 wherein the above rings are unsubstituted, or the R12 above rings are Substituted with 1 to 3 Substituents indepen dently Selected from the group consisting of halogen, alkyl, R N cycloalkyl, -CF, cyano, -OCH, and -NO; each R7 and R is independently selected is from the group consist \ f ing of: H, alkyl (e.g., methyl, ethyl, t-butyl, and isopropyl), fluoroalkyl (such as, -CF and -CFCH), cycloalkyl R2 R3 R2 (e.g., cyclopropyl, and cyclohexyl), and cycloalkylalkyl (e.g., cyclopropylmethyl); and R is selected from the group R3 S R11 consisting of H, halogen, alkyl, cycloalkyl, -CF, cyano, -OCH, and -NO, and SC (b)
0144) wherein R to R and R' to R'' are as defined R8a, and above. US 2004/O147559 A1 Jul. 29, 2004 12
0156 each R'' and R'' is independently selected from -continued the group consisting of hydrogen, halogen, -CF, R7 R8 -NR'R'', -NRC(O)NR'R'', -C(O)OR', -SH, -SONR'R'',(t) -SOR", -NHC(O)R', NR -NHSONR'R'', -NHSOR', -C(O)NR'R'', –C(O)NR'OR'', –OC(O)R', -COR. -OR', and cyano, 0148 wherein each R" and R is independently selected 0157 each R" and R'' is independently selected from from the group consisting of: H, alkyl (e.g., methyl, ethyl, the group consisting of H, methyl, ethyl, isopropyl and t-butyl, and isopropyl), fluoroalkyl (Such as, -CF and t-butyl; or -CFCH), cycloalkyl (e.g., cyclopropyl, and cyclohexyl), and cycloalkylalkyl (e.g., cyclopropylmethyl); wherein R 0158) R' and R' when taken together with the nitrogen is as defined in formula IA, and wherein R is selected from they are attached to in the groups -NR'R'', the group consisting of H, halogen, alkyl, cycloalkyl, -C(O)NR'R''. SONR'R'', -OC(O)NR'R'', -CF, cyano, -OCH, and -NO; each R" and R is - CONR'R'', -NRC(O)NR'R'', -SONR'R'', independently Selected from the group consisting of H, -NHSO’NR'R'' form an unsubstituted or substituted alkyl (e.g., methyl, ethyl, t-butyl, and isopropyl), fluoroalkyl Saturated heterocyclic ring (preferably a 3 to 7 membered (Such as, -CF and -CFCH), cycloalkyl (e.g., cyclopro ring) optionally having one additional heteroatom Selected pyl, and cyclohexyl), and cycloalkylalkyl (e.g., cyclopropy from the group consisting of O, S or NR; wherein R is lmethyl); and Selected from the group consisting of H, alkyl, aryl, het eroaryl, -C(O)R', -SOR'' and –C(O)NR'R'': 0149 (2) Substituent B in formula IA is more pref wherein each R'' and R is independently selected from the erably Selected from the group consisting of: group consisting of alkyl, aryl and heteroaryl; wherein there are 1 to 3 substituents on the substituted cyclized R" and R groups (i.e., the substituents on the ring formed when R' R5 R5 and R'' are taken together with the nitrogen to which they R R6 R R6 are bound) and each Substituent is independently selected from the group consisting of: alkyl, aryl, hydroxy, hydroxy alkyl, alkoxy, alkoxyalkyl, arylalkyl, fluoroalkyl, cycloalkyl, 3 cycloalkylalkyl, heteroaryl, heteroarylalkyl, amino, R \ –C(O)OR, -C(O)NR'R'', - SONRR, R2 -N –C(O)R', - SOR" provided that R' is not H, N Yi -NHC(O)NR'R'' and halogen; and wherein each R', and R12 R12 R" is independently selected from the group consisting: of H, alkyl, aryl, arylalkyl, cycloalkyl and heteroaryl. R3 N R10 R 3 NN \ / \ f 0159. In the methods of this invention: 0160 (1) substituent A in formula IA is even more R2 R2 preferably Selected from the group consisting of: R12 (a) N R3 S R11 R7 R8 R7 R8 \\ , , and \ | R3 R2 R2 r2N. r2 : R7 R8 R7 R8 O 0150 wherein N s n1 0151 R is selected from the group consisting of H, OH, –NHC(O)R' or and -NHSOR; 4N 21 0152 R is selected from the group consisting of: R7 R8 R7 R8 R7 R8 –SONR'R'', -NO, cyano, -C(O)NR'R'', 4NO 4No - O s -SOR'; and –C(O)OR'; 7 s s V 0153) R' is selected from the group consisting of H, le \ulle Q-N R7 R8 -NO, cyano, -CH, halogen, and -CF, R7 R8 0154 R is selected from the group consisting of H, -CF, -NO, halogen and cyano; 0155 R is selected from the group consisting of H, alkyl and -CF, US 2004/O147559 A1 Jul. 29, 2004 13
consisting of H, -CF, -CFCH methyl, ethyl, isopro -continued pyl, cyclopropyl and t-butyl; and R is H; and
(b)
O R8, R8, and R9 0166 wherein R is selected from the group consisting of H, -CF, -CFCH methyl, ethyl, isopropyl, cyclo propyl and t-butyl; and R is H; and R is as defined for formula IA. 0167 (2) Substituent B in formula IA is preferably Selected from the group consisting of: 0.161 wherein the above rings are unsubstituted, or the above rings are Substituted with 1 to 3 Substituents indepen dently Selected from the group consisting of H, F, Cl, Br, alkyl, cycloalkyl, and -CF; R is selected from the group consisting of: H, fluoroalkyl, alkyl and cycloalkyl; R is and \ / Selected form the group consisting of H, alkyl, -CFCH and-CF; and R is selected from the group consisting of: H, F, Cl, Br, alkyl or -CF; and
(b) 0168 wherein: 0169 R is selected from the group consisting of: H, OH, -NHC(O)R and -NHSOR: 0170 R is selected from the group consisting of: –C(O)NR'R'', -SONR'R'', -NO, cyano, 0162 wherein R is selected from the group consisting -SOR"; and –C(O)OR'; of H, fluoroalkyl, alkyl and cycloalkyl; R is selected form 0171) R' is selected from the group consisting of H, the group consisting of H, alkyl, -CFCH and -CF, and R is as defined for formula IA. -NO, cyano, -CH or -CF; 0172 R is selected from the group consisting of: H, 0163. In the methods of this invention: -CF, -NO, halogen and cyano; and 0164 (1) Substituent A in formula IA is still even 0173 R is selected from the group consisting of: H, alkyl more preferably Selected from the group consisting and -CF, 0174) R' is selected from the group consisting of H, halogen and alkyl, and (a) 0175 each R" and R' is independently selected from the group consisting of H, methyl, ethyl, isopropyl and t-butyl; or 0176) R' and R' when taken together with the nitrogen they are attached to in the groups -NR'R'', -C(O)NR'R'', -SONR'R'', -OC(O)NR'R'', - CONR'R'', -NRC(O)NR'R'', -SONR'R'', -NHSONR'R'' form an unsubstituted or substituted Saturated heterocyclic ring (preferably a 3 to 7 membered ring) optionally having one additional heteroatom Selected from O, S or NR' wherein R is selected from H, alkyl, aryl, heteroaryl, –C(O)R', –SOR' and —C(O)NR'R'', wherein each R'' and R is independently 0.165 wherein the above rings are unsubstituted, or the Selected from alkyl, aryl and heteroaryl, wherein there are 1 above rings are Substituted with 1 to 3 Substituents indepen to 3 substituents on the substituted cyclized R' and R' dently Selected from the group consisting of H, F, Cl, Br, groups (i.e., on the ring formed when R' and R'' are taken alkyl, cycloalkyl, and -CF3; R is selected from the group together with the nitrogen to which they are bound) and each US 2004/O147559 A1 Jul. 29, 2004
Substituent is independently Selected from the group con 0181 (2) Substituent B in formula IA is preferably Sisting of alkyl, aryl, hydroxy, hydroxyalkyl, alkoxy, Selected from the group consisting of: alkoxyalkyl, arylalkyl, fluoroalkyl, cycloalkyl, cycloalkyla lkyl, heteroaryl, heteroarylalkyl, amino, -C(O)OR', -C(O)NR'R'', -SONR'R'', -C(O)R', -SOR R5 provided that R is not H, -NHC(O)NR'R'' and halogen; and wherein each R" and R' is independently selected Rt. R6 from the group consisting of H, alkyl, aryl, arylalkyl, and cycloalkyl and heteroaryl. R3 0177. In the methods of this invention: R2 0178 (1) substituent Ain formula IA is yet even still R3 S R11 more preferably Selected from the group consisting of: R2
0182 wherein: 0183) R is selected from the group consisting of: H, OH, -NHC(O)R and -NHSOR; 0184 R is selected from the group consisting of: –C(O)NR'R''-SONR'R'', -NO, cyano, and –SOR: 0185) R' is selected from the group consisting of: H, -NO, cyano, -CH or -CF; 0186 R is selected from the group consisting of H, -CF, -NO, halogen and cyano; and 0187 R is selected from the group consisting of: H, alkyl and -CF, 0188 R'' is selected from the group consisting of H, halogen and alkyl, and 0189 each R" and R'' is independently selected from the group consisting of methyl and ethyl. 0179 wherein the above rings are unsubstituted, or the above rings are Substituted with 1 to 3 Substituents indepen 0190. In the methods of this invention: dently Selected from the group consisting of F, Cl, Br, alkyl, 0191 (1) substituent A in formula IA is most pref cycloalkyl, and -CF3; R is selected from the group con erably Selected from the group consisting of: Sisting of H, -CF, -CFCH methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R is H; and CF3
(b)
0180 wherein R7 is selected from the group consisting of H, -CF, -CFCH methyl, ethyl, isopropyl, cyclo propyl and t-butyl; and R is H; and R is as defined for formula IA. US 2004/O147559 A1 Jul. 29, 2004 15
-continued -continued DC. O1 voC X1). 2 CF C C X1). CF N-1 7O S / Y)-y 1
1
CF NA and
; and
0192 (2) Substituent B in formula IA is preferably Selected from the group consisting of:
R5
R6 RR34 and 2 3 s
0193 wherein: 0194 Ris-OH: 0195 R is selected from the group consisting of: - SO2NR'R'' and CONR'R''; US 2004/O147559 A1 Jul. 29, 2004 16
0196) R' is selected form the group consisting of H, -CH, and -CF3; -continued 0197) R is selected from the group consisting of: H and R7 R8 R7 R8 cyano, 0198 R is selected from the group consisting of H, -CH, and -CF3; 0199 R'' is H; and 0200) R' and R'' are methyl. R9 0201 The novel compounds of this invention are com pounds of formula IA: R7 R8 R7 R8 S
7ANO &O (IA) eN, s O O
R7 R8 B A. n N N1 H H X R8 0202) and their pharmaceutically acceptable Salts (e.g., X Sodium or calcium salt) and Solvates thereof, wherein: X, s 0203) A is selected from the group consisting of: R8 R8 R7 R8 )p -O (1) R7 R8 R7 R8 R8 s s
R7 R8 R7 R8 rs2N. r2 : -S R7 R8 R7 R8 N y s r b. 1 21 2 Nn, R7 R8 R7 R8 R7 R8 nN.1 O, Ns s 21 2 R7 R8 R7 R8 R7 R8
a (NS s 7(No. s a ØNo s N N le le le R7 R8
R7 R8 O C.S. US 2004/O147559 A1 Jul. 29, 2004 17
-continued -continued 7 8 7 8
R7 R8 R12 R7 R8 R R R. R S
&M
// \ s and R' eR ) - v'sN=/ y \'orle R7 R8
(2) R8R7 R8 R7 R8 OD R8AC and
R8
N N 0204 wherein the above rings of said A groups are 2 2N substituted with 1 to 6 substituents each independently s No. Selected from the group consisting of R groups;
nN.1 O, N s R7 R8 R7 R8 (3) 2 21 O -S US 2004/O147559 A1 Jul. 29, 2004
-continued
(5) R7 R8 R7 R8 eN O O R9 S. / N / R9 N NN
R7 R8 R7 R8 R7 R8 R9
CN S S- M 2 s R9 N N R7 R8 R7 R8 N R9, S
C.S. NN,X-R R7 R8 R' R7 R8 , and N n R8, Ra and
0207 B is selected from the group consisting of: 0205 wherein one or both of the above rings of said A groups are Substituted with 1 to 6 Substituents each inde pendently selected from the group consisting of R groups; R5 (1)
R R6 (4) R7 R8 R3 R2
O and b K. 0208 provided that R for this group is selected from the R9 R8 group consisting of: -C(O)NR'R'', R7 R8 R13 OR 13, R31 N1 N and I P-R31, R14 CQ O | R14 O N b- (- R9 R30 (2) R9 R12 NN-NY : 0206 wherein the above phenyl rings of said A groups R3 are substituted with 1 to 3 substituents each independently R2 Selected from the group consisting of: R groups; and US 2004/O147559 A1 Jul. 29, 2004 19
-continued -continued
(3) (11)
R2 (12) (4)
(5) (13)
(6) (14)
(7) W
/ (15)
(8)
(16) (9)
(10) (17)
N R R3 1sy 11 ; and US 2004/O147559 A1 Jul. 29, 2004
heteroaryl group and each Substituent is independently -continued selected from the group consisting of R groups; (18) 0217 each R" and R is independently selected from the R S group consisting of H, unsubstituted or Substituted alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or Substituted arylalkyl, unsubsti tuted or substituted heteroarylalkyl, unsubstituted or substi R3 R2 tuted cycloalkyl, unsubstituted or Substituted cycloalkyla lkyl, -COR', -CONR'R'', alkynyl, alkenyl, and cycloalkenyl; and wherein there are one or more (e.g., 1 to 0209 n is 0 to 6; 6) substituents on said substituted R7 and R groups, wherein each Substituent is independently Selected from the group 0210 p is 1 to 5; consisting of: 0211 X is O, NH, or S; 0218 a) halogen, 0212 Z is 1 to 3; 0213 R’ is selected from the group consisting of hydro 0219 b) –CF, gen, OH, -C(O)OH, -SH, -SO2NR'R'', -NH 0220, c) –COR', C(O)R', -NHSONR'R'', -NHSOR', -NR'R'', 0221 d) –OR', -C(O)NR'R'', -C(O)NHOR', -C(O)NR'OH, -S(O)OH, -OC(O)R', an unsubstituted heterocyclic 0222 e)-NR'R'' acidic functional group, and a Substituted heterocyclic acidic 0223) f)-NO, functional group; wherein there are 1 to 6 Substituents on Said Substituted heterocyclic acidic functional group each 0224 g) -CN, Substituent being independently Selected from the group consisting of R groups; 0225 h) -SOR, 0226 i) -Si(alkyl), wherein each alkyl is indepen 0214) each R and R' is independently selected from the dently Selected, group consisting of hydrogen, cyano, halogen, alkyl, alkoxy, -OH, -CF, -OCF, -NO, -C(O)R', 0227 j) -Si(aryl), wherein each alkyl is indepen –C(O)OR, –C(O)NHR'7, -C(O)NR'R'', dently Selected, –SONR'R'', -SOR", –C(O)NR'OR', unsubsti 0228 k) –(R)-R'Si,2 wherein each R' is inde tuted or substituted aryl, unsubstituted or substituted het pendently Selected, eroaryl, 0229) 1) –COR',
31 13 0230 m) -C(O)NR'R'', 0231 n) -SONR'R'', P-R31, -N and 0232 o) –SOR, so-N 0233 p) –OC(O)R', OR 13 0234 q) –OC(O)NR'R'' N A. 0235 r)-NRC(O)R', and CY. s 0236 s) -NRCOR'; 0237 (fluoroalkyl is one non-limiting example of an alkyl group that is Substituted with halogen); 0215 wherein there are 1 to 6 substituents on said 0238) R is selected from the group consisting of hydro Substituted aryl group and each Substituent is independently gen, alkyl, cycloalkyl and cycloalkylalkyl, selected from the group consisting of R groups; and wherein there are 1 to 6 substituents on said Substituted 0239) each R is independently selected from the group heteroaryl group and each Substituent is independently consisting of: selected from the group consisting of: R groups; 0240) a) –R', 0216) each R and Rare the same or different and are 0241 b) halogen, independently Selected from the group consisting of hydro gen, halogen, alkyl, alkoxy, -CF, -OCF, -NO, 0242 c) -CF, –C(O)R', –C(O)OR', –C(O)NR 13R 14, 0243 d) –COR', –SONR'R'', -C(O)NR'R'', cyano, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl 0244 e) –OR', group, wherein there are 1 to 6 Substituents on Said Substi 0245 f)-NR'R'' tuted aryl group and each Substituent is independently selected from the group consisting of R groups; and 0246 g) -NO, wherein there are 1 to 6 substituents on said Substituted 0247 h) –CN, US 2004/O147559 A1 Jul. 29, 2004 21
0248) i) -SOR, 0260) R' and R' taken together with the nitrogen they are attached to in the groups -C(O)NR'R'' and 0249 j) -SONR'R'', -SONR'R'' form an unsubstituted or substituted satu 0250) k) – NRCOR rated heterocyclic ring (preferably a 3 to 7 membered heterocyclic ring), said ring optionally containing one addi 0251 l) -CONR'R'' tional heteroatom Selected from the group consisting of O, 0252 m)-NRCOR'', S and NR'; wherein there are 1 to 3 substituents on the substituted cyclized R' and R' groups (i.e., there is 1 to 3 0253) n) –COR', substituents on the ring formed when the R' and R' groups are taken together with the nitrogen to which they are bound) and each Substituent is independently Selected from the O) group consisting of alkyl, aryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, arylalkyl, fluoroalkyl, cycloalkyl, N cycloalkylalkyl, heteroaryl, heteroarylalkyl, amino, % N. –C(O)OR', -C(O)NR'R'', - SONR'R'', // N-N —C(O)R', -SOR" provided that R is not H, M -NHC(O)NR'R'', -NHC(O)OR', halogen, and a het H erocylcoalkenyl group (i.e., a heterocyclic group that has at least one, and preferably one, double bond in a ring, e.g., 0254 p) alkyl substituted with one or more (e.g., one) -OH groups (e.g., -(CH2), OH, wherein q is 1-6, usually 1 to 2, and preferably 1), 0255 q) alkyl substituted with one or more (e.g., one) —NR'R'' group (e.g., -(CH.)NR'R'', wherein q is 1-6, usually 1 to 2, and preferably 1), and 0256 r)-N(R')SOR' (e.g., R is H and R' is 0261) each R" and R' is independently selected from alkyl, Such as methyl); the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl and heteroaryl; 0257) each R'' and R'' is independently selected from the group consisting of R', hydrogen, alkyl (e.g., C to C, 0262 R7 is selected from the group consisting of: such as methyl), halogen, -CF, -OCF, -NR'R'', -SO-alkyl, -SOaryl, -SOcycloalkyl, and -NRC(O)NR'R'', -OH, -C(O)OR', -SH, -SO-heteroaryl; –SONR'R'', -SOR", -NHC(O)R', 0263) R' is selected from the group consisting of H, -NHSONR'R'', -NHSOR', -C(O)NR'R'', alkyl, aryl, heteroaryl, -C(O)R', -SOR'' and –C(O)NR'OR'', –OC(O)R and cyano; -C(O)NR'R'; 0258) R' is selected from the group consisting of hydro gen, -C(O)OR', unsubstituted or substituted aryl, unsub 0264 each R' and R is independently selected from stituted or substituted heteroaryl, unsubstituted or substi the group consisting of alkyl, aryl and heteroaryl; tuted arylalkyl, unsubstituted or Substituted cycloalkyl, 0265 R is selected from the group consisting of: alkyl, unsubstituted or substituted alkyl, unsubstituted or substi cycloalkyl, -CN, -NO, or -SOR" provided that R' is tuted cycloalkylalkyl, and unsubstituted or Substituted het not H; eroarylalkyl group; wherein there are 1 to 6 Substituents on the Substituted R' groups and each Substituent is indepen 0266) each R is independently selected from the group dently selected from the group consisting of R groups; consisting of unsubstituted alkyl, unsubstituted or Substi tuted aryl, unsubstituted or Substituted heteroaryland unsub 0259 each R', and R'' is independently selected from stituted or substituted cycloalkyl; wherein there are 1 to 6 the group consisting of H, unsubstituted or Substituted Substituents on said Substituted R' groups and each Sub alkyl, unsubstituted or Substituted aryl, unsubstituted or Stituent is independently Selected from the group consisting substituted heteroaryl, unsubstituted or substituted arylalkyl, of alkyl, halogen, and -CF, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted 0267) each R" is independently selected from the group cycloalkylalkyl, unsubstituted or Substituted heterocyclic, consisting of H, alkyl and cycloalkyl, and unsubstituted or substituted fluoroalkyl, and unsubstituted or substituted heterocycloalkylalkyl (wherein “heterocy 0268 t is 0, 1 or 2. loalkyl” means heterocyclic); wherein there are 1 to 6 substituents on said substituted R' and R'groups and each 0269 Representative embodiments of the novel com Substituent is independently Selected from the group con pounds of this invention are described below. The embodi Sisting of alkyl, -CF, -OH, alkoxy, aryl, arylalkyl, ments have been numbered for purposes of reference fluroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, het thereto. eroarylalkyl, -N(R'), —C(O)OR', -C(O)NR'R'', 0270 Embodiment No. 1 is directed to the novel com –S(O)NR'R'', -C(O)R', -SOR" provided that R' pounds of formula IA wherein B is selected from the group is not H, halogen, and -NHC(O)NR'R''; or consisting of: US 2004/O147559 A1 Jul. 29, 2004 22
-continued (1) R5 (7) R4 R R6 W S R3 R3 2 R2 R2
0271) provided that R for this group is selected from the 0272 wherein all substituents are as defined for the novel group consisting of: -C(O)NR'R'', compounds of formula IA. 0273 Embodiment No. 2 is directed to the novel com pounds of formula IA wherein B is:
O N R30
12 (2) R n N1 NN S. R3 0274 wherein R is selected from the group consisting R2 of: -C(O)NR'R'', (3) R11 31 13
$1 N P-R31, N and S. R3 | R14 R2 so (4) R12 N OR 13 M N M CY. R3 R2 0275 and all other substituents are as defined in formula IA. (5) 0276 Embodiment No. 3 is directed to the novel com pounds of formula IA wherein B is:
R5 R R6 (6) R13 R12 N 10 M R N R 141 No / ; and O R2 R3 R2 0277 and all other substituents are as defined in formula IA. US 2004/O147559 A1 Jul. 29, 2004 23
0278 Embodiment No. 4 is directed to the novel com 0285 Embodiment No. 7 is directed to the novel com pounds of formula IA wherein B is pounds of formula IA wherein B is
R5 R R6 R13 V R14 C O R2
0279) R' and R'' are each the same or different alkyl group, and all other Substituents are as defined in formula IA 0280 Embodiment No. 5 is directed to the novel com pounds of formula IA wherein B is 31 13 P-R31, N and R14 R5 O R R6 so R13 V N OR13 M 11 ne C s O R2 Y.
0281) and (1) R' is -OH, and all other substituents are as defined in formula IA, or (2) R is-OH, and R' and R' 0287 R’ is -OH, and all other substituents are as are each the same or different alkyl group, and all other defined in formula IA. Substituents are as defined in formula IA. 0288 Embodiment No. 8 is directed to compounds of 0282) Embodiment No. 6 is directed to the novel com formula IA wherein B is: pounds of formula IA wherein B is
R5 R R6
R3 R2 0289 R, R', and R'' are as defined for compounds of formula IA, and all other Substituents are as defined in 0283) R is selected from the group consisting of: formula IA. 0290 Embodiment No. 9 is directed to the novel com R31 R13 pounds of formula IA wherein B is:
|-R s R14 Y and O R301 N N-OR' M CY. 0291 R is -OH, R' and R'' are as defined for com 0284 and all other substituents are as defined in formula pounds of formula and all other Substituents are as defined IA. in formula IA. US 2004/O147559 A1 Jul. 29, 2004 24
0292 Embodiment No. 10 is directed to the novel com pounds of formula IA wherein B is: -continued
R12 10 A R N
R3 R2
0293 R’ is as defined for compounds of formula IA, R' and R'' are the same or different alkyl group, and all other 0300 wherein all substituents are as defined for formula Substituents areas defined for compounds of formula IA. IA. 0294 Embodiment No. 11 is directed to the novel com 0301 Embodiment No. 16 is directed to compounds of pounds of formula IA wherein B is: formula IA wherein B is:
R11 $1 N S. R3 R2 0295), R is -OH, R' and R'' are the same or different alkyl group, and all other Substituents areas defined for compounds of formula IA. 0302 wherein all substituents are as defined for formula 0296 Embodiment No. 12 is directed to novel com IA. pounds of formula IA wherein B is as described in Embodi ment No. 6, R is H, R is H, R is H, and all other 0303 Embodiment No. 17 is directed to compounds of Substituents areas defined for compounds of formula IA. formula IA wherein B is: 0297 Embodiment No. 13 is directed to novel com pounds of formula IA wherein B is as described in Embodi ment No. 7, R" is H, R is H, R is H, and all other Substituents areas defined for compounds of formula IA. R11 0298 Embodiment No. 14 is directed to novel com pounds of formula IA wherein B is as described in Embodi ments Nos. 4, 5, 8 and 9, except that R' and R'' are each methyl, and all other Substituents are as defined in formula IA. 0299 Embodiment No. 15 is directed to novel com pounds of formula IA wherein B is selected from the group 0304) R' is H, and all other substituents are as defined in consisting of: formula IA. 0305 Embodiment No. 18 is directed to compounds of R11 formula IA wherein B is:
and 0306 R is -OH, and all other substituents are as defined in formula IA. US 2004/O147559 A1 Jul. 29, 2004 25
0307 Embodiment No. 19 is directed to compounds of 0315 Embodiment No. 23 is directed to compounds of formula IA wherein B is: formula IA wherein B is:
0316 R is -OH, R is –C(O)NR'R'', R is H, and all other Substituents are as defined in formula IA. 0308 R is –C(O)NR'R'', and all other substituents 0317 Embodiment No. 24 is directed to compounds of are as defined in formula IA. formula IA wherein B is: 0309 Embodiment No. 20 is directed to compounds of formula IA wherein B is:
0318 Ris–S(O)NR'R'' (e.g., t is 2), each R', and R' are the same or different and are Selected from the group consisting of H and alkyl (e.g., methyl, ethyl, isopropyl and t-butyl). In this embodiment, each R" and R'' are generally 0310 R is -S(O)NR'R'' (e.g., t is 2), and all other Selected from the group consisting of H and ethyl, and Substituents are as defined in formula IA. preferably R' and R'' are ethyland all other substituents are as defined in formula IA. 0311 Embodiment No. 21 is directed to compounds of 03.19 Embodiment No. 25 is directed to compounds of formula IA wherein B is: formula IA wherein B is:
0320 R is –S(O)NR'R'' (e.g., t is 2), R is H, and 0312 R is -OH, R is –C(O)NR'R'', and all other each R', and R'' are the same or different and are selected Substituents are as defined in formula IA. from the group consisting of H and alkyl (e.g., methyl, ethyl, isopropyl and t-butyl). In this embodiment, each R' 0313 Embodiment No. 22 of this invention is directed to and R'' are generally selected from the group consisting of: compounds of formula IA wherein B is: H and ethyl, and preferably R' and R'' are ethyland all other Substituents are as defined in formula IA. 0321 Embodiment No. 26 is directed to compounds of formula IA wherein B is:
R11
0314 R is -OH, and Ris-S(O)NR'R'' (e.g., t is 2), and all other Substituents are as defined in formula IA. US 2004/O147559 A1 Jul. 29, 2004 26
0322 R is-OH, Ris–S(O)NR'R' (e.g., t is 2), R' 0329 Embodiment No. 30 is directed to compounds of is H, and all other Substituents are as defined in formula IA. formula IA wherein B is: 0323 Embodiment No. 27 is directed to compounds of formula LA wherein B is: N \ | N R2
0330 and all substituents are as defined in formula IA. 0331 Embodiment No. 31 is directed to novel com pounds of formula IA wherein B is as described in any one (0.324) R’ is -OH, R is –C(O)NR'R'', R'' is H, and of the Embodiment Nos. 1 to 30, and A is as defined in any R and R'' are independently selected from the group of the above preferred descriptions describing. A for the consisting of: alkyl, unsubstituted heteroaryland Substituted compounds of formula IA used in the methods of treatment. heteroaryl, and all other Substituents are as defined in 0332 Embodiment No. 32 is directed to novel com formula IA. In general, one of R' or R'' is alkyl (e.g., pounds of formula IA wherein B is as described in any one methyl). An example of a Substituted heteroaryl group is of the Embodiment Nos. 1 to 30, and A is:
R7 R8 1 N ** Qu7
0333 wherein the furan ring is unsubstituted or substi 0325 Embodiment No. 28 is directed to compounds of tuted as described in the definition of A for formula IA, and formula IA wherein B is: all other Substituents are as defined for formula IA. 0334 Embodiment No. 33 is directed to novel com pounds of formula IA wherein B is described in any one of the Embodiment Nos. 1 to 30, and A is
ANO Qu7 0326 R is-OH, Ris–S(O)NR'R' (e.g., t is 2), R' is H, and each R" and R'' are the same or different and are 0335 wherein the furan ring is substituted and all other Selected from the group consisting of H and alkyl (e.g., Substituents are as defined for formula IA. methyl, ethyl, isopropyl and t-butyl), and all other Substitu ents are as defined in formula IA. In this embodiment, each 0336 Embodiment No. 34 is directed to novel com R" and R'' are generally selected from the group consisting pounds of formula IA wherein B is as described in any one of H and ethyl, and preferably R' and R'' are ethyl. of the Embodiment Nos. 1 to 30, and A is 0327 Embodiment No. 29 is directed to compounds of formula IA wherein B is: A No Quw
0337 wherein the furan ring is substituted with at least one (e.g., 1 to 3, or 1 to 2) alkyl group and all other Substituents are as defined for formula IA. 0338 Embodiment No. 35 is directed to novel com pounds of formula IA wherein B is as described in any one 0328 and all substituents are as defined in formula IA. of the Embodiment Nos. 1 to 30, A is US 2004/O147559 A1 Jul. 29, 2004 27
0346 Embodiment No. 39 is directed to the novel com pounds of formula IA wherein: R7 R8 0347 (1) substituent A in formula IA is preferably ANO Selected from the group consisting of:
R7 R8 R7 R8 0339 wherein the furan ring is substituted with one alkyl N NN group and all other Substituents are as defined for formula IA. 2N. 2 R7 R8 R7 R8 0340 Embodiment No. 36 is directed to novel com pounds of formula IA wherein B is as described in any one N N of the Embodiment Nos. 1 to 30, and A is 2 2 N R7 R8 R7 R8 f nN.1 O, N 2 2 R7 R8 R7 R8 WNo (No 0341 wherein the furan ring is substituted with one C, to 7 N C. alkyl group (e.g., methyl or isopropyl), and all other e , e , Substituents are as defined for formula IA. R7 R8 & S R7 R8 0342 Embodiment No. 37 is directed to novel com M s s pounds of formula IA wherein B is as described in any one of the Embodiment Nos. 1 to 30, and A is R7 R8 R7 R8 ANO 7 and eN,
O O R8 R9 0343) as defined in any one of the Embodiment Nos. 32 )p to 36, except that R and R are the same or different and R8 each is Selected from the group consisting of H and alkyl.
0344) Embodiment No. 38 is directed to novel com 0348 wherein the above rings are unsubstituted or Sub pounds of formula IA wherein B is as described in any one stituted, as described for formula IA: and of the Embodiment Nos. 1 to 30, and A is
(b)
0345 as defined in any one of the Embodiment Nos. 32 to 36, except that R7 is H, and R is alkyl (e.g., ethyl or t-butyl). US 2004/O147559 A1 Jul. 29, 2004 28
0349 and wherein in (a) and (b) above: each R7 and R is independently Selected from the group consisting of H, -continued unsubstituted or substituted alkyl, unsubstituted or substi R7 R8 R7 R8 tuted aryl, unsubstituted or Substituted heteroaryl, unsubsti O N tuted or substituted arylalkyl, unsubstituted or substituted nN.1 s n s heteroarylalkyl, unsubstituted or Substituted cycloalkyl, unsubstituted or substituted cycloalkylalkyl, -COR', 2 21 -CONR'R'', fluoroalkyl, alkynyl, alkenyl, and cycloalk enyl, wherein said substituents on said R7 and Rsubstituted R7 R8 R7 R8 groups are Selected from the group consisting of: a) cyano, ANO % No b) –COR', c) –C(O)NR'R'', d) -SONR'R'', e) 7 s N s -NO, f–CF, g) —OR', h)-NR'R'', i) —OC(O)R', le le j) —OC(O)NR'R'', and k) halogen; and R and Rare as defined in formula IA; and R7 R8 S R7 R8 0350 (2) substituent B in formula IA is preferably N Selected from the group consisting of: R7 R8 R7 R8 R5 ANO w s and R R6 e-N R13 R12 V O surne s R N R10, O R8 \ || R9 R2 )p R8 R NN -N \ f \ | 0354 wherein the above rings are unsubstituted, or the , and above rings are Substituted with 1 to 3 Substituents indepen R2 s R3 R2 dently Selected from the group consisting of halogen, alkyl, cycloalkyl, -CF, cyano, -OCH, and -NO; each R7 R S R11 and R is independently selected from the group consisting of H, alkyl (e.g., methyl, ethyl, t-butyl, and isopropyl), fluoroalkyl (such as, -CF and -CFCH), cycloalkyl (e.g., cyclopropyl, and cyclohexyl), and cycloalkylalkyl R2 (e.g., cyclopropylmethyl); and R is selected from the group consisting of H, halogen, alkyl, cycloalkyl, -CF, cyano, -OCH, and -NO; and 0351 wherein R* to R and R9 to R' are as defined above for the novel compounds of formula IA. (b) 0352 Embodiment No. 40 is directed to the novel com R7 R8 R7 R8 R9 pounds of formula IA wherein: 2 0353 (1) substituent A in formula IA is more pref R8a, and erably Selected from the group consisting of: R7 R8 NR (a) R7 R8 R7 R8
N s NN s 0355 wherein each R7 and R is independently selected 2N 21 from the group consisting of: H, alkyl (e.g., methyl, ethyl, t-butyl, and isopropyl), fluoroalkyl (Such as, -CF and R7 R8 R7 R8 -CFCH), cycloalkyl (e.g., cyclopropyl, and cyclohexyl), N and cycloalkylalkyl (e.g., cyclopropylmethyl); wherein R is as defined in formula IA, and wherein R is selected from the group consisting of H, halogen, alkyl, cycloalkyl, 2 2NS -CF, cyano, is -OCH, and -NO; each R'' and R is independently Selected from the group consisting of H, US 2004/O147559 A1 Jul. 29, 2004 29 alkyl (e.g., methyl, ethyl, t-butyl, and isopropyl), fluoroalkyl Selected from the group consisting of H, alkyl, aryl, het (Such as, -CF and -CFCH), cycloalkyl (e.g., cyclopro eroaryl, -C(O)R', -SOR'' and –C(O)NR'R'': pyl, and cyclohexyl), and cycloalkylalkyl (e.g., cyclopropy wherein each R'' and R” is independently selected from the lmethyl); and group consisting of alkyl, aryl and heteroaryl; wherein there are 1 to 3 Substituents on the Substituted cyclized R" and 0356 (2) Substituent B in formula IA is more pref R groups (i.e., the substituents on the ring formed when R' erably Selected from the group consisting of: and R'' are taken together with the nitrogen to which they are bound) and each Substituent is independently selected from the group consisting of: alkyl, aryl, hydroxy, hydroxy R5 alkyl, alkoxy, alkoxyalkyl, arylalkyl, fluoroalkyl, cycloalkyl, R R6 cycloalkylalkyl, heteroaryl, heteroarylalkyl, amino, R13 R12 –C(O)OR', -C(O)NR'R'', - SONR'R'', V -C(O)R', SOR" provided that R is not H, surne s R N R10, -NHC(O)NR'R'' and halogen; and wherein each R', and R" is independently selected from the group consisting: of \ | H, alkyl, aryl, arylalkyl, cycloalkyl and heteroaryl. R2 0366 Embodiment No. 41 is directed to the novel com pounds of formula IA wherein: R12 R12 0367 substituent A in formula IA is even more R3 NN N preferably Selected from the group consisting of: \ f \ | , and (a) R2 s R3 R2 R7 R8 R7 R8 R S R11 N , SN s 2N 2 R2 R7 8 R7 R8 O N s nN.1 wherein 0357) 2NS 2 0358 R is selected from the group consisting of H, OH, O –NHC(O)R and -NHSOR: R7 R8 R7 R8 0359 R is selected from the group consisting of: ANO (No –SONR'R'', -NO, cyano, -C(O)NR'R'', w s N s -SOR"; and –C(O)OR'; e le 0360) R' is selected from the group consisting of H, R7 R8 -NO, cyano, -CH, halogen, and -CF, (No R7 R8 S 0361) R' is selected from the group consisting of H, ( , & s -CF, -NO, halogen and cyano; e-N N 0362 R is selected from the group consisting of H, alkyl and -CF, R7 R8 R7 R8 0363) each R'' and R'' is independently selected from the group consisting of: R', hydrogen, halogen, -CF, -NR'R'', -NRC(O)NR'R'', -C(O)OR', -SH, –SONR'R 14, -SOR", -NHC(O)R', O -NHSONR'R'', -NHSOR', -C(O)NR'R'', O –C(O)NR'OR'', –OC(O)R', -COR', -OR', and R8 cyano, R9 0364 each R" and R' is independently selected from the group consisting of H, methyl, ethyl, isopropyl and , and t-butyl; or 0365) R' and R' when taken together with the nitrogen R8 R8 they are attached to in the groups -C(O)NR'R'' and -SO2NR'R' form an unsubstituted or substituted satu rated heterocyclic ring (preferably a 3 to 7 membered ring) optionally having one additional heteroatom Selected from 0368 wherein the above rings are unsubstituted, or the the group consisting of O, S or NR'; wherein R is above rings are Substituted with 1 to 3 Substituents indepen US 2004/O147559 A1 Jul. 29, 2004 30 dently Selected from the group consisting of H, F, Cl, Br, 0373) wherein R is selected from the group consisting alkyl, cycloalkyl, and -CF; R is selected from the group of H, -CF, -CFCH methyl, ethyl, isopropyl, cyclo consisting of: H, fluoroalkyl, alkyl and cycloalkyl; R is propyl and t-butyl; and R is H; and R is as defined for Selected form the group consisting of H, alkyl, -CFCH formula IA. and-CF; and R is selected from the group consisting of: 0374 (2) Substituent B in formula IA is preferably H, F, Cl, Br, alkyl or -CF; and Selected from the group consisting of:
(b) R5 R R6 R's and R14 C 0369 wherein R7 is selected from the group consisting O R2 of H, fluoroalkyl, alkyl and cycloalkyl; R is selected form R3 S R11 the group consisting of H, alkyl, -CFCH and -CF, and R is as defined for formula IA. R2 0370 Embodiment No. 42 is directed to the novel com pounds of formula IA wherein: 0371 (1) Substituent A in formula IA is still even 0375 wherein: more preferably Selected from the group consisting 0376 R is selected from the group consisting of: H, OH, of: -NHC(O)R and -NHSOR: 0377 R is selected from the group consisting of: al 7 8 R7 R8 (a) -C(O)NR'R'', -SONR'R'', -NO, cyano, R R -SOR"; and –C(O)OR'; (2NS 0378 R"is selected from the group consisting of H, s W s -NO, cyano, -CH or -CF; le 0379 R is selected from the group consisting of: H, R7 R8 -CF, -NO, halogen and cyano; and (7 No 0380 R is selected from the group consisting of: H, alkyl W s , and and -CF, le 0381) R' is selected from the group consisting of H, halogen and alkyl, and 0382 each R" and R'' is independently selected from the group consisting of H, methyl, ethyl, isopropyl and t-butyl; or 0383) R' and R' when taken together with the nitrogen they are attached to in the groups -C(O)NR'R'' and -SONR'R'' form an unsubstituted or substituted satu rated heterocyclic ring (preferably a 3 to 7 membered ring) optionally having one additional heteroatom Selected from O, S or NR' wherein R is selected from H, alkyl, aryl, 0372 wherein the above rings are unsubstituted, or the heteroaryl, -C(O)R', -SOR" and –C(O)NR'R'', above rings are Substituted with 1 to 3 Substituents indepen wherein each R'' and R is independently selected from dently Selected from the group consisting of H, F, Cl, Br, alkyl, aryl and heteroaryl, wherein there are 1 to 3 Substitu alkyl, cycloalkyl, and -CF; R is selected from the group ents on the substituted cyclized R' and R' groups (i.e., on consisting of H, -CF, -CFCH methyl, ethyl, isopro the ring formed when RandR'' are taken together with the pyl, cyclopropyl and t-butyl; and R is H; and nitrogen to which they are bound) and each Substituent is independently Selected from the group consisting of: alkyl, aryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, arylalkyl, (b) fluoroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, het eroarylalkyl, amino, C(O)OR, —C(O)NR'R'', –SONR'R'' -C(O)R', -SOR" provided that R is not H, -NHC(O)NR'R'' and halogen; and wherein each R and R' is independently selected from the group con Sisting of H. alkyl, aryl, arylalkyl, cycloalkyl and het eroaryl. US 2004/O147559 A1 Jul. 29, 2004
0384 Embodiment No. 43 is directed to the novel com 0391) R' is selected from the group consisting of: pounds of formula IA wherein: –C(O)NR'R''-SONR'R'', -NO, cyano, and 0385 (1) substituent Ain formula IA is yet even still –SOR: more preferably Selected from the group consisting 0392) R' is selected from the group consisting of H, of: -NO, cyano, -CH or -CF; 0393 R is selected from the group consisting of: H, al -CF, -NO, halogen and cyano; and 7 8 R7 R8 (a) R R 0394 R is selected from the group consisting of: H, alkyl (NS and -CF, s w s le 0395) R' is selected from the group consisting of H, halogen and alkyl, and R7 R8 0396 each R" and R'' is independently selected from (7 No the group consisting of methyl and ethyl. 7 s , and 0397 Embodiment No. 44 is directed to the novel com le pounds of formula IA wherein: 0398 (1) substituent A in formula IA is most pref erably Selected from the group consisting of:
CF3
0386 wherein the above rings are unsubstituted, or the above rings are Substituted with 1 to 3 Substituents indepen dently Selected from the group consisting of F, Cl, Br, alkyl, cycloalkyl, and -CF3; R is selected from the group con sisting of H, -CF, -CFCH methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R is H; and
(b)
0387 wherein R is selected from the group consisting of H, -CF, -CFCH methyl, ethyl, isopropyl, cyclo propyl and t-butyl; and R is H; and R is as defined for formula IA; 0388 (2) substituent B in formula IA is yet even still more preferably Selected from the group consisting of:
R5 R R6 R S R11 R13 VN \ / R14 No , and R2 O R2
0389) wherein: 0390 R is selected from the group consisting of H, OH, –NHC(O)R and -NHSOR: US 2004/O147559 A1 Jul. 29, 2004 32
-continued -continued
; and
0399 (2) substituent B in formula IA is most pref erably Selected from the group consisting of:
R5 E CF R R6 R S R11 : F, R13 \ || N R14 No and s R2 O R2
0400 wherein: 0401] Ris-OH: 0402 R is selected from the group consisting of: - SO2NR'R'' and CONR'R''; 0403) R' is selected form the group consisting of: H, -CH, and -CF3; 04.04 R is selected from the group consisting of H and cyano, 04.05 R is selected from the group consisting of H, -CH, and -CF3; 0406 R'' is H; and 04.07 R and R'' are methvl.y CF 04.08 Embodiment No. 45 is directed to the novel com CF pounds of formula IA wherein: O O 04.09 (1) Substituent A in formula IA is selected / s / s from the group consisting of:
(a) R7 R8 R7 R8
N n N US 2004/O147559 A1 Jul. 29, 2004 33
–OC(O)R',j)-OC(O)NR'R'', and k) halogen; and R' -continued and R are as defined in formula IA; and R7 R8 R7 R8 0412) (2) substituent B in formula IA is: N
s r N 2 2 No. R11 R7 R8 R7 R8 N N- N , 2 2 R7 R8 R7 R8 0413 wherein R, RandR'' are as defined above for the novel compounds of formula IA. 7 N ** (WNo 0414 Embodiment No. 46 is directed to the novel com pounds of formula IA wherein: R7 R8 ( R7 R8 S. 0415 (1) Substituent A in formula IA is selected 1\ s s from the group consisting of:
R7 R8 R7 R8 (a) ANO R7 R8 R7 R8 7 and 2N, N , NN s O 2N 2 O 7 R7 R8 R7 R8 R9 N N , N s )p 21 2 N R8 R7 R8 R7 R8 O N 0410 wherein the above rings are unsubstituted or Sub nN.1 s n s stituted, as described for formula IA: and 2 21 R7 R8 R7 R8 9 (b) R7 R8 R7 R8 R ANO % No 7 s N s le le vs. and R7 R8 S R7 R8 R7 R8 N NR , and R7 R8 R7 R8 ANO 0411 wherein in (a) and (b) above: each R7 and R is w s and independently Selected from the group consisting of H, e-N unsubstituted or substituted alkyl, unsubstituted or substi O tuted aryl, unsubstituted or Substituted heteroaryl, unsubsti tuted or substituted arylalkyl, unsubstituted or substituted O heteroarylalkyl, unsubstituted or Substituted cycloalkyl, R8 unsubstituted or substituted cycloalkylalkyl, -COR', R9 -CONR'R'', fluoroalkyl, alkynyl, alkenyl, and cycloalk )p enyl, wherein said substituents on said R7 and Rsubstituted groups are Selected from the group consisting of: a) cyano, R8 b) –COR', c) –C(O)NR'R'', d) -SONR'R'', e) -NO, f) -CF, g) —OR', h) -NR'R'', i) US 2004/O147559 A1 Jul. 29, 2004 34
0416 wherein the above rings are unsubstituted or Sub eroaryl, -C(O)R', -SOR'' and –C(O)NR'R'': stituted, as described for formula IA: and wherein each R'' and R is independently selected from the group consisting of alkyl, aryl and heteroaryl; wherein there are 1 to 3 substituents on the substituted cyclized R" and (b) R groups (i.e., the substituents on the ring formed when R' R7 R8 R7 R8 R9 and R'' are taken together with the nitrogen to which they 2 are bound) and each Substituent is independently selected R8a, and from the group consisting of: alkyl, aryl, hydroxy, hydroxy alkyl, alkoxy, alkoxyalkyl, arylalkyl, fluoroalkyl, cycloalkyl, R7 R8 cycloalkylalkyl, heteroaryl, heteroarylalkyl, amino, –C(O)OR, -C(O)NR'R'', - SONRR, NR –C(O)R', SO.R.' provided that R' is not H, -NHC(O)NR'R'' and halogen; and wherein each R', and R" is independently selected from the group consisting: of H, alkyl, aryl, arylalkyl, cycloalkyl and heteroaryl. 0417 and 0425 Embodiment No. 47 is directed to the novel com 0418 wherein in (a) and (b) above: each R" and R is pounds of formula IA wherein: independently Selected from the group consisting of H, 0426 (1) Substituent A in formula IA is selected unsubstituted or substituted alkyl, unsubstituted or substi from the group consisting of: tuted aryl, unsubstituted or Substituted heteroaryl, unsubsti tuted or substituted arylalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or Substituted cycloalkyl, (a) unsubstituted or substituted cycloalkylalkyl, -COR', R7 R8 R7 R8 -CONR'R'', fluoroalkyl, alkynyl, alkenyl, and cycloalk enyl, wherein said substituents on said R7 and Rsubstituted groups are Selected from the group consisting of: a) cyano, b) –COR', c) –C(O)NR'R'', d) -SONR'R'', e) 2N 21 -NO, f) -CF, g) —OR', h) -NR'R'', i) R7 R8 R7 R8 —OC(O)R',j)-OC(O)NR'R'', and k) halogen; and R' N and R are as defined in formula IA; and S. , N s 0419 (2) substituent B in formula IA is: 21 2 N R7 R8 R7 R8 O R S R11 O N nN.1 s S. , 21 2 R7 R8 R7 R8 ANO % No 0420 R is selected from the group consisting of H, OH, 7 s N s –NHC(O)R and -NHSOR: le le 0421) R' is selected from the group consisting of: –SONR'R'', -NO, cyano, -C(O)NR'R'', R7 R8 S R7 R8 -SOR"; and –C(O)OR'; 0422) R' is selected from the group consisting of R", N hydrogen, halogen, -CF, NR'R'', R7 R8 R7 R8 -NRC(O)NR'R'', –C(O)OR', -SH, –SONR'R'', -SOR", -NHC(O)R’ WNo -NHSONR'R'",13, 14 -NHSOR"13 -C(O)NR'R'',13, 14 7 s and e-N
O 0423) each R" and R' is independently selected from O the group consisting of H, methyl, ethyl, isopropyl and R8 t-butyl; or R9 0424) R' and R' when taken together with the nitrogen they are attached to in the groups -C(O)NR'R'' and )p -SONR'R'', form an unsubstituted or substituted satu R8 rated heterocyclic ring (preferably a 3 to 7 membered ring) optionally having one additional heteroatom Selected from the group consisting of O, S or NR'; wherein R is 0427 wherein the above rings are unsubstituted, or the Selected from the group consisting of H, alkyl, aryl, het above rings are Substituted with 1 to 3 Substituents indepen US 2004/O147559 A1 Jul. 29, 2004 35 dently Selected from the group consisting of halogen, alkyl, unsubstituted or Substituted Saturated heterocyclic ring cycloalkyl, -CF, cyano, -OCH, and -NO; each R7 (preferably a 3 to 7 membered ring) optionally having one and R is independently selected from the group consisting additional heteroatom Selected from the group consisting of: of H, alkyl (e.g., methyl, ethyl, t-butyl, and isopropyl), O, S or NR'; wherein R' is selected from the group fluoroalkyl (such as, -CF and -CFCH), cycloalkyl consisting of H, alkyl, aryl, heteroaryl, -C(O)R', (e.g., cyclopropyl, and cyclohexyl), and cycloalkylalkyl –SO'R'' and –C(O)NR'R'; wherein each R'' and R is (e.g., cyclopropylmethyl); and R is selected from the group independently Selected from the group consisting of: alkyl, consisting of H, halogen, alkyl, cycloalkyl, -CF, cyano, aryl and heteroaryl; wherein there are 1 to 3 Substituents on -OCH, and -NO; and the substituted cyclized R' and R' groups (i.e., the sub stituents on the ring formed when R and R'' are taken together with the nitrogen to which they are bound) and each (b) Substituent is independently Selected from the group con R7 R8 R7 R8 R9 Sisting of alkyl, aryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, arylalkyl, fluoroalkyl, cycloalkyl, cycloalkyla R8a, and lkyl, heteroaryl, heteroarylalkyl, amino, -C(O)OR', -C(O)NR'R'', -SONR'R'', -C(O)R, -SOR R7 R8 provided that R is not H, -NHC(O)NR'R'' and halogen; NR and wherein each R" and R' is independently selected from the group consisting: of H, alkyl, aryl, arylalkyl, cycloalkyl and heteroaryl. 0428 wherein each R7 and R is independently selected 0436 Embodiment No. 48 is directed to the novel com from the group consisting of: H, alkyl (e.g., methyl, ethyl, pounds of formula IA wherein: t-butyl, and isopropyl), fluoroalkyl (Such as, -CF and 0437 (1) Substituent A in formula IA is selected -CFCH), cycloalkyl (e.g., cyclopropyl, and cyclohexyl), from the group consisting of: and cycloalkylalkyl (e.g., cyclopropylmethyl); wherein R is as defined in formula IA, and wherein R is selected from the group consisting of H, halogen, alkyl, cycloalkyl, -CF, cyano, -OCH, and -NO; each R7 and R is independently Selected from the group consisting of H, alkyl (e.g., methyl, ethyl, t-butyl, and isopropyl), fluoroalkyl (Such as, -CF and -CFCH), cycloalkyl (e.g., cyclopro pyl, and cyclohexyl), and cycloalkylalkyl (e.g., cyclopropy lmethyl); and 0429 (2) substituent B in formula IA is: (7 No W s , and le R S R11
0430 wherein 0431) R' is selected from the group consisting of H, OH, –NHC(O)R' or and -NHSOR; 0438 wherein the above rings are unsubstituted, or the 0432 R is -SONR'R''; above rings are Substituted with 1 to 3 Substituents indepen 0433) R' is selected from the group consisting of R', dently Selected from the group consisting of H, F, Cl, Br, hydrogen, halogen, -CF, NR1R1, alkyl, cycloalkyl, and -CF3; R is selected from the group -NRC(O)NR'R'', –C(O)OR', -SH, consisting of H, -CF, -CFCH methyl, ethyl, isopro –SONR'R'', -SOR', -NHC(O)R', pyl, cyclopropyl and t-butyl; and R is H; and -NHSONR'R'', -NHSOR', -C(O)NR'R'', –C(O)NR'OR'', –OC(O)R', -COR', -OR', and cyano, (b) 0434 each R" and R' is independently selected from the group consisting of H, methyl, ethyl, isopropyl and t-butyl; or 0435) R' and R' when taken together with the nitrogen they are attached to in the group -SO2NR'R'' form an US 2004/O147559 A1 Jul. 29, 2004 36
0439 wherein R is selected from the group consisting 0449) wherein R is selected from the group consisting of H, -CF, -CFCH methyl, ethyl, isopropyl, cyclo of H, -CF, -CFCH methyl, ethyl, isopropyl, cyclo propyl and t-butyl; and R is H; and R is as defined for propyl and t-butyl; and R is H; and R is as defined for formula IA. formula IA; 0440 (2) substituent B in formula IA is: 0450 (2) substituent B in formula IA is:
R S R11 R3 S R11
0441 wherein: 0451 wherein: 0442 R is selected from the group consisting of H, OH, 0452 R is selected from the group consisting of: H, OH, –NHC(O)R and -NHSOR: -NHC(O)R and -NHSOR' (preferably -OH); 0443) R is selected from the group consisting of: 0453 Ris-SONR'R''; –C(O)NR'R'', -SONR'R'', -NO, cyano, 0454) R' is selected from the group consisting of H, -SOR'; and –C(O)OR'; halogen and alkyl (preferably H); and 0444) R' is selected from the group consisting of H, 0455 each R" and R' is independently selected from halogen and alkyl, and the group consisting of H and ethyl, preferably R' and R' 0445 each R', and R'' is independently selected from are ethyl. the group consisting of H, methyl, ethyl, isopropyl and 04.56 Embodiment No. 50 is directed to the novel com t-butyl. pounds of formula IA wherein: 0446 Embodiment No. 43 is directed to the novel com 0457 (1) substituent A in formula IA is selected pounds of formula IA wherein: from the group consisting of: 0447 (1) Substituent A in formula IA is selected from the group consisting of: CF
R7 R8 R7 R8 R7 R8 ANS (7 No w Qu s Qu s e s CF 1
R8, and
0448 wherein the above rings are unsubstituted, or the above rings are Substituted with 1 to 3 Substituents indepen dently Selected from the group consisting of F, Cl, Br, alkyl, cycloalkyl, and -CF3; R is selected from the group con sisting of H, -CF, -CFCH methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R is H; and
(b) US 2004/O147559 A1 Jul. 29, 2004 37
-continued -continued 1 1 Y NJ
O CF.
Cl CF3 E d s : al O U2 s
Br V O E 1 ; and F ro s 0458 (2) substituent B in formula IA is:
CF 3 1 s R3 S R11 \ . \ | R2
O 0459 wherein: Z / 0460 R isIS-UF1, -OH 0461) R is:S --SONR'R'' N-1 CF 0462) R' is H; and 0463) R' and R'' are ethyl. O S 0464 Embodiment No. 51 is directed to compounds of / s / s formula IA wherein B is Selected from the group consisting of: CF CF
S O (1) US 2004/O147559 A1 Jul. 29, 2004 38
0465 provided that R for this group is selected from the group consisting of: -C(O)NR'R'', -continued
9 R13 R12 (9) R31 -R 141 N Rt. N O | s R and O N 21 R30 R3 N OR OH 4. Y. s R4 (10) (2) 1. "S-N N21 S. s R3 N R3 R2 OH 11 (3) R (11) R N S N 21
S. s s R3 R3 S. R2 (4) OH ,' 2 R12 (12) N-N 4 s O N R R3 / ; and R2 R3 S
(5) OH (13)
R12 (6) RIQ NA
R3 0466 wherein all other substituents are as defined for R2 formula IA. R4 (7) 0467 Embodiment No. 52 is directed- 0 to compounds of formula IA wherein B is Selected from the group consisting 7 S of: R le s
R2 R12 (1) (8) R3 Sn R N O \ f R3 21 R2 US 2004/O147559 A1 Jul. 29, 2004 39
0471 Embodiment No. 54 is directed to compounds of -continued formula IA wherein B is:
(2)
OH
(3) R e' 0472) wherein all Substituents are as defined for formula IA. 0473 Embodiment No. 55 is directed to compounds of Cly formula IA wherein B is: OH
(4) Rt. N R12 2 O N R4 R3 S
OH R3 N ; and
OH 0474 wherein all substituents are as defined for formula IA. 0475 Embodiment No. 56 is directed to compounds of formula IA wherein B is: (5)
R12 O N R4
R3 N
0468 wherein all substituents are as defined for formula OH IA. 0469 Embodiment No. 53 is directed to compounds of 0476 wherein all substituents are as defined for formula formula IA wherein B is: IA. 0477 Embodiment No. 57 is directed to compounds of formula IA wherein B is:
R12 R N O
R3 21
OH
0470 wherein all substituents are as defined for formula 0478 wherein all substituents are as defined for formula IA. IA. US 2004/O147559 A1 Jul. 29, 2004 40
0479 Embodiment No. 58 is directed to compounds of 0487. Embodiment No. 62 is directed to compounds of formula IA wherein B is: formula IA wherein B is Selected from the group consisting of:
0488 wherein all substituents are as defined for formula IA. 0480 wherein all substituents are as defined for formula IA. 0489 Embodiment No. 63 is directed to compounds of 0481 Embodiment No. 59 is directed to compounds of formula IA wherein B is described in any of Embodiment formula IA wherein B is: Nos. 51 to 62 and A is as described in any of Embodiments NOS. 31-44. 0490 Embodiment No. 64 is directed to any one of the R5 Embodiment Nos. 1 to 63 wherein the novel compound of Rt. R6 formula IA is a pharmaceutically acceptable Salt. 0491 Embodiment No. 65 is directed to any one of the Embodiment Nos. 1 to 63 wherein the novel compound of N formula IA is a Sodium Salt. 0492 Embodiment No. 66 is directed to any one of the R10)-- Embodiment Nos. 1 to 63 wherein the novel compound of formula IA is a calcium salt. 0493 Embodiment No. 67 is directed to a pharmaceuti 0482 wherein all substituents are as defined for formula cally acceptable Salt of any one of the representative novel IA. compounds described below. 0483 Embodiment No. 60 is directed to compounds of formula IA wherein B is: 0494 Embodiment No. 68 is directed to a sodium salt of any one of the representative novel compounds described below. 0495 Embodiment No. 69 is directed to a calcium salt of any one of the representative novel compounds described below. 0496 Embodiment No. 70 is directed to a pharmaceutical composition comprising at least one (e.g., 1 to 3, usually 1) novel compound of formula IA as described in any one of the Embodiment Nos. 1 to 69 in combination with a phar maceutically acceptable carrier (or diluent). 0484 wherein all substituents are as defined for formula 0497 Embodiment No. 71 is directed to a method of IA. treating any one of the diseases described herein (e.g., the 0485 Embodiment No. 61 is directed to compounds of chemokine mediated diseases, and cancer) comprising formula IA wherein B is: administering to a patient in need of Such treatment an effective amount (e.g., a therapeutically effective amount) of a novel compound of formula IA as described in any one of the Embodiment Nos. 1 to 69. 0498 Embodiment No. 72 is directed to novel com pounds of Examples 2006, 2010, 2015, 2029, 2034, 2035, 2038, 2039, 2047, 2050, 2074, 2079, and 2087. R11 0499 Embodiment No. 73 is directed to a pharmaceutical composition comprising at least one (e.g., 1 to 3, usually 1) N-NH novel compound of Embodiment No. 72 (or a pharmaceu tically acceptable Salt or Solvate thereof, e.g., a calcium or 0486 wherein all substituents are as defined for formula Sodium salt) in combination with a pharmaceutically accept IA. able carrier (or diluent). US 2004/O147559 A1 Jul. 29, 2004 41
0500 Embodiment No. 74 is directed to a method of treating any one of the diseases described herein (e.g., the -continued chemokine mediated diseases, and cancer) comprising 1. administering to a patient in need of Such treatment an E effective amount (e.g., a therapeutically effective amount) of O : F at least one (e.g., 1 to 3, usually 1) compound of N N N OH H 0501) Embodiment No. 72 (or a pharmaceutically accept- 1 N. able Salt or Solvate thereof, e.g., a calcium or Sodium salt). O O 0502 Representative compounds of the invention include N ( s but are not limited to: 1. N N S
O OH. H. H /
H
N N 1 1 O N rOH O OH
l, Cl, ) ( )ic) US 2004/O147559 A1 Jul. 29, 2004 42
-continued -continued
ly N r r i OH
HO
O O HO
O O O 1. O /N N N H N S. O OH O HO O O F F F
O S A -N-N OH H H / O O -
-\\ N
OH H \U/ O Yi M Q O ( O 1 O HO H Y^,h O O 1 N s 1.
O OH H US 2004/O147559 A1 Jul. 29, 2004 43
-continued -continued
O O \ ce, - 1. N Cl Ciro O OH H H
O O ( O O 1. Cl 1 N ls O OH H H O OH H H O O N O O S N s 1 1 N 1N M N O OH H H 1. N 1S O O O OH h h O O N
N O OH H H 1. 6, O O O HO H H N NH2 1. N N M O OH H H O O O
N s 1.
O OH H H O O O O 1. Cl O HO H H O O
F
O
-N-N OH H H US 2004/O147559 A1 Jul. 29, 2004 44
-continued -continued
O O O O 1 N N JOO 1. 1 Cl O OH H H O OH H H F O O O O
1 N -N N ( 1n1 uC O OH H H O OH H H O "Y- s N : 1. O O O OH H H O O 1 N Yry O OH H H / 1. N 6, \ 7" V O HO H H O N : 1.
O O O OH H H F O O HN : O OH H H 1. Cl O O O OH h h O N OC) O O N O OH H H O O 1 C. O OH H H 1. O O N : H1
O OH H H 1. N 1
O OH H H O O
-N N 1n-1 O OH h h US 2004/O147559 A1 Jul. 29, 2004 45
-continued -continued
O O 1. N Cl O O O OH H H O O
N N N H H 1 O O O OH H H O O N X 1. 1. N O HO H H O O OH O OH H H O O
N
N O OH H H 1. O O O OH H H S
O O 1 N -O O OH H H E 1. N
s O OH H H S O O O O
1. N O
O OH H H O OH H H O O 1. 'llŠs O O
1.
O OH H H O O O OH H H Šs O O 1. N x N O OH H H 1. O O O OH H H 1 N 5 O OH H H US 2004/O147559 A1 Jul. 29, 2004 46
-continued -continued
O O N
O O - O ClOH h Nh
O O
h h H -N N CON O OH h h O O 1. N s 1. N 1)N
O OH H H
O O
O OH H H 1. O O
O OH H H 1N ON
O OH H H O O N O O 1. N s 1. r\ 1. N N 1N1 On O OH H H O OH H H O O O O
1. N -O \ N N O OH H H -N N H h O O / OH O O O N : 1. O O OH H H / O O C. NY 1NN OH h h
1. N O
US 2004/O147559 A1 Jul. 29, 2004 49
-continued -continued
O O O O e' N-1 1 N : 1N N N N1\ 1. O OH h h O HO H H
O O r 1 O OE F -N1-S-1Ns. 1 F O OH h h O s S 1. N N OH H H / O O O O 1. Y 1 N --SS,O OH h h 1\ 1 y O O O OH H H O | 1 1 O O ---,O OH h hN
\ O O O OH O N N \ uN (
1N N 1N O OH h h O O
O : S N A 1 NS OH H H /
US 2004/O147559 A1 Jul. 29, 2004 51
-continued -continued O O F. F \ O O
\ N N O s V / N N H H 1. N N
O O OH H H s F F O O 1 N 1 O N N N /y OH S. H C.21 ore Yu ro O O O
N-N S. . (. Y- and -N N (N AV N. O O N N O O OH H H V W
y O O N-Ns ( ( s- -N N N S 4\, N N N O O OH h h / OH Yi h W 2 O
-N N N S 0503 Preferred compounds of the invention include: O OH H H /
O O
N -k 1. N N N O N H. H. | || / OH O OH H H / O
O O O O
N 1. N
O OH H H 1. O OH. H. H r/
O O O O 1.
-N N N S -N N N S US 2004/O147559 A1 Jul. 29, 2004 52
-continued -continued
O
1 O ClHO h
O
O HO H
O
1 N
O OH H
O
1 N
O OH H
O
1. N O
O OH H O
N
O HO H
7 N Cy\
\/N OH O O US 2004/O147559 A1 Jul. 29, 2004 53
-continued -continued
O O O O 1 HN s -N NDOC, N XF O a h O OH H H O O O~ 1 y - r ( N N N s \ - CiOH iro O OH H H O O O
O O 1 1. N O OH H H NN N N \2\\ O O OH O O N F HO 1. O O O OH H H
ODI F O O
O OH H H 1YS rooO 1. N ( OC)S
O OH H H O O
OH 1. N
O OH H H O O
O OH N O O 1.
O OH H H O s F N) O?N O O 1 NS OH ro 1. N 6, OS. O HO H H
US 2004/O147559 A1 Jul. 29, 2004 55
-continued -continued
O O F F O O \l- O S N -N 1 N N -N-N OH H H / O OH H H O O O O
O ( S 1. | Cl 1. O OH H H H H 1N OH / CN O O O O X 1 1. N C. s 1 N - O OH H H O OH H H / O O O O
1. N O O HO H H O HO O O 1. N s 1. O OH H H / O O
1. N O
O OH H H Z
O O O 1. O O 1. N N s 1 O OH H H O O OH H H / O O
N / O O N O1 N-N S 1 Sr. N O HO H H N N O O US 2004/O147559 A1 Jul. 29, 2004 56
0504. A more preferred group of compounds includes: -continued
s S \ N N O N s
-N H H / 1. O OH 2 O OH H H
O O F F ( Y-r O O
N W 1. N O / H H 2 N N O OH O OH h h \ / O O O O FY-r F N ( s -N N N & \ N N O A N W O OH. H. H / bH " H 2 O O 1. O
y O O O N N F N-N S and M s 6 O Sl N N Š O -N-N OH H O H O OH h h W 2 ( Y -N
y O O O OH. H. 'N N-N S ( S O O N. N. IY, bit N N (C)O 1 N ( O US 2004/O147559 A1 Jul. 29, 2004 57
-continued -continued
CN O O 1 r N s r 1 OH
O OH H H HO
O O 1 N : 1 N 1N O OH h h O O 1 1. N
O OH H H / CN O O
1. N O OH H H CN O O 1 N s 1 N 1N O OH h h O O 1 O OH N : 1. -N N (?N \ O O HO H H O O OH h /
O O
O O 1 N :
O OH H H 7 -N ( \ O CN O OH H / O O 1 1. N
O OH H H 7 US 2004/O147559 A1 Jul. 29, 2004 58
0505) A most preferred group of compounds includes: -continued S O O 1 1. N N ( : O O O
4. \, OH H H / -N N N O OH h h O O ". O O / y Y.V I C -N O O O OH H H O O O O \A- S. N s 1. N 1n N V O A / OH H H W 21 O OH H H O O O 1 N : 1. N 1N
O OH H H
N N O h / O bH " H W 2 O O 1
N O O y F 1. O OH H H
N V O / O bH " H W 21 h O O
N S O OH H H O/V O \ N V O and O O OH H H / 2 1 1. N O y O O O OH H H / Yr C.D.C. O O /\, Nulls’V N, O OH H H W N s 2 1. N N-N US 2004/O147559 A1 Jul. 29, 2004 59
-continued -continued
N N O H H 9
s F F
N N s O VH Hrt - O CyO F F NS N ClO s y N N O and H H -
O O
N (N O H H -
0506 Certain compounds of the invention may exist in different Stereoisomeric forms (e.g., enantiomers, diastere oisomers and atropisomers). The invention contemplates all Such Stereoisomers both in pure form and in admixture, including racemic mixtures. Isomers can be prepared using conventional methods. N 2 0507 Certain compounds will be acidic in nature, e.g. S those compounds which possess a carboxyl or phenolic sF hydroxyl group. These compounds may form pharmaceuti cally acceptable Salts. Examples of Such Salts may include Sodium, potassium, calcium, aluminum, gold and Silver > H 2 Salts. Also contemplated are Salts formed with pharmaceu tically acceptable amines Such as ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine and the like. US 2004/O147559 A1 Jul. 29, 2004 60
0508 Certain basic compounds also form pharmaceuti 0515 Liquid form preparations include solutions, Sus cally acceptable Salts, e.g., acid addition Salts. For example, pensions and emulsions. AS an example may be mentioned the pyrido-nitrogen atoms may form Salts with Strong acid, water or water-propylene glycol Solutions for parenteral while compounds having basic Substituents Such as amino injection or addition of Sweeteners and opacifiers for oral groups also form Salts with weaker acids. Examples of Solutions, Suspensions and emulsions. Liquid form prepara Suitable acids for Salt formation are hydrochloric, Sulfuric, tions may also include Solutions for intranasal administra phosphoric, acetic, citric, Oxalic, malonic, Salicylic, malic, tion. fumaric, Succinic, ascorbic, maleic, methaneSulfonic and other mineral and carboxylic acids well known to those 0516 Aerosol preparations suitable for inhalation may skilled in the art. The Salts are prepared by contacting the include Solutions and Solids in powder form, which may be free base form with a Sufficient amount of the desired acid in combination with a pharmaceutically acceptable carrier, to produce a Salt in the conventional manner. The free base Such as an inert compressed gas, e.g. nitrogen. forms may be regenerated by treating the Salt with a Suitable 0517. Also included are solid form preparations which dilute aqueous base Solution Such as dilute aqueous NaOH, are intended to be converted, Shortly before use, to liquid potassium carbonate, ammonia and Sodium bicarbonate. The form preparations for either oral or parenteral administra free base forms differ from their respective salt forms tion. Such liquid forms include Solutions, Suspensions and Somewhat in certain physical properties, Such as Solubility in emulsions. polar Solvents, but the acid and base Salts are otherwise equivalent to their respective free base forms for purposes of 0518. The compounds of the invention may also be the invention. deliverable transdermally. The transdermal composition can take the form of creams, lotions, aerosols and/or emulsions 0509 All such acid and base salts are intended to be and can be included in a transdermal patch of the matrix or pharmaceutically acceptable Salts within the Scope of the reservoir type as are conventional in the art for this purpose. invention and all acid and base Salts are considered equiva lent to the free forms of the corresponding compounds for 0519 Preferably the compound is administered orally. purposes of the invention. 0520 Preferably, the pharmaceutical preparation is in a 0510 Compounds of formula IA can exist in unsolvated unit dosage form. In Such form, the preparation is Subdi and Solvated forms, including hydrated forms. In general, Vided into Suitably sized unit doses containing appropriate the Solvated forms, with pharmaceutically acceptable Sol quantities of the active component, e.g., an effective amount vents Such as water, ethanol and the like, are equivalent to to achieve the desired purpose. the unsolvated forms for the purposes of this invention. 0521. The quantity of active compound in a unit dose of 0511. In a preferred embodiment of the treatment of preparation may be varied or adjusted from about 0.01 mg cancer, a compound of formula IA is administered in com to about 1000 mg, preferably from about 0.01 mg to about bination with one of the following antineoplastic agents: 750 mg, more preferably from about 0.01 mg to about 500 gemcitabine, paclitaxel (Taxol.B), 5-Fluorourcil (5-FU), mg, and most preferably from about 0.01 mg to about 250 cyclophosphamide (Cytoxane), temozolomide, or Vincris mg, according to the particular application. tine. 0522 The actual dosage employed may be varied 0512. In another preferred embodiment, the present depending upon the requirements of the patient and the invention provides a method of treating cancer, comprising severity of the condition being treated. Determination of the administering, concurrently or Sequentially, and effective proper dosage regimen for a particular situation is within the amount of a compound of formula IA and a microtubule skill of the art. For convenience, the total dosage may be affecting agent e.g., paclitaxel. divided and administered in portions during the day as 0513. Another embodiment of the invention is directed to required. a method treating cancer, comprising administering to a 0523 The amount and frequency of administration of the patient in need thereof, concurrently or Sequentially, a compounds of the invention and/or the pharmaceutically therapeutically effective amount of (a) a compound of acceptable Salts thereof will be regulated according to the formula IA, and (b) an antineoplastic agent, microtubule judgment of the attending clinician considering Such factors affecting agent or anti-angiogenesis agent. as age, condition and size of the patient as well as Severity 0514 For preparing pharmaceutical compositions from of the Symptoms being treated. A typical recommended daily the compounds described by this invention, inert, pharma dosage regimen for oral administration can range from about ceutically acceptable carriers can be either Solid or liquid. 0.04 mg/day to about 4000 mg/day, in two to four divided Solid form preparations include powders, tablets, dispersible doses. granules, capsules, cachets and Suppositories. The powders 0524 Classes of compounds that can be used as the and tablets may be comprised of from about 5 to about 95 chemotherapeutic agent (antineoplastic agent) include: alky percent active ingredient. Suitable Solid carriers are known lating agents, antimetabolites, natural products and their in the art, e.g., magnesium carbonate, magnesium Stearate, derivatives, hormones and steroids (including Synthetic ana talc, Sugar or lactose. Tablets, powders, cachets and capsules logs), and Synthetics. Examples of compounds within these can be used as Solid dosage forms Suitable for oral admin istration. Examples of pharmaceutically acceptable carriers classes are given below. and methods of manufacture for various compositions may 0525 Alkylating agents (including nitrogen mustards, be found in A. Gennaro (ed.), Remington's Pharmaceutical ethylenimine derivatives, alkyl Sulfonates, nitroSoureas and Sciences, 18" Edition, (1990), Mack Publishing Co., Easton, triaZenes): Uracil mustard, Chlormethine, Cyclophospha Pa. mide (Cytoxan(R), Ifosfamide, Melphalan, Chlorambucil, US 2004/O147559 A1 Jul. 29, 2004
Pipobroman, Triethylene-melamine, Triethylenethiophos (1997) Cancer Res. 57:3344-3346; Nicolaou (1997) Nature phoramine, BuSulfan, Carmustine, Lomustine, Streptozocin, 387:268-272; Vasquez (1997) Mol. Biol. Cell. 8:973-985; Dacarbazine, and Temozolomide. Panda (1996) J. Biol. Chem. 271:29807-29812. 0526 Antimetabolites (including folic acid antagonists, 0533 Particularly preferred agents are compounds with pyrimidine analogs, purine analogs and adenosine deami paclitaxel-like activity. These include, but are not limited to nase inhibitors): Methotrexate, 5-Fluorouracil, Floxuridine, paclitaxel and paclitaxel derivatives (paclitaxel-like com Cytarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabine pounds) and analogues. Paclitaxel and its derivatives are phosphate, Pentostatine, and Gemcitabine. available commercially. In addition, methods of making 0527 Natural products and their derivatives (including paclitaxel and paclitaxel derivatives and analogues are well Vinca alkaloids, antitumor antibiotics, enzymes, lymphok known to those of skill in the art (see, e.g., U.S. Pat. Nos. ines and epipodophyllotoxins): Vinblastine, Vincristine, 5,569,729; 5,565,478; 5.530,020; 5,527,924; 5,508.447; Vindesline, Bleomycin, Dactinomycin, Daunorubicin, DOXO 5,489,589; 5,488,116; 5,484.809; 5,478,854; 5,478,736; rubicin, Epirubicin, Idarubicin, paclitaxel (paclitaxel is com 5,475,120; 5,468,769; 5,461,169; 5,440,057; 5,422,364; mercially available as Taxolf) and is described in more 5,411,984; 5,405,972; and 5,296,506). detail below in the Subsection entitled “Microtubule Affect 0534 More specifically, the term “paclitaxel” as used ing Agents'), Mithramycin, Deoxyco-formycin, Mitomycin herein refers to the drug commercially available as Taxole C, L-Asparaginase, Interferons (especially IFN-a), Etopo (NSC number: 125973). Taxol?F) inhibits eukaryotic cell Side, and TenipoSide. replication by enhancing polymerization of tubulin moieties into stabilized microtubule bundles that are unable to reor 0528 Hormones and steroids (including synthetic ana ganize into the proper Structures for mitosis. Of the many logs): 17o-Ethinylestradiol, Diethylstilbestrol, Testosterone, available chemotherapeutic drugs, paclitaxel has generated Prednisone, Fluoxymesterone, DromoStanolone propionate, interest because of its efficacy in clinical trials against Testolactone, Megestrolacetate, Tamoxifen, Methylpred drug-refractory tumors, including ovarian and mammary nisolone, Methyl-testosterone, Prednisolone, Triamcino lone, Chlorotrianisene, Hydroxyprogesterone, Aminoglute gland tumors (Hawkins (1992) Oncology, 6:17-23, Horwitz thimide, Estramustine, Medroxyprogesteroneacetate, (1992) Trends Pharmacol. Sci. 13: 134-146, Rowinsky Leuprolide, Flutamide, Toremifene, ZoladeX. (1990).J. Natl. Canc. Inst. 82:1247-1259). 0535 Additional microtubule affecting agents can be 0529) Synthetics (including inorganic complexes such as assessed using one of many Such assays known in the art, platinum coordination complexes): Cisplatin, Carboplatin, e.g., a Semiautomated assay which measures the tubulin Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitox polymerizing activity of paclitaxel analogs in combination antrone, Levamisole, and Hexamethylmelamine. with a cellular assay to measure the potential of these 0530 Methods for the safe and effective administration compounds to block cells in mitosis (see Lopes (1997) of most of these chemotherapeutic agents are known to those Cancer Chemother. Pharmacol. 41:3747). skilled in the art. In addition, their administration is 0536 Generally, activity of a test compound is deter described in the Standard literature. For example, the admin mined by contacting a cell with that compound and deter istration of many of the chemotherapeutic agents is mining whether or not the cell cycle is disrupted, in par described in the “Physicians Desk Reference” (PDR), e.g., ticular, through the inhibition of a mitotic event. Such 2002 edition (Medical Economics Company, Montvale, N.J. inhibition may be mediated by disruption of the mitotic 07645-1742, USA); the disclosure of which is incorporated apparatus, e.g., disruption of normal Spindle formation. herein by reference thereto. Cells in which mitosis is interrupted may be characterized 0531. As used herein, a microtubule affecting agent is a by altered morphology (e.g., microtubule compaction, compound that interferes with cellular mitosis, i.e., having increased chromosome number, etc.). an anti-mitotic effect, by affecting microtubule formation 0537) Compounds with possible tubulin polymerization and/or action. Such agents can be, for instance, microtubule activity can be Screened in vitro. In a preferred embodiment, Stabilizing agents or agents that disrupt microtubule forma the compounds are Screened against cultured WR21 cells tion. (derived from line 69-2 wap-ras mice) for inhibition of proliferation and/or for altered cellular morphology, in par 0532 Microtubule affecting agents useful in the inven ticular for microtubule compaction. In Vivo Screening of tion are well known to those of skill in the art and include, positive-testing compounds can then be performed using but are not limited to allocolchicine (NSC 406042), Hali nude mice bearing the WR21 tumor cells. Detailed protocols chondrin B (NSC 609395), colchicine (NSC 757), colchi for this screening method are described by Porter (1995) cine derivatives (e.g., NSC 33410), dolastatin 10 (NSC 376128), maytansine (NSC 153858), rhizoxin (NSC Lab. Anim. Sci., 45(2):145-150. 332598), paclitaxel (Taxolog), NSC 125973), Taxol?F) deriva 0538. Other methods of screening compounds for desired tives (e.g., derivatives (e.g., NSC 608832), thiocolchicine activity are well known to those of skill in the art. Typically (NSC 361792), trityl cysteine (NSC 83265), vinblastine Such assays involve assays for inhibition of microtubule sulfate (NSC 49842), Vincristine sulfate (NSC 67574), assembly and/or disassembly. ASSays for microtubule epothilone A, epothilone, and discodermolide (see Service, assembly are described, for example, by Gaskin et al. (1974) (1996) Science, 274:2009) estramustine, nocodazole, J. Molec. Biol., 89: 737-758. U.S. Pat. No. 5,569,720 also MAP4, and the like. Examples of Such agents are also provides in vitro and in Vivo assays for compounds with described in the Scientific and patent literature, See, e.g., paclitaxel-like activity. Bulinski (1997) J. Cell Sci. 110:3055-3064; Panda (1997) 0539 Methods for the safe and effective administration Proc. Natl. Acad. Sci. USA 94:10560-10564; Muhlradt of the above-mentioned microtubule affecting agents are US 2004/O147559 A1 Jul. 29, 2004 62 known to those skilled in the art. In addition, their admin 0545. The compound of formula IA, and chemotherapeu istration is described in the Standard literature. For example, tic agent and/or radiation may be administered concurrently the administration of many of the chemotherapeutic agents (e.g., simultaneously, essentially simultaneously or within is described in the “Physicians’ Desk Reference” (PDR), the same treatment protocol) or sequentially, depending e.g., 1996 edition (Medical Economics Company, Montvale, upon the nature of the proliferative disease, the condition of N.J. 07645-1742, USA); the disclosure of which is incor the patient, and the actual choice of chemotherapeutic agent porated herein by reference thereto. and/or radiation to be administered in conjunction (i.e., 0540. The amount and frequency of administration of the within a single treatment protocol) with the compound of compounds of formula IA and the chemotherapeutic agents formula or IA. and/or radiation therapy will be regulated according to the 0546). If the compound of formula IA, and the chemo judgment of the attending clinician (physician) considering therapeutic agent and/or radiation are not administered Such factors as age, condition and size of the patient as well Simultaneously or essentially simultaneously, then the initial as Severity of the disease being treated. A dosage regimen of order of administration of the compound of formula IA, and the compound of formula IA can be oral administration of the chemotherapeutic agent and/or radiation, may not be from 10 mg to 2000 mg/day, preferably 10 to 1000 mg/day, important. Thus, the compound of formula IA may be more preferably 50 to 600 mg/day, in two to four (preferably administered first, followed by the administration of the two) divided doses, to block tumor growth. Intermittant chemotherapeutic agent and/or radiation; or the chemothera therapy (e.g., one week out of three weeks or three out of peutic agent and/or radiation may be administered first, four weeks) may also be used. followed by the administration of the compound of formula 0541. The chemotherapeutic agent and/or radiation IA. This alternate administration may be repeated during a therapy can be administered according to therapeutic pro Single treatment protocol. The determination of the order of tocols well known in the art. It will be apparent to those administration, and the number of repetitions of administra skilled in the art that the administration of the chemothera tion of each therapeutic agent during a treatment protocol, is peutic agent and/or radiation therapy can be varied depend well within the knowledge of the skilled physician after ing on the disease being treated and the known effects of the evaluation of the disease being treated and the condition of chemotherapeutic agent and/or radiation therapy on that the patient. disease. Also, in accordance with the knowledge of the 0547 For example, the chemotherapeutic agent and/or skilled clinician, the therapeutic protocols (e.g., dosage radiation may be administered first, especially if it is a amounts and times of administration) can be varied in view cytotoxic agent, and then the treatment continued with the of the observed effects of the administered therapeutic administration of the compound of formula IA followed, agents (i.e., antineoplastic agent or radiation) on the patient, where determined advantageous, by the administration of and in view of the observed responses of the disease to the the chemotherapeutic agent and/or radiation, and So on until administered therapeutic agents. the treatment protocol is complete. 0542. In the methods of this invention, a compound of 0548 Thus, in accordance with experience and knowl formula IA is administered concurrently or Sequentially with edge, the practicing physician can modify each protocol for a chemotherapeutic agent and/or radiation. Thus, it is not the administration of a component (therapeutic agent-i.e., necessary that, for example, the chemotherapeutic agent and the compound of formula IA, chemotherapeutic agent or the compound of formula IA, or the radiation and the radiation) of the treatment according to the individual compound of formula IA, should be administered Simulta patient's needs, as the treatment proceeds. neously or essentially simultaneously. The advantage of a Simultaneous or essentially simultaneous administration is 0549. The attending clinician, in judging whether treat well within the determination of the skilled clinician. ment is effective at the dosage administered, will consider the general well-being of the patient as well as more definite 0543. Also, in general, the compound of formula IA and Signs. Such as relief of disease-related Symptoms, inhibition the chemotherapeutic agent do not have to be administered of tumor growth, actual Shrinkage of the tumor, or inhibition in the same pharmaceutical composition, and may, because of metastasis. Size of the tumor can be measured by Standard of different physical and chemical characteristics, have to be methods Such as radio-logical Studies, e.g., CAT or MRI administered by different routes. For example, the com pound of formula IA may be administered orally to generate Scan, and Successive measurements can be used to judge and maintain good blood levels thereof, while the chemo whether or not growth of the tumor has been retarded or therapeutic agent may be administered intravenously. The even reversed. Relief of disease-related Symptoms Such as determination of the mode of administration and the advis pain, and improvement in overall condition can also be used ability of administration, where possible, in the same phar to help judge effectiveness of treatment. maceutical composition, is well within the knowledge of the BIOLOGICAL EXAMPLES skilled clinician. The initial administration can be made 0550 The compounds of the present invention are useful according to established protocols known in the art, and in the treatment of CXC-chemokine mediated conditions then, based upon the observed effects, the dosage, modes of and diseases. This utility is manifested in their ability to administration and times of administration can be modified inhibit IL-8 and GRO-O. chemokine as demonstrated by the by the skilled clinician. following in Vitro assayS. 0544 The particular choice of a compound of formula 0551 Receptor Binding Assays: IA, and chemotherapeutic agent and/or radiation will depend upon the diagnosis of the attending physicians and their 0552) CXCR1 SPA Assay judgement of the condition of the patient and the appropriate 0553 For each well of a 96 well plate, a reaction mixture treatment protocol. of 10 ughCXCR1-CHO overexpressing membranes (Bio US 2004/O147559 A1 Jul. 29, 2004 signal) and 200 ug?well WGA-SPA beads (Amersham) in or GRO-O. (R&D Systems) concentrations were prepared 4x 100 ul was prepared in CXCR1 assay buffer (25 mM in wash buffer+0.1% BSA and added to their respective HEPES, pH 7.8, 2 mM CaCl, 1 mM MgCl, 125 mM NaCl, 0.1% BSA) (Sigma). A 0.4 nM stock of ligand, 125I-IL-8 Wells in Second addition plate. (NEN) was prepared in the CXCR1 assay buffer. 20x stock 0559 Culture plate and both addition plates were then solutions of test compounds were prepared in DMSO (Sigma). A 6x stock solution of IL-8 (R&D) was prepared in placed in the FLIPR imaging System to determine change in CXCR2 assay buffer. The above solutions were added to a calcium fluorescence upon addition of compound and then 96-well assay plate (PerkinElmer) as follows: 10 ul test ligand. Briefly, 50 ul of compound solutions or DMSO compound or DMSO, 40 ul CXCR1 assay buffer or IL-8 Solution was added to respective wells and change in cal stock, 100 ul of reaction mixture, 50 ul of ligandstock (Final Ligand=0.1 nM). The assay plates were shaken for 5 cium fluorescence measured by the FLIPR for 1 minute. minutes on plate Shaker, then incubated for 8 hours before After a 3 minute incubation within the instrument, 50 ul of cpm/well were determined in Microbeta Trilux counter ligand was then added and the change in calcium fluores (PerkinElmer). % Inhibition of Total binding-NSB (250 nM cence measured by the FLIPR instrument for 1 minute. The IL-8) was determined for IC50 values. Compounds of this area under each Stimulation curve was determined and invention had an ICs of <20 uM. The most preferred values used to determine % Stimulation by compound compounds had a K within the range of 3 nM to 1120 nM. (agonist) and % Inhibition of Total Calcium response to 0554 CXCR2 SPA Assay ligand (0.3 nM IL-8 or GRO-O.) for IC50 values of the test compounds. 0555 For each well of a 96 well plate, a reaction mixture of 4 ug hCXCR2-CHO overexpressing membranes (Biosig 0560 Chemotaxis Assays for 293-CXCR2 nal) and 200 ug?well WGA-SPA beads (Amersham) in 100 0561 Achemotaxis assay is setup using Fluorblok inserts ul was prepared in CXCR2 assay buffer (25 mM HEPES, pH (Falcon) for 293-CXCR2 cells (HEK-293 cells overexpress 7.4, 2 mM CaCl, 1 mM MgCl). A 0.4 nM stock of ligand, ing human CXCR2). The standard protocol used at present 125I-IL-8 (NEN), was prepared in the CXCR2 assay is as follows: buffer. 20x Stock Solutions of test compounds were prepared in DMSO (Sigma). A 6x stock solution of GRO-O. (R&D) 0562) 1. Inserts are coated with collagenIV (2 ug/ml) was prepared in CXCR2 assay buffer. The above solutions for 2 hrs at 37 C. were added to a 96-well assay plate (PerkinElmer or Corn 0563. 2. The collagen is removed and inserts are ing) as follows: 10 ul test compound or DMSO, 40 ul allowed to air dry overnight. CXCR2 assay buffer or GRO-O. Stock, 100 ul of reaction mixture, 50 ul of ligand stock (Final Ligand=0.1 nM). 0564) 3. Cells are labeled with 10 uM calcein AM When 40x stock solutions of test compounds in DMSO were (Molecular Probes) for 2 hrs. Labeling is done in prepared, then the above protocol was used except instead 5 complete media with 2% FBS. All test compound or DMSO and 45 ul CXCR2 assay buffer 0565. 4. Dilutions of compound are made in minimal were used. The assay plates were Shaken for 5 minutes on a media (0.1% BSA) and placed inside the insert which plate shaker, then incubated for 2-8 hours before cpm/well is positioned inside the well of a 24 well plate. Within were determined in Microbeta Trilux counter (PerkinElmer). the well is IL-8 at a concentration of 0.25 nM in %. Inhibition of total binding minus non-specific binding minimal media. Cells are washed and resuspended in (250 nM Gro-C. or 50 uM antagonist) was determined and minimal media and placed inside the insert at a con IC50 values calculated. Compounds of this invention had an ICs of <5 uM. The most preferred compounds had a K. centration of 50,000 cells per insert. within the range of 0.8 nM to 40 nM. The compound of 0566 5. Plate is incubated for 2 hrs and inserts are Example 360.31 had a K of 3 nM. The compound of removed and placed in a new 24 well. Fluorescence is Example 360.106 had a K of 0.8 nM. detected at excitation=485 nM and emission=530 nM. 0556) Calcium Fluorescence Assay (FLIPR) 0567 Cytotoxicity Assays 0557 HEK 293 cells stably transfected with hCXCR2 0568 A cytotoxicity assay for CXCR2 compounds is and GC.L/q were plated at 10,000 cells per well in a Poly conducted on 293-CXCR2 cells. Concentrations of com D-Lysine Black/Clear plate (Becton Dickinson) and incu pounds are tested for toxicity at high concentrations to bated 48 hours at 5% CO., 37° C. The cultures were then determine if they may be used for further evaluation in incubated with 4 mM fluo-4, AM (Molecular Probes) in Dye binding and cell based assays. The protocol is as follows: Loading Buffer (1% FBS, HBSS w. Ca & Mg, 20 mM 0569 1. 293-CXCR2 cells are plated overnight at a HEPES (Cellgro), 2.5 mM Probenicid (Sigma) for 1 hour. concentration of 5000 cells per well in complete media. The cultures were washed with wash buffer (HBSS w Ca, & Mg, 20 mM HEPES, Probenicid (2.5 mM)) three times, then 0570) 2. Dilutions of compound are made in minimal 100 ul/well wash buffer was added. media w/0.1% BSA. Complete media is poured off and the dilutions of compound are added. Plates are incu 0558 During incubation, compounds were prepared as bated for 4, 24 and 48 hrs. Cells are labeled with 10 uM 4x stocks in 0.4% DMSO (Sigma) and wash buffer and calcein AM for 15 minutes to determine cell viability. added to their respective wells in the first addition plate. IL-8 Detection method is the same as above. US 2004/O147559 A1 Jul. 29, 2004 64
0571 Soft Agar Assay 0572) 10,000 SKMEL-5 cells/well are placed in a mix ture of 1.2% agar and complete media with various dilutions of compound. Final concentration of agar is 0.6%. After 21 days viable cell colonies are stained with a solution of MTT (1 mg/ml in PBS). Plates are then scanned to determine N -- colony number and size. ICso is determined by comparing R14 S NH2 O total area VS. compound concentration. OH 0573 Compounds of formula IA may be produced by processes known to those skilled in the art, in the following O O reaction Schemes, and in the preparations and examples --- below. 0574. A general procedure for the preparation of com EtO OEt pounds of formula IA is as follows: O O R13V Z \ N Scheme 1 R141 S N OEt 21 O H R HO Step A OH Her N-H -- N Step B O NO O O R14 OH R13V Z \ ---A-NH2 R13 N Y 21 R 141 S OEt 1 O H R14 1.N OH O NH2 O O OH R13 VN Z \ A. O O R 141 S. N N1 V I O H H A. Her HN1 -- OH EtO OEt
O O 0575 Scheme 1 0576 An amine is condensed (Step A) with a nitrosali A. -- cylic acid under Standard coupling conditions and the result EtO N1 V ing nitrobenzamide is reduced (Step B) under hydrogen H atmosphere in the presence of a Suitable catalyst. The remaining partner required for the Synthesis of the final R13 target is prepared by condensing an aryl amine with the Y 21 1 commercially available diethylSquarate to give the amino R14 tSn ethoxySquarate product. Subsequent condensation of this O NH2 intermediate with the aminobenzamide prepared earlier pro OH vides the desired chemokine antagonist (Scheme 1).
R13 O O 0577 Scheme 2 Y 21 Y 0578 Alternatively, the aminobenzamide of Scheme 1 is R14 CN A. first condensed with commercially available diethylSquarate O N N1 H H to give an alternate monoethoxy intermediate. Condensation of this intermediate with an amine gives the desired chemok ine antagonist. US 2004/0147559 A1 Jul. 29, 2004
Scheme 3 R5 Rs R6 R4 R4 NO NH2 NO N 2 Y-N-N HN N H NH2
R4
HN
0579 Scheme 3 earlier (Scheme 1) provides the desired chemokine antago nist. 0580 Benztriazole compounds of Formula (I) or IA are 0581) Scheme 4 prepared by stirring nitrophenylenediamines with Sodium 0582 Condensation of nitrophenylenediamines with nitrite in acetic acid at 60° C. to afford the nitrobenzotriazole anhydrides or activated acids at reflux (Scheme 4) affords intermediate (Scheme 3). Reduction of the nitro group in the benzimidazole intermediates which after reduction with presence of palladium catalyst and hydrogen atmosphere hydrogen gas and palladium catalyst and condensation with provides the amine compound. Subsequent condensation of the aminoethoxysquarate previously prepared (Scheme 1) this intermediate with the aminooethoxysquarate prepared affords benzimidazole chemokine antagonists. US 2004/O147559 A1 Jul. 29, 2004
Scheme 5 R5 R5 R4 R6 R4 R6
He R R 10 \ NO 10 \ NH2 N-NH N-NH O O
A. B
EtO N-A Rs I R6 O O H R4
R10 N N1 A. \ H H N-NH
C
Scheme 6 R5 R5 R4 R6 R4 R6
-- R R 10 \ NO 10 NH2 NH \ NH O O R9 R9 A. B - A EtO N R5 R6 O O H R4
R A. 10 N N Y \ H H NH
0583 Scheme 5 A (J. Med. Chem. 1995, 38, 1942-1954) to give aminoindole 0584) Indazole structures of Formula (I) or IA can be B and Subsequent condensation with the aminoethoX prepared according to Scheme 5 by reduction of nitroinda ySquarate prepared earlier (Scheme 1). zole A (J. Am. Chem Soc. 1943, 65, 1804-1805) to give aminoindazole B and Subsequent condensation with the 0587. The invention disclosed herein is exemplified by aminoethoxySquarate prepared earlier (Scheme 1). the following preparations and examples which should not 0585 Scheme 6 be construed to limit the Scope of the disclosure. Alternative 0586 Indole structures of Formula (I) or IA can be mechanistic pathways and analogous Structures may be prepared according to Scheme 6 by reduction of nitroindole apparent to those skilled in the art. US 2004/O147559 A1 Jul. 29, 2004 67
Preparative Example 1 0591 Step A 0588) 0592) 3-Nitrosalicylic acid (9.2 g), bromotripyrrolidino phosphonium hexafluorophosphate (PyBroP, 23 g) and N,N- diisopropylethylamine (DIEA, 26 mL) in anhydrous CHCl (125 mL) were combined and stirred at 25 C. for 30 min. (R)-(+)-3-pyrrolidinol (8.7g) in CHCl (25 mL) was added over 25 min and the resulting Suspension was stirred at room N-H NO + --- temperature overnight. The mixture was extracted with 1M HOC NaOH (aq) and the organic phase was discarded. The OH aqueous phase was acidified with 1M HCl (aq), extracted OH with EtOAc, dried over anhydrous NaSO, filtered and concentrated in vacuo to afford the crude product (7 g) which was used without further purification. 0593) Step B NO2 N 0594. The crude product from Step A above was stirred OH with 10% Pd/C (0.7g) in MeOH (100 mL) under a hydrogen O gas atmosphere overnight. The reaction mixture was filtered through celite, the filtrate concentrated in vacuo, and the OH resulting residue purified by column chromatography (silica gel, 10% MeOH/CHCl saturated with NHOH) to give the 0589) 3-Nitrosalicylic acid (500 mg, 2.7 mmol), DCC product (2.5g, 41%, MH---223). (563 mg) and ethyl acetate (10 mL) were combined and stirred for 10 min. (R)-(–)-2-pyrrolidinemethanol (0.27 mL) Preparative Example 2.1 was added and the resulting Suspension was stirred at room temperature overnight. The solid was filtered and the filtrate 0595) washed with 1N NaOH. The aqueous phase was acidified and extracted with EtOAc. The resulting organic phase was dried over anhydrous MgSO, filtered and concentrated in vacuo. Purification of the residue by preparative plate chro matography (silica gel, 5% MeOH/CHCl saturated with NBoc AcOH) gave the product (338 mg, 46%, MH"=267). HN Preparative Example 2
0590 O ls NH N N H H
HO HO Step A NO + Nin -- H O OH 0596) To N-BOC-3-(amino)piperidine (0.5 g) dissolved in CHCl (10 mL) was added benzylisocyanate (3 mmol). After stirring for 2 hrs, amine Scavenger resin (1.9 mmol) was added and the mixture was Stirred overnight, filtered, to-ON -asStep B the resin back-washed with CH2Cl and methanol, and the NO2 organics concentrated in vacuo. Stirring of the crude mate O OH rial in 4N HCl/dioxane (40 mL) for 2.5 hrs before concen trating in vacuo gave the title compound (41%, MH---369).
HO Preparative Example 2.2-2.6 N NH2 0597 Following the procedures set forth in Preparative O OH Example 2.1 but using the isocyanate (or chloroformate) indicated in the Table below, the amines were obtained and used without further purification. US 2004/O147559 A1 Jul. 29, 2004
Prep Ex. Amine Isocyanate Amine
2.2 O
HN NCO
2.3 O
HN NH NCO Ol ls Ol
2.4 1Noo O NH ls NH
2.5 O O NH 1 No Cl 1a us NH HN O
2.6 O
NH 1Noo ls NH HN 1n N H H
Preparative Example 2.7 -continued 0598 O 1 O O. O N ClO V/ O OH NBoc F Sn NH O HN N H F H F N CO2H
0599) To N-BOC-3-(amino)piperidine (5 mmol) dis C r Step B solved in CHCl (30 mL) was added trifluoromethane O sulfonic anhydride (5 mmol) and the mixture was stirred r Step C overnight. The mixture was concentrated in vacuo, diluted N with CHCl (10 mL) and treated with trifluoroacetic acid NO (10 mL). After stirring for 2 hr, the mixture was concentrated HOC O OH in vacuo to give the title compound (43%, MH+=233.1). 2 Preparative Example 2.8 O r 0600) NH2 HOC O OH
Step A 0601 Step A HOC NO2 0602 3-Nitrosalicylic acid (5 mmol) and N-hydroxysuc OH cinimide (5 mmol) were added to a solution of 2% DMF/ CHCl, followed by DCC (5 mmol). After stirring for 2 hr, US 2004/O147559 A1 Jul. 29, 2004 69 the mixture was filtered and concentrated in vacuo and the parative Example 2.9 Step A above, the desired compound residue used directly in Step B. was obtained (41%, MH+=374). 0603 Step B 0612) Step C 0604. The product from Step A above was suspended in DMF and to this was added morpholino-2-carboxylic acid 0613 Following a similar procedure as in Preparative HCl (5 mmol) in CHCl (10 mL)/DMF (5 mL) and diiso Example 2, Step B, but using the product from Step Babove, propylethylamine (10 mmol). The mixture was stirred over the desired compound was obtained (99%, MH+=344). night, filtered, basified with 1N NaOH (50 mL), washed with CHCl, acidified with 5N HCl and extracted with EtOAc. Preparative Example 2.10 The organic phase was dried over NaSO, filtered and concentrated in vacuo to give the desired compound which 0.614 was used directly in Step C (MH+=296). 0605 Step C Step A 0606 Following a similar procedure as in Preparative -3- Example 2 Step B, but using the product from Step Babove, the title compound was obtained (23%, MH--=267). HOC NO Preparative Example 2.9 O O 0607) N1 NO O O H Step B N CO2H / \, \ \, , --- -- C r Step A FN C-CCO2H N
H N / \ A V Step B N N-H Ho CS.--> Step C FN \-( NO2 CO2H t 21 N HOC O
susN N Step C -- N NO C N NH2 HOC O OH O HOC O OH NH -> 0615) Step A N NH2 0616) Following a similar procedure as Preparative Example 2.8, Step A except using 3-nitrobenzoic acid, the HOC O OH desired compound was obtained and used directly in Step B. 0617 Step B 0608) Step A 0618. Following a similar procedure as Preparative 0609 2-Piperazinecarboxylic acid and 2-chloro-1,3-py Example 2.8, Step B except using the products from Pre rimidine were stirred with triethylamine and MeOH. After parative Example 2.9, Step A and Preparative Example 2.10, Stirring overnight at reflux, the mixture was filtered and concentrated in vacuo to give the desired compound which Step A, the desired compound was obtained (86%). was used directly in Step B (MH+=209). 0619 Step C 0610 Step B 0620. Following a similar procedure as in Preparative 0611) Following a similar procedure as Preparative Example 2, Step B, but using the product from Step Babove, Example 2.8, Step B except using the product from Pre the desired compound was obtained (67%, MH+=331). US 2004/O147559 A1 Jul. 29, 2004 70
Preparative Example 2.11 vacuo, diluted with water, basified to pH 14 and extracted with ether. The organic phase was dried over Na2SO, 0621) filtered and concentrated in vacuo to give the desired prod uct (98%) which was used directly in Step B. 0629 Step B Step A He 0630. The product from Step A above (500 mg) was N dissolved in MeOH (20 mL) and to this was added NaBH O (50 mg). After Stirring for 10 min, the Solution was concen Step B trated in vacuo to give the desired compound which was He HO N used directly in Step C without purification. 0631 Step C 0632. The product from Step B above was diluted with HO MeOH (20 mL) and to this was added AcOH (0.1 mL), a catalytic amount of Pd/C (10%) and the mixture stirred under H2 atmosphere (balloon) overnight. The mixture was filtered, 4N HCl in dioxane (1 mL) was added, and the 0622 Step A mixture was concentrated in vacuo to give the desired 0623 N-Benzylpiperidone (2 g, HCl salt, hydrate) was compound that was used directly without purification. stirred with THF (20 mL), concentrated to dryness, and placed under high vac. The residue was diluted in THF (20 Preparative Example 2.13 mL), and methyllithium was added (2.5 eq of 1.6N in EtO) Via Syringe. After Stirring for 3 hr, the mixture was concen 0633) trated in vacuo, diluted with water, extracted with CHCl, and dried over NaSO. Filtration and concentrating in HCI vacuo gave the desired product (50%, MH---205). Step A 0624) Step B MeO3CN- NH2 -- H Step B 0625. Following a similar procedure as in Preparative He Example 2, Step B, but using the product from Step A above, N the title compound was obtained (95%, MH--=116). r NO2 Preparative Example 2.12 HOC O OH 0626) | N r NH2 Step A HOC O OH He H1 N 0634) Step A Step B --- 0635. Following a similar procedure as Preparative Example 2, Step A except using methyl glycinate, the N~ N desired ester was obtained. The mixture was poured into 200 O mL of 1N NaOH, then extracted with dichloromethane. The pH was adjusted to 1 and NaCl was added until saturation. Step C He After Several hours, the resulting precipitate was filtered and washed with cold water to give the desired product (42%). N 0636) Step B OH 0637 Following a similar procedure as in Preparative Example 2 Step B, but using the product from Step A above, the title compound was obtained (95%). Preparative Example 2.14 0638) 0627 Step A 0628 To N-benzyl-N-methylamine (20 mmol) dissolved HCI in acetone (50 mL) was added concentrated HCl (20 mmol), paraformaldehyde (30 mmol) and 2-propanol (2 mL). After MeOC''2'-N-Nn PA Stirring at reflux overnight, the mixture was concentrated in US 2004/O147559 A1 Jul. 29, 2004
-continued -continued
Step B
r NO2 EtO HOC O OH ?o
| HO N N r NH2 H O OH HOC O OH OHo 0644. The cyclobutenedione intermediate from Prepara tive Example 87 (200 mg), DIEA (100 ul), 3-aminosalicylic 0639 Step A acid (120 mg) and EtOH (4 ml) were combined and heated 0640 Following a similar procedure as in Preparative to reflux overnight to give the title compound (90%, MH--- Example 2.13, Step A except using methyl N-methylglyci 367). nate, the desired product was obtained (18%). Preparative Example 2.16 0645) 0641) Step B 0642 Following a similar procedure as in Preparative Example 2, Step B, but using the product from Step A above, O O the title compound was obtained (95%, MH--=225). N a n N Preparative Example 2.15 2 21 0643) 0646) The above n-oxide (2 g) was combined with HNMe/HO (15 cm) and heated to 140° C. overnight. Potassium carbonate (1.3 g) added and the mixture concen trated in vacuo. Extraction with EtOH and concentration of the filtrate in vacuo gave 1.56 g of crudeamine (MH+=125).
-- Preparative Example 3-10.50 HO 0647. Following the procedures set forth in Preparative NH2 Examples 1-2 but using the carboxylic acid, amine, and O OH coupling agent DCC (Prep. Ex. 1) or PyBrop (Prep. Ex. 2) listed in the Table below, the indicated amide products were obtained and used without further purification.
1. Coupling Agent Prep Carboxylic 2% Yield Ex. acid Amine Product 3. MH
3 \ 1. ... PyBrop N-H 87%, 86% NO2 / 181 HOC OH OH US 2004/O147559 A1 Jul. 29, 2004 72
-continued . Coupling Agent Prep Carboxylic % Yield Ex. acid Amine s 4 ... PyBroP 49% 209 NO HOC COH NH, ... PyBroP 95% 153 NO HOC OH ... PyBroP 83% 167 NO HOC OH ... PyBroP 76% 223 NO2 HOC OH ... PyBroP 65, 53 209 NO2 HOC OH ... PyBroP
NO2 Kl HOC OH
1O ... PyBroP 49, 86 237 NO HOC OH
10.1 ... PyBroP 30, 88 193 NO NH2 HOC OH O OH
10.2 ... PyBroP 26, 87 195 NO H NH2 HOC OH US 2004/O147559 A1 Jul. 29, 2004 73
-continued . Coupling Agent Prep Carboxylic 2.9% Yield Ex. acid Amine
10.3 ... PyBroP N-1N1 NH2 38 s 209 NO HOC OH
10.4 ... PyBroP 29 209 NO HOC OH
10.5 ... PyBroP 38 223 NO2 HOC OH
10.6 2.7 ... PyBroP 32, 99 i 367.9 NO NH HOC OH 1N
10.7 ... PyBroP 35, 99 237 NO2
HOC OH OH
OH
10.8 DCC 30, 99 s 269 NO2 HOC OH
10.9 ... PyBroP 58, 95 233.1 NO HOC OH HO
10.10 ... PyBroP 42, 95 238.9 NO HOC OH HO OH US 2004/O147559 A1 Jul. 29, 2004
-continued
1. Coupling Agent Prep Carboxylic 2.9% Yield Ex. acid Amine Product 3. MH
10.13 1. PyBroP 2.51, 95 2.4 s O 3.307
NO O l N 2 1YN1) NH2 HOC 1n N N H H OH H H O OH
10.14 2.2 1. PyBroP O 2.55 NO O Ox l N 3.347 HOC N N OH H H O OH
10.15 2.1 1. PyBroP O 2. 41 O l N 3.369.1 NO2 l NH NH2 HOC O OH OH
10.16 2.3 1. PyBroP O 2.56 O l N 3.354.9 NO2 l NH NH2 HOC NH NH O OH OH
10.17 2.5 1. PyBroP O 2.56 O 3.308 NO2 1n N ul NH O NH2 HOC OH 1n 1\ H O OH
10.18 12.4 OH 1. PyBroP 2. 10, 95 OH 3. 252.9 NO HOC O OH O N NH NH2 O OH
10.19 H 1. PyBroP N 2.42, 95 N 3. 249 NO2 O NH2 HOC OH N OH US 2004/O147559 A1 Jul. 29, 2004 75
-continued 1. Coupling Agent Prep Carboxylic 2.9% Yield Ex. acid Amine 3. MH
10.2O H 1. ... PyBroP HO N 15, 95 264.9 NO HOC OH
10.21 NH2 1. PyBroP HO 64, 95 273 NO HOC OH
10.22 H 1. PyBroP HO N-1 2.45, 95 3. 273 NO2 HOC OH
1. PyBroP 2.44, 95 10.23 NO2 > N~"O 3. 281 HOC OH
10.24 N1 N N 1. 1. PyBroP H 2.41, 95 3. 281.1 NO 21 HOC OH N 21 US 2004/O147559 A1 Jul. 29, 2004 76
-continued
. Coupling Agent Prep Carboxylic % Yield Ex. acid Amine MH
10.25 ... PyBroP 48, 95 H 257 NO Orr NH2 HOC COH OH c) 10.26 DCC 15, 99 s 235 NO 1CH HOC COH 1CCO OH
10.28 H ... PyBroP N 52, 95 237.1 NO2 HOC COH N ClOH r
10.29 OH 1. PyBroP 2. 31, 95 3. 259.1 NO N O HOC HO COH N ClOH N
10.30 H 1. PyBroP N 2. 54,95 3. 250.9 NO O HOC ro COH N ClOH
10.31 1. PyBroP 2. 64, 95 3. 210.9 NO O NH2 HOC COH o1N1 N OH US 2004/O147559 A1 Jul. 29, 2004
-continued
1. Coupling Agent Prep Carboxylic % Yield Ex. acid Amine Product 3. MH
10.32 NH2 ... PyBroP HO1N1 47, 95 s 197 NO2 O NH2 HOC COH NH OH to 1N1
10.33 ... PyBroP 47, 95 273 NO O NH2 HOC COH N OH o1N1
10.34 NH ... PyBroP 51, 95 237.1 NO O NH2 HOC HO COH N OH
HO
10.35 NH2 ... PyBroP 60, 90 OH 224 NO 1. NH2 O HOC COH NH2 O
10.36 NH2 ... PyBroP 65, 99 OH 252 NO O HOC COH NMe2
O
10.37 NH2 ... PyBroP 58, 99 OH 239 NO2 1. OMe HOC COH US 2004/O147559 A1 Jul. 29, 2004
-continued . Coupling Agent Prep Carboxylic i. % Yield Ex. acid A.mi e Product MH
10.38 NH2 ... PyBroP 35, 99 OH 221.1 NO2 HOC COH O O
10.39 NH2 ... PyBroP 42, 99 OH 235.2 NO HOC COH O O
10.40 NH2 DCC 32, 99 OH s 293.1 NO2
HOC N COH to's OEt O O
10.41 HO NH2 ... PyBroP 45, 99 OH 223.1 NO2 O HOC N COH OH
O
10.42 HO HO ... PyBroP 55, 81 251.1 NO HOC COH C. NH2 O OH
10.43 ... PyBroP 68, 66 224.9 NO2 HO 1N1 N NH2 HOC COH O OH
10.44 OH OH ... PyBroP 68, 66 241.1 NO
HOC NH COH 1N1 N HO1N1 HO NH2
O OH US 2004/O147559 A1 Jul. 29, 2004
-continued
1. Coupling Agent Prep Carboxylic 2.9% Yield Ex. acid Amine Product 3. MH
10.45 1. PyBroP 2. 44, 40 3. 295 O NO NH O/N NH2 HOC N OH O O OH O ) O
10.46 1. DCC 2.37, 81 3. 265
NO NH N NH2 HOC OH O OH HO O HO O
10.47 1. PyBroP 2. 71,95 2.6 3.293.1
NO2 O NH N O NH2 HOC 1n OH 1n N O OH H H
10.48 1. PyBroP N 2.35, 99 NH2 3. 220.9 N1 S H NO2 \- N -N N N1 N NH2 HOC W OH N-N O OH
10.49 1. DCC 2. 16, 99 NH2 3. 209.O H NO N NH2 HOC OH O OH
10.50 1. DCC 2. 18, 99 264.O
NO2 HN NH HOC COH O - O C O COH US 2004/O147559 A1 Jul. 29, 2004
Preparative Example 10.55 -continued Alternative Procedure for Preparative Example 3 0648)
Step A 0651) A mixture of the product from step B above (6 g), HO 10% Pd/C (0.6 g), and EtOH (80 mL) was stirred in a parr NO2 Shaker under hydrogen (40 psi) at room temperature for 2 O OH days. Filtration through celite and concentration in vacuo afforded the title product (5.1 g, 99%, MH"=181). Preparative Example 11 Cl 0652) NO
0649) To the nitrosalicylic acid (3 g) dissolved dichlo Step A romethane (150 mL) at room temperature was added oxalyl HC-- chloride (4.3 mL) and DMF (0.01 eq.). After stirring for one HOC day the mixture was concentrated in a vacuum to give a Semi OH solid which was used directly in step B.
Step B Step B - -ss 1. N N C NO2 OH
Step C HC-- N 1 N NO2
OH
0650. To the material from step A diluted in dichlo romethane (50 mL) and cooled to 0°C. was added dimethyl N amine in THF (2N solution, 24.6 mL) and triethylamine (4 1. N NH2 eq.). After Stirring for 24 hours at room temperature the OH mixture was concentrated in vacuo, diluted with 1M Sodium hydroxide (30 mL) and after a half hour was washed with dichloromethane. The aqueous phase was acidified with 6M 0653 Step A HCl (aq), extracted with dichloromethane and the organic 0654 Following a similar procedure as in Preparative phase was washed with water, dried over NaSO and Example 1 except using dimethylamine (2M in THF, 33 mL) concentrated to give the title compound (3.2g, 93%). and 5-methylsalicylic acid (5 g), the desired product was prepared (6.5 g). Step C 0655 Step B 0656 Nitric acid (0.8 mL) in HSO was added to a cooled (-20° C) suspension of the product from Step A above (3 g) in HSO (25 mL). The mixture was treated with 50% NaOH (aq) dropwise, extracted with CHCl, dried over anhydrous MgSO, filtered and concentrated in vacuo to give the product as a crude solid (2.1 g, 44%, MH"=225). US 2004/O147559 A1 Jul. 29, 2004
0657 Step C 0665 Following the procedures set forth in Preparative 0658. The product was prepared in the same manner as Example 11.1, Steps A and B, but using N-methylmethoxy described in Step B of Preparative Example 2 (0.7g, 99%, lamine, the title compound was obtained (86%, MH---181). MH'-195). Preparative Example 11.10 Preparative Example 11.1 0666) 0659
HQ OH
NH HO He HO He NH NO2 NO s O OH
O OH Ho-\ O
OH --- N NO2 O OH
OH
N NH2 O OH t H
0660 Step A NH2 0661 The above amine was reacted with the acid using Ho-V O OH the procedure set forth in Preparative Example 2, Step A to O yield the desired amide (54%). 0662 Step B 0667 Step A 0663 NaSO (1.22 g) was dissolved in water (4 ml) followed by the addition of NH/HO (300 ul). The solution 0668 Following the procedure set forth in Preparative ws then added to the product from Step A (200 mg) in Example 1, but using N-hydroxysuccinimide and 2% DMF dioxane (4 ml) and stirred for 30 min. The crude material in CHCl, the desired amide was obtained (33%, MH--- was purified via flash column chromatography (CH2Cl2/ 297). MeOH, 20:1) to give 100mg of product (56%, MH+=251). 0669 Step B Preparative Example 11.2 0670) Following the procedure set forth in Preparative 0664) Example 2, Step B, the amine was prepared (99%, MH--- 267). Preparative Example 11.11-11.18
O NH2 0671 Following the procedures set forth in Preparative Examples 11.11 but using the carboxylic acid, amine, and coupling agent DCC indicated, the indicated amide products were obtained and used without further purification. US 2004/O147559 A1 Jul. 29, 2004
Prep Carboxylic 1.% Yield Ex. acid Amine Product 2. MH 11.11 1.45, 92 2. 31.O.O OH
NO, N N N H NH2 HOC OH OH O OH 1112 1.45, 95 2. 247.2 H N NO2 \ f NH s NH2 HOC HN OH CIHHN le O OH
11.13 1.85, 85 2. 251.1
NO NH N NH2 HOC O OH O OH OH O OH
11.14 1.99, 92 2. 211.1 OH OH NH2 H NO N NH2 HOC OH O OH 11.15 1. 48,84 2. 265 O O C- NO2 HO HO HOC OH NH N NH2 O OH 1116 1. 78,91 2. 238.1 N NH NO2 1S-1 N1N1 N / N NH2 HOC / OH O OH 11.17 1. 67,90 2. 265.1
NO2 HO NH HO N NH2 HOC OH O O O OH 11.18 1. 28, 99 r O 2. 2.267 NO2 HO NH HO N NH2 HOC OH O O O OH US 2004/O147559 A1 Jul. 29, 2004 83
Preparative Example 12 with 1M HCl (aq) gave an organic solution which was dried over anhydrous MgSO, filtered and concentrated in vacuo 0672) to afford the product (7.3 g, 57%, MH"=337). 0677 Step C Step A --- 0678 The product from Step B above (3.1 g) was com HO bined with DMF(50 mL) and MeI (0.6 mL). NaH (60% in N NO2 mineral oil, 0.4 g) was added portionwise and the mixture O OH was Stirred overnight. Concentration in vacuo afforded a residue which was diluted with CHCl, washed with 1M Step B NaOH (aq), dried over anhydrous MgSO, filtered and --- N concentrated in vacuo. Purification through a Silica gel 1. N NO2 column (EtOAc/Hex, 1:1) gave the desired compound (1.3 g, 41%, MH"-351). O OH 0679 Step D 0680 The product from Step D above (200 mg), Zn(CN) Step C -- (132 mg), Pd(PPh) (130 mg) and DMF(5 mL) were heated N at 80° C. for 48 hrs, then cooled to room temperature and 1. N NO2 diluted with EtOAc and 2M NHOH. After shaking well, the O OH organic extract was dried over anhydrous MgSO, filtered, concentrated in vacuo and purified by preparative plate chromatography (Silica, EtOAC/Hex, 1:1) to give the desired compound (62 mg, 44%, MH"=250). Step D --- N 0681 Step E 1. N NO2 0682 BBr (1.3 mL, 1M in CHCl) was added to a O OMe CHCl, solution (5 mL) of the product from step D above CN (160 mg) and stirred for 30 min. The mixture was diluted with water, extracted with CHCl, dried over anhydrous Step E MgSO, filtered, and concentrated in vacuo to give the --- desired compound (158 mg, MH"=236). -N N NO2 0683 Step F O OMe 0684. A mixture of the product from step E above (160 CN mg), platinum oxide (83%, 19 mg), and EtOH (20 mL) was stirred under hydrogen (25-40 psi) for 1.5 hr. Filtration Step F through celite and concentration in vacuo afforded the --- product (165 mg, MH"=206). N 1. N NO2 Preparative Example 12.1 O OH CN 0685)
N N 21 Step A 1. N NH2 N NH O OH N
N 0673) Step A CluN NO2 Step B 0674) Following a similar procedure as described in Preparative Example 2 Step A except using dimethylamine O OH in place of R-(+)-3-pyrrolidinol, the desired product was O prepared. l 0675) Step B Step C 0676 The product from step A above (8 g) was combined Clu with iodine (9.7g), silver sulfate (11.9 g), EtOH (200 mL) and water (20 mL) and stirred overnight. Filtration, concen C-Cl.O OH tration of the filtrate, re-dissolution in CH2Cl and washing US 2004/O147559 A1 Jul. 29, 2004 84
0695) Step B -continued 0696. Following a similar procedure as in Preparative Example 2, Step B, but using the product from Step A above, the desired compound was obtained (95%, MH+=1 67.9). Preparative Example 12.3 0697) OH
0686 Step A 0687. Following a similar procedure as in Preparative Example 2, Step A except using 3-(methylaminomethyl)py ridine and 3-nitroSalicylic acid, the desired compound was prepared (41%). 0688 Step B 0689) The compound from Step A above ( 0.3 g) was diluted with chloroform (15 mL) and stirred with mCPBA (0.4 g) for 2 hr. Purification by column chromatography (silica, 10% MeOH/CHCl) gave the pyridyl N-oxide (0.32 0698 To morpholine-2-carboxilic acid (200 mg) in EtOH g, 100%, MH'=303.9). (40 mL) at 0°C. was added acetyl chloride (3 mL) and the 0690 Step C mixture was Stirred at reflux overnight. Concentration in vacuo, dilution with CHCl and washing with NaHCO (aq) 0691. Following a similar procedure as in Preparative gave the title compound (99%, MH"=160.1). Example 11.1, Step B, but using the product from Step B above, the desired compound was obtained (15%, MH+= Preparative Example 12.4 274). 0699) Preparative Example 12.2 0692) OH
Step A O O He HO NO N- NBoc N- NHHCI O OH 0700 To N-Boc morpholine-2-carboxylic acid (2 g) in Step B THF (5 ml) at 0°C. was added a solution of borane. THF Ha complex (1N, 10.38 ml) and the mixture was stirred for 30 O min at 0°C., and for 2 hr at room temperature. Water (200 1. NO ml) was added to the reaction and the mixture extracted with CHCl, dried with NaSO, and concentrated in vacuo to O OH give 490 mg of product (26%). The product was then stirred in 4N HCl/dioxane to give the amine salt. Preparative Example 13 O 1. NH2 0701 O OH
0693 Step A 0694) 3-Nitrosalicylic acid (4 g) in MeOH (100 mL) and Step A concentrated HSO (1 mL) were stirred at reflux overnight, HO concentrated in vacuo, diluted with CHCl2, and dried over NaSO. Purification by column chromatography (silica, 5% OH MeOH/CHCl) gave the methyl ester (2.8 g. 65%). US 2004/O147559 A1 Jul. 29, 2004 85
the title product after purification by preparative plate chro -continued matography (Silica, 10% MeOH/CHCl, saturated with NHOH) to give the product (92 mg, 22%, MH"=195). Step B Preparative Example 13.1 -N N 0710)
O OH Br
Step A Step C -- HO -N N O OH O OH Br
\ --Step B Step D 1. N 1N1s1\so, O OH Br O OH
\ HerStep C N 1. NO 1. N NH2 O OH O OH Br
0702) Step A 0703. Following a similar procedure as in Preparative N Example 1 except using dimethylamine (2M in THF, 50 mL) 1. NH2 and 4-methylsalicylic acid (15g), the desired compound was O OH prepared (6.3 g, 35%). 0704) Step B 0711 Step A 0705 The product from step A above (1.5 g) was com bined with iodine (2.1 g), NaHCO (1.1 g), EtOH (40 mL) 0712 Following a similar procedure as in Preparative and water (10 mL) and stirred overnight. Filtration, concen Example 2, Step A except using dimethylamine (2M in THF, tration of the filtrate, re-dissolution in CH2Cl and washing 23 ml) and 5-bromosalicylic acid (5 g), the desired com with 1M HCl (aq) gave an organic solution which was dried pound was prepared (4.2g, 75%, MH---244). over anhydrous MgSO, filtered and concentrated in vacuo. 0713) Step B Purification by flash column chromatography (silica gel, 0.5-0.7% MeOH/CHCl) gave the product (0.5g, 20%, 0714) Nitric acid (10 ml) in AcOH (100 ml) was added to MH"=306). the product from Step A above (2 g) and the mixture was stirred for 20 min. The mixture was diluted with water and 0706) Step C extracted with CHCl, dried over anhydrous MgSO, fil 0707 Nitric acid (3.8 mL) in AcOH (10 mL) was added tered and concentrated in vacuo to give the product as a to the product from Step Babove (0.8 g) and the mixture was yellow solid (1.9 g, 80%, MH+=289). stirred for 40 min. The mixture was diluted with water and extracted with CHCl, dried over anhydrous MgSO, fil 0715) Step C tered and concentrated in vacuo to give the product as an 0716 The product from Step B above (1.9 g) was par orange solid (0.8 g., 92%, MH"=351). tially dissolved in EtOH (50 ml). Conc HCl in EtOH (5 ml in 40 ml), followed by SnCl2.2H2O (5.74 g) was added and 0708 Step D Stirred at room temperature overnight. The crude reaction 0709) A mixture of the product from step C above (800 was concentrated in vacuo, diluted with CH2Cl and washed mg), 10% Pd/C (100 mg), and EtOH/MeOH (40 mL) was with NaHCO, dried over anhydrous MgSO, filtered and Stirred in a parr Shaker under hydrogen (45 psi) for 1.5 hr. concentrated in vacuo to give the product as a Solid (185 mg, Filtration through celite and concentration in vacuo afforded 9%, MH+=259). US 2004/0147559 A1 Jul. 29, 2004 86
Preparative Example 13.2 Preparative Example 13.3 0717 0724)
Cl Step A Hip HO Step A NO2 HO OH O OH Step B Cl NO2 \ Step B OH 1. N Step C
O OH 1. NO2 Cl X-ClOMe \ Step C Step D - N 1. NO2
O OH OMe CI Br Y. Step E 1. NH2 N OMe O OH Br
0718) Step A NH2 0719. Following a similar procedure as in Preparative OH Example 2, Step A, except using dimethylamine (2M in THF, 29 ml) and 5-chlorosalicylic acid (5 g), the desired compound was prepared (4.5 g., 78%, MH---200). 0725) Step A 0720) Step B 0726) 3-Nitrosalicylic acid (10 g), PyBroP (20.52g), and DIEA (28 ml) in anhydrous CHCl (200 ml) were combined 0721) Nitric acid (10 ml) in AcOH (100 ml) was added to and stirred at room temperature for 10 min. Dimethylamine the product from Step A above (2 g) and the mixture was (2M in THF, 55 ml) was added and let the reaction stir over stirred for 20 min. The mixture was diluted with water and the weekend. The mixture was extracted with 1N NaOH (aq) extracted with CHCl, dried over anhydrous MgSO4, fil and the organic phase was discarded. The aqueous phase was tered and concentrated in vacuo to give the product as a Solid acidified with 1N HCl (aq), extracted with CHCl, dried (2.2g, 88%, MH+=245). over anhydrous MgSO, filtered and concentrated in Vacuo. The oil was taken up in ether and a Solid crashed out, 0722) Step C triterated in ether to give 4.45g of a solid (39%, MH---211). 0723) The product from Step B above (2.2 g) was par 0727) Step B tially dissolved in EtOH (50 ml). Conc HCl in EtOH (5 ml in 40 ml), followed by SnCl2.2H2O (7.01 g) was added and 0728) The product from Step A (2.99g), KCO (9.82 g), stirred at room temperature overnight. The crude reaction and iodomethane (8.84 ml) were combined in acetone and was concentrated in vacuo, diluted with CH2Cl2 and neu heated to reflux overnight. The reaction was filtered and tralized with NaOH. The entire emulsion was filtered though concentrated in vacuo. The oil was taken up in CH2Cl and celite, the layers were separated and the organic layer was washed with 1N NaOH, dried over anhydrous MgSO, dried over anhydrous MgSO, filtered and concentrated in filtered and concentrated in vacuo to give 3.3 g of an oil vacuo to give a solid (540 mg, 22%, MH---215). (99%, MH+=225). US 2004/O147559 A1 Jul. 29, 2004 87
0729) Step C -continued 0730) The crude product from Step B (3.3 g) was stirred with 10% Pd/C (350 mg) in EtOH (50 ml) under a hydrogen gas atmosphere at 20 psi overnight. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to give 2.34 g of a solid (85%, MH--=195). 0731 Step D 0732. The product from Step C (469 mg) was dissolved in AcOH (6 ml). 1.95M Br in AcOH (1.23 ml) was added dropwise to the reaction and the mixture was stirred at room temperature for 1 hour. 50% NaOH was added to the reaction at 0°C. and the mixture was extracted with CHCl, dried over anhydrous MgSO, filtered and concentrated in vacuo. The crude mixture was purified by preparative plate chromatography (Silica, 5% MeOH/CHCl) to give the desired product (298 mg, 23%, MH+=273).
0733 Step E 0736) Step A 0734 BBr (2.14 ml, 1M in CHCl) was added to a 0737 To the product from Preparative Example 13.3 Step CHCl, solution (8 ml) of the product from Step D above D (200 mg) was added phenylboronic acid (98 mg), (290 mg) and stirred overnight. A solid formed and was PdCl(PPh3). (51 mg), and NaCO, (155 mg) in THF/HO filtered, taken up in MeOH/CH2Cl and purified by prepara (4 ml/1 ml). The solution was heated at 80° C. overnight. tive plate chromatography (Silica, 5% MeOH/CHCl) to EtOAc was added to reaction and washed with 1N NaOH. give the desired product (137 mg, 49%, MH---259). The organic layer was dried over anhydrous MgSO, filtered and concentrated in vacuo. The crude mixture was purified Preparative Example 13.4 by preparative plate chromatography (5% MeOH/CHCl) to give 128 mg of an oil (65%, MH---271). 0735) 0738 Step B 0739. Following a similar procedure as in Preparative Example 13.3 Step E and using the product from Step A above, the desired compound was prepared (0.1 g, 69%, Br MH+=257.1). \ Step A N Preparative Example 13.5-13.7 1. NH2 0740 Following the procedures set forth in Preparative O OMe Example 13.4 but using the boronic acid from the Prepara tive Example indicated in the Table below, the amine prod ucts were obtained.
1. Yield (%) Prep Ex. Boronic Acid Product 2. MH
13.5 1.15% N N 2. 258 e e
B(OH)2 N 1. NH2 US 2004/O147559 A1 Jul. 29, 2004 88
-continued 1. Yield (%) Prep Ex. Boronic Acid Product 2. MH 13.6 1.32%
2. 325
13.7 1.18% 2. 325
Preparative Example 13.8 0744) Step B 0741) 0745) Nitric acid (0.034 ml) in AcOH (5 ml) was added to the product from Step A above (100 mg) in AcOH and the mixture was allowed to stir for 1 hr. CHCl and HO were Step A Step B added to reaction. The organic layer was dried over anhy He- He H drous MgSO, filtered and concentrated in vacuo to give an N NC M oil. Trituration in ether gave the product as a Solid (12 mg, N 9%, MH+=208). OH N-N OH N 0746 Step C Step C He H 0747 The product from step C (56 mg) was stirred with N M NO2 10% Pd/C (20 mg) in EtOH/MeOH (15 ml) under a hydro N gen gas atmosphere overnight. The reaction mixture was \ -N OH filtered through celite, the filtrate was concentrated in vacuo to give 29 mg is of a solid (62%, MH---178). Preparative Example 13.9 H N M NH2 0748) N V N OH N e
Cl 0742 Step A 0743 2-Cyanophenol (500 mg), sodium azide (819 mg), and triethylamine hydrochloride (1.73 g) were combined in S NH2 anhydrous toluene and heated to 99 C. overnight. After the reaction cooled down, product was extracted with H2O. Aqueous layer was acidified with conc. HCl dropwise giving a precipitate, which was filtered to give the product (597 mg, 0749. The amine was prepared following the procedure 87%, MH+=163). disclosed in WO Patent Application 01/68570. US 2004/O147559 A1 Jul. 29, 2004 89
Preparative Example 13.10 0759 Step D 0750) 0760. The imine from Step C (560 mg) was dissolved in ether (8 ml). 3N HCl (5 ml) added and let stir at room temperature overnight. The ether layer was separated and concentrated in vacuo to give 400 mg of the amine hydro chloride product (93%). Preparative Example 13.12 O OH 0761)
0751. The amine was prepared following the procedure CF disclosed in WO Patent Application 01/68570. O Preparative Example 13.11 CIHHN 0752) 0762. The title compound was prepared similarly as in O Preparative Example 13.11, but using the 2-S-methylbenzy O O lamine instead of 2-R-methylbenzylamine (69%). (1 Step A FC Step B Preparative Example 13.13 0763)
O OH
O Step A O Step B " V * \ , O
O Step C FC \ f He \ FC N Step D He N s Ph O FC w / \
N N HerStep E 0753 Step A 0754) Following the procedure described in Preparative N Example 88.2, Step A, the ketone was prepared (6.4g, 36%). Ph 0755) Step B CF 0756 To a solution of ketone (1 g) and 2-R-methylben Zylamine (0.73 ml) in anhydrous toluene (20 ml) was added 1N TiCl, in toluene (3 ml) at room temperature for 1.5 hrs. The precipitate was filtered and the filtrate was concentrated in vacuo and purified via flash column chromatography (Hex/EtOAc, 18/1) to give 800 mg of product (71%). 0764) Step A 0765 At room temperature, CsP (60 mg) was added to a 0757. Step C mixture of furfuraldehyde (1.3 ml) and TMS-CF (2.5 g) and 0758. The imine from above (760 mg) and DBU (800 ul) Stirred at room temperature (24 h) and refluxed for another were stirred without solvent for 4 hr. The crude reaction was 12h.3N HCl (40 ml) was added and after 4 hr, the mixture concentrated in vacuo and purified via flash column chro was extracted with ether, washed with brine, dried over matography (Hex/EtOAc, 8/1) to give 600 mg of product MgSO4, and concentrated in vacuo to give the product (2.6 (79%). g, 100%). US 2004/O147559 A1 Jul. 29, 2004 90
0766) Step B 0768 Step C 0767 To a solution of alcohol from above (2.6 g) in 0769. Following the procedures described in Preparative CHCl2 at room temperature was added Dess-Martin reagent Example 13.11, Steps B, C and D, the amine salt was (10g) portionwise and 1 drop of water. After stirring for 3 prepared. hr at room temperature, 10% Na2S2O (60 ml) was added and after Stirring overnight, the Solid was filtered off and the Preparative Examples 13.15-13.17B filtrate was extracted with CH2Cl2. The organic layer was washed with Saturated Sodium bicarbonate, dried with 0770. Following the procedure set forth in Preparative MgSO, filtered and concentrated in vacuo. Ether/hexane Example 13.13, but using the prepared or commercially (1:2; 30 ml) was added to the residue, filtered, and filtrate available aldehydes, the optically pure amine products in the concentrated in vacuo to give the product (2 g, 78%). Table below were obtained.
Prep Ex. Aldehyde Amine Product Yield (%)
13.15 20% 34:12 E CF3 O O O HN CIHHN \ / " / C
C
1316 31% O E CF3 O H O HN CIHHN \ f
Br Br
13.17 O E CF3 66%
O O
C O HN r OX
13.17A 34.8 CF3 CF3 38% O O O O HN CIHHN " V \ | \ | 13.17B 'o. ro.CF3 roCF3 31% US 2004/O147559 A1 Jul. 29, 2004
Preparative Example 13.18 with CHCl (100 mLX2, 50 mL). The combined organic extracts were washed with brine (40 mL), dried with 0771) Na2SO, and concentrated under reduced preSSure to a Solid, 10.0 g (100%, over two steps) of 3-methoxy-4-bromo-2- thiophenecarboxylic acid (MH"=237.0). CF 0778 Step C FC -- CIH.HN 0779) To a stirred solution of 3-methoxy-4-bromo-2- thiophenecarboxylic acid (6.5g, 27.4 mmol) in 140 mL of CHCl, obtained from step B, was added bromo-tripyrro lidinophosphonium hexafluorophosphate (PyBrop, 12.8 g., 27.5 mmol), a 2.0 M solution of dimethyl amine in THF 0772 The title compound was prepared from trifluo (34.5 mL, 69.0 mmol), and diisopropylethyl amine (12.0 rophenylketone according to the procedures described in mL, 68.7 mmol). After 3 d, the mixture was diluted with 100 mL of CHCl, and washed with a 1.0 M sodium hydroxide Preparative Example 13.11, Steps B, C, and D (68%). aqueous solution (30 mLX3) and brine (30 mL). The organic solution was dried with NaSO, filtered, and concentrated Preparative Example 13.19 to an oil. This crude oil product was purified by flash column 0773) chromatography, eluting with CH2Cl2-hexanes (1:1, V/v).
O O O - S StepPA- A - S StepPP- B r S HO Br MeO Br MeO Bl
Step C
O O O S S N N Step E N S Step D N V W Ph MeO Br HO NH2 MeO S-( Ph
0774) Step A Removal of solvents afforded a solid, further dried on high 0775 Methyl-3-hydroxy-4-bromo-2-thiophenecarboxy vacuum, yielding 6.76 g (93%) of N,N'-dimethyl-3-meth late (10.0g, 42.2 mmol) was dissolved in 250 mL of acetone. oxy-4-bromo-2-thiophenecarboxamide (MH"=265.0, M+2= Potassium carbonate (30.0g, 217.4 mmol) was added fol 266.1). lowed by a solution of iodomethane (14.5 mL, 233.0 mmol). 0780 Step D The mixture was heated to reflux and continued for 6 h. After cooled to room temperature, the mixture was filtered, the 0781. An oven dried three-neck round bottom flask was solid material was rinsed with acetone (-200 mL). The equipped with a refluxing condenser, charged Sequentially filtrate and rinsing were concentrated under reduced pres with palladium acetate (95 mg, 0.42 mmol), (R)-BINAP Sure to a Solid, further dried on high Vacuum, yielding 13.7 (353 mg, 0.57 mmol), cesium carbonate (9.2 g, 28.33 g (100%) of methyl-3-methoxy-4-bromo-2-thiophenecar mmol), and N,N'-dimethyl-3-methoxy-4-bromo-2-thiophen boxylate (MH"=251.0). ecarboxamide (3.74g, 14.2 mmol, from step C). The solid mixture was flushed with nitrogen. Toluene (95 mL) was 0776) Step B added to the solid mixture followed by benzophenone imine 0777 Methyl-3-methoxy-4-bromo-2-thiophenecarboxy (3.6 mL, 21.5 mmol). The mixture was heated to reflux and late (13.7g), available from step A, was dissolved in 75 mL continued for 10 h. A second batch of palladium acetate (95 of THF, and added with a 1.0 M Sodium hydroxide aqueous mg, 0.42 mmol) and (R)-BINAP (353 mg, 0.57 mmol) in 5 solution (65 mL, 65.0 mmol). The mixture was stirred at mL of toluene was added. Refluxing was continued for 14 h. room temperature for 24 h. A 1.0 M hydrogen chloride The third batch of palladium acetate (30 mg, 0.13 mmol) and aqueous Solution was added dropwise to the mixture until (R)-BINAP (88 mg, 0.14 mmol) was added, and reaction pH was approximately 2. The acidic mixture was extracted continued at 110° C. for 24 h. The mixture was cooled to US 2004/O147559 A1 Jul. 29, 2004 92 room temperature, diluted with ether (50 mL), filtered through a layer of Celite, rinsing with ether. The filtrate and -continued rinsing were concentrated under reduced pressure to an oil, O which was purified twice by flash column chromatography using CHCl and CH-Cl-MeOH (200:1) as eluents. NN S Br \ f H-e-Step B Removal of solvents afforded 4.1 g (79%) of the amido Ph thiophene diphenylimine product as a solid (MH"=365.1). MeO s={ 0782 Step E Ph O 0783 To a stirred solution of thiophene imine (5.09 g, 13.97 mmol), obtained from step D, in 140 mL of CHCI n S B at -78 C. was added dropwise a 1.0 M solution of boron W ) tribromide in CHC1. The mixture was stirred for 3 h while the temperature of the cooling bath was increased slowly HO NH2 from -78° C. to -15° C. 100 mL of HO was added, the mixture was stirred at room temperature for 30 min, then the two layers were separated. The organic layer (as A) was 0785) Step A extracted with HO (30 mLx2). The aqueous layer and 0786) To the product from Preparative Example 13.19 aqueous extracts were combined, washed with CHCl (30 Step D (1.56 g) in CHCl (55 ml) was added potassium mL), and adjusted to pH -8 using a saturated NaHCO carbonate (1.8 g) followed by dropwise addition of bromine (0.45 ml). After 5 hr of mixing, water (100 ml) was added aqueous Solution. The neutralized aqueous Solution was to the reaction and the layers were separated. The aqueous extracted with CHCl (100 mLX3), the extracts were layer was extracted with CHCl, which was then washed washed with brine, dried with NaSO, and concentrated with brine, Saturated Sodium bicarbonate, and brine again. under reduced pressure to a light yellow Solid, 1.49 g of The organic layer was dried with Na2SO, and concentrated N,N'-dimethyl-3-hydroxy-4-amino-2-thiophenecarboxam in vacuo. The residue was purified via flash column chro ide (first crop). The previous separated organic layer A and matography (CHCl) to yield 1.6 g of product (83%). organic washing were combined, stirred with 30 mL of a 1.0 0787 Step B M HCl acqueous solution for 1 h. The two layers were 0788. The product from above was reacted in the proce Separated, the aqueous layer was washed with CHCl (30 dure set forth in Preparative Example 13.19 Step C to give mL) and adjusted to pH -8 using a saturated NaHCO the amine. aqueous Solution, and the Separated organic layer and organic Washing were combined as organic layer B. The Preparative Example 13.21 neutralized aqueous Solution was extracted with CH2Cl (30 0789) mLx4), the extracts were washed with brine, dried by Na2SO, and concentrated under reduced pressure to give 0.48g of a Solid as the Second crop of the titled product. O Organic layer B from above was washed with brine, and N S Br concentrated to an oil, which was separated by preparative N Step A TLC (CH.Cl-MeOH=50:1) to afford 0.45g of a solid as the | \, ( , Sena third crop of the titled product. The overall yield of the product, N,N'-dimethyl-3-hydroxy-4-amino-2-thiophen MeO s={ Ph ecarboxamide, is 2.32 g (89%) (MH"=1870). O Preparative Example 13.20 N S N Step B 0784) r Serb MeO N-( Ph O
N S Step A N \ 4 MeO N=( HO NH2 US 2004/O147559 A1 Jul. 29, 2004
0790 Step A Preparative Example 13.23 0791) To the product from Preparative Example 13.20, 0799) Step A (300 mg) in THF (7 ml) at -78° C. was added a solution of n-BuLi (1.6M in hexanes, 0.54 ml). After 1 hr, iodomethane (0.42 ml) was added dropwise. After 3 hrs of O Stirring at -78 C., the reaction was warmed to room temperature overnight. Saturated ammonium chloride and HO \ S f H-e-Step A water were added to the reaction and extracted with CHC1. The organic layer was washed with Saturated Sodium bicar bonate and brine, dried over Na2SO, and concentrated in MeO Br vacuo. The crude product was purified by preparative plate O- O chromatography (CH2Cl-MeOH=70:1 to 50:1) to afford the N S Step B product (111 mg, 43%). N - -ss 0792 Step B fi W / 0793. The product from above was reacted in the proce MeO Br dure set forth in Preparative Example 13.19, Step E to give O- O the amine. N S Step C Preparative Example 13.22
0794) MeO Br ONN O O Oll N N S 1. \ f Ph Step D N Step A ) ( , Sena MeO s={ MeO S—( Ph Ph ONN O O Oll N S Cl N ) ( , SerbStep B - W ) MeO s={ HO NH2 Ph O 0800 Step A N S C 0801) To a stirred solution of acid (630 mg) from Pre N parative Example 13.19, Step B in CHCl (25 ml) was \ / added oxalyl chloride (235 ul) followed by a catalytic amount of DMF (10 ul). The mixture was stirred for 1 hr, HO NH2 then potassium carbonate (1.8 g) was added followed by 3-amino-5-methylisoxazole (443 mg). The reaction stirred overnight and was quenched with water (25 ml). Layers 0795) Step A were separated and the organic layer was washed with brine, dried over NaSO, and concentrated in vacuo. The crude 0796) To the product from Preparative Example 13.19 product was purified by preparative plate chromatography (400 mg), Step D in CHCl2-pyridine (14 ml) was added (CHCl) to afford the product (580 mg, 78%, MH+=317, N-chlorosuccinimide (220 mg). The mixture was stirred for 319). 5 hr and then diluted with CHCl and washed with water, Saturated Sodium bicarbonate and brine, and concentrated in 0802 Step B vacuo. The crude product was purified via preparative plate 0803) The acid from the above (750 mg) step was reacted chromatography (CH.Cl-MeOH=50:1) to give 180 mg of following the procedure set forth in Preparative Example product (64%). 13.3, Step B to yield 625 mg of product (80%, MH+=331). 0797 Step B 0804) Step C 0798. The product from above (274 mg) was reacted in 0805. The product from above was reacted following the the procedure set forth in Preparative Example 13.19, Step procedure set forth in Preparative Example 13.19, Step D to E to give the amine (89 mg, 58%). yield 365 mg of product (53%) US 2004/O147559 A1 Jul. 29, 2004 94
0806) Step D 0807. The product from above was reacted following the -continued procedure set forth in Preparative Example 13.19, Step E to OH give the amine product (MH+=254). O Step B CFs \ f StePe Preparative Example 13.25 N 0808) O Step C CFs \ f O Step A ( - so O OH HN FC \ O f Step B
N 0816) Step A O Step C 0817 Perfluoroiodide (3.6 ml) was condensed at -78° C. FC Ether (125 ml) was added followed by the methyllithium \ | lithiumbromide complex (1.5M in ether, 18.4 ml). After 15 F min, a solution of 5-methylfuraldehyde (2.5 ml) in ether was F F added dropwise. The reaction was warmed to 45 C. and let stir for 2 hr. Saturated ammonium chloride (30 ml) and water (30 ml) were added and let stir at room temperature for 1 hr. The layers were separated and the aqueous layer was extracted with CHCl2. The organic layer was washed with O brine, dried with NaSO, filtered and concentrated in vacuo HN to give 5.86 g of product (100%). 0818 Step B 0819. The alcohol from above was reacted to form the 0809 Step A azide using the procedure Set forth in Preparative Example 0810) To a solution of 2-methylfuran (1g) in ether (30 75.75 Step B. ml) was added n-BuLi(5.32 ml) at -78°C. The reaction was 0820) Step C warmed to room temperature and then refluxed at 38 C. for 1 hr. The reaction was cooled back down to -78 C. where 0821. The azide from above was reacted to form the the furyl lithium was quenched with trifluorobutyraldehyde racemic amine using the procedure Set forth in Preparative and let Stir at room temperature overnight. Saturated ammo Example 75.75 Step C. nium chloride added and extracted with ether. Purified via flash column chromatography to yield pure product (2 g, Preparative Example 13.27 80%) 0822) 0811 Step B 0812. The azide was prepared using the procedure from Preparative Example 75.75, Step B and the alcohol (1 g) Step A from above and carried on crude to Step C below. O H-e- 0813) Step C f 0814. The amine was prepared using the procedure from Preparative Example 75.75, Step C to yield 400 mg of an oil (53%). cry Step B Preparative Example 13.26 0815) cry Step C Step A --- Step D US 2004/O147559 A1 Jul. 29, 2004 95
Preparative Example 13.28 -continued 0834)
xx' O Step E NS Step A
\ || --Step B NO O 0823) Step A S Step C 0824. Following the procedure set forth in Preparative \ || Example 13.26, Step A, the alcohol was prepared (100%). NH2 0825) Step B O 0826 To a solution of the alcohol (500 mg) from step A S Step D above in CHCl (20 ml) was added N-methyl-morpholine \ f monohydrate (575 mg) and a catalytic amount of tetrapropyl ammonium perruthenate (76 mg). After 3 hr, the mixture NMs was diluted with hexane (10 ml) and filtered through a silica O pad, rinsing with hexane: CHCl (200 ml). The filtrate was S concentrated in vacuo to give 350 mg of product (70.7%) \ f H-e-Step E 0827) Step C NHMS 0828 The ketone (1.19 g) from Step B was dissolved in 1 OH THF (9.5 ml) and cooled to 0° C. A solution of S-methyl N oxazoborolidine (1M in toluene, 1 ml) followed by a solu o tion of borane complexed with dimethylsulfide (9.5 ml, 2M \ f ---Step F in THF) was added to the solution. The mixture was stirred at 0° C. for 30 min and continued at room temperature for NHMS 5 hr. The mixture was cooled back down to 0 C. and NH2 methanol (15 ml) was added dropwise to the mixture. After 30 min, the mixture was concentrated in vacuo to give an oily residue. 0829. The residue was dissolved in CH2Cl and washed NHMS with 1N HCl, water, and brine. Dried with NaSO, filtered and concentrated in vacuo. The crude material was purified via flash column chromatography (HeX/CH2Cl2, 1:1) to 0835) Step A afford 1.14 g of an oil (67%). 0836 To a stirred solution of 1-(2-thienyl)-1-propanone (3 g) in acetic anhydride (6 ml) at 0°C. was added dropwise 0830) Step D a Solution of fuming nitric acid in acetic acid (2 ml in 10 ml). 0831 The alcohol (1.14 g) from above was reacted to After 30 min, the reaction was warmed to room temperature form the azide using the procedure Set forth in Preparative and let Stir for 5 hrs where a Solid precipitated out. Ice was Example 75.75 Step B. added to the reaction and the Solid was filtered. The Solid was purified by flash column chromatography (HeX/CHCl, 0832) Step E 3:1 and 2:1) to yield 800 mg of desired product (20%). 0833. The azide (1.11 g) from above was stirred with 10% Pd/C (280 mg) in EtOH (40 ml) under a hydrogen gas 0837 Step B atmosphere overnight. The reaction was filtered through 0838 The above nitro-thiophene compound (278 mg) celite, the filtrate was concentrated in vacuo to give 700 mg was reduced using the procedure Set forth in Preparative of product (70%). Example 2, Step B to give 54 mg of product (23%). US 2004/O147559 A1 Jul. 29, 2004 96
0839 Step C added as well as water (1 ml) dropwise and let stir for 15 min. The mixture was filtered and the filtrate was concen 0840 The above amine (395 mg), TEA (1 ml) and tratred in vacuo. The crude product was purified by prepara methanesulfonylchloride (0.5 ml) were combined in CHCl tive plate chromatography (MeOH/CHCl2, 15:1) to give the (35 ml) and stirred at room temperature for 1 hr. The reaction amine product (40 mg, 14%). was quenched with Saturated Sodium bicarbonate (15 ml). The organic layer was washed with brine, dried over Preparative Example 13.29 Na2SO, filtered and concentrated in vacuo to afford product (854 mg, 100%). 0847)
S On S O N Step A s Step B on) S C N S O A N \ O -v \ V
Step C
O ony S O NM \ seStep E os\ S oS S N Step D 1. \ Br 1. \ Br -e- 1 v N O \ HO HO r O O S "N. ss p Os\N N \ Step G \S N 1 \(\ll 1S --- NH O 1. \ HO 2
0841) Step D 0848 Step A 0842) To the above product (854 mg) in THF (25 ml) was 0849. To a solution of 3-methoxythiophene (3 g) in added dropwise a Solution of tetrabutylammonium fluoride (1M in THF, 2.8 ml). The mixture was stirred overnight, then dichloromethane (175 mL) at -78°C. was added chlorosul diluted with CHCl (30 ml), washed with ammonium fonic acid (8.5 mL) dropwise. The mixture was stirred for 15 chloride and brine, dried over over NaSO, filtered and min at -78 C. and 1.5 h at room temp. Afterwards, the concentrated in vacuo to afford product (2.36 g, >100%). mixture was poured carefully into crushed ice, and extracted 0843 Step E with dichloromethane. The extracts were washed with brine, dried over magnesium Sulfate, filtered through a 1-in Silica 0844. The ketone (2.36 g) above was reacted via the gel pad. The filtrate was concentrated in vacuo to give the procedure set forth in Preparative Example 88.2, Step B to yield 547 mg of product (86.6%). desired compound (4.2 g). 0845 Step F 0850 Step B 0846. To the product from step E (310 mg) in dimethoxy 0851. The product from Step A above (4.5 g) was dis ethane (12 ml) was added dropwise a solution of LAH (1M solved in dichloromethane (140 mL) and added with tri in ether, 3.8 ml). The mixture was heated to reflux overnight. ethylamine (8.8 mL) followed by diethylamine in THF (2M, The reaction was cooled to room temperature, SiO2 was 21 mL). The resulting mixture was stirred at room tempera US 2004/O147559 A1 Jul. 29, 2004 97 ture overnight. The mixture was washed with brine and was poured into an aqueous mixture of Sodium hydroxide Saturated bicarbonate (aq) and brine again, dried over (1.0 M aq, 50 mL) and ether (100 mL). The two layers were Sodium Sulfate, filtered through a 1-in Silica gel pad. The Separated. The aqueous layer was washed with ether three filtrate was concentrated in vacuo to give the desired com pound (4.4 g). times. The combined ether washings were re-extracted with HO once. The aqueous layers were combined, washed once 0852) Step C with dichloromethane, adjusted to pH-6 using 3.0 M and 0.5 0853) The product from Step B above (4.3 g) was dis M hydrogen chloride aqueous Solutions, and extracted with solved in dichloromethane (125 mL) and cooled in a -78°C. dichloromethane. The organic extracts were combined, bath. A solution of boron tribromide (1.0 M in dichlo washed with brine, dried over Sodium Sulfate, and concen romethane, 24.3 mL) was added. The mixture was stirred for 4 h while the temperature was increased slowly from -78 trated in vacuo to give 1.2 g of desired amine compound. C. to 10° C. HO was added, the two layers were separated, and the aqueous layer was extracted with dichloro-methane. Preparative Examples 13.30-13.32 The combined organic layer and extracts were washed with 0862 Following the procedures set forth in Preparative brine, dried over magnesium Sulfate, filtered, and concen Example 13.29, but using commercially available amines, trated in vacuo to give 3.96 g of the desired hydroxy hydroxy-amino-thiophene products in the Table below were compound. obtained. 0854) Step D 0855. The product from step C above (3.96 g) was dissolved in 125 mL of dichloromethane, and added with potassium carbonate (6.6 g) followed by bromine (2 mL). Yield (%) The mixture was stirred for 5 h at room temperature, Prep Ex. Amine Product MH quenched with 100 mL of HO. The aqueous mixture was adjusted to pH-5 using a 0.5N hydrogen chloride aqueous 13.30 Bin-NH 10% O. O 375.1 Solution, and extracted with dichloromethane. The extracts were washed with a 10% NaSO aqueous solution and Bn \/S is brine, dried over Sodium Sulfate, and filtered through a celite pad. The filtrate was concentrated in vacuo to afford 4.2 g of Bn the desired bromo-compound. HO NH2 0856) Step E 0857 The product from Step D (4.2 g) was dissolved in 13.31 MeBNH 14% 100 mL of acetone and added with potassium carbonate (10 O. O 299.O g) followed by iodomethane (9 mL). The mixture was heated B \/ S to reflux and continued for 3.5 h. After cooled to room temperature, the mixture was filtered through a Celite pad. n \ f The filtrate was concentrated in vacuo to a dark brown residue, which was purified by flash column chromatogra HO NH2 phy eluting with dichloromethane-hexanes (1:1, V/v) to give 2.7 g of the desired product. 13.32 EtBNH 22% 0858 Step F O O 0859. The product from step E (2.7 g) was converted to B \/ S the desired imine compound (3 g), following the similar procedure to that of Preparative Example 13.19 step D. ry , Et 0860) Step G HO NH2 0861) The imine product from step F (3 g) was dissolved in 80 mL of dichloromethane and cooled in a -78 C. bath. 13.32A (Et)NH 25% A solution of boron tribromide (1.0 M in dichloromethane, 9.2 mL) was added dropwise. The mixture was stirred for O. O 4.25 h from -78° C. to 5° C. HO (50 mL) was added, and \/ the layers were separated. The aqueous layer was extracted Et n1 S with dichloromethane. The organic layer and extracts were combined, washed with brine, and concentrated to an oily Et residue. The residue was dissolved in 80 mL of methanol, HO NH2 Stirred with Sodium acetate (1.5 g) and hydroxyamine hydro chloride (0.95 g) at room temperature for 2 h. The mixture US 2004/O147559 A1 Jul. 29, 2004 98
Preparative Example 13.33 O863)
O sy,O s O SAs, s'O S M Step A N N Step B M Cl N -e- Et 1. Y. He- E1 NY. N O\ \ HO
Step C
O S. O O sy S Step E ony on) S \ N -e- M Step D is E1 Br E1 N N Br E1 N N Bn Br V V Bn HO
Step F
O O osy S Step G ony Ph S. S M He- M Step H On E.1 N\ N Br E1 N\ N als1N Hess \S Sl O O E.1 \ HO 2
0864) Step A 0872) Step E 0865 2-Chlorosulfonyl-3-methoxy-thiophene (4.0 g, 0873. The product from Step D above (4.82 g, 12.36 18.8 mmol), the product from step A of Preparative Example mmol) was stirred with concentrated Sulfuric acid (5 mL) at 13.29, was converted to 3-methoxy-2-ethylbenzylsulfonyl room temperature for 3 h. Ice water (30 mL) was added to thiophene (5.5 g., 94%, MH"=312.1) by using ethylbenzyl the mixture followed by CHCl (50 mL). The aqueous amine, following the procedure Set forth in Preparative mixture was adjusted to pH-6 using a 1.0 M NaOH acqueous Example 13.29, Step B. Solution. The layers were separated. The aqueous layer was 0866) Step B extracted with CHCl (50 mLX3). The combined organic layers were washed with brine, dried over NaSO, and 0867. The product from step A above (5.5g, 17.70 mmol) concentrated to a dark brown oil, which was purified by flash was demethylated following the procedure Set forth in column chromatography, eluting with CH2Cl2-hexanes (1:1, Preparative Example 13.29, Step C. The alcohol product was v/v). Removal of solvents afforded 3.03 g (82%) of the obtained in 4.55 g (87%, MH"=298.0). debenzylated product (M"=300.0, M+2=302.0). 0868) Step C 0874) Step F 0869. The product from Step B above (4.55 g, 15.30 0875. The product from Step E (1.34g, 4.45 mmol) was mmol) was brominated using the procedure set forth in methylated using the procedure Set forth in Preparative Preparative Example 13.29, Step D. The corresponding Example 13.29, Step E. The desired product was obtained in bromide was obtained in 4.85 g (84%). 1.36 g (97%, M*=314.1, M+2 =316.0). 0870 Step D 0876) Step G 0871) The bromo-alcohol from Step C above (4.84 g, 0877. The product from Step F (1.36 g, 4.33 mmol) was 12.86 mmol) was methylated using the procedure set forth converted to imine product (1.06 g, 55%, MH"=415.1) using in Preparative Example 13.29, Step E. The product was the procedure set forth in Preparative Example 13.29, Step obtained in 4.82 g (96%). F. US 2004/O147559 A1 Jul. 29, 2004 99
O878 Step H from Step B above (0.45 g, 1.56 mmol) in 2 mL of 0879 The imine product from Step G (1.06 g, 2.56 N,N'-dimethylforamide in a round bottom flask. The flask mmol) was converted to the desired hydroxy-amino was Sealed with a ground glass Stopper, and the mixture was thiophene compound (0.26 g., 43%) using the procedure set heated at 90-95 C. for 4 h. After cooled to room tempera forth in Preparative Example 13.29, Step G. ture, the mixture was poured into 20 mL of a 1.0 M NaOH aqueous solution, further rinsed with 20 mL of HO. The Preparative Example 13.34 aqueous mixture was washed with diethyl ether (30 mLx2), 0880) adjusted to PH-5 using a 0.5 M HCl acqueous solution, and
O O SS S Os oSa OsallO Cl1 \ W StepT A - HN SS -S Step B n SS S Step C n SS S N= \ / N= N V N= N V H3CO One R f O 2 OV a HO Sepp O O Osall O O Step F NSSOs - S Step E SSS.Osl -S S! S Step G as \ S f N \ } - N V \ / N N= N= OneN= HO NH2 d 2 OV N={ Oa R Br One HO Br
0881 Step A extracted with CHCl (50 mLx4). The combined extracts were washed with brine, dried (NaSO), and concentrated 0882 2-Chlorosulfonyl-3-methoxy-thiophene (3.8 g. to a dark yellow solution. This was dissolved in 50 mL of 17.87 mmol), the product from step A of Preparative ethyl acetate, washed with HO (30 mLx2) and brine (30 Example 13.29, was dissolved in 100 mL of CHCl and 20 mL), dried over NaSO. Evaporation of solvent gave 0.422 mL of pyridine. 3-Amino-5-methyl-isoxazole (3.5g, 35.68 g of the alcohol product (99%, MH"=275.0). mmol) was added. The mixture was stirred for 20 hat room temperature, diluted with 100 mL of CHCl, and washed 0887 Step D with a 0.5 NHCl aqueous solution (50 mLX2), HO (50 0888. The alcohol obtained from Step C above (0.467 g, mL), and brine (50 mL). The organic solution was dried with 1.70 mmol) was brominated using the procedure set forth in NaSO, and concentrated in vacuo to a brown oil. This oil Preparative Example 13.29, Step D, to afford the corre was dissolved in 100 mL of CHCl, washed again with a 0.5 sponding bromide in 0.607 g (100%). M HCl aqueous solution (30 mLX3) and brine. After dried over NaSO, the organic Solution was concentrated in 0889 Step E vacuo to a yellow solid, 4.48 g (91%, MH"=275.0) of the 0890) The bromide obtained from Step D above (0.607 g. desired product. 1.72 mmol) was methylated using the procedure set forth in 0883 Step B Preparative Example 13.29, Step E, to give the desired product in 0.408 g (65%, M=367, M+2=369.1). 0884 The product from Step A above (4.48 g, 16.33 mmol) was dissolved in acetone (100 mL), added with 0891) Step F potassium carbonate (5.63 g, 40.80 mmol) and iodomethane 0892. The product (0.405 g, 1.103 mmol) from Step E (10.1 mL, 163.84 mmol). The mixture was stirred at room above was converted to the imine compound (0.29 g, 56%) temperature for 1.5 h, diluted with 100 mL of hexanes and using the procedure set forth in Preparative Example 13.29, 50 mL of CH2Cl2, and filtered through a 1-in silica gel pad, Step F. rinsing with CHC1. The filtrate was concentrated under reduced pressure to give 4.23 g (90%, MH"=289.0) of the 0893) Step G desired product as a light yellow Solid. 0894. The imine product obtained from Step F above 0885) Step C (0.29 g, 0.61 mmol) was demethylated using the procedure Set forth in Step C above to give the corresponding alcohol 0886 To a stirred suspension of sodium hydride (130 mg, as a dark yellow oil, which was dissolved in 5 mL methanol 95%, 5.4 mmol) in 8 mL of N,N'-dimethylforamide at room and added with Sodium acetate (0.12 g, 1.46 mmol) and temperature was added ethanethiol (0.45 mL, 6.0 mmol) hydroxyamine hydrochloride (0.075 g, 1.08 mmol). The dropwise. After 5 min, the mixture became a clear Solution, resulting mixture was Stirred at room temperature for 3 h, and was added to a Stirred Solution of the product obtained and poured into 10 mL of 1.0 M NaOH aqueous solution. 30